Conditions: Amyotrophic Lateral Sclerosis
Keywords: ALS Placebo-Controlled Double-Blind Regimen-Specific Appendix Lou Gehrig's Disease Zilucoplan Ra Pharmaceuticals
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 162
Healthy volunteers: no

Brief summary:
The HEALEY ALS Platform Trial is a perpetual multi-center, multi-regimen clinical trial evaluating the safety and efficacy of investigational products for the treatment of ALS.

Regimen A will evaluate the safety and efficacy of a single study drug, zilucoplan, in participants with ALS.

Detailed description:
The HEALEY ALS Platform Trial is a perpetual multi-center, multi-regimen clinical trial evaluating the safety and efficacy of investigational products for the treatment of ALS. This trial is designed as a perpetual platform trial. This means that there is a single Master Protocol dictating the conduct of the trial. The HEALEY ALS Platform Trial Master Protocol is registered as NCT04297683.

Once a participant enrolls into the Master Protocol and meets all eligibility criteria, the participant will be eligible to be randomized into any currently enrolling regimen. All participants will have an equal chance of being randomized to any currently enrolling regimen.

If a participant is randomized to Regimen A - Zilucoplan, the participant will complete a screening visit to assess additional Regimen A eligibility criteria. Once Regimen A eligibility criteria are confirmed, participants will complete a baseline assessment and be randomized in a 3:1 ratio to either active zilucoplan or matching placebo.

Regimen A will enroll by invitation, as participants may not choose to enroll in Regimen A. Participants must first enroll into the Master Protocol and be eligible to participate in the Master Protocol before being able to be randomly assigned to Regimen A.

For a list of enrolling sites, please see the HEALEY ALS Platform Trial Master Protocol under NCT04297683.

Arms:
arm 1: Drug: Zilucoplan Administration: Subcutaneous injection

Dosage: 0.3mg/kg administered daily arm 2: Administration: Subcutaneous injection

Dosage: Daily subcutaneous injection

Interventions: intervention 1: Zilucoplan intervention 2: Matching Placebo
Intervention descriptions: intervention 1: Drug: Zilucoplan Administration: Subcutaneous injection

Dosage: 0.3mg/kg administered daily intervention 2: Drug: Matching Placebo

Administration: Subcutaneous injection

Dosage: Daily subcutaneous injection

Protocol document:
Prot_000.pdf: 
HEALEY ALS Platform Trial - Regimen A Zilucoplan 
NCT04436497 
Document Date: 15 Jul 2021 


REGIMEN-SPECIFIC APPENDIX A 
 
FOR ZILUCOPLAN 
 
 
Regimen-Specific Appendix Date:  15 July 2021 
Version Number:  5.0 
 
 
 


 
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Regimen-Specific Appendix A, Zilucoplan 
 
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TABLE OF CONTENTS 
 
SIGNATURE PAGE .................................................................................................................................... 5 
LIST OF ABBREVIATIONS .................................................................................................................... 6 
Regimen-Specific Appendix SUMMARY ................................................................................................. 7 
SCHEDULE OF ACTIVITIES ................................................................................................................. 9 
1 
INTRODUCTION ............................................................................................................................ 13 
1.1 
Zilucoplan Background Information ...................................................................................... 13 
1.1.1 
Clinical Trial Experience with Zilucoplan .......................................................................... 14 
1.2 
Zilucoplan- US FDA IND Background ................................................................................... 14 
2 
OBJECTIVES .................................................................................................................................. 15 
2.1 Study Objectives and Endpoints ................................................................................................... 15 
3 RSA DESIGN ......................................................................................................................................... 17 
3.1 
Scientific Rationale for RSA Design ........................................................................................ 17 
3.2 
 End of Participation Definition ............................................................................................... 23 
3.3 
End of Regimen Definition ....................................................................................................... 24 
4 RSA Enrollment ..................................................................................................................................... 25 
4.1 
Number of Study Participants ................................................................................................. 25 
4.2 
Inclusion and Exclusion Criteria ............................................................................................. 25 
4.2.1    RSA Inclusion Criteria ........................................................................................................... 25 
4.2.2    RSA Exclusion Criteria .......................................................................................................... 25 
5 
INVESTIGATIONAL PRODUCT ................................................................................................. 26 
5.1 
Investigational Product Manufacturer ................................................................................... 26 
5.2 
Acquisition, Storage, and Preparation .................................................................................... 27 
5.3      Study Medication/Intervention, Administration, Escalation, and Duration ........................ 28 
5.4 
Drug Returns and Destruction................................................................................................. 28 
5.5      Justification for Dosage ............................................................................................................. 29 
5.5.1   Additional Scientific Justification for Dose Selection ............................................................ 30 
5.6 
Dosage Changes ......................................................................................................................... 32 
5.7      Participant Compliance............................................................................................................. 32 
5.8      Overdose ..................................................................................................................................... 33 
5.9      Prohibited Medications ............................................................................................................. 33 


 
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5.10 
Zilucoplan Known Potential Risks and Benefits .................................................................... 33 
5.10.1 
Known Potential Risks ........................................................................................................ 33 
5.10.2 
Known Potential Benefits ................................................................................................... 34 
5.11  Treatment Assignment Procedures ......................................................................................... 34 
6  REGIMEN SCHEDULE ...................................................................................................................... 35 
6.1 
Placebo-Controlled Period ....................................................................................................... 35 
6.1.1 
Regimen-Specific Screening Visit ...................................................................................... 36 
6.1.2  
Baseline Visit ...................................................................................................................... 37 
6.1.3 
Week 2 Telephone Visit ...................................................................................................... 37 
6.1.4 
Week 4 Visit ....................................................................................................................... 37 
6.1.5 
Week 8 Visit ....................................................................................................................... 38 
6.1.6 
Week 12 Telephone Visit .................................................................................................... 38 
6.1.7 
Week 16 Visit ..................................................................................................................... 38 
6.1.8 
Week 20 Telephone Visit .................................................................................................... 39 
6.1.9 
Week 24 Visit or Early Termination Visit .......................................................................... 39 
6.1.10    Follow-Up Safety Call ......................................................................................................... 40 
6.1.11    Process for Early Terminations ............................................................................................ 40 
6.2 
Open Label Extension ............................................................................................................... 41 
6.2.1 
Week 2 OLE Telephone Visit ............................................................................................. 41 
6.2.2 
Week 4 OLE Visit ............................................................................................................... 41 
6.2.3 
Week 8 OLE Visit ............................................................................................................... 42 
6.2.4  Week 12 OLE Telephone Visit ................................................................................................ 42 
6.2.5  Week 16 OLE Visit .................................................................................................................. 43 
6.2.6  Week 20 OLE Telephone Visit ................................................................................................ 43 
6.2.7  Week 24 OLE Telephone Visit ................................................................................................ 44 
6.2.8  Week 28 and Q12 Weeks OLE Visits ...................................................................................... 44 
7 CLINICAL ASSESSMENTS AND OUTCOME MEASURES ..................................................... 46 
7.1  
Voice Analysis ............................................................................................................................ 46 
7.2     ALSAQ-40 ................................................................................................................................... 46 
7.3    Center for Neurologic Study Bulbar Function Scale ................................................................ 46 
7.4 Home Spirometry ........................................................................................................................... 47 
8  
BIOFLUID COLLECTION ..................................................................................................... 48 


 
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8.1  
Anti-drug Antibody Sampling ................................................................................................. 48 
8.2  
Zilucoplan Plasma PK Analysis ............................................................................................... 48 
8.3  
Zilucoplan Pharmacodynamic Analysis .................................................................................. 48 
8.4  
Zilucoplan Peripheral Blood Biomarker Samples ................................................................. 48 
9  
REGIMEN-SPECIFIC STATISTICAL CONSIDERATIONS ............................................ 49 
9.1  Deviations from the Default Master Protocol Trial Design ....................................................... 49 
9.2 
Regimen Specific Operating Characteristics .......................................................................... 49 
9.3  Sharing of Controls from other Regimens .................................................................................. 49 
Appendix I: The ALSAQ-40 .................................................................................................................... 50 
Appendix II: The Bulbar Function Scale (CNS-BFS) ........................................................................... 59 
REFERENCES ..................................................................................................................................... 61 
List of Figures and Tables 
Figure 1: Mechanism of Action of Zilucoplan in the Complement System ........................................ 13 
Figure 2: Terminal complement activation products in the serum and CSF of healthy controls 
versus ALS patients. Data represents individual patients with mean + standard deviation. Data on 
record at Ra Pharma. ............................................................................................................................ 18 
Figure 3: Mechanism of Action of Zilucoplan in the Complement System ........................................ 20 
Figure 4: PK/PD Relationship for Zilucoplan in Cynomolgus Monkeys and Translation to the Clinic
 
22 
Figure 5: Complement C5 concentrations in healthy donors (n=14), age range 40–77yrs and ALS 
patients (n=17 of which n=15 sporadic ALS and n=2 familial ALS), age range 40-81yrs. ................ 30 
Figure 6: Functional potency of zilucoplan in healthy donors (n=13) and ALS patients (n=16) 
plasma. ................................................................................................................................................... 31 
Figure 7: Pharmacokinetic / Pharmacodynamic relationship of zilucoplan in Phase 2, dose ranging 
study in generalized myasthenia gravis (IND 134340). ........................................................................ 32 
 
Table 1: Pharmacological potency of zilucoplan (IC50) in species tested .......................................... 21 
Table 2: Rodent Quantitative Whole-Body Radiography of [14C]-zilucoplan .................................... 23 
Table 3: Zilucoplan Dose Presentations by Weight Brackets .............................................................. 27 
 
 


 
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SIGNATURE PAGE 
I have read the attached Regimen-Specific Appendix (RSA) entitled, “Regimen A: Zilucoplan,” 
dated July 15, 2021 (Version 5.0) and agree to abide by all described RSA procedures.  I agree to 
comply with the International Conference on Harmonisation Tripartite Guideline on Good Clinical 
Practice, applicable FDA regulations and guidelines identified in 21 CFR Parts 11, 50, 54, and 
312, central Institutional Review Board (IRB) guidelines and policies, and the Health Insurance 
Portability and Accountability Act (HIPAA). 
 
By signing the RSA, I agree to keep all information provided in strict confidence and to request 
the same from my staff. Study documents will be stored appropriately to ensure their 
confidentiality. I will not disclose such information to others without authorization, except to the 
extent necessary to conduct the study.  
 
 
 
 
Site Name: 
 
 
 
 
Site Investigator: 
 
 
 
 
Signed: 
 
 
 
 
 
Date: 
 
 


 
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LIST OF ABBREVIATIONS 
 
ALS 
 
Amyotrophic Lateral Sclerosis 
ALSAQ-40 
Amyotrophic Lateral Sclerosis Assessment Questionnaire-40 
C5 
 
Complement component 5 
CNS-BFS  
Center for Neurologic Study Bulbar Function Scale 
Covid-19 
Coronavirus Disease 2019 
FVC  
Forced Vital Capacity 
gMG  
Generalized Myasthenia Gravis 
IMNM  
Immune-mediated Necrotizing Myopathy 
IP 
 
Investigational product 
ITT 
 
Intent-to-Treat 
IV 
 
Intravenous 
OLE 
 
Open Label Extension 
PD 
 
Pharmacodynamic 
PK 
 
Pharmacokinetic 
RBC 
 
Red blood cells 
RSA 
 
Regimen-Specific Appendix 
SOC 
 
Standard of care 
SVC 
 
Slow Vital Capacity 
VC 
 
Vital Capacity 


 
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REGIMEN-SPECIFIC APPENDIX SUMMARY 
Regimen-Specific Appendix A 
For 0.3mg/kg SC zilucoplan administered once daily and placebo 
 
Allocation to Treatment Regimens 
Participants must first be screened under the Master Protocol and before they are randomized to 
an RSA.  
 
As soon as pre-defined criteria for futility for the RSA are met, or the target number of 
randomized participants has been reached, enrollment will stop in the RSA.   
 
Number of Planned Participants and Treatment Groups 
The number of planned participants for this regimen is approximately 160.   
 
There are 2 treatment groups for this regimen, active and placebo. Participants will be 
randomized in a 3:1 ratio to active treatment or placebo (i.e., 120 active: 40 placebo).   
 
Planned Number of Sites 
Research participants will be enrolled from approximately 60 centers in the US.   
 
Treatment Duration  
The maximum duration of the placebo-controlled portion is 24 weeks.  
 
Follow-up Duration 
At the conclusion of the 24-week placebo-controlled period of the study, all participants will 
either schedule a 40-day follow up safety phone call and end their participation in the regimen or 
have the option to receive zilucoplan in the Open Label Extension phase of the study.  
 
In the Open Label Extension, zilucoplan will be provided by Ra Pharmaceuticals, Inc. until 
zilucoplan is approved and available in the United States, or Ra Pharmaceuticals, Inc. terminates 
development of zilucoplan for ALS.  
 
Total Planned Trial Duration 
For participants completing the placebo-controlled treatment period of the study, the planned 
amount of time in the trial is up to 36 weeks, or about 9 months.  This duration assumes a 6-week 
screening window, a 24-week placebo-controlled treatment period, and a 40-day safety follow-
up period for those participants who do not enter the Open Label Extension.  
 


 
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Regimen-Specific Appendix A, Zilucoplan 
 
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If participants opt into the subsequent Open Label Extension, their participation in the trial will 
have no set endpoint. The Open Label Extension will continue until zilucoplan is approved and 
available in the territory, or Ra Pharmaceuticals, Inc. terminates development of zilucoplan for 
ALS.  For participants continuing into the OLE, their total planned participation in the trial will 
include the 6-week screening window, 24-week placebo-controlled period, and the open-ended 
Open Label Extension.  
 
 
 
 


 
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SCHEDULE OF ACTIVITIES  
As per the Schedule of Activities (SOA) below, visits must occur every 4 weeks and will be alternatively clinic-, phone-, or telemedicine-based, as 
applicable.  There is a maximum 24-week duration of placebo-controlled treatment for a Regimen. 
 
Screening 
 
 
 
 
 
 
 
 
 
Open Label Extension (Optional) 
Activity (page 1 of 3) 
(Master Protocol or 
Regimen-Specific) 
 
Master 
Protocol 
Screening1 
Regimen 
Specific 
Screening1 
Baselin
e 
Week 
2 
Week 
423 
Week 
822, 23 
Week 
12 
Week 
1622, 23 
Week 
20 
Week 
24 or 
Early 
Term. 
Visit16, 
22 
Follow
-Up 
Safety 
Call15, 
16 
Week 
2 
Week 
423 
Week 
823 
Week 
12 
Week 
1622, 23 
Week 
20 
Week 
24 
Week 
28 and 
Q12 
Wks22, 
23 
Clinic 
Clinic 
Clinic 
Phone 
Clinic 
Clinic 
Phone 
Clinic 
Phone 
Clinic 
Phone 
Phone 
Clinic 
Clinic 
Phone 
Clinic 
Phone 
Phone 
Clinic 
-42 to -1 
Days 
-41 to -14 
Days 
Day 0 
Day 
14 ±3 
Day 
28 ±7 
Day 
56 ±7 
Day 
84 ±3 
Day 
112 
±7 
Day 
140 
±3 
Day 
168 ±7 
40d ±3 
after 
last 
dose 
Day 
14 
±3 
Day 
28 ±7 
Day 
56 
±7 
Day 84 
±3 
Day 
112 
±7 
Day 
140  ±3 
Day 
168  ±3 
q12w 
±14d 
Written 
Informed 
Consent -
Placebo-
Controlled 
Period2 
Master 
X 
X25 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Written 
Informed 
Consent -OLE 
Regimen 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/ 
Exclusion 
Review 
Master 
X 
X3 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ALS & Medical 
History 
Master 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
Master 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical 
Examination 
Master 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Neurological 
Exam 
Master 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs4 
Master 
X 
 
X 
 
X 
X 
 
X 
 
X 
 
 
X 
X 
 
X 
 
 
X 
Slow Vital 
Capacity 
Master 
X24 
 
X 
 
 
X 
 
X 
 
X 
 
 
X 
X 
 
X 
 
 
X 
Home 
Spirometry 
Regimen 
X24 
 
X 
 
 
X 
 
X 
 
X 
 
 
X 
X 
 
X 
 
 
X 
Muscle 
Strength 
Assessment  
Master 
 
 
X 
 
 
X 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
ALSFRS-R 
Master 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
ALSAQ-40 
Regimen 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X20 
CNS Bulbar 
Function Scale 
Regimen 
 
 
X 
 
 
X 
 
X 
 
X 
 
 
 
X 
 
X 
 
 
X21 


 
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Regimen-Specific Appendix A, Zilucoplan 
 
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Screening 
 
 
 
 
 
 
 
 
 
Open Label Extension (Optional) 
Activity (page 1 of 3) 
(Master Protocol or 
Regimen-Specific) 
 
Master 
Protocol 
Screening1 
Regimen 
Specific 
Screening1 
Baselin
e 
Week 
2 
Week 
423 
Week 
822, 23 
Week 
12 
Week 
1622, 23 
Week 
20 
Week 
24 or 
Early 
Term. 
Visit16, 
22 
Follow
-Up 
Safety 
Call15, 
16 
Week 
2 
Week 
423 
Week 
823 
Week 
12 
Week 
1622, 23 
Week 
20 
Week 
24 
Week 
28 and 
Q12 
Wks22, 
23 
Clinic 
Clinic 
Clinic 
Phone 
Clinic 
Clinic 
Phone 
Clinic 
Phone 
Clinic 
Phone 
Phone 
Clinic 
Clinic 
Phone 
Clinic 
Phone 
Phone 
Clinic 
-42 to -1 
Days 
-41 to -14 
Days 
Day 0 
Day 
14 ±3 
Day 
28 ±7 
Day 
56 ±7 
Day 
84 ±3 
Day 
112 
±7 
Day 
140 
±3 
Day 
168 ±7 
40d ±3 
after 
last 
dose 
Day 
14 
±3 
Day 
28 ±7 
Day 
56 
±7 
Day 84 
±3 
Day 
112 
±7 
Day 
140  ±3 
Day 
168  ±3 
q12w 
±14d 
12-Lead ECG 
Master 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
Clinical Safety 
Labs5 
Master 
X 
 
X 
 
X 
X 
 
X 
 
X 
 
 
X 
X 
 
X 
 
 
X 
Anti-drug 
Antibody 
Sampling 
Regimen 
 
 
X 
 
 
X 
 
X 
 
X 
 
 
 
 
 
X 
 
 
 
X18 
Zilucoplan PK 
Analysis11 
Regimen 
 
 
X 
 
 
X 
 
X 
 
X 
 
 
 
 
 
X 
 
 
X18 
Zilucoplan PD 
Analysis12 
Regimen 
 
 
X 
 
 
X 
 
X 
 
X 
 
 
 
 
 
X 
 
 
X18 
Zilucoplan 
Biomarker 
Samples13 
Regimen 
 
 
X 
 
 
X 
 
X 
 
X 
 
 
 
 
 
X 
 
 
X18 
Biomarker 
Blood 
Collection13 
Master 
 
 
X 
 
 
X 
 
X 
 
X 
 
 
 
 
 
X 
 
 
X18 
Biomarker 
Urine 
Collection13 
Master 
 
 
X 
 
 
X 
 
X 
 
X 
 
 
 
 
 
X 
 
 
X18 
DNA 
Collection7 
(optional) 
Master 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CSF Collection 
(optional) 
Master 
 
 
X 
 
 
 
 
X19 
 
 
 
 
 
 
 
 
 
 
 
Concomitant 
Medication 
Review 
Master 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Event 
Review6 
Master 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Columbia-
Suicide 
Severity Rating 
Scale 
Master 
 
 
X 
 
X 
X 
 
X 
 
X 
 
 
X 
X 
 
X 
 
 
X 
Install 
Smartphone 
App26 
Regimen 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Voice 
Recording8 
Regimen 
 
 
X 
 
X 
X 
 
X 
 
X 
 
 
 
 
 
 
 
 
 


 
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Screening 
 
 
 
 
 
 
 
 
 
Open Label Extension (Optional) 
Activity (page 1 of 3) 
(Master Protocol or 
Regimen-Specific) 
 
Master 
Protocol 
Screening1 
Regimen 
Specific 
Screening1 
Baselin
e 
Week 
2 
Week 
423 
Week 
822, 23 
Week 
12 
Week 
1622, 23 
Week 
20 
Week 
24 or 
Early 
Term. 
Visit16, 
22 
Follow
-Up 
Safety 
Call15, 
16 
Week 
2 
Week 
423 
Week 
823 
Week 
12 
Week 
1622, 23 
Week 
20 
Week 
24 
Week 
28 and 
Q12 
Wks22, 
23 
Clinic 
Clinic 
Clinic 
Phone 
Clinic 
Clinic 
Phone 
Clinic 
Phone 
Clinic 
Phone 
Phone 
Clinic 
Clinic 
Phone 
Clinic 
Phone 
Phone 
Clinic 
-42 to -1 
Days 
-41 to -14 
Days 
Day 0 
Day 
14 ±3 
Day 
28 ±7 
Day 
56 ±7 
Day 
84 ±3 
Day 
112 
±7 
Day 
140 
±3 
Day 
168 ±7 
40d ±3 
after 
last 
dose 
Day 
14 
±3 
Day 
28 ±7 
Day 
56 
±7 
Day 84 
±3 
Day 
112 
±7 
Day 
140  ±3 
Day 
168  ±3 
q12w 
±14d 
Uninstall 
Smartphone 
App 
Regimen 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
Assignment to 
the Regimen 
Master 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
within the 
Regimen 
Master 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Administer/ 
Dispense  
Investigational 
Product (IP) 
Regimen 
 
 
X9 
 
X 
X 
 
X 
 
X14 
 
 
X 
X 
 
X 
 
 
 
 
X27 
IP 
Accountability/
Compliance 
Master 
 
 
 
X28 
X 
X 
X28 
X 
X28 
X 
 
X28 
X 
X 
X28 
X 
X28 
 
X28 
X 
Exit 
Questionnaire 
Master 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
N. meningitidis 
Vaccination10 
Regimen 
 
X 
 
 
X 
X 
 
 
 
 
 
 
 
 
 
X10 
 
 
 
Vital Status 
Determination17 
Master 
 
 
 
 
 
 
 
 
 
X17 
 
 
 
 
 
 
 
 
 
1. 
Master Protocol Screening procedures must be completed within 42 days to 1 day prior to Baseline Visit.  
2. 
During the Master Protocol Screening Visit, participants will be consented via the Master Protocol informed consent form (ICF). After a participant is randomized to a regimen, participants will be 
consented a second time via the regimen-specific ICF.  
3. 
At the Regimen Specific Screening Visit, participants will have regimen-specific inclusion and exclusion criteria assessed.   
4. 
Vital signs include weight, systolic and diastolic pressure, respiratory rate, heart rate and temperature.  Height measured at Master Protocol Screening Visit only. 
5. 
Clinical safety labs include hematology (CBC with differential), complete chemistry panel, thyroid function and urinalysis. Serum pregnancy testing will occur in women of child-bearing potential at the 
Master Protocol Screening Visit and as necessary during the study. Pregnancy testing is only repeated as applicable if there is a concern for pregnancy. 
6. 
Adverse events that occur after signing master protocol consent form will be recorded.  
 


 
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7. 
The DNA sample can be collected after Baseline Visit if a baseline sample is not obtained or the sample is not usable. 
8. 
In addition to study visits outlined in the SOA, participants will be asked to complete twice weekly voice recordings at home. During weeks when a participant is doing a voice recording in-clinic, 
he or she would only do one other voice recording at home that week. 
9. 
Administer first dose of investigational product (IP) only after Baseline Visit procedures are completed 
10. To reduce the risk of meningococcal infection (Neisseria meningitidis), all participants must be vaccinated against meningococcal infections (with a quadrivalent vaccine and serogroup B vaccine) 
prior to initiating study drug. Booster vaccinations should be administered in accordance with the vaccination and booster guidance document for this regimen and may occur at different study 
visits in the OLE based on the vaccine brand.  To mitigate the risk of infection, participants 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 participant. 
11. Blood samples for PK analysis (zilucoplan and metabolites) should be obtained prior to administration of study drug at each clinic visit (i.e., pre-dose). 
12. Blood samples for PD analysis (sheep RBC hemolysis assay, Wieslab alternative pathway assay, C5 levels) should be obtained prior to administration of study drug at each clinic visit (i.e., pre-
dose). 
13. Blood samples for biomarker analysis should be obtained prior to administration of study drug at each clinic visit (i.e., pre-dose). 
14. Drug will only be dispensed at this visit if the participant continues in the OLE. 
15. Participants will only have a Follow-Up Safety Call at this time if they do not continue into the OLE.   
16. Participants who continue into the OLE and then early terminate will be asked to complete an Early Termination Visit and Follow-Up Safety Call as described in the body of this RSA. 
17. Vital status, defined as a determination of date of death or death equivalent or date last known alive, will be determined for each randomized participant at the end of the placebo-controlled portion 
of their follow-up (generally the Week 24 Visit, as indicated). If at that time the participant is alive, his or her vital status should be determined again at the time of the last participant’s last visit 
(LPLV) of the placebo-controlled portion of a given regimen. We may also ascertain vital status at later time points by using publicly available data sources as described in section 8.15 of the 
Master Protocol. 
18. During the OLE, Master Biomarker Blood Collection, Master Biomarker Urine Collection, and all regimen-specific samples will occur at OLE Weeks 16, 28, and 52 only. 
19. If the CSF collection is unable to be performed for logistical reasons, such as scheduling, at the Week 16 Visit, it may be performed at the Week 24 Visit 
20. The ALSAQ-40 is done only at Week 28 and Week 52 during OLE 
21. The CNS Bulbar Function Scale is done only at Weeks 8, 16, 28, 40 and 52 during OLE. 
22. Participants should be instructed to hold the morning dose of study drug on the day of the study visit. Study drug should not be taken until after study visit procedures are complete. 
23. Visit may be conducted via phone or telemedicine with remote services instead of in-person if this is needed to protect the safety of the participant due to a pandemic, or other reason. During the 
OLE, the Week 4, 8, 16, 28, and 40 Visits may be done remotely.  The Week 52 Visit should still be done in clinic. 
24. If required due to pandemic-related restrictions, Forced Vital Capacity (FVC) performed by a Pulmonary Function Laboratory evaluator or with a study-approved home spirometer, or sustained 
phonation using a study approved method may be used for eligibility (Master Protocol Screening ONLY).    
25. If a participant chooses to obtain the vaccination from their local provider, Regimen A informed consent may be completed remotely to allow a participant to consent to the regimen prior to 
obtaining the vaccination so that the participant does not need to attend an in-person screening visit to obtain the vaccination. The process for obtaining remote consent is detailed in section 6.1.1.  
26. Two smartphone apps should be installed on the participant’s phone, once to collect the voice recordings and one to collect home spirometry. 
27. Investigational product is not administered at the participant’s final in-clinic visit at the completion of the OLE.   
28. Drug accountability will not be done at phone visits. A drug compliance check-in should be held during phone visits to ensure participant is taking drug per dose regimen and to note any report of 
missed doses.  
  


 
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1 INTRODUCTION 
 
Regimen 1: Zilucoplan 
 
1.1 
Zilucoplan Background Information 
 
Zilucoplan targets C5, a component of the terminal complement activation pathway. Zilucoplan 
binds to C5 with high affinity and prevents its cleavage by C5 convertases into the cleavage 
products C5a and C5b. Inhibition of C5 cleavage prevents the downstream assembly and 
cytolytic activity of the MAC. 
 
Using surface plasmon resonance and analysis of a high-resolution co-crystal structure, 
zilucoplan has been shown to bind to a specific site on C5 and to exhibit a strong and rapid 
association with C5, coupled with a slow dissociation rate. Zilucoplan binds to the portion of C5 
which corresponds to C5b. In binding to this region of C5, should any C5b be formed, it will be 
blocked from binding to C6 by zilucoplan, which further prevents the subsequent assembly of 
the MAC (C5b-9). 
 
Thus, zilucoplan inhibits MAC formation by a dual mechanism (4): 
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 complement C5 
inhibitory monoclonal antibody eculizumab. Nishimura and colleagues have described 11 
patients in Japan (≈3.2% of the PNH population) who carry mutations in the C5 gene that 
prevent the binding of eculizumab to C5 and who are resistant to treatment with the antibody 


 
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(Nishimura et al. 2014). Zilucoplan has been shown to effectively bind to C5 from blood samples 
from patients with this mutation, and to inhibit complement activation in vitro. 
Pharmacologically, zilucoplan has demonstrated dose-dependent inhibition of C5a and C5b 
formation following activation of classical or alternative complement pathways, as well as 
inhibition of red blood cell (RBC) lysis in the serum/plasma from various species. Zilucoplan is a 
potent complement inhibitor in humans and primates and a poor inhibitor in most other 
laboratory animal species.  
 
1.1.1 Clinical Trial Experience with Zilucoplan 
 
The experience in clinical trials with zilucoplan can be referenced in the most current version of 
the Investigator’s Brochure (IB). 
 
1.2 
Zilucoplan- US FDA IND Background 
 
Zilucoplan has ongoing clinical trials to assess the safety and efficacy for the treatment of 
patients with PNH (Paroxysmal Nocturnal Hemoglobinuria), gMG (generalized Myasthenia 
Gravis), and IMNM (Immune Mediated Necrotizing Myopathy), Coronavirus Disease 2019 
(COVID-19)-associated respiratory syndrome, amyotrophic lateral sclerosis (ALS), and 
potentially for other complement-mediated diseases.  Clinical trials in the US are being 
conducted under the US FDA IND oversight process.  To support clinical studies in multiple 
diseases, zilucoplan has undergone extensive preclinical characterization to understand the 
pharmacology, pharmacokinetics, safety pharmacology, and toxicology of the drug.  The 
preclinical data package has been extensively reviewed by the FDA’s Division of Neurology 
Products, Office of Hematology and Oncology Product, as well as the FDA DPARP (Division of 
Pulmonary, Allergy, Rheumatology Products). Additionally, clinical safety data generated from 
completed clinical trials has been reviewed by the FDA as part of the IND review process. The 
FDA has determined the benefit/risk to be suitable for clinical investigations of zilucoplan for the 
treatment of multiple neurodegenerative diseases. 
 
The Regimen A protocol was designed with input from the US FDA as well as designed to be 
consistent with FDA’s Guidance for Industry for ALS. This includes overall study design, 
appropriate ALS clinical study endpoints, as well as long-term safety follow-up.   
 
 
 
 
 
 


 
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2 OBJECTIVES 
 
2.1 Study Objectives and Endpoints  
 
Primary Efficacy Objective: 
To evaluate the efficacy of zilucoplan as compared to placebo on ALS disease progression.  
 
Secondary Efficacy Objective: 
• To evaluate the effect of zilucoplan on selected secondary measures of disease 
progression, including survival. 
 
Safety Objective: 
• To evaluate the safety of zilucoplan for ALS. 
 
Exploratory Efficacy Objective: 
• To evaluate the effect of zilucoplan on selected biomarkers and endpoints. 
 
Primary Efficacy Endpoint: 
Change in disease severity as measured by the ALS Functional Rating Scale-Revised (ALSFRS-
R) total score using a Bayesian repeated measures model that accounts for loss to follow-up due 
to mortality.  
 
Secondary Efficacy Endpoints: 
• Change in respiratory function as assessed by slow vital capacity (SVC). 
• Change in muscle strength as measured isometrically using hand-held dynamometry 
(HHD) and grip strength. 
• Survival. 
 
Safety Endpoints: 
• Treatment-emergent adverse and serious adverse events. 
• Changes in laboratory values and treatment-emergent and clinically significant laboratory 
abnormalities. 
• Changes in ECG parameters and treatment-emergent and clinically significant ECG 
abnormalities. 
• Treatment-emergent suicidal ideation and suicidal behavior. 
 
Exploratory Efficacy Endpoints: 
• Changes in quantitative voice characteristics. 
• Changes in biofluid biomarkers of neurodegeneration. 
• Changes in patient reported outcomes.  
• Change in respiratory function as assessed by home spirometry. 


 
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• Change in circulating complement pathway biomarker levels (e.g. sC5b-9) 
• Optional CSF sampling for complement pathway biomarkers in CNS (e.g. sC5b-9) 
• Optional CSF sampling for pharmacokinetics of zilucoplan in CNS 
• Optional CSF sampling for pharmacodynamics of zilucoplan in CNS 
 
 
 
 
 
 
 


 
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3. RSA DESIGN 
3.1 
Scientific Rationale for RSA Design 
 
This RSA is designed to correspond with the design of the Master Protocol and the goals of the 
Platform Trial. 
 
Rationale for Complement Inhibition in ALS 
 
The complement cascade is one of the most potent effector mechanisms in the immune system 
which, through the formation of the terminal membrane attack complex (C5b-9 or MAC) and the 
recruitment of inflammatory cells via the potent anaphylatoxin C5a, has great potential to cause 
tissue injury. All components of the complement cascade can be locally synthesized in the CNS, 
specifically by neurons, astrocytes, oligodendrocytes and microglia (Barnum, 1995; Gasque et 
al., 1997; O'Barr et al., 2001). Hyperactivation of the complement system has been shown to 
participate in several neurodegenerative diseases including Alzheimer's disease, Parkinson's 
disease, Huntington's disease and ALS (Kjaeldgaard et al., 2018; Loeffler et al., 2006; Morgan, 
2018; Singhrao et al., 1999). At the time of study design, no complement inhibitor had been 
investigated in a clinical trial of ALS, although substantial preclinical and clinical data provide 
rationale to do so. 
 
The predominant pathway involved in ALS pathophysiology is the classical complement 
pathway. This is primarily activated by the recognition molecule C1q, which binds to antigen 
antibody complexes and endogenous pattern recognition molecules. Elevations in biomarkers of 
classical pathway activation such as C1q and C4 have been shown to be associated with ALS in 
serum, cerebrospinal fluid, CNS parenchyma (motor cortex and spinal cord) and skeletal muscle 
tissue (Bahia El Idrissi et al., 2016a; Sta et al., 2011; Trbojevic- Cepe et al., 1998). In house data 
has also identified marked elevations in serum and cerebrospinal fluid markers of terminal 
complement pathway activation (C5a and C5b-9) in patients with ALS as compared with healthy 
controls (Figure ). 
 


 
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Figure 2: Terminal complement activation products in the serum and CSF of healthy controls 
versus ALS patients. Data represents individual patients with mean + standard deviation. Data on 
record at Ra Pharma. 
Healthy
ALS
0
10
20
30
40
C5a (ng/mL)
C5a in Serum samples
          p=0.0001***
Healthy
ALS
0
1000
2000
3000
4000
5000
SC5b-9 [ng/mL]
sC5b-9 in Serum samples
          p<0.0001 ****
 
Healthy
ALS
0.0
0.5
1.0
1.5
2.0
C5a (ng/mL)
C5a in CSF samples
          p=0.0087**
Healthy
ALS
0
20
40
60
80
100
SC5b-9 [ng/mL]
sC5b-9 in CSF samples
          p=0.0006 ***
 
 
Peripheral nervous involvement of the classical complement pathway has also been documented, 
suggesting that pharmacological inhibition of the complement cascade outside the CNS may also 
deliver therapeutic benefit in ALS. In a study by Bahia El Idrissi et al., 2016 on post-mortem 
intercostal muscle from ALS patients and control donors, increased levels of C1q on the axons 
innervating the motor end plates of ALS patients were identified but C1q was undetectable in 
control (p=0.001). Additionally, C1q was deposited on innervated motor endplates prior to 
denervation, suggesting that classical pathway activation may play an early role in the 
degradation of the neuromuscular junction, the so-called “dying-back” mechanism (Chou and 
Norris 1993), suggesting that effective complement inhibition at the neuromuscular junction (as 
achieved by zilucoplan in Ra Pharma’s gMG Phase 2 trial: RA101495-02.201) could salvage 
early motor junction deterioration in ALS and prevent further loss. 
 


 
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With regard to investigation into the role of complement C5 in animal models of ALS this has 
been limited. The contribution of C5a and C5b have been investigated separately and support the 
concept that broader inhibition of complement C5 could be effective in ALS. SOD1G93A rats 
and mice were treated with the specific C5aR1 antagonist, PMX205.  Chronic administration of 
PMX205 in SOD1G93A rats markedly delayed the onset of motor symptoms and increased 
survival (Woodruff et al., 2008). PMX205 treatment in SOD1G93A mice also extended survival, 
improved motor function (i.e. hind-limb grip strength) and slowed disease progression (Lee et 
al., 2017). Furthermore, deletion of the C5a receptor 1 (CD88) in SOD1G93A mice resulted in a 
significant extension in survival compared to control SOD1G93A mice in both sexes, also 
supporting a pathogenic role for C5a in this model of ALS (Woodruff et al., 2014). With respect 
to the MAC forming C5b product this has been implicated by antisense inhibition of C6 (another 
MAC pore-forming protein) which also resulted in delayed disease progression and extended 
survival in SOD1G93A mice (Bahia El-Idrissi et al., 2016b).  
 
These data have been supported by broader description of classical complement pathway 
activation in several animal models of ALS at the transcript level. In SOD1G93A mice, up-
regulation of C1qA and C1qB mRNA transcripts was observed in the spinal cord at later stages 
of disease (Olsen et al., 2001) and was subsequently confirmed by RT-PCR in isolated lumbar 
motor neurons from other SOD1 models: SOD1G93A, SOD1G37R and SOD1G85R mice 
(Ferraiuolo et al., 2007; Lobsiger et al., 2007; Perrin et al., 2005). Similarly, in non-SOD1 
models increases in C1qB and C4 mRNA levels in the lumbar spinal cord of TDP43Q331K 
transgenic mice have also been identified (Lee et al., 2018). Downstream of C1q an upregulation 
of C3 mRNA and protein expression is observed in SOD1G93A and TDP43Q331K rodents' 
spinal cord (Heurich et al., 2011; Lee et al., 2013, 2018; Woodruff et al., 2008). C3b, the 
activated fragment of C3, is found localized with activated glia and dying motor neurons, 
consistent with its role as an opsonin. 
 
Analysis of peripheral changes in classical complement proteins using SOD1G93A and 
TDP43Q331K mice has demonstrated upregulated mRNA expression of C1qB and C4 in the 
tibialis anterior at the mid-stage and end stages of disease (Lee et al., 2018; Wang et al., 2017) 
and at the motor end-plates of SOD1G93A mice, (Bahia El Idrissi et al., 2016a; Heurich et al., 
2011). Increases in downstream markers such as C3, C5, C5b9 (MAC) deposition at the motor 
end plates and nerve terminals, starting at the pre-symptomatic stage, have been observed in 
SOD1G93A mice, as well as TDP43 models. 
 
In summary, there are numerous studies documenting activation of the complement cascade in 
both the peripheral and central pathophysiology of ALS. In the periphery, studies suggest that 
activation of complement may temporally precede motor end plate degeneration and therefore 
complement inhibition could be disease modifying. In the CNS, complement activation is closely 
associated with the ongoing neuroinflammatory process. More broadly, complement activation 
has been documented in association with a diverse set of other neurodegenerative disorders 
including trauma, MS, Alzheimer's disease, Parkinson's disease and Huntington's disease. In all 
cases, the presence of terminal complement components C5a and C5b, potent inflammatory and 
membrane attack moieties, respectively, suggests that inhibition of C5 activation could 
contribute to the treatment of ALS and other neurodegenerative diseases. 


 
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Zilucoplan and the Complement Cascade 
 
Zilucoplan has undergone extensive preclinical characterization to understand the pharmacology, 
pharmacokinetics, safety pharmacology and toxicology of the drug. The preclinical data package 
has been reviewed by all major regulatory agencies including the FDA’s Division of Neurology 
Products. 
  
Zilucoplan targets C5, a component of the terminal complement activation pathway. Zilucoplan 
binds to C5 with high affinity and prevents its cleavage by C5 convertases into the cleavage 
products C5a and C5b. Inhibition of C5 cleavage prevents the downstream assembly and 
cytolytic activity of the MAC (Figure ). 
 
Figure 3: 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. 
 
Zilucoplan shows species selectivity for non-human primate and human complement C5 only. 
The primary pharmacology of zilucoplan was established in vitro using direct binding and 
functional inhibition of complement assays, as well as enzyme-linked immunosorbent assays 
(ELISAs). Using surface plasmon resonance and analysis of a high-resolution co-crystal 
structure, zilucoplan has been shown to bind to a specific site on C5 and to exhibit a strong and 
rapid association with C5, as well as a slow dissociation rate. The binding site is distinct from 
that of the complement C5 inhibitor monoclonal antibody eculizumab and therefore is not 
affected by mutations in complement C5 known to prevent binding of eculizumab in patients of 
Asian and Han-Chinese descent (Nishimura et al. 2014). Target (C5) binding was confirmed 
using a competitive ELISA employing biotinylated zilucoplan to capture C5. Additionally, 
zilucoplan demonstrated dose-dependent inhibition of C5a and C5b formation following 
activation of classical or alternative pathways, as well as inhibition of RBC lysis in 
serum/plasma. Zilucoplan is a potent complement inhibitor in primates and humans and a 
weak/poor inhibitor in all other animal species tested (see below).  


 
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Species 
IC50 (nM) 
Human 
6.6 
Non-human primate 
 
Baboon 
 
Chimpanzee 
 
Cynomolgus 
 
Rhesus 
 
5.2 
11.7 
3.5 
17.6 
Dog 
> 4,700 
Rabbit 
> 67,000 
Porcine 
 
Mini-pig 
 
Pig 
 
51.9 
118.6 
Rodents 
 
Mouse 
 
Rat 
 
Guinea Pig 
 
> 36,000 
591.2 
> 100,000 
 
Table 1: Pharmacological potency of zilucoplan (IC50) in species tested 
 
Zilucoplan is slowly absorbed in preclinical species after single SC administration, with mean 
Tmax ranging from approximately 5 to 8 hours post-dose. The mean elimination half-life in 
plasma is 7 days in monkeys and humans. The slow elimination kinetics are largely driven by 
high affinity interaction with the target protein C5 and a much lower affinity interaction with 
albumin and other plasma proteins. Metabolism of zilucoplan is well-characterized and studies 
have identified two primary metabolites that occur in similar ratios in both monkeys and humans. 
Excretion of parent and major metabolites is predominantly hepatobiliary. 
 
The PK/PD relationship of zilucoplan has been extensively investigated in cynomolgus monkeys. 
An EC90 of 2500 ng/mL was determined in monkeys which translated nearly precisely to the 
clinical experience in generalized myasthenia gravis trials (Figure ). 
 
 
 
 
 
 
 
 
 
 
 


 
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Figure 4: PK/PD Relationship for Zilucoplan in Cynomolgus Monkeys and Translation to the 
Clinic 
 
A) Zilucoplan PK/PD in Cynomolgus Monkeys   
B) Zilucoplan PK/PD in Phase 2 gMG trial 
 
 
Quantitative whole-body autoradiography studies in rats have been conducted using [14C]-
zilucoplan to determine the in vivo biodistribution of zilucoplan. Importantly, zilucoplan 
biodistribution to ALS disease compartments such as muscle, spinal cord and brain are enhanced 
when compared to literature data of therapeutic monoclonal antibodies (see below). Furthermore, 
as this rodent study was carried out in “normal” animals, the blood brain barrier would be intact, 
potentially analogous to current understanding of ALS blood brain barrier integrity. Ra Pharma 
believes that this biodistribution advantage is conferred by smaller molecular size of a 
macrocyclic peptide (3.5 kDa) versus a monoclonal antibody (approx. 140 kDa). Therefore, 
zilucoplan may be ideally suited to test the hypothesis of both peripheral and CNS involvement 
of complement in ALS.  
 


 
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Table 2: Rodent Quantitative Whole-Body Radiography of [14C]-zilucoplan:  
Improved biodistribution into tissue vs. literature values of typical mAb taken from Shah DK, 
Betts AM (2013). Ra data represent tissue AUC0-24 as a percentage of plasma. 
 
In summary, preclinical studies have extensively characterized the pharmacokinetics, 
pharmacology, safety, and toxicology of zilucoplan. The biodistribution advantages of zilucoplan 
when compared to monoclonal antibodies particularly with respect to access to the muscle and 
brain/spinal cord compartments may be an important determinant of success in treating ALS. 
Literature data support a strong activation of complement in the peripheral and central nervous 
system in both patients and animal models of ALS.  
  
3.2 
 End of Participation Definition 
 
 
A participant is considered to have ended his or her participation in the placebo-controlled period 
of the Regimen if they: 
• Complete planned placebo-controlled period visits, as described in the SOA, including 
participants on or off study drug 
• Early terminate from the study and complete the Early Termination Visit and Follow-Up 
Phone call as described in Section 6.1.11 


 
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• Withdraw consent to continue participation in the study, or are lost to follow up 
If a participant initiates open-label study drug in the OLE period, he or she is considered to have 
completed his or her participation in the OLE period of the Regimen if they choose to withdraw 
or all planned OLE period visits, including the last visit or the last scheduled procedure shown in 
the SOA, have been completed.  
3.3    End of Regimen Definition 
 
The end of the placebo-controlled period in a Regimen occurs when all randomized participants 
have completed their participation in the placebo-controlled period as defined in section 3.2. 
The end of the OLE period in a Regimen occurs when all participants who initiated open-label 
study drug in the OLE period have completed their participation in the OLE period as defined in 
Section 3.2. 
 
 
 
 
 


 
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4. RSA ENROLLMENT 
4.1 
Number of Study Participants 
 
Approximately 160 participants will be randomized for this Regimen.   
 
4.2 
Inclusion and Exclusion Criteria 
 
To be randomized to an RSA, participants must meet the Master Protocol eligibility criteria.  In 
addition, participants meeting all the following inclusion and exclusion criteria will be allowed to 
enroll in this Regimen:  
 
4.2.1    RSA Inclusion Criteria 
 
 
1. Vaccination with a quadrivalent meningococcal vaccine and meningococcal serotype B 
vaccine at least 14 days prior to the first dose of study drug at the Baseline (Day 0) visit. 
Meningococcal vaccines (including boosters) should be administered in accordance with 
the study’s vaccination worksheet. 
 
4.2.2    RSA Exclusion Criteria  
 
1. History of meningococcal disease. 
2. Prior treatment with a complement inhibitor. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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5 INVESTIGATIONAL PRODUCT 
 
5.1     Investigational Product Manufacturer 
 
Zilucoplan injection is manufactured in accordance with current Good Manufacturing Practices. 
 
Drug Substance 
RA101495 sodium drug substance is comprised of all L-α-amino acids.  There are 15 L-α-amino 
acids in the main chain and an additional L-glutamic acid in the side-chain group on lysine15.  
This side-chain group on lysine15 contains a palmitic acid, a γ-linked L-glutamic acid, and then 
an amino-ethylene-glycol-acid spacer (EG24) attached to the ε-group of lysine15.  Using IUPAC 
naming convention for peptides and writing the EG24 as a polyoxygenated long-chain fatty acid, 
the name of RA101495 sodium is:   
Acetyl‐[L-lysyl1-L-valyl2-L-glutamyl3-L-arginyl4-L-phenylalanyl5-L-aspartyl6] -N-
methyl-L-aspartyl7-L-tert-leucyl8-L-tyrosyl9-L-7-azatryptophyl10-L-glutamyl11-L-tyrosyl12-
L-prolyl13-L-cyclohexylglycyl14-[L-lysyl15, Nε-palmitoyl-γ-L-glutamyl-(1-amino-
3,6,9,12,15,18,21,24,27,30,33,36,39,42,45,48,51,54, 57,60,63,66,69,72-
tetracosaoxapentaheptacontan-75-oyl)], cyclic (Lactam 1-6), tetra sodium 
 
Excipients 
The excipients used in the manufacture of zilucoplan injection are commonly used excipients in 
the pharmaceutical industry for parenteral dosage forms.  All excipients comply with the 
requirements of the relevant monographs in the United States Pharmacopeia (USP)/National 
Formulary (NF), European Pharmacopoeia (Ph. Eur.), the British Pharmacopoeia (BP) and the 
Japanese Pharmacopoeia (JP).  The purpose of the formulation components are as follows: 
phosphate buffer to maintain product pH (6.5 to 7.5) and saline to maintain an isotonic product 
(270 to 330 mOsm/kg). 
 
The excipients used in the manufacture of zilucoplan placebo drug product for injection are the 
same as those used to produce 40 mg/mL zilucoplan drug product, however the molar quantities 
of the formulation ingredients differ in order to account for absence of active zilucoplan drug 
substance and to produce an isotonic solution within specified pH range.  All excipients comply 
with the requirements of their respective monographs in the USP/NF and Pharm. Eur., as well as 
the Japanese Pharmacopoeia (JP), as applicable. 
 
Drug Product / Investigational Product (IP) 
Zilucoplan for injection is packaged into a Beckton Dickinson (BD) 1 mL long glass syringe 
with a 29-gauge ½” long staked in needle.  The glass syringe is closed with a West 4423/50 


 
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Bromobutyl rubber B2/40 coated, Teflon-faced stopper. The zilucoplan injection syringes are 
then placed into the secondary packaging BD UltraSafe Plus. The Becton Dickinson UltraSafe 
Plus device is a non-sterile, non-measuring, single use needle safety shield system.  The device 
does not perform, interfere with or in any way impact the delivery of the drug, which is 
accomplished by the prefilled syringe.   
 
Drug product will be provided in prefilled syringes for self-injection using weight bracketed 
dosing (i.e., participants will be provided prefilled syringes based on their weight containing 
fixed amounts of zilucoplan, and each fixed amount will cover a range of participant weights). 
As shown in Table 3, 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 to a maximum dose of 0.42 mg/kg 
daily. 
 
Placebo will be provided in 1 presentation of 0.574 mL. 
 
Nominal Target Dose 
(mg/kg) 
Actual Dose 
(mg) 
Injection Volume 
(mL) 
Weight Range 
(kg) 
Dose Range 
(mg/kg) 
0.3 
16.6 
0.416 
≥43 to <56 
0.30 to 0.39 
0.3 
23.0 
0.574 
≥56 to <77 
0.30 to 0.41 
0.3 
32.4 
0.810 
≥77 to 150 
0.22 to 0.42 
Table 3: Zilucoplan Dose Presentations by Weight Brackets 
 
Participants who present with a lower body weight (<43 kg) or a higher body weight (≥150 kg) 
will be accommodated on a case-by-case basis, in consultation with the medical monitor. 
 
5.2     Acquisition, Storage, and Preparation 
 
Zilucoplan and placebo should be stored at 2°C to 8°C at the study site. Once dispensed to 
participants, zilucoplan and placebo may be stored at room temperature. Storage of zilucoplan 
and placebo outside of room temperatures should be avoided, eg, it should not be refrigerated 
once it has been removed to room temperature. Please refer to the Regimen specific pharmacy 
manual for additional details. 
 
Participants will receive secure containers to dispose of used syringes while at home. At each 
visit, the participant should return the disposal container containing all used syringes to the site. 
The participant should also bring any unused study drug (i.e., unused syringes) back to the site at 
each in-person study visit.  
 


 
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All unused study drug syringes and disposal containers containing used syringes must be 
returned to the site at the end of the participant’s participation in the Regimen.  For participants 
not continuing on in the OLE, this would be the Week 24 Visit or earlier if study participation is 
terminated early. Participants who enter the OLE and end their participation in the OLE early 
should also return all unused study drug syringes and disposal containers containing used 
syringes to the site once their participation in the OLE ends. 
 
5.3      Study Medication/Intervention, Administration, Escalation, and Duration 
 
The drug product, 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. Participants will be instructed to self-administer SC 
doses daily; when necessary the SC injections may be administered by a caregiver. Three dosage 
strengths of zilucoplan will be supplied as shown in 6. 
 
All eligible participants will be randomized 3:1 to receive 0.3 mg/kg zilucoplan or placebo 
administered SC at the Baseline (Day 0) visit, which will be performed by the site staff at the 
study visit. Following in-clinic education and training, all participants and/or caregivers will 
inject daily SC doses of study drug at approximately the same time each day for the remainder of 
the 24-week Treatment Period. 
  
Dosing on study visit days as outlined in the SOA should be held until all assessments have been 
completed. At each clinic study visit, dosing should be supervised to ensure the correct injection 
technique is being followed by participants and/or caregivers. 
 
Participants and caregivers will be instructed to inject SC doses daily at approximately the same 
time each day. The participant/caregiver will subcutaneously inject study drug into the abdomen 
only. 
 
All participants 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. 
 
5.4 Drug Returns and Destruction 
At each in person visit the steps outlined in the Manual of Procedures must be followed for study 
drug accountability and compliance, as well as study drug return and destruction.  
 
Prior to study drug destruction, all partial and empty kits require a second accountability 
verification to be completed by a different study team member, and both verifications should be 
documented on the study destruction logs. No study drug may be destroyed on-site until written 


 
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approval is provided by the study monitoring team. Sites should comply with their local drug 
destruction policies. 
 
5.5      Justification for Dosage 
 
 
The dosage of 0.3 mg/kg daily is selected for this study based on its well-understood safety and 
efficacy profile from prior clinical trial experience in neurology.  In Ra Pharma’s Phase 2 gMG 
study (RA101495-02.201), the 0.3mg/kg dose demonstrated superior efficacy, greater inhibition 
of the terminal complement pathway, with a similar safety and tolerability profile as compared 
with the 0.1 mg/kg and placebo arms.  The magnitude and speed of improvement on the primary 
(Quantitative Myasthenia Gravis Score, QMG) and key secondary (MG Activities of Daily 
Living, 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. The superior efficacy of the 0.3 mg/kg dose was 
further demonstrated by participants’ complete freedom from the need for rescue therapy with 
IVIG or PLEX in the 0.3mg/kg arm, as compared with a 7% rescue rate in the 0.1mg/kg arm, and 
a 20% rescue rate in the placebo arm. A higher proportion of participants achieved minimal 
symptom expression (Vissing 2018), defined as an MG-ADL of 0 or 1, in the 0.3mg/kg arm 
(35.7%) as compared with the 0.1mg/kg arm (26.7%) and placebo (13.3%). 
 
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 participants 
receiving the 0.3 mg/kg dose while the 0.1 mg/kg group achieved only submaximal (88%) 
inhibition of the terminal complement pathway.  
 
The once daily dosing interval used in study RA101495-02.201 will be retained in this study 
because pharmacokinetic simulations indicate that longer dosing intervals cannot achieve 
adequate exposures and fail to maintain the depth of complement inhibition needed for 
maximum therapeutic benefit.  For example, once every other day dosing is estimated to reduce 
the zilucoplan trough concentration by approximately 50%, resulting in inadequate 
pharmacodynamic effect. 
 
The same weight brackets as used in study RA101495-02.201 have been selected for use in this 
study. Study drug will be provided in prefilled syringes for self-injection using weight bracketed 
dosing (i.e., participants will be provided prefilled syringes containing fixed amounts of 
zilucoplan based on their weight, and each fixed amount will cover a range of participant 
weights).  
 


 
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5.5.1   Additional Scientific Justification for Dose Selection 
 
Although activation of the complement system has been shown to participate in several 
neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, Huntington's 
disease and ALS (Kjaeldgaard et al., 2018; Loeffler et al., 2006; Morgan, 2018; Singhrao et al., 
1999), basal levels of unactivated complement C5 are unchanged in ALS when compared to 
healthy controls. It is therefore apparent that ALS pathophysiology is driven, in part, by 
hyperactivation of complement system rather than over expression / elevated levels of the 
individual fluid phase proteins. This is exemplified by the below figure (Error! Reference 
source not found.) whereby complement C5 levels in plasma and CSF in ALS patients remain 
in the physiological range and comparable to healthy volunteer samples. 
 
Figure 5: Complement C5 concentrations in healthy donors (n=14), age range 40–77yrs and ALS 
patients (n=17 of which n=15 sporadic ALS and n=2 familial ALS), age range 40-81yrs. 
 
*Statistical difference assessed using unpaired, non-parametric, 2-tailed Mann-Whitney test in Prism 
(also called Wilcoxon rank sum test. Data is shown as mean ± Standard Deviation) 
 
With respect to dose selection for this trial, as drug levels (complement C5) are within the 
normal range and comparable with healthy volunteers (see above) and myasthenia gravis patients 
(not shown) no special dose adjustment for the ALS population is necessary. Furthermore, the 
sponsor assessed the apparent functional potency of zilucoplan in ALS plasma using a bioassay 
of pharmacodynamic activity (Error! Reference source not found.). The potency of zilucoplan 
to inhibit complement activation is unchanged relative to potency observed in healthy volunteer 
plasma samples.  
 
 
 
 
 


 
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Figure 6: Functional potency of zilucoplan in healthy donors (n=13) and ALS patients (n=16) 
plasma.  
 
 
 
 
 
 
 
 
 
Donor plasma (1% v/v) was incubated with antibody sensitized sheep erythrocytes. Hemolysis 
was assessed using OD412nm absorbance of the supernatant. A 10-pt dose-response curve with 
zilucoplan was generated for each sample to assess the IC50 and IC90 values. Samples are from 
the same patients and healthy volunteers as described in Error! Reference source not found.. 
 
Based on similar target:drug stoichiometry across patient populations studied in the clinical 
development program of zilucoplan and unchanged functional potency of zilucoplan in ALS 
biomatrices, a daily dose of 0.3mg/kg/day will provide complete inhibition of complement C5 
activity. The PK/PD relationship for zilucoplan in the phase 2, dose ranging study in a 
comparable neuromuscular disorder generalized myasthenia gravis is shown in Error! 
Reference source not found.. 
Samples 
IC50 (nM) 
Mean ± SD 
IC90 (nM) 
Mean ± SD 
Healthy (n=13)  5.7 ± 1.3 
13.4 ± 3.5 
ALS (n=16) 
5.4 ± 1.3 
12.4 ± 2.5 


 
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Figure 7: Pharmacokinetic / Pharmacodynamic relationship of zilucoplan in Phase 2, dose ranging 
study in generalized myasthenia gravis (IND 134340).  
 
 
Finally, data supports the blood-brain barrier permeability of zilucoplan in preclinical species 
(rats and non-human primates). Quantitative whole-body autoradiography studies in rats have 
been conducted using [14C]-zilucoplan to determine the in vivo biodistribution of zilucoplan). In 
rats with a fully intact blood brain barrier approximately 1% (AUC0-24 as a percentage of 
plasma) of dosed compound was detected in the CNS compartment. Microdialysis studies in 
non-human primates also with an intact blood brain barrier have also been conducted and support 
these findings. 
 
In summary 0.3mg/kg/day in the current study, should provide complete inhibition of circulating 
complement C5 in ALS patients. Furthermore, irrespective of blood brain barrier status 
(compromised vs intact) zilucoplan is expected to enter the CNS and engage complement C5. 
Pharmacodynamic biomarkers and pharmacokinetic analysis will be employed in this trial in 
both peripheral and CNS compartments to support interpretation of clinical data. 
 
5.6      Dosage Changes 
 
Not applicable. 
 
5.7      Participant Compliance 
 
Study personnel will assess study drug compliance at every in-person visit to record whether any 
doses were missed. During phone visits, drug compliance check-in will be discussed to ensure 
participant is taking drug per dose regimen and to note any report of missed doses. If a 
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scheduled and the investigator should be contacted as soon as possible. If a participant misses 2 
or more doses, he/she must notify the investigator immediately and the medical monitor should 
be consulted.  
 
If a participant misses 10 or more consecutive doses, he/she must notify the investigator 
immediately, the medical monitor should be consulted, and this will be considered a major 
protocol deviation. 
 
5.8      Overdose  
 
Certain safety events that occur in association with study drug may require reporting. These 
safety events include, but are not limited to, the following: 
• Overdose of the study drug, where ‘overdose’ is defined as a participant receiving ≥ 2 times 
the intended dose for any given SC injection 
• Suspected abuse/misuse of the study drug 
• Inadvertent or accidental exposure to the study drug 
• Medication error involving study drug (with or without participant exposure to the study 
drug, e.g., name confusion) 
These safety events should be reported to the Coordination Center whether they result in an 
AE/SAE or not. Safety events associated with an AE/SAE should also be reported in the EDC. 
 
In the event of overdose, study staff should monitor the participant and provide supportive care 
as needed. The SI should also contact the Medical Monitor within 24 hours of the SI’s 
awareness.  
 
5.9      Prohibited Medications 
 
Participants are prohibited from receiving another complement inhibitor and/or any other 
investigational products while on study.  All other medications are permitted while on study. 
Participants are expected to remain on stable doses of permitted SOC therapy for ALS 
throughout the Treatment Period of the study.  
 
5.10 
      Zilucoplan Known Potential Risks and Benefits 
 
5.10.1 Known Potential Risks 
 
There are potential benefits and risks with the administration of any new investigational medicine 
as the effects are not fully known. To date, zilucoplan has shown good tolerability and a favorable 
safety profile across studies as described in the current version of the IB.  
 


 
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It is well established that inhibition of C5 and the terminal complement pathway increases the 
susceptibility to infection with encapsulated bacteria, in particular N. meningitidis. This risk is 
also described in the prescribing information for eculizumab (Soliris® USPI 2017). Given the 
increased risk for N. meningitidis with C5 inhibition or deficit, patients who participate in 
zilucoplan clinical trials will be required to have documentation of N. meningitidis vaccination 
(and booster if appropriate) prior to study entry. In addition, while on treatment with zilucoplan, 
participants will be monitored closely for signs and symptoms of N. meningitidis infection. More 
information on the safety profile of zilucoplan can be found in the IB.  
 
5.10.2 Known Potential Benefits 
 
The potential benefits of zilucoplan comprise improved control of complement-mediated disease 
processes (e.g., such effects have already demonstrated on muscle weakness due to impaired 
neuromuscular signaling in patients with gMG).  In ALS we hypothesize that zilucoplan can inhibit 
complement-mediated tissue damage in the CNS and the neuromuscular junction, and that this 
may translate into improved neurological function as assessed by ALSFRS-R. 
 
5.11  Treatment Assignment Procedures 
 
Each participant who meets all eligibility criteria for the RSA will be randomized to receive 
either 0.3 mg/kg zilucoplan daily or placebo for approximately 24 weeks of placebo-controlled 
treatment (with the option of an Open Label Extension).   
 
 
 
 
 
 
 
 
 
 


 
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6  REGIMEN SCHEDULE  
6.1 
Placebo-Controlled Period  
 
In addition to procedures in the Master protocol, the following regimen specific procedures will 
be conducted during the study: 
 
• Home Spirometry 
o Note: Home spirometry should be collected within the visit window but will occur 
while the participant is not in the clinic (at home or other remote location).  
• ALSAQ-40 
• CNS Bulbar Function Scale 
• Smartphone installation and removal 
• Voice recording 
• Dispense investigational product to participant 
• Neisseria Meningitidis Vaccination 
o Note: Booster vaccinations should be administered in accordance with SOC.  
Please refer to SOC and vaccination worksheet for details about timing. 
• Anti-drug Antibody Sampling 
• Zilucoplan Plasma PK Analysis 
• Zilucoplan Pharmacodynamic Analysis 
• Zilucoplan Peripheral Blood Biomarker Samples 
 
Participants may be required to reconsent to the regimen if new procedures or information is 
added in the future. Should a participant need to reconsent, this should occur during the 
participant’s next in-person visit. If the participant’s next in-clinic visit is conducted remotely, 
reconsent may also be completed remotely using the following procedures: 
 
1. The site staff sends a copy of the informed consent form to the participant. 
2. The participant reads through the consent form but does not sign.  
3. The Site Investigator, or other study staff member approved and delegated to obtain informed 
consent, contacts the participant and reviews the informed consent form with the participant.  
4. The participant signs the informed consent form and returns the original signed consent form 
back to the site. 
5. Once received at the site, the individual who consented the participant signs the informed 
consent form. 
 
 


 
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Modifications to Regimen Schedule  
Designated visits in the Schedule of Activities (i.e., Week 4, Week 8, and Week 16) may be 
conducted via telemedicine (or phone if telemedicine is not available) with remote services 
instead of in-person if needed to protect the safety of the participant due to a pandemic or other 
reason. If a planned in-clinic visit is conducted via telemedicine (or phone if telemedicine is not 
available) with remote services, only selected procedures will be performed. Instructions on how 
to document missed procedures are included in the MOP.  
 
In addition to the procedures in the Master Protocol that should be conducted during the phone or 
telemedicine and remote visits, the following regimen-specific procedures should be completed:  
 
• Home Spirometry (Week 8 and 16 only) 
• Voice Recording 
• CNS Bulbar Function Scale (Week 8 and 16 only)  
• Neisseria Meningitidis Vaccination booster shots 
 
Details on collection of the CNS Bulbar Function Scale, dispensing IP during remote visits, and 
documenting participants’ willingness to participate in OLE are described in the MOP. 
Blood samples for anti-drug antibody sampling, PK and PD analyses, and peripheral blood 
biomarker samples are not collected during the remote visits by the home health agency and this 
should be recorded as such in the applicable source documentation and EDC.  
 
6.1.1 Regimen-Specific Screening Visit  
 
This visit will take place in-person after the Master Protocol randomization to a regimen. The 
visit must occur at least 14 days prior to the Baseline Visit. This is because the 
meningococcal vaccine needs 14 days to take effect.  Participants must not start study drug 
until the 14-day period has elapsed.   The following procedures will be performed: 
 
• Neisseria Meningitidis Vaccination 
 
The regimen-specific screening may occur remotely if the participant would like to obtain the 
vaccination from their local provider, rather than traveling to the study site to obtain the 
vaccination during the screening visit. If the regimen-specific screening visit occurs remotely, 
then informed consent must be obtained remotely. The site should follow the steps below for 
obtaining remote consent from the participant prior to when the participant receives the 
vaccination: 
 


 
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• 
The site staff sends the informed consent form to the participant. 
• 
The participant reads through the consent form but does not sign.  
• 
The Site Investigator, or other study staff member approved and delegated to obtain informed 
consent, contacts the participant and reviews the informed consent form with the participant. 
• 
The participant signs the informed consent form and returns the original signed consent form 
back to the site. 
• 
Once received at the site, the individual who consented the participant signs the informed 
consent form. 
 
6.1.2  Baseline Visit 
 
This visit will take place in-person at least 14 days after the Regimen-Specific Screening Visit. 
The following procedures will be performed: 
 
• ALSAQ-40 
• CNS Bulbar Function Scale 
• Install Smartphone Apps 
• Home Spirometry 
• Voice Recording 
• Anti-drug Antibody Sampling 
• Zilucoplan Plasma PK Analysis 
• Zilucoplan Pharmacodynamic Analysis 
• Zilucoplan Peripheral Blood Biomarker Samples 
• Dispense investigational product to participant 
• Administer investigational product to participant once all other Baseline procedures are 
complete 
• Remind participant to bring investigational product to the next visit 
 
6.1.3 Week 2 Telephone Visit 
 
This visit will take place 14 ± 3 days after the Baseline Visit via telephone.  No regimen-specific 
procedures will be performed at this visit. 
 
 
6.1.4 Week 4 Visit 
 
This visit will take place in-person 28 ± 7 days after the Baseline Visit The following procedures 
will be performed: 


 
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• Voice Recording 
• Dispense investigational product to participant 
• Remind participant to bring investigational product to the next visit 
 
6.1.5 Week 8 Visit 
 
Participants should be instructed to hold study drug on the day of the study visit. Study drug 
should not be taken until after study visit procedures are complete. 
 
This visit will take place in-person 56 ± 7 days after the Baseline Visit.  The following 
procedures will be performed: 
 
• Home Spirometry  
• CNS Bulbar Function Scale 
• Voice Recording 
• Anti-drug Antibody Sampling 
• Zilucoplan Plasma PK Analysis 
• Zilucoplan Pharmacodynamic Analysis 
• Zilucoplan Peripheral Blood Biomarker Samples 
• Dispense investigational product to participant 
• Remind participant to bring investigational product to the next visit 
 
6.1.6 Week 12 Telephone Visit 
 
This visit will take place 84 ± 3 days after the Baseline Visit via telephone.  No regimen-specific 
procedures will be performed at this visit. 
 
6.1.7 Week 16 Visit 
 
Participants should be instructed to hold study drug on the day of the study visit. Study drug 
should not be taken until after study visit procedures are complete. 
 
This visit will take place in-person 112 ± 7 days after the Baseline Visit. The following 
procedures will be performed: 
 
• Home Spirometry 
• CNS Bulbar Function Scale 


 
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• Voice Recording 
• Anti-drug Antibody Sampling 
• Zilucoplan Plasma PK Analysis 
• Zilucoplan Pharmacodynamic Analysis 
• Zilucoplan Peripheral Blood Biomarker Samples 
• Document participant’s willingness to participate in the OLE 
o If OLE consent is not obtained at Week 16, it may be obtained at Week 24. 
• Dispense investigational product to participant 
• Remind participant to bring investigational product to the next visit 
 
6.1.8 Week 20 Telephone Visit 
 
This visit will take place 140 ± 3 days after the Baseline Visit via telephone. No regimen-specific 
procedures will be performed at this visit. 
 
6.1.9 Week 24 Visit or Early Termination Visit 
 
Participants should be instructed to hold study drug on the day of the study visit. Study drug 
should not be taken until after study visit procedures are complete. 
 
The Week 24 Visit will take place in-person 168 ± 7 days after the Baseline Visit.  The following 
procedures will be performed at either the Week 24 Visit or the Early Termination Visit: 
 
• Home Spirometry  
• ALSAQ-40 
• CNS Bulbar Function Scale 
• Voice Recording 
• Uninstall Smartphone App 
• Anti-drug Antibody Sampling 
• Zilucoplan Plasma PK Analysis 
• Zilucoplan Pharmacodynamic Analysis 
• Zilucoplan Peripheral Blood Biomarker Samples 
• Dispense investigational product to participant [See note below.] 
• Remind participant to bring investigational product to the next visit (only if continuing in 
OLE) 
 


 
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Note: Drug is only dispensed at this visit if the participant is continuing in the Open Label 
Extension. Participants should be instructed to continue using effective contraception for at 
least 40 days after their last dose of study drug.  
 
6.1.10    Follow-Up Safety Call 
 
Participants will have a Follow-Up Safety Call about 40 days after their last dose of study drug.  
Only those participants NOT continuing on in the Open Label Extension will have the Follow-
Up Safety Call following the end of their participation in the placebo-controlled portion of the 
trial.  The following procedures will be performed: 
 
• Assess and document AEs, including Key Study Events (see section 10.3 of Master Protocol) 
 
6.1.11    Process for Early Terminations 
 
Participants who early terminate from the study and do not complete the protocol will be asked 
to be seen for an in-person Early Termination Visit and complete a Follow-Up Safety Call. If a 
participant is not able to be seen in-person, safety assessments and others that can be conducted 
remotely should be performed. 
 
The in-person Early Termination Visit should be scheduled as soon as possible after a participant 
early terminates. If the participant early terminates during the placebo-controlled portion of the 
Regimen, all assessments that are collected at the Week 24 in-clinic visit should be conducted. If 
the participant early terminates during the OLE phase, all assessments that are collected at the 
OLE Week 52 in-clinic visit should be conducted. The Follow-Up Safety Call should be 
completed approximately 40 days after the last dose of study drug.   
 
If the Early Termination Visit occurs approximately 40±3 days after the last dose of study drug, 
the information from the Follow-Up Safety Call can be collected during the Early Termination 
Visit, and a separate Follow-Up Safety Call does not need to be completed. If the in-person Early 
Termination Visit does not occur within 40±3 days of the last dose of study drug, the Follow-Up 
Safety Call should occur approximately 40±3 days after the last dose of study drug and the Early 
Termination Visit will be completed after the Follow-Up Safety Call.      
 
Note: Participants should be instructed to continue using effective contraception for at least 
40 days after their last dose of study drug.  
 
 
 


 
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6.2 
Open Label Extension  
 
Participants who have completed the placebo-controlled portion of the trial on drug, will be 
eligible to continue on in the Open Label Extension.  The Open Label Extension of the study will 
continue until zilucoplan is approved and available in the territory, or the Sponsor terminates 
development of zilucoplan for ALS. 
 
Modifications to OLE Schedule  
Designated visits in the Schedule of Activities for the OLE (i.e. Week 4, Week 8, Week 16, 
Week 28, and Week 40) may be conducted via telemedicine (or phone if telemedicine is not 
available) with remote services instead of in-person if needed to protect the safety of the 
participant due to a pandemic or other reason. If a planned in-clinic visit is conducted via 
telemedicine (or phone if telemedicine is not available) with remote services, only selected 
procedures will be performed. Instructions on how to document missed procedures are included 
in the MOP.  
 
In addition to the procedures in the Master Protocol that should be conducted during the phone or 
telemedicine and remote visits, the following regimen-specific procedures should be completed:  
 
• Home Spirometry  
• CNS Bulbar Function Scale (Not done at OLE Week 4).  
• Neisseria Meningitidis Vaccination booster shot 
 
Blood samples for anti-drug antibody sampling, PK and PD analyses, and peripheral blood 
biomarker samples are not collected during the remote visits by the home health agency and this 
should be recorded as such in the applicable source documentation and EDC.  
 
6.2.1 Week 2 OLE Telephone Visit 
 
This visit will take place via telephone 14 ± 3 days after the Week 24 Visit of the placebo-
controlled portion of the trial. The following procedures will be performed: 
 
• 
Review concomitant medications 
• 
Assess and document AEs, including Key Study Events (see section 10.3 of Master Protocol) 
• 
Compliance Check-In  
• 
Remind participant to bring investigational product to the next visit 
 
6.2.2 Week 4 OLE Visit 
 


 
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This visit will take place in-person 28 ± 7 days after the Week 24 Visit of the placebo-controlled 
portion of the trial. The following procedures will be performed: 
 
• 
Collect vital signs including weight 
• 
Perform SVC 
• 
Collect Home Spirometry 
• 
Administer ALSFRS-R questionnaire 
• 
Collect blood samples for Clinical Safety Labs and, for WOCBP, for pregnancy test if 
applicable 
• 
Review concomitant medications 
• 
Assess and document AEs, including Key Study Events (see section 10.3 of Master Protocol) 
• 
Administer the C-SSRS Since Last Visit questionnaire  
• 
Perform investigational product compliance 
• 
Dispense investigational product to participant 
• 
Remind participant to bring investigational product to the next visit 
 
6.2.3 Week 8 OLE Visit 
 
This visit will take place in-person at 56 ± 7 days after the Week 24 Visit of the placebo-
controlled portion of the trial. The following procedures will be performed: 
 
• 
Collect vital signs including weight 
• 
Perform SVC 
• 
Collect Home Spirometry 
• 
Administer ALSFRS-R questionnaire 
• 
CNS Bulbar Function Scale 
• 
Collect blood samples for Clinical Safety Labs and, for WOCBP, for pregnancy test if 
applicable 
• 
Review concomitant medications 
• 
Assess and document AEs, including Key Study Events (see section 10.3 of Master Protocol) 
• 
Administer the C-SSRS Since Last Visit questionnaire  
• 
Perform investigational product compliance 
• 
Dispense investigational product to participant 
• 
Remind participant to bring investigational product to the next visit 
 
6.2.4  Week 12 OLE Telephone Visit 
 
This visit will take place via telephone at 84 ± 3 days after the Week 24 Visit of the placebo-
controlled portion of the trial. The following procedures will be performed: 


 
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• 
Administer ALSFRS-R questionnaire 
• 
Assess and document AEs, including Key Study Events (see section 10.3 of Master Protocol) 
• 
Compliance Check-In  
• 
Remind participant to bring investigational product to the next visit 
 
6.2.5  Week 16 OLE Visit 
 
Participants should be instructed to hold study drug on the day of the study visit. Study drug 
should not be taken until after study visit procedures are complete. 
 
This visit will take place in-person at 112 ± 7 days after the Week 24 Visit of the placebo-
controlled portion of the trial. The following procedures will be performed: 
 
• 
Collect vital signs including weight 
• 
Perform SVC 
• 
Collect Home Spirometry 
• 
Administer ALSFRS-R questionnaire 
• 
CNS Bulbar Function Scale 
• 
Collect blood samples for Clinical Safety Labs and, for WOCBP, for pregnancy test if 
applicable 
• 
Review concomitant medications 
• 
Assess and document AEs, including Key Study Events (see section 10.3 of Master Protocol) 
• 
Administer the C-SSRS Since Last Visit questionnaire  
• 
Perform investigational product compliance 
• 
Collect urine sample biomarker analyses 
• 
Collect blood sample for biomarker analyses 
• 
Anti-drug Antibody Sampling 
• 
Zilucoplan Plasma PK Analysis 
• 
Zilucoplan Pharmacodynamic Analysis 
• 
Zilucoplan Peripheral Blood Biomarker Samples 
• 
Dispense investigational product to participant 
• 
Remind participant to bring investigational product to the next visit 
 
6.2.6  Week 20 OLE Telephone Visit 
 
This visit will take place via telephone at 140 ± 3 days after the Week 24 Visit of the placebo-
controlled portion of the trial. The following procedures will be performed: 
 
• 
Administer ALSFRS-R questionnaire 


 
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• 
Review concomitant medications 
• 
Assess and document AEs, including Key Study Events (see section 10.3 of Master Protocol) 
• 
Compliance Check-In  
• 
Remind participant to bring investigational product to the next visit 
 
6.2.7  Week 24 OLE Telephone Visit 
 
This visit will take place via telephone at 168 ± 3 days after the Week 24 Visit of the placebo-
controlled portion of the trial. The following procedures will be performed: 
 
• 
Administer ALSFRS-R questionnaire 
• 
Review concomitant medications 
• 
Assess and document AEs, including Key Study Events (see section 10.3 of Master Protocol) 
• 
Compliance Check-In  
• 
Remind participant to bring investigational product to the next visit 
 
6.2.8  Week 28 and Q12 Weeks OLE Visits 
 
Participants should be instructed to hold study drug on the day of the study visit. Study drug 
should not be taken until after study visit procedures are complete. 
The Week 28 OLE Visit will take place in-person 196 ± 14 days after the Week 24 Visit of the 
placebo-controlled portion of the trial.  Following the Week 28 OLE Visit, visits will occur every 
12 weeks ± 14 days.  The following procedures will be performed: 
 
• 
Collect vital signs including weight 
• 
Perform SVC 
• 
Collect Home Spirometry 
• 
Administer ALSFRS-R questionnaire 
• 
ALSAQ-40 [Only done at OLE Weeks 28 and 52 Visits] 
• 
CNS Bulbar Function Scale [Only done at OLE Weeks 28, 40, and 52 Visits] 
• 
Collect blood samples for Clinical Safety Labs and, for WOCBP, for pregnancy test if 
applicable 
• 
Review concomitant medications 
• 
Assess and document AEs, including Key Study Events (see section 10.3 of Master Protocol) 
• 
Administer the C-SSRS Since Last Visit questionnaire  
• 
Perform investigational product compliance 
• 
Collect urine sample biomarker analyses [Only done at OLE Weeks 16, 28, and 52 Visits] 
• 
Collect blood sample for biomarker analyses [Only done at OLE Weeks 16, 28, and 52 
Visits] 


 
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• 
Anti-drug Antibody Sampling [Only done at OLE Weeks 16, 28, and 52 Visits] 
• 
Zilucoplan Plasma PK Analysis [Only done at OLE Weeks 16, 28, and 52 Visits] 
• 
Zilucoplan Pharmacodynamic Analysis [Only done at OLE Weeks 16, 28, and 52 Visits] 
• 
Zilucoplan Peripheral Blood Biomarker Samples [Only done at OLE Weeks 16, 28, and 52 
Visits] 
• 
Dispense investigational product to participant 
• 
Remind participant to bring in investigational product to the next visit 
 
 
 
 
 
 
 
 
 


 
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7. CLINICAL ASSESSMENTS AND OUTCOME MEASURES 
For all assessments listed below, please refer to the Manual of Procedures for detailed 
instructions. 
7.1  
Voice Analysis 
Voice samples will be collected twice per week, using an app installed on either an android or 
iOS based smartphone.  The app characterizes ambient noise, then asks patients to perform a set 
of speaking tasks: reading sentences -- 5 fixed and 5 chosen at random from a large sentence 
bank-- repeating a consonant-vowel sequence, producing a sustained phonation, and counting on 
a single breath. Voice signals are uploaded to a HIPAA-compliant web server, where an AI-
based analysis identifies relevant vocal attributes. Quality control (QC) of individual samples 
will occur by evaluation of voice records by trained personnel. 
 
The voice analysis app is only available in English, therefore participants who do not speak 
English should not complete the voice recording. Caregivers cannot provide language assistance 
when the participant is completing the voice recording. 
 
7.2     ALSAQ-40 
 
The Amyotrophic Lateral Sclerosis Assessment Questionnaire-40 (ALSAQ-40) is a patient self-
report health status patient-reported outcome. The ALSAQ-40 consists of forty questions that are 
specifically used to measure the subjective well-being of patients with ALS and motor neuron 
disease. 
 
Participants will be handed the questionnaire and asked to write their answers themselves.  
Caregivers can also help, if needed. 
 
7.3    Center for Neurologic Study Bulbar Function Scale 
 
The Center for Neurologic Study Bulbar Function Scale (CNS-BFS) is a patient self-report scale 
that has been developed for use as an endpoint in clinical trials and as a clinical measure for 
evaluating and following ALS patients. The CNS-BFS consists of three domains (swallowing, 
speech, and salivation), which are assessed with a 21-question, self-report questionnaire. 
 
Participants will be handed the questionnaire and asked to write their answers themselves.  
Caregivers can also help, if needed. 
 
Instructions on administering the questionnaire during a phone or telemedicine visit will be 
included in the MOP. 


 
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7.4 Home Spirometry 
Home-based forced vital capacity will be conducted via telemedicine (or phone if telemedicine is 
not available) and will be measured with the MIR Spirobank Smart spirometer. Instructions for 
use will be provided to the participant.  The participant will perform the vital capacity maneuver 
with real time video coaching (or phone coaching, if video is not available) by the evaluator.  
Three to five vital capacity maneuvers will be performed, consistent with the manner vital 
capacity is obtained in clinic.   
   
 
 
 
 
 


 
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8.  
BIOFLUID COLLECTION 
8.1  
Anti-drug Antibody Sampling 
 
All participants will provide blood samples for anti-drug antibody sampling. 
 
8.2  
Zilucoplan Plasma PK Analysis 
 
All participants will provide blood samples for PK analysis (zilucoplan and metabolites).  These 
blood samples should be obtained prior to administration of study drug at each clinic visit (i.e., 
pre-dose). 
 
8.3  
Zilucoplan Pharmacodynamic Analysis 
 
All participants will provide blood samples for pharmacodynamic analysis (e.g., sheep RBC 
hemolysis assay, Wieslab alternative pathway assay, C5 levels). Blood samples should be 
obtained prior to administration of study drug at each clinic visit (i.e., pre-dose). 
 
8.4  
Zilucoplan Peripheral Blood Biomarker Samples 
 
All participants will provide blood samples for biomarker analysis.  Blood samples should be 
obtained prior to administration of study drug at each clinic visit (i.e., pre-dose). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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9.  
REGIMEN-SPECIFIC STATISTICAL CONSIDERATIONS 
9.1  Deviations from the Default Master Protocol Trial Design 
The statistical design for this regimen will be in accordance with the default statistical design 
described in Appendix I of the Master Protocol with only one deviation. This regimen will not 
include interim analyses for early success.  
 
9.2  Regimen Specific Operating Characteristics  
Clinical trial simulation is used to quantify operating characteristics for this regimen (refer to the 
regimen SAP for further details).   
 
9.3  Sharing of Controls from other Regimens 
 
The primary analysis of this regimen will include sharing of all controls from the other 
regimens.  This is justified by the minor differences in inclusion/exclusion criteria of the RSA, 
such that there are no expected systematic differences in the primary endpoint between the 
controls across regimens.   
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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APPENDIX I: THE ALSAQ-40 
 


 
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APPENDIX II: THE BULBAR FUNCTION SCALE (CNS-BFS)  
BULBAR FUNCTION SCALE (CNS-BFS) 
SIALORRHEA 
Does 
Not 
Apply 
(1) 
Applies 
Rarely 
(2) 
   Applies 
Occasionally 
(3) 
Applies 
Frequently  
(4) 
Applies 
Most of 
the Time 
(5) 
 
1. Excessive saliva is a concern to 
me. 
 
 
 
 
 
2. I take medication to control 
drooling. 
 
 
 
 
 
3. Saliva causes me to gag or 
choke. 
 
 
 
 
 
4. Drooling causes me to be 
frustrated or embarrassed. 
 
 
 
 
 
5. In the morning I notice saliva on 
my pillow. 
 
 
 
 
 
6. My mouth needs to be dabbed to 
prevent drooling. 
 
 
 
 
 
7. My secretions are not 
manageable. 
 
 
 
 
 
  
TOTAL Sialorrhea Score: _____ 
SPEECH 
Does 
Not 
Apply 
(1) 
Applies 
Rarely 
(2) 
   Applies 
Occasionally 
(3) 
Applies 
Frequently  
(4) 
Applies 
Most of 
the Time 
(5) 
Unable to 
Communicate 
by Speaking 
(6) 
1. My speech is difficult to 
understand. 
 
 
 
 
 
 
2. To be understood I repeat myself. 
 
 
 
 
 
 
3. People who understand me tell 
other people what I said.  
 
 
 
 
 
 
4. To communicate I write things 
down or use devices such as a 
computer. 
 
 
 
 
 
 
5. I am talking less because it takes 
so much effort to speak. 
 
 
 
 
 
 


 
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6. My speech is slower than usual. 
 
 
 
 
 
 
7. It is hard for people to hear me. 
 
 
 
 
 
 
  
TOTAL Speech Score: _____ 
SWALLOWING 
Does 
Not 
Apply 
(1) 
Applies 
Rarely 
(2) 
   Applies 
Occasionally 
(3) 
Applies 
Frequently  
(4) 
Applies 
Most of 
the Time 
(5) 
  
    Feeding tube is in place 
1. Swallowing is a problem. 
 
 
 
 
 
2. Cutting my food makes it easier 
to chew and swallow. 
 
 
 
 
 
3. To get food down I have 
switched to a soft diet. 
 
 
 
 
 
4. After swallowing I gag or choke. 
 
 
 
 
 
5. It takes longer to eat. 
 
 
 
 
 
6. My weight is dropping because I 
can't eat normally. 
 
 
 
 
 
7. Food gets stuck in my throat. 
 
 
 
 
 
  
TOTAL Swallowing Score: _____ 
OVERALL SCORE: _____ 
 
 
 
 
 
 
 
 


 
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REFERENCES 
Bahia El Idrissi, N., et al., 2016a. Complement activation at the motor end-plates in 
amyotrophic lateral sclerosis. J. Neuroinflammation 13, 72. 
Bahia El Idrissi, N., et al., 2016b. Complement component C6 inhibition decreases 
neurological disability in female transgenic SOD1G93A mouse model of amyotrophic 
lateral sclerosis. Ann Neurodegener Dis. 1, 1015. 
Barnum, S.R., 1995. Complement biosynthesis in the central nervous system. Crit. Rev. 
Oral Biol. Med. 6, 132–146. 
Chou SM, Norris FH, 1993. Amyotrophic lateral sclerosis: lower motor neuron disease 
spreading to upper motor neurons. Muscle & Nerve;16:864–9. 
Ferraiuolo, L., et al., 2007. Microarray analysis of the cellular pathways involved in the 
adaptation to and progression of motor neuron injury in the SOD1 G93A mouse model of 
familial ALS. J. Neurosci. 27, 9201–9219. 
Gasque, P., et al., 1997. Expression of the receptor for complement C5a (CD88) is 
upregulated on reactive astrocytes, microglia, and endothelial cells in the inflamed human 
central nervous system. Am. J. Pathol. 150, 31–41. 
Heurich, B., et al., 2011. Complement upregulation and activation on motor neurons and 
neuromuscular junction in the SOD1 G93A mouse model of familial amyotrophic lateral 
sclerosis. J. Neuroimmunol. 235, 104–109. 
Kjaeldgaard, A.L., et al., 2018. Amyotrophic lateral sclerosis: the complement and 
inflammatory hypothesis. Mol. Immunol. 102, 14–25. 
Lee, J.D., et al., 2013. Dysregulation of the complement cascade in the hSOD1G93A 
transgenic mouse model of amyotrophic lateral sclerosis. J. Neuroinflammation 10,119. 
Lee, J.D., et al., 2017. Pharmacological inhibition of complement C5a-C5a1 receptor 
signalling ameliorates disease pathology in the hSOD1G93A mouse model of amyotrophic 
lateral sclerosis. Br. J. Pharmacol. 174, 689–699. 
Lee, J.D., et al., 2018. Complement components are upregulated and correlate with disease 
progression in the TDP-43(Q331K) mouse model of amyotrophic lateral sclerosis. J. 
Neuroinflammation 15, 171. 
 
Lobsiger, C.S., et al., 2007. Toxicity from different SOD1 mutants dysregulates the 
complement system and the neuronal regenerative response in ALS motor neurons. Proc. 
Natl. Acad. Sci. U. S. A. 104, 7319–7326. 


 
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Loeffler, D.A., et al., 2006. Complement activation in the Parkinson's disease substantia 
nigra: an immunocytochemical study. J. Neuroinflammation 3, 29. 
Morgan, B.P., 2018. Complement in the pathogenesis of Alzheimer's disease. Semin. 
Immunopathol. 40, 113–124 
Nishimura, J. et al., 2014 Genetic Variants in C5 and Poor Response to Eculizumab N Engl 
J Med. 370:632-639 
O'Barr, S.A., et al., 2001. Neuronal expression of a functional receptor for the C5a 
complement activation fragment. J. Immunol. 166, 4154–4162. 
Perrin, F.E., et al., 2005. No widespread induction of cell death genes occurs in pure 
motoneurons in an amyotrophic lateral sclerosis mouse model. Hum. Mol. Genet. 14,3309–
3320. 
Shah DK, Betts AM, 2013. Antibody biodistribution coefficients: inferring tissue 
concentrations of monoclonal antibodies based on the plasma concentrations in several 
preclinical species and human. mAbs 5:297-305  
Singhrao, S.K., et al., 1999. Increased complement biosynthesis by microglia and 
complement activation on neurons in Huntington's disease. Exp. Neurol. 159, 362–376 
Sta, M., et al., 2011. Innate and adaptive immunity in amyotrophic lateral sclerosis: 
evidence of complement activation. Neurobiol. Dis. 42, 211–220. 
Trbojevic-Cepe, M., et al., 1998. Cerebrospinal fluid complement activation in neurological 
diseases. J. Neurol. Sci. 154, 173–181. 
Vissing J, O'Brien F, Wang JJ, Howard JF., 2018. Correlation between myasthenia gravis-
activities of daily living (MG-ADL) and quantitative myasthenia gravis (QMG) assessments 
of anti-acetylcholine receptor antibody-positive refractory generalized myasthenia gravis in 
the phase 3 regain study. Muscle Nerve;58(2): E21-E22 
Wang, H.A., et al., 2017. Complement C5a-C5aR1 signaling drives skeletal muscle 
macrophage recruitment in the hSOD1G93A mouse model of amyotrophic lateral sclerosis. 
Skelet. Muscle 7, 10. 
Woodruff, T.M., et al., 2008. The complement factor C5a contributes to pathology in a rat 
model of amyotrophic lateral sclerosis. J. Immunol. 181, 8727–8734. 
Woodruff, T.M., et al., 2010. The role of the complement system and the activation 
fragment C5a in the central nervous system. NeuroMolecular Med. 12, 179–192. 
Woodruff, T.M., et al., 2014. Role for terminal complement activation in amyotrophic 
lateral sclerosis disease progression. Proc. Natl. Acad. Sci. U. S. A. 111, E3–E4. 

SAP_001.pdf: 
HEALEY ALS Platform Trial - Regimen A Zilucoplan 
NCT04436497 
Document Date: 22 Jul 2022 


Cudkowicz (PI) HEALEY ALS Platform Trial: RGA Statistical Analysis Plan 
Version 3.0, 22 Jul 2022 
 
Page 1 of 2 
 
 
RGA REGIMEN-SPECIFIC STATISTICAL ANALYSIS PLAN (R-SAP) 
Master Protocol 
Platform Trial for the Treatment of Amyotrophic Lateral 
Sclerosis (ALS):  A perpetual multi-center, multi-regimen, 
clinical trial evaluating the safety and efficacy of 
investigational products for the treatment of ALS 
Regimen 
RGA: Zilucoplan 
Regimen Partner 
Ra Pharmaceuticals now part of UCB, Inc. 
Regulatory Sponsor 
Merit E. Cudkowicz, MD 
Master Protocol Version 
4.0, 31 Aug 2020 
RSA Version 
5.0, 15 Jul 2021 
Master SAP Version 
1.0, 24 Jun 2020 
R-SAP Version 
3.0, 22 Jul 2022 
 
SAP APPROVAL SIGNATURES 
 
 
Merit E. Cudkowicz, MD, MSc 
Principal Investigator and Regulatory Sponsor 
Date 
 
 
Sabrina Paganoni, MD, PhD 
Co-Principal Investigator 
Date 
 
 
Paul Mahoney, PhD 
Ra Pharmaceuticals now part of UCB, Inc. 
Date 
07/22/2022
07/25/2022
07/22/2022


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Page 2 of 3 
 
 
 
Ben Saville, PhD 
Senior Statistical Scientist, Berry Consultants 
Date 
 
 
Eric A. Macklin, PhD 
Study Biostatistician 
Date 
07/22/2022
07/22/2022


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Version 3.0, 22 Jul 2022 
 
Page 3 of 4 
 
SAP REVISION HISTORY 
Version 
Date 
Description of Changes 
1.0 
17 Mar 2022 Initial version 
2.0 
06 May 2022 Revision of Section 5.9 Survival to specify that both PAV-free 
survival and overall survival will be evaluated at both the Week 
24 Visit time point and the last-participant-last-visit time point 
and to specify that PAV-free survival to the Week 24 Visit time 
point is the primary analysis of survival in this analysis plan. 
Revision of Section 6.5.5 CAFS to specify the following: 
1. CAFS will be used as a supportive analysis for the secondary 
efficacy endpoints of HHD upper and lower extremity 
percentage and SVC,  
2. Secondary CAFS analyses will use multiple imputation to 
extend follow-up for participants who early terminate, 
withdraw consent, or are lost to follow-up,  
3. Secondary CAFS analyses will use time to death alone 
independent of any death equivalent, and  
4. Primary inference from CAFS analyses will compare survival 
by time to death or death equivalent and will compare change 
in function to the last jointly observed time point. 
3.0 
22 Jul 2022 
Revision of Section 4.2 Exploratory Endpoints to identify serum 
creatinine and serum and CSF neurofilament light chain (NfL) as 
exploratory biomarkers of neurodegeneration and neuromuscular 
degeneration and to include ALSAQ-40 domain scores and 
symptom index (SI) as exploratory endpoints. 
Revision of Section 5.1 ALSFRS-R to specify details of the 
calculation of pre-baseline slope. 
Revision of Section 5.5 Quantitative Voice Characteristics to 
include predicted vital capacity as an additional metric at the 
Baseline Visit. 
Revision of Section 5.6 Biofluid Biomarkers of 
Neurodegeneration to specify the assay techniques used to 
quantify serum creatinine and serum and CSF NfL. 
Revision of Section 5.7 ALSAQ-40 to specify calculation of 
domain scores and to revise calculation of overall ALSAQ-40 SI. 
Revision of Section 5.8 CNS-BFS to specify that the total score is 
referenced. 


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Page 4 of 5 
 
Version 
Date 
Description of Changes 
3.0 
(continued) 
22 Jul 2022 
(continued) 
Revision of Section 5.9 Survival to specify that time at risk 
begins at each participant's Baseline Visit and to specify that the 
date of PAV initiation, where applicable, will be imputed as the 
fifteenth day of a month if not specified more precisely. 
Revision of Section 6.1 Analysis Sets to add the Efficacy 
Common Mode of Administration (ECM) analysis set, to remove 
the restriction on protocol deviations that could be considered for 
exclusion from the Efficacy Per-protocol (EPP) analysis set must 
be classified as major protocol deviations, to specify the time 
point at which data is excluded from the EPP analysis set in the 
case of time-dependent exclusions, and to specify that data from 
placebo participants from other regimens would not be excluded 
from the EPP analysis set due to non-adherence to protocol-
specified dosing. 
Revision of Section 6.2 Baseline Characterization to include 
ALSAQ-40 domain scores and SI. 
Revision of Section 6.5.2 Repeated-measures Model to add a 
fixed term for treatment group (removing the shared-baseline 
assumption at the recommendation of the FDA) and to specify a 
separate supportive analysis that includes fixed terms for centered 
baseline serum NfL level, and centered baseline serum NfL level 
× visit interaction. 
Revision of Section 6.5.3 Random-slopes Model to add a fixed 
term for treatment group (removing the shared-baseline 
assumption) and to specify a separate supportive analysis that 
includes fixed terms for centered baseline serum NfL level, and 
centered baseline serum NfL level × study month interaction. 
Revision of Section 6.5.4 Survival and Time to Clinical Events to 
clarify that survival analyses that include follow-up beyond the 
placebo-controlled period will be analyzed in the ERO analysis 
set, to include baseline age as an additional covariate in adjusted 
models given strong prognostic value, and to specify an 
additional adjusted analysis that includes baseline serum NfL 
level as a covariate. 
Revision of Section 6.5.5 CAFS to clarify that the primary CAFS 
analysis is specified in the ALS Master Protocol Recommended 
Statistical Analysis, Design and Simulation Report and to add 
two additional sets of CAFS analyses that adjust rank scores in 
linear models, one set that adjusts for time from ALS symptom 
onset, delta-FRS, baseline use of riluzole, and one set that adjusts  


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Version 
Date 
Description of Changes 
3.0 
(continued) 
22 Jul 2022 
(continued) 
for the same set of covariates plus baseline use of edaravone, and 
baseline serum NfL level. 
Revision of Section 6.5.6 HHD0 and HHD02 to remove reference 
to the shared-baseline assumption of the repeated-measures 
mixed model of Section 6.5.2 and to specify a separate analysis 
that adds baseline serum NfL level as an additional covariate. 
Revision of Section 6.5.7 Quantitative Voice Measures to remove 
reference to the shared-baseline assumption of the random-slopes 
mixed model of Section 6.5.3 and to add a fixed term for 
treatment group (removing the shared-baseline assumption) and 
to specify a separate analysis that includes fixed terms for 
centered baseline serum NfL level, and centered baseline serum 
NfL level × B-spline interaction. 
Revision of Section 6.5.8 Placebo Multiple Imputation to specify 
regression over sequential visits by the fully conditional 
specification method, to remove reference to the shared-baseline 
assumption of the repeated-measures mixed model of Section 
6.5.2, and to specify a separate analysis that adds baseline serum 
NfL level as an additional covariate. 
Revision of Section 6.5.11 Comparison of Controls across 
Regimens to specify separate analyses that add baseline serum 
NfL level as an additional covariate. 


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ABBREVIATIONS 
ADA 
Anti-drug Antibody 
ALP 
Alkaline Phosphatase 
ALS 
Amyotrophic Lateral Sclerosis 
ALSAQ-40 
Amyotrophic Lateral Sclerosis Assessment Questionnaire, 40-item version 
ALSFRS-R 
Amyotrophic Lateral Sclerosis Functional Rating Scale, Revised 
ALT 
Alanine Transaminase 
AST 
Aspartate Transaminase 
ATS 
American Thoracic Society 
BLQ 
Below the Limit of Quantitation 
BMI 
Body Mass Index 
C-SSRS 
Columbia Suicide Severity Rating Scale 
CAFS 
Combined Assessment of Function and Survival 
CBC 
Complete Blood Count 
CKD 
Chronic Kidney Disease 
CH50 
50% Complement Activity 
COVID-19 
Coronavirus Disease 2019 
CNS-BFS 
Center for Neurologic Study Bulbar Function Scale 
CSF 
Cerebrospinal Fluid 
CSR 
Clinical Study Report 
CTCAE 
Common Terminology Criteria for Adverse Events  
delta-FRS 
Pre-baseline Slope in ALSFRS-R  
DAP 
Data Analysis Plan 
DILI 
Drug-induced Liver Injury 
DNA 
Deoxyribonucleic Acid 
DRR 
Disease Rate Ratio 
ECC 
Efficacy Concurrent Control 
ECG 
Electrocardiography or Electrocardiogram 
eGFR 
Estimated Glomerular Filtration Rate 
EPP 
Efficacy Per-protocol 
ERO 
Efficacy Regimen-only 
ELISA 
Enzyme-linked Immunosorbent Assay 


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Version 3.0, 22 Jul 2022 
 
Page 7 of 8 
 
ABBREVIATIONS (continued) 
FAS 
Full Analysis Set 
FVC 
Forced Vital Capacity 
GLI 
Global Lung Initiative 
hCG 
Human Chorionic Gonadotropin 
HHD 
Hand-held Dynamometry 
HLT 
MedDRA High Level Term 
ICF 
Informed Consent Form 
ITT 
Intention-to-treat Principle 
M-SAP 
Master Statistical Analysis Plan 
MDRD 
Modification of Diet in Renal Disease  
MedDRA 
Medical Dictionary for Regulatory Activities 
MP 
Master Protocol 
MPRDR 
ALS Master Protocol Recommended Statistical Analysis, Design and 
Simulation Report 
MSR 
Minimum Significant Ratio 
NAb 
Neutralizing Antibody 
NCI 
National Cancer Institute 
NEALS 
Northeast ALS 
NfL 
Neurofilament Light Chain 
NIV 
Noninvasive Ventilation 
OLE 
Open-label Extension 
PAV 
Permanent Assisted Ventilation 
PEG 
Polyethylene Glycol 
PD 
Pharmacodynamics 
PK 
Pharmacokinetics 
PT 
MedDRA Preferred Term 
RBC 
Red Blood Cell 
RDW 
RBC distribution width 
RGA 
Regimen A (zilucoplan) 
RSA 
Regimen-specific Appendix 
R-SAP 
Regimen-specific Statistical Analysis Plan 
 


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Page 8 of 9 
 
ABBREVIATIONS (continued) 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SGOT 
Serum Glutamic Oxaloacetic Transaminase 
SGPT 
Serum Glutamic Pyruvic Transaminase 
SI 
Symptom Index 
SoA 
Schedule of Activities 
SOC 
MedDRA System Organ Class 
SRO 
Safety Regimen-only 
STF 
Safety and Tolerability Full 
STN 
Safety and Tolerability Narrow 
SVC 
Slow Vital Capacity 
TBL 
Total Bilirubin 
TEAE 
Treatment-emergent Adverse Event 
TSH 
Thyroid Stimulating Hormone 
ULN 
Upper Limit of Normal 
WBC 
White Blood Cell 
 


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Page 9 of 10 
 
Table of Contents 
1. 
Governing Documents ...................................................................................................................... 11 
2. 
Study Design ..................................................................................................................................... 11 
2.1 
Overview ....................................................................................................................................................... 11 
2.2 
Study Objectives ........................................................................................................................................... 12 
2.3 
Study Population ........................................................................................................................................... 12 
2.4 
Participant Flow ............................................................................................................................................ 12 
2.5 
Regimen Allocation ....................................................................................................................................... 12 
2.6 
Treatment Allocation ..................................................................................................................................... 12 
2.7 
Treatment Administration ............................................................................................................................. 12 
2.8 
Allocation Concealment ................................................................................................................................ 13 
2.9 
RGA Schedule of Activities (SoA) ............................................................................................................... 13 
3. 
General Considerations for Data Analysis ..................................................................................... 16 
3.1 
Statistical Software ........................................................................................................................................ 16 
3.2 
Summary Statistics ........................................................................................................................................ 16 
3.3 
Precision ........................................................................................................................................................ 16 
3.4 
Transformations ............................................................................................................................................ 16 
3.5 
Multiplicity Adjustments ............................................................................................................................... 16 
3.6 
Missing Data ................................................................................................................................................. 16 
4. 
Study Endpoints ............................................................................................................................... 16 
4.1 
Efficacy Endpoints ........................................................................................................................................ 16 
4.2 
Exploratory Endpoints ................................................................................................................................... 16 
4.3 
Safety Endpoints ........................................................................................................................................... 17 
5. 
Measurement Definitions ................................................................................................................. 17 
5.1 
ALSFRS-R .................................................................................................................................................... 17 
5.2 
SVC ............................................................................................................................................................... 18 
5.3 
Home Spirometry .......................................................................................................................................... 18 
5.4 
HHD and Grip Strength ................................................................................................................................. 18 
5.5 
Quantitative Voice Characteristics ................................................................................................................ 18 
5.6 
Biofluid Biomarkers of Neurodegeneration .................................................................................................. 19 
5.7 
ALSAQ-40 .................................................................................................................................................... 19 
5.8 
CNS-BFS ....................................................................................................................................................... 19 
5.9 
Survival ......................................................................................................................................................... 19 
5.10 
King's ALS Clinical Staging System ........................................................................................................ 19 
5.11 
Hospitalization and Other Clinical Events................................................................................................ 20 
5.12 
Pharmacodynamic Biomarkers ................................................................................................................. 20 
5.13 
Clinical Safety Laboratory Tests .............................................................................................................. 21 
5.14 
Immunogenicity ........................................................................................................................................ 21 
6. 
Statistical Methodology .................................................................................................................... 22 
6.1 
Analysis Sets ................................................................................................................................................. 22 
6.2 
Baseline Characterization .............................................................................................................................. 23 
6.3 
Primary Efficacy Analysis and Supportive Analyses .................................................................................... 23 
6.4 
Interim Analysis ............................................................................................................................................ 23 
6.5 
Secondary Efficacy Analyses ........................................................................................................................ 24 
6.5.1 
Hierarchical Testing ............................................................................................................................. 24 
6.5.2 
Repeated-measures Model ................................................................................................................... 24 
6.5.3 
Random-slopes Model ......................................................................................................................... 26 
6.5.4 
Survival and Time to Clinical Events .................................................................................................. 27 
6.5.5 
CAFS ................................................................................................................................................... 28 
6.5.6 
HHD0 and HHD02 ............................................................................................................................... 28 
6.5.7 
Quantitative Voice Measures ............................................................................................................... 29 
6.5.8 
Placebo Multiple Imputation................................................................................................................ 29 
6.5.9 
Additional Sensitivity Analyses of Primary and Key Secondary Outcomes ....................................... 30 
6.5.10 
Subgroup Analyses .............................................................................................................................. 30 
6.5.11 
Comparison of Controls across Regimens ........................................................................................... 31 


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6.5.12 
Pharmacokinetic Analyses ................................................................................................................... 31 
6.5.13 
Pharmacodynamic Biomarker Analyses .............................................................................................. 31 
6.6 
Safety Analyses ............................................................................................................................................. 32 
6.6.1 
Treatment-emergent Adverse Events ................................................................................................... 32 
6.6.2 
Safety Labs .......................................................................................................................................... 32 
6.6.3 
ECG Results......................................................................................................................................... 33 
6.6.4 
Vital Signs and Weight ........................................................................................................................ 33 
6.6.5 
Suicidality ............................................................................................................................................ 33 
6.6.6 
Immunogenicity ................................................................................................................................... 33 
6.7 
Other Analyses .............................................................................................................................................. 33 
6.7.1 
Participant Disposition ......................................................................................................................... 33 
6.7.2 
Study Drug Compliance and Tolerance ............................................................................................... 34 
6.7.3 
Concomitant Medication Use .............................................................................................................. 34 
6.7.4 
Medical History ................................................................................................................................... 34 
6.7.5 
Blindedness .......................................................................................................................................... 34 
6.7.6 
Protocol Deviations.............................................................................................................................. 34 
6.7.7 
Impact of COVID-19 Pandemic .......................................................................................................... 34 
7. 
Validation .......................................................................................................................................... 35 
7.1 
Primary Efficacy Analysis ............................................................................................................................. 35 
7.2 
Secondary, Exploratory, and Safety Analyses ............................................................................................... 35 
8. 
References ......................................................................................................................................... 35 
Appendix 1. Treatment-emergent Adverse Events of Interest ............................................................. 36 
Appendix 2. Immunogenicity Analyses ................................................................................................... 39 


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1. Governing Documents 
This Regimen-specific Statistical Analysis Plan (R-SAP) for the zilucoplan regimen (RGA) 
specifies any modification from the default outcome measures, analysis samples, and planned 
analyses for the placebo-controlled period of the HEALEY ALS Platform Trial as specified in 
the Master SAP (M-SAP). The M-SAP and this R-SAP supplement the Master Protocol, the 
"ALS Master Protocol Recommended Statistical Analysis, Design and Simulation Report" 
(Appendix 1 to the Master Protocol), and the RGA Regimen-specific Appendix (RSA). Please 
refer to the Master Protocol and the RGA RSA for details on the rationale for the study design, 
eligibility criteria, conduct of the trial, clinical assessments and schedule of assessments, 
definitions and reporting of adverse events, data management conventions, and regulatory 
oversight and compliance procedures. The "ALS Master Protocol Recommended Statistical 
Analysis, Design and Simulation Report" (MPRDR) and any regimen-specific deviations 
described in the RGA RSA and this R-SAP are authoritative in defining the primary and interim 
analyses. In case of discrepancies between the RGA RSA and this R-SAP concerning use of 
shared placebos, this R-SAP is authoritative. In case of discrepancies between either SAP and the 
Master Protocol and the RGA RSA concerning matters of analysis other than the primary and 
interim analyses and use of shared placebos, the M-SAP and this R-SAP are authoritative. In 
case of discrepancies between the M-SAP and this R-SAP, this R-SAP is authoritative. On all 
matters not related to analysis, the Master Protocol and the RGA RSA are authoritative. The 
following table describes relationships among the relevant documents in adjudicating possible 
discrepancies with higher numbers indicating greater authority. 
Issues potentially requiring adjudication 
Master 
Protocol 
RGA 
RSA 
MPRDR 
M-SAP 
RGA  
R-SAP 
Use of shared placebos 
1 
4 
2 
3 
5 
Primary and interim analysis specifications not 
related to use of shared placebo 
1 
5 
4 
2 
3 
Statistical analysis specifications not related to use 
of shared placebo or primary and interim analyses 
1 
3 
2 
4 
5 
All matters not related to statistical analysis 
4 
5 
1 
2 
3 
2. Study Design 
2.1 
Overview 
The HEALEY ALS Platform Trial is a perpetual multi-center, multi-regimen clinical trial 
evaluating the safety and efficacy of investigational products for the treatment of ALS. RGA 
evaluates the safety and efficacy of zilucoplan administered subcutaneously once daily at a 
dosage of approximately 0.3 mg/kg vs. placebo. The RGA RSA describes the nature of the 
intervention and its mechanism of action, the mode and frequency of administration, additional 
eligibility criteria beyond those specified in the Master Protocol, additional enrollment 
procedures, and additions and modifications of safety and efficacy assessments relative to those 
outlined in the Master Protocol. 


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2.2 
Study Objectives 
Primary Efficacy Objective: 
• To evaluate the efficacy of zilucoplan as compared to placebo on ALS disease 
progression. 
Secondary Efficacy Objectives: 
• To evaluate the effect of zilucoplan on selected secondary measures of disease 
progression, including survival. 
Safety Objectives: 
• To evaluate the safety of zilucoplan in ALS patients. 
Exploratory Efficacy Objectives: 
• To evaluate the effect of zilucoplan on selected biomarkers and endpoints. 
2.3 
Study Population 
In addition to eligibility criteria specified in the Master Protocol, participants in RGA must be 
vaccinated with a quadrivalent meningococcal vaccine and meningococcal serotype B vaccine at 
least 14 days prior to the first dose of study drug, must be free of a history of meningococcal 
disease, and must not have previously received treatment with a complement inhibitor. 
Participants will be recruited from approximately 60 centers located throughout the US that are 
part of the Northeast ALS (NEALS) Consortium. 
2.4 
Participant Flow 
Participants in RGA follow the consenting, Master screening, regimen assignment, regimen-
specific screening, randomization to active or placebo treatment, and follow-up procedures and 
timing described in the M-SAP. Detailed descriptions of study procedures and timing are 
specified in the Master Protocol and the RGA RSA. 
2.5 
Regimen Allocation 
Participants in RGA are those determined eligible for Master Protocol-level inclusion and 
exclusion criteria and randomly assigned to RGA, stratified by use of riluzole, edaravone, both, 
or neither at the time of screening for the Master Protocol. Details of regimen assignment are 
described in the Platform Trial Regimen Assignment Plan.  
2.6 
Treatment Allocation 
Participants in RGA are randomly allocated in a 3:1 ratio to active or placebo treatment based on 
a pre-specified permuted-block randomization schedule, stratified by use of riluzole, edaravone, 
both, or neither at the time of screening for the Master Protocol. 
2.7 
Treatment Administration 
Zilucoplan and placebo are supplied as a sterile, preservative-free, aqueous solution prefilled into 
1 mL glass syringes with 29-gauge, ½-inch, staked needles as a self-administration device. One 


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of three dosage strengths of zilucoplan will be supplied based on the weight of each participant at 
screening to achieve a dosage of approximately 0.3 mg/kg as specified in the table below. 
Nominal Target Dose 
(mg/kg) 
Actual Dose 
(mg) 
Injection Volume 
(mL) 
Weight Range 
(kg) 
Dose Range 
(mg/kg) 
0.3 
16.6 
0.416 
≥43 to <56 
0.30 to 0.39 
0.3 
23.0 
0.574 
≥56 to <77 
0.30 to 0.41 
0.3 
32.4 
0.810 
≥77 to 150 
0.22 to 0.42 
Placebo 
  0.0 
0.574 
All weights 
0.00 to 0.00 
Participants with a screening weight less than 43 kg or equal to or greater than 150 kg will be 
accommodated on a case-by-case basis, in consultation with the Medical Monitor. 
Study drug is administered subcutaneously into the abdomen once daily at approximately the 
same time each day by self-administration or with the assistance of a caregiver.  
Additional details of treatment administration are described in the RGA RSA. 
2.8 
Allocation Concealment 
Allocation concealment is the same as described in the M-SAP. 
2.9 
RGA Schedule of Activities (SoA) 
Activity 
MP 
Scrn1 
RGA 
Scrn2 
Base-
line 
Week 
2 
Week 
4 
Week 
83 
Week 
12 
Week 
163 
Week 
20 
Week 
243 
Final 
Call4 
Cln 
Cln 
Cln 
Phn 
Cln5 
Cln5 
Phn 
Cln5 
Phn 
Cln 
Phn 
-42d  
to -1d 
-41d  
to 0d 
Day  
0 
Day 
14±3 
Day 
28±7 
Day 
56±7 
Day 
84±3 
Day 
112±7 
Day 
140±3 
Day 
168±7 
40d ±3 
ALD 
Written Informed Consent6 
X 
X7 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Review8 
X 
X 
 
 
 
 
 
 
 
 
 
ALS & Medical History 
X 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
Physical Examination 
X 
 
 
 
 
 
 
 
 
 
 
Neurological Exam 
X 
 
 
 
 
 
 
 
 
 
 
Vital Signs9 
X 
 
X 
 
X 
X 
 
X 
 
X 
 
Slow Vital Capacity 
X10 
 
X 
 
 
C 
 
C 
 
X 
 
Home Spirometry 
X10 
 
X 
 
 
X 
 
X 
 
X 
 
Muscle Strength Assessment 
 
 
X 
 
 
C 
 
C 
 
X 
 
ALSFRS-R 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
 
ALSAQ-40 
 
 
X 
 
 
 
 
 
 
X 
 
CNS-BFS  
 
 
X 
 
 
X 
 
X 
 
X 
 
12-Lead ECG 
X 
 
 
 
 
 
 
 
 
X 
 
Clinical Safety Labs11 
X 
 
X 
 
X 
X 
 
X 
 
X 
 
Anti-drug Antibody Sampling 
 
 
X 
 
 
C 
 
C 
 
X 
 
Zilucoplan PK Analysis12 
 
 
X 
 
 
C 
 
C 
 
X 
 
Zilucoplan PD Analysis12 
 
 
X 
 
 
C 
 
C 
 
X 
 
Zilucoplan Biomarker Samples12 
 
 
X 
 
 
C 
 
C 
 
X 
 
Biomarker Blood Collection12 
 
 
X 
 
 
C 
 
C 
 
X 
 
Biomarker Urine Collection12 
 
 
X 
 
 
C 
 
C 
 
X 
 
DNA Collection13 (optional) 
 
 
X 
 
 
 
 
 
 
 
 
CSF Collection (optional) 
 
 
X 
 
 
 
 
C14 
 
 
 
Concomitant Medication Review 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Adverse Event Review15 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Suicidality C-SSRS 
 
 
X 
 
X 
X 
 
X 
 
X 
 


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Activity 
MP 
Scrn1 
RGA 
Scrn2 
Base-
line 
Week 
2 
Week 
4 
Week 
83 
Week 
12 
Week 
163 
Week 
20 
Week 
243 
Final 
Call4 
Cln 
Cln 
Cln 
Phn 
Cln5 
Cln5 
Phn 
Cln5 
Phn 
Cln 
Phn 
-42d  
to -1d 
-41d  
to 0d 
Day  
0 
Day 
14±3 
Day 
28±7 
Day 
56±7 
Day 
84±3 
Day 
112±7 
Day 
140±3 
Day 
168±7 
40d ±3 
ALD 
Install Smartphone Apps16 
 
 
X 
 
 
 
 
 
 
 
 
Smartphone Voice Recording17 
 
 
X 
 
X 
X 
 
X 
 
X 
 
Uninstall Smartphone App 
 
 
 
 
 
 
 
 
 
X 
 
Regimen Assignment 
X 
 
 
 
 
 
 
 
 
 
 
Randomization within RGA 
 
 
X 
 
 
 
 
 
 
 
 
Administer/Dispense Study Drug 
 
 
X18 
 
X 
C 
 
C 
 
 
 
Drug Accountability/Compliance 
 
 
 
X19 
X 
X 
X19 
X 
X19 
X 
 
Exit Questionnaire 
 
 
 
 
 
 
 
 
 
X 
 
N. meningitidis Vaccination 
 
X20 
 
 
X 
X 
 
 
 
X 
 
Vital Status 
 
 
 
 
 
 
 
 
 
X21 
 
Abbreviations: ALD = after last dose, ALS = amyotrophic lateral sclerosis, ALSAQ-40 = ALS 
Assessment Questionnaire, ALSFRS-R = ALS Functional Rating Scale Revised, BP = blood 
pressure, C = completed only if the visit is conducted in-clinic, CBC = complete blood count, 
Cln = Clinic visit, CNS-BFS = Center for Neurologic Study Bulbar Function Scale, CSF = 
cerebrospinal fluid, C-SSRS = Columbia-Suicide Severity Rating Scale, d = day, DNA = 
deoxyribonucleic acid, ECG = electrocardiogram, LFTs = liver function tests, MP = Master 
Protocol, PD = pharmacodynamic, Phn = Phone visit, PK = pharmacokinetic, RGA = the 
zilucolan regimen, Scrn = Screening Visit. 
1 Master Protocol (MP) screening procedures must be completed between 42 days and 1 day 
prior to the Baseline Visit. If initial administration of conjugate and serotype B meningococcal 
vaccines is required, then MP screening procedures must be completed no fewer than 14 days 
prior to the Baseline Visit. 
2 RGA regimen-specific screening procedures must be completed no more than 41 days prior to 
the Baseline Visit. If initial administration of conjugate and serotype B meningococcal vaccines 
is required, then RGA regimen-specific screening procedures must be completed no fewer than 
14 days prior to the Baseline Visit. Otherwise, RGA regimen-specific screening procedures may 
be completed on the same day as the Baseline Visit. 
3 Participants should be instructed to hold the morning dose of study drug on the day of the Week 
8, 16, and 24 study visits. Study drug should not be taken until after study visit procedures are 
complete. 
4 Participants who are participating into the Open-label Extension (OLE) at the time scheduled 
for the Follow-up Safety Call will not complete a Follow-up Safety Call. Participants who 
continue into the OLE and then terminate prior to the time scheduled for the Follow-up Safety 
Call should be asked to complete a Follow-Up Safety Call. 
5 The Week 4, 8, and 16 visits may be conducted via telemedicine (or via phone if telemedicine 
is not available) with remote services instead of in-clinic if this is needed to protect the safety of 
the participant due to a pandemic. If a planned in-clinic visit is conducted via telemedicine (or 
via phone if telemedicine is not available) with remote services, only selected procedures will be 
performed: ALSFRS-R, home spirometry (Weeks 8 and 16 only), Center for Neurologic Study 
Bulbar Function Scale (CNS-BFS, Weeks 8 and 16 only), voice recording, adverse event review, 
Columbia Suicide Severity Rating Scale, concomitant medications, study drug 


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accountability/compliance, and administer/dispense study drug. Additionally, selected vital signs 
(systolic and diastolic pressure, respiratory rate, heart rate, and temperature), clinical safety labs, 
and administration of conjugate and serotype B meningococcal boosters will be performed by a 
home health agency. 
6 During the Master Protocol Screening Visit, participants will be consented using the Master 
Protocol informed consent form (ICF). After a participant is randomly assigned to RGA, he or 
she will be consented a second time using the RGA ICF. 
7 If a participant chooses to obtain meningococcal vaccination from their local provider prior to 
attending an in-person RGA regimen-specific screening visit, RGA informed consent may be 
completed remotely according to procedures described in Section 6.1.1 of the RGA RSA. 
8 At the MP Screening Visit, participants will have MP inclusion and exclusion criteria assessed. 
At the RGA Screening Visit, participants will have regimen-specific inclusion and exclusion 
criteria assessed. 
9 At all visits, whether conducted in-clinic or via telemedicine (or via phone if telemedicine is 
not available), vital signs include systolic and diastolic blood pressure, heart rate, respiratory 
rate, and temperature. At all in-clinic visits, vital signs include weight. At the MP Screening 
Visit only, vital signs include height measured in cm. 
10 If required due to pandemic-related restrictions, forced vital capacity (FVC) performed by a 
Pulmonary Function Laboratory evaluator or with a study-approved home spirometer or 
sustained phonation using a study-approved method may be used for eligibility (Master Protocol 
Screening ONLY). 
11 Clinical safety labs include hematology (CBC with differential), complete chemistry panel, 
liver function tests, thyroid function, and urinalysis. Serum pregnancy testing will occur in 
women of child-bearing potential at the Master Protocol Screening Visit and as necessary during 
participation. Pregnancy testing is only repeated as applicable if there is a concern for pregnancy. 
12 Blood for PK and PD samples and blood and urine for biomarker samples should be obtained 
prior to the first daily dose of study drug at each applicable clinic visit. 
13 If the participant consents to DNA sample collection but a DNA sample is not obtained at the 
Baseline Visit or if that sample is not usable, a DNA sample can be collected after the Baseline 
Visit. 
14 If the participant consents to CSF sample collection but a CSF sample is not obtained at the 
Week 16 Visit, a CSF sample can be collected at the Week 24 Visit. 
15 Adverse events that occur after signing the RGA ICF will be recorded. 
16 Two smartphone apps should be installed on the participant’s phone, one to collect home 
spirometry and one to collect voice recordings. 
17 In addition to study visits specified in the SoA for collection of voice recordings, participants 
should complete twice weekly voice recordings at home. During weeks when a participant 
completes a voice recording in-clinic, he or she should only complete one other voice recording 
at home. 
18 Administer first dose of investigational product only after Baseline Visit procedures are 
completed. 


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19 Drug accountability will not be done at phone visits. A drug compliance check-in should be 
held during phone visits to ensure participant is taking drug per dose regimen and to note any 
report of missed doses. 
20 Initial administration of conjugate and serotype B meningococcal vaccines must occur at least 
14 days prior to the Baseline Visit. Participants must not start study drug until 14 days after 
initial administration of conjugate and serotype B meningococcal vaccines.  
21 Vital status, a determination of date of death or death equivalent or date last known alive, will 
be made for each randomized participant at the end of their double-blind follow-up (generally the 
Week 24 Visit as indicated) and again, if previously alive, after the end of double-blind follow-
up of all participants randomized to RGA. Vital status may also be ascertained at later time 
points by using publicly available data sources. 
3. General Considerations for Data Analysis 
3.1 
Statistical Software 
Statistical software use for analyses is the same as described in the M-SAP. 
3.2 
Summary Statistics 
Data summaries are the same as described in the M-SAP. 
3.3 
Precision 
Precision of reported results is the same as described in the M-SAP. 
3.4 
Transformations 
Data transformations are the same as described in the M-SAP. 
3.5 
Multiplicity Adjustments 
Handling of multiplicity adjustments is the same as described in the M-SAP. 
3.6 
Missing Data 
Handling of missing data is the same as described in the M-SAP. Clinic-based assessments that 
are missing due to COVID-19 restrictions or disruptions are considered missing at random. 
4. Study Endpoints 
4.1 
Efficacy Endpoints 
The primary and secondary efficacy endpoints are the same as described in the M-SAP. 
ALSFRS-R total score is considered the primary efficacy endpoint and hand-held dynamometry 
(HHD) upper and lower extremity percentages, slow vital capacity (SVC), and survival are 
considered key secondary efficacy endpoints in RGA. 
4.2 
Exploratory Endpoints 
The following categories of exploratory endpoints will be evaluated: 


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• Change in ALSFRS-R domain scores,  
• Change in strength: HHD global percentage, HHD0, and HHD02,  
• Change in quantitative voice characteristics as measured by Aural Analytics: maximum 
phonation time, pause rate, breathy vocal quality, pitch instability, regulation of voicing, 
articulatory precision, speaking rate, articulation rate, and monotonicity,  
• Change in biofluid biomarkers of neurodegeneration and neuromuscular degeneration: serum 
creatinine and serum and cerebrospinal fluid (CSF) neurofilament light chain (NfL),  
• Change in patient-reported outcomes: ALSAQ-40 physical mobility, independence in 
activities of daily living, eating and drinking, communications, and emotional reactions 
domain scores and ALSAQ-40 symptom index, CNS-BFS total score,  
• Change in respiratory function as assessed by home spirometry,  
• Time to clinical events: first hospitalization due to a serious adverse event (SAE), first 
hospitalization due to an ALS-related SAE, first use of assisted ventilation, first placement of 
a feeding tube, first time reaching King's stage 4a or 4b, and first instance of any of the 
following events: hospitalization for an SAE, feeding tube placement, tracheostomy, 
initiation of permanent assisted ventilation (PAV), or death,  
• Pharmacokinetics of zilucoplan and its two major metabolites (RA102758 and RA103488) in 
plasma and CSF, and  
• Change in complement pathway biomarker levels in blood and CSF: sheep red blood cell 
(RBC) hemolysis assay and C5 levels. 
4.3 
Safety Endpoints 
In addition to the safety endpoints described in the M-SAP, the following RGA regimen-specific 
safety endpoint will be evaluated: 
• Immunogenicity against zilucoplan as assessed by incidence of anti-drug antibodies (ADA) 
and anti-PEG antibodies (anti-PEG-ADA). 
5. Measurement Definitions 
5.1 
ALSFRS-R 
The definitions of ALSFRS-R scores are the same as described in the M-SAP. Pre-baseline slope 
in ALSFRS-R (delta-FRS) is defined as 48 minus the baseline ALSFRS-R total score then 
divided by the number of months from onset of symptomatic weakness to the Baseline Visit. The 
number of months will be calculated as the difference in days from onset of symptomatic 
weakness to the Baseline Visit multiplied by 12 / 365.25. The date of onset of symptomatic 
weakness will be imputed as the fifteenth day of a month if not specified more precisely. 
ALSFRS-R domain scores are exploratory measures of the primary efficacy endpoint ALSFRS-
R total score. 


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5.2 
SVC 
The derivation of SVC percent-predicted of normal is the same as described in the M-SAP with 
age calculated as number of days from date of birth to the date of a given SVC assessment 
divided by 365.25 and with the following correspondence between self-identified race and race 
defined by Global Lung Initiative (GLI) classification: 
Self-identified Race 
GLI-defined Race 
American Indian or Alaska Native 
Mixed/Other 
Asian 
South East Asian 
Black or African American 
African American 
Native Hawaiian or Other Pacific Islander 
Mixed/Other 
White 
Caucasian 
Unknown 
Caucasian 
Not reported 
Caucasian 
More than one race indicated 
Mixed/Other 
5.3 
Home Spirometry 
Home spirometry assesses FVC remotely using a smartphone app (ZEPHYRx, Albany, NY) and 
a handheld spirometer (Spirobank Smart, Medical International Research, Rome, Italy). 
Coordinators guide participants through 3 to 8 maneuvers with live-video coaching using the 
ZEPHYRx platform. Flow loops are classified for acceptability and repeatability using American 
Thoracic Society (ATS) criteria and are manually reviewed by the NEALS Outcomes Center 
(Barrow Neurological Institute, Phoenix, AZ). The maximum FVC accepted by the NEALS 
Outcomes Center is converted to percent of predicted normal using GLI norms based on sex, age 
at time of assessment, height at time of screening, and race. Age is calculated as number of days 
from date of birth to the date of a given home spirometry assessment divided by 365.25. Higher 
values indicate greater respiratory function. 
5.4 
HHD and Grip Strength 
The derivation of HHD upper and lower extremity scores and HHD0 are the same as described in 
the M-SAP with the revision that HHD0 is a composite endpoint with death or death equivalent, 
whichever occurs first. 
A second HHD time-to-event endpoint is defined as the time from the Baseline Visit to the 
second post-baseline occurrence of a muscle with a strength recording of 0 among those muscles 
that were non-zero at baseline or time to death or death equivalent, whichever occurs first 
(HHD02).  
Time at risk for HHD0 and HHD02 will be censored at the last date at which an HHD assessment 
was performed up to the end of the Week 24 Visit window. 
HHD global average percentage, HHD0, and HHD02 are exploratory measures of the secondary 
endpoint HHD and grip strength. 
5.5 
Quantitative Voice Characteristics 
Voice samples will be collected using the Aural Analytics app installed on either an Android or 
iOS-based smartphone. At each assessment, participants perform a set of speaking tasks: reading 


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5 prespecified sentences, reading 5 sentences chosen at random from a large sentence bank, 
repeating a consonant-vowel sequence, producing a sustained phonation, and counting on a 
single breath. Speech analysis will be performed by Aural Analytics to derive the following 
quantitative voice characteristics: maximum phonation time, pause rate, breathy vocal quality, 
pitch instability, regulation of voicing, articulatory precision, speaking rate, articulation rate, and 
monotonicity. Aural Analytics will use quantitative voice characteristics data and participant age, 
sex, race, height, and weight to derive a prediction of vital capacity at the Baseline Visit. 
5.6 
Biofluid Biomarkers of Neurodegeneration 
Blood biomarkers of neurodegeneration, including biomarkers of neuromuscular dysfunction, 
will be assayed. These will include serum creatinine and serum and CSF neurofilament light 
chain (NfL). Serum creatinine will be assayed by the kinetic Jaffe method (test 001370, Labcorp, 
Burlington, NC). NfL will be assayed by single-molecule array (Simoa; Quanterix, Billerica, 
MA). Levels of serum and CSF NfL that are reported to be below the limit of quantitation will be 
imputed at the limit of quantitation. Levels of serum and CSF NfL will be log-transformed in all 
analyses. 
5.7 
ALSAQ-40 
The description of the ALSAQ-40 instrument and item-level scores are the same as described in 
the M-SAP. Each of the five domains will be scored as the mean of all domain-specific items 
multiplied by 25 (range 0 to 100). An overall symptom index (SI) will be scored as the mean of 
the five domain scores. A domain score will be missing if more than 20% of the items are 
missing; otherwise, item non-response will be mean-imputed from other completed items from 
the same assessment. The ALSAQ-40 SI will be missing if any domain scores are missing. 
Higher scores indicate worse quality of life. 
5.8 
CNS-BFS 
The definition of CNS-BFS total score is the same as described in the M-SAP. 
5.9 
Survival 
The primary definition of survival time is the same as described in the M-SAP with the 
clarification that PAV is defined as more than 22 hours per day of noninvasive or invasive 
mechanical ventilation for more than seven consecutive days. The date of PAV initiation, where 
applicable, will be imputed as the fifteenth day of a month if not specified more precisely. A 
secondary survival endpoint of death alone, independent of any death equivalent, is also defined. 
Time at risk for the composite endpoint of death or death equivalent and time at risk for the 
endpoint of death alone will be measured from each participant's Baseline Visit. Time at risk will 
be censored at two time points: (1) at the Week 24 Visit as defined in the M-SAP, and (2) at a 
subsequent assessment of death or death equivalent scheduled approximately at the end of 
placebo-controlled follow-up of the last RGA participant. The primary analysis of survival will 
evaluate PAV-free survival to the Week 24 Visit time point. 
5.10 King's ALS Clinical Staging System 
The King's ALS Clinical Staging System (Roche et al. 2012) is a 4-level ordinal scale with the 
first three levels indicating the number (1, 2, or 3) of distinct central nervous system regions 


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(bulbar, upper limb, and lower limb) with neuromuscular dysfunction and levels 4a and 4b 
indicating nutritional or respiratory failure secondary to ALS, respectively. 
Participants will be classified to King's stage 1, 2, 3, 4a, or 4b based on scores from ALSFRS-R 
assessments according to a published derivation (Balendra et al. 2014). Bulbar involvement is 
defined as a score less than 4 on any of the ALSFRS-R questions in the bulbar domain (questions 
1, 2, and 3). Upper limb involvement is defined as a score less than 4 on either of the ALSFRS-R 
questions related to hand function (questions 4 and 5A). Lower limb involvement is defined as a 
score less than 4 on the ALSFRS-R question about walking (question 8). Nutritional failure is 
defined as responding that the participant uses gastrostomy for greater than 50% of their 
nutrition. Respiratory failure is defined as a score of 0 on the ALSFRS-R question addressing 
dyspnea (question 10 or R-1) or a score less than 4 on the ALSFRS-R question about use of 
mechanical ventilation (question 12 or R-3). Participants without evidence by ALSFRS-R scores 
of involvement of any of the three central nervous system regions will be scored as King's stage 
1 due to their confirmed diagnosis with ALS. Participant may meet criteria for both King's stage 
4a and 4b. 
5.11 Hospitalization and Other Clinical Events 
Times to the following clinically relevant events are defined: 
• Time to first hospitalization due to a serious adverse event (SAE),  
• Time to first hospitalization due to an ALS-related SAE,  
• Time to first use of assisted ventilation,  
• Time to first placement of a feeding tube,  
• Time to King's stage 4a or 4b, and  
• Time to first instance of hospitalization for an SAE, feeding tube placement, tracheostomy, 
initiation of PAV, or death. 
Time at risk for each event will be measured from each participant's Baseline Visit. Time to first 
hospitalization excludes hospitalizations for elective procedures. ALS-related SAEs are those 
indicated as related to ALS disease progression by the site investigator. Participants who are 
already using assisted ventilation or have a feeding tube at the time of the Baseline Visit will be 
excluded from analysis of those endpoints. Death or death equivalent will be considered an 
outcome for each of the events listed, forming a composite endpoint. 
Time at risk for these events will be censored at the Week 24 Visit, if completed, the date of 
consent withdrawal, if withdrawn, or the last date at which the status of each endpoint is known 
prior to the end of the Week 24 Visit window for participants lost to follow-up. Time to King's 
stage 4a or 4b is interval censored between ALSFRS-R assessments. 
5.12 Pharmacodynamic Biomarkers 
Complement functional activity will be assessed by complement-mediated lysis using the sheep 
RBC hemolysis assay and will be quantified by the serum or CSF dilution resulting in 50% 
haemolytic complement (CH50) activity. C5 concentrations in plasma and CSF will be assessed 
by enzyme-linked immunosorbent assay (ELISA). 


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5.13 Clinical Safety Laboratory Tests 
Clinical safety labs include hematology, blood chemistry panel, liver function tests, thyroid 
function, urinalysis, and pregnancy testing in women of childbearing potential as specified in 
Section 9.1.2 Clinical Safety Laboratory Tests of the Master Protocol: 
• Hematology: hematocrit, hemoglobin, platelet count, red blood cell (RBC) count, mean 
corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin 
concentration, RBC distribution width (RDW), RBC morphology, white blood cell (WBC) 
count, and counts and percentages of basophils, eosinophils, lymphocytes, monocytes, and 
neutrophils; 
• Blood chemistry panel: bicarbonate, chloride, potassium, sodium, calcium, magnesium, 
phosphate, blood urea nitrogen, creatinine, estimated glomerular filtration rate (eGFR) 
calculated using the Modification of Diet in Renal Disease (MDRD) four-variable equation, 
creatinine clearance calculated using the Cockcroft-Gault equation, and glucose; 
• Liver function tests: alanine aminotransferase (ALT [SGPT]), aspartate aminotransferase 
(AST [SGOT]), alkaline phosphatase (ALP), albumin, total protein, total bilirubin (TBL); 
• Thyroid function tests: thyroid-stimulating hormone (TSH); 
• Urinalysis: clarity, color, specific gravity, pH, microalbumin, protein, glucose, ketones, 
bilirubin, urobilinogen, nitrite, leukocyte esterase, and blood; and  
• Pregnancy: qualitative and quantitative serum human chorionic gonadotropin (hCG). 
Clinical safety labs will also include derived measures of potential drug-induced liver injury 
(DILI), including those that potentially meet the Hy’s law criteria, as distinct safety lab 
outcomes. 
Three potential DILI criteria will be defined: 
• ALT or AST >3x ULN with TBL >1.5x ULN 
• AST or ALT >3x ULN with TBL >2x ULN 
• AST or ALT >3x ULN with TBL >2x ULN and ALP <2x ULN (potential Hy’s Law cases) 
where ULN is upper level of normal and all levels are measured on the same day. 
5.14 Immunogenicity 
Blood samples will be screened for ADA and anti-PEG-ADA by ELISA. Samples screening 
positive will be further tested for immunodepletion. The ADA and anti-PEG-ADA status of each 
sample will be classified as follows:  
• Negative: sample values that are either "negative screen" or "positive screen" and "negative 
immunodepletion",  
• Positive: sample values that are "positive screen" and "positive immunodepletion", or  
• Missing: samples that could not be tested due to inadequate sample volume, mishandling, or 
errors in sample collection, processing, or storage. 


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6. Statistical Methodology 
6.1 
Analysis Sets 
The ITT analysis set is henceforth referred to as the Full Analysis Set (FAS) and defined as 
follows: 
• Full Analysis Set (FAS): Participants who were randomized within RGA plus placebo 
participants from specified regimens, classified according to their randomized treatment 
assignment. Observations made after premature permanent discontinuation of study drug are 
included in this sample, should such participants remain on study. Observations completed 
after regimen data lock are excluded. Participants determined to not meet ALS diagnostic 
criteria are excluded. 
The definition of the STF analysis set is revised as follows: 
• Safety Full (STF) Set: Participants who initiated treatment within RGA plus placebo 
participants from specified regimens who are not known to be ineligible for RGA and who 
initiated treatment in their respective regimen, classified according to the treatment they 
actually received. Observations made after premature permanent discontinuation of study 
drug are included in this sample, should such participants remain on study. Observations 
completed after regimen data lock are excluded. 
An analysis set restricting shared placebo participants to those regimens in which study drug is 
administered by the same route as RGA is defined as follows: 
• Efficacy Common Mode of Administration (ECM) Set: The subset of participants in the FAS 
analysis set who are in regimens in which study drug is administered by the same route as 
RGA. 
The definitions of the ECC, ERO, STN, and SRO analysis sets are the same as described in the 
M-SAP with reference to the ITT analysis set now referencing the FAS analysis set. The 
following analysis set is specific to RGA: 
• Efficacy Per-protocol (EPP) Set: The subset of participants in the FAS analysis set who 
initiated study treatment and who were not involved in protocol deviations that affected the 
scientific integrity of the trial as documented prior to data lock, classified according to the 
treatment they actually received. Inclusion or exclusion from the EPP analysis set of any 
participant for whom treatment assignment was unblinded prior to data lock will be governed 
by the prespecified criteria above. If a participant's data is truncated for inclusion in the EPP 
analysis set due to non-adherence to protocol-specified dosing, clinical events observed up to 
40 days after the censoring event will be included in the EPP analysis set. For all other events 
leading to truncation of a participant's data, no events beyond that date will be included. Data 
from placebo participants shared from other regimens will not be truncated due to non-
adherence to protocol-specified dosing. 
Applicable analysis sets (FAS, EPP, and STF) will include shared placebo participants from 
regimens B, C, and D. Data from shared placebo participants will include visits and events that 
occurred on or before the date of the final placebo-controlled period follow-up of an RGA 
participant. As only concurrently enrolling regimens are contributing to efficacy analyses, the 
FAS and ECC analysis sets are synonymous and only the FAS analysis set will be referenced. As 


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RGA is the only regimen administering study drug by subcutaneous injection among those 
contributing to safety analyses, the ECM and ERO analysis sets and the STN and SRO analysis 
sets are synonymous and only the ERO and SRO analysis sets will be referenced. 
6.2 
Baseline Characterization 
The baseline characteristics summarized for participants randomized within RGA are the same as 
specified in the M-SAP with the addition of ALSAQ-40 domain scores and SI, CNS-BFS total 
score, King's stage, weight, body mass index (BMI), serum urate concentration, serum creatinine 
concentration, and serum NfL concentration. 
6.3 
Primary Efficacy Analysis and Supportive Analyses 
The primary analysis for RGA is a Bayesian shared-parameter, repeated-measures model of 
ALSFRS-R that accounts for loss of follow-up due to mortality. Details of the model, including 
documentation of operating characteristics under a range of scenarios, are provided in the "ALS 
Master Protocol Recommended Statistical Analysis, Design and Simulation Report" (Appendix 1 
to the Master Protocol). The Bayesian shared-parameter, repeated-measures model will be 
applied to the FAS analysis set as the primary analysis, to the ERO analysis set as a sensitivity 
analysis, and to the EPP analysis set as a supportive analysis. 
The estimand of the primary analysis is the relative rate of disease progression (the "disease rate 
ratio" or DRR) of active treatment relative to placebo in the FAS population under an assumption 
that active treatment slows mean time to death or death equivalent by the same proportion as 
treatment slows the mean rate of functional progression as measured by change in ALSFRS-R 
total score over time. The estimand is defined by the following attributes: 
• Treatment: zilucoplan administered subcutaneously once daily at a dosage of approximately 
0.3 mg/kg vs. placebo. 
• Population: FAS population as defined in Section 6.1. 
• Variables: time to death or death equivalent and rate of change in ALSFRS-R total score 
from baseline to the Week 24 Visit. 
• Intercurrent event 1: treatment discontinuation due to death: no ALSFRS-R data from 
participants who reach the death or death equivalent endpoint are included in the analysis, 
handled via mortality component in model, composite variable strategy approach. 
• Intercurrent event 2: treatment discontinuation not due to death: handled via treatment policy 
approach, all data will be used including data collected during the placebo-controlled period 
after treatment discontinuation regardless of concomitant medication, for those participants 
who have not been censored due to mortality. Missing data post-treatment will not be 
imputed, handled via missing at random assumption. 
• Population-level summary: mean ratio of hazard or progression rate of active treatment 
relative to placebo. 
6.4 
Interim Analysis 
RGA will be considered for early stopping for futility according to the interim analysis schedule 
and definition specified in the "ALS Master Protocol Recommended Statistical Analysis, Design 


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and Simulation Report" (Appendix 1 to the Master Protocol). RGA will not be stopped early for 
success. 
6.5 
Secondary Efficacy Analyses 
6.5.1 Hierarchical Testing 
Primary inference for secondary efficacy endpoints will be based on analysis of the FAS analysis 
set using a repeated-measures linear mixed model for functional endpoints (see Section 6.5.2 
below) and by Kaplan-Meier product-limit estimates and log-rank test for the primary survival 
endpoint (see Section 6.5.4 below). The sequence for testing secondary efficacy endpoints is the 
following: 
1. HHD upper extremity percentage,  
2. SVC,  
3. HHD lower extremity percentage, and  
4. Survival. 
If the primary analysis indicates a significant slowing in disease progression from the Bayesian 
shared-parameter, repeated-measures model of ALSFRS-R and mortality, then each secondary 
efficacy endpoint in succession would be declared significant in the specified sequence using a 
comparison-wise criterion of two-tailed p < 0.05. After the first failure to declare significance, no 
endpoints lower in the hierarchy can be significant. This sequential closed-testing procedure 
controls the overall type 1 error rate at 5%. Nominal comparison-wise p-values for secondary 
efficacy endpoints will also be reported. 
6.5.2 Repeated-measures Model 
The specification of the repeated-measures linear mixed model and the primary linear contrast 
for estimating differences in 24-week change from baseline in a given continuous efficacy 
endpoint (ALSFRS-R total and domain scores, HHD upper extremity, lower extremity, and 
global average percentages, SVC, FVC by home spirometry, serum creatinine, serum NfL, 
ALSAQ-40 domain scores and SI, and CNS-BFS total score) are revised from those specified in 
the M-SAP to include a main effect of treatment. 
The model will include fixed terms for discrete visit, treatment group, treatment group × visit 
interaction, centered time since symptom onset and centered time since symptom onset × visit 
interaction, centered delta-FRS and centered delta-FRS × visit interaction, centered baseline 
riluzole use and centered baseline riluzole × visit interaction, and centered baseline edaravone 
use and centered baseline edaravone × visit interaction. The following equations describe the 
model with regimen random effects: 
𝑌𝑌𝑖𝑖𝑖𝑖= 𝑎𝑎𝑘𝑘(𝑖𝑖) + 𝛾𝛾1𝑡𝑡𝑖𝑖+ 𝛾𝛾2,𝑗𝑗𝑣𝑣𝑗𝑗+ 𝜸𝜸𝟑𝟑
′ 𝒛𝒛𝒊𝒊+ 𝛾𝛾4,𝑗𝑗 𝑡𝑡𝑖𝑖𝑣𝑣𝑗𝑗+ 𝜸𝜸𝟓𝟓,𝒋𝒋
′ 𝒛𝒛𝑖𝑖 𝑣𝑣𝑗𝑗+ 𝜖𝜖𝑖𝑖𝑖𝑖 
𝑎𝑎𝑘𝑘 ~ 𝑁𝑁(0, 𝜎𝜎𝑟𝑟
2), 𝝐𝝐𝒊𝒊∙ ~ 𝑁𝑁(𝟎𝟎, 𝑹𝑹), Cov൫𝑏𝑏𝑘𝑘(𝑖𝑖), 𝜖𝜖𝑖𝑖𝑖𝑖൯= 0 
(eqn. 1)
where Yij is a given efficacy endpoint measured in participant i at visit j, ak(i) is a random 
intercept for regimen k to which participant i was assigned, vj is an indicator variable for visit j, zi 
is the vector of covariates (centered time since onset, centered delta-FRS, centered baseline 
riluzole use, and centered baseline edaravone use) for participant i, ti is an indicator variable for 
treatment t to which participant i was assigned, γ1, γ2,j, γ3, γ4,j, and γ5,j are estimated parameters 


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and vectors of parameters for the fixed effects, and ϵij is the residual for participant i at visit j. 
The regimen-specific random effects are normally distributed with mean 0 and variance σ2r. The 
vector of residuals for a given participant are normally distributed with mean 0 and an 
unstructured covariance matrix R. The regimen-specific random effect for a given participant 
and residuals for that participant are uncorrelated. 
The following SAS code specifies the model: 
proc mixed data=xxx method=reml; 
  class regimen id trtrnd visit; 
  model Value = trtrnd|visit  
                sx2bl|visit dFRS|visit rlz|visit edv|visit / solution cl; 
  random intercept / subject=regimen type=vc; 
  repeated visit / subject=id type=un; 
where id is a participant study identifier, trtrnd is the randomly assigned treatment group, 
visit is the visit identifier, Value is value of the efficacy endpoint being tested for a given 
participant at a given visit, sx2bl is years since ALS symptom onset centered at the sample 
median, dFRS is pre-baseline slope centered at the sample median, rlz is an indicator of riluzole 
use at baseline centered at the sample median, and edv is an indicator of edaravone use at 
baseline centered at the sample median. The primary estimate will be the treatment-dependent 
difference in change from baseline to the Week 24 Visit. The estimate and its 95% Wald 
confidence bounds will be obtained by a linear contrast of adjusted means. The following SAS 
code specifies the linear contrast for a regimen with one active treatment assuming an endpoint 
measured every 8 weeks and that the sort order for treatment group has the active group last and 
visits are sorted chronologically: 
  estimate "3|Act vs Plb|dWk 24" trtrnd*visit 1 0 0 -1  -1 0 0 1 / cl; 
A significant difference in 24-week change from baseline in the direction of greater 
improvement or less worsening among participants randomized to active treatment would 
support inference of benefit from active treatment for the efficacy endpoint being tested.The 
estimand estimated by the primary linear contrast of the repeated-measures linear mixed model is 
the mean difference in 24-week change from baseline of a given continuous efficacy endpoint in 
the active treatment group relative to the placebo group in the FAS population. The estimand is 
defined by the following attributes: 
• Treatment: zilucoplan administered subcutaneously once daily at a dosage of approximately 
0.3 mg/kg vs. placebo. 
• Population: FAS population as defined in Section 6.1. 
• Variables: absolute change in endpoint from baseline to the Week 24 Visit. 
• Intercurrent event: treatment discontinuation: handled via treatment policy approach, all data 
will be used including data collected during the placebo-controlled period after treatment 
discontinuation. Missing data post-treatment, including data missing due to death, will not be 
imputed, handled via missing at random assumption. 
• Population-level summary: difference in conditional means of active treatment relative to 
placebo. 


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Inference from this analysis is supportive of inference from the Bayesian shared-parameter, 
repeated-measures model for the primary endpoint and is the primary analysis for secondary 
endpoints. A separate supportive analysis will include centered baseline serum NfL level and the 
interaction of centered baseline serum NfL level and visit as additional covariates. 
6.5.3 Random-slopes Model 
The specification of the random-slopes linear mixed model and the primary linear contrast for 
estimating differences in mean rate of progression in a given continuous efficacy endpoint 
(ALSFRS-R total and domain scores, HHD upper extremity, lower extremity, and global average 
percentages, SVC, FVC by home spirometry, quantitative voice characteristics, serum creatinine, 
serum NfL, ALSAQ-40 domain scores and SI, and CNS-BFS total score) are revised from those 
specified in the M-SAP to include a main effect of treatment and to specify that study months are 
calculated as the difference in days from the Baseline Visit to the date of assessment of a given 
endpoint multiplied by 12 / 365.25. 
The model will include fixed terms for month since the Baseline Visit, treatment group, 
treatment group × month interaction, centered years since ALS symptom onset and centered 
years since ALS symptom onset × month interaction, centered delta-FRS and centered delta-FRS 
× month interaction, centered baseline riluzole use and centered baseline riluzole use × month 
interaction, centered baseline edaravone use and centered baseline edaravone use × month 
interaction, and centered baseline serum NfL level and centered baseline serum NfL level × 
month interaction. The following equations describe the model with regimen random effects: 
𝑌𝑌𝑖𝑖𝑖𝑖= 𝛾𝛾1 + 𝑎𝑎𝑘𝑘(𝑖𝑖)
0
+ 𝑏𝑏𝑖𝑖
0 + 𝛾𝛾2𝑡𝑡𝑖𝑖+ 𝜸𝜸𝟑𝟑
′ 𝒛𝒛𝒊𝒊
+ ൫𝛾𝛾4 + 𝑎𝑎𝑘𝑘(𝑖𝑖)
1
+ 𝑏𝑏𝑖𝑖
1 + 𝛾𝛾5𝑡𝑡𝑖𝑖+ 𝜸𝜸𝟔𝟔
′ 𝒛𝒛𝒊𝒊൯ 𝑚𝑚𝑖𝑖𝑖𝑖+ 𝜖𝜖𝑖𝑖𝑖𝑖 
{𝑎𝑎𝑘𝑘
0, 𝑎𝑎𝑘𝑘
1} ~ 𝑁𝑁(𝟎𝟎, 𝚺𝚺𝒓𝒓), {𝑏𝑏𝑘𝑘
0, 𝑏𝑏𝑘𝑘
1} ~ 𝑁𝑁൫𝟎𝟎, 𝚺𝚺𝒑𝒑൯, 𝜖𝜖𝑖𝑖𝑖𝑖 ~ 𝑁𝑁(0, 𝜎𝜎𝜖𝜖
2) 
Cov(𝒂𝒂𝑘𝑘, 𝒃𝒃𝑘𝑘) = 𝟎𝟎, Cov(𝒂𝒂𝑘𝑘, 𝝐𝝐𝑖𝑖∙) = 𝟎𝟎, and Cov(𝒃𝒃𝑘𝑘, 𝝐𝝐𝑖𝑖∙) = 𝟎𝟎 
(eqn. 2)
where Yij is a given efficacy endpoint measured in participant i at visit j, a0k(i) and a1k(i) are 
random intercept and slope for regimen k to which participant i was assigned, b0i and b1i are 
random intercept and slope for participant i, zi is the vector of covariates (centered time since 
onset, centered delta-FRS, centered baseline riluzole use, and centered baseline edaravone use) 
for participant i, mij is the time from baseline to observation j for participant i in months 
calculated as days x 12 / 365.25, ti is an indicator variable for treatment t to which participant i 
was assigned, γ1, γ2, γ3, γ4, γ5, and γ6 are estimated parameters and vectors of parameters for the 
fixed effects, and ϵij is the residual for observation j for participant i. The regimen-specific 
random effects are normally distributed with mean 0 and unstructured covariance matrix Σr. The 
participant-specific random effects are normally distributed with mean 0 and unstructured 
covariance matrix Σp. The residuals for a given participant are normally distributed with mean 0 
and variance σ2ϵ. The regimen-specific random effects, participant-specific random effects, and 
residuals are uncorrelated. 
The following SAS code specifies the model: 
proc mixed data=xxx method=reml; 
  class regimen id trtrnd; 
  model Value = trtrnd|month  
                sx2bl|month dFRS|month rlz|month edv|month / solution cl; 


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  random intercept month / subject=regimen type=un; 
  random intercept month / subject=id type=un; 
where month is time in months from the Baseline Visit (assuming 12 months in an average of 
365.25 days per year) and other fields are the same as identified above in Section 6.5.2. The 
primary estimand will be the treatment-dependent difference in slopes. The estimate and its 95% 
Wald confidence bounds will be obtained by a linear contrast of adjusted means. The following 
SAS code specifies the linear contrast for a regimen with one active treatment assuming that the 
sort order for treatment group has the active group last: 
  estimate "3|Act vs Plb|Slope (/mn)" month 0 trtrnd*month -1 1 / cl; 
A significant difference in slopes in the direction of greater improvement or less worsening 
among participants randomized to active treatment would support inference of benefit from 
active treatment for the efficacy endpoint being tested. 
The estimand estimated by the primary linear contrast of the random-slopes linear mixed model 
is the difference in mean rate of progression of a given continuous efficacy endpoint in the active 
treatment group relative to the placebo group in the FAS population. The estimand is defined by 
the following attributes: 
Treatment: zilucoplan administered subcutaneously once daily at a dosage of approximately 
0.3 mg/kg vs. placebo. 
Population: FAS population as defined in Section 6.1. 
Variables: mean rate of change in endpoint from baseline to the Week 24 Visit. 
Intercurrent event: treatment discontinuation: handled via treatment policy approach, all data 
will be used including data collected during the placebo-controlled period after treatment 
discontinuation. Missing data post-treatment will not be imputed, handled via missing at 
random assumption. 
Population-level summary: difference in conditional mean slopes of active treatment relative 
to placebo. 
Inference from these analyses is supportive of inference from the Bayesian shared-parameter, 
repeated-measures model for the primary endpoint and inference from the repeated-measures 
linear mixed model for secondary endpoints. A separate supportive analysis will include centered 
baseline serum NfL level and the interaction of centered baseline serum NfL level and study 
month as additional covariates. 
6.5.4 Survival and Time to Clinical Events 
Survival and time to hospitalizations and clinical events will be analyzed in the FAS, ERO, EPP, 
STF, and SRO analysis sets. Survival analyses that include follow-up beyond the placebo-
controlled period will be analyzed in the ERO analysis set. The summaries and analyses of time 
to death or death equivalent are the same as specified in the M-SAP with the addition of baseline 
age as an additional covariate in adjusted models, with the addition that the endpoints of time to 
death independent of occurrence of death equivalents and time to each of the hospitalization and 
clinical events will be separately analyzed using the same models, and with an additional 
adjusted analysis that includes baseline serum NfL level as a covariate. Analysis of time to 


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King's stage 4a or 4b will accommodate interval censoring between ALSFRS-R assessments and 
will be stratified by baseline King's stage. 
Listings of all participants in the FAS, ERO, EPP, STF, and SRO analysis sets will document 
whether each participant had died, had reached a death equivalent endpoint, or was alive and free 
of a death equivalent and the study day of death, death equivalent, or last know alive and free of 
a death equivalent for each analysis timepoint. 
6.5.5 CAFS 
The primary CAFS analysis is as specified in the MPRDR. Additional, unadjusted CAFS 
analyses are the same as specified in the M-SAP, including specification that pair-wise 
comparison of change in ALSFRS-R total score for participants who cannot be ranked by time to 
death or death equivalent is to the maximum follow-up time at which both participants have an 
observation, and with the following additions: 
1. HHD upper and lower extremity percentage and SVC will be analyzed by CAFS by 
substituting change from baseline for those secondary efficacy endpoints in place of 
ALSFRS-R total score,  
2. An additional set of CAFS analyses will use multiple imputation to extend follow-up of 
ALSFRS-R total score, HHD upper and lower extremity percentage and SVC for 
participants who early terminate, withdraw consent, or are lost to follow-up, 
3. An additional set of CAFS analyses will use time to death alone independent of any death 
equivalent,  
4. An additional set of CAFS analyses for ALSFRS-R total score, HHD upper and lower 
extremity percentage, and SVC will adjust rank scores in a linear model with the 
following covariates: time from ALS symptom onset, delta-FRS, baseline use of riluzole, 
and baseline use of edaravone, and  
5. An additional set of CAFS analyses for ALSFRS-R total score, HHD upper and lower 
extremity percentage, and SVC will adjust rank scores in a linear model with the 
following covariates: time from ALS symptom onset, delta-FRS, baseline use of riluzole, 
baseline use of edaravone, and baseline serum NfL level.. 
The multiple imputation model used to extend follow-up of functional scores for participants 
who early terminate, withdraw consent, or are lost to follow-up will use linear regression with 
covariates of time since symptom onset, delta-FRS, baseline riluzole use, baseline edaravone use, 
and each observed functional score prior to a missing assessment. 
Inference from CAFS analyses is supportive of inference from the Bayesian shared-parameter, 
repeated-measures model for the primary outcome and supportive of inference from the 
repeated-measures model for the secondary outcomes of HHD upper extremity score, SVC, and 
HHD lower extremity score. Primary inference from CAFS analyses will compare survival by 
time to death or death equivalent, will compare change in function to the last jointly observed 
time point, and will adjust for the specified covariates. 
6.5.6 HHD0 and HHD02 
Analyses of HHD0 are the same as specified in the M-SAP with the addition of parallel analyses 
of HHD02, with a separate analysis that includes baseline serum NfL level as a covariate, and 
with the clarification that time to zero strength for both analyses is interval censored between 
HHD assessments. 


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Inference from these analyses is supportive of inference from the repeated-measures linear mixed 
model for HHD upper and lower extremity scores. 
6.5.7 Quantitative Voice Measures 
Given the high frequency of voice recordings, a repeated-measures analysis with unstructured 
covariance is overly flexible but the assumption of linear change required by the random-slopes 
model may be overly rigid. To complement estimates from the random-slopes linear mixed 
model, quantitative voice characteristics will be analyzed in a linear mixed model in which the 
temporal profile for both fixed and random terms is modeled using cubic B-splines with knots at 
8 and 16 weeks. The model will include fixed terms for B-splines (4 terms), treatment group (2 
levels), treatment group × B-spline interaction, centered time since symptom onset and centered 
time since symptom onset × B-spline interaction, centered delta-FRS and centered delta-FRS × 
B-spline interaction, centered baseline riluzole use and centered baseline riluzole × B-spline 
interaction, and centered baseline edaravone use and centered baseline edaravone × B-spline 
interaction. The model will include random regimen-specific intercepts and slopes with 
unstructured covariance, random participant-specific B-splines (5 terms) with unstructured 
covariance, and a first-order autoregressive structure for residuals. A simplified covariance 
structure assuming no regimen-level covariance, heterogeneous compound symmetric covariance 
among the random B-splines, conditional independence of residuals, or a combination of the 
three simplifying assumptions will be used if the full model fails to converge. The primary 
estimand will be the treatment-dependent difference in 24-week change from baseline. The 
estimate and its 95% Wald confidence bounds will be obtained by a linear contrast of adjusted 
means. A separate analysis will include centered baseline serum NfL level and the interaction of 
centered baseline serum NfL level and B-splines as additional covariates. 
6.5.8 Placebo Multiple Imputation 
Placebo multiple imputation analyses are the same as specified in the M-SAP and will be applied 
to ALSFRS-R total score, HHD upper and lower extremity percentages, and SVC. 
The following SAS code specifies the imputation for an endpoint measured every 8 weeks: 
proc mi data=work.outcomes seed=xxx nimpute=50 out=work.out_mi01  
        minimum=. . . . . x x x x maximum=. . . . . y y y y minmaxiter=1000; 
  class rlz edv trtrnd; 
  fcs reg(Wk08 = sx2bl dFRS rlz edv Wk00); 
  fcs reg(Wk16 = sx2bl dFRS rlz edv Wk00 Wk08); 
  fcs reg(Wk24 = sx2bl dFRS rlz edv Wk00 Wk08 Wk16); 
  mnar model( Wk08 Wk16 Wk24 / modelobs=(trtrnd="0")); 
  var sx2bl dFRS rlz edv Wk00 Wk08 Wk16 Wk24; 
run; 
where Wk00, Wk08, Wk16, and Wk24 are the values of a given efficacy endpoint at the Baseline, 
Week 8, Week 16, and Week 24 Visits, respectively, trtrnd has a value of zero (0) for 
participants randomized to placebo, and x and y take appropriate values to specify the range of a 
given outcome measure (i.e., 0 and 48 for ALSFRS-R total score; 0 and . for HHD upper and 
lower extremity percentages and SVC). 
Inference from these analyses is supportive of inference from the Bayesian shared-parameter, 
repeated-measures model for the primary endpoint and assess sensitivity to the missing data 


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assumption of the repeated-measures linear mixed model for secondary endpoints in the FAS 
analysis set. A separate analysis will include centered baseline serum NfL level as an additional 
covariate in both imputation stages. 
6.5.9 Additional Sensitivity Analyses of Primary and Key Secondary Outcomes 
Sensitivity analyses of primary and key secondary efficacy outcomes are the same as specified in 
the M-SAP. 
6.5.10 Subgroup Analyses 
In addition to the subgroups specified in the M-SAP, the following additional subgroups will be 
analyzed in the random-slope model (see Section 6.5.3) for primary and secondary efficacy 
endpoints in the FAS analysis set: 
• Baseline use of riluzole and edaravone (neither, riluzole only, edaravone only, both),  
• Age (less than 65 years vs. 65 years or older),  
• Sex (female vs. male),  
• Race (white vs. any minority race with greater than 5% prevalence in the sample),  
• Ethnicity (Hispanic or Latino vs. non-Hispanic or Latino),  
• Weight (less than 43 kg, 43 to less than 56 kg, 56 to less than 77 kg, 77 to less than 150 kg, 
150 kg or more),  
• BMI (less than 18.5 kg/m2, 18.5 to less than 25 kg/m2, 25 to less than 30 kg/m2, 30 to less 
than 40 kg/m2, 40 kg/m2 or more),  
• Chronic kidney disease (CKD) stage (stage 1 or better [eGFR 90 mL/min/1.73m2 or more], 
stage 2 [eGFR 60 to 89 mL/min/1.73m2], stage 3 [eGFR 30 to 59 mL/min/1.73m2], stage 4 
[eGFR 15 to 29 mL/min/1.73m2], stage 5 [eGFR less than 15 mL/min/1.73m2]),  
• Time since onset of weakness (less than 18 months vs. 18 months or longer),  
• El Escorial and time since onset of weakness (El Escorial definite and less than 18 months 
vs. not both),  
• Baseline symptom severity (all ALSFRS-R questions scored 2 or greater vs. any question 
scored 0 or 1),  
• Early disease state (all ALSFRS-R questions scored 2 or greater, SVC 80%-predicted or 
greater, and time since symptom onset less than 24 months vs. not meeting all three criteria),  
• Baseline serum urate concentration (less than 5.5 mg/dL vs. 5.5 mg/dL or greater),  
• Baseline serum NfL concentration (by median split), and  
• Site (individual sites with at least 5 participants per treatment group and all participants from 
sites with fewer than 5 participants per treatment group pooled). 
For each classification, unknown, not reported, and missing will be considered one group. All 
individuals not included in a specified subgroup will be combined into a mixed, "other" group. 
The "other" group will be included in analyses if its prevalence is greater than 5%; otherwise, the 
"other" group will be excluded. 


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In cases where a model for a given subgroup and endpoint fails to converge, the covariance 
terms for the regimen-specific random effects will be simplified from unstructured covariance of 
intercepts and slopes to separate, uncorrelated variance components for intercepts and slopes. If 
convergence still fails, regimen-specific intercepts and slopes will be modeled as fixed effects. If 
convergence still fails, the participant-specific random effects will be simplified from 
unstructured covariance of intercepts and slopes to separate, uncorrelated variance components 
for intercepts and slopes. 
6.5.11 Comparison of Controls across Regimens 
Comparisons of placebo participants across regimens are the same as specified in the M-SAP 
with separate analyses that include baseline serum NfL level as an additional covariate in 
adjusted analyses plus applicable interaction terms as relevant to a given model. 
6.5.12 Pharmacokinetic Analyses 
Pre-dose concentrations of zilucoplan and its two major metabolites (RA102758 and RA103488) 
in plasma and CSF will be summarized by treatment group and visit in the ERO sample. 
Concentrations below the limit of quantitation (BLQ) will be replaced with one half of the lower 
limit of quantitation. Summaries will include number of observations, number and percentage 
with concentrations BLQ, arithmetic mean, median, standard deviation, minimum, maximum, 
geometric mean, geometric coefficient of variation (calculated as sqrt(exp(variance of log-
transformed concentrations) – 1)), and 95% confidence bounds for the geometric mean assuming 
log-normally distributed data. 
Plasma concentration data of zilucoplan and its two major metabolites may be subjected to 
population pharmacokinetic analysis to derive population estimates of pharmacokinetic 
parameters and test the effect of various covariates such as anti-drug antibodies, age, weight, and 
sex. Details of the analysis will be described in a separate DAP. This analysis may be performed 
by combining data from the current study with data from other studies of zilucoplan, if deemed 
appropriate. The population pharmacokinetic analysis will be performed by UCB Ra Pharma and 
reported in a separate modelling report. The results of the population PK analysis will not be 
reported in the clinical study report (CSR). 
6.5.13 Pharmacodynamic Biomarker Analyses 
Complement functional activity in serum and CSF measured as CH50 values estimated by the 
sheep RBC hemolysis assay and plasma and CSF C5 levels measured by ELISA will be 
summarized by treatment group and visit in the ERO sample. Summary statistics will be 
provided for the values, change from baseline, and percent change from baseline at each 
scheduled assessment time point. 
Population pharmacodynamic or population pharmacokinetic/pharmacodynamic analyses may be 
conducted. Details of such analyses will be described in a separate DAP and will be performed 
by UCB Ra Pharma. The results of the analyses will be reported in a separate report and will not 
be reported in the CSR. 


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6.6 
Safety Analyses 
6.6.1 Treatment-emergent Adverse Events 
Summaries and analyses of treatment-emergent adverse events (TEAE) are the same as specified 
in the M-SAP with the following revisions. 
TEAEs are defined as those adverse events with onset dates in the interval from double-blind 
treatment initiation to the earliest of the Final Safety Visit, the date the participant dies, early 
terminates, or is lost to follow-up, 40 days after last dose of study drug, or the date of first dose 
of study drug during participation in the OLE, if so exposed. Adverse events with onset on the 
day of double-blind treatment initiation and adverse events with incompletely specified onset 
date where the ambiguous date spans the day of double-blind treatment initiation or the earliest 
of the events above that define the end of the treatment-emergence interval will be assumed to be 
treatment emergent except for those known to precede first exposure to study drug. 
In addition to summaries specified in the M-SAP, all adverse events, including those not 
classified as TEAEs, will be summarized by Medical Dictionary for Regulatory Activities 
(MedDRA) system organ class and preferred term and serious TEAEs will be summarized by 
MedDRA system organ class, high level term, and preferred term for all TEAEs. In addition, 
TEAEs will be summarized by MedDRA system organ class and preferred term for fatal TEAEs, 
TEAEs that occurred during a participant's COVID-19 infection (defined as 5 days prior to 
symptom onset to end of COVID-19 symptoms or the earlier of 91 days after symptom onset or 
the end of double-blind follow-up, if ongoing), TEAEs of interest, TEAEs of interest stratified 
by severity, serious TEAEs of interest, and TEAEs and serious TEAEs stratified by the following 
subgroups: baseline riluzole use, baseline edaravone use, age, sex, race, ethnicity, weight, BMI, 
and CKD stage. Subgroup classifications will be the same as described in Section 6.5.10 
Subgroup Analyses except that the "other" group will be retained regardless of prevalence. 
TEAEs indicating COVID-19 infection are the following: Asymptomatic COVID-19, COVID-
19, COVID-19 pneumonia, COVID-19 treatment, Post-acute COVID-19 syndrome, SARS-CoV-
2 antibody test positive, SARS-CoV-2 RNA increased, SARS-CoV-2 sepsis, SARS-CoV-2 test 
false negative, SARS-CoV-2 test positive, SARS-CoV-2 viraemia, Suspected COVID-19. 
TEAEs of interest are defined in Appendix 1 of this R-SAP. 
Treatment-dependent differences in the proportion of participants experiencing a given type of 
TEAE will not be tested. Treatment-dependent differences in TEAE incidence rates in units of 
number per 100 participant years will be estimated as differences rather than ratios and will 
include comparison-wise 95% confidence intervals with variance estimates obtained by the delta 
method. 
6.6.2 Safety Labs 
Summaries and analyses of clinical safety labs are the same as specified in the M-SAP with the 
revision  that lab results collected more than 40 days after last dose of study drug will not be 
tabulated, that abnormal levels will be classified to a toxicity grade based on quantitative grading 
using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events 
(CTCAE) version 5.0 and with the addition that maximum toxicity over all post-baseline 
assessments that occur within 40 days or fewer after last dose of study drug will be included in 
shift tables along with visit-specific shifts. 


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6.6.3 ECG Results 
Summaries of ECG parameters and findings are the same as specified in the M-SAP with the 
revision that ECG parameters and findings collected more than 40 days after last dose of study 
drug will not be tabulated. 
6.6.4 Vital Signs and Weight 
Summaries and analyses of vital signs and weight are the same as specified in the M-SAP with 
the revision that vital signs and weight collected more than 40 days after last dose of study drug 
will not be tabulated. 
6.6.5 Suicidality 
Summaries of suicidality are the same as specified in the M-SAP with the revision that 
suicidality noted more than 40 days after last dose of study drug will not be tabulated. 
6.6.6 Immunogenicity 
The proportion of participants positive, negative, and missing for ADA and anti-PEG-ADA 
immunogenicity endpoints will be summarized by treatment group and visit and at any post-
baseline visit that occurs within 40 days or fewer after last dose of study drug in the SRO 
analysis set. 
Additional immunogenicity analyses are described in Appendix 2 of this R-SAP. These 
additional analyses will be performed by UCB Ra Pharma and reported in a separate 
immunogenicity report. 
6.7 
Other Analyses 
6.7.1 Participant Disposition 
All participants consented to the Master Protocol between the time of the first and last consent of 
a participant assigned to a regimen included in the FAS analysis set will be summarized as a 
single set for the following events: consented to the Master Protocol, failed screening for the 
Master Protocol, other reasons not assigned to a regimen (including timing out of the screening 
window, death, withdrawal of consent, early termination, and administrative termination), and 
assigned to a regimen. Reasons for Master Protocol screen failure will be summarized. 
All participants in the above sample assigned to a regimen will be summarized as two sets (final 
screening for RGA vs. final screening for a non-RGA regimen) for the following events: 
consented to a regimen, failed screening for a regimen, other reasons not randomized within a 
regimen (including timing out of the screening window, death, withdrawal of consent, early 
termination, and administrative termination), and randomized within a regimen. If a given 
individual is screened multiple times prior to randomization within a regimen, then the final 
screening experience of that individual will be summarized. Reasons for RGA screen failure will 
be summarized separately for all participants screened for RGA whether that was their final 
screening experience or not. 
All participants in the FAS analysis set will be summarized as two sets (randomization to active 
study drug vs. randomization to placebo) for the following events: initiated regimen-specific 
study drug, prematurely terminated study participation due to death, withdrawal of consent, early 
termination, loss to follow-up, or administrative termination, completed 24-week follow up, and 


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completed a safety follow-up visit vs. continued into the OLE. Reasons for withdrawal of 
consent or early termination after randomization will be summarized. 
Any randomized participants excluded from the FAS and EPP analysis sets or included in the 
FAS analysis set but not contributing to the primary analysis will be identified in a listing 
together with the reason for their exclusion. 
6.7.2 Study Drug Compliance and Tolerance 
Summaries of study drug compliance and tolerance are the same as specified in the M-SAP with 
the clarification that summaries will be reported for the ERO and SRO analysis sets and that date 
of permanent discontinuation of study drug is the date of last use of double-blind study drug 
among all participants in a given analysis set. 
The number of days of exposure to study drug will be calculated in three ways: 
• as the number of days from dose initiation to the final safety assessment during the placebo-
controlled period, inclusive,  
• as the number of days from dose initiation to drug withdrawal, inclusive, less any interval 
during which use of study drug was interrupted (individual missed doses will not be 
subtracted unless noted in the dosage management log), and  
• as the number of days from dose initiation to the earlier of final contact during the placebo-
controlled period or 40 days after last dose of study drug, inclusive. 
6.7.3 Concomitant Medication Use 
Summaries of concomitant medication use are the same as specified in the M-SAP. 
6.7.4 Medical History 
Medical histories will be summarized by MedDRA system organ class, high level term, and 
preferred term in the STF and SRO analysis sets. 
6.7.5 Blindedness 
The proportions of participants and site investigators who report on the Exit Questionnaire a 
guess of active vs. placebo treatment assignment, each level of surety of that guess, and each of 
five pre-specified reasons for making a treatment assignment will be summarized by treatment 
group in the FAS, ERO, and EPP analysis sets. Treatment-dependent differences in the 
proportion guessing active treatment assignment will be tested among all respondents and among 
those stating they are at least somewhat sure of their guess by Fisher's exact test and the 
difference in proportion guessing active treatment assignment will be estimated with confidence 
bounds. 
6.7.6 Protocol Deviations 
The number of major and minor protocol deviations will be summarized by type of deviation and 
treatment group in all analysis sets. Listings of all protocol deviations will be produced. 
6.7.7 Impact of COVID-19 Pandemic 
The proportions of planned assessments missed due to COVID-19 restrictions or disruptions will 
be summarized by treatment group, visit, and type of assessment in the FAS and ERO analysis 
sets. Protocol deviations that resulted from COVID-19 restrictions or disruptions will be 


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summarized by treatment group and type of deviation in the FAS and ERO analysis sets and 
listed. 
7. Validation 
7.1 
Primary Efficacy Analysis 
Validation of the primary efficacy analysis is the same as specified in the M-SAP. 
7.2 
Secondary, Exploratory, and Safety Analyses 
Validation of secondary, exploratory, and safety analyses are the same as specified in the M-
SAP. 
8. References 
The following references are cited in addition to those specified in the M-SAP: 
Balendra R, Jones A, Jivraj N, Knights C, Ellis CM, Burman R, Turner MR, Leigh PN, Shaw 
CE, Al-Chalabi A. Estimating clinical stage of amyotrophic lateral sclerosis from the ALS 
Functional Rating Scale. Amyotroph Lateral Scler Frontotemporal Degener. 2014 Jun;15(3-
4):279-84. 
Roche JC, Rojas-Garcia R, Scott KM, Scotton W, Ellis CE, Burman R, Wijesekera L, Turner 
MR, Leigh PN, Shaw CE, Al-Chalabi A. A proposed staging system for amyotrophic lateral 
sclerosis. Brain. 2012 Mar;135(Pt 3):847-52. 
 
 


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Appendix 1. Treatment-emergent Adverse Events of Interest 
Events 
MedDRA Search Strategy 
Infections 
SOC “Infections and infestations” 
Neisseria infections 
HLT “Neisseria infections” 
Potential anaphylactic reactions 
Potential anaphylactic reactions are defined via a 
MedDRA algorithmic approach, which combines a 
number of different TEAEs/ anaphylactic reaction 
symptoms that are reported on the same day or on 2 
consecutive days, under the condition that use of study 
drug was still ongoing at the first of these 2 days. Some 
cases are dependent on the presence of multiple 
symptoms/ TEAEs and these multiple TEAEs must be on 
the same onset day or on 2 consecutive days, 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. For 
cases dependent on multiple symptoms the onset date of 
the reaction will be the onset date of the first preferred 
term/ symptom experienced, whilst the onset date of 
serious reactions will be set to the date of the first serious 
preferred term/symptom. When the reaction consists of 
multiple TEAEs of different severities, the severity of the 
reaction is the maximum (i.e., most severe) severity. 
Similarly, a reaction is classified as related by the 
investigator if at least one TEAE is related. 
Hypersensitivity reactions 
SMQ “Hypersensitivity (narrow scope)” 
Injection site reactions 
TEAEs in MedDRA HLT “Injection site reactions” or 
HLT “Administration site reactions NEC”. 
Drug related hepatic disorders 
Narrow SMQ 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)” 
Malignant or unspecified tumours 
SMQ “Malignant or unspecified tumours (SMQ)” 
Malignant tumours 
SMQ “Malignant tumours (SMQ)” 
 
 
 


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MedDRA Algorithmic Approach to Anaphylaxis 
The standardized MedDRA query (SMQ) “Anaphylactic reaction” consists of three parts:  
A narrow search containing PTs that represent core anaphylactic reaction terms: 
 
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: Upper Airway/Respiratory 
 
 
 


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Category C: Angioedema/Urticaria/Pruritus/Flush 
 
 
 
Category D: Cardiovascular/Hypotension 
 
An algorithmic approach which combines a number of anaphylactic reaction symptoms in order 
to increase specificity. A potential anaphylactic reaction is defined as meeting at least one of 
the following criteria where the different terms occur on either the same day as when an 
injection was administered or one day after:  
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);  
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)]  
 
 


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Appendix 2. Immunogenicity Analyses 
The incidence of anti-drug antibodies (ADA) and anti-PEG antibodies (anti-PEG-ADA) 
(immunogenicity against zilucoplan) will be measured via dual assay strategy consisting of 
measuring ADA and anti-PEG-ADA. 
The ADA and anti-PEG-ADA status for both active and placebo participants will be determined 
for each pre-treatment (Baseline) and post-treatment visits (i.e., week 8, week 16 and week 24) 
where samples are taken for ADA analysis. 
• Sample values that are either ‘negative screen’ or ‘positive screen’ and ‘negative 
immunodepletion’ will be defined as ADA negative 
• Sample values that are ‘positive screen’ and ‘positive immunodepletion’ will be defined 
as ADA positive 
• Samples that could not be tested for ADA status due to inadequate sample volume, 
mishandling, or errors in sample collection, processing, storage, etc, will be defined as 
Missing. 
 
The following ADA classifications will be derived from the sample ADA status. 
Table:  
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 
4 
Pre-ADA positive – treatment 
unaffected ADA 
Includes participants who are ADA positive 
at Baseline and ADA positive at any 
sampling point post-Baseline (including 
Observation Period) with titer values of the 
same magnitude as Baseline (less than a 
predefined fold difference from the 
Baseline value which will be defined within 
the validation of the assay, i.e., MSR of the 
assay). 


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Table:  
ADA Classification 
Classification Classification Label 
Definition 
5 
Pre-ADA positive – treatment 
boosted ADA positive 
Includes participants who are ADA positive 
at Baseline and ADA positive at any 
sampling point post-Baseline (including 
Observation Period) with increased titer 
values compared to Baseline (greater than a 
predefined fold difference increase from 
Baseline value which will be defined within 
the validation of the assay, i.e., MSR of the 
assay). 
6 
Inconclusive 
Participants who have an ADA positive 
Baseline sample and some post-Baseline 
samples are missing, while other post-
Baseline samples are ADA negative.  
7 
Treatment emergent ADA 
positive  
Combination of 2 and 5 
8 
Pre-ADA positive 
Combination of 3, 4, and 5 
MSR=minimum significant ratio. 
 
In addition to the ADA classifications above, for the purpose of exploring the impact of ADA on 
PK, and safety endpoints, the following definitions will be used: 
• Cumulative ADA status (positive/negative). If a study participant has had at least one 
positive sample at any time point (including unscheduled visits) up to and including the 
given time point, that study participant will be counted as positive at that time point, 
regardless of any subsequent negative measurements.  
• Overall ADA status. A study participant will be classified as overall ADA Positive if at 
least one post-Baseline measurement (including unscheduled visits) is Positive. A study 
participant will be classified as overall ADA Negative if at all post-Baseline visits the 
ADA status is Negative. 
 
The same definitions and classifications will be used for anti-PEG-ADA. 
 
The following outputs will be presented for the SRO sample. 
• Number and percentage of study participants with positive, negative or missing sample 
ADA status at each visit will be summarized by treatment group. 
• Number and percentage of study participants in each of the ADA classifications 
presented will be summarized by treatment group. 
• The prevalence of immunogenicity (Classification 2, 3, 4 and 5), defined as the 
(cumulative) proportion of study participants having ADA positive samples (including 
pre-ADA positive) at any point up to and including that time point will be summarized by 
treatment group. Missing samples will not be included in the denominator. 


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• The first occurrence of treatment-emergent ADA positive (Classification 2 and 5) will be 
summarized using frequency and percentage at each post-Baseline visit by treatment 
group. Study participants will be counted only once in the numerator based on the earliest 
visit at which treatment-emergent ADA positivity is observed. At other visits, study 
participants will be counted in the denominator (assuming a measurement is available). 
Missing measurements will not be included in the denominator. 
• The time to achieving treatment-emergent ADA positivity, separated by treatment group, 
will be summarized and analyzed based on Kaplan-Meier methods. Study participants 
will be considered to have an event at the time point at which treatment-emergent ADA 
positive is first achieved. Participants who never had a treatment-emergent ADA 
positivity will be censored at the date of their last visit. This will also be plotted 
graphically. 
 
The same tables will be provided for anti-PEG-ADA by treatment group. 
 
Relationship between ADA and Safety Endpoints 
TEAEs will be summarized by ADA status using the following categories:  
• AEs starting before first treatment emergent ADA positive result 
• AEs starting on or after first treatment emergent ADA positive result 
• AEs for study participants who were overall ADA negative  
Each TEAE will be classified according to whether it occurred before the first treatment 
emergent positive result, on or after the first treatment positive result, or for a study participant 
that remained treatment negative post-baseline. If a participant has multiple reports of the same 
AE (i.e., those which code to the same preferred term) emerging both prior to first ADA positive 
result and after first ADA positive result, both events will be counted in the appropriate category. 
The following AE outputs will be presented this way: 
• Overall summary of TEAEs (i.e., the number of events and proportion of participants 
experiencing any TEAE, any serious TEAE, any severe TEAE, any related TEAE, any 
TEAE leading to discontinuation of study drug, and any fatal TEAEs) by treatment group 
and by ADA status 
• Incidence of TEAEs of interest by treatment group and by ADA status 
Presented for any hypersensitivity reactions and any injections site reactions (as defined in 
Appendix 1) and any autoimmune disorders (defined by the MedDRA HLGT of Autoimmune 
disorders). 
 
The AE analyses above will be repeated by anti-PEG-ADA status. 
 


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Relationship between ADA and PK Endpoints 
• A plot of geometric mean with 95% CI of plasma concentrations of zilucoplan data by 
cumulative ADA status (positive/negative) at each scheduled visit will be presented. 
• A plot of geometric mean with 95% CI of plasma concentrations of zilucoplan data by 
cumulative anti-PEG-ADA status (positive/negative) at each scheduled visit will be 
presented. 
 
Relationship between ADA and PD Endpoints 
• A plot of mean change in sRBC lysis activity by cumulative ADA status 
(positive/negative) at each scheduled visit will be presented. 
• A plot of mean change in sRBC lysis activity by cumulative anti-PEG-ADA status 
(positive/negative) at each scheduled visit will be presented. 
• A plot of mean levels of C5 complement by cumulative ADA status (positive/negative) at 
each scheduled visit will be presented. 
• A plot of mean levels of C5 complement by cumulative anti-PEG-ADA status 
(positive/negative) at each scheduled visit will be presented. 
 


Certificate Of Completion
Envelope Id: DE41F373C526454EA40B7A4ED3633EE7
Status: Completed
Subject: Please DocuSign: HEALEY ALS Platform RGA R-SAP v3.0 20220722_unsigned.pdf
Source Envelope: 
Document Pages: 42
Signatures: 5
Envelope Originator: 
Certificate Pages: 6
Initials: 0
Marianne   Chase
AutoNav: Enabled
EnvelopeId Stamping: Disabled
Time Zone: (UTC-05:00) Eastern Time (US & Canada)
mchase@mgh.harvard.edu
IP Address: 73.60.69.9     
Record Tracking
Status: Original
             7/22/2022 2:26:29 PM
Holder: Marianne   Chase
             mchase@mgh.harvard.edu
Location: DocuSign
Signer Events
Signature
Timestamp
Ben Saville
ben@berryconsultants.net
Ben Saville
Security Level: Email, Account Authentication 
(Required), Logged in
Signature Adoption: Pre-selected Style
Signature ID: 
50221BD2-F3C9-432B-9863-2C6FEC7283AD
Using IP Address: 72.182.14.11
With Signing Authentication via DocuSign password
With Signing Reasons (on each tab): 
   I approve this document
Sent: 7/22/2022 2:34:41 PM
Viewed: 7/22/2022 3:21:39 PM 
Signed: 7/22/2022 4:40:39 PM
Electronic Record and Signature Disclosure: 
      Accepted: 6/24/2020 5:24:44 PM
      ID: 0826203a-7d83-4395-a4f0-c1a7f44f1ee4
Eric A. Macklin
emacklin@mgh.harvard.edu
Instructor in Medicine
Eric Macklin
Security Level: Email, Account Authentication 
(Required)
Signature Adoption: Pre-selected Style
Signature ID: 
8E847DD4-0E85-42A1-B334-DFC089673751
Using IP Address: 173.48.212.201
With Signing Authentication via DocuSign password
With Signing Reasons (on each tab): 
   I approve this document
Sent: 7/22/2022 2:34:41 PM
Viewed: 7/22/2022 2:46:07 PM 
Signed: 7/22/2022 2:46:44 PM
Electronic Record and Signature Disclosure: 
      Accepted: 5/8/2020 9:17:52 AM
      ID: 2308ba7c-abcd-4949-872e-021ea95dc489


Signer Events
Signature
Timestamp
Merit Cudkowicz
cudkowicz.merit@mgh.harvard.edu
Chief of Neurology
Security Level: Email, Account Authentication 
(Required)
Signature Adoption: Pre-selected Style
Signature ID: 
9F8FE418-0E50-4C6A-B0A6-7B835E80C644
Using IP Address: 108.26.176.128
With Signing Authentication via DocuSign password
With Signing Reasons (on each tab): 
   I approve this document
Sent: 7/22/2022 2:34:41 PM
Viewed: 7/22/2022 7:45:44 PM 
Signed: 7/22/2022 7:46:00 PM
Electronic Record and Signature Disclosure: 
      Accepted: 7/22/2022 7:45:44 PM
      ID: 746ff682-4054-4451-8c34-9580fe4209c2
Paul Mahoney
Paul.Mahoney@ucb.com
Security Level: Email, Account Authentication 
(Required)
Signature Adoption: Pre-selected Style
Signature ID: 
FBEC2F18-1B52-494E-9192-2DA48097CCFA
Using IP Address: 81.159.180.247
With Signing Authentication via DocuSign password
With Signing Reasons (on each tab): 
   I approve this document
Sent: 7/22/2022 2:34:42 PM
Resent: 7/24/2022 1:33:42 PM
Resent: 7/24/2022 1:33:56 PM
Resent: 7/25/2022 4:38:55 PM
Viewed: 7/25/2022 4:58:28 PM 
Signed: 7/25/2022 4:59:20 PM
Electronic Record and Signature Disclosure: 
      Accepted: 7/25/2022 4:58:28 PM
      ID: fb37b7cf-8bd2-44c9-a683-c3c9a611f3bd
Sabrina Paganoni
Spaganoni@mgh.harvard.edu
MD PhD
MGH
Security Level: Email, Account Authentication 
(Required)
Signature Adoption: Pre-selected Style
Signature ID: 
58705BF6-1CB8-42A8-8752-1BEB826294FA
Using IP Address: 73.182.245.163
With Signing Authentication via DocuSign password
With Signing Reasons (on each tab): 
   I approve this document
Sent: 7/22/2022 2:34:41 PM
Viewed: 7/22/2022 3:51:21 PM 
Signed: 7/22/2022 3:51:40 PM
Electronic Record and Signature Disclosure: 
      Accepted: 7/22/2022 3:51:21 PM
      ID: 0302636d-6183-4094-91b9-ec6be738cde6
In Person Signer Events
Signature
Timestamp
Editor Delivery Events
Status
Timestamp
Agent Delivery Events
Status
Timestamp
Intermediary Delivery Events
Status
Timestamp
Certified Delivery Events
Status
Timestamp


Carbon Copy Events
Status
Timestamp
Witness Events
Signature
Timestamp
Notary Events
Signature
Timestamp
Envelope Summary Events
Status
Timestamps
Envelope Sent
Hashed/Encrypted
7/22/2022 2:34:42 PM
Certified Delivered
Security Checked
7/22/2022 3:51:21 PM
Signing Complete
Security Checked
7/22/2022 3:51:40 PM
Completed
Security Checked
7/25/2022 4:59:20 PM
Payment Events
Status
Timestamps
Electronic Record and Signature Disclosure


ELECTRONIC RECORD AND SIGNATURE DISCLOSURE  
From time to time, Insight OBO The Massachusetts General Hospital (we, us or Company) may 
be required by law to provide to you certain written notices or disclosures. Described below are 
the terms and conditions for providing to you such notices and disclosures electronically through 
the DocuSign system. Please read the information below carefully and thoroughly, and if you can 
access this information electronically to your satisfaction and agree to this Electronic Record and 
Signature Disclosure (ERSD), please confirm your agreement by selecting the check-box next to 
‘I agree to use electronic records and signatures’ before clicking ‘CONTINUE’ within the 
DocuSign system. 
 
Getting paper copies  
At any time, you may request from us a paper copy of any record provided or made available 
electronically to you by us. You will have the ability to download and print documents we send 
to you through the DocuSign system during and immediately after the signing session and, if you 
elect to create a DocuSign account, you may access the documents for a limited period of time 
(usually 30 days) after such documents are first sent to you. After such time, if you wish for us to 
send you paper copies of any such documents from our office to you, you will be charged a 
$0.00 per-page fee. You may request delivery of such paper copies from us by following the 
procedure described below. 
 
Withdrawing your consent  
If you decide to receive notices and disclosures from us electronically, you may at any time 
change your mind and tell us that thereafter you want to receive required notices and disclosures 
only in paper format. How you must inform us of your decision to receive future notices and 
disclosure in paper format and withdraw your consent to receive notices and disclosures 
electronically is described below. 
 
Consequences of changing your mind  
If you elect to receive required notices and disclosures only in paper format, it will slow the 
speed at which we can complete certain steps in transactions with you and delivering services to 
you because we will need first to send the required notices or disclosures to you in paper format, 
and then wait until we receive back from you your acknowledgment of your receipt of such 
paper notices or disclosures. Further, you will no longer be able to use the DocuSign system to 
receive required notices and consents electronically from us or to sign electronically documents 
from us. 
 
All notices and disclosures will be sent to you electronically  
Electronic Record and Signature Disclosure created on: 3/31/2020 3:10:31 PM
Parties agreed to: Ben Saville, Eric A. Macklin, Merit Cudkowicz, Paul Mahoney, Sabrina Paganoni


Unless you tell us otherwise in accordance with the procedures described herein, we will provide 
electronically to you through the DocuSign system all required notices, disclosures, 
authorizations, acknowledgements, and other documents that are required to be provided or made 
available to you during the course of our relationship with you. To reduce the chance of you 
inadvertently not receiving any notice or disclosure, we prefer to provide all of the required 
notices and disclosures to you by the same method and to the same address that you have given 
us. Thus, you can receive all the disclosures and notices electronically or in paper format through 
the paper mail delivery system. If you do not agree with this process, please let us know as 
described below. Please also see the paragraph immediately above that describes the 
consequences of your electing not to receive delivery of the notices and disclosures 
electronically from us. 
 
How to contact Insight OBO The Massachusetts General Hospital:  
You may contact us to let us know of your changes as to how we may contact you electronically, 
to request paper copies of certain information from us, and to withdraw your prior consent to 
receive notices and disclosures electronically as follows: 
To contact us by email send messages to: jhenrique@mgh.harvard.edu 
 
To advise Insight OBO The Massachusetts General Hospital of your new email address  
To let us know of a change in your email address where we should send notices and disclosures 
electronically to you, you must send an email message to us at jhenrique@mgh.harvard.edu and 
in the body of such request you must state: your previous email address, your new email 
address.  We do not require any other information from you to change your email address.  
If you created a DocuSign account, you may update it with your new email address through your 
account preferences.  
 
To request paper copies from Insight OBO The Massachusetts General Hospital  
To request delivery from us of paper copies of the notices and disclosures previously provided 
by us to you electronically, you must send us an email to jhenrique@mgh.harvard.edu and in the 
body of such request you must state your email address, full name, mailing address, and 
telephone number. We will bill you for any fees at that time, if any. 
 
To withdraw your consent with Insight OBO The Massachusetts General Hospital  
To inform us that you no longer wish to receive future notices and disclosures in electronic 
format you may: 


i. decline to sign a document from within your signing session, and on the subsequent page, 
select the check-box indicating you wish to withdraw your consent, or you may; 
ii. send us an email to jhenrique@mgh.harvard.edu and in the body of such request you must 
state your email, full name, mailing address, and telephone number. We do not need any other 
information from you to withdraw consent..  The consequences of your withdrawing consent for 
online documents will be that transactions may take a longer time to process.. 
 
Required hardware and software  
The minimum system requirements for using the DocuSign system may change over time. The 
current system requirements are found here: https://support.docusign.com/guides/signer-guide-
signing-system-requirements.  
 
Acknowledging your access and consent to receive and sign documents electronically  
To confirm to us that you can access this information electronically, which will be similar to 
other electronic notices and disclosures that we will provide to you, please confirm that you have 
read this ERSD, and (i) that you are able to print on paper or electronically save this ERSD for 
your future reference and access; or (ii) that you are able to email this ERSD to an email address 
where you will be able to print on paper or save it for your future reference and access. Further, 
if you consent to receiving notices and disclosures exclusively in electronic format as described 
herein, then select the check-box next to ‘I agree to use electronic records and signatures’ before 
clicking ‘CONTINUE’ within the DocuSign system. 
By selecting the check-box next to ‘I agree to use electronic records and signatures’, you confirm 
that: 
 
You can access and read this Electronic Record and Signature Disclosure; and 
 
You can print on paper this Electronic Record and Signature Disclosure, or save or send 
this Electronic Record and Disclosure to a location where you can print it, for future 
reference and access; and 
 
Until or unless you notify Insight OBO The Massachusetts General Hospital as described 
above, you consent to receive exclusively through electronic means all notices, 
disclosures, authorizations, acknowledgements, and other documents that are required to 
be provided or made available to you by Insight OBO The Massachusetts General 
Hospital during the course of your relationship with Insight OBO The Massachusetts 
General Hospital.