A Phase 2/3 Open-Label, Single-Arm Trial to Evaluate the Safety and Activity of Eculizumab in Pediatric Patients With Relapsing Neuromyelitis Optica Spectrum Disorder
Phase: PHASE2
Conditions: Neuromyelitis Optica, Neuromyelitis Optica Spectrum Disorder
Sponsor: Alexion Pharmaceuticals, Inc.

Protocol Amendment 2.2 
ECU-NMO-303 
TITLE PAGE 
Protocol Title: 
A Phase 2/3 Open-Label, Single-Arm Trial to Evaluate the Safety 
and Activity of Eculizumab in Pediatric Patients with Relapsing 
Neuromyelitis Optica Spectrum Disorder 
Protocol Number: 
ECU-NMO-303 
Amendment Number 
2.2 (Italy) 
Compound: 
Eculizumab 
Short Title: 
A Phase 2/3 Open-Label Safety and Activity Study of 
Eculizumab in Pediatric Patients with Relapsing Neuromyelitis 
Optica Spectrum Disorder 
Sponsor Name 
Alexion Pharmaceuticals, Inc. (Alexion) 
Legal Registered 
Address: 
121 Seaport Boulevard 
Boston, MA 02210, USA 
Regulatory Agency 
Identifying Number: 
IND Number: 116,207 
EudraCT 
2019-001829-26 
Approval Date: 
03 May 2021 
Page 1 of 117 
Alexion Confidential 
NCT : NCT04155424

Protocol Amendment 2.2
ECU-NMO-303
SPONSOR SIGNATORY
Alexion Pharmaceuticals, Inc. 
Date
Medical Monitor Name and Contact Information
121 Seaport Boulevard
Boston, MA 02210 USA
mobile 
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Protocol Amendment 2.2 
ECU-NMO-303 
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE 
DOCUMENT HISTORY 
Document 
Date 
Amendment 2.2 (Italy) 
03 May 2021 
Amendment 2.1 (Germany) 
03 May 2021 
Amendment 2 
03 May 2021 
Amendment 1.4 (Germany) 
31 Aug 2020 
Amendment 1.3 (Italy) 
03 Jun 2020 
Amendment 1.2 (Italy) 
27 Apr 2020 
Amendment 1.1 (Germany) 
02 Apr 2020 
Amendment 1 
08 Jul 2019 
Original Protocol 
18 Apr 2019 
Amendment 2.2 (Italy) 03 May 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 due to 
the following key changes that are being implemented: 
•
20% reduction in the number of patients to be enrolled in the study
•
Addition of a washout period for immunosuppressive therapies to avoid confounding
factors for efficacy assessment
•
Revision of exclusion criteria related to active infections and current treatment with a
biologic medication that may affect immune system functioning to enhance patient
safety
Overall Rationale for the Amendment: 
Protocol update necessitated from regulatory submission and update to planned number of 
patients. Local amendment was aligned with global amendment where possible. 
Section # and Name 
Description of Change 
Brief Rationale 
Throughout the protocol 
Updated amendment number and 
approval date. 
Administrative change. 
Section 1.1 Synopsis, 
Section 4.1.1 Overall 
Design/Methodology, 
Section 9.2 Sample Size 
Determination 
Reduced of the number of patients 
enrolled from 15 to 12, and 
reduced the number of evaluable 
patients for the primary analysis 
from 12 to 10. 
Based on updated sample size calculations, 
total sample size was decreased for the study. 
Section 1.1 Synopsis, 
Section 1.2 Schedule of 
Activities (Table 9), 
Section 4.1.5 Safety 
Follow-up Period 
(8 Weeks Following the 
Last Dose of 
Eculizumab) 
Removed the term “commercially 
available” with regard to 
eculizumab. 
Patients may transition to eculizumab through 
other noncommercial programs; therefore, the 
language was broadened. 
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Protocol Amendment 2.2 
ECU-NMO-303 
Section # and Name 
Description of Change 
Brief Rationale 
Section 1.1 Synopsis 
(Table 1), Section 4.1.3 
Primary Treatment 
Period, Section 4.1.4 
Extension Treatment 
Period, Section 6.1 
(Table 13) 
Table 1 and Table 13 footnotes: 
For study drug infusions given 
remotely, the patient’s body weight 
from the prior study visit may be 
used to calculate the dose. 
To allow use of the most currently recorded 
body weight at remote or home visits. 
Section 1.2 Schedule of 
Activities (Table 9), 
Section 8.3.6 Vaccine 
and Antibiotic 
Prophylaxis 
Added text to clarify that 
vaccination will be per local and 
country-specific immunization 
guidelines for appropriate age 
groups. 
Clarification. 
Section 2.4.2.3 
Coronavirus Disease 
2019, Section 10.15 
COVID-19 Risk 
Assessment 
The benefit-risk assessment related 
to coronavirus disease 2019 
(COVID-19) was added. 
To provide a clear assessment of the specific 
risks created by the COVID-19 pandemic as 
well as mitigation strategies. 
Section 4.1.1 Overall 
Design/Methodology 
Added study design schematic. 
To enhance clarity. 
Section 4.1.2 Screening 
Period (1 – 6 weeks) 
Text on vaccination requirements 
for screened patients was removed. 
To clarify that vaccination can occur at any 
point during the Screening Period. 
Section 5.1 Inclusion 
Criteria, Section 6.6.1.2 
Immunosuppressive 
Therapy 
Text was added to specify that 
supportive immunosuppressive 
therapies (ISTs) must remain stable 
during the Screening Period. 
To clarify that ISTs cannot be changed during 
the Screening Period. 
Section 5.1 Inclusion 
Criteria 
A washout period for ISTs was 
added. 
To minimize any effects of recently 
discontinued ISTs on study patients. 
Section 5.2 Exclusion 
Criteria  
Criterion 5: Text was revised to 
clarify that a potential patient with 
active bacterial, viral, or fungal 
infection within 14 days prior to 
study drug administration would be 
excluded. 
Created a separate criterion (9) to 
exclude patients currently treated 
with a biologic medication that 
may affect immune system 
functioning. 
To enhance patient safety in the study, by 
confirming that no patient with an active 
infection will start treatment with eculizumab. 
To clarify exclusion criteria for prior use of 
biologic medications that may affect immune 
system functioning. 
Section 6.6.1.3 
Treatment of On-Trial 
Relapse 
Clarified that the treatment 
regimen for On-Trial Relapse 
would be determined by the 
Investigator. 
To enhance clarity. 
Section 6.6.2 
Disallowed Medications 
and Therapies 
Specified that biologic medications 
that may affect immune system 
functioning are not allowed. 
To clarify that biologic medications that may 
affect immune system functioning are not 
allowed during the study. 
Section 6.8 Intervention 
After the End of the 
Study 
Removed this section. 
Section not applicable, as no intervention will 
be performed after the end of the study. 
Section 8.1 Efficacy 
Assessments 
Corrected the name of the Pediatric 
Quality of Life Inventory 
assessment tool. 
Administrative. 
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Protocol Amendment 2.2 
ECU-NMO-303 
Section # and Name 
Description of Change 
Brief Rationale 
Section 8.1.4 Expanded 
Disability Status Scale, 
Section 10.9 Appendix 9 
Expanded Disability 
Status Scale 
Updated the Expanded Disability 
Status Scale (EDSS) used in this 
study from the Kurtzke EDSS to 
the Neurostatus EDSS. 
Administrative update to correctly describe the 
version of the EDSS evaluation already being 
used in the study. 
Section 9.2 Sample Size 
Determination 
Updated sample size calculation 
based on data available from 
Study ECU-NMO-301. 
Updated total sample size as data from 
Study ECU-NMO-301 became available. 
Section 9.3 Populations 
for Analyses 
Revised the description of the 
PK/PD analysis set to specify 
inclusion of all patients who 
receive at least 1 dose of 
eculizumab and have PK/PD 
assessments. 
Clarification. 
Section 9.4.5.2. 
Secondary Efficacy 
Analysis 
Hauser Ambulation Index (HAI) 
added for continuous secondary 
efficacy endpoints. 
To clarify the continuous secondary efficacy 
endpoints included in the secondary efficacy 
analyses. 
Section 10.4.2 
Contraception Guidance 
Text was revised to define women 
of childbearing potential 
(WOCBP) and to state that 
WOCBP must be on hormonal 
contraception at least 6 weeks prior 
to Day 1. 
In order to clearly state the time a patient must 
be on oral contraception prior to starting study 
drug. 
Throughout the protocol 
Minor grammatical/editorial 
changes, including key 
abbreviations. 
To enhance clarity. 
Abbreviations: CTCAE = Common Terminology Criteria for Adverse Events; ECG = electrocardiogram; 
PD = pharmacodynamic(s); PK = pharmacokinetic(s) 
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Protocol Amendment 2.2 
ECU-NMO-303 
INVESTIGATOR’S AGREEMENT 
I have read the ECU-NMO-303 (Amendment 2.2) 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 2.2 
ECU-NMO-303 
TABLE OF CONTENTS 
TITLE PAGE ...................................................................................................................................1 
SPONSOR SIGNATORY ...............................................................................................................2 
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE ............................................3 
INVESTIGATOR’S AGREEMENT ...............................................................................................6 
TABLE OF CONTENTS .................................................................................................................7 
LIST OF TABLES .........................................................................................................................12 
LIST OF FIGURES .......................................................................................................................13 
1.
PROTOCOL SUMMARY ..........................................................................................14 
1.1. 
Synopsis ......................................................................................................................14 
1.2. 
Schedule of Activities .................................................................................................19 
2.
INTRODUCTION ......................................................................................................35 
2.1. 
Study Rationale ...........................................................................................................35 
2.2. 
Eculizumab in Patients with Neuromyelitis Optica Spectrum Disorder ....................35 
2.3. 
Background .................................................................................................................36 
2.3.1. 
Clinical Presentation of Neuromyelitis Optica Spectrum Disorder ............................36 
2.3.2. 
Unmet Medical Need ..................................................................................................36 
2.3.3. 
Role of Complement in Neuromyelitis Optica Spectrum Disorder ............................37 
2.4. 
Benefit/Risk Assessment ............................................................................................37 
2.4.1. 
Potential Benefits ........................................................................................................37 
2.4.2. 
Identified and Potential Risks .....................................................................................37 
2.4.2.1. 
Meningococcal Infection and Other Encapsulated Bacterial Infections .....................37 
2.4.2.2. 
Immunogenicity ..........................................................................................................37 
2.4.2.3. 
Coronavirus Disease 2019 ..........................................................................................37 
3.
OBJECTIVES AND ENDPOINTS ............................................................................39 
4.
STUDY DESIGN .......................................................................................................41 
4.1. 
Overall Design ............................................................................................................41 
4.1.1. 
Overall Design/Methodology .....................................................................................41 
4.1.2. 
Screening Period (1 – 6 weeks) ..................................................................................41 
4.1.3. 
Primary Treatment Period (Day 1 – Week 52/53) ......................................................42 
4.1.4. 
Extension Treatment Period (104 weeks) ...................................................................42 
4.1.5. 
Safety Follow-up Period (8 Weeks Following the Last Dose of Eculizumab) ...........43 
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Protocol Amendment 2.2 
ECU-NMO-303 
4.2. 
Methodology of Relapse Evaluation ..........................................................................43 
4.2.1. 
Historical Relapse .......................................................................................................43 
4.2.2. 
On-Trial Relapse .........................................................................................................43 
4.2.3. 
Severity of Relapse .....................................................................................................43 
4.2.4. 
Investigator .................................................................................................................44 
4.2.5. 
The Expanded Disability Status Scale Rater ..............................................................44 
4.2.6. 
Review of Investigator-Reported On-Trial Relapses .................................................45 
4.3. 
Scientific Rationale for Study Design ........................................................................45 
4.4. 
Justification for Dose ..................................................................................................46 
4.5. 
End of Study Definition ..............................................................................................47 
5.
STUDY POPULATION .............................................................................................48 
5.1. 
Inclusion Criteria ........................................................................................................48 
5.2. 
Exclusion Criteria .......................................................................................................49 
5.3. 
Screen Failures ............................................................................................................50 
6.
STUDY DRUG ...........................................................................................................51 
6.1. 
Study Drug Administered ...........................................................................................51 
6.2. 
Supplemental Doses ....................................................................................................52 
6.3. 
Preparation/Handling/Storage/Accountability ............................................................52 
6.3.1. 
Study Drug Storage .....................................................................................................52 
6.3.2. 
Study Drug Preparation ..............................................................................................53 
6.3.3. 
Study Drug Administration .........................................................................................53 
6.3.4. 
Study Drug Accountability .........................................................................................54 
6.3.5. 
Study Drug Handling and Disposal ............................................................................55 
6.4. 
Measures to Minimize Bias ........................................................................................55 
6.5. 
Study Intervention Compliance ..................................................................................55 
6.6. 
Concomitant Therapy .................................................................................................55 
6.6.1. 
Allowed Medication ...................................................................................................56 
6.6.1.1. 
Palliative and Supportive Care ...................................................................................56 
6.6.1.2. 
Immunosuppressive Therapy ......................................................................................56 
6.6.1.3. 
Treatment of On-Trial Relapse ...................................................................................57 
6.6.2. 
Disallowed Medications and Therapies ......................................................................57 
6.7. 
Dose Modification ......................................................................................................57 
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Protocol Amendment 2.2 
ECU-NMO-303 
7.
DISCONTINUATION OF STUDY INTERVENTION AND
PARTICIPANT DISCONTINUATION/WITHDRAWAL .......................................58 
7.1. 
Discontinuation of Study Intervention ........................................................................58 
7.2. 
Lost to Follow Up .......................................................................................................58 
8.
STUDY ASSESSMENTS AND PROCEDURES ......................................................60 
8.1. 
Efficacy Assessments .................................................................................................60 
8.1.1. 
Annualized Relapse Rate ............................................................................................60 
8.1.2. 
Time to First Relapse ..................................................................................................60 
8.1.3. 
Neurologic Examination .............................................................................................60 
8.1.4. 
Expanded Disability Status Scale ...............................................................................60 
8.1.5. 
Hauser Ambulation Index ...........................................................................................61 
8.1.6. 
Visual Acuity ..............................................................................................................61 
8.1.7. 
Ophthalmologic Examination .....................................................................................62 
8.1.7.1. 
Confrontational Visual Fields .....................................................................................62 
8.1.7.2. 
Color Vision ................................................................................................................62 
8.1.8. 
Investigator-Reported On-Trial Relapse .....................................................................62 
8.1.9. 
Optic Spinal Impairment Score ..................................................................................63 
8.1.10. 
Pediatric Quality of Life Inventory .............................................................................63 
8.1.11. 
Euro Quality of Life-5 Dimensions-Youth .................................................................63 
8.2. 
Safety Assessments .....................................................................................................64 
8.2.1. 
Physical Examination .................................................................................................64 
8.2.2. 
Vital Signs ..................................................................................................................64 
8.2.3. 
Electrocardiograms .....................................................................................................64 
8.2.4. 
Clinical Safety Laboratory Assessments ....................................................................64 
8.3. 
Adverse Events and Serious Adverse Events .............................................................65 
8.3.1. 
Time Period and Frequency for Collecting Adverse Events and Serious 
Adverse Events Information .......................................................................................65 
8.3.2. 
Method of Detecting Adverse Events and Serious Adverse Events ...........................65 
8.3.3. 
Follow-up of Adverse Events and Serious Adverse Events .......................................66 
8.3.4. 
Regulatory Reporting Requirements for Serious Adverse Events .............................66 
8.3.5. 
Pregnancy ...................................................................................................................66 
8.3.6. 
Vaccine and Antibiotic Prophylaxis ...........................................................................66 
8.4. 
Pharmacokinetics ........................................................................................................67 
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Protocol Amendment 2.2 
ECU-NMO-303 
8.5. 
Pharmacodynamics .....................................................................................................68 
8.6. 
Genetics ......................................................................................................................68 
8.7. 
Biomarkers ..................................................................................................................68 
8.7.1. 
Exploratory biomarkers ..............................................................................................68 
8.8. 
Healthcare Resource Utilization and Health Economics ............................................68 
8.9. 
Blood Sample Volumes ..............................................................................................69 
9.
STATISTICAL CONSIDERATIONS .......................................................................70 
9.1. 
Statistical Hypotheses .................................................................................................70 
9.1.1. 
Primary Hypothesis ....................................................................................................70 
9.2. 
Sample Size Determination ........................................................................................70 
9.3. 
Populations for Analyses ............................................................................................70 
9.4. 
Statistical Analyses .....................................................................................................70 
9.4.1. 
Demographics and Baseline Characteristics ...............................................................71 
9.4.2. 
Patient Disposition ......................................................................................................71 
9.4.3. 
Medical/Surgical History and Neuromyelitis Optica Spectrum Disorder 
History ........................................................................................................................71 
9.4.4. 
Prior and Concomitant Medications ...........................................................................71 
9.4.5. 
Efficacy Analyses .......................................................................................................71 
9.4.5.1. 
Primary Efficacy Analysis ..........................................................................................72 
9.4.5.2. 
Secondary Efficacy Analysis ......................................................................................72 
9.4.5.3. 
Tertiary Efficacy Analysis ..........................................................................................73 
9.4.6. 
Safety Analyses ..........................................................................................................73 
9.4.6.1. 
Analysis of Adverse Events ........................................................................................73 
9.4.6.2. 
Analysis of Clinical Laboratory Parameters, Vital Sign Measurements, and 
Electrocardiogram Parameters ....................................................................................73 
9.4.6.3. 
Other Safety Analyses ................................................................................................74 
9.4.7. 
Pharmacokinetics/Pharmacodynamics .......................................................................74 
9.5. 
Interim Analyses .........................................................................................................74 
9.5.1. 
Data Monitoring and Relapse Adjudication Committees ...........................................74 
10.
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS ..................................................................................................76 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations ....................76 
10.1.1. 
Regulatory and Ethical Considerations ......................................................................76 
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Protocol Amendment 2.2 
ECU-NMO-303 
10.1.2. 
Informed Consent Process ..........................................................................................76 
10.1.3. 
Data Protection ...........................................................................................................77 
10.1.4. 
Dissemination of Clinical Study Data ........................................................................77 
10.1.5. 
Data Quality Assurance ..............................................................................................77 
10.1.6. 
Source Documents ......................................................................................................78 
10.1.7. 
Study and Site Closure ................................................................................................78 
10.1.8. 
Publication Policy .......................................................................................................79 
10.2. 
Appendix 2: Clinical Laboratory Tests .......................................................................80 
10.3. 
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting ........................................................................81 
10.3.1. 
Adverse Event .............................................................................................................81 
10.3.2. 
Serious Adverse Event ................................................................................................81 
10.3.3. 
Suspected Unexpected Serious Adverse Reactions ....................................................82 
10.3.4. 
Recording and Follow-Up of Adverse Event and/or Serious Adverse Event ............82 
10.3.5. 
Reporting of Serious Adverse Events .........................................................................84 
10.4. 
Appendix 4: Contraceptive Guidance and Collection of Pregnancy 
Information .................................................................................................................85 
10.4.1. 
Definitions ..................................................................................................................85 
10.4.2. 
Contraception Guidance .............................................................................................85 
10.4.3. 
Pregnancy Testing ......................................................................................................86 
10.4.4. 
Collection and Reporting of Pregnancy Information ..................................................86 
10.5. 
Appendix 5: Standard Protocol Definitions ................................................................88 
10.6. 
Appendix 6: 2015 International Panel for NMO Diagnosis Diagnostic 
Criteria for Neuromyelitis Optica Spectrum Disorder ................................................89 
10.7. 
Appendix 7: Euro Quality of Life 5 Dimensions-Youth ............................................90 
10.8. 
Appendix 8: Euro Quality of Life 5 Dimensions-Youth (Proxy) ...............................93 
10.9. 
Appendix 9: Expanded Disability Status Scale ..........................................................96 
10.10. 
Appendix 10: Hauser Ambulatory Index ....................................................................98 
10.11. 
Appendix 11: Pediatric Quality of Life Inventory ......................................................99 
10.11.1. 
Pediatric Quality of Life Inventory Child Form (Age 5 to 7-year-old) ......................99 
10.11.2. 
Pediatric Quality of Life Inventory Child Form (Age 8 to 12 year-old) ..................102 
10.11.3. 
Pediatric Quality of Life Inventory Child Form (Age 13 to 18 year-old) ................104 
10.11.4. 
Pediatric Quality of Life Inventory Parent Proxy Form (For Patients Aged 
≥ 2 to < 5 years-old) ..................................................................................................106 
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Protocol Amendment 2.2 
ECU-NMO-303 
10.12. 
Appendix 12: Optic Spinal Impairment Score ..........................................................108 
10.13. 
Appendix 13: Snellen Eye Chart ..............................................................................109 
10.14. 
Appendix 14: LEA Symbols Eye Chart ....................................................................110 
10.15. 
Appendix 15: COVID-19 Risk Assessment .............................................................111 
10.16. 
Appendix 16: Abbreviations .....................................................................................113 
11.
REFERENCES .........................................................................................................115 
LIST OF TABLES 
Table 1: 
Weight-based Dosing Regimen of Eculizumab ..........................................................17 
Table 2: 
Schedule of Assessments Part I: Weight Cohorts ≥ 40 kg, 30 to < 40 kg, and 
20 to < 30 kg ...............................................................................................................19 
Table 3: 
Schedule of Assessments Part II: Weight Cohorts ≥ 40 kg, 30 to < 40 kg, and 
20 to < 30 kg ...............................................................................................................21 
Table 4: 
Schedule of Assessments Part I: Weight Cohort 10 to < 20 kg ..................................23 
Table 5: 
Schedule of Assessments Part II: Weight Cohort 10 to < 20 kg ................................25 
Table 6: 
Schedule of Assessments (Extension Period): Year 2 (All Weight Cohorts) .............27 
Table 7: 
Schedule of Assessments (Extension Period): Year 3 (All Weight Cohorts) .............29 
Table 8: 
Schedule of Assessments – Relapse Evaluation Period .............................................31 
Table 9: 
Schedule of Assessments – Footnotes ........................................................................32 
Table 10: Relapse Severity as Measured by Optic Spinal Impairment Scale .............................44 
Table 11: Roles and Responsibilities of the Investigator and EDSS Rater ................................45 
Table 12: Study Drug Administered ...........................................................................................51 
Table 13: Weight-Based Dosing Regimen of Eculizumab .........................................................51 
Table 14: Supplemental Dosing Regimen of Eculizumab for 
Plasma Exchange/Plasmapheresis ..............................................................................52 
Table 15: Study Drug Reconstitution .........................................................................................53 
Table 16: Minimum Required Blood Volumes Collected by Weight Cohort and Study 
Visit .............................................................................................................................69 
Table 17: Minimum Required Blood Volumes Collected Following a Relapse by 
Weight Cohort and Relapse Evaluation Visit .............................................................69 
Table 18: Potential Risks and Mitigation Measures due to COVID-19 ...................................111 
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Protocol Amendment 2.2 
ECU-NMO-303 
LIST OF FIGURES 
Figure 1: 
Schematic Design for Study ECU-NMO-303 ............................................................41 
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Protocol Amendment 2.2 
ECU-NMO-303 
1.
PROTOCOL SUMMARY
1.1. 
Synopsis 
Protocol Title: A Phase 2/3 Open-Label, Single-Arm Trial to Evaluate the Safety and Activity 
of Eculizumab in Pediatric Patients with Relapsing Neuromyelitis Optica 
Spectrum Disorder 
Short Title: A Phase 2/3 Open-Label Safety and Activity Study of Eculizumab in Pediatric 
Patients with Relapsing Neuromyelitis Optica Spectrum Disorder 
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. The prevalence of NMOSD in adults is estimated at 0.5 
to 4.4/100,000. Neuromyelitis Optica Spectrum Disorder occurs even less frequently in the 
pediatric population, with an estimated prevalence of 0.02 to 0.03/100,000. In various pediatric 
populations the median age of onset has been reported as 10 to 14 years, with a range from 
1.9 to 18 years. The incidence of NMOSD in patients younger than 2 years is exceedingly rare, 
with no cases reported in Europe or in the USA. In both the adult and pediatric populations 
females are much more commonly affected than males, with a female to male ratio of at least 
3:1. Currently there are no approved therapies for the treatment of pediatric NMOSD. 
Similarities in clinical presentation, serologic findings, and disease course strongly suggest that 
the pathophysiology of NMOSD in pediatric and adult patients is essentially the same. Given 
that eculizumab has been proven to be beneficial in adult patients, this study is being undertaken 
to inform on the efficacy and safety in pediatric patients. 
Objectives and Endpoints 
Objectives 
Endpoints 
Primary Treatment Perioda: Primary: Efficacy 
•
Evaluate the efficacy of eculizumab in
relapsing pediatric patients with
Neuromyelitis Optica Spectrum Disorder
(NMOSD).
•
The change from Baseline in the Annualized
Relapse Rate (ARR) at 52/53 Weeks.b
•
Time to First Relapse (TFR).
Primary Treatment Perioda: Secondary: Safety 
•
Evaluate the safety and tolerability of
eculizumab treatment in relapsing pediatric
patients with NMOSD.
•
Incidence of treatment-emergent adverse
events (TEAEs), serious adverse events
(SAEs), and adverse events leading to study
drug discontinuation.
•
Incidence of antidrug antibodies (ADA).
•
Changes from Baseline in vital signs,
electrocardiogram (ECG) parameters, and
clinical laboratory assessments.
•
Change from Baseline in both weight and
height.
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Protocol Amendment 2.2 
ECU-NMO-303 
Objectives 
Endpoints 
Primary Treatment Perioda: Secondary: Efficacy 
•
Evaluate the efficacy of eculizumab by
additional efficacy measures including:
•
Disease-related disability
•
Change from Baseline in Expanded Disability
Status Scale (EDSS) score at 52/53 weeks in
patients ≥5 years of age.
•
Change from Baseline in the Hauser
Ambulatory Index (HAI) score at
52/53 weeks.
•
Quality of life
•
Change from Baseline in Pediatric Quality of
Life Inventory (PedsQL) at 52/53 weeks in
patients ≥5 years of age.
•
Change from Baseline in Pediatric Quality of
Life Inventory Parent Proxy (PedsQL Parent
Proxy) at 52/53 weeks in patients < 5 years of
age.
•
Change in ophthalmologic examination
findings
•
Change from Baseline in Visual Acuity (VA)
as measured by the Snellen or LEA symbols
Eye Chart examination at 52/53 weeks in all
patients.
•
Change from Baseline in Confrontational
Visual Fields (VF) as measured during
ophthalmologic examination at 52/53 weeks
in all patients.
•
Change from Baseline in color vision as
measured during ophthalmologic examination
at 52/53 weeks in all patients.
Primary Treatment Perioda: Secondary: PK/PD 
•
Describe the pharmacokinetics (PK) and
pharmacodynamics (PD) of eculizumab in
relapsing pediatric patients with NMOSD.
•
Changes in serum eculizumab concentration
over time.
•
Changes in serum free complement protein 5
(C5) concentrations and in vitro hemolytic
activity over time.
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Protocol Amendment 2.2 
ECU-NMO-303 
Objectives 
Endpoints 
Primary Treatment Perioda: Tertiary Efficacy Assessment 
•
Evaluate the efficacy of eculizumab by
additional efficacy measures including
•
Quality of life
•
Change from Baseline in the European
Quality of Life-5 Dimensions-Youth
(EQ-5D-Y) score for patients ≥8 years of age
and EQ-5D-Y Proxy score for patients aged
between 5-7 years, at 52/53 weeks.
Extension Treatment Periodc: Secondary Safety and Efficacy 
•
Characterize long-term safety of eculizumab
treatment in pediatric patients with NMOSD.
•
Characterize long-term efficacy of eculizumab
treatment in pediatric patients with NMOSD.
•
The safety and efficacy endpoints of the
Primary Treatment Period will be evaluated
during the Extension Treatment Period.
a Open-label eculizumab intravenous (IV) infusion, for a total of 52/53 weeks. 
b For patients who start in weight cohort 10 to <20 kg, the one-year evaluation will occur on Week 53, an 
odd-numbered week, because maintenance dosing, which is administered every 2 weeks, begins on Week 1. For 
all other cohorts the one-year evaluation will occur on Week 52, because maintenance dosing begins on an 
even-numbered week. Hence, the end of the Primary Treatment Period is designated as Week 52/53 throughout the 
protocol. 
c After completing the Primary Treatment Period, patients will continue receiving open-label eculizumab in the 
Extension Treatment Period for 104 weeks. 
Note: Statistical analysis of the primary endpoints will be limited to the change from Baseline to Week 52/53 
On-Trial ARR. TFR results will be considered descriptive; therefore, no adjustments for multiplicity will be made. 
Overall Design: 
This is a Phase 2/3 open-label, single-arm study to evaluate the safety and efficacy of eculizumab 
in pediatric patients (aged 2 to < 18 years) with relapsing NMOSD. A total of approximately 
12 eligible patients will be enrolled, with a minimum target of 10 evaluable patients. Of the 
10 evaluable patients, at least 3 of the patients will be aged 2 to < 12 years at the time of 
enrollment, and at least 5 patients will be aged 12 to < 18 years at the time of enrollment. 
There are 4 periods in this study: the Screening Period, the Primary Treatment Period, the 
Extension Treatment Period, and the Safety Follow-up Period. 
Patients who withdraw or discontinue from the study at any time, for any reason after receiving 
any amount of eculizumab, will be required to complete an Early Termination (ET) Visit at the 
time of withdrawal and a Safety Follow-up Visit at 8 weeks from the date of the patient’s last 
dose of eculizumab. Adverse events (AEs) leading to patient discontinuation from the study will 
be followed until the AE has resolved or the patient’s condition is medically stable, in the 
opinion of the Investigator. 
Patients who complete the study without transitioning to uninterrupted treatment with 
eculizumab must complete both an End of Study Visit at the time of study completion and a 
Safety Follow-up Visit, which will occur 8 weeks from the date the patient’s last dose of 
eculizumab was administered. Patients who complete the study and transition to uninterrupted 
treatment with eculizumab will not be required to complete the Safety Follow-up Visit at 
8 weeks from the date of the last dose. 
Page 16 of 117 
Alexion Confidential 

Protocol Amendment 2.2 
ECU-NMO-303 
Number of Patients: 
Approximately 12 patients will be enrolled to achieve the minimum of 10 evaluable patients. Of 
the 10 evaluable patients, at least 3 of the patients will be aged 2 to < 12 years at the time of 
enrollment, and at least 5 patients will be aged 12 to < 18 years at the time of enrollment. 
Intervention Groups and Duration: 
All patients who meet the inclusion criteria and none of the exclusion criteria, who have been 
vaccinated against Neisseria meningitidis (N meningitidis), Haemophilus influenzae (Hib), and 
Streptococcus pneumoniae (S pneumoniae), in accordance with the national vaccination 
recommendations for each age group, and have been cleared by the Investigator, will be enrolled 
in the study. 
All patients will receive open-label eculizumab intravenous (IV) infusion, during the Primary 
Treatment Period, starting on Day 1 for a total of 52/53 weeks. The dosing regimen will be based 
on the pediatric patient’s body weight, as indicated in Table 1. Body weight is expected to 
change during this pediatric study and, therefore, a patient’s weight cohort may change during 
the study. 
Table 1: 
Weight-based Dosing Regimen of Eculizumab 
Weight Cohorta,c 
Induction Periodb 
Maintenance Phase 
≥ 40 kg 
900 mg weekly × 4 doses 
1200 mg at Week 4; then every 2 weeks 
30 to < 40 kg 
600 mg weekly × 2 doses 
900 mg at Week 2; then every 2 weeks 
20 to < 30 kg 
600 mg weekly × 2 doses 
600 mg at Week 2; then every 2 weeks 
10 to < 20 kg 
600 mg weekly × 1 dose 
300 mg at Week 1; then every 2 weeks 
a Day 1 and maintenance period dose regimen will be based on the current visit's recorded body weight. If 
site/institutions policies prohibit study drug to be prepared on the day of visit, the weight from the most recent 
study visit should be used. If a patient is receiving an infusion at a remote facility or at home, the weight from the 
prior study visit may be used to calculate the dose. 
b During the initial induction period, the dose regimen will be based on the patient’s weight on Day 1 (Visit 2). 
c All patients will remain in the same weight cohort throughout the induction period, regardless of change in weight. 
Notes: 
•
Dosage and treatment regimen are based on results of a modelling and simulation study.
•
Eculizumab will be administered by intravenous (IV) infusion.
Data Monitoring Committee 
An independent Data Monitoring Committee (DMC) will conduct interim monitoring of safety 
data. 
The DMC will have access to all safety data. The DMC may make recommendations to the 
Sponsor regarding safety issues, study conduct, and modifying, extending, or stopping the study. 
In addition, the DMC will receive reports concerning patients who have discontinued. 
Notification of study discontinuation and reason for the discontinuation will be sent to the DMC 
according to the schedule defined in the Charter. The DMC will also review summaries of all 
relapses. 
A separate DMC Charter will document all DMC procedures for this study. 
Page 17 of 117 
Alexion Confidential 

Protocol Amendment 2.2 
ECU-NMO-303 
Relapse Adjudication Committee 
The role of the Relapse Adjudication Committee (RAC) will be to determine whether an 
Investigator-Reported On-Trial Relapse meets the protocol definition of a relapse by rendering a 
Yes/No decision through the adjudication process. The RAC will be comprised of 3 members: a 
Chair and 2 additional individuals, all of whom will have expertise in NMOSD. A separate 
Charter will define the structure, responsibilities, and membership of the RAC, outline the 
process for RAC review of study data, and outline the procedures for adjudication of an 
Investigator-Reported Relapse. 
Page 18 of 117 
Alexion Confidential 

Protocol Amendment 2.2 
ECU-NMO-303 
1.2. 
Schedule of Activities 
Table 2: 
Schedule of Assessments Part I: Weight Cohorts ≥ 40 kg, 30 to < 40 kg, and 20 to < 30 kg
Period /Phase 
Screening1 
Primary Treatment Period 
Visit LocationΔ 
In Clinic 
In Clinic 
In Clinic or Remote 
In 
Clinic 
Study Visit 
Screening Visit 
(1) 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
Study Week 
-1 to -6 weeks
D1 
W1 
W2 
W3 
W4 
W6 
W8 
W10 
W12 W14 W16 
W18 W20 W22 W24 
W26 
Window (Days) 
±2 
Informed Consent2
X 
Medical History 
X 
NMOSD History3
X 
NMOSD diagnosis via 2015 
IPND Criteria4
X 
Neurologic Examination 
X 
X 
X 
X 
Ophthalmological Examination 
X 
X 
X 
X 
Snellen or LEA Symbols 
Chart35
X 
X 
X 
X 
Weight6,7,29 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height8 
X 
X 
X 
X 
Vital Signs9 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical Examination10 
X 
X 
X 
12-Lead ECG11 
X 
X 
X 
Concomitant Medication12 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Event13 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
OCT14
X 
MRI (contrast optional)14 
X 
Expanded Disability Status 
Scale (EDSS)5 
X 
X 
X 
X 
Hauser Ambulation Index 
(HAI)
X 
X 
X 
X 
Optic Spinal Impairment Score 
(OSIS)
X 
EQ-5D-Y/EQ-5D-Y Proxy15 
X 
X 
X 
Pediatric Quality of Life 
Inventory (PedsQL)/PedsQL 
Proxy32 
X 
X 
X 
Page 19 of 117 
Alexion Confidential 

Protocol Amendment 2.2 
ECU-NMO-303 
Table 2: 
Schedule of Assessments Part I: Weight Cohorts ≥ 40 kg, 30 to < 40 kg, and 20 to < 30 kg
Period /Phase 
Screening1 
Primary Treatment Period 
Visit LocationΔ 
In Clinic 
In Clinic 
In Clinic or Remote 
In 
Clinic 
Study Visit 
Screening Visit 
(1) 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
Study Week 
-1 to -6 weeks
D1 
W1 
W2 
W3 
W4 
W6 
W8 
W10 
W12 W14 W16 
W18 W20 W22 W24 
W26 
Window (Days) 
±2 
anti-AQP4 Ab-positive 
(Serum)16,18,34
X 
X 
X 
Clinical Laboratory Tests16 
X 
X 
X 
X 
Serum Pregnancy Test17 
X 
Urine Pregnancy Test17 
X 
X 
X 
X 
X 
X 
X 
PK, Hemolysis, Free C518 
B/P 
24h 
T/P 
T/P 
T/P 
T/P 
Exploratory biomarkers 
B 
T 
T 
T 
ADA18
B 
T 
T 
Enrollment19 
X 
N meningitidis Vaccination20 
X 
H influenzae Vaccination21 
X 
S pneumonia Vaccination21 
X 
Patient Safety Information 
Cards22 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Study Drug Infusion (mg) 
10 to < 20 kg23,25,29,30 
300 
N/A 
300 
300 
300 
300 
300 
300 
300 
300 
300 300 
300 
300 
Study Drug Infusion (mg) 
20 to < 30 kg7,23,25,29 
600 
600 
600 
N/A 
600 
600 
600 
600 
600 
600 
600 
600 
600 600 
600 
600 
Study Drug Infusion (mg) 
30 to < 40 kg7,23,25,29 
600 
600 
900 
N/A 
900 
900 
900 
900 
900 
900 
900 
900 
900 900 
900 
900 
Study Drug Infusion (mg) 
≥ 40 kg7,23,25,29
900 
900 
900 
900 
1200 
1200 
1200 
1200 
1200 1200 1200 
1200 1200 1200 1200 
1200 
Page 20 of 117 
Alexion Confidential 

Protocol Amendment 2.2 
ECU-NMO-303 
Table 3: 
Schedule of Assessments Part II: Weight Cohorts ≥ 40 kg, 30 to < 40 kg, and 20 to < 30 kg 
Period /Phase 
Primary Treatment Period Continued 
Visit Location Δ 
In Clinic or Remote 
In 
Clinic 
In Clinic or Remote 
In Clinic 
Study Visit 
18 
19 
20 
21 
22 
23 
24 
25 
26 
27 
28 
29 
30 
ET28 
F/U26
Study Weeks 
W28 W30 W32 W34 W36 W38 
W40 W42 W44 W46 W48 
W50 
W52 
+W8
Window (Days) 
±2 
±2 
Weight6,7,29 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height8 
X 
X 
X 
Vital Signs9
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical Examination10 
X 
X 
X 
Neurologic Examination 
X 
X 
X 
Ophthalmological Examination 
X 
X 
X 
Snellen or LEA Symbols Chart35 
X 
X 
X 
12-Lead ECG11 
X 
X 
Concomitant Medication12 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Event13 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Expanded Disability Status Scale 
(EDSS)5 
X 
X 
X 
Hauser Ambulation Index (HAI)
X 
X 
X 
EQ-5D-Y/EQ-5D-Y Proxy15
X 
X 
X 
Pediatric Quality of Life Inventory 
(PedsQL)/PedsQL Proxy32 
X 
X 
X 
anti-AQP4 Ab-positive 
(Serum)16,18,34
X 
X 
X 
Clinical Laboratory Tests16 
X 
X 
X 
Serum Pregnancy Test17 
X 
Urine Pregnancy Test17 
X 
X 
X 
X 
X 
X 
X 
X 
PK, Hemolysis, Free C518 
T/P 
T/P 
X 
Exploratory biomarkers 
T 
X 
ADA18
T 
T 
X 
Patient Safety Information Cards22 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Study Drug Infusion (mg) 
10 to < 20 kg23,25,29,30 
300 
300 
300 
300 
300 
300 
300 
300 
300 
300 
300 
300 
300 
Study Drug Infusion (mg) 
20 to < 30 kg7,23,25,29 
600 
600 
600 
600 
600 
600 
600 
600 
600 
600 
600 
600 
600 
Study Drug Infusion (mg) 
30 to < 40 kg7,23,25,29 
900 
900 
900 
900 
900 
900 
900 
900 
900 
900 
900 
900 
900 
Page 21 of 117 
Alexion Confidential 

Protocol Amendment 2.2 
ECU-NMO-303 
Period /Phase 
Primary Treatment Period Continued 
Visit Location Δ 
In Clinic or Remote 
In 
Clinic 
In Clinic or Remote 
In Clinic 
Study Visit 
18 
19 
20 
21 
22 
23 
24 
25 
26 
27 
28 
29 
30 
ET28 
F/U26
Study Weeks 
W28 W30 W32 W34 W36 W38 
W40 W42 W44 W46 W48 
W50 
W52 
+W8
Window (Days) 
±2 
±2 
Study Drug Infusion (mg) 
≥40 kg7,23,25,29
1200 1200 1200 1200 1200 1200 
1200 1200 1200 1200 1200 
1200 
1200 
Transition follow-up call31 
X 
Page 22 of 117 
Alexion Confidential 

Protocol Amendment 2.2 
ECU-NMO-303 
Table 4: 
Schedule of Assessments Part I: Weight Cohort 10 to < 20 kg
Period /Phase 
Screening1 
Primary Treatment Period 
Visit Location Δ 
In Clinic 
In Clinic 
In Clinic or Remote 
In 
Clinic 
Study Visit 
Screening 
Visit (1) 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
Study Weeks 
-1 to -6
weeks
D1 
W1 
W3 
W5 
W7 
W9 
W11 
W13 W15 W17 W19 W21 W23 W25 
W27 
Window (Days) 
±2 
Informed Consent2
X 
Medical History 
X 
NMOSD History3
X 
NMOSD diagnosis via 2015 IPND 
Criteria4
X 
Neurologic Examination 
X 
X 
X 
X 
Ophthalmological Examination 
X 
X 
X 
X 
Snellen or LEA Symbols Chart35 
X 
X 
X 
X 
Weight6,7,29 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height8 
X 
X 
X 
X 
Vital Signs9
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical Examination10 
X 
X 
X 
12-Lead ECG11 
X 
X 
X 
Concomitant Medication12 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Event13 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
OCT14
X 
MRI (contrast optional)14 
X 
Expanded Disability Status Scale 
(EDSS)5 
X 
X 
X 
X 
Hauser Ambulation Index (HAI)
X 
X 
X 
X 
Optic Spinal Impairment Score (OSIS)
X 
EQ-5D-Y/EQ-5D-Y Proxy15 
X 
X 
X 
Pediatric Quality of Life Inventory 
(PedsQL)/PedsQL Proxy32 
X 
X 
X 
anti-AQP4 Ab-positive (Serum)16,18,34
X 
X 
X 
Clinical Laboratory Tests16 
X 
X 
X 
X 
Serum Pregnancy Test17 
X 
Urine Pregnancy Test17 
X 
X 
X 
X 
X 
X 
X 
PK, Hemolysis, Free C518 
B/P/24h 
T/P 
T/P 
T/P 
T/P 
Page 23 of 117 
Alexion Confidential 

Protocol Amendment 2.2 
ECU-NMO-303 
Table 4: 
Schedule of Assessments Part I: Weight Cohort 10 to < 20 kg
Period /Phase 
Screening1 
Primary Treatment Period 
Visit Location Δ 
In Clinic 
In Clinic 
In Clinic or Remote 
In 
Clinic 
Study Visit 
Screening 
Visit (1) 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
Study Weeks 
-1 to -6
weeks
D1 
W1 
W3 
W5 
W7 
W9 
W11 
W13 W15 W17 W19 W21 W23 W25 
W27 
Window (Days) 
±2 
Exploratory biomarkers 
B 
T 
T 
ADA18
B 
T 
T 
Enrollment19 
X 
N meningitidis Vaccination20 
X 
H influenzae Vaccination21 
X 
S pneumonia Vaccination21 
X 
Patient Safety Information Cards22
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Study Drug Infusion (mg) 
10 to < 20 kg7,23,25,29 
600 
300 
300 
300 
300 
300 
300 
300 
300 
300 
300 300 300 300 
300 
Study Drug Infusion (mg) 
20 to < 30 kg23,25,33 
600 
600 
600 
600 
600 
600 
600 
600 
600 
600 600 600 600 
600 
Study Drug Infusion (mg) 
30 to < 40 kg23,25,33 
900 
900 
900 
900 
900 
900 
900 
900 
900 
900 900 900 900 
900 
Study Drug Infusion (mg) 
≥ 40 kg23,25,33 
1200 
1200 
1200 
1200 
1200 
1200 
1200 1200 1200 1200 1200 1200 1200 
1200 
Page 24 of 117 
Alexion Confidential 

Protocol Amendment 2.2 
ECU-NMO-303 
Table 5: 
Schedule of Assessments Part II: Weight Cohort 10 to < 20 kg
Period /Phase 
Primary Treatment Period Continued 
Visit Location Δ 
In Clinic/Remote 
In 
Clinic 
In Clinic/Remote 
In Clinic 
Study Visit 
17 
18 
19 
20 
21 
22 
23 
24 
25 
26 
27 
28 
29 
ET28* 
F/U26 
Study Weeks 
W29 
W31 
W33 
W35 
W37 
W39 
W41 
W43 
W45 
W47 
W49 
W51 
W53 
+W8
Window (Days) 
±2 
±2 
Weight6,7,29 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height8 
X 
X 
X 
Vital Signs9
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical Examination10 
X 
X 
X 
Neurologic Examination 
X 
X 
X 
Ophthalmological Examination 
X 
X 
X 
Snellen or LEA Symbols Chart35 
X 
X 
X 
12-Lead ECG11 
X 
X 
Concomitant Medication12 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Event13 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Expanded Disability Status 
Scale (EDSS)5 
X 
X 
X 
Hauser Ambulation Index (HAI) 
X 
X 
X 
EQ-5D-Y/EQ-5D-Y Proxy15 
X 
X 
X 
Pediatric Quality of Life 
Inventory (PedsQL)/ PedsQL 
Proxy32 
X 
X 
X 
anti-AQP4 Ab-positive 
(Serum)16,18,34
X 
X 
X 
Clinical Laboratory Tests16 
X 
X 
X 
Serum Pregnancy Test17 
X 
Urine Pregnancy Test17 
X 
X 
X 
X 
X 
X 
X 
X 
PK, Hemolysis, Free C518 
T/P 
T/P 
X 
Exploratory biomarkers 
T 
X 
ADA18
T 
T 
X 
Patient Safety Information 
Cards22 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Study Drug Infusion (mg) 
10 to < 20 kg7,23,25,29 
300 
300 
300 
300 
300 
300 
300 
300 
300 
300 
300 
300 
300 
Page 25 of 117 
Alexion Confidential 

Protocol Amendment 2.2 
ECU-NMO-303 
Table 5: 
Schedule of Assessments Part II: Weight Cohort 10 to < 20 kg
Period /Phase 
Primary Treatment Period Continued 
Visit Location Δ 
In Clinic/Remote 
In 
Clinic 
In Clinic/Remote 
In Clinic 
Study Visit 
17 
18 
19 
20 
21 
22 
23 
24 
25 
26 
27 
28 
29 
ET28* 
F/U26 
Study Weeks 
W29 
W31 
W33 
W35 
W37 
W39 
W41 
W43 
W45 
W47 
W49 
W51 
W53 
+W8
Window (Days) 
±2 
±2 
Study Drug Infusion (mg) 
20 to < 30 kg23,25,33 
600 
600 
600 
600 
600 
600 
600 
600 
600 
600 
600 
600 
600 
Study Drug Infusion (mg) 
30 to < 40 kg23,25,33 
900 
900 
900 
900 
900 
900 
900 
900 
900 
900 
900 
900 
900 
Study Drug Infusion (mg) 
≥ 40 kg23,25,33 
1200 
1200 
1200 
1200 
1200 
1200 
1200 
1200 
1200 
1200 
1200 
1200 
1200 
Transition follow-up call31 
X 
Page 26 of 117 
Alexion Confidential 

Protocol Amendment 2.2 
ECU-NMO-303 
Table 6: 
Schedule of Assessments (Extension Period): Year 2 (All Weight Cohorts)
Phase 
Extension Treatment Period 
Visit Location Δ 
In Clinic/Remote 
In Clinic 
In Clinic 
Year 2 Visit/Week 
V31/W54 
(V30/W55) 
V32/W56 
(V31/W57) 
V33/W58 
(V32/W59) 
V34/W60 
(V33/W61) 
V35/W62 
(V34/W63) 
V36/W64 
(V35/W65) 
ET28 
F/U26 
(+W8) 
Year 2 Visit/Week 
V37/W66 
(V36/W67) 
V38/W68 
(V37/W69) 
V39/W70 
(V38/W71) 
V40/W72 
(V39/W73) 
V41/W74 
(V40/W75) 
V42/W76 
(V41/W77) 
ET28 
F/U26 
(+W8) 
Year 2 Visit/Week 
V43/W78 
(V42/W79) 
V44/W80 
(V43/W81) 
V45/W82 
(V44/W83) 
V46/W84 
(V45/W85) 
V47/W86 
(V46/W87) 
V48/W88 
(V47/W89) 
ET28 
F/U26 
(+W8) 
Year 2 Visit/Week 
V49/W90 
(V48/W91) 
V50/W92 
(V49/W93) 
V51/W94 
(V50/W95) 
V52/W96 
(V51/W97) 
V53/W98 
(V52/W99) 
V54/W100 
(V53/W101) 
ET28 
F/U26 
(+W8) 
Year 2 Visit/Week 
V55/W102 
(V54/W103) 
V56/W104 
(V55/W105) 
ET28 
F/U26 
(+W8) 
Window (Days) 
±2 
(±2) 
Weight6,7,29 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height8 
X 
X 
Vital Signs9 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical Examination10 
X 
X 
Neurologic Examination 
X 
X 
Ophthalmological Examination 
X 
X 
Snellen or LEA Symbols Chart35 
X 
X 
12-Lead ECG11 
X 
X 
Concomitant Medication12 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Event13 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Expanded Disability Status Scale 
(EDSS)5 
X 
X 
Hauser Ambulation Index (HAI)
X 
X 
EQ-5D-Y/EQ-5D-Y Proxy15 
X 
X 
Pediatric Quality of Life 
Inventory (PedsQL)/PedsQL 
Proxy32 
X 
X 
anti-AQP4 Ab-positive 
(Serum)16,18,34
X 
X 
Clinical Laboratory Tests16 
X 
X 
Serum Pregnancy Test17 
X 
Page 27 of 117 
Alexion Confidential 

Protocol Amendment 2.2 
ECU-NMO-303 
Table 6: 
Schedule of Assessments (Extension Period): Year 2 (All Weight Cohorts)
Phase 
Extension Treatment Period 
Visit Location Δ 
In Clinic/Remote 
In Clinic 
In Clinic 
Year 2 Visit/Week 
V31/W54 
(V30/W55) 
V32/W56 
(V31/W57) 
V33/W58 
(V32/W59) 
V34/W60 
(V33/W61) 
V35/W62 
(V34/W63) 
V36/W64 
(V35/W65) 
ET28 
F/U26 
(+W8) 
Year 2 Visit/Week 
V37/W66 
(V36/W67) 
V38/W68 
(V37/W69) 
V39/W70 
(V38/W71) 
V40/W72 
(V39/W73) 
V41/W74 
(V40/W75) 
V42/W76 
(V41/W77) 
ET28 
F/U26 
(+W8) 
Year 2 Visit/Week 
V43/W78 
(V42/W79) 
V44/W80 
(V43/W81) 
V45/W82 
(V44/W83) 
V46/W84 
(V45/W85) 
V47/W86 
(V46/W87) 
V48/W88 
(V47/W89) 
ET28 
F/U26 
(+W8) 
Year 2 Visit/Week 
V49/W90 
(V48/W91) 
V50/W92 
(V49/W93) 
V51/W94 
(V50/W95) 
V52/W96 
(V51/W97) 
V53/W98 
(V52/W99) 
V54/W100 
(V53/W101) 
ET28 
F/U26 
(+W8) 
Year 2 Visit/Week 
V55/W102 
(V54/W103) 
V56/W104 
(V55/W105) 
ET28 
F/U26 
(+W8) 
Window (Days) 
±2 
(±2) 
Urine Pregnancy Test17 
X 
X 
X 
X 
X 
PK, Hemolysis, Free C518 
Only to be collected in the event of a relapse or an ET 
X 
Exploratory biomarkers 
Only to be collected in the event of a relapse or an ET 
X 
ADA18 
Only to be collected in the event of a relapse or an ET 
X 
Patient Safety Information 
Cards22 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Study Drug Infusion (mg) 
10 to < 20 kg 7,23,25,29 
300 
300 
300 
300 
300 
300 
300 
Study Drug Infusion (mg) 
20 to < 30 kg 7,23,25,29 
600 
600 
600 
600 
600 
600 
600 
Study Drug Infusion (mg) 
30 to < 40 kg 7,23,25,29 
900 
900 
900 
900 
900 
900 
900 
Study Drug Infusion (mg) 
≥ 40 kg 7,23,25,29 
1200 
1200 
1200 
1200 
1200 
1200 
1200 
Transition follow-up call31 
X 
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Protocol Amendment 2.2 
ECU-NMO-303 
Table 7: 
Schedule of Assessments (Extension Period): Year 3 (All Weight Cohorts)
Phase 
Extension Treatment Period 
Visit Location Δ 
In Clinic/Remote 
In Clinic 
In Clinic 
Year 3 Visit/Week 
V57/W106 
(V56/W107) 
V58/W108 
(V57/W109) 
V59/W110 
(V58/W111) 
V60/W112 
(V59/W113) 
ET28 
F/U26 
(+W8) 
Year 3 Visit/Week 
V61/W114 
(V60/W115) 
V62/W116 
(V61/W117) 
V63/W118 
(V62/W119) 
V64/W120 
(V63/W121) 
V65/W122 
(V64/W123) 
V66/W124 
(V65/W125) 
ET28 
F/U26 
(+W8) 
Year 3 Visit/Week 
V67/W126 
(V66/W127) 
V68/W128 
(V67/W129) 
V69/W130 
(V68/W131) 
V70/W132 
(V69/W133) 
V71/W134 
(V70/W135) 
V72/W136 
(V71/W137) 
ET28 
F/U26 
(+W8) 
Year 3 Visit/Week 
V73/W138 
(V72/W139) 
V74/W140 
(V73/W141) 
V75/W142 
(V74/W143) 
V76/W144 
(V75/W145) 
V77/W146 
(V76/W147) 
V78/W148 
(V77/W149) 
ET28 
F/U26 
(+W8) 
Year 3 Visit/Week 
V79/W150 
(V78/W151) 
V80/W152 
(V79/W153) 
V81/W154 
(V80/W155) 
ET/EOS27,28,* 
/ V82/W156 
(V81/W157) 
F/U26 
(+W8) 
Window (Days) 
±2 
(±2) 
Weight6,7,29 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height8 
X 
X 
Vital Signs9
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical Examination10 
X 
X 
Neurologic Examination 
X 
X 
Ophthalmological Examination 
X 
X 
Snellen or LEA Symbols Chart35 
X 
X 
12-Lead ECG11 
X 
X 
Concomitant Medication12 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Event13 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Expanded Disability Status Scale 
(EDSS)5 
X 
X 
Hauser Ambulation Index (HAI)
X 
X 
EQ-5D-Y/EQ-5D-Y Proxy15 
X 
X 
Pediatric Quality of Life 
Inventory (PedsQL)/PedsQL 
Proxy32 
X 
X 
anti-AQP4 Ab-positive 
(Serum)16,18,34
X 
X 
Clinical Laboratory Tests16 
X 
X 
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Protocol Amendment 2.2 
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Table 7: 
Schedule of Assessments (Extension Period): Year 3 (All Weight Cohorts)
Phase 
Extension Treatment Period 
Visit Location Δ 
In Clinic/Remote 
In Clinic 
In Clinic 
Year 3 Visit/Week 
V57/W106 
(V56/W107) 
V58/W108 
(V57/W109) 
V59/W110 
(V58/W111) 
V60/W112 
(V59/W113) 
ET28 
F/U26 
(+W8) 
Year 3 Visit/Week 
V61/W114 
(V60/W115) 
V62/W116 
(V61/W117) 
V63/W118 
(V62/W119) 
V64/W120 
(V63/W121) 
V65/W122 
(V64/W123) 
V66/W124 
(V65/W125) 
ET28 
F/U26 
(+W8) 
Year 3 Visit/Week 
V67/W126 
(V66/W127) 
V68/W128 
(V67/W129) 
V69/W130 
(V68/W131) 
V70/W132 
(V69/W133) 
V71/W134 
(V70/W135) 
V72/W136 
(V71/W137) 
ET28 
F/U26 
(+W8) 
Year 3 Visit/Week 
V73/W138 
(V72/W139) 
V74/W140 
(V73/W141) 
V75/W142 
(V74/W143) 
V76/W144 
(V75/W145) 
V77/W146 
(V76/W147) 
V78/W148 
(V77/W149) 
ET28 
F/U26 
(+W8) 
Year 3 Visit/Week 
V79/W150 
(V78/W151) 
V80/W152 
(V79/W153) 
V81/W154 
(V80/W155) 
ET/EOS27,28,* 
/ V82/W156 
(V81/W157) 
F/U26 
(+W8) 
Window (Days) 
±2 
(±2) 
Serum Pregnancy Test17 
X 
Urine Pregnancy Test16 
X 
X 
X 
X 
X 
PK, Hemolysis, Free C518 
Only to be collected in the event of a relapse or an ET 
X 
Exploratory biomarkers 
Only to be collected in the event of a relapse or an ET 
X 
ADA18 
Only to be collected in the event of a relapse or an ET 
X 
Patient Safety Information 
Cards22 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Study Drug Infusion (mg) 
10 to < 20 kg 7,23,25,29 
300 
300 
300 
300 
300 
300 
300 
Study Drug Infusion (mg) 
20 to < 30 kg 7,23,25,29 
600 
600 
600 
600 
600 
600 
600 
Study Drug Infusion (mg) 
30 to < 40 kg 7,23,25,29 
900 
900 
900 
900 
900 
900 
900 
Study Drug Infusion (mg) 
≥ 40 kg 7,23,25,29 
1200 
1200 
1200 
1200 
1200 
1200 
1200 
Transition follow-up call31 
X 
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Protocol Amendment 2.2 
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Table 8: 
Schedule of Assessments – Relapse Evaluation Period 
Assessment 
Relapse Evaluation 
Visit24 
Follow- Up Relapse Evaluation Visits24 
Study Week 
Within 24-48 hours 
+W1
+W4
+W6
Unscheduled 
Window (Days) 
-- 
±2 
-- 
Weight6,7,29 
-- 
-- 
-- 
X 
Procedures, tests, and 
assessments will be performed at 
the discretion of the Investigator. 
Refer to Section 4.2.4 and 
Table 11 for further details. 
Vital Signs9 
X 
X 
X 
X 
Physical Examination10 
-- 
-- 
-- 
X 
Neurologic Examination 
X 
X 
X 
X 
Ophthalmological Examination 
X 
X 
X 
X 
Snellen or LEA Symbols Chart35 
X 
X 
X 
X 
Electrocardiogram (ECG)11 
-- 
-- 
-- 
X 
Concomitant Medication12 
X 
X 
X 
X 
Adverse Events (AEs)13 
X 
X 
X 
X 
OCT14 
X 
-- 
-- 
-- 
MRI with or w/o contrast14 
X 
-- 
-- 
-- 
Expanded Disability Status Scale (EDSS)5 
X 
X 
X 
X 
Hauser Ambulation Index (HAI)
X 
X 
X 
X 
Optic Spinal Impairment Score (OSIS)
X 
X 
X 
X 
EQ-5D-Y/EQ-5D-Y Proxy15 
-- 
-- 
-- 
X 
Pediatric Quality of Life Inventory (PedsQL)/PedsQL Proxy32 
-- 
-- 
-- 
X 
anti-AQP4 Ab-positive (serum)16,18,34 
X 
-- 
-- 
X 
Clinical Laboratory Tests16 
X 
-- 
-- 
X 
Pregnancy test (serum)17 
-- 
-- 
-- 
-- 
Pregnancy Test (urine)17 
X 
-- 
-- 
X 
PK/PD/Free C5 (serum)18 
T/P 
T/P 
T/P 
T/P 
Exploratory biomarkers 
T 
T 
T 
T 
ADA18
-- 
-- 
-- 
X 
Patient Safety Information Cards22 
X 
X 
X 
X 
Study drug Infusion7,23,25,29 
Continue every 1 to 2 weeks (±2 days) as scheduled 
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Protocol Amendment 2.2 
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Table 9: 
Schedule of Assessments – Footnotes
Footnote 
Description 
1. 
All Screening procedures must be completed within 1-6 weeks prior to the enrollment at Baseline (Visit 2 [Day 1]). Patients who experience a relapse 
during the Screening Period will be considered a Screening failure. Such patients may be rescreened for enrollment into the study. Re-Screening 
procedures should be confirmed with the Sponsor to determine if all Screening procedures are necessary. 
2. 
The patient’s signed and dated informed consent form (ICF) must be obtained before conducting any study procedures. 
3. 
The Investigator will review the patient’s history and diagnosis and document the following at the Screening Visit: NMOSD diagnosis date as well as 
prior Magnetic Resonance Imaging (MRI) imaging that contributed to the diagnosis; the number of relapses (onset dates), and the clinical 
presentation of each relapse (eg, optic neuritis (ON), transverse myelitis (TM), longitudinally extensive transverse myelitis (LETM), brainstem, area 
postrema, or other).  
4. 
All available information about relapses that meet the protocol definition of Historical Relapse, which have occurred within the 2 years prior to 
Screening, including relapse onset date, clinical presentation, acute and maintenance treatments, dosing regimens, any disability measurements such 
as the Expanded Disability Status Scale (EDSS) scores, will be recorded. 
5. 
The blinded EDSS Rater will perform the Kurtzke neurological assessment and document the Functional Systems Score (FSS) and EDSS score. 
EDSS will not be performed on patients aged 2-4 years. 
6. 
Collect weight with minimal clothing. 
7. 
During the induction period, the dosing regimen will be based on the patient’s weight at Day 1 (Visit 2). 
8. 
Collect height with no shoes or footwear. 
9. 
Vital signs include assessments of systolic and diastolic blood pressure (BP), temperature, respiratory rate (RR) and heart rate (HR). Vital signs will 
be obtained after the patient has been supine or seated for at least 5 minutes. Ideally, each patient’s BP should be measured using the same arm. 
10. 
Additional Physical Examinations can be performed as medically indicated during the study at the Investigator’s discretion. 
11. 
Additional ECGs may be performed if the Investigator feels it is clinically warranted. 
12. 
Concomitant medications will be recorded at the Screening Visit as described in the protocol. Use of concomitant medication will be evaluated during 
the study and all new medications or changes to concomitant medications will be recorded. 
13. 
Serious adverse events and nonserious adverse events are recorded from time of signed consent. 
14. 
Baseline MRI with or without contrast and Optical Coherence Tomography Examinations should be performed. Follow-up assessments should be 
performed promptly after relapse if Investigator decides these are indicated. Exceptions may be granted (eg, based on a recent historical result being 
available for the study) if approved by the Alexion Medical Monitor. 
15. 
The QoL self- assessments (EQ-5D-Y), or Proxy version if patient is aged 5-7 years old, will be performed by the patient or parent/caregiver before 
any other study procedures at all study visits. This test will not be performed in patients aged 2-4 years old. 
16. 
Clinical laboratory tests (chemistry, hematology and urinalysis) will be performed by a central laboratory. Refer to the study protocol for a summary 
of the clinical laboratory tests to be measured. 
17. 
Pregnancy test must be performed on all women of childbearing potential at specified timepoints. Pregnancy test (urine or serum) may also be 
performed at any time during the study at the Investigator’s discretion. Patients must practice an effective, reliable and medically approved 
contraceptive regimen during the study and for up to 5 months following discontinuation of treatment. If a patient or a patient’s partner becomes or is 
found pregnant while in the study, the Sponsor will be notified in accordance with the study protocol. 
18. 
Obtain Baseline and trough blood samples for anti-AQP4 Ab, PK, hemolysis, free C5, and ADA tests 5 – 90 minutes before study drug infusion. 
Obtain peak blood samples for PK, hemolysis, and free C5 tests 60-120 minutes after the completion of study drug infusion. Obtain 24-hour 
post-dose blood samples for PK, hemolysis, and free C5 after study drug infusion at Visit 2 (Day 1). For the sample collected at 24 hours, there will 
be a window of ±1 hour for collecting the sample. 
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Protocol Amendment 2.2 
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Table 9: 
Schedule of Assessments – Footnotes
Footnote 
Description 
19. 
Both the Investigator and the Sponsor must approve patient eligibility prior to enrollment. Enrollment will be done by using an IXRS system on 
Day 1. 
20. 
To reduce the risk of meningococcal infection, all patients must be vaccinated against meningococcal infections within the 3 years prior to, or at the 
time of, initiating study drug. Patients who initiate study drug treatment 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). 
21. 
Vaccinate patients against H influenzae and S pneumoniae, as per local and country-specific immunization guidelines for the appropriate age group if 
not already vaccinated, at least 2 weeks prior to receiving the first eculizumab infusion. 
22. 
Patients and their parents/guardians will receive information about signs and symptoms of an NMOSD relapse. Patients and their parents/guardians 
will also receive a separate safety card providing information about the risk of meningococcal infection. 
23. 
During the Study Period, study drug will be administered IV over approximately 1 to 4 hours in pediatric patients. For patients who reach ≥ 18 years 
of age during the study, the study drug should be administered IV over approximately 35 (± 10) minutes. If an AE occurs during administration of the 
study drug, the infusion may be slowed or stopped at the discretion of the Investigator, depending upon the nature and severity of the event; however, 
the overall duration should not exceed 2 hours from the start of the infusion in patients aged ≥ 18 years and 4 hours from the start of infusion in 
pediatric patients. 
24. 
Patient should be evaluated within 24-48 hours of notification of the Investigator of a potential relapse, and no later than 48 hours. All potential 
relapses must be evaluated by both the Investigator and the blinded EDSS Rater. Follow-Up Relapse Evaluation Visits will be performed at 1, 4 and 
6 weeks after the onset of relapse. Additional Relapse Evaluation Visits (Unscheduled Visits) are permitted at the discretion of the Investigator. Tests, 
procedures, and assessments listed under the Unscheduled Visits are to be performed at the discretion of the Investigator. All investigations/tests 
related to the relapse evaluation (eg, MRIs, computerized tomography (CTs), lumbar punctures, etc.) should be recorded in the source documents and 
in the eCRF; copies of all reports should be sent to the Sponsor. 
25. 
Administer study drug after completion of all other tests and procedures, excluding the peak blood sampling for PK, hemolysis, and free C5 assay. 
26. 
Patients who complete the study and transition to uninterrupted treatment with eculizumab will not be required to complete the 8-week Safety 
Follow-up Visit. 
27. 
The end of the Primary Treatment Period Week 52/53 (time of endpoint assessment) is differentiated from the end of the study (EOS) at 
Week 156/157. 
28. 
Early Termination (ET) is defined as any time the patient leaves the study before Week 156/157. If a patient withdraws from the study or 
discontinues eculizumab treatment at any time prior to Week 156/157, the patient will be required to complete an ET Visit at the time of withdrawal 
and a Safety Follow-up Visit 8 weeks following the last dose of study drug. 
29. 
All patients will remain in the same weight cohort throughout the induction period, regardless of change in weight. 
30. 
This dosing would be applicable only if a patient started on 20 to < 30 kg weight cohort and the patient’s weight decreased to 10 to < 20 kg. 
31. 
The Investigator must confirm with the patient or their guardian/caregiver by telephone that the transition to eculizumab occurred within 2 weeks of 
the last scheduled dose during the study. In the event that treatment with eculizumab is delayed, an unscheduled Safety Follow-up Visit should occur 
on the day of initiating eculizumab treatment or as soon as feasible. 
32. 
The test is designed for self-completion in patients aged ≥5 years by respondents (with 3 age-appropriate PedsQL tests available for ages 5-7, 8-12, 
and 13-18 years old), and by a Proxy in patients aged ≥2 to < 5 years. 
33. 
This dosing would be applicable only if a patient started on 10 to < 20 kg weight cohort and the patient’s weight increased to higher weight cohorts. 
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Protocol Amendment 2.2 
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Table 9: 
Schedule of Assessments – Footnotes
Footnote 
Description 
34. 
Patients need to be anti-AQP4 Ab-positive to be eligible for enrollment into the study. 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 Alexion prior to enrollment. 
35. 
The Snellen eye chart will be used in patients ≥6 years and a LEA symbols eye chart will be used in patients who are aged 2-5 years. 
Δ 
In Clinic – visits must be conducted at the investigational sites; Remote – visits may be conducted 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. 
* 
EOS Visit will occur at the end of all study visits and before the Safety Follow-up Visit, while ET will occur at the time the patient withdraws. 
Abbreviations 
Abbreviations: ADA = anti-drug antibodies; AQP4 Ab = aquaporin 4 antibody; B = Baseline sample; C5 = complement protein 5; D = day; 
ECG = electrocardiogram; eCRF = electronic case report form; EOS = End of Study; EQ-5D-5L = European Quality of Life-5 Dimensions-5L; 
EQ-5D-Y = European Quality of Life 5-Dimension Youth; ET = Early Termination; F/U = Follow-up; IPND = International Panel for NMO 
Diagnosis; IXRS = Interactive Voice/Web Response System; N/A = not applicable; NMOSD = Neuromyelitis Optica Spectrum Disorder; P = peak 
sample; OCT = Optical Coherence Tomography; OSIS = Optic Spinal Impairment Score; PD = pharmacodynamics; PK = pharmacokinetics; 
QoL = quality of life; T = trough sample; W = week 
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Protocol Amendment 2.2 
ECU-NMO-303 
2.
INTRODUCTION
Neuromyelitis Optica Spectrum Disorder (NMOSD) is an ultra-rare, severe, disabling 
autoimmune inflammatory disorder of the CNS that predominantly affects the optic nerves and 
spinal cord, and is often characterized by a relapsing course. The prevalence of NMOSD in 
adults is estimated at 0.5 to 4.4/100,000. Neuromyelitis Optica Spectrum Disorder occurs even 
less frequently in the pediatric population, with an estimated prevalence of 0.02 to 0.03/100,000. 
In various pediatric populations the median age of onset has been reported as 10 to 14 years, with 
a range from 1.9 to 18 years (Pandit, 2015). The incidence of NMOSD in patients younger than 
2 years is exceedingly rare, with no cases reported in Europe or in the USA. In both the adult and 
pediatric populations, females are much more commonly affected than males, with a female to 
male ratio of at least 3:1 (Fujioka, 1989; McKeon, 2008; Mealy, 2012; Tillema, 2012). 
Currently there are no approved therapies for the treatment of pediatric patients with NMOSD. 
2.1. 
Study Rationale 
Eculizumab (h5G1.1-mAb) is a humanized monoclonal antibody (mAb) that was derived from 
the murine anti-human complement protein 5 (C5) antibody (Ab) m5G1.1. Eculizumab 
specifically binds the terminal complement protein C5, thereby inhibiting its cleavage to C5a and 
C5b during complement activation. This strategic blockade of the complement cascade at C5 
prevents the release of proinflammatory mediators and the formation of the cytolytic pore, while 
preserving the early components of complement activation that are essential for the opsonization 
of microorganisms and clearance of immune complexes. 
Similarities in clinical presentation, serologic findings, and disease course strongly suggest that 
the pathophysiology of NMOSD in pediatric and adult patients is essentially the same. Given 
that eculizumab has been proven to be beneficial in adult patients, this study is being undertaken 
to inform on the efficacy and safety in pediatric patients (Pittock, 2019; Pittock, 2013). 
2.2. 
Eculizumab in Patients with Neuromyelitis Optica Spectrum 
Disorder 
In 2013, an Investigator-initiated study designed to evaluate the safety and efficacy of 
eculizumab in patients with anti- aquaporin-4 (AQP4) Ab-positive NMOSD demonstrated 
preliminary safety and efficacy in relapsing NMOSD (Pittock, 2013). After 12 months of 
treatment, 12/14 (86%) patients were attack-free, and 2 had possible attacks. The median 
annualized relapse rate (ARR) declined from 3 (pre-eculizumab, range 2-4) to 
0 (post-eculizumab, range 0-1; p<0.0001). 
In 2018, a multinational, double-blind, parallel-group Phase 3 time-to-event study, PREVENT, 
reported on the efficacy and safety of eculizumab compared to placebo for the treatment of adult 
patients with anti- AQP4 auto Ab-positive NMOSD. Treatment with eculizumab reduced the risk 
of NMOSD relapse by 94.2% compared to placebo (p<0.0001). At 48 weeks, 97.9% of patients 
receiving eculizumab were free of relapse compared to 63.2% of patients receiving placebo. 
Treatment with eculizumab also reduced the adjudicated On-Trial ARR compared to placebo, a 
key secondary endpoint, by 95.5% (p<0.0001). Eculizumab was generally well tolerated with a 
safety profile consistent with that seen in previous clinical studies and real-world use in its 3 
approved indications (Pittock, 2019). 
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Protocol Amendment 2.2 
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2.3. 
Background 
2.3.1. 
Clinical Presentation of Neuromyelitis Optica Spectrum Disorder 
The most common clinical hallmarks of NMOSD are acute optic neuritis (ON) and transverse 
myelitis (TM) that frequently involves greater than 3 vertebral levels, described as longitudinally 
extensive transverse myelitis (LETM) (Oh, 2012). These clinical events can occur either 
simultaneously or in isolation (Wingerchuk, 2007). Signs and symptoms attributable to lesions 
beyond the optic nerves and spinal cord, such as brainstem or cerebral lesions, also occur in 
patients with NMOSD (Popescu, 2011; Poppe, 2005; Wingerchuk, 1999). 
The clinical presentation of NMOSD can be quite variable and may elude diagnosis at the time 
of the first or even the second attack. The diagnosis of NMOSD can be even more challenging in 
children. Although cerebral lesions in children and in adults are detected at the same rate 
(~60%), children are often more symptomatic, presenting with cerebral symptoms that resemble 
other demyelinating disorders, and may precede the typical features of ON or TM by several 
months (Fardet, 2003; Fragoso, 2014; McKeon, 2008). In children, cerebral presentations are 
variable and can include symptoms such as encephalopathy, ophthalmoparesis, ataxia, seizures, 
intractable vomiting, hiccups, or vertigo (Banwell, 2008); (Chelimsky, 2004); (Chitnis, 2013); 
(Fardet, 2003); (McKeon, 2008). 
Recent studies have shown that in more than 90% of the anti-AQP4 Ab-positive pediatric cases, 
NMOSD is a relapsing disease (Wingerchuk, 2008). Once a relapsing course has been 
established, recurrent attacks result in a stepwise accumulation of neurologic disability. In 
patients with NMOSD, the disability accumulation is associated with relapse  
(Wingerchuk, 2007). Therefore, relapse prevention is paramount for successful treatment of 
relapsing NMOSD (Banwell, 2008; Wingerchuk, 2007; Wingerchuk, 2008). 
The prognosis of untreated NMOSD is poor. Before universal recognition of NMOSD as a 
disease distinct from multiple sclerosis (MS), and thus requiring a very different treatment 
paradigm, the 5-year mortality of NMOSD was reported to be 30%; 50% of patients sustain 
permanent, severe visual (blind in one or both eyes) or ambulatory (requiring a wheelchair) 
disability. Most deaths result from neurogenic respiratory failure secondary to a high cervical 
cord or brainstem lesion (Wingerchuk, 1999). A more recent 2012 investigation of the clinical 
outcomes and prognostic characteristics of patients who are anti-AQP4 Ab-positive from the 
United Kingdom and Japan showed that frequent, early relapses predict a poor prognosis. In that 
study, approximately 1/5 (18%) patients developed permanent visual disability; 1/3 (34%) 
developed permanent motor disability; approximately 1/4 (23%) became wheelchair-dependent, 
and nearly 1/10 (9%) of patients died after a median disease duration of 75 months  
(Kitley, 2012). 
2.3.2. 
Unmet Medical Need 
Currently, no therapies are approved for the treatment of NMOSD in pediatric patients. Thus, 
supportive treatment, including corticosteroids and other immunosuppressive therapies (ISTs), is 
used based on clinical experience and consensus (Trebst, 2014). Despite the use of ISTs as 
supportive therapy, a significant number of patients (>50%) continue to experience disease 
relapses that result in additional and permanent neurologic deficits and disability 
(Bichuetti, 2015; Bichuetti, 2010; Costanzi, 2011; Jacob, 2009; Kim, 2011). 
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Protocol Amendment 2.2 
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Given the seriousness of the disease and the limitations of the small number of currently 
available supportive treatments, there remains a significant unmet medical need for an effective 
and safe treatment for NMOSD in the pediatric population. 
2.3.3. 
Role of Complement in Neuromyelitis Optica Spectrum Disorder 
Complement activation is a major determinant of disease pathogenesis in patients with NMOSD 
(Hinson, 2009; Nytrova, 2014; Papadopoulos, 2012; Verkman, 2012). Binding of anti-AQP4 
autoantibodies 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 component 1, the first step in activation of the 
complement cascade (Diebolder, 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 
antibodies and complement. 
2.4. 
Benefit/Risk Assessment 
2.4.1. 
Potential Benefits 
Given that NMOSD is a severe, disabling disease with relapse and cumulative disability 
occurring in more than 90% of cases (Wingerchuk, 2008), pediatric patients with NMOSD are at 
risk of substantial morbidity and mortality. The efficacy and safety of eculizumab compared to 
placebo for the treatment of adult patients with anti-AQP4 Ab-positive NMOSD has recently 
been demonstrated in a multinational, double-blind, parallel-group Phase 3 time-to-event study, 
PREVENT, in which treatment with eculizumab reduced the risk of NMOSD relapse by 94.2% 
compared to placebo (p<0.0001) (Pittock, 2019). Given that the pathogenesis of the disease in 
pediatric patients is similar to that in adults, treatment with eculizumab may result in reduction of 
relapses in pediatric patients as well. 
2.4.2. 
Identified and Potential Risks 
2.4.2.1. 
Meningococcal Infection and Other Encapsulated Bacterial Infections 
Eculizumab blocks terminal complement; therefore, patients may have increased susceptibility to 
serious infections, and in particular, Neisseria meningitidis (N meningitidis). Children treated 
with eculizumab may be at increased risk of developing serious infections due to 
Streptococcus pneumoniae (S pneumoniae) and Haemophilus influenzae type b (Hib). Specific 
risk mitigation measures in place are described in Section 8.3.6. 
2.4.2.2. 
Immunogenicity 
As with any humanized mAb, administration of eculizumab may be associated with the 
development of anti-drug Abs (ADA). Monitoring of immunogenicity is planned, as described in 
Section 8.2.4 and Section 1.2. 
2.4.2.3. 
Coronavirus Disease 2019 
The coronavirus disease 2019 (COVID-19) global pandemic is active at the time of this 
amendment in many countries. Given this unique circumstance, specific consideration has been 
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given to the risks and benefits of the study as they relate to COVID-19 and the global and local 
changes that exist as a result of the pandemic. This assessment is described in Section 10.15; 
Appendix 15. 
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3.
OBJECTIVES AND ENDPOINTS
Objectives 
Endpoints 
Primary Treatment Perioda: Primary: Efficacy 
•
Evaluate the efficacy of eculizumab in
relapsing pediatric patients with
Neuromyelitis Optica Spectrum Disorder
(NMOSD).
•
The change from Baseline in the Annualized
Relapse Rate (ARR) at 52/53 Weeks.b
•
Time to First Relapse (TFR)
Primary Treatment Perioda: Secondary: Safety 
•
Evaluate the safety and tolerability of
eculizumab treatment in relapsing pediatric
patients with NMOSD.
•
Incidence of treatment-emergent adverse
events (TEAEs), serious adverse events
(SAEs), and adverse events leading to study
drug discontinuation.
•
Incidence of antidrug antibodies (ADAs).
•
Changes from Baseline in vital signs,
electrocardiogram (ECG) parameters, and
clinical laboratory assessments.
•
Change from Baseline in both weight and
height.
Primary Treatment Perioda: Secondary: Efficacy 
•
Evaluate the efficacy of eculizumab by
additional efficacy measures including:
•
Disease-related disability
•
Change from Baseline in Expanded Disability
Status Scale (EDSS) score at 52/53 weeks in
patients ≥ 5 years of age.
•
Change from Baseline in the Hauser
Ambulatory Index (HAI) score at
52/53 weeks.
•
Quality of life
•
Change from Baseline in Pediatric Quality of
Life Inventory (PedsQL) at 52/53 weeks in
patients ≥ 5 years of age.
•
Change from Baseline in Pediatric Quality of
Life Inventory Parent Proxy (PedsQL Parent
Proxy) at 52/53 weeks in patients < 5 years of
age.
•
Change in ophthalmologic
examination findings
•
Change from Baseline in Visual Acuity (VA)
as measured by the Snellen or LEA symbols
Eye Chart examination at 52/53 weeks in all
patients.
•
Change from Baseline in Confrontational
Visual Fields (VF) as measured during
ophthalmologic examination at 52/53 weeks
in all patients.
•
Change from Baseline in color vision as
measured during ophthalmologic examination
at 52/53 weeks in all patients.
Primary Treatment Perioda: Secondary: PK/PD 
•
Describe the pharmacokinetics (PK)
and pharmacodynamics (PD) of
eculizumab in relapsing pediatric
patients with NMOSD.
•
Changes in serum eculizumab concentration
over time.
•
Changes in serum free complement protein 5
(C5) concentrations and in vitro hemolytic
activity over time.
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Objectives 
Endpoints 
Primary Treatment Perioda: Tertiary: Efficacy Assessment 
•
Evaluate the efficacy of eculizumab by
additional efficacy measures including
•
Quality of life
•
Change from Baseline in the European
Quality of Life-5 Dimensions-Youth
(EQ-5D-Y) score for patients ≥ 8 years of age
and EQ-5D-Y Proxy score for patients aged
between 5-7 years, at 52/53 weeks.
Extension Treatment Periodc: Secondary: Safety and Efficacy 
•
Characterize long-term safety of eculizumab
treatment in pediatric patients with NMOSD.
•
Characterize long-term efficacy of eculizumab
treatment in pediatric patients with NMOSD.
•
The safety and efficacy endpoints of the
Primary Treatment Period will be evaluated
during the Extension Treatment Period.
a Open-label eculizumab intravenous (IV) infusion, for a total of 52/53 weeks. 
b For patients who start in weight cohort 10 to < 20 kg, the one-year evaluation will occur on Week 53, an odd 
numbered week, because maintenance dosing, which is administered every 2 weeks, begins on Week 1. For all 
other cohorts the one-year evaluation will occur on Week 52, because maintenance dosing begins on an even 
numbered week. Hence, the end of the Primary Treatment Period is designated as Week 52/53 throughout the 
protocol. 
c After completing the Primary Treatment Period, patients will continue receiving open-label eculizumab in the 
Extension Treatment Period for 104 weeks. 
Note: Statistical analysis of the primary endpoints will be limited to the change from Baseline to Week 52/53 
On-Trial ARR. TFR results will be considered descriptive; therefore, no adjustments for multiplicity will be made. 
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4.
STUDY DESIGN
4.1. 
Overall Design 
4.1.1. 
Overall Design/Methodology 
The study design is depicted in Figure 1. 
This is a Phase 2/3 open-label, single-arm study to evaluate the safety and efficacy of eculizumab 
in pediatric patients (aged 2 to < 18 years) with relapsing NMOSD. A total of approximately 
12 eligible patients will be enrolled, with a minimum target of 10 evaluable patients. Of the 
10 evaluable patients, at least 3 of the patients will be aged 2 to < 12 years at the time of 
enrollment, and at least 5 patients will be aged 12 to < 18 years at the time of enrollment. 
There are 4 periods in this study: the Screening Period, the Primary Treatment Period, the 
Extension Treatment Period, and the Safety Follow-up Period. 
Figure 1: 
Schematic Design for Study ECU-NMO-303 
4.1.2. 
Screening Period (1 – 6 weeks) 
At the Screening Visit, after obtaining the informed assent of the patient (if applicable) and the 
informed consent of the parent or other legal guardian, the patient will be screened for study 
eligibility through medical history review, demographic data, physical examination, concomitant 
medications, and clinical laboratory assessments (including evaluation for anti-AQP4 
Ab-seropositivity). A complete neurologic assessment to include neurologic examination, 
Expanded Disability Status Scale (EDSS) evaluation, and other assessments, as per the schedule 
of activities (SoA; Section 1.2), will be performed. Baseline magnetic resonance imaging (MRI) 
(contrast optional) and Optical Coherence Tomography (OCT) examinations are required per the 
protocol; however, exceptions may be granted (eg, based on the availability of recent historical 
results) at the discretion of the Alexion Medical Monitor. 
The medical history review will include confirmation of the NMOSD diagnosis as defined by the 
International Panel for NMO Diagnosis (IPND) criteria described in Wingerchuk, 2015 
(Section 10.6; Appendix 6); only patients who are both anti-AQP4 Ab-positive and otherwise 
meet the 2015 IPND criteria will be eligible. All available information about relapses, which 
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occurred within the 2 years prior to Screening and that meet the protocol definition of Historical 
Relapse (Section 4.2.1) will be recorded, including relapse onset date, clinical presentation, acute 
and maintenance treatments, dosing regimens, and any disability measurements such as EDSS 
scores. Screening laboratory assessments will include evaluation for anti-AQP4 Ab 
seropositivity. 
4.1.3. 
Primary Treatment Period (Day 1 – Week 52/53) 
All eligible patients will receive open-label eculizumab IV infusion, starting on Day 1 for a total 
of 52/53 weeks. The dosing regimen will be based on the pediatric patient’s body weight 
(Table 13). Weight may change for an individual patient during the study; therefore, when 
possible, dose regimen will be based on the current visit’s recorded body weight (Section 6.1). 
However, all patients will remain in the same weight cohort throughout the induction period, 
regardless of change in weight. If site/institution policies prohibit study drug to be prepared on 
the day of visit, the weight from the most recent study visit should be used. Patients may have an 
opportunity to receive eculizumab 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. If a patient is receiving an infusion at a remote facility or at home, the weight from 
the prior study visit may be used to calculate the dose. 
Clinical measures and laboratory tests, as described in Section 10.2; Appendix 2, will be 
routinely performed to assess safety, efficacy, neurological function, and other clinical 
parameters associated with physical growth and cognition for patients continuing in the 
Treatment Period (Section 1.2). The Primary Treatment Period ends on Week 53 for patients 
who were enrolled in the 10 to < 20 kg weight cohort, because for this weight cohort, the 
maintenance dose, administered every 2 weeks, begins on Week 1; for all other weight cohorts 
the Primary Treatment Period will end at Week 52 because the maintenance dosing begins on 
even-numbered weeks. 
Identification of potential relapse is critical for patient safety and for the study. Patients and their 
parents/guardians will receive a Patient Education Card detailing the signs and symptoms of a 
potential relapse, including instructions to contact the study site at the first sign or symptom of a 
potential relapse. Patients should be seen within 24 to 48 hours of notification of a possible 
relapse so that the Investigator can evaluate the patient and determine whether or not the patient 
meets the definition of Investigator-Reported On-Trial Relapse as defined by this protocol 
(Section 4.2; Section 8.1.8). 
4.1.4. 
Extension Treatment Period (104 weeks) 
After completing the 52/53-week Primary Treatment Period, patients may continue receiving 
eculizumab in the Extension Treatment Period for 104 weeks. Weight may change for an 
individual patient during the study; therefore, when possible, dose regimen will be based on the 
current visit’s recorded body weight (Section 6.1). If site/institution policies prohibit study drug 
to be prepared on the day of visit, the weight from the most recent study visit should be used. 
Patients may have an opportunity to receive eculizumab 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 
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regulatory authorities. If a patient is receiving an infusion at a remote facility or at home, the 
weight from the prior study visit may be used to calculate the dose. 
Clinical measures and laboratory tests will be routinely performed on patients to assess safety, 
efficacy, neurological function, and other clinical parameters associated with physical growth 
and cognition throughout in the Extension Treatment Period (Section 1.2). 
Identification of potential relapse is critical for patient safety and for the study. Patients and their 
parents/guardians will receive a Patient Education Card detailing the signs and symptoms of a 
potential relapse, including instructions to contact the study site at the first sign or symptom of a 
potential relapse. Patients should be seen within 24 to 48 hours of notification of a possible 
relapse so that the Investigator can evaluate the patient and determine whether or not the patient 
meets the definition of Investigator-Reported On-Trial Relapse as defined by this protocol 
(Section 4.2; Section 8.1.8). 
4.1.5. 
Safety Follow-up Period (8 Weeks Following the Last Dose of Eculizumab) 
Patients who withdraw or discontinue treatment at any time and for any reason after receiving 
any amount of eculizumab will be required to complete both an Early Termination (ET) Visit at 
the time of withdrawal and a Safety Follow-up Visit at 8 weeks following the last eculizumab 
dose. Adverse events leading to patient discontinuation from the study are followed until 
resolution or are medically stable in the opinion of the Investigator. 
Patients who complete the study without transitioning to uninterrupted treatment with 
eculizumab or ravulizumab must complete both an End of Study (EOS) Visit at the time of study 
completion and a Safety Follow-up Visit, which will occur 8 weeks from the date the patient’s 
last dose of eculizumab was administered. Patients who complete the study and transition to 
uninterrupted treatment with eculizumab will not be required to complete the Safety Follow-up 
Visit at 8 weeks. 
4.2. 
Methodology of Relapse Evaluation 
4.2.1. 
Historical Relapse 
Historical relapses are the relapses that occurred prior to the Screening Visit, including the first 
NMOSD attack. Please refer Section 10.5; Appendix 5 for further details. 
4.2.2. 
On-Trial Relapse 
On-Trial Relapses are acute attacks that occur during the study. Please refer Section 10.5; 
Appendix 5 for further details. 
4.2.3. 
Severity of Relapse 
Severity of an Investigator-Reported On-Trial Relapse will be measured by the Optic Spinal 
Impairment Score (OSIS) (Section 10.12; Appendix 12). 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. OSIS score will be 
assessed by the Investigator at the time of the relapse. 
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Table 10: 
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 
4.2.4. 
Investigator 
The Investigator will be responsible for the overall patient management including patient 
eligibility evaluation, supervision of study drug administration, recording and treating the 
adverse events (AEs) and monitoring of safety assessment. At the time of a relapse, the 
Investigator will perform a complete neurologic examination, determine if a patient experiences 
a relapse, and may treat the patient’s relapse according to the recommended regimen for 
treatment of On-Trial Relapse described in Section 6.6.1.3. Treatment for relapse, as well as any 
changes in the ISTs following relapse, are at the discretion of the Investigator. 
4.2.5. 
The Expanded Disability Status Scale Rater 
The blinded EDSS Rater will be responsible for performing the EDSS assessments throughout 
the study including at the time of a relapse. The EDSS Rater must remain blinded to all other 
study data as well as all other patient clinical data. The EDSS Rater will perform a complete 
Kurtzke neurologic examination, as described in Section 10.9; Appendix 9 and document the 
Functional Systems Score (FSS) and the EDSS score (Kurtzke, 1983). 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. For specific 
requirements for EDSS Rater qualification, refer to the training materials. 
Table 11 below provides roles and responsibilities of Investigator and EDSS Rater. 
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Table 11: 
Roles and Responsibilities of the Investigator and EDSS Rater 
Investigator 
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 neurological assessment
•
Document FSS
•
Record EDSS score
At the time of relapse: 
•
Initial patient assessment
•
Have the EDSS Rater record Functional Systems
(FS) 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 field, and color
vision
•
Assess ambulation by HAIa
•
Have the patient/Proxy complete the
EQ-5D-Y / EQ-5D-Y Proxy
•
Have the patient/Proxy complete the
PedsQL/PedsQL Proxy
•
Treat relapse
At the time of relapse: 
•
Perform the Kurtzke neurologic assessment
•
Document FSS
•
Record EDSS score
a Can be performed by the Investigator or a designee 
Abbreviations: EDSS = Expanded Disability Status Scale; EQ 5D Y / EQ 5D-5L = Euro Quality of life-5 
Dimensions-Youth; FSS = Functional Systems Score; HAI = Hauser Ambulatory Index; OSIS = Optic spinal 
impairment score; PedsQL = Pediatric Quality of Life Inventory; VA = Visual Acuity 
4.2.6. 
Review of Investigator-Reported On-Trial Relapses 
While Investigator-Reported On-Trial Relapses will be used to determine the primary endpoint, 
all relapses will be independently reviewed by the Relapse Adjudication Committee (RAC). The 
Committee, consisting of medical experts, who have particular expertise in NMOSD, will 
conduct independent reviews for all relapse events identified by the Investigators. The 
Committee will decide by majority vote whether each Investigator-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. 
4.3. 
Scientific Rationale for Study Design 
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 primary endpoint in ECU-NMO-303. During the EMEA NMO Workshop held in October 
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2014, a consensus was achieved regarding the use of time to first relapse (TFR) as the primary 
endpoint for adult pivotal studies to demonstrate efficacy of new compounds developed in 
NMOSD. However, no agreement regarding the primary endpoint to be used in pediatric studies 
has been reached, highlighting differences in clinical study methodology for the 2 populations. 
In this long-term, single-arm study, the occurrence of relapses is evaluated using the co-primary 
endpoints ARR and TFR. The effect of eculizumab on the reduction of frequency of relapses will 
be measured using the ARR, with the change in On-Trial ARR compared to the Historical ARR. 
Time to first relapse also provides useful information regarding the efficacy of eculizumab. In 
clinical practice, many neurologists initiate, change, or modify treatment following a relapse. 
Since effectiveness of a treatment can be based on delaying and/or reducing the occurrence of 
relapses, TFR is an appropriate co-primary efficacy endpoint for prospectively designed studies 
in NMOSD (Weinshenker, 2015a; Weinshenker, 2015b). A Kaplan-Meier graphical analysis will 
be performed to illustrate the TFR from the start of eculizumab treatment. 
4.4. 
Justification for Dose 
The doses of eculizumab to be administered in this study have been selected based on the results 
of a modeling and simulation study completed to support the planned body weight-categorized 
dose regimens, described below. 
The demonstration of pharmacokinetic (PK)-bridging between patients aged ≥ 18 years with 
atypical hemolytic uremic syndrome (aHUS) and NMOSD was critical to the selection of dose 
regimens for pediatric patients with NMOSD; while substantial data has been generated for 
pediatric patients with aHUS, there is no prior PK data from pediatric patients with NMOSD. 
The successful PK-bridging enabled extrapolation of all pediatric aHUS data and the 
corresponding PK model to pediatric patients with NMOSD. Simulations using the aHUS-PK 
model and NMOSD-PK model, respectively, demonstrated the comparability of eculizumab 
serum concentration time profiles between patients with aHUS and patients with NMOSD for 
body weight ≥ 40 kg. 
Demonstrating pharmacodynamic (PD) bridging between patients aged ≥ 18 years with 
aHUS/paroxysmal nocturnal hemoglobinuria (PNH) and those with NMOSD was also important. 
Using PK and PD data from patients aged ≥ 18 years and pediatric patients with aHUS and 
patients aged ≥ 18 years and pediatric patients with PNH, the PK/PD (hemolysis) analysis 
identified an eculizumab threshold concentration range of 50-100 μg/mL to achieve complete 
inhibition of hemolysis. 
Using PK and PD data from patients aged ≥ 18 years with NMOSD from Study ECU-NMO-301, 
the PK/PD analysis of hemolysis or free complement 5 (C5) identified an eculizumab threshold 
serum concentration of 85 μg/mL to achieve complete inhibition of hemolysis, which is within 
the range (50-100 μg/mL) identified above in aHUS. Therefore, the PD bridging was 
successfully demonstrated between the 2 indications. 
In both aHUS and NMOSD-PK models, body weight was identified as the only important 
covariate; therefore, categorical body weight-based dosing is recommended in the pediatric 
population. The body weight exponent for the aHUS-PK model was used, because the aHUS-PK 
model leveraged the prior pediatric PK data within the weight range of interest. 
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The aHUS-PK model was used to simulate eculizumab concentration time profiles for pediatric 
patients with NMOSD. The simulation results showed that, overall, the proposed dosing 
regimens essentially maintained therapeutic levels of eculizumab, across the body weight 
categories. Hence, the proposed body weight-categorized dosing regimens are expected to 
achieve immediate, sustained, and complete inhibition of terminal complement in pediatric 
patients with NMOSD. 
Complete and sustained inhibition of complement activity will be confirmed with PK/PD data 
derived from this study. 
The dosing regimen will be based on the pediatric patient’s body weight (Table 13). Body weight 
is expected to change during this pediatric study; therefore, a patient’s weight cohort may change 
during the study. 
4.5. 
End of Study Definition 
A patient is considered to have completed the study if: 
•
The patient has completed all periods of the study including the last visit of the Extension
Period and, if applicable, the Safety Follow-up Visit, or
•
In the event the study is terminated early by the Sponsor, the patient has completed all
applicable periods of the study including the EOS Visit and Safety Follow-up Visit.
The end of the study is defined as the date of the last visit of the last patient (including the Safety 
Follow-up, if applicable) in the study. 
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5.
STUDY POPULATION
The study population will be comprised of pediatric patients with NMOSD who are 
2 to < 18 years of age and who meet the study entry criteria listed below. 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: 
Demographic Characteristics 
1. Male or female patients aged 2 years to < 18 years at time of assent/consent.
2. Male or female patients with body weight ≥ 10 kg.
Type of Participant and Disease Characteristics 
3. Vaccinated against N meningitidis within 3 years prior to, or at the time of initiating
eculizumab. 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.
4. Documented vaccination against Hib and S pneumoniae infections at least 2 weeks prior
to dosing as per local and country-specific immunization guidelines for the appropriate
age group.
5. Anti-AQP4 Ab-positive and diagnosis of NMOSD as defined by the 2015 IPND criteria
(Section 10.6; Appendix 6).
6. Historical Relapse Rate (as defined by protocol, Section 4.2.1) of at least 2 relapses in the
last 2 years, and with at least 1 relapse in the year prior to Screening.
7. Expanded Disability Status Scale score ≤ 7 (Section 10.9; Appendix 9).
8. Patients who enter the study receiving supportive IST(s) (eg, corticosteroid, azathioprine
[AZA], mycophenolate mofetil [MMF], methotrexate [MTX], tacrolimus [TAC],
cyclosporin [CsA], or cyclophosphamide [CYC]) for the prevention of relapse, either in
combination or monotherapy, must be on a stable dosing regimen of adequate duration prior
to Screening, as follows, and remain on a stable dosing regimen during the Screening Period:
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, CsA, TAC,
or CYC), 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 has recently discontinued any of the above medications, a period of time
equal to the stable dose requirement listed above for that medication (eg, ≥ 2 months
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for AZA or ≥ 4 weeks for corticosteroids) must have passed prior to the first day of 
the Screening Period. 
9. For patients who enter the study receiving corticosteroid therapy, the daily dose of
corticosteroids must not exceed 0.5 mg/kg/day of prednisone or equivalent and in no case
may the dose exceed 20 mg/day.
10. Female patients of childbearing potential must have a negative pregnancy test (serum
human chorionic gonadotropin [HCG]) at Screening (Section 10.4; Appendix 4).
11. Female patients of childbearing potential (ie, have achieved menarche) must follow
protocol-specified contraception guidance for avoiding pregnancy while on treatment and
for 5 months after the last dose of eculizumab (Section 10.4; Appendix 4).
12. Male patients with a female 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 5 months after the last dose of eculizumab (Section 10.4; Appendix 4).
Informed Consent 
13. Willing and capable to give informed assent (if applicable, as determined by the central
Institutional Review Boards (IRBs)/Independent Ethics Committees (IECs) and in
accordance with local requirements) and whose parent/legal guardian are willing and able
to give written informed consent, as described in Section 10.1.2; Appendix 1, which
includes compliance with the requirements and restrictions listed in the informed consent
form (ICF) and in this protocol.
5.2. 
Exclusion Criteria 
Participants are excluded from the study if any of the following criteria apply: 
Demographic Characteristics 
1. Parent or legal guardian is an Alexion employee.
Medical Conditions 
2. Pregnant, breastfeeding, or intending to conceive during the course of the study.
3. Patients known to be human immunodeficiency virus (HIV) positive or with congenital
immunodeficiency.
4. Unresolved meningococcal or other serious infection.
5. Active systemic bacterial, viral, or fungal infection within 14 days prior to study drug
administration on Day 1.
6. Known medical or psychological condition(s) or risk factor that, in the opinion of the
Investigator, might interfere with the patient’s full participation in the study, pose any
additional risk for the patient, or confound the assessment of the patient or outcome of the
study.
7. Hypersensitivity to murine proteins or to one of the excipients of eculizumab.
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Prior/Concomitant Therapy 
8. Use of rituximab within 6 months prior to Screening.
9. 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.
10. Use of mitoxantrone within 3 months prior to Screening.
11. Use of intravenous immunoglobulin (IVIg) or plasma exchange (PE) within 3 weeks
prior to Screening.
12. Use of immunomodulatory therapies for MS including: interferon beta-1b, interferon
beta-1a, glatiramer acetate, natalizumab, alemtuzumab, and fingolimod within 3 months
prior to Screening.
Prior/Concurrent Clinical Study Experience 
13. Participation in any other investigational drug study or exposure to an investigational
drug or device within 30 days of Screening or within 5 half-lives of that investigational
product, whichever is greater.
14. Has previously received treatment with eculizumab or other complement inhibitors.
5.3. 
Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently enrolled. A minimal set of screen failure information is required to ensure 
transparent reporting of screen failure participants to meet the Consolidated Standards of 
Reporting Trials (CONSORT) publishing requirements and to respond to queries from regulatory 
authorities. Minimal information includes demography, eligibility criteria, and any serious 
adverse event (SAE). 
A patient who experiences a relapse that meets the protocol definition of an On-Trial Relapse 
(Section 4.2) during the Screening Period will be considered a Screening failure. Such patients 
may be rescreened with Sponsor approval (once they are treated for relapse and considered 
medically stable by the Investigator). At least 30 days of clinical stability must exist prior to 
enrollment. The patient must meet the enrollment criteria at Re-Screening in order to enter the 
study. 
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened based on discussion and agreement between the Investigator and the Medical 
Monitor. 
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6.
STUDY DRUG
The study drug, eculizumab, will be manufactured and supplied by Alexion or a contract 
manufacturing organization in single 30 mL vials as a solution concentration of 10 mg/mL. Each 
vial contains 300 mg of eculizumab for intravenous (IV) administration. Eculizumab will be 
individually packaged in kits. Both vials and kits will be labeled according to the protocol and 
local regulatory requirements. 
Study drug orders will be released to each site upon receipt of all required documents based upon 
applicable regulations. Details are provided in the Pharmacy Manual. 
6.1. 
Study Drug Administered 
Eculizumab is formulated at pH 7 and each 30 mL vial contains 300 mg of eculizumab, 
polysorbate 80 (6.6 mg) (vegetable origin), sodium chloride (263.1 mg), sodium phosphate 
dibasic (53.4 mg), sodium phosphate monobasic (13.8 mg), and Water for Injection, US 
Pharmacopeia (USP). Additional details are provided in Table 12. 
Table 12: 
Study Drug Administered 
Product Name 
Eculizumab 
Dosage Form 
Concentrate for solution for infusion 
Unit Dose 
300 mg 
Route of Administration 
Intravenous infusion 
Physical Description 
30 mL vial 
Manufacturer 
Alexion or a contract manufacturing organization 
Study drug will be administered, according to the pediatric patient’s body weight, as indicated in 
Table 13. Body weight is expected to change during this pediatric study; therefore, a patient’s 
weight cohort may change during the study. 
Table 13: 
Weight-Based Dosing Regimen of Eculizumab 
Weight Cohorta,c 
Induction Periodb 
Maintenance Phase 
≥ 40 kg 
900 mg weekly × 4 doses 
1200 mg at Week 4; then every 2 weeks 
30 to < 40 kg 
600 mg weekly × 2 doses 
900 mg at Week 2; then every 2 weeks 
20 to < 30 kg 
600 mg weekly × 2 doses 
600 mg at Week 2; then every 2 weeks 
10 to < 20 kg 
600 mg weekly × 1 dose 
300 mg at Week 1; then every 2 weeks 
a Day 1 and maintenance period dose regimen will be based on the current visit’s recorded body weight. If 
site/institutions policies prohibit study drug to be prepared on the day of visit, the weight from the most recent 
study visit should be used. If a patient is receiving an infusion at a remote facility or at home, the weight from 
the prior study visit may be used to calculate the dose. 
b During the initial induction period, the dose regimen will be based on the patient’s weight on Day 1 (Visit 2). 
c All patients will remain in the same weight cohort throughout the induction period, regardless of change in 
weight. 
Notes: 
•
Dosage and treatment regimen are based on results of a modelling and simulation study.
•
Eculizumab will be administered by IV infusion.
Abbreviations: IV = intravenous. 
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6.2. 
Supplemental Doses 
If the patient undergoes PE/plasmapheresis (PP) for an Investigator-Reported On-Trial Relapse 
on a day that study drug administration is not routinely scheduled, a supplemental dose of 
eculizumab (Table 14) must be administered, preferably within 1 to 2 hours, after each PE/PP. If 
PE/PP is administered on the day of regularly scheduled study drug administration, there would 
not be any supplemental dose given and patients will receive the regularly scheduled number of 
vials, preferably within 1 to 2 hours, after each PE. 
If the patient receives PE/PP and study drug infusion at the Relapse Evaluation Visit, 3 blood 
samples for PK, PD and free C5 should be collected at the following intervals: 
1. Approximately 5 to 90 minutes prior to PE/PP
2. After PE/PP and before study drug infusion
3. At least 60 minutes after the completion of study drug infusion
If a patient receives PE/PP at any visit other than the Relapse-Evaluation Visit, blood samples for 
PK, PD, and free C5 assays will be collected immediately before and after each session of 
PE/PP. A peak sample, (ie, 1 hour after completion of supplemental study drug infusion), will 
also be collected. 
Table 14: 
Supplemental Dosing Regimen of Eculizumab for 
Plasma Exchange/Plasmapheresis 
Type of 
Intervention 
Most Recent 
Eculizumab 
Dose 
Supplemental Eculizumab 
Dose With Each Plasma 
Exchange/ Plasmapheresis 
Intervention 
Timing of 
Supplemental 
Eculizumab Dose 
Plasmapheresis (PP) or 
Plasma Exchange (PE) 
300 mg 
300 mg/each PP or PE session 
Within 1 to 2 hours after 
each PE or PP session 
600 mg or more 
600 mg/each PP or PE session 
6.3. 
Preparation/Handling/Storage/Accountability 
6.3.1. 
Study Drug Storage 
Upon arrival at the center, the study drug should be promptly removed from the shipping cooler 
and stored in refrigerated conditions between 2°C to 8°C (36°F to 46°F). The study drug must be 
stored in a secure, limited-access storage area, and temperature must be monitored daily. On-site 
storage temperature excursions must be reported to the Sponsor in a timely manner. 
Diluted solutions of study drug (dosing solutions) may be stored between 2°C to 8°C 
(36°F to 46°F) and/or at room temperature for a maximum of 24 hours. The 24-hour expiration 
includes preparation time, storage time, warming time, and infusion time. The solution should be 
allowed to warm to room temperature prior to administration. The material must not be heated 
(eg, by using a microwave or other heat source) other than by ambient air temperature. 
Refer to the Pharmacy Manual for additional instructions. 
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6.3.2. 
Study Drug Preparation 
Infusions of study drug should be prepared using aseptic technique. Each vial of study drug 
contains 300 mg of active ingredient in 30 mL of product solution. Withdraw the required 
amount of study drug from the vials. Transfer the recommended dose to an infusion bag. Dilute 
the study drug to a final concentration of 5 mg/mL by addition to the infusion bag of the 
appropriate amount (equal volume) of 0.9% Sodium Chloride Injection, United States 
Pharmacopeia (USP); 0.45% Sodium Chloride Injection, USP; 5% Dextrose in Water Injection, 
USP; or Ringer’s Injection, USP. The final volume of a 5 mg/mL diluted study drug solution is 
60 mL for 300 mg doses (1 vial), 120 mL for 600 mg doses (2 vials), 180 mL for 900 mg doses 
(3 vials), and 240 mL for 1200 mg doses (4 vials) as shown in Table 15. 
Table 15: 
Study Drug Reconstitution 
Study Drug 
Volume of 
Study Drug 
Volume of Diluenta 
Total Volume of Administration 
300 mg (1 vial) 
30 mL 
30 mL 
60 mL 
600 mg (2 vials) 
60 mL 
60 mL 
120 mL 
900 mg (3 vials) 
90 mL 
90 mL 
180 mL 
1200 mg (4 vials) 
120 mL 
120 mL 
240 mL 
a Choose one of the following diluents: 1) 0.9% sodium chloride; 2) 0.45% sodium chloride; 3) 5% dextrose in 
water; 4) Ringer’s injection 
Gently invert the infusion bag containing the diluted study drug solution to ensure thorough 
mixing of the product and diluents. Discard any unused portion left in a vial, as the product 
contains no preservatives. The diluted solution should be allowed to warm to room temperature 
by exposure to ambient air prior to administration. 
6.3.3. 
Study Drug Administration 
Doses of study drug must only be prepared and dispensed by qualified study personnel. Study 
drug is to be dispensed only to enrolled patients who are confirmed eligible for participation in 
this study. Once study drug is prepared for a patient, it can only be administered to that patient. 
Vials of study drug are for one-time use only, and any drug product remaining in the vial must 
not be used for another patient. Any drug remaining in the infusion tubing or infusion bag should 
not be used for another patient. Further details on preparation and dose administration of 
eculizumab, as well as disposal of the study drug, can be found in the Pharmacy Manual. 
Drug must be administered at the study site during the initial 12/13 weeks of the study. Drug 
may be administered at a medical facility located near or at the patient’s home during the 
Primary Treatment Period and Extension Period according to the SoA, Section 1.2. Remote visit 
options will 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 signs or symptoms of NMOSD relapses will 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 NMOSD relapse, the patient will need to be evaluated at the study site. 
Study drug should only be administered via IV infusion, using a weight-based schedule 
(Section 6.1). DO NOT ADMINISTER AS AN IV PUSH OR BOLUS INJECTION. 
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Prior to study drug administration, the diluted solution should be allowed to warm to room 
temperature by exposure to ambient air. The diluted solution must not be heated in a microwave 
or with any heat source other than ambient air temperature. Parenteral drug products should be 
inspected visually for particulate matter and discoloration prior to administration. 
The diluted study drug should be IV administered over 1 to 4 hours in pediatric patients. For 
those patients who reach ≥ 18 years of age during the study, the study drug should be 
administered IV over 35 (± 10) minutes. It is not necessary to protect the infusion bags from light 
while study drug is being administered to the patient. The patient should be monitored for at least 
1 hour following infusion. 
If an AE occurs during administration of the study drug, the infusion may be slowed or stopped 
at the discretion of the Investigator, depending upon the nature and severity of the event; 
however, the overall duration should not exceed 2 hours from the start of the infusion in patients 
aged ≥ 18 years and 4 hours from the start of infusion in pediatric patients. The AE must be 
captured in the patient’s source document and electronic case report form (eCRF). 
The actual start and stop times of all dose administrations will be recorded in the patient’s source 
documents and eCRF. Refer to the Pharmacy Manual for additional directions on study drug 
administration. 
Sites must have resuscitation equipment, emergency drugs, and appropriately trained staff 
available during the infusion, and for at least 1 hour after patients have completed their infusion. 
6.3.4. 
Study Drug Accountability 
When a study drug shipment is received at the site, the pharmacist should verify the contents, 
sign the packing invoice provided with the shipment, and maintain the original copy for review 
by the study monitor. Additionally, reception of study drug (as well as reception conditions) 
must be reported to the Interactive Response Technology (IRT) system to allow drug 
randomization, resupply, estimations, and drug expiration control. 
Unless notified otherwise, empty vials and vials with residual materials should be kept for 
inspection and accountability by the study monitor prior to their destruction or handled per local 
pharmacy standard operating procedures (SOPs) for clinical study drugs. Destruction of used and 
unused vials, either locally or centrally, must be properly documented. Drug accountability will 
be managed through the IRT system and detailed instructions on managing the IRT drug 
accountability module will be included in the IRT User Guide. The pharmacist or designee must 
maintain accurate records demonstrating dates and amount of study drug received, to whom 
dispensed (patient-by-patient accounting), and accounts of any study drug accidentally or 
deliberately destroyed. These drug accountability records must be readily available upon request, 
and will be reviewed throughout the study. 
Each kit will have a label and a place for the pharmacist to record the patient number and initials. 
The study monitor will examine the inventory during the study. Additionally, the inventory 
records must be readily available to regulatory authorities, the local regulatory agency, or an 
independent auditor’s inspection at any time. 
Refer to the Pharmacy Manual for additional information. 
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6.3.5. 
Study Drug Handling and Disposal 
All clinical study material provided to the Investigator will be stored in a secure place, and 
allocated and dispensed by appropriately trained personnel. Detailed records of the amounts of 
the study drug received, dispensed, and destroyed will be maintained. 
To satisfy regulatory requirements regarding drug accountability, all remaining eculizumab 
inventory will be reconciled and destroyed or returned to Alexion at the EOS according to 
applicable regulations. 
Refer to the Pharmacy Manual for further information. 
6.4. 
Measures to Minimize Bias 
Although this is an open-label, single arm study, the co-primary endpoint, On-Trial ARR, will be 
compared to the patient’s Historical ARR, allowing patients to act as their own controls. 
Additionally, while the primary endpoint will be assessed based on Investigator reported 
relapses, the RAC will also adjudicate all relapses. 
6.5. 
Study Intervention Compliance 
The infusion of study drug into patients will be under the supervision of the Investigator or their 
designee to ensure that the patients received the appropriate dose at the appropriate timepoints 
during the study. 
If a patient fails to return, or is otherwise unavailable, for a scheduled visit within the acceptable 
visit window (± 2 days), the site study staff must make a reasonable attempt to contact the 
patient/patient’s parent or guardian to determine the reason for missing the appointment. Patients 
should be advised to return to the investigational site for evaluation, if relapse or an AE is 
suspected to have occurred. In this event, the investigational site will make a reasonable attempt 
to obtain all relevant medical records, and enter relevant data in the eCRF, as appropriate. 
6.6. 
Concomitant Therapy 
Prior medications (including vitamins and herbal preparations), including those discussed in the 
exclusion criteria (Section 5.2), and procedures (any therapeutic intervention, such as 
surgery/biopsy or physical therapy) the patient takes or undergoes within the 30 days prior to the 
start of Screening until the first dose of study drug, will be recorded in the patient’s eCRF. In 
addition, history of meningococcal, Hib, and S pneumoniae vaccinations and ISTs (including 
steroids) must be collected. 
All medications used and procedures undertaken during the study will be recorded in the 
patient’s source document/medical chart and eCRF. This record will include all prescription 
drugs, herbal products, vitamins, minerals, over-the-counter medications, and any other current 
medications. When possible, concomitant medications will be recorded from the first infusion of 
study drug until the patient has discontinued or completed the study. Any changes in 
concomitant medications also will be recorded in the patient’s source document/medical chart 
and eCRF. Any concomitant medication deemed necessary for the patient’s standard of 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 6.6.2, may be given at the discretion of the 
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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. 
6.6.1. 
Allowed Medication 
6.6.1.1. 
Palliative and Supportive Care 
Palliative and supportive care is permitted during the course of the study for underlying 
conditions. 
6.6.1.2. 
Immunosuppressive Therapy 
Patients who enter the study receiving supportive IST(s) (eg, corticosteroid, AZA, MMF, MTX, 
TAC, CsA, or CYC) for the prevention of relapse, either in combination or monotherapy, must 
be on a stable dosing regimen of adequate duration prior to Screening 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, CsA, TAC,
or CYC), 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.
The patient must remain on that dose regimen during the Screening Period and for the Primary 
Treatment Period (52/53 weeks). During the Primary Treatment Period, the patient’s IST dose 
may be adjusted on the basis of weight/body-surface/age to account for the child’s growth. No 
other adjustment in IST dosage and no new ISTs will be permitted, unless the patient experiences 
a relapse or a safety event, and a change in IST dose would be deemed necessary by the 
Investigator to guarantee the patient’s safety. 
Once the patient completes the Primary Treatment Period or experiences a relapse, there are no 
restrictions on ISTs used for relapse prevention; the dose and/or type of IST may be changed, 
supplemented, or discontinued and new medications may be added, as long as any new 
medications are not prohibited medications. In the event that a change in the dose or dosing 
regimen is considered due to a known toxicity or side-effects associated with the given IST, the 
Sponsor should be notified of the potential change. 
The restriction on ISTs during the Primary Treatment Period is only applicable to ISTs used for 
relapse prevention. Concomitant use of ISTs (eg, the use of IVIg for the treatment of parvovirus 
B19 infection, or concurrent administration of intravenous methylprednisolone [IVMP] with 
antivirals for the treatment of herpes simplex virus) to treat underlying conditions, is not 
restricted during the study. 
The choice of IST agents is at the discretion of the Investigator with the exception of disallowed 
medications (Section 6.6.2). Standard recommended dosing should be used for the chosen IST. 
Use of corticosteroids is permitted; however, the total daily dose must not exceed 0.5 mg/kg/day 
of prednisone or equivalent and in no case may the dose exceed 20 mg/day. 
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6.6.1.3. 
Treatment of On-Trial Relapse 
During this study, the treatment of relapse is at the discretion of the Investigator. The following 
is an example of a standardized treatment regimen for an On-Trial Relapse, in accordance with 
expert opinion (Kimbrough, 2012). However, the ultimate treatment regimen and order will be 
determined by the Investigator: 
•
30 mg/kg (not to exceed 1 gram) IVMP administered daily for 3-5 days followed by
oral prednisone tapering. If the patient improves, then continue the study assessments
as per schedule of this protocol.
•
If there is no or minimal response to IVMP, PE/PP will be allowed at the discretion of
the treating neurologist.
•
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, preferably
within 1-2 hours (Section 6.2). After receiving the supplemental dose, patients are to
continue protocol-specified dosing.
6.6.2. 
Disallowed Medications and Therapies
The following medications and therapies, except when used in the treatment of On-Trial Relapse 
(Section 6.6.1.3) or when permitted by the Investigator and Sponsor, if applicable, are prohibited 
during the study: 
•
Mitoxantrone
•
Rituximab or other biologicals that affect immune system functioning, such as
tocilizumab
•
IVIg for relapse prevention
•
PE for relapse prevention
•
Use of immunomodulatory therapies including: interferon beta-1b; interferon beta-1a,
glatiramer acetate, natalizumab, alemtuzumab, and fingolimod.
6.7. 
Dose Modification
Not applicable. 
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7.
DISCONTINUATION OF STUDY INTERVENTION AND
PARTICIPANT DISCONTINUATION/WITHDRAWAL
7.1. 
Discontinuation of Study Intervention
A patient may withdraw from the study at any time at his/her own request, or at the request of the 
parent/guardian, or may be withdrawn at any time at the discretion of the Investigator for safety, 
behavioral, compliance, or administrative reasons. If a patient discontinues treatment from the 
study, the Investigator will attempt to perform (if the patient agrees) assessments specified for 
the ET Visit, or if not possible, a Safety Follow-up phone call to be conducted 8 weeks after the 
last dose of study drug has been administered (SoA, Section 1.2). The Sponsor and site monitor 
will be notified as soon as possible. If a patient is withdrawn from the study or withdraws 
consent no further data will be collected. Patients who withdraw from the study will not be 
replaced. 
Patients should be discontinued from study drug if any of the following occur during the study: 
1. Serious hypersensitivity reaction (such as bronchospasm with wheezing or requiring
ventilator support or symptomatic hypotension, or serum sickness-like reactions
manifesting 1 to 14 days after study drug administration);
2. Use of disallowed medication as defined in Section 6.6.2;
3. Pregnancy or planned pregnancy; or
4. Sponsor deems it is in the best interest of the patient.
The Investigator should contact the Alexion Medical Monitor prior to discontinuing a patient 
from study drug. If a patient discontinues from treatment, the patient is required to complete an 
ET Visit (SoA, Section 1.2) and a Safety Follow-up Visit 8 weeks from the date the patient’s last 
dose of study drug was administered. 
The reason for the treatment discontinuation (ie, patient withdraws consent, patient withdrawal 
from procedures, physician decision, AE, or other reason specified in eCRF) will be recorded in 
the eCRF. 
If a female patient is permanently discontinued from study drug due to pregnancy, the 
Investigator will make a reasonable attempt to follow-up, in accordance with local laws and 
regulations, until the outcome of the pregnancy is known (Section 10.4; Appendix 4). 
If the patient withdraws consent for disclosure of future information, the Sponsor may retain and 
continue to use all data collected before such a withdrawal of consent. 
If a patient withdraws from the study, the patient may request destruction of any samples taken 
and not tested, and the Investigator must document this in the site study records as well as inform 
the site monitor and Sponsor. 
7.2. 
Lost to Follow Up 
A patient will be considered lost to follow-up if the patient 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 participate in a required study visit: 
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1. The site must attempt to contact the patient or the patient’s parent(s) and/or guardian(s)
and reschedule the missed visit as soon as possible and counsel the patient or the patient’s
parent(s) and/or guardian(s) on the importance of maintaining the assigned visit schedule
and ascertain whether or not the patient or the patient’s parent(s) and/or guardian(s)
wishes to and/or should continue/allow the patient to continue in the study.
2. 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.
3. Should the patient continue to be unreachable, the patient will be considered to have
withdrawn consent and future missed visits will not be considered protocol deviations.
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8.
STUDY ASSESSMENTS AND PROCEDURES
8.1. 
Efficacy Assessments
All efficacy assessments will be administered according to the SoA (Section 1.2). The efficacy 
assessments that are age-appropriate for a patient at the start of the study will be used for that 
patient throughout the study. Change in age during the study will not constitute a patient 
changing the type of survey completed (eg, for patients aged ≥ 2 years to < 5 years, the Pediatric 
Quality of Life Inventory [PedsQL] parent proxy will be used throughout the study). 
8.1.1. 
Annualized Relapse Rate 
Baseline ARR for all patients will be calculated using Historical Relapse data for each patient in 
the 2-year period prior to Screening for this study. The On-Trial ARR for the Primary Treatment 
Period will be calculated for the time period from the first dose of eculizumab through 
Week 52/53 or ET from the Primary Treatment Period. All Investigator-Reported On-Trial 
Relapses will additionally be adjudicated by the RAC as part of a sensitivity analysis, as 
described in Section 9.5.1. 
8.1.2. 
Time to First Relapse 
Time to First Relapse will be measured, in days, beginning at the time the patient’s first dose of 
eculizumab is administered until the patient’s first On-Trial Relapse is reported by the 
Investigator. All Investigator-Reported On-Trial Relapses will additionally be adjudicated by the 
RAC as part of a sensitivity analysis, as described in Section 9.5.1. 
8.1.3. 
Neurologic Examination 
A complete general neurologic examination will be performed at the appropriate visits. The 
complete general neurologic examination will include assessments of the following systems: 
mental status, fundus examination, cranial nerves, deep tendon reflexes, plantar responses, 
power/strength, sensation, coordination, and gait/balance. For consistency, all efforts should be 
made to have the neurologic examination performed by the same qualified study staff at these 
visits. 
8.1.4. 
Expanded Disability Status Scale 
The 10-point Kurtzke EDSS is a widely accepted clinical disability scale (Section 10.9; 
Appendix 9). For this study, the Neurostatus EDSS (minorly modified from the original Kurtzke 
EDSS) will be used. 
The EDSS is considered the standard for monitoring patients with NMOSD, including those in 
NMOSD clinical research, although NMOSD is difficult to assess because of the differences in 
signs and symptoms. 
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The EDSS assigns a severity score to the patient’s clinical status using FSS that evaluate 
dysfunction in the following 7 functional systems (FS): 
•
Pyramidal
•
Cerebellar
•
Brainstem
•
Sensory
•
Bowel and bladder
•
Visual
•
Cerebral
The FS 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. 
In contrast, the total EDSS score is determined by 2 factors: gait and FS scores. EDSS scores 
below 4.0 are determined by the FS scores alone. People with EDSS scores of 4.0 and above may 
have some degree of gait impairment. Scores between 4.0 and 9.5 are determined by both gait 
abilities and the FS scores. For simplicity, many experts gauge the EDSS scores between 4.0 and 
9.5 entirely by gait, without considering the FS scores. The EDSS is widely used and accepted as 
a valid tool to clinically measure and evaluate level of functioning in patients with NMOSD 
(Kurtzke, 1983). This assessment will be used for all patients ≥ 5 years old. 
8.1.5. 
Hauser Ambulation Index 
The Hauser Ambulation Index (HAI) is a rating scale developed to assess mobility by evaluating 
the time and degree of assistance required to walk 25 feet (Section 10.10; Appendix 10). 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 11 gradations  
(Bethoux, 2011). This assessment will be performed for all patients in this study. 
8.1.6. 
Visual Acuity 
Visual acuity is usually affected by ON, progressing over a period of hours to days. The Snellen 
chart (Section 10.13; Appendix 13) or the LEA symbols eye chart (Section 10.14; Appendix 14) 
will be used to assess VA. The Snellen chart quantifies ability to read letters of varying sizes at a 
fixed distance in relation to the distance at which a patient with normal vision could read the 
same letters. The test is performed at a standard distance, typically 6 meters or 20 feet. The 
Snellen chart is typically recorded as acuity ratio distance (6 meters or 20 feet), so for normal 
VA it would be recorded as 20/20 or 6/6. Sometimes this is entered as the denominator of the 
Snellen fraction (in US) or as a decimal (ex-US). The test should always be done with the best 
possible correction (ie, wearing glasses) as needed. Patients will continue to be evaluated based 
on the survey initially completed upon entry into the study. Note: A LEA symbols eye chart will 
be used in patients who are aged 2-5 years. 
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8.1.7. 
Ophthalmologic Examination 
8.1.7.1. 
Confrontational Visual Fields 
The ophthalmological examination will evaluate confrontational visual fields (VF). 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 experiencing ON; however, visual field defects can present with a broad spectrum of 
patterns (Keltner, 1999). This assessment will be performed for all patients in this study. 
8.1.7.2. 
Color Vision 
Color vision will be assessed using Ishihara Plates. This will be assessed in all patients in this 
study. Loss of color vision can be a marker of ON and is therefore an important assessment tool 
in NMOSD. 
8.1.8. 
Investigator-Reported On-Trial Relapse 
Patients will be monitored for On-Trial Relapses throughout the study. The Investigator or a 
designee will review, in detail, the signs and symptoms of a potential relapse with the patient 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 of notification of signs or symptoms suggestive of a 
potential relapse, and no later than 48 hours. The evaluation of On-Trial Relapses will include: 
•
Complete neurological examination to determine whether the clinical signs,
symptoms and examination findings meet the definition of an On-Trial Relapse
(Section 4.2.2).
•
Assessment of relapse severity based on the OSIS (Section 10.12; Appendix 12).
•
Evaluation of the neurological FS based on the Kurtzke’s FSS and the disability level
based on the EDSS score (Section 10.9; Appendix 9).
•
Ambulatory function assessment using the HAI (Section 10.10; Appendix 10).
•
Ophthalmological examination including VA (Section 10.13; Appendix 13 and
Section 10.14; Appendix 14), confrontational VF, and color vision.
•
MRI +/- gadolinium and/or OCT Examinations should be performed to evaluate a
potential relapse, at discretion of the Investigator.
•
Additional tests are included in the SoA (Section 1.2).
•
If the event is confirmed as an Investigator-Reported On-Trial Relapse, the patient
will be treated at the discretion of the Investigator. An example of a standardized
treatment regimen for an Investigator-Reported On-Trial Relapse Treatment regimen
is included in Section 6.6.1.3.
The evolution of the relapse will be assessed during the Relapse Evaluation Period at 
1, 4, and 6 weeks after the relapse onset. Additional unscheduled Relapse Evaluation Visits are 
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permitted at the discretion of the Investigator. Eculizumab administration will be continued as 
outlined in the protocol dose administration schedule. 
Following the relapse, the patient may continue in the study, or may exit, based on the 
Investigator’s discretion. 
An independent RAC will review all Investigator-Reported On-Trial Relapse events using the 
protocol-defined criteria and a consistent process outlined in the RAC Charter. For more details 
refer to the RAC Section 9.5.1. 
8.1.9. 
Optic Spinal Impairment Score 
The OSIS will be used as a scoring system for the severity of a relapse. 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. OSIS score will be 
assessed by the Investigator at the time of the relapse. (Section 10.12; Appendix 12). 
8.1.10. 
Pediatric Quality of Life Inventory 
The PedsQL is a brief, standardized, generic assessment instrument that systematically assesses 
patients’ and their parents’ perceptions of health-related quality of life (HRQOL) in pediatric 
patients with chronic health conditions using pediatric cancer as an exemplary model. The 
PedsQL is based on a modular approach to measuring HRQOL and consists of a 15-item core 
measure of global HRQOL and 8 supplemental modules assessing specific symptom or treatment 
domains. The PedsQL was empirically derived from data collected from 291 pediatric cancer 
patients and their parents at various stages of treatment (Section 10.11; Appendix 11). Items are 
reverse scored and linearly transformed to a 0-100 scale, so that higher scores indicate better 
HRQOL. The test is designed for self-completion in patients aged ≥ 5 years by respondents (with 
3 age-appropriate PedsQL tests available for ages 5-7, 8-12, and 13-18 years old), and by a 
Proxy in patients aged ≥ 2 to < 5 years. Attempts should be made to have the same proxy 
complete the evaluation at each visit. 
8.1.11. 
Euro Quality of Life-5 Dimensions-Youth 
The European Quality of Life (EuroQoL)-5D-Youth (EQ-5D-Y) is based on the EQ-5D and is 
designed for use in patients aged ≥ 4 to < 18 years. The EQ-5D-Y will be used in this study for 
self-completion in patients enrolled between the ages ≥ 8 to < 18 years by respondents, and by a 
Proxy in patients enrolled between the ages ≥ 5 to < 8 years. Attempts should be made to have 
the same proxy complete the evaluation at each visit. Children < 5 years will not have EQ-5D-Y 
assessed in the study. 
The EQ-5D-Y consists of 2 pages: the EQ-5D-Y descriptive system (page 2) and the EQ visual 
analog scale (EQ VAS) (page 3). The descriptive system comprises the same 5-component scale 
as the EQ-5D-5L, including mobility, self-care, usual activities, pain/discomfort, and 
anxiety/depression, but uses child-friendly wording (ie, mobility, looking after myself, doing 
usual activities, having pain or discomfort, feeling worried, sad, or unhappy). Each dimension 
has 3 levels and is rated on a scale that describes the degree of problems in that area: “no 
problems”, “some problems”, “a lot of problems” with Level 1 indicating the lowest degree of 
problems and Level 3 indicating the greatest degree of problems. Respondents are asked to 
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indicate their health state by ticking (or placing a cross) in the box that best describes their health 
status. 
The EQ-5D VAS is an overall health scale where the rater selects a number between 0-100 to 
describe the condition of their health, with 100 being ‘The best health you can imagine’ and 0 
being ‘The worst health 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 (Wille, 2010) (Section 10.7; Appendix 7 and Section 10.8; Appendix 8). 
8.2. 
Safety Assessments 
Planned timepoints for all safety assessments are provided in the SoA (Section 1.2). 
8.2.1. 
Physical Examination 
A physical examination will include assessments of the following organs/body systems: skin, 
head, ears, eyes, nose, throat, neck, lymph nodes, pulse, chest, heart, abdomen, extremities; 
musculoskeletal and general neurologic examination. A targeted physical examination consists 
of a body-system relevant examination based upon Investigator judgment and patient symptoms. 
For consistency, all efforts should be made to have the physical examination performed by the 
same qualified study staff. 
8.2.2. 
Vital Signs 
Vital signs will be measured at every visit and will include assessments of systolic and diastolic 
blood pressure (BP) (mm Hg), temperature (°C or °F), respiratory rate (RR), and heart rate (HR) 
(beats/minute). Vital signs will be obtained after the patient has been supine or seated for at least 
5 minutes. Ideally, each patient’s BP should be measured using the same arm. 
8.2.3. 
Electrocardiograms 
A single 12-lead electrocardiogram (ECG) will be obtained as outlined in the SoA (Section 1.2) 
using an ECG machine that automatically calculates the HR and measures 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 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 on the eCRF. 
8.2.4. 
Clinical Safety Laboratory Assessments 
Laboratory assessments will be tested at a central laboratory facility. Any clinically significant 
abnormal results should be followed until resolution or stabilization. 
All protocol-required laboratory assessments, as defined in Section 10.2; Appendix 2, must be 
conducted in accordance with the Laboratory Manual and the SoA (Section 1.2). 
The Investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the study in the AE section of the eCRF. The 
laboratory reports must be filed with the source documents. 
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Clinically significant abnormal laboratory findings associated with the underlying disease are not 
considered AEs unless they are judged by the Investigator to be more severe than expected for 
the patient’s condition. 
If such values do not return to normal or the Baseline level within a period of time judged 
reasonable by the Investigator, the etiology should be identified and the Sponsor notified. 
8.3. 
Adverse Events and Serious Adverse Events 
Adverse events will be reported to the Investigator or qualified designee by the patient (or when 
appropriate, by a caregiver, surrogate, or the patient’s legally authorized representative). All 
observed or volunteered AEs, regardless of Treatment Group or causal relationship, will be 
reported by the Investigator. 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 
intervention or study procedures, or that caused the participant to discontinue the study drug 
(Section 7). For each AE however, only the Investigator will be responsible for assessing 
seriousness, severity, and relationship of the AE to study drug. 
Definitions and procedures for recording, evaluating, follow-up, and reporting AEs and SAEs are 
outlined in Section 10.3; Appendix 3. 
8.3.1. 
Time Period and Frequency for Collecting Adverse Events and Serious Adverse 
Events Information 
All AEs will be collected from the signing of the ICF until the last visit (Safety Follow-up Visit) 
of the Extension Period, as specified in Table 7. In the event the patient discontinues or 
completes the study prior to the end of the extension period, the last visit will be considered to be 
the 8-week Safety Follow-up Visit. 
All SAEs will be recorded and reported to the Sponsor or designee within 24 hours, as indicated 
in Section 10.3; Appendix 3. The Investigator will submit any updated SAE data to the Sponsor 
within 24 hours of the updated information being available. 
Investigators are not obligated to actively seek AEs or SAEs after conclusion of the study 
participation. However, if the Investigator learns of any SAE, including a death, at any time after 
a patient has been discharged from the study, and he/she considers the event to be reasonably 
related to the study intervention or study participation, the Investigator must promptly notify the 
Sponsor. 
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Section 10.3; 
Appendix 3. 
8.3.2. 
Method of Detecting Adverse Events and Serious Adverse Events 
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. 
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8.3.3. 
Follow-up of Adverse Events and Serious Adverse Events 
After the initial AE/SAE report, the Investigator is required to proactively follow each 
participant at subsequent visits/contacts. All SAEs will be followed until resolution, stabilization, 
the event is otherwise explained, or the participant is lost to follow-up (as defined in 
Section 7.2). Further information on follow-up procedures is given in Section 10.3; Appendix 3. 
8.3.4. 
Regulatory Reporting Requirements for Serious Adverse Events 
•
The Investigator must notify the Sponsor of an SAE within 24 hours of the first
awareness of the event.
•
The Sponsor has a legal responsibility to notify both the local regulatory authority
and other regulatory agencies about the safety of a study drug under clinical
investigation. The Sponsor will comply with country-specific regulatory requirements
relating to safety reporting to the regulatory authority, IRB/IEC, and Investigators.
•
The Council for International Organizations of Medical Sciences (CIOMS) or
MedWatch reports must be prepared for suspected unexpected serious adverse
reactions (SUSARs) (Section 10.3; Appendix 3) 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
review and acknowledge the report and notify the IRB/IEC, if appropriate, according
to local requirements.
8.3.5. 
Pregnancy
Contraception guidance that must be followed for the study duration is detailed in Section 10.4; 
Appendix 4. 
For female patients of childbearing potential, a serum or urine pregnancy test (ie, beta-HCG) will 
be performed as indicated in the SoA (Section 1.2). A negative pregnancy test is required prior to 
administering eculizumab to patients of childbearing potential. 
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; 
Appendix 4. 
Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, and ectopic pregnancy) are considered SAEs and should be reported as described in 
Section 10.3; Appendix 3. 
8.3.6. 
Vaccine and Antibiotic Prophylaxis 
As with any terminal complement antagonist, the use of eculizumab 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 
prior to, or at the time of, initiating study drug. 
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•
Patients who initiate study drug treatment 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 against N meningitidis serotypes A, C, Y, W-135, and B,
where available, to prevent common pathogenic meningococcal serotypes.
•
Patients must be vaccinated or revaccinated according to current national vaccination
guidelines or local practice for vaccination use with complement inhibitors (eg,
eculizumab).
•
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.
In addition to meningococcal vaccination, patients must be vaccinated against Hib and 
S pneumoniae at least 2 weeks prior to initiating study drug according to local and 
country-specific immunization guidelines for each age group, and strictly adhere to the national 
vaccination recommendations for each age group. 
To increase risk awareness and promote quick disclosure of any potential signs or symptoms of 
infection experienced by the patients during the course of the study patients will be provided a 
Patient Safety Information Card to carry with them at all times. Additional discussion and 
explanation of the potential risks, signs, and symptoms will occur at each visit as part of the 
review of the patient safety card as described in the SoA (Section 1.2).Vaccination(s) for 
N meningitidis, Hib, and S pneumoniae will be recorded on the patient’s eCRF. 
8.4. 
Pharmacokinetics 
Blood samples will be obtained to assess pre- and post-treatment serum eculizumab 
concentrations at the timepoints and within the windows indicated in the SoA (Section 1.2). 
Pharmacokinetic parameters such as maximum concentration and concentration after the first 
dose, and during the induction and maintenance treatment phase will be obtained. Clearance and 
terminal half-life will be estimated. 
Baseline PK samples will be collected 5-90 minutes prior to the first dose, and peak samples will 
be collected 60-120 minutes after the first dose and at other timepoints in the SoA. An 
intermediate blood sample will also be collected 24 hours after completion of the first dose. 
For the sample collected at 24 hours, there will be a window of ± 1 hour for collecting the 
sample. The date and exact time of collection must be recorded on the eCRF and the central 
laboratory requisition form. 
Samples obtained outside of the allotted windows will be considered protocol deviations. Unused 
samples may be retained for a period of up to 5 years to perform additional assessments as 
necessary. 
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Additional details on sample collection, including blood volume requirements, are provided in 
the Laboratory Manual. 
8.5. 
Pharmacodynamics 
Blood samples will be obtained to assess pre- and post-treatment serum hemolytic activity and, 
therefore, C5 complement activity inhibition at the timepoints and within the windows indicated 
in the SoA (Section 1.2). 
Baseline PD samples will be collected 5-90 minutes prior to the first dose, and peak samples will 
be collected 60-120 minutes after the first dose and at other timepoints in the SoA. An 
intermediate blood sample will also be collected 24 hours after completion of the first dose. 
For the sample collected at 24 hours, there will be a window of ± 1 hour for collecting the 
sample. The date and exact time of collection must be recorded on the eCRF and the central 
laboratory requisition form. 
Samples obtained outside of the allotted windows will be considered protocol deviations. Unused 
samples may be retained for a period of up to 5 years to perform additional assessments as 
necessary. 
Additional details on sample collection, including blood volume requirements, are provided in 
the Laboratory Manual. 
8.6. 
Genetics 
Genetics will not be evaluated in this study. 
8.7. 
Biomarkers 
Blood samples for assay of the AQP4-Ab will be collected at Screening and other timepoints as 
specified in the SoA (Section 1.2). 
8.7.1. 
Exploratory biomarkers 
Exploratory biomarkers of PD effect may include, but are not limited to, change from baseline in 
levels of markers of complement dysregulation, neuroinflammation (eg, interleukin [IL]-6), and 
neural injury (eg, neurofilament light chain [NfL]). Additional assessments may include 
biomarkers related to disease activity/progression or treatment response. 
8.8. 
Healthcare Resource Utilization and Health Economics 
Medical resource utilization and health economics data, associated with medical encounters, may 
be collected by the Investigator or designee for all patients throughout the study. Data will be 
recorded in the eCRF. Protocol-required procedures, tests, and encounters will be excluded. 
The data collected may be used to conduct exploratory economic analyses and may include: 
•
Number of medical care encounters, including outpatient visits, emergency room
visits, surgeries, and other selected procedures (inpatient and outpatient)
•
Duration of hospitalization
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•
Number and type of diagnostic and therapeutic tests and procedures
8.9. 
Blood Sample Volumes
Blood will be collected for clinical safety laboratory, PK, PD and biomarker assessments. In 
accordance with the guidance set forth by the EU, the required blood draw for all pediatric 
patients treated on this study will not exceed 1% of total blood volume in a single 24-hour period 
or 3% of total blood volume over a 4-week period. 
The minimum required blood volume (in mL) to be collected by weight cohort and study visit is 
presented in Table 16. 
Table 16: 
Minimum Required Blood Volumes Collected by Weight Cohort and Study 
Visit 
Weight 
Cohort 
Study Visit 
Screen 
Day 1 
Wk 1 
Wks 4 
and 7 
Wk 
12/ 13 
Wk 
26 / 
27 
Wk 
40 / 
41 
Wk 
52 / 
53 
Wks 
76 / 77, 
100 /101, 
124 /125, 
148 / 149 
ET / 
EOS 
10 to < 20 
kg 
4.5 
8.6 
2.4 
3.4 
7.9 
8.9 
7.9 
8.9 
4.5 
8.9 
20 to > 40 
kg 
4.5 
8.6 
2.4 
3.4 
8.9 
8.9 
7.9 
8.9 
4.5 
8.9 
Note: All minimum volumes are reported in mL. 
Abbreviation: ET = end of treatment; EOS = end of study; Wk = week 
If a patient has an Investigator-assessed relapse, additional blood samples will be collected. The 
minimum required blood volume (in mL) to be collected by weight cohort and relapse evaluation 
visit is presented in Table 17. 
Table 17: 
Minimum Required Blood Volumes Collected Following a Relapse by Weight 
Cohort and Relapse Evaluation Visit 
Weight Cohort 
Relapse Visit 
(24-48 hours) 
Relapse Visit 
(Week 1) 
Relapse Visit 
(Week 4) 
Relapse Visit 
(Week 6) 
10 to < 20 kg 
7.9 
3.4 
3.4 
8.9 
20 to > 40 kg 
7.9 
3.4 
3.4 
8.9 
Note: All minimum volumes are reported in mL. 
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9.
STATISTICAL CONSIDERATIONS
9.1. 
Statistical Hypotheses 
9.1.1. 
Primary Hypothesis 
The primary hypothesis for this study is: 
Eculizumab significantly reduces ARR as compared to Baseline ARR. 
The study will be considered to have met its primary efficacy endpoint if a statistically 
significant p-value (<0.05) is observed for the change in ARR between the Baseline ARR and the 
Primary Treatment Period ARR (as reported by the Investigator) in favor of eculizumab 
treatment using the Wilcoxon signed rank test. 
9.2. 
Sample Size Determination 
Approximately 12 patients will be enrolled to achieve the minimum of 10 evaluable patients. Of 
the 10 evaluable patients, at least 3 of the patients will be aged 2 to < 12 years at the time of 
enrollment, and at least 5 patients will be aged 12 to < 18 years at the time of enrollment. 
In this pediatric study, patients will act as their own controls. As such the Historical ARR, which 
will be called the Baseline ARR, will be compared with the ARR of the patient while on 
eculizumab during the Primary Treatment Period. A sample size of 12 patients (10 evaluable 
patients) will provide approximately 85% power to detect a statistically significant treatment 
effect of eculizumab to reduce the ARR, assuming a 2-sided significance level of 0.05, by the 
Wilcoxon signed rank test, and a dropout rate of 15%. The sample size calculation also assumes 
a Baseline ARR of at least 1 relapse/year. Likewise, the sample size calculation also assumes an 
eculizumab-treated ARR of 0.082 relapse/year with a standard deviation of the difference in 
relapse rates of 0.8 relapses/year, based on Study ECU-NMO-301, which was a randomized, 
double-blind, placebo-controlled, multicenter study designed to evaluate the safety and efficacy 
of eculizumab in patients aged ≥ 18 years with anti-AQP4 Ab-positive NMOSD. 
9.3. 
Populations for Analyses 
For purposes of analysis, the following populations are defined: 
Population 
Description 
Full Analysis Set (FAS) 
The FAS includes all patients who have received at least 1 dose of 
eculizumab. 
Safety Analysis Set 
The Safety Analysis Set includes all patients who have received at least 1 dose 
of eculizumab. 
PK/PD Analysis Set 
The PK/PD Analysis Set includes all patients who have received at least 
1 dose of eculizumab and have PK/PD data assessments during the study. 
9.4. 
Statistical Analyses 
Summary statistics will be computed and displayed 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 
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analyses will be performed based on a 2-sided Type I error of 5% unless noted otherwise. 
Missing data will not be imputed. 
The statistical analysis plan (SAP) will be developed and finalized prior to the primary analysis 
and will provide further details. The primary analysis will be conducted when all patients have 
completed the 52/53-week Primary Treatment Period or discontinued prior to the completion of 
the Primary Treatment Period. This analysis will include all efficacy, safety, and PK/PD study 
data for regulatory submission purpose. Another SAP will be developed and finalized prior to the 
completion of the entire study (including the Extension Treatment Period). Additional interim 
analyses during the Extension Treatment Period may be performed at the discretion of the 
Sponsor. 
Analyses will be performed using the SAS® software Version 9.4 or higher. 
9.4.1. 
Demographics and Baseline Characteristics 
Patient demographic and baseline characteristics will be summarized for the Safety Analysis Set. 
Summary statistics will be presented. No formal hypothesis testing will be performed. 
9.4.2. 
Patient Disposition 
The number of patients screened and the number of patients in different analysis sets will be 
summarized. The number and percentage of patients discontinued will be summarized along with 
reasons for discontinuation in the Safety Analysis Set. 
The number and percentage of patients with important protocol deviations will be summarized 
overall and by prespecified deviation categories. 
9.4.3. 
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 System Organ Class (SOC) and Preferred Term. 
NMOSD History will also be summarized. 
9.4.4. 
Prior and Concomitant Medications 
For analysis and reporting purpose, any medication started prior to first dose of study drug will 
be considered as prior medications; and medications that were 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. Medications will be coded using 
the World Health Organization Drug Dictionary (WHODrug; the most current version available 
at the time of the analyses). 
9.4.5. 
Efficacy Analyses 
Efficacy analyses will be performed on the FAS. 
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9.4.5.1. 
Primary Efficacy Analysis 
Primary Treatment Period 
The primary efficacy endpoint is the change from baseline in the ARR at 52/53 weeks. Baseline 
ARR for all patients will be calculated using Historical Relapse data for each patient in the 
2-year period prior to Screening for this study. Baseline ARR will be compared to rates
calculated for the On-Trial ARR, the time period from the first dose of eculizumab through
Week 52/53 or ET from the Primary Treatment Period. The study will be considered to have met
its primary efficacy endpoint if a statistically significant p-value (<0.05) is observed for the
change in ARR between the Baseline ARR and the Primary Treatment Period ARR (as reported
by the Investigator) in favor of eculizumab treatment using the Wilcoxon signed rank test.
The TFR and the percentage of patients who are relapse-free while on eculizumab treatment 
along with 95% confidence intervals will be computed using the Kaplan-Meier method. Time to 
First Relapse results will be considered descriptive; no adjustments for multiplicity will be made. 
A sensitivity analysis will be performed for the change in ARR between the Baseline ARR and 
the adjudicated Investigator-Reported On-Trial ARR using a Wilcoxon signed rank test. The 
percentage of patients who are relapse-free while on eculizumab treatment in Study ECU-NMO-
303 along with 95% confidence intervals will also be computed using the Kaplan-Meier method 
for the adjudicated On-Trial Relapses. Summaries of the primary efficacy endpoints by age 
subgroups (Baseline age 2 to < 12 years and age 12 to < 18 years) may be also be produced. 
Extension Treatment Period 
The On-Trial ARR for the final analysis of the study and any interim analyses of the Extension 
Treatment Period will be calculated for the On-Trial Treatment Period, the time from the first 
dose of eculizumab through the last dose of study drug. Further computational details will be 
included in the interim and/or final SAPs. 
9.4.5.2. 
Secondary Efficacy Analysis 
Secondary endpoints are as follows. 
•
Change from Baseline in EDSS score at 52/53 weeks in patients ≥ 5 years of age.
•
Change from Baseline in the HAI score at 52/53 weeks in all patients.
•
Change from Baseline in PedsQL scores at 52/53 weeks in patients ≥ 5 years of age.
•
Change from Baseline in PedsQL Parent Proxy at 52/53 weeks in patients < 5 years
of age.
•
Change from Baseline in VA as measured by the Snellen or LEA symbols Eye Chart
examination at 52/53 weeks in all patients.
•
Change from Baseline in Confrontational VF as measured during ophthalmologic
examination at 52/53 weeks in all patients.
•
Change from Baseline in color vision as measured during ophthalmologic
examination at 52/53 weeks in all patients.
Baseline is defined as the last available assessment prior to the first dose of eculizumab. 
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Changes from Baseline for the continuous secondary efficacy endpoints will be summarized at 
the Week 52/53 Visit as well as over the applicable study visits during the Primary Treatment 
Period and the Extension Treatment Period. Summaries will include 95% confidence intervals of 
the median. Continuous secondary efficacy endpoints include the EDSS, the HAI, and the 
PedsQL scores. Summaries will be presented by instrument (eg, Parent Proxy PedsQL, and Self-
Reported PedsQL). 
Visual Acuity, Confrontational VF, and Color Vision assessments will be summarized as 
frequencies and percentages at each applicable study visit and as shifts from Baseline to each 
study visit. 
Further details of the summaries and analyses for these endpoints will be described in the SAP. 
9.4.5.3. 
Tertiary Efficacy Analysis 
The tertiary endpoint is as follows: 
•
Change from Baseline in the EQ-5D-Y/EQ-5D-Y Proxy score at 52/53 weeks.
Relapse severity is determined by OSIS score and will be summarized. Further details of the 
analyses of the tertiary endpoints for the analysis of the Primary Treatment Period and the 
Extension Treatment Period will be described in the SAP. 
9.4.6. 
Safety Analyses 
The safety and tolerability of eculizumab will be assessed based on the following: 
•
Incidence of treatment-emergent adverse events (TEAEs), SAEs, and AEs leading to
study drug discontinuation.
•
Incidence of ADA.
•
Changes from Baseline in vital signs, ECG parameters, and clinical laboratory
assessments.
•
Growth and development: change from Baseline in both weight and height.
All safety analyses will be performed on the Safety Analysis Set. 
9.4.6.1. 
Analysis of Adverse Events 
Treatment-emergent adverse events (TEAEs) are defined as any AE with onset during or after 
the first dose of study drug. Summary tables will include patient counts and percentages and will 
be presented as separate tabulations for all adverse events, SAEs, adverse events leading to 
treatment discontinuation or withdrawal, and adverse events leading to death. 
9.4.6.2. 
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 descriptively. Significant ECG and vital signs will 
also be summarized using descriptive statistics. 
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9.4.6.3. 
Other Safety Analyses 
Changes from Baseline in growth parameters (height and weight) will be summarized by visit. 
Immunogenicity as measured by ADA will be summarized in tabular form and in a by-patient 
listing. 
9.4.7. 
Pharmacokinetics/Pharmacodynamics 
Pharmacokinetic and PD assessments will be made at the timepoints indicated in the SoA. The 
PK, PD and biomarker exploratory analyses will be described in the SAP. The population PK 
analysis and PD analysis will be performed according to a separate analysis plan and the results 
presented separately from the main clinical study report (CSR). 
The PK/PD parameters of interest for the study include: 
•
Maximum plasma drug concentration (Cmax)
•
Terminal half-life (t½)
•
Trough (concentration at the end of the dosage interval [Ctrough])
•
Clearance
•
Change in serum Free C5 concentration
•
Change in the in vitro hemolytic activity
9.5. 
Interim Analyses
Additional interim analyses during the Extension Treatment Period may be performed at the 
discretion of the Sponsor. 
The SAP will describe the planned interim analyses in greater detail. 
9.5.1. 
Data Monitoring and Relapse Adjudication Committees 
Data Monitoring Committee 
An independent Data Monitoring Committee (DMC) will conduct interim monitoring of safety 
data. 
The DMC will have access to all safety data. The DMC may make recommendations to the 
Sponsor regarding safety issues, study conduct, and modifying, extending, or stopping the study. 
In addition, the DMC will receive reports concerning patients who have discontinued. 
Notification of study discontinuation and reason for the discontinuation will be sent to the DMC 
according to the schedule defined in the Charter. The DMC will also review summaries of all 
relapses. 
A separate DMC Charter will document all DMC procedures for this study. 
Relapse Adjudication Committee 
The role of the Relapse Adjudication Committee (RAC) will be to determine whether an 
Investigator-Reported On-Trial Relapse meets the protocol definition of a relapse by rendering a 
Yes/No decision through the adjudication process. The RAC will be comprised of 3 members: a 
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Chair and 2 additional individuals, all of whom will have expertise in NMOSD. A separate 
Charter will define the structure, responsibilities, and membership of the RAC, outline the 
process for RAC review of study data, and outline the procedures for adjudication of an 
Investigator-Reported Relapse. 
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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 CIOMS International Ethical Guidelines
−
Applicable International Conference on Harmonisation (ICH) Good Clinical
Practice (GCP) Guidelines
−
Applicable laws and regulations
•
The protocol, protocol amendments, ICF, Investigator Brochure (IB), 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 Code of Federal Regulations (CFR), ICH guidelines, the
IRB/IEC, European regulation 536/2014 for clinical studies (if applicable), and all
other applicable local regulations
10.1.2. 
Informed Consent Process 
•
The Investigator or his/her representative will explain the nature of the study to the
patient and/or his/her legally authorized representative and answer all questions
regarding the study.
•
Patients and their guardians/legal representatives must be informed that the patient’s
participation is voluntary. Patients or their legally authorized representative [parent or
other legal guardian] 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.
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•
As used in the protocol, the term “informed consent” includes all informed assent
given by patients, informed permission by legally authorized representative, or, as
applicable, informed consent by the patient during study participation.
•
The medical record must include a statement that written informed consent was
obtained before the participant was enrolled in the study and the date the written
consent was obtained. The authorized person obtaining the informed consent must
also sign the ICF.
•
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 participant or the patient’s legally
authorized representative.
•
A patient who is rescreened is not required to sign another ICF unless an updated ICF
is available.
10.1.3. 
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.
•
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.
10.1.4. 
Dissemination of Clinical Study Data 
Study-related information and study results may be posted on the US National Institutes of 
Health website www.clinicaltrials.gov, the EU website www.clinicaltrialsregister.eu/, or other 
publicly accessible websites as appropriate and in accordance with local regulations. 
10.1.5. 
Data Quality Assurance 
•
All patient data relating to the study will be recorded on printed case report forms
(CRFs) or eCRFs unless transmitted to the Sponsor or designee electronically (eg,
laboratory data). The Investigator is responsible for verifying that data entries are
accurate and correct by physically or electronically signing the CRF.
•
The Investigator must maintain accurate documentation (source data) that supports
the information entered in the CRF.
•
The Investigator must permit study-related monitoring, audits, IRB/IEC review, and
regulatory agency inspections and provide direct access to source data documents.
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•
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. Study monitors will communicate with investigative sites on
a regular basis regarding the study and all protocol deviations will be appropriately
documented by the Investigator or designee, and study monitors.
•
Records and documents, including signed ICFs, pertaining to the conduct of this
study must be retained by the Investigator for 5 years after study completion 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.
10.1.6. 
Source Documents 
•
Source documents provide evidence for the existence of the patient and substantiate
the integrity of the data collected. Source documents are filed at the investigative site.
•
The Investigator or designee will prepare and maintain adequate and accurate source
documents (medical records, ECGs, AE and concomitant medication reporting, and
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.
10.1.7. 
Study and Site Closure 
The Sponsor designee reserves the right to close the study site or terminate the study at any time 
for any reason at their sole discretion. 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. 
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
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•
Discontinuation of further eculizumab development
10.1.8. 
Publication Policy 
The full terms regarding publication of the results of this study are outlined in the applicable 
Clinical Study Agreement. 
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10.2. 
Appendix 2: Clinical Laboratory Tests 
Chemistry Panel 
Sodium 
Potassium 
Chloride 
Bicarbonate 
Blood urea nitrogen 
Creatinine 
Glucose 
Alkaline phosphatase 
Alanine amino transferase 
Aspartate amino transferase 
Total bilirubin 
Albumin 
Total protein 
Uric acid 
Urinalysis 
Appearance 
Specific gravity 
PH 
Protein 
Blood 
Glucose 
Ketone 
Bilirubin 
Urobilinogen 
Nitrite 
Complete Blood Count and Differential 
White blood cell count 
White blood cell differential 
Red blood cell count (RBC) 
RBC mean corpuscular volume 
RBC distribution width 
Hemoglobin 
Hematocrit 
Platelet count 
Other 
Human chorionic gonadotropin (urine pregnancy 
test) 
Anti-aquaporin 4 (AQP4) antibody 
Pharmacokinetics 
Pharmacodynamics 
Free complement component 5 
Anti-drug antibody  
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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 
Adverse Event Definition 
•
An AE is any untoward medical occurrence in a patient administered a pharmaceutical product and which
does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable
or unintended sign (eg, an abnormal laboratory finding), symptom, or disease temporally associated with the
use of a medicinal product, whether or not considered related to the medicinal product.
Events Meeting the Adverse Event 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 intervention 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.
•
"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.
•
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 Adverse Event Definition 
•
Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to the procedure is
the AE. Situations in which an untoward medical occurrence did not occur (eg, hospitalization for elective
surgery if planned before the signing the ICF, admissions for social reasons or for convenience).
•
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or detected at the start
of the study that do not worsen.
•
Lack of drug effect is not an AE in clinical studies, because the purpose of the clinical study is to establish
drug effect.
•
A medication error (including intentional misuse, abuse, and overdose of the product) or use other than what
is defined in the protocol is not considered an AE unless there is an untoward medical occurrence as a result
of a medication error.
•
Cases of pregnancy that occur during maternal or paternal exposure to study drug are to be reported within
24 hours of Investigator/site awareness. Data on fetal outcome and breastfeeding will be collected for
regulatory reporting and safety evaluation.
10.3.2. 
Serious Adverse Event 
If an event is not an AE per definition above, then it cannot be an SAE even if serious conditions 
are met (eg, hospitalization for signs/symptoms of the disease under study, death due to 
progression of disease). 
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A serious adverse event is defined as any untoward medical occurrence that, at any dose: 
•
Results in death
•
Is life-threatening
The term 'life-threatening' in the definition of 'serious' refers to an event in which the participant 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.
•
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.
•
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.
•
Is a congenital anomaly/birth defect
•
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 participant 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.
10.3.3. 
Suspected Unexpected Serious Adverse Reactions 
Suspected Unexpected Serious Adverse Reactions Definition 
Suspected unexpected serious adverse reactions are serious events that are not listed in the IB and that the 
Investigator identifies as related to study drug or procedure. The US 21CFR312.32 and EU Clinical Trial 
Directive 2001/20/EC and the associated detailed guidance documents or national regulatory requirements in 
participating countries require the reporting of SUSARs. Alexion has procedures that will be followed for the 
recording and expedited reporting of SUSARs that are consistent with global regulations and the associated 
detailed guidance documents. Suspected unexpected serious adverse reactions will be reported to the national 
competent authority and IRBs/IECs where applicable. 
10.3.4. 
Recording and Follow-Up of Adverse Event and/or Serious Adverse Event 
Adverse Event and Serious Adverse Event Recording 
•
When an AE or 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/SAE information in the CRF.
•
It is not acceptable for the Investigator to send photocopies of the patient’s medical records to Alexion or
designee in lieu of completion of the AE/SAE report. If applicable, additional information such as relevant
medical records, should be submitted with a signed SAE cover page to Alexion Global Pharmacovigilance
(GDS) via ClinicalSAE@alexion.com or via Facsimile: + 1.203.439.9347. In this case, all patient
identifiers, with the exception of the patient number, will be redacted on the copies of the medical records
before sending to Global Pharmacovigilance (GDS).
•
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 or SAE.
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Adverse Event and Serious Adverse Event Recording 
Assessment of Event Severity 
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 or higher. Each CTCAE term is a Lowest Level Term (LLT) per MedDRA. Each LLT will 
be coded to a MedDRA Preferred Term: 
1.
Grade 1: Mild (asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention
not indicated)
2.
Grade 2: Moderate (minimal, local, or noninvasive intervention indicated; limiting age-appropriate
instrumental Activities of Daily Living [ADL])
3.
Grade 3: Severe (severe or medically significant, but not immediately life-threatening; hospitalization or
prolongation of hospitalization indicated; disabling; limiting self-care ADL)
4.
Grade 4: Life-threatening (urgent intervention indicated)
5.
Grade 5: Fatal (death related to AE)
Severity and seriousness must be differentiated: severity describes the intensity of an AE, while the term 
seriousness refers to an AE that has met specific criteria for an SAE as described above. 
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:
o
Not related (unrelated): This relationship suggests that there is no causal association between the
study drug and the reported event.
o
Related: This relationship suggests that there is causal association between the investigational
product and the reported event.
•
The Investigator will use clinical judgment to determine the relationship to the study drug.
•
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 IB 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 IB in his/her assessment.
•
There may be situations in which an SAE has occurred and the Investigator has minimal information to
include in the initial report to Alexion or designee. However, it is very important that the Investigator
always makes an assessment of causality for every event before the transmission of the SAE data
to Alexion GDS.
•
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 or designee 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 or designee with a copy of any postmortem findings including histopathology, if
available.
•
The site will enter new or updated SAE data into the electronic system as soon as it becomes available, but
no later than 24 hours. The Investigator will submit any updated SAE data to the GDS within 24 hours of
awareness of the information.
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10.3.5. 
Reporting of Serious Adverse Events 
Serious Adverse Event Reporting to Alexion or Designee via the RAVE Safety Gateway 
All SAEs must be reported to Alexion GDS within 24 hours of the Investigator or site staff awareness. These 
timelines for reporting SAE information to the Sponsor need to be followed for the initial SAE report and for all 
follow-up SAE information. 
The Investigator or designee must record the SAE data in the eCRF and verify the accuracy of the information 
with corresponding source documents. The SAE report should be submitted electronically via the RAVE Safety 
Gateway. 
In the event that either the electronic data capture (EDC) or the RAVE Safety Gateway is unavailable at the 
site(s), the SAE must be reported on the paper SAE Contingency Form accompanied by an Investigator signed 
cover page. Facsimile transmission or email may be used in the event of electronic submission failure. 
For all SAEs, the Investigator must provide the following: 
•
Appropriate and requested follow-up information in the time frame detailed below
o
Causality of the SAE(s).
o
Treatment of/intervention for the SAE(s).
o
Outcome of the SAE(s).
o
Supporting medical records and laboratory/diagnostic information.
o
The primary mechanism for reporting an SAE to Alexion or designee will be the RAVE Safety
Gateway.
•
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 facsimile or email. Facsimile
transmission or email may be used in the event of electronic submission failure.
Email: clinicalsae@alexion.com
Facsimile: + 1.203.439.9347
•
As soon as the EDC becomes available, the data should be entered in the eCRF and forwarded to
Alexion GDS via the RAVE Safety Gateway.
•
When further information becomes available, the eCRF should be updated with the new information and
an updated SAE report should be submitted to Alexion GDS via the RAVE Safety Gateway.
•
After the study is completed at a given site, the EDC will be taken offline to prevent the entry of new
data or changes to existing data.
•
If a site identifies 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 offline, then the site can report this
information on a paper SAE form to Alexion GDS.
SAE Reporting to Alexion or Designee via Paper Contingency Case Report Form 
•
If applicable, additional information such as relevant medical records should be submitted to Alexion
GDS via the email address or facsimile number noted above.
•
All paper forms and follow-up information submitted to the Sponsor outside of the RAVE Safety
Gateway (eg, discharge summary) should be kept in the appropriate section of the study file.
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10.4. 
Appendix 4: Contraceptive Guidance and Collection of Pregnancy 
Information 
10.4.1. 
Definitions 
Woman of Childbearing Potential (WOCBP) 
A woman is considered fertile following menarche and until becoming post-menopausal unless 
permanently sterile (see below). 
If fertility is unclear (eg, secondary amenorrhea in adolescents or athletes) and a menstrual cycle 
cannot be confirmed before first dose of study intervention, additional evaluation should be 
considered. 
Women in the following categories are not considered WOCBP 
1. Premenarchal
2. Premenopausal female with one 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 participant’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 1 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 
Female patients of childbearing potential and male patients with female partners of childbearing 
potential, pregnant, or breastfeeding, must use effective methods of contraception (as defined 
below), starting at Screening and continuing for at least 5 months after the last dose of study 
drug. 
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Highly effective contraceptive methods include: 
1. Hormonal contraception associated with inhibition of ovulation at least 6 weeks prior to
Day 1
2. Intrauterine device
3. Intrauterine hormone-releasing system
4. Bilateral tubal occlusion
5. Vasectomized partner, provided 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: 
7. A combination of male condom with either a 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. 
10.4.3. 
Pregnancy Testing 
Women 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 timepoints specified in the SoA 
(Section 1.2). 
10.4.4. 
Collection and Reporting of Pregnancy Information 
1. Pregnancy data will be collected during this study for all patients and a female
spouse/partner of male patients. Exposure during pregnancy (also referred to as exposure
in utero) can be the result of either maternal exposure or transmission of drug product via
semen following paternal exposure.
2. If a female patient or a male patient’s female partner becomes pregnant during the
conduct of this study, the Investigator must submit the “Pregnancy Reporting and
Outcome/Breastfeeding” form to Alexion GDS via facsimile or email. When the outcome
of the pregnancy becomes known, the form should be updated and submitted to Alexion
GDS. If additional follow-up is required, the Investigator will be asked to provide the
information.
3. Exposure of an infant to an Alexion product during breastfeeding must also be reported
(via the “Pregnancy Reporting and Outcome Form/Breastfeeding”) and any AEs
experienced by the infant must be reported to Alexion GDS or designee via email or
facsimile.
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4. Pregnancy in itself is not regarded as an AE unless there is a suspicion that the study drug
may have interfered with the effectiveness of a contraceptive medication. However,
complications of pregnancy and abnormal outcomes of pregnancy are AEs and may meet
the criteria for an SAE (eg, ectopic pregnancy, spontaneous abortion, intrauterine fetal
demise, neonatal death, or congenital anomaly). Elective abortions without complications
should not be reported as AEs (Section 8.3.5).
5. Any female patient who becomes pregnant while participating in the study will be
discontinued from study drug.
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10.5. 
Appendix 5: Standard Protocol Definitions 
Historical Relapse 
Historical relapses are the relapses that occurred prior to 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, or IVIg. Events that 
occur within a 30-day interval are considered as 1 relapse. 
On-Trial Relapse 
On-Trial Relapses are acute attacks that occur during the study. 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 Investigator. 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 is not considered an On-Trial Relapse. The relapse must be 
preceded by at least 30 days of clinical stability. The Investigator is not required to wait 24 hours 
prior to initiating treatment for the relapse. 
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10.6. 
Appendix 6: 2015 International Panel for NMO Diagnosis 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
strongly recommended)
3. Exclusion of alternative diagnosis
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10.7. 
Appendix 7: Euro Quality of Life 5 Dimensions-Youth 
Describing your health TODAY 
Please check the ONE box that best describes your health TODAY. 
Mobility (walking around) 
I have no problems walking around 
 
I have some problems walking around 
 
I have a lot of problems walking around 
 
Taking care of myself 
I have no problems taking a bath or shower by myself or getting 
dressed by myself 
 
I have some problems taking a bath or shower by myself or getting 
dressed by myself 
 
I have a lot of problems taking a bath or shower by myself or getting 
dressed by myself 
 
Doing usual activities (for example, going to school, hobbies, sports, 
playing, doing things with family or friends) 
I have no problems doing my usual activities 
 
I have some problems doing my usual activities 
 
I have a lot of problems doing my usual activities 
 
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Having pain or discomfort 
I have no pain or discomfort 
 
I have some pain or discomfort 
 
I have a lot of pain or discomfort 
 
Feeling worried, sad, or unhappy 
I am not worried, sad, or unhappy 
 
I am a little worried, sad, or unhappy 
 
I am very worried, sad, or unhappy 
 
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How good is your health TODAY 
•
We would like to know how good or bad your health is TODAY.
•
This line is numbered from 0 to 100.
•
100 means the best health you can imagine.
0 means the worst health you can imagine.
•
Please mark an X on the line to show how good or bad your
health is TODAY.
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10.8. 
Appendix 8: Euro Quality of Life 5 Dimensions-Youth (Proxy) 
Describing the child’s health TODAY 
Under each heading, please check the ONE box that you think best describes 
the child’s health TODAY. 
Mobility (walking around) 
He/she has no problems walking around 
 
He/she has some problems walking around 
 
He/she has a lot of problems walking around 
 
Taking care of him/herself 
He/she has no problems taking a bath or shower by him/herself or getting 
dressed by him/herself 
 
He/she has some problems taking a bath or shower by him/herself or getting 
dressed by him/herself 
 
He/she has a lot of problems taking a bath or shower by him/herself or 
getting dressed by him/herself 
 
Doing usual activities (for example, going to school, hobbies, sports, playing, 
doing things with family or friends) 
He/she has no problems doing his/her usual activities 
 
He/she has some problems doing his/her usual activities 
 
He/she has a lot of problems doing his/her usual activities 
 
Having pain or discomfort 
He/she has no pain or discomfort 
 
He/she has some pain or discomfort 
 
He/she has a lot of pain or discomfort 
 
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Feeling worried, sad or unhappy 
He/she is not worried, sad or unhappy 
 
He/she is a little worried, sad or unhappy 
 
He/she is very worried, sad or unhappy 
 
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The child’s health TODAY 
•
We would like to know how good or bad you think the
child’s health is TODAY.
•
This line is numbered 0 to 100.
•
100 means the best health you can imagine.
0 means the worst health you can imagine.
•
Please mark an X on the line to show how good or bad
you think the child’s health is TODAY.
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10.9. 
Appendix 9: Expanded Disability Status Scale 
The Neurostatus EDSS is a method of quantifying disability in MS. The EDSS replaced the 
previous Disability Status Scales used in MS. 
The EDSS quantifies disability in 7 FS and allows neurologists to assign an FSS in each of these. 
The FS are: 
pyramidal 
cerebellar 
brainstem 
sensory 
bowel and bladder 
visual 
cerebral 
EDSS steps 1.0 to 4.5 refer to people with MS who are fully ambulatory. EDSS steps 5.0 to 9.5 
are defined by the impairment to ambulation. 
Expanded Disability Status Scale 
0 
Normal neurological exam (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) 
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 
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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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Pr ot oc ol A me n d me nt 2. 2  
E C U -N M O -3 0 3  
1 0. 1 0.  
A p pe n di x 1 0: H a user A m b ul at or y I n de x  
� 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 hair1 
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.  
1 T 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.  
Pa g e 9 8  o f 1 1 7  
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10.11. 
Appendix 11: Pediatric Quality of Life Inventory 
10.11.1. 
Pediatric Quality of Life Inventory Child Form (Age 5 to 7-year-old) 
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10.11.2. 
Pediatric Quality of Life Inventory Child Form (Age 8 to 12 year-old) 
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10.11.3. 
Pediatric Quality of Life Inventory Child Form (Age 13 to 18 year-old) 
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10.11.4. 
Pediatric Quality of Life Inventory Parent Proxy Form (For Patients Aged 
≥ 2 to < 5 years-old) 
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10.12. 
Appendix 12: Optic Spinal Impairment Score 
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 grade 5- or 4+) in affected limb(s) 
3 
Moderate weakness (grade 3 or 4) in 1 or 2 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 plegia (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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10.13. 
Appendix 13: Snellen Eye Chart 
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10.14. 
Appendix 14: LEA Symbols Eye Chart 
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10.15. 
Appendix 15: COVID-19 Risk Assessment 
Neuromyelitis optica spectrum disorder is a severe disease that can cause irreversible morbidity, 
and even mortality, if untreated. As such, and due to the limited number of available treatment 
options, the benefit a patient may receive from a therapeutic study is potentially significant. In 
this particular case, the fact that the study is open label and every patient is treated with the study 
drug also contributes to the potential benefit a patient may derive from participating in the study. 
However, 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 on 
immunosuppression. There is no specific data to inform this risk further, however. The Principal 
Investigator will therefore balance the risk/benefit considerations in their patient, taking these 
factors into account. 
The potential risks identified and mitigation measures put in place in light of the COVID-19 
pandemic are provided in Table 18. 
Table 18: 
Potential Risks and Mitigation Measures due to COVID-19 
Risks category 
Summary of Data/ 
Rationale for Risk 
Mitigation Strategy 
Potential risks 
Potentially higher risk 
population for 
COVID-19 infection 
Patients with NMOSD are at times on other 
immunosuppressants aside from eculizumab. It is 
unknown how this may impact their risk for 
COVID-19 infection. 
During the time that the 
COVID-19 pandemic is active, 
Alexion will recommend that 
sites in a position to start the 
study and enroll patients follow 
the national and institutional 
guidance regarding prevention 
of COVID-19 infection. 
Additionally, in that time 
period, it is expected that 
Investigators and their staff will 
take all possible precautions in 
order to minimize a patient’s 
potential exposure to 
COVID-19 infection. 
Depending on the site, this will 
consist of measures such as 
social distancing, temperature 
screening, enhanced cleaning, 
and personal protective 
equipment for patients, staff, 
and caregivers as necessary. 
Healthcare institution 
availability for 
non-COVID-19 
related activities  
COVID-19 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 they have the 
resourcing and capabilities to 
perform the study as per 
protocol. 
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Table 18: 
Potential Risks and Mitigation Measures due to COVID-19 
Risks category 
Summary of Data/ 
Rationale for Risk 
Mitigation Strategy 
Data 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 monitoring and quality personnel 
to conduct in-person visits to exercise adequate 
oversight of study execution at investigational sites. 
Missing data (COVID-19 pandemic may impact 
study visit schedules and increase missed visits 
and/or participant study discontinuations 
inadvertently resulting in missing data [eg, for 
protocol-specified procedures]). 
During the time that the 
COVID-19 pandemic is active, 
Alexion will only open study 
sites that report enough 
personnel capacity to 
sufficiently conduct clinical 
study related activities.  
During this timeframe, site 
capacity will be reviewed by the 
Principal 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 participant study 
discontinuations due to 
COVID-19). 
Abbreviations: COVID-19 = Coronavirus Disease 2019; eCRF = electronic case report form; 
NMOSD = neuromyelitis optica spectrum disorder 
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10.16. 
Appendix 16: Abbreviations 
Abbreviation 
Definition 
Ab 
antibody 
ADA 
antidrug antibody 
ADL 
Activities of Daily Living 
AE 
adverse event 
aHUS 
atypical hemolytic uremic syndrome 
AQP4 
aquaporin-4 
ARR 
annualized relapse rate 
AZA 
azathioprine 
BP 
blood pressure 
C5 
complement component 5 
CFR 
Code of Federal Regulations 
CIOMS 
Council for International Organizations of Medical Sciences 
Cmax 
maximum plasma drug concentration 
CNS 
central nervous system 
CONSORT 
Consolidated Standards of Reporting Trials 
COVID-19 
coronavirus disease 2019 
CRF 
case report form 
CSR 
clinical study report 
CTCAE 
Common Terminology Criteria for Adverse Events 
Ctrough 
concentration at the end of the dosage interval 
CsA 
cyclosporine 
CYC 
cyclophosphamide 
DMC 
Data Monitoring Committee 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EDC 
electronic data capture 
EDSS 
Expanded Disability Status Scale 
EOS 
end of study 
EQ-5D 
European Quality of Life Health 5-item questionnaire 
EQ VAS 
European Quality of Life Visual Analog Scale 
ET 
early termination 
EuroQoL 
European Quality of Life 
FAS 
full analysis set 
FS 
functional system(s) 
FSH 
follicle stimulating hormone 
FSS 
Functional System Scores 
GCP 
Good Clinical Practice 
GDS 
Global Pharmacovigilance 
HAI 
Hauser Ambulation Index 
HCG 
human chorionic gonadotropin 
Hib 
Haemophilus influenzae type b 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
human immunodeficiency virus 
HR 
heart rate 
HRQOL 
health-related quality of life 
HRT 
hormonal replacement therapy 
IB 
Investigator’s brochure 
ICF 
informed consent form 
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Abbreviation 
Definition 
ICH 
The International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
IEC 
Independent Ethics Committee 
IgG 
immunoglobulin G 
IPND 
International Panel for NMO Diagnosis 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
IST 
immunosuppressive therapy 
IV 
intravenous(ly) 
IVIg 
intravenous immunoglobulin 
IVMP 
intravenous methylprednisolone 
LETM 
Longitudinally extensive transverse myelitis 
LLT 
lowest level term 
mAb 
monoclonal antibody 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMF 
mycophenolate mofetil 
MRI 
magnetic resonance imaging 
MS 
multiple sclerosis 
MTX 
methotrexate 
NMO 
neuromyelitis optica 
NMOSD 
neuromyelitis optica spectrum disorder 
OCT 
Optical Coherence Tomography 
ON 
Optic Neuritis 
OSIS 
Optic Spinal Impairment Score 
PD 
pharmacodynamic(s) 
PE 
plasma exchange 
PedsQL 
Pediatric Quality of Life Inventory 
PK 
pharmacokinetic(s) 
PNH 
paroxysmal nocturnal hemoglobinuria 
PP 
plasmapheresis 
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 
RR 
respiration rate 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SoA 
schedule of activities 
SOC 
System Organ Class 
SUSAR 
suspected unexpected serious adverse reactions 
t½ 
terminal half-life 
TAC 
tacrolimus 
TEAE 
treatment-emergent adverse event 
TFR 
time to first relapse 
TM 
transverse myelitis 
USP 
United States Pharmacopeia 
VA 
visual acuity 
VF 
visual field 
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11.
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Wingerchuk DM, Weinshenker BG. Neuromyelitis Optica. Curr Treatment Options Neurology. 
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