Conditions: Amyotrophic Lateral Sclerosis ALS
Keywords: Ravulizumab ALXN1210 Ultomiris Motor Neuron Disease Amyotrophic Lateral Sclerosis ALS
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 382
Healthy volunteers: no

Brief summary:
The purpose of the study is to assess the efficacy and safety of ravulizumab for the treatment of adult participants with ALS.

Detailed description:

Arms:
arm 1: Participants will receive ravulizumab for the duration of the study. arm 2: Participants will receive placebo during the 50-week Randomized Controlled Period of the study, after which they will enter the Open-label Extension Period of the study and switch to receive ravulizumab.

Interventions: intervention 1: Placebo intervention 2: Ravulizumab
Intervention descriptions: intervention 1: Single loading dose via intravenous infusion, followed by regular maintenance dosing, based on weight. intervention 2: Single loading dose via intravenous infusion, followed by regular maintenance dosing, based on weight.

Protocol document:
Prot_002.pdf: 
A Phase 3, Double-Blind, Randomized, Placebo-Controlled, 
Parallel Group, Multicenter Study With an Open-Label 
Extension to Evaluate the Efficacy and Safety of 
Ravulizumab in Patients With Amyotrophic Lateral 
Sclerosis (ALS) 
Unique Protocol ID: 
ALXN1210-ALS-308 
NCT Number: 
NCT04248465 
EudraCT Number: 
2019-004619-30 
Date of Protocol: 
23 June 2021 


Protocol Amendment 6.0
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TITLE PAGE
Protocol Title: A Phase 3, Double-Blind, Randomized, Placebo-Controlled, Parallel Group, 
Multicenter Study with an Open-Label Extension to Evaluate the Efficacy and Safety of 
Ravulizumab in Patients With Amyotrophic Lateral Sclerosis (ALS)
Protocol Number: ALXN1210-ALS-308
Amendment Number: 6
Compound: Ravulizumab (ALXN1210)
Study Phase: 3
Short Title: An Efficacy and Safety Study of Ravulizumab in ALS Patients
Sponsor Name: Alexion Pharmaceuticals, Inc.
Legal Registered Address: 121 Seaport Boulevard, Boston, MA 02210, USA
Regulatory Agency Identifier Numbers: 
EudraCT Number: 2019-004619-30
IND Number: 145660
Approval Date: 23 Jun 2021
Sponsor Signatory:
 MD, PhD
Executive Medical Director 
Alexion Pharmaceuticals, Inc.
Date
Medical Monitor Contact Information can be found in the Study Contact List distributed 
to study sites.
04-Aug-2021 | 13:09:29 EDT
PPD
PPD


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Investigator’s Agreement 
I have read the ALXN1210-ALS-308 study protocol and agree to conduct the study in 
accordance with this protocol, all applicable government regulations, the principles of the ICH 
E6 Guidelines for Good Clinical Practice, and the principles of the World Medical Association 
Declaration of Helsinki. I also agree to maintain the confidentiality of all information received or 
developed in connection with this protocol.  
 
 
 
 
 
____________________________________ 
Printed Name of Investigator 
_____________________________________ 
Signature of Investigator 
_______________ 
Date 


Protocol Amendment 6.0 
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PROTOCOL AMENDMENT SUMMARY OF CHANGES 
DOCUMENT HISTORY 
Document 
Date 
Amendment 6 (Global) 
23 Jun 2021 
Amendment 6 (Global) (23 Jun 2021) 
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of 
Directive 2001/20/EC of the European Parliament and the Council of the European Union. 
The complete protocol amendment history is described in Section 10.16, Appendix 16.  
Overall Rationale for the Amendment: 
The main purposes of this amendment are: 
• To allow patients to switch from the 10 mg/mL formulation to the 100 mg/mL 
formulation of ravulizumab with no change to the weight-based dose regimen at or after 
Week 52 in the Open-Label Extension Period 
• To remove the second planned interim analysis 
Other changes are presented in the table below. 
 
Section # and Name 
Description of Change 
Brief Rationale 
1.1 Synopsis 
Added the content below to the Overall 
Design: Patients may be allowed to switch 
from the 10 mg/mL to the 100 mg/mL 
formulation of ravulizumab with no change to 
the weight-based dose regimen at or after 
Week 52 in the OLE Period. 
To provide the overall 
description that allows patients 
to switch from the 10 mg/mL to 
the100 mg/mL formulation of 
ravulizumab during the OLE 
Period. 
1.1 Synopsis; 
4 Objectives and Endpoints; 
 
Change in the description of the endpoint from 
“Change from baseline in NfL concentration 
in serum at Week 50” to “NfL concentration 
in serum at Week 50.” 
Clarification in endpoint 
definition. 
1.1 Synopsis;  
1.2 Schema Figure 1;  
3.1 Overall Design;  
3.2.1 Study Population and 
Treatment Duration; 
9.5 Interim Analysis 
Change from 2 planned interim analyses to 1 
planned interim analysis. 
 
Due to faster than expected 
enrollment, the operational 
complexities associated with 
interim analysis 2 outweighed 
the anticipated gain in time in 
completing the 
Randomized-controlled Period 
due to early efficacy vs. full 
50-week follow-up. 


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Section # and Name 
Description of Change 
Brief Rationale 
1.2 Schema Figure 1;  
3.1 Overall Design;  
9.5 Interim Analysis 
The following text has been added to provide 
clarity: 
“The study may be stopped if considered 
futile.” 
 
The following text has been deleted as a result 
of this change: 
“The second interim analysis will be 
performed when approximately all patients 
have completed the Week 26 visit. At this 
time, a futility analysis will be conducted first. 
If the study is not considered futile, an 
analysis to determine early stopping for 
efficacy will be performed. If the efficacy 
analysis meets prespecified criteria, the 
Randomized Controlled Period may be 
stopped for success, and all patients in the 
Randomized Controlled Period may transition 
to the Open-Label Extension Period of the 
study.” 
 
The text has been altered to 
reflect the change from 2 to 1 
interim analysis.  
 
1.2 Schema, Figure 1;  
1.3 Schedule of Activities, 
Tables 2 and 3 
Added the following note to the footnotes: 
Note: Patients may be allowed to switch from 
the 10 mg/mL to the 100 mg/mL formulation 
of ravulizumab with no change to the 
weight-based dose regimen at or after 
Week 52 in the OLE Period. 
To provide the description 
allowing patients to switch to 
the100 mg/mL formulation of 
ravulizumab in the OLE Period. 
1.3.1 Screening to Week 50, 
Table 1 
Changed assessment for ventilator utilization 
at Weeks 6, 14, and 22 from “in clinic” to 
allow that it can be performed “in clinic, by 
home visit, or by telephone contact”. When 
performed by telephone, the telephone 
interview version of the questionnaire should 
be used, if available. 
To allow for more flexibility in 
obtaining information on 
ventilator utilization. 
1.3.2 Week 50 to 116, Table 2 
Added collection of clinical laboratory tests at 
Week 52. 
To correct inadvertent omission 
requiring collection of 
laboratory tests at Week 52. 
3.1 Overall Design;  
3.2.1 Study Population and 
Treatment Duration;  
8.1.4.2 Open Label Extension 
Period 
Added information that allows patients to 
switch from the 10 mg/mL to the 100 mg/mL 
formulation of ravulizumab with no change to 
the weight-based dose regimen at or after 
Week 52 in the OLE Period. 
To provide study design of 
switch to the 100 mg/mL 
formulation of ravulizumab in 
the OLE Period. 


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Section # and Name 
Description of Change 
Brief Rationale 
3.1 Overall Design 
8.1.4 Study Drug 
Administration 
The following text has been deleted: 
“In the event that the Randomized Controlled 
Period is stopped for success, any patient who 
is still in the Randomized Controlled Period 
will transition to the Open-Label Extension 
Period at their next scheduled dosing visit. 
Regardless of previous visit number, when the 
patient returns for the next scheduled dosing 
visit, the patient will follow the procedures 
outlined in Visit 13 in the SoA and continue 
all subsequent visits as outlined to the End of 
Study Visit. For patients who are in the Open-
Label Extension Period when the Randomized 
Controlled Period is stopped for success, there 
will be no change to the visit schedule.” 
This text is deleted as a result of 
change to 1 interim analysis. 
3.2.1 Study Population and 
Treatment Duration 
The text below has been modified; text in 
bold has been added and text in strikethrough 
has been deleted. 
“A study design with an interim 
analysesanalysis was chosen to allow 
consideration for early stopping in the case of 
futility or efficacy. The interim analyses, 
which would minimize exposing patientsthe 
duration of exposure to an ineffective 
therapy or prolonged exposure to placebo in 
the event of detecting efficacy earlier.” 
Provides rationale for a single 
interim analysis, and removes 
analysis to stop the study for 
efficacy. 
3.2.1 Study Population and 
Treatment Duration 
The following text has been added: 
“In this study patients may be allowed to 
switch from the 10 mg/mL to the 100 mg/mL 
formulation of ravulizumab with no change to 
the weight-based dose regimen during the 
OLE period. The 100 mg/mL IV formulation 
of ULTOMIRIS® (ravulizumab) was 
approved in 2020 by the FDA and the 
European Commission for the treatment of 
paroxysmal nocturnal hemoglobinuria (PNH) 
and atypical hemolytic uremic syndrome 
(aHUS). The 100 mg/mL ravulizumab is a 
higher concentration IV formulation which 
provides shorter preparation and infusion 
times while delivering comparable PK, safety 
and efficacy to the 10 mg/mL formulation of 
ravulizumab. Clinical data from Study 
ALXN1210-PNH-201 and Study ALXN1210-
PNH-302 shows no change in the benefit/risk 
profile of ravulizumab following 
administration of the approved weight-based 
doses of ravulizumab using the 100 mg/mL 
formulation in patients with PNH.” 
To provide information 
supporting the benefit:risk of 
switching from the 10 mg/mL to 
the 100 mg/mL formulation, and 
provide current status of 
regulatory approval for the 100 
mg/mL formulation. 
4 Objectives and Endpoints;  
9.4.5.3 Analysis of 
Exploratory Efficacy 
Endpoints 
Any increase from baseline stage on the 
King’s staging system at Week 50. 
Clarification of endpoint 
language from “decline” to 
“increase”. 


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Section # and Name 
Description of Change 
Brief Rationale 
6.1 Study Drug(s) 
Administered, Table 5 
Addition of 100 mg/mL formulation of 
ravulizumab. 
To add in the 100 mg/mL 
formulation and to provide 
instruction on administering 
ravulizumab using the 
100 mg/mL formulation.  
6.5.2 Disallowed Medications 
and Therapies 
Added the following text: 
“Note: Use of systemic corticosteroids for 
≥ 14 days may be considered on a 
case-by-case basis in consultation with the 
Medical Monitor”. 
To correct an overly restrictive 
concomitant medication 
prohibition that is necessary 
neither for patient safety nor for 
treatment efficacy. 
6.6 Dose Modification 
Added the following bold text: 
Dose modification is not permitted for this 
study. However, in the event of a missed or 
incomplete dose, and with the guidance of 
the Sponsor, supplemental dosing may be 
employed to maintain therapeutic steady 
state concentrations from disruptions in 
scheduled study drug dosing. 
Clarification added to address 
any potential missed or 
incomplete doses. 
7.2 Patient 
Discontinuation/Withdrawal 
from the Study 
Added collection of VAFS at End of 
Study/Early Discontinuation Visit. 
Corrected omission, this is 
correct in the Schedule of 
Activities. 
7.2 Patient 
Discontinuation/Withdrawal 
from the Study 
The text below has been deleted: 
“This phone call can be omitted if it falls 
within 5 days of the ED visit.” 
Consistency with the footnotes 
in the Schedules of Activities  
7.2 Patient 
Discontinuation/Withdrawal 
from the Study 
Added a new bullet point: 
“If a patient withdraws from the study, the 
patient may request destruction of any 
samples taken and not tested, and the 
Investigator must document this in the site 
study records as well as inform the site 
monitor and Sponsor.” 
Conformance with current 
protocol template and 
clarification for sample 
management. 
8.2.2 Ventilation Assistance-
Free Survival (VAFS) 
The text below has been modified; text in 
bold has been added and text in strikethrough 
has been deleted. 
AttemptsAn attempt will be made to obtain 
information about survival even after at the 
patient has discontinued therapyfollow up 
phone call. 
Clarifies the timing for the final 
attempt to obtain assessment 
using the VAFS. 


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Section # and Name 
Description of Change 
Brief Rationale 
9.1.2 Secondary Hypotheses 
The secondary hypothesis “Change in 
ALSAQ-40 score” has been changed to 
“Neurofilament light chain concentration”. 
The text below has been modified; text in 
bold has been added and text in strikethrough 
has been deleted. 
“4. 
Change in ALSAQ-40 score 
Neurofilament light chain (NfL) 
concentration: The alternative hypothesis is 
that treatment with ravulizumab will show 
improvement in lower the change from 
baseline in ALSAQ-40 NfL concentration at 
Week 50 compared to placebo 
To reflect secondary objectives 
as outlined in Section 4. 
9.4.5.1.1 Primary Analysis 
9.4.5.1.1.1 Alternate Primary 
analysis 
The text below has been modified; text in 
bold has been added and text in strikethrough 
has been deleted. 
“A p-value less than the adjustedType I error 
(Section )= 0.05 associated with the higher 
mean rank in ravulizumab group compared to 
placebo will indicate a statistically significant 
treatment benefit 
To reflect the omission of the 
interim analysis 2 for early 
efficacy. 
9.4.5.1.1.1 Alternate Primary 
Analysis 
9.4.5.1.2.1 Mixed-Effect 
Model for Repeated Measures 
(MMRM) Sensitivity 
Analysis 
9.4.5.1.2.3 Vonesh Shared 
Parameter Model 
9.4.5.2 Analyses of Secondary 
Efficacy Endpoints 
The text in strikethrough below has been 
deleted: 
“In addition, the patient-specific random 
intercept and slope will be added to the model 
with an unstructured variance-covariance 
matrix to model the correlations among 
repeated measurements within each patient.” 
To reflect the change in the 
proposed statistical model. 
9.4.5.2 Analysis of Secondary 
Efficacy Endpoints 
The text indicated below in strikethrough has 
been deleted: 
Change in Neurofilament light chain 
concentration 
Clarification in endpoint 
definition. 
Abbreviations: NfL = neurofilament light chain; OLE = Open-Label Extension; SoA = Schedule of Activities; 
VAFS = ventilation assistance-free survival 


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TABLE OF CONTENTS 
TITLE PAGE ...................................................................................................................................1 
PROTOCOL AMENDMENT SUMMARY OF CHANGES ..........................................................3 
TABLE OF CONTENTS .................................................................................................................8 
LIST OF TABLES .........................................................................................................................13 
LIST OF FIGURES .......................................................................................................................14 
1. 
PROTOCOL SUMMARY ..........................................................................................15 
1.1. 
Synopsis ......................................................................................................................15 
1.2. 
Schema ........................................................................................................................18 
1.3. 
Schedule of Activities (SoA) ......................................................................................19 
1.3.1. 
Screening to Week 50 .................................................................................................19 
1.3.2. 
Week 50 to Week 116 .................................................................................................25 
1.3.3. 
Week 124 to End of Study ..........................................................................................27 
2. 
INTRODUCTION ......................................................................................................29 
2.1. 
Study Rationale ...........................................................................................................29 
2.2. 
Background .................................................................................................................29 
2.2.1. 
Amyotrophic Lateral Sclerosis ...................................................................................29 
2.2.2. 
Complement Activation in ALS and Ravulizumab ....................................................30 
2.3. 
Benefit/Risk Assessment ............................................................................................31 
2.3.1. 
Risk Assessment .........................................................................................................31 
2.3.1.1. 
Coronavirus Disease 2019 ..........................................................................................32 
2.3.2. 
Benefit Assessment .....................................................................................................33 
2.3.3. 
Overall Benefit:Risk Conclusion ................................................................................33 
3. 
STUDY DESIGN .......................................................................................................34 
3.1. 
Overall Design ............................................................................................................34 
3.2. 
Scientific Rationale for Study Design ........................................................................34 
3.2.1. 
Study Population and Treatment Duration .................................................................34 
3.2.2. 
Rationale for Primary Endpoint: ALSFRS-R .............................................................36 
3.2.3. 
Rationale for Secondary Endpoints Included in the Multiplicity Adjustment ...........36 
3.2.3.1. 
Ventilation Assistance-Free Survival (VAFS) ...........................................................36 
3.2.3.2. 
Slow Vital Capacity (SVC) ........................................................................................36 


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3.3. 
Justification for Dose ..................................................................................................36 
3.4. 
End of Study Definition ..............................................................................................37 
4. 
OBJECTIVES AND ENDPOINTS ............................................................................38 
5. 
STUDY POPULATION .............................................................................................40 
5.1. 
Inclusion Criteria ........................................................................................................40 
5.2. 
Exclusion Criteria .......................................................................................................41 
5.3. 
Lifestyle Considerations .............................................................................................42 
5.4. 
Screen Failures ............................................................................................................42 
6. 
STUDY DRUG ...........................................................................................................44 
6.1. 
Study Drug(s) Administered .......................................................................................44 
6.2. 
Preparation/Handling/Storage/Accountability ............................................................46 
6.3. 
Measures to Minimize Bias: Randomization and Blinding ........................................46 
6.3.1. 
Randomization ............................................................................................................46 
6.3.2. 
Blinding ......................................................................................................................46 
6.4. 
Study Drug Compliance .............................................................................................47 
6.5. 
Concomitant Therapy .................................................................................................47 
6.5.1. 
Allowed Medications and Therapies ..........................................................................47 
6.5.1.1. 
Palliative and Supportive Care ...................................................................................47 
6.5.1.2. 
ALS-Specific Therapies ..............................................................................................48 
6.5.1.3. 
Other Allowed Therapies ............................................................................................48 
6.5.2. 
Disallowed Medications and Therapies ......................................................................48 
6.6. 
Dose Modification ......................................................................................................49 
6.7. 
Intervention after the End of the Study .......................................................................49 
7. 
DISCONTINUATION OF STUDY DRUG AND PATIENT 
DISCONTINUATION/WITHDRAWAL ..................................................................50 
7.1. 
Discontinuation of Study Drug ...................................................................................50 
7.2. 
Patient Discontinuation/Withdrawal from the Study ..................................................50 
7.3. 
Lost to Follow-up .......................................................................................................51 
8. 
STUDY ASSESSMENTS AND PROCEDURES ......................................................52 
8.1. 
General Assessments ..................................................................................................52 
8.1.1. 
Medical History and ALS History and Diagnosis ......................................................52 
8.1.2. 
Vaccine and Antibiotic Prophylaxis ...........................................................................52 
8.1.3. 
Inclusion/Exclusion Criteria .......................................................................................53 


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8.1.4. 
Study Drug Administration .........................................................................................53 
8.1.4.1. 
Randomized Controlled Period ...................................................................................54 
8.1.4.2. 
Open-Label Extension Period .....................................................................................54 
8.1.5. 
Visits at Home or Alternative Healthcare Facilities ...................................................55 
8.2. 
Efficacy Assessments .................................................................................................55 
8.2.1. 
Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-
R) ................................................................................................................................55 
8.2.2. 
Ventilation Assistance-Free Survival (VAFS) ...........................................................55 
8.2.3. 
Slow Vital Capacity (SVC) ........................................................................................56 
8.2.4. 
Handheld Dynamometry (HHD) ................................................................................56 
8.2.5. 
Amyotrophic Lateral Sclerosis Assessment Questionnaire (ALSAQ-40) ..................56 
8.2.6. 
EuroQoL 5 Dimensions (EQ-5D-5L) .........................................................................57 
8.2.6.1. 
EQ-5D-5L Descriptive System ...................................................................................57 
8.2.6.2. 
EQ Visual Analogue Scale .........................................................................................57 
8.2.7. 
Short Form Health Survey (SF-36) .............................................................................57 
8.2.8. 
Treatment Satisfaction Questionnaire for Medication (TSQM) .................................57 
8.3. 
Safety Assessments .....................................................................................................57 
8.3.1. 
Physical Examinations ................................................................................................58 
8.3.2. 
Neurologic Examination .............................................................................................58 
8.3.3. 
Height and Weight ......................................................................................................58 
8.3.4. 
Vital Signs ..................................................................................................................58 
8.3.5. 
Electrocardiograms .....................................................................................................58 
8.3.6. 
Patient Safety Card .....................................................................................................59 
8.3.7. 
Prior and Concomitant Medication Review ...............................................................59 
8.3.7.1. 
Prior Medications ........................................................................................................59 
8.3.7.2. 
Concomitant Medications ...........................................................................................59 
8.3.8. 
Clinical Safety Laboratory Assessments ....................................................................60 
8.3.9. 
Suicidal Ideation and Behavior Risk Evaluation ........................................................60 
8.3.10. 
Pregnancy ...................................................................................................................61 
8.4. 
Adverse Events and Serious Adverse Events .............................................................61 
8.4.1. 
Time Period and Frequency for Collecting AE and SAE Information .......................61 
8.4.2. 
Method of Detecting AEs and SAEs ..........................................................................62 
8.4.3. 
Follow-up of AEs and SAEs .......................................................................................62 


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8.4.4. 
Regulatory Reporting Requirements for SAEs ...........................................................62 
8.4.5. 
Adverse Events of Special Interest .............................................................................62 
8.5. 
Treatment of Overdose ...............................................................................................63 
8.6. 
Pharmacokinetics and Pharmacodynamics .................................................................63 
8.7. 
Genetics ......................................................................................................................64 
8.8. 
Biomarkers ..................................................................................................................64 
8.8.1. 
Biomarker Research ....................................................................................................64 
8.8.2. 
Future Biomarker Research ........................................................................................64 
8.9. 
Immunogenicity Assessments ....................................................................................65 
8.10. 
Medical Resource Utilization and Health Economics ................................................65 
9. 
STATISTICAL CONSIDERATIONS .......................................................................66 
9.1. 
Statistical Hypotheses .................................................................................................66 
9.1.1. 
Primary Hypothesis ....................................................................................................66 
9.1.2. 
Secondary Hypotheses ................................................................................................66 
9.2. 
Sample Size Determination ........................................................................................66 
9.2.1. 
Stratification ...............................................................................................................67 
9.3. 
Populations for Analyses ............................................................................................67 
9.4. 
Statistical Analyses .....................................................................................................68 
9.4.1. 
Enrollment and Disposition ........................................................................................68 
9.4.2. 
Demographics, Baseline Characteristics, Inclusion and Exclusion Criteria, 
and Protocol Deviations ..............................................................................................68 
9.4.3. 
Medical/Surgical History, Physical Examination, and Amyotrophic Lateral 
Sclerosis History .........................................................................................................68 
9.4.4. 
Prior and Concomitant Medications ...........................................................................68 
9.4.5. 
Efficacy Analyses .......................................................................................................69 
9.4.5.1. 
Analyses of Primary Efficacy Endpoint .....................................................................69 
9.4.5.2. 
Analyses of Secondary Efficacy Endpoint(s) .............................................................70 
9.4.5.3. 
Analyses of Exploratory Endpoint(s) .........................................................................71 
9.4.5.4. 
Multiplicity Adjustment ..............................................................................................73 
9.4.6. 
Safety Analyses ..........................................................................................................73 
9.4.6.1. 
Analysis of Adverse Events ........................................................................................73 
9.4.6.2. 
Analysis of Clinical Laboratory Parameters, Vital Sign Measurements, 
Weight, and Electrocardiogram Parameters ...............................................................73 


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9.4.6.3. 
Other Safety Analyses ................................................................................................73 
9.4.7. 
Analysis of Pharmacokinetics and Pharmacodynamics, and Antidrug 
Antibody Analyses ......................................................................................................73 
9.4.8. 
Analysis of Exploratory Biomarkers ..........................................................................74 
9.5. 
Interim Analysis ..........................................................................................................74 
9.6. 
Delayed-Start Analysis of Long-term ALSFRS-R .....................................................74 
9.7. 
Data Monitoring Committee .......................................................................................74 
10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS ..................................................................................................76 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations ....................76 
10.1.1. 
Regulatory and Ethical Considerations ......................................................................76 
10.1.2. 
Financial Disclosure ...................................................................................................76 
10.1.3. 
Informed Consent Process ..........................................................................................77 
10.1.4. 
Data Protection ...........................................................................................................77 
10.1.5. 
Dissemination of Clinical Study Data ........................................................................78 
10.1.6. 
Data Quality Assurance ..............................................................................................78 
10.1.7. 
Source Documents ......................................................................................................79 
10.1.8. 
Study and Site Start and Closure ................................................................................79 
10.1.9. 
Publication Policy .......................................................................................................79 
10.2. 
Appendix 2: Clinical Laboratory Tests .......................................................................80 
10.3. 
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting ........................................................................82 
10.3.1. 
Adverse Event Definition ...........................................................................................82 
10.3.2. 
Serious Adverse Event Definition ..............................................................................83 
10.3.3. 
Recording and Follow-Up of Adverse Event and/or Serious Adverse Event ............83 
10.3.4. 
Reporting of Serious Adverse Events .........................................................................85 
10.4. 
Appendix 4: Contraceptive Guidance and Collection of Pregnancy 
Information .................................................................................................................86 
10.4.1. 
Definitions ..................................................................................................................86 
10.4.2. 
Contraception Guidance .............................................................................................86 
10.4.3. 
Collection of Pregnancy Information .........................................................................87 
10.4.3.1. 
Male Patients With Partners who Become Pregnant ..................................................88 
10.4.3.2. 
Female Patients who Become Pregnant ......................................................................88 
10.5. 
Appendix 5: El Escorial Criteria .................................................................................90 


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10.6. 
Appendix 6: Amyotrophic Lateral Sclerosis Functional Rating Scale-
Revised (ALSFRS-R) .................................................................................................91 
10.7. 
Appendix 7: Amyotrophic Lateral Sclerosis Assessment Questionnaire 
(ALSAQ-40) ...............................................................................................................93 
10.8. 
Appendix 8: EuroQoL 5 Dimensions (EQ-5D-5L) ..................................................102 
10.8.1. 
EQ-5D-5L Version for In-Clinic Use .......................................................................102 
10.8.2. 
EQ-5D-5L Version for Phone Interview ..................................................................105 
10.9. 
Appendix 9: Short Form Health Survey (SF-36) ......................................................109 
10.10. 
Appendix 10: Treatment Satisfaction Questionnaire for Medication (TSQM-
9) ...............................................................................................................................115 
10.11. 
Appendix 11: Columbia Suicide Severity Rating Scale  (C-SSRS) - 
Screening/Baseline ...................................................................................................118 
10.12. 
Appendix 12: Columbia-Suicide Severity Rating Scale (C-SSRS) - Since 
Last Visit ...................................................................................................................121 
10.13. 
Appendix 13: Management of Potential Infusion-Associated Adverse Events 
During Study Drug Administration ..........................................................................124 
10.14. 
Appendix 14: COVID-19 Risk Assessment .............................................................126 
10.15. 
Appendix 15: Abbreviations .....................................................................................128 
10.16. 
Appendix 16: Protocol Amendment History ............................................................130 
11. 
REFERENCES .........................................................................................................131 
LIST OF TABLES 
Table 1: 
Schedule of Activities: Screening to Week 50 ...........................................................19 
Table 2: 
Schedule of Activities: Week 50 to Week 116 ...........................................................25 
Table 3: 
Schedule of Activities: Week 124 to End of Study ....................................................27 
Table 4: 
Ravulizumab Identified and Potential Risks ...............................................................32 
Table 5: 
Study Drugs ................................................................................................................45 
Table 6: 
Weight-based Doses of Ravulizumab .........................................................................54 
Table 7:  
Stratification Scheme ..................................................................................................67 
Table 8: 
Analysis Sets ...............................................................................................................68 
Table 9: 
Protocol-Required Laboratory Assessments ...............................................................81 
Table 10: Clinical Criteria for Diagnosing Anaphylaxis ..........................................................125 
Table 11: Potential Risks and Mitigation Measures due to COVID-19 ...................................126 
Table 12: ALXN1210-ALS-308 Protocol History ...................................................................130 


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LIST OF FIGURES 
Figure 1: 
Study Design Schematic .............................................................................................18 
 


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1. 
PROTOCOL SUMMARY 
1.1. 
Synopsis 
Protocol Title: A Phase 3, Double-Blind, Randomized, Placebo-Controlled, Parallel Group, 
Multicenter Study With an Open-Label Extension to Evaluate the Efficacy and Safety of 
Ravulizumab in Patients With Amyotrophic Lateral Sclerosis (ALS)  
Short Title: An Efficacy and Safety Study of Ravulizumab in ALS Patients 
Rationale: 
Amyotrophic lateral sclerosis (ALS) is a debilitating neurodegenerative disease characterized by 
progressive degeneration of upper and lower motor neurons leading to severe disability and 
eventually death. Currently, riluzole and edaravone are the only available medications approved 
for the treatment of ALS that may slow disease progression. Management of ALS is otherwise 
supportive, palliative, and symptom based. Given the seriousness of the disease and limitations 
of the available treatments, there is a substantial unmet need for developing additional treatments 
that are efficacious and safe for patients with ALS. 
The pathogenesis of ALS is largely unknown, but immune dysregulation and neuroinflammation 
have been implicated as potential mediators of disease. The therapeutic rationale for complement 
component 5 (C5) inhibition in ALS is supported by evidence of dysregulation of the 
complement system in tissue from patients with ALS. Furthermore, functional and survival 
benefits of C5 signaling blockade have been demonstrated in animal models of ALS. 
Ravulizumab (Ultomiris®) is a recombinant, humanized monoclonal antibody with high 
specificity for human C5. Ravulizumab has been shown to achieve immediate, complete, and 
sustained inhibition of terminal complement in adult patients with paroxysmal nocturnal 
hemoglobinuria (approved in the US, European Union, and Japan) and in pediatric and adult 
patients with atypical hemolytic uremic syndrome (approved in the US). It is expected that the 
same dosing regimen will also achieve comparable inhibition of complement-mediated damage 
in patients with ALS, which may slow ALS disease progression. The primary objective of this 
study is to investigate the efficacy and safety of ravulizumab in adult patients with ALS. 
Objectives and Endpoints: 
Objective 
Endpoints 
Primary 
To evaluate the effect of ravulizumab compared with 
placebo on amyotrophic lateral sclerosis functional rating 
scale-revised (ALSFRS-R) score in adult patients with 
amyotrophic lateral sclerosis (ALS) 
Change from baseline in ALSFRS-R total score at 
Week 50 
Secondary 
To evaluate the effect of ravulizumab compared with 
placebo on ventilation assistance-free survival (VAFS) in 
adult patients with ALS 
Time to the earliest occurrence of 1 of the following 
events during the 50-week Randomized Controlled 
Period: 
• All-cause mortality 
• First use of non-invasive ventilation (NIV) for 
≥ 22 hours per day for ≥ 10 consecutive days 
• First use of permanent assisted ventilation (PAV) for 
≥ 22 hours per day for ≥ 7 consecutive days 


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Objective 
Endpoints 
To evaluate the effect of ravulizumab compared with 
placebo on respiratory function in adult patients with 
ALS  
Change from baseline in percent (%) predicted slow 
vital capacity (SVC) at Week 50 
To evaluate the safety of ravulizumab compared with 
placebo in adult patients with ALS 
Incidence of treatment-emergent adverse events 
(TEAEs), treatment-emergent serious adverse events 
(TESAEs), and TEAEs leading to study drug 
discontinuation  
To evaluate the effect of ravulizumab compared with 
placebo on muscle strength in adult patients with ALS 
Percent change in combined muscle megascore from 
baseline at Week 50 as assessed by handheld 
dynamometry (HHD) 
To evaluate the effect of ravulizumab compared with 
placebo on neurofilament light chain (NfL) 
concentrations in adult patients with ALS 
NfL concentration in serum at Week 50 
To characterize the pharmacokinetics (PK) of 
ravulizumab in adult patients with ALS 
Change in serum ravulizumab concentration over the 
study duration 
To characterize the pharmacodynamics (PD) of 
ravulizumab in adult patients with ALS 
Change in serum free complement component 5 (C5) 
concentration over the study duration 
To characterize the immunogenicity of ravulizumab in 
adult patients with ALS  
Presence and titer of antidrug antibodies (ADAs) 
Overall Design 
Study ALXN1210-ALS-308 is a Phase 3, double-blind, randomized, placebo-controlled, parallel 
group, multicenter study to evaluate the efficacy and safety of ravulizumab in adult patients with 
ALS. There are 3 periods in this study: Screening Period, Randomized Controlled Period, and 
Open-Label Extension Period. 
Patients will be screened for eligibility for up to 4 weeks during the Screening Period. 
Approximately 354 eligible adult patients with ALS from North America, Europe, and the 
Asia-Pacific region will be enrolled into the study. Patients who are not taking or who are on a 
stable regimen of riluzole and/or edaravone at screening will be considered for participation. 
Eligible patients will be randomized in a 2:1 ratio to receive weight-based intravenous (IV) 
infusion of ravulizumab or matching placebo until Week 50 during the double-blind Randomized 
Controlled Period. Randomization will be stratified based on the site of ALS muscle weakness 
onset (bulbar vs other) and background ALS treatment (riluzole and/or edaravone vs neither ALS 
therapy). For each patient, the Randomized Controlled Period ends and the Open-Label 
Extension Period starts when the patient has completed the Week 50 visit assessments. 
Regardless of prior treatment allocation, all patients will receive ravulizumab treatment during 
the Open-Label Extension Period. The Open-Label Extension Period will continue for up to 
2 years, or until ravulizumab is approved and/or available (in accordance with country-specific 
regulations), whichever occurs first. Patients may be allowed to switch from the 10 mg/mL to the 
100 mg/mL formulation of ravulizumab with no change to the weight-based dose regimen at or 
after Week 52 in the OLE Period. After the end of treatment visit or early discontinuation (ED), 
patients will be followed for an additional 8 weeks after their last dose of study drug. Treatment 
allocation will be blinded to patients, study site, the Sponsor, and the Sponsor’s delegates 
throughout the Randomized Controlled Period. Blind to prior assignment will be maintained for 
patients and providers during the Open-Label Extension Period until end of the study. 
One interim analysis for futility is planned during the Randomized Controlled Period. An 
independent data monitoring committee will be established to conduct the unblinded interim 


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analysis and periodic review of accumulating data for patient safety and efficacy during the 
study. 
Disclosure Statement: This is a parallel group intervention study with 2 treatment arms 
followed by an Open-Label Extension Period.  
Number of Patients: 
Approximately 354 eligible adult patients will be enrolled. 
Intervention Groups and Duration: 
Eligible patients will be enrolled into the study and will be randomized in a 2:1 ratio to receive 
IV ravulizumab or placebo. 
The study drug dose for each patient will be based on body weight. The dosing regimen consists 
of a loading dose followed by maintenance doses administered every 8 weeks (q8w). The 
maintenance dosing should be initiated 2 weeks after the loading dose administration. 
For each patient, the total duration of study participation will be up to 160 weeks, including the 
Screening Period (up to 4 weeks), the Randomized Controlled Period (50 weeks), and the 
Open-Label Extension Period (up to 106 weeks). 
Data Monitoring Committee: Yes


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1.2. 
Schema 
Figure 1: 
Study Design Schematic 
 
Abbreviations: ALS = amyotrophic lateral sclerosis; PD = pharmacodynamics; PK = pharmacokinetics; q8w = every 8 weeks 
a  During the double-blind Randomized Controlled Period, patients will receive a weight-based loading dose of ravulizumab or matching placebo on Day 1, 
followed by a weight-based maintenance dose on Day 15, then q8w up to Week 42 (inclusive). 
b  During the Open-Label Extension Period, patients in the ravulizumab group will continue to receive ravulizumab, with a blinded 900 mg dose at Week 50, 
followed by an open-label ravulizumab maintenance dose at Week 52, then open-label ravulizumab maintenance doses q8w until the end of Open-Label 
Extension Period when all patients have completed up to 106 weeks of treatment or ravulizumab is approved and/or available (in accordance with 
country-specific regulations). 
c  During the Open-Label Extension (OLE) Period, patients in the placebo group will switch treatment to receive ravulizumab, with a blinded loading dose at 
Week 50, followed by an open-label maintenance dose at Week 52. Patients may be allowed to switch from the 10 mg/mL to the 100 mg/mL formulation of 
ravulizumab with no change to the weight-based dose regimen at or after Week 52 in the OLE Period. Patients will continue to receive open-label ravulizumab 
maintenance doses q8w until the end of the Open-Label Extension Period when all patients have completed up to 106 weeks of treatment or ravulizumab is 
approved and/or available (in accordance with country-specific regulations).  
d  The Randomized Controlled Period ends when all patients have completed the Week 50 visit. The primary analysis will be conducted based on the efficacy, 
safety, and PK/PD/immunogenicity data from the Randomized Controlled period to support the registration of ravulizumab for the treatment of ALS. 
e  One interim analysis for futility is planned during the Randomized Controlled Period (Section 9.5). The interim analysis for futility will be conducted when 
approximately 33% patients have completed the Week 26 (6 months) visit. The study may be stopped if considered futile. 


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1.3. 
Schedule of Activities (SoA) 
1.3.1. 
Screening to Week 50 
Table 1: 
Schedule of Activities: Screening to Week 50 
Period 
Screen
-ing 
Randomized Controlled Period 
Notes 
Visita 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12b 
13 
Additional visits can be 
performed as needed. An ED 
Visit should be performed if 
patients discontinue early. 
Week 
Up to  
4 W 
  
W2 
W6 
W10 
W14 
W18 
W22 
W26 
W34 
W42 
W46 
W50/ 
ED in 
RCPc 
Days and 
Window 
  
D1 
D15 
± 2 
D43 
± 3 
D71 
± 3 
D99 
± 3 
D127 
± 3 
D155 
± 3 
D183 
± 3 
D239 
± 3 
D295 
± 3 
D323 
± 3 
D351 
± 3  
General Assessments/Procedures 
Informed 
consent 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
Medical history 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
ALS history/ 
diagnosis 
X 
  
  
  
  
  
  
  
 
  
  
  
 
KSS  
X  
 
 
 
 
 
 
 
X 
 
 
 
X 
 
Inclusion/ 
exclusion 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
Demographics 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
Weightd 
X 
X 
X 
  
X 
  
X 
  
X 
X 
X 
  
X 
  
Height 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
Neisseria 
meningitidis 
vaccination 
X 
  
  
  
  
  
  
  
  
  
  
  
  
Vaccination against 
meningococcal infection, and 
revaccination during the 
study if needed 
(Section 8.1.2). 
HIV test 
X 
  
  
  
  
  
  
  
  
  
  
  
  
Including HIV-1 and HIV-2. 


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Table 1: 
Schedule of Activities: Screening to Week 50  
Period 
Screen
-ing 
Randomized Controlled Period 
Notes 
Visita 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12b 
13 
Additional visits can be 
performed as needed. An ED 
Visit should be performed if 
patients discontinue early. 
Week 
Up to  
4 W 
  
W2 
W6 
W10 
W14 
W18 
W22 
W26 
W34 
W42 
W46 
W50/ 
ED in 
RCPc 
Days and 
Window 
  
D1 
D15 
± 2 
D43 
± 3 
D71 
± 3 
D99 
± 3 
D127 
± 3 
D155 
± 3 
D183 
± 3 
D239 
± 3 
D295 
± 3 
D323 
± 3 
D351 
± 3  
Pregnancy test  
(WOCBP only) 
X 
X 
X 
  
X 
  
X 
  
X 
X 
X 
  
X 
Local urine testing will be 
standard for the protocol 
unless serum testing is 
required by local regulation 
or ethics committees. Testing 
at indicated visits and when 
necessary at Investigator’s 
discretion (Section 8.3.10). 
General Assessments/Procedures 
Dispense patient 
safety card  
X 
  
  
  
  
  
  
  
  
  
  
  
  
Instruct patients to carry 
safety card at all times and 
bring it to the scheduled 
visits.  
Efficacy Assessments 
ALSFRS-Re,f 
X 
X 
X 
H 
X 
H 
X 
H 
X 
X 
X 
 
X 
Collect in clinic (X) or by 
phone (H)h. 
SVCe,g 
X 
X 
X 
 
X 
 
X 
 
X 
X 
X 
 
X 
Collect in clinic and at homeg 
HHDe 
  
X 
 
 
X 
  
 
  
X 
 
 
  
X 
 
Ventilator 
utilization 
X 
X 
X 
H 
X 
H 
X 
H 
X 
X 
X 
X 
X 
Collect in clinic (X) or by 
phone (H)h. 
ALSAQ-40 
X 
X 
  
  
 
  
 
  
X 
 
 
  
X 
 
EQ-5D-5Lf 
X 
X 
X  
H  
X 
H 
X 
H 
X 
X 
X 
 
X 
Collect in clinic (X) or by 
phone (H)h. 
SF-36 
X 
X 
  
  
 
  
 
  
X 
 
 
  
X 
TSQM 
 
X 
 
 
 
 
 
 
X 
 
 
 
X 
 


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Table 1: 
Schedule of Activities: Screening to Week 50 
Period 
Screen
-ing 
Randomized Controlled Period 
Notes 
Visita 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12b 
13 
Additional visits can be 
performed as needed. An ED 
Visit should be performed if 
patients discontinue early. 
Week 
Up to  
4 W 
  
W2 
W6 
W10 
W14 
W18 
W22 
W26 
W34 
W42 
W46 
W50/ 
ED in 
RCPc 
Days and 
Window 
  
D1 
D15 
± 2 
D43 
± 3 
D71 
± 3 
D99 
± 3 
D127 
± 3 
D155 
± 3 
D183 
± 3 
D239 
± 3 
D295 
± 3 
D323 
± 3 
D351 
± 3  
Safety Assessments 
Neurologic 
examination 
X 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
Physical 
examination 
X 
X  
  
  
  
  
  
  
  
  
  
  
X  
An abbreviated physical 
examination can be 
performed at any visit after 
Day 1. 
Vital signs 
X 
X 
X 
 
X 
 
X 
 
X 
X 
X 
 
X 
 
ECG 
X 
 
  
  
  
  
  
  
X 
  
  
  
X 
 
Prior 
medications and 
procedures 
X 
 
 
Concomitant 
medications and 
procedures 
 
Continuous monitoring 
 
AEs 
Continuous monitoring 
 
Safety Assessments 
 
Clinical 
laboratory tests 
X 
X 
X 
 
X 
 
X 
 
X 
X 
X 
 
X 
Coagulation panel required at 
screening (W18, and W42 
required only for patients in 
optional CSF cohort). 
Patient safety 
card review 
 
X 
X 
 
X 
 
X 
 
X 
X 
X 
 
X 
 


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Table 1: 
Schedule of Activities: Screening to Week 50 
Period 
Screen
-ing 
Randomized Controlled Period 
Notes 
Visita 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12b 
13 
Additional visits can be 
performed as needed. An ED 
Visit should be performed if 
patients discontinue early. 
Week 
Up to  
4 W 
  
W2 
W6 
W10 
W14 
W18 
W22 
W26 
W34 
W42 
W46 
W50/ 
ED in 
RCPc 
Days and 
Window 
  
D1 
D15 
± 2 
D43 
± 3 
D71 
± 3 
D99 
± 3 
D127 
± 3 
D155 
± 3 
D183 
± 3 
D239 
± 3 
D295 
± 3 
D323 
± 3 
D351 
± 3  
C-SSRSe 
  
B 
  
 
X 
 
X 
 
X 
X 
X 
 
X 
C-SSRS Screening/baseline 
version (B) to be performed 
at Day 1 and Since Last Visit 
version (X) at all other 
timepoints. 
Pharmacokinetic and Pharmacodynamic Assessments 
Blood samples 
for PK/free C5  
 
B/P 
T/P 
  
T/P 
  
T/P 
 
T/P 
T/P 
T/P 
 
T 
At ED visit, samples can be 
anytime. 
Blood samples 
for ADA 
 
B 
 
  
T 
  
  
  
T 
  
  
  
T 
At ED visit, samples can be 
anytime. 
Biomarker Research 
Blood samples 
for biomarker 
 
B 
T 
 
T 
 
 
 
T 
T 
 
 
T 
At ED visit, samples can be 
anytime. 
Blood samples 
for DNA and 
RNA  
 
B 
T 
 
 
 
 
 
T 
 
 
 
 
Optional; collect samples 
from patients who consent to 
DNA and RNA collection. 
The blood sample for RNA is 
collected at all time points 
and the blood sample for 
DNA is collected on Day 1.i  
Urine samples 
for biomarkers 
 
X 
X 
  
 
  
  
 
X 
 
  
  
X 
 


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Table 1: 
Schedule of Activities: Screening to Week 50 
Period 
Screen
-ing 
Randomized Controlled Period 
Notes 
Visita 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12b 
13 
Additional visits can be 
performed as needed. An ED 
Visit should be performed if 
patients discontinue early. 
Week 
Up to  
4 W 
  
W2 
W6 
W10 
W14 
W18 
W22 
W26 
W34 
W42 
W46 
W50/ 
ED in 
RCPc 
Days and 
Window 
  
D1 
D15 
± 2 
D43 
± 3 
D71 
± 3 
D99 
± 3 
D127 
± 3 
D155 
± 3 
D183 
± 3 
D239 
± 3 
D295 
± 3 
D323 
± 3 
D351 
± 3  
CSF Cohort Sample Collection (Optional for Consenting Patients) 
CSF samples for 
PK/free C5 and 
biomarkersj 
B 
 
  
  
  
  
  
X 
  
  
  
X 
  
Participation in CSF cohort is 
optional; after consenting, 
samples are collected at all 
timepoints indicated. 
Blood samples 
for PK/free C5 
and biomarkers 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
Administration of Study Drug 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Ravulizumab or 
placebo 
  
X 
X 
  
X 
  
X 
  
X 
X 
X 
  
  
Administer after all other 
required tests/procedures. 
Note: B = baseline (Day 1); P = postdose; T = trough (predose); X = anytime. 
Abbreviations: ADA = antidrug antibody; AE = adverse event; ALSAQ-40 = amyotrophic lateral sclerosis assessment questionnaire; ALSFRS-R = amyotrophic lateral sclerosis 
functional rating scale-revised; CBC = complete blood count; CSF = cerebrospinal fluid; C-SSRS = Columbia-suicide severity rating scale; ECG = electrocardiogram; ED = 
early discontinuation; EQ-5D-5L = European Quality of Life Health 5-item questionnaire; HHD = handheld dynamometry; KSS = King’s staging system; 
PK = pharmacokinetics; RCP = Randomized Controlled Period; SF-36 = short form health survey; SVC = slow vital capacity; TSQM = Treatment Satisfaction Questionnaire for 
Medication; W = week; WOCBP = women of childbearing potential 
a Under reasonable occasional circumstances where a patient is not able to attend a study visit on site, a home visit (where available) or visit at an alternative healthcare facility 
may be permitted by the Sponsor after discussing with the Alexion Medical Monitor (or delegate). This will be a case-by-case decision (Section 8.1.5). 
b This visit is optional. It should be completed only by patients who consent to optional CSF collection. 
c  For patients who discontinue the study prior to the end of the Randomized Controlled Period, the ED in RCP visit should be completed as soon as possible. In addition, a Follow-
up Phone Call will be performed 8 weeks (56 days) ± 5 days following the patient’s last dose of study drug to collect concomitant medications, nonpharmacological therapies 
and procedures, VAFS, and AEs. 
d  Ravulizumab dosing is based on the last recorded study visit body weight. When possible, weights should be obtained at every dosing visit; consecutive weights must not be 
more than 16 weeks apart. 
e  Performed by the Investigator or any designee who has been properly trained and certified for the evaluation, preferably the same Investigator or designee, throughout the study. 
When possible, ALSFRS-R should be performed first, SVC second, and HHD should be performed as last assessment prior to dosing. 
f At the time points specified, or if a patient is not able to attend the scheduled onsite visit, the ALSFRS-R and EQ-5D-5L can be assessed via a phone call by the Investigator or 
trained designee. 


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g In addition to SVC in the clinic, home SVC (where regionally available) should be performed using a provided spirometer and under the direction of study staff properly trained 
for the evaluation (Section 8.2.3). In the event that an SVC measurement cannot be obtained in the clinic due to the COVID-19 pandemic, only home evaluation is required for 
that visit. Home SVC at screening should be performed after informed consent and after the patient has received training on the spirometer. For subsequent visits, including Day 
1, home SVC should be performed within 3 days prior to the scheduled clinic visit. 
h  Assessments denoted by H can be performed in clinic, by home visit, or by telephone contact. When performed by telephone, the telephone interview version of the 
questionnaire should be used, if available. 
i If Day 1 sample collection is missed, the DNA sample can be collected at any scheduled visit thereafter. 
j Most recent CBC and coagulation panel should be reviewed prior to CSF sample collection. Lumbar punctures must be performed after all assessments are completed and the 
investigator confirms the patient is eligible for randomization. 


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1.3.2. 
Week 50 to Week 116 
Table 2: 
Schedule of Activities: Week 50 to Week 116 
Period 
Open-Label Extension Period 
Notes 
Visita 
 
14 
15 
16 
17 
18 
19 
20 
21 
22 
Additional visits can be performed as needed. 
An ED Visit should be performed if patients 
discontinue early (Table 3). 
Week 
W50 
W52 
W60 
W68 
W76 
W84 
W92 
W100 
W108 
W116 
Days and Window 
D351 
± 3 
D365 
± 3 
D421 
± 7 
D477 
± 7 
D533 
± 7 
D589 
± 7 
D645 
± 7 
D701 
± 7 
D757 
± 7 
D813 
± 7 
General Assessments/Procedures 
Weightb 
  
X 
X 
X 
X 
X 
X 
X 
X 
 
  
Neisseria meningitidis 
vaccination 
  
  
  
  
  
  
  
  
  
  
Patients must be vaccinated against 
meningococcal infection, and revaccinated 
during the study if needed (Section 8.1.2). 
Pregnancy test (WOCBP 
only) 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urine test at indicated visits and when necessary 
at Investigator’s discretion (Section 8.3.10). 
Efficacy Assessments 
ALSFRS-Rc,d 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
SVCc,e 
  
 
X 
 
X 
 
X 
 
X 
 
Collect in clinic and at home.e SVC at Visit 21 
is optional, as patient condition permits. 
Ventilator utilization 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
EQ-5D-5Ld 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
Safety Assessments 
Neurologic examination 
 
 
 
 
X 
 
 
 
 
 
 
Abbreviated physical 
examination 
  
 
 
 
 
 
 
 
 
 
An abbreviated physical examination can be 
performed at any visit after Day 1. 
Vital signs 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
ECG 
  
  
  
  
  
  
X 
 
 
  
  
Concomitant medications  
Continuous monitoring 
  
AEs 
Continuous monitoring 
  
Clinical laboratory tests 
 
X 
 
X 
 
X 
 
X 
 
X 
  
Patient safety card review 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
C-SSRSc 
  
  
  
X 
  
X 
  
X 
X 
 
Perform C-SSRS since last visit assessment. 
Pharmacokinetic and Pharmacodynamic Assessments 
Blood samples for PK/free 
C5 
P 
T/P 
T/P 
  
 
T/P 
 
  
T/P 
  
 
Blood samples for ADA  
  
 
T 
  
 
T  
  
  
T 
  
 


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Table 2: 
Schedule of Activities: Week 50 to Week 116  
Period 
Open-Label Extension Period 
Notes 
Visita 
 
14 
15 
16 
17 
18 
19 
20 
21 
22 
Additional visits can be performed as 
needed. An ED Visit should be performed 
if patients discontinue early (Table 3). 
Week 
W50 
W52 
W60 
W68 
W76 
W84 
W92 
W100 
W108 
W116 
Days and Window 
D351 
± 3 
D365 
± 3 
D421 
± 7 
D477 
± 7 
D533 
± 7 
D589 
± 7 
D645 
± 7 
D701 
± 7 
D757 
± 7 
D813 
± 7 
Biomarker Research 
Blood samples for biomarker 
  
 
T 
 
 
T 
  
 
T 
  
 
Blood samples for DNA and 
RNA  
 
 
 
 
 
 
 
 
T 
 
Optional; samples collected from patients 
who consent to DNA and RNA collection. 
The blood sample for RNA is collected at 
all time points and the blood sample for 
DNA is collected on Day 1.f 
Urine samples for 
biomarkers 
  
 
X 
 
 
X 
  
 
X 
  
Administration of Study Drug 
Ravulizumabh 
Xg 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Administer after all other required 
tests/procedures. 
Note: P = postdose; T = trough (predose); X = anytime. 
Abbreviations: ADA = antidrug antibody; AE = adverse event; ALSFRS-R = revised amyotrophic lateral sclerosis functional rating scale; C5 = complement component 5; 
C-SSRS = Columbia-suicide severity rating scale; D = day; ECG = electrocardiogram; ED = early discontinuation; EQ-5D-5L = European Quality of Life Health 5-item 
questionnaire; HHD = handheld dynamometry; PK = pharmacokinetics; SVC = slow vital capacity; W = week; WOCBP = women of childbearing potential 
a Under reasonable occasional circumstances where a patient is not able to attend a study visit on site, a home visit (where available) or visit at an alternative healthcare facility 
may be permitted by the Sponsor after discussing with the Alexion Medical Monitor (or delegate). This will be a case-by-case decision (Section 8.1.5). 
b Ravulizumab dosing is based on the last recorded study visit body weight. When possible, weights should be obtained at every dosing visit; consecutive weights must not be 
more than 16 weeks apart. 
c Performed by the Investigator or any designee who has been properly trained and certified for the evaluation, preferably the same Investigator or designee, throughout the 
study. When possible, ALSFRS-R should be performed first, SVC second, and HHD should be performed as last assessment prior to dosing.  
d If a patient is not able to attend the scheduled onsite visit, the ALSFRS-R and EQ-5D-5L can be assessed via a phone call by the Investigator or trained designee. 
e In addition to SVC in the clinic, home SVC (where regionally available) should be performed using a provided spirometer and under the direction of study staff properly 
trained for the evaluation (Section 8.2.3). In the event that an SVC measurement cannot be obtained in the clinic due to the COVID-19 pandemic, only home evaluation is 
required for that visit. Home SVC at screening should be performed after informed consent and after the patient has received training on the spirometer. For subsequent visits, 
including Day 1, home SVC should be performed within 3 days prior to the scheduled clinic visit. 
f If Day 1 sample collection is missed, the DNA sample can be collected at any scheduled visit thereafter. 
g If this is an ED visit, no dose of study drug is given. 
h Patients may be allowed to switch from the 10 mg/mL to the 100 mg/mL formulation of ravulizumab with no change to the weight-based dose regimen at or after Week 52 in 
the Open-Label Extension (OLE) Period (Section 3.1). 


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1.3.3. 
Week 124 to End of Study 
Table 3: 
Schedule of Activities: Week 124 to End of Study 
Period 
Open-Label Extension Period 
Notes 
Visita 
23 
24 
25 
26 
27 
Additional visits can be performed as needed. An ED Visit 
should be performed if patients discontinue early. 
Week 
W124 
W132 
W140 
W148/ EOT 
W156/ 
EOS/ED 
in OLEb 
Days and Window 
D869 
± 7 
D925 
± 7 
D981 
± 7 
D1037 
± 7 
D1093 
± 7 
General Assessments/Procedures 
Weightc 
X 
 
X 
 
X 
  
Neisseria meningitidis vaccination 
  
  
  
  
  
Patients must be vaccinated against meningococcal 
infection, and revaccinated during the study if needed 
(Section 8.1.2). 
Pregnancy test (WOCBP only) 
X 
X 
X 
X 
X 
Urine test at indicated visits and when necessary at 
Investigator’s discretion (Section 8.3.10). 
Efficacy Assessments 
ALSFRS-Rd,e 
X 
X 
X 
X 
X 
 
SVCd,f 
X 
 
X 
 
X 
Collect in clinic and at home.f  
Optional as patient’s condition permits.  
Ventilator Utilization 
X 
X 
X 
X 
X 
 
EQ-5D-5Le 
X 
X 
X 
X 
X 
TSQM 
 
 
 
 
X 
 
Safety Assessments 
Neurologic examination 
 
 
 
 
X 
  
Abbreviated physical examination 
 
 
 
 
X 
An abbreviated physical examination can be performed at 
any visit after Day 1. 
Vital signs 
X 
X 
X 
X 
X 
  
ECG 
  
  
  
  
X 
  
Concomitant medications  
Continuous monitoring 
  
AEs 
Continuous monitoring 
  
Clinical laboratory tests 
X 
 
X 
 
X 
  
Patient safety card review 
X 
X 
X 
X 
X 
  
C-SSRSd 
X 
 
X 
 
X 
Perform C-SSRS since last visit assessment. 
Pharmacokinetic and Pharmacodynamic Assessments 
Blood samples for PK/free C5 
 
T/P 
 
 
X 
 
Blood samples for ADA 
 
T 
 
 
X 
 


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Table 3: 
Schedule of Activities: Week 124 to End of Study 
Period 
Open-Label Extension Period 
Notes 
Visita 
23 
24 
25 
26 
27 
Additional visits can be performed as needed. An ED Visit 
should be performed if patients discontinue early. 
Week 
W124 
W132 
W140 
W148/ EOT 
W156/ 
EOS/ED 
in OLEb 
Days and Window 
D869 
± 7 
D925 
± 7 
D981 
± 7 
D1037 
± 7 
D1093 
± 7 
Biomarker Research 
Blood samples for biomarkers 
 
T 
 
 
X 
 
Blood samples for DNA and RNA  
 
 
 
 
X 
Optional; samples collected from patients who consent to 
DNA and RNA collection. The blood sample for RNA is 
collected at all time points and the blood sample for DNA is 
collected on Day 1.g 
Urine biomarker samples 
 
X 
 
  
X 
Administration of Study Drug 
Ravulizumabh 
X 
X 
X 
X 
 
Administer after all other required tests/procedures. 
Note: P = postdose; T = trough (predose); X = anytime. 
Abbreviations: ADA = antidrug antibody; AE = adverse event; ALSFRS-R = revised amyotrophic lateral sclerosis functional rating scale; C5 = complement component 5; 
C-SSRS = Columbia-suicide severity rating scale; D = day; ECG = electrocardiogram; ED = early discontinuation; EOS = end of study; EQ-5D-5L = European Quality of Life 
Health 5-item questionnaire; OLE = Open-Label Extension; PK = pharmacokinetics;; SVC = slow vital capacity; TSQM= Treatment Satisfaction Questionnaire for Medication; 
W = week; WOCBP = women of childbearing potential 
a Under reasonable occasional circumstances where a patient is not able to attend a study visit on site, a home visit (where available) or visit at an alternative healthcare facility 
may be permitted by the Sponsor after discussing with the Alexion Medical Monitor (or delegate). This will be a case-by-case decision (Section 8.1.5). 
b Patients who discontinue the study during the open-label extension period, the ED in OLE visit should be completed as soon as possible. In addition, a Follow-up Phone Call will 
be performed 8 weeks (56 days) ± 5 days following the patient’s last dose of study drug to collect concomitant medications, nonpharmacological therapies and 
procedures,VAFS, and AEs. 
c Ravulizumab dosing is based on the last recorded study visit body weight. When possible, weights should be obtained at every dosing visit; consecutive weights must not be 
more than 16 weeks apart. 
d Performed by the Investigator or any designee who has been properly trained and certified for the evaluation, preferably the same Investigator or designee, throughout the study. 
When possible, ALSFRS-R should be performed first and SVC second.  
e If a patient is not able to attend the scheduled onsite visit, the ALSFRS-R and EQ-5D-5L can be assessed via a phone call by the Investigator or trained designee. 
f In addition to SVC in the clinic, home SVC (where regionally available) should be performed using a provided spirometer and under the direction of study staff properly trained 
for the evaluation (Section 8.2.3). In the event that an SVC measurement cannot be obtained in the clinic due to the COVID-19 pandemic, only home evaluation is required for 
that visit. Home SVC at screening should be performed after informed consent and after the patient has received training on the spirometer. For subsequent visits, including Day 
1, home SVC should be performed within 3 days prior to the scheduled clinic visit. 
g If Day 1 sample collection is missed, the DNA sample can be collected at any scheduled visit thereafter. 
h Patients may be allowed to switch from the 10 mg/mL to the 100 mg/mL formulation of ravulizumab with no change to the weight-based dose regimen at or after Week 52 in the 
Open-Label Extension (OLE) Period (Section 3.1). 


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2. 
INTRODUCTION 
2.1. 
Study Rationale 
Amyotrophic lateral sclerosis (ALS) is a debilitating neurodegenerative disease characterized by 
progressive degeneration of upper and lower motor neurons leading to severe disability and 
eventually death. Currently, riluzole and edaravone are the only available medications approved 
for the treatment of ALS that may slow disease progression. Management of ALS is otherwise 
supportive, palliative, and symptom based. Given the seriousness of the disease and limitations 
of the available treatments, there is a substantial unmet need for developing additional treatments 
that are efficacious and safe for patients with ALS. 
The pathogenesis of ALS is largely unknown, but immune dysregulation and neuroinflammation 
have been implicated as potential mediators of the disease. The therapeutic rationale for 
complement component 5 (C5) inhibition in ALS is supported by evidence of dysregulation of 
the complement system in tissues from patients with ALS. Furthermore, functional and survival 
benefits of C5 signaling blockade have been demonstrated in animal models of ALS. 
Ravulizumab (Ultomiris®) is a recombinant, humanized monoclonal antibody (mAb) with high 
specificity for human C5. Ravulizumab has been shown to achieve immediate, complete, and 
sustained inhibition of terminal complement in adult patients with paroxysmal nocturnal 
hemoglobinuria (PNH; approved in the US, EU, and Japan) and in pediatric and adult patients 
with atypical hemolytic uremic syndrome (aHUS; approved in the US). It is expected that the 
same dosing regimen will also achieve comparable inhibition of complement-mediated damage 
in patients with ALS, which may slow ALS disease progression. The primary objective of this 
study is to investigate the efficacy and safety of ravulizumab in adult patients with ALS. 
2.2. 
Background 
2.2.1. 
Amyotrophic Lateral Sclerosis 
Amyotrophic lateral sclerosis is a debilitating neurodegenerative disease characterized by 
progressive degeneration of upper and lower motor neurons leading to severe disability and 
eventually death. In Europe and North America, the incidence has been estimated as 1-3 per 
100,000 (Couratier, 2016; Orsini, 2015). The burden of ALS is substantial with an average life 
expectancy from symptom onset between 2 and 5 years (Mehta, 2018). Typically, the onset of 
ALS occurs in the fifth or sixth decade of life and is marked by a progressive loss of motor 
neurons leading to variable amounts of weakness and spasticity in the limb, bulbar, and 
respiratory muscles (Swinnen, 2014). Most patients present with limb onset, also referred to as 
spinal onset, with asymmetric painless weakness in a limb, but in approximately 20% of patients, 
weakness may be of bulbar onset manifesting as dysarthria or dysphagia. Bulbar onset patients 
have a poorer prognosis. Patients develop progressive disability limiting ambulation, 
communication, nourishment, and independence. Declining respiratory function can lead to 
respiratory insufficiency and failure which often is the cause for death, unless permanent 
mechanical ventilation is elected (Paulukonis, 2015). 


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The etiology of ALS is complex. Sporadic ALS, which occurs in individuals who have no 
apparent family history of the disease, comprises the majority of cases (85% – 90%) whereas 
familial ALS, with a Mendelian pattern of inheritance occurring in at least 2 people in the same 
family, accounts for a small fraction of all cases (10% – 15%) (Nowicka, 2019). Gene mutations 
in ALS have implicated multiple cellular processes in the pathogenesis of ALS, including defects 
in the regulation of protein homeostasis, RNA homeostasis, and cytoskeletal dynamics (Brown, 
2017). Downstream of these proximal events, abnormalities in protein and RNA aggregation, 
protein degradation, mitochondrial function, endoplasmic reticulum stress, nucleocytoplasmic 
transport, neuronal excitability, neuronal transport, immune regulation, and neuroinflammation 
may have negative influences on motor neuron viability in ALS (Beers, 2019; Brown, 2017). 
2.2.2. 
Complement Activation in ALS and Ravulizumab 
While the etiology of ALS is largely unknown, neuroinflammation may be a key event in disease 
pathology (Boillee, 2006; Kjaeldgaard, 2018). Immune dysregulation and neuroinflammation in 
both the central and peripheral nervous system are common features of familial and sporadic 
ALS and have negative influences on motor neuron viability in ALS (Beers, 2019). The 
complement system is a major component of the innate immune system that comprises more than 
30 proteins and plays an essential role in pathogen killing, stimulation of phagocytosis, 
chemoattraction of inflammatory cells, and disposal of self-debris (Chen, 2010). Upregulation of 
proximal and terminal components of the complement system and its regulators has been 
identified in the biofluids, neural tissue, and skeletal muscle of patients with ALS and has been 
corroborated by data from ALS animal models (Parker, 2019). Complement dysregulation likely 
occurs early in ALS pathogenesis as its deposition has been identified at the neuromuscular 
junction prior to nerve cell death, making it a potential mediator of the proposed “dying back” 
effect where motor neuron loss results from axonal damage at the neuromuscular junction  
(Bahia El Idrissi, 2016; Kjaeldgaard, 2018). Further, quantitative analyses in multiple ALS 
mouse models show that complement deposition increases over time and correlates with disease 
progression (Lee, 2017). 
Terminal complement, specifically, has been shown to play an important role in the pathology of 
ALS (Parker, 2019). While plasma levels of proximal complement are similar in ALS patients 
and normal controls, serum levels of the membrane attack complex, as well as serum and 
leukocyte levels of C5a, are increased in ALS patients (Mantovani, 2014). Terminal complement 
is also found to correlate with mediators of neuroinflammation in ALS. Inflammatory M1 
macrophages and microglia are associated with disease progression in ALS and these invading 
cells at the neuromuscular junction express the complement receptor C5aR1  
(Lee, 2017; Liao, 2012). Both pharmacologic inhibition and genetic deletion of C5aR1 receptor 
signaling diminishes recruitment of these inflammatory cells to affected tissue and potentially 
decreases denervation induced by inflammation (Lee, 2017). Inhibition of terminal complement 
can alter the course of disease in animal models of ALS. When transgenic hSOD1G93A mice and 
rats were treated with an inhibitor of C5aR1, both prior to symptom onset and at an early stage of 
disease, survival was prolonged. Functional benefit as evidenced by a delay in time to significant 
loss of hind limb strength was also observed. Similar results were observed in animals with a 
genetic knockout of the C5aR1 receptor, but not when proximal complement components such as 
C3 were targeted (Lobsiger, 2013; Woodruff, 2014). 


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The potential for terminal complement inhibition to modify disease progression of ALS is likely 
dependent on the ability to have a biological effect in the central nervous system (CNS) and 
neuromuscular junction. Evidence for a potent, selective C5 inhibitor to have biological activity 
on CNS inflammation is evident with the benefit that has been established for eculizumab 
(Soliris®) in the treatment of neuromyelitis optica spectrum disorder (NMOSD) (Soliris United 
States Prescribing Information [USPI]). In NMOSD, an inflammatory disorder of the CNS, 
treatment with the terminal complement inhibitor eculizumab significantly reduced the risk of 
relapse (Pittock, 2019). Treatment with eculizumab in NMOSD patients was further shown to 
produce immediate, complete, and sustained inhibition of serum terminal complement which was 
shown, in a small cohort of patients, to be mirrored in the cerebrospinal fluid (CSF)  
(Pittock, 2019; Pittock, 2013). Similarly, evidence for biological activity of selective C5 
inhibition at the neuromuscular junction has been demonstrated through the significant treatment 
effect of eculizumab in generalized myasthenia gravis (gMG) (Soliris USPI). In gMG, a 
neuroinflammatory disease of the neuromuscular junction, treatment with eculizumab 
significantly improved patient function in measures of activities of daily living and muscle 
weakness (Dhillon, 2018). Clinical development programs evaluating the efficacy and safety of 
ravulizumab for the treatment of patients with gMG and NMOSD are currently ongoing. 
Ravulizumab is a novel C5 inhibitor with the potential to alter the disease course of ALS. 
Ravulizumab has been shown to achieve immediate, complete, and sustained inhibition of 
terminal complement in patients with PNH and patients with aHUS, for which ravulizumab is 
approved in the US. The same dosing regimen is expected to achieve comparable inhibition of 
complement activation in patients with ALS, and it is hypothesized that this inhibition will slow 
disease progression in these patients through suppression of complement-induced central and 
peripheral neuroinflammation and associated neuronal death. 
2.3. 
Benefit/Risk Assessment 
2.3.1. 
Risk Assessment 
Based on clinical study experience and cumulative clinical study safety data of ravulizumab in 
PNH and aHUS, ravulizumab has been demonstrated to be well tolerated and safe, and exposure 
to ravulizumab in humans has not raised any unexpected safety concerns. 
Ravulizumab functions by blocking terminal complement; therefore, patients have increased 
susceptibility to serious infections, in particular Neisseria meningitidis (Table 4). Specific risk 
mitigation measures in place are described in Section 8.1.2. 
As with any therapeutic protein, administration of ravulizumab may lead to the development of 
antidrug antibodies (ADAs). Monitoring of immunogenicity is planned, as described in 
Section 8.9. Administration of any investigational product may result in infusion reactions. 
Management of potential infusion reactions is described in Section 10.13. 


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Table 4: 
Ravulizumab Identified and Potential Risks 
Risks of Clinical 
Significance 
Summary of Data/ 
Rationale for Risk 
Mitigation Strategy 
Identified risk 
Meningococcal infection 
Complement C5 inhibition is known to 
increase the susceptibility to infections 
caused by Neisseria meningitidis. 
Patients must be vaccinated or 
revaccinated according to current 
national vaccination guidelines for 
vaccination use prior to or at the time of 
initiating dosing with complement 
inhibitors (eg, eculizumab or 
ravulizumab). 
Potential risks 
Serious infection 
This potential risk is based on the mode of 
action of ravulizumab and experience with 
the use of eculizumab. Since the relevance 
of serious infection with ravulizumab 
therapy has not been confirmed in clinical 
studies, this remains a potential risk. 
Increased awareness of healthcare 
professionals and patients about the 
potential risk of serious infection. 
Monitoring for signs and symptoms of 
serious infections will be conducted as 
part of routine safety assessments for 
this study 
Immunogenicity  
Treatment with any therapeutic protein has 
the potential to induce an immune 
response. Potential clinical consequences 
may include severe hypersensitivity type 
reactions, decrease in efficacy and 
induction of autoimmunity, including 
antibodies to the endogenous form of the 
protein (Casadevall, 2002; Li, 2001). 
Protein therapies administered 
intravenously have the potential risk of 
causing local (infusion-site reactions) and 
systemic reactions (infusion-associated 
reactions). 
In PNH and aHUS patients (N = 333), 
only 2 (0.60%) treatment-emergent 
ADA have been reported with 
ravulizumab. Both were transient in 
nature and low titer, and no apparent 
correlation of antibody development to 
altered pharmacokinetic profile, clinical 
response, or adverse events was 
observed 
Pregnancy 
exposure/lactation 
No studies of ravulizumab have been 
conducted in pregnant women. There are 
no data available on excretion of 
ravulizumab in breast milk. 
Pregnant or nursing female patients are 
excluded from the clinical study. 
Patients enrolled in the study, and their 
spouses/partners, must use a highly 
effective or acceptable method of 
contraception for a period of 8 months 
following the last dose of ravulizumab. 
Breastfeeding should be discontinued 
during treatment and up to 8 months 
after treatment with ravulizumab. 
2.3.1.1. 
Coronavirus Disease 2019 
The coronavirus disease 2019 (COVID-19) pandemic is active in many countries at the time of 
this protocol amendment. Given this unique circumstance, specific consideration has been given 
to the risks and benefits of the study as they relate to COVID-19, and the global and local 
changes that exist as a result of the pandemic. This assessment is described in Section 10.14. 


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2.3.2. 
Benefit Assessment 
Amyotrophic lateral sclerosis is a devastating neurodegenerative disease with a poor prognosis, 
rapid progression, and limited treatment options for which discovery of new therapies is 
important to address unmet medical need. Clinical research provides the best modality to identify 
effective treatments with the potential to slow disease progression and improve survival which 
are of critical importance to patients with ALS and their providers. Although the efficacy of 
ravulizumab has not been previously studied in patients with ALS, it represents an appropriate 
candidate for investigation due to its plausible mechanism of action in ALS and reliable 
pharmacokinetic (PK) and pharmacodynamic (PD) properties as well as the demonstrable 
functional benefit of complement inhibition in ALS animal models and in the treatment of other 
neuroinflammatory conditions. The scientific and therapeutic hypothesis for the potential benefit 
in ALS is discussed in Section 2.2.2. 
2.3.3. 
Overall Benefit:Risk Conclusion 
Given the severity of ALS, collective consideration of the unmet medical need and plausible 
mechanism of action with the expected safety profile and mitigation measures in place provides 
support for initiation of a Phase 3 clinical study with ravulizumab. 
More detailed information about the known and expected benefits and risks and reasonably 
expected adverse events (AEs) of ravulizumab is provided in the Investigator’s Brochure. 
 


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3. 
STUDY DESIGN 
3.1. 
Overall Design 
Study ALXN1210-ALS-308 is a Phase 3, double-blind, randomized, placebo-controlled, parallel 
group, multicenter study to evaluate the efficacy and safety of ravulizumab in adult patients with 
ALS. There are 3 periods in this study: Screening Period, Randomized Controlled Period, and 
Open-Label Extension Period.  
Patients will be screened for eligibility for up to 4 weeks during the Screening Period. 
Approximately 354 eligible adult patients with ALS from North America, Europe, and the 
Asia-Pacific region will be enrolled into the study. Patients who are not taking or who are on a 
stable regimen of riluzole and/or edaravone at Screening will be considered for participation. 
Eligible patients will be randomized in a 2:1 ratio to receive weight-based intravenous (IV) 
infusion of ravulizumab or matching placebo until Week 50 during the double-blind Randomized 
Controlled Period. Randomization will be stratified based on the site of ALS muscle weakness 
onset (bulbar vs other) and background ALS treatment (riluzole and/or edaravone vs neither ALS 
therapy) (Section 9.2.1; Table 7). For each patient, the Randomized Controlled Period ends and 
the Open-Label Extension Period starts when the patient has completed the Week 50 visit 
assessments. Regardless of prior treatment allocation, all patients will receive ravulizumab 
treatment during the Open-Label Extension Period. The Open-Label Extension Period will 
continue for up to 2 years, or until ravulizumab is approved and/or available (in accordance with 
country-specific regulations), whichever occurs first. Patients may be allowed to switch from the 
10 mg/mL to the 100 mg/mL formulation of ravulizumab with no change to the weight-based 
dose regimen at or after Week 52 in the OLE Period. After the end of treatment visit or early 
discontinuation, patients will be followed for an additional 8 weeks after the last dose of study 
drug. Treatment allocation will be blinded to patients, study sites, and Alexion throughout the 
Randomized Controlled Period and will remain blinded to patients and study sites until end of 
the study. 
One interim analysis is planned during the Randomized Controlled Period (Section 9.5). An 
independent data monitoring committee (IDMC) will be established to conduct the unblinded 
interim analysis and periodic review of accumulating data for patient safety and efficacy during 
the study. The interim analysis for futility will be conducted when approximately 33% of 
patients have completed the Week 26 (6 months) visit. The study may be stopped if considered 
futile.  
3.2. 
Scientific Rationale for Study Design 
3.2.1. 
Study Population and Treatment Duration  
Neuroinflammation and complement dysregulation are hypothesized to be common pathways in 
both sporadic and familial ALS. Complement dysregulation may be important to disease 
progression both early and throughout the course of disease, and thus a broad study population is 
targeted. The eligible study population fulfills the El Escorial diagnostic criteria of possible, 
probable, probable laboratory supported, or definite ALS, is within 36 months or less from 
disease onset, and demonstrates a slow vital capacity (SVC) of 65% predicted or more and not 
yet requiring respiratory support. Given that the typical time from onset of muscle weakness to 


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diagnosis is approximately 1 year, these characteristics will likely permit enrollment of patients 
in the early to mid-stages with mild to moderate manifestations of the disease. Given the 
heterogenous nature of ALS, including rates of disease progression across patients, a minimal 
prestudy progression criteria of 0.3 points per month or worse on the amyotrophic lateral 
sclerosis functional rating scale-revised (ALSFRS-R), calculated as (48 – ALSFRS-R at 
Screening)/(months from onset to Screening) will be used to enrich for patients more likely to 
demonstrate disease progression in the course of the study. The selected population is 
hypothesized to better allow for the potential detection of a treatment benefit. 
A randomized, double-blind, placebo-controlled study design is selected to provide the most 
robust evidence of the effectiveness of the intervention on disease progression and safety. 
Randomization minimizes the effects of baseline differences and confounding factors on the 
study population. The use of a placebo comparator allows for the true treatment effect of the 
intervention to be established while also allowing for study management, drug administration, 
and assessments to be conducted similarly between treatment groups, thus minimizing the 
potential for bias. An unequal randomization scheme was chosen to decrease the number of 
patients receiving placebo. Patients may continue to receive standard of care treatment for ALS, 
which may include riluzole and/or edaravone as detailed in the inclusion/exclusion criteria. To 
reduce the heterogeneity in the study results, a stratification scheme has been implemented. This 
stratification includes the use of background therapies which are permitted, but not mandated, in 
accordance with ethical standards. 
A 50-week primary evaluation period was selected to ensure characterization of effects on 
multiple functional and survival endpoints. This timeframe allows for a rigorous assessment of 
ALSFRS-R in which potential differences can both be detected and characterized for magnitude 
and durability of response. The 50-week treatment period also allows the opportunity to 
characterize potential treatment effects on other important endpoints, such as survival, which 
may take longer to demonstrate than the ALSFRS-R.  
A study design with an interim analysis was chosen to allow consideration for early stopping in 
the case of futility, which would minimize the duration of exposure to an ineffective therapy. 
An OLE Period was chosen to ensure that all patients participating in this study have the 
opportunity to receive active treatment after the completion of the Randomized Controlled 
Period of the study. This period also allows for further evaluation of longer term safety and 
efficacy of the study intervention. 
In this study patients may be allowed to switch from the 10 mg/mL to the 100 mg/mL 
formulation of ravulizumab with no change to the weight-based dose regimen during the OLE 
Period. The 100 mg/mL IV formulation of ULTOMIRIS® (ravulizumab) was approved in 2020 
by the FDA and the European Commission for the treatment of paroxysmal nocturnal 
hemoglobinuria (PNH) and atypical hemolytic uremic syndrome (aHUS). The 100 mg/mL 
ravulizumab is a higher concentration IV formulation which provides shorter preparation and 
infusion times while delivering comparable PK, safety and efficacy to the 10 mg/mL formulation 
of ravulizumab. Clinical data from Study ALXN1210-PNH-201 and Study 
ALXN1210-PNH-302 shows no change in the benefit/risk profile of ravulizumab following 
administration of the approved weight-based doses of ravulizumab using the 100 mg/mL 
formulation in patients with PNH.  


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3.2.2. 
Rationale for Primary Endpoint: ALSFRS-R 
The ALSFRS-R is a validated instrument and the most widely used instrument to measure 
physical function in performance of daily living activities across the 4 domains of gross motor 
activity, fine motor activity, bulbar, and respiratory function in patients with ALS  
(Cedarbaum, 1999; Section 8.2.1). The scale is composed of 12 items with a maximum score of 
48, with lower scores associated with declining function. Changes in ALSFRS-R total score have 
been shown to be reproducible over time and to correlate with survival and other functional 
measures. It is considered an important efficacy endpoint in clinical studies and clinical practices 
(Castrillo-Viguera, 2010).  
3.2.3. 
Rationale for Secondary Endpoints Included in the Multiplicity Adjustment 
3.2.3.1. 
Ventilation Assistance-Free Survival (VAFS) 
Survival is accepted as a clinically relevant outcome measure in ALS clinical studies. However, 
overall survival in ALS can be significantly influenced by the use of noninvasive ventilation 
(NIV) or permanent assisted ventilation (PAV) which can prolong overall survival without 
altering the underlying disease pathology. To account for the prolongation of survival in the 
absence of disease modification, ventilation assistance-free survival (VAFS), a composite 
endpoint accounting for survival and severe respiratory failure, is defined. In the absence of 
uniform guidelines for the initiation of NIV and PAV, this endpoint is defined around 
dependence based on the continuous or nearly continuous need for ventilation assistance. 
Therefore, VAFS is defined for this study as the time to the earliest occurrence of one of the 
following events: all-cause mortality; first use of NIV for ≥ 22 hours per day for 
≥ 10 consecutive days; or first use of PAV for ≥ 22 hours per day for ≥ 7 consecutive days.  
3.2.3.2. 
Slow Vital Capacity (SVC) 
Slow vital capacity is defined as the amount of air expelled from the lungs during a slow, gentle 
breath, which has been shown to correlate with clinical events such as use of assisted ventilation, 
tracheostomy, and ultimately, death. Patients with slower decline in SVC could breathe 
unassisted and survive longer than patients whose SVC declined faster (Andrews, 2018). 
Compared with forced vital capacity (FVC), SVC may be easier to measure in ALS patients as 
patients with loss of muscle function in the face and mouth are still able to perform the gentler 
test and it is less subject to the fatigue and bronchospasm that can underestimate lung capacity 
measured by FVC. 
Slow vital capacity is considered as a prognostic marker in the clinic and may predict disease 
progression, respiratory functional decline, and survival. 
3.3. 
Justification for Dose 
The dosing regimen of ravulizumab was designed to target immediate, complete, and sustained 
inhibition of terminal complement in patients. The weight-based doses of ravulizumab in the 
PNH program were based on PK/PD data from early and late clinical development studies in 
healthy adult volunteers and patients with PNH. The proposed ravulizumab dosage regimen is 
the approved regimen for the treatment of patients with PNH and aHUS in the Ultomiris USPI, 
the European Commission in the EU and the Pharmaceuticals and Medical Devices Agency in 


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Japan. In ALS patients and preclinical models, dysregulation of the complement system has been 
identified prior to the onset of neurodegeneration. Inhibition of terminal complement may 
therefore diminish neuroinflammatory damage in ALS. Based on this and the PK, PD, ADA, 
efficacy, and safety data generated in the ravulizumab development program, the body weight-
based dosage regimen for treating adult patients with PNH and aHUS has been selected for this 
study, and is expected to be beneficial in treating patients with ALS through immediate, 
complete and sustained inhibition of terminal complement activation. 
3.4. 
End of Study Definition 
A patient is considered to have completed the study if he/she has completed all phases of the 
study including the last scheduled procedure shown in the Schedule of Activities (SoA; 
Section 1.3). 
The end of the study is defined as the date the last patient completes the last visit shown in the 
SoA. 


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4. 
OBJECTIVES AND ENDPOINTS 
Objective 
Endpoints 
Primary 
To evaluate the effect of ravulizumab compared with 
placebo on amyotrophic lateral sclerosis functional rating 
scale-revised (ALSFRS-R) score in adult patients with 
amyotrophic lateral sclerosis (ALS) 
Change from baseline in ALSFRS-R total score at 
Week 50 
Secondary 
To evaluate the effect of ravulizumab compared with 
placebo on ventilation assistance-free survival (VAFS) in 
adult patients with ALS 
Time to the earliest occurrence of 1 of the following 
events during the 50-week Randomized Controlled 
Period: 
• All-cause mortality 
• First use of non-invasive ventilation (NIV) for 
≥ 22 hours per day for ≥ 10 consecutive days 
• First use of permanent assisted ventilation (PAV) for 
≥ 22 hours per day for ≥ 7 consecutive days 
To evaluate the effect of ravulizumab compared with 
placebo on respiratory function in adult patients with 
ALS  
Change from baseline in percent (%) predicted slow vital 
capacity (SVC) at Week 50 
To evaluate the safety of ravulizumab compared with 
placebo in adult patients with ALS 
Incidence of treatment-emergent adverse events 
(TEAEs), treatment-emergent serious adverse events 
(TESAEs), and TEAEs leading to study drug 
discontinuation  
To evaluate the effect of ravulizumab compared with 
placebo on muscle strength in adult patients with ALS 
Percent change in combined muscle megascore from 
baseline at Week 50 as assessed by handheld 
dynamometry (HHD) 
To evaluate the effect of ravulizumab compared with 
placebo on neurofilament light chain (NfL) concentration 
in adult patients with ALS 
NfL concentration in serum at Week 50 
To characterize the pharmacokinetics (PK) of 
ravulizumab in adult patients with ALS 
Change in serum ravulizumab concentration over the 
study duration 
To characterize the pharmacodynamics (PD) of 
ravulizumab in adult patients with ALS 
Change in serum free complement component 5 (C5) 
concentration over the study duration 
To characterize the immunogenicity of ravulizumab in 
adult patients with ALS  
Presence and titer of antidrug antibodies (ADAs)  
Exploratory  
To evaluate the effect of ravulizumab compared with 
placebo on respiratory function in adult patients with 
ALS  
Time to first instance of SVC < 50% predicted during the 
50-week Randomized Controlled Period 
To evaluate the effect of ravulizumab compared with 
placebo on overall health-related quality of life in adult 
patients with ALS 
• Change from baseline in Short Form Health Survey 
(SF-36) at Week 50 
• Change from baseline in European Quality of Life 
Health 5-item questionnaire (EQ-5D-5L) at Week 50 
To evaluate the safety of ravulizumab compared with 
placebo in adult patients with ALS 
• Shifts from baseline in Columbia-suicide severity 
rating scale (C-SSRS) at Week 50 
• Change from baseline in vital signs, electrocardiogram 
(ECG) parameters, and clinical laboratory assessments  
To characterize biomarkers in adult patients with ALS 
Change from baseline in levels of biomarkers of 
complement dysregulation, neuroinflammation and 
neurodegeneration 


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Objective 
Endpoints 
To evaluate the effect of ravulizumab compared with 
placebo on ALS-related health quality of life in adult 
patients with ALS 
Change from baseline in ALS assessment questionnaire 
(ALSAQ-40) score at Week 50 
To characterize the effect of ravulizumab compared to 
placebo on disease stage in adult patients with ALS 
Any increase from baseline stage on the King’s staging 
system at Week 50 
To evaluate the long-term efficacy of ravulizumab in 
adult patients with ALS 
Change in ALSFRS-R total score, VAFS, SVC, HHD, 
and patient-reported outcome measures over time in all 
patients exposed to ravulizumab during the Open-Label 
Extension Period 
To evaluate the long-term safety of ravulizumab in adult 
patients with ALS 
Incidence of TEAEs, TESAEs, and TEAEs leading to 
study drug discontinuation during the Open-Label 
Extension Period 


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5. 
STUDY POPULATION 
Prospective approvals of protocol deviations to enrollment criteria, also known as protocol 
waivers or exemptions, are not permitted. 
5.1. 
Inclusion Criteria 
Patients are eligible to be included in the study only if all of the following criteria apply: 
Age 
1. 18 years of age or older, at the time of signing the informed consent. 
Type of Patient and Disease Characteristics 
2. A diagnosis of ALS, defined as meeting the possible, laboratory-supported probable, 
probable, or definite criteria for a diagnosis of ALS according to the revised World 
Federation of Neurology El Escorial criteria. Patients diagnosed with either sporadic or 
familial ALS are eligible for enrollment. 
3. ALS onset, defined as time of onset of first muscle weakness (eg, limb weakness, 
dysarthria, dysphagia, shortness of breath), ≤ 36 months from the Screening Visit. 
4. Prestudy ALSFRS-R progression between disease onset and screening of -0.3 points per 
month or worse (calculated by ALSFRS-R total score decline from 48 divided by the 
months since onset of ALS symptoms).  
5. Upright SVC ≥ 65% predicted at Screening. 
6. Vaccinated against N. meningitidis within 3 years prior to, or at the time of, initiating 
ravulizumab. Patients who initiate study drug treatment less than 2 weeks after receiving 
a meningococcal vaccine must receive appropriate prophylactic antibiotics until 2 weeks 
after the vaccination.  
7. Patients who enter the study receiving standard of care for ALS (ie, riluzole and/or 
edaravone), either in combination or monotherapy, must be on a stable dosing regimen of 
adequate duration prior to screening with no plan to discontinue or to change the dose 
during the study period as follows:  
• If a patient who enters the study is receiving riluzole, the patient must have been on a 
stable dose of riluzole for ≥ 30 days prior to Day 1. 
• If a patient who enters the study is receiving edaravone, the patient must have 
initiated edaravone ≥ 60 days (2 treatment cycles) prior to Day 1. 
Note: Patients who are naïve to ALS therapies or have not taken approved ALS therapies for at 
least 30 days before screening are allowed to enroll. 
Weight 
8. Body weight ≥ 40 kg at Screening. 
Sex 
9. Male and/or female 


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Contraceptive use by men or women should be consistent with local regulations regarding 
the methods of contraception for those participating in clinical studies. 
• Male patients: 
a. Male patients must agree to use contraception as detailed in the protocol 
(Section 10.4) during the treatment period and for at least 8 months after the last dose of 
study drug and refrain from donating sperm during this period. 
• Female patients: 
− A female patient is eligible to participate if she is not pregnant, not breastfeeding, 
and meets at least one of the following conditions: 
o Not a woman of childbearing potential (WOCBP) (Section 10.4.1) 
• OR 
o Is a WOCBP and using a highly effective or acceptable contraceptive method as 
described in Section 10.4 during the treatment period and for a minimum of 8 months 
after the last dose of study drug. 
The Investigator should evaluate the effectiveness of the contraceptive method in 
relationship to the first dose of study drug. A WOCBP must have a negative pregnancy 
test at Screening and before the first dose of study drug. Additional requirements for 
pregnancy testing during and after study drug are described in Section 10.4. The 
Investigator is responsible for review of medical history, menstrual history, and recent 
sexual activity to decrease the risk for inclusion of a woman with an early undetected 
pregnancy. 
Informed Consent 
10. Capable of giving written or verbal informed consent as described in Section 10.1.3, 
which includes compliance with the requirements and restrictions listed in the informed 
consent form (ICF) and in this protocol 
5.2. 
Exclusion Criteria  
Patients are excluded from the study if any of the following criteria apply: 
Medical Conditions 
1. History of N. meningitidis infection. 
2. Human immunodeficiency virus (HIV) infection (evidenced by HIV-1 or HIV-2 antibody 
titer). 
3. History of unexplained infections. 
4. Active systemic bacterial, viral, or fungal infection within 14 days prior to study drug 
administration on Day 1. 
5. Presence of fever ≥ 38°C (100.4°F) within 7 days prior to study drug administration on 
Day 1. 
6. Hypersensitivity to murine proteins or to 1 of the excipients of ravulizumab.  


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7. Dependence on invasive or non-invasive mechanical ventilation. Dependence on 
mechanical ventilation is defined as being unable to lie flat (supine) without it, unable to 
sleep without it, or daytime use > 6 hours per day for > 3 days per week. Non-invasive 
ventilation for sleep apnea is allowed subject to discussion with Medical Monitor. 
8. Any medical condition that, in the opinion of the Investigator, might interfere with the 
patient’s participation in the study, poses any added risk for the patient, or confounds the 
assessment of the patient. 
9. The presence of unstable psychiatric disease or dementia that might interfere with the 
patient’s participation in the study, poses any added risk for the patient, or confounds the 
assessment of the patient. 
10. History of drug and/or alcohol abuse (according to Diagnostic and Statistical Manual of 
Mental Disorders) within 1 year of screening that would limit patient participation in the 
study as determined by the Investigator. 
11. History of Parkinson’s disease, myasthenia gravis, multiple sclerosis, or any other 
neurological disorder that may confound the diagnosis or assessment of the patient as 
determined by the Investigator. 
Prior/Concomitant Therapy 
12. Previously or currently treated with a complement inhibitor.  
13. Use of IV immunoglobulin (IVIg) within 3 weeks prior to screening. 
14. Has a diaphragm pacing system (DPS) at study entry or anticipate DPS placement during 
the course of the study. 
Prior/Concurrent Clinical Study Experience 
15. Participation in any other investigational product study or exposure to an investigational 
drug or device within 30 days of screening or 5 half-lives of the study drug, whichever is 
greater or any prior exposure to gene therapy. 
16. Receipt of stem cell transplant therapy as an investigational treatment for ALS < 90 days 
from the date of last transplant. 
Other Exclusions 
17. Pregnant, breastfeeding, or intending to conceive during the course of the study.  
5.3. 
Lifestyle Considerations 
There is no lifestyle restriction for this study. 
5.4. 
Screen Failures 
Screen failures are defined as patients who consent to participate in the clinical study but are not 
subsequently randomly assigned to study drug. A minimal set of screen failure information is 
required to ensure transparent reporting of screen failures to meet the Consolidated Standards of 
Reporting Trials (CONSORT) publishing requirements and to respond to queries from regulatory 
authorities. Minimal information includes demography, screen failure details (eg, failed 


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eligibility criteria), and any adverse events (AEs), including any serious adverse events (SAEs) 
and any related concomitant medication, occurring during the screening period. 
Individuals who do not meet the criteria for participation in this study (screen failure) due to a 
reason that is expected to resolve or has resolved may be rescreened based on discussion and 
agreement between the Investigator and the Medical Monitor. 


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6. 
STUDY DRUG 
Study drug is defined as any investigational drug(s), marketed product(s), placebo, or medical 
device(s) intended to be administered to a study participant according to the study protocol. 
6.1. 
Study Drug(s) Administered 
In this study, patients will be randomized 2:1 to receive blinded ravulizumab or placebo 
treatment during the Randomized Controlled Period; during the Open-Label Extension period, all 
patients will receive open-label ravulizumab treatment (Table 5; Figure 1). 
Refer to Section 8.1.4 for study drug dosage and administration and Section 1.3 SoA for dosing 
schedules. Detailed description of the study drug is provided in the Pharmacy Manual. 


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Table 5: 
Study Drugs 
Study drug name 
Ravulizumab  
Placebo 
Dose formulation 
Vial 
Vial 
Physical description 
Liquid solution practically free from particles 
Liquid solution practically free from particles 
Unit dose strength(s) 
300 mg (10 mg/mL concentrated solution or 100 mg/mL 
formulation) 
Placebo 
Dosage level(s)a  
Weight-based dosing; starting 2 weeks after the initial loading 
dose, maintenance dose q8w 
Weight-based dosing; starting 2 weeks after the initial loading 
dose, maintenance dose q8w 
Route of administration 
IV infusion 
IV infusion 
Use 
Experimental 
Placebo comparator 
IMP and NIMP 
IMP  
IMP 
Sourcing 
Provided centrally by Alexion or contracted manufacturing 
organization 
Provided centrally by Alexion or contracted manufacturing 
organization 
Packaging and labeling 
Ravulizumab will be provided in glass vials and stoppered with 
a butyl rubber stopper with an aluminum overseal and a flip-off 
cap. Study drug will be supplied in kits and labeled as required 
per country requirement. 
Placebo will be provided in glass vials and stoppered with a 
butyl rubber stopper with an aluminum overseal and a flip-off 
cap. Placebo will be supplied in kits and labeled as required 
per country requirement. 
a Detailed information of study drug dose administration is provided in Section 8.1.4. 
Abbreviations: IMP = investigational medicinal product; IV = intravenous; NIMP = non-investigational medicinal product; q8w = every 8 weeks 


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6.2. 
Preparation/Handling/Storage/Accountability 
Upon arrival of the study drug at the study site, the study drug kits should be removed from the 
shipping container and stored in their original cartons under refrigerated conditions at 2°C to 8°C 
(35°F to 47°F) and protected from light. Study drugs should not be frozen. 
Study drugs must be stored in a secure, limited-access storage area with temperature monitored 
daily. 
Infusions of study drug should be prepared using aseptic technique. Ravulizumab and placebo 
will be further diluted in a 1:1 ratio with compatible diluent. Ravulizumab and placebo will be 
filtered with a 0.2 micron filter during infusion. 
• The Investigator or designee must confirm appropriate temperature conditions have 
been maintained during transit for all study drug received and any discrepancies are 
reported and resolved before use of the study drug. 
• Only patients enrolled in the study may receive the study drug and only authorized 
site staff may supply or administer the study drug. All study drug must be stored in a 
secure, environmentally controlled, and monitored (manual or automated) area in 
accordance with the labeled storage conditions with access limited to the Investigator 
and authorized site staff. 
• The Investigator, institution, or the head of the medical institution (where applicable) 
is responsible for study drug accountability, reconciliation, and record maintenance 
(ie, receipt, reconciliation, and final disposition records). 
• Further guidance and information for the final disposition of unused study drugs are 
provided in the Pharmacy Manual. 
6.3. 
Measures to Minimize Bias: Randomization and Blinding 
6.3.1. 
Randomization 
Patients will be randomly allocated on Day 1 to one of two treatment groups after the 
Investigator and Medical Monitor have verified that they are eligible. Patients will be stratified 
by site of muscle weakness onset (bulbar vs other) and background ALS treatment (riluzole 
and/or edaravone vs neither ALS therapy) (Section 9.2.1) and randomized 2:1 either to 
ravulizumab IV infusion or placebo IV infusion. Patients will be centrally randomized using 
Interactive Response Technology (IRT).  
6.3.2. 
Blinding 
Patients, all investigative site personnel and any Sponsor employee or delegate directly 
associated with the conduct of the study will be blinded to patient treatment assignments. The 
blinding will be maintained by using identical study drug kits and labels for ravulizumab and 
placebo. The placebo will have an identical appearance to that of ravulizumab. The 
randomization code will be maintained by the IRT provider. Patients who elect to continue 
treatment after completion of the Randomized Controlled Period enter the Open-Label Extension 
Period at the end of the Week 50 visit after completing all scheduled assessments and before 


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receiving ravulizumab. To maintain blinding to the patient’s treatment assignment during the 
Randomized Controlled Period, patients in the placebo group will receive a blinded loading dose 
of ravulizumab, and patients in the ravulizumab group will receive a blinded ravulizumab dose 
of 900 mg. Starting at Week 52, all patients will begin open-label ravulizumab maintenance 
doses every 8 weeks (q8w). For patients in the ravulizumab group, a blinded ravulizumab dose 
of 900 mg was chosen to ensure maintenance of complete C5 inhibition until the next scheduled 
maintenance dose at Week 52. Investigators are to avoid any unscheduled clinical laboratory 
tests which could potentially unblind study patients (eg, complement activity via assays such as 
CH50). Blind to prior assignment will be maintained for patients and providers (study site) 
during the Open-Label Extension Period. 
In case of an emergency, the Investigator has the sole responsibility for determining if 
unblinding of a patient’s intervention assignment is warranted. Patient safety must always be the 
first consideration in making such a determination. If the investigator decides that unblinding is 
warranted, the investigator should make every effort to contact the sponsor prior to unblinding a 
patient’s intervention assignment unless this could delay emergency treatment of the patient. The 
Investigator will be able to unblind the patient’s treatment allocation using the IRT. If a patient’s 
intervention assignment is unblinded, Alexion must be notified within 24 hours after breaking 
the blind. The date and reason that the blind was broken must be recorded in the source 
documentation, as applicable. 
When unblinding is the result of an AE which is unexpected or related and serious, the blind will 
be broken for that specific patient only. The blind with regard to treatment allocation for that 
specific patient will be maintained for all persons responsible for the ongoing conduct of the 
study (such as the management, monitors, Investigators, etc) and those responsible for data 
analysis and interpretation of results at the conclusion of the study, such as biometrics personnel. 
Unblinded information will only be accessible to those who need to be involved in the safety 
reporting to Health Authorities, Independent Ethics Committees (IECs), Institutional Review 
Boards (IRBs), and/or IDMC. 
Any patient who is unblinded during the Randomized Controlled Period will be discontinued 
from the study.  
6.4. 
Study Drug Compliance 
The infusion of study drug into patients will be under the supervision of the Investigator or their 
designee to ensure that patients receive the appropriate dose at the appropriate time points during 
the study. 
The date and time of each dose administered will be recorded in the source documents and CRF. 
6.5. 
Concomitant Therapy 
6.5.1. 
Allowed Medications and Therapies 
6.5.1.1. 
Palliative and Supportive Care 
Palliative and supportive care is permitted during the course of the study for underlying 
conditions. 


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6.5.1.2. 
ALS-Specific Therapies 
There are 2 therapies currently available for treating ALS that may slow disease progression: 
riluzole and edaravone.  
• Patients who are naïve to ALS therapies or have not taken ALS therapies for at least 
30 days before screening are allowed to enroll. 
• For a patient who is on one or more ALS-specific therapies at Day 1 of the study, the 
patient must be on a stable dose regimen of riluzole for at least 30 days and/or on a stable 
treatment of edaravone for at least 60 days (2 treatment cycles) prior to Day 1 and has no 
plan to discontinue or change dose during the study. 
− Temporary discontinuations or dose modifications of riluzole or edaravone are 
acceptable at the discretion of the Investigator for medical reasons. 
− Patients receiving edaravone should not receive edaravone infusions on days 
when study drug is to be administered. 
• Patients who do not enter the study on riluzole and/or edaravone will not be permitted to 
start treatment with either drug during the Randomized Controlled Period. Initiation of 
riluzole and/or edaravone is permitted during the Open-Label Extension Period. 
6.5.1.3. 
Other Allowed Therapies 
• Vitamin B12, vitamin E, creatine, coenzyme Q10, biotin supplements, and l-serine are 
permitted in this study. Patients who take any or all of these supplements should be on a 
stable dose beginning 14 days prior to first dose of study drug and remain on a stable 
dose for the duration of the Randomized Controlled Period of the study unless alteration 
in dose is deemed medically necessary or reviewed with the Medical Monitor.  
• All other vitamins and supplements are permitted on this study. Patients are encouraged 
to remain on stable dosing for the duration of the Randomized Controlled Period of the 
study. 
• Patients who received stem cell transplant therapy as an investigational treatment for 
ALS are permitted to enroll in the study after a minimum washout period of 90 days from 
date of last transplant. 
6.5.2. 
Disallowed Medications and Therapies  
The following medications and therapies are prohibited during the study: 
• Chronic treatment with IVIg for ALS disease management during the study is prohibited, 
Note: If IVIg is deemed necessary for treatment of an acute condition for which IVIg is 
an indicated therapy, acute treatment with IVIg may be considered on a case by case 
basis in consultation with the Medical Monitor. 
• Chronic use of plasmapheresis/plasma exchange (PP/PE) is prohibited during the study. 
However, if it is deemed necessary by the Investigator for treatment of an acute condition 
for which PP/PE is indicated, acute treatment of PP/PE may be considered on a case by 
case basis in consultation with the Medical Monitor. No more than 1 treatment cycle of 
PP/PE will be allowed. 


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• Eculizumab or other complement inhibitory agent is prohibited. 
• Chronic systemic use of immunosuppressive therapies, defined as using any systemic 
immunosuppressive agent for ≥ 14 days, is prohibited during the study. 
Note: Topical and inhaled immunosuppressive agents are permitted. 
Note: Use of systemic corticosteroids for ≥ 14 days may be considered on a case-by-case 
basis in consultation with the Medical Monitor 
• Rituximab and other biologic or immunomodulatory therapies are prohibited during the 
study.  
• Tauroursodeoxycholic acid (TUDCA) and sodium phenylbutyrate in combination or as 
individual therapies are prohibited during the study. 
• Any off-label usage of an approved product currently under investigational use for the 
treatment of ALS during the study is prohibited.  
6.6. 
Dose Modification  
Dose modification is not permitted for this study. However, in the event of a missed or 
incomplete dose, and with the guidance of the Sponsor, supplemental dosing may be employed 
in order to maintain therapeutic steady state concentrations from disruptions in scheduled study 
drug dosing. 
6.7. 
Intervention after the End of the Study 
Ravulizumab will not be provided to the patients after the last scheduled dosing (Section 1.3). 
After the end of therapy visit or ED, all patients will be followed for an additional 8 weeks after 
the last dose of study drug. 


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7. 
DISCONTINUATION OF STUDY DRUG AND PATIENT 
DISCONTINUATION/WITHDRAWAL 
7.1. 
Discontinuation of Study Drug 
In rare instances, it may be necessary for a patient to permanently discontinue study drug. If 
study drug is permanently discontinued, the patient should complete the ED visit (Section 1.3) 
for safety follow-up before discontinuing from the study. See the SoA (Section 1.3) for data to be 
collected at the time of discontinuation of study drug and follow-up and for any further 
evaluations that need to be completed. 
Patients should be considered for discontinuation from study drug if any of the following occur 
during the study: 
• Serious hypersensitivity reaction; 
• Severe uncontrolled infection; 
• Use of disallowed medication as defined in Section 6.5.2;  
• Pregnancy or planned pregnancy; or 
• Sponsor or the Investigator deems it is in the best interest of the patient. 
7.2. 
Patient Discontinuation/Withdrawal from the Study 
• All efforts should be made to ensure patients are willing to comply with study 
participation prior to conducting the screening procedures. The study staff should notify 
Alexion and their site monitor of all study withdrawals as soon as possible. The reason 
for patient discontinuation must be recorded in the source documents and electronic CRF 
(eCRF). 
• A patient may withdraw from the study at any time at his/her own request or may be 
withdrawn at any time at the discretion of the Investigator for safety, behavioral 
compliance, or administrative reasons. 
• At the time of discontinuing from the study, if possible, an ED visit corresponding with 
the period of the study the patient is in should be conducted. The ED visit should be 
conducted as soon as possible, and no later than 8 weeks after the last dose of study drug, 
as shown in the SoA (Section 1.3). A follow-up phone call will be performed at 8 weeks 
(56 days) ± 5 days following the patient’s last dose of study drug to collect concomitant 
medications, non-pharmacologic therapies, VAFS, procedures, and AEs.  
o The patient will be permanently discontinued both from the study drug and from 
the study at that time. 
• If the patient withdraws consent for disclosure of future information, Alexion may retain 
and continue to use any data collected before such a withdrawal of consent. 
• If a patient withdraws from the study, the patient may request destruction of any samples 
taken and not tested, and the Investigator must document this in the site study records as 
well as inform the site monitor and Sponsor. 


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7.3. 
Lost to Follow-up 
If a patient fails to return, or is otherwise unavailable, for a scheduled visit within the acceptable 
visit window (Section 1.3), the site study staff must make a reasonable attempt to contact the 
patient to determine the reason for missing the appointment. As it is vital to obtain any patient’s 
missing visit information to ensure the missed appointment was not due to an AE, every effort 
must be made to undertake protocol-specified safety follow-up procedures.  
In the exceptional circumstance where a patient cannot or does not come to the study site for 
examination, the patient will be instructed to see his or her local neurologist or physician. In this 
event, if possible, the Investigator or designee will contact the local neurologist or physician to 
obtain as much information as possible about the patient’s medical and neurological condition, 
and provide clinical guidance, if needed. The study site will obtain relevant medical records as 
documentation from the local physician’s examination and enter relevant data in the eCRF as 
appropriate.  
A patient will be considered lost to follow-up if he or she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the study site. 
The following actions must be taken if a patient fails to return to the clinic for a required study 
visit: 
• The site must attempt to contact the patient and reschedule the missed visit as soon as 
possible and counsel the patient on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the patient wishes to and/or should continue in the 
study. 
• Before a patient is deemed lost to follow-up, the Investigator or designee must make 
every effort to regain contact with the patient (where possible, 3 telephone calls and, if 
necessary, a certified letter to the patient’s last known mailing address or local equivalent 
methods). These contact attempts should be documented in the patient’s medical record. 
• Should the patient continue to be unreachable, he/she will be considered as lost to 
follow-up.  
Discontinuation of specific sites or of the study as a whole are described in Section 10.1.8.  


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8. 
STUDY ASSESSMENTS AND PROCEDURES 
• Study procedures and their timing are summarized in the SoA (Section 1.3). Protocol 
waivers or exemptions are not allowed. 
• Immediate safety concerns should be discussed with Alexion immediately upon 
occurrence or awareness to determine if the patient should receive study drug. 
• Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct. 
• All screening evaluations must be completed and reviewed to confirm that potential 
patients meet all eligibility criteria. The Investigator will maintain a screening log to 
record details of all patients screened and to confirm eligibility or record reasons for 
screening failure, as applicable. 
• Procedures conducted as part of the patient’s routine clinical management (eg, blood 
count) and obtained before signing of the ICF may be utilized for screening or 
baseline purposes provided the procedures met the protocol-specified criteria and 
were performed within the time frame defined in the SoA. 
8.1. 
General Assessments 
8.1.1. 
Medical History and ALS History and Diagnosis 
The Principal Investigator or Sub-Investigator will review the patient’s medical history including 
ALS history and diagnosis.  
The following will be evaluated and documented at the Screening Visit and/or other visits as 
specified in the SoA (Section 1.3): 
• Time of ALS onset (defined as time of onset of first muscle weakness symptom date). 
• Date of ALS diagnosis. 
• Criteria for ALS diagnosis, defined as meeting the clinically possible, 
laboratory-supported probable, probable, or definite criteria for a diagnosis of ALS 
according to the revised World Federation of Neurology El Escorial criteria (Brooks, 
2000) (Section 10.5). 
• ALS stage will be evaluated using King’s staging system (KSS) (Balendra, 2019) by the 
Investigator or trained designee. Stage will be assigned based on the number of involved 
CNS regions and nutritional and respiratory status. 
8.1.2. 
Vaccine and Antibiotic Prophylaxis 
As with any terminal complement antagonist, the use of ravulizumab increases the patient’s 
susceptibility to meningococcal infection (N. meningitidis). To reduce the risk of meningococcal 
infection, all patients must be vaccinated against meningococcal infections within the 3 years 
before or at the time of initiating study drug.  


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• Patients who initiate study drug less than 2 weeks after receiving a meningococcal 
vaccine must receive treatment with appropriate prophylactic antibiotics from the first 
day of study drug treatment until 2 weeks after vaccination. 
• Patients must be vaccinated or revaccinated according to current national vaccination 
guidelines or local practice for vaccination use with complement inhibitors (eg, 
eculizumab, ravulizumab). 
• Vaccines against serotypes A, C, Y, W135, and B, where available, are recommended to 
prevent common pathogenic meningococcal serotypes. 
• Vaccination may not be sufficient to prevent meningococcal infection. Consideration 
should be given according to official guidance and local practice on the appropriate use 
of antibacterial agents. 
• All patients should be monitored for early signs of meningococcal infection, evaluated 
immediately if infection is suspected, and treated with appropriate antibiotics, if 
necessary. 
• It is recommended that sites also follow relevant national vaccination guidelines and local 
practice for patients with ALS (eg, pneumococcal and influenza [flu] vaccination).  
8.1.3. 
Inclusion/Exclusion Criteria 
All inclusion (Section 5.1) and exclusion (Section 5.2) criteria must be reviewed by the 
Investigator or qualified designee to ensure the patient qualifies for study participation. 
Both the Investigator and Alexion must approve patient eligibility before enrollment. 
8.1.4. 
Study Drug Administration 
This section describes the dosage regimen of study drugs. At the scheduled dosing visits 
(Section 1.3), study drug infusion should be performed after all other tests and procedures have 
been completed, excluding the postdose blood sampling for PK and free C5. 
Refer to Section 6 for additional information on study drugs including preparation, handling, 
storage, and accountability. For detailed instructions, refer to the Pharmacy Manual. 
The ravulizumab dose for each patient will be based on last recorded body weight. The dosing 
regimen (Table 6) consists of a loading dose followed by maintenance dosing administered q8w. 
The maintenance dose should be initiated 2 weeks after the loading dose administration. 


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Table 6: 
Weight-based Doses of Ravulizumab 
 
Body Weight (kg)a, b 
Dose (mg) 
Loading dose 
≥ 40 to < 60 
2400 
≥ 60 to < 100 
2700 
≥ 100 
3000 
Maintenance dose 
≥ 40 to < 60 
3000 
≥ 60 to < 100 
3300 
≥ 100 
3600 
a Dose regimen will be based on the last recorded study visit body weight.  
b In the event that a patient drops below 40 kg during the course of the study the approved ravulizumab aHUS 
dosing for patients weighing 30 - 40 kg will be used: a loading dose of 1200 mg and maintenance dose of 
2700 mg, and in the event that a patient drops below 30 kg during the course of the study the approved 
ravulizumab aHUS dosing for patients weighing 20 - 30 kg will be used: a loading dose of 900 mg and 
maintenance dose of 2100 mg. 
Abbreviation: aHUS = atypical hemolytic uremic syndrome 
For each patient, the entire treatment duration is up to 156 weeks, consisting of a Randomized 
Controlled Period (50 weeks) and an Open-Label Extension Period (up to 106 weeks). Study 
drug administration will end when all patients have completed the 2-year Open-Label Extension 
Period, or ravulizumab is approved and/or available (in accordance with country-specific 
regulations), or anytime during the Open-Label Extension Period at the discretion of Alexion, 
whichever occurs first.  
8.1.4.1. 
Randomized Controlled Period 
The Randomized Controlled Period is a double-blind, randomized, placebo-controlled period. 
Eligible patients will be randomized 2:1 to receive blinded doses of ravulizumab or placebo 
during the Randomized Controlled Period (Day 1 through Week 42). 
• Patients in the ravulizumab group will receive a blinded loading dose of ravulizumab on 
Day 1, followed by a blinded maintenance dose on at Week 2 (Table 6), then once q8w 
up to Week 42 (inclusive) (Table 6). 
• Patients in the placebo group will receive a blinded matching placebo dose via IV 
infusion on Day 1, followed by a blinded matching placebo maintenance dose at Week 2, 
then q8w up to Week 42 (inclusive). 
8.1.4.2. 
Open-Label Extension Period 
Patients who elect to continue treatment after completion of the Randomized Controlled Period 
enter the Open-Label Extension Period at the completion of all scheduled predose assessments 
for the Week 50 visit and before receiving ravulizumab.  
• Patients in the placebo group may switch to receive a blinded loading dose of 
ravulizumab at Week 50 (Table 6). 
• To ensure treatment allocation remains blinded to patients, Investigators, and site 
staff, as well as Sponsor staff or delegates, patients in the ravulizumab group will 
receive a blinded ravulizumab dose of 900 mg at Week 50. The 900 mg dose at Week 


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50 is chosen to ensure maintenance of complete C5 inhibition until the next scheduled 
maintenance dose. 
Starting at Week 52, all patients will receive open-label ravulizumab maintenance doses q8w 
(Table 6) until the end of the Open-Label Extension Period when all patients have completed 
2 years of ravulizumab or ravulizumab is approved and/or available (in accordance with 
country-specific regulations). Patients may be allowed to switch from the 10 mg/mL to the 
100 mg/mL formulation of ravulizumab with no change to the weight-based dose regimen at or 
after Week 52 in the OLE Period. 
8.1.5. 
Visits at Home or Alternative Healthcare Facilities 
If available, patients may have an opportunity to receive study drug administration remotely at a 
medical facility that is located near the patient’s home or at the patient’s home with the 
permission of the Investigator, after discussion with the Alexion medical monitor (or delegate), 
in accordance with all national, state, and local laws or regulations of the pertinent regulatory 
authorities. Home infusions may be considered only for patients who have tolerated previous 
drug infusions well, without clinically significant infusion reactions, at the study site. 
Remote visit options may be at the Investigator’s discretion and oversight, in accordance with 
the local regulations, and conducted by a qualified medical professional. Information about AEs, 
concomitant medications, and ALS signs or symptomatology must be sent to the Investigator’s 
site for evaluation on the day of the remote visit. In case of any signs or symptoms indicating an 
SAE, the patient may need to be evaluated at the study site or in an emergency room setting. 
Monitoring, treatment, and management of infusion reactions for patients receiving drug 
infusions at home are described in Section 10.13. 
8.2. 
Efficacy Assessments 
8.2.1. 
Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) 
The ALSFRS-Revised (Cedarbaum, 1999) is a validated instrument for evaluating the levels of 
the functional status of patients with ALS in 4 areas, including bulbar, gross motor activity, fine 
motor activity, and respiratory functions. The scale includes 12 functional items and each item is 
rated on a 0 to 4 scale, with a maximum total score of 48 (Section 10.6). A higher score indicates 
greater retention of function. 
In this study, the ALSFRS-R will be performed throughout the study by the Investigator or any 
designee who has been properly trained for the evaluation. When possible, it is highly 
recommended that all assessments be performed by the same assessor.  
The ALSFRS-R will be assessed as indicated in the SoA (Section 1.3). At the time points 
specified in the SoA, or if a patient is not able to attend the scheduled onsite visit, the 
ALSFRS-R can be assessed via a phone call by the Investigator or trained designee. 
8.2.2. 
Ventilation Assistance-Free Survival (VAFS) 
Ventilation Assistance-Free Survival is a composite endpoint of survival and severe and 
irreversible respiratory decline. The use of VAFS allows for the collection of survival data that is 
not impacted by survival prolongation from noninvasive or permanent ventilatory interventions 


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which can prolong life without impacting underlying disease progression. The composite 
endpoint of VAFS (Paganoni, 2014) that will be used as a secondary endpoint for this study will 
be defined as the first occurrence of: 
• All-cause mortality 
• First use of NIV for ≥ 22 hours per day for ≥ 10 consecutive days 
• First use of PAV for ≥ 22 hours per day for ≥ 7 consecutive days 
Information on the components of VAFS will be assessed at every dosing visit by the 
Investigator or designee (see Section 1.3) using the ventilator assistance utilization form. An 
attempt will be made to obtain information about survival at the Follow-up phone call. 
8.2.3. 
Slow Vital Capacity (SVC) 
Slow vital capacity is a spirometry technique that utilizes slow and gradual expulsion of air from 
the lungs. The full volume of expired air is measured as a proportion of the expected vital 
capacity of the patient based on biometric features such as age, height, and sex. 
Slow vital capacity evaluation will be performed in the clinic by the Investigator, or any designee 
who has been properly trained for the evaluation, at screening and time points specified in the 
SoA (Section 1.3). When possible, it is highly recommended that all assessments be performed 
by the same assessor. In addition to SVC in the clinic, home SVC (where regionally available) 
should be performed using a provided spirometer and under the direction of study staff properly 
trained for the evaluation. In the event that an SVC measurement cannot be obtained in the clinic 
due to the COVID-19 pandemic, only home evaluation is required for that visit. Home SVC at 
screening should be performed after informed consent and after the patient has received training 
on the spirometer. For subsequent visits, including Day 1, home SVC should be performed 
within 3 days prior to the scheduled clinic visit.  
8.2.4. 
Handheld Dynamometry (HHD) 
Handheld dynamometry (HHD) (Shefner, 2016) is a procedure for quantitative strength testing. 
This testing will be conducted by the Investigator or any designee who has been properly trained 
for the quantitative muscle strength evaluation. When possible, it is highly recommended that all 
assessments be performed by the same assessor. Muscle strength testing will be performed on 
prespecified muscles in the upper and lower extremities bilaterally and the force measurements 
recorded. Handheld dynamometry will be assessed at the time points specified in the SoA 
(Section 1.3).  
8.2.5. 
Amyotrophic Lateral Sclerosis Assessment Questionnaire (ALSAQ-40) 
The ALSAQ-40 is a validated ALS-specific instrument for measuring quality of life in patients 
with ALS. There are 40 items covering 5 discrete categories (physical mobility, activities of 
daily living and independence, eating and drinking, communication, and emotional reactions) 
(Section 10.7). Patients will be asked about the difficulties they have experienced in the past 
2 weeks and the frequency of each event by selecting 1 of the 5 available options. The 
ALSAQ-40 will be self-assessed by patients. 


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8.2.6. 
EuroQoL 5 Dimensions (EQ-5D-5L) 
The European Quality of Life (EQ-5D-5L) (Section 10.8) is a self-assessed, standardized 
instrument to measure health-related quality of life and has been used in a wide range of health 
conditions, including ALS (Schrag, 2000). The EQ-5D-5L consists of 2 pages: the EQ-5D-5L 
descriptive system and the EQ visual analogue scale (EQ VAS). At time points specified in the 
SoA (Section 1.3), or if a patient is not able to attend the scheduled onsite visit, EQ-5D-5L can 
be assessed via a phone call. 
8.2.6.1. 
EQ-5D-5L Descriptive System 
The descriptive system is a 5-component scale including mobility, self-care, usual activities, 
pain/discomfort, and anxiety/depression (Section 10.8). Each level is rated on a scale that 
describes the degree of problems in that area. 
8.2.6.2. 
EQ Visual Analogue Scale  
The EQ-5D-5L VAS is an overall health state scale where the patient selects a number between 
0 and 100 to describe the condition of their health, with 100 being ‘The best health state you can 
imagine’ and 0 being ‘The worst health state you can imagine’ (Section 10.8). 
This information can be used as a quantitative measure of health outcome as judged by the 
individual respondents. Previously published studies by EuroQol Group members showed 
preliminary evidence of the instrument’s feasibility, reliability, and validity. 
8.2.7. 
Short Form Health Survey (SF-36) 
The SF-36 (Section 10.8.2) is a 36-item self-report of health-related quality of life (Stewart, 
1988; Ware, 1992). It contains 8 subscales measuring different domains of health-related quality 
of life: physical functioning, role limitations due to physical problems, bodily pain, general 
health perceptions, vitality, social functioning, role limitations due to emotional problems, and 
mental health. The SF-36 will be conducted at screening and at timepoints specified per SoA 
(Section 1.3) The 2 summary scores are the physical component summary and the mental 
component summary. There is no single overall score for the SF-36. 
8.2.8. 
Treatment Satisfaction Questionnaire for Medication (TSQM) 
The Treatment Satisfaction Questionnaire for Medication (TSQM-9) assesses 3 key dimensions 
of treatment satisfaction: Effectiveness (3 items); Convenience (3 items); and Global Satisfaction 
(3 items) (Bharmal, 2009). The instrument has been validated in chronic diseases including ALS 
(Meyer, 2019). The recall period for the TSQM is the previous 2 to 3 weeks or since last use. 
The TSQM-9 can be used to estimate total TSQM score, score for effectiveness, and score for 
convenience. The TSQM-9 will be administered at Day 1 and at timepoints specified in the SoA 
(Section 1.3). 
8.3. 
Safety Assessments 
The planned schedule for all safety assessments is provided in the SoA (Section 1.3). 


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8.3.1. 
Physical Examinations 
• A complete physical examination will include, at a minimum, assessments of the 
following organs/body systems: skin, head, ears, eyes, nose, throat, neck, lymph nodes, 
chest, heart, abdomen, extremities, and musculoskeletal. 
• An abbreviated physical examination will include, at a minimum, a body-system relevant 
examination based upon Investigator judgment and patient symptoms. 
• Examiners should pay special attention to clinical signs related to previous serious 
illnesses. 
• For consistency, all efforts should be made to have the physical examination performed 
by the same qualified study staff at each study visit. 
• Additional physical examinations can be performed as medically indicated during the 
study at the Investigator’s discretion. 
8.3.2. 
Neurologic Examination 
A general neurologic examination will be performed by the Investigator, Sub-Investigator, or 
designee at the scheduled visits (Section 1.3). The general neurologic examination includes 
assessments of the following systems: mental status, cranial nerves, deep tendon reflexes, 
power/strength, sensation, muscle fasciculations, and muscle atrophy. 
8.3.3. 
Height and Weight 
Body weight will be measured in pounds or kilograms. Height will be measured in inches or 
centimeters (Section 1.3). 
8.3.4. 
Vital Signs 
• Body temperature (°C or °F), pulse rate, respiratory rate, and systolic and diastolic blood 
pressure (mm Hg) will be assessed (Section 1.3). 
• Blood pressure and pulse measurements will be assessed seated with a completely 
automated device. Manual techniques will be used only if an automated device is not 
available. 
• Blood pressure and pulse measurements should be preceded by at least 5 minutes of rest 
for the patient in a quiet setting without distractions (eg, television, cell phones). Ideally, 
the same arm for each patient should be used for measurements. 
8.3.5. 
Electrocardiograms 
• Single 12-lead electrocardiogram (ECG) will be performed at protocol specified visits in 
the SoA (Section 1.3) using an ECG machine to obtain heart rate and measures of PR, 
QRS, QT, and corrected QT intervals. 
• Patients must be supine for approximately 5 to 10 minutes before ECG collection and 
remain supine but awake during ECG collection. For patients who are unable to remain 
supine, the ECG procedure may occur in an inclined or seated position. 


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• The Investigator or Sub-Investigator will be responsible for reviewing the ECG to assess 
whether the ECG is within normal limits and determine the clinical significance of the 
results. These assessments will be recorded in the source documents and the eCRF. 
8.3.6. 
Patient Safety Card 
Before the first dose of study drug, a Patient Safety Card will be provided to patients to carry 
with them at all times. The card is provided to increase patient awareness of the risk of 
infections, especially meningococcal infection, and to promote quick recognition and disclosure 
of any potential signs or symptoms of infection experienced by patients during the course of the 
study and to inform patients on what actions must be taken if they are experiencing signs or 
symptoms of infection. 
At each visit throughout the study, the study staff will ensure that the patient has the Patient 
Safety Card (Section 1.3). 
8.3.7. 
Prior and Concomitant Medication Review 
It is important for Investigators or a designee to review each medication the patient is taking 
before starting the study and at each visit (Section 1.3). 
8.3.7.1. 
Prior Medications 
Prior medications and/or vaccines (including vitamins, herbal preparations, and those discussed 
in the exclusion criteria [Section 5.2]) and procedures (any therapeutic drug, such as 
surgery/biopsy or physical therapy) that the patient takes or undergoes within 30 days before the 
start of screening or during the Screening Period before the first dose of study drug, as well as 
any meningococcal vaccine administered within the last 3 years, will be recorded in the patient’s 
eCRF. Additionally, all medications or therapies ever used for treating ALS before the first dose 
of study drug must be collected. 
8.3.7.2. 
Concomitant Medications 
Concomitant medications (including any medication, vitamin, herbal preparation or supplement) 
and procedures (defined in Section 6.5) are those received on or after the first study treatment 
date (Day 1), including those started before Day 1 and continued after Day 1. At each study visit, 
patients should be questioned about any new medication or non-drug therapies or changes to 
concomitant medications and nondrug therapies since the last visit. Concomitant medications and 
non-drug therapies should be recorded in the source documents and the patient’s eCRF. 
Concomitant medications must be recorded in the patient’s source document/medical chart and 
eCRF along with: 
• Reason for use 
• Dates of administration including start and end dates 
• Dosage information including dose and frequency 
Information regarding the use of ALS specific treatment including riluzole and edaravone must 
be collected. Meningococcal vaccination and antibiotics administered for prophylaxis of 
meningococcal infection (if applicable) will also be recorded. 


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Any concomitant medication deemed necessary for the patient’s care during the study, or for the 
treatment of any AE, along with any other medications, other than those listed as disallowed 
medications in Section 6.5.1.3, may be given at the discretion of the Investigator. However, it is 
the responsibility of the Investigator to ensure that details regarding all medications are recorded 
in full in the patient’s source document/medical chart and eCRF. 
The Medical Monitor should be contacted if there are any questions regarding concomitant or 
prior therapy. 
8.3.8. 
Clinical Safety Laboratory Assessments 
• See Section 10.2 for the list of clinical laboratory tests to be performed and the SoA 
(Section 1.3 for the timing and frequency). 
• The Investigator must review the laboratory report, document this review, and record 
any clinically relevant changes occurring during the study in the AE section of the 
eCRF. The laboratory reports must be filed with the source documents. Clinically 
significant abnormal laboratory findings are those which are not associated with the 
underlying disease, unless judged by the Investigator to be more severe than expected 
for the patient's condition. 
• All laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 8 weeks after the last dose of study drug should be 
repeated until the values return to normal or baseline or are no longer considered 
clinically significant by the Investigator or medical monitor. 
− If such values do not return to normal/baseline within a period of time judged 
reasonable by the Investigator, the etiology should be identified and Alexion 
notified. 
− All protocol-required laboratory assessments, as defined in Section 10.2, must be 
conducted in accordance with the Laboratory Manual and the SoA. 
− If laboratory values from non-protocol specified laboratory assessments 
performed at the institution’s local laboratory require a change in patient 
management or are considered clinically significant by the Investigator (eg, 
serious adverse event (SAE) or AE or dose modification), then the results must be 
recorded in the CRF. 
8.3.9. 
Suicidal Ideation and Behavior Risk Evaluation 
Patients being treated with a study drug for a neurologic indication should be evaluated 
prospectively for suicidal ideation or behavior during the study. 
In this study, the Columbia-suicide severity rating scale (C-SSRS) will be used to monitor 
suicidal ideation and behavior. The Baseline/Screening version (Section 10.11) will assess 
lifetime risk as well as risk in the past 12 months. Intervention-emergent suicidal ideation and 
behavior will be monitored using the C-SSRS-Since Last Visit version (Section 10.12). 


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The C-SSRS will be performed by the Investigator or an appropriately trained designee at visits 
specified in the SoA (Section 1.3) to ensure that patients who are experiencing suicidal thoughts 
or behavior are properly recognized and adequately managed or referred for further evaluation. 
Additional C-SSRS assessments are permitted as needed. 
8.3.10. 
Pregnancy 
Pregnancy testing must be performed on all WOCBP at protocol-specified time points in the SoA 
(Section 1.3). Pregnancy tests (local urine testing will be standard unless serum testing is 
required by local regulation or IRB/IEC) may also be performed at any time during the study at 
the Investigator’s discretion. 
WOCBP must have a negative pregnancy test (serum if required per country regulations) before 
study drug administration. 
• Details of all pregnancies in female patients and, if indicated, female partners of male 
patients will be collected after the start of study drug and until the termination of the 
pregnancy. 
• If a pregnancy is reported, the Investigator should inform Alexion within 24 hours of 
learning of the pregnancy and should follow the procedures outlined in Section 10.4.  
• Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs. Pregnancy alone is 
not considered an AE. 
• If a patient becomes pregnant, the study drug must be immediately discontinued, and 
Alexion must be notified as per Section 10.4. Each pregnancy will be followed to 
term and Alexion notified regarding the outcome (Section 10.4.3). 
8.4. 
Adverse Events and Serious Adverse Events 
The definitions of AEs and serious SAEs are specified in Section 10.3. 
Adverse events will be reported to the Investigator by the patient (or, when appropriate, by a 
caregiver, surrogate, or the patient's legally authorized representative). 
The Investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible for following 
up AEs that are serious, considered related to the study drug or study procedures, or that caused 
the patient to discontinue the study drug (Section 7). 
8.4.1. 
Time Period and Frequency for Collecting AE and SAE Information 
All AEs and SAEs will be collected from the signing of the ICF until the last visit specified in 
the SoA (Section 1.3). 
All SAEs will be recorded and reported to Alexion or designee immediately and under no 
circumstance should this exceed 24 hours, as indicated in Section 1.3. The Investigator will 
submit any updated SAE data to Alexion within 24 hours of awareness. 


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Investigators are not obligated to actively seek AEs or SAEs after conclusion of the study 
participation. However, if the Investigator learns of any SAE, including a death, at any time after 
a patient has been discharged from the study, and he/she considers the event to be reasonably 
related to the study drug or study participation, the Investigator must promptly notify Alexion. 
8.4.2. 
Method of Detecting AEs and SAEs 
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Section 10.3. 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the patient is the preferred method to inquire about 
AE occurrences. 
8.4.3. 
Follow-up of AEs and SAEs 
After the initial AE/SAE report, the Investigator is required to proactively follow each patient at 
subsequent visits/contacts. All SAEs and AEs of special interest (AESI; as defined in 
Section 8.4.5) will be followed until resolution, stabilization, the event is otherwise explained, or 
the patient is lost to follow-up (as defined in Section 7.3). Every effort will be made to undertake 
protocol-specified safety follow-up procedures. Further information on follow-up procedures is 
provided in Section 10.3. 
8.4.4. 
Regulatory Reporting Requirements for SAEs 
• Prompt notification by the Investigator to Alexion of a SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of patients and the safety of 
a study drug under clinical investigation are met. 
• The Sponsor has a legal responsibility to notify both the local regulatory authority 
and other regulatory agencies about the safety of a study drug under clinical 
investigation. The Sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, IRB/IEC, and Investigators. 
• Suspected unexpected serious adverse reactions must be reported according to local 
regulatory requirements and Sponsor policy and forwarded to Investigators as 
necessary. 
• An Investigator who receives an Investigator safety report describing a SAE or other 
specific safety information (eg, summary or listing of SAEs) from Alexion will 
review and then file it along with the Investigator’s Brochure and will notify the 
IRB/IEC, if appropriate according to local requirements. 
8.4.5. 
Adverse Events of Special Interest  
Meningococcal infections will be collected as AESIs. 


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8.5. 
Treatment of Overdose 
For this study, any dose of study drug greater than that specified in the protocol will be 
considered an overdose. If dose cannot be established during the Randomized Controlled Period 
due to blinding, suspected overdose should be defined by volume administered. 
Accidental overdose or suspected overdose without any association with laboratory 
abnormalities or clinical symptoms should not be considered as an AE. Overdose must be 
reported by the Investigator within 24 hours to Alexion regardless of whether an AE occurred. 
The Sponsor does not recommend specific treatment for an overdose or suspected overdose. 
In the event of an overdose or suspected overdose, the Investigator should: 
• Contact the Medical Monitor immediately. 
• Closely monitor the patient for any AE/SAE 
• Obtain a plasma sample for PK analysis if requested by the Medical Monitor 
(determined on a case-by-case basis). 
• For unblinded patients, document the quantity of the excess dose as well as the timing 
of the overdose in the CRF. 
Decisions regarding dose interruptions will be made by the Investigator in consultation with the 
Medical Monitor based on the clinical evaluation of the patient. 
8.6. 
Pharmacokinetics and Pharmacodynamics 
• Blood samples for determination of serum drug concentrations and PD assessments 
will be collected before and after administration of study drug at the time points 
specified in the SoA (Section 1.3). 
• Cerebrospinal fluid (CSF) samples for PK and PD assessments are optional at 
protocol-specified time points (Section 1.3). Samples will only be obtained from 
patients who consent to CSF collection (CSF Cohort). Collection should be 
performed at the screening visit after all other assessments are complete and 
eligibility has been confirmed. 
− Lumbar punctures will be performed to collect CSF samples and may only be 
performed on patients who have consented to CSF sample collection. Patients 
who are on therapeutic doses of anticoagulants will be deemed ineligible for the 
optional lumbar puncture procedures in this study. In addition, patients may be 
deemed ineligible to undergo lumbar puncture at the discretion of the Investigator 
after consideration of medical history, physical examination findings, laboratory 
assessments required as part of the SoA or other factors. 
• Instructions for the collection and handling of biological samples will be provided by 
Alexion. The actual date and time (24-hour clock time) of each sample will be 
recorded on the eCRF and the central laboratory requisition form. 
• Additional information on sample collection, including blood volume requirements, is 
provided in the Laboratory Manual. 


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• Baseline and trough PK and PD blood samples will be collected at predose, within 
90 minutes before administering study drug at visits specified in the SoA 
(Section 1.3). The predose blood sample may be drawn through the venous access 
created for the dose infusion, prior to administration of the dose. 
• Postdose PK and PD blood samples will be collected postdose, within 60 minutes 
after completing study drug infusion. The postdose blood samples will be drawn from 
the patient's opposite, noninfused arm. 
• Blood samples at a nondosing visit can be collected at any time. 
• In the event of an unscheduled visit, PK and PD blood sample will be collected as 
soon as possible. 
8.7. 
Genetics 
There are no prespecified genetic analyses in this study. 
8.8. 
Biomarkers 
8.8.1. 
Biomarker Research 
Blood and urine samples for biomarker research will be collected from all patients, as described 
in Section 8.6, at the time points specified in the SoA (Section 1.3). Blood samples for 
biomarkers will be collected before administration of study drug, and biomarker urine samples 
may be collected at any time during the scheduled visit.  
CSF samples are optional samples for biomarker research and should only be collected from 
patients who have consented to CSF sample collection. For biomarker CSF sample collection, 
refer to Section 8.6 and follow the same instructions on lumbar punctures for PK/PD 
assessments.  
Biomarkers will be measured and include, but are not limited to, assessments of the following: 
• Markers of neurodegeneration, such as neurofilament light chain (NfL) 
• Complement proteins  
• Markers of neuroinflammation, such as levels of proinflammatory cytokines and 
inflammatory cells 
8.8.2. 
Future Biomarker Research 
Blood samples for DNA and RNA isolation will be collected from patients who have consented 
to participate in the future genetic analysis component of the study. Future DNA and RNA 
testing on these samples includes, but is not limited to, specific candidate genes/genome-wide 
analysis. 
Remaining samples from PK, PD, immunogenicity, and biomarker testing will be stored for 
future biomarker research. Analyses may be performed on biomarker variants thought to play a 
role in ALS activity/progression or treatment response to ravulizumab. These samples may also 
be used to develop methods, assays, prognostics and/or companion diagnostics related to the 


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study drug target, disease process, pathways associated with disease state, other complement-
related diseases, and/or mechanism of action of the study drug. 
Samples may be stored for a maximum duration according to local regulations following the last 
patient’s last visit for the study at a facility selected by Alexion to enable further analyses. 
8.9. 
Immunogenicity Assessments 
Antidrug antibodies (ADAs) to study drug will be evaluated in serum samples collected predose 
(within 5 to 90 minutes prior to the start of infusion of study drug) from all patients according to 
the SoA (Section 1.3). 
Additionally, serum samples should also be collected at the final visit from patients who 
discontinued study drug or were withdrawn from the study. 
Serum samples will be screened for antibodies binding to ravulizumab and the titer of confirmed 
positive samples will be reported. Other analyses may be performed to verify the stability of 
antibodies to ravulizumab and/or further characterize the immunogenicity of ravulizumab. 
The detection and characterization of antibodies to ravulizumab will be performed using a 
validated assay method by or under the supervision of Alexion. Samples may be further 
characterized to determine the titer and the presence of neutralizing antibodies if deemed 
necessary. Samples may be stored for a maximum duration according to local regulations 
following the last patient’s last visit for the study at a facility selected by Alexion to enable 
further analysis of immune responses to ravulizumab. 
8.10. 
Medical Resource Utilization and Health Economics 
Medical resource utilization and health economics data associated with medical encounters will 
be collected in study eCRFs by the Investigator and study-site personnel for all patients 
throughout the study. Protocol-mandated procedures, tests, and encounters are excluded. 
The data collected, which may be used to conduct exploratory economic analyses, include the 
following: 
• Number of surgeries, and other selected procedures (inpatient and outpatient) 
• Number and duration of hospitalizations  
• Use of ventilator use and duration of use  
• Use of wheelchair 
• Use of feeding tube 


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9. 
STATISTICAL CONSIDERATIONS 
Statistical methods described in this section will be further detailed in a separate Statistical 
Analysis Plan (SAP). The SAP will be developed and finalized prior to the database lock for the 
Randomized Controlled period. Statistical analyses will include tabulations of summary data, 
inferential analyses, by-patient listings and figures. Inference from efficacy analyses will be 
based on a 2-sided Type I error (α) = 5% unless stated otherwise. The summary statistics for 
continuous variables will include but not be limited to the number of patients, mean, standard 
deviation, minimum, median, and maximum. For categorical variables, frequencies and 
percentages will be presented. The baseline value for analysis and reporting will be based on the 
last nonmissing measurement on or prior to the first dose of study drug unless stated otherwise. 
The treatment groups for analysis and reporting will be based on the conventions outlined in 
Table 8. A ‘Total’ treatment group will be formed to report demographics, baseline 
characteristics, and other prestudy information including, medical and ALS history, and prior 
medications and SAEs captured between screening and first infusion. Details for imputation of 
efficacy data will be described in the SAP. Missing safety data will not be imputed. 
Analyses will be performed using the SAS® software Version 9.4 or higher. 
9.1. 
Statistical Hypotheses 
9.1.1. 
Primary Hypothesis 
The primary null hypothesis is that the effect of ravulizumab is no different than placebo in 
functional decline measured by the change from baseline in ALSFRS-R total score at Week 50. 
The alternative hypothesis is that ravulizumab will slow the disease progression by reducing the 
decline from baseline in ALSFRS-R total score at Week 50 compared to placebo. 
9.1.2. 
Secondary Hypotheses 
The null hypotheses associated with the secondary objectives are that ravulizumab is no different 
than placebo for the respective endpoints; the alternative hypotheses are described below:  
1. Time to VAFS: The alternative hypothesis is that treatment with ravulizumab will 
prolong the time to VAFS compared to placebo.  
2. Change in SVC: The alternative hypothesis is that treatment with ravulizumab will slow 
the decline from baseline in SVC at Week 50 compared to placebo.  
3. Change in muscle strength (HHD): The alternative hypothesis is that treatment with 
ravulizumab will slow the decline from baseline in muscle strength at Week 50 compared 
to placebo.  
4. Neurofilament light chain (NfL) concentration: The alternative hypothesis is that 
treatment with ravulizumab will lower the NfL concentration at Week 50 compared to 
placebo. 
9.2. 
Sample Size Determination 
The sample size calculations were based on information extracted from the PRO-ACT (Pooled 
Resource Open-Access ALS Clinical Trials, https://nctu.partners.org/ProACT) database 


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consisting of data pooled from 23 Phase 2/3 ALS clinical studies. Approximately 354 patients 
will be randomized to ravulizumab or placebo in a 2:1 ratio.  
The mean change in ALSFRS-R total score in the placebo arm at Week 50 is estimated as -14.3 
(assuming a monthly linear slope of decline of 1.19 calculated based on the proposed study 
inclusion criteria). Assuming a 30% relative reduction in monthly slope in the ravulizumab 
group, which is considered a clinically meaningful treatment effect  
(Castrillo-Viguera, 2010; Writing Group for Edaravone ALS Study, 2017), the mean change in 
ALSFRS-R total score at Week 50 is estimated as -10. A common standard deviation of 10.3 was 
estimated for the change from baseline in ALSFRS-R total score. A total of 282 patients will be 
required to ensure at least 90% nominal power based on a 2-sided t-test (Type I error = 0.05) for 
detecting a non-zero treatment effect for ALSFRS-R (defined as the difference between 
ravulizumab and placebo in the mean change from baseline in ALSFRS-R total score at Week 
50). The total sample size is estimated as 354 after adjusting for a 20% dropout 
 (Cudkowicz, 2013). Furthermore, assuming approximately 82% 1-year survival rate for placebo 
group and 50% relative reduction in hazard ratio for mortality due to treatment with 
ravulizumab, this sample size will provide at least 90% nominal power based on the primary 
analysis (CAFS). 
9.2.1. 
Stratification 
Amyotrophic lateral sclerosis is a heterogeneous disease the progression of which is impacted by 
intrinsic disease factors and concomitant ALS medication use. Patients with bulbar onset ALS 
are well described to have a poorer prognosis than other ALS patients (Swinnen, 2014). To 
control this heterogeneity the study will be stratified based on known prognostic factors and 
concomitant ALS medication use. 
The site of muscle weakness onset (bulbar vs other) and riluzole use at study entry will be used 
as stratification factors (Cudkowicz, 2013). In addition, patients on stable edaravone will also be 
employed in the stratification scheme. It is anticipated that a relatively low percentage of patients 
will be on edaravone without concomitant riluzole use; the stratification scheme based on this 
assumption is provided in Table 7. 
Table 7:  
Stratification Scheme 
Stratum 
Bulbar Onset 
Riluzole Use at Screening 
Edaravone Use at Screening 
1 
No 
No 
Yes, No 
2 
No 
Yes 
Yes 
3 
No 
Yes 
No 
4 
Yes 
No 
Yes, No 
5 
Yes 
Yes 
Yes 
6 
Yes 
Yes 
No 
 
9.3. 
Populations for Analyses 
Analysis sets are defined in Table 8. 


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Table 8: 
Analysis Sets 
Population 
Description 
Randomized Set  
All randomized patients grouped by randomized treatment group (for 
reporting disposition, demographics, and baseline characteristics) 
Full Analysis Set (FAS) 
All randomized patients who receive at least 1 dose of study drug grouped by 
randomized treatment group (for reporting efficacy data) 
Per Protocol Set 
All randomized patients who receive at least 1 dose of study drug and without 
any major protocol deviations. 
Safety Set (SS) 
All patients who receive at least 1 dose of study drug grouped by treatment 
actually received (for reporting exposure and safety data). For a patient to be 
analyzed according to the treatment they actually received and not according 
to the randomization schedule, they would have to receive that treatment for 
the entire duration of Randomized Controlled Period. 
Pharmacokinetic Analysis Set 
(PKAS) 
All patients who receive at least 1 dose of study drug and have at least 1 
postdose pharmacokinetic sample 
Open-label Extension Set 
All patients who receive at least 1 dose of ravulizumab starting from Week 50 
onward (for reporting all data from the Open-Label Extension Period) 
9.4. 
Statistical Analyses 
9.4.1. 
Enrollment and Disposition 
The number of patients screened, screen failures, and randomized patients will be presented. 
Enrollment information will be presented by stratification factor and treatment group. Number of 
patients discontinued and reasons for discontinuation from the Randomized Controlled Period, 
Open-Label Extension Period, and the overall study will be summarized. 
9.4.2. 
Demographics, Baseline Characteristics, Inclusion and Exclusion Criteria, and 
Protocol Deviations 
All demographic information and baseline characteristics will be reported by treatment group 
and overall. No statistical test will be performed for homogeneity among treatment groups. The 
number and percentage of patients not meeting specific inclusion or exclusion criterion will be 
summarized. Similar summary will be provided for major protocol deviations based on 
prespecified categories. 
9.4.3. 
Medical/Surgical History, Physical Examination, and Amyotrophic Lateral 
Sclerosis History 
The medical and surgical history will be summarized by System Organ Class (SOC) and 
Preferred Term using the Medical Dictionary for Regulatory Activities (MedDRA) Version 20.1 
or higher. Amyotrophic lateral sclerosis history and abnormal physical examination will also be 
summarized. 
9.4.4. 
Prior and Concomitant Medications 
For analysis and reporting purpose, any medication started prior to first dose of study drug will 
be considered as prior medication and any medication taken by a patient that overlaps with the 
intake of study drug will be considered as concomitant medication. All prior and concomitant 
medications including ALS-specific medications during the study, if any, will be summarized. 


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9.4.5. 
Efficacy Analyses 
9.4.5.1. 
Analyses of Primary Efficacy Endpoint 
9.4.5.1.1. Primary Analysis 
The analysis of the primary endpoint will be conducted based on the Full Analysis Set. For 
patients who do not survive until Week 50, ALSFRS-R total scores will be missing which, if not 
adequately accounted for, may bias the evaluation of clinical benefit. A joint rank analysis 
(CAFS) recommended in the Food and Drug Administration guidance document on ALS 
(Sep 2019) that combines deaths and ALSFRS-R will be performed as the primary analysis. The 
CAFS is an analysis that evaluates function while accounting for missing data due to deaths in 
ALS where CAFS ranks patients’ clinical outcomes based on survival time and change in the 
ALSFRS-R total score (Berry, 2013). Each patient will be ranked either based on their last 
available change from baseline in ALSFRS-R total score within Week 50 or the time to death. 
The analysis of CAFS ranks will be based on an analysis of covariance model. The model will 
include the CAFS ranks as the dependent variable and following list of independent variables: 
treatment indicator (0 = placebo, 1 = ravulizumab), age, sex, baseline ALSFRS-R total score, 
baseline SVC, time from muscle weakness onset, and the stratification factors. A p-value less 
than the Type I error = 0.05 associated with the higher mean rank in ravulizumab group 
compared to placebo will indicate a statistically significant treatment benefit. 
9.4.5.1.1.1. Alternate Primary Analysis  
Per Committee for Medicinal Products for Human Use recommendation, an MMRM (mixed-
effects model repeated measures) based analysis of the primary endpoint will be conducted for 
EMA submission. For this analysis, the missing ALSFRS-R scores due to deaths will be imputed 
as zero (worst score imputation) and other missing data will be imputed according to placebo-
based mean trajectories. The model will include the change from baseline in ALSFRS-R total 
score at each nominal visit as the dependent variable and the following list of independent 
variables as fixed effects: actual time on study (months), the interaction between time and 
treatment (0 = placebo, 1 = ravulizumab), age, sex, baseline ALSFRS-R total score, baseline 
SVC, time from muscle weakness onset, and the stratification factors. In addition, the patient-
specific random slope will be added to the model with an unstructured variance-covariance 
matrix to model the correlations among repeated measurements within each patient. Other 
covariance structures will be implemented if a convergence issue occurs (details to be provided 
in SAP). The Kenward-Rogers method will be used to estimate the denominator degrees of 
freedom. A p-value less than the Type I error = 0.05 associated with the higher mean change in 
ALSFRS-R total score in the ravulizumab group compared to placebo will indicate a statistically 
significant treatment benefit. 
9.4.5.1.2. Sensitivity Analyses 
To establish the robustness of the primary analysis and to quantify the treatment effect 
magnitude, the following sensitivity analyses will be conducted. 


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9.4.5.1.2.1. Mixed-Effect Model for Repeated Measures (MMRM) Sensitivity Analysis 
The mixed-effect model for repeated measures (MMRM) analysis will be conducted using all 
available longitudinal data (either complete or partial). The model will include the change from 
baseline in ALSFRS-R total score at each nominal visit as the dependent variable and the 
following list of independent variables as fixed effects: actual time on study (months), the 
interaction between time and treatment (0 = placebo, 1 = ravulizumab), age, sex, baseline 
ALSFRS-R total score, baseline SVC, time from muscle weakness onset, and the stratification 
factors. In addition, the patient-specific random slope will be added to the model with an 
unstructured variance-covariance matrix to model the correlations among repeated measurements 
within each patient. Other covariance structures will be implemented if a convergence issue 
occurs (details to be provided in SAP). The Kenward-Rogers method will be used to estimate the 
denominator degrees of freedom.  
No imputation for the missing data will be performed after discontinuation from the study 
assuming the data are missing at random (MAR). The treatment effect will be evaluated via the 
estimated treatment-by-visit interaction term at Week 50.  
9.4.5.1.2.2. MMRM Sensitivity Analysis With Placebo-based Imputation 
To examine the deviation from MAR assumption, another MMRM analysis will be considered 
based on the Missing Not At Random mechanism for the missing data. The missing ALSFRS-R 
total scores after discontinuation of ravulizumab during the Randomized Controlled Period will 
be imputed based on the assumption that those patients will follow the trajectory of outcomes 
similar to the placebo arm. Patients who prematurely discontinue from the placebo arm will be 
assumed to have unobserved outcomes similar to that of placebo patients who remain on their 
randomized treatment. Missing data due to deaths will not be imputed (see Section 9.4.5.1.1.1 for 
the analysis related to the worst score imputation due to deaths). 
9.4.5.1.2.3. Vonesh Shared Parameter Model 
In addition, parametric modeling (Vonesh shared parameter model) may also be performed 
(Vonesh, 2006). In this model, both the longitudinal changes in the ALSFRS-R total score and 
the time to death are modeled together assuming a patient-specific random slope for ALSFRS-R 
trajectory. The model also assumes that a patient’s survival time has a Weibull distribution with 
a hazard that is a function of the patient’s ALSFRS-R trajectory; the treatment effect of 
ravulizumab on ALSFRS-R and mortality will be estimated separately from this joint model. 
9.4.5.1.2.4. Sensitivity Analysis by Only Including the Stratification Factors 
An analysis similar to the primary analysis for EMA submission (Section 9.4.5.1.1.1) will be 
conducted by incorporating the treatment and the stratification factors only and excluding all 
other covariates. 
9.4.5.2. 
Analyses of Secondary Efficacy Endpoint(s) 
Analysis of the secondary endpoints will be performed as follows: 


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• Time to VAFS: The treatment effect on the time to VAFS will be analyzed based on 
a Cox’s regression model treatment as a fixed effect adjusting for age, sex, baseline 
ALSFRS-R total score, baseline SVC, disease duration, and the stratification factor. 
The components of VAFS will be analyzed separately using similar models. 
• Change in SVC: The treatment effect on SVC will be evaluated based on a MMRM 
with the change from baseline in SVC percent predicted as the dependent variable 
and following list of independent variables as fixed effects: actual time on study 
(months), time and treatment interaction, age, sex, baseline ALSFRS-R total score, 
baseline SVC, disease duration, and the stratification factor. In addition, the patient-
specific random slope will be added to the model with an unstructured variance-
covariance matrix. The Kenward-Rogers method will be used to estimate the 
denominator degrees of freedom. No imputation for the missing data will be 
performed after discontinuation assuming the data are MAR. This analysis will be 
based on the endpoint defined as the change from baseline in SVC based on the in-
clinic assessment or the at-home assessment when in-clinic assessment is not 
available. 
• Change in muscle strength (HHD): For each patient, a megascore will be calculated 
at each visit by summing scores from all muscles. The scores will be normalized by 
the baseline megascore multiplied by 100 (hence the baseline score is always 100%). 
The change from the baseline score of 100% will be used for analysis. The treatment 
effect on HHD will be evaluated based on a MMRM with the change from baseline in 
HHD as the dependent variable and following list of independent variables as fixed 
effects: actual time on study (months), time and treatment interaction, age, sex, 
baseline HHD megascore, baseline ALSFRS-R total score, baseline SVC, disease 
duration, and the stratification factor. In addition, the patient-specific random slope 
will be added to the model with an unstructured variance-covariance matrix. The 
Kenward-Rogers method will be used to estimate the denominator degrees of 
freedom. No imputation for the missing data will be performed after discontinuation 
assuming the data are MAR.  
• Neurofilament light chain (NfL) concentration: The treatment effect of ravulizumab 
on NfL vs placebo will be evaluated based on a MMRM with log(NfL) as the response 
variable and with adjustments for treatment, age, and log(baseline NfL). The model will 
further include a visit-by-treatment interaction. An unstructured covariance matrix will be 
used. 
9.4.5.3. 
Analyses of Exploratory Endpoint(s) 
• Time to first instance of SVC < 50% predicted: The treatment effect on the time to 
first instance of SVC < 50% will be evaluated based on a Cox’s regression model 
with treatment as a fixed effect adjusting for age, sex, baseline ALSFRS-R total 
score, baseline SVC, disease duration, and the stratification factor. 
• Change in SF-36: The treatment effect on SF-36 physical component score (PCS) 
will be evaluated based on a MMRM with the change from baseline in SF-36 PCS as 
the dependent variable and following list of independent variables as fixed effects: 


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categorical visits, treatment and visit interaction, age, sex, baseline SF-36 PCS, 
baseline ALSFRS-R total score, baseline SVC, disease duration, and the stratification 
factor. The Kenward-Rogers method will be used to estimate the denominator degrees 
of freedom. An unstructured within subject variance-covariance matrix will be used. 
No imputation for the missing data will be performed after discontinuation assuming 
the data are MAR. 
Similar analysis will be based on SF-36 mental component score (MCS). 
• Change in EQ-5D-5L index score: The treatment effect on EQ-5D-5L index score 
will be evaluated based on a MMRM with the change from baseline in the index 
score as the dependent variable and following list of independent variables as fixed 
effects: categorical visits, treatment and treatment and visit interaction, age, sex, 
baseline EQ-5D-5L index score, baseline ALSFRS-R total score, baseline SVC, 
disease duration, and the stratification factor. The Kenward-Rogers method will be 
used to estimate the denominator degrees of freedom. An unstructured within subject 
variance-covariance matrix will be used. No imputation for the missing data will be 
performed after discontinuation assuming the data are MAR. 
• Change in EQ-5D-5L VAS score: The treatment effect on EQ-5D-5L VAS score 
will be evaluated based on a MMRM with the change from baseline in the index 
score as the dependent variable and following list of independent variables as fixed 
effects: categorical visits, treatment and treatment and visit interaction, age, sex, 
baseline EQ-5D-5L VAS score, baseline ALSFRS-R total score, baseline SVC, 
disease duration, and the stratification factor. The Kenward-Rogers method will be 
used to estimate the denominator degrees of freedom. An unstructured within subject 
variance-covariance matrix will be used. No imputation for the missing data will be 
performed after discontinuation assuming the data are MAR. 
• Change in ALSAQ-40 score: A single index score is created by adding all of the 
responses (0, 1, 2, 3, or 4) of 40 items of ALSAQ-40, dividing this total score by the 
maximal score of 160 and finally multiplying by 100. An index score of 0 indicates 
perfect health and 100 indicates worst possible health status. The treatment effect on 
ALSAQ-40 index score will be evaluated based on a MMRM with the change from 
baseline in the index score as the dependent variable and following list of 
independent variables as fixed effects: categorical visits, treatment and treatment and 
visit interaction, age, sex, baseline ALSAQ-40 index score, baseline ALSFRS-R total 
score, baseline SVC, disease duration, and the stratification factor. The 
Kenward-Rogers method will be used to estimate the denominator degrees of 
freedom. An unstructured within subject variance-covariance matrix will be used. No 
imputation for the missing data will be performed after discontinuation assuming the 
data are MAR. 
• Increase in KSS: The proportion of patients with any increase from the baseline KSS 
at Week 50 will be compared between ravulizumab and placebo. A logistic regression 
analysis will be conducted with treatment indicator as the fixed effect adjusting for 
the baseline KSS. An estimate of the odds ratio and 95% confidence interval will be 
generated. 


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9.4.5.4. 
Multiplicity Adjustment 
If the primary analysis is statistically significant, the study wise Type I error will be controlled 
using Hochberg method for multiplicity adjustment of the p-values corresponding to the two 
secondary endpoints (VAFS and change in SVC). 
9.4.6. 
Safety Analyses 
The safety and tolerability of ravulizumab will be assessed based on AEs, clinical laboratory 
findings, vital sign findings, and ECG abnormalities. Safety analyses will be performed on the 
Safety Set and Open-label extension Set based on the study period under consideration. 
9.4.6.1. 
Analysis of Adverse Events 
Analysis and reporting for AEs will be based on treatment-emergent AEs, including treatment-
emergent SAEs (TESAEs) defined as an AE with onset on or after first dose of study drug 
administration in the Randomized Controlled Period. Treatment-emergent AEs and TESAEs will 
be summarized by MedDRA SOC and Preferred Term and by relationship to the study drug; 
TEAEs will also be summarized by severity. Patient-years adjusted event rates will be generated 
to characterize long-term safety profile. 
9.4.6.2. 
Analysis of Clinical Laboratory Parameters, Vital Sign Measurements, Weight, 
and Electrocardiogram Parameters 
Laboratory measurements as well as their changes from baseline at each visit and shift from 
baseline, if applicable, will be summarized descriptively. Weight, ECG, and vital signs will also 
be summarized using descriptive analyses. 
9.4.6.3. 
Other Safety Analyses 
The number and percentage of patients in each of the C-SSRS categories and shift analyses will 
be presented. Results from pregnancy tests will be summarized. Number and percentage of 
patients in each category of the neurologic assessments will be summarized. 
9.4.7. 
Analysis of Pharmacokinetics and Pharmacodynamics, and Antidrug Antibody 
Analyses 
Individual serum concentration data for all patients who receive at least 1 dose of the study drug 
and have at least 1 post-dose PK sample will be used to derive PK parameters for ravulizumab. 
Graphs of mean serum concentration-time profiles will be constructed. Graphs of serum 
concentration-time profiles for individual patients may also be provided. Actual dose 
administration and sampling times will be used for all calculations. Descriptive statistics will be 
calculated for serum concentration data at each sampling time, as appropriate. Assessment of 
population-PK may be considered using data from this study or in combination with data from 
other studies. 
Pharmacodynamic analyses will be performed for all patients who receive at least 1 dose of 
ravulizumab and who have evaluable PD data. 
Descriptive statistics will be presented for all ravulizumab PD endpoints at each sampling time. 
The PD effects of ravulizumab will be evaluated by assessing the absolute values and changes 


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and percentage changes from baseline in free C5 serum concentrations over time, as appropriate. 
Assessments of ravulizumab PK/PD relationships may be explored using data from this study or 
in combination with data from other studies. 
For assessment of immunogenicity, the presence of confirmed positive ADAs will be 
summarized. Additionally, following confirmation of positive ADAs, samples will be assessed 
for ADA titer and presence of neutralizing antibodies.  
9.4.8. 
Analysis of Exploratory Biomarkers 
For exploratory biomarker analyses, summary statistics will be presented for observed values, 
change and percentage change from baseline. Additional details will be provided in the SAP. 
9.5. 
Interim Analysis 
One interim analysis for futility will be conducted by an IDMC to determine if the study is 
unlikely to meet its objective. If futility criteria are met, the study (both the Randomized 
Controlled Period and Open-Label Extension Period) may be terminated early, thereby limiting 
patient exposure to an ineffective drug. 
This interim analysis will be conducted when approximately 33% of patients complete the 
Week 26 visit. The futility assessment will be performed using all available ALSFRS-R data.  
The criteria for futility will be prespecified in the IDMC charter or the interim analysis plan. 
9.6. 
Delayed-Start Analysis of Long-term ALSFRS-R 
To provide additional evidence of a disease modifying effect of treatment with ravulizumab on 
disease progression, a delayed start analysis will be conducted based on an MMRM approach 
and by incorporating all data from the Randomized Controlled Period (referred to as early start) 
and the first 50 weeks of the Open-Label Extension Period (referred to as delayed start). In this 
model, the patients initially randomized to placebo will be assumed to have different ALSFRS-R 
slopes for the Randomized Controlled Period and the Open-Label Extension Period whereas for 
the patients randomized to ravulizumab, a slope common to both periods will be assumed. The 
treatment effects will be quantified by the estimated differences between the groups based on 
their original treatment arms (ravulizumab vs placebo) for both early and delayed start periods; 
the estimated difference at the end of the delayed start period will be assessed for noninferiority 
compared to the estimated difference at the end of the early start period (Liu-Seifert, 2015). 
Further details will be provided in the SAP. 
9.7. 
Data Monitoring Committee  
The safety and efficacy data of this study will be monitored by an IDMC appointed by Alexion. 
Minimally, the IDMC members will include external physicians and a statistician who have 
expertise in both the field of ALS and clinical study conduct and with no direct relationship to 
the study. Each member of the IDMC will be required to sign an agreement, including 
confidentiality and financial disclosure statements, assuring no conflicts of interest as a condition 
for membership on the committee.  


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All statistical analyses presented to the IDMC will be performed by an independent statistical 
center. The IDMC will independently evaluate safety and efficacy data from the study 
periodically and at prespecified enrollment-dependent time points. The IDMC will make 
recommendations regarding study modification or continuation based on their review and in 
accordance with the agreed upon IDMC charter. Recommendations from the IDMC will be 
relayed to an Alexion Executive Representative who will make a determination about 
implementing recommendations to modify or discontinue the study. All appropriate regulatory 
authorities and ethics committees will be notified of significant actions taken as a result of IDMC 
recommendations. To maintain study integrity and to prevent the potential introduction of bias, 
all study team members will remain blinded until the final analysis of the Randomized 
Controlled Period is conducted. Details of this process will be documented in the IDMC charter. 


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10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations 
10.1.1. 
Regulatory and Ethical Considerations 
• This study will be conducted in accordance with the protocol and with the following: 
− Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines 
− Applicable International Conference on Harmonisation (ICH) Good Clinical 
Practice (GCP) Guidelines 
− Applicable laws and regulations 
• The protocol, protocol amendments, ICF, Investigator Brochure, and other relevant 
documents (eg, advertisements) must be submitted to an IRB/IEC by the Investigator 
and reviewed and approved by the IRB/IEC before the study is initiated.  
• Any amendments to the protocol will require IRB/IEC approval before 
implementation of changes made to the study design, except for changes necessary to 
eliminate an immediate hazard to study participants.  
• The investigator will notify the IRB/IEC of deviations from the study protocol or 
GCP as defined by UK legislation as a serious breach or as required by IRB/IEC 
procedures. 
• The Investigator will be responsible for the following: 
− Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC 
− Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures 
− Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 Code of Federal Regulations (CFR), ICH guidelines, the 
IRB/IEC, European regulation 536/2014 for clinical studies (if applicable), and all 
other applicable local regulations 
10.1.2. 
Financial Disclosure 
Investigators and Sub-Investigators will provide Alexion with sufficient, accurate financial 
information as requested to allow Alexion to submit complete and accurate financial certification 
or disclosure statements to the appropriate regulatory authorities. Investigators are responsible 
for providing information on financial interests during the course of the study and for 1 year after 
completion of the study.  


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10.1.3. 
Informed Consent Process 
• It is the responsibility of the investigator to obtain signed informed consent from all 
study participants prior to any study-related procedures including screening 
assessments. If a patient is not able to sign and date the ICF due to physical 
constraint, verbal consent given by the patient and witnessed by a third party or 
legally authorized representative is allowed to complete the ICF for the patient. 
• The Investigator or his/her representative will explain the nature of the study 
(including but not limited to the objectives, potential benefits and risk, 
inconveniences, and the participant’s rights and responsibilities) to the participant or 
his/her legally authorized representative, defined according to local and country 
regulations where the study is taking place, and answer all questions regarding the 
study.  
• Participants must be informed that their participation is voluntary. Participants or 
their legally authorized representative, will be required to sign a statement of 
informed consent, or a certified translation if applicable, that meets the requirements 
of 21 CFR 50, local regulations, EU General Data Protection Regulation (GDPR), 
ICH guidelines, Health Insurance Portability and Accountability Act (HIPAA) 
requirements, where applicable, and the IRB/IEC or study center.  
• The medical record must include a statement that informed consent was obtained 
before the participant was screened in the study and the date the written consent was 
obtained. The authorized person obtaining the informed consent must also sign the 
ICF(s). 
• Participants must be re-consented to the most current version of the ICF(s) during 
their participation in the study.  
• A copy of the signed informed consent documentation (ie, a complete set of 
participant information sheets and fully executed signature pages) must be provided 
to the participant or the participant’s legally authorized representative. This document 
may require translation into the local language. Signed consent forms must remain in 
each participant’s study file and must be available for verification at any time. 
Participants who are rescreened (Section 5.4) are not required to sign a new ICF unless the prior 
ICF is dated outside of the current screening window. 
The ICF will contain a separate section that addresses the use of remaining mandatory samples 
for optional exploratory research. The participant will be required to document agreement to 
allow any remaining specimens to be used for this purpose. Participants who decline to 
participate in this optional research will document that they do not agree in this section. 
10.1.4. 
Data Protection 
• Participants will be assigned a unique identifier by Alexion. Any participant records 
or datasets that are transferred to Alexion will contain the identifier only; participant 
names or any information which would make the participant identifiable will not be 
transferred.  


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• The participant must be informed that his/her personal study-related data will be used 
by Alexion in accordance with local data protection law. The level of disclosure must 
also be explained to the participant who will be required to give consent for their data 
to be used as described in the informed consent  
• The participant must be informed that his/her medical records may be examined by 
Clinical Quality Assurance auditors or other authorized personnel appointed by 
Alexion, by appropriate IRB/IEC members, and by inspectors from regulatory 
authorities.  
10.1.5. 
Dissemination of Clinical Study Data 
Study-related information and study results may be posted on publicly accessible clinical study 
databases (eg, the US website www.clinicaltrials.gov or the EU website 
www.clinicaltrialsregister.eu), as appropriate, and in accordance with national, regional, and 
local regulations.  
10.1.6. 
Data Quality Assurance 
• All participant data relating to the study will be recorded on printed or eCRF unless 
transmitted to Alexion or designee electronically (eg, laboratory data). The 
Investigator is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF.  
• The Investigator must maintain accurate documentation (source data) that supports 
the information entered in the CRF. 
• The Investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents. 
• The Sponsor or designee is responsible for the data management of this study 
including quality checking of the data. 
• Study monitors will perform ongoing source data verification to confirm that data 
entered into the CRF by authorized site personnel are accurate, complete, and 
verifiable from source documents; that the safety and rights of participants are being 
protected; and that the study is being conducted in accordance with the currently 
approved protocol and any other study agreements, ICH GCP, and all applicable 
regulatory requirements. 
• Records and documents, including signed ICFs, pertaining to the conduct of this 
study must be retained by the Investigator for 2 years after the last marketing 
application approval, or if not approved, 2 years following the discontinuance of the 
study drug, unless local regulations or institutional policies require a longer retention 
period. No records may be destroyed during the retention period without the written 
approval of Alexion. No records may be transferred to another location or party 
without written notification to Alexion. 


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10.1.7. 
Source Documents 
• Source documents provide evidence for the existence of the participant and 
substantiate the integrity of the data collected. The Investigator or designee will 
prepare and maintain adequate and accurate source documents (eg, medical records, 
ECGs, AE and concomitant medication reporting, raw data collection forms) 
designed to record all observations and other pertinent data for each patient. 
• Data reported on the CRF that are transcribed from source documents must be 
consistent with the source documents or the discrepancies must be explained. The 
Investigator may need to request previous medical records or transfer records, 
depending on the study. Also, current medical records must be available. Source 
documents are filed at the Investigator’s site. 
10.1.8. 
Study and Site Start and Closure 
The study start date is the date on which the first participant is consented. 
The Sponsor reserves the right to close the study site or terminate the study at any time for any 
reason at the sole discretion of Alexion. Study sites will be closed after the study is completed or 
following the decision to close or terminate the study. A study site is considered closed when all 
patients have completed the end of study or ED visit, all data have been collected and entered 
into electronic data capture (EDC), all required documents and study supplies have been 
collected, and a study-site closure visit has been performed. 
The Investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by Alexion or Investigator may include but are not 
limited to: 
• Failure of the Investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, Alexion’s procedures, or GCP guidelines 
• Inadequate recruitment of participants by the Investigator 
• Discontinuation of further study drug development 
If the study is prematurely terminated or suspended, Alexion shall promptly inform the 
Investigators, the IECs/IRBs, the regulatory authorities, and any contract research 
organization(s) used in the study of the reason for termination or suspension, as specified by the 
applicable regulatory requirements. The Investigator shall promptly inform the patient and 
should assure appropriate patient therapy and/or follow-up. 
10.1.9. 
Publication Policy 
The full terms regarding publication of the results of this study are outlined in the applicable 
Clinical Study Agreement. 


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10.2. 
Appendix 2: Clinical Laboratory Tests 
• The tests detailed in Table 9 will be performed by the central laboratory. 
• Local laboratory results are only required in the event that the central laboratory 
results are not available in time for either study drug administration and/or response 
evaluation. If a local sample is required, it is important that the sample for central 
analysis is obtained at the same time. Additionally, if the local laboratory results are 
used to make either a study drug decision or response evaluation, the results must be 
entered into the CRF. 
• Protocol-specific requirements for inclusion or exclusion of participants are detailed 
in Section 5 of the protocol. 
• Additional tests may be performed at any time during the study as determined 
necessary by the Investigator or required by local regulations. 
• Women of childbearing potential should only be enrolled after a negative serum or 
urine pregnancy test.  Urine pregnancy testing will be standard for the protocol unless 
serum testing is required by local regulation or IRB/IEC and should be performed per 
the time points specified in the SoA (Section 1.3). 
• Investigators must document their review of each laboratory safety report.  


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Table 9: 
Protocol-Required Laboratory Assessments 
Chemistry Panel  
Sodium 
Potassium 
Chloride 
Bicarbonate 
Blood urea nitrogen  
Creatinine 
Glucose 
Alkaline phosphatase 
Alanine amino transferase (ALT) 
Aspartate amino transferase (AST) 
Total and direct bilirubin 
Albumin 
Total protein 
Uric acid 
Calcium 
Magnesium 
Others 
HIV (1 and 2) testing 
Human chorionic gonadotropin (β-HCG) 
pregnancy test (as needed for women of 
childbearing potential)a 
Follicle-stimulating hormone (FSH)b 
Coagulation profile (including international 
normalized ratio [INR], activated partial 
thromboplastin time [APTT])c 
Complete Blood Count (CBC) & Differential 
White blood cell count (WBC) 
WBC differential 
Red blood cell count (RBC) 
RBC mean corpuscular volume (MCV) 
RBC distribution width 
Hemoglobin 
Hematocrit 
Platelet count 
Urinalysis 
Appearance  
Specific gravity  
pH 
Protein 
Blood  
Glucose 
Ketone 
Bilirubin 
Urobilinogen 
Nitrite 
a Local urine testing will be standard for the protocol unless serum testing is required by local regulation or ethics 
committees. 
b  FSH to be performed at Screening in selected female patients to confirm postmenopausal status. 
c Coagulation to be performed at Screening for all patients and at Week 18 and Week 42 for patients in CSF 
cohort. 


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10.3. 
Appendix 3: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting 
10.3.1. 
Adverse Event Definition 
Adverse Event Definition 
• 
An AE is any untoward medical occurrence in a patient, temporally associated with the use of study drug, 
whether or not considered related to the study drug. 
• 
NOTE: An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease (new or exacerbated) temporally associated with the use of study drug. 
Events Meeting the AE Definition  
• 
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or other safety 
assessments (eg, ECG, radiological scans, vital signs measurements), including those that worsen from 
baseline, considered clinically significant in the medical and scientific judgment of the Investigator (ie, not 
related to progression of underlying disease). 
• 
Exacerbation of a chronic or intermittent pre-existing condition including either an increase in frequency 
and/or intensity of the condition. 
• 
New conditions detected or diagnosed after study drug administration even though it may have been present 
before the start of the study. 
• 
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
• 
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study drug or a concomitant 
medication. Overdose per se will not be reported as an AE/SAE unless it is an intentional overdose taken 
with possible suicidal/self-harming intent. Such overdoses should be reported regardless of sequelae. 
• 
"Lack of efficacy" or "failure of expected pharmacological action" per se will not be reported as an AE or 
SAE. Such instances will be captured in the efficacy assessments. However, the signs, symptoms, and/or 
clinical sequelae resulting from lack of efficacy will be reported as AE or SAE if they fulfil the definition of 
an AE or SAE. 
Events NOT Meeting the AE Definition  
• 
Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to the procedure is the 
AE. Situations in which an untoward medical occurrence did not occur (eg, hospitalization for elective 
surgery if planned before the signing the ICF, admissions for social reasons or for convenience).  
• 
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or detected at the start of 
the study that do not worsen.  
• 
A medication error (including intentional misuse, abuse, and overdose of the product) or use other than what 
is defined in the protocol is not considered an AE unless there is an untoward medical occurrence as a result 
of a medication error.  
• 
Cases of pregnancy that occur during maternal or paternal exposure to study intervention are to be reported 
within 24 hours of Investigator/site awareness. Data on fetal outcome and breastfeeding will be collected for 
regulatory reporting and safety evaluation.  
• 
Any clinically significant abnormal laboratory findings or other abnormal safety assessments which are 
associated with the underlying disease, unless judged by the investigator to be more severe than expected for 
the participant's condition. 
• 
The disease/disorder being studied or expected progression, signs, or symptoms of the disease/disorder being 
studied, unless more severe than expected for the participant's condition. 
• 
Situations in which an untoward medical occurrence did not occur (social and/or convenience admission to a 
hospital). 


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10.3.2. 
Serious Adverse Event Definition 
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (eg, hospitalization for signs/symptoms of the disease under study, 
death due to progression of disease). 
An SAE is defined as an AE that, at any dose: 
1. Results in death 
2. Is life-threatening 
The term 'life-threatening' in the definition of 'serious' refers to an event in which the patient was at risk of death 
at the time of the event. It does not refer to an event, which hypothetically might have caused death, if it were 
more severe.  
3. Requires inpatient hospitalization or prolongation of existing hospitalization 
In general, hospitalization signifies that the patient has been detained (usually involving at least an overnight 
stay) at the hospital or emergency ward for observation and/or treatment that would not have been appropriate in 
the physician’s office or outpatient setting. Complications that occur during hospitalization are AEs. If a 
complication prolongs hospitalization or fulfills any other serious criteria, the event is serious. When in doubt as 
to whether “hospitalization” occurred or was necessary, the AE should be considered serious. 
Hospitalization for elective treatment of a pre-existing condition that did not worsen from baseline is not 
considered an AE. 
4. Results in persistent disability/incapacity 
• 
The term disability means a substantial disruption of a person’s ability to conduct normal life functions. 
• 
This definition is not intended to include experiences of relatively minor medical significance such as 
uncomplicated headache, nausea, vomiting, diarrhea, influenza, and accidental trauma (eg, sprained ankle) 
which may interfere with or prevent everyday life functions but do not constitute a substantial disruption. 
5. Is a congenital anomaly/birth defect 
6. Other situations: 
• 
Medical or scientific judgment should be exercised in deciding whether SAE reporting is appropriate in other 
situations such as important medical events that may not be immediately life-threatening or result in death or 
hospitalization but may jeopardize the patient or may require medical or surgical intervention to prevent one 
of the other outcomes listed in the above definition. These events should usually be considered serious. 
• 
Examples of such events include invasive or malignant cancers, intensive treatment in an emergency room or 
at home for allergic bronchospasm, blood dyscrasias or convulsions that do not result in hospitalization, or 
development of drug dependency or drug abuse. 
10.3.3. 
Recording and Follow-Up of Adverse Event and/or Serious Adverse Event 
Adverse Event and Serious Adverse Event Recording 
• 
When an AE/SAE occurs, it is the responsibility of the Investigator to review all documentation (eg, hospital 
progress notes, laboratory reports, and diagnostics reports) related to the event. 
• 
The Investigator will then record all relevant AE or SAE information in the CRF. 
• 
It is not acceptable for the Investigator to send photocopies of the patient’s medical records to Alexion in lieu 
of completion of the AE/SAE CRF page. 
• 
There may be instances when copies of medical records for certain cases are requested by Alexion. In this 
case, all patient identifiers, with the exception of the patient number, will be redacted on the copies of the 
medical records before submission to Alexion. 
• 
The Investigator will attempt to establish a diagnosis of the event based on signs, symptoms, and/or other 
clinical information. Whenever possible, the diagnosis (not the individual signs/symptoms) will be 
documented as the AE/SAE. 


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Assessment of Intensity 
The Investigator will make an assessment of intensity for each AE and SAE reported during the study and assign 
it to 1 of the following categories from National Cancer Institute CTCAE v5.0, published 27 Nov 2017:  
• 
Grade 1: Mild (awareness of sign or symptom, but easily tolerated) 
• 
Grade 2: Moderate (discomfort sufficient to cause interference with normal activities) 
• 
Grade 3: Severe (incapacitating, with inability to perform normal activities) 
• 
Grade 4: Life-threatening 
• 
Grade 5: Fatal 
 
Changes in the severity of an AE should be documented to allow an assessment of the AE duration at each 
level of intensity to be evaluated. Adverse events characterized as intermittent require documentation of 
onset and duration of each episode, if the severity of the intermittent event changes. 
 
An event is defined as ‘serious’ when it meets at least 1 of the predefined outcomes as described in the 
definition of an SAE, NOT when it is rated as severe. 
 
Assessment of Causality 
• 
The Investigator is obligated to assess the relationship between the study drug and each occurrence of each 
AE or SAE. An Investigator causality assessment must be provided for all AEs (both nonserious and serious). 
This assessment must be recorded in the eCRF and on any additional forms, as appropriate. The definitions 
for the causality assessments are as follows: 
− 
Not related: There is no reasonable possibility the study intervention caused the adverse event.  
 
The adverse event has a more likely alternative etiology; it may be due to underlying or 
concurrent illness, complications, concurrent treatments, or effects of another concurrent 
drug.  
 
The event does not follow a reasonable temporal relationship to administration of the study 
intervention. 
− 
Related: There is a reasonable possibility the study intervention caused the adverse event. 
 
The adverse event has a temporal relationship to the administration of the study intervention. 
 
The event does not have a likely alternative etiology.  
 
The event corresponds with the known pharmaceutical profile of the study intervention. 
− 
There is improvement on discontinuation and/or reappearance on rechallenge. 
• 
The Investigator will use clinical judgment to determine the relationship. 
• 
Alternative causes, such as underlying disease(s), concomitant therapy, and other risk factors, as well as the 
temporal relationship of the event to study drug administration will be considered and investigated. 
• 
This protocol will use the current Investigator’s Brochure as the Reference Safety Document. The 
expectedness and reporting criteria of an SAE will be determined by Alexion, based on the Reference Safety 
Document. The Investigator will also consult the Investigator’s Brochure in his/her assessment. 
• 
For each AE/SAE, the Investigator must document in the medical notes that he/she has reviewed the AE/SAE 
and has provided an assessment of causality. 
− 
There may be situations in which an SAE has occurred, and the Investigator has minimal information to 
include in the initial report to Alexion. However, it is very important that the Investigator always 
makes an assessment of causality for every event before the initial transmission of the SAE data to 
Alexion or designee. 
• 
The Investigator may change his/her opinion of causality in light of follow-up information and send a SAE 
follow-up report with the updated causality assessment. 
• 
The causality assessment is one of the criteria used when determining regulatory reporting requirements.  
Follow-up of Adverse Events and Serious Adverse Events 
• 
The Investigator is obligated to perform or arrange for the conduct of supplemental measurements and/or 
evaluations as medically indicated or as requested by Alexion to elucidate the nature and/or causality of the 
AE or SAE as fully as possible. This may include additional laboratory tests or investigations, 
histopathological examinations, or consultation with other health care professionals. 


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Assessment of Causality 
• 
If a patient dies during participation in the study or during a recognized follow-up period, the Investigator 
will provide Alexion with a copy of any post-mortem findings including histopathology. 
• 
New or updated information will be recorded in the originally completed eCRF. 
• 
The Investigator will submit any updated SAE data to Alexion within 24 hours of receipt of the information. 
10.3.4. 
Reporting of Serious Adverse Events 
Serious Adverse Event Reporting to Alexion or designee via an Electronic Data Collection Tool 
• 
All SAEs will be recorded and reported to Alexion or designee immediately and within 24 hours of 
awareness.  
• 
The primary mechanism for reporting an SAE to Alexion or designee will be the EDC tool. 
• 
If the electronic system is unavailable at the time that the Investigator or site becomes aware of an SAE, the 
site will use the paper Contingency Form for SAE reporting via fax or email. Facsimile transmission or email 
may be used in the event of electronic submission failure. 
− 
Email: clinicalsae@alexion.com or Fax: + 1.203.439.9347 
• 
The site will enter the SAE data into the electronic system as soon as it becomes available. 
• 
When further information becomes available, the EDC should be updated within 24 hours with the new 
information and an updated SAE report should be submitted to Alexion Global Drug Safety (GDS). 
• 
After the study is completed at a given site, the electronic data collection tool will be taken off-line to prevent 
the entry of new data or changes to existing data. 
• 
If a site receives a report of a new SAE from a study patient or receives updated data on a previously reported 
SAE after the electronic data collection tool has been taken off-line, then the site can report this information 
on a paper SAE form to the Alexion medical monitor by telephone. 
Serious Adverse Event Reporting to Alexion or designee via Paper Safety Reporting Form 
• 
All SAEs will be recorded and reported to Alexion or designee immediately and within 24 hours awareness. 
• 
SAEs will be reported using the Safety Reporting Form and submitted to Alexion GDS. The Investigator 
must complete, sign, and date the SAE pages, verify the accuracy of the information recorded on the SAE 
pages with the corresponding source documents, and send a copy via email or facsimile to the contact 
information provided below: 
− 
Email: ClinicalSAE@alexion.com or Fax: + 1.203.439.9347 
• 
Additional follow-up information, if required or available, should be entered into the eCRF and sent to 
Alexion GDS within 24 hours of the Investigator or study site staff becoming aware of this additional 
information via the reporting process outlined above. 
• 
For all SAEs, the Investigator must provide the following: 
− 
Appropriate and requested follow-up information in the time frame detailed above 
− 
Causality of the serious event(s) 
− 
Treatment of/intervention for the SAE(s) 
− 
Outcome of the serious event(s) 
− 
Medical records and laboratory/diagnostic information 
• 
All forms and follow-up information submitted to Alexion GDS MUST be accompanied by a cover page 
signed by the Investigator. 
• 
Paper source documents and/or reports should be kept in the appropriate section of the study file. 


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10.4. 
Appendix 4: Contraceptive Guidance and Collection of Pregnancy 
Information 
10.4.1. 
Definitions 
Woman of Childbearing Potential (WOCBP) 
A woman is considered fertile following menarche and until becoming post-menopausal unless 
permanently sterile (see below). 
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot be 
confirmed before first dose of study drug, additional evaluation should be considered. 
Women in the following categories are not considered WOCBP: 
1. Premenarchal 
2. Premenopausal female with 1 of the following: 
• Documented hysterectomy 
• Documented bilateral salpingectomy 
• Documented bilateral oophorectomy 
For individuals with permanent infertility due to an alternate medical cause other than the 
above (eg, mullerian agenesis, androgen insensitivity), Investigator discretion should be 
applied to determining study entry. 
Note: Documentation can come from the site personnel’s: review of the patient’s medical 
records, medical examination, or medical history interview. 
3. Postmenopausal female 
• A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause.  
− A high follicle stimulating hormone (FSH) level in the postmenopausal range may 
be used to confirm a postmenopausal state in women not using hormonal 
contraception or hormonal replacement therapy (HRT). However, in the absence 
of 12 months of amenorrhea, confirmation with more than one FSH measurement 
is required.  
• Females on HRT and whose menopausal status is in doubt will be required to use one 
of the non-estrogen hormonal highly effective contraception methods if they wish to 
continue their HRT during the study. Otherwise, they must discontinue HRT to allow 
confirmation of postmenopausal status before study enrollment. 
10.4.2. 
Contraception Guidance 
Before receiving study drug, female patients who consider themselves to be postmenopausal 
must provide evidence of postmenopause based on amenorrhea for at least 1 year prior to Day 1 
visit. Confirmatory serum FSH level (> 30 IU/L) may be obtained by the Investigator at 
Screening. In the absence of 1 year of amenorrhea, multiple elevated FSH levels will be required. 


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The reason for not obtaining an FSH should be documented by the Investigator at the time of 
Screening. 
Female patients of childbearing potential must use a highly effective or acceptable method of 
contraception (as defined below) starting at Screening and continuing for at least 8 months after 
the last dose of study drug. 
Highly effective contraceptive methods include: 
• Hormonal contraception associated with inhibition of ovulation 
• Intrauterine device 
• Intrauterine hormone-releasing system 
• Bilateral tubal occlusion 
• Vasectomized partner provided that the partner is the patient’s sole sexual partner 
• Sexual abstinence defined as refraining from heterosexual intercourse during the 
entire period of risk associated with the study drug treatment; reliability of sexual 
abstinence needs to be evaluated in relation to the duration of the clinical study and 
the preferred and usual lifestyle of the patient  
Acceptable contraceptive methods include:  
• A combination of male condom with either cap, diaphragm, or sponge with 
spermicide (double barrier methods)  
The above-listed method(s) of contraception chosen for an individual patient can be determined 
by the Investigator with consideration for the patient’s medical history and concomitant 
medications. 
Patients with a spouse/partner of childbearing potential or a pregnant or breastfeeding spouse or 
partner must agree to use double barrier contraception (male condom plus appropriate barrier 
method for the female partner) while on treatment and for at least 8 months after the last dose of 
study drug. Double barrier contraception is required even with documented medical assessment 
of surgical success of a vasectomy. 
Male patients must not donate sperm and female patients must not donate ova while on treatment 
and for at least 8 months after the last dose of study drug. 
10.4.3. 
Collection of Pregnancy Information 
Pregnancy data will be collected during this study for all female participants and female 
spouses/partners of male participants, from the first dose of study intervention. Exposure during 
pregnancy (also referred to as exposure in utero) can be the result of either maternal exposure or 
transmission of drug product via semen following paternal exposure. If a female participant or a 
male participant’s female partner becomes pregnant during the conduct of this study, the 
Investigator must submit the “Pregnancy Reporting and Outcome/Breastfeeding” form to 
Alexion GDS via facsimile or email. When the outcome of the pregnancy becomes known, the 
form should be updated and submitted to Alexion GDS. If additional follow-up is required, the 
Investigator will be requested to provide the information.  


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Exposure of an infant to an Alexion product during breastfeeding must also be reported (via the 
“Pregnancy Reporting and Outcome Form/Breastfeeding”) and any AEs experienced by the 
infant must be reported to Alexion GDS or designee via email or facsimile.  
Pregnancy is not regarded as an AE unless there is a suspicion that the study intervention may 
have interfered with the effectiveness of a contraceptive medication. However, complications of 
pregnancy and abnormal outcomes of pregnancy are AEs and may meet the criteria for an SAE 
(eg, ectopic pregnancy, spontaneous abortion, intrauterine fetal demise, neonatal death, or 
congenital anomaly). Elective abortions without complications should not be reported as AEs.  
Any female participant who becomes pregnant while participating in the study will be 
discontinued from study intervention. 
10.4.3.1. Male Patients With Partners who Become Pregnant 
• The Investigator will attempt to collect pregnancy information on any male patient’s 
female partner who becomes pregnant while the male patient is in this study. This 
applies only to male patients who receive study drug. 
• After obtaining the necessary signed informed consent from the pregnant female 
partner directly, the Investigator will record pregnancy information on the appropriate 
form and submit it to Alexion within 24 hours of learning of the partner’s pregnancy. 
The female partner will also be followed to determine the outcome of the pregnancy. 
Information on the status of the mother and child will be forwarded to Alexion. 
Generally, the follow-up will be up to 3 months following the estimated delivery date. 
Any termination of the pregnancy will be reported regardless of fetal status (presence 
or absence of anomalies) or indication for the procedure. 
10.4.3.2. Female Patients who Become Pregnant 
• The Investigator will collect pregnancy information on any female patient who 
becomes pregnant while participating in this study. The initial Information will be 
recorded on the Pregnancy Outcome and Breastfeeding Form and submitted to 
Alexion within 24 hours of learning of a patient's pregnancy. 
• The patient will be followed to determine the outcome of the pregnancy. The 
Investigator will collect follow-up information on the patient and the neonate and the 
information will be forwarded to Alexion. Generally, follow-up will not be required 
for longer than 3 months beyond the estimated delivery date. Any termination of 
pregnancy will be reported, regardless of fetal status (presence or absence of 
anomalies) or indication for the procedure. 
• While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy for medical reasons will be 
reported as an AE or SAE. A spontaneous abortion (occurring at < 22 weeks 
gestational age) or still birth (occurring at > 22 weeks gestational age) is always 
considered to be an SAE and will be reported as such. Any post-study pregnancy 
related SAE considered reasonably related to the study drug by the Investigator will 
be reported to Alexion as described in Section 10.3.4. While the Investigator is not 


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obligated to actively seek this information in former study patients, he or she may 
learn of an SAE through spontaneous reporting. 
• Any female patient who becomes pregnant while participating in the study will 
discontinue study drug, and each pregnancy will be followed to term and Alexion 
notified regarding the outcome. 
 
 


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10.5. 
Appendix 5: El Escorial Criteria  
 
 


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10.6. 
Appendix 6: Amyotrophic Lateral Sclerosis Functional Rating Scale-
Revised (ALSFRS-R) 
 
 


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Appendix 6:  Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) 
(Continued) 
  


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10.7. 
Appendix 7: Amyotrophic Lateral Sclerosis Assessment 
Questionnaire (ALSAQ-40)  
 


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Appendix 7:  Amyotrophic Lateral Sclerosis Assessment Questionnaire (ALSAQ-40) 
(Continued) 
 


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Appendix 7:  Amyotrophic Lateral Sclerosis Assessment Questionnaire (ALSAQ-40) 
(Continued) 
 


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Appendix 7:  Amyotrophic Lateral Sclerosis Assessment Questionnaire (ALSAQ-40) 
(Continued) 
 


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Appendix 7:  Amyotrophic Lateral Sclerosis Assessment Questionnaire (ALSAQ-40) 
(Continued) 
 


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Appendix 7: Amyotrophic Lateral Sclerosis Assessment Questionnaire (ALSAQ-40) 
(Continued) 
 


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Appendix 7: Amyotrophic Lateral Sclerosis Assessment Questionnaire (ALSAQ-40) 
(Continued) 
 


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Appendix 7:  Amyotrophic Lateral Sclerosis Assessment Questionnaire (ALSAQ-40) 
(Continued) 
 


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Appendix 7:  Amyotrophic Lateral Sclerosis Assessment Questionnaire (ALSAQ-40) 
(Continued) 
 


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10.8. 
Appendix 8: EuroQoL 5 Dimensions (EQ-5D-5L) 
10.8.1. 
EQ-5D-5L Version for In-Clinic Use 
 


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Appendix 8: EQ-5D-5L Version for In-Clinic Use (Continued) 
 


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Appendix 8: EQ-5D-5L Version for In-Clinic Use (Continued) 
 


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10.8.2. 
EQ-5D-5L Version for Phone Interview 
 


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Appendix 8: EQ-5D-5L Version for Phone Interview (Continued) 
 


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Appendix 8: EQ-5D-5L Version for Phone Interview (Continued) 
 


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Appendix 8: EQ-5D-5L Version for Phone Interview (Continued) 
 


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10.9. 
Appendix 9: Short Form Health Survey (SF-36) 
 
 


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Appendix 9: Short Form Health Survey (SF-36) (Continued) 
 
 


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Appendix 9: Short Form Health Survey (SF-36) (Continued) 
 


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Appendix 9: Short Form Health Survey SF-36 (Continued) 
 
 


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Appendix 9: Short Form Health Survey SF-36 (Continued) 
 


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Appendix 9: Short Form Health Survey SF-36 (Continued) 
 


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10.10. 
Appendix 10: Treatment Satisfaction Questionnaire for Medication 
(TSQM-9) 
 


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Appendix 10: Treatment Satisfaction Questionnaire for Medication (TSQM-9) (Continued) 
 


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Appendix 10: Treatment Satisfaction Questionnaire for Medication (TSQM-9) (Continued) 
 


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10.11. 
Appendix 11: Columbia Suicide Severity Rating Scale  
(C-SSRS) - Screening/Baseline 
 


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Appendix 11: Columbia Suicide Severity Rating Scale (C-SSRS) - Screening/Baseline 
(Continued) 
 


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Appendix 11: Columbia Suicide Severity Rating Scale (C-SSRS) - Screening/Baseline 
(Continued) 
 


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10.12. 
Appendix 12: Columbia-Suicide Severity Rating Scale 
(C-SSRS) - Since Last Visit 
 


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Appendix 12: Columbia-Suicide Severity Rating Scale (C-SSRS) - Since Last Visit 
(Continued) 
 


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Appendix 12: Columbia-Suicide Severity Rating Scale (C-SSRS) - Since Last Visit 
(Continued) 
 


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10.13. 
Appendix 13: Management of Potential Infusion-Associated Adverse 
Events During Study Drug Administration 
Intravenous and infusion-associated reactions are a potential risk with the use of mAbs; these 
reactions can be nonimmune or immune-mediated (eg, hypersensitivity reactions). Signs and 
symptoms may include headache, fever, facial flushing, pruritus, myalgia, nausea, chest 
tightness, dyspnea, vomiting, erythema, abdominal discomfort, diaphoresis, shivers, 
hypertension, lightheadedness, hypotension, palpitations, and somnolence. Signs and symptoms 
of hypersensitivity or allergic reactions may include hives, swollen face, eyelids, lips, or tongue, 
or trouble with breathing. 
All administration-, IV-, and infusion-associated reactions will be reported to the Investigator 
and qualified designee. The Investigator and qualified designee are responsible for detecting, 
documenting, and recording events that meet the definition of AE or SAE and remain 
responsible for following up events that are serious, considered related to the study drug, or 
study procedures; or that caused the patient to discontinue the study drug (Section 7). 
Definitions and procedures for recording, evaluating, follow-up, and reporting AEs and SAEs are 
outlined in Section 10.3. 
Patients who experience a reaction during the administration of study drug should be treated 
according to institutional guidelines.  
Patients who experience a severe reaction during administration of study drug resulting in 
discontinuation of study drug should undergo all scheduled safety, PK, and PD evaluations 
required by the protocol. The Sponsor must be notified within 24 hours of any infusion reaction 
requiring interruption or discontinuation of study drug. All AEs that may indicate an 
infusion-related response will be graded according to the CTCAE v5.0 or higher. 
If anaphylaxis occurs according to the criteria listed in Table 10, then administration of SC 
epinephrine (1/1000, 0.3 mL to 0.5 mL, or equivalent) should be considered. In the case of 
bronchospasm, treatment with an inhaled beta agonist also should be considered. Patients 
administered an antihistamine for the treatment or prevention of an infusion reaction should be 
given appropriate warnings about drowsiness and impairment of driving ability before being 
discharged from the center. 
 


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Table 10: 
Clinical Criteria for Diagnosing Anaphylaxis 
Anaphylaxis is highly likely when any 1 of the following 3 criteria is fulfilled: 
• 
Acute onset of an illness (minutes to several hours) with involvement of the skin, mucosal tissue, or both 
(eg, generalized hives, pruritus or flushing, swollen lips-tongue-uvula), and at least 1 of the following: 
o 
Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, reduced PEF, hypoxemia) 
o 
Reduced BP or associated symptoms of end-organ dysfunction (eg, hypotonia [collapse], syncope, 
incontinence) 
• 
Two or more of the following that occur rapidly after exposure to a likely allergen for that patient (minutes 
to several hours): 
o 
Involvement of the skin-mucosal tissue (eg, generalized hives, itch-flush, swollen lips/tongue/uvula) 
o 
Respiratory compromise (eg, dyspnea, wheeze/bronchospasm, stridor, reduced PEF, hypoxemia) 
o 
Reduced BP or associated symptoms (eg, hypotonia [collapse], syncope, incontinence) 
o 
Persistent gastrointestinal symptoms (eg, crampy abdominal pain, vomiting) 
• 
Reduced BP after exposure to known allergen for that patient (minutes to several hours): 
o 
Systolic BP of less than 90 mmHg or greater than 30% decrease from that patient’s baseline 
Abbreviations: BP = blood pressure; PEF = peak expiratory flow 
Source: (Sampson, 2006) 
 
 


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10.14. 
Appendix 14: COVID-19 Risk Assessment  
ALS is a severe disease that can cause irreversible morbidity and even mortality, if untreated. As 
such, and due to the limited number of available treatment options, the benefit a patient may 
receive from a therapeutic study is potentially significant. Ravulizumab inhibits terminal 
complement activation. Apart from the predictable risk of infection with Neisseria species, which 
is well-known and directly related to its mechanism of action, the mechanism which might lead 
to other serious infections including viral infections in patients treated with ravulizumab remains 
unclear. The Principal Investigator will therefore balance the risk/benefit considerations in their 
patient, taking these factors into account.  
The potential risks identified and mitigation measures put in place in light of the COVID-19 
pandemic are provided in Table 11. 
Table 11: 
Potential Risks and Mitigation Measures due to COVID-19 
Risks Category 
Summary of Data/ 
Rationale for Risk 
Mitigation Strategy 
Potential risks 
Potentially higher risk 
population for 
SARS-CoV-2 
infection 
ALS is a vulnerable patient population in whom a 
respiratory infection may have severe consequences. 
It is unknown how ALS may impact the risk for 
COVID-19 infection. 
During the time that the 
COVID-19 pandemic is active, 
Alexion will recommend that 
sites in a position to start the 
study and enroll participants 
follow the national and 
institutional guidances 
regarding prevention of 
SARS-CoV-2 infection. 
 
Additionally, during that time 
period, it is expected that 
Investigators and their staff will 
take all possible precautions in 
order to minimize a 
participant’s potential exposure 
to SARS-CoV-2 infection. 
Depending on the site, this will 
consist of measures such as 
social distancing, temperature 
screening, enhanced cleaning, 
and use of personal protective 
equipment for participants, 
staff, and caregivers as 
necessary. 
Healthcare institution 
availability for 
non-COVID-19 
related activities  
COVID-19 pandemic may impact the workload of 
healthcare institutions globally and may reduce staff 
availability to perform non-urgent activities and 
non-COVID-19 related activities. 
 
During the time that the 
COVID-19 pandemic is active, 
Alexion will not open study 
sites or enroll new participants 
at sites unless the sites have the 
resourcing and capabilities to 
implement the study per 
protocol. 


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Table 11: 
Potential Risks and Mitigation Measures due to COVID-19 
Risks Category 
Summary of Data/ 
Rationale for Risk 
Mitigation Strategy 
Potential risks 
Data quality and 
integrity 
Lack of availability of site personnel to perform 
study assessments and capture study specific data in 
a timely manner and to maintain adequate quality 
standards. 
 
Lack of availability of site personnel to ensure 
adequate and continuous chain of custody, storage 
conditions, and monitoring for investigational 
product and biological samples. 
 
Inability of study monitors and quality personnel to 
conduct in-person visits to exercise adequate 
oversight of study execution at investigational sites. 
 
Missing data (COVID-19 pandemic may impact 
study visit schedules, and increase missed visits 
and/or participant study discontinuations 
inadvertently resulting in missing data [eg, for 
protocol-specified procedures]). 
During the time that the 
COVID-19 pandemic is active, 
Alexion will only open study 
sites that report enough 
personnel capacity to 
sufficiently conduct clinical 
study-related activities.  
 
During this timeframe, 
participants eligibility as well as 
site capacity will be reviewed 
by the site Investigator and the 
study Medical Monitor (or 
delegate) prior to Screening. 
Each site is also evaluated for 
the capacity to perform remote 
monitoring visits and remote 
source data verification. 
 
During the time that the 
COVID-19 pandemic is active, 
it will be important to capture 
specific information in the 
eCRF that explains the reason 
the data are missing (eg, missed 
study visits or participant study 
discontinuations due to 
COVID-19). 
Abbreviation: ALS = amyotrophic lateral sclerosis; COVID-19 = coronavirus disease 2019; eCRF = electronic case 
report form; SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2 
 


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10.15. 
Appendix 15: Abbreviations 
Abbreviation 
Definition 
ADA 
antidrug antibody 
AE 
adverse event 
AESI 
adverse event of special interest 
aHUS 
atypical hemolytic uremic syndrome 
ALS 
amyotrophic lateral sclerosis 
ALSAQ-40 
amyotrophic lateral sclerosis assessment questionnaire 
ALSFRS-R 
revised amyotrophic lateral sclerosis functional rating scale 
ANCOVA 
analysis of covariance 
C5 
complement component 5 
CAFS 
combined analysis of function and survival 
CFR 
Code of Federal Regulations 
CIOMS 
Council for International Organizations of Medical Sciences 
CNS 
central nervous system 
COVID-19 
coronavirus disease 2019 
CRF 
case report form 
CSF 
cerebrospinal fluid 
C-SSRS 
Columbia-suicide severity rating scale 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
ED 
early discontinuation 
EDC 
electronic data capture 
EOS 
End of Study 
EOT 
End of Treatment 
EQ-5D-5L 
European Quality of Life Health 5-item questionnaire 
EQ VAS 
European Quality of Life Visual Analog Scale 
EuroQoL 
European Quality of Life 
FSH 
follicle stimulating hormone 
FVC 
forced vital capacity 
GCP 
Good Clinical Practice 
GDS 
Global Drug Safety 
gMG 
generalized myasthenia gravis 
HHD 
handheld dynamometry 
HIV 
human immunodeficiency virus 
HRT 
hormonal replacement therapy 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IDMC 
Independent Data Monitoring Committee 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
IV 
intravenous 
IVIg 
intravenous immunoglobulin 
KSS 
King’s staging system 


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Abbreviation 
Definition 
mAb 
monoclonal antibody 
MAR 
missing at random 
MedDRA 
Medical Dictionary for Regulatory Activities 
NfL 
neurofilament light chain  
NIV 
noninvasive ventilation 
NMOSD 
neuromyelitis optica spectrum disorder 
P 
postdose (sample) 
PAV 
permanent assisted ventilation 
PD 
pharmacodynamic(s) 
PE 
plasma exchange 
PK 
pharmacokinetic(s) 
PNH 
paroxysmal nocturnal hemoglobinuria 
PP 
plasmapheresis 
q8w 
every eight weeks 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SARS-CoV-2 
severe acute respiratory syndrome coronavirus 2 
SF-36 
short form health survey 
SoA 
schedule of activities 
SOC 
System Organ Class 
SVC 
slow vital capacity 
T 
trough (predose) 
TEAE 
treatment-emergent adverse event 
TESAE 
treatment-emergent serious adverse event 
USPI 
United States Prescribing Information 
VAFS 
ventilation assistance-free survival 
WOCBP 
woman of child-bearing potential 
 
 


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10.16. 
Appendix 16: Protocol Amendment History 
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the Table of Contents (TOC). Minor country-specific changes to protocol 
ALXN1210-ALS-308 have been implemented with country-specific amendments (Table 12). 
Changes from these amendments have been included in the current amendment if appropriate for 
global execution. 
Table 12: 
ALXN1210-ALS-308 Protocol History 
Document 
Date of Issue 
Overall Rationale for the Amendment 
Original Protocol 
26 Nov 2019 
 
Amendment 1 (Sweden) 
09 Mar 2020 
To provide a minor update on the contraception methods. 
Amendment 2 (France) 
08 Apr 2020 
To provide minor updates on the schedule of C-SSRS 
screening/baseline assessment and coagulation test sample 
collection, as well as the treatment allocation unblinding 
procedure. 
Amendment 2.1 (France) 
25 Sep 2020 
To add allowance for home and alternate clinic visits. 
Amendment 3 (Germany) 
14 Apr 2020 
To provide a minor update on the contraception methods. 
Amendment 4 (Denmark) 
26 May 2020 
To provide a minor update on the expected end-of-study 
date. 
Amendment 5 (Global) 
15 Oct 2020 
To update study procedures: ventilator utilization at all 
visits, timing of PK and ADA sampling, allowance of home 
or alternative healthcare facility visits and home slow vital 
capacity (SVC) assessment, and deletion of selected Short-
Form Health Survey (SF-36) assessments, selected 
DNA/RNA sample collections, and selected handheld 
dynamometry (HHD) assessments. Updates also included 
addition of a second methodology for the primary analysis. 
Amendment 5.1 (Sweden) 
04 Nov 2020 
To implement changes in global Amendment 5 and retain 
consistency with country-specific changes detailed in 
Amendment 1. 
Amendment 5.2 (France) 
04 Nov 2020 
To implement changes in global Amendment 5 and retain 
consistency with country-specific changes detailed in 
Amendments 2 and 2.1. 
Amendment 5.3 (Denmark) 
04 Nov 2020 
To implement changes in global Amendment 5 and retain 
consistency with country-specific changes detailed in 
Amendment 4. 
Amendment 5.4 (Germany) 
20 Apr 2021 
To implement changes in global Amendment 5, retain 
consistency with country-specific changes detailed in 
Amendment 3, and add the option for remote source data 
verification wherever permitted by local regulations when 
onsite study monitoring activities are restricted as a result 
of the COVID-19 pandemic. 
Amendment 5.5 (United 
Kingdom) 
27 Apr 2021 
To provide guidance to study sites in the United Kingdom 
(UK) that reflects the current practices for 
recommendations related to COVID-19 vaccinations. 
Amendment 6.0 (Global) 
 
To allow patients to switch from the 10 mg/mL to the 
100 mg/mL formulation of ravulizumab with no change in 
weight-based dosing at or after Week 52 in the OLE Period 
and to change from 2 to 1 planned interim analysis. 
Abbreviations: ADA = antidrug antibody; COVID-19 = coronavirus disease 2019; C-SSRS = Columbia-suicide 
severity rating scale; DNA = deoxyribonucleic acid; OLE = Open-Label Extension; PK = pharmacokinetic(s); 
RNA = ribonucleic acid 


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Lobsiger CS, Boillée S, Pozniak C, et al. C1q induction and global complement pathway 
activation do not contribute to ALS toxicity in mutant SOD1 mice. Proceedings of the National 
Academy of Sciences. 2013;110(46):E4385-E4392. 
 
Mantovani S, Gordon R, Macmaw JK, et al. Elevation of the terminal complement activation 
products C5a and C5b-9 in ALS patient blood. J Neuroimmunol. 2014;276(1-2):213-218. 
 
Mehta P, Kaye W, Raymond J, et al. Prevalence of Amyotrophic Lateral Sclerosis - United 
States, 2015. MMWR Morb Mortal Wkly Rep. 2018;67(46):1285-1289. 
 
Meyer T, Funke A, Munch C, et al. Real world experience of patients with amyotrophic lateral 
sclerosis (ALS) in the treatment of spasticity using tetrahydrocannabinol:cannabidiol 
(THC:CBD). BMC neurology. 2019;19(1):222. 
 
Nowicka N, Juranek J, Juranek JK, Wojtkiewicz J. Risk Factors and Emerging Therapies in 
Amyotrophic Lateral Sclerosis. International journal of molecular sciences. 2019;20(11). 
 


Protocol Amendment 6.0 
ALXN1210-ALS-308 
23 Jun 2021 
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Orsini M, Oliveira AB, Nascimento OJ, et al. Amyotrophic lateral sclerosis: new perpectives and 
update. Neurol Int. 2015;7(2):5885. 
Paganoni S, Cudkowicz M, Berry JD. Outcome measures in amyotrophic lateral sclerosis clinical 
trials. Clin Invest. 2014;4(7):605-618. 
Parker SE, Hanton AM, Stefanou SN, Noakes PG, Woodruff TM, Lee JD. Revisiting the role of 
the innate immune complement system in ALS. Neurobiol Dis. 2019;127:223-232. 
Paulukonis ST, Roberts EM, Valle JP, Collins NN, English PB, Kaye WE. Survival and Cause of 
Death among a Cohort of Confirmed Amyotrophic Lateral Sclerosis Cases. PLOS ONE. 2015. 
Pittock SJ, Lennon VA, McKeon A, et al. Eculizumab in AQP4-IgG-positive relapsing 
neuromyelitis optica spectrum disorders: an open-label pilot study. The Lancet Neurology. 
2013;12(6):554-562. 
Pittock SJ, Berthele A, Fujihara K, et al. Eculizumab in aquaporin-4–positive neuromyelitis 
optica spectrum disorder. N Engl J Med. 2019;381(7):614-625. 
Sampson HA, Munoz-Furlong A, Campbell RL, et al. Second symposium on the definition and 
management of anaphylaxis: summary report--Second National Institute of Allergy and 
Infectious Disease/Food Allergy and Anaphylaxis Network symposium. J Allergy Clin Immunol. 
2006;117(2):391-397. 
Schrag A, Selai C, Jahanshahi M, Quinn NP. The EQ-5D--a generic quality of life measure-is a 
useful instrument to measure quality of life in patients with Parkinson's disease. J Neurol 
Neurosurg Psychiatry. 2000;69(1):67-73. 
Shefner JM, Liu D, Leitner ML, et al. Quantitative strength testing in ALS clinical trials. 
Neurology. 2016;87(6):617-624. 
Stewart AL, Hays RD, Ware JE, Jr. The MOS short-form general health survey. Reliability and 
validity in a patient population. Med Care. 1988;26(7):724-735. 
Swinnen B, Robberecht W. The phenotypic variability of amyotrophic lateral sclerosis. Nature 
Reviews Neurology. 2014;10:661-670. 
Vonesh EF, Greene T, Schluchter MD. Shared parameter models for the joint analysis of 
longitudinal data and event times. Stat Med. 2006;25(1):143-163. 
Ware J, Sherbourne C. The MOS 36-item short-form health survey (SF-36): I. conceptual 
framework and item selection. Med Care. 1992;30:473-483. 
Woodruff TM, Lee JD, Noakes PG. Role for terminal complement activation in amyotrophic 
lateral sclerosis disease progression. Proc Natl Acad Sci U S A. 2014;111(1):E3-4. 


Protocol Amendment 6.0 
ALXN1210-ALS-308 
23 Jun 2021 
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Writing Group for Edaravone ALS Study. Safety and efficacy of edaravone in well defined 
patients with amyotrophic lateral sclerosis: a randomised, double-blind, placebo-controlled trial. 
Lancet Neurol. 2017;16(7):505-512. 


 
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SAP_001.pdf: 
A Phase 3, Double-Blind, Randomized, Placebo-Controlled, 
Parallel Group, Multicenter Study With an Open-Label 
Extension to Evaluate the Efficacy and Safety of 
Ravulizumab in Patients With Amyotrophic Lateral 
Sclerosis (ALS) 
Unique Protocol ID: 
ALXN1210-ALS-308 
NCT Number: 
NCT04248465 
EudraCT Number: 
2019-004619-30 
Date of SAP: 
18 November 2021 
 


Alexion Pharmaceuticals 
Statistical Analysis Plan 
Protocol Number: ALXN1210-ALS-308 (Amendment 6) 
18Nov2021, Version 2.0 
Page 1 of 49 
Alexion Confidential 
TITLE PAGE 
STATISTICAL ANALYSIS PLAN 
Final Analysis of Study 
Version Number: 2.0 
Protocol Title: A Phase 3, Double-Blind, Randomized, Placebo-Controlled, Parallel-Group, 
Multicenter Study with an Open-Label Extension to Evaluate the Efficacy and Safety of 
Ravulizumab in Patients With Amyotrophic Lateral Sclerosis (ALS) 
 
Protocol Number: ALXN1210-ALS-308  
 
Protocol Amendment Number: 6 
 
Compound Number: ALXN1210 
 
Short Title: An Efficacy and Safety Study of Ravulizumab in ALS Patients 
Sponsor Name: Alexion Pharmaceuticals Inc.  
Legal Registered Address: 121 Seaport Boulevard, Boston, MA 02210 
 
 
 
 
 
 
 
 
 
 
 
 
Author: 
 Ph.D., 
 Ph.D. 
Version Date: 18Nov2021 
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Alexion Pharmaceuticals 
Statistical Analysis Plan 
Protocol Number: ALXN1210-ALS-308 (Amendment 6) 
18Nov2021, Version 2.0 
Page 2 of 49 
Alexion Confidential 
TABLE OF CONTENTS 
TITLE PAGE ...................................................................................................................................1 
VERSION HISTORY ......................................................................................................................6 
APPROVAL SIGNATURES...........................................................................................................7 
1. 
INTRODUCTION ........................................................................................................8 
1.1. 
Objectives, Estimands and/or Endpoints ......................................................................8 
1.2. 
Study Design .................................................................................................................9 
2. 
STATISTICAL HYPOTHESES ................................................................................11 
2.1. 
Primary Hypothesis ....................................................................................................11 
2.2. 
Secondary Hypotheses ................................................................................................11 
2.2.1. 
Key Secondary Hypotheses ........................................................................................11 
2.2.2. 
Supportive Secondary Hypotheses .............................................................................11 
2.3. 
Tertiary Hypotheses ....................................................................................................11 
3. 
SAMPLE SIZE DETERMINATION .........................................................................12 
4. 
ANALYSIS SETS ......................................................................................................12 
5. 
STATISTICAL ANALYSES .....................................................................................13 
5.1. 
General Considerations ...............................................................................................13 
5.2. 
Study Participants .......................................................................................................14 
5.3. 
Primary Estimand and Analysis..................................................................................15 
5.3.1. 
Estimand .....................................................................................................................15 
5.3.2. 
Main Analytical Approach .........................................................................................17 
5.3.3. 
Sensitivity Analysis ....................................................................................................17 
5.3.3.1. 
Sensitivity Analysis: Mixed-effect Model for Repeated Measures ............................17 
5.3.4. 
Other Analyses ............................................................................................................18 
5.4. 
Secondary Estimands and/or Endpoints Analysis ......................................................19 
5.4.1. 
Key Secondary Estimands ..........................................................................................19 
5.4.1.1. 
Time to Ventilation Assistance Free Survival ............................................................19 
5.4.1.2. 
Slow Vital Capacity Percent Predicted .......................................................................20 
5.4.1.3. 
Other Analyses for Slow Vital Capacity ....................................................................21 
5.4.2. 
Supportive Secondary Endpoints and Analysis ..........................................................21 
5.4.2.1. 
Muscle Strength Measured by Handheld Dynamometry ............................................21 
5.4.2.2. 
Neurofilament Light Chain (NfL) Concentration .......................................................21 


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Statistical Analysis Plan 
Protocol Number: ALXN1210-ALS-308 (Amendment 6) 
18Nov2021, Version 2.0 
Page 3 of 49 
Alexion Confidential 
5.5. 
Tertiary/Exploratory Endpoints and Analyses............................................................21 
5.6. 
Safety Analyses ..........................................................................................................21 
5.6.1. 
Extent of Exposure .....................................................................................................21 
5.6.2. 
Adverse Events ...........................................................................................................23 
5.6.3. 
Laboratory Tests .........................................................................................................27 
5.6.4. 
Vital Signs ..................................................................................................................28 
5.6.5. 
Electrocardiogram .......................................................................................................29 
5.6.6. 
Physical Examination .................................................................................................30 
5.6.7. 
Neurological Examination ..........................................................................................30 
5.6.8. 
Columbia-Suicide Severity Rating Scale ....................................................................30 
5.6.9. 
Coronavirus Disease 2019 Exposure ..........................................................................31 
5.7. 
Other Analyses ............................................................................................................31 
5.7.1. 
Pharmacokinetic Analyses ..........................................................................................31 
5.7.2. 
Pharmacodynamic Analyses .......................................................................................31 
5.7.3. 
Biomarker Assessments ..............................................................................................32 
5.7.4. 
Immunogenicity ..........................................................................................................32 
5.7.5. 
Subgroup Analyses .....................................................................................................32 
5.7.5.1. 
Subgroup Analyses for Adverse Events .....................................................................32 
5.7.5.2. 
Subgroup Analyses for Laboratory Data ....................................................................32 
5.8. 
Interim Analyses .........................................................................................................32 
5.8.1. 
Data Monitoring Committee .......................................................................................32 
6. 
SUPPORTING DOCUMENTATION ........................................................................33 
6.1. 
Appendix 1: Demographics, Baseline Characteristics, Inclusion/Exclusion 
Criteria, Protocol Deviations, Medical/Surgical History, Prior/Concomitant 
Medication ..................................................................................................................33 
6.1.1. 
Demographics and Other Baseline Characteristics .....................................................33 
6.1.1.1. 
Demographics .............................................................................................................33 
6.1.1.2. 
Baseline Characteristics ..............................................................................................34 
6.1.2. 
Inclusion/Exclusion Criteria .......................................................................................36 
6.1.3. 
Protocol Deviations ....................................................................................................36 
6.1.4. 
Medical and Surgical History .....................................................................................36 
6.1.5. 
Prior and Concomitant Medications / Therapies ........................................................36 
6.1.5.1. 
Stable Riluzole or Edaravone Use ..............................................................................37 


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Statistical Analysis Plan 
Protocol Number: ALXN1210-ALS-308 (Amendment 6) 
18Nov2021, Version 2.0 
Page 4 of 49 
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6.2. 
Appendix 2: Technical Specifications for Derived Variables ....................................37 
6.2.1. 
Derivation of Treatment-emergent Adverse Events for Missing or 
Incomplete Date of Onset ...........................................................................................37 
6.2.2. 
Derivation of Prior and Concomitant Medication for Missing or Incomplete 
Dates ...........................................................................................................................38 
6.2.3. 
Combined Assessment of Function and Survival Scoring Example ..........................39 
6.2.4. 
Short-Form Health Survey ..........................................................................................41 
6.2.5. 
Amyotrophic Lateral Sclerosis Assessment Questionnaire ........................................41 
6.2.6. 
Handheld Dynamometry .............................................................................................41 
6.2.7. 
Treatment Satisfaction Questionnaire for Medicine ...................................................41 
6.2.8. 
European Quality of Life Health 5-item Questionnaire Health State Index 
Calculations ................................................................................................................42 
6.2.9. 
Analysis Windows ......................................................................................................43 
6.2.9.1. 
Rules for Selecting the Analysis Records ...................................................................44 
6.3. 
Appendix 3: List of Abbreviations .............................................................................44 
6.4. 
Appendix 4: Changes to Protocol-planned Analyses .................................................46 
7. 
REFERENCES ...........................................................................................................49 
 
LIST OF TABLES 
Table 1: 
Randomization Strata ..................................................................................................10 
Table 2: 
Analysis Sets ...............................................................................................................12 
Table 3: 
Overview of Estimands, Intercurrent Events, and Analyses Related to the 
Primary Endpoint ........................................................................................................18 
Table 4: 
Variables for Study Duration, Exposure, and Treatment Compliance .......................22 
Table 5: 
Definition of TEAEs ...................................................................................................24 
Table 6: 
Overview of Adverse Event Analysis by Study Period ..............................................25 
Table 7: 
Abnormality Criteria for Liver Function Laboratory Values and Analysis 
Timepoints ..................................................................................................................27 
Table 8: 
Overview of Analysis of Laboratory Data for RCP (SS) ...........................................28 
Table 9: 
Potentially Clinically Significant Abnormality Criteria for the Vital Signs ...............28 
Table 10: Overview of Analysis of Vital Sign Data for RCP (SS) .............................................29 
Table 11: Potentially Clinically Significant Abnormality Criteria for QT and QTcF ................29 
Table 12: Overview of Analysis of ECG Data for RCP (SS) .....................................................30 
Table 13: C-SSRS Categories for Reporting ..............................................................................30 


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Statistical Analysis Plan 
Protocol Number: ALXN1210-ALS-308 (Amendment 6) 
18Nov2021, Version 2.0 
Page 5 of 49 
Alexion Confidential 
Table 14: Composite Endpoints Based on C-SSRS ....................................................................31 
Table 15: Race Categories ..........................................................................................................33 
Table 16: Ethnicity Categories ....................................................................................................34 
Table 17: Baseline Characteristics ..............................................................................................34 
Table 18: Protocol Deviation Categories ....................................................................................36 
Table 19: Example of CAFS Scoring and Ranking ....................................................................40 
Table 20: Algorithms for ALSAQ-40 Subscore Calculation ......................................................41 
Table 21: Algorithms for TSQM-9 Domain Score Calculation ..................................................41 
Table 22: EQ-5D-5L US Composite Time Trade-off Value Set ................................................42 
Table 23: Analysis Windows for Randomized Controlled Period..............................................43 
Table 24: Analysis Windows for Open-Label Extension Period ................................................43 
 
LIST OF FIGURES 
Figure 1: 
Study Design Schematic .............................................................................................11 
Figure 2: 
Participant Disposition Flowchart ..............................................................................15 
 
 


Alexion Pharmaceuticals 
Statistical Analysis Plan 
Protocol Number: ALXN1210-ALS-308 (Amendment 6) 
18Nov2021, Version 2.0 
Page 6 of 49 
Alexion Confidential 
VERSION HISTORY 
 
This statistical analysis plan (SAP) for study ALXN1210-ALS-308 is based on protocol 
amendment 6 dated 23Jun2021.  
SAP Version 
Version Date 
Change 
Rationale 
1 
2July2021 
Not Applicable 
Original version 
2 
18Nov2021 
See Section 6.4 
(Appendix 4) for 
detailed changes. 
Due to the study meeting the pre-specified futility 
criterion during the first interim analysis conducted 
by IDMC, the scope of the analyses for this study 
has been revised and is reflected in this SAP 
amendment 
 
 


Alexion Pharmaceuticals
Statistical Analysis Plan
Protocol Number: ALXN1210-ALS-308 (Amendment 6)
18Nov2021, Version 2.0
Page 7 of 49
Alexion Confidential
APPROVAL SIGNATURES
 Associate Director, Biostatistics
Date dd Mmm yyyy
Date dd Mmm yyyy
Date dd Mmm yyyy
Date dd Mmm yyyy
 Executive Director, Clinical development
Date dd Mmm yyyy
PPD
PPD
PPD
PPD
PPD
PPD
PPD


Alexion Pharmaceuticals 
Statistical Analysis Plan 
Protocol Number: ALXN1210-ALS-308 (Amendment 6) 
18Nov2021, Version 2.0 
Page 8 of 49 
Alexion Confidential 
1. 
INTRODUCTION 
This statistical analysis plan (SAP) describes the statistical methods for analyzing data for the 
study ALXN1210-ALS-308, “A Phase 3, Double-Blind, Randomized, Placebo-Controlled, 
Parallel-Group, Multicenter Study With an Open-Label Extension to Evaluate the Efficacy and 
Safety of Ravulizumab in Patients With Amyotrophic Lateral Sclerosis (ALS)”. 
The scope of the analyses for this study has been revised and is reflected in this SAP amendment 
due to the study meeting the prespecified futility criterion. This SAP amendment will be 
finalized prior to the final database lock. No separate SAP will be developed for the Open-Label 
Extension (OLE) Period of the study. 
The table, figure, and listing specifications will be provided in a separate data presentation plan 
document. 
1.1. 
Objectives, Estimands and/or Endpoints 
Objective 
Estimand/Endpoint 
Primary 
To evaluate the effect of ravulizumab compared with 
placebo on amyotrophic lateral sclerosis functional 
rating scale-revised (ALSFRS-R) score in adult 
patients with ALS 
Estimand: Difference in mean combined assessment of 
function and survival (CAFS) score between 
ravulizumab and placebo in the eligible ALS patient 
population after accounting for the intercurrent event 
(ICE) of death into the CAFS score calculation using 
the composite strategy. See Section 5.3 for details. 
Secondary 
To evaluate the effect of ravulizumab compared with 
placebo on ventilation assistance-free survival (VAFS) 
in adult patients with ALS 
Estimand: Hazard ratio (ravulizumab versus placebo) 
of VAFS event in the eligible ALS patient population 
using treatment-policy strategy 
To evaluate the effect of ravulizumab compared with 
placebo on respiratory function in adult patients with 
ALS 
Estimand: Difference in mean change in slow vital 
capacity (SVC) percent predicted score between 
ravulizumab and placebo at Week 50 in the eligible 
ALS patient population using treatment-policy strategy 
To evaluate the safety of ravulizumab compared with 
placebo in adult patients with ALS 
Endpoint: Incidence of treatment-emergent adverse 
events (TEAEs), treatment-emergent serious adverse 
events (TESAEs), and TEAEs leading to study drug 
discontinuation 
To evaluate the effect of ravulizumab compared with 
placebo on muscle strength in adult patients with ALS 
Endpoint: Percent change in combined muscle 
megascore from Baseline at Week 50 as assessed by 
handheld dynamometry (HHD) 
To evaluate the effect of ravulizumab compared with 
placebo on neurofilament light chain (NfL) 
concentrations in adult patients with ALS 
Endpoint: NfL concentrations in serum at Week 50 
To characterize the pharmacokinetics (PK) of 
ravulizumab in adult patients with ALS 
Endpoint: Change in serum ravulizumab concentration 
over the study duration 
To characterize the pharmacodynamics (PD) of 
ravulizumab in adult patients with ALS 
Endpoint: Change in serum-free complement 
component 5 (C5) concentration over the study 
duration 
To characterize the immunogenicity of ravulizumab in 
adult patients with ALS  
Endpoint: Presence and titer of anti-drug antibodies 
(ADAs) 


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Statistical Analysis Plan 
Protocol Number: ALXN1210-ALS-308 (Amendment 6) 
18Nov2021, Version 2.0 
Page 9 of 49 
Alexion Confidential 
Objective 
Estimand/Endpoint 
Exploratory 
To evaluate the effect of ravulizumab compared with 
placebo on respiratory function in adult patients with 
ALS 
Endpoint: Time to the first instance of SVC < 50% 
predicted during the 50-week Randomized Controlled 
Period (RCP) 
To evaluate the effect of ravulizumab compared with 
placebo on overall health-related quality of life in adult 
patients with ALS 
Endpoint: Change from Baseline in Short-Form Health 
Survey (SF-36) at Week 50; 
Change from Baseline in European Quality of Life 
Health 5-item questionnaire (EQ-5D-5L) at Week 50 
To evaluate the safety of ravulizumab compared with 
placebo in adult patients with ALS 
Endpoint: Shifts from Baseline in Columbia-Suicide 
Severity Rating Scale (C-SSRS) at Week 50; 
Change from Baseline in vital signs, electrocardiogram 
(ECG) parameters, and clinical laboratory assessments  
To characterize biomarkers in adult patients with ALS 
Endpoint: Change from Baseline in levels of 
biomarkers of complement dysregulation, 
neuroinflammation, and neurodegeneration 
To evaluate the effect of ravulizumab compared with 
placebo on ALS-related health quality of life in adult 
patients with ALS 
Endpoint: Change from Baseline in ALS assessment 
questionnaire (ALSAQ-40) score at Week 50 
To characterize the effect of ravulizumab compared to 
placebo on disease stage in adult patients with ALS 
Endpoint: Any increase from the baseline stage on the 
King’s staging system (KSS) at Week 50 
To evaluate the long-term efficacy of ravulizumab in 
adult patients with ALS 
Endpoint: Change in ALSFRS-R total score, VAFS, 
SVC, HHD, and patient-reported outcome measures 
over time in all patients exposed to ravulizumab during 
the OLE Period 
To evaluate the long-term safety of ravulizumab in 
adult patients with ALS 
Endpoint: Incidence of TEAEs, TESAEs, and TEAEs 
leading to study drug discontinuation during the OLE 
Period 
1.2. 
Study Design 
Study ALXN1210-ALS-308 is a Phase 3, double-blind, randomized, placebo-controlled, 
parallel-group, multicenter study with an OLE to evaluate the efficacy and safety of ravulizumab 
in adult patients with amyotrophic lateral sclerosis (ALS). There are 3 periods in this study:  
Screening Period: Patients will be screened for eligibility for up to 4 weeks during the 
Screening Period. Patients who are not taking or who are on a stable riluzole and/or edaravone 
regimen at Screening will be considered for participation. 
RCP: Eligible adult ALS patients will be randomized in a 2:1 ratio to ravulizumab or placebo 
arm within each stratum as defined in Table 1. Approximately 354 patients will be enrolled in 
North America, Europe, and the Asia-Pacific region. Weight-based intravenous infusion of 
ravulizumab or matching placebo will be administered in a blinded fashion until Week 42 during 
the RCP. The primary endpoint will be evaluated at Week 50. 


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Statistical Analysis Plan 
Protocol Number: ALXN1210-ALS-308 (Amendment 6) 
18Nov2021, Version 2.0 
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Table 1: 
Randomization Strata 
Strata 
ALS Muscle Weakness at 
the Onset 
Background ALS Therapy (Riluzole or Edaravone) 
at Study Entry 
(Bulbar vs. Not) 
On Stable Riluzole 
On Stable Edaravone 
1 
Not bulbar 
No 
Yes, No 
2 
Not bulbar 
Yes 
Yes 
3 
Not bulbar 
Yes 
No 
4 
Bulbar 
No 
Yes, No 
5 
Bulbar 
Yes 
Yes 
6 
Bulbar 
Yes 
No 
a Stable riluzole: at least 30 days on riluzole prior to Day 1. 
b Stable edaravone: at least 60 days on edaravone prior to Day 1. 
Abbreviations: ALS = amyotrophic lateral sclerosis; vs = versus 
Patients who do not enter the study on riluzole and/or edaravone will not be permitted to start 
treatment with either drug during the RCP. 
One unblinded interim analysis for futility is planned when approximately 33% of originally 
planned patients (N = 354) complete the Week 26 visit for the RCP. An independent data 
monitoring committee (IDMC) will be established to conduct this unblinded interim analysis and 
periodic review of accumulating data for patient safety and efficacy during the study. Details of 
the interim analysis methods are described in a separate interim analysis plan (IAP). 
OLE Period: For each participant, the RCP ends, and the OLE Period starts, when the 
participant has completed the Week 50 visit assessments and received the first dose for the OLE. 
Regardless of the randomized assignment, all patients will receive ravulizumab during the OLE 
Period. Blind to the randomized treatment assignment will be maintained for patients and 
providers during the OLE Period until the end of the study. Initiation of riluzole and/or 
edaravone is permitted during the OLE Period. The first dose of the OLE Period will be 
administered in a blinded fashion to accommodate the loading dose for the patients originally 
randomized to placebo (see protocol for further details). 
The OLE Period will continue for up to 2 years or until ravulizumab is approved and/or available 
(per country-specific regulations), whichever occurs first. 
After the End of Treatment Visit or early discontinuation, patients will be followed for an 
additional 8 weeks after their last dose of the study drug. 


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Protocol Number: ALXN1210-ALS-308 (Amendment 6) 
18Nov2021, Version 2.0 
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Figure 1: 
Study Design Schematic 
 
2. 
STATISTICAL HYPOTHESES  
2.1. 
Primary Hypothesis  
The primary null hypothesis is that the effect of ravulizumab is no different from placebo in 
functional decline measured by the change from Baseline in ALSFRS-R total score at Week 50. 
The alternative hypothesis is that ravulizumab will slow the disease progression by reducing the 
decline from Baseline in ALSFRS-R total score at Week 50 compared to placebo.  
2.2. 
Secondary Hypotheses  
The null hypotheses associated with the secondary objectives are that ravulizumab is no different 
from placebo for the respective endpoints; the alternative hypotheses are described below: 
2.2.1. 
Key Secondary Hypotheses 
• Time to VAFS: The alternative hypothesis is that treatment with ravulizumab will 
prolong the time to VAFS compared to placebo. 
• Change in SVC percent predicted: The alternative hypothesis is that treatment with 
ravulizumab will slow the decline from Baseline in SVC at Week 50 compared to 
placebo. 
2.2.2. 
Supportive Secondary Hypotheses 
• Change in muscle strength (HHD): The alternative hypothesis is that treatment with 
ravulizumab will slow the decline from Baseline in muscle strength at Week 50 
compared to placebo.  
• Neurofilament concentration (NfL): The alternative hypothesis is that treatment 
with ravulizumab will reduce the NfL concentration level at Week 50 compared to 
placebo. 
2.3. 
Tertiary Hypotheses 
• Change in SF-36: The alternative hypothesis is that treatment with ravulizumab will 
reduce the worsening from Baseline in SF-36 physical component summary (PCS) 
and mental component summary (MCS) at Week 50 compared to placebo. 


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• Change in EQ-5D-5L: The alternative hypothesis is that treatment with ravulizumab 
will reduce the worsening from Baseline in EQ-5D-5L visual analog scale (VAS) and 
Health Stage Index at Week 50 compared to placebo. 
• Time to the first instance of SVC percent predicted < 50: The alternative 
hypothesis is that treatment with ravulizumab will prolong the time to the first 
instance of SVC percent predicted < 50 compared to placebo.  
• Change in ALSAQ-40 score: The alternative hypothesis is that treatment with 
ravulizumab will reduce the worsening from Baseline in ALSAQ-40 at Week 50 
compared to placebo. 
• Change in KSS: The alternative hypothesis is that treatment with ravulizumab will 
reduce the worsening in KSS at Week 50 compared to placebo. 
3. 
SAMPLE SIZE DETERMINATION  
The sample size calculations were based on information extracted from the PRO-ACT (Pooled 
Resource Open-Access ALS Clinical Trials) database consisting of clinical trials data pooled 
from 23 Phase 2/3 ALS clinical trials. Approximately 354 patients will be randomized to 
ravulizumab or placebo in a 2:1 ratio.  
The mean change in ALSFRS-R total score in the placebo arm at Week 50 is estimated as −14.3 
(assuming a monthly linear slope of the decline of 1.19 calculated based on the proposed study 
inclusion criteria). Assuming a 30% relative reduction in the monthly slope in the ravulizumab 
group is considered a clinically meaningful treatment effect (Castrillo-Viguera, 2010; Writing 
Group for Edaravone ALS Study., 2017), the mean change in ALSFRS-R total score at Week 50 
is estimated as −10. A common standard deviation (SD) of 10.3 was estimated for the change 
from Baseline in ALSFRS-R total score. A total of 282 patients will be required to ensure at least 
90% nominal power based on a 2-sided t-test (Type I error = 0.05) for detecting a non-zero 
treatment effect for ALSFRS-R (defined as the difference between ravulizumab and placebo in 
the mean change from Baseline in ALSFRS-R total score at Week 50). The total sample size is 
estimated as 354 after adjusting for a 20% dropout (Cudkowicz, 2013). Furthermore, assuming 
approximately 82% 1-year survival rate for placebo group and 50% relative reduction in the HR 
for mortality due to treatment with ravulizumab, this sample size will provide at least 90% 
nominal power based on the primary analysis (CAFS). 
4. 
ANALYSIS SETS 
Table 2: 
Analysis Sets 
Analysis Set 
Description 
Screened Set 
All consented participants 
Randomized Set 
All randomized participants grouped by randomized treatment group (for reporting 
disposition, demographics, and baseline characteristics) 
SS 
All participants who received at least 1 dose of the study drug (ravulizumab or 
placebo) in RCP. Participants will be compared for safety according to the treatment 
they actually received. For a participant to be analyzed according to the treatment they 
actually received and not according to the randomization schedule, they would have to 
receive that treatment for the entire duration of the RCP.  


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Table 2: 
Analysis Sets 
Analysis Set 
Description 
FAS 
All randomized participants who received at least 1 dose of the study drug 
(ravulizumab or placebo) in RCP. The primary population for efficacy assessment is 
the FAS. Participants will be compared for efficacy according to the treatment they 
were randomized to, regardless of the treatment received. 
PKAS 
All participants who receive at least 1 dose of the study drug and have at least 
1 postdose PK sample  
PDAS 
All participants who receive at least 1 dose of the study drug and have at least 
1 postdose PD sample 
OLES 
All participants who received at least 1 dose of ravulizumab starting from Week 50 
Abbreviations: FAS = Full Analysis Set; OLE = Open-Label Extension; OLES = Open-Label Extension Set; 
PD = pharmacodynamic; PDAS = Pharmacodynamic Analysis Set; PK = pharmacokinetic; 
PKAS = pharmacokinetic analysis set; RCP = Randomized Controlled Period; SS = Safety Set 
If the Randomized Set is identical to the Full Analysis Set (FAS), then the FAS will be used for 
disposition, demographics, and baseline characteristics. 
5. 
STATISTICAL ANALYSES 
5.1. 
General Considerations  
All data collected in this study will be presented using summary tables, figures, and data listings.  
• For the RCP, data summaries and inferential analyses will be presented by the 
treatment arms (“Ravulizumab” and “Placebo”). For certain noninferential summaries 
(demographics, baseline characteristics, and other prestudy information, including 
medical and ALS history, prior medications, and SAEs captured between screening 
and first infusion), a “Total” group may be formed by combining participants from 
both treatment arms. No “Total” group will be formed for efficacy and safety-related 
summaries. 
• For the OLE Period, data summaries will be presented by the treatment arms 
(“Ravulizumab/Ravulizumab” and “Placebo/Ravulizumab”). A “Total” group may be 
formed by combining participants from both treatment arms. 
Statistical analyses will include tabulations of summary data, inferential analyses, by-patient 
listings, and figures. The summary statistics for continuous variables will include, but not be 
limited to, the number of participants, mean, SD, minimum, median, and maximum. For 
categorical variables, frequencies and percentages will be presented. Inference from efficacy 
analyses will be based on a 2-sided Type I error (α) = 5% unless stated otherwise. The 95% 
confidence intervals (CI) will be produced where applicable. All p-values and CIs will be used 
for descriptive purposes only due to the study meeting the futility criterion. 
Since the study has stopped for futility, multiplicity adjustment will not be considered.  
 
The baseline value for analysis and reporting will be based on the last non-missing measurement 
on or prior to the first dose of the study drug unless stated otherwise.  
Missing safety data will not be imputed.  


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Analyses will be performed using the SAS® software Version 9.4 or higher. Adverse events 
(AEs) will be coded with Medical Dictionary for Regulatory Activities (MedDRA) Version 24.0 
or later. Prior and concomitant medications will be coded with World Health Organization 
(WHO) Drug Dictionary Version 202103 or later. 
5.2. 
Study Participants  
The following information will be summarized: 
• The number and percentage of participants for the categories provided below 
(Figure 2 provides a flowchart related to the disposition) 
− Screened 
− Screen failure reasons (including coronavirus disease [COVID]-19 related screen 
failures) 
− Randomized 
− Treated 
− Included in the interim analysis 1 
− Completed RCP 
− Discontinuation reasons (RCP) 
− Did not roll over to OLE 
− Treated in OLE 
− Discontinuation reasons (OLE) 
− Completed OLE/study 
• The number and percentage of participants randomized to placebo or ravulizumab 
within each of the 6 stratification levels (Table 1); the percentages will be calculated 
based on the total number of participants within each stratification level 
− By planned randomization strata (derived strata based on the bulbar onset and 
stable riluzole or edaravone use) 
− By actual randomization strata (observed stratification) 
• A cross-tabulation of participants by planned and actual randomization strata for 
quantifying the mis-stratification 
• The number and percentage of participants by protocol scheduled visits during RCP 
• The number and percentage of participants in analysis datasets and reason for 
exclusion from specific datasets 
• The number and percentage of participants who missed a study visit along with 
associated reasons including reasons related to COVID-19 
• The number and percentage of participants who had a delayed visit along with 
associated reasons including reasons related to COVID-19 


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• The number and percentage of participants with a visit modification along with 
associated reasons including reasons related to COVID-19  
Details will be presented in the listings. 
Figure 2: 
Participant Disposition Flowchart 
 
5.3. 
Primary Estimand and Analysis 
The primary endpoint for this study is based on ALSFRS-R. It is a validated instrument for 
evaluating the levels of the physical functional status of patients with ALS in 4 areas, including 
bulbar, gross motor activity, fine motor activity, and respiratory functions. The scale includes 
12 functional items, and each item is rated on a 0 to 4 scale, with a maximum total score of 48. A 
higher score indicates greater retention of function. The ALSFRS-R assessment schedule is 
provided in the Schedule of Activities in the protocol. If a participant is unable to attend the 
scheduled onsite visit, the ALSFRS-R can be assessed via a phone call by the Investigator or 
trained designee. 
A joint rank analysis (referred to as CAFS) recommended in the Food and Drug Administration 
(FDA) guidance document on ALS, 2019, which combines deaths and ALSFRS-R, will be 
performed for the analysis of the primary endpoint. This analysis will be conducted based on the 
FAS. 
5.3.1. 
Estimand 
The 5 attributes for the primary estimand are described below: 
• Treatment: ravulizumab or placebo with or without the use of stable riluzole and 
edaravone 
• Population: adult participants with ALS as defined by the protocol 
inclusion/exclusion criteria 


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• Variable: CAFS score (defined below) based on the monthly slope in ALSFRS-R 
(change from Baseline in ALSFRS-R total score at last visit on or before Week 50 
divided by the corresponding time [month]) and time (months) to death during RCP 
• ICE: death 
− The composite strategy will be adopted to account for death in analysis for the 
primary endpoint (see Section 5.3.2 for details) 
• Population-level summary: mean CAFS score (defined below) 
− The treatment effect will be quantified by the difference in mean between 
ravulizumab and the placebo arms 
For participants who do not survive until Week 50, ALSFRS-R total scores will be missing, 
which may bias the evaluation of clinical benefit if not adequately accounted. This joint rank 
analysis evaluates function while accounting for missing data due to deaths in ALS by 
calculating a CAFS score for each participant.  
CAFS scoring: For calculating the CAFS score, each participant will be compared individually 
to all other participants (irrespective of treatment assignment) in a pairwise fashion (Berry, 
2013). For each pairwise comparison, the participant who fares better earns a point (+1), and the 
participant who fares worse loses a point (-1). In the case of a tie, no points (0) are added or 
subtracted. Each participant’s summary score (CAFS score) is the sum of the comparisons (+1, 
0, -1) against all other participants.  
1. If both participants die, the participant surviving longer will earn a point (+1) and the 
participant with a shorter survival time will lose a point (-1); no points (0) are added or 
subtracted if the survival times are identical. 
2. If only 1 participant survives, then that participant will earn a point (+1) 
3. If both participants survive, the participant with the smaller decline in the slope of 
ALSFRS-R will earn a point (+1), the participant with the larger decline will lose a point 
(-1), and no points (0) are added or subtracted in the case of a tie. The slope will be 
calculated based on the change from Baseline in ALSFRS-R total score at the last 
available visit normalized by the number of months between the first study drug and the 
last available visit. For a participant that discontinued early without any information on 
death or change in ALSFRS-R, the slope will be assumed zero as it is unlikely that the 
ALSFRS-R score will change significantly within a short period.  
Participants will be ranked based on the CAFS score, as calculated above, irrespective of the 
treatment assignment. The first participant who dies will have the lowest score and is ranked the 
lowest; the last to die is ranked above all others who die; among survivors, the participant with 
the greatest decline in ALSFRS-R slope is ranked immediately above the last participant who 
died; the surviving participant with the least decline in ALSFRS-R slope is assigned the highest 
rank. Participants with the same CAFS scores will be ranked with average ranks.  
Section 6.2.3 provides examples of CAFS scoring. 


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5.3.2. 
Main Analytical Approach 
The analysis of CAFS ranks will be based on an analysis of covariance model. The model will 
include the CAFS ranks as the dependent variable and the following list of independent 
variables: treatment indicator (0 = placebo, 1 = ravulizumab), age, sex, baseline ALSFRS-R total 
score, baseline SVC percent predicted, months since first muscle weakness onset at Baseline, and 
the stratification factors.  
If the 2-sided p-value associated with the higher mean rank in the ravulizumab group compared 
to the placebo is less than α = 0.05, a statistically significant treatment benefit will be 
established. The least squares (LS)-means and the 95% CIs of the CAFS ranks for each treatment 
arm and the difference between the arms will be calculated. Details will be provided in a listing. 
This analysis will be conducted for sake of completion and will not support efficacy conclusion 
as the study met the pre-specified futility criteria. 
5.3.3. 
Sensitivity Analysis 
The following sensitivity analysis will be conducted to quantify the treatment effect magnitude. 
5.3.3.1. 
Sensitivity Analysis: Mixed-effect Model for Repeated Measures 
As the CAFS method is based on ranks and cannot quantify the magnitude of the treatment effect 
for ALSFRS-R, a sensitivity analysis will be performed, including all ALSFRS-R longitudinal 
data (either complete or partial), to estimate the treatment effect, ie, the difference in mean 
change from Baseline between ravulizumab and placebo. 
5.3.3.1.1. Estimand  
The 5 attributes for the estimand are described below: 
• Treatment: ravulizumab or placebo with or without the use of stable riluzole and 
edaravone 
• Population: adult participants with ALS as defined by the protocol 
inclusion/exclusion criteria 
• Variable: change from Baseline in ALSFRS-R total score at the postbaseline visits 
during RCP up to and including Week 50. 
• ICE: none 
− The treatment policy will be adopted, and all ALSFRS-R data will be used; no 
imputation will be performed for missing data due to death or discontinuation 
• Population-level summary: mean change from Baseline in ALSFRS-R total score 
− The treatment effect will be quantified by the difference in mean between 
ravulizumab and the placebo arms.  
5.3.3.1.2. Analytical Details for Sensitivity Analysis 
The model will include the change from Baseline in ALSFRS-R total score at each study visit as 
the dependent variable and the following list of independent variables as fixed effects: actual 
time on the study (months), the interaction between time and treatment (0 = placebo, 
1 = ravulizumab), age, sex, baseline ALSFRS-R total score, baseline SVC percent predicted, 


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months since first muscle weakness onset at Baseline, and the stratification factors. The 
participant-specific random slope will also be added to the model with an unstructured 
variance-covariance matrix to model the correlations among repeated measurements within each 
participant. The following covariance structures will be implemented if a convergence issue 
occurs in the specified order:  
• Heterogeneous toeplitz (TOEPH)  
• Heterogeneous autoregressive (1) (ARH (1))  
• Heterogeneous compound symmetry (CSH)  
• Toeplitz structure (TOEP)  
• Autoregressive (1) (AR (1))  
• Compound symmetry (CS)  
The first covariance structure that converges will be used. The Kenward-Rogers method will be 
used to estimate the denominator degrees of freedom.  
No imputation for the missing data will be performed after discontinuation (death or dropout) 
from the study, assuming the data are missing at random (MAR).  
Section 6.2.9 provides details on implementing analysis windows. 
A 2-sided p-value less than α = 0.05 associated with the higher mean change in ALSFRS-R total 
score in the ravulizumab group compared to placebo will indicate a statistically significant 
treatment benefit. The LS-means and the 95% CIs of the mean change from Baseline at Week 50 
for each treatment arm and the difference between the arms will be calculated. The treatment 
effect will be evaluated via the estimated treatment-by-visit interaction term at Week 50 
(Month 11.5). Details will be provided in a listing. 
5.3.4. 
Other Analyses 
The ALSFRS-R total score and change from Baseline will be summarized descriptively by visit.  
Details will be provided in a listing. 
Mean score and mean change from Baseline over time, along with 95% CI, will be plotted for 
ALSFRS-R total score. 
Table 3: 
Overview of Estimands, Intercurrent Events, and Analyses Related to the 
Primary Endpoint 
Analysis 
Reference Section 
ICE 
Estimand Strategy 
Primary Analysis - CAFS 
Section 5.3  
Death 
Composite strategy 
Sensitivity Analysis 
Section 5.3.3.1  
None 
Treatment policy strategy 
Abbreviations: CAFS = combined assessment of function and survival; ICE = intercurrent event 


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5.4. 
Secondary Estimands and/or Endpoints Analysis 
5.4.1. 
Key Secondary Estimands 
5.4.1.1. 
Time to Ventilation Assistance Free Survival 
5.4.1.1.1. Estimand 
The 5 attributes for the estimand related to VAFS are described as follows: 
• Treatment: ravulizumab or placebo with or without the use of stable riluzole and 
edaravone 
• Population: adult participants with ALS as defined by the protocol 
inclusion/exclusion criteria 
• Variable: time (months) from Day 1 (first dose of study drug in RCP) to a VAFS 
event during the RCP; the VAFS event is defined as the earliest of  
− Death 
− The first use of noninvasive ventilation (NIV) for ≥ 22 hours per day for 
≥ 10 consecutive days 
− The first use of permanent assisted ventilation (PAV) for ≥ 22 hours per day for 
≥ 7 consecutive days VAFS 
• ICE: none. the treatment-policy estimand will be used 
• Population-level summary: HR (ravulizumab versus placebo) 
5.4.1.1.2. Main Analytical Approach 
The treatment effect on the time to VAFS will be analyzed based on a Cox proportional hazards 
model with treatment as a fixed effect adjusting for age, sex, baseline ALSFRS-R total score, 
baseline SVC percent predicted, months since first muscle weakness at Baseline, and the 
stratification factor. A censoring indicator will be equal to 1 if the participant did not experience 
a VAFS event (considered “censored”), and 0 if the participant experienced an event. Censored 
participants will include participants who discontinue the study without a VAFS event or 
complete the RCP without a VAFS event. 
The HR of ravulizumab versus placebo will be estimated with its associated 95% CIs. A 2-sided 
p-value less than α = 0.05 associated with the HR<1 will indicate a statistically significant 
treatment benefit.  
The components of VAFS will be analyzed separately using similar models to decompose the 
contribution of each component to VAFS, ie, using the first event of the 3 components. The total 
number of participants experiencing the first event will be equal to the total number of 
participants experiencing the VAFS event. Given the composite nature of VAFS, the p-value 
associated with each component (death, NIV, and PAV) need not be significant. 
5.4.1.1.3. Other Analyses Related to VAFS and Components of VAFS (NIV, PAV and 
Mortality) 
An analysis for time (months) to NIV, PAV, and death will be performed separately with a Cox 
proportional hazards model similarly to that described in Section 5.4.1.1.2. However, these 


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analyses are different from the analyses of the VAFS components; for example, a participant 
may experience an event of NIV followed by death; hence, NIV will contribute to VAFS, but 
death will not. Hence the total number of participants experiencing any of these events may be 
greater than the total number of participants experiencing the VAFS event. 
For VAFS and its components, the Kaplan-Meier curves by treatment group will be produced. 
Estimated survival probabilities at Week 50 (Month 11.5) will be provided for both treatment 
groups. The number and percentage of participants experiencing a VAFS event and its 
components will be provided. In addition, the number and percentage of deaths will be 
summarized by the associated reasons. 
The number and percentage of participants with ventilator use (regardless of the number of 
hours) at least once during RCP, NIV, and PAV will be summarized. Details will be provided in 
listings.  
5.4.1.2. 
Slow Vital Capacity Percent Predicted 
5.4.1.2.1. Estimand 
The 5 attributes for the estimand related to SVC percent predicted are described as follows: 
• Treatment: ravulizumab or placebo with or without the use of stable riluzole and 
edaravonee 
• Population: adult participants with ALS as defined by the protocol 
inclusion/exclusion criteria and included in the FAS 
• Variable: change from Baseline in SVC percent predicted at Week 50 based on the 
in-clinic assessment or the at-home assessment when in-clinic assessment is not 
available 
• ICE: none. The treatment-policy strategy will be adopted.  
• Population-level summary: mean change from Baseline in SVC percent predicted at 
Week 50; the treatment effect will be quantified by the difference in mean between 
ravulizumab and the placebo arms. 
5.4.1.2.2. Main Analytical Approach 
The treatment effect on SVC percent predicted will be evaluated based on a mixed-effect model 
repeated measure with the change from Baseline in SVC percent predicted as the dependent 
variable and the following list of independent variables as fixed effects: actual time on study 
(months), time and treatment interaction, age, sex, baseline ALSFRS-R total score, baseline 
SVC, disease duration, and the stratification factor. In addition, the participant-specific random 
slope will be added to the model with an unstructured variance-covariance matrix. The strategy 
for selecting other covariance structures outlined in Section 5.3.3.1.2 will be used if a 
convergence issue occurs. The Kenward-Rogers method will be used to estimate the 
denominator degrees of freedom. No imputation for the missing data will be performed after 
death or discontinuation, assuming the data are MAR. 
A 2-sided p-value less than α = 0.05 associated with the higher mean change in SVC percent 
predicted in the ravulizumab group compared to placebo will indicate a statistically significant 
treatment benefit. The LS-means and the 95% CIs of the mean change from Baseline at Week 50 


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(month 11.5) for each treatment arm and the difference between the arms will be calculated. 
Details will be provided in a listing.  
5.4.1.3. 
Other Analyses for Slow Vital Capacity 
The absolute values and changes from Baseline will be summarized by visits for the SVC data. 
Figures of the mean values and the changes from Baseline over time will be provided, along with 
95% CIs. Details will be provided in listings.  
5.4.2. 
Supportive Secondary Endpoints and Analysis 
5.4.2.1. 
Muscle Strength Measured by Handheld Dynamometry 
The absolute values and changes from Baseline will be summarized by visits for the HHD data. 
Figures of the mean values and the changes from Baseline over time will be provided along with 
95% CIs. Details will be provided in listings. See Section 6.2.6 for additional details. 
5.4.2.2. 
Neurofilament Light Chain (NfL) Concentration  
The absolute values and the log-transformed values will be summarized by visits. Figures of the 
geometric means over time will be provided along with 95% CIs. Details will be provided in 
listings. 
5.5. 
Tertiary/Exploratory Endpoints and Analyses  
No analyses and no any summary tables or listings will be done for any tertiary/exploratory 
endpoints. 
 
5.6. 
Safety Analyses  
The safety analyses will be descriptive in nature and will include the following: 
• Exposure to IP 
• AEs 
• Laboratory data 
• Vital signs 
• ECG 
• Physical examination 
• Neurological examination 
• C-SSRS 
• Exposure to COVID-19 
All safety analyses for the RCP and OLE Period will be conducted based on the Safety Set (SS) 
and OLE Set. 
5.6.1. 
Extent of Exposure 
Descriptive statistics will be generated for the variables described in Table 4.  


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Table 4: 
Variables for Study Duration, Exposure, and Treatment Compliance 
Variable (Unit) 
Study Period 
(Population) 
Definition 
Calculation 
Duration 
Duration of RCP 
participation 
(days) 
RCP (SS) 
Number of days from informed consent to last 
day in RCP.  
 
Note: The last day in RCP is defined as the 
latest of RCP completion, discontinuation date, 
date of death, or date of the follow-up visit 
from RCP. 
Date of last day in RCP -date of 
informed consent + 1 
Duration of study 
participation 
(days) 
RCP and Study 
(SS) 
Number of days from informed consent to last 
day in study.  
 
Note: The last day in the study is defined as the 
latest of study completion or discontinuation 
date or date of death or date of the follow-up 
visit from the study 
Date of last day in the study -
date of informed consent + 1 
Treatment duration 
(days) - RCP 
RCP (SS) 
Number of days on study treatment from first 
study drug infusion until the last study drug 
infusion during RCP. 
 
Note: Week 50 dosing will not be included in 
this calculation. 
Last study drug infusion date in 
RCP - first RCP study drug 
infusion date + 1  
Treatment duration 
(days) – OLE 
OLE (OLES) 
Number of days on study treatment from first 
OLE study drug infusion until the last study 
drug infusion during OLE. 
Last study drug infusion date in 
OLE - first OLE study drug 
infusion date + 1  
Duration of RCP 
(days) 
RCP (SS) 
Number of days from first study drug infusion 
to last day in RCP.  
Date of last day in RCP - date 
of the first infusion in RCP + 1 
Total patient-years 
(years) – RCP 
RCP (SS) 
Total RCP duration (years) for all participants. 
Sum of RCP duration (days) 
/ 365.25 for all participants 
Duration of OLE 
(days) 
OLE (OLES) 
Number of days from first OLE study drug 
infusion to last day in OLE.  
Date of last day in OLE - date 
of the first infusion in OLE + 1 
Total patient-years 
(years) – OLE 
OLE (OLES) 
Total OLE duration (years) for all participants. 
Sum of OLE duration (days) 
/ 365.25 for all participants 
Exposure 
Total number of 
infusions 
RCP (SS) 
Total number of infusions in RCP 
 
Note: Infusions with an interruption at the same 
visit will be counted once. 
The total number of infusions 
in RCP. 
Total number of 
loading dose 
infusions 
RCP (SS) 
Total number of loading dose infusions 
The total number of loading 
dose infusions in RCP. 
Total number of 
maintenance dose 
infusions 
RCP (SS) 
Total number of maintenance dose infusions 
The total number of 
maintenance dose infusions in 
RCP. 
Total dose 
administered (mg) 
RCP (SS) 
Total dose administered 
Sum of all doses in RCP. 
Note: Placebo kits will 
contribute to zero doses. 
OLE (OLES) 
Total dose administered 
Sum of all doses in OLE. 
Note: Placebo kits will 
contribute to zero doses. 
Total infusion 
volume (mL) 
RCP (SS) 
Total infusion volume 
Sum of all infusion volume in 
RCP. 
OLE (OLES) 
Total infusion volume 
Sum of all infusion volume in 
OLE. 


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Table 4: 
Variables for Study Duration, Exposure, and Treatment Compliance 
Variable (Unit) 
Study Period 
(Population) 
Definition 
Calculation 
 
Treatment Compliance 
Number of 
participants with 
an infusion 
interruption for 
any reason 
RCP (SS) 
Number of participants with an infusion 
interruption at any time (for any reason) during 
loading dose or maintenance dose infusion in 
RCP. 
Count of participants with an 
infusion interruption (for any 
reason) at any time during 
loading dose or maintenance 
dose infusion in RCP. 
Number of 
interrupted 
infusions for any 
reason per 
participant 
RCP (SS) 
Total number of interrupted infusions (for any 
reason) per participant at any time during 
loading dose or maintenance dose infusion in 
RCP. 
Sum of all instances of infusion 
interruption (for any reason) in 
RCP. 
Number of 
participants with 
an infusion 
interruption for 
AEs 
RCP (SS) 
Number of participants with an infusion 
interruption at any time (for AEs) during 
loading dose or maintenance dose infusion in 
RCP. 
Count of participants with an 
infusion interruption (for AEs) 
at any time during loading dose 
or maintenance dose infusion in 
RCP 
Number of 
interrupted 
infusions for AEs 
per participant 
RCP (SS) 
Total number of interrupted infusions (for AEs) 
per participant at any time during loading dose 
or maintenance dose infusion in RCP. 
Sum of all instances of infusion 
interruption (for AEs) in RCP 
Percent 
compliance 
RCP (SS) 
Percentage of the total number of infusions 
administered out of the total number of 
expected infusions during RCP. 
100 × (Total number of 
infusions administered in RCP) 
/ (Total number of expected 
infusions in RCP) 
Percent 
compliance 
category 
RCP (SS) 
Percent compliance categories range from 
100% to 0% by decrements of 10% per 
category. 
100%, 90% to < 100%, 80% to 
< 90%, etc. 
Abbreviations: AE = adverse event; OLE = Open-Label Extension; OLES = Open-Label Extension Set; RCP = Randomized 
Controlled Period; SS = Safety Set 
5.6.2. 
Adverse Events 
AEs will be coded to the corresponding system organ class (SOC) and preferred term (PT) using 
the latest available version of the MedDRA. 
The definitions of TEAE provided in Table 5 will be used to analyze AEs for different study 
periods. The TEAE (RCP) and TEAE (OLE) represent TEAEs during RCP and OLE, 
respectively. For handling missing dates of onset, refer to Section 6.2.1. AEs with onset prior to 
the first administration of study drug will be summarized as pretreatment AEs. 


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Table 5: 
Definition of TEAEs 
TEAE (RCP) 
TEAE (OLE) 
For RCP participants entering the OLE, a TEAE will be 
defined as any AE with onset on or after the first dose of IP 
in the RCP up to and including the day prior to the first 
OLE dose.  
A TEAE will be defined as any AE with onset on 
or after first dose of OLE.  
For RCP participants not entering the OLE, TEAE will be 
defined as an AE with onset on or after the first RCP dose 
of IP. 
If the time of the AE onset is available, it will be used to determine the treatment emergence by comparing with 
the time of the first study drug infusion, ie, if the AE onset time is prior to the time of infusion, it will not be 
considered as treatment-emergent. 
Abbreviations: AE = adverse event; IP = investigational product; OLE = Open-Label Extension; 
RCP = Randomized Controlled Period; TEAE = treatment-emergent adverse event 
The incidence, toxicity, and relationship to IP will be summarized by the treatment group. 
Specific AEs will be counted once for each participant for calculating percentages (e.g., overall, 
SOC, PT). In addition, if the same AE occurs multiple times for a participant, the highest 
severity and relationship to IP observed will be reported. All TEAEs will be summarized overall 
and categorized by MedDRA SOC and PT. The ordering of SOC will be alphabetical, and the 
ordering for PT will be most prevalent (using percentage) PT within each SOC based on the 
ravulizumab (RCP analysis) or total column (OLE). PTs with the same number of participants 
(eg, to break ties) will be further sorted by the number of events and then alphabetically.  
Table 6 provides an overview of the tabular summaries of AEs for different periods, underlying 
analysis sets, and treatment group display convention. An “X” in the table represents that an 
analysis will be performed for the period. For incidence tables, the number of participants and 
percentage will be tabulated; percentages will be based on the number of participants in the 
respective treatment groups. For event-rate tables, the rate per 100 patient-years will be 
calculated as follows (see Table 4 for the definition of patient-years): 
= 100 × Total number of TEAEs for specific reporting period
Total Person years for specific reporting period 
 
The following participant-level listings will be generated for AE data: 
• All AEs 
• All SAEs 
• AEs leading to study drug discontinuation 
• AEs leading to death 
• AEs of special interest 
• Infusion reaction related AEs 
• COVID-19 AEs 


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Table 6: 
Overview of Adverse Event Analysis by Study Period 
Type of Analysis 
Period 
Analysis Set 
Treatment Group Display Convention 
Additional Notes 
Screening 
SS 
Ravulizumab, 
Placebo, Total 
RCP 
SS 
Ravulizumab, 
Placebo 
OLE 
OLES 
Ravulizumab/Ravulizumab, 
Placebo/Ravulizumab, Total 
Overall summary of TEAEs 
 
X 
X 
 
TEAEs by SOC and PT 
 
X 
X 
 
TESAEs by SOC and PT 
 
X 
X 
 
Nonserious TEAEs by SOC and PT 
 
X 
X 
 
TEAEs leading to study drug withdrawal by SOC 
and PT 
 
X 
X 
 
TEAEs leading to death by SOC and PT 
 
X 
X 
 
TEAEs by SOC and PT by highest relationship to 
IP 
 
X 
 
Relationship to IP: related, 
not related 
TEAEs by SOC, PT, and highest severity 
 
X 
 
Severity: Grade 1, 2, 3, 4, 
and 5 
TEAEs (IP-related) by SOC, PT, and highest 
severity 
 
X 
 
 
TEAEs (IP-related) by SOC and PT 
 
X 
 
 
TESAEs (IP-related) by SOC and PT 
 
X 
 
 
TESAEs by SOC, PT, and highest relationship to 
IP 
 
X 
 
Relationship to IP: related, 
not related 
TEAEs (≥ 1%) by SOC and PT 
 
X 
 
≥ 1% in all participants 
TEAEs by SOC sorted by decreasing frequency 
 
X 
 
Decreasing frequency by 
ravulizumab arm (RCP), all 
participants (OLE) 
TEAEs by PT sorted by decreasing frequency 
 
X 
 
 
TESAEs by PT sorted by decreasing frequency 
 
X 
 
 


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Table 6: 
Overview of Adverse Event Analysis by Study Period 
Type of Analysis 
Period 
Analysis Set 
Treatment Group Display Convention 
Additional Notes 
Screening 
SS 
Ravulizumab, 
Placebo, Total 
RCP 
SS 
Ravulizumab, 
Placebo 
OLE 
OLES 
Ravulizumab/Ravulizumab, 
Placebo/Ravulizumab, Total 
TEAEs (IP-related) by PT sorted by decreasing 
frequency 
 
X 
 
 
AESI by SOC and PT 
 
X 
 
AESI: Meningococcal 
infection 
Infusion reaction related TEAEs by SOC and PT 
 
X 
 
 
Infusion reaction related TESAEs by SOC and 
PT 
 
X 
 
 
Infusion reaction related TEAEs (IP related) by 
SOC and PT 
 
X  
 
 
Overall Summary of COVID-19 related TEAEs 
 
X 
 
 
COVID-19 related TEAEs by SOC and PT 
 
X  
 
 
COVID-19 related TESAEs by SOC and PT 
 
X 
 
 
AEs during Screening Period by SOC and PT 
X 
 
 
 
Abbreviations: AE = adverse event; AESI = adverse event of special interest; IP = investigational product; OLE = Open-Label Extension; 
OLES = Open-Label Extension Set; PT = preferred term; RCP = Randomized Controlled Period; SOC = system organ class; SS = Safety Set; 
TEAE = treatment-emergent adverse event; TESAE = treatment-emergent serious adverse event 


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5.6.3. 
Laboratory Tests 
The analysis of central laboratory parameters (hematology, clinical chemistry, and urinalysis) 
will be summarized descriptively. Laboratory results based upon standardized units will be used 
for analyses. The last record will be used if there are multiple records of laboratory 
measurements at Baseline or post-Baseline Visits. The following analyses will be 
performed: 
• Actual laboratory results, baseline values, and changes from Baseline will be 
summarized using descriptive statistics (mean, SD, etc.) for each scheduled study 
visit and for the last visit within each period for the respective laboratory parameter. 
• Shift analyses will be conducted by calculating the number and percentage of 
participants in the low, normal, and high category combinations at both Baseline and 
post-Baseline Visits; the total number of participants with nonmissing values at both 
Baseline and post-Baseline Visits will be used as the denominator for the percentage 
calculation. 
• The number (%) of participants meeting the criteria in Table 7 for the liver 
function-related laboratory values (alanine aminotransferase [ALT], aspartate 
aminotransferase [AST], alkaline phosphatase [ALP], and total bilirubin [TBL]) will 
be provided. 
Table 7: 
Abnormality Criteria for Liver Function Laboratory Values and Analysis 
Timepoints 
Criteria 
Analysis Timepoints 
ALT 
• 
> 3 × ULN 
• 
> 5 × ULN 
• 
> 10 × ULN 
• 
> 20 × ULN 
• 
By scheduled visit 
• 
Any post-Baseline value 
AST  
• 
> 3 × ULN 
• 
> 5 × ULN 
• 
> 10 × ULN 
• 
> 20 × ULN 
• 
By scheduled visit 
• 
Any post-Baseline value 
ALT > 3 × ULN and TBL > 2 × ULN 
• 
By scheduled visit 
ALT > 3 × ULN and ALP < 2 × ULN and TBL ≥ 2 × ULN 
• 
By scheduled visit 
Criteria involving multiple laboratory analytes should be evaluated concurrently, ie, based on the same sample. 
For any post-Baseline value, a participant can contribute to multiple categories. 
Abbreviations: ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
TBL = total bilirubin; ULN = upper limit of normal 
Table 8 provides an overview of the laboratory data analyses for different periods, underlying 
analysis sets, treatment group display convention, the definition of baseline values, and 
laboratory data analyses. An “X” in the table represents that an analysis will be performed for the 
period. 


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Table 8: 
Overview of Analysis of Laboratory Data for RCP (SS) 
Type of Analysis 
Assessment Performed 
Additional Notes 
Actual value and change from 
Baseline 
X 
 
Abnormal laboratory values (with 
respect to normal range) 
X 
 
Shift analysis of abnormality 
compared to Baseline 
X 
 
Liver function abnormality 
X 
 
Box plots 
X 
ALT, AST, creatinine, glucose, 
hematocrit, hemoglobin, 
lymphocytes neutrophils, 
leukocytes, and platelets 
The treatment group display convention is “Ravulizumab, Placebo”, and the definition of baseline values is “Last 
nonmissing value prior to first RCP study drug infusion.” 
Abbreviations: ALT = alanine aminotransferase; AST = aspartate aminotransferase; RCP = Randomized 
Controlled Period; SS = Safety Set 
5.6.4. 
Vital Signs 
The analysis of the following vital signs will be summarized descriptively: systolic blood 
pressure (mmHg), diastolic blood pressure (mmHg), heart rate (beats/min), respiratory rate 
(breaths/min), weight (kg), and temperature (°C). 
If there are multiple records of vital sign measurements at Baseline or post-Baseline 
Visits, the last record will be used. The following analyses will be performed: 
• Actual vital sign measurements, baseline values, and changes from Baseline will be 
summarized using descriptive statistics (mean, SD, etc.) for each scheduled study 
visit. 
• The number (%) of participants meeting the potentially clinically significant 
abnormality criteria (Table 9) at least once during the RCP will be provided. 
Table 9: 
Potentially Clinically Significant Abnormality Criteria for the Vital Signs 
Vital Sign Measurement 
Criteria 
Systolic blood pressure  
< 90, > 140, > 160 
Diastolic blood pressure  
< 50, > 90, > 100 
Heart rate  
< 60, > 100 
Respiratory rate  
< 12, > 20 
Weight 
Decrease of ≥ 7% from Baseline; increase of ≥ 7% from Baseline  
Temperature 
> 38.0, < 36.0  
Table 10 provides an overview of the analyses of the vital sign data for different periods, 
underlying analysis sets, treatment group display convention, the definition of baseline values, 
and analyses of the vital sign data. An “X” in the table represents that an analysis will be 
performed for the period. 


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Table 10: 
Overview of Analysis of Vital Sign Data for RCP (SS) 
Type of Analysis 
Assessment Performed 
Actual value and change from Baseline 
X 
Potentially clinically significant abnormality criteria 
X 
The treatment group display convention is “Ravulizumab, Placebo”, and the definition of baseline values is “Last 
nonmissing value prior to first RCP study drug infusion.” 
Abbreviations: RCP = Randomized Controlled Period; SS = Safety Set 
5.6.5. 
Electrocardiogram 
The analysis of the following ECG measurements will be summarized descriptively: heart rate 
(beats/min), PR interval (msec), QRS duration (msec), RR interval (msec), QT interval (msec), 
corrected QT interval by Fridericia (QTcF; msec), and overall interpretation. 
If there are multiple records of ECG measurements at Baseline or post-Baseline 
Visits, the last record will be used. The following analyses will be performed: 
• Actual ECG measurements, baseline values, and changes from Baseline will be 
summarized using descriptive statistics (mean, SD, etc.) for each scheduled study 
visit 
• The number (%) of participants with abnormal ECG findings (normal, abnormal – not 
clinically significant, and abnormal – clinically significant). 
• The number (%) of participants meeting the potentially clinically significant 
abnormality criteria (Table 11) for QT and QTcF at least once during the RCP will be 
provided. 
Table 11: 
Potentially Clinically Significant Abnormality Criteria for QT and QTcF 
ECG Measurement 
Criteria 
QT, QTcF absolute value 
> 450, > 480, > 500 
QT, QTcF absolute value 
> 450 to ≤ 480, > 480 to ≤ 500, > 500 
QT, QTcF change from Baseline  
> 30, > 60 
QT, QTcF change from Baseline  
> 0 to ≤ 30, > 30 to ≤ 60, > 60 
Note: Maximum post-Baseline value or maximum change from Baseline will be used for these evaluations. 
 
Table 12 provides an overview of the different periods, underlying analysis sets, treatment group 
display convention, the definition of baseline values, and analyses of ECG data. An “X” in the 
table represents that an analysis will be performed for the period. 


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Table 12: 
Overview of Analysis of ECG Data for RCP (SS) 
Type of Analysis 
Assessment Performed 
Actual value and change from Baseline 
X 
Abnormal ECG findings 
X 
Potentially clinically significant abnormality 
criteria for QT and QTcF 
X 
The treatment group display convention is “Ravulizumab, Placebo”, and the definition of baseline values is “Last 
nonmissing value prior to first RCP study drug infusion.” 
Abbreviations: ECG = electrocardiogram; QTcF = corrected QT interval by Fridericia; RCP = Randomized 
Controlled Period; SS = Safety Set 
5.6.6. 
Physical Examination 
Details will be provided in a listing. 
5.6.7. 
Neurological Examination 
Details will be provided in a listing. 
5.6.8. 
Columbia-Suicide Severity Rating Scale 
The following C-SSRS categories with a yes/no binary response have been re-ordered from the 
actual scale to facilitate the definitions of the composite and comparative endpoints and enable 
clarity in presenting the results.  
Table 13: 
C-SSRS Categories for Reporting 
Category No. 
Category 
1 
Wish to be Dead  
2 
Nonspecific Active Suicidal Thoughts  
3 
Active Suicidal Ideation With Any Methods (Not Plan) Without Intent to Act 
4 
Active Suicidal Ideation With Some Intent to Act, Without Specific Plan 
5 
Active Suicidal Ideation With Specific Plan and Intent 
6 
Preparatory Acts or Behavior  
7 
Aborted Attempt  
8 
Interrupted Attempt  
9 
Actual Attempt (Nonfatal) 
10 
Completed Suicide 
Abbreviations: C-SSRS = Columbia-Suicide Severity Rating Scale; No. = number 
In addition, the response to the “Self-injurious behavior without suicidal intent (not suicide-
related)” question will also be summarized.  
Table 14 provides the definitions for the composite endpoints based on the categories provided in 
Table 13.  


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Table 14: 
Composite Endpoints Based on C-SSRS 
Endpoint 
Description 
Suicidal ideation 
A “yes” answer to any of the 5 suicidal ideation questions (Categories 1-5) on the 
C-SSRS. 
Suicidal behavior 
A “yes” answer to any of the 5 suicidal behavior questions (Categories 6-10) on the 
C-SSRS. 
Suicidal ideation or 
behavior 
A “yes” answer to any 1 of the 10 suicidal ideation and behavior questions 
(Categories 1-10) on the C-SSRS. 
The following analyses will be performed: 
• The number and percentage of participants who experience an event at Baseline 
(“Lifetime” and “past 12 months,” separately) and at least once during the treatment 
period will be summarized by the treatment group for 
− Each of the 3 composite endpoints in Table 14  
− The self-injurious behavior without suicidal intent 
• A shift tabulation from Baseline (“Lifetime” and “past 12 months,” separately) will 
be produced by treatment group during the RCP against the 3 composite endpoints for 
each of the 3 following groupings:  
− No suicidal ideation or behavior,  
− Composite endpoint of suicidal ideation, and  
− Composite endpoint of suicidal behavior. Each participant is counted once in 
1 cell only for each of the 2 tabulations. Participants with both suicidal ideation 
and suicidal behavior are included in the suicidal behavior category for the shift 
analysis. 
5.6.9. 
Coronavirus Disease 2019 Exposure 
Details will be provided in a listing. 
5.7. 
Other Analyses 
5.7.1. 
Pharmacokinetic Analyses 
Individual serum concentration data for all participants in PKAS will be summarized 
descriptively. Descriptive statistics (mean, SD, coefficient of variation [CV], median, minimum, 
maximum, geometric mean, and geometric %CV) will be calculated for serum concentration data 
at each sampling time, as appropriate. Graphs of mean serum concentration-time profiles will be 
constructed. Graphs of serum concentration-time profiles for individual participants may also be 
provided.  
5.7.2. 
Pharmacodynamic Analyses 
PD analyses will be performed for all participants in PDAS. Descriptive statistics will be 
presented for all ravulizumab PD endpoints at each sampling time. The PD effects of 
ravulizumab will be evaluated by assessing the absolute values, changes, and percentage changes 
from Baseline in free C5 serum concentrations over time, as appropriate.  


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Assessments of ravulizumab PK/PD relationships may be explored using data from this study or 
in combination with data from other studies. 
5.7.3. 
Biomarker Assessments  
Analysis of Neurofilament Light Chain (NfL) concentration can be found in Section 5.4.2.2. All 
other biomarkers may be analyzed by treatment and visits.  
5.7.4. 
Immunogenicity 
The number and percentage of participants developing confirmed positive ADAs and anti-drug 
neutralizing antibodies, where applicable, will be summarized by treatment group and visit. 
ADA titer values will be listed. 
5.7.5. 
Subgroup Analyses 
5.7.5.1. 
Subgroup Analyses for Adverse Events 
The TEAEs during the RCP will be summarized for the following subgroups (no p-value will be 
produced for these subgroup analyses): 
• Sex 
• Race 
• Region 
• Age category (< median, ≥ median) 
• Baseline weight category (< median, ≥ median) 
5.7.5.2. 
Subgroup Analyses for Laboratory Data 
The abnormality criteria for liver function laboratory values (Table 7) will be summarized for the 
following subgroups; no p-value will be produced for these subgroup analyses: 
• Stable use of riluzole at baseline (yes, no) 
• Stable use of edaravone at baseline (yes, no) 
5.8. 
Interim Analyses 
An unblinded interim analysis is planned to assess futility when approximately 33% of planned 
354 participants complete Week 26. The interim analysis will be conducted by an IDMC. Details 
have been described in a separate IAP document.  
5.8.1. 
Data Monitoring Committee 
The safety and efficacy data of this study will be monitored by an IDMC composed of external 
physicians and a statistician who have expertise in both the field of ALS and clinical trial 
conduct and with no direct relationship to the study. An independent statistical center will 
perform all statistical analyses presented to the IDMC. The IDMC will independently evaluate 
safety and efficacy data from the study periodically and at prespecified enrollment-dependent 
time points. The IDMC will make recommendations regarding study modification or 
continuation based on their review and in accordance with the agreed-upon IDMC charter. To 
maintain study integrity and prevent the potential introduction of bias, all study team members 


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will remain blinded until the final analysis of the RCP is conducted. Details of this process are 
documented in the IDMC charter. 
6. 
SUPPORTING DOCUMENTATION  
6.1. 
Appendix 1: Demographics, Baseline Characteristics, 
Inclusion/Exclusion Criteria, Protocol Deviations, Medical/Surgical 
History, Prior/Concomitant Medication 
6.1.1. 
Demographics and Other Baseline Characteristics 
The following demographics and baseline characteristics (including ALS disease history) will be 
summarized using the FAS by treatment group and overall. No statistical test will be performed 
for homogeneity among treatment groups. The continuous data will be summarized with 
descriptive statistics (number of participants with nonmissing data [n], mean, SD, minimum, and 
maximum), and the categorical data will be summarized with the number of participants with 
non-missing data (n) and percentages (%) for each category. The denominator will not include 
the missing data for percentage calculation. 
6.1.1.1. 
Demographics 
• Sex (male, female, undifferentiated, unknown) – n (%) 
• Race – n (%) (as characterized in Section IV of the FDA guidance titled, “Collection 
of Race and Ethnicity Data in Clinical Trials”); Table 15 provides both the primary 
and the detailed categories with mapping per the FDA guidance. The primary race 
category will be used for subgroup analysis. 
• Ethnicity – n (%) (as characterized in Section IV of the FDA guidance titled, 
“Collection of Race and Ethnicity Data in Clinical Trials”); Table 16 provides both 
the primary and the detailed categories with mapping per the FDA guidance. 
• Age (years) at screening – descriptive statistics  
• Age category (< 45, 45 to < 65, ≥ 65 years) – n (%) 
• Weight (kg) – descriptive statistics 
• Weight category (< 40, ≥ 40 to < 60, ≥ 60 to < 100, ≥ 100 kg) – n (%) 
• Height (cm) measured at screening – descriptive statistics 
• Body mass index (BMI) (kg/m2) – descriptive statistics 
• BMI categories (<18.5, ≥ 18.5 to < 25, ≥ 25 to < 30, ≥ 30) – n (%) 
Table 15: 
Race Categories 
Primary (section IV.D of FDA guidance 
document) 
Detailed (section IV.E of FDA guidance document and 
as recorded on the case report form) 
American Indian or Alaska Native  
American Indian or Alaska Native  
Asian 
Asian Indian, Chinese, Filipino, Japanese, Korean, 
Vietnamese, Other Asian 
Black or African American  
Black or African American  


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Table 15: 
Race Categories 
Primary (section IV.D of FDA guidance 
document) 
Detailed (section IV.E of FDA guidance document and 
as recorded on the case report form) 
Native Hawaiian or Other Pacific Islander 
Native Hawaiian, Guamanian or Chamorro, Samoan, Other 
Pacific Islander 
White  
White  
 
 
Table 16: 
Ethnicity Categories 
Primary (section IV.D of FDA 
guidance document) 
Detailed (section IV.E of FDA guidance document and as recorded on 
the case report form) 
Hispanic or Latino 
• 
Mexican, Mexican American, Chicano/a  
• 
Puerto Rican  
• 
Cuban  
• 
Another Hispanic, Latino/a or Spanish origin 
Not Hispanic or Latino 
Not of Hispanic, Latino/a, or Spanish origin 
Not reported 
Not reported 
Unknown 
Unknown 
Age, weight, and BMI will be reported based on the most recent data on or before Day 1 (the 
first study drug infusion). 
6.1.1.2. 
Baseline Characteristics 
Table 17 provides the list of baseline characteristics to summarize along with the type of 
summary. 
Table 17: 
Baseline Characteristics 
Baseline Characteristics 
Definition 
Time (months) since first muscle weakness at 
Screening – descriptive statistics 
12 × [date of informed consent – date of first muscle 
weakness] / 365.25 (rounded to nearest 1) 
Time (months) since first muscle weakness at Baseline 
– descriptive statistics 
12 × [date of Day 1 – date of first muscle weakness] / 
365.25 (rounded to nearest 1) 
Time since first muscle weakness at Baseline category 
– n (%) 
< 12, 12 to ≤ 24, > 24 months 
Time (months) since initial diagnosis of ALS at 
Baseline  
12 × [date of Day 1 – date of diagnosis] / 365.25 
(rounded to nearest 1) 
Time (months) since first muscle weakness to the 
initial diagnosis of ALS – descriptive statistics  
12 × [date of diagnosis – date of first muscle weakness] 
/ 365.25 (rounded to nearest 1) 
Site of muscle weakness onset – n (%) 
Bulbar, other 
El Escorial Diagnostic Criteria – n (%) 
Possible; Probable; Probable, Laboratory-supported; 
Definite 
Type of ALS disease – n (%) 
Sporadic, Familial 
ALS gene mutation – n (%) 
C9ORF72, SOD1, TDP43, FUS, No known mutation, 
Other 


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Table 17: 
Baseline Characteristics 
Baseline Characteristics 
Definition 
Ventilation use at Screening – n (%)  
• 
PAV use 
• 
PAV use for ≥ 22 hours for ≥ 7 consecutive days 
• 
NIV use 
• 
NIV use for ≥ 22 hours for ≥ 10 consecutive days 
King’s ALS Clinical Staging at Baseline – n (%) 
Stage 1, Stage 2, Stage 3, Stage 4 
King’s ALS Clinical Staging assessment, region 
affected – n (%) 
Bulbar, Upper extremity, Lower extremity 
King’s ALS Clinical Staging assessment, nutritional 
status – n (%) 
• 
Lost > 10% from predisease weight  
• 
Feeding tube needed 
King’s ALS Clinical Staging assessment, evidence of 
respiratory failure – n (%) 
NIV use, SVC < 50% predicted, SVC 50% to < 80% 
predicted with respiratory symptoms, None of the 
above 
Dependence on mechanical ventilation – n (%) 
Yes, No 
Type of dependence on ventilation – n (%)  
  
• 
Unable to lie flat (supine) without it 
• 
Unable to sleep without it 
• 
Daytime use > 6 hours per day for > 3 days per 
week 
Stable riluzole or edaravone at Screening – n (%) 
 
• 
Riluzole 
• 
Edaravone 
• 
Riluzole, not edaravone 
• 
Edaravone, not riluzole 
• 
Both riluzole and edaravone 
• 
No riluzole or edaravone 
Stable riluzole or edaravone at any time prior to 
Screening – n (%) 
 
• 
Riluzole 
• 
Edaravone 
• 
Riluzole, not edaravone 
• 
Edaravone, not riluzole 
• 
Both riluzole and edaravone 
• 
No riluzole or edaravone 
Time (months) since the first use of riluzole at baseline 
– descriptive statistics 
12 × [date of Day 1 – date of first riluzole use] / 365.25 
(rounded to nearest 1) 
Time (months) since the first use of edaravone at 
Baseline – descriptive statistics  
12 × [date of Day 1 – date of first edaravone use] / 
365.25 (rounded to nearest 1) 
ALSFRS-R total score at Screening and Baseline – 
descriptive statistics 
 
ALSFRS-R total score at Screening categories – n (%) 
< 34, 34 to 38, > 38 to 40, > 40 
ALSFRS-R total score at Baseline categories – n (%) 
< 34, 34 to 38, > 38 to 40, > 40 
Prestudy monthly ALSFRS-R progression rate at 
Screening – descriptive statistics 
As collected on the case report form 
Prestudy monthly ALSFRS-R progression rate at Day 1 
– descriptive statistics 
[48-ALSFRS-R total score at Day 1] / Time (months) 
since first muscle weakness at Day 1 – descriptive 
statistics 
Progression rate of ALSFRS-R at Screening 
categories –  n (%) 
< −1, −1 to < −0.7, −0.7 to < −0.5, −0.5 to −0.3, > −0.3 
Progression rate of ALSFRS-R at Baseline 
categories – n (%) 
< −1, −1 to < −0.7, −0.7 to < −0.5, −0.5 to −0.3, > −0.3 


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Table 17: 
Baseline Characteristics 
Baseline Characteristics 
Definition 
SVC volume (L) at Screening and 
Baseline – descriptive statistics 
 
SVC percent predicted at Screening and Baseline – 
descriptive statistics 
 
Baseline SVC percent predicted categories – n (%) 
< 50, 50 to < 65, 65 to < 75, 75 to < 85, >=85 
Premorbid weight (kg) – descriptive statistics 
 
Abbreviations: ASL = amyotrophic lateral sclerosis; ALSFRS-R = amyotrophic lateral sclerosis functional rating 
scale revised; NIV = noninvasive ventilation; PAV = permanent assisted ventilation; SVC = slow vital capacity 
6.1.2. 
Inclusion/Exclusion Criteria 
The number and percentage of participants not meeting specific inclusion or exclusion criteria 
will be summarized. 
6.1.3. 
Protocol Deviations 
All protocol deviations will be listed for all randomized participants. The number and percentage 
of participants with important protocol deviations for the categories provided in Table 18 will be 
summarized by treatment group and overall. 
Table 18: 
Protocol Deviation Categories 
1. Eligibility and entry criteria 
2. Investigational product 
3. Concomitant medication 
4. Informed consent 
5. Laboratory assessment 
6. Visit schedule 
7. Study procedure/tests 
8. Randomization 
9. Safety reporting 
10. Source document 
11. Other 
 The following protocol deviations will be determined programmatically: 
1. Participants who did not take at least 80% of the required treatment doses in RCP 
2. Participants who were incorrectly stratified 
6.1.4. 
Medical and Surgical History 
The medical and surgical history will be summarized by SOC and PT using MedDRA using the 
latest version in use at the time of analysis. The number and percentage of participants for each 
category will be reported by treatment group and overall for the FAS. 
6.1.5. 
Prior and Concomitant Medications / Therapies 
Prior medications are defined as medications with a start date occurring before the first study 
dose of the RCP. Concomitant medications (RCP) are defined as medications taken during RCP, 
i.e., either with a stop date after the first study dose of RCP or ongoing during RCP. Concomitant 
medications (OLE) are defined as medications taken during OLE, i.e., either with a stop date 
after the first study dose of OLE or ongoing during OLE. 
Medications will be coded using the WHODrug Dictionary version in use at the time of the 
analysis. The number (%) of participants using prior and concomitant medications will be 
summarized based on the WHO Anatomical Therapeutic Chemical Level 3 Class code and 


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generic name for FAS. All meningococcal vaccinations and prophylactic antibiotic medications 
after receiving meningococcal vaccine for subjects who initiated study drug will be listed 
separately as well. 
Nonpharmacologic therapies and procedures will be reported by treatment group and overall for 
the SS using SOC and PT. 
6.1.5.1. 
Stable Riluzole or Edaravone Use 
The number and percentage of participants will be summarized for the following categories 
during RCP 
• Riluzole use (discontinued versus stable) 
• Edaravone use (discontinued versus stable) 
Participants will be considered “stable” on the respective medications if not discontinued. 
6.2. 
Appendix 2: Technical Specifications for Derived Variables 
6.2.1. 
Derivation of Treatment-emergent Adverse Events for Missing or Incomplete 
Date of Onset 
If both start and end dates of AEs are completely missing, no imputation will be performed, and 
those AEs will be considered treatment-emergent. 
If the start date is partial: 
1. If only the day is missing: 
1.1. If the month/year of the start date is the same as those of the first study drug 
administration date, then the missing day will be imputed as the smaller non-missing 
value of (day of first study drug administration, day of the AE end date). 
1.2. Otherwise, impute the missing day as “01”. 
2. If both day and month are missing: 
2.1. If the year of the AE start date coincides with the year of the first study drug 
administration date, the partial start date will be set as the first study drug date. If this 
leads to a date after the AE end date, then the missing day and month of the AE start 
date will be imputed as the day and month of the AE end date. 
2.2. If the year of the AE start date is different from the year of the first study drug 
administration date, the missing day and month of the AE start date will be imputed as 
the “01” and “01”. 
If the stop date is partial: 
1. If only the day is missing: 
1.1. The missing day will be imputed as the last of the month, adjusting for the leap year. 
2. If both day and month are missing: 
2.1. If the year of the AE end date coincides with the maximum of (the year of first study 
drug administration date or the year of the last study drug administration), then the 
missing month will be imputed as the month of the corresponding study drug 


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administration date (first or last) and the missing day will be imputed as the last of the 
month adjusting for the leap year.  
2.2. Otherwise, the missing day and month of the AE stop date will be imputed as the “31” 
and “12”. 
6.2.2. 
Derivation of Prior and Concomitant Medication for Missing or Incomplete 
Dates 
If both start and end dates of medications are completely missing, no imputation will be 
performed, and those medications will be considered both prior and concomitant medications. 
If the end date is partial: 
1. If only the day is missing  
1.1. If the year and month coincide with those of the last study drug administration date, then 
the end of medication will be set to the last study drug administration date. 
1.2. If the year and month do not coincide with those of the last study drug administration 
date, then the missing day will be imputed as the last day of the month considering leap 
year and month in consideration. 
2. If both day and month are missing 
2.1. If the year coincides with that of the last study drug administration date, then missing 
month and day will be imputed as the month and day of the last study drug 
administration. 
2.2. If the year does not coincide with that of the last study drug administration date, then the 
missing month and day will be imputed as “12” and “31”, respectively. 
If the start date is partial: 
1. If only the day is missing 
1.1. If the year coincides with that of the first study drug administration date, then do the 
following: 
1.2. If the month does not coincide with that of the first study drug administration date, then 
impute the missing day as “01”. 
1.3. If the month coincides with that of the first study drug administration date  
1.3.1. If the end date is greater than the first study drug administration date, then impute 
the missing day as the day of the first study drug administration date  
1.3.2. If the end date is less than or equal to the first study drug administration date, then 
impute the missing day as the day of the end date of medication. 
1.4. If the year and the month do not coincide with those of the first dose date, then impute 
the missing day as “01”. 
2. If both day and month are missing: 
2.1. If the year does not coincide with that of the first study drug administration date, then 
impute missing month as “01” and missing day as “01”. 
2.2. If the year coincides with that of the first study drug administration date 
2.2.1. If the end date is greater than the first study drug administration date, then impute 
the missing day and month as those of the first study drug administration. 


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2.2.2. If the end date is less than or equal to the first study drug administration date, then 
impute the missing day and month as those of the end date of the medication. 
2.3. If the start date is completely missing, the missing start date will be set as the earlier of 
the first study drug administration date and end of the medication date. 
For meningococcal vaccination, the missing end date will not be imputed. 
6.2.3. 
Combined Assessment of Function and Survival Scoring Example 
Table 19 provides an example of the CAFS scoring technique and associated ranking. For each 
of the 9 participants (3 in the placebo arm and 6 in the ravulizumab arm), the ALSFRS-R change 
from Baseline, the death or study withdrawal information is provided. Each participant is 
followed for a maximum of 12 months. Participants 
 died at Months 
 and 
 
respectively, with the last available ALSFRS-R change scores being –12 and –7. Participant
dropped out at Month 1, with the last ALSFRS-R change score being 3 (showing improvement). 
For the rest of the participants that completed 12 months of follow-up, the last ALSFRS-R 
change from Baseline scores are shown in the fifth column. The ALSFRS-R slopes are 
calculated based on the ratio of change from Baseline score and the time on study; for example, 
for Participant
the slope is calculated as –17/12 = –1.41. Columns c1 to c9 provide the points 
(–1, 0, 1) based on the pairwise comparison for each participant with the rest of the 
8 participants. Columns c2 and c9 are shaded for ease of identification, as both these participants 
died. Note, a point of 0 is assigned to each participant against himself by default. 
Let us first consider the nondeaths for which the points will be awarded solely based on the 
ALSFRS-R slopes. Participant
slope = 0.0) gets a positive point (+1) when 
 slope is 
compared with the slopes for Participants 
 as each of those participants has 
declined at a higher rate (corresponding slopes being –1.41, –0.33, –0.25 and –1.0, respectively). 
When compared with Participants 
 Participant
eceives a negative point (–1), as those 
participants declined at a lower rate (in fact, improved) with corresponding slopes being 0.16 and 
3.0, respectively). Lastly, when compared with the 2 participants who died, Participant
automatically receives a positive point (+1) because of 
 survival until the end of the study. By 
summing all of these points, the total CAFS score for Participant
ecomes 4. Participant
receives a positive point (+1) when compared with the rest of the participants because of 
 
highest positive change (least decline) and survival; the CAFS score for Participant
becomes 8. 
The scores for the remaining nondeath participants can be derived similarly, as shown in the 
16th column. 
Let us now consider the participants who died. For example, Participant
ets a negative point 
(–1) for all pairwise comparisons; the negative point is awarded as all participants (except 
Participan
survived. When compared with Participant
a negative point (–1) is awarded to 
Participant
because Participan
survived longer than Participan
Hence, the CAFS score for 
Participant
becomes –8. 
The CAFS scores are ranked irrespective of the treatment groups, with the lowest score receiving 
Rank 1 and the highest score receiving Rank 9. 
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


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Table 19: 
Example of CAFS Scoring and Ranking 
Treatment 
Participant 
Time-to-
death 
(months) 
Time on 
study 
(months) 
ALSFRS-R 
Pairwise scores for CAFS calculation 
CAFS 
Change 
from 
baseline 
Slope 
c1 
c2 
c3 
c4 
c5 
c6 
c7 
c8 
c9 
Score 
Rank 
Placebo 
. 
12 
0 
0.0 
0 
1 
1 
-1 
-1 
1 
1 
1 
1 
4 
7 
 
. 
-12 
. 
-1 
0 
-1 
-1 
-1 
-1 
-1 
-1 
-1 
-8 
1 
 
. 
12 
-17 
-1.41 
-1 
1 
0 
-1 
-1 
-1 
-1 
-1 
1 
-4 
3 
Ravulizumab 
. 
12 
2 
0.16 
1 
1 
1 
0 
-1 
1 
1 
1 
1 
6 
8 
 
. 
1 
3 
3.0 
1 
1 
1 
1 
0 
1 
1 
1 
1 
8 
9 
 
. 
12 
-4 
-0.33 
-1 
1 
1 
-1 
-1 
0 
-1 
1 
1 
0 
5 
 
. 
12 
-3 
-0.25 
-1 
1 
1 
-1 
-1 
1 
0 
1 
1 
2 
6 
 
. 
12 
-12 
-1.0 
-1 
1 
1 
-1 
-1 
-1 
-1 
0 
1 
-2 
4 
 
. 
-7 
. 
-1 
1 
-1 
-1 
-1 
-1 
-1 
-1 
0 
-6 
2 
PPD
PPD
PPD


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6.2.4. 
Short-Form Health Survey 
The 8 different dimensions of SF-36, PCS and MCS, will be calculated based on the software 
developed by Optum. 
6.2.5. 
Amyotrophic Lateral Sclerosis Assessment Questionnaire 
The 5 ALSAQ-40 subscores will be derived per Table 20.  
Table 20: 
Algorithms for ALSAQ-40 Subscore Calculation 
Domain 
Formula 
Physical mobility 
 
100 × Sum(Item 1 to Item 10)
40
 
Activities of daily 
living/independence 
100 × Sum(Item 11 to Item 20)
40
 
Eating and drinking 
100 × Sum(Item 21 to Item 23)
12
 
Communication 
100 × Sum(Item 24 to Item 30)
28
 
Emotional functioning 
100 × Sum(Item 31 to Item 40)
40
 
6.2.6. 
Handheld Dynamometry  
The HHD megascores will be derived as follows for Baseline and post-Baseline visits: 
• For each muscle, calculate the ratio over baseline as 100 × (visit raw value/Baseline raw 
value) 
• Three megascores (ie, upper, lower, and total) are defined as the average of the 
nonmissing ratios for the muscles involved (upper limb, lower limb, total). 
• Megascore is always 100 at Baseline when HHD assessment is available. 
If both Baseline and post-Baseline raw values are 0, then the ratio will be defined as 100. If the 
Baseline raw value is 0, but the post-Baseline value > 0, then the ratio will be set to missing. 
6.2.7. 
Treatment Satisfaction Questionnaire for Medicine 
Scores for each domain are computed by adding the TSQM items in each domain and then 
transforming the composite score into a value ranging from 0 to 100. Of note, a score can be 
computed for a domain only if no more than 1 item is missing from that domain. The 
calculations specific to each domain are presented in detail below. 
Table 21: 
Algorithms for TSQM-9 Domain Score Calculation 
Domain 
Item Missingness 
Formula 
Effectiveness 
(Items 1 to 3) 
If items 1, 2, and 3 are nonmissing 
100 × [Sum(Item 1 to Item 3) –  3]
18
 
If 1 item is missing 
100 × [Sum(the two completed items) –  2]
12
 
Convenience  
(Items 4 to 6) 
If items 4, 5, and 6 are nonmissing 
100 × [Sum(Item 4 to Item 6) –  3]
18
 


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Table 21: 
Algorithms for TSQM-9 Domain Score Calculation 
Domain 
Item Missingness 
Formula 
If 1 item is missing 
100 × [Sum(the two completed items) –  2]
12
 
Global 
Satisfaction 
(Items 7 to 9) 
If items 7, 8, and 9 are nonmissing 
100 × [Sum(Item 7 to Item 9) –  3]
14
 
If either Item 7 or Item 8 is missing 
100 × [Sum(the two completed items) –  2]
10
 
If Item 9 is missing 
100 × [Sum(item 7 and item 8) –  2]
8
 
Abbreviation: TSQM-9 = Treatment Satisfaction Questionnaire for Medication 
6.2.8. 
European Quality of Life Health 5-item Questionnaire Health State Index 
Calculations 
The responses to the 5 EQ-5D-5L dimensions can be converted into a single number called an 
index value. The index value can be calculated by subtracting the appropriate weights listed in 
Table 22 for each dimension level of health state from 1. The weight for this study is provided by 
the US composite time trade-off (cTTO) method. The calculation is illustrated in Table 22. 
Table 22: 
EQ-5D-5L US Composite Time Trade-off Value Set 
US TTO 
  
Example: the value for health state 21354 
Full health (11111) 
  
Full health = 1 
Mobility 
Mobility level 2 
–0.096 
–0.096 
Mobility level 3 
–0.122 
 
Mobility level 4 
–0.237 
 
Mobility level 5 
–0.322 
 
Self-care 
Self-care level 2 
–0.089 
0 
Self-care level 3 
–0.107 
 
Self-care level 4 
–0.220 
 
Self-care level 5 
–0.261 
 
Usual activity 
 
 
Usual activity level 2 
–0.068 
 
Usual activity level 3 
–0.101 
–0.101 
Usual activity level 4 
–0.255 
 
Usual activity level 5 
–0.255 
 
Pain/discomfort 
 
 
Pain/discomfort level 2 
–0.06 
 
Pain/discomfort level 3 
–0.098 
 
Pain/discomfort level 4 
–0.318 
 
Pain/discomfort level 5 
–0.414 
–0.414 
Anxiety/depression 
Anxiety/depression level 2 
–0.057 
 
Anxiety/depression level 3 
–0.123 
 
Anxiety/depression level 4 
–0.299 
–0.299 
Anxiety/depression level 5 
–0.321 
 


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Table 22: 
EQ-5D-5L US Composite Time Trade-off Value Set 
US TTO 
  
Example: the value for health state 21354 
Health State Index Score 
 
= 1 - 0.096 + 0-0.101 - 0.414 - 0.299 = 0.090 
Abbreviations: EQ-5D-5L = European Quality of Life Health 5-item questionnaire; TTO = time trade-off; US = 
United States  
6.2.9. 
Analysis Windows 
Since the actual study visits for a participant may not exactly coincide with their targeted visit 
date, the actual visit date will be mapped to the analysis visits as described below. 
 
The analysis visits for the RCP will be derived using prespecified windows around the number of 
days during the study since the first dose of the study drug (called Day 1). The lower and the 
upper limits of the analysis windows are described in Table 23 .  
Table 23: 
Analysis Windows for Randomized Controlled Period 
Analysis Visit 
Target Day 
Low 
High 
Week 2 
15 
2 
29 
Week 6 
43 
30 
57 
Week 10 
71 
58 
85 
Week 14 
99 
86 
113 
Week 18 
127 
114 
141 
Week 22 
155 
142 
169 
Week 26 
183 
170 
211 
Week 34 
239 
212 
267 
Week 42 
295 
268 
323 
Week 50 
351 
324 
For participants entering OLE, the day of first dose in 
OLE; the last day in the study for other participants 
The analysis visits for the OLE Period will be derived using prespecified windows around the 
number of days during the study since the first dose of the OLE Period. The lower and the upper 
limits of the analysis windows are described in Table 24.  
Table 24: 
Analysis Windows for Open-Label Extension Period 
Analysis Visit 
Target Day 
Low 
High 
Week 2 
15 
2 
43 
Week 10 
71 
44 
99 
Week 18 
127 
100 
155 
Week 26 
183 
156 
211 
Week 34 
239 
212 
267 
Week 42 
295 
268 
323 
Week 50 
351 
324 
379 
Week 58 
407 
380 
435 
Week 66 
463 
436 
491 
Week 74 
519 
492 
547 


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Table 24: 
Analysis Windows for Open-Label Extension Period 
Analysis Visit 
Target Day 
Low 
High 
Week 82 
575 
548 
603 
Week 90 
631 
604 
659 
Week 98 
687 
660 
715 
Week 106 
743 
716 
- 
6.2.9.1. 
Rules for Selecting the Analysis Records 
Only 1 record per analysis window will be selected for analysis. The following defines the 
selection rule. 
1. Only scheduled visits of the specific endpoint will be selected and summarized in the 
tables and figures. If the earlier versions of the protocol and the final version of the 
protocol have different assessment schedules, then both scheduled visits will be used for 
the descriptive summary, as appropriate. Only the scheduled visits in the latest protocol 
will be selected for inferential analysis. 
a. For example, an unscheduled SVC assessment may fall into the Week 22 analysis 
window. However, because Week 22 is not a scheduled visit for SVC, this record 
will not be flagged for descriptive and inferential analysis. 
2. If there are multiple non-missing records within the same analysis window, the record 
closest to the target day will be selected. 
3. If there are records with equal distance from the target day, the later record will be 
selected. 
4. For CAFS analysis, only the last nonmissing record of ALSFRS-R will be selected. 
Similar visit windows will be implemented for the OLE Period. 
6.3. 
Appendix 3: List of Abbreviations 
The following abbreviations are used in this SAP. 
Table 25: 
Abbreviations 
Abbreviation 
Definition 
ADA 
Antidrug antibody 
AE 
Adverse event 
ALP 
Alkaline phosphatase 
ALS 
Amyotrophic lateral sclerosis 
ALSAQ-40 
ALS assessment questionnaire 
ALSFRS-R 
Amyotrophic lateral sclerosis functional rating scale revised 
ALT 
Alanine aminotransferase 
ANCOVA 
Analysis of Covariance 
AST 
Aspartate aminotransferase 
ATC 
Anatomical therapeutic chemical 
BMI 
Body mass index 
CAFS 
Combined assessment of function and survival 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CV 
Coefficient of variation 


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Table 25: 
Abbreviations 
Abbreviation 
Definition 
ECG 
Electrocardiogram 
ED 
Early discontinuation 
EQ-5D-5L 
European Quality of Life Health 5-item questionnaire 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
HHD 
Handheld dynamometry 
HR 
Hazard ratio 
IAP 
Interim analysis plan 
ICE 
Intercurrent Event  
IDMC 
Independent data monitoring committee 
IP 
Investigational product 
IV 
Intravenous 
KSS 
King’s staging system 
LS 
Least squares 
MAR 
Missing at random 
MCS 
Mental component summary 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
Mixed-effects model repeated measures 
NfL 
Neurofilament 
NIV 
Noninvasive ventilation 
OLE 
Open-Label Extension 
OLES 
Open-Label Extension Set  
PAV 
Permanent assisted ventilation 
PCS 
Physical component summary 
PD 
Pharmacodynamics 
PDAS 
Pharmacodynamic Analysis Set 
PK 
Pharmacokinetics 
PKAS 
Pharmacokinetic Analysis Set 
PRO-ACT 
Pooled Resource Open-Access ALS Clinical Trials 
PT 
Preferred term 
PTAEs 
Pre-Treatment Adverse Events 
RCP 
Randomized-controlled period 
SAP 
Statistical analysis plan 
SD 
Standard deviation 
SF-36 
Short-Form Health Survey 
SoA 
Schedule of activities 
SOC 
System organ class 
SS 
Safety Set 
SVC 
Slow vital capacity 
TBL 
Total bilirubin 
TEAE 
Treatment-emergent adverse event 
TSQM-9 
Treatment Satisfaction Questionnaire for Medication 
ULN 
Upper limit of normal 
VAFS 
Ventilation assistance-free survival 
VAS 
Visual analog scale 
WHO 
World health organization 


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6.4. 
Appendix 4: Changes to Protocol-planned Analyses 
The following table summarizes the changes in the planned analyses compared to the SAP 
version 1.0. 
Section # and Name 
Description of Changes 
Brief Rationale 
1.INTRODUCTION 
The following texts have been deleted: 
 
The scope of this analysis plan includes all 
efficacy, safety, pharmacokinetics, 
pharmacodynamics, and immunogenicity data 
collected during the randomized-controlled 
period. It will also include select analyses for the 
open-label extension period data available at the 
time of database lock for submission to the 
regulatory agencies. A separate analysis plan will 
be created to describe the planned analysis 
methods for the open-label extension period 
before the final database lock (study closeout). 
 
The table, figure, and listing specifications will be 
provided in a separate Data Presentation Plan 
document. 
 
The following texts have been added: 
 
The scope of the analyses for this study has been 
revised and is reflected in this SAP amendment 
due to the study meeting the pre-specified futility 
criterion. The amendment will be finalized prior 
to the final database lock and randomization code 
release. No separate SAP will be developed for 
the open-label extension period of the study. 
 
Describe the reason for the 
SAP amendment and some 
corresponding plan. 
 
 
 
 
 
 
4.ANALYSIS 
Table 25: Analysis Sets 
 
Per-Protocol Set (PPS) and Ravulizumab 
Exposure Set (RTS) have been deleted from Table 
2. 
 
The PPS analyses are not 
meaningful as the study 
stopped due to futility.  
 
Given a small amount of data 
for the open-label extension 
period, the analyses based on 
RTS will be redundant. 
5.1 General Consideration 
The following texts have been added: 
 
All p-values and confidence intervals will be used 
for descriptive purposes only due to the study 
meeting the futility criterion. 
To explain how the p-values 
and confidence intervals will 
be interpreted. 
5.2 Study Participants 
Deleted the randomized by region information 
Reduced scope for the 
abbreviated CSR. 
5.3.3 Alternate Primary Estimand and 
Analysis  
 
Deleted this section 
Not meaningful given the 
futility decision. 
5.3.4 Other Analyses 
Deleted the ALSFRS-R subscore summaries. 
Reduced scope for the 
abbreviated CSR. 
5.3.4.2 -5.3.4.8 Sensitivity Analysis 2-
8 
Deleted 
Not meaningful given the 
futility decision. 
5.3.5 Supplementary Analyses 
 
Deleted 
Not meaningful given the 
futility decision. 


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5.3.6 Other Analyses  
Deleted the following sentence: 
 
In addition, longitudinal changes in ALSFRS-R 
subscores will be modeled using the analytical 
approach described in Section 5.3.4.1 
Not meaningful given the 
futility decision. 
5.4.1.1.3 Sensitivity Analysis of VAFS 
 
Deleted 
Not meaningful given the 
futility decision. 
5.4.1.1.4 Other Analyses Related to 
VAFS and Components of VAFS 
(NIV, PAV and Mortality) 
 
 
Deleted the following sentences: 
The log-rank tests will also be performed for these 
endpoints. 
The Vonesh Shared Parameter model described in 
Section 5.3.4.3 will be used for joint estimation of 
treatment effect on mortality and ALSFRS-R. 
Not meaningful given the 
futility decision. 
5.4.1.3 Sensitivity Analysis: Slow 
Vital Capacity Percent Predicted 
 
Deleted 
Not meaningful given the 
futility decision. 
5.4.1.4 Other Analyses for Slow Vital 
Capacity 
Deleted the following: 
An analysis of the change from baseline in slow 
vital capacity volume (Liter) will be conducted 
similar to the method described in 
Section 5.4.1.2.2. 
 
Not meaningful given the 
futility decision. 
5.4.2 Supportive Secondary Endpoints 
and Analysis 
 
 Deleted the MMRM analyses for HHD and NfL. 
 
Not meaningful given the 
futility decision. 
5.5 Tertiary/Exploratory Endpoints 
and Analyses  
 
Deleted all the analyses for tertiary/exploratory 
endpoints 
Reduced scope for the 
abbreviated CSR. 
5.6 Safety Analyses 
Deleted all analyses related to Ravulizumab 
Exposure Set. 
 
Deleted all summary analyses for OLE except the 
first 6 TEAE tables in Table 6. 
 
For RCP, added the following in Table 6: 
-TEAEs (IP related) by SOC and PT; 
-TESAEs by SOC and PT and by Highest 
Relationship to IP; 
Changed the following in Table 6: 
-TESAEs (IP related) by SOC, PT and by Highest 
Severity to  
-TESAEs (IP related) by SOC and PT  
 
Added the following listings and tables: 
Lisitngs: 
-Infusion reaction related AEs 
-COVID-19 AEs 
 
Tables: 
- Infusion reaction related AEs by SOC and PT 
-Infusion reaction related SAEs by SOC and PT 
- Infusion reaction related AEs (IP-related)  by 
SOC and PT 
- Overall Summary of COVID-19 related AEs 
- COVID-19 related AEs by SOC and PT 
- COVID-19 related SAEs by SOC and PT 
 
Given a small amount of data 
for the open-label extension 
period, the analyses based on 
RTS or OLES will be 
redundant or not not 
meaningful. 
 
Additional output to support 
safety evaluation of 
ravulizumab. 


Alexion Pharmaceuticals 
Statistical Analysis Plan 
Protocol Number: ALXN1210-ALS-308 (Amendment 6) 
18Nov2021, Version 2.0 
Page 48 of 49 
Alexion Confidential 
5.6.1 Extent of Exposure 
Deleted the worst post baseline value analyses 
 
 
5.6.3 Laboratory Tests 
Deleted the following variables from Table 4: 
Ravulizumab Treatment Duration(days) 
Total Patient-years (years) Ravulizumab exposure 
Total number of ravulizumab infusions 
RTS was dropped. 
5.6.6 Physical Examination 
Deleted the following: 
 
The number and percentage of participants with 
normal and abnormal findings for each physical 
examination category will be reported by visit for 
the RCP and the OLE. Participants reporting ‘not 
done’ will not be included in the denominator for 
the percentage calculation. 
 
Reduced scope for the 
abbreviated CSR. 
5.6.7 Neurological Examination 
Deleted the following: 
 
The number and percentage of participants with 
different findings for each neurological 
examination category will be reported by visit for 
the RCP and the OLE. 
 
Not meaningful given the 
futility decision. 
 
Reduced scope for the 
abbreviated CSR. 
5.6.9 COVID-19 Exposure 
Deleted the following: 
 
The number and percentage of participants with 
COVID-19 exposure will be summarized. 
Small amount of COVID-19 
Exposure data. 
5.7.2 Pharmacodynamics  
Deleted the following: 
 
Details for PK/PD analyses and potential 
exposure-response analyses will be described in a 
separate PK/PD analysis plan. 
 
Not meaningful given the 
futility decision. 
5.7.3 Biomarker Assessments 
The exploratory biomarker analyses may be 
instead of will be performed. 
Reduced scope for the 
abbreviated CSR. 
5.7.5 Healthcare Resource Utilization 
 
Deleted 
 
 
Reduced scope for the 
abbreviated CSR. 
5.7.6.1 Subgroup Analyses for 
Efficacy 
Deleted 
Not meaningful given the 
futility decision. 
6.1.5 Prior and Concomitant 
Medications/Therapies  
Added the following listing: 
 
Prophylactic antibiotic medications after 
receiving meningococcal vaccine for subjects who 
initiated study drug 
Reduced scope for the 
abbreviated CSR. 
6.2.9. Analysis Windows 
Added the following: 
 
Table 24. Analysis Windows for Open Label 
Extension 
Incorporating OLE in this 
SAP. 
6.3 Appendix 3. Additional details on 
Statistical Methods  
Deleted 
Not needed anymore after 
analyses updates. 
6.4 Appendix 4. Changes to Protocol-
planned Analyses 
Section renumbered. 
Section renumbered. 
7. References 
Deleted the following reference: 
 
5.Vonesh EF, Greene T, Schluchter MD. Shared 
parameter models for the joint analysis of 
longitudinal data and event times. Stat Med. 
2006;25(1):143-163. doi:10.1002/sim.2249 
 
Not needed anymore after 
analyses updates. 


Alexion Pharmaceuticals 
Statistical Analysis Plan 
Protocol Number: ALXN1210-ALS-308 (Amendment 6) 
18Nov2021, Version 2.0 
Page 49 of 49 
Alexion Confidential 
7. 
REFERENCES 
1. Berry JD, Miller R, Moore DH, et al. The Combined Assessment of Function and 
Survival (CAFS): a new endpoint for ALS clinical trials. Amyotroph Lateral Scler 
Frontotemporal Degener. 2013;14(3):162-168. DOI:10.3109/21678421.2012.762930 
2. Castrillo-Viguera C, Grasso DL, Simpson E, Shefner J, Cudkowicz ME. Clinical 
significance in the change of decline in ALSFRS-R. Amyotroph Lateral Scler. 
2010;11(1-2):178-180. 
3. Cudkowicz ME, van den Berg LH, Shefner JM, et al. Dexpramipexole versus placebo for 
patients with amyotrophic lateral sclerosis (EMPOWER): a randomised, double-blind, 
phase 3 trial. Lancet Neurol. 2013;12(11):1059-1067. 
4. https://www.fda.gov/regulatory-information/search-fda-guidance-
documents/amyotrophic-lateral-sclerosis-developing-drugs-treatment-guidance-industry 
5. Writing Group for Edaravone ALS Study. Safety and efficacy of edaravone in well 
defined patients with amyotrophic lateral sclerosis: a randomised, double-blind, placebo-
controlled trial. Lancet Neurol. 2017;16(7):505-512.