A Phase 3, External Placebo-Controlled, Open-Label, Multicenter Study to Evaluate the Efficacy and Safety of Ravulizumab in Adult Patients With Neuromyelitis Optica Spectrum Disorder (NMOSD)
Phase: PHASE3
Conditions: Neuromyelitis Optica, Neuromyelitis Optica Spectrum Disorder
Sponsor: Alexion Pharmaceuticals, Inc.

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TITLE PAGE 
Protocol Title: A Phase 3, External Placebo-Controlled, Open-Label, Multicenter Study to 
Evaluate the Efficacy and Safety of Ravulizumab in Adult Patients with Neuromyelitis Optica 
Spectrum Disorder (NMOSD) 
Protocol Number: ALXN1210-NMO-307 
Amendment Number: 2.0 
Compound: Ravulizumab (ALXN1210) 
Study Phase: 3 
Short Title: A Phase 3 Efficacy and Safety Study of Ravulizumab in Adult Patients with 
NMOSD 
Sponsor Name: Alexion Pharmaceuticals, Inc. 
Legal Registered Address: 121 Seaport Boulevard, Boston, MA 02210, USA 
Regulatory Agency Identifier Number(s) 
IND: 144,187 
EudraCT: 2019-003352-37 
Approval Date: 01 Sep 2021 
NCT #: NCT04201262

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INVESTIGATOR’S AGREEMENT 
 
I have read the ALXN1210-NMO-307 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 
 
 
 

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PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE 
Document History 
Document 
Date 
Amendment 2.0 (Global) 
01 Sep 2021 
Amendment 1.2 (United Kingdom) 
07 Jun 2021 
Amendment 1.1 (Germany) 
28 Apr 2021 
Amendment 1.0 (Global) 
06 Jul 2020 
Original Protocol 
12 Aug 2019 
Amendment 2.0 (Global) (01 Sep 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.  
Overall Rationale for the Amendment: 
The main purpose of this amendment is to allow a switch in study drug formulation during the 
Long-term Extension Period, add visits to reflect the Treatment Period of up to 4.5 years, update 
the statistical methods, and incorporate administrative changes, as appropriate. 
Section # and Name 
Description of Change 
Brief Rationale 
Throughout the protocol 
Updated amendment number and approval 
date. 
Administrative change. 
Section 1.1 Synopsis, 
Section 1.2 Schema, 
Section 1.3 Schedule of 
Activities (SoA), 
Section 4.3.1 Ravulizumab, 
Section 8.1.6.1 
Ravulizumab 
Added the following content to the overall 
study design: Patients may be switched 
from the 10 mg/mL to the 100 mg/mL 
formulation of ravulizumab with no 
change to the weight-based dose regimen 
during the Long-Term Extension Period. 
To provide language that allows 
patients to be switched from the 
10 mg/mL to the 100 mg/mL 
formulation of ravulizumab. 
Section 1.1 Synopsis, 
Section 1.2 Schema, 
Section 4.1 Overall Design, 
Section 4.2.3 Rationale for 
the Duration of the Primary 
Treatment Period, 
Section 4.4 End of Primary 
Treatment 
Changed the term “relapse” to “On-trial 
Relapse” when defining the end of the 
Primary Treatment Period. 
To improve clarity. 
Section 1.3 Schedule of 
Activities (SoA) 
Added study visits at Weeks 210, 218, 
226, and 234, and added additional SoA 
table to accommodate new study visits. 
To reflect the Treatment Period of up to 
approximately 4.5 years, with study 
visits occurring every 8 weeks. 
Section 4.2.2.1 Efficacy 
Endpoints 
Changed the term “time to first relapse” to 
“time to first adjudicated On-trial Relapse” 
when reference is made to the study 
endpoint. 
To improve clarity. 
Section 4.4 End of Primary 
Treatment, Section 9.3 
Populations for Analyses 
The mFAS and related text were removed. 
In response to regulatory feedback. 
Section 6.1 
Added 100 mg/mL dose strength. 
To align with the change allowing 
patients to be switched to the 

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Section # and Name 
Description of Change 
Brief Rationale 
100 mg/mL formulation of 
ravulizumab. 
Section 6.5.1.3 Standardized 
Treatment for Relapse 
Added text clarifying that treatment for 
relapse is ultimately at the discretion of the 
Investigator. 
To improve clarity. 
Section 8.2.5 Expanded 
Disability Status Scale 
(EDSS), Section 8.2.5.1 
Expanded Disability Status 
Scale, Section 8.2.5.2 
Functional Systems Scores, 
Section 10.6 Appendix 6: 
Expanded Disability Status 
Scale (EDSS) 
Revised text clarifying the EDSS. 
To more completely describe the EDSS 
evaluation performed in the trial. 
Section 8.2.10.3 Visual 
Acuity  
Clarified the Landolt C assessment 
procedure. 
To provide clarity regarding the visual 
acuity measurement process in the trial. 
Section 8.3.3 Vital Signs 
Clarified that body temperature may be 
oral, temporal, or axillary. 
To provide clarity on methods allowed 
for temperature assessment. 
Section 9.1 Statistical 
Hypotheses 
The hypothesis statement for the 
adjudicated On-trial ARR is revised from 
emphasis on the upper 95% confidence 
interval to being based on the mean 
adjudicated On-trial ARR. 
To provide a hypothesis consistent with 
a 2-sided p-value approach for this 
endpoint. 
Section 9.2 Sample Size 
Determination 
Changed the term “time to first relapse” to 
“time to first adjudicated On-trial 
Relapse.” 
To improve clarity. 
Section 9.4 Statistical 
Analysis; and 9.5 Interim 
Analysis 
Added that immunogenicity study data will 
be included in the final analysis of the 
Primary Treatment Period. 
Added for completeness. 
Section 9.4.1 Efficacy 
Analyses 
Removed the statement that the mFAS 
would be the primary analysis set to 
account for potential differences resulting 
from missed or delayed dosing due to the 
COVID-19 pandemic. Also clarified that 
sensitivity analyses would account for 
baseline imbalances between the treatment 
groups. 
Removed the mFAS in response to 
regulatory feedback and added 
sensitivity analysis statement for 
clarity. 
Section 9.4.1.1 Primary 
Endpoint 
Added that Firth’s Penalized Likelihood 
will be used to estimate the hazard ratio, 
risk reduction, and the profile likelihood 
95% CIs if there is no observed event in a 
treatment arm. 
Added for clarification of analysis. 
Section 9.4.1.1 Primary 
Endpoint 
Added language on censoring. 
Added for clarification of analysis. 
Section 9.4.1.2 Secondary 
Endpoint(s) 
Added a statement regarding how the 
change from baseline to the 6-week 
post-relapse/EOPT Period analysis time 
point will be calculated for patients who 
missed a dose for reasons related to 
COVID-19. 
Added to address potential impact of 
COVID-19 pandemic on study results. 
Section 9.4.1.2.1 
Adjudicated On-trial ARR 
Changed the language regarding what 
would be considered statistically 
significant from the 95% CI approach to 
Reframed analysis from 95% CI 
approach to 2-sided p-value approach 

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Section # and Name 
Description of Change 
Brief Rationale 
the 2-sided p-value approach. Also added 
language to describe how the ARR will be 
calculated in the event that a patient 
missed a dose for COVID-19 related 
reasons. 
and added details in the calculation for 
clarity. 
Section 9.4.1.2.2 EuroQoL 
5 Dimension (EQ-5D) Index 
Score and EQ-5D VAS 
The nonparametric ANCOVA approach 
described for analysis of the EQ-5D 
endpoints is replaced with an ANCOVA 
on the ranks of the change from baseline in 
which treatment is a factor and the ranks of 
the baseline values is a covariate. 
Changed to use an analysis more 
suitable for a nonrandomized trial. 
Section 9.4.1.2.5 
Accounting for Multiple 
Comparisons 
Removed reference to the upper 95% CI 
when describing statistical significance. 
Reframed analysis of ARR from 95% 
CI approach to 2-sided p-value 
approach. 
Section 10.1.3 Informed 
Consent Process 
Removed the term “his/her legally 
authorized representative” and content 
related to this term when regarding 
enrollment. 
Based on enrollment criteria, patients 
participating in this study are capable 
of providing consent. Therefore, 
content related to legally authorized 
representative is removed from the 
informed consent process. Enrollment 
is closed, and no incapacitated patients 
were enrolled. 
Section 10.1.8 Study and 
Site Start and Closure 
Added the conditions below to the list of 
reasons for site early closure or 
termination: 
• 
Withdrawal of the favorable opinion 
or the approval  
• 
Inability to adjust the required 
maximum sum of insurance  
To specify additional criteria that may 
result in study termination. 
Section 10.16, Appendix 16 
Remote Source Data 
Verification During 
COVID-19 Pandemic 
Added description of remote source data 
verification during COVID-19 pandemic. 
Use of remote source data verification 
when onsite study monitoring activities 
are restricted is being implemented to 
ensure study integrity. 
Section 10.17, Appendix 17 
COVID-19 Risk 
Assessment 
Added COVID-19 risk assessment 
language. 
Section newly added to provide 
potential risks identified and mitigation 
measures put in place in light of the 
COVID-19 pandemic 
Section 10.18 Appendix 18: 
Protocol Amendment 
History 
Updated to reflect protocol amendment 
history. 
Administrative change. 
Throughout the document 
Minor grammatical, editorial, and 
document formatting revisions, including 
renumbering of Appendices 16 through 19. 
To enhance clarity. 
AE = adverse event; ANCOVA = analysis of covariance; ARR = annualized relapse rate; CI = confidence interval; 
COVID-19 = coronavirus disease 2019; EOPT = End of Primary Treatment; EQ-5D = European Quality of Life 
Health 5-item questionnaire; EQ VAS = European Quality of Life Visual Analog Scale; mFAS = modified Full 
Analysis Set; SAP = Statistical Analysis Plan 
 

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TABLE OF CONTENTS 
TITLE PAGE ...................................................................................................................................1 
INVESTIGATOR’S AGREEMENT ...............................................................................................3 
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE ............................................4 
TABLE OF CONTENTS .................................................................................................................7 
TABLE OF TABLES ....................................................................................................................13 
TABLE OF FIGURES ...................................................................................................................14 
1. 
PROTOCOL SUMMARY ..........................................................................................15 
1.1. 
Synopsis ......................................................................................................................15 
1.2. 
Schema ........................................................................................................................18 
1.3. 
Schedule of Activities (SoA) ......................................................................................19 
2. 
INTRODUCTION ......................................................................................................34 
2.1. 
Study Rationale ...........................................................................................................34 
2.2. 
Background .................................................................................................................34 
2.2.1. 
Neuromyelitis Optica Spectrum Disorder ..................................................................34 
2.2.2. 
Unmet Medical Need ..................................................................................................35 
2.2.3. 
Role of Complement Activation in NMOSD .............................................................35 
2.3. 
Benefit/Risk Assessment ............................................................................................36 
2.3.1. 
Risk Assessment .........................................................................................................36 
2.3.2. 
Benefit Assessment .....................................................................................................36 
2.3.3. 
Overall Benefit: Risk Conclusion ...............................................................................36 
3. 
OBJECTIVES AND ENDPOINTS ............................................................................37 
4. 
STUDY DESIGN .......................................................................................................38 
4.1. 
Overall Design ............................................................................................................38 
4.2. 
Scientific Rationale for Study Design ........................................................................38 
4.2.1. 
External Placebo-Controlled, Open-Label Design .....................................................38 
4.2.2. 
Rationale for the Selected Endpoints ..........................................................................39 
4.2.2.1. 
Efficacy Endpoints ......................................................................................................39 
4.2.3. 
Rationale for the Duration of the Primary Treatment Period .....................................39 
4.2.4. 
Rationale for the Selected Patient Population ............................................................40 
4.3. 
Justification for Dose ..................................................................................................40 
4.3.1. 
Ravulizumab ...............................................................................................................40 

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4.3.2. 
Supplemental Dose .....................................................................................................41 
4.4. 
End of Primary Treatment ..........................................................................................41 
4.5. 
End of Study Definition ..............................................................................................42 
5. 
STUDY POPULATION .............................................................................................43 
5.1. 
Inclusion Criteria ........................................................................................................43 
5.2. 
Exclusion Criteria .......................................................................................................44 
5.3. 
Lifestyle Considerations .............................................................................................45 
5.4. 
Screen Failures ............................................................................................................45 
6. 
STUDY DRUG ...........................................................................................................47 
6.1. 
Study Drug(s) Administered .......................................................................................47 
6.2. 
Preparation/Handling/Storage/Accountability ............................................................47 
6.3. 
Measures to Minimize Bias: Randomization and Blinding ........................................48 
6.4. 
Study Drug Compliance .............................................................................................48 
6.5. 
Concomitant Therapy .................................................................................................49 
6.5.1. 
Allowed Medications and Therapies ..........................................................................49 
6.5.1.1. 
Palliative and Supportive Care ...................................................................................49 
6.5.1.2. 
Immunosuppressive Agents ........................................................................................49 
6.5.1.3. 
Standardized Treatment for Relapse ...........................................................................50 
6.5.2. 
Disallowed Medications and Therapies ......................................................................50 
6.6. 
Dose Modification ......................................................................................................51 
6.7. 
Intervention after the End of the Study .......................................................................51 
7. 
DISCONTINUATION OF STUDY DRUG AND PATIENT 
DISCONTINUATION/WITHDRAWAL ..................................................................52 
7.1. 
Discontinuation of Study Drug ...................................................................................52 
7.2. 
Patient Discontinuation/Withdrawal from the Study ..................................................52 
7.3. 
Lost to Follow-up .......................................................................................................52 
8. 
STUDY ASSESSMENTS AND PROCEDURES ......................................................54 
8.1. 
General Assessments and Procedures .........................................................................54 
8.1.1. 
Informed Consent .......................................................................................................54 
8.1.2. 
Treating Physician ......................................................................................................54 
8.1.3. 
Medical History and NMOSD History .......................................................................54 
8.1.4. 
Vaccine and Antibiotic Prophylaxis ...........................................................................55 
8.1.5. 
Inclusion/Exclusion Criteria .......................................................................................55 

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8.1.6. 
Study Drug Administration .........................................................................................56 
8.1.6.1. 
Ravulizumab ...............................................................................................................56 
8.1.6.2. 
Supplemental Dose .....................................................................................................56 
8.1.7. 
Visits at Home or Alternative Healthcare Facilities ...................................................57 
8.2. 
Efficacy Assessments .................................................................................................58 
8.2.1. 
Neurologic Examination .............................................................................................58 
8.2.2. 
NMO Symptom Card and Evaluation .........................................................................58 
8.2.3. 
Relapse ........................................................................................................................58 
8.2.3.1. 
Historical Relapse .......................................................................................................58 
8.2.3.2. 
On-trial Relapse ..........................................................................................................59 
8.2.4. 
Case of Interest ...........................................................................................................60 
8.2.5. 
Expanded Disability Status Scale (EDSS) ..................................................................61 
8.2.5.1. 
Expanded Disability Status Scale ...............................................................................61 
8.2.5.2. 
Functional Systems Scores .........................................................................................61 
8.2.5.3. 
EDSS and FSS Rater ..................................................................................................61 
8.2.6. 
EuroQoL 5 Dimensions (EQ-5D) ...............................................................................62 
8.2.6.1. 
EQ-5D Descriptive System .........................................................................................62 
8.2.6.2. 
EQ Visual Analogue Scale .........................................................................................63 
8.2.7. 
Short Form Health Survey (SF-36) .............................................................................63 
8.2.8. 
Hauser Ambulation Index (HAI) ................................................................................63 
8.2.9. 
Optic Spinal Impairment Score (OSIS) ......................................................................63 
8.2.10. 
Ophthalmologic Examination .....................................................................................63 
8.2.10.1. 
Confrontational Visual Fields .....................................................................................63 
8.2.10.2. 
Color Vision ................................................................................................................64 
8.2.10.3. 
Visual Acuity ..............................................................................................................64 
8.2.11. 
Magnetic Resonance Imaging and Optical Coherence Tomography .........................64 
8.3. 
Safety Assessments .....................................................................................................65 
8.3.1. 
Physical Examinations ................................................................................................65 
8.3.2. 
Height and Weight ......................................................................................................65 
8.3.3. 
Vital Signs ..................................................................................................................65 
8.3.4. 
Electrocardiograms .....................................................................................................65 
8.3.5. 
Patient Safety Card .....................................................................................................66 
8.3.6. 
Prior and Concomitant Medical Review .....................................................................66 

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8.3.6.1. 
Prior Medications ........................................................................................................66 
8.3.6.2. 
Concomitant Medications ...........................................................................................66 
8.3.7. 
Clinical Safety Laboratory Assessments ....................................................................66 
8.3.8. 
Suicidal Ideation and Behavior Risk Monitoring .......................................................67 
8.4. 
Adverse Events and Serious Adverse Events .............................................................67 
8.4.1. 
Time Period and Frequency for Collecting Adverse Event and Serious 
Adverse Event Information .........................................................................................68 
8.4.2. 
Method of Detecting AEs and SAEs ..........................................................................68 
8.4.3. 
Follow-up of AEs and SAEs .......................................................................................68 
8.4.4. 
Regulatory Reporting Requirements for SAEs ...........................................................68 
8.4.5. 
Pregnancy ...................................................................................................................69 
8.4.6. 
Adverse Events of Special Interest .............................................................................69 
8.5. 
Treatment of Overdose ...............................................................................................69 
8.6. 
Pharmacokinetics and Pharmacodynamics .................................................................70 
8.6.1. 
Sample Collection During the Study Period ...............................................................70 
8.6.2. 
Sample Collection During On-trial Relapse ...............................................................70 
8.7. 
Genetics ......................................................................................................................71 
8.8. 
Biomarker Research ....................................................................................................71 
8.8.1. 
Exploratory Biomarker Research ...............................................................................71 
8.8.2. 
Future Biomarker Research ........................................................................................71 
8.9. 
Immunogenicity Assessments ....................................................................................72 
8.10. 
Medical Resource Utilization and Health Economics ................................................72 
9. 
STATISTICAL CONSIDERATIONS .......................................................................73 
9.1. 
Statistical Hypotheses .................................................................................................73 
9.2. 
Sample Size Determination ........................................................................................73 
9.3. 
Populations for Analyses ............................................................................................74 
9.4. 
Statistical Analyses .....................................................................................................74 
9.4.1. 
Efficacy Analyses .......................................................................................................75 
9.4.1.1. 
Primary Endpoint ........................................................................................................75 
9.4.1.2. 
Secondary Endpoint(s) ................................................................................................75 
9.4.1.3. 
Tertiary/exploratory endpoint(s) .................................................................................77 
9.4.2. 
Safety Analyses ..........................................................................................................77 
9.4.2.1. 
Analysis of Adverse Events ........................................................................................77 

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9.4.2.2. 
Analysis of Clinical Laboratory Parameters, Vital Sign Measurements and 
Electrocardiogram Parameters ....................................................................................77 
9.4.2.3. 
Other Safety Analyses ................................................................................................77 
9.4.3. 
Demographics and Baseline Characteristics ...............................................................77 
9.4.4. 
Patient Disposition ......................................................................................................77 
9.4.5. 
Medical/Surgical History and Neuromyelitis Optica Spectrum Disorder 
History ........................................................................................................................78 
9.4.6. 
Prior and Concomitant Medications ...........................................................................78 
9.4.7. 
Pharmacokinetic, Pharmacodynamic, and Anti-Drug Antibody Analyses ................78 
9.4.8. 
Medical Resource Utilization and Health Economics ................................................78 
9.5. 
Interim Analysis ..........................................................................................................79 
9.6. 
Data Monitoring Committee (DMC) ..........................................................................79 
10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS ..................................................................................................80 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations ....................80 
10.1.1. 
Regulatory and Ethical Considerations ......................................................................80 
10.1.2. 
Financial Disclosure ...................................................................................................80 
10.1.3. 
Informed Consent Process ..........................................................................................81 
10.1.4. 
Data Protection ...........................................................................................................81 
10.1.5. 
Dissemination of Clinical Study Data ........................................................................81 
10.1.6. 
Data Quality Assurance ..............................................................................................81 
10.1.7. 
Source Documents ......................................................................................................82 
10.1.8. 
Study and Site Start and Closure ................................................................................82 
10.1.9. 
Publication Policy .......................................................................................................83 
10.2. 
Appendix 2: Clinical Laboratory Tests .......................................................................83 
10.3. 
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting ........................................................................85 
10.3.1. 
Adverse Event Definition ...........................................................................................85 
10.3.2. 
Serious Adverse Event Definition ..............................................................................85 
10.3.3. 
Recording and Follow-Up of Adverse Event and/or Serious Adverse Event ............86 
10.3.4. 
Reporting of Serious Adverse Events .........................................................................88 
10.4. 
Appendix 4: Contraceptive Guidance and Collection of Pregnancy 
Information .................................................................................................................89 
10.4.1. 
Definitions ..................................................................................................................89 

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10.4.1.1. 
Woman of Childbearing Potential (WOCBP) ............................................................89 
10.4.1.2. 
Women in the Following Categories Are Not Considered WOCBP ..........................89 
10.4.2. 
Contraception Guidance: ............................................................................................89 
10.4.3. 
Pregnancy Testing ......................................................................................................90 
10.4.4. 
Collection of Pregnancy Information .........................................................................91 
10.4.4.1. 
Male Patients with Partners Who Become Pregnant ..................................................91 
10.4.4.2. 
Female Patients Who Become Pregnant .....................................................................91 
10.5. 
Appendix 5: Diagnostic Criteria for Neuromyelitis Optica Spectrum 
Disorder ......................................................................................................................92 
10.6. 
Appendix 6: Expanded Disability Status Scale (EDSS) .............................................93 
10.7. 
Appendix 7: EuroQoL 5 Dimensions (EQ-5D-3L) ....................................................95 
10.8. 
Appendix 8: Short Form Health Survey (SF-36) ......................................................101 
10.9. 
Appendix 9: Hauser Ambulation Index (HAI) .........................................................107 
10.10. 
Appendix 10: Optic Spinal Impairment Score (OSIS) .............................................108 
10.11. 
Appendix 11: Relapse Severity ................................................................................109 
10.12. 
Appendix 12: Columbia Suicide Severity Rating Scale  (C-SSRS)-
Screening/Baseline ...................................................................................................110 
10.13. 
Appendix 13: Columbia-Suicide Severity Rating Scale (C-SSRS)-Since Last 
Visit ...........................................................................................................................112 
10.14. 
Appendix 14: Management of Potential Infusion-Associated Adverse Events 
During Study Drug Administration ..........................................................................113 
10.15. 
Appendix 15: Identification of Cases of Interest ......................................................115 
10.16. 
Appendix 16: Remote Source Data Verification During COVID-19 
Pandemic ...................................................................................................................117 
10.17. 
Appendix 17: COVID-19 Risk Assessment .............................................................119 
10.18. 
Appendix 18: Protocol Amendment History ............................................................121 
10.19. 
Appendix 19: Abbreviations .....................................................................................122 
11. 
REFERENCES .........................................................................................................125 

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TABLE OF TABLES 
Table 1: 
Schedule of Activities (Screening Through Week 58) ...............................................19 
Table 2: 
Schedule of Activities (Week 66 Through Week 138) ...............................................23 
Table 3: 
Schedule of Activities (Week 146 Through Week 234) .............................................26 
Table 4: 
Schedule of Activities (End of Primary Treatment, End of Treatment/Early 
Discontinuation, Follow-Up) ......................................................................................29 
Table 5: 
Schedule of Activities (Relapse Evaluation Period) ...................................................32 
Table 6 
Study Drugs ................................................................................................................47 
Table 7: 
Weight-based Doses of Ravulizumab .........................................................................56 
Table 8: 
Supplemental Dose of Ravulizumab Administered at Nonscheduled Dosing 
Visits After PE/PP Treatment for On-trial Relapse ....................................................57 
Table 9: 
Roles and Responsibilities of the Treating Physician and EDSS Rater .....................62 
Table 10: Populations for Analyses ............................................................................................74 
Table 11: Clinical Laboratory Tests ...........................................................................................84 
Table 12: Relapse Severity as Measured by Optic Spinal Impairment Scale ...........................109 
Table 13: Clinical Criteria for Diagnosing Anaphylaxis ..........................................................114 
Table 14 
List of Example AE Terms to be Flagged as Sentinel AEs and Used to 
Identify Cases of Interest ..........................................................................................116 
Table 15: Potential Risks and Mitigation Measures due to COVID-19 ...................................119 
 

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TABLE OF FIGURES 
Figure 1 
Study ALXN1210-NMO-307 Schematic ...................................................................18 
 

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1. 
PROTOCOL SUMMARY 
1.1. 
Synopsis 
Protocol Title: A Phase 3, External Placebo-Controlled, Open-Label, Multicenter Study to 
Evaluate the Efficacy and Safety of Ravulizumab in Adult Patients with Neuromyelitis Optica 
Spectrum Disorder (NMOSD) 
Short Title: A Phase 3 Efficacy and Safety Study of Ravulizumab in Adult Patients with 
NMOSD 
Rationale: 
Neuromyelitis optica spectrum disorder (NMOSD) is an ultra-rare, severe, disabling autoimmune 
inflammatory disorder of the central nervous system (CNS) that predominantly affects the optic 
nerves and spinal cord. In June 2019, the U.S. Food and Drug Administration (FDA) approved 
SOLIRIS® (eculizumab), a first-generation complement inhibitor, for the treatment of NMOSD 
in adult patients who are anti-aquaporin-4 (AQP4) antibody (Ab) positive. Findings from the 
clinical development program of eculizumab in patients with NMOSD support the rationale for 
complement component 5 (C5) inhibition as a therapeutic approach for reducing the risk of 
relapses in NMOSD. Ravulizumab has a longer elimination half-life than eculizumab while 
binding the same epitope on C5, which enables an extended dosing interval while maintaining 
the high degree of specificity for C5 achieved by eculizumab in inhibiting terminal complement 
activity. 
Given that eculizumab has been proven to reduce the risk of relapse in adult patients with 
NMOSD, and considering the similar mechanism of action and binding site between 
ravulizumab and eculizumab, this study is being undertaken to evaluate the efficacy and safety of 
ravulizumab in adult patients with NMOSD. The goal of this study is to provide NMOSD 
patients with a treatment option that reduces overall treatment burden by requiring less frequent 
infusions relative to eculizumab, while maintaining a comparable benefit/risk profile. 
Objectives and Endpoints: 
Objectives 
Endpoints 
Primary 
• 
To evaluate the effect of ravulizumab on 
adjudicated On-triala Relapses in adult patients 
with NMOSD 
• 
Time to first adjudicated On-trial Relapse and 
relapse risk reduction 
Secondary 
• 
To evaluate the safety of ravulizumab in adult 
patients with NMOSD 
• 
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 on 
adjudicated annualized relapse rate (ARR) in adult 
patients with NMOSD 
• 
Adjudicated On-trial ARR 
• 
To evaluate the effect of ravulizumab on disease-
related disability in adult patients with NMOSD 
• 
Clinically important worsening from baseline in 
expanded disability status scale (EDSS)  
• 
To evaluate the effect of ravulizumab on quality of 
life (QoL) in adult patients with NMOSD 
• 
Change from baseline in EuroQoL-5D (EQ-5D)  

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Objectives 
Endpoints 
• 
To evaluate the effect of ravulizumab on 
neurologic function in adult patients with NMOSD 
• 
Clinically important change from baseline in 
Hauser ambulation index (HAI)  
• 
To characterize the pharmacokinetics (PK) of 
ravulizumab in adult patients with NMOSD 
• 
Change in serum ravulizumab concentration over 
the study duration 
• 
To characterize the pharmacodynamics (PD) of 
ravulizumab in adult patients with NMOSD 
• 
Change in serum free C5 concentration over the 
study duration 
• 
To characterize the immunogenicity of 
ravulizumab in adult patients with NMOSD  
• 
Presence and titer of anti-drug antibodies (ADAs) 
over the study duration 
a On-trial Relapses refer to relapses as determined by the Treating Physician that occur during the study treatment 
period. All relapses will be adjudicated by a separate Adjudication Committee 
Overall Design 
Study ALXN1210-NMO-307 is a Phase 3, external placebo-controlled, open-label, multicenter 
study to evaluate the efficacy and safety of ravulizumab in adult patients with NMOSD. 
Approximately 55 eligible adult patients with NMOSD will be enrolled. 
This study will employ a single-arm treatment design, utilizing the placebo group from Study 
ECU-NMO-301 (conducted 2014 to 2018) as an external placebo control. This will allow for a 
robust assessment of ravulizumab as a treatment option for NMOSD. 
There are 4 periods in this study: Screening Period, Primary Treatment Period, Long-Term 
Extension Period, and Safety Follow-up Period. Patients will be screened for eligibility for up to 
6 weeks during the Screening Period. The end of the Primary Treatment Period will be triggered 
when either (1) 2 patients have had an adjudicated On-trial Relapse; or (2) all patients have 
completed, or discontinued prior to, the Week 26 Visit; whichever comes later. However, if 
2 patients have not had an adjudicated On-trial Relapse by the time all patients have completed, 
or discontinued prior to, the Week 50 visit, the end of the Primary Treatment Period will be 
triggered at that time. Note that patients who complete the visits indicated above (Week 26 or 
Week 50) will remain on the study in the Primary Treatment Period until the Primary Treatment 
Period ends.  For examples of different scenarios of the end of the Primary Treatment Period, 
please refer to Section 4.4.  Based on the estimated enrollment rate, the duration of the Primary 
Treatment Period for each patient is expected to be between 26 weeks and approximately 
2.5 years. The Primary Treatment Period ends and the Long-Term Extension Period starts when 
all patients have completed their End of Primary Treatment (EOPT) Visit within the timeframe 
specified in Section 4.4. All patients will continue to receive ravulizumab during the Long-Term 
Extension Period for up to approximately 2 years, or until ravulizumab is approved and/or 
available (in accordance with country-specific regulations), whichever occurs first. The total 
treatment duration for each patient will be up to approximately 4.5 years. After the last dose of 
study drug or early discontinuation (ED), patients will be followed for 8 weeks. 
Disclosure Statement: This is a single-arm treatment study with no masking. 
Number of Patients: 
Approximately 55 eligible patients will be enrolled. 
Study Drug Groups and Duration: 
Eligible patients will enroll into the study to receive intravenous infusions of ravulizumab. 

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The ravulizumab dose for each patient will be based on body weight. The dosing regimen 
consists of a loading dose followed by maintenance dosing administered every 8 weeks (q8w). 
The maintenance dosing should be initiated 2 weeks after the loading dose administration.  
Patients may be switched from the 10 mg/mL to the 100 mg/mL formulation of ravulizumab 
with no change to the weight-based dose regimen during the Long-Term Extension Period. 
For each patient, the total duration of study participation will be up to approximately 4.75 years, 
including the Screening Period (up to 6 weeks), the Primary Treatment Period (between 
26 weeks and approximately 2.5 years), the Long-Term Extension Period (up to approximately 
2 years), and the Safety Follow-up Period (8 weeks). 
Data Monitoring Committee: No 
Relapse Adjudication Committee: Yes 
 

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1.2. 
Schema 
Figure 1 
Study ALXN1210-NMO-307 Schematic 
 
1All eligible patients will receive open-label ravulizumab during the Primary Treatment Period. The end of the Primary Treatment Period will be triggered either 
when (1) 2 patients have had an adjudicated On-trial Relapse; or (2) all patients have completed, or discontinued prior to, the Week 26 Visit; whichever comes 
later. However, if 2 patients have not had an adjudicated On-trial Relapse by the time all patients have completed, or discontinued prior to, the Week 50 visit, 
the end of the Primary Treatment Period will be triggered at that time. Note that patients who complete the visits indicated above (Week 26 or Week 50) will 
remain on the study in the Primary Treatment Period until the Primary Treatment Period ends. Based on the estimated enrollment rate, the duration of the 
Primary Treatment Period for each patient is expected to be between 26 weeks and approximately 2.5 years. 
2 The Primary Treatment Period ends and the Long-Term Extension Period starts when all patients have completed their End of Primary Treatment (EOPT) Visit 
within the time frame specified in Section 4.4. Patients will continue to receive ravulizumab during the Long-Term Extension Period for up to approximately 
2 years, or until ravulizumab is approved and/or available (in accordance with country-specific regulations), whichever occurs first.  
3The primary analysis for regulatory submission will be conducted at the end of the Primary Treatment Period, and will include all available efficacy, safety, and 
PK/PD/ADA data collected from the Primary Treatment Period. 
Note: Patients may be switched from the 10 mg/mL to the 100 mg/mL formulation of ravulizumab with no change to the weight-based dose regimen during the 
Long-Term Extension Period. 
 

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1.3. 
Schedule of Activities (SoA) 
Table 1: 
Schedule of Activities (Screening Through Week 58) 
 
Screening 
Treatment 
Notes 
Visit1 
W-6 to -1 
 
W2 
W6 
W10 
W18 
W26 
W34 
W42 
W50 
W58 
Phone2 
Additional evaluation visits can be 
scheduled at the discretion of the 
Investigator. An ED Visit should be 
performed if patients discontinue 
early 
Days and Window 
 
D1 
D15 
± 2 
D43 
± 2 
D71 
± 2 
D127 
± 2 
D183 
± 2 
D239 
± 7 
D295 
± 7 
D351
± 7 
D407 
± 7 
 
General Assessments/Procedures 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
NMOSD 
History/Diagnosis 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Anti-AQP4 Ab Test 
(Serum) 
X 
 
 
 
 
 
 
 
 
 
 
 
Refer to Section 5.1 for testing requirements. 
Inclusion/Exclusion 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
  
Weight 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
  
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
  
N. meningitidis 
Vaccination 
X 
 
 
 
 
 
 
 
 
 
 
 
Patients must be vaccinated against 
meningococcal infection, and revaccinated 
during the study if needed (Section 8.1.4)  
HIV Test 
X 
 
 
 
 
 
 
 
 
 
 
 
Test includes HIV-1 and HIV-2 
Pregnancy Test 
(WOCBP only) 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
Serum test at screening is required. Urine test 
at indicated visits and when necessary at 
Investigator’s discretion 
Dispense Patient Safety 
Card and NMO 
Symptom Card 
X 
 
 
 
 
 
 
 
 
 
 
 
Instruct patients to carry safety card at all 
times and bring both cards to scheduled visits 
(Section 8.2.2; Section 8.3.5 ) 
Pharmacokinetic and Pharmacodynamic Assessments 
PK/Free C5 Blood 
Samples  
 
B/P 
T/P 
X 
T/P 
T/P 
T/P 
T/P 
 
T/P 
 
 
Collect B (baseline), T (predose), P 
(postdose), and X (anytime) samples 
(Section 8.6) 

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Screening 
Treatment 
Notes 
Visit1 
W-6 to -1 
 
W2 
W6 
W10 
W18 
W26 
W34 
W42 
W50 
W58 
Phone2 
Additional evaluation visits can be 
scheduled at the discretion of the 
Investigator. An ED Visit should be 
performed if patients discontinue 
early 
Days and Window 
 
D1 
D15 
± 2 
D43 
± 2 
D71 
± 2 
D127 
± 2 
D183 
± 2 
D239 
± 7 
D295 
± 7 
D351
± 7 
D407 
± 7 
 
PK/Free C5 CSF 
Samples 
 
B 
 
 
 
 
T 
 
 
 
 
 
Optional; collect B (baseline) and T 
(predose) samples from patients who consent 
to CSF collection (Section 8.6 ) 
ADA Blood Samples 
 
B 
 
 
 
 
T 
 
 
T 
 
 
Collect B (baseline) and T (predose) samples 
(Section 8.9) 
Safety Assessments 
Physical Examination 
X 
 
 
 
 
 
 
 
 
 
 
 
  
Targeted Physical 
Examination 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Perform when deemed necessary by the 
Investigator (Section 8.3.1) 
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
  
ECG 
X 
X 
 
 
 
 
X 
 
 
X 
 
 
  
Prior Medications 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant 
Medications 
Continuous monitoring 
  
Concomitant Non-Drug 
Therapies/Procedures 
Continuous monitoring 
  
AE 
Continuous monitoring 
  
Clinical Laboratory 
Tests 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
Refer to Section 10.2 for the list of tests  
Patient Safety Card 
Review 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Review signs and symptoms of infections 
(Section 8.3.5) 
C-SSRS 
 
X 
 
X 
 
X 
X 
 
X 
 
X 
 
2 types of C-SSRS assessments: Baseline 
(Day 1) and Since last visit (Section 8.3.8) 
Efficacy Assessments 
Neurologic 
Examination3 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
  
NMO Symptom Card 
and Evaluation  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
NMOSD symptoms will be evaluated by the 
Investigator (Section 8.2.2) 

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Screening 
Treatment 
Notes 
Visit1 
W-6 to -1 
 
W2 
W6 
W10 
W18 
W26 
W34 
W42 
W50 
W58 
Phone2 
Additional evaluation visits can be 
scheduled at the discretion of the 
Investigator. An ED Visit should be 
performed if patients discontinue 
early 
Days and Window 
 
D1 
D15 
± 2 
D43 
± 2 
D71 
± 2 
D127 
± 2 
D183 
± 2 
D239 
± 7 
D295 
± 7 
D351
± 7 
D407 
± 7 
 
EQ-5D 
X 
X 
 
X 
 
X 
X 
 
X 
 
X 
 
When possible, administer before other 
procedures  
SF-36 
X 
X 
 
X 
 
X 
X 
 
X 
 
X 
 
When possible, administer before other 
procedures 
EDSS (including FSS) 
X 
X 
 
X 
 
X 
X 
 
X 
 
X 
 
Conducted by a blinded EDSS Rater 
(Section 8.2.5) 
HAI 
X 
X 
 
X 
 
X 
X 
 
X 
 
X 
 
Performed by the Investigator or trained 
designee 
OSIS3 
 
X 
 
 
 
 
 
 
 
 
 
 
  
Ophthalmological 
Examination 
X 
X 
 
X 
 
X 
X 
 
X 
 
X 
 
Including confrontational field test1, color 
vision and visual acuity (Section 8.2.10) 
OCT 
X 
 
 
 
 
 
 
 
 
 
 
 
  
MRI 
X 
 
 
 
 
 
 
 
 
 
 
 
Brain, cervical spine, and thoracic spine; 
contrast is optional 
Biomarker Research 
Blood samples 
 
X 
X 
X 
 
 
X 
 
 
X 
 
 
Blood samples for DNA and RNA are 
optional; blood sample for DNA is only 
collected on Day 1.  
CSF samples 
 
X 
 
 
 
 
X 
 
 
 
 
 
Optional 
Administration of Study Drug 
Ravulizumab4 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
Administered after all other required 
tests/procedures, except those to be 
performed postdosing 
1 Under reasonable occasional circumstances where a patient is not able to attend a study visit on site, a home visit or visit at an alternative healthcare facility may be permitted by the 
Sponsor after discussing with the Alexion Medical Monitor. This will be a case-by-case decision (Section 8.1.7). 
2 Biweekly phone visit will be conducted between the visits to monitor NMOSD symptoms and safety (Section 8.2.2). 
3 Performed by the Treating Physician who is an Investigator and has been properly trained for the evaluation, preferably the same Treating Physician, throughout the study. 
4 Patients may be switched from the 10 mg/mL to the 100 mg/mL formulation of ravulizumab with no change to the weight-based dose regimen during the Long-Term Extension 
Period (Section 8.1.6.1). 

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Screening 
Treatment 
Notes 
Visit1 
W-6 to -1 
 
W2 
W6 
W10 
W18 
W26 
W34 
W42 
W50 
W58 
Phone2 
Additional evaluation visits can be 
scheduled at the discretion of the 
Investigator. An ED Visit should be 
performed if patients discontinue 
early 
Days and Window 
 
D1 
D15 
± 2 
D43 
± 2 
D71 
± 2 
D127 
± 2 
D183 
± 2 
D239 
± 7 
D295 
± 7 
D351
± 7 
D407 
± 7 
 
Abbreviations: ADA = antidrug antibody; AE = adverse event; AQP4 Ab = aquaporin 4 antibody; B = baseline sample; C5 = complement component 5; CSF = cerebrospinal fluid; 
C-SSRS = Columbia-suicide severity rating scale; D = day; DNA =  deoxyribonucleic acid; ECG = electrocardiogram; ED = early discontinuation; EDSS = expanded disability 
status scale; EQ-5D = EuroQoL-5D; FSS = functional system score; HAI = Hauser ambulation index; HIV = human immunodeficiency virus; MRI = magnetic resonance imaging; 
NMOSD = neuromyelitis optica spectrum disorder; OCT = optical coherence tomography; OSIS = optic spinal impairment score; P = postdose sample; PK =  pharmacokinetic(s); 
RNA = ribonucleic acid; SF-36 = short form health survey; T = trough sample; W = week(s); WOCBP = women of childbearing potential 
 
 

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Table 2: 
Schedule of Activities (Week 66 Through Week 138) 
  
Treatment 
Notes 
Visit1 
W66 
W74 
W82 
W90 
W98 
W106 
W114 
W122 
W130 
W138 
Phone2 
Additional evaluation visits can 
be scheduled at the discretion of 
the Investigator. An ED Visit 
should be performed if patients 
discontinue early. 
Days and Window 
D463 
± 7 
D519 
± 7 
D575 
± 7 
D631 
± 7 
D687 
± 7 
D743 
± 7 
D799 
± 7 
D855 
± 7 
D911 
± 7 
D967 
± 7 
 
General Assessments/Procedures 
Weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
  
N. meningitidis 
Vaccination 
 
 
 
 
 
 
 
 
 
 
 
Patients must be vaccinated against 
meningococcal infection, and 
revaccinated during the study if needed 
(Section 8.1.4) 
Pregnancy Test 
(WOCBP only) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Serum test at screening is required. 
Urine test at indicated visits and when 
necessary at Investigator’s discretion 
Pharmacokinetic and Pharmacodynamic Assessments 
PK/Free C5 Blood 
Samples  
T/P 
 
T/P 
 
 
T/P 
 
 
T/P 
 
 
Collect T (predose) and P (postdose) 
samples (Section 8.6) 
PK/Free C5 CSF Samples 
 
 
T 
 
 
 
 
 
T 
 
 
Optional; collect sample T (predose) 
from patients who consent to CSF 
sample collection (Section 8.6) 
ADA Blood Samples 
 
 
T 
 
 
T 
 
 
T 
 
 
Collect T (predose) samples 
(Section 8.9) 
Safety Assessments 
Targeted Physical 
Examination 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Perform when deemed necessary by the 
Investigator (Section 8.3.1) 
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
  
ECG 
 
 
 
 
 
X 
 
 
 
 
 
  
Concomitant Medications 
Continuous Monitoring 
  
Concomitant Non-Drug 
Therapies/Procedures 
Continuous Monitoring 
  
AE 
Continuous Monitoring 
  

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Treatment 
Notes 
Visit1 
W66 
W74 
W82 
W90 
W98 
W106 
W114 
W122 
W130 
W138 
Phone2 
Additional evaluation visits can 
be scheduled at the discretion of 
the Investigator. An ED Visit 
should be performed if patients 
discontinue early. 
Days and Window 
D463 
± 7 
D519 
± 7 
D575 
± 7 
D631 
± 7 
D687 
± 7 
D743 
± 7 
D799 
± 7 
D855 
± 7 
D911 
± 7 
D967 
± 7 
 
Clinical Laboratory Tests 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Refer to Section 10.2 for the list of 
tests. 
Patient Safety Card 
Review 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Review signs and symptoms of 
infections (Section 8.3.5) 
C-SSRS 
 
X 
 
X 
 
X 
 
 
X 
 
 
Conduct C-SSRS-Since Last Visit 
assessment (Section 8.3.8) 
Efficacy Assessments 
Neurologic Examination3 
 
X 
 
X 
 
X 
 
 
X 
 
 
  
NMO Symptom Card and 
Evaluation 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
NMOSD symptoms will be evaluated 
by the Investigator (Section 8.2.2) 
EQ-5D 
 
X 
 
X 
 
X 
 
 
X 
 
 
When possible administer before other 
procedures 
SF-36 
 
X 
 
X 
 
X 
 
 
X 
 
 
When possible administer before other 
procedures 
EDSS (including FSS) 
 
X 
 
X 
 
X 
 
 
X 
 
 
Conducted by a blinded EDSS Rater 
(Section 8.2.5) 
HAI 
 
X 
 
X 
 
X 
 
 
X 
 
 
Performed by an Investigator or trained 
designee 
Ophthalmological 
Examination 
 
X 
 
X 
 
X 
 
 
X 
 
 
Including confrontational field test1, 
color vision and visual acuity (Landolt 
C ring) (Section 8.2.10) 
Biomarker Research 
Blood samples 
 
 
X 
 
 
X 
 
 
X 
 
 
Blood samples for RNA are optional  
CSF samples 
 
 
X 
 
 
 
 
 
X 
 
 
Optional 
Administration of Study Drug 
Ravulizumab4 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Administered after all other required 
tests/procedures, except those to be 
performed postdosing 
1 Under reasonable occasional circumstances where a patient is not able to attend a study visit on site, a home visit or visit at an alternative healthcare facility may be permitted 
by the Sponsor after discussing with the Alexion Medical Monitor. This will be a case-by-case decision (Section 8.1.7). 

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Treatment 
Notes 
Visit1 
W66 
W74 
W82 
W90 
W98 
W106 
W114 
W122 
W130 
W138 
Phone2 
Additional evaluation visits can 
be scheduled at the discretion of 
the Investigator. An ED Visit 
should be performed if patients 
discontinue early. 
Days and Window 
D463 
± 7 
D519 
± 7 
D575 
± 7 
D631 
± 7 
D687 
± 7 
D743 
± 7 
D799 
± 7 
D855 
± 7 
D911 
± 7 
D967 
± 7 
 
2 Biweekly phone visits will be conducted between the visits to monitor NMOSD symptoms and safety (Section 8.2.2). 
3 Performed by the Treating Physician who is an Investigator and has been properly trained for the evaluation, preferably the same Treating Physician, throughout the study. 
4 Patients may be switched from the 10 mg/mL to the 100 mg/mL formulation of ravulizumab with no change to the weight-based dose regimen during the Long-Term 
Extension Period (Section 8.1.6.1). 
Abbreviations: ADA = antidrug antibody; AE = adverse event; B = baseline sample; C5 = complement component 5; CSF = cerebrospinal fluid; C-SSRS = Columbia-suicide 
severity rating scale; D = day; ECG = electrocardiogram; ED = early discontinuation; EDSS = expanded disability status scale; EQ-5D = EuroQoL-5D; FSS = functional 
system score; HAI = Hauser ambulation index; NMO = neuromyelitis optica; NMOSD = neuromyelitis optica spectrum disorder; P = postdose sample; 
PK = pharmacokinetic(s); RNA =  ribonucleic acid; SF-36 = short form health survey; T = trough sample; W = week(s); WOCBP = women of childbearing potential 
 
 

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Table 3: 
Schedule of Activities (Week 146 Through Week 234) 
  
Treatment 
Notes 
Visit1 
W 
146 
W 
154 
W 
162 
W 
170 
W 
178 
W 
186 
W 
194 
W 
202 
W 
210 
W 
218 
W 
226 
W 
234 
Phone2 
Additional evaluation visits 
can be scheduled at the 
discretion of the 
Investigator. An ED Visit 
should be performed if 
patient discontinues early. 
Days and Window 
D 
1023 
± 7 
D 
1079 
± 7 
D 
1135 
± 7 
D 
1190 
± 7 
D 
1247 
± 7 
D 
1303 
± 7 
D 
1359 
± 7 
D 
1415 
± 7 
D 
1471 
± 7 
D 
1527 
± 7 
D 
1583 
± 7 
D 
1639 
± 7 
 
General Assessments/Procedures 
Weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
  
N. meningitidis 
Vaccination 
 
 
 
 
 
 
 
 
 
 
 
 
 
Patients must be vaccinated 
against meningococcal 
infection, and revaccinated 
during the study if needed 
(Section 8.1.4) 
Pregnancy Test 
(WOCBP only) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Serum test at screening is 
required. Urine test at indicated 
visits and when necessary at 
Investigator’s discretion 
Pharmacokinetic and Pharmacodynamic Assessments 
PK/Free C5 Blood 
Samples 
  
 
T/P 
 
 
 
T/P 
 
 
 
T/P 
 
 
Collect T (predose) and P 
(postdose) samples 
(Section 8.6) 
PK/Free C5 CSF 
Samples 
 
 
 
 
 
 
T 
 
 
 
 
 
 
Optional; obtain at predose 
from patients who consent to 
CSF sample collection 
(Section 8.6) 
ADA Blood Samples 
 
 
T 
 
 
 
T 
 
 
 
T 
 
 
Collect T (predose) and X 
(anytime) samples (Section 8.9) 
Safety Assessments 
Targeted Physical 
Examination 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Perform when deemed 
necessary by the Investigator 
(Section 8.3.1) 
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
  
ECG 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
  
Concomitant 
Medication 
 
Continuous Monitoring 
  

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Treatment 
Notes 
Visit1 
W 
146 
W 
154 
W 
162 
W 
170 
W 
178 
W 
186 
W 
194 
W 
202 
W 
210 
W 
218 
W 
226 
W 
234 
Phone2 
Additional evaluation visits 
can be scheduled at the 
discretion of the 
Investigator. An ED Visit 
should be performed if 
patient discontinues early. 
Days and Window 
D 
1023 
± 7 
D 
1079 
± 7 
D 
1135 
± 7 
D 
1190 
± 7 
D 
1247 
± 7 
D 
1303 
± 7 
D 
1359 
± 7 
D 
1415 
± 7 
D 
1471 
± 7 
D 
1527 
± 7 
D 
1583 
± 7 
D 
1639 
± 7 
 
Concomitant 
Non-Drug 
Therapies/Procedures 
 
Continuous Monitoring 
  
AE 
 
Continuous Monitoring 
  
Clinical Laboratory 
Tests 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Refer to Section 10.2 for the list 
of tests 
Patient Safety Card 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Review signs and symptoms of 
infections (Section 8.3.5 ) 
C-SSRS 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
C-SSRS-Since Last Visit 
assessment (Section 8.3.8) 
Efficacy Assessments 
Neurologic 
Examination3 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
  
NMO Symptom Card 
and Evaluation 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
NMOSD symptoms will be 
evaluated by the Investigator 
(Section 8.2.2) 
EQ-5D 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
When possible, administer 
before other procedures 
SF-36 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
When possible, administer 
before other procedures 
EDSS 
 (including FSS) 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
Conducted by a blinded EDSS 
Rater (Section 8.2.5) 
HAI 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
Performed by an Investigator or 
trained designee 
Ophthalmological 
Examination 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
Including confrontational field 
test1, color vision and visual 
acuity (Landolt C ring) 
(Section 8.2.10). 

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Treatment 
Notes 
Visit1 
W 
146 
W 
154 
W 
162 
W 
170 
W 
178 
W 
186 
W 
194 
W 
202 
W 
210 
W 
218 
W 
226 
W 
234 
Phone2 
Additional evaluation visits 
can be scheduled at the 
discretion of the 
Investigator. An ED Visit 
should be performed if 
patient discontinues early. 
Days and Window 
D 
1023 
± 7 
D 
1079 
± 7 
D 
1135 
± 7 
D 
1190 
± 7 
D 
1247 
± 7 
D 
1303 
± 7 
D 
1359 
± 7 
D 
1415 
± 7 
D 
1471 
± 7 
D 
1527 
± 7 
D 
1583 
± 7 
D 
1639 
± 7 
 
Biomarker Research 
Blood Samples 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
Blood samples for RNA are 
optional 
CSF Samples 
 
 
 
 
 
 
X 
 
 
 
 
 
 
Optional 
 
Administration of Study Drug  
Ravulizumab4 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Administered after all other 
required tests/procedures, 
except those to be performed 
postdosing  
1 Under reasonable occasional circumstances where a patient is not able to attend a study visit on site, a home visit or visit at an alternative healthcare facility may be permitted 
by the Sponsor after discussing with the Alexion Medical Monitor. This will be a case-by-case decision (Section 8.1.7). 
2 Biweekly phone visits will be conducted between the visits to monitor NMOSD symptoms and safety (Section 8.2.2). 
3 Performed by the Treating Physician who is an Investigator and has been properly trained for the evaluation, preferably the same Treating Physician, throughout the study. 
4 Patients may be switched from the 10 mg/mL to the 100 mg/mL formulation of ravulizumab with no change to the weight-based dose regimen during the Long-Term 
Extension Period (Section 8.1.6.1). 
Abbreviations: ADA = antidrug antibody; AE = adverse event; B = baseline sample; C5 = complement component 5; CSF = cerebrospinal fluid; C-SSRS = Columbia-suicide 
severity rating scale; D = day; ECG = electrocardiogram; ED = Early Discontinuation; EDSS = expanded disability status scale; EQ-5D = EuroQoL-5D; FSS = functional 
system score; HAI = Hauser ambulation index; NMO = neuromyelitis optic; NMOSD = neuromyelitis optica spectrum disorder; P = postdose sample; 
PK = pharmacokinetic(s); PT = primary treatment; RNA = ribonucleic acid; SF-36 = short form health survey; T = trough sample; W = week(s); WOCBP = women of 
childbearing potential 
 
 

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Table 4: 
Schedule of Activities (End of Primary Treatment, End of Treatment/Early Discontinuation, Follow-Up) 
  
Treatment 
FU 
Notes 
Visit1 
EOPT 
EOT/ED 
FU 
Additional evaluation visits can be 
scheduled at the discretion of the 
Investigator. Refer to Section 4.4 for 
EOPT. An ED Visit should be performed 
if patient discontinues early. 
Days and Window 
Within 14 D after 
PT 
 
 
General Assessments/Procedures 
Weight 
X 
X 
 
N. meningitidis 
Vaccination 
 
 
 
Patients must be vaccinated against 
meningococcal infection, and revaccinated 
during the study if needed (Section 8.1.4) 
Pregnancy Test 
(WOCBP only) 
X 
X 
X 
Serum test at screening is required. Urine test at 
indicated visits and when necessary at 
Investigator’s discretion 
Pharmacokinetic and Pharmacodynamic Assessments 
PK/Free C5 Blood 
Samples 
 
T/P 
 
Collect T (predose) and P (postdose) samples 
(Section 8.6) 
PK/Free C5 CSF 
Samples 
 
T 
 
Optional; obtain at predose from patients who 
consent to CSF sample collection (Section 8.6) 
ADA Blood Samples 
 
T 
 
Collect T (predose) and X (anytime) samples 
(Section 8.9) 
Safety Assessments 
Targeted Physical 
Examination 
X 
X 
X 
Perform when deemed necessary by the 
Investigator (Section 8.3.1) 
Vital Signs 
X 
X 
X 
 
ECG 
 
X 
 
Concomitant 
Medication 
 
Continuous Monitoring 
Concomitant Non-Drug 
Therapies/Procedures 
 
Continuous Monitoring 
AE 
 
Continuous Monitoring 
Clinical Laboratory 
Tests 
X 
X 
X 
Refer to Section 10.2 for the list of tests 
Patient Safety Card 
X 
X 
X 
Review signs and symptoms of infections 
(Section 8.3.5 ) 

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Treatment 
FU 
Notes 
Visit1 
EOPT 
EOT/ED 
FU 
Additional evaluation visits can be 
scheduled at the discretion of the 
Investigator. Refer to Section 4.4 for 
EOPT. An ED Visit should be performed 
if patient discontinues early. 
Days and Window 
Within 14 D after 
PT 
 
 
C-SSRS 
X 
X 
X 
C-SSRS-Since Last Visit assessment 
(Section 8.3.8) 
Efficacy Assessments 
Neurologic 
Examination2 
X 
X 
X 
NMO Symptom Card 
and Evaluation 
X 
X 
X 
NMOSD symptoms will be evaluated by the 
Investigator (Section 8.2.2) 
EQ-5D 
X 
X 
 
When possible, administer before other 
procedures 
SF-36 
X 
X 
 
When possible, administer before other 
procedures 
EDSS 
 (including FSS) 
X 
X 
 
Conducted by a blinded EDSS Rater 
(Section 8.2.5) 
HAI 
X 
X 
 
Performed by an Investigator or trained designee 
Ophthalmological 
Examination 
X 
X 
 
Including confrontational field test1, color vision 
and visual acuity (Landolt C ring) 
(Section 8.2.10). 
Biomarker Research 
Blood Samples 
 
X 
 
Blood samples for RNA are optional 
CSF Samples  
 
X 
 
Optional 
Administration of Study Drug  
Ravulizumab3 
X4 
X 
 
Administered after all other required 
tests/procedures, except those to be performed 
postdosing  
1 Under reasonable occasional circumstances where a patient is not able to attend a study visit on site, a home visit or visit at an alternative healthcare 
facility may be permitted by the Sponsor after discussing with the Alexion Medical Monitor. This will be a case-by-case decision (Section 8.1.7). 
2 Performed by the Treating Physician who is the Investigator and has been properly trained for the evaluation, preferably the same Treating Physician, 
throughout the study. 

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Treatment 
FU 
Notes 
Visit1 
EOPT 
EOT/ED 
FU 
Additional evaluation visits can be 
scheduled at the discretion of the 
Investigator. Refer to Section 4.4 for 
EOPT. An ED Visit should be performed 
if patient discontinues early. 
Days and Window 
Within 14 D after 
PT 
 
 
3 Patients may be switched from the 10 mg/mL to the 100 mg/mL formulation of ravulizumab with no change to the weight-based dose regimen during the 
Long-Term Extension Period (Section 8.1.6.1). 
4 If EOPT visit coincides with a scheduled dosing visit, ravulizumab dose should be administered. 
Abbreviations: ADA = antidrug antibody; AE = adverse event; B = baseline sample; C5 = complement component 5; CSF = cerebrospinal fluid; 
C-SSRS = Columbia-suicide severity rating scale; D = day; ECG = electrocardiogram; ED = Early Discontinuation; EDSS = expanded disability status 
scale; EOPT = end of primary treatment; EOT = end of treatment; EQ-5D = EuroQoL-5D; FSS = functional system score; FU = follow-up; HAI = Hauser 
ambulation index; NMO = neuromyelitis optic; NMOSD = neuromyelitis optica spectrum disorder; P = postdose sample; PK = pharmacokinetic(s); 
PT = primary treatment; RNA = ribonucleic acid; SF-36 = short form health survey; T = trough sample; W = week(s); WOCBP = women of childbearing 
potential 
 
 
 

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Table 5: 
Schedule of Activities (Relapse Evaluation Period) 
 
Relapse Evaluation Period 
Notes 
Visits 
Relapse 
Evaluation 
Visit 
Relapse FU Visits 
Every effort must be made to evaluate potential 
relapses within 24 hours of notification of the 
Investigator of a possible relapse, and no later 
than 48 hours. 
Weeks 
Within 24 to 
48 hours 
+1 
Week 
+4 
Weeks 
+6 Weeks 
Unscheduled1 
Days and Window 
RD1 
RD8±2 
RD29±2 
RD43±2 
NA 
General Assessments/Procedures 
Anti-AQP4 Ab (serum) 
X 
 
 
X 
X 
  
 Pharmacokinetic and Pharmacodynamic Assessments 
PK/Free C5 Blood 
Samples 
X 
X 
X 
X 
X 
Refer to Section 8.6 for sample collection during 
relapse  
Safety Assessments 
Vital Signs 
X 
X 
X 
X 
X 
Vital signs will also be collected during relapse visits 
when study drug is administered  
Concomitant Medication 
Continuous Monitoring 
  
Concomitant Non-Drug 
Therapies/Procedures 
Continuous Monitoring 
 
AE 
Continuous Monitoring 
  
Pregnancy Test (WOCBP 
only) 
 
 
 
 
 
Perform urine test when study drug is administrated at 
a relapse visit 
Clinical laboratory Tests 
X 
 
 
X 
X 
Refer to Section 10.2 for the list of tests 
Patient Safety Card 
X 
X 
X 
X 
X 
Review signs and symptoms of infections (Section 
8.3.5) 
C-SSRS 
 
 
 
X 
 
Conduct C-SSRS-Since Last Visit assessment 
(Section 8.3.8) 
Efficacy Assessments 
Neurologic Examination2 
X 
X 
X 
X 
X 
  
NMO Symptom Card and 
Evaluation  
X 
X 
X 
X 
X 
NMO symptoms will be evaluated by the Treating 
Physician (Section 8.2.2) 

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Relapse Evaluation Period 
Notes 
Visits 
Relapse 
Evaluation 
Visit 
Relapse FU Visits 
Every effort must be made to evaluate potential 
relapses within 24 hours of notification of the 
Investigator of a possible relapse, and no later 
than 48 hours. 
Weeks 
Within 24 to 
48 hours 
+1 
Week 
+4 
Weeks 
+6 Weeks 
Unscheduled1 
Days and Window 
RD1 
RD8±2 
RD29±2 
RD43±2 
NA 
EQ-5D 
X 
X 
X 
X 
X 
When possible, administer before other procedures 
SF-36 
X 
X 
X 
X 
X 
When possible, administer before other procedures 
EDSS (including FSS) 
X 
X 
X 
X 
X 
Conducted by a blinded EDSS Rater (Section 8.2.5) 
HAI 
X  
X 
X 
X 
X 
Performed by an Investigator or trained designee 
OSIS2 
X 
X 
X 
X 
X 
  
Ophthalmologic 
Examination 
X 
X 
X 
X 
X 
Including confrontational field test2, color vision and 
visual acuity (Landolt C ring) (Section 8.2.10)  
MRI 
X 
 
 
 
 
Perform if deemed clinically necessary by the 
Investigator (Section 8.2.11) 
OCT 
X 
 
 
 
 
Perform if deemed clinically necessary by the 
Investigator (Section 8.2.11) 
Biomarker Research 
Blood Samples 
X 
X 
 
X 
X 
Blood samples for RNA are optional. 
CSF samples  
X 
 
 
 
 
Optional 
Administration of Study Drug 
Ravulizumab 
 
 
 
 
 
Refer to Section 8.1.6 for the instruction of study drug 
administration during relapse 
1 Additional unscheduled Follow-up Relapse Evaluation Visits are permitted at the discretion of the Investigator. 
2 Performed by the Treating Physician who is an Investigator and has been properly trained for the evaluation, preferably the same Treating Physician, throughout 
the study. 
Abbreviations: ADA = antidrug antibody; AE = adverse event; AQP4 Ab = aquaporin 4 antibody; C5 = complement component 5; CSF = cerebrospinal fluid; 
C-SSRS = Columbia-suicide severity rating scale; EDSS = expanded disability status scale; EQ-5D = EuroQoL-5D; FSS = functional system score; 
FU = follow-up; HAI = Hauser ambulation index; MRI = magnetic resonance imaging; NA = not applicable; NMO = neuromyelitis optica; OCT = optical 
coherence tomography; OSIS = optic spinal impairment score; PK = pharmacokinetic(s); RD = relapse day; RNA = ribonucleic acid; SF-36 = short form health 
survey; T = trough sample; W = week(s); WOCBP = women of childbearing potential 

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2. 
INTRODUCTION 
Complement activation is a key element in the development of CNS injury in neuromyelitis 
optica spectrum disorder (NMOSD). Ravulizumab is a recombinant, humanized monoclonal 
antibody (mAb) with high specificity against human complement component 5 (C5). It is 
currently being developed as a treatment for NMOSD in adult patients. 
2.1. 
Study Rationale 
The basis of developing ravulizumab for NMOSD stems from prior experience with eculizumab 
(SOLIRIS®), a first-generation complement inhibitor, which is approved by the U.S. FDA for 
the treatment of NMOSD in adult patients who are anti-AQP4 Ab positive. Findings from the 
clinical development program for eculizumab in NMOSD support the rationale for C5 inhibition 
as a therapeutic approach for reducing the risk of relapses in patients with NMOSD  
(Pittock SJ, 2019). 
Ravulizumab shares > 99% amino acid sequence homology with eculizumab. Ravulizumab and 
eculizumab share the same mechanism of action, targeting the same C5 epitope with high 
specificity. However, as a result of 4 amino acid substitutions, the serum elimination half-life of 
ravulizumab is prolonged, enabling an extended dosing interval. Despite a longer dosing interval, 
ravulizumab has demonstrated a similar degree of terminal complement inhibition compared to 
eculizumab in patients with paroxysmal nocturnal hemoglobinuria (PNH), another complement-
mediated disease, for which both products are approved in the US. Complement inhibition is the 
only mechanism of action of eculizumab in NMOSD, and the fact that it has been proven to 
significantly reduce the risk of relapse provides a strong rationale for studying ravulizumab in 
NMOSD. 
This study is being undertaken to demonstrate the efficacy and safety of ravulizumab in adult 
patients with NMOSD, using the placebo group from Study ECU-NMO-301 as an external 
control. If successful, this may provide patients with a treatment option that reduces overall 
disease burden by requiring less frequent infusions relative to eculizumab, while maintaining a 
comparable benefit/risk profile. 
Detailed information about ravulizumab can be found in the Investigator’s Brochure. 
2.2. 
Background 
2.2.1. 
Neuromyelitis Optica Spectrum Disorder 
Neuromyelitis optica spectrum disorder is a severe disabling autoimmune inflammatory disorder 
of the CNS that predominately affects the optic nerves and spinal cord, and less commonly the 
brain. The disorder is ultra-rare, affecting 0.5 to 4.4 per 100,000 worldwide inhabitants  
(Pandit L, 2015). 
The most common manifestations of NMOSD are characterized by recurrent, severe relapses of 
optic neuritis or transverse myelitis (TM), which result in a stepwise accumulation of relapse-
related neurologic disability that can be irreversible (Wingerchuk DM, 2006). The annualized 
relapse rate (ARR) for patients with NMOSD is estimated to be about 1 relapse per year per 

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patient, with the vast majority of patients experiencing relapse (Flanagan EP, 2016; Ghezzi A, 
2004; Jarius S, 2012). 
In a study of AQP4-Ab positive neuromyelitis optica (NMO) patients, morbidity was significant 
with 18% experiencing permanent visual disability, 34% experiencing permanent motor 
disability, and 23% experiencing wheelchair dependency during the follow-up period  
(Kitley J, 2012). 
2.2.2. 
Unmet Medical Need 
SOLIRIS® (eculizumab), the first-in-class complement component C5 inhibitor, is the only 
therapy approved by the U.S. FDA for the treatment of NMOSD in adult patients who are anti-
AQP4 Ab positive. Supportive treatments, including corticosteroids and other 
immunosuppressive therapies (ISTs), have been used based on clinical experience and consensus 
(Trebst C, 2014). Despite the use of ISTs as supportive therapy, a significant number of patients 
(> 50%) continued to experience disease relapses that resulted in incremental and permanent 
neurologic deficits and disability (Bichuetti DB, 2010; Jacob A, 2009). 
Eculizumab has been demonstrated to be effective in reducing relapse risk. After the initial 
induction dose, eculizumab is administered every 2 weeks (q2w) to maintain adequate 
complement suppression. Neuromyelitis optica spectrum disorder is a chronic disease, and a 
frequent dosage regimen may impose a significant burden on patients, many of whom are 
disabled and require assistance with transportation. 
Ravulizumab has a longer serum terminal elimination half-life and corresponding duration of 
pharmacologic activity relative to eculizumab. Ravulizumab was designed based on 
comprehensive modelling and simulation analyses to maintain efficacious concentrations across 
a longer dosing interval. The q8w dosage regimen is less burdensome for patients and has 4-fold 
fewer pharmacokinetic (PK) troughs, leading to fewer opportunities for achieving incomplete 
complement inhibition associated with sub-therapeutic exposure. The reduction in infusion 
frequency offers the potential to provide patients and physicians with an additional option for 
effective treatment of NMOSD while also improving quality of life (QoL) through fewer missed 
days of work, better treatment adherence, and improved accessibility. 
2.2.3. 
Role of Complement Activation in NMOSD 
Complement activation is a major determinant of disease pathogenesis in patients with NMOSD 
(Hinson SR, 2009; Nytrova, 2014; Papadopoulos MC, 2012; Verkman, 2012). Binding of AQP4 
IgG to the AQP4 water channel, which is highly expressed on astrocytic surfaces in the CNS, has 
been shown to lead to hexameric assembly of immunoglobulin G (IgG). This in turn recruits and 
activates complement C1, the first step in activation of the complement cascade (Diebolder CA, 
2014). Complement activation initiates an inflammatory cascade that induces permeabilization of 
the blood brain barrier and astrocyte necrosis. Lesions that form during this process are 
indicative of NMOSD and are positive for anti-AQP4 Abs and complement (Papadopoulos MC, 
2012). 
The therapeutic role of inhibition of terminal complement activation was demonstrated with 
eculizumab in Study ECU-NMO-301. Study ECU-NMO-301 was a randomized, double-blind, 
placebo-controlled, multicenter study that evaluated the safety and efficacy of eculizumab in 
patients with relapsing NMOSD. A significant effect on the time to first adjudicated On-trial 

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Relapse was observed for eculizumab compared with placebo (p<0.0001). An approximately 
94.2% reduction in the risk of relapse was observed in patients who received eculizumab 
compared with placebo (Pittock SJ, 2019). In conjunction with the efficacy results, the serum 
free C5 results indicated that immediate, complete, and sustained terminal complement inhibition 
was achieved. 
2.3. 
Benefit/Risk Assessment 
More detailed information about the known and expected benefits and risks and expected 
adverse events (AEs) of ravulizumab may be found in the Investigator’s Brochure. 
2.3.1. 
Risk Assessment 
Ravulizumab functions by blocking terminal complement; therefore, patients have increased 
susceptibility to serious infections, in particular, Neisseria meningitidis (N meningitidis). 
Specific risk mitigation measures in place are described in Section 8.1.4. 
Based on the past human experience and cumulative clinical trial safety data of ravulizumab in 
PNH and atypical hemolytic uremic syndrome (aHUS), ravulizumab has been demonstrated to 
be well tolerated and safe, and exposure to ravulizumab in humans has not raised any unexpected 
safety concerns. 
As with any humanized mAb, administration of ravulizumab may lead to the development of 
anti-drug 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 10.14. 
2.3.2. 
Benefit Assessment 
Neuromyelitis optica spectrum disorder is a severe, disabling disease with relapses and 
cumulative disability occurring in more than 90% of cases (Wingerchuk DM, 2006). The 
efficacy and safety of eculizumab compared to placebo in the treatment of adult patients with 
anti-AQP4 Ab-positive NMOSD has been demonstrated in Study ECU-NMO-301, a 
multinational, double-blind, parallel-group Phase 3 time-to-event study, in which treatment with 
eculizumab reduced the risk of NMOSD relapse by 94.2% compared to placebo (p<0.0001) 
(Pittock SJ, 2019). Given the high homology and specificity to complement component C5 
between ravulizumab and eculizumab, treatment with ravulizumab is expected to result in 
comparable reduction in the risk of relapses in adult NMOSD patients. 
2.3.3. 
Overall Benefit: Risk Conclusion 
Taking into account the measures taken to minimize risk to patients participating in this study, 
the potential risks identified in association with ravulizumab are justified by the anticipated 
benefits that may be afforded to patients with NMOSD. 
 

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3. 
OBJECTIVES AND ENDPOINTS 
Objectives 
Endpoints 
Primary 
• 
To evaluate the effect of ravulizumab on 
adjudicated On-triala Relapses in adult patients 
with NMOSD 
• 
Time to first adjudicated On-trial Relapse and 
relapse risk reduction 
Secondary 
• 
To evaluate the safety of ravulizumab in adult 
patients with NMOSD 
• 
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 on 
adjudicated annualized relapse rate (ARR) in adult 
patients with NMOSD 
• 
Adjudicated On-trial ARR 
• 
To evaluate the effect of ravulizumab on disease-
related disability in adult patients with NMOSD 
• 
Clinically important worsening from baseline in 
expanded disability status scale (EDSS)  
• 
To evaluate the effect of ravulizumab on QoL in 
adult patients with NMOSD 
• 
Change from baseline in EuroQoL-5D (EQ-5D)  
• 
To evaluate the effect of ravulizumab on 
neurologic function in adult patients with NMOSD 
• 
Clinically important change from baseline in 
Hauser ambulation index (HAI)  
• 
To characterize the PK of ravulizumab in adult 
patients with NMOSD 
• 
Change in serum ravulizumab concentration over 
the study duration 
• 
To characterize the pharmacodynamics (PD) of 
ravulizumab in adult patients with NMOSD 
• 
Change in serum free C5 concentration over the 
study duration 
• 
To characterize the immunogenicity of 
ravulizumab in adult patients with NMOSD  
• 
Presence and titer of ADAs over the study 
duration 
Exploratory 
• 
To evaluate the effect of ravulizumab on severity 
of adjudicated On-trial Relapse in adult patients 
with NMOSD  
• 
Change from baseline in Optic Spinal Impairment 
Score (OSIS) 
• 
To evaluate the effect of ravulizumab on 
neurologic function in adult patients with NMOSD 
• 
Characterize the change from baseline in visual 
acuity, color vision, and confrontational visual 
fields  
• 
To evaluate the effect of ravulizumab on QoL in 
adult patients with NMOSD 
• 
Change from baseline in Short Form Health 
Survey (SF-36)  
• 
To evaluate the safety of ravulizumab in adult 
patients with NMOSD 
• 
Change from baseline in vital signs, 
electrocardiogram (ECG) parameters, and clinical 
laboratory assessments  
• 
Shifts from Baseline in Columbia-suicide severity 
rating scale (C-SSRS)  
• 
To characterize biomarkers in adult patients with 
NMOSD 
• 
Change from baseline in levels of biomarkers of 
complement dysregulation, neuroinflammation 
and neural injury 
• 
Blood and cerebrospinal fluid (CSF) NMO-Ig 
(AQP4 Ab) concentration 
a On-trial Relapses refer to relapses as determined by the Treating Physician that occur during the study treatment 
period. All relapses will be adjudicated by a separate Adjudication Committee. 

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4. 
STUDY DESIGN 
4.1. 
Overall Design 
Study ALXN1210-NMO-307 is a Phase 3, external placebo-controlled, open-label, multicenter 
study to evaluate the efficacy and safety of ravulizumab in adult patients with NMOSD. 
Approximately 55 eligible adult patients with NMOSD from North America, Europe, and the 
Asia Pacific region will be enrolled into the study. Enrollment for each geographic region will be 
approximately 28% to 40% of the total population (Section 6.3). 
There are 4 periods in this study: Screening Period, Primary Treatment Period, Long-Term 
Extension Period, and Safety Follow-up Period. Patients will be screened for eligibility for up to 
6 weeks during the Screening Period. The end of the Primary Treatment Period will be triggered 
when either (1) 2 patients have had an adjudicated On-trial Relapse; or (2) all patients have 
completed, or discontinued prior to, the Week 26 Visit; whichever comes later. However, if 
2 patients have not had an adjudicated On-trial Relapse by the time all patients have completed, 
or discontinued prior to, the Week 50 visit, the end of the Primary Treatment Period will be 
triggered at that time. Note that patients who complete the visits indicated above (Week 26 or 
Week 50) will remain on the study in the Primary Treatment Period until the Primary Treatment 
Period ends.  For examples of different scenarios of the end of the Primary Treatment Period, 
please refer to Section 4.4. Based on the estimated enrollment rate, the duration of the Primary 
Treatment Period for each patient is expected to be between 26 weeks and approximately 
2.5 years. The Primary Treatment Period ends and the Long-Term Extension Period starts when 
all patients have completed their End of Primary Treatment (EOPT) Visit within the timeframe 
specified in Section 4.4. All patients will continue to receive ravulizumab during the Long-Term 
Extension Period for up to approximately 2 years, or until ravulizumab is approved and/or 
available (in accordance with country-specific regulations), whichever occurs first. Based on the 
estimated enrollment rate of NMOSD patients, the total treatment duration for each patient will 
be up to approximately 4.5 years. After the last dose of study drug or early discontinuation (ED), 
patients will be followed for 8 weeks. The total study duration for each patient will be up to 
approximately 4.75 years. 
4.2. 
Scientific Rationale for Study Design 
The study has been designed to provide data that adequately characterize the benefit-risk profile 
of ravulizumab for the treatment of patients with NMOSD, using placebo data from Study ECU-
NMO-301 as an external control. 
4.2.1. 
External Placebo-Controlled, Open-Label Design 
Study ECU-NMO-301 demonstrated the efficacy of eculizumab in reducing NMOSD relapses, 
with a 94.2% reduction in the risk of relapse as compared with placebo (Pittock SJ, 2019). As a 
derivative of eculizumab, ravulizumab targets an identical C5 motif to inhibit terminal 
complement activity and is expected to have a similar effect on relapses as that produced by 
eculizumab. 
The recent approval of Soliris for NMOSD, the first approved therapy for NMOSD, is expected 
to change the treatment landscape and make it challenging to randomize patients to a placebo 

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group. However, it is important to employ a comparator group to provide adequate assessment of 
the safety and efficacy of ravulizumab. 
A single-arm design, utilizing the placebo group from Study ECU-NMO-301 (conducted 2014 to 
2018) as an external placebo control, allows for a robust assessment of ravulizumab as a 
treatment option for NMOSD. Whenever possible, in order to ensure a valid comparison, 
constancy will be maintained with Study ECU-NMO-301, including the inclusion of similar 
patient populations, permitted concomitant medications, adjudication procedures, and endpoints. 
4.2.2. 
Rationale for the Selected Endpoints 
4.2.2.1. 
Efficacy Endpoints 
In NMOSD, the measurable, biological aspects include relapse and disability. Disability in 
NMOSD is a direct consequence of relapse, supporting the relevance of measuring relapses as 
the efficacy endpoint in Study ALXN1210-NMO-307. 
In this study, the occurrence of relapses is evaluated using the primary endpoint time to first 
adjudicated On-trial Relapse and the secondary endpoint ARR. Time to first adjudicated On-trial 
Relapse provides useful information regarding the efficacy of ravulizumab. Since effectiveness 
of a treatment can be based on delaying and/or reducing the occurrence of relapses, a time to first 
relapse endpoint is an appropriate efficacy endpoint for prospectively designed studies in 
NMOSD (Weinshenker, 2015). The external placebo group from Study ECU-NMO-301 will be 
utilized as an appropriate control group given that the primary endpoint in that trial was also time 
to first adjudicated On-trial Relapse and the adjudication process and relapse definition will 
remain constant between the two trials. 
Additionally, the effect of ravulizumab on the frequency of relapses will be measured using the 
Adjudicated On-trial ARR. A 95% confidence interval will be calculated around the ARR. 
4.2.3. 
Rationale for the Duration of the Primary Treatment Period 
In Study ALXN1210-NMO-307, the end of the Primary Treatment Period will be triggered when 
either (1) 2 patients have had an adjudicated On-trial Relapse; or (2) all patients have completed, 
or discontinued prior to, the Week 26 Visit; whichever comes later. However, if 2 patients have 
not had an adjudicated On-trial Relapse by the time all patients have completed, or discontinued 
prior to, the Week 50 visit, the end of the Primary Treatment Period will be triggered at that 
time. Note that patients who complete the visits indicated above (Week 26 or Week 50) will 
remain on the trial in the Primary Treatment Period until the Primary Treatment Period ends. 
Based on the estimated enrollment rate, the first patient enrolled will have been in the Primary 
Treatment Period for up to approximately 2.5 years, with the remaining patients having been in 
the Primary Treatment Period ranging between 26 weeks and up to approximately 2.5 years. 
The cut-off of 26 weeks for the last patient was chosen for several reasons. In 
Study ECU-NMO-301, key observations could already be made by that time: 2 of the 
3 adjudicated On-trial Relapses observed in the eculizumab group were observed, and 12 of 
20 adjudicated On-trial Relapses had been observed in the placebo group. Given the similarities 
of ravulizumab and eculizumab, we expect to see a similar response in the first 26 weeks of 
treatment with ravulizumab. This design ensures that there will be limited number of patients 
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Relapse: in Study ECU-NMO-301, only 5 out of 143 (3.5%) patients had discontinued study 
treatment within the first 26 weeks (4 in the eculizumab arm and 1 in the placebo arm). It is also 
recognized that based on expected enrollment timelines, many of the patients will have been on 
treatment for more than 1 year by the time the last patient completes their Week 26 Visit, 
providing efficacy and safety data over time that allows for a robust comparison with data 
collected over a similar timeframe in the placebo group of Study ECU-NMO-301. 
In the event that 2 patients have not experienced an adjudicated On-trial Relapse by the time the 
last patient has completed the Week 26 visit, all patients will remain in the Primary Treatment 
Period until 2 patients have experienced an adjudicated On-trial Relapse, or until the last patient 
has completed the Week 50 Visit. The criteria of the maximal additional follow-up time and the 
2 adjudicated On-trial Relapses in 2 patients are chosen in part to more closely approximate the 
mean time on treatment (89.4 weeks) and the adjudicated On-trial ARR (0.02) of patients in the 
eculizumab arm of Study ECU-NMO-301. Furthermore, if the full additional 24 weeks of 
follow-up occur, this will ensure that all patients who do not discontinue pre-maturely will have 
a minimum of 50 weeks of follow-up. 
4.2.4. 
Rationale for the Selected Patient Population 
Complement activation is a major determinant of disease pathogenesis in patients with 
anti-AQP4 positive NMOSD (Nytrova, 2014). Inhibiting terminal complement activation with 
ravulizumab, therefore, represents a biologically rational approach for the treatment of patients 
with anti-AQP4 positive NMOSD. Study entry criteria were carefully selected to reflect an adult 
patient population consistent with the anti-AQP4 positive NMOSD population likely to be 
treated with ravulizumab in clinical practice. 
4.3. 
Justification for Dose 
4.3.1. 
Ravulizumab 
Targeting complete terminal complement inhibition as a therapeutic strategy in the treatment of 
patients with NMOSD has been validated by data from the eculizumab clinical program. 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 premised on PK/PD data from early and late clinical development studies in 
healthy adult volunteers and patients with PNH. The proposed ravulizumab dosage regimen 
(Section 6.1; Section 8.1.6.1) is the approved regimen for the treatment of patients with PNH 
ULTOMIRIS® United States Prescribing Information (USPI), and the same dose regimen is also 
included in the initial marketing authorization application (MAA) in the EU. Therefore, the same 
dosage regimen is selected for this study. Additional PK/PD information supporting the selected 
dose regimen can be found in the current Investigator’s Brochure (IB). 
Patients may be switched from the 10 mg/mL to the 100 mg/mL formulation of ravulizumab 
with no change to the weight-based dose regimen during the Long-Term Extension Period. The 
100 mg/mL IV formulation of ULTOMIRIS® (ravulizumab) is commercially approved in the 
United States, European Union, and Japan 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 

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infusion times while delivering comparable PK, safety, and efficacy to the 10 mg/mL 
formulation of ravulizumab. 
4.3.2. 
Supplemental Dose 
Supplemental doses of ravulizumab (Section 8.1.6.2) may be administered to patients who 
receive plasma exchange (PE)/plasmapheresis (PP) (Section 6.5.1.3) or IVIg (Section 6.5.2) as 
acute therapy following an On-trial Relapse. The supplemental dose of ravulizumab has been 
selected based on PK simulations. Consistent with approved eculizumab labeling for treating 
adult and pediatric patients with aHUS, adult patients with generalized myasthenia gravis (gMG) 
and adult patients with NMOSD, supplemental dosing of ravulizumab in the amount of 50% 
(rounded up if not an integral of 300 mg due to vial configuration) will be given in the setting of 
concomitant PP/PE therapy. 
4.4. 
End of Primary Treatment 
The end of the Primary Treatment Period will be triggered when either (1) 2 patients have had an 
adjudicated On-trial Relapse; or (2) all patients have completed, or discontinued prior to, the 
Week 26 Visit; whichever comes later. However, if 2 patients have not had an adjudicated On-
trial Relapse by the time all patients have completed, or discontinued prior to, the Week 50 visit, 
the end of the Primary Treatment Period will be triggered at that time. Note that patients who 
complete the visits indicated above (Week 26 or Week 50) will remain on the study in the 
Primary Treatment Period until the Primary Treatment Period ends. 
The 3 ways that the Primary Treatment Period may end, given the above criteria, are as described 
in the following examples: 
1. If 2 adjudicated On-trial Relapses have been observed by the time all patients have 
completed, or discontinued prior to, Week 26, the end of the Primary Treatment 
Period will be triggered. 
2. If all patients have completed Week 26, or discontinued prior to Week 26, and 
2 adjudicated On-trial Relapses have not yet been observed, but 2 adjudicated On-
trial Relapses are then observed before all patients have completed, or discontinued 
prior to, Week 50, then the end of the Primary Treatment Period will be triggered 
when the second adjudicated On-trial Relapse has been adjudicated positively. 
3. If 2 adjudicated On-trial Relapses have not been observed by the time all patients 
have completed Week 50, or discontinued prior to Week 50, then the end of the 
Primary Treatment Period would be triggered at that time. 
If the EOPT Visit coincides with an upcoming scheduled study visit, patients will be required to 
complete all assessments for the EOPT Visit and can also be administered their scheduled dose 
of ravulizumab. 
The end of the Primary Treatment Period is defined as the end of the 14-day window of the 
EOPT Visit. 

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4.5. 
End of Study Definition 
A patient is considered to have completed the study by satisfying either one of the following 
conditions: 
1. The patient has completed all phases of the study including the last visit shown in the 
Schedule of Activities. 
2. The patient has completed the study early because ravulizumab has become registered 
or approved. 
The end of the study is defined as the date of the last visit of the last patient (Section 1.3) in the 
trial globally. 

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5. 
STUDY POPULATION 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is 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. Patient must be 18 years of age or older, at the time of signing the informed consent. 
Type of Patient and Disease Characteristics 
2. Anti-AQP4 Ab-positive at screening and a diagnosis of NMOSD as defined by the 2015 
international consensus diagnostic criteria (Wingerchuk, 2015). A historically positive 
anti-AQP4 Ab test may be acceptable if the test was performed using an acceptable, 
validated cell-based assay from an accredited laboratory. In this setting, the historical test 
result and related information need to be reviewed and approved by the Sponsor’s 
Medical Monitor prior to initiating study treatment. 
3. At least 1 attack or relapse in the last 12 months prior to the Screening Period 
NOTE: Patients with a single life-time attack will be considered to satisfy inclusion 
criterion #3 if the attack occurred in the last 12 months. 
4. Expanded Disability Status Scale (EDSS) score ≤ 7 
5. Patients who enter the trial receiving supportive IST (eg, corticosteroids, azathioprine 
[AZA], mycophenolate mofetil [MMF], methotrexate [MTX], and tacrolimus [TAC]) for 
the prevention of relapse, either in combination or monotherapy, must be on a stable 
dosing regimen of adequate duration prior to Screening with no plan to change the dose 
during the study period (defined as from the screening visit through the end of the study) 
as follows: 
a. If patients who enter the study are receiving AZA, they must have been on AZA for 
≥ 6 months and have been on a stable dose for ≥ 2 months prior to Screening. 
b. If patients who enter the study are receiving other ISTs (eg, MMF, MTX, or TAC), 
they must have been on the IST for ≥ 3 months and have been on a stable dose for 
≥ 4 weeks prior to Screening. 
c. If patients who enter the study are receiving oral corticosteroids, they must have been 
on a stable dose for ≥ 4 weeks prior to Screening. 
d. If a patient enters the trial receiving oral corticosteroid(s) with or without other 
IST(s), the daily corticosteroid dose must be no more than prednisone 20 mg/day (or 
equivalent) prior to 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. 
Weight 
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Sex 
8. Male or female 
Contraceptive use by men or women should be consistent with local regulations regarding 
the methods of contraception for those participating in clinical studies. 
a. Male patients: 
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 last dose of study drug and refrain from 
donating sperm during this period. 
b. Female patients: 
A female patient is eligible to participate if she is not pregnant, not breastfeeding, and at least 1 
of the following conditions applies: 
• Not a woman of childbearing potential (WOCBP) 
OR 
• 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 
serum pregnancy test at screening and a negative urine pregnancy test 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 
9. Capable of giving signed 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 
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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 
7. Any medical condition that, in the opinion of the Investigator, might interfere with the 
patient’s participation in the trial, poses any added risk for the patient, or confounds the 
assessment of the patient 
Prior/Concomitant Therapy 
8. Previously or currently treated with a complement inhibitor. 
9. Use of rituximab within 3 months prior to Screening 
10. Use of mitoxantrone within 3 months prior to Screening 
11. Use of Intravenous Immunoglobulin (IVIg) within 3 weeks prior to Screening 
Prior/Concurrent Clinical Study Experience 
12. Participation in any other investigational drug study or exposure to an investigational 
drug or device within 30 days of Screening or 5 half-lives of the investigational drug, 
whichever is greater 
Other Exclusions 
13. Pregnant, breastfeeding, or intending to conceive during the course of the study  
14. Patient is currently treated with a biologic medication that may affect immune system 
functioning, or has stopped treatment with a biologic medication that may affect immune 
system functioning, and 5 half-lives of the medication have not elapsed by the time of the 
Screening visit, unless otherwise specified in the protocol. 
15. Participation in the PREVENT study (ECU-NMO-301), regardless of the study drug 
received (eculizumab or placebo) 
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 treated with study drug. 
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. 
A patient who experiences a relapse that meets the protocol definition of an On-trial Relapse 
(Section 8.2.3.2) during the Screening Period will be considered a screening failure. Such 
patients may be rescreened for enrollment into the trial after receiving treatment for the relapse 
and when, in the opinion of the Investigator and the Medical Monitor, the patient is medically 

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stable (Section 5.1; Section 5.2). The patient must meet the enrollment criteria at re-screening in 
order to enter the study. 

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6. 
STUDY DRUG 
Study drug is defined as any study drug(s), marketed product(s), placebo, or medical device(s) 
intended to be administered to a study patient according to the study protocol. 
6.1. 
Study Drug(s) Administered 
In this study, patients will receive open-label ravulizumab during the entire treatment period 
(Table 6). Detailed description of the study drug is provided in the Pharmacy Manual. 
Refer to Section 8.1.6 for study drug dosage and administration and Section 1.3 SoA for dosing 
schedules. 
Table 6 
Study Drugs 
Study drug name 
Ravulizumab 10 mg/mL, 30 mL vial 
Ravulizumab 100 mg/mL, 11 mL vial 
Type 
Biologic 
Biologic 
Dose formulation 
Concentrated sterile, preservative-free solution 
with a concentration of (10 mg/mL) in 
single-use 30 mL vials, 30 mL extractable 
volume 
Concentrated sterile, preservative-free 
aqueous solution (100 mg/mL) in 
single-use 11 mL vials, 11 mL 
extractable volume 
Physical description 
Clear to translucent, slight whitish color, 
practically free from particles 
Liquid solution practically free from 
particles 
Unit dose strength(s) 
300 mg (10 mg/mL concentrated solution) 
1100 mg (100 mg/mL concentrated 
solution) 
Dosage level(s)1 
Weight-based dose, starting 2 weeks after the 
initial loading dose, then maintenance dose 
q8w 
Weight-based maintenance dose 
Route of administration 
IV infusion 
IV infusion 
Use 
Experimental 
Experimental 
IMP and NIMP 
IMP  
IMP 
Sourcing 
Supplies provided by Alexion 
Supplies provided by Alexion 
Packaging and labeling 
The solution is packaged in a 30 mL single-use 
vial with an extractable volume of 30 mL and a 
grey rubber stopper and with an aluminum 
overseal and a flip-off cap.  Study drug will be 
supplied in kits and labeled as required per 
country requirement. 
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. 
1 Detailed information of study drug dose administration is provided in Section 8.1.6. 
Abbreviations: IMP = investigational medicinal product; IV = intravenous; NIMP = non-investigational medicinal 
product; q8w = once every 8 weeks 
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. Ravulizumab should not be frozen. 
Study drug 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 will be further 
diluted in a 1:1 ratio with compatible diluent. Ravulizumab will be filtered with a 0.2 micron 
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1. 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. 
2. Only patients enrolled in the study may receive study drug and only authorized site staff 
may supply or administer 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. 
3. 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). 
4. Further guidance and information for the final disposition of unused study drugs are 
provided in the Pharmacy Manual. 
For detailed instruction on study drug preparation, handling, storage, and accountability, refer to 
the Pharmacy Manual. 
6.3. 
Measures to Minimize Bias: Randomization and Blinding 
This is a single-arm, open-label study. All study patients, site personnel, Sponsor staff, Sponsor 
designees, and all staff directly associated with the conduct of the trial will be unblinded to 
patient treatment assignments. 
To minimize potential for bias in this open-label study, operational measures will be employed 
regarding the efficacy endpoints and adjudication process. The trial database will be monitored 
according to prespecified guidelines in order to confirm that all potential relapses are collected 
and analyzed. An independent Relapse Adjudication Committee will evaluate each On-trial 
Relapse and confirm whether it meets the protocol defined criteria for an NMOSD relapse 
(Section 8.2.3.2). Additionally, while the EDSS Raters will be aware that all patients are on 
ravulizumab, the EDSS Raters will be blinded to all trial data when making their assessments. 
The external control will be the placebo arm of Study ECU-NMO-301, a randomized double-
blind study conducted from 2014 to 2018, and upon which this study is based. The design is 
similar in most aspects: the inclusion criteria are the same in most cases, with modifications that 
include using the most recently updated NMOSD diagnostic criteria and updated historical 
relapse rate parameters. To minimize any biases arising from slight differences in study designs 
and unforeseen enrollment differences, statistical analyses will include covariate adjustment 
techniques as warranted. 
Enrollment for each geographic region will be approximately 28% to 40% of the total 
population. This will allow for relative maintenance of constancy from a regional standpoint 
between the ALXN1210-NMO-307 and the ECU-NMO-301 study populations. 
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 the patients receive the appropriate dose at the appropriate timepoints 
during the study. 

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The date and time of each dose administered will be recorded in the source documents and 
recorded in the case report form (CRF). 
6.5. 
Concomitant Therapy 
Any medication (including over-the-counter or prescription medicines, vitamins, minerals, 
and/or herbal supplements) or vaccine that the patient is receiving at the time of enrollment or 
receives during the study must be recorded in the patient’s source document/medical chart and 
electronic case report form (eCRF) along with: 
• Reason for use 
• Dates of administration including start and end dates 
• Dosage information including dose and frequency 
Any changes in concomitant medications also will be recorded in the patient’s source 
document/medical chart and eCRF. When possible, concomitant medications will be recorded 
from the first infusion of ravulizumab until the patient has discontinued or completed the study. 
Information regarding the use of ISTs including steroids must be collected. Meningococcal 
vaccination and antibiotics administered for prophylaxis of meningococcal infection (if 
applicable) will also be recorded. 
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 6.5.2, 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. 
6.5.1. 
Allowed Medications and Therapies 
The following concomitant medications and therapies are allowed in this study. 
6.5.1.1. 
Palliative and Supportive Care 
Palliative and supportive care is permitted during the course of the trial for underlying 
conditions. 
6.5.1.2. 
Immunosuppressive Agents 
The supportive immunosuppressive therapies (ISTs) for relapse prevention, either in 
combination or monotherapy, are permitted at the discretion of the Investigator, such as: 
• corticosteroids 
• azathioprine (AZA) 
• mycophenolate mofetil (MMF) 
• methotrexate (MTX) 

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• tacrolimus (TAC) 
• cyclosporine 
• cyclophosphamide 
If a patient receives supportive ISTs prior to the study and continues to receive stable 
maintenance therapy during the study, refer to inclusion criteria (Section 5.1) for the 
requirements on ISTs to ensure that the patient is on a stable dose within limits required for this 
study as described in study criteria (Section 5). 
For each patient, no adjustment in IST dosage and no new ISTs will be permitted for the first 
106 weeks, unless the patient experiences a relapse or a safety event, and a change in IST dose or 
regimen is deemed necessary by the Investigator to guarantee the patient’s safety. 
Any changes in immunosuppressive therapy will be recorded in the source documents and eCRF 
page for concomitant medication. 
6.5.1.3. 
Standardized Treatment for Relapse 
The treatment of relapse is at the discretion of the Treating Physician. While the exact treatment 
for a potential relapse is ultimately at the discretion of the Investigator, the following 
standardized treatment regimen for a confirmed On-trial Relapse (Section 8.2.3.2) is 
recommended, in accordance with expert opinion:   
One gram (1 g) intravenous methylprednisolone (IVMP) administered daily for 3-5 days 
followed by oral prednisone tapering. 
• If the patient improves, then continue the trial assessments as per schedule of this 
protocol. 
• If there is no or minimal response to IVMP, or if the Investigator determines that PE/PP 
is the appropriate initial option, PE/ PP will be allowed at the discretion of the treating 
neurologist. Five cycles of PE, each removing 1.0 to 1.5 volumes of circulating plasma, 
are recommended for treatment of attacks that do not respond to IVMP. 
o If a patient undergoes PE/PP for an On-trial Relapse during the Treatment Period, a 
supplemental dose of study drug should be administered after each PE/PP as 
described under Supplemental Dose in Section 8.1.6.2. After receiving the 
supplemental dose, the patient will continue on the protocol-specified dosing 
schedule in the SoA (Section 1.3). 
6.5.2. 
Disallowed Medications and Therapies 
The following medications and therapies are prohibited during the study. 
• Mitoxantrone 
• Rituximab or other biologics that may affect immune system functioning (eg, 
tocilizumab, ocrelizumab, satralizumab, or inebilizumab) 
• Immunomodulatory therapies, including interferon beta-1b; interferon beta-1a, glatiramer 
acetate, natalizumab, alemtuzumab, dimethyl fumarate, teriflunomide, siponimod, and 
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• IVIg or subcutaneous Ig used as maintenance therapy 
• Note: IVIg used acutely for relapse treatment is allowed. 
• PE for relapse prevention 
• Bruton tyrosine kinase (BTK) inhibitors 
6.6. 
Dose Modification 
Dose modification is not permitted for this study. 
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). 
All patients will be followed for safety for an additional 8 weeks after the last dose of study drug 
or early discontinuation. 

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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 (definitive 
discontinuation) study drug. If study drug is definitively discontinued, the patient should remain 
in the study to be evaluated for the 8-week safety follow up visit. See the SoA 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 will be discontinued from study drug if any of the following occur during the study: 
1. Serious hypersensitivity reaction; 
2. Severe uncontrolled infection; 
3. Use of disallowed medication as defined in Section 6.5.2; 
4. Pregnancy or planned pregnancy; or 
5. Sponsor or the Investigator deems it is necessary for the patient. 
See the SoA (Section 1.3 ) for data to be collected at the time of study drug discontinuation and 
follow-up and for any further evaluations that need to be completed. 
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 the Sponsor and their site 
monitor of all trial withdrawals as soon as possible. The reason for patient discontinuation must 
be recorded in the source documents and 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. This is expected to be uncommon. 
• At the time of discontinuing from the study, if possible, an early discontinuation visit 
should be conducted, as shown in the SoA (Section 1.3). Patients who discontinue 
early should be followed for safety for an additional 8 weeks and for any further 
evaluations that need to be completed. 
• 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, the Sponsor may 
retain and continue to use any data collected before such a withdrawal of consent. 
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. 

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Patients who fail to return for a scheduled visit must be contacted by the site’s study staff 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 or potential relapse, 
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 Treating Physician 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 
Relapse Evaluation Visit form or in the AE form 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 handled as part of 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 the Sponsor 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 and Procedures 
8.1.1. 
Informed Consent 
The Investigator or qualified designee must obtain a signed and dated informed consent form 
from each patient prior to conducting any study procedures. All efforts should be made to ensure 
patients are willing to comply with trial participation prior to conducting the screening 
procedures. 
8.1.2. 
Treating Physician 
The Treating Physician is the Principal Investigator (PI) /Sub-Investigator for the study who will 
be responsible for the overall patient management including patient eligibility evaluation, 
supervision of the study drug administration, recording and treating of AEs and monitoring of 
safety assessments. 
At the time of a relapse, the Treating Physician will perform a complete neurologic examination 
and determine if the patient's symptoms and signs meet the criteria for an On-trial Relapse 
(Section 8.2.3.2). They may also treat the patient’s relapse according to the recommended 
On-trial Relapse Treatment regimen. Ultimately, treatment and treatment options for On-trial 
Relapse as well as any changes in the ISTs following an On-trial Relapse are at the discretion of 
the Treating Physician. 
8.1.3. 
Medical History and NMOSD History 
The Investigator will review the patient’s history and diagnosis and document the following at 
the Screening Visit: 
• Medical history including all relevant medical/surgical history 

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• NMOSD diagnosis date as well as prior Magnetic Resonance Imaging (MRIs) that 
contributed to the diagnosis. Confirmation of the NMOSD diagnosis as defined by the 
International Panel for NMO Diagnosis (IPND) criteria (Section 10.5), including the 
specific criteria the patient met for the diagnosis. Only patients who are both anti AQP4 
Ab-positive and otherwise meet the 2015 IPND criteria will be eligible for participation.  
• Information about relapses which occurred before screening and that meet the protocol 
definition of Historical Relapse (Section 8.2.3.1) will be recorded. For relapses that 
occurred in the last 24 months, this information will include the following  
o The number of relapses (onset dates) 
o The clinical presentation of each relapse (eg, optic neuritis [ON], TM, brainstem, 
area postrema, or other) 
o Acute and maintenance treatments and dosing regimens 
8.1.4. 
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. 
• Patients who initiate study drug less than 2 weeks after receiving a meningococcal 
vaccine must receive treatment with appropriate prophylactic antibiotics 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 per 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. 
8.1.5. 
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 the Sponsor must approve patient eligibility before enrollment. 

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8.1.6. 
Study Drug Administration 
This section describes the dosage regimen of study drugs. At the scheduled dosing visits 
(Section 1.3), study drug administration 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. 
8.1.6.1. 
Ravulizumab 
Patients will receive a weight-based loading dose of ravulizumab via IV infusion on Day 1, 
followed by a weight-based maintenance dose on Day 15 (Table 7), then once every 8 weeks 
(q8w) thereafter (Table 7). The entire treatment duration is up to approximately 4.5 years, when 
all patients complete the 2-year Long-Term Extension Period or until ravulizumab is approved 
and/or available (in accordance with country-specific regulations), whichever occurs first. 
Patients may be switched from the 10 mg/mL to the 100 mg/mL formulation of ravulizumab 
with no change to the weight-based dose regimen during the Long-Term Extension Period. 
Table 7: 
Weight-based Doses of Ravulizumab 
 
Body Weight (kg)a 
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. This will commonly be the current 
visit as weight will be measured prior to dose preparation on the day of the visit. If the study drug is prepared 
the night before a visit, the weight from the most recent prior study visit should be used. 
Depending on when a relapse occurs, ravulizumab scheduled dosing visits may or may not 
overlap with the Relapse Evaluation Visit and/or Follow-Up Relapse Evaluation Visits. 
Ravulizumab dosing should continue as scheduled during the Relapse Evaluation Period. 
8.1.6.2. 
Supplemental Dose 
During the study, PE/PP or IVIg will be allowed at the discretion of the Treating Physician for 
On-trial Relapse (Section 6.5.1.3). 
• If PE/PP is administered on a non-dosing visit as specified in the SoA (Section 1.3), a 
supplemental dose will be administered within 4 hours after each session of PE/PP is 
completed, and will be based on the most recently administered ravulizumab dose 
(Table 8). 
• If PE/PP is administered on a scheduled dosing visit as specified in the SoA 
(Section 1.3 ), a ravulizumab supplemental dose will not be administered. Patients 
will receive their regular dose of ravulizumab (Section 8.1.6.1) 60-120 minutes after 
that session of PE/PP is completed. 

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• It is noted that PE/PP is typically administered in multiple sessions over the course of 
1-2 weeks. If one session occurs on the day of a scheduled dosing visit, then the 
regular dose of ravulizumab is administered on that day. However, for the other 
sessions in the same 1-2 week course that do not occur on the scheduled dosing visit 
day, only the supplemental dose will be given. 
• If IVIg is administered, ravulizumab supplemental dosing is only required after the 
last dose of IVIg in the series. 
− If the last dose of IVIg in the series is given on a non-dosing visit as specified in 
the SoA (Section 1.3), a supplemental dose of 600 mg ravulizumab will be 
administered within 4 hours after the completion of the IVIg infusion. 
− If the last dose of IVIg in the series is administered on the same day as a 
scheduled dosing visit as specified in the SoA (Section 1.3), then a ravulizumab 
supplemental dose will not be administered, and patients will receive their regular 
dose of ravulizumab (Section 8.1.6.1) 60-120 minutes after the completion of the 
IVIg infusion. 
Refer to Section 8.6.2 for PK and free C5 sample collection during On-trial Relapse. 
After receiving the supplemental dose, patients are to continue study drug infusion according to 
the protocol-specified dosing schedule (Section 1.3). 
Table 8: 
Supplemental Dose of Ravulizumab Administered at Nonscheduled Dosing 
Visits After PE/PP Treatment for On-trial Relapse 
Dose Name 
Most Recently Scheduled 
Dose 
Supplemental Dose (mg) 
Loading dose 
2400 
1200 
2700 
1500 
3000 
1500 
Maintenance dose 
3000 
1500 
3300 
1800 
3600 
1800 
8.1.7. 
Visits at Home or Alternative Healthcare Facilities 
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 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 NMO 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 or a potential relapse, the patient will need to be evaluated at the study site. 

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Monitoring, treatment, and management of infusion reactions for patients receiving drug 
infusions at home are described in detail in the Nursing Instruction Manual and Section 10.14. 
8.2. 
Efficacy Assessments 
8.2.1. 
Neurologic Examination 
A complete general neurologic examination will be performed at the scheduled visits 
(Section 1.3) by the Treating Physician (Section 8.1.2) who is a study Investigator and has been 
properly trained as clinical evaluator, preferably the same Treating Physician, throughout the 
study. 
The complete general neurologic examination includes assessments of the following systems: 
mental status, fundus examination, cranial nerves, deep tendon reflexes, plantar responses, 
power/strength, sensation, coordination, and gait/balance. 
8.2.2. 
NMO Symptom Card and Evaluation 
Before receiving the first dose of study drug at the Day 1 Visit, patients are given an NMO 
Symptom Card, which lists potential signs and symptoms of NMOSD relapse and contact 
information. 
At each visit throughout the study, study staff should ensure that the patient has the NMO 
Symptom Card. The Treating Physician will review and assess the patient for any signs or 
symptoms indicative of relapse. 
To minimize the risk of non-reporting or delayed reporting of a relapse when a patient is 
experiencing relapse symptoms, biweekly phone call visits will be implemented by study sites 
between the scheduled dosing visits (Section 1.3). A phone visit at Week 6, a scheduled non-
dosing visit, will not be necessary. At each phone visit, patients will be queried about safety and 
any neurologic symptoms suggestive of a relapse that are ongoing or that have occurred since the 
last visit. If a potential relapse is identified, the patient will be asked to have an onsite relapse 
evaluation visit to determine whether this patient’s symptomatology meets the protocol defined 
criteria for relapse. 
8.2.3. 
Relapse 
8.2.3.1. 
Historical Relapse 
Historical relapses are the relapses that occurred before the Screening Visit, including the first 
NMOSD attack. For this protocol, historical relapse is defined as a new onset of neurologic 
symptoms or worsening of existing neurologic symptoms with an objective change on neurologic 
examination (clinical findings or MRI findings, or both) that persisted for more than 24 hours 
and/or the new onset of neurologic symptoms or worsening of existing neurologic symptoms that 
required treatment. Treatment is defined as use of high-dose IV steroids, PE/PP or IVIg. Events 
that occur within a 30-day interval are considered as one relapse. 

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8.2.3.2. 
On-trial Relapse 
8.2.3.2.1. Definition of On-trial Relapse 
On-trial Relapses are acute attacks that occur during the study treatment period. For this 
protocol, On-trial Relapse is defined as a new onset of neurologic symptoms or worsening of 
existing neurologic symptoms with an objective change (clinical sign) on neurologic 
examination that persists for more than 24 hours as confirmed by the Treating Physician 
(Section 8.1.2). The signs and symptoms must be attributed to NMOSD, ie, not caused by an 
identifiable cause such as infection, excessive exercise, or excessively high ambient temperature. 
Isolated changes on MRI or other imaging investigation with no related clinical findings are not 
considered an On-trial Relapse. 
8.2.3.2.2. Evaluation of On-trial Relapse 
On-trial Relapses will be monitored throughout the study. The Investigator or a qualified 
designee will review the signs and symptoms of a potential relapse with the patient in detail at 
each visit. 
Patients will be educated on the potential signs and symptoms of NMOSD relapse and will be 
instructed to contact the study site at the first sign or symptom of a potential relapse. 
Patients should be evaluated within 24 hours (and no later than 48 hours) of notification of signs 
or symptoms suggestive of a potential relapse. 
Evaluation of On-trial Relapses includes the following: 
• Complete neurological examination to determine whether the clinical signs, 
symptoms and examination findings meet the definition of an On-trial Relapse 
• Assessment of relapse severity based on the OSIS (Section 8.2.9; Section 10.10). The 
OSIS Visual Acuity (VA) Subscale Scores will be used to categorize the severity of 
ON. The OSIS Motor Subscale Scores and Sensory Subscale Scores will be used to 
categorize the severity of TM. 
• Evaluation of the neurological functional systems based on the Kurtzke’s Functional 
System Scores (FSS) and the disability level based on the EDSS score (Section 8.2.5). 
• Ambulatory function assessment using the HAI (Section 8.2.8). 
• Ophthalmological examination including VA, confrontational visual fields (VF), and 
color vision (Section 8.2.10). 
• MRI +/- gadolinium and/or optical coherence tomography (OCT) examinations 
should be performed to evaluate a potential relapse as determined by the Investigator 
(Section 8.2.11).  
• Additional tests and the follow-up evaluation as specified in the SoA (Section 1.3). 
8.2.3.2.3. Treatment for On-trial Relapse 
At the time of a suspected relapse, the Treating Physician (Section 8.1.2) will perform a 
complete neurologic examination to determine if a patient is experiencing an On-trial Relapse. If 

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the event is determined as an On-trial Relapse by the Treating Physician, treatment for relapse, 
as well as any changes in the ISTs following relapse, are at the discretion of the Investigator. 
The recommended standardized treatment for On-trial Relapse is provided in Section 6.5.1. 
Refer to Section 8.1.6 for administration of ravulizumab supplemental dose during an On-trial 
Relapse. 
8.2.3.2.4. On-trial Relapse Follow-up 
Relapse Evaluation Visits to monitor the course of the relapse will be performed according to the 
schedule specified in the SoA (Section 1.3). Additional (unscheduled) Follow-up Relapse 
Evaluation Visits outside the specified time points will be made at the discretion of the 
Investigator or the sub-Investigator. 
Following a relapse, a patient may continue in the trial if the patient and the 
Investigator/sub-Investigator decide that it is appropriate to continue to receive study drug. 
All reports of possible relapses and actions taken for the possible relapse must be documented in 
the patient’s source documents and recorded in the eCRF. 
8.2.3.2.5. Adjudication of On-trial Relapse 
On-trial Relapses will be independently reviewed by the Relapse Adjudication Committee 
(RAC), which consists of physicians who have particular expertise in NMOSD and will conduct 
independent reviews of all On-trial Relapses. The Committee will decide by majority vote 
whether each reported On-trial Relapse meets the objective criteria for an On-trial Relapse. A 
separate Charter will document all adjudication criteria and procedures for this study. 
8.2.4. 
Case of Interest 
Accurate identification of potential relapses is crucial for the scientific integrity of the study. In 
order to achieve this, the database will be analyzed for potential events (Cases of Interest) that 
were not reported by the Treating Physician as a relapse. 
A Case of Interest is an event judged by the Treating Physician to not be an On-trial Relapse (ie, 
it is not an Investigator confirmed On-trial Relapse), but which meets the following criteria to be 
considered a Case of Interest and submitted to the RAC for adjudication: 
• Patients who were seen by the Treating Physician for a 24- to 48-hour relapse 
evaluation visit and where the Treating Physician concluded that an On-trial Relapse 
did not occur, OR 
• A sentinel AE (eg, AEs of weakness, sensory changes, especially in a dermatomal 
distribution, characteristic visual changes of NMOSD, or pseudo exacerbation of 
NMOSD) AND either: 
o An MRI was performed contemporaneously OR 
o Neurological symptoms were treated (by hospitalization or IVMP) OR 
o Contemporaneous objective worsening of the Treating Physician’s Neurologic 
Examination (defined by answer of “worse” to clinically meaningful change 
question). 

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Note: a Case of Interest is also referred to as a ‘pseudo relapse’. The terms may be used 
interchangeably. 
Refer to Section 10.15 for additional description of the Case of Interest identification process. 
8.2.5. 
Expanded Disability Status Scale (EDSS)  
The 10-point Neurostatus EDSS (modified Kurtzke EDSS), described in Section 10.6, is widely 
used and accepted as a valid tool for quantifying disability and monitoring changes in disability 
over time (Kurtzke, 1983). 
The EDSS scale ranges from 0 to 10.0 in 0.5 unit increments. 
8.2.5.1. 
Expanded Disability Status Scale 
The total EDSS score is determined by 2 factors: gait and FSS (Section 8.2.5.2). 
• EDSS scores below 4.0 are determined by the FSS alone. 
• People with EDSS scores of 4.5 and above may have some degree of gait impairment. 
• EDSS scores between 4.5 and 9.5 are determined by both gait abilities and the FSS. 
8.2.5.2. 
Functional Systems Scores 
A functional system (FS) represents a network of neuronal systems responsible for particular 
tasks/functions. The EDSS assigns a severity score to the patient's clinical status using FSS that 
evaluate dysfunction in the following 7 FSs (Section 10.6). 
The FS of functional systems 1 through 7 are scored on a scale of 0 (low level of problems) to 5 
or 6 (high level of problems) to best reflect the level of disability observed clinically. 
8.2.5.3. 
EDSS and FSS Rater 
The EDSS and FSS should be administered in person by a trained rater. The EDSS Rater will 
perform a complete Kurtzke neurologic examination and document the FSS and the EDSS score. 
• The EDSS Rater shall not be the PI and cannot be directly involved in the trial 
patient’s management. When possible, the EDSS Rater should be a physician. If a 
non-physician EDSS Rater (eg, specialized nurse) will be used, the rater must be 
approved by the Sponsor before performing the assessments. 
• The EDSS Rater must remain blinded to all other study data as well as all other 
patient clinical data. 
• The blinded EDSS Rater will be responsible for performing the EDSS assessments 
throughout the study including at the time of a relapse. When possible, the same 
blinded rater should perform the EDSS for each patient at visits specified in the SoA. 
• The EDSS Rater will perform a complete Kurtzke neurologic examination, as 
described in Section 10.6 and document the Functional Systems Scores (FSS) and the 
EDSS score (Kurtzke, 1983). 
For specific requirements for EDSS Rater qualification, refer to the training materials provided 
by the Sponsor. 

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Refer to Table 9 for the roles and responsibilities of Investigator and EDSS Rater. 
Table 9: 
Roles and Responsibilities of the Treating Physician and EDSS Rater 
Treating Physician 
EDSS Rater 
At protocol-specified timepoints: 
• Determine patient eligibility for the study 
• Overall patient management during the study, 
including study drug administration and safety 
assessments. 
At protocol-specified timepoints: 
• Kurtzke neurologic assessment 
• Document FSS 
• Record EDSS score 
At the time of relapse: 
• Initial patient assessment 
• Have the EDSS Rater record FSS and EDSS 
scorea 
• Perform a complete neurologic examination 
• Determine if the patient has experienced an 
On-trial Relapse 
• Determine relapse severity by OSIS 
• Assess VAa, confrontational visual fields, and 
color visiona 
• Assess ambulation by HAIa 
• Have the patient complete the EQ-5D and SF-36 
• Treat relapse 
At the time of relapse: 
• Perform the Kurtzke neurologic assessment 
• Document FSS 
• Record EDSS score 
EDSS = Expanded Disability Status Scale; EQ-5D = Euro Quality of life-5 Dimensions; FSS = functional 
systems score; HAI = Hauser ambulation index; OSIS = Optic spinal impairment score; SF-36=short form health 
survey; VA = visual acuity. 
a Can be performed by the Investigator or a designee 
8.2.6. 
EuroQoL 5 Dimensions (EQ-5D) 
The Euro Quality of Life (EQ-5D) (Section 10.7) is a self-assessed, standardized instrument to 
measure health-related QoL, which has been used in a wide range of health conditions, including 
NMOSD (Schrag, 2000). The EQ-5D consists of 2 pages: the EQ-5D descriptive system and the 
EQ visual analogue scale (EQ VAS) (Section 10.7 ). EQ-5D should be administered prior to 
other study procedures at each visit. For patients who are blind, the script for face-to-face 
interview administration version of EQ-5D will be used (Section 10.7). 
8.2.6.1. 
EQ-5D Descriptive System 
The descriptive system is a 5-component scale including mobility, self-care, usual activities, 
pain/discomfort, and anxiety/depression. Each level is rated on a scale that describes the degree 
of problems in that area. 

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8.2.6.2. 
EQ Visual Analogue Scale 
The EQ-5D VAS is an overall health state scale where the patient selects a number between 0 to 
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’. 
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 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 
two 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. 
Hauser Ambulation Index (HAI)  
The HAI (Hauser, 1983) is a rating scale developed to assess mobility by evaluating the time and 
degree of assistance required to walk 25 feet (Section 10.9). 
The Treating Physician or an appropriately trained designee will perform the HAI test at the 
protocol specified visits (Section 1.3). 
• Patients are asked to walk a marked 25-foot course as quickly and safely as possible. 
• The examiner records the time and type of assistance (eg, cane, walker, crutches) needed. 
The rating scale also has categories for patients who are unable to walk. 
Although the patient's walking is timed, the time is not used directly but is utilized in conjunction 
with other factors to rate the patient on an ordinal scale with 10 gradations (Bethoux, 2011). This 
assessment will be performed for all patients in this study. 
8.2.9. 
Optic Spinal Impairment Score (OSIS) 
The OSIS is a scoring system for evaluating the severity of a relapse (Section 10.10). The OSIS 
VA Subscale Scores will be used to categorize the severity of ON. The OSIS Motor Subscale 
Scores and Sensory Subscale Scores will be used to categorize the severity of TM. 
The OSIS will be assessed at baseline and at the time of On-trial Relapse by the Treating 
Physician. Further instruction on OSIS evaluation of On-trial Relapse is provided 
in Section 8.2.3.2. 
8.2.10. 
Ophthalmologic Examination 
8.2.10.1. Confrontational Visual Fields 
Confrontational VF will be evaluated by the Treating Physician. It is critical for these 
assessments that the baseline ophthalmologic status be known so that changes in the examination 
can be used to evaluate prior or ongoing ON. Central scotomas are common in patients 

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experiencing ON; however, visual field deficits can present with a broad spectrum of patterns 
(Keltner, 1999). 
8.2.10.2. Color Vision 
Color vision will be assessed by the Treating Physician or any appropriately trained designee 
using Ishihara Plates. Loss of color vision can be a marker of ON and is therefore an important 
assessment tool in NMOSD. Color vision will be assessed in this study using the first 21 Ishihara 
Plates. 
8.2.10.3. Visual Acuity 
Visual acuity is usually affected by ON, progressing over a period of hours to days. The Landolt 
C ring chart will be used to assess VA. 
The Landolt C consists of a ring that has a gap, thus looking similar to the letter C. The gap can 
be at various positions (usually left, right, bottom, top and the 45° positions in between) and the 
task of the tested person is to decide on which side the gap is. The size of the C and its gap are 
reduced until the patient makes a specified rate of errors. The minimum perceivable angle of the 
gap is taken as measure of the visual acuity. 
The Treating Physician or an appropriately trained designee will perform the VA test at the 
protocol specified visits (Section 1.3). 
• The test is performed at a distance of 4 meters or 13 feet. 
• The Landolt chart is typically recorded as acuity ratio distance (4 meters or 13 feet), so 
for normal VA it would be recorded as 13/13 or 4/4. Despite being assessed at a distance 
of 4 meters or 13 feet, sites can also report results using a denominator of 6 (for patients 
assessed in meters) or 20 (for patients assessed in feet). The appropriate score for each 
line using these denominators is indicated on the supplied Landolt C ring chart. In this 
case, a normal VA would be recorded as 20/20 or 6/6. Sites can also choose to enter the score 
as a decimal, where a normal VA would be 1.0. 
• The test should always be done with the best possible correction (ie, wearing glasses) as 
needed and each eye should be tested independently. 
8.2.11. 
Magnetic Resonance Imaging and Optical Coherence Tomography 
Baseline MRI of brain, cervical spine, and thoracic spine (contrast is optional) and OCT 
examinations should be performed. Exceptions may be granted (eg, based on a recent historical 
result being available for the study) if approved by the Alexion Medical Monitor. 
At the time of relapse, MRI of brain, cervical spine, and/or thoracic spine (contrast is optional) 
and/or OCT should be performed to evaluate a potential relapse at the discretion of the 
Investigator when deemed clinically relevant. 
Follow-up assessments should be performed promptly after On-trial Relapse if the Investigator 
decides these are indicated (Section 8.2.3). 

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8.3. 
Safety Assessments 
Planned time points for all safety assessments are provided in the SoA (Section 1.3). 
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, pulse, chest, heart, abdomen, extremities and musculoskeletal. 
• A targeted physical examination will include, at a minimum, a body-system relevant 
examination based upon Investigator judgment and patient symptoms. 
• Investigators 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. 
Height and Weight 
Body weight will be measured in pounds or kilograms. Height will be measured in inches or 
centimeters. 
8.3.3. 
Vital Signs 
• Oral, temporal, or axillary temperature (°C or °F), pulse rate, respiratory rate (RR), 
and systolic and diastolic blood pressure (BP) (mmHg) will be assessed. 
• 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. 
8.3.4. 
Electrocardiograms 
• Single 12-lead ECG will be performed at protocol specified visits in the SoA (see 
Section 1.3) using an ECG machine to obtain heart rate and measures of PR, QRS, 
QT, and QTc intervals. 
• Patients must be supine for approximately 5-10 minutes before ECG collection and 
remain supine but awake during ECG collection. 
• The Investigator or qualified designee 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. 

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8.3.5. 
Patient Safety Card 
Before the first dose of study drug, a Patient Safety Card will be provided to study 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 promote quick recognition and disclosure of 
any potential signs or symptoms of infection experienced by study 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. 
8.3.6. 
Prior and Concomitant Medical Review 
It is important for Investigators or a qualified designee to review each medication the patient is 
taking before starting the study and at each visit. 
8.3.6.1. 
Prior Medications 
Prior medications and/or vaccines (including vitamins, herbal preparations, and those discussed 
in the exclusion criteria Section 5.2)  and non-drug therapies/procedures (any therapeutic 
intervention, 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 ravulizumab, any meningococcal vaccine administered within the last 3 years, and any 
investigational drugs taken within a year of screening, will be recorded in the patient’s eCRF. 
Additionally, all medications or therapies ever used for relapse prevention or acute treatment of 
NMOSD (including steroids) before the first dose of ravulizumab must be collected. 
8.3.6.2. 
Concomitant Medications 
Use of concomitant medications and non-drug therapies/procedures (Section 6.5) will be 
evaluated during the study. At each visit, patients should be questioned about any new 
medication or non-drug therapies or changes to concomitant medications and non-drug therapies 
since the last visit. Concomitant medications and non-drug therapies should be recorded in the 
source documents and the patient’s eCRF. 
8.3.7. 
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 
CRF. 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 

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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 the Sponsor 
notified. 
− All protocol-required laboratory assessments, as defined in Appendix 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, SAE 
or AE or dose modification), then the results must be recorded in the CRF. 
8.3.8. 
Suicidal Ideation and Behavior Risk Monitoring 
As the study drug is being evaluated for a neurologic indication, patients being treated with the 
study drug should be monitored appropriately and observed closely for suicidal ideation or 
behavior or any other unusual changes in behavior, especially at the beginning and end of the 
course of study drug, or at the time of dose changes. 
Baseline assessment of suicidal ideation and behavior as well as intervention-emergent suicidal 
ideation and behavior will be monitored during this study using the Columbia-suicide severity 
rating scale (C-SSRS). 
There are 2 types of C-SSRS assessments that will be conducted during the study: C-SSRS at 
Baseline (Section 10.12) and C-SSRS-Since Last Visit (Section 10.13). C-SSRS will be 
performed by the Treating Physician 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. 
8.4. 
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 (see Section 7). 
For this trial, information about relapses that do not meet the SAE criteria (Section 10.3) should 
be recorded in source documents and in the eCRF as part of the Relapse Evaluation Visits and 
not reported as AEs. 

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8.4.1. 
Time Period and Frequency for Collecting Adverse Event and Serious Adverse 
Event Information 
All AEs and SAEs will be collected from the signing of the ICF until the last visit at the time 
points specified in the SoA (Section 1.3). 
All SAEs will be recorded and reported to the Sponsor 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 the Sponsor within 24 hours of awareness. 
Investigators are not obligated to actively seek AE or SAE 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 the 
Sponsor. 
8.4.2. 
Method of Detecting AEs and SAEs 
The method of recording, evaluating, and assessing causality of AE and SAE 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 8.4.6), 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 the Sponsor 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, Institutional Review Boards 
(IRB)/Independent Ethics Committees (IEC), and Investigators. 
• Suspected unexpected serious adverse reactions (SUSAR) 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 the Sponsor will 

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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. 
Pregnancy 
Pregnancy testing must be performed on all WOCBP at protocol-specified timepoints in the SoA 
(Section 1.3). Pregnancy tests (urine or serum) may also be performed at any time during the 
study at the Investigator’s discretion. 
A negative pregnancy test is required for WOCBP 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 the Sponsor 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 the Sponsor 
must be notified as per Section 10.4. Each pregnancy will be followed to term and the Sponsor 
notified regarding the outcome. 
8.4.6. 
Adverse Events of Special Interest  
Meningococcal infections will be collected as adverse events of special interest (AESI). 
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. 
Accidental 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 the Sponsor regardless of its association with or without an AE. 
The Sponsor does not recommend specific treatment for an overdose. 
In the event of an overdose, the Investigator should: 
1. Contact the Medical Monitor immediately. 
2. Closely monitor the patient for any AE/SAE. 
3. Obtain a plasma sample for PK analysis if requested by the Medical Monitor (determined 
on a case-by-case basis). 
4. Document the quantity of the excess dose as well as the timing of the overdose in the 
CRF. 

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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 as 
specified in the SoA (Section 1.3). 
• Cerebrospinal fluid (CSF) samples for PK and PD assessments are optional at 
protocol specified timepoints (Section 1.3) and will only be obtained from patients 
who consent to CSF collection. 
• Instructions for the collection and handling of biological samples will be provided by 
the Sponsor. 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. 
8.6.1. 
Sample Collection During the Study Period 
• Baseline (B) and trough (T) 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 (P) 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, non-infused arm. 
• Blood samples at a non-dosing 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. 
8.6.2. 
Sample Collection During On-trial Relapse 
Blood sample for PK and PD analyses will be collected at any time during the scheduled Relapse 
Evaluation Visit. 
However, if the relapse-associated blood sample collection schedule coincides with a regular 
sample collection specified in the SoA (Section 1.3), the directions for regular PK and PD 
sample collection during the study (Section 8.6.1) should be followed. 
During On-trial Relapse, if the patient receives PE/PP and a supplemental dose of ravulizumab at 
the Relapse Evaluation Visit, 3 blood samples for PK and PD should be collected at the 
following intervals: 
1. Approximately 5 to 90 minutes prior to PE/PP/IVIg 
2. After PE/PP/IVIg and before study drug infusion 
3. Within 60 minutes after the completion of study drug infusion 

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If a patient receives PE/PP/IVIg at any visit other than the Relapse-Evaluation Visit, blood 
samples for PK and PD will be collected immediately before and after each session of 
PE/PP/IVIg. A postdose sample, (ie, within 1 hour after completion of supplemental study drug 
infusion), will also be collected. 
8.7. 
Genetics 
There are no prespecified genetic analyses in this study. 
8.8. 
Biomarker Research 
8.8.1. 
Exploratory Biomarker Research 
Blood samples for biomarker research will be collected from all patients at timepoints specified 
in the SoA (Section 1.3): 
CSF samples are optional samples for biomarker research and should only be collected from 
patients who have consented to CSF sample collection. 
• Biomarkers will be measured and include, but are not limited to, assessments of the 
following: 
o AQP4-Ab at protocol-specified time points (Section 1.3 SoA), including during 
the Relapse Evaluation Period (see Section 8.2.3.2 for details). 
o Complement products 
o Markers of neuroinflammation, such as interleukin 6 (IL-6) 
o Markers of neural injury, such as neurofilament light chain (NfL) 
Deoxyribonucleic acid (DNA) and ribonucleic acid (RNA) sample collection is optional. DNA 
and RNA blood samples must only be collected from patients that consent to it. DNA and RNA 
testing on these samples include assessments of the following including, but not limited to, 
specific candidate genes/genome-wide analysis: 
• Research related to ravulizumab, NMOSD, and related diseases 
• Developing tests/assays, including diagnostic tests related to ravulizumab and 
NMOSD 
8.8.2. 
Future Biomarker Research 
For patients that consent to DNA and RNA testing, future DNA and RNA testing on these 
samples include assessments of the following: 
• Research related to ravulizumab, NMOSD, and related diseases 
• Developing tests/assays, including diagnostic tests related to ravulizumab and 
NMOSD 
Remaining samples from pharmacokinetic, pharmacodynamic, immunogenicity, and biomarker 
testing will be stored for future biomarker research. Analyses may be performed on biomarker 
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ravulizumab. These samples may also be used to develop methods, assays, prognostics and/or 
companion diagnostics related to the study drug target, disease process, pathways associated with 
disease state, 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 the Sponsor to enable further analyses. 
8.9. 
Immunogenicity Assessments 
Anti-drug antibodies (ADAs) to ravulizumab will be evaluated in serum samples collected 
predose (within 5-90 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 the Sponsor. 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 the Sponsor 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 the CRF by the Investigator and study-site personnel for all patients throughout 
the study. Protocol-mandated procedures, tests, and encounters are excluded. 
The data collected may be used to conduct exploratory economic analyses and will include: 
• Number of surgeries, and other selected procedures (inpatient and outpatient) 
• Duration of hospitalization 
• Number and type of diagnostic and therapeutic tests and procedures 

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9. 
STATISTICAL CONSIDERATIONS 
9.1. 
Statistical Hypotheses 
The time to first adjudicated On-trial Relapse will be evaluated using the log-rank test; the null 
hypothesis will be that there is no difference in the survival curves of the ravulizumab and the 
placebo treatment groups. The alternative hypothesis will be that there is a difference between 
the two survival curves, and ravulizumab is superior to placebo. 
The adjudicated On-trial ARR will be presented with a 95% confidence interval (CI) to provide 
an estimate of the adjudicated On-trial ARR for patients treated with ravulizumab. The null 
hypothesis will be that the mean adjudicated On‑trial ARR is equal to 0.25 relapse/patient‑year. 
The alternative hypothesis will be that the mean adjudicated On-trial ARR is not equal to 0.25.  
For HAI the null hypothesis will be that the odds of a better outcome are the same between the 
ravulizumab arm and the placebo arm. The alternative hypothesis will be that there is a 
difference in the odds of a better outcome between the treatment arms and that ravulizumab has a 
higher odds of a better outcome. 
For the EQ-5D index and the EQ-5D VAS, the null hypothesis will be that there is no difference 
between the distribution of the ravulizumab arm and the placebo arm. The alternative hypothesis 
will be that there is a difference between the distribution of the treatment arms and that 
ravulizumab is superior to placebo. 
For the EDSS the null hypothesis will be that the odds of a worse outcome are the same between 
the ravulizumab arm and the placebo arm. The alternative hypothesis will be that there is a 
difference in the odds of a worse outcome between the treatment arms and that the odds of a 
worse outcome are higher in the placebo arm. 
9.2. 
Sample Size Determination 
This is an open-label, external placebo-controlled study to evaluate ravulizumab in NMOSD 
patients with the primary endpoint of time to first adjudicated On-trial Relapse. The placebo 
treatment arm in Study ECU-NMO-301 will serve as the external control. 
The sample size and power calculation assumptions for this study using the primary endpoint, 
time to first adjudicated On-trial Relapse, are as follows: 
• Log-rank test for comparison of ravulizumab to placebo 
• 47 patients in the placebo treatment group 
• Power 90% 
• Two-sided 5% level of significance 
• Drop-out rate 2-10% 
• Relapse-free rate of 92% for the ravulizumab arm at 12 months 
• Relapse-free rate of 63% for the placebo arm at 12 months 

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With these assumptions, a maximum sample size of approximately 55 patients in the 
ravulizumab treatment group provides at least 90% power to detect a treatment difference in time 
to first positively adjudicated On-trial Relapse. 
9.3. 
Populations for Analyses 
For purposes of analysis, the following populations are defined: 
Table 10: 
Populations for Analyses 
Population 
Description 
Full Analysis Set (FAS) 
All patients who receive at least 1 dose of study drug. 
Safety Set 
All patients who receive at least 1 dose of study drug. 
Per Protocol Set (PPS) 
The PPS is a subset of the FAS, excluding patients with important protocol 
deviations. The PP population will include all patients who: 
• 
Have no important protocol deviations or key inclusion/exclusion 
criteria deviations that might potentially affect efficacy, 
• 
Patients who took at least 80% of the required treatment doses while 
they were in the treatment period. 
Further details will be provided in the statistical analysis plan (SAP). 
Pharmacokinetic and 
Pharmacodynamic Analysis Set 
(PKPDAS) 
All patients who receive at least 1 dose of study drug and who have at least 
one evaluable PK or PD result.  
9.4. 
Statistical Analyses 
The primary analysis will be conducted when all patients have completed the Primary Treatment 
Period. This analysis will include all efficacy, safety, PK/PD, and immunogenicity study data for 
regulatory submission purposes and will be the final analysis of the Primary Treatment Period. 
The original SAP to support the primary analysis was developed and finalized shortly after the 
original protocol was final. If necessary, a final SAP will be developed prior to the completion of 
the long-term extension period to describe any additional long-term efficacy and safety analyses. 
This section is a summary of the planned statistical analyses of the primary and secondary 
efficacy endpoints and the safety analyses. 
Summary statistics will be computed and displayed by treatment group and by visit, where 
applicable. Descriptive statistics for continuous variables will minimally include the number of 
patients, mean, standard deviation, minimum, median, and maximum. For categorical variables, 
frequencies, and percentages will be presented. Graphical displays will be provided as 
appropriate. All statistical analyses will be performed based on a 2-sided Type I error of 5% 
unless noted otherwise. Missing data will not be imputed unless otherwise indicated in the 
described analysis in the SAP. 
Analyses will be performed using the SAS® software Version 9.4 or higher. 

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9.4.1. 
Efficacy Analyses 
To account for potential differences in baseline characteristics between the ravulizumab group 
and the external placebo control, sensitivity analyses of efficacy endpoints will include covariate 
adjustment methodologies, as warranted. Details are provided in the SAP. 
9.4.1.1. 
Primary Endpoint 
The primary efficacy endpoint is time to first adjudicated On-trial Relapse. The trial will be 
considered to have met its primary efficacy objective if a statistically significant difference 
(ie, p-value ≤ 0.05) is observed between the ravulizumab treatment group and the placebo group 
for the primary endpoint of the time to first adjudicated On-trial Relapse. The comparison of the 
treatment groups for the primary endpoint will use a log-rank test. Hazard ratio and risk 
reduction will be summarized from a Cox proportional hazards model. If there is no observed 
event in a treatment arm, then Firth’s Penalized Likelihood (Heinze, 2001) will be used to 
estimate the hazard ratio, risk reduction, and the profile likelihood 95% CIs. Confidence intervals 
(95%) will be presented for the estimated proportion of patients that are relapse-free at various 
timepoints (eg, Week 24, Week 48) based on the complementary log-log transformation. 
Kaplan-Meier curves for both treatment groups will be produced. 
Those patients who, for COVID‑19‑related reasons as determined by the Investigator and 
documented in the eCRF (eg, infected with or exposure to COVID‑19, quarantine, travel 
restrictions), received a dose of ravulizumab > 35 days late or missed a dose altogether will be 
censored at the time of the missed dose, if the missed or delayed dose occurred before the EOPT 
Visit or the first adjudicated On-trial Relapse.  To balance the evaluation period, patients in the 
placebo treatment group who were followed longer than patients in the ravulizumab treatment 
group will be censored at the maximum time observed in the ravulizumab treatment group. Any 
relapses that had been observed among patients in the placebo group after that time will not be 
included in the primary analysis. 
Sensitivity analyses of the primary endpoint will be described in the SAP. 
9.4.1.2. 
Secondary Endpoint(s) 
For those patients who, for COVID‑19 related reasons as determined by the Investigator and 
documented in the eCRF (eg, infected with or exposure to COVID‑19, quarantine, travel 
restrictions), received a dose of ravulizumab > 35 days late or missed a dose altogether, for 
endpoints involving the change from baseline, the change from baseline to the last value before 
the missed dose, if the missed or delayed dose occurred before the EOPT Visit or the 6‑week 
Post‑relapse Visit, will be summarized and analyzed. 
9.4.1.2.1. Adjudicated On-trial ARR 
The adjudicated On-trial ARR will be presented showing the ravulizumab treatment group 
estimate and 95% CI from a Poisson regression model in which the log of time in the study 
period will be used as the offset variable and historical ARR will be a covariate in the model. 
This endpoint will be considered statistically significant if the 2‑sided p‑value is ≤ 0.05, and if 
the adjudicated On-trial ARR < 0.25 or if 0 relapses are observed. 

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For those patients who, for COVID‑19 related reasons as determined by the Investigator and 
documented in the eCRF (eg, infected with or exposure to COVID‑19, quarantine, travel 
restrictions), received a dose of ravulizumab > 35 days late or missed a dose altogether, any 
relapse that occurred during the time interval from the missed dose until the start of the next dose 
will be excluded from the ARR calculations and summaries. 
9.4.1.2.2. EuroQoL 5 Dimension (EQ-5D) Index Score and EQ-5D VAS 
The change from baseline in the EQ-5D index score to the 6-week post-relapse/End of Primary 
Treatment Period time point (ie, for the placebo arm: 6 weeks post-relapse for the patients who 
have relapses, or Study ECU-NMO-301 end of study (EOS) for patients who did not have 
relapses; for the ravulizumab arm: the 6 week post-relapse visit for the first observed relapse for 
the patients who have relapses and the EQ-5D index score from the End of Primary Treatment 
Period visit for patients who did not have a relapse) will be analyzed using an analysis of 
covariance (ANCOVA), in which the ranks of the change from baseline will be the dependent 
variable, with treatment as a factor and the ranks of the baseline values as a covariate. Baseline is 
defined as the last available assessment prior to treatment for all patients regardless of their 
treatment group. 
The changes from baseline to the 6-week post-relapse/EOPT Period time point in EQ-5D VAS 
will be analyzed as described for the change in EQ-5D index score. 
9.4.1.2.3. Expanded Disability Status Scale (EDSS) 
The change from baseline in the EDSS score to the 6-week post-relapse/EOPT Period analysis 
time point will be calculated as described for the EQ-5D endpoints. For the EDSS, this change 
from baseline will be categorized into clinically important worsening (no worsening, clinical 
worsening). This endpoint will be analyzed using a logistic regression model including treatment 
group and baseline EDSS as a covariate. Details will be provided in the SAP. 
9.4.1.2.4. Hauser Ambulation Index (HAI) 
The change from baseline in the HAI score to the 6-week post-relapse/EOPT Period analysis 
time point will be calculated as described for the EQ-5D endpoints. For the HAI, this change 
from baseline will be categorized into clinically important changes (clinical improvement, stable, 
clinical worsening). This 3-level endpoint will be analyzed using a proportional odds model 
including treatment group and baseline HAI as a covariate. Details will be provided in the SAP. 
9.4.1.2.5. Accounting for Multiple Comparisons 
A closed testing procedure will be applied to control the type I error for the analyses of the 
primary and secondary endpoints. If the primary endpoint is statistically significant in favor of 
ravulizumab, the secondary endpoints will be evaluated according to the following rank order: 
1. Adjudicated On-trial ARR 
2. Clinically important changes from baseline in ambulatory function as measured by HAI  
3. Change from baseline in EQ-5D index score 
4. Change from baseline in EQ-5D VAS score 

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5. Clinically important worsening from baseline in EDSS score 
The hypothesis testing will proceed from highest rank (#1) the adjudicated On-trial ARR to the 
lowest rank (#5) EDSS score, and if statistical significance is not achieved at an endpoint 
(p > 0.05), then endpoints of lower rank will not be considered to be statistically significant. 
Confidence intervals and p-values will be presented for all secondary efficacy endpoints for 
descriptive purposes, regardless of the outcome of the closed testing procedure. 
Additional information on multiple comparisons is detailed in the SAP. 
9.4.1.3. 
Tertiary/exploratory endpoint(s) 
Summaries and analyses of tertiary and exploratory endpoints will be described in the SAP. 
9.4.2. 
Safety Analyses 
All safety data will be summarized using the Safety Set. 
9.4.2.1. 
Analysis of Adverse Events 
The analysis and reporting of AEs will be based on treatment-emergent adverse events (TEAEs), 
defined as AEs with onset on or after the first dose of ravulizumab. The incidence of TEAEs will 
be summarized by system organ class (SOC) and preferred term, with additional summaries 
showing severity, relationship to study drug, TEAEs leading to study drug discontinuation, and 
TEAEs resulting in death. Summaries of treatment-emergent serious adverse events (TESAEs) 
will also be summarized by SOC and preferred term, with an additional summary showing 
relationship to study drug. These summaries will be presented by treatment group (ravulizumab, 
placebo). 
9.4.2.2. 
Analysis of Clinical Laboratory Parameters, Vital Sign Measurements and 
Electrocardiogram Parameters 
Laboratory measurements as well as their changes from Baseline at each visit and shift from 
baseline, if applicable, will be summarized. ECGs, including ECG interpretation heart rate, PR, 
QRS, QT, and QTc intervals, and vital signs will also be summarized. 
9.4.2.3. 
Other Safety Analyses 
The number and percentage of patients in each of the C-SSRS categories as well as shifts from 
baseline will be presented. 
9.4.3. 
Demographics and Baseline Characteristics 
Patient demographic and baseline characteristics will be summarized by treatment group, using 
the Safety Set. Summary statistics will be presented. No formal hypothesis testing will be 
performed. 
9.4.4. 
Patient Disposition 
The number of patients screened, treated, completing the study, discontinued the study, reasons 
for discontinuation, and those included in each analysis set will be summarized. 
Important protocol deviations will be summarized by prespecified deviation categories. 

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9.4.5. 
Medical/Surgical History and Neuromyelitis Optica Spectrum Disorder History 
The medical and surgical history will be summarized by the Medical Dictionary for Regulatory 
(MedDRA) Activities, Version 21.0, or later by SOC and PT. NMOSD History will also be 
summarized. 
9.4.6. 
Prior and Concomitant Medications 
Any medication taken prior to the first dose of study drug will be considered as prior 
medications; and any medication taken on or after the first dose of study drug will be considered 
as concomitant medications. Prior and concomitant medications will be summarized for all 
patients in the Safety Analysis Set, including ISTs for relapse prevention and acute relapse 
treatment. Medications will be coded using the World Health Organization Drug Dictionary 
(WHO Drug; the most current version available at the time of the analyses). 
9.4.7. 
Pharmacokinetic, Pharmacodynamic, and Anti-Drug Antibody Analyses 
Individual serum concentration data for all patients who receive at least 1 dose of ravulizumab 
and who have evaluable PK data 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 
(Section 1.3). The PD effects of ravulizumab will be evaluated by assessing the absolute values 
and changes 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. 
Medical Resource Utilization and Health Economics 
Descriptive statistics will be provided for the following: 
• The number of days of hospitalizations for the 2 years prior to Screening (for all 
hospitalizations, and those related to NMOSD Relapse) and the ratio of the number of 
days of hospitalization in the 2-year period. 
• The number of days of hospitalizations during the study period (for all 
hospitalizations, and for adjudicated On-trial Relapses) and the ratio of the number of 
days of hospitalizations and days in the Study Period. 

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The following endpoints will be summarized by treatment group showing total counts, event 
rates as per patient-years of follow-up in the study period, and the number and percentage of 
patients: 
• With surgeries, and other selected procedures (inpatient or outpatient) 
• With any diagnostic or therapeutic test or procedures 
• For each type of diagnostic and therapeutic test and procedure, as coded by MedDRA 
(version 21.0 or higher) by SOC and Preferred Term. 
9.5. 
Interim Analysis 
The primary analysis will be conducted when all patients have completed the Primary Treatment 
Period. This analysis will include all efficacy, safety, PK/PD, and immunogenicity study data for 
regulatory submission purposes and will be the final analysis of the Primary Treatment Period. 
This analysis will not be considered an interim analysis. Interim analyses that include data 
collected during the Long-term Extension may be performed to support submission 
requirements. 
9.6. 
Data Monitoring Committee (DMC) 
This study will not include a DMC. 

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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 Council for 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 patients. 
• 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 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 the Sponsor with sufficient, accurate financial 
information as requested to allow the Sponsor 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 
• The Investigator or his/her representative will explain the nature of the study to the 
patient and answer all questions regarding the study. 
• Patients must be informed that their participation is voluntary. Patients will be 
required to sign a statement of informed consent that meets the requirements of 
21 CFR 50, local regulations, 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 written informed consent was 
obtained before the patient 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). 
• Patients must be re-consented to the most current version of the ICF(s) during their 
participation in the study. 
• A copy of the ICF(s) must be provided to the patient. 
Patients who are rescreened are required to sign a new ICF (see Section 5.4). 
10.1.4. 
Data Protection 
• Patients will be assigned a unique identifier by the Sponsor. Any patient records or 
datasets that are transferred to the Sponsor will contain the identifier only; patient 
names or any information which would make the patient identifiable will not be 
transferred. 
• The patient must be informed that his/her personal study-related data will be used by 
the Sponsor in accordance with local data protection law. The level of disclosure must 
also be explained to the patient who will be required to give consent for their data to 
be used as described in the informed consent 
• The patient must be informed that his/her medical records may be examined by 
Clinical Quality Assurance auditors or other authorized personnel appointed by the 
Sponsor, 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: 
Http://www.clinicaltrialsregister.eu), as appropriate, and in accordance with national, regional, 
and local regulations. 
10.1.6. 
Data Quality Assurance 
• All patient data relating to the study will be recorded on a printed or electronic CRF 
unless transmitted to the Sponsor or designee electronically (eg, laboratory data). The 

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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 patients 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 
test article for investigation, 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 the Sponsor. No records may be transferred to another 
location or party without written notification to the Sponsor. 
10.1.7. 
Source Documents 
• Source documents provide evidence for the existence of the patient 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 or entered in the eCRF 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 clinical study will be open for recruitment of 
patients and will be marked by the date that the first site is opened. 
The Sponsor designee reserves the right to close the study site or terminate the study at any time 
for any reason at the sole discretion of the Sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed. 

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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 the Sponsor 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, the Sponsor's procedures, or GCP guidelines 
• Inadequate recruitment of patients by the Investigator 
• Discontinuation of further study drug development 
• Withdrawal of the favorable opinion or the approval   
• Inability to adjust the required maximum sum of insurance 
If the study is prematurely terminated or suspended, the Sponsor 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. 
• The results of this study may be published or presented at scientific meetings. If this 
is foreseen, the Investigator agrees to submit all manuscripts or abstracts to the 
Sponsor before submission. This allows the Sponsor to protect proprietary 
information and to provide comments. 
• The Sponsor will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, the Sponsor will generally 
support publication of multicenter studies only in their entirety and not as individual 
site data. In this case, a coordinating Investigator will be designated by mutual 
agreement. 
• Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements. 
10.2. 
Appendix 2: Clinical Laboratory Tests 
• The tests detailed in Table 11 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. 

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• Protocol-specific requirements for inclusion or exclusion of patients 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 
pregnancy test. Additional pregnancy testing (urine or serum) should be performed 
per the time points specified in the SoA (Section 1.3). 
• Investigators must document their review of each laboratory safety report. 
Table 11: 
Clinical Laboratory Tests 
Chemistry Panel  
Sodium 
Potassium 
Chloride 
Bicarbonate 
Blood urea nitrogen 
Creatinine 
Glucose 
Alkaline phosphatase 
Alanine amino transferase (ALT)  
Aspartate amino transferase (AST)  
Total bilirubin 
Albumin 
Total protein 
Uric acid 
Calcium 
Magnesium 
HIV (1 and 2) testing 
Complete Blood Count (CBC) & Differential 
White blood cell count (WBC) 
White blood cell 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 
Others 
Human Chorionic Gonadotropin (β-HCG) 
Anti-Aquaporin 4 Antibody (AQP4-IgG Ab) 
Serum Pharmacokinetics (PK) and Serum Free 
 
Complement Factor 5 (Free C5) 
Anti-drug Antibody (ADA) 
FSH1 
1 To confirm postmenopausal status in selected female patients. 

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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 or clinical study 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  
• 
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 patient’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 patient’s condition. 
• 
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 (social and/or convenience 
admission to a hospital). 
• 
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. 
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 
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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. 
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 Common Terminology Criteria for 
Adverse Events (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) 

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• 
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 (unrelated): There is no causal association with study drug 
− 
Related: There is causal (temporal) association to the study drug. Other conditions 
(concurrent illness, concurrent medication reaction, or progression/expression of 
disease state) do not appear to explain the event; the event corresponds with the 
known pharmaceutical profile; improvement on discontinuation; 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 the Sponsor, based on the 
Reference Safety Document. The Investigator will also consult the Investigator’s Brochure (IB) 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 the Sponsor 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. 
• 
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. 

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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 electronic data 
capture (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: 
 or Fax: 
 
• 
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 Alexion GDS. 
 
Serious Adverse Event Reporting to Alexion via Paper Report Form 
• 
All SAEs will be recorded and reported to Alexion or designee immediately and within 24 hours of 
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: 
 or Fax: 
 
−  
• 
Additional follow-up information, if required or available, should be entered into the eCRF and sent 
to Sponsor 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 paper 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 
10.4.1.1. 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. 
10.4.1.2. 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 follicle-stimulating hormone level (> 30 IU/L) may be obtained by the 
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will be required. The reason for not obtaining an FSH should be documented by the Investigator 
at the time of screening. 
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: 
1. Hormonal contraception associated with inhibition of ovulation 
2. Intrauterine device 
3. Intrauterine hormone-releasing system 
4. Bilateral tubal occlusion 
5. Vasectomized partner provided that the partner is the patient’s sole sexual partner 
6. 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. 
Pregnancy Testing 
Patients of childbearing potential should only be included after a menstrual period and a negative 
highly sensitive serum pregnancy test. 
Additional pregnancy testing should be performed per the time points specified in the SoA 
(Section 1.3). 
Pregnancy testing will be performed whenever a menstrual cycle is missed or when pregnancy is 
otherwise suspected. 

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10.4.4. 
Collection of Pregnancy Information 
10.4.4.1. 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 the Sponsor 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 the 
Sponsor. Generally, the follow-up will be no longer than 6 to 8 weeks 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. 
10.4.4.2. 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 the 
Sponsor 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 the Sponsor. 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 the Sponsor as described in Section 8.4. While the Investigator is not 
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 the Sponsor 
notified regarding the outcome. 

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10.5. 
Appendix 5: Diagnostic Criteria for Neuromyelitis Optica Spectrum 
Disorder 
International Panel for NMO Diagnosis Diagnostic Criteria for NMOSD with AQP4-IgG 
(Wingerchuk, 2015): All 3 criteria must be met for a diagnosis of NMOSD in this study. 
1. At least 1 core clinical characteristic: 
a. Optic neuritis 
b. Acute myelitis 
c. Area postrema syndrome: episode of otherwise unexplained hiccups or nausea and 
vomiting 
d. Acute brainstem syndrome 
e. Symptomatic narcolepsy or acute diencephalic clinical syndrome with NMOSD 
typical diencephalic MRI lesions 
f. Symptomatic cerebral syndrome with NMOSD-typical brain lesions visualized on 
MRI 
2. Positive test for anti-AQP4 Ab using best available detection method (cell-based assay 
required in this study) 
3. Exclusion of alternative diagnosis 
 
 

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10.6. 
Appendix 6: Expanded Disability Status Scale (EDSS) 
The Neurostatus EDSS (using the Kurtzke neurologic evaluation) is a method of quantifying 
disability in Multiple Sclerosis (MS). The EDSS replaced the previous Disability Status Scales 
used in MS. 
The EDSS quantifies disability in 7 Functional Systems (FS) and allows neurologists to assign a 
Functional System Score (FSS) in each of these. The FS are: 
• pyramidal 
• cerebellar 
• brainstem 
• sensory 
• bowel and bladder 
• visual 
• cerebral 
EDSS steps 1.0 to 4.0 refer to people with MS who are fully ambulatory. EDSS steps 4.5 to 9.5 
are predominantly defined by the impairment to ambulation. 
Neurostatus Expanded Disability Status Scale 
0 
Normal neurological examination (all FS grade 0) 
1.0 No disability, minimal signs in one FS (one FS grade 1) 
1.5 No disability, minimal signs in more than one FS (more than one FS grade 1) 
2.0 Minimal disability in one FS (one FS grade 2, others 0 or 1) 
2.5 Minimal disability in two FS (two FS grade 2, others 0 or 1) 
3.0 Moderate disability in one FS (one FS grade 3, others 0 or 1) though fully ambulatory; or 
mild disability in three or four FS (three/four FS grade 2, others 0 or 1) though fully 
ambulatory 
3.5 Fully ambulatory but with moderate disability in one FS (one FS grade 3) and mild 
disability in one or two FS (one/two FS grade 2) and others 0 or 1; or fully ambulatory 
with two FS grade 3 (others 0 or 1); or fully ambulatory with five FS grade 2 (others 0 or 
1) 

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4.0 Ambulatory without aid or rest for ≥ 500 meters; up and about some 12 hours a day 
despite relatively severe disability consisting of one FS grade 4 (others 0 or 1) or 
combinations of lesser grades exceeding limits of previous steps 
4.5 Ambulatory without aid or rest for ≥ 300 meters; up and about much of the day, 
characterized by relatively severe disability usually consisting of one FS grade 4 and 
combination of lesser grades exceeding limits of previous steps 
5.0 Ambulatory without aid or rest for ≥ 200 meters (usual FS equivalents include at least one 
FS grade 5, or combinations of lesser grades usually exceeding specifications for step 4.5) 
5.5 Ambulatory without aid or rest for ≥ 100 meters 
6.0 Unilateral assistance (cane or crutch) required to walk at least 100 meters with or without 
resting 
6.5 Constant bilateral assistance (canes or crutches) required to walk at least 20 meters 
without resting 
7.0 Unable to walk 5 meters even with aid, essentially restricted to wheelchair; wheels self 
and transfers alone; up and about in wheelchair some 12 hours a day 
7.5 Unable to take more than a few steps; restricted to wheelchair; may need some help in 
transferring and in wheeling self 
8.0 Essentially restricted to bed or chair or perambulated in wheelchair, but out of bed most of 
day; retains many self-care functions; generally has effective use of arms 
8.5 Essentially restricted to bed much of the day; has some effective use of arm(s); retains 
some self-care functions 
9.0 Helpless bed patient; can communicate and eat 
9.5 Totally helpless bed patient; unable to communicate effectively or eat/swallow 
10.0 Death due to MS 
 

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10.7. 
Appendix 7: EuroQoL 5 Dimensions (EQ-5D-3L) 
 

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10.8. 
Appendix 8: Short Form Health Survey (SF-36) 

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Pr ot oc ol A me n d me nt  
 
Versi o n 2. 0  
A L X N 1 2 1 0 -N M O -3 0 7  
 
0 1 Se p 2 0 2 1  
Pa ge 1 0 7  of 1 2 6  
Ale xi o n C o nfi de ntial  
1 0. 9.  
A p pe n di x 9: H a user A m b ul ati o n I n de x ( H AI)  
� 0 = As y m pt o matic; f ull y acti ve.  
� 1 = Wal ks n or mall y, b ut re p orts fati g ue t hat i nterferes wit h at hletic or ot her de ma n di n g 
acti vities. 
� 2 = A b n or mal gait or e pis o dic i m bala nce; gait dis or der is n otice d b y fa mil y a n d frie n ds; a ble 
t o wal k 2 5 feet ( 8 meters) i n 1 0 sec o n ds or less. 
� 3 = Wal ks i n de pe n de ntl y; a ble t o wal k 2 5 feet i n 2 0 sec o n ds or less. 
� 4 = Re q uires u nilateral s u p p ort (ca ne or si n gle cr utc h) t o wal k; wal ks 2 5 feet i n 2 0 sec o n ds or 
less. 
� 5 = Re q uires bilateral s u p p ort (ca nes, cr utc hes, or wal ker) a n d wal ks 2 5 feet i n 2 0 sec o n ds or 
less; or re q uires u nilateral s u p p ort b ut nee ds m ore t ha n 2 0 sec o n ds t o wal k 2 5 feet. 
� 6 = Re q uires bilateral s u p p ort a n d m ore t ha n 2 0 sec o n ds t o wal k 2 5 feet; ma y use w heelc hair 1 
o n occasi o n. 
� 7 = Wal ki n g li mite d t o se veral ste ps wit h bilateral s u p p ort; u na ble t o wal k 2 5 feet; ma y use 
w heelc hair 1 f or m ost acti vities. 
� 8 = Restricte d t o w heelc hair; a ble t o tra nsfer self i n de pe n de ntl y.  
� 9 = Restricte d t o w heelc hair; u na ble t o tra nsfer self i n de pe n de ntl y.  
 
 
 
 
 
1T he use of a w heelc hair ma y be deter mi ne d b y lifest yle a n d m oti vati o n. It is e x pecte d t hat 
patie nts i n Gra de 7 will use a w heelc hair m ore fre q ue ntl y t ha n t h ose i n Gra des 5 or 6. 
Assi g n me nt of a gra de i n t he ra n ge of 5 t o 7, h o we ver, is deter mi ne d b y t he patie nt’s a bilit y t o 
wal k a gi ve n dista nce, a n d n ot b y t he e xte nt t o w hic h t he patie nt uses a w heelc hair.  
 
 

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10.10. 
Appendix 10: Optic Spinal Impairment Score (OSIS) 
Visual Acuity (VA) 
0 
Normal 
1 
Scotoma but VA (corrected) better than 20/30 
2 
VA 20/30 - 20/59 
3 
VA 20/60 - 20/100 
4  
VA 20/ 101 - 20/200 
5 
VA 20/201 - 20/800 
6  
Count fingers only 
7  
Light perception only 
8 
No light perception 
Motor Function 
0 
Normal 
1 
Abnormal signs (hyperreflexia, Babinski sign) without weakness 
2 
Mild weakness (Medical Research Council [MRC] grade 5- or 4+) in affected limb(s) 
3 
Moderate weakness (grade 3 or 4) in 1 or 2 upper motor neuron (UMN) muscles in 
affected limb(s) 
4 
Moderate weakness (grade 3 or 4) in 3 UMN muscles in affected limb(s) 
5 
Severe weakness (grade 2) in 1 or more muscles in affected limb(s) 
6 
Some plegic (grade 0 or 1) muscles in 1 or more limbs 
7 
Plegia (grade 0 or 1) of all muscles in 1 or more limbs 
Sensory Function 
0 
Normal 
1 
Mild decrease in vibration 
2 
Mild decrease in pinprick/temperature/proprioception or moderate decrease in vibration 
3 
Moderate decrease in touch/pin/proprioception or essentially lost vibration sense 
4 
Loss of all sensory modalities 
5 
Unknown 
Sphincter Function 
0  
Normal 
1 
Mild urinary urgency or hesitancy; constipation 
2 
Moderate urinary urgency, hesitancy, or retention of bladder or bowel, infrequent urinary 
incontinence (less than once/week) 
3 
Frequent incontinence or retention requiring intermittent bladder catheterization or 
aggressive (manual) bowel assistance 
4 
Indwelling urinary catheter or absence of sphincter control 
5 
Unknown 
 
 

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10.11. 
Appendix 11: Relapse Severity  
Table 12: 
Relapse Severity as Measured by Optic Spinal Impairment Scale 
Optic Neuritis 
Visual Acuity Subscale Score (taken from the eye with the 
largest change at the time of the event) 
Relapse Descriptor 
Pre-Relapse 
Post-Relapse 
0-1 
0-2 
Minor 
0-1 
3+ 
Major 
2-7 
Increase by 1 point 
Minor 
2-7 
Increase by ≥ 2 points 
Major 
Transverse Myelitis 
Motor Subscale Score 
Relapse Descriptor 
Pre-Relapse 
Post-Relapse 
0-1 
0-2 
Minor 
0-1 
3+ 
Major 
2-6 
Increase by 1 point 
Minor 
2-6 
Increase by ≥ 2 points 
Major 
Sensory Subscale Score 
Relapse Descriptor 
Based on proprioceptive loss only 
If severe loss in ≥ 1 or more limbs 
with prior normal function or with 
mild proprioceptive loss 
Major 
 
 

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10.12. 
Appendix 12: Columbia Suicide Severity Rating Scale  
(C-SSRS)-Screening/Baseline 
 

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10.13. 
Appendix 13: Columbia-Suicide Severity Rating Scale 
(C-SSRS)-Since Last Visit 
 

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10.14. 
Appendix 14: 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 13, 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 13: 
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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10.15. 
Appendix 15: Identification of Cases of Interest 
A Case of Interest is an event judged by the Treating Physician to not be an On-trial Relapse 
(ie, it is not an Investigator confirmed On-trial Relapse), but which meets the following criteria 
to be considered a Case of Interest and submitted to the RAC for adjudication: 
• Patients who were seen by the Treating Physician for a 24- to 48-hour relapse 
evaluation visit and where the Treating Physician concluded that an On-trial Relapse 
did not occur, OR 
• A sentinel AE (eg, AEs of: weakness, sensory changes, especially in a dermatomal 
distribution, characteristic visual changes of NMOSD, or pseudo exacerbation of 
NMOSD) AND either: 
o An MRI was performed contemporaneously OR 
o Neurologic symptoms were treated (by hospitalization or IVMP) OR 
o Contemporaneous objective worsening of the Treating Physician’s Neurologic 
Examination (defined by answer of “worse” to clinically meaningful change 
question). 
Cases of Interest involving a patient seen for a potential relapse where the Treating Physician 
concluded that an On-trial Relapse did not occur will be identified in real-time as they occur 
throughout the study. 
Additionally, periodically throughout the study, searching for sentinel AEs associated with 
neurologic changes on the Treating Physician’s Neurologic Examination, MRI, and/or treatment 
with hospitalization or IVMP will be done. This process will occur mid study, at 25% 
completion, 75% completion, and the end of the study. A meeting to review potential cases will 
be held and attended by at least one representative for Medical, Biostatistics, and Clinical 
Operations with optional attendance from Data Management. Events reviewed in this meeting 
that do not meet the definition of a Case of Interest will be recorded along with a brief 
description of the reason they do not meet the criteria for a Case of Interest. 
Case of Interest Sentinel AE term identification 
Review of the AE term list to identify sentinel events will be done at least 4 times during the 
study. This list will be updated based on a review of SAEs, MRI indications, neurologic 
examination changes and treatments associated with AEs. At the time the study is 80% complete 
a final review will be conducted to update terms and to search AEs again to identify all sentinel 
AEs in the search term list. 
The following AE terms are examples of ones to be flagged as sentinel AEs and used to identify 
Cases of Interest. 
The final list of AE terms will be maintained by Biostatistics in the SAS environment. 
 
 

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Table 14 
List of Example AE Terms to be Flagged as Sentinel AEs and Used to 
Identify Cases of Interest 
Abdominal discomfort 
Hemiparaesthesia 
Neuralgia 
Abdominal pain 
Hiccups 
Neuromyelitis optica spectrum disorder 
Abdominal pain lower 
Hyperaesthesia 
Optic neuritis 
Abdominal pain upper 
Hypersensitivity 
Pain 
Ataxia 
Hypoaesthesia 
Pain in extremity 
Back pain 
Hypoaesthesia oral 
Paraesthesia 
Bladder disorder 
Micturition disorder 
Photophobia 
Burning sensation 
Micturition urgency 
Pruritus 
Chest pain 
Muscle contractions involuntary 
Pruritus generalised 
Constipation 
Muscle contracture 
Sensory disturbance 
Dysaesthesia 
Muscle spasms 
Skin burning sensation 
Dysphonia 
Muscle spasticity 
Spinal pain 
Dysuria 
Muscle tightness 
Tinnitus 
Eructation 
Muscular weakness 
Uhthoff's phenomenon 
Eye pain 
Musculoskeletal discomfort 
Urinary retention 
Fall 
Musculoskeletal pain 
Urinary tract disorder 
Flank pain 
Musculoskeletal stiffness 
Vision blurred 
Gait disturbance 
Myalgia 
Visual acuity reduced 
Groin pain 
Nausea/Vomiting 
Visual impairment 
Hemianopia 
Neck pain 
  
 
 

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10.16. 
Appendix 16: Remote Source Data Verification During COVID-19 
Pandemic 
To ensure the rights, safety, and well-being of study patients, as well as the integrity of the trial 
and its data during the COVID-19 pandemic, when onsite study monitoring activities are 
restricted, remote source data verification (rSDV) may be employed wherever permitted by local 
regulations. 
Study ALXN1210-NMO-307 is a Phase 3, pivotal study in patients with NMOSD, a rare and 
devastating neurological disease. Alexion has assessed that the inability to complete ongoing 
SDV could pose a risk to the robustness of the study data. Delaying ongoing verification of key 
efficacy (primary and secondary) endpoints and important safety endpoints could result in late 
identification of incorrect or missing data, which could impact the integrity of the study data.  
Remote SDV will be carried out in written agreement with the Investigator and, if applicable, the 
institution, under conditions ensuring adequate data protection and patients’ rights. Depending 
on local regulation and agreement with the site Investigator and institution preference, rSDV 
may be conducted through direct and controlled read-only monitor access to institution electronic 
medical records systems, passive access to source documents via live image transmission, and/or 
sharing of redacted copies of source documents via a secure, validated, and access-restricted 
system. Regarding the electronic sharing of redacted copies of source documents, the following 
requirements must be followed:  
• Scanned or electronic documents to be uploaded (as PDF, jpeg, or other image 
format) that are of sufficient resolution to ensure readability, in black and white or 
color. 
• To ensure completeness of the shared content, the monitor will prepare a written 
request to the investigative site listing the source data needed to conduct rSDV and 
will perform a quality check on the list of documents shared by the site against the list 
of requested source data. 
• Site staff must perform a quality check ensuring source documents are redacted 
before making them available to monitors. A data breach management policy and a 
security team will be in place to identify violations and to ensure correct and timely 
action. 
• To prevent loss of or unauthorized access to source data, investigative site personnel 
will need to actively grant access to their specific monitor. The monitor will only 
have viewing rights, thereby preventing loss, alteration, or download of source data. 
• Traceability of pseudonymized documents reviewed remotely will be kept by the 
monitor for verification onsite. 
The detailed scope of rSDV will be outlined in supporting study plans (eg, Clinical Monitoring 
Plan). Conduct of rSDV will only be performed during the COVID-19 pandemic. 

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The following data will require rSDV to ensure oversight of patients’ safety and integrity of the 
trial data. 
Data 
Assessments 
Safety 
Eligibility assessments, investigational product exposure, adverse events, 
concomitant medications and non-drug therapies, laboratory assessments, 
ECGs, vital signs, C-SSRS 
Efficacy Endpoints 
EDSS, OSIS, HAI, EQ-5D, SF-36, ophthalmologic examination, neurologic 
examination, On-trial Relapse evaluation  
 
 
 

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10.17. 
Appendix 17: COVID-19 Risk Assessment 
Neuromyelitis optica spectrum disorder 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 joining an investigational study with a therapeutic treatment is 
potentially significant. The fact that Study ALXN1210-NMO-307 is open-label and every patient 
is treated with ravulizumab also contributes to the potential benefit a patient may derive from 
participating in the study. Given that treatment for NMOSD does involve immunosuppression, 
there is a theoretical concern that the risk for infection may be higher than in patients not 
receiving immunosuppressants. However, there is no specific data to further inform this risk. The 
site Investigator will therefore balance the risk/benefit considerations in the study 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 15. 
Table 15: 
Potential Risks and Mitigation Measures due to COVID-19 
Risks Category 
Summary of Data/ 
Rationale for Risk 
Mitigation Strategy 
Potential risks 
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 patients at 
sites unless the sites have the 
resourcing and capabilities to 
implement the study per 
protocol. 

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Table 15: 
Potential Risks and Mitigation Measures due to COVID-19 
Risks Category 
Summary of Data/ 
Rationale for Risk 
Mitigation Strategy 
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 patient 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, site 
capacity will be reviewed by the 
site Investigator and the study 
Medical Monitor 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 is missing (eg, missed 
study visits or patient study 
discontinuations due to 
COVID-19). 
Abbreviations: COVID-19 = coronavirus disease 2019; eCRF = electronic case report form 
 
 
 
 

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10.18. 
Appendix 18: Protocol Amendment History 
The protocol amendment summary of changes table for the current amendment is located 
directly before the Table of Contents. 
DOCUMENT HISTORY 
Document 
Summary of Key Changes 
Amendment 1.2 
(United Kingdom)  
07 Jun 2021 
The purpose of this country-specific amendment was to include coronavirus disease 2019 (COVID-19) 
risk assessment and COVID-19 vaccine risk assessment language in the appendices. 
Amendment 1.1 
(Germany)  
28 Apr 2021 
The purpose of this country-specific amendment was to update the safety criteria for study 
termination, and to include language for remote source data verification during the COVID-19 
pandemic, to comply with German regulation. 
Amendment 1.0 
(Global) 
06 Jul 2020 
The main purpose of this amendment was to provide updated criteria and an updated definition for the 
End of Primary Treatment (EOPT) Period, to establish the modified Full Analysis Set as the primary 
analysis set for efficacy endpoints, to add biweekly phone visits, to provide guidance on regional 
enrollment limits, and to provide further instruction on off-site visits, infusion reactions, and minor 
updates on the statistical analysis and operational aspects of the protocol.  
Original Protocol 
(Global)  
12 Aug 2019 
Not applicable 
 
 
 

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10.19. 
Appendix 19: Abbreviations 
Abbreviation 
Definition 
Ab 
antibody 
ADA 
antidrug antibody 
AE 
adverse event 
AESI 
adverse event of special interest 
aHUS 
atypical hemolytic uremic syndrome 
ANCOVA 
analysis of covariance 
AQP4 
aquaporin-4 
ARR 
annualized relapse rate 
AZA 
azathioprine 
B 
baseline (sample) 
BP 
blood pressure 
C5 
complement component 5 
CFR 
Code of Federal Regulations 
CI 
Confidence interval 
CIOMS 
Council for International Organizations of Medical Sciences 
COVID-19 
Coronavirus Disease 2019 
CNS 
central nervous system 
CRF 
case report form 
CSF 
cerebrospinal fluid 
C-SSRS 
Columbia-suicide severity rating scale 
CTCAE 
Common Terminology Criteria for Adverse Events 
D 
day 
DMC 
Data Monitoring Committee 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
ED 
early discontinuation 
EDC 
electronic data capture 
EDSS 
expanded disability status scale 
EOPT 
End of Primary Treatment  
EOS 
End of Study 
EOT 
End of Treatment 
EQ-5D 
European Quality of Life Health 5-item questionnaire 
EQ VAS 
European Quality of Life Visual Analog Scale 
EuroQoL 
European Quality of Life 
FAS 
full analysis set 
FDA 
Food and Drug Administration 
FS 
functional system 
FSS 
functional system scores 

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Abbreviation 
Definition 
FU 
Follow-up 
GCP 
Good Clinical Practice 
gMG 
generalized myasthenia gravis 
HAI 
Hauser Ambulation Index 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
human immunodeficiency virus 
HRT 
hormonal replacement therapy 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IgG 
immunoglobulin G 
IL-6 
interleukin 6  
IMP 
Investigational medicinal product 
IPND 
International Panel for NMO Diagnosis 
IRB 
Institutional Review Board 
IST 
immunosuppressive therapy 
IV 
intravenous 
IVIg 
intravenous immunoglobulin 
IVMP 
intravenous methylprednisolone 
L 
low 
MAA 
marketing authorization application 
mAb 
monoclonal antibody 
MCV 
mean corpuscular volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMF 
mycophenolate mofetil 
MRC 
Medical Research Council 
MRI 
magnetic resonance imaging 
MS 
multiple sclerosis 
MTX 
methotrexate 
N 
normal 
NA 
not applicable 
NfL 
neurofilament light chain  
NMO 
neuromyelitis optica 
NMOSD 
neuromyelitis optica spectrum disorder 
OCT 
Optical Coherence Tomography 
ON 
optic neuritis 
OSIS 
Optic Spinal Impairment Score 
P 
postdose (sample) 
PD 
pharmacodynamic(s) 
PE 
plasma exchange 

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Abbreviation 
Definition 
PI 
Principal Investigator 
PK 
pharmacokinetic(s) 
PKPDAS 
Pharmacokinetic and Pharmacodynamic Analysis Set 
PNH 
paroxysmal nocturnal hemoglobinuria 
PP 
plasmapheresis 
PT 
primary treatment 
q2w 
every two weeks 
q8w 
every eight weeks 
QoL 
quality of life 
QT 
interval between the start of the Q wave and the end of the T wave in an ECG 
QTc 
corrected QT interval 
RAC 
Relapse Adjudication Committee 
RBC 
red blood cell 
RD 
relapse day 
RNA 
ribonucleic acid 
RR 
respiratory rate 
rSDV 
remote source data verification 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SF 
short form health survey 
SoA 
schedule of activities 
SOC 
System Organ Class 
SUSAR 
suspected unexpected serious adverse reactions 
T 
Trough 
TAC 
tacrolimus 
TEAE 
treatment-emergent adverse event 
TESAE 
treatment-emergent serious adverse event 
TM 
transverse myelitis 
UMN 
upper motor neuron 
USPI 
United States Prescribing Information 
VA 
visual acuity 
VAS 
visual analogue scale 
VF 
Visual Fields 
W 
week(s) 
WBC 
white blood cell 
WHODrug 
World Health Organization Drug Dictionary 
WOCBP 
woman of childbearing potential 
 
 

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