A Phase III, Open-label, Extension Trial of ECU-NMO-301 to Evaluate the Safety and Efficacy of Eculizumab in Patients With Relapsing Neuromyelitis Optica (NMO)
Phase: PHASE3
Conditions: Neuromyelitis Optica, Neuromyelitis Optica Spectrum Disorder
Sponsor: Alexion Pharmaceuticals, Inc.

A Phase III, Open-label, Extension Trial of ECU-NMO-301 
to Evaluate the Safety and Efficacy of Eculizumab in 
Patients with Relapsing Neuromyelitis Optica (NMO) 
Unique Protocol ID: 
NCT Number: 
EudraCT Number: 
Date of Protocol: 
ECU-NMO-302 
NCT02003144 
2013-001151-12 
22 March 2018 

1. 
TITLE PAGE 
ECULIZUMAB 
ECU-NMO-302 
A PHASE III, OPEN-LABEL, EXTENSION TRIAL OF ECU-NMO-301 TO EVALUATE THE 
SAFETY AND EFFICACY OF ECULIZUMAB IN PATIENTS WITH RELAPSING 
NEUROMYELITIS OPTICA (NMO) 
IND 116,207 
EudraCT Number: 2013-001151-12 
Sponsor: 
Alexion Pharmaceuticals, Inc. 
100 College Street 
New Haven, CT 06510, USA 
 
Sponsor Contact: 
 
Clinical Project Leader, Alexion Pharma GmbH 
Giesshübelstrasse 30, 8045 Zürich, Switzerland 
Telephone: 
 
Mobile: 
 
Medical Monitor: 
 
 Alexion Pharmaceuticals, Inc. 
33 Hayden Road. 
Lexington, MA 02421, USA 
Telephone: 
 
Facsimile:
 
Amendment: 
6 
Date of Protocol: 
22 March 2018 
Amended: 
Amendment 1 – Global 25 October 2013 
Amendment 2 – Global 7 April 2015 (not submitted) 
Amendment 3 – Global 01 June 2015 
Amendment 4 – Global 03 August 2016 
Amendment 5 – Global 16 February 2018 (only submitted to the US 
FDA) 
Amendment 6 – Global 22 March 2018 
Proprietary Notice: This confidential information about an investigational agent is provided 
for the exclusive use of investigators of this agent and is subject to recall 
at any time. The information in this document may not be disclosed unless 
such disclosure is required by federal or state law or regulations subject to 
the foregoing. This information may be disclosed only to those persons 
involved in the trial who have a need to know with the obligation not to 
further disseminate this information. These restrictions on disclosure will 
apply equally to all future oral or written information supplied to you by 
Alexion, which is designated as “privileged” or “confidential.” 
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Protocol ECU-NMO-302 Amendment 6 
 
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22 March 2018 
INVESTIGATOR’S AGREEMENT 
 
 
PROTOCOL TITLE: 
A Phase III, Open-Label, Extension Trial of ECU-NMO-301 to 
Evaluate the Safety and Efficacy of Eculizumab in Patients with Relapsing Neuromyelitis 
Optica (NMO) 
PROTOCOL NUMBER: 
ECU-NMO-302 
 
 
 
I have received and read the Investigator’s Brochure for eculizumab. I have read the ECU-NMO-
302 protocol and agree to conduct the trial as outlined. I agree to maintain the confidentiality of 
all information received or developed in connection with this protocol. I agree to conduct the 
trial in accordance with ethical principles that have their origin in the Declaration of Helsinki and 
are consistent with International Conference on Harmonization (ICH)/Good Clinical Practice 
(GCP) and applicable regulatory requirements. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Printed Name of Investigator 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Investigator 
 
 
 
 
 
 
 
 
Date 
 
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PROCEDURES IN CASE OF EMERGENCY 
 
Table 1: 
Emergency Contact Information 
Role in Trial 
Name 
Address and Telephone Number 
Clinical Trial Leader 
 
Alexion Pharma GmbH 
Giesshübelstrasse 30, 8045 Zürich, 
Switzerland 
Tel: 
 
Mobile: 
 
Email: 
  
Responsible Physician (Medical 
Monitor) 
 
Alexion Pharmaceuticals, Inc. 
33 Hayden Ave., Lexington, MA 02421, 
USA 
Tel: 
 
Mobile: 
 
Fax: 
 
Email:
 
Drug Safety Physician 
 
Alexion Pharmaceuticals, Inc. 
33 Hayden Ave, Lexington MA 02421, 
USA 
 
Tel: 
 
Mobile: 
 
Email: 
 
24-Hour Emergency Contact 
24 Hour Telephone Number 
North America 
Tel: 
  
Europe 
Tel: 
 
 
Australia: 
Tel: 
 
Serious Adverse Event Reporting 
Alexion Pharmaceuticals, Inc. 
Alexion Pharmaceuticals, Inc. 
100 College Street 
New Haven, CT 06510 
 
Email: 
  
Fax Number: 
 
Investigational Product Supply 
Almac Clinical Services 
USA: 
Almac Clinical Services 
4204 Technology Drive 
Durham, NC 27704 
Tel: 
 
Fax: 
 
Europe: 
Almac Clinical Services 
9 Charlestown Road 
Seagoe Industrial Estate 
Portadown BT63 5PW 
United Kingdom 
Tel: 
 
 
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Role in Trial 
Name 
Address and Telephone Number 
Clinical Laboratory 
ACM Medical Laboratory 
North America and Latin America: 
ACM Medical Laboratory 
160 Elmgrove Park 
Rochester, NY 14624 
Tel: 
 
Fax: 
 
Europe: 
ACM Global Central Laboratory Limited 
23 Hospital Fields Road 
York, YO10 4DZ, UK 
Tel: 
 
Fax: 
 
 
Asia-Pacific: 
Dorevitch Pathology 
18 Banksia Street 
Heidelberg, VIC 3084, Australia 
Tel: 
 
 
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2. 
SYNOPSIS 
Name of Sponsor/Company: Alexion Pharmaceuticals, Inc. 
Name of Investigational Product: Eculizumab 
Name of Active Ingredient: h5G1.1-mAb 
Title of Trial: A Phase III, Open-Label, Extension Trial of ECU-NMO-301 to Evaluate the Safety and Efficacy of 
Eculizumab in Patients with Relapsing Neuromyelitis Optica (NMO) 
Trial center(s): Approximately 80 centers in North America, South America, Europe, and Asia-Pacific. 
Principal Investigator: TBD 
Investigators: A list containing all Investigators will be provided when site selection is completed. 
Studied period (years):  
Actual date first patient enrolled: 12 Jan 2015 
Estimated date last patient completed: 30 Jun 2020 
Phase of development: 3 
 
Objectives:  
Primary: 
• 
Evaluate the long-term safety of eculizumab in patients with relapsing NMO.  
Secondary: 
• 
Evaluate the long-term efficacy of eculizumab in patients with relapsing NMO as measured by 
annualized relapsing rate (ARR) 
• 
Evaluate long-term efficacy of eculizumab by additional efficacy measures including: 
• 
Disability  
• 
Quality of life (QOL) 
• 
Neurologic functions 
• 
Describe the pharmacokinetics (PK) and pharmacodynamics (PD) of eculizumab in relapsing NMO 
patients. 
Methodology:  
This is an open-label trial. All NMO or NMO Spectrum Disorder (NMOSD) patients who have completed the 
double-blind, randomized, placebo-controlled ECU-NMO-301 (PREVENT) trial may be eligible to participate in 
this extension trial. Prior to initiating any extension trial procedures, an informed consent form must be signed and 
inclusion/exclusion criteria must be obtained, evaluated, and met. Throughout this protocol, the term NMO refers to 
both NMO and NMOSD. 
 
Patients who exit the ECU-NMO-301 trial due to relapse will have their first extension trial visit once the Week 6 
Follow-up Relapse Evaluation Visit is completed and no later than 2 weeks (14 days ±2 days) after the last 
investigational product (IP) dose; patients who exit the ECU-NMO-301 trial due to trial completion will have their 
first extension trial visit once the End of Study (EOS) Visit is completed and no later than 2 weeks (14 days ±2 
days) after the last IP administration in the ECU-NMO-301 trial. Patients who have been unblinded in ECU-NMO-
301 may not continue in ECU-NMO-302. 
 
Blind Induction Phase (Visits 1 – 4) 
To preserve the blinded nature of ECU-NMO-301 trial, all patients must undergo a blind induction phase prior to 
entering the open-label phase of this trial (ie, all patients will receive 4 vials of blinded IP weekly for 4 doses). 
Patients who were randomized to the placebo arm in the ECU-NMO-301 trial will start with the induction dose (ie, 
they will receive blinded IP [3 vials/900 mg eculizumab plus 1 vial placebo] at Visits 1 to 4). Patients who were 
randomized to the eculizumab arm in the ECU-NMO-301 trial will continue with the maintenance dose (ie, they 
will receive blinded IP [4 vials/1200 mg eculizumab every 2 weeks (±2 days) at Visits 1 and 3 and 4 vials of 
placebo at Visits 2 and 4]). All patients will receive 4 vials/1200 mg eculizumab open-label at Visit 5 and onward 
throughout the trial.  
 
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Open-Label Maintenance Phase  
All patients will receive open-label eculizumab (4 vials/1200 mg) every 2 weeks during the maintenance phase. All 
patients must be present at the trial site, as applicable per Schedule of Assessments, for visit-specific 
procedures/assessments including IP administration. For other visits, patients may have an opportunity to receive IP 
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 Principal Investigator (PI) and in accordance with all national, state, and local laws or regulations 
of the pertinent regulatory authorities. These visits will be conducted by a qualified staff member from the medical 
facility near the patient’s home or by home-care health professionals who are under the supervision of the 
Investigator. The trial medication will be prepared and administered at the patient’s home or at the medical facility. 
During a remote dosing visit, information on adverse events (AEs), concomitant medications, and signs or 
symptoms of NMO relapses will be collected and sent to the Investigator’s site for evaluation on the day of the 
visit. Patients must go to the trial site for evaluation if the patient reports any signs or symptoms that suggest a 
serious adverse event (SAE) or NMO relapse.  
 
Supportive immunosuppressive therapy (IST) for relapse prevention is allowed during this extension trial at the 
Treating Physician’s discretion. Change in IST or its dose/schedule will be allowed if due to relapse, intolerance, or 
medically indicated at the discretion of the Treating Physician. However, use of rituximab, mitoxantrone, or other 
biologic agents such as tocilizumab is prohibited during the trial. Patients may continue participation in this trial 
and receive the IP until the product is registered and available to treat patients diagnosed with relapsing NMO (in 
accordance with country specific regulations) or for a maximum of 5.5 years from the time the first patient was 
enrolled, whichever occurs first. 
 
Relapse Evaluation 
Identification of potential relapse is critical for patient safety and for the integrity of the trial. Patients will receive a 
Patient Education Card that details signs and symptoms of a potential relapse and instructions to contact the study 
site at the first sign or symptom of a potential relapse. The Investigator or his/her designee should review, in detail, 
this information and any additional warning signs of a relapse specific to that patient’s clinical picture at each visit. 
Patients should be evaluated within 24 hours of notification of the Investigator of a possible relapse, and no later 
than 48 hours. All reports of possible relapses and actions taken for the possible relapse must be documented in the 
patient’s source documents and recorded on the electronic case report form (eCRF).  
 
At the Relapse Evaluation Visit, a blinded Expanded Disability Status Scale (EDSS) Rater will perform the Kurtzke 
neurologic assessment to determine the Functional System scores (FSS) and Expanded Disability Status Scale 
(EDSS) score. The Treating Physician will perform a complete neurologic examination and document the 
Optic-Spinal Impairment Score (OSIS). The Treating Physician or appropriately trained designee will perform the 
visual acuity (VA) test (Snellen Chart) and Hauser Ambulatory Index (HAI) as outlined in the Relapse Evaluation 
Period section (Section 7.1.3 ). The Treating Physician will make the decision as to whether the clinical signs, 
symptoms and the neurologic change (objective findings on neurologic examination) meet the definition of an On-
Trial Relapse (Section 7.2.1). If the event is confirmed as an On-Trial Relapse, the patient may be treated according 
to the recommended Standardized On-Trial Relapse Treatment Plan. Relapse treatment is at the Treating 
Physician’s discretion. The treatment with IP will be continued per the specified dose administration schedule for 
the patient.  
 
Follow-up Relapse Evaluation Visits to monitor the course of the relapse will be performed at 1, 4 and 6 weeks 
after the onset of relapse. Additional (unscheduled) Follow-up Relapse Evaluation Visits outside the specified time 
points will be made at the discretion of the Treating Physician. Patients may continue the trial participation if the 
patient and the Treating Physician decide that it is appropriate to continue to receive eculizumab treatment.  
 
Adjudication of On-Trial Relapse Events 
An independent Relapse Adjudication Committee will confirm all On-Trial Relapse events using objective and 
consistent clinical criteria described in a Relapse Endpoint Adjudication Charter. The Adjudication Committee will 
consist of three independent medical experts in neurology/neuroophthalmology who are each experienced in the 
management of patients with NMO. The Adjudication Committee will decide by majority vote whether each On-
Trial Relapse (as determined by the treating PI) meets the pre-defined objective criteria for an adjudicated On-Trial 
Relapse, as described in the Relapse Adjudication Charter.  
 
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Safety Follow-Up Period (8 weeks) 
If a patient withdraws from this extension trial or discontinues eculizumab treatment at any time after receiving any 
amount of IP, the patient will be required to complete an Early Termination (ET) Visit at the time of the withdrawal 
and a safety Follow-up Visit, 8 weeks after the last dose of IP administration. If a patient is discontinued due to an 
adverse event (AE), the event will be followed until it is resolved or in the opinion of the Investigator is determined 
medically stable. Patients who withdraw from this extension trial and transition to treatment with commercially 
available eculizumab will not be required to complete a Follow-Up Visit.  
 
Post-Treatment Follow-up (a Maximum of 2 years):  
The Sponsor may seek to collect follow-up information concerning NMO status in patients who have prematurely 
discontinued from the trial for up to a maximum of 2 years from the last dose of eculizumab.  
Number of patients (planned):  
This is an extension trial to the ECU-NMO-301 trial. A maximum of 132 patients will be enrolled in the 
ECU-NMO-301 trial. Patients who complete the ECU-NMO-301 trial may potentially enter this extension trial.  
Diagnosis and main criteria for inclusion:  
Inclusion Criteria: 
1. Patient completed the ECU-NMO-301 trial (ie, completed either Week 6 Follow-up Relapse Evaluation 
Visit or End of Study Visit) 
2. Patient has given written informed consent  
3. Patient is willing and able to comply with the protocol requirements for the duration of the trial 
4. Female patients of child-bearing potential must have a negative pregnancy test (serum human chorionic 
gonadotropin [HCG]). All patients must practice an effective, reliable, and medically approved 
contraceptive regimen during the trial and for up to 5 months following discontinuation of treatment.  
Exclusion Criteria: 
1. Patient withdrew from the ECU-NMO-301 trial as a result of an AE related to IP 
2. Female patients who are pregnant, breastfeeding, or intend to conceive during the course of the trial  
3. Any medical condition or circumstances that, in the opinion of the Investigator, might interfere with the 
patient’s participation in the trial, pose any added risk for the patient, or confound the assessment of the 
patient.  
Investigational product, dosage and mode of administration:  
IP (eculizumab or placebo during the blind-induction phase), will be given by intravenous (IV) administration over 
approximately 35 minutes.  
Blind Induction Phase: To maintain the blind of the ECU-NMO-301 trial, all patients will undergo a blind induction 
phase. IP will be administered weekly for 4 weeks during the induction phase according to the following schedule: 
 
ECU-NMO-301 
(PREVENT) Cohort 
Dose 
Visit # 
Eculizumab arm 
4 vials IP (eculizumab 1200 mg) 
1, 3 
4 vials IP (placebo)  
2, 4 
Placebo arm 
4 vials IP (3 vials eculizumab 900 mg + 1 vial placebo)  
1, 2, 3, 4 
 
Open-label Maintenance Phase: All patients will receive 4 vials eculizumab (1200 mg) every 2 weeks (±2 days) 
from Visit 5 and onward throughout the trial. 
 
Supplemental Dose: If a patient undergoes plasmapheresis or plasma exchange (PE) for an On-Trial Relapse during 
the Study Period, a supplemental dose of IP must be administered after each PE session, preferably within 
1-2 hours. If the relapse occurs during the blinded induction phase, and the PE coincides with the day of a regularly 
 
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scheduled IP infusion: 
• 
For Visit 1 (Day1) and Visit 3 (Week 2), administer the scheduled 4 vials of blinded IP  
• 
For Visit 2 (Week 1) and Visit 4 (Week 3) administer only a supplemental IP dose, ie, 2 vials eculizumab 
(600 mg) 
If the relapse occurs during the open-label maintenance phase, and the PE coincides with the day of a regularly 
scheduled IP infusion, administer the scheduled IP dose (4 vials/1200 mg eculizumab). In all other cases, 
administer only a supplemental IP dose, ie, 2 vials eculizumab (600 mg).  
 
After receiving the supplemental dose, patients are to continue IP infusion according to the protocol-specified 
dosing regimen. 
Duration of treatment:  
The maximum total trial duration is 5.5 years from the time the first patient was enrolled. Trial duration for an 
individual patient will vary depending on when the patient enters the trial; participation may continue until the 
product is registered and available to treat patients with NMO (in accordance with country specific regulations) or 
until the trial ends, whichever occurs first. 
Reference therapy, dosage and mode of administration:  
Not applicable.  
Criteria for evaluation: 
Efficacy: 
Duration of treatment commences with the first IP infusion (eculizumab). 
• 
On-Trial Relapses will be monitored closely throughout the trial and evaluated as described in the above 
section “Study Period, Relapse Evaluation”. PI-determined On-Trial Relapses will be adjudicated by the 
Adjudication Committee and if confirmed by the Adjudication Committee, will be used for the ARR 
assessment. 
• 
Disability will be assessed by the EDSS and modified Rankin Scale (mRS) scores comparing the change 
from baseline. The EDSS Rater, who is blinded to all other trial data, as well as all other patient clinical 
data, will be responsible for performing the Kurtzke neurological assessments throughout the trial at the 
protocol-specified time points as well as at the Relapse Evaluation Visits. The Treating Physician or 
designee will perform the mRS throughout the trial at the protocol-specified time points. 
• 
Neurologic function will be assessed based on the EDSS FSS. Ambulatory function will be assessed by 
HAI scale and visual function will be measured by VA using the Snellen chart. In addition, the EDSS 
visual (optic) FSS will be used for statistical analysis of changes in VA. Neurologic function evaluation 
will be assessed at the protocol-specified time points as well as at the On-Trial Relapse Evaluation 
Visit(s). 
• 
QOL will be assessed by the patient self-assessment using both the EuroQoL (EQ-5D) and Short Form 
Health Survey (SF-36) instruments at the protocol-specified time points. 
 
Safety: 
• 
The safety of eculizumab will be assessed based on treatment emergent AEs (TEAEs), SAEs, and changes 
from baseline through trial completion in vital signs (VS), routine clinical laboratory tests (chemistry and 
hematology), Columbia-Suicide Severity Rating Scale (C-SSRS), and pregnancy tests for female patients 
of childbearing potential. 
• 
Immunogenicity: Blood samples will be collected for evaluation for human-anti-human antibodies 
(HAHA) at specified time points to describe the presence or absence of an immune response to 
eculizumab and to evaluate, if antibodies are detected, whether the antibodies neutralize the activity of 
eculizumab. 
• 
The same independent Data Monitoring Committee (DMC) that will conduct the monitoring of safety data 
for ECU-NMO-301 trial will be used in this extension trial. Since its primary function will be to ensure 
patient safety, the DMC will have access to all safety data. The DMC may make recommendations to the 
Sponsor regarding safety issues, trial conduct, and modifying, extending or stopping the trial. A separate 
DMC Charter will document all DMC procedures and processes for the trial. Data and analysis for the 
DMC will be prepared by an independent statistical group. 
 
Biomarker 
• 
Blood samples and cerebrospinal fluid (CSF) samples for NMO-IgG (AQP4-Ab) will be measured at 
 
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protocol-specified time points and during the On-Trial Relapse Evaluation Period. CSF samples will be 
obtained only from patients who have provided consent for lumbar puncture to obtain CSF samples. 
 
PK and PD 
• 
The population PK analysis of eculizumab in NMO patients will be performed to assess the concentration 
of eculizumab versus time. PK parameters such as maximum concentration as well as trough and peak 
eculizumab concentration during the induction and maintenance treatment phases will be reported. 
Clearance and terminal half-life will be estimated. PD analysis will be performed to assess pre- and post-
treatment serum hemolytic activity and therefore C5 complement activity inhibition. Free C5 
concentration also may be measured.  
• 
CSF samples for PK and free C5 from patients who have opted to provide consent will be measured at 
protocol-specified time points and during the On-Trial Relapse Evaluation Period. 
Statistical methods: 
Analyses will be produced using the data from this trial alone as well as combined analyses that will include data 
from the ECU-NMO-301 trial. The analyses will include safety, efficacy, and PK/PD analyses. The statistical 
analysis plan will cover both the stand-alone trial analyses and the combined ECU-NMO-301 and ECU-NMO-302 
trial analyses.  
 
SAFETY: 
Safety analyses will be performed on the Extension Safety Population and the Combined Safety Population from 
both studies. The Extension Safety Population includes all patients who receive at least 1 dose of eculizumab in this 
trial. The Combined Safety Population includes all patients who receive at least 1 dose of eculizumab in the ECU-
NMO-301 trial or this trial.  
 
Note: Baseline for the extension trial alone analyses is defined as the last available assessment prior to starting 
treatment with eculizumab in the extension trial. Baseline for the combined trial safety analyses is defined as the 
last available assessment prior to starting treatment with eculizumab in ECU-NMO-301 or in this trial for patients 
who have received placebo in the ECU-NMO-301 trial. 
 
Safety Analyses: 
For the extension trial alone, AEs onset on or after the first dose date for eculizumab in the extension trial will be 
summarized by incidence, system organ class (SOC), preferred term, (PT), seriousness, severity, and relationship to 
treatment. Concomitant medications taken during the extension trial will be summarized. Changes in IST usage (ie, 
increases, decreases, switching ISTs, etc) will be summarized. 
For the Combined Safety Population, AEs that occurred on or after the first dose of eculizumab whether in the 
ECU-NMO-301 or this extension trial will be summarized by incidence, SOC, PT, seriousness, severity, and 
relationship to treatment. Concomitant medications taken during eculizumab treatment regardless of the trial will be 
summarized. 
 
Changes from baseline in laboratory assessments (chemistry and hematology) will be summarized for the extension 
trial alone as well as for the two studies combined. Likewise, shift tables (L [low], N [normal], H [high]) will be 
produced for clinical laboratory tests for the extension trial alone as well as for the two studies combined. 
Pregnancy tests will be summarized in patient listings. Electrocardiogram (ECG) data will be summarized for the 
extension trial. Shift tables for the C-SSRS will be produced for the extension trial. 
 
Immunogenicity as measured by HAHA will be summarized in tabular form as well as a patient listing for the 
extension trial alone as well as for the two studies combined. 
 
EFFICACY: 
Efficacy analyses will be performed on the Extension Trial Full Analysis Set (Extension FAS) population as well as 
the Extension Trial Per-Protocol (Extension PP) population. In addition, efficacy analyses will be performed on the 
Combined Full Analysis Set (Combined FAS) population as well as the Combined Per-Protocol (Combined PP) 
population from the combined ECU-NMO-301 trial and the extension trial. 
 
Extension FAS Population: The population on which primary, secondary, and tertiary efficacy analyses will be 
performed consists of all patients who have received at least 1 dose of eculizumab in this extension trial and have a 
 
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post-IP infusion efficacy assessment. 
 
Extension PP Population: A subset of the Extension FAS population, excluding patients with major extension trial 
protocol deviations. The Extension PP population will include all patients who: 
• 
Have no major protocol deviations or key inclusion/exclusion criteria deviations that might potentially 
affect efficacy 
• 
Patients who took at least 80% of the required eculizumab doses during participation in the extension 
trial  
Combined FAS Population: The population on which primary, secondary, and tertiary efficacy analyses will be 
performed consists of all patients who have received at least 1 dose of eculizumab in either ECU-NMO-301 or this 
trial and have a post-IP infusion efficacy assessment. 
 
Combined PP Population: A subset of the Combined FAS population, excluding patients with major protocol 
deviations from either the ECU-NMO-301 or extension trial. The Combined PP population will include all patients 
who: 
• 
Have no major protocol deviations or key inclusion/exclusion criteria deviations that might potentially 
affect efficacy 
• 
Patients who took at least 80% of the required eculizumab doses during participation in ECU-NMO-
301 and/or this trial  
The Extension PP population as well as the Combined PP population will be determined prior to database lock. 
 
Primary Efficacy Analysis: 
The primary efficacy endpoint is ARR including all relapses as identified by the Investigator. Baseline ARR for all 
patients will be calculated starting 1 year prior to enrollment in the ECU-NMO-301 trial. Baseline ARR will be 
compared to rates calculated for the time period that patients are on eculizumab in ECU-NMO-302. The trial 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 On-Trial ARR when on eculizumab treatment in ECU-
NMO-302 using a Wilcoxon signed rank test. Confidence intervals (95%) for the change and percentage change in 
the ARR will be presented. The percentage of patients who are relapse-free based on On-Trial Relapse events while 
on eculizumab treatment in ECU-NMO-302 along with 95% confidence intervals will be computed using the 
Kaplan-Meier method. A sensitivity analysis will be performed for the change in ARR between the baseline ARR 
and the adjudicated On-Trial ARR when on eculizumab treatment in ECU-NMO-302 using a Wilcoxon signed rank 
test. The percentage of patients who are relapse-free while on eculizumab treatment in ECU-NMO-302 along with 
95% confidence intervals will also be computed using the Kaplan-Meier method for the adjudicated On-Trial 
relapses. 
 
Additional analyses will be performed on the combined data from ECU-NMO-301and ECU-NMO-302 trials. 
Baseline ARR for all patients will be calculated starting 1 year prior to enrollment in the ECU-NMO-301 trial and 
will include all On-Trial attacks (as identified by the Investigator) that occur in the ECU-NMO-301 trial for 
patients randomized to placebo. Baseline ARR for patients who were randomized to eculizumab in the ECU-NMO-
301 trial will be calculated starting one year prior to enrollment in the ECU-NMO-301 trial. Baseline ARR will be 
compared to rates calculated for the time period that patients are on eculizumab. For patients who are treated in the 
placebo arm of the ECU-NMO-301 trial, the ARR for comparison with baseline will be calculated once the patient 
transitions to eculizumab treatment. A Wilcoxon signed rank test will be used to assess the change in ARR between 
the baseline ARR and the On-Trial ARR when on eculizumab treatment. Confidence intervals (95%) for the change 
and percentage change in the ARR will be presented. The percentage of patients who are relapse-free based on On-
Trial Relapse events while on eculizumab treatment along with 95% confidence intervals will be computed using 
the Kaplan-Meier method. A sensitivity analysis will be performed for the change in ARR between the baseline 
ARR and the adjudicated On-Trial ARR when on eculizumab treatment using a Wilcoxon signed rank test. The 
percentage of patients who are relapse-free while on eculizumab treatment along with 95% confidence intervals 
will also be computed using the Kaplan-Meier method for the adjudicated On-Trial relapses. 
 
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Secondary Efficacy Analysis for the Trial Period: 
Baseline for the extension trial alone is defined as the last available assessment prior to starting treatment with 
eculizumab in the extension trial.  Baseline for the combined trial efficacy analyses is defined as the last available 
assessment prior to starting treatment with eculizumab in ECU-NMO-301 or this trial for all patients. 
Changes from baseline for the various secondary efficacy endpoints will be summarized over the applicable visits. 
1. Change from baseline in EDSS score  
2. Change from baseline in EQ-5D  
3. Change from baseline in mRS score  
4. Change from baseline in HAI in patients with abnormal baseline ambulatory function  
5. Change from baseline in VA in patients with abnormal baseline visual function  
The primary analysis for the change from baseline in EDSS score at a particular visit will be based on the repeated 
measures model with effects for baseline EDSS and visit. Changes from baseline in the HAI, VA, EQ-5D index 
score, EQ-5D visual analog scale, and mRS will be analyzed in a similar manner as changes in EDSS score using 
the baseline and visit as covariates in the modeling. In addition, summary statistics for the changes from baseline in 
the mRS score will be produced by visit. Likewise, shift tables from baseline in the mRS score will be produced by 
visit. By-patient listings of the secondary endpoints assessments and changes from baseline in the secondary 
endpoints will be produced. 
 
For the secondary endpoints, some summaries by subgroups will be produced. Patients will belong to one of four 
possible subgroups: 
(a) patients randomized to eculizumab who did not have relapses in the ECU-NMO-301 trial, 
(b) patients randomized to eculizumab who did have relapses in the ECU-NMO-301 trial,  
(c) patients randomized to placebo who did not have relapses in the ECU-NMO-301 trial, and 
(d) patients randomized to placebo who did have relapses in the ECU-NMO-301 trial. 
 
For the patients in sub-group (a), baseline is defined as the baseline assessment (last available assessment) prior to 
dosing in the ECU-NMO-301 trial. For the patients in sub-group (c), baseline is defined as the last available 
assessment prior to dosing with eculizumab in this trial. For the patients in subgroups (b) and (d), baseline for these 
subgroup analyses is defined as the last available assessment prior to eculizumab dosing in this extension trial in 
consideration of neurologic changes and recoveries as a result of relapse in the ECU-NMO-301 trial. Changes from 
baseline for the various secondary efficacy endpoints will be summarized separately for the 4 subgroups of patients 
over the applicable visits. Missing secondary endpoint assessments will not be imputed.  
 
Tertiary Efficacy Analysis for the Trial Period: 
Like the secondary efficacy endpoint, the tertiary endpoint analyses will be based on changes from baseline. 
1. Change from baseline in HAI score  
2. Change from baseline in VA  
3. Change from baseline in the SF-36  
4. Change from baseline in the EDSS FSS  
Changes from baseline in the HAI score and VA will be analyzed in a similar manner to the secondary endpoint 
analyses described for HAI with abnormal baseline ambulatory function and VA with abnormal baseline visual 
function using repeated measures models. 
 
Change from baseline in QOL will be summarized as appropriate to the QOL instrument and analyses will be 
performed as specified in the statistical analysis plan (SAP). 
 
Changes from baseline in the EDSS FSS will be analyzed in a similar manner to the secondary endpoint analyses 
described for the EDSS score using repeated measures models. 
 
In addition, summaries of changes from baseline like those for the secondary efficacy endpoints will also be created 
for the tertiary efficacy endpoints for the 4 subgroups of patients from the ECU-NMO-301 trial who are treated in 
the extension trial.  
 
 
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Other Efficacy Analyses: On-Trial Relapses: 
For patients with a PI-determined On-Trial relapse(s), summary tables of the types of relapses and the severity of 
the relapses will be produced. Summary tables will also be produced only for those patients with adjudicated On-
Trial relapse(s). A by-patient listing of the PI-determined On-Trial relapses, including the subsequent adjudication 
outcome will be produced. The severity of a relapse will be determined using the OSIS scale. Severity will be 
assessed at the time of the relapse.  
 
Changes from baseline to all of the trial-collected time-points after a relapse (and before the next relapse if the 
patient happens to have more than one relapse) will be summarized for EDSS, HAI, and VA. Changes from the last 
assessment prior to the relapse to all trial collected time-points after a relapse (and before the next relapse if the 
patient happens to have more than one relapse) will be summarized for EDSS, HAI, and VA. Likewise, changes 
from the assessment 1 week after the relapse to all trial collected time-points after that time point (and before the 
next relapse if the patient happens to have more than one relapse) will be summarized for EDSS, HAI, and VA. 
These summaries will be produced for patients with a PI-determined On-Trial relapse(s) as well as for only those 
patients with adjudicated On-Trial relapse(s).  Patient listings for the EDSS, HAI, and VA assessments before and 
after a relapse will be created for the patients with all On-Trial relapses as determined by the PI(s), including the 
subsequent adjudication outcome. 
 
Biomarker Analysis for the Trial Period: 
Changes from baseline for NMO-IgG assessments will be summarized and patient listings for the NMO biomarker 
data will be created. 
 
PK/PD for the Trial Period: 
Population PK analysis of eculizumab in NMO patients will be performed to assess the concentration of 
eculizumab versus time. PK parameters such as maximum concentration as well as trough and peak eculizumab 
concentration during the induction and maintenance treatment phases will be reported. Clearance and terminal half-
life will be estimated. PD analysis will be performed to assess pre- and post-treatment serum hemolytic activity and 
therefore C5 complement activity inhibition. Free C5 concentration also may be measured. 
 
Rationale for Number of Patients:  
This is an extension trial to ECU-NMO-301 trial. A maximum of 132 patients are planned to be enrolled in the 
ECU-NMO-301 trial. This extension trial will be open to all patients who have completed the ECU-NMO-301 trial 
and meet the eligibility criteria.  
 
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3. 
TABLE OF CONTENTS AND LIST OF TABLES  
TABLE OF CONTENTS 
1. 
TITLE PAGE ................................................................................................................1 
2. 
SYNOPSIS ...................................................................................................................6 
3. 
TABLE OF CONTENTS AND LIST OF TABLES ..................................................14 
4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS.............................20 
5. 
INTRODUCTION ......................................................................................................22 
6. 
TRIAL OBJECTIVES AND PURPOSE ....................................................................23 
6.1. 
Primary Objective .......................................................................................................23 
6.2. 
Secondary Objectives .................................................................................................23 
7. 
INVESTIGATIONAL PLAN .....................................................................................24 
7.1. 
Overall Trial Design ...................................................................................................24 
7.1.1. 
Blind Induction Phase (Visits 1 – 4) ...........................................................................24 
7.1.2. 
Open-Label Maintenance Phase .................................................................................24 
7.1.3. 
Relapse Evaluation .....................................................................................................25 
7.1.4. 
Safety Follow-up Period (Post-Treatment) .................................................................26 
7.1.5. 
Post-Treatment Follow-up (a Maximum of 2 Years) .................................................26 
7.2. 
Standard Protocol Definitions .....................................................................................26 
7.2.1. 
On-Trial Relapse .........................................................................................................26 
7.2.2. 
Severity of Relapse .....................................................................................................26 
7.2.3. 
The Treating Physician ...............................................................................................27 
7.2.4. 
The (Blinded) EDSS Rater .........................................................................................27 
7.3. 
Number of Patients .....................................................................................................29 
7.4. 
Treatment Assignment ................................................................................................29 
7.5. 
Schedule of Assessments ............................................................................................29 
7.6. 
Trial Visit Procedures .................................................................................................38 
7.6.1. 
Trial Period .................................................................................................................38 
7.6.1.1. 
Induction Phase (Visit 1 until Visit 5 [Week 4]) ........................................................38 
7.6.1.2. 
Open-label Phase (Visit 6 [Week 6] until End of Study / Early Termination 
Visit) ...........................................................................................................................41 
7.6.2. 
Relapse Evaluation Period ..........................................................................................43 
 
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7.6.2.1. 
Relapse Evaluation Visit (Within 24-48 Hours) .........................................................43 
7.6.2.2. 
Follow-up Relapse Evaluation Visits (Week 1, 4 and 6) ............................................45 
7.6.2.3. 
Unscheduled Visit .......................................................................................................46 
7.6.2.4. 
Adjudication of On-Trial Relapse Events ...................................................................46 
7.6.3. 
Safety Follow-up Period (post-treatment) ..................................................................47 
7.6.4. 
Post-Treatment Follow-up (a Maximum of 2 years) ..................................................47 
8. 
SELECTION AND WITHDRAWAL OF PATIENTS ..............................................48 
8.1. 
Patient Inclusion Criteria ............................................................................................48 
8.2. 
Patient Exclusion Criteria ...........................................................................................48 
8.3. 
Patient Withdrawal Criteria ........................................................................................48 
8.3.1. 
Withdrawal of Patients From the Trial .......................................................................48 
8.3.2. 
Handling of Withdrawals ............................................................................................48 
8.3.3. 
Sponsor’s Termination of Trial ..................................................................................49 
9. 
TREATMENT OF PATIENTS ..................................................................................50 
9.1. 
Investigational Product Dosage and Administration ..................................................50 
9.2. 
Concomitant Medications ...........................................................................................51 
9.2.1. 
Allowed Medications ..................................................................................................51 
9.2.1.1. 
Palliative and Supportive Care ...................................................................................51 
9.2.1.2. 
Immunosuppressive Agents ........................................................................................51 
9.2.1.3. 
Recommended Standardized Relapse Treatment .......................................................51 
9.2.2. 
Disallowed Medications .............................................................................................51 
9.3. 
Treatment Compliance ................................................................................................52 
9.4. 
Randomization and Blinding ......................................................................................52 
9.4.1. 
Randomization ............................................................................................................52 
9.4.2. 
Blinding and Unblinding ............................................................................................52 
10. 
INVESTIGATIONAL PRODUCT MATERIALS AND MANAGEMENT .............53 
10.1. 
Investigational Product ...............................................................................................53 
10.2. 
Investigational Product Packaging and Labeling .......................................................53 
10.3. 
Investigational Product Storage ..................................................................................53 
10.4. 
Investigational Product Preparation ............................................................................54 
10.5. 
Investigational Product Administration ......................................................................54 
10.6. 
Investigational Product Accountability ......................................................................55 
10.7. 
Investigational Product Handling and Disposal .........................................................55 
 
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11. 
ASSESSMENT OF EFFICACY ................................................................................56 
11.1. 
Efficacy Parameters ....................................................................................................56 
11.1.1. 
Relapses ......................................................................................................................56 
11.1.2. 
Disability .....................................................................................................................57 
11.1.3. 
Neurologic Functions ..................................................................................................57 
11.1.4. 
Quality of Life ............................................................................................................57 
12. 
ASSESSMENT OF SAFETY .....................................................................................58 
12.1. 
Safety Parameters .......................................................................................................58 
12.1.1. 
Demographic/Medical History ...................................................................................58 
12.1.2. 
Vital Signs ..................................................................................................................58 
12.1.3. 
Weight .........................................................................................................................58 
12.1.4. 
Physical Examination .................................................................................................58 
12.1.5. 
Electrocardiogram .......................................................................................................59 
12.1.6. 
Laboratory Assessments .............................................................................................59 
12.1.7. 
Columbia-Suicidal Severity Rating Scale (C-SSRS) .................................................59 
12.2. 
Adverse Events and Serious Adverse Events .............................................................60 
12.2.1. 
Definition of Adverse Events .....................................................................................60 
12.2.1.1. 
Adverse Event .............................................................................................................60 
12.2.1.2. 
Abnormal Test Finding ...............................................................................................60 
12.2.1.3. 
Serious Adverse Events ..............................................................................................61 
12.2.1.4. 
Lack of Efficacy .........................................................................................................61 
12.2.1.5. 
Hospitalization ............................................................................................................61 
12.2.1.6. 
Procedures ...................................................................................................................62 
12.2.1.7. 
Other Adverse Events .................................................................................................62 
12.2.1.8. 
Severity Assessment ...................................................................................................62 
12.2.1.9. 
Causality Assessment .................................................................................................62 
12.2.1.10. Exposure during Pregnancy and Lactation .................................................................63 
12.2.1.11. Withdraw due to an Adverse Event ............................................................................64 
12.2.1.12. Obtaining Adverse Event ............................................................................................64 
12.2.1.13. Reporting Period .........................................................................................................64 
12.2.1.14. Reporting Requirements for Adverse Events .............................................................64 
12.2.1.15. Sponsor Reporting Requirements ...............................................................................65 
12.2.1.16. Investigator Reporting Requirements .........................................................................65 
 
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12.2.1.17. Reference Safety Document .......................................................................................65 
12.2.1.18. Data Monitoring Committee .......................................................................................65 
13. 
ASSESSMENT OF BIOMARKER ............................................................................66 
13.1. 
NMO Biomarker .........................................................................................................66 
14. 
ASSESSMENT OF PHARMACOKINETICS AND 
PHARMACODYNAMICS ........................................................................................67 
15. 
STATISTICS ..............................................................................................................68 
15.1. 
General Considerations ...............................................................................................68 
15.2. 
Determination of Sample Size ....................................................................................68 
15.3. 
Analysis Sets ...............................................................................................................68 
15.3.1. 
Extension Trial Full Analysis Set Population .............................................................69 
15.3.2. 
Extension Trial Per-Protocol Set Population ..............................................................69 
15.3.3. 
Combined Full Analysis Set Population .....................................................................69 
15.3.4. 
Combined Per-Protocol Set Population ......................................................................69 
15.3.5. 
Extension Safety Set Population .................................................................................69 
15.3.6. 
Other Set(s) .................................................................................................................69 
15.4. 
Demographics and Baseline Characteristics ...............................................................70 
15.5. 
Patient Disposition and Treatment Compliance .........................................................70 
15.6. 
Prior and Concomitant Medications ...........................................................................70 
15.7. 
Efficacy Analyses .......................................................................................................70 
15.7.1. 
Primary Efficacy Analysis ..........................................................................................70 
15.7.2. 
Secondary Efficacy Analysis for the Trial Period ......................................................71 
15.7.3. 
Tertiary Efficacy Analysis for the Trial Period ..........................................................72 
15.7.4. 
Other Efficacy Analyses: On-Trial Relapses ..............................................................73 
15.8. 
Safety Analyses ..........................................................................................................73 
15.8.1. 
Physical Examinations and Vital Signs ......................................................................73 
15.8.2. 
Laboratory Assessments .............................................................................................74 
15.8.3. 
Adverse Events ...........................................................................................................74 
15.8.3.1. 
Columbia-Suicide Severity Rating Scale ....................................................................74 
15.8.4. 
Other Safety Endpoints ...............................................................................................74 
15.9. 
Pharmacokinetic/Pharmacodynamic Analyses ...........................................................74 
15.10. 
Biomarker Analysis ....................................................................................................74 
15.11. 
Other Statistical Issues ................................................................................................75 
 
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15.11.1. 
Significance Levels .....................................................................................................75 
15.11.2. 
Missing or Invalid Data ..............................................................................................75 
16. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS.........................................76 
16.1. 
Trial Monitoring .........................................................................................................76 
16.2. 
Audits and Inspections ................................................................................................76 
16.3. 
Institutional Review Board/Independent Ethics Committee ......................................77 
16.4. 
Data Monitoring Committee .......................................................................................77 
17. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................78 
18. 
ETHICS ......................................................................................................................79 
18.1. 
Ethics Review .............................................................................................................79 
18.2. 
Ethical Conduct of the Trial .......................................................................................79 
18.3. 
Written Informed Consent ..........................................................................................79 
19. 
DATA HANDLING AND RECORDKEEPING .......................................................80 
19.1. 
Inspection of Records .................................................................................................80 
19.2. 
Retention of Records ..................................................................................................80 
20. 
LIST OF REFERENCES ............................................................................................81 
21. 
APPENDICES ............................................................................................................82 
APPENDIX 1: 2006 DIAGNOSTIC CRITERIA FOR NMO .......................................................83 
APPENDIX 2: 2007 DIAGNOSTIC CRITERIA FOR NMO SPECTRUM DISORDER ...........84 
APPENDIX 3: KURTZKE EXPANDED DISABILITY STATUS SCALE (EDSS) ...................85 
APPENDIX 4: OPTIC-SPINAL IMPAIRMENT SCORE (OSIS) ...............................................87 
APPENDIX 5: HAUSER AMBULATION INDEX .....................................................................88 
APPENDIX 6: SHORT FORM HEALTH SURVEY (SF-36) ...................................................89 
APPENDIX 7: EUROQOL (EQ-5D) ............................................................................................95 
APPENDIX 8: CLINICAL LABORATORY TESTS ...................................................................98 
APPENDIX 9: MODIFIED RANKIN SCALE .............................................................................99 
APPENDIX 10: COLUMBIA-SUICIDE SEVERITY RATING SCALE (C-SSRS) – 
SINCE LAST VISIT .................................................................................................100 
APPENDIX 11: COLLECTION OF FOLLOW-UP INFORMATION FROM 
PATIENTS WHO WITHDRAW FROM THE STUDY ..........................................104 
 
 
LIST OF TABLES 
 
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Table 1: 
Emergency Contact Information ...................................................................................4 
Table 2: 
Abbreviations and Specialist Terms ...........................................................................20 
Table 3: 
Relapse Severity as Measured by OSIS ......................................................................27 
Table 4: 
Roles and Responsibilities of Treating Physician and EDSS Rater ...........................28 
Table 5: 
Schedule of Assessments – Visits 1-16 ......................................................................30 
Table 6: 
Schedule of Assessments – Visits 17-29 ....................................................................32 
Table 7: 
Schedule of Assessments - Study Period (Beyond Visit 29/Week 52 to 
EOS/ET) .....................................................................................................................33 
Table 8: 
Schedule of Assessments – Relapse Evaluation Period .............................................35 
Table 9: 
Schedule of Assessments – Safety Follow-up Visit ...................................................36 
Table 10: Schedule of Assessments – Footnotes ........................................................................37 
Table 11: Investigational Product Dosage and Administration ..................................................50 
Table 12: Investigational Product ...............................................................................................53 
Table 13: Investigational Product Preparation and Reconstitution.............................................54 
 
 
 
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4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
The following abbreviations and specialist terms are used in this trial protocol. 
Table 2: 
Abbreviations and Specialist Terms  
Abbreviation or Specialist Term 
Explanation 
AE 
Adverse event 
ARR 
Annualized Relapsing Rate 
AQP4-Ab 
Aquaporin-4 Antibody 
AZA 
Azathioprine 
BP 
Blood Pressure 
C5 
Complement Protein 5 
CNS 
Central Nervous System 
CSF 
Cerebrospinal fluid 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CT 
Computed Tomography 
DMC 
Data Monitoring Committee 
eCRF 
Electronic Case Report Form 
ECG 
Electrocardiogram  
EDSS 
Expanded Disability Status Scale 
EIU 
Exposure in-utero 
EOS 
End of Study  
EQ-5D 
EuroQol 
ET 
Early Termination 
FAS 
Full Analysis Set 
FSS 
Functional System Scores  
GCP 
Good Clinical Practice 
HAHA 
Human Anti-human Antibody 
HAI 
Hauser Ambulation Index 
HCG 
Human Chorionic Gonadotropin 
HR 
Heart Rate 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
ICU 
Intensive Care Unit  
IEC 
Independent Ethics Committee 
IgG 
Immunoglobulin G 
IP 
Investigational Product 
IRB 
Institutional Review Board 
IST 
Immunosuppressant Therapy 
IV 
Intravenous  
IVIg 
Intravenous Immunoglobulin 
IVMP 
Intravenous Methylprednisolone 
IXRS 
Interactive voice or web Response System 
mAb 
Monoclonal Antibody 
MMF 
Mycophenolate Mofetil 
MRI 
Magnetic Resonance Imaging 
mRS 
Modified Rankin Scale 
NMO 
Neuromyelitis Optica 
NMO-IgG 
Neuromyelitis Optica antibody 
OAE 
Other Significant Adverse Event 
 
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Abbreviation or Specialist Term 
Explanation 
OSIS 
Optic Spinal Impairment Score  
PD 
Pharmacodynamics 
PE 
Plasmapheresis Or Plasma Exchange 
PI 
Principal Investigator 
PK 
Pharmacokinetics  
PP 
Per-Protocol  
QOL 
Quality Of Life  
RR 
Respiration Rate 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SF-36 
Short Form Health Survey 
SOC 
System Organ Class 
TEAE 
Treatment Emergent Adverse Events 
VA 
Visual Acuity 
VS 
Vital Signs 
 
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5. 
INTRODUCTION 
Neuromyelitis Optica (NMO) or NMO Spectrum Disorder (NMOSD), also known as Devic’s 
Disease, is a rare, severe disabling autoimmune inflammatory disorder of the central nervous 
system (CNS) that predominately affects the optic nerves and spinal cord, and is often 
characterized by a relapsing course (1;2). Currently there are no approved therapies for the 
treatment of NMO. Complement activation is a key element in the development of CNS lesions 
in NMO. Eculizumab (h5G1.1-mAb) is a terminal complement inhibitor that blocks conversion 
of C5 to C5a and C5b thus blocking terminal complement activation. The mechanism of action 
of eculizumab as a terminal complement inhibitor suggests that it may provide therapeutic 
benefit in the management of NMO by reducing NMO relapses and thus reducing disability (see 
the Investigator’s Brochure (IB) for more information).  
A phase 3 clinical trial, Protocol ECU-NMO-301, to evaluate the safety and efficacy of 
eculizumab in the treatment of relapsing NMO, has been initiated. Protocol ECU-NMO-302 is an 
extension trial designed to provide the patients who have participated in the ECU-NMO-301 trial 
an opportunity to continue receiving eculizumab and to collect clinical data that will provide 
long term safety and efficacy information on eculizumab in patients with relapsing NMO. 
Throughout this document, the term NMO refers to both NMO and NMOSD. 
Refer to Protocol ECU-NMO-301 and to the current IB for additional information on the safety 
and efficacy data of eculizumab.  
 
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6. 
TRIAL OBJECTIVES AND PURPOSE 
6.1. 
Primary Objective 
• Evaluate the long-term safety of eculizumab in patients with relapsing NMO.  
6.2. 
Secondary Objectives 
• Evaluate the long-term efficacy of eculizumab in patients with relapsing NMO as 
measured by annualized relapsing rate (ARR) 
• Evaluate long-term efficacy of eculizumab by additional efficacy measures including: 
o Disability  
o Quality of life (QOL) 
o Neurologic functions 
• Describe the pharmacokinetics (PK) and pharmacodynamics (PD) of eculizumab in 
relapsing NMO patients. 
 
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7. 
INVESTIGATIONAL PLAN 
7.1. 
Overall Trial Design 
This is an open-label trial. All patients who have completed the trial ECU-NMO-301 may be 
eligible to participate in this extension trial. Prior to initiating any extension trial procedures, an 
Informed Consent Form (ICF) must be signed and inclusion/exclusion criteria must be obtained, 
evaluated and met. Patients who exit the ECU-NMO-301 trial due to a relapse will have their 
first extension trial visit once the Week 6 Follow-up Relapse Evaluation Visit is completed and 
no later than 2 weeks (14 days ±2 days) after the last IP dose; patients who exit the ECU-NMO-
301 trial due to trial completion will have their first extension trial visit once the End of Study 
(EOS) Visit is completed and no later than 2 weeks (14 days ±2 days) after the last IP 
administration in the ECU-NMO-301 trial.  
Due to the length of this extension trial, patients may need to be revaccinated for N meningitidis 
to provide active coverage as specified by the vaccine manufacturer or according to current 
medical/country guidelines.  
Patients who have been unblinded in ECU-NMO-301 may not continue in ECU-NMO-302. 
7.1.1. 
Blind Induction Phase (Visits 1 – 4) 
To preserve the blinded nature of the ECU-NMO-301 trial, all patients must undergo a blind 
induction phase prior to entering the open-label phase of this trial, ie, all patients will receive 4 
vials of blinded investigational product (IP) weekly (±2 days) for 4 doses. Patients who had been 
randomized to the placebo arm in the ECU-NMO-301 trial will start with the induction dose (ie, 
they will receive blinded IP [3 vials/900 mg eculizumab plus 1 vial placebo] at Visits 1 to 4). 
Patients who were randomized to the eculizumab arm in the ECU-NMO-301 trial will continue 
with the maintenance dose (ie, they will receive blinded IP [4 vials/1200 mg eculizumab every 
two weeks (±2 days) at Visits 1 and 3 and 4 vials of placebo at Visits 2 and 4]). All patients will 
receive open-label 4 vials/1200 mg eculizumab at Visit 5 and onward. 
7.1.2. 
Open-Label Maintenance Phase  
All patients will receive open-label eculizumab (4 vials/1200 mg) every 2 weeks (±2 days) 
during the maintenance phase. The end of the trial occurs a maximum of 5.5 years after the first 
patient was enrolled in this study, therefore for each individual patient the number of visits and 
the relative timing of the EOS Visit will vary. 
All patients must be present at the trial site, as applicable, for visit-specific 
procedures/assessments including IP administration (see Schedule of Assessments in 
Section 7.5). For other visits, patients may have an opportunity to receive IP 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. These visits will be conducted by a qualified 
staff member from the medical facility near the patient’s home or by home-care health 
professionals, who are under the direct supervision of the Investigator. The trial medication will 
be prepared and administered at the patient’s home or at the medical facility. During a remote 
 
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dosing visit, information on adverse events (AEs), concomitant medications, and signs or 
symptoms of NMO relapses will be collected and sent to the Investigator’s site for evaluation on 
the day of the visit. Patients must go to the trial site for evaluation if the patient reports any signs 
or symptoms that suggest a serious adverse event (SAE) or NMO relapse.  
Supportive immunosuppressive therapy (IST) for relapse prevention is allowed during the 
extension trial at the Treating Physician’s discretion. However, use of rituximab, mitoxantrone, 
or other biologic agents such as tocilizumab is prohibited during the trial. 
Patients may continue participation in this trial and receive the IP until the product is registered 
and available to treat patients diagnosed with relapsing NMO (in accordance with country 
specific regulations) or for a maximum of 5.5 years from the time the first patient was enrolled, 
whichever occurs first. 
7.1.3. 
Relapse Evaluation 
Identification of potential relapse is critical for patient safety and for the integrity of this trial. 
Patients will receive a Patient Education Card that details signs and symptoms of a potential 
relapse and instructions to contact the study site at the first sign or symptom of a potential 
relapse. The Investigator or his/her designee should review, in detail, this information and any 
additional warning signs of a relapse specific to that patient’s clinical picture at each visit. 
Patients should be evaluated within 24 hours of notification of the Investigator of a possible 
relapse, and no later than 48 hours. All reports of possible relapses and actions taken for the 
possible relapse must be documented in the patient’s source documents and recorded on the 
electronic case report forms (eCRFs).  
At the Relapse Evaluation Visit, a blinded Expanded Disability Status Scale (EDSS) Rater will 
perform the Kurtzke neurologic assessment and document the Functional System scores (FSS) to 
determine the EDSS score. The Treating Physician will perform a complete neurologic 
examination and document the Optic-Spinal Impairment Score (OSIS). Treating Physician or 
appropriately trained designee will perform the visual acuity (VA) test (Snellen Chart) and 
Hauser Ambulatory Index (HAI) as outlined in the Relapse Evaluation Period (section 7.6.2).  
The Treating Physician will make the decision as to whether the clinical signs, symptoms and 
neurologic change (objective findings on neurologic examination) meet the definition of an On-
Trial Relapse (Section 7.2.1). The blinded EDSS Rater will complete the Kurtzke neurologic 
assessment and document the FSS and EDSS scores. If the event is confirmed as an On-Trial 
Relapse, the patient may be treated according to the recommended Standardized On-Trial 
Relapse Treatment Plan (Section 9.2.1.3). Relapse treatment is at the Treating Physician’s 
discretion. The IP administration will be continued as scheduled every 1 week (if during the 
induction phase) or every 2 weeks (if during the maintenance phase) until the EOS.  
Follow-up Relapse Evaluation visits to monitor the course of the relapse will be performed at 1, 
4 and 6 weeks after the onset of relapse. Additional (unscheduled) Follow-up Relapse Evaluation 
Visits outside the specified time points will be made at the discretion of the Treating Physician. 
Following a relapse, a patient may continue in the trial if the patient and the Treating Physician 
decide that it is appropriate to continue to receive eculizumab treatment.  
All reports of possible relapses and actions taken for the possible relapse must be documented in 
the patient’s source documents and recorded in the eCRF.  
 
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An independent Relapse Endpoint Adjudication Committee will confirm all On-Trial Relapse 
events using objective and consistent clinical criteria described in a Relapse Endpoint 
Adjudication Charter. The Adjudication Committee will consist of three independent medical 
experts in neurology/neuroophthalmology who are each experienced in the management of 
patients with NMO. The Adjudication Committee will decide by majority vote whether each 
relapse meets the pre-defined objective criteria for an adjudicated On-Trial Relapse, as described 
in the Relapse Adjudication Charter. 
7.1.4. 
Safety Follow-up Period (Post-Treatment) 
If a patient withdraws from this extension trial at any time after receiving any amount of IP, the 
patient will be required to complete an Early Termination (ET) Visit at the time of the 
withdrawal and a safety Follow-up Visit, 8 weeks after the last IP administration. If a patient is 
discontinued due to an AE, the event will be followed until it is resolved or, in the opinion of the 
Principal Investigator (PI), is determined medically stable. Patients who withdraw from the 
extension trial and transition to treatment with the commercially available eculizumab will not be 
required to complete a safety Follow-up Visit. 
7.1.5. 
Post-Treatment Follow-up (a Maximum of 2 Years) 
The Sponsor may seek to collect follow-up information concerning NMO status in patients who 
have prematurely discontinued from the trial for a maximum of 2 years from the last dose of 
eculizumab (refer to Appendix 11). 
7.2. 
Standard Protocol Definitions 
7.2.1. 
On-Trial Relapse 
On-Trial Relapses are acute attacks that occur during the trial. For this protocol, On-Trial 
Relapse is defined as a new onset of neurologic symptoms or worsening of existing neurologic 
symptoms with an objective change (clinical sign) on neurologic examination that persists for 
more than 24 hours as confirmed by the Treating Physician. The signs and symptoms must be 
attributed to NMO, ie, not caused by an identifiable cause such as infection, excessive exercise, 
or excessively high ambient temperature. Isolated changes on magnetic resonance imaging 
(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 Treating 
Physician is not required to wait 24 hours prior to initiating treatment for the relapse.  
All PI-determined relapses will be reviewed by the Adjudication Committee; to determine if they 
meet protocol-defined criteria for an On-Trial relapse event. 
7.2.2. 
Severity of Relapse 
Severity of an On-trial Relapse will be measured by OSIS. The OSIS Visual Acuity (VA) 
Subscale Scores will be used to categorize the severity of optic neuritis relapse. The OSIS Motor 
Subscale Scores and Sensory Subscale Scores will used to categorize the severity of transverse 
myelitis. OSIS scores will be assessed by the Treating Physician at the time of the relapse as in 
Table 3 below.  
 
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Table 3: 
Relapse Severity as Measured by OSIS 
Optic Neuritis  
Visual Acuity (VA) Subscale Score 
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 
 
Based on 
proprioceptive loss 
only 
Severe loss in one or more limbs with 
prior normal function or mild 
proprioceptive loss 
Major 
7.2.3. 
The Treating Physician 
The Treating Physician is the PI or the Sub-Investigator for the trial, and will be responsible for 
overall patient management including patient eligibility evaluation, the supervision of the 
blinded (induction phase) and open label (maintenance phase) IP administration, the recording 
and treating of AEs and the monitoring of safety assessment. In addition, the Treating Physician 
or an appropriately trained designee will perform mRS and C-SSRS assessments. At the time of 
a relapse the Treating Physician will perform a complete neurologic exam and determine if a 
patient experiences an On-Trial Relapse, determine relapse severity by OSIS, assess VA test 
(Snellen Chart), ambulation (HAI), have the patient complete EQ-5D and SF-36, and may treat 
the patient’s relapse at his/her discretion, according to the recommended Standardized On-Trial 
Relapse Treatment plan (section 9.2.1.3). Treatment for On-Trial Relapse and any changes in the 
ISTs are at the discretion of the Treating Physician. 
7.2.4. 
The (Blinded) EDSS Rater 
The blinded EDSS Rater will be responsible for performing the EDSS assessments throughout 
the trial at protocol-specified time points including at the time of a relapse. The EDSS Rater will 
perform the Kurtzke neurologic assessment (5) and document the FSS and EDSS score. The 
EDSS Rater shall not be the PI or the Treating Physician, and cannot be directly involved in the 
trial patient’s management. The EDSS Rater must remain blinded to all other trial data as well as 
 
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all other patient clinical data. 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 prior to initiation of the study. For specific requirements for EDSS Rater qualifications, 
refer to the training materials provided to the sites. 
The table below provides roles and responsibilities of Treating Physician and EDSS Rater. 
Table 4: 
Roles and Responsibilities of Treating Physician and EDSS Rater 
Treating Physician 
EDSS Rater 
Blinded to the patient’s treatment assignment 
during the Induction Phase 
• Determine patient eligibility for the trial 
• Overall patient management during the 
trial, including IP administration and 
safety assessments.  
• Perform modified Rankin Scale (mRS)* 
• Perform Columbia-Suicide Severity 
Rating Scale (C-SSRS)* 
Blinded to all other trial data as well as all 
other patient clinical chart data  
At protocol-specified time points: 
• Kurtzke neurologic assessment 
• Document FSS  
• Record EDSS score 
 
 
At relapse evaluation visits: 
• Initial patient assessment  
• Have the EDSS Rater record FSS and 
EDSS score 
• Perform a complete neurologic 
examination  
• Determine if the patient has experienced 
an On-Trial Relapse 
• Determine relapse severity by OSIS 
• Assess VA, Snellen Chart* 
• Assess ambulation, HAI* 
• Have the patient complete EuroQoL EQ-
5D and Short Form Health Survey (SF-
36)*  
• Treat relapse 
At relapse evaluation visits: 
• Perform Kurtzke neurologic 
assessment 
• Document FSS  
• Record EDSS score 
* Can be performed by the Treating Physician or his/her designee. 
 
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7.3. 
Number of Patients 
This is an extension trial to the ECU-NMO-301 trial. A maximum of 132 patients are expected to 
enroll in the ECU-NMO-301 trial. Patients who complete the ECU-NMO-301 trial may 
potentially enter this extension trial. 
7.4. 
Treatment Assignment 
This is an open-label extension trial to the ECU-NMO-301 trial. All patients will be administered 
intravenous (IV) eculizumab. To maintain the blind of the ECU-NMO-301 trial, all patients will 
undergo a blind induction phase as described in Section 9.1.  
7.5. 
Schedule of Assessments 
The Schedules of Assessments are presented in Table 5 through Table 10. Note that when a 
patient continues beyond Visit 29 (end of first year), the visit schedule and assessments scheme 
for the second year and beyond will restart from the equivalent of Visit 30 onward. These visits 
and assessments in the second year and beyond are included in the Schedule of Assessments in 
Table 7 .  
 
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Table 5: 
Schedule of Assessments – Visits 1-16 
Phase 
Induction  
Open-label Maintenance 
Visit Location ∆ 
In Clinic 
In 
Clinic/ 
Remote 
In 
Clinic 
In 
Clinic/ 
Remote 
In 
Clinic 
In Clinic/Remote 
In Clinic 
Trial Visit Year 1 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
V11 
V12 
V13 
V14 
V15 
V16 
Trial Week Year 1 
Day 1 
W1 
W2 
W3 
W4 
W6 
W8 
W10 
W12 
W14 
W16 
W18 
W20 
W22 
W24 
W26 
Informed Consent  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical exam 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Weight  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Vital Signs  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Electrocardiogram (ECG)  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Concomitant Medication  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse events (AEs) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Clinical Laboratory Tests 1 
X 
 
 
 
X 
 
X 
 
X 
 
 
 
 
 
 
X 
Pregnancy serum test 2 
X 
 
 
 
X 
 
X 
 
X 
 
 
 
 
 
 
X 
NMO-IgG (serum)  
X 
 
 
 
X 
 
X 
 
X 
 
 
 
 
 
 
X 
NMO-IgG (CSF) 3 
See 
Footnote 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
PK/PD/Free C5 (serum) 4 
T/P 
 
 
 
T/P 
 
T/P 
 
T/P 
 
 
 
 
 
 
T/P 
HAHA (serum)  
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
X 
PK and Free C5 (CSF) 3 
See 
Footnote 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
EuroQol (EQ-5D)  
X 
 
 
 
X 
 
X 
 
X 
 
 
 
 
 
 
X 
Short Form Health Survey (SF-
36)  
X 
 
 
 
X 
 
X 
 
X 
 
 
 
 
 
 
X 
Columbia-Suicide Severity Scale 
(C-SSRS)7 
X 
 
 
 
X 
 
X 
 
X 
 
 
 
 
 
 
X 
Expanded Disability Status Scale 
(EDSS)  5 
X 
 
 
 
X 
 
X 
 
X 
 
 
 
 
 
 
X 
Modified Rankin Scale (mRS) 
X 
 
 
 
X 
 
X 
 
X 
 
 
 
 
 
 
X 
Patient Education Card and NMO 
Symptom Evaluation 6 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Neurologic Examination 6 
X 
 
 
 
X 
 
X 
 
X 
 
 
 
 
 
 
X 
Optic Spinal Impairment Score 
(OSIS) 6 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
VA test (Snellen chart) 7 
X 
 
 
 
X 
 
X 
 
X 
 
 
 
 
 
 
X 
Hauser Ambulation Index (HAI) 
7 
X 
 
 
 
X 
 
X 
 
X 
 
 
 
 
 
 
X 
Medically indicated tests 8 
 
 
 
•
 
 
 
 
 
 
 
 
 
 
 
 
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Review Inclusion / Exclusion 
criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
N meningitidis Revaccination 9 
See Footnote 
Patient Safety Identification Card 
9 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Investigational Product (IP) 
Infusion 10 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
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Table 6: 
Schedule of Assessments – Visits 17-29 
Phase 
Open-label Maintenance 
Visit Location ∆ 
In Clinic/Remote 
In Clinic 
In Clinic/Remote 
In Clinic 
Trial Visit Year 1 
V17 
V18 
V19 
V20 
V21 
V22 
V23 
V24 
V25 
V26 
V27 
V28 
V29 
Trial Week Year 1 
W28 
W30 
W32 
W34 
W36 
W38 
W40 
W42 
W44 
W46 
W48 
W50 
W52 
Physical exam 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Weight  
 
 
 
 
 
 
 
 
 
 
 
 
X 
Vital Signs  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Electrocardiogram (ECG)  
 
 
 
 
 
 
 
 
 
 
 
 
X 
Concomitant Medication  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse events (AEs) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Clinical Laboratory Tests 1 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
Pregnancy serum test 2 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
NMO-IgG (serum)  
 
 
 
 
 
 
X 
 
 
 
 
 
X 
NMO-IgG (CSF) 3 
Only to be collected in the event of a relapse 
PK/PD/Free C5 (serum) 4 
 
 
 
 
 
 
T/P 
 
 
 
 
 
T/P 
HAHA (serum)  
 
 
 
 
 
 
X 
 
 
 
 
 
X 
PK and Free C5 (CSF) 3 
Only to be collected in the event of a relapse 
EuroQol (EQ-5D)  
 
 
 
 
 
 
X 
 
 
 
 
 
X 
Short Form Health Survey (SF-36)  
 
 
 
 
 
 
X 
 
 
 
 
 
X 
Columbia-Suicide Severity Scale 
(C-SSRS)7 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
Expanded Disability Status Scale 
(EDSS) 5 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
Modified Rankin Scale (mRS) 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
Patient Education Card and NMO 
Symptom Evaluation 6 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Neurologic Examination 6 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
Optic Spinal Impairment Score (OSIS) 6 
 
 
 
 
 
 
 
 
 
 
 
 
 
VA test (Snellen chart) 7 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
Hauser Ambulation Index (HAI) 7 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
Medically indicated tests 8 
 
 
 
 
 
 
 
 
 
 
 
 
 
N meningitidis Revaccination 9 
See Footnote 
Patient Safety Identification Card 9 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Investigational Product (IP) Infusion 10 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
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Table 7: 
Schedule of Assessments - Study Period (Beyond Visit 29/Week 52 to EOS/ET) 
 
Maintenance Phase 
 
Trial Visit 
In Clinic/Remote 
Short Visit 
In Clinic 
Long Visit 
In Clinic 
End of Study (EOS) / 
Early Termination (ET) 
Visit 
In Clinic 
Unscheduled 
Trial Week from Year 2 Onwards 
Every 2nd week after Week 52 visit 
except Long Visits  
Alternating every 14 or 12 
Weeks from Week 52 visit 
(Weeks 66, 78, 92, 104, 118, 
130, 144, 156, 170, 182, 196, 
208, 222, 234, 248, 260, 274, 
286) 
Procedures, 
tests, and 
assessments will 
be performed at 
the discretion of 
the Investigator.  
Refer to Section 
7.6.2.3 for 
further details. 
 
Physical Exam 
 
Only on annual basis (Week 
104, 156, 208, 260, etc.) 
X 
Weight  
 
Only on annual basis (Week 
104, 156, 208, 260, etc.) 
X 
Electrocardiogram (ECG)  
 
Only on annual basis (Week 
104, 156, 208, 260, etc.) 
X 
Vital Signs  
X 
X 
X 
Concomitant Medication  
X 
X 
X 
Adverse Events (AEs) 
X 
X 
X 
Clinical Laboratory Tests 1 
 
X 
X 
Pregnancy serum test 2 
 
X 
X 
NMO-IgG (serum)  
 
X 
X 
HAHA (serum) 
 
Only at Weeks 78, 130, 182, 
234, 286) 
 
NMO-IgG (CSF) 3 
Only to be collected in the event of a relapse 
PK/PD/Free C5 (serum) 4 
Only to be collected in the event of a relapse 
PK and Free C5 (CSF) 3 
Only to be collected in the event of a relapse 
EuroQol (EQ-5D)  
 
X 
X 
Short Form Health Survey (SF-36)  
 
X 
X 
Columbia-Suicide Severity Scale (C-SSRS)7 
 
X 
X 
Expanded Disability Status Scale (EDSS) 5 
 
X 
X 
Modified Rankin Scale (mRS) 
 
X 
X 
Patient Education Card and NMO Symptom 
Evaluation 6 
X 
X 
X 
Neurologic Examination 6 
 
X 
X 
VA Test (Snellen chart) 7 
 
X 
X 
Hauser Ambulation Index (HAI) 7 
 
X 
X 
Medically Indicated Tests 8 
 
 
 
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Maintenance Phase 
 
Trial Visit 
In Clinic/Remote 
Short Visit 
In Clinic 
Long Visit 
In Clinic 
End of Study (EOS) / 
Early Termination (ET) 
Visit 
In Clinic 
Unscheduled 
Trial Week from Year 2 Onwards 
Every 2nd week after Week 52 visit 
except Long Visits  
Alternating every 14 or 12 
Weeks from Week 52 visit 
(Weeks 66, 78, 92, 104, 118, 
130, 144, 156, 170, 182, 196, 
208, 222, 234, 248, 260, 274, 
286) 
Procedures, 
tests, and 
assessments will 
be performed at 
the discretion of 
the Investigator.  
Refer to Section
N meningitidis Revaccination 9 
See Footnote 
Patient Safety Identification Card 9 
X 
X 
X 
Investigational Product (IP) Infusion 10 
X 
X 
X 
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Table 8: 
Schedule of Assessments – Relapse Evaluation Period 
Visit Location ∆ 
In Clinic 
Assessment 
Relapse Evaluation Visit11 
Follow-up Relapse Evaluation Follow-up Visits 
Trial Week 
Within 24-48 hours 
+1 Week 
+4 Weeks 
+6 Weeks 
Unscheduled12 
Vital Signs  
X 
X 
X 
X 
X 
Concomitant Medication  
X 
X 
X 
X 
X 
Adverse events (AEs) 
X 
X 
X 
X 
X 
Clinical Laboratory Tests 1 
X 
 
 
X 
X 
NMO-IgG (serum)  
X 
 
 
X 
X 
NMO-IgG (CSF) 3 
X 
 
 
X 
X 
PK/PD/Free C5 (serum) 4 
T/P 
T/P 
T/P 
T/P 
T/P 
PK and Free C5 (CSF) 3 
X 
 
 
X 
X 
EuroQol (EQ-5D)  
 
 
 
X 
X 
Short Form Health Survey (SF-36)  
 
 
 
X 
X 
Columbia-Suicide Severity Scale (C-SSRS)7 
 
 
 
X 
 
Expanded Disability Status Scale (EDSS) 5 
X 
X 
X 
X 
X 
Modified Rankin Scale (mRS) 
 
 
 
X 
 
Patient Education Card and NMO Symptom 
Evaluation 6 
X 
X 
X 
X 
X 
Neurologic Examination 6 
X 
X 
X 
X 
X 
Optic Spinal Impairment Score (OSIS) 6 
X 
X 
X 
X 
X 
VA test (Snellen chart) 7 
X 
X 
X 
X 
X 
Hauser Ambulation Index (HAI) 7 
X 
X 
X 
X 
X 
Medically indicated tests 8 
X 
X 
X 
X 
X 
N meningitides Revaccination 9 
See Footnote 
Patient Safety Identification Card 9 
X 
X 
X 
X 
X 
Investigational Product (IP) Infusion 10 
Continue every 1 week ±2 days (blind induction phase) or  
every 2 weeks ±2 days (open-label maintenance phase), as scheduled 
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Table 9: 
Schedule of Assessments – Safety Follow-up Visit 
Visit Location ∆ 
In-Clinic13 
Trial Visit 
Safety Follow Up 
Trial Weeks 
+8 W 
Vital Signs  
X 
Concomitant Medication  
X 
Adverse events (AEs) 
X 
Columbia-Suicide Severity Scale (C-SSRS)7 
X 
Patient Education Card and NMO Symptom Evaluation 6 
X 
Patient Safety Identification Card 9 
X 
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Table 10: 
Schedule of Assessments – Footnotes 
Footnote 
Description 
1. 
Clinical laboratory tests will be performed at a central laboratory. Reference Appendix 8 for a summary of the clinical laboratory test panels and tests.  
2. 
Serum samples for pregnancy test must be performed on all women of childbearing potential at a central laboratory at specified time points. Pregnancy test (urine or 
serum) may also be performed at any time during the trial at the Investigator’s discretion.  
3. 
Patients may choose not to have CSF samples collected and will still be eligible for trial participation. CSF sampling will be collected at Day 1/Visit 1 only for patients 
who have provided consent and did not already provide a sample at the EOS Visit in Study ECU-NMO-301. 
4. 
Trough samples for PK/PD and free C5 level testing are to be taken approximately 5-90 minutes before the IP infusion. Peak samples are to be taken at least 60 
minutes after completion of the IP infusion.  
5. 
The blinded EDSS Rater will perform the Kurtzke neurologic assessment and document the FSS and EDSS score. See Section 7.2.4 for more detail 
6. 
The Treating Physician will be responsible for assessment of the patient for any signs or symptoms indicative of relapse at every visit and perform a complete 
neurologic examination at the specified time points. The Treating Physician will document the Optic-Spinal Impairment Score (OSIS).  
7. 
The Treating Physician or appropriately trained designee will perform the VA test using Snellen chart, the Hauser Ambulatory Index (HAI) and the C-SSRS (Since 
Last Visit).  
8. 
Additional tests/procedures may be performed as medically indicated at the Investigator’s discretion. If additional medically indicated tests/procedures are performed 
these procedures / tests must be recorded in source documents and on the electronic case report form (eCRF).  
9. 
Patients may be revaccinated for N meningitidis to provide active coverage as specified by the vaccine manufacturer or according to current medical/country 
guidelines. Patients will be given a Patient Safety Identification Card prior to the first dose of trial medication. At each visit throughout the trial, trial staff will ensure 
that the patient has the Patient Safety Identification Card. 
10. 
Patients will undergo a blind induction phase at Visits 1 – 4. All patients will receive open-label IP at Visits 5 and onward and throughout the trial. If a patient 
undergoes plasma exchange (PE) for On-Trial Relapse, a supplemental dose of IP must be administered after each PE session, preferably within 1-2 hours, according 
to the regimen described under Supplemental Dose in Section 9.1.  
11. 
Relapse Evaluation Visit: every effort should be made to evaluate potential relapses within 24 hours of notification of the Investigator of a possible relapse, and no 
later than 48 hours. All potential relapses must be evaluated by both the Treating Physician and the EDSS Rater. 
12. 
Additional unscheduled Follow-up Relapse Evaluation Visits are permitted at the discretion of the Investigator. 
13. 
If a patient is unable to attend the safety follow-up visit as deemed medically necessary by the Investigator, the Investigator may perform the follow-up visit by 
telephone. All visit assessments should be performed with exception of vital signs. 
∆ 
In Clinic visits must be conducted at the study 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.  
† 
For patients who reach visit 29 (end of first year), the visit schedule and assessment scheme for the second year and beyond will restart from Visit 30 onward (Table 7) 
through the EOS Visit. 
* 
If a patient withdraws early from the trial an Early Termination (ET) visit will be performed.  
Abbreviations: AEs = adverse events; C5 = complement factor 5; CSF = cerebrospinal fluid; C-SSRS = Columbia-Suicide Severity Scale; ECG = electrocardiogram; 
eCRF = electronic case report form; EDSS = Expanded Disability Status Scale; EOS = End of Study; EQ-5D = EuroQol; ET = early termination visit; FSS = Functional Status 
Score; HAHA = human anti-human antibody; HAI = Hauser Ambulatory Index; IgG = immunoglobulin G; IP = investigational product; mRS = Modified Rankin Scale; N 
meningitidis = Neisseria meningitidis; NMO = neuromyelitis optica; OSIS = Optic-Spinal Impairment Score; P = peak sample; PD = pharmacodynamics; PE = plasma exchange; 
PK = pharmacokinetics; SF-36 = Short Form Health Survey; T = trough sample; V = visit; VA = visual acuity; W = week 
 
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7.6. 
Trial Visit Procedures 
7.6.1. 
Trial Period 
Visit intervals during induction phase (Visits 1 to 5) are weekly (every 7 ±2 days). Visit intervals 
during the open-label maintenance phase (Visits 6 – 107) are every 2 weeks (every 14 days 
±2 days). Patients who fail to return for a scheduled visit/dosing appointment must be contacted 
by the site’s study staff to determine the reason for missing the appointment. Patients will be 
strongly encouraged to return to the study site for evaluation if a relapse or AE is suspected to 
have occurred. In the exceptional circumstance where a patient cannot or does not come to the 
study site for examination, then the patient will be instructed to see his or her local neurologist or 
physician. In this event, the study site will obtain relevant medical records as documentation 
from the local physician’s examination and enter relevant data in the Relapse Evaluation Visit 
form or AE form, as appropriate.  
As it is vital to obtain information on any patient’s missing visit to ensure the missed 
appointment was not due to an AE or potential relapse, every effort must be made to undertake 
protocol-specified safety follow-up procedures. Follow-up due diligence documentation will 
consist of 3 phone calls followed by 1 registered letter to the patient’s last known address. 
7.6.1.1. 
Induction Phase (Visit 1 until Visit 5 [Week 4]) 
7.6.1.1.1. Visit 1 
All patients who have completed the ECU-NMO-301 trial may be eligible to participate in this 
extension trial. Prior to initiating any extension trial procedures, an ICF must be signed and 
inclusion/exclusion criteria must be obtained, evaluated and met.  
At Visit 1, patients must be registered in the interactive voice or web response system (IXRS) to 
be assigned IP. Patients maintain the identification number that they were assigned in ECU-
NMO-301. 
Patients who exit the ECU-NMO-301 trial due to relapse will have their first extension trial visit 
once the Week 6 Relapse Evaluation Visit is completed and no later than 2 weeks (14 days 
±2 days) after the last IP dose in the ECU-NMO-301 trial; patients who exit the ECU-NMO-301 
trial due to trial completion will have their first extension trial visit once the EOS Visit is 
completed and no later than 2 weeks (14 days ±2 days) after the last IP administration visit in the 
ECU-NMO-301 trial. 
Once all of the Visit 1 procedures have been performed and the eligibility criteria have been 
confirmed by the PI, the patient will be assigned to a blinded induction treatment on Day 1 based 
on the treatment the patient received in the ECU-NMO-301 trial (please refer to Section 9.1 for 
treatment assignment). The following tests and procedures will be completed at Visit 1: 
• Contact the IXRS to get IP kits assignation 
• Questionnaires to evaluate QOL (EQ-5D and SF-36) 
• The EDSS Rater will perform the Kurtzke neurologic assessment to determine the 
FSS and EDSS score.  
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• The Treating Physician will perform the following assessments:  
− Review Inclusion/Exclusion criteria 
− Review and assess the patient for any potential signs or symptoms indicative of 
relapse. Ensure the patient has the Patient Education Card and remind the patient 
to contact the study site at the first signs or symptoms of potential relapse.  
− Perform a complete neurologic examination 
− Document the OSIS 
• The Treating Physician or appropriately trained designee will perform the following 
assessments:  
− Perform mRS 
− Perform VA test (Snellen chart) 
− Perform HAI 
− Perform C-SSRS (Since Last Visit) 
− Vital signs (VS) include assessments of systolic and diastolic blood pressure (BP), 
temperature, respiration rate (RR) and heart rate (HR) 
− Any new medications or changes to concomitant medications will be recorded 
− AEs since the previous visit will be evaluated and recorded 
− Clinical laboratory tests (chemistry, hematology and urinalysis) 
− Pregnancy test must be performed on all women of childbearing potential. 
Pregnancy test (urine or serum) may also be performed at any time during the trial 
at the Investigator’s discretion 
− Collect blood samples for NMO-IgG 
− Collect baseline trough blood samples for PK, PD, free C5 and HAHA assays 
approximately 5-90 minutes before the IP infusion 
− Perform lumbar puncture to collect baseline CSF samples for NMO-IgG and PK, 
and free C5 assays before the IP infusion. Patients may choose not to have CSF 
samples collected and will still be eligible for trial participation. CSF sampling 
will be collected at Day 1/Visit 1 only for patients who have provided consent and 
did not already provide a sample at the EOS Visit in Study ECU-NMO-301. 
− Patients may be revaccinated for N meningitidis to provide active coverage as 
specified by the vaccine manufacturer or according to current medical/country 
guidelines  
− Instruct the patient on the signs and symptoms of N. meningitidis.  
− Provide the Patient Safety Identification Card describing the IP and emergency 
contact information to the patient prior to the first dose of IP. 
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− IP will be administered and patients will be observed for at least 1 hour following 
the end of the IP infusion.  
− Collect peak blood samples for PK, PD and free C5 assays at least 60 minutes 
after completing the IP infusion 
7.6.1.1.2. Visits 2-4 (Weeks 1-3) 
Patients will return for weekly (7 ±2 days) IP infusions during the induction phase including 
Visit 2 (Week 1), Visit 3 (Week 2), and Visit 4 (Week 3). The following tests and procedures 
will be completed: 
• The Treating Physician will review and assess the patient for any potential signs or 
symptoms indicative of relapse. Ensure the patient has the Patient Education Card and 
remind the patient to contact the study site at the first signs or symptoms of potential 
relapse.  
• VS include assessments of systolic and diastolic BP, temperature, RR and HR 
• Any new medications or changes to concomitant medications will be recorded 
• Any new AEs or changes in AEs since the previous visit will be evaluated and 
recorded 
• Patients may be revaccinated for N meningitidis to provide active coverage as 
specified by the vaccine manufacturer or according to current medical/country 
guidelines  
• Ensure that the patient has the Patient Safety Identification Card describing the IP and 
emergency contact information 
• Contact the IXRS to get IP kits assignation 
• IP will be administered and patients will be observed for at least 1 hour following the 
end of the IP infusion 
7.6.1.1.3. Visit 5 (Week 4) 
At Visit 5 (Week 4), patients will return for an IP infusion for the final visit in the induction 
phase. The following tests and procedures will be completed: 
• Questionnaires to evaluate QOL (EQ-5D and SF-36) 
• The EDSS Rater will perform the Kurtzke neurologic assessment to determine the 
FSS and EDSS score.  
• The Treating Physician will perform the following assessments:  
− Review and assess the patient for any potential signs or symptoms indicative of 
relapse. Ensure the patient has the Patient Education Card and remind the patient 
to contact the study site at the first signs or symptoms of potential relapse.  
− A complete neurologic examination 
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• The Treating Physician or appropriately trained designee will perform the following 
assessments:  
− mRS 
− VA test (Snellen chart) 
− HAI 
− C-SSRS 
− VS include assessments of systolic and diastolic BP, temperature, RR and HR 
− Any new medications or changes to concomitant medications will be recorded 
− Any new AEs or changes in AEs since the previous visit will be evaluated and 
recorded 
− Clinical laboratory tests (chemistry, hematology and urinalysis) 
− Pregnancy test must be performed on all women of childbearing potential. 
Pregnancy test (urine or serum) may also be performed at any time during the trial 
at the Investigator’s discretion. 
− Collect blood samples for NMO-IgG 
− Collect trough blood samples for PK, PD, free C5, and HAHA approximately 5-
90 minutes before the IP infusion 
− Patients may be revaccinated for N meningitidis to provide active coverage as 
specified by the vaccine manufacturer or according to current medical/country 
guidelines  
− Ensure that the patient has the Patient Safety Identification Card describing the IP 
and emergency contact information 
− Contact the IXRS to get IP kits assignation. IP will be administered and patients 
will be observed for at least 1 hour following the end of the IP infusion. 
− Collect peak blood samples for PK, PD and free C5 assays at least 60 minutes 
after completing the IP infusion 
7.6.1.2. 
Open-label Phase (Visit 6 [Week 6] until End of Study / Early Termination Visit) 
Patients will receive IP infusions every two weeks (14 ±2 days) during the Open-label Phase.  
All patients must be present at the trial site, as applicable, for visit-specific 
procedures/assessments including IP administration (see Schedule of Assessments in 
Section 7.5). Note that when a patient continues beyond Visit 29 (end of first year), the visit 
schedule and assessments scheme for the second year and beyond will restart from the equivalent 
of Visit 30 onward. These visits and assessments in the second year and beyond are included in 
the Schedule of Assessments in Table 7.  
For other visits, patients may have an opportunity to receive IP administration remotely at a 
medical facility that is located near the patient’s home or at the patient’s home with the 
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permission of the PI in accordance with all national, state, and local laws or regulations of the 
pertinent regulatory authorities.  
The maximum total trial duration is 5.5 years from the time the first patient was enrolled. Trial 
duration for an individual patient will vary depending on when the patient enters the trial; 
participation may continue until the product is registered and available to treat patients diagnosed 
with relapsing NMO (in accordance with country specific regulations) or until the trial ends, 
whichever occurs first. 
The following tests and procedures will be completed at every visit beginning at Visit 6 
(Week 6) and continuing until the ET or EOS: 
• VS include assessments of systolic and diastolic BP, temperature, RR and HR 
• Any new medications or changes to concomitant medications will be recorded 
• Any new AEs or changes in AEs since the previous visit will be evaluated and 
recorded 
• The Treating Physician will review and assess the patient for any potential signs or 
symptoms indicative of relapse. Ensure the patient has the Patient Education Card and 
remind the patient to contact the study site at the first signs or symptoms of potential 
relapse.  
• Ensure that the patient has the Patient Safety Identification Card describing the IP and 
emergency contact information 
• Contact the IXRS to get IP kits assignation. IP will be administered and patients will 
be observed for at least 1 hour following the end of the IP infusion. 
The following additional procedures will also be completed at certain visits (see Schedule of 
Assessments in Section 7.5): 
• Questionnaires to evaluate QOL (EQ-5D and SF-36) 
• The EDSS Rater will perform the Kurtzke neurologic assessment to determine the 
FSS and EDSS score. 
• The Treating Physician will perform a complete neurologic examination 
• The Treating Physician or appropriately trained designee will perform the following 
assessments:  
− mRS 
− VA test (Snellen chart) 
− HAI 
− C-SSRS 
− Physical exam  
− Body weight  
− ECG  
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− Clinical laboratory tests (chemistry, hematology and urinalysis) 
− Pregnancy test must be performed on all women of childbearing potential. 
Pregnancy test (urine or serum) may also be performed at any time during the trial 
at the Investigator’s discretion. 
− Collect blood samples for NMO-IgG 
• Collect trough samples for PK, PD, free C5 and HAHA assays approximately 5-90 
minutes before the IP infusion 
− Perform lumbar puncture to collect CSF for NMO-IgG and PK and free C5 assays 
before IP infusion at Visits 9 and 16 and in the event of a relapse only. Patients 
may choose not to have CSF samples collected and will still be eligible for trial 
participation. 
− Collect peak blood samples for PK, PD, and free C5 assays at least 60 minutes 
after completing the IP infusion 
• Patients may be revaccinated for N. meningitidis to provide active coverage as 
specified by the vaccine manufacturer or according to current medical/country 
guidelines. 
7.6.2. 
Relapse Evaluation Period 
Patients 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 the Investigator of a 
possible relapse, and no later than 48 hours. All potential relapses must be evaluated by both the 
Treating Physician and the EDSS Rater.  
Follow-up Relapse Evaluation Visits will be performed at 1, 4 and 6 weeks after the onset of 
relapse. Additional (Unscheduled) Relapse Evaluation Visits are permitted at the discretion of 
the Investigator. 
7.6.2.1. 
Relapse Evaluation Visit (Within 24-48 Hours) 
• The EDSS Rater will perform the Kurtzke neurologic assessment to determine the 
FSS and EDSS score. 
• The Treating Physician will perform the following assessments: 
− A complete neurologic examination 
− OSIS 
• The Treating Physician or appropriately trained designee will perform the following 
assessments: 
− VA test (Snellen chart) 
− HAI 
− VS include assessments of systolic and diastolic BP, temperature, RR and HR 
− Any new medications or changes to concomitant medications will be recorded 
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− Any new AEs or changes in AEs since the previous visit will be evaluated and 
recorded 
− Clinical laboratory tests (chemistry, hematology and urinalysis) 
− Collect blood samples for NMO-IgG  
− Perform lumbar puncture to collect CSF sample for NMO-IgG, PK and free C5 
assays. Patients may choose not to have CSF samples collected and will still be 
eligible for trial participation. 
• If medically indicated for evaluation of relapse, additional tests (eg, MRI, CT scan, 
laboratory tests, etc.) may be performed at the discretion of the Investigator. If 
additional medically indicated tests/procedures are performed, the results must be 
recorded in source documents and on the eCRFs, and copies of reports should be sent 
to the Sponsor. 
• The Treating Physician determines if the clinical signs, symptoms and neurologic 
change (objective findings on the examination) meet the definition for On-Trial 
Relapse as outlined in this protocol (see Section 7.2.1). 
• Ensure that the patient has the Patient Safety Identification Card describing the IP and 
emergency contact information 
• After all specified relapse procedures are complete; the recommended standardized 
treatment regimen for confirmed relapse outlined in this protocol can be initiated at 
the discretion of the Treating Physician (Section 9.2.1.3). 
• IP administration: 
− Patients will continue IP administration in accordance with protocol-specified IP 
administration schedule, ie, every week (7days ±2 days) during the blind 
induction phase and every two weeks (14 days ±2 days) during the open-label 
phase. 
− If patients undergo PE, a supplemental dose must be administered after each PE 
session, preferably within 1-2 hours, according to the regimen described under 
Supplemental Dose in Section 9.1. 
− If IP will be administered at this visit, obtain IP kit assignation through the IXRS 
• PK, PD and free C5 sampling – the number of samples to be collected at this visit will 
depend upon whether or not the patients receive IP infusion and/or PE at this visit. 
− Collect one blood sample for PK, PD and free C5 (if no IP and/or no PE 
administration at this visit) 
− If only IP is administered at this evaluation visit according to the IP 
administration schedule, collect two blood samples: a trough and a peak sample 
for PK, PD and free C5, approximately 5-90 minutes prior to IP infusion and at 
least 60 minutes after the completion of the IP infusion, respectively. 
− If the patient receives PE and IP infusion, three blood samples for PK, PD and 
free C5 collection should be collected [1] approximately 5-90 minutes prior to PE 
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[2] after PE and before IP infusion, and [3] at least 60 minutes after the 
completion of IP infusion. 
7.6.2.2. 
Follow-up Relapse Evaluation Visits (Week 1, 4 and 6) 
The following tests and procedures will be completed at the Follow-up Relapse Evaluation visit: 
• The EDSS Rater will perform the Kurtzke neurologic assessment to determine the 
FSS and EDSS score. 
• The Treating Physician will perform the following assessments: 
− A complete neurologic examination 
− OSIS 
• Ensure the patient has the Patient Education Card and remind the patient to contact 
the study site at the first signs or symptoms of potential relapse. 
• The Treating Physician or appropriately trained designee will perform the following 
assessments: 
− mRS (Week 6 only) 
− VA test (Snellen chart) 
− HAI 
− C-SSRS (Week 6 only) 
− VS include assessments of systolic and diastolic BP, temperature, RR and HR 
− Any new medications or changes to concomitant medications will be recorded 
− Any new AEs or changes in AEs since the previous visit will be evaluated and 
recorded 
• If medically indicated for evaluation of relapse, additional tests (eg, MRI, CT scan, 
laboratory tests, etc.) may be performed at the discretion of the Investigator. If 
additional medically indicated tests/procedures are performed, the results must be 
recorded in the source documents and in the eCRFs, and copies of reports should be 
sent to the Sponsor. 
• IP administration during the relapse evaluation period: 
− Patients will continue IP administration in accordance with protocol-specified IP 
administration schedule, i.e. every week (7 days ±2 days) during the blind 
induction phase and every two weeks (14 days ±2 days) during the open-label 
phase.  
− If patients undergo PE, a supplemental dose must be administered after each PE 
session, preferably within 1-2 hours, according to the regimen described under 
Supplemental Dose in Section 9.1. 
− If IP will be administered at this visit, obtain IP kit assignation through the IXRS 
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• For patients who undergo PE, blood samples for PK, PD and free C5 assays will be 
collected immediately before and after each session of PE. A peak sample, ie, one 
hour after completion of IP infusion, will also be collected. 
• Questionnaires to evaluate QOL (EQ-5D and SF-36) at Week 6 only 
• Clinical laboratory tests (chemistry, hematology and urinalysis) at Week 6 only  
• Collect blood samples for NMO-IgG at Week 6 only  
• PK, PD, and free C5 sampling at Week 6 only– the number of samples to be collected 
at this visit will depend up whether or not the patients receive IP infusion and/or PE at 
this visit.  
− Collect one blood sample for PK, PD and free C5 (if no IP and/or no PE 
administration at this visit). 
− If only IP is administered at this evaluation visit, according to the IP 
administration schedule, collect two blood samples: a trough and a peak blood 
sample for PK, PD, and free C5, approximately 5-90 minutes prior to IP infusion 
and at least 60 minutes after the completion of the IP infusion, respectively.  
− If the patient receives PE and IP infusion, three blood samples for PK, PD and 
free C5 collection should be collected: [1] approximately 5-90 minutes prior to PE 
[2] after PE and before IP infusion, and [3] at least 60 minutes after the 
completion of IP infusion.  
Note: Trough and peak blood samples for PK, PD and free C5 will be collected at the 
IP administration visits, if per protocol scheduled IP administration does not coincide 
with the relapse evaluation visit. Vitals signs, information on concomitant medication 
and AE will be collected at the IP administration visit.  
• Perform lumbar puncture to collect CSF for NMO-IgG and PK and free C5 assays 
before IP infusion at Week 6 only. Patients may choose not to have CSF samples 
collected and will still be eligible for trial participation. 
• If IP will be administered, patients will be observed for 1 hour following the end of 
the IP infusion. 
• Ensure that the patient has the Patient Safety Identification Card describing the IP and 
emergency contact information 
7.6.2.3. 
Unscheduled Visit 
Additional (unscheduled) Follow-up Relapse Evaluation Visits outside the specified visits are 
permitted at the discretion of the Investigator. Procedures, tests and assessments listed under the 
Relapse Evaluation Visit may be performed at the discretion of the Investigator. Any procedures, 
tests or assessments performed at the unscheduled visit must be recorded on the eCRF. 
7.6.2.4. 
Adjudication of On-Trial Relapse Events 
An independent Relapse Adjudication Committee will confirm all On-Trial Relapse events using 
objective and consistent clinical criteria described in a Relapse Adjudication Charter. The 
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Adjudication Committee will consist of three independent medical experts in 
neurology/neuroophthalmology who are each experienced in the management of patients with 
NMO. The Adjudication Committee will decide by majority vote whether each relapse meets the 
pre-defined objective criteria for an adjudicated On-Trial Relapse, as described in the Relapse 
Adjudication Charter. 
7.6.3. 
Safety Follow-up Period (post-treatment) 
If a patient withdraws from the trial or discontinues eculizumab treatment at any time during the 
trial after receiving any amount of IP (eculizumab or placebo), a follow-up visit for safety 
assessments is required at 8 weeks after the last dose of IP. Patients who withdraw from the 
extension trial and transition to treatment with the commercially available eculizumab will not be 
required to complete a Follow-up Visit. The following tests and procedures will be completed at 
the follow-up visit: 
• VS include assessments of systolic and diastolic BP, temperature, RR and HR 
• Any new medications or changes to concomitant medications will be recorded 
• Any new AEs or changes in AEs since the previous visit will be evaluated and 
recorded 
• Perform C-SSRS 
• The Treating Physician will assess the patient for any signs or symptoms indicative of 
relapse 
• Ensure that the patient has the Patient Safety Identification Card 
If a patient is discontinued due to an AE, the event will be followed until it is resolved or, in the 
opinion of the Investigator, is determined medically stable. 
If a patient is unable to attend the safety follow-up visit as deemed medically necessary by the 
Investigator, the follow-up visit may be performed by telephone. All visit assessments should be 
performed with exception of vital signs.  
7.6.4. 
Post-Treatment Follow-up (a Maximum of 2 years) 
The Sponsor may seek to collect follow-up information concerning NMO status in patients who 
have prematurely discontinued from the trial for a maximum of 2 years from the last dose of 
eculizumab (refer to Appendix 11). 
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8. 
SELECTION AND WITHDRAWAL OF PATIENTS 
8.1. 
Patient Inclusion Criteria 
1. Patient completed the ECU-NMO-301 trial (ie, patients completed Week 6 Follow-up 
Relapse Evaluation Visit or EOS Visit)  
2. Patient has given written informed consent  
3. Patient is willing and able to comply with the protocol requirements for the duration of 
the trial 
4. Female patients of child-bearing potential must have a negative pregnancy test (serum 
human chorionic gonadotropin [HCG]). All patients must practice an effective, reliable, 
and medically approved contraceptive regimen during the trial and for up to 5 months 
following discontinuation of treatment. 
8.2. 
Patient Exclusion Criteria 
1. Patient withdrew from the ECU-NMO-301 trial as a result of an AE related to IP 
2. Female patients who are pregnant, breastfeeding, or intend to conceive during the course 
of the trial  
3. Any medical condition or circumstances that, in the opinion of the Investigator, might 
interfere with the patient’s participation in the trial, pose any added risk for the patient, or 
confound the assessment of the patients 
8.3. 
Patient Withdrawal Criteria 
8.3.1. 
Withdrawal of Patients From the Trial 
Patients are allowed to withdraw consent at any time. All efforts should be made to ensure 
patients are willing to comply with trial participation prior to conducting the screening 
procedures. The trial staff should notify the Sponsor and their site monitor of all trial 
withdrawals as soon as possible. The reason for patient discontinuation must be recorded in the 
source documents and eCRF. 
Reproduction and development studies with eculizumab have not been performed; therefore 
eculizumab should not be administered to pregnant women. At the time of the last follow-up 
visit, all patients of childbearing potential must continue to use adequate contraception for up to 
5 months following discontinuation of eculizumab treatment. If a patient becomes pregnant, the 
IP must be immediately discontinued and the Sponsor must be notified as per Section 12.2.1.10 . 
Each pregnancy will be followed to term and the Sponsor notified regarding the outcome. 
8.3.2. 
Handling of Withdrawals 
When a patient withdraws or is withdrawn from the trial, the Investigator shall record the 
withdrawal reason(s) in the source documents and eCRF. At the time of withdrawal, all patients 
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who prematurely withdraw from the trial will undergo all assessments at the ET visit for safety 
as per the Schedule of Assessments. 
An additional follow-up visit for safety assessment is required 8 weeks after the last dose of IP 
administration. 
If a patient is discontinued due to an AE, the event will be followed until it is resolved or in the 
opinion of the PI the patient is determined to be medically stable. Every effort will be made to 
undertake protocol-specified safety follow-up procedures. 
Patients who fail to return for final assessments will be contacted by the site’s trial staff in an 
attempt to have them comply with the protocol. As it is vital to obtain follow-up data on any 
patient withdrawn because of an AE or SAE, follow-up due diligence documentation will consist 
of 3 phone calls followed by 1 registered letter to the patient’s last known address. In any case, 
every effort must be made to undertake protocol-specified safety follow-up procedures. 
8.3.3. 
Sponsor’s Termination of Trial 
The Sponsor or a regulatory authority may discontinue the trial at any time for any reason 
including, for example, clinical or administrative reasons. 
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9. 
TREATMENT OF PATIENTS 
9.1. 
Investigational Product Dosage and Administration 
IP, eculizumab or placebo (during the blind-induction phase), will be administered intravenously 
over approximately 35 minutes.  
Blind-Induction Phase 
To maintain the blind of ECU-NMO-301 trial, all patients will undergo a blind-induction phase. 
IP (eculizumab or placebo) will be administered weekly during the induction phase according to 
the following schedule:  
Table 11: 
Investigational Product Dosage and Administration 
ECU-NMO-301 
(PREVENT) Cohort 
Dose 
Visit # 
Eculizumab arm 
 
4 vials IP (eculizumab 1200 mg) 
1, 3 
4 vials IP (placebo)  
2, 4 
Placebo arm 
4 vials IP (3 vials eculizumab 900 mg + 1 vial placebo)  
1, 2, 3, 4 
Open-label Maintenance Phase 
All patients will receive 4 vials eculizumab (1200 mg) every 2 weeks from Visit 5 and onward 
throughout the trial. 
Supplemental Dose 
If a patient undergoes PE for an On-Trial Relapse during the Study Period, the patient must be 
administered IP after each PE session, preferably within 1-2 hours, as outlined below: 
• If the relapse occurs during the blinded induction phase, and the PE coincides with 
the day of a regularly scheduled IP infusion, 
−  For Visit 1 (Day1) and Visit 3 (Week 2), administer the 4 vials of blinded IP 
indicated in Table 11 above; 
− For Visit 2 (Week 1) and Visit 4 (Week 3) administer only a supplemental IP 
dose, ie, 2 vials eculizumab (600 mg) 
• If the relapse occurs during the maintenance phase, and the PE coincides with the day 
of a regularly scheduled IP infusion,  
− administer the scheduled IP dose (4 vials/1200 mg eculizumab) 
• In all other cases, administer only a supplemental IP dose, ie, 2 vials eculizumab (600 
mg) 
After receiving the supplemental dose, patients are to continue eculizumab infusion according to 
the protocol-specified dosing regimen. 
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9.2. 
Concomitant Medications 
9.2.1. 
Allowed Medications 
9.2.1.1. 
Palliative and Supportive Care 
Palliative and supportive care is permitted during the course of the trial for underlying 
conditions. 
9.2.1.2. 
Immunosuppressive Agents 
• Immunosuppressive agents, eg, corticosteroid, azathioprine (AZA), mycophenolate 
mofetil (MMF), methotrexate, tacrolimus, or cyclophosphamide either in combination 
or mono-therapy are allowed at the discretion of the Investigator.  
• Change in IST or its dose/schedule will be allowed if due to relapse, intolerance, or 
medically indicated at the discretion of the Treating Physician. Any changes in 
immunosuppressive therapy will be recorded in the eCRF page for concomitant 
medication. 
9.2.1.3. 
Recommended Standardized Relapse Treatment 
For this protocol, the treatment of relapse is at the discretion of the Treating Physician. The 
following standardized treatment regimen for a confirmed On-Trial Relapse is recommended, in 
accordance with expert opinion (1): 
• One gram intravenous methylprednisolone (IVMP) administered daily for 3-5 days 
followed by an oral prednisone tapering. If the patient improves, then continue the 
trial assessments as per schedule of this protocol. 
• If there is no or minimal response to IVMP, PE will be allowed at the discretion of 
the treating neurologist. Five cycles of PE, each removing 1.0-1.5 volumes of 
circulating plasma, are recommended for treatment of attacks that do not respond to 
IVMP. 
If a patient undergoes PE for an On-Trial Relapse during the Treatment Period, a supplemental 
dose of IP should be administered after each PE, preferably within 1-2 hours, as described under 
Supplemental Dose in Section 9.1 above. After receiving the supplemental dose, patients are to 
continue protocol-specified dosing until the Week 6 Follow-up Visit.  
9.2.2. 
Disallowed Medications 
The following medications are prohibited during the trial: 
• Concomitant use of rituximab with eculizumab is contraindicated  
• Use of mitoxantrone  
• Use of immunomodulatory therapies including: interferon beta-1b; interferon beta-1a, 
and glatiramer acetate 
• Other biologic agents such as tocilizumab 
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• Intravenous immunoglobulin (IVIg) for relapse prevention. 
• PE for relapse prevention  
9.3. 
Treatment Compliance 
Patients will be infused with IP under the supervision of the Treating Physician or designee to 
ensure that the patient receives the appropriate dose at the appropriate time-points during the 
trial. 
Patients who fail to return for a scheduled visit must be contacted by the site’s study staff to 
determine the reason for missing the appointment. Patients will be strongly encouraged to return 
to the study site for evaluation if a relapse or AE is suspected to have occurred. In the 
exceptional circumstance where a patient cannot or does not come to the study site for 
examination, then the patient will be instructed to see his or her local neurologist or physician. In 
this event, the study site will obtain relevant medical records as documentation from the local 
physician’s examination, and enter relevant data in the Relapse Evaluation Visit form or AE 
form as appropriate. As it is vital to obtain any patient’s missing visit to assure the missed 
appointment was not due to an AE or potential relapse, every effort must be made to undertake 
protocol-specified safety follow-up procedures. Follow-up due diligence documentation will 
consist of 3 phone calls followed by 1 registered letter to the patient’s last known address. 
9.4. 
Randomization and Blinding 
9.4.1. 
Randomization 
This is a long-term, open-label extension of the ECU-NMO-301 trial. Patients who enter this trial 
are required to complete the ECU-NMO-301 trial. No randomization of patients will be 
performed. The patient identification number and IP kits assignation will be provided by the 
IXRS. 
9.4.2. 
Blinding and Unblinding 
This is an open-label trial; therefore, unblinding is not applicable. All subjects will receive 
eculizumab during the trial, including during the 4-week blind induction phase and during the 
open-label maintenance phase.  
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10. 
INVESTIGATIONAL PRODUCT MATERIALS AND 
MANAGEMENT 
10.1. 
Investigational Product 
Each vial of IP contains eculizumab 300 mg or matching placebo for IV administration. 
Table 12: 
Investigational Product 
 
Investigational Product 
Product Name: 
Eculizumab 
Placebo 
Dosage Form: 
Concentrate solution for infusion 
Solution for infusion  
Unit Dose: 
300 mg 
0 mg 
Route of Administration: 
Intravenous Infusion 
Intravenous Infusion 
Physical Description: 
30 mL vial 
30 mL vial  
Manufacturer: 
Alexion Pharmaceuticals, Inc. or 
selected contract manufacturing 
organization 
Alexion Pharmaceuticals, Inc. or 
selected contract manufacturing 
organization 
 
10.2. 
Investigational Product Packaging and Labeling 
The active IP, eculizumab, is manufactured and supplied by Alexion Pharmaceuticals, Inc., or 
selected contract manufacturing organization in single 30 mL vials as a solution concentration of 
10 mg/mL. The comparator product is manufactured by Alexion Pharmaceuticals, Inc., or 
selected contract manufacturing organization as a matching sterile, clear, colorless solution with 
the same buffer components but without active ingredient, in an identical 30 mL vial. 
IP vials will be individually packaged into kits. Both vials and kits will be labeled according to 
the protocol and local regulatory requirements. IP will be shipped and released to each 
participating trial center upon receipt of all required essential documents based upon federal, 
state, and local regulations. Each IP kit will have a unique kit number and have a booklet label 
describing the contents and a place for the pharmacist to record the patient number, patient 
initials and Investigator name. 
10.3. 
Investigational Product Storage 
IP will be released to the site upon receipt of all required essential documents based upon 
federal, state, and local regulations.  
Upon arrival at the center, the IP should be promptly removed from the shipping cooler and 
stored in refrigerated conditions at 2°C to 8°C with minimal light exposure. The pharmacist 
should immediately record the receipt of the IP in the IXRS and notify the distributor and the 
Sponsor if vials are damaged and/or if temperature excursions have occurred during 
transportation. IP must be stored in a secure, limited-access storage area, and temperature should 
be monitored daily. 
Diluted solutions of IP are stable for 24 hours at 2 to 8°C (36-46°F) and at room temperature.  
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10.4. 
Investigational Product Preparation 
Infusions of IP should be prepared using aseptic technique and the dose regimen described in 
Section 9.1. Each vial of IP contains 300 mg of active ingredient in 30 mL of product solution or 
matching placebo. 
Withdraw the required amount of IP from the vials. Transfer the recommended dose to an 
infusion bag. Dilute IP to a final concentration of 5 mg/mL by addition to the infusion bag of the 
appropriate amount (equal volume) of one of the following diluents: 0.9% Sodium Chloride 
Injection, 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 IP solution is 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 13. 
Table 13: 
Investigational Product Preparation and Reconstitution 
Investigational Product 
Volume of IP 
Volume of Diluent
a 
Total Volume of 
Administration 
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: a. 0.9% sodium chloride; b. 0.45% sodium chloride; c. 5% dextrose in 
water; d. Ringer’s injection 
 
Gently invert the infusion bag containing the diluted IP 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 24-hour expiration period includes preparation, storage at room temperature and under 
refrigeration, warming and infusion. 
10.5. 
Investigational Product Administration 
DO NOT ADMINISTER AS AN IV PUSH OR BOLUS INJECTION.  
IP should only be administered via IV infusion via gravity feed, a syringe-type pump, or an 
infusion pump, and must be diluted to a final concentration of 5 mg/mL prior to administration. 
Prior to administration, if the diluted solution is refrigerated, it 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 IP should be intravenously administered over approximately 35 minutes.Diluted IP is 
stable for 24 hours at 2-8°C (36-46°F) and at room temperature. It is not necessary to protect the 
infusion bags from light while IP is being administered to the patient. The patients will be 
monitored for at least 1 hour following the infusion for signs or symptoms of an infusion 
reaction. 
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If an AE occurs during the administration of the IP, the infusion may be slowed or stopped at the 
discretion of the Investigator, depending upon the nature and severity of the event. The AE must 
be captured in the patient’s source document and eCRF. 
10.6. 
Investigational Product Accountability 
When an IP 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 
trial monitor. A signed copy should be faxed to the contact provided on the packing list and the 
duplicate copy kept in the pharmacy binder.  
Additionally, reception of IP (as well as reception conditions) must be reported to the IXRS to 
allow IP resupply, estimations and expiration control. 
Accountability logs and Inventory logs will be provided to assist the pharmacist in maintaining 
current and accurate inventory records covering receipt, dispensing, and disposition of the IP. 
During the trial, the following information must be noted in the accountability log: the patient 
number(s), initials of patient(s) to whom IP is dispensed, kit number, the date(s) and time that the 
IP is prepared, and the initials of the pharmacist or designee who prepared the IP. Sites should 
keep a running total of their IP supply. Empty vials and vials with residual materials should be 
kept for inspection and accountability by the CRA prior to their destruction and handled per local 
site pharmacy standard operating procedures for clinical IPs. Destruction of used and unused 
vials, either locally or centrally, must be properly documented. Refer to the Pharmacy Manual 
for detailed instructions on general receipt, storage, preparation, administration, destruction and 
return of IP. 
Each kit label will have a place for the pharmacist to record the patient number and initials.  
The CRA will examine the inventory during the trial. Additionally, the inventory records must be 
readily available and may be subject to regulatory authorities, the local regulatory agency, or an 
independent auditor’s inspection at any time. 
10.7. 
Investigational Product Handling and Disposal 
At the completion of the trial, in order to satisfy regulatory requirements regarding drug 
accountability, all remaining IP inventory will be reconciled and retained or destroyed according 
to applicable provincial and federal regulations. 
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11. 
ASSESSMENT OF EFFICACY 
This extension trial is designed to provide the patients who have participated in the ECU-NMO-
301 trial with an opportunity to receive eculizumab and to collect clinical data that will provide 
long term safety and tolerability information on eculizumab in patients with relapsing NMO. 
Efficacy is a secondary objective of this trial. The long-term efficacy of eculizumab in patients 
with relapsing NMO will be measured by determining the ARR. 
Duration of treatment commences with the first IP infusion (eculizumab). 
11.1. 
Efficacy Parameters 
Primary Efficacy Endpoint:  
Annualized Relapse Rate (ARR) including all relapses as identified by the Investigator. 
 
Secondary Efficacy Endpoints:  
1. Change from baseline in EDSS score  
2. Change from baseline in EQ-5D  
3. Change from baseline in mRS score  
4. Change from baseline in HAI in patients with abnormal baseline ambulatory function  
5. Change from baseline in VA in patients with abnormal baseline visual function 
 
Tertiary Efficacy Endpoints:  
1. Change from baseline in HAI score  
2. Change from baseline in VA  
3. Change from baseline in the SF-36  
4. Change from baseline in the EDSS FSS 
11.1.1. 
Relapses 
On-Trial Relapses will be monitored throughout the trial. Patients will be educated on the 
potential signs and symptoms of NMO relapse. The Investigator or his/her designee will review, 
in detail, the signs and symptoms of a potential relapse with the patient at each visit. The patients 
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 the Investigator or the appropriate 
designee for any signs or symptoms suggestive of a potential relapse, and no later than 48 hours. 
All potential relapses must be evaluated by both the Treating Physician and the EDSS Rater. The 
Treating Physician will make the decision as to whether the clinical signs, symptoms, and 
neurologic change (objective findings on neurological examination) meet the definition for On-
Trial Relapse and may treat the patient’s relapse according to the recommended Standardized 
On-Trial Relapse Treatment Plan (Section 9.2.1.3). The relapse treatment is at the Treating 
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Physician’s discretion. All investigations/tests related to the relapse evaluation (eg, MRIs, 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. 
Follow-up Relapse Evaluation Visits, to monitor the course of the relapse until stabilization, will 
be performed at 1, 4, and 6 weeks after the onset of the relapse. Additional (unscheduled) 
Follow-up Relapse Evaluation Visits will be made at the Treating Physician’s discretion. All 
reports of possible relapses and actions taken must be documented in the patient’s source 
documents and recorded in the eCRF; copies of reports should be sent to the Sponsor. 
Relapses that do not meet the criteria for SAE (see Section 12.2.1.3 ) should be reported as part 
of the relapse evaluation visits, and not as AEs. 
All PI-determined relapses will be reviewed by the Adjudication Committee; if confirmed by the 
Committee, these events qualify as adjudicated On-Trial Relapses. Adjudicated events will be 
used in the ARR assessment. 
11.1.2. 
Disability 
Disability will be assessed by the EDSS and mRS scores comparing the change from baseline. 
The EDSS Rater, who is blinded to all other trial data as well as all other patient clinical data, 
will be responsible for performing the EDSS assessments throughout the trial at the protocol-
specified time points as well as at visits during the Relapse Evaluation Period. The Treating 
Physician or designee will perform the mRS throughout the trial at the protocol-specified time 
points. 
11.1.3. 
Neurologic Functions 
Neurologic function will be assessed based on the EDSS FSS. Ambulatory function will be 
assessed by HAI scale and visual function will be measured by VA test using the Snellen chart. 
In addition, the EDSS visual (optic) FSS will be used for statistical analysis of changes in VA.  
The Snellen chart should be positioned at 6 meters (20 feet) distance, in a well-illuminated area, 
and the best available visual correction should be used (eg, the patient should use their latest 
eyeglasses or eye lenses). The patient can miss one letter per row to score that row. If the patient 
is unable to read the chart, then test the patients’ ability to count fingers (at approximately 1 
meter distance), distinguish hand motion or perceive light (by shining bright light in the eye). 
Neurologic function evaluation will be assessed at the protocol-specified time points as well as at 
visits during the Relapse Evaluation Period. 
11.1.4. 
Quality of Life 
QOL will be assessed by the patient self-assessment using both the EQ-5D and SF-36 
instruments at the protocol-specified time points. 
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12. 
ASSESSMENT OF SAFETY 
12.1. 
Safety Parameters 
The safety of eculizumab will be assessed based on treatment-emergent AEs (TEAEs), SAEs, 
and changes from baseline through trial completion in VS, routine clinical laboratory tests 
(chemistry, hematology, and urinalysis), C-SSRS, and pregnancy tests for female patients of 
childbearing potential. 
Blood samples will be collected for evaluation for HAHA at specified time points to describe the 
presence or absence of an immune response to eculizumab and to evaluate, if antibodies are 
detected, whether the antibodies neutralize the activity of eculizumab. 
The same independent DMC that will conduct the monitoring of safety data for the ECU-NMO-
301 trial will be used in this extension trial. Since its primary function will be to ensure patient 
safety, the DMC will have access to all safety data. The DMC may make recommendations to 
the Sponsor regarding safety issues, trial conduct, and modifying, extending or stopping the trial. 
A separate DMC Charter will document all DMC procedures and processes for the trial. Data 
and analysis for the DMC will be prepared by an independent statistical group. 
12.1.1. 
Demographic/Medical History 
At Visit 1, patients’ initials, date of birth, race or ethnic origin and sex will be collected. Medical 
history, including relevant medical/surgical history and NMO history, will be reviewed and 
recorded in the ECU-NMO-302 trial. 
12.1.2. 
Vital Signs 
VS will be measured at every visit and will include assessments of systolic and diastolic blood 
pressure (BP), temperature, RR and heart rate (HR). VS 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. Systolic and diastolic BPs will be documented in mmHg. Temperature will be 
obtained in degrees Celsius or Fahrenheit. HR will be documented in beats per minute. 
12.1.3. 
Weight 
Body weight will be measured in pounds or kilograms. Body weight will be measured at visits 
specified in the Schedule of Assessments in Section 7.5.  
12.1.4. 
Physical Examination 
A complete physical examination will be performed at visits specified in the Schedule of 
Assessments in Section 7.5. The complete physical examination will include assessments of the 
following organ/body systems: skin, head, ears, eyes, nose, throat, neck, lymph nodes, pulse, 
chest, heart, abdomen, extremities, musculoskeletal, and general neurologic examination. For 
consistency, all efforts should be made to have the physical examination performed by the same 
qualified study staff at these visits. 
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12.1.5. 
Electrocardiogram  
A 12-lead ECG will be conducted at visits specified in the Schedule of Assessments in 
Section 7.5. Additional ECG assessments are permitted at the Investigator’s discretion. The 
Investigator or designee will be responsible for reviewing the ECG to assess whether the ECG is 
within normal limits and to determine the clinical significance of the results. These assessments 
will be indicated on the eCRF. For any clinically significant abnormal ECG results, the 
Investigator must contact the Sponsor to discuss the patient’s continued eligibility to participate 
in this protocol. 
12.1.6. 
Laboratory Assessments 
Patients will have biologic samples collected for analysis of various parameters. The central 
laboratory will supply established or generally acknowledged methods, normal reference ranges, 
and shipping instructions. 
Chemistry panel, complete blood count and urinalysis, hemolytic markers, renal function 
measures, and serum pregnancy test (See Appendix 8 for details) will be prepared and shipped 
according to the instructions in the laboratory manual to the central laboratory. Samples will be 
analyzed at the central laboratory. Leukopenia has been reported in about 10% of patients with 
aHUS treated with eculizumab. In the NMO patient population, who may also be treated with 
immunosuppressive agents that are known to affect WBC counts, close monitoring of cell counts 
is imperative. Routine hematology laboratory assessment including CBC will be performed at 
various time points as specified by the protocol and should be reviewed as soon as the lab result 
is available. Additional assessments to monitor WBC counts can be performed at the discretion 
of the Treating Physician as medically indicated. Treatment of leukopenia is at the discretion of 
the Treating Physician and consultation with hematologist is encouraged as medically indicated. 
Blood samples for PK, PD, free C5 and HAHA and CSF samples for PK and free C5 analysis 
will be prepared and shipped according to the instructions in the laboratory manual to the central 
laboratory. Sample analysis will be conducted at Alexion Pharmaceuticals, Inc. or a contracted 
organization. Patients may choose not to have CSF samples collected and will still be eligible for 
trial participation. 
Samples for NMO-IgG will be prepared and shipped according to the instructions in the central 
laboratory manual. Sample analysis will be conducted at a central laboratory. 
AEs and events related to the patients’ underlying disease that have occurred during the trial will 
be collected at every visit (see Section 12.2 Adverse and Serious Adverse Events Section). 
Any clinically significant, abnormal laboratory result is to be reported as an AE. 
12.1.7. 
Columbia-Suicidal Severity Rating Scale (C-SSRS) 
The C-SSRS- Since Last Visit will be performed by the Treating Physician or an appropriately 
trained designee at visits specified in the Schedule of Assessments in Section 7.5. Additional C-
SSRS assessments are permitted as needed. This is to ensure that patients who are experiencing 
suicidal thoughts or behavior are properly recognized and adequately managed or referred for 
further evaluation.  
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12.2. 
Adverse Events and Serious Adverse Events 
12.2.1. 
Definition of Adverse Events 
12.2.1.1. Adverse Event 
All observed or volunteered AEs regardless of causal relationship will be reported as described 
in the sections below. 
For all AEs the Investigator must obtain adequate information for the following: 1) determine the 
outcome of the AE; 2) determine if the event meets criteria for an SAE; 3) assess the severity of 
the AE, and 4) determine the causality of the AE. For AEs with a causal relationship to the IP, 
the Investigator must follow-up on the outcome of the event until the event or sequelae either 
resolve or stabilize. 
As this is an extension to the ECU-NMO-301 trial, patients may sign the informed consent for 
the extension trial while still enrolled in the ECU-NMO-301 trial. AEs with an onset date before 
Study Day 1 of the extension trial (ECU-NMO-302) will be recorded in eCRF of ECU-NMO-
301 regardless of when the patient signed the ICF for the extension trial. Any ongoing AEs at the 
time of Study Day 1 of the extension trial will be transferred to the extensions trial eCRF. AEs 
with an end date before Study Day 1 of ECU-NMO-301 will be recorded only on the ECU-
NMO-301 eCRF. 
An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding, for example), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product (ICH Harmonised Tripartite 
Guideline Clinical Safety Data Management: Definitions and Standards for Expedite Reporting 
E2A. Step 4 version, dated 27 October, 1994). In clinical studies, an AE can include an 
undesirable medical condition occurring at any time, including baseline or washout periods, even 
if no study treatment has been administered. AEs can be classified into non-serious AEs or 
SAEs. 
For this trial, information about relapses that do not meet the SAE criteria below (Section 
12.2.1.3 ) should be recorded in source documents and in the eCRF as part of the relapse 
evaluation visits and not reported as AEs. 
12.2.1.2. Abnormal Test Finding 
Abnormal test findings may be considered AEs or SAEs at the Investigator’s discretion; 
however, Investigators are strongly encouraged to report the diagnosis, sign or symptom instead 
of just the abnormal result. The criteria for an abnormal test finding being classified as an AE or 
SAE are as follows: 
• Test result is associated with a sign or symptom; 
• Test result requires additional diagnostic testing; 
• Test result requires a medical or surgical intervention; 
• Test result leads to a change in trial dosing outside of the protocol defined dosing or 
discontinuation from the trial;  
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• Test result requires significant additional treatment 
12.2.1.3. Serious Adverse Events 
Any AE that fulfills one or more of the criteria listed below must be recorded as a SAE. A SAE 
(experience) or reaction is any untoward medical occurrence that at any dose: 
• Results in death 
• Is life-threatening 
NOTE: The term "life-threatening" in the definition of "serious" refers to an event in which 
the patient was at risk of death at the time of the event; it does not refer to an event which 
hypothetically might have caused death if it were more severe. 
• Requires inpatient hospitalization or prolongation of existing hospitalization 
• Results in persistent or significant disability/incapacity 
• Is a congenital anomaly/birth defect 
• Important medical event 
Medical and scientific judgment should be exercised in deciding whether expedited reporting is 
appropriate in other situations, such as important medical events that may not be immediately 
life-threatening or result in death or hospitalization but may jeopardize the patient or may require 
intervention to prevent one of the other outcomes listed in the definition above. These should 
also usually be considered serious. Examples of such events are intensive treatment in an 
emergency room or at home for allergic bronchospasm; blood dyscrasias or convulsions that do 
not result in hospitalization; or development of drug dependency or drug abuse. 
12.2.1.4. Lack of Efficacy 
Since eculizumab treatment in relapsing NMO patients is not an approved indication, lack of 
efficacy need not be reported as an AE.  
12.2.1.5. Hospitalization 
AEs that are associated with hospitalization or prolongation of hospitalization are considered 
SAEs. All admissions to a health care facility meet this criteria, even if less than 24 hours. 
Criteria for seriousness are also met if transfer within the hospital is done to receive more intense 
medical / surgical care (eg, medical floor to the intensive care unit [ICU]). 
Hospitalization does not include the following: 
• Rehabilitation facility 
• Hospice facility 
• Nursing facility 
• Emergency Room 
• Same day surgery 
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Hospitalization or prolongation of hospitalization not associated with an AE is not an SAE; 
examples include: 
• Admission for a pre-existing condition not associated with either a new AE or with 
worsening of a pre-existing AE 
• Protocol-specified admission 
• Pre-planned admission 
12.2.1.6. Procedures 
Diagnostic and therapeutic procedures (invasive and non-invasive) such as surgery or 
angiography should not be reported as an AE or SAE. However, the medical condition or the 
diagnosis that was responsible for the procedure should be recorded. The procedure should be 
recorded in the narrative as treatment for the AE or SAE; for example: “Laparoscopic 
cholecystectomy is the procedure or treatment for an SAE of necrotic gall bladder”. 
12.2.1.7. Other Adverse Events 
Other AEs (OAEs) will be identified by the Drug Safety Physician and if applicable also by the 
Clinical Trial Team Physician during the evaluation of safety data for the Clinical Study Report. 
Significant AEs of particular clinical importance, other than SAEs and those AEs leading to 
discontinuation of the patient/subject from the trial, will be classified as OAEs. For each OAE, a 
narrative may be written and included in the Clinical Study Report. 
12.2.1.8. Severity Assessment  
AE severity will be rated by the Investigator as mild, moderate, or severe using the following 
criteria: 
• Mild: events require minimal or no treatment and do not interfere with the patient’s 
daily activities. 
• Moderate: events result in a low level of inconvenience or concerns with the 
therapeutic measures. Moderate events may cause some interference with 
functioning. 
• Severe: events interrupt a patient’s usual daily activity and may require systemic drug 
therapy or other treatment. Severe events are usually incapacitating. 
Change in severity of an AE should be documented based on specific guidelines in the eCRF 
Completion Guidelines. 
Severity and seriousness must be differentiated. Severity describes the intensity of an AE, while 
the term seriousness refers to an AE that has met the criteria for an SAE. 
12.2.1.9. Causality Assessment  
An Investigator causality assessment (Unrelated, Unlikely, Possible, Probable, or Definite) must 
be provided for all AEs (both serious and non-serious). This assessment must be recorded in the 
source documents and eCRF and any additional SAE forms as appropriate. The definitions for 
the causality assessments appear below. 
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• Not related (unrelated): This relationship suggests that there is no association between 
the IP and the reported event. 
• Unlikely related: This relationship suggests that the clinical picture is highly 
consistent with a cause other than the IP but attribution cannot be made it absolute 
certainty and a relationship between the IP and AE cannot be excluded with complete 
confidence. 
• Possibly related: This relationship suggests that treatment with the IP may have 
caused or contributed to the AE, ie, the event follows a reasonable temporal sequence 
from the time of IP administration and/or follows a known response pattern to the IP, 
but could also have been produced by other factors. 
• Probably related: This relationship suggests that a reasonable temporal sequence of 
the event with the IP administration exists and the likely association of the event with 
the IP. This will be based upon the known pharmacological action of the IP, known or 
previously reported adverse reactions to the IP or class of drugs, or judgment based 
on the PI’s clinical experience. 
• Definitely related: Temporal relationship to the IP, other conditions (concurrent 
illness, concurrent medication reaction, or progression/expression of disease state) do 
not appear to explain event, corresponds with the known pharmaceutical profile, 
improvement on discontinuation, re-appearance on re-challenge. 
12.2.1.10. Exposure during Pregnancy and Lactation  
Pregnancy data will be collected during this trial extension for all patients. 
Investigational product exposure during pregnancy must be recorded and followed. Exposure 
during pregnancy, also called exposure in-utero (EIU), can be the result of either maternal 
exposure or transmission of drug product via semen following paternal exposure. 
If a patient or a patient’s partner becomes or is found pregnant while treated or exposed to 
eculizumab, the Investigator must submit a pregnancy form to the Sponsor via the same method 
as SAE reporting. The Sponsor will supply the Investigator with a copy of a “Pregnancy 
Reporting and Outcome Form / Breast Feeding”. The Sponsor must be notified via the same 
method as SAE reporting. 
Exposure of an infant to IP during breastfeeding needs to be reported in the “Pregnancy 
Reporting and Outcome Form / Breast Feeding”, and any AE an infant may experience following 
breastfeeding needs to be reported to the Sponsor. 
The patient or patient’s partner should be followed until the outcome of the pregnancy is known 
(spontaneous miscarriage, elective termination, normal birth or congenital abnormality), even if 
the patient discontinued IP or discontinues from the trial. When the outcome of the pregnancy 
becomes known the form should be completed and returned to the Sponsor. If additional follow-
up is required, the Investigator will be requested to provide the information. 
Pregnancy in itself is not regarded as an AE unless there is a suspicion that IP may have 
interfered with the effectiveness of a contraceptive medication. However, complications of 
pregnancy and abnormal outcomes of pregnancy are AEs and may meet criteria for a SAE. 
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Complications of pregnancy and abnormal outcomes of pregnancy such as ectopic pregnancy, 
spontaneous abortion, intrauterine fetal demise, neonatal death or congenital anomaly would 
meet criteria of an SAE and thus, should be reported as an SAE. Elective abortions without 
complications should not be handled as AEs. 
12.2.1.11. Withdraw due to an Adverse Event  
Withdrawal due to an AE or SAE event must be clearly differentiated from withdrawal due to 
other reasons. 
12.2.1.12. Obtaining Adverse Event  
The Investigator must collect all AEs observed, obtained by direct questioning or volunteered 
from the trial patient. 
12.2.1.13. Reporting Period  
For SAEs the reporting period to the Sponsor begins following the patient’s signing of the ICF 
(providing consent to participate in the trial) and continues through 8 weeks after the last dose of 
IP. No time limit exists on reporting SAEs that are thought to be possibly or probably or 
definitely related to the IP. 
For non-serious AE the reporting period starts following first dose of IP (Day 1) and continues 
through the last visit, including the safety Follow-up Visit. AEs, particularly causally related, are 
to be followed until the event or sequalae resolve or are determined to be medically stable. 
12.2.1.14. Reporting Requirements for Adverse Events 
All AEs must be assessed by the Investigator to determine if they meet criteria for an SAE. If 
criteria are met for an SAE the event must be reported to the Sponsor as per SAE reporting 
requirements in Section 12.2.1.14.2 , Serious Adverse Events. 
12.2.1.14.1. 
Reporting Requirements for Non-serious Adverse Events 
All non-serious AEs must be recorded in the eCRF system upon awareness or prior to the next 
patient visit. 
12.2.1.14.2. 
Reporting Requirements for Serious Adverse Events 
For SAEs, the Sponsor must be notified immediately or within 24 hours of the Investigator site 
becoming aware of the event, regardless of the presumed relationship to the IP. If the event 
meets the fatal or life threatening SAE criteria, the Investigator should notify the Sponsor 
immediately. The SAE report should be submitted electronically via the Safety Gateway. These 
reporting timelines need to be followed for all initial SAE cases and follow-up versions to the 
initial case. 
In the event that either the electronic data capture (EDC) or the Safety Gateway is unavailable at the 
site(s), the SAE must be reported on paper. The Investigator must complete, sign, and date the 
SAE pages, verify the accuracy of the information recorded on the SAE pages with the 
corresponding source documents, and send a copy via Email or fax to contact information 
provided below: 
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Email: 
 
Fax: 
 
Additional follow-up information, if required or available, should be sent via the Safety Gateway 
to the Sponsor or Sponsor’s designee within 24 hours of the Investigator becoming aware of this 
additional information. Follow-up information should be recorded on the SAE eCRF and placed 
with the original SAE information and kept with the appropriate section of the original subject 
records and/or trial file. For all SAEs the Investigator must provide the following: 
• Appropriate and requested follow-up information in the time frame detailed above 
• Causality of the serious event(s) 
• Outcome of the serious event(s) 
• Medical records and laboratory / diagnostic information 
12.2.1.15. Sponsor Reporting Requirements 
The Sponsor or legal representative is responsible for notifying the relevant regulatory 
authorities of SAEs meeting the reporting criteria as per regional and local regulations. 
12.2.1.16. Investigator Reporting Requirements 
The Investigator must fulfill all local regulatory obligations required for trial Investigators. It is 
the PI’s responsibility to notify the IRB or Independent Ethics Committee (IEC) of all SAEs that 
occur at his or her site. Investigators will also be notified of all unexpected, serious, drug-related 
events (7/15 Day Safety Reports) that occur during the clinical trial. These additional SAEs are 
required to be reported to the IRB or IEC according to local regulations. 
12.2.1.17. Reference Safety Document 
This protocol will use the current IB as the Reference Safety Document. The expectedness of a 
SAE is determined by the Sponsor from the Reference Safety Information section of the IB. 
12.2.1.18. Data Monitoring Committee  
An independent DMC will conduct interim monitoring of unblinded data as described in Section 
16.4. 
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13. 
ASSESSMENT OF BIOMARKER 
13.1. 
NMO Biomarker 
Blood samples (from all patients) and CSF samples (from patients who have consented to CSF 
testing) will be measured for NMO-IgG (AQP4-Ab) at protocol-specified time points, including 
during the Relapse Evaluation Period (see Section 7.5 for details) for all consented patients. 
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14. 
ASSESSMENT OF PHARMACOKINETICS AND 
PHARMACODYNAMICS 
The population PK analysis of eculizumab in NMO patients will be performed to assess the 
concentration of eculizumab versus time. PK parameters such as maximum concentration as well 
as trough and peak eculizumab concentration during the induction and maintenance treatment 
phases will be reported. Clearance and terminal half-life will be estimated. PD analysis will be 
performed to assess pre- and post-treatment serum hemolytic activity and therefore C5 
complement activity inhibition. Free C5 concentration also may be measured. 
CSF samples for PK and free C5 will be measured at the protocol-specified time points, 
including during the Relapse Evaluation Period, for all consented patients. 
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15. 
STATISTICS 
Analyses will be produced using the data from this trial alone as well as combined analyses that 
will include data from the ECU-NMO-301 trial. The analyses will include safety, efficacy, and 
PK/PD analyses. The statistical analysis plan will cover both the standalone trial analyses and the 
combined ECU-NMO-301 and extension trial (ECU-NMO-302) analyses. 
15.1. 
General Considerations 
ECU-NMO-302 is an extension of the Phase 3 Trial ECU-NMO-301. At the completion of the 
trial, the Sponsor will analyze the trial data. Analyses will be produced using the data from this 
trial alone as well combined analyses that will include data from the ECU-NMO-301 trial. The 
analyses will include safety, efficacy, and PK/PD analyses. The statistical analysis plan will 
cover both the standalone trial analyses and the combined ECU-NMO-301 and ECU-NMO-302 
trial analyses.  
The Sponsor will be responsible for data collection and editing, reviewing and validating all the 
information in the eCRFs, statistical analysis, and generation of the clinical report. 
Prior to locking the database, all data editing will be completed and decisions regarding the 
evaluability of all patient data for inclusion in the statistical analysis for the extension trial and 
Combined Per-Protocol (Combined PP) Sets will be made. The rationale for excluding any data 
from the statistical analyses will be prospectively defined, and classification of all or part of a 
patient's data as non-evaluable will be completed before the statistical analysis is begun. The 
statistical analysis will not begin until the entire database is locked and signed-off. 
The Alexion Biostatistics Department will perform the statistical analysis of the data derived 
from this trial. The analysis will be performed using the SAS® statistical software system 
Version 9.2 or higher. 
A DMC will conduct periodic safety reviews.  
All summary statistics will be computed and displayed by scheduled assessment time. Summary 
statistics for continuous variables will minimally include n, mean, standard deviation, minimum, 
median, and maximum. For categorical variables, frequencies and percentages will be presented. 
Graphical displays will be provided as appropriate. 
15.2. 
Determination of Sample Size 
This is an extension trial to ECU-NMO-301 trial. A maximum of 132 patients will be enrolled in 
the ECU-NMO-301 trial. Patients who complete the ECU-NMO-301 trial may participate in this 
extension trial. 
15.3. 
Analysis Sets 
Efficacy analyses will be performed on the Extension Trial Full Analysis Set (Extension FAS) 
population as well as the Extension Trial Per-Protocol (Extension PP) population. In addition, 
efficacy analyses will be performed on the Combined Full Analysis Set (Combined FAS) 
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population as well as the Combined PP population from the combined ECU-NMO-301 trial and 
the extension trial. 
15.3.1. 
Extension Trial Full Analysis Set Population 
The Extension FAS population, on which primary, secondary, and tertiary efficacy analyses and 
other efficacy analyses will be performed, consists of all patients who have received at least 1 
dose of eculizumab in this extension trial and have a post-IP-infusion efficacy assessment.  
15.3.2. 
Extension Trial Per-Protocol Set Population 
The Extension PP population is a subset of the Extension FAS population, excluding patients 
with major extension trial protocol deviations. The Extension PP population will include all 
patients who: 
• Have no major protocol deviations or key inclusion/exclusion criteria deviations that 
might potentially affect efficacy 
• Took at least 80% of the required treatment doses during participation in the 
extension trial 
15.3.3. 
Combined Full Analysis Set Population 
The Combined FAS population, on which primary, secondary, and tertiary efficacy analyses will 
be performed, consists of all patients who have received at least 1 dose of eculizumab in either 
ECU-NMO-301 or this trial and have a post-IP-infusion efficacy assessment. 
15.3.4. 
Combined Per-Protocol Set Population 
The Combined PP population is a subset of the Combined FAS population, excluding patients 
with major protocol deviations from either the ECU-NMO-301 or extension trial. The Combined 
PP population will include all patients who: 
• Have no major protocol deviations or inclusion/exclusion criteria deviations that 
might potentially affect efficacy 
• Took at least 80% of the required eculizumab doses during participation in ECU-
NMO-301 and/or this trial 
The Extension PP population as well as the Combined PP population will be determined prior to 
database lock.  
15.3.5. 
Extension Safety Set Population 
Safety analyses will be performed on the Extension Safety Set Population and the Combined 
Safety Population from both studies. The Extension Safety Set Population includes all patients 
who receive at least 1 dose of eculizumab in this trial. The Combined Safety Population includes 
all patients who receive at least 1 dose of eculizumab in trial ECU-NMO-301 or this trial. 
15.3.6. 
Other Set(s)  
PK/PD analyses will be performed on the PK/PD Analysis Set. The PK/PD Analysis Set includes 
all NMO patients who have PK/PD data assessments during the trial. 
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15.4. 
Demographics and Baseline Characteristics 
All demographic and baseline characteristics information will be summarized using the 
following sets: Extension FAS, Extension PP, Combined FAS, Combined PP, Extension Safety 
Set, and Combined Safety Set. No formal hypothesis testing will be performed. Summary 
statistics will be presented.  
15.5. 
Patient Disposition and Treatment Compliance 
The number of patients, treated, completing the trial, and included in the safety and efficacy 
analysis sets will be tabulated by counts and percentage of patients combined. Reasons for any 
patient withdrawals will be provided. 
Treatment compliance with IP will be summarized using descriptive statistics. The extra usage of 
IP for patients who are treated with PE during the trial will be summarized and listings will be 
produced. 
15.6. 
Prior and Concomitant Medications 
Prior and concomitant medications will be summarized. Listings of prior and concomitant 
medications will be produced. 
Supportive ISTs are allowed during the trial. Thus, supportive IST treatment will be summarized. 
Listings of supportive ISTs will be produced. Changes in ISTs during the trial will be 
summarized. 
For patients with On-Trial Relapses, the use of methylprednisolone and PE will be summarized 
by treatment group. Listings of methylprednisolone, plasmapheresis, and plasma exchange usage 
by patients with On-Trial Relapses will be produced. 
Medications will be coded using the World Health Organization Drug Dictionary (WHODrug). 
15.7. 
Efficacy Analyses 
Efficacy analyses will be performed on the Extension FAS population as well as the Extension 
PP population. In addition, Efficacy analyses will be performed on the Combined FAS 
population as well as the Combined PP population from the combined ECU-NMO-301 trial and 
the Extension trial. 
15.7.1. 
Primary Efficacy Analysis 
The primary efficacy endpoint is ARR including all relapses as identified by the Investigator. 
Baseline ARR for all patients will be calculated starting 1 year prior to enrollment in the ECU-
NMO-301 trial. Baseline ARR will be compared to rates calculated for the time period that 
patients are on eculizumab in ECU-NMO-302. The trial 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 On-Trial ARR when on eculizumab treatment in 
ECU-NMO-302 using a Wilcoxon signed rank test. Confidence intervals (95%) for the change 
and percentage change in the ARR will be presented. The percentage of patients who are relapse-
free based on On-Trial Relapse events while on eculizumab treatment in ECU-NMO-302 along 
with 95% confidence intervals will be computed using the Kaplan-Meier method. A sensitivity 
analysis will be performed for the change in ARR between the baseline ARR and the adjudicated 
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On-Trial ARR when on eculizumab treatment in ECU-NMO-302 using a Wilcoxon signed rank 
test. The percentage of patients who are relapse-free while on eculizumab treatment in ECU-
NMO-302 along with 95% confidence intervals will also be computed using the Kaplan-Meier 
method for the adjudicated On-Trial relapses. 
 
Additional analyses will be performed on the combined data from ECU-NMO-301and ECU-
NMO-302 trials. Baseline ARR for all patients will be calculated starting 1 year prior to 
enrollment in the ECU-NMO-301 trial and will include all On-Trial attacks (as identified by the 
Investigator) that occur in the ECU-NMO-301 trial for patients randomized to placebo. Baseline 
ARR for patients who were randomized to eculizumab in the ECU-NMO-301 trial will be 
calculated starting one year prior to enrollment in the ECU-NMO-301 trial. Baseline ARR will 
be compared to rates calculated for the time period that patients are on eculizumab. For patients 
who are treated in the placebo arm of the ECU-NMO-301 trial, the ARR for comparison with 
baseline will be calculated once the patient transitions to eculizumab treatment. A Wilcoxon 
signed rank test will be used to assess the change in ARR between the baseline ARR and the On-
Trial ARR when on eculizumab treatment. Confidence intervals (95%) for the change and 
percentage change in the ARR will be presented. The percentage of patients who are relapse-free 
based on On-Trial Relapse events while on eculizumab treatment along with 95% confidence 
intervals will be computed using the Kaplan-Meier method. A sensitivity analysis will be 
performed for the change in ARR between the baseline ARR and the adjudicated On-Trial ARR 
when on eculizumab treatment using a Wilcoxon signed rank test. The percentage of patients 
who are relapse-free while on eculizumab treatment along with 95% confidence intervals will 
also be computed using the Kaplan-Meier method for the adjudicated On-Trial relapses. 
15.7.2. 
Secondary Efficacy Analysis for the Trial Period 
Note: Baseline for the extension trial alone is defined as the last available assessment prior to 
starting treatment with eculizumab in the extension trial.  Baseline for the combined trial efficacy 
analyses is defined as the last available assessment prior to starting treatment with eculizumab in 
ECU-NMO-301 or this trial for all patients. 
Changes from baseline for the various secondary efficacy endpoints will be summarized over the 
applicable visits. 
• Change from baseline in EDSS score  
• Change from baseline in EQ-5D  
• Change from baseline in mRS score 
• Change from baseline in HAI in patients with abnormal baseline ambulatory function  
• Change from baseline in VA in patients with abnormal baseline visual function 
The primary analysis for the change from baseline in EDSS score at a particular visit for will be 
based on the repeated measures model with effects for baseline EDSS and visit. Changes from 
baseline in the HAI, VA, EQ-5D index score, EQ-5D visual analog scale, and mRS score will be 
analyzed in a similar manner as changes in EDSS score using the baseline and visit as covariates 
in the modeling. In addition, summary statistics for the changes from baseline in the mRS score 
will be produced by visit. Likewise, shift tables from baseline in the mRS score will be produced 
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by visit. By-patient listings of the secondary endpoints assessments and changes from baseline in 
the secondary endpoints will be produced. 
For the secondary endpoints, some summaries by subgroups will be produced. Patients will 
belong to one of four possible subgroups:  
(a) patients randomized to eculizumab who did not have relapses in the ECU-NMO-301 trial,  
(b) patients randomized to eculizumab who did have relapses in the ECU-NMO-301 trial,  
(c) patients randomized to placebo who did not have relapses in the ECU-NMO-301 trial, and  
(d) patients randomized to placebo who did have relapses in the ECU-NMO-301 trial.  
 
For the patients in sub-group (a), baseline is defined as the baseline assessment (last available 
assessment) prior to dosing in the ECU-NMO-301 trial. For the patients in sub-group (c), 
baseline is defined as the last available assessment prior to dosing with eculizumab in this trial. 
For the patients in subgroups (b) and (d), baseline for these subgroup analyses is defined as the 
last available assessment prior to eculizumab dosing in this extension trial in consideration of 
neurologic changes and recoveries as a result of relapse in the ECU-NMO-301 trial. Changes 
from baseline for the various secondary efficacy endpoints will be summarized separately for the 
4 subgroups of patients over the applicable visits. 
Missing secondary endpoint assessments will not be imputed.  
15.7.3. 
Tertiary Efficacy Analysis for the Trial Period 
Like the secondary efficacy endpoint, the tertiary endpoint analyses will be based on changes 
from baseline. 
• Change from baseline in HAI score  
• Change from baseline in VA  
• Change from baseline in the SF-36  
• Change from baseline in the EDSS FSS 
Changes from baseline in the HAI score and VA will be analyzed in a similar manner to the 
secondary endpoint analyses described for HAI with abnormal baseline ambulatory function and 
VA with abnormal baseline visual function using repeated measures models. 
Change from baseline in QOL will be summarized as appropriate to the QOL instrument and 
analyses will be performed as specified in the statistical analysis plan (SAP). 
Changes from baseline in the EDSS FSS will be analyzed in a similar manner to the secondary 
endpoint analyses described for the EDSS score using repeated measures model. 
In addition, summaries of changes from baseline like those for the secondary efficacy endpoints 
will also be created for the tertiary efficacy endpoints for the 4 subgroups of patients from the 
ECU-NMO-301 trial who are treated in the extension trial.  
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15.7.4. 
Other Efficacy Analyses: On-Trial Relapses 
For patients with a PI-determined On-Trial relapse(s), summary tables of the types of relapses 
and the severity of the relapses will be produced. Summary tables will also be produced only for 
those patients with adjudicated On-Trial relapse(s). A by-patient listing of the On-Trial relapses, 
including the adjudication outcome will be produced. The severity of a relapse will be 
determined using the OSIS scale. Severity will be assessed at the time of the relapse. 
Changes from baseline to all of the trial collected time-points after a relapse (and before the next 
relapse if the patient happens to have more than one relapse) will be summarized for EDSS, HAI, 
and VA. Changes from the last assessment prior to the relapse to all trial collected time-points 
after a relapse (and before the next relapse if the patient happens to have more than one relapse) 
will be summarized for EDSS, HAI, and VA. Likewise, changes from the assessment 1 week 
after the relapse to all trial collected time points after that time point (and before the next relapse 
if the patient happens to have more than one relapse) will be summarized for EDSS, HAI, and 
VA. These summaries will be produced for patients with a PI-determined On-Trial relapse(s) as 
well as for only those patients with adjudicated On-Trial relapse(s).  Patient listings for the 
EDSS, HAI, and VA assessments before and after a relapse will be created for the patients with 
all On-Trial relapses as determined by the PI(s), including the subsequent adjudication outcome. 
15.8. 
Safety Analyses 
Safety analyses will be performed on the Extension Safety Population and the Combined Safety 
Population from both studies. The Extension Safety Population includes all patients who receive 
at least 1 dose of eculizumab in this trial. The Combined Safety Population includes all patients 
who receive at least 1 dose of eculizumab in trial ECU-NMO-301 or this trial.  
For the extension trial alone, AEs onset on or after the first dose date for eculizumab in the 
extension trial will be summarized by incidence, system organ class (SOC), preferred term, 
seriousness, severity, and relationship to treatment. Concomitant medications taken during the 
extension trial will be summarized. Changes in IST usage (i.e. increases, decreases, switching 
ISTs, etc) will be summarized. 
For the Combined Safety Population, AEs that occurred on or after the first dose of eculizumab 
whether in the ECU-NMO-301or this extension trial will be summarized by incidence, preferred 
term, SOC, seriousness, severity, and relationship to treatment. Concomitant medications taken 
during eculizumab treatment will be summarized. 
Changes from baseline in laboratory assessments (chemistry and hematology,) will be 
summarized for the extension trial alone as well as for the two studies combined. Likewise, shift 
tables (L [low], N [normal], H [high]) will be produced for clinical laboratory tests for the 
extension trial alone as well as for the two studies combined. Pregnancy tests will be summarized 
in patient listings. ECG data will be summarized for the extension trial. Shift tables for the C-
SSRS will be produced for the extension trial. 
15.8.1. 
Physical Examinations and Vital Signs 
Physical examinations will be summarized for the extension trial. VS (systolic and diastolic BP, 
temperature, and sitting or lying HR, and weight and changes from baseline in VS (including 
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weight) will be summarized for the extension trial. Listings of physical exams and VS will be 
produced. 
15.8.2. 
Laboratory Assessments 
Changes from baseline in laboratory assessments (chemistry, hematology, and urinalysis) will be 
summarized for the extension trial alone as well as for the two trials combined. Likewise, shift 
tables (L [low], N [normal], H [high]) for the extension trial alone as well as for the two trials 
combined will be produced for clinical laboratory tests. Listings of laboratory data will be 
produced. 
15.8.3. 
Adverse Events 
Treatment emergent AEs (TEAEs) are AEs that onset after the start of treatment in the trial. 
TEAEs will be summarized by incidence, SOC, preferred term, seriousness, severity, and 
relationship to treatment for the extension trial alone as well as for the two trials combined. 
Serious AEs will be summarized for the extension trial alone as well as for the two trials 
combined. TEAEs and SAEs will be summarized by gender, by race, and by region (of the 
world) for the extension trial alone as well as for the two trials combined. 
AEs and general medical/surgical histories will be coded by primary SOC and preferred term 
using the Medical Dictionary for Regulatory Activities (MedDRA) (version 13.0 or higher). 
15.8.3.1. Columbia-Suicide Severity Rating Scale 
The C-SSRS will be summarized by visit. Shift tables for the C-SSRS will be produced by visit. 
Patient listings for the C-SSRS will also be produced. 
15.8.4. 
Other Safety Endpoints 
The ECG parameters will be summarized by visit including QT and QTc level categories. ECG 
results will be summarized in patient listings. 
Pregnancy tests will be summarized in patient listings. 
Immunogenicity as measured by HAHA will be summarized in tabular form as well as a patient 
listing for the extension trial alone as well as for the two trials combined.  
15.9. 
Pharmacokinetic/Pharmacodynamic Analyses 
The population PK analysis of eculizumab in NMO patients will be performed to assess the 
concentration of eculizumab versus time. PK parameters such as maximum concentration as well 
as trough and peak eculizumab concentrations during the induction and maintenance treatment 
phases will be reported. Clearance and terminal half-life will be estimated. PD analysis will be 
performed to assess pre- and post-treatment serum hemolytic activity and therefore C5 
complement activity inhibition. Free C5 concentration also may be measured. 
15.10. 
Biomarker Analysis 
Changes from baseline for NMO-IgG assessments will be summarized and patient listings for the 
NMO biomarker data will be created. 
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15.11. 
Other Statistical Issues 
15.11.1. 
Significance Levels 
For all analyses, hypothesis testing will be two-sided and performed at the 0.05 level of 
significance, unless otherwise specified. Estimates of treatment effect on efficacy parameters 
will be accompanied by two-sided 95% confidence intervals.  
15.11.2. 
Missing or Invalid Data 
For secondary and tertiary efficacy analyses, missing post-baseline efficacy and safety data will 
not be imputed unless indicated in the described analysis in the SAP. 
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16. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
16.1. 
Trial Monitoring 
Before a study site can enter a patient into the trial, a representative of the Sponsor or its 
designee will visit the investigational trial site to: 
• Determine the adequacy of the facilities 
• Discuss with the Investigator(s) and other personnel their responsibilities with regard to 
protocol adherence, and the responsibilities of the Sponsor or the Sponsor’s designee or 
its representatives. This will be documented in a Clinical Trial Agreement between the 
Sponsor or the Sponsor’s designee and the Investigator. 
During the trial, a monitor from the Sponsor or the Sponsor’s designee or representative will 
have regular contacts with the study site, for the following: 
• Provide information and support to the Investigator(s) 
• Confirm that facilities remain acceptable 
• Confirm that the investigational team is adhering to the protocol, that data are being 
accurately recorded in the eCRFs, and that IP accountability checks are being performed 
• Perform source data verification. This includes a comparison of the data in the eCRFs 
with the patient’s medical records at the hospital or practice, and other records relevant to 
the trial. This will require direct access to all original records for each patient (e.g. clinic 
charts). 
• Record and report any protocol deviations not previously sent to the Sponsor or the 
Sponsor’s designee. 
• Confirm AEs and SAEs have been properly documented on eCRFs and confirm any 
SAEs have been forwarded to the Sponsor or the Sponsor’s designee and those SAEs that 
met criteria for reporting have been forwarded to the IRB or IEC. 
The monitor will be available between visits if the Investigator(s) or other staff needs 
information or advice. 
16.2. 
Audits and Inspections 
Authorized representatives of the Sponsor or the Sponsor’s designee or its representative, a 
regulatory authority, an IEC or an IRB may visit the site to perform audits or inspections, 
including source data verification. The purpose of an audit or inspection is to systematically and 
independently examine all trial-related activities and documents to determine whether these 
activities were conducted, and data were recorded, analyzed, and accurately reported according 
to the protocol, GCP guidelines of the International Conference on Harmonization (ICH), and 
any applicable regulatory requirements. The Investigator should contact the Sponsor or the 
Sponsor’s designee immediately if contacted by a regulatory agency about an inspection. 
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16.3. 
Institutional Review Board/Independent Ethics Committee 
The PI, or Sponsor or Sponsor’s designee, depending on country requirements, must obtain 
IRB/IEC approval for the investigation. Initial IRB/IEC approval, and all materials that have 
been submitted and approved by the IRB/IEC for this trial, including the patient ICF form and 
recruitment materials, must be maintained by the Investigator and made available for inspection. 
16.4. 
Data Monitoring Committee 
An independent DMC will conduct interim monitoring of unblinded safety data. Since its 
primary function will be to ensure patient safety, the DMC will have access to all safety data. 
The DMC may make recommendations to the Sponsor regarding safety issues, trial conduct, and 
modifying, extending or stopping the trial. A separate DMC Charter will document all DMC 
procedures and processes for the trial. 
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17. 
QUALITY CONTROL AND QUALITY ASSURANCE 
To ensure compliance with Good Clinical Practices (GCPs) and all applicable regulatory 
requirements, the Sponsor or the Sponsor’s designee or its representative may conduct a quality 
assurance audit. Please see Section 16.2 for more details regarding the audit process. 
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18. 
ETHICS 
18.1. 
Ethics Review 
The final trial protocol, including the final version of the Informed Consent Form, must be 
approved or given a favorable opinion in writing by an IRB or IEC as appropriate. The 
Investigator must submit a copy of the written approval to the Sponsor or the Sponsor’s designee 
before he or she can enroll any patient/subject into the trial. 
The PI, or Sponsor or Sponsor’s designee, depending on country requirements, is responsible for 
informing the IRB or IEC of any amendment to the protocol in accordance with local 
requirements. In addition, the IRB or IEC must approve all advertising used to recruit patients 
for the trial. The protocol must be re-approved by the IRB or IEC upon receipt of amendments 
and annually, per local regulations. 
The PI is also responsible for providing the IRB or IEC with reports of any reportable serious 
adverse drug reactions from any other trial conducted with the IP. The Sponsor or the Sponsor’s 
designee will provide this information to the PI. 
Progress reports and notifications of serious adverse drug reactions will be provided to the IRB 
or IEC according to local regulations and guidelines. 
18.2. 
Ethical Conduct of the Trial 
The trial will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with ICH/Good Clinical Practice, applicable 
regulatory requirements. 
18.3. 
Written Informed Consent 
The PI(s) at each center will ensure that the patient is given full and adequate oral and written 
information about the nature, purpose, possible risk and benefit of the trial. Patients must also be 
notified that they are free to discontinue from the trial at any time. The patient should be given 
the opportunity to ask questions and allowed time to consider the information provided. 
The patient’s signed and dated ICF must be obtained before conducting any trial procedures. 
The PI(s) must maintain the original, signed ICF. A copy of the signed ICF must be given to the 
patient. 
Local regulations should be followed for blind or other disabled patients. If there are not clear 
requirements, it is strongly recommended that at the very minimum an impartial witness or, if 
applicable, a Legal Guardian, is present during the consent process and signs the consent., 
Additionally, the PI should discuss with the Local EC/IRB the recommended consent process for 
these patients and adhere to it. 
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19. 
DATA HANDLING AND RECORDKEEPING 
19.1. 
Inspection of Records 
The Sponsor or the Sponsor’s designee will be allowed to conduct site visits to the investigation 
facilities for the purpose of monitoring any aspect of the trial. The Investigator agrees to allow 
the monitor to inspect the IP storage area, IP stocks, IP accountability records, patient charts and 
trial source documents, and other records relative to trial conduct. 
19.2. 
Retention of Records 
The PI must maintain all documentation relating to the trial according to the local regulations or 
a minimum period of 2 years after the last marketing application approval worldwide, or if not 
approved 2 years following the discontinuance of the test article for investigation. The PI must 
also maintain the confidentiality of all study documentation, and take measures to prevent 
accidental or premature destruction of these documents. If it becomes necessary for the Sponsor 
or the Sponsor’s designee or the Regulatory Authority to review any documentation relating to 
the trial, the Investigator must permit access to such records. 
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20. 
LIST OF REFERENCES 
 
 
 
(1)  Kimbrough D, Fujihara K, Jacob A, et al. Treatment of neuromyelitis optica: Review and 
recommendations. Multiple Sclerosis and Related Disorders 2012;1:180-7. 
 
(2)  Mata S, Lolli F. Neuromyelitis optica: an update. J Neurol Sci 2011 Apr 15;303(1-2):13-
21. 
 
(3)  Wingerchuk DM, Lennon VA, Pittock SJ, Lucchinetti CF, Weinshenker BG. Revised 
diagnostic criteria for neuromyelitis optica. Neurology 2006 May 23;66(10):1485-9. 
 
(4)  Wingerchuk DM, Lennon VA, Lucchinetti CF, Pittock SJ, Weinshenker BG. The 
spectrum of neuromyelitis optica. Lancet Neurol 2007 Sep;6(9):805-15. 
 
(5)  Kurtzke JF. Rating neurologic impairment in multiple sclerosis: an expanded disability 
status scale (EDSS). Neurology 1983 Nov;33(11):1444-52. 
 
(6)  Hauser SL, Dawson DM, Lehrich JR, Beal MF, Kevy SV, Propper RD, et al. Intensive 
immunosuppression in progressive multiple sclerosis. A randomized, three-arm study of 
high-dose intravenous cyclophosphamide, plasma exchange, and ACTH. N Engl J Med 
1983 Jan 27;308(4):173-80. 
 
(7)  Rankin J. Cerebral vascular accidents in patients over the age of 60. SCOTT MED J 
1957;2:200-15. 
 
(8)  Bonita R, Beaglehole R. Modified Rankin Scale; Recovery of Motor function After 
Stroke. Stroke 1988 Dec;19(12):1497-500. 
 
(9)  Van Swieten J, Koudstaal P, Visser M, Schouten H. Interobserver Agreement for the 
Assessment of Handicap in Stroke Patients. Stroke 1988;19(5):604-7. 
 (10)  Posner K, Brent D, Lucas C, Gould M, Stanley B, Brown G, et al. COLUMBIA-
SUICIDE SEVERITY RATING SCALE (C-SSRS) Since Last Visit. 2009.  
Ref Type: Online Source 
 
 
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21. 
APPENDICES 
Appendix 1: Diagnostic Criteria for NMO (2006) (3) 
Appendix 2: Diagnostic Criteria for NMO spectrum disorder (2007) (4) 
Appendix 3: Kurtzke Expanded Disability Status Scale (EDSS) (5) 
Appendix 4: Optic-Spinal Impairment Scale (OSIS) 
Appendix 5: Hauser Ambulation Index (HAI) (6) 
Appendix 6: Short Form Health Survey (SF-36) 
Appendix 7: EuroQoL (EQ-5D) 
Appendix 8: Clinical Laboratory Tests 
Appendix 9: Modified Rankin Scale (mRS) (7-9) 
Appendix 10: Columbia-Suicide Severity Rating Scale (C-SSRS)-Since Last Visit (10) 
Appendix 11: Collection of Follow-Up Information From Patients Who Withdraw From the 
Study  
 
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APPENDIX 1: 2006 DIAGNOSTIC CRITERIA FOR NMO 
 
Definite NMO 
Optic neuritis 
Acute myelitis 
At least two of three supportive criteria 
1. Contiguous spinal cord MRI lesion extending over 3 vertebral segments 
2. Brain MRI not meeting diagnostic criteria for multiple sclerosis 
3. NMO-IgG seropositive status 
 
 
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APPENDIX 2: 2007 DIAGNOSTIC CRITERIA FOR NMO SPECTRUM 
DISORDER 
 
Neuromyelitis optica  
Limited forms of neuromyelitis optica 
• Idiopathic single or recurrent events of longitudinally extensive myelitis (≥ 3 vertebral 
segment spinal cord lesion seen on MRI 
• Optic neuritis: recurrent or simultaneous bilateral  
Asian optic-spinal multiple sclerosis  
Optic neuritis or longitudinally extensive myelitis associated with systemic autoimmune disease  
Optic neuritis or myelitis associated with brain lesions typical of neuromyelitis optica 
(hypothalamic, corpus callosal, periventricular, or brainstem) 
 
 
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APPENDIX 3: KURTZKE EXPANDED DISABILITY STATUS SCALE 
(EDSS) 
 
The Kurtzke Expanded Disability Status Scale (EDSS) (5) is a method of quantifying disability 
in multiple sclerosis. The EDSS replaced the previous Disability Status Scales used in Multiple 
Sclerosis (MS). 
The EDSS quantifies disability in eight Functional Systems (FS) and allows neurologists to 
assign a Functional System Score (FSS) in each of these. The Functional Systems are:  
pyramidal 
cerebellar 
brainstem 
sensory  
bowel and bladder 
visual 
cerebral 
other 
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. 
 
 
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Kurtzke Expanded Disability Status Scale 
0.0 Normal neurological examination 
1.0 No disability, minimal signs in one FS 
1.5 No disability, minimal signs in more than one FS 
2.0 Minimal disability in one FS 
2.5 Mild disability in one FS or minimal disability in two FS 
3.0 Moderate disability in one FS, or mild disability in three or four FS. Fully ambulatory 
3.5 Fully ambulatory but with moderate disability in one FS and more than minimal disability in several others 
4.0 Fully ambulatory without aid, self-sufficient, up and about some 12 hours a day despite relatively severe 
disability; able to walk without aid or rest some 500 meters 
4.5 Fully ambulatory without aid, up and about much of the day, able to work a full day, may otherwise have 
some limitation of full activity or require minimal assistance; characterized by relatively severe disability; able 
to walk without aid or rest some 300 meters. 
5.0 Ambulatory without aid or rest for about 200 meters; disability severe enough to impair full daily activities 
(work a full day without special provisions) 
5.5 Ambulatory without aid or rest for about 100 meters; disability severe enough to preclude full daily activities 
6.0 Intermittent or unilateral constant assistance (cane, crutch, brace) required to walk about 100 meters with or 
without resting 
6.5 Constant bilateral assistance (canes, crutches, braces) required to walk about 20 meters without resting 
7.0 Unable to walk beyond approximately five meters even with aid, essentially restricted to wheelchair; wheels 
self in standard wheelchair 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 aid in transfer; wheels self but cannot 
carry on in standard wheelchair a full day; May require motorized wheelchair 
8.0 Essentially restricted to bed or chair or perambulated in wheelchair, but may be out of bed itself much of the 
day; retains many self-care functions; generally has effective use of arms 
8.5 Essentially restricted to bed much of day; has some effective use of arms retains some self care functions 
9.0 Confined to bed; can still 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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APPENDIX 4: OPTIC-SPINAL IMPAIRMENT SCORE (OSIS) 
 
Visual Acuity (VA) 
0 Normal 
1 Scotoma but VA (corrected) better than 20/30 
2 VA 20/30 - 20/59 
3 VA 20/60-20/100 
4  VA 20/ I 0 I - 201200 
5 VA 20/20 I - 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 (MRC 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 plcgic (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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Pr ot oc ol E C U -N M O -3 0 2, A me n d me nt 6 
 
Ale xi o n P har mace uticals, I nc.  
2 2 Marc h 2 0 1 8  
A P P E N DI X 5 : H A U S E R A M B U L A TI O N I N D E 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 nt erferes 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 m eters) 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 nilater al 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 bilater al s u p p ort (ca nes, cr utc h es, or wal ker) a n d w al ks 2 5 feet i n  2 0 sec o n ds or 
less; or re q uires u nilater al 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 bilater al 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 heel c hair * 
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 heel c h air * f or m ost acti vities.  
 
� 8 = Restricte d t o w heelc hair; a ble t o tra nsfer s elf 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. 
* T he use of a w heelc hair ma y b e deter mi ne d b y lifest yl e 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 d e 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 n t uses a w heelc hair. 
 
 
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APPENDIX 6: SHORT FORM HEALTH SURVEY (SF-36) 
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APPENDIX 7: EUROQOL (EQ-5D) 
 
 
 
 
Health Questionnaire 
(English version for the United States) 
 
 
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By placing a checkmark in one box in each group below, please indicate which statements best 
describe your own health state today. 
Mobility 
I have no problems in walking about  
 
 
 
 
 
 
 
I have some problems in walking about  
 
 
 
 
 
 
I am confined to bed  
 
 
 
 
 
 
 
 
 
 
 
Self-Care 
I have no problems with self-care 
 
 
 
 
 
 
 
 
I have some problems washing or dressing myself  
 
 
 
I am unable to wash or dress myself  
 
 
 
 
 
 
 
Usual Activities (e.g. work, study, housework, family or 
leisure activities) 
I have no problems with performing my usual activities  
 
 
I have some problems with performing my usual activities  
 
I am unable to perform my usual activities  
 
 
 
 
 
Pain/Discomfort 
I have no pain or discomfort  
 
 
 
 
 
 
 
 
 
I have moderate pain or discomfort  
 
 
 
 
 
 
 
I have extreme pain or discomfort 
 
 
 
 
 
 
 
 
Anxiety/Depression 
I am not anxious or depressed 
 
 
 
 
 
 
 
 
 
I am moderately anxious or depressed 
 
 
 
 
 
 
 
I am extremely anxious or depressed  
 
 
 
 
 
 
 
 
 
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To help people say how good or bad a health state is, we have drawn a scale (rather like a 
thermometer) on which the best state you can imagine is marked 100 and the worst state you can 
imagine is marked 0. 
We would like you to indicate on this scale how good 
or bad your own health is today, in your opinion. 
Please do this by drawing a line from the box below to 
whichever point on the scale indicates how good or  
bad your health state is today. 
 
 
 
Your own 
health state 
today 
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APPENDIX 8: CLINICAL LABORATORY TESTS 
 
Chemistry Panel  
Sodium 
Potassium 
Chloride 
Bicarbonate 
Blood urea nitrogen 
Creatinine 
Glucose 
Alkaline phosphatase 
Alanine amino transferase (ALT) 
Aspartate amino transferase (AST) 
Total bilirubin 
Albumin 
Total protein 
Uric acid 
 
Complete Blood Count (CBC) & Differential 
White blood cell count (WBC) 
White blood cell differential 
Red blood cell count (RBC) 
RBC mean corpuscular volume (MCV) 
RBC distribution width 
Hemoglobin 
Hematocrit 
Platelet count 
 
Urinalysis 
Appearance  
Specific gravity  
PH 
Protein 
Blood  
Glucose 
Ketone 
Bilirubin 
Urobilinogen 
Nitrite 
 
Human Chorionic 
Gonadotropin (β-HCG) 
 
Auto Aquaporin 4 antibody 
(AQP4-Ab or NMO-IgG) 
 
 
Pharmacokinetics (PK) and 
Pharmacodynamics (PD) 
 
Complement factor 5 (C5) 
 
Human Anti-human Antibody 
(HAHA) 
 
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APPENDIX 9: MODIFIED RANKIN SCALE  
 
MODIFIED   
 
 
 
 
 
Patient Name: ___________________________ 
RANKIN 
Rater Name: ___________________________ 
SCALE (mRS) 
Date: ___________________________ 
 
Score   
Description 
 
0   
 
No symptoms at all 
 
1  
No significant disability despite symptoms; able to carry out all usual duties and 
activities 
 
2  
Slight disability; unable to carry out all previous activities, but able to look after own 
affairs without assistance 
 
3   
 
Moderate disability; requiring some help, but able to walk without assistance 
 
4  
Moderately severe disability; unable to walk without assistance and unable to attend 
to own bodily needs without assistance 
 
5  
Severe disability; bedridden, incontinent and requiring constant nursing care and 
attention 
 
6   
 
Dead 
 
TOTAL (0–6): _______ 
 
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APPENDIX 10: COLUMBIA-SUICIDE SEVERITY RATING SCALE (C-
SSRS) – SINCE LAST VISIT 
 
SUICIDAL IDEATION 
Ask questions 1 and 2. If both are negative, proceed to “Suicidal Behavior” section. If the answer 
to question 2 is “yes”, ask questions 3, 4 and 5. If the answer to question 1 and/or 2 is “yes”, 
complete “Intensity of Ideation” section below. 
 
Since Last 
Visit 
1. Wish to be Dead 
Subject endorses thoughts about a wish to be dead or not alive anymore, or wish to fall asleep and not wake up. 
Have you wished you were dead or wished you could go to sleep and not wake up? 
 
If yes, describe: 
 
Yes 
No 
□ 
□ 
2. Non-Specific Active Suicidal Thoughts 
General, non-specific thoughts of wanting to end one’s life/commit suicide (eg, “I’ve thought about killing myself”) without 
thoughts of ways to kill oneself/associated methods, intent, or plan during the assessment period. 
Have you actually had any thoughts of killing yourself? 
 
If yes, describe: 
 
Yes 
No 
□ 
□ 
3. Active Suicidal Ideation with Any Methods (Not Plan) without Intent to Act 
Subject endorses thoughts of suicide and has thought of at least one method during the assessment period. This is different 
than a specific plan with time, place or method details worked out (eg, thought of method to kill self but not a specific plan). 
Includes person who would say, “I thought about taking an 
overdose but I never made a specific plan as to when, where or how I would actually do it…and I would never go through 
with it.” 
Have you been thinking about how you might do this? 
 
If yes, describe: 
 
Yes 
No 
□ 
□ 
4. Active Suicidal Ideation with Some Intent to Act, without Specific Plan 
Active suicidal thoughts of killing oneself and subject reports having some intent to act on such thoughts, as opposed to “I 
have the thoughts but I 
definitely will not do anything about them.” 
Have you had these thoughts and had some intention of acting on them? 
 
If yes, describe: 
 
Yes 
No 
□ 
□ 
5. Active Suicidal Ideation with Specific Plan and Intent 
Thoughts of killing oneself with details of plan fully or partially worked out and subject has some intent to carry it out. 
Have you started to work out or worked out the details of how to kill yourself? Do you intend to carry out this plan? 
 
If yes, describe: 
 
Yes 
No 
□ 
□ 
INTENSITY OF IDEATION 
The following features should be rated with respect to the most severe type of ideation (ie, 1-5 from above, 
with 1 being the least severe and 5 being the most severe). 
 
Most Severe Ideation: 
  
 
Type # (1-5) 
Description of Ideation 
 
 
Most 
Severe 
Frequency 
How many times have you had these thoughts? 
(1) Less than once a week    (2) Once a week   (3) 2-5 times in week    (4) Daily or almost daily   (5) Many times each day 
 
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SUICIDAL IDEATION 
Duration 
When you have the thoughts, how long do they last? 
Fleeting - few seconds or minutes 
(4) 4-8 hours/most of day 
Less than 1 hour/some of the time 
(5) More than 8 hours/persistent or continuous 
1-4 hours/a lot of time 
 
Controllability 
Could/can you stop thinking about killing yourself or wanting to die if you want to? 
Easily able to control thoughts 
(4) Can control thoughts with a lot of difficulty 
Can control thoughts with little difficulty 
(5) Unable to control thoughts 
Can control thoughts with some difficulty 
(0) Does not attempt to control thoughts 
 
Deterrents 
Are there things - anyone or anything (eg, family, religion, pain of death) - that stopped you 
from wanting to die or acting on thoughts of committing suicide? 
Deterrents definitely stopped you from attempting suicide 
(4) Deterrents most likely did not stop you 
Deterrents probably stopped you 
(5) Deterrents definitely did not stop you 
Uncertain that deterrents stopped you 
(0) Does not apply 
 
Reasons for Ideation 
What sort of reasons did you have for thinking about wanting to die or killing yourself? Was it 
to end the pain or stop the way you were feeling (in other words you couldn’t go on living with 
this pain or how you were feeling) or was it to get attention, revenge or a reaction from others? 
Or both? 
Completely to get attention, revenge or a reaction from others 
(4) Mostly to end or stop the pain (you couldn’t 
go on 
Mostly to get attention, revenge or a reaction from others 
living with the pain or how you were 
feeling) 
Equally to get attention, revenge or a reaction from others              (5) Completely to end or stop the pain (you couldn’t go 
on 
            and to end/stop the pain                                                                              living with the pain or how you were  
feeling) 
                            (0) Does not apply 
 
SUICIDAL BEHAVIOR 
(Check all that apply, so long as these are separate events; must ask about all types) 
Since Last 
Visit 
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SUICIDAL IDEATION 
Actual Attempt: 
A potentially self-injurious act committed with at least some wish to die, as a result of act. Behavior was in part thought of 
as method to kill oneself. Intent does not have to be 100%. If there is any intent/desire to die associated with the act, then it 
can be considered an actual suicide attempt. There does not have to be any injury or harm, just the potential for 
injury or harm. If person pulls trigger while gun is in mouth but gun is broken so no injury results, this is considered an 
attempt. 
Inferring Intent: Even if an individual denies intent/wish to die, it may be inferred clinically from the behavior or 
circumstances. For example, a highly lethal act that is clearly not an accident so no other intent but suicide can be inferred 
(eg, gunshot to head, jumping from window of a high floor/story). Also, if someone denies intent to die, but they thought 
that what they did could be lethal, intent may be inferred. 
Have you made a suicide attempt?  
  Have you done anything to harm yourself? 
  Have you done anything dangerous where you could have died? 
What did you do? 
Did you as a way to end your life? 
Did you want to die (even a little) when you_ 
? 
Were you trying to end your life when you _? 
Or did you think it was possible you could have died from 
? 
Or did you do it purely for other reasons / without ANY intention of killing yourself (like to 
relieve stress, feel better, get sympathy, or get something else to happen)? (Self-Injurious Behavior 
without suicidal intent) 
If yes, describe: 
 
 
Has subject engaged in Non-Suicidal Self-Injurious Behavior? 
 
 
 
 Yes 
    
No 
  □         □ 
 
 
 
 
 Total # of 
Attempts 
 
   ____ 
 
 
 
 
 
 
 
 
 Yes 
     
No 
   □        □ 
 
Interrupted Attempt: 
When the person is interrupted (by an outside circumstance) from starting the potentially self-
injurious act (if not for that, actual attempt would have occurred). 
 
Overdose: Person has pills in hand but is stopped from ingesting. Once they ingest any pills, this 
becomes and attempt rather than an interrupted attempt. Shooting: Person has gun pointed toward 
self, gun is taken away by someone else, or is somehow prevented from pulling trigger. Once they 
pull the trigger, even if the gun fails to fire, it is an attempt. Jumping: Person is poised to jump, is 
grabbed and taken down from ledge. Hanging: Person has noose around neck but has not yet 
started to hang – is stopped from doing so.  
Has there been a time when you started to do something to end your life but someone or 
something stopped you before you actually did anything? 
If yes, describe: 
Yes 
 
No 
  □        □ 
 
 
 
 
 
 
Total # of    
interrupted 
 
 
____ 
 
Aborted Attempt: 
When person begins to take steps toward making a suicide attempt, but stops themselves before 
they actually have engaged in any self-destructive behavior. Examples are similar to interrupted 
attempts, except that the individual stops him/herself, instead of being stopped by something else. 
Has there been a time when you started to do something to try to end your life but you stopped 
yourself before you actually did anything? 
If yes, describe: 
 Yes     No 
  □        □ 
 
Total # of    
aborted 
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SUICIDAL IDEATION 
Preparatory Acts or Behavior: 
Acts or preparation towards imminently making a suicide attempt. This can include anything 
beyond a verbalization or thought, such as assembling a specific method (eg, buying pills, 
purchasing a gun) or preparing for one’s death by suicide (eg, giving things away, writing a 
suicide note). 
Have you taken any steps towards making a suicide attempt or preparing to kill yourself (such 
as collecting pills, getting a gun, giving valuables away or writing a suicide note)? 
If yes, describe: 
 
 Yes    No 
   □       □ 
Suicidal Behavior: 
Suicidal behavior was present during the assessment period? 
 Yes    No 
  □      □ 
Suicide: 
 Yes    No 
   □   
□ 
Answer for Actual Attempts Only 
Most 
Lethal 
Attempt  
Date: 
Actual Lethality/Medical Damage: 
  0. No physical damage or very minor physical damage (eg, surface scratches). 
Minor physical damage (eg, lethargic speech; first-degree burns; mild bleeding; sprains). 
Moderate physical damage; medical attention needed (eg, conscious but sleepy, somewhat 
responsive; second degree burns; bleeding of major vessel). 
Moderately severe physical damage; medical hospitalization and likely intensive care required 
(eg, comatose with reflexes intact; third-degree burns less than 20% of body; extensive blood loss 
but can recover; major fractures). 
Severe physical damage; medical hospitalization with intensive care required (eg, comatose 
without reflexes; third-degree burns over 20% of body; extensive blood loss with unstable vital 
signs; major damage to a vital area). 
 Enter 
Code 
 
 
 
     ______ 
Potential Lethality: Only Answer if Actual Lethality=0 
Likely lethality of actual attempt if no medical damage (the following examples, while having no 
actual medical damage, had potential for very serious lethality: put gun in mouth and pulled the 
trigger but gun fails to fire so no medical damage; laying on train tracks with oncoming train but 
pulled away before run over). 
 
0 = Behavior not likely to result in injury 
1 = Behavior likely to result in injury but not likely to cause death 
2 = Behavior likely to result in death despite available medical care 
Enter Code 
 
 
 
 
    ______ 
 
 
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APPENDIX 11: COLLECTION OF FOLLOW-UP INFORMATION FROM 
PATIENTS WHO WITHDRAW FROM THE STUDY 
To gain understanding of the patient’s post-treatment disease status, the Sponsor may request 
additional follow-up information from patients who discontinue prematurely. An updated ICF 
(and/or an ICF Addendum) will be provided to all patients describing the following: the reason 
for collecting follow-up information from patients who discontinue prematurely, the information 
that will be collected, that the information will be collected for up to 2 years after the last dose of 
eculizumab, and how the information will be used. The updated ICF (and/or ICF Addendum) 
will clearly state that the patient has the option to accept or reject, and that either decision will 
have no impact on their medical benefits. Prior to collecting any follow-up information, the 
updated ICF (and/or ICF Addendum) must be signed by the patient. 
The Sponsor may obtain patient post-treatment data by querying the patient’s medical records, 
through the study physician, or through the patient’s current treating physician. The follow-up 
data to be collected from the physician may include the following:  
• Immunosuppressive medications (eg, azathioprine, mycophenolate mofetil, 
corticosteroids) and their dose regimen that the patient has received since Study ECU-
NMO-302 for the prevention of relapses of NMOSD 
• Any NMOSD relapses the patient has experienced since discontinuing Study ECU-NMO-
302 including: 
o Date of relapse(s) 
o Type of relapse(s) 
o Outcome of the relapse(s) 
o Whether the patient was hospitalized and/or admitted to the ICU for the relapse(s) 
o Acute treatment for the relapse(s) 
o Has the patient required acute relapse treatment with IV corticosteroids, plasma 
exchange, IVIg, or other therapies? 
• Since leaving Study ECU-NMO-302, has the patient experienced any NMOSD related 
hospitalizations? If yes, how many times? 
This information will not be entered into the trial Electronic Data Capture systems and will not 
be part of any safety or efficacy analysis that will be included in the ECU-NMO-302 clinical 
study report. 
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