Conditions: Neuromyelitis Optica and Neuromyelitis Optica Spectrum Disorders
Keywords: NMO, NMOSD, Neuromyelitis Optica, Neuromyelitis Optica Spectrum Disorders, autoimmune, demyelination, MEDI-551, monoclonal antibody, Devic's syndrome, B-cell
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 231
Healthy volunteers: no

Brief summary:
To compare the efficacy of inebilizumab (MEDI-551) versus placebo in reducing the risk of an neuromyelitis optica/neuromyelitis optica- spectrum disorders (NMO/NMOSD) attack in participants with NMO/NMOSD.

Detailed description:
Inebilizumab is a genetically engineered humanized monoclonal antibody that binds to the B cell specific surface antigen cluster of differentiation (CD19) resulting in the depletion of B cells. Inebilizumab depletes antibody-secreting plasmablasts and some plasma cells, which are generally CD19 positive and CD20 negative.

The main objective of this study is to determine whether inebilizumab compare to placebo decreases the risk of an attack in participants with NMO/NMOSD.

This is a multicenter, multinational, randomized, double-masked, placebo controlled study with an open-label extension period to evaluate the efficacy and safety of intravenous (IV) inebilizumab in adult participants with NMO/NMOSD. After a screening period, eligible participants will enter a randomized-controlled period (RCP) of maximum 197 days where they will be randomized in a 3:1 ratio to receive either IV inebilizumab or placebo. NMO/NMOSD attacks will be evaluated by the investigator and confirmed against the attack criteria by an independent Adjudication Committee (AC). Participants for whom the attack was confirmed by the AC will be given the option to enroll into an open label period (OLP) with inebilizumab treatment. Participants who complete the RCP without experiencing an attack will be given the option to enroll into an OLP with inebilizumab treatment. The OLP will continue for a minimum of 1 year and a maximum of 3 years after the last participant enter the OLP. All participants who discontinue from the RCP or the OLP will continue in a Safety Follow-up for a total of 12 months from last dose to evaluate the long-term safety of the investigational product.

Arms:
arm 1: Aquaporin-4-antibody (AQP4-IgG) sero positive and sero negative participants will receive IV dose of placebo matched to inebilizumab on Day 1 and Day 15 of the RCP. The participants who enter OLP will receive IV inebilizumab 300 mg on both Day 1 and Day 15, followed by a single IV dose of inebilizumab 300 mg every 6 months until maximum of 3 years after the last participant enters the OLP. Participants will have choice to enter in the SFP at any point during RCP or OLP and will be free to pursue other treatment options otherwise prohibited during the RCP and OLP. Participants will continue in the SFP for 12 months from last dose of study drug. arm 2: AQP4-IgG sero positive and sero negative participants will IV dose of inebilizumab 300 mg on Day 1 and Day 15 of RCP. The participants who enter OLP will receive IV inebilizumab 300 mg on Day 1 and matching placebo on Day 15, followed by a single IV dose of inebilizumab 300 mg every 6 months until maximum of 3 years after the last participant enters the OLP. Participants will have choice to enter in the SFP at any point during RCP or OLP and will be free to pursue other treatment options otherwise prohibited during the RCP and OLP. Participants will continue in the SFP for 12 months from last dose of study drug.

Interventions: intervention 1: Inebilizumab intervention 2: Placebo
Intervention descriptions: intervention 1: Participants will receive IV inebilizumab 300 mg. intervention 2: Participants will receive IV placebo matched to inebilizumab.

Protocol document:
Prot_000.pdf: 
MedImmune 
Protocol CD-IA-MEDI-551-1155 Amendment 6 
MEDI-551 
11Oct2018; Final 
CONFIDENTIAL AND PROPRIETARY 
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A Double-masked, Placebo-controlled Study with Open-label 
Period to Evaluate the Efficacy and Safety of MEDI-551 in Adult 
Subjects with Neuromyelitis Optica and Neuromyelitis Optica 
Spectrum Disorders 
 
Sponsor Protocol Number: CD-IA-MEDI-551-1155 
Application Number: 
IND 117295 
 
EudraCT number: 2014-000253-36 
Investigational Product: 
MEDI-551 
Phase: 
2/3 
Sponsor: 
MedImmune, LLC, a wholly owned subsidiary of 
AstraZeneca PLC, One MedImmune Way, Gaithersburg, 
Maryland, 20878, USA 
Medical Monitor: 
, 
 
, Clinical Development, Viela Bio, Inc. 
Phone: 
; Fax: 
 
Protocol History, Date: 
Original Protocol, 13Jan2014  
 
 
 
 
 
 
 
 
Amendment 1, 01Jul2014 
 
 
 
 
 
 
 
 
Administrative Change 1, 18Feb2015 
 
 
 
 
 
 
 
 
Amendment 2, 10Dec2015 
 
 
 
 
 
 
 
 
Amendment 3, 18Oct2016 
 
 
 
 
 
 
 
 
Amendment 4, 08Mar2017 
 
 
 
 
 
 
 
 
Amendment 5, 16Jul2018 
Amendment 6, 11Oct2018 
 
 
 
 
 
PPD
PPD
PPD
PPD
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Protocol Synopsis 
TITLE  
A Double-masked, Placebo-controlled Study with Open-label Period to Evaluate the Efficacy and Safety of 
MEDI-551 in Adult Subjects with Neuromyelitis Optica and Neuromyelitis Optica Spectrum Disorders    
HYPOTHESES 
The primary hypothesis for this study is that by depleting cluster of differentiation (CD)19+ B cells including 
plasmablasts and plasma cells, MEDI-551 is effective in reducing the risk of neuromyelitis 
optica/neuromyelitis optica- spectrum disorders (NMO/NMOSD) attack compared to placebo, thus 
effectively reducing the risk of irreversible disability caused by such attacks.  
Secondary Hypotheses:  
• 
Depletion of CD19+ B cells by MEDI-551 reduces worsening in Kurtzke Expanded Disability Severity 
Scale (EDSS) and decreases the loss of low-contrast visual acuity in adult subjects with 
NMO/NMOSD. 
• 
Depletion of CD19+ B cells by MEDI-551 reduces NMO/NMOSD-related in-patient hospitalizations. 
• 
Depletion of CD19+ B cells by MEDI-551 reduces the cumulative number of active lesions found on 
magnetic resonance imaging (MRI).  
OBJECTIVES:   
Primary Objective: To compare the efficacy of MEDI-551 versus placebo in reducing the risk of an 
NMO/NMOSD attack in subjects with NMO/NMOSD. 
Secondary Objectives: 
1. 
To compare the efficacy of MEDI-551 versus placebo on the reduction of EDSS worsening in subjects 
with NMO/NMOSD. 
2. 
To compare the efficacy of MEDI-551 versus placebo on the change from baseline of low-contrast 
visual acuity score in subjects with NMO/NMOSD. 
3. 
To compare the efficacy of MEDI-551 versus placebo in reducing the cumulative active MRI lesion 
count (new gadolinium [Gd]-enhancing or new/enlarging T2). 
4. 
To compare the efficacy of MEDI-551 versus placebo in reducing NMO/NMOSD-related in-patient 
hospitalizations in subjects with NMO/NMOSD. 
5. 
To characterize the long-term efficacy of MEDI-551 by means of annualized attack rate. 
6. 
To evaluate the safety and tolerability of a single course of MEDI-551 in subjects with NMO/NMOSD 
in the Randomized-controlled Period (RCP) and repeated doses of MEDI-551 in the Open Label Period 
(OLP). 
7. 
To characterize the pharmacokinetic (PK) profile and immunogenicity of MEDI-551 in NMO/NMOSD 
subjects. 
Exploratory Objectives: 
1. 
To compare the effect of MEDI-551 versus placebo on health-related quality of life (HRQoL) as 
measured by the 4-week recall Short Form-36 (SF-36) Health Survey physical component score (PCS) 
and mental component score (MCS) in NMO/NMOSD subjects. 
2. 
To compare the effect of MEDI-551 versus placebo on pain as measured using the pain numeric rating 
scale (NRS). 
3. 
To characterize the pharmacodynamic (PD) profile (B cells and plasma cell signature) of MEDI-551 in 
NMO/NMOSD subjects.  


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4. 
To compare the effect of MEDI-551 versus placebo on aquaporin-4-antibody (AQP4-IgG) titer. 
5. 
To compare the effect of MEDI-551 versus placebo on soluble biomarkers (eg, cytokines, chemokines, 
and immunoglobulins) and genomic (ribonucleic acid [RNA; microRNA]) biomarkers and other 
relevant cells (eg, T cells, astrocytes) in NMO/NMOSD subjects. 
STUDY ENDPOINTS 
Primary Endpoint: The primary endpoint is the time (days) from Day 1 to onset of an Adjudication 
Committee (AC)-determined NMO/NMOSD attack on or before Day 197. The definition of an 
NMO/NMOSD attack is the presence of a new symptom(s) or worsening of an existing symptom(s) related 
to NMO/NMOSD that meets at least ONE of the protocol-defined criteria for an NMO/NMOSD attack.  
Secondary Endpoints: 
Endpoints 1, 2, 3, and 4 are key secondary endpoints to be considered for studywise Type I error control. 
1. 
Worsening from baseline in EDSS at last visit during the RCP. 
2. 
Change from baseline in low-contrast visual acuity binocular score measured by low-contrast Landolt C 
Broken Rings Chart, at last visit during RCP. 
3. 
Cumulative total active MRI lesions (new Gd-enhancing or new/enlarging T2) during the RCP. 
4. 
Number of NMO/NMOSD-related in-patient hospitalizations. In-patient hospitalization is defined as 
more than an overnight stay. 
5. 
Annualized attack rate (total number of AC-determined NMO/NMOSD attacks normalized by 
personyears-) during any exposure to MEDI-551.  
6. 
Treatment-emergent adverse events (TEAEs), including treatment-emergent serious adverse events 
(TESAEs). Laboratory measurements as well as their changes or shift from baseline over time. 
7. 
Pharmacokinetic profile of MEDI-551. 
8. 
Incidence of anti-drug antibodies (ADAs) directed against MEDI-551 for the duration of the study, both 
predose and postdose for each subject.
Exploratory Endpoints: 
1. 
Change from baseline in the 4-week recall SF-36 PCS and MCS at the last visit during the RCP.  
2. 
Change from baseline in pain NRS in 5 locations at the last visit during the RCP. 
3. 
B-cell counts (total and subsets). 
4. 
Change from baseline in plasma cell gene signature. 
5. 
Serum AQP4-IgG titers. 
STUDY DESIGN 
This is a multicenter, multinational, randomized, double-masked, placebo-controlled- study with an open-
label extension period to evaluate the efficacy and safety of intravenous (IV) MEDI-551 in adult subjects 
with AQP4-IgG seropositive and seronegative NMO and NMOSD. Enrollment of subjects into the study will 
stop when a total of 67 AC-determined NMOSD attacks have occurred, when 252 subjects have been 
randomized and dosed, or following a recommendation by the independent Data Monitoring Committee 
(DMC) to stop enrollment, whichever occurs first. Following a screening period of up to 28 days, subjects 
will be randomized in a 3:1 ratio to receive IV MEDI-551 (300 mg at Day 1 and 300 mg at Day 15) or 
placebo for a period of 197 days (RCP).  
Subjects who complete the RCP without experiencing an NMO/NMOSD attack will be given the option to 
enroll into an OLP and will initiate or continue treatment with MEDI-551. Subjects who experience an AC-
determined NMO/NMOSD attack during the RCP will be given the option to enroll- into the OLP following 


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rescue therapy. Subjects for whom the NMO/NMOSD attack is not determined by the AC will continue in 
the RCP until Day 197 (or until another attack occurs that is determined by the AC). 
The OLP will continue for a minimum of 1 year and a maximum of 3 years after the last subject enters the 
OLP, or until regulatory approval for MEDI-551 as treatment for NMO in the participating country, or until 
the Sponsor discontinues development of MEDI-551 in this indication, whichever occurs first. Subjects can 
choose to exit the OLP at any time for any reason, including seeking alternative treatment options, at which 
point they will enter the Safety Follow-up Period (SFP; unless consent is withdrawn). 
All subjects will continue in the SFP for a total of 12 months from last dose to evaluate the long-term safety 
of the investigational product. 
Screening Period 
Subjects with the diagnosis of NMO/NMOSD will be screened over a 28-day period to establish their 
eligibility to participate in the study based on the inclusion and exclusion criteria. AQP4-IgG serostatus will 
be determined by the central laboratory. For subjects who are found to be AQP4-IgG negative in the 
screening period, relevant data documenting their NMO disease will be assessed by an independent 
Eligibility Committee to ensure that the data are consistent with the diagnosis of NMO. All subjects who 
fulfill eligibility criteria will then be randomized into the study.  
Subjects undergoing screening at the time when the 252nd subject is randomized and dosed, subjects in 
screening at the time the 67th AC-determined attack is confirmed, or subjects undergoing screening at the 
time enrollment is terminated for any other reason, will not be randomized. 
Randomization (Day 1) 
Two hundred and fifty-two subjects will be randomized into the study in a 3:1 ratio to receive IV MEDI-551 
or placebo as described below. Randomization will occur on Day 1 and will be stratified by AQP4-IgG 
serostatus (in a ratio of approximately 80:20 seropositive and seronegative subjects, respectively) and by 
region (Japan vs non-Japan). 
Randomized-controlled Period (Day 1 to Day 197) 
Following randomization on Day 1, subjects will be treated with MEDI-551 or placebo on Day 1 and Day 
15. An oral corticosteroid course will be initiated on Day 1 (prednisone 20 mg/day or equivalent oral
glucocorticoid) and continue until Day 14. Tapering the oral corticosteroids will occur from Day 15 to Day
21. By Day 21, tapering must be completed.
The planned duration of the RCP for each subject will be 197 days. All subjects who complete the RCP
without experiencing an NMO/NMOSD attack will be given the option to enter the OLP. Subjects who are in
the RCP when a total of 67 AC-determined NMOSD attacks have occurred or subjects who are in the RCP
when enrollment is discontinued upon recommendation of the independent DMC based on evidence of
efficacy and safety, will discontinue the RCP as soon as possible, preferably within 14 days, and be given the
option to enter the OLP.
Subjects will be monitored for new or worsening symptoms related to NMO/NMOSD during scheduled
study visits and with follow-up phone calls every 2 weeks between study visits (or if a scheduled visit is
missed).
When a possible new or worsening symptom(s) related to NMO/NMOSD is identified, subjects will be
required to inform the site. If an Assessment Visit is deemed necessary, this must be scheduled as soon as
possible but within 72 hours of reporting of the symptom to the site. At the Assessment Visit, subjects will
initially undergo evaluations to determine if the symptoms are related to NMO/NMOSD; if related, the
subjects will undergo further evaluations to determine if the symptoms meet at least ONE of the protocol-
defined criteria for an NMO/NMOSD attack. In cases where a new or worsening symptom(s) does not meet
at least one of the protocol-defined criteria for an NMO/NMOSD attack, the subject will continue in the
RCP.


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Assessment of new symptoms or worsening of existing symptoms should be completed within 5 days to 
determine if an attack has occurred. Treatment of an attack should preferably be initiated after completion of 
the attack assessment and the determination that the protocol attack criteria have been met. However, the 
Principal Investigator can initiate rescue therapy at any time before full assessment is completed. Rescue 
therapy will be given as directed by the investigator. This may include IV corticosteroids, intravenous 
immunoglobulin (IVIG), and/or plasma exchange (PLEX). 
Upon completion of the Assessment Visit, the complete set of data generated from the assessments will be 
sent to the AC regardless of whether an NMO/NMOSD attack was diagnosed according to the protocol 
criteria by the Principal Investigator. The adjudication process will be completed within 14 days (+ 3 days) 
from initiation of the Assessment Visit and the AC determination will be communicated to the Principal 
Investigator.  
Subjects for whom the diagnosis of an NMO/NMOSD attack is not determined by the AC will be given the 
option to continue in the RCP until Day 197. Subjects for whom the diagnosis of an NMO/NMOSD attack is 
determined by the AC will be given the option to enter the OLP. In addition, subjects who experience an 
NMO/NMOSD attack that requires rescue treatment and meets the protocol-defined criteria, regardless of the 
outcome of the AC review, will undergo an Attack Follow-up Visit 28 days from Day 1 of the Assessment 
Visit. This visit may correspond with an OLP or SFP visit or may be scheduled separately. 
If subjects do not wish to enter the OLP or wish to leave the RCP at any point, they will continue to the SFP 
(unless consent is withdrawn). 
Enrollment of subjects into the study will stop when a total of 67 AC-determined NMOSD attacks have 
occurred, when 252 subjects have been randomized and dosed, or following a recommendation by the 
independent Data Monitoring Committee (DMC) to stop enrollment, whichever occurs first. 
Open-label Period 
Subjects will be given the option to enter the OLP if they 1) complete 197 days of the RCP, or 2) experience 
an AC-determined NMO/NMOSD attack during the RCP, 3) are in the RCP at the time that 67 AC-
determined attacks have occurred, or 4) are in the RCP at the time the Sponsor discontinues enrollment upon 
recommendation of the independent DMC based on evidence of efficacy and safety. 
Subjects who discontinue the RCP for reasons other than one of these four mentioned above will not be 
eligible for the OLP. Reasons for subjects not entering the OLP will be captured. These subjects will be 
followed for safety in the SFP. 
The first day of the OLP will be Day 1 (OLP Day 1). Upon entering the OLP, subjects will receive 
MEDI-551. During the OLP, subjects will be followed at scheduled study visits and will continue on 
MEDI-551 therapy. The OLP will continue for minimum of 1 year and a maximum of 3 years (after the last 
subject enters), or until regulatory approval for MEDI-551 in the participating country, or until the Sponsor 
discontinues development of MEDI-551 in this indication, whichever occurs first. Subjects can choose to 
exit the OLP at any time for any reason, including seeking alternative treatment options, at which point they 
will enter the SFP (unless consent is withdrawn). 
Subjects will be followed for NMO/NMOSD attacks in the same fashion as in the RCP and events will be 
centrally adjudicated. 
Safety Follow-up Period 
The SFP will start when a subject prematurely discontinues from the RCP or OLP. The length of the SFP 
will be determined by the time elapsed from the time of the last dose of the investigational product to the 
time of the premature discontinuation, to complete a total of 52 weeks.  During the SFP, the subject will be 
monitored for adverse events/serious adverse events, B-cell levels, ADAs, and immunoglobulin levels. 
During the SFP, a subject may receive standard treatment for their NMO/NMOSD at the discretion of the 
investigator.  


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TARGET SUBJECT POPULATION 
The subjects in this study will be adult women and men (aged 18 years and above) with a diagnosis of NMO 
or NMOSD at the time of screening and a documented history of 1 or more NMO/NMOSD acute relapses 
that required rescue therapy within the last year or 2 or more NMO/NMOSD acute relapses that required 
rescue therapy within the 2 years prior to screening. Both AQP4-IgG seropositive and seronegative subjects 
will be enrolled in the study to fully capture the entire spectrum of this potentially fatal and rare 
demyelinating neurological disease. 
INVESTIGATIONAL PRODUCT, DOSAGE, AND MODE OF ADMINISTRATION 
Randomized-controlled Period 
• 
Treatment Arm 1: 300 mg IV MEDI-551 on Day 1 and Day 15 
• 
Treatment Arm 2: IV Placebo on Day 1 and Day 15 
Additionally, all subjects entering the RCP will be treated for 2 weeks (Day 1 to Day 14) with oral 
corticosteroids (prednisone 20 mg/day or equivalent oral glucocorticoid). A tapering schedule will be 
implemented from Day 15 to Day 21.  
Open-label Period 
Subjects randomized to Treatment Arm 1 during the RCP will receive:  
• 
300 mg IV MEDI-551 on OLP Day 1, masked IV placebo on OLP Day 15, then 300 mg IV MEDI-551 
every 26 weeks (Q26W) thereafter 
Subjects randomized to Treatment Arm 2 during the RCP will receive:  
• 
300 mg IV MEDI-551 on OLP Day 1, masked 300 mg IV MEDI-551 on OLP Day 15, then 300 mg IV 
MEDI-551 Q26W thereafter 
Dosing of subjects enrolling into the OLP following an adjudicated NMO/NMOSD attack, following the 
occurrence of the 67th adjudicated NMO/NMOSD attack, or following termination of enrollment upon 
recommendation of the independent DMC based on evidence of efficacy and safety, will follow the OLP 
dosing regimen described above. 
For both the RCP and the OLP, investigational product will be administered as a 90-minute IV infusion via 
an infusion pump. All subjects will be premedicated on Day 1 and Day 15 (OLP Day 1 and OLP Day 15) 
and at subsequent dosing visits with IV methylprednisolone (100 mg or equivalent glucocorticoid), oral (PO) 
diphenhydramine (25-50 mg or equivalent antihistamine), and PO paracetamol (acetaminophen; 500-650 
mg) prophylactically to prevent infusion reactions. 
STATISTICAL ANALYSIS PLAN: 
The primary analysis of time to onset of AC-determined attack employs a sequential testing procedure that 
initially compares treatment groups within AQP4-IgG seropositive subjects, and if statistically significant 
(two-sided α = 0.05), further compares treatment groups (two-sided α = 0.05) within the broader Intent-to-
Treat (ITT) population, defined as all subjects who are randomized and receive at least one dose of 
investigational product. Furthermore, these analyses will analyze subjects according to the initial 
randomization regardless of actual treatment received. The treatment effect in the seropositive cohort will be 
assessed using the Cox proportional hazards model with treatment indicator (MEDI-551 or placebo) as an 
explanatory factor; whereas for the ITT population, the model will also include serostatus as an additional 
explanatory factor. Subjects who complete Day 197 of the RCP or discontinue the study before Day 197 for 
reasons other than an AC-determined- NMO/NMOSD attack will be censored in this model at the time of the 
Day 197/discontinuation visit. An evaluation of consistency of treatment effect in Japanese subjects with that 
observed in the global study will be determined. The data cutoff for the primary analysis will be when the 
last subject completes the discontinuation visit following the 67th AC-determined attack, after all subjects 
complete the RCP if 67 AC-determined attacks do not occur, or when the last subject completes the 
discontinuation visit following discontinuation of enrollment upon recommendation of the independent DMC 


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based on evidence of efficacy and safety. Subjects who are in the RCP when a total of 67 AC-determined 
NMOSD attacks have occurred, or when enrollment is discontinued upon recommendation of the 
independent DMC based on evidence of efficacy and safety, will discontinue the RCP as soon as possible, 
preferably within 14 days.  
Control of Type I Error 
The study is designed to strongly control the overall Type I error rate of α = 0.05. The primary null 
hypothesis will be hierarchically tested first at α = 0.05 in the seropositive cohort, and if significant, it will be 
further tested in the ITT population at α = 0.05. If, and only if, the treatment group comparison is statistically 
significant within the ITT population, the secondary hypotheses will be tested. Null hypotheses for the 4 key 
secondary endpoints will follow the same sequential testing strategy as the primary analysis (testing within 
seropositive subjects first, followed by the ITT population if the comparison within seropositive subjects is 
statistically significant). Each secondary hypothesis will be initially tested based on the Bonferroni method at 
two-sided α=0.05/4 = 0.0125. If the null hypothesis for a particular secondary endpoint is rejected across 
both seropositive and ITT populations, the Type I error saved will be propagated equally to other non-
rejected secondary null hypotheses. The testing procedure will be repeated until all null hypotheses are 
rejected or no further null hypothesis can be rejected. 
The safety data will be presented using the as-treated population, which will include all subjects who receive 
any investigational product analyzed according to treatment received. Specifically, subjects randomized to 
MEDI-551 who received all placebo doses will be included in the placebo group for safety analyses; 
conversely, subjects who received at least one dose of MEDI-551 will be included in the active treatment 
group for safety analyses. Efficacy and safety data from the OLP will be presented based on subjects who 
receive at least one dose during the OLP. Unless otherwise specified, all statistical inference will be 
performed at a significance level of two-sided D ൌͲǤͲͷǤ 
Sample Size and Power Calculations 
The current study is being planned to detect a target relative reduction of 60% in risk for time from Day 1 to 
onset of AC-determined NMO/NMOSD attack on or before Day 197 with at least 90% power and α = 0.05 
(two-sided). A total of 67 AC-determined NMO/NMOSD attacks are required for the ITT population. 
Subjects will be randomized in a 3:1 ratio to receive either MEDI-551 or placebo within both AQP4-IgG 
seropositive and seronegative strata. The stratification ratio is anticipated to be approximately 80:20 with 
higher allocation to the seropositive cohort. If the seropositive cohort has 80% of the attacks, the study will 
have approximately 82% power to detect the target relative reduction of 60%. 
Two hundred and fifty-two subjects will be randomized and dosed. This sample size is based on a blinded 
review of the attack rate for the first 78 subjects to complete the RCP and a simulation based on these 
subjects that indicates a > 90% probability of achieving the required 67 AC-determined attacks with 252 
subjects.  
Within each AQP4-IgG stratum, randomization will also be stratified by region (Japan versus non-Japan). 
The number of Japanese subjects will be determined primarily by feasibility and will not depend on a 
minimum number of NMO/NMOSD attacks to be observed from Japanese subjects. The study may conclude 
enrollment regardless of the number of subjects in Japan versus non-Japan regions. 
Interim Analysis 
An unmasked interim analysis will be conducted for futility assessment by an independent Data Monitoring 
Committee when approximately 34 AC-determined NMO/NMOSD attacks occur in this study. The study 
may be declared as “futile” if calculated predictive power at interim is < 20%.  
 


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TABLE OF CONTENTS 
1 
INTRODUCTION ................................................................................................ 18 
1.1 
Disease Background ............................................................................................. 18 
1.2 
MEDI-551 Background ........................................................................................ 19 
1.3 
Summary of Nonclinical Experience .................................................................... 20 
1.4 
Summary of Clinical Experience .......................................................................... 21 
1.5 
Rationale for Study ............................................................................................... 22 
1.6 
Research Hypotheses ............................................................................................ 23 
1.6.1 
Primary Hypothesis .............................................................................................. 23 
1.6.2 
Secondary Hypotheses .......................................................................................... 23 
2 
OBJECTIVES ....................................................................................................... 23 
2.1 
Objectives ............................................................................................................. 23 
2.1.1 
Primary Objective ................................................................................................. 23 
2.1.2 
Secondary Objectives ........................................................................................... 23 
2.1.3 
Exploratory Objectives ......................................................................................... 24 
2.2 
Study Endpoints .................................................................................................... 24 
2.2.1 
Primary Endpoint .................................................................................................. 24 
2.2.2 
Secondary Endpoints ............................................................................................ 24 
2.2.3 
Exploratory Endpoint(s) ....................................................................................... 25 
3 
STUDY DESIGN ................................................................................................. 25 
3.1 
Description of the Study ....................................................................................... 25 
3.1.1 
Overview………................................................................................................... 25 
3.1.1.1 
Screening Period ................................................................................................... 28 
3.1.1.2 
Randomization (Day 1)......................................................................................... 28 
3.1.1.3 
Randomized-controlled Period (Day 1 to Day 197) ............................................. 28 
3.1.1.4 
Open-label Period ................................................................................................. 30 
3.1.1.5 
Safety Follow-up Period ....................................................................................... 30 
3.1.2 
Treatment Regimen .............................................................................................. 30 
3.1.3 
Management of Study Medication Related Toxicities ......................................... 32 
3.2 
Study Design and Dose Rationale ........................................................................ 35 
3.2.1 
Study Design Rationale ........................................................................................ 35 
3.2.2 
Dose Rationale ...................................................................................................... 36 
3.2.3 
Rationale for Study Population ............................................................................. 37 
3.2.4 
Rationale for Endpoints ........................................................................................ 39 
3.2.4.1 
Primary Endpoint .................................................................................................. 39 
3.2.4.2 
Secondary Endpoints ............................................................................................ 39 
3.2.4.3 
Exploratory Endpoints .......................................................................................... 41 
3.2.4.4 
Exploratory Investigations .................................................................................... 43 
4 
MATERIALS AND METHODS ......................................................................... 43 
4.1 
Subjects ................................................................................................................. 43 
4.1.1 
Number of Subjects .............................................................................................. 43 
4.1.2 
Inclusion Criteria .................................................................................................. 44 


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4.1.3 
Exclusion Criteria ................................................................................................. 46 
4.1.4 
Subject Enrollment and Randomization ............................................................... 49 
4.1.4.1 
Enrollment ............................................................................................................ 49 
4.1.4.2 
Randomization Process ......................................................................................... 50 
4.1.5 
Withdrawal from the Study .................................................................................. 50 
4.1.6 
Discontinuation of Investigational Product .......................................................... 50 
4.1.7 
Replacement of Subjects....................................................................................... 51 
4.1.8 
Withdrawal of Informed Consent for Donated Biological Samples ..................... 51 
4.2 
Schedule of Study Procedures .............................................................................. 52 
4.2.1 
Enrollment/Screening Period ................................................................................ 52 
4.2.1.1 
Eligibility Committee ........................................................................................... 55 
4.2.2 
Treatment Period .................................................................................................. 55 
4.2.2.1 
Randomized-controlled Treatment Period ............................................................ 55 
4.2.2.2 
Open-label Period ................................................................................................. 59 
4.2.3 
Study Procedures for Assessment Visit ................................................................ 64 
4.2.4 
Managing Subjects With Worsening Attacks ....................................................... 67 
4.2.5 
Study Procedures for Attack Follow-up Visit ...................................................... 67 
4.2.6 
Safety Follow-up Period ....................................................................................... 68 
4.3 
Description of Study Procedures .......................................................................... 69 
4.3.1 
Efficacy………. .................................................................................................... 69 
4.3.1.1 
Identification, Assessment, and Adjudication of an NMO/NMOSD Attack........ 69 
4.3.1.2 
Neuroaxis Magnetic Resonance Imaging Scan .................................................... 79 
4.3.1.3 
Independent Ophthalmology Assessments ........................................................... 80 
4.3.1.4 
Expanded Disability Status Scale and Functional Systems Scores ...................... 84 
4.3.1.5 
Independent Adjudication Committee .................................................................. 84 
4.3.1.6 
Healthcare Resource Utilization ........................................................................... 85 
4.3.2 
Patient-reported Outcomes ................................................................................... 86 
4.3.2.1 
Pain NRS .............................................................................................................. 86 
4.3.2.2 
Short Form-36 Health Survey ............................................................................... 87 
4.3.2.3 
Collection of PRO Endpoints ............................................................................... 87 
4.3.3 
Medical History and Physical Examination, Electrocardiogram, Weight, Vital 
Signs, and Chest X-ray ......................................................................................... 87 
4.3.3.1 
Medical History .................................................................................................... 87 
4.3.3.2 
Physical and Neurological Examination ............................................................... 88 
4.3.3.3 
Body Weight and Height ...................................................................................... 88 
4.3.3.4 
Electrocardiogram................................................................................................. 88 
4.3.3.5 
Vital Signs ............................................................................................................ 89 
4.3.3.6 
Chest X-ray ........................................................................................................... 89 
4.3.4 
Columbia-Suicide Severity Rating Scale.............................................................. 89 
4.3.5 
Modified Rankin Scale ......................................................................................... 90 
4.3.6 
Clinical Laboratory Tests ..................................................................................... 91 
4.3.7 
Pharmacokinetic Evaluation and Methods ........................................................... 93 
4.3.8 
Immunogenicity Evaluation and Methods ............................................................ 93 
4.3.9 
Biomarker Evaluations and Methods.................................................................... 93 
4.3.9.1 
Exploratory Investigations .................................................................................... 94 
4.3.10 
Estimate of Volume of Blood to Be Collected ..................................................... 95 


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4.4 
Study Suspension or Termination ......................................................................... 96 
4.5 
Investigational Products........................................................................................ 97 
4.5.1 
Identity of Investigational Product(s) ................................................................... 97 
4.5.1.1 
Investigational Product Dose Preparation ............................................................ 98 
4.5.1.2 
Treatment Administration ................................................................................... 100 
4.5.1.3 
Monitoring of Dose Administration ................................................................... 103 
4.5.1.4 
Reporting Product Complaints ........................................................................... 103 
4.5.2 
Additional Study Medications ............................................................................ 104 
4.5.2.1 
Oral Corticosteroid Use ...................................................................................... 104 
4.5.2.2 
Rescue Medications ............................................................................................ 104 
4.5.3 
Dose Adjustments and Missed Doses ................................................................. 105 
4.5.4 
Labeling………. ................................................................................................. 105 
4.5.5 
Storage………. ................................................................................................... 105 
4.5.6 
Treatment Compliance........................................................................................ 105 
4.5.7 
Accountability..................................................................................................... 105 
4.6 
Treatment Assignment and Masking .................................................................. 106 
4.6.1 
Methods for Assigning Treatment Groups ......................................................... 106 
4.6.2 
Methods for Ensuring Masking .......................................................................... 106 
4.6.3 
Methods for Reducing Bias ................................................................................ 106 
4.6.4 
Methods for Unmasking ..................................................................................... 107 
4.6.4.1 
Unmasking in the Event of a Medical Emergency ............................................. 108 
4.6.4.2 
Unmasking for Interim Analysis Purposes ......................................................... 108 
4.6.4.3 
Unmasking due to Known or Hypothesized Effects of MEDI-551 .................... 108 
4.7 
Restrictions During the Study and Concomitant Treatment(s)........................... 109 
4.7.1 
Permitted Concomitant Medications .................................................................. 109 
4.7.1.1 
Immunosuppressive Medications During the Screening Period ......................... 109 
4.7.2 
Prohibited Concomitant Medications ................................................................. 110 
4.8 
Statistical Evaluation .......................................................................................... 111 
4.8.1 
General Considerations ....................................................................................... 111 
4.8.2 
Sample Size and Power Calculations ................................................................. 111 
4.8.3 
Efficacy ............................................................................................................... 112 
4.8.3.1 
Primary Efficacy Analysis .................................................................................. 112 
4.8.3.2 
Additional Analyses of the Primary Endpoint .................................................... 113 
4.8.3.3 
Secondary Efficacy Analyses ............................................................................. 114 
4.8.3.4 
Subgroup Analyses ............................................................................................. 114 
4.8.4 
Safety………. ..................................................................................................... 114 
4.8.4.1 
Analysis of Adverse Events ................................................................................ 114 
4.8.4.2 
Analysis of Clinical Laboratory Parameters, Physical Examination Findings, 
and Vital Sign Measurements ............................................................................. 115 
4.8.5 
Patient-reported Outcomes ................................................................................. 115 
4.8.5.1 
Short Form-36 Health Survey ............................................................................. 115 
4.8.5.2 
Pain NRS ............................................................................................................ 115 
4.8.6 
Analysis of Immunogenicity, Pharmacokinetics, and Exploratory Biomarkers . 115 
4.8.6.1 
Analysis of Immunogenicity............................................................................... 115 
4.8.6.2 
Analysis of Pharmacokinetics............................................................................. 115 
4.8.6.3 
Analysis of Exploratory Biomarkers .................................................................. 116 


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4.8.7 
Additional Analyses............................................................................................ 116 
4.8.8 
Data Monitoring Committee ............................................................................... 116 
4.8.9 
Control of Type I Error ....................................................................................... 117 
4.8.10 
Interim Analysis for Futility ............................................................................... 117 
5 
ASSESSMENT OF SAFETY............................................................................. 117 
5.1 
Definition of Adverse Events ............................................................................. 117 
5.2 
Definition of Serious Adverse Events ................................................................ 118 
5.3 
Definition of Adverse Events of Special Interest ............................................... 119 
5.4 
Recording of Adverse Events ............................................................................. 119 
5.4.1 
Time Period for Collection of Adverse Events................................................... 120 
5.4.2 
Follow-up of Unresolved Adverse Events .......................................................... 120 
5.5 
Reporting of Serious Adverse Events ................................................................. 120 
5.6 
Other Events Requiring Immediate Reporting ................................................... 121 
5.6.1 
Overdose………. ................................................................................................ 121 
5.6.2 
Hepatic Function Abnormality ........................................................................... 121 
5.6.3 
Progressive Multifocal Leukoencephalopathy ................................................... 122 
5.6.4 
Pregnancy………. .............................................................................................. 122 
6 
STUDY AND DATA MANAGEMENT ........................................................... 123 
6.1 
Training of Study Site Personnel ........................................................................ 123 
6.2 
Monitoring of the Study ..................................................................................... 123 
6.2.1 
Source Data ......................................................................................................... 124 
6.2.1.1 
Direct Access to Source Data ............................................................................. 124 
6.2.2 
Study Agreements ............................................................................................... 124 
6.2.3 
Archiving of Study Documents .......................................................................... 124 
6.3 
Study Timetable and End of Study ..................................................................... 125 
6.3.1 
Discontinuation or Suspension of the Study Program ........................................ 126 
6.3.2 
Completion of the Study ..................................................................................... 126 
6.4 
Data Management ............................................................................................... 126 
6.5 
Medical Monitor Coverage ................................................................................. 126 
7 
ETHICAL AND REGULATORY REQUIREMENTS ..................................... 127 
7.1 
Ethical Conduct of the Study .............................................................................. 127 
7.2 
Subject Data Protection ...................................................................................... 127 
7.3 
Ethics and Regulatory Review............................................................................ 127 
7.3.1 
Ethics and Regulatory Review in Japan ............................................................. 128 
7.4 
Informed Consent ............................................................................................... 128 
7.5 
Changes to the Protocol and Informed Consent Form........................................ 129 
7.5.1 
Deviation From the Clinical Study Protocol ...................................................... 129 
7.6 
Audits and Inspections ........................................................................................ 130 
8 
REFERENCES ................................................................................................... 131 
9 
CHANGES TO THE PROTOCOL .................................................................... 136 
 


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LIST OF IN-TEXT TABLES 
Table 1 
Randomized-controlled Period Treatment Regimen ................................... 31 
Table 2 
Open-label Period Treatment Regimen ....................................................... 31 
Table 3 
An Approach to Management of Anaphylactic, Hypersensitivity, and 
Infusion Reactions ....................................................................................... 33 
Table 4 
Highly Effective Methods of Contraception ............................................... 45 
Table 5 
Schedule of Screening Procedures .............................................................. 53 
Table 6 
Schedule of Randomized-controlled Treatment Period Study Procedures . 56 
Table 7 
Schedule of Open-label Period Study Procedures ...................................... 61 
Table 8 
Schedule of Study Procedures for the Assessment Visit ............................ 65 
Table 9 
Schedule of Study Procedures for the Attack Follow-up Visit ................... 67 
Table 10 
Schedule of Procedures for Safety Follow-up Period ................................. 68 
Table 11 
Protocol-defined Criteria for an NMO/NMOSD Attack ............................. 73 
Table 12 
Pupil Response Scoring Criteria for Relative Afferent Pupillary Defect ... 83 
Table 13 
Healthcare Resource Utilization Information to be Collected and 
Frequency .................................................................................................... 86 
Table 14 
Estimate of Blood Volume to Be Collected ................................................ 95 
Table 15 
Identification of Investigational Products ................................................... 98 
Table 16 
Infusion Times for IV Administration of MEDI-551 300 mg or Placebo 102 
Table 17 
Open-label Cohort Studies in Neuromyelitis Optica ................................ 202 
Table 18 
Estimated Pretreatment Hazard Rate for Time to Relapse ........................ 202 
Table 19 
Calculated Yearly Constant Hazard Rate Based on Relapse-free Subjects 
in First 12 Months of Treatment ............................................................... 206 
Table 20 
Relative Reduction in Risk of Relapse Based on Calculated Hazard Rate 
From Azathioprine and Rituximab NMO Studies .................................... 207 
Table 21 
List of Null Hypotheses Considered Under Multiplicity Adjustment 
Procedure ................................................................................................... 210 
Table 22 
Alpha Allocation Rule ............................................................................... 212 
Table 23 
Alpha Propagation Rule ............................................................................ 212 
 


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LIST OF IN-TEXT FIGURES 
Figure 1 
Study Flow Diagram ................................................................................... 27 
Figure 2 
PD Model Simulation Supporting Dosing Regimen ................................... 37 
Figure 3 
Flow Chart of Assessment and Diagnosis of an NMO/NMOSD Attack .... 69 
Figure 4 
Process for Assessing Symptoms Affecting the Eye .................................. 75 
Figure 5 
Process for Assessing Symptoms Affecting the Spinal Cord ..................... 76 
Figure 6 
Process for Assessing Symptoms Affecting the Brain or Brainstem .......... 77 
Figure 7 
Neuromyelitis Optica Spectrum of Disorders Relapses Before and After 
Treatment with Azathioprine for 70 Patients with More Than 12 Months 
Follow Up .................................................................................................. 203 
Figure 8 
Attack Frequency Before, During, and After Eculizumab Treatment ...... 204 
Figure 9 
Relapses in Patients with Neuromyelitis Optica Before and After 
Treatment with Rituximab ........................................................................ 204 
Figure 10 
Disease Course of Patients Treated with Rituximab ................................. 205 
Figure 11 
Relapses in Patients with Neuromyelitis Optica Before and After 
Treatment with Rituximab ........................................................................ 206 
Figure 12 
Estimated Predictive Power Against Observed Interim Treatment Effect 
When 50% of AC-determined NMO/NMOSD Attacks are Available ..... 209 
Figure 13 
Multiplicity Adjustment Strategy .............................................................. 211 
 
LIST OF APPENDICES 
Appendix 1 
Signatures .................................................................................................. 167 
Appendix 2 
National Institute of Allergy and Infectious Diseases and Food Allergy 
and Anaphylaxis Network Guidance for Anaphylaxis Diagnosis ............. 170 
Appendix 3 
Additional Safety Guidance ...................................................................... 171 
Appendix 4 
Kurtzke Expanded Disability Status Scale and Functional Systems 
Scores ........................................................................................................ 173 
Appendix 5 
Pain NRS ................................................................................................... 184 
Appendix 6 
Short Form-36v2 ....................................................................................... 186 
Appendix 7 
Columbia-Suicide Severity Rating Scale:  Baseline/Screening Version .. 193 
Appendix 8 
Columbia-Suicide Severity Rating Scale: Since Last Visit Version ......... 197 
Appendix 9 
Sample Size Calculation ........................................................................... 201 
Appendix 10 
Details of Futility Analysis ....................................................................... 209 
Appendix 11 
Type I Error Control .................................................................................. 210 
Appendix 12 
Assessment and Collection of Adverse Events ......................................... 213 


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List of Abbreviations 
Abbreviation or 
Specialized Term 
Definition 
AC 
Adjudication Committee 
ADA 
anti-drug antibody 
ADCC 
antibody-dependent cellular cytotoxicity 
ADCP 
antibody-dependent cellular phagocytosis 
AE 
adverse event 
AESI 
adverse event of special interest 
ALT 
alanine transaminase 
AQP4 
aquaporin-4 
AQP4-IgG/NMO-IgG 
autoantibodies against aquaporin-4 
AST 
aspartate transaminase 
AZA 
azathioprine 
βHCG 
beta human chorionic gonadotropin 
BAFF 
B-cell activating factor
BCG 
Bacillus of Calmette and Guérin 
BP 
blood pressure 
CD 
cluster of differentiation 
CD19+ 
CD19 positive 
CD20+ 
CD20 positive 
CD20- 
CD20 negative 
CDC 
complement-dependent cytotoxicity 
CDER 
Center for Drug Evaluation and Research 
CF 
counting fingers 
CI 
confidence interval 
CNS 
central nervous system 
CSF 
cerebrospinal fluid 
C-SSRS
Columbia-Suicide Severity Rating Scale 
DEHP 
di(2-ethylhexyl) phthalate 
DMC 
Data Monitoring Committee 
DNA 
deoxyribonucleic acid 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EDSS 
(Kurtzke) Expanded Disability Status Scale 
EDV 
Early Discontinuation Visit 


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Abbreviation or 
Specialized Term 
Definition 
EFD 
embryo-fetal development 
ETDRS 
Early Treatment Diabetic Retinopathy Study 
EU 
European Union 
FAAN 
Food Allergy and Anaphylaxis Network 
FDA 
Food and Drug Administration 
FS 
Functional Systems 
FSS 
Functional Systems Scores  
FWER 
family wise error rate 
GCP 
Good Clinical Practice 
Gd 
gadolinium 
GFR 
glomerular filtration rate 
GMP 
Good Manufacturing Practice 
HbA1c 
glycosylated hemoglobin 
HBc 
hepatitis B core antigen 
HCRU 
Healthcare Resource Utilization 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
human immunodeficiency virus 
HM 
hand movement 
HR 
hazard ratio 
HRQoL 
health-related quality of life 
huCD19 TG 
human CD19 transgenic 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
Ig 
immunoglobulin 
IgA/E/G/M 
immunoglobulin A/E/G/M 
IgG1 
immunoglobulin G1 
IgG1κ 
immunoglobulin G1 kappa 
INR 
international normalized ratio 
IRB 
Institutional Review Board 
ITT 
Intent-to-Treat 
IV 
intravenous 
IVIG 
intravenous immunoglobulin 


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Abbreviation or 
Specialized Term 
Definition 
IVRS 
interactive voice response system 
IWRS 
interactive web response system 
JCV 
polyomavirus John Cunningham 
kDa 
kilodalton 
KM 
Kaplan-Meier 
LETM 
longitudinally extensive transverse myelitis 
LLN 
lower limit of normal 
LP 
light perception 
mAb 
monoclonal antibody 
MCS 
mental component score 
MedDRA 
Medical Dictionary for Regulatory Activities 
MHLW 
Ministry of Health, Labour, and Welfare (Japan) 
MMF 
mycophenolate mofetil 
MOG 
myelin-oligodendrocyte glycoprotein 
MRI 
magnetic resonance imaging 
mRNA 
messenger ribonucleic acid 
mRS 
Modified Rankin Scale 
MS 
multiple sclerosis 
MTD 
maximum tolerated dose 
NaCl 
sodium chloride 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events 
NIAID 
National Institute of Allergy and Infectious Diseases 
NK 
natural killer 
NLP 
no light perception 
NMO 
neuromyelitis optica 
NMOSD 
neuromyelitis optica spectrum disorders 
NOAEL 
no observed adverse effect level 
NRS 
numeric rating scale 
OCT 
optical coherence tomography 
OLP 
Open-label Period 
ON 
optic neuritis 
PCS 
physical component score 
PD 
pharmacodynamic 
PEF 
peak expiratory flow 


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Abbreviation or 
Specialized Term 
Definition 
PLEX 
plasmapheresis; plasma exchange  
PK 
pharmacokinetic 
PML 
progressive multifocal leukoencephalopathy 
PO 
oral 
PRO 
patient-reported outcome 
PVC 
polyvinyl chloride 
Q12W 
every 12 weeks 
Q26W 
every 26 weeks 
RAPD 
relative afferent pupillary defect 
RCP 
Randomized-controlled Period 
RNA 
ribonucleic acid 
RNFL 
retinal nerve fiber layer 
SAE 
serious adverse event 
SC 
subcutaneous 
SF-36 
Short Form-36 Health Survey 
SF-36v2 
Short Form-36 Health Survey, version 2 
SFP 
Safety Follow-up Period 
SID 
subject identification 
SSc 
systemic sclerosis 
SUSAR 
suspected unexpected serious adverse reactions 
TB 
tuberculosis 
TEAE 
treatment-emergent adverse event 
TESAE 
treatment-emergent serious adverse event 
TM 
transverse myelitis 
US FDA 
United States Food and Drug Administration 
ULN 
upper limit of normal 
USA 
United States of America 
w/v 
weight per volume 
 


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1 
INTRODUCTION 
1.1 
Disease Background 
Neuromyelitis optica (NMO; also known as Devic’s syndrome) is a rare, chronic, 
autoimmune, inflammatory, demyelinating disorder of the central nervous system (CNS) 
characterized by attacks of predominantly optic neuritis (ON) and longitudinally extensive 
transverse myelitis (LETM). Commonly reported symptoms include unilateral and bilateral 
loss of visual acuity, ocular pain, loss of sensation, severe paraplegia, bladder and bowel 
dysfunction, paroxysmal tonic spasms of the trunk and limbs, and Lhermitte’s phenomenon. 
Brain and brain stem involvement are rare but can occur, usually as an extension of a severe 
cervical myelitis, and may cause symptoms such as nausea, intractable vomiting, hiccups, and 
acute neurogenic respiratory failure (Wingerchuk et al, 1999; Misu et al, 2005). Up to 90% of 
patients with NMO have relapsing episodes of ON and myelitis rather than a monophasic 
course (Ghezzi et al 2004; Wingerchuk et al 1999). Relapses occur within 1 year of onset in 
60% of patients and within 3 years in 90%. Relapses can be severe and result in blindness, 
paralysis, and even death due to neurogenic respiratory failure (Oh and Levy, 2012). 
Incomplete recovery from attacks is typical, and accumulative disabilities arise from the 
severity and frequency of attacks. By some estimates, within 5 years, > 50% of patients are 
blind in one or both eyes or require ambulatory help (Wingerchuk et al, 2007). Historically, 
mortality in NMO was as high as 30% at 5 years, but a more recent study suggests 9% at 6 
years (Kitley, Leite et al, 2012).  
Once thought to be a variant of multiple sclerosis (MS), NMO/neuromyelitis optica spectrum 
disorders (NMOSD) are now recognized as a distinct disease (Wingerchuk et al, 2007). A 
defining feature of NMO is the presence of serum autoantibodies against aquaporin-4 (AQP4) 
(ie, AQP4-immunoglobulin G [IgG] or NMO-IgG), which is detected in 60% to 90% of 
NMO/NMOSD patients (Jarius and Wildemann, 2010). Aquaporin-4 is the most abundant 
water channel expressed on the plasma membrane of astrocytes throughout the CNS. AQP4-
IgG is thought to be pathogenic by causing astrocyte loss through activation of lytic 
complement components, antibody-dependent cellular phagocytosis (ADCP) and antibody-
dependent cellular cytotoxicity (ADCC) and/or by unfavorably altering astrocyte physiology 
by reducing expression of key water channel proteins. AQP4-IgG is produced by CD19 
positive (CD19+) B-lineage plasmablasts (Chihara et al, 2011), and that the presence of these 
plasmablasts correlates with disease activity in NMO (Chihara et al, 2011; 
Kim et al, Sept 2011; Greenberg et al, 2012). It has been demonstrated that subpopulations of 
CD19+ and CD20 negative (CD20-) B cells showing morphological and phenotypical 
properties of plasmablasts are increased selectively in the peripheral blood of NMO patients 
and that anti-AQP4 antibodies are produced by these cells. These subsets of B cells have 
shown to expand in the 2 weeks prior to and during NMO attacks. 


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Neuromyelitis optica spectrum disorders include limited forms of NMO, which include severe 
or bilateral ON, transverse myelitis (TM), recurrent ON or TM, brainstem disorders (including 
intractable hiccup, nausea, or vomiting), hypothalamic disorders (including hypersomnia and 
syndrome of inappropriate antidiuretic hormone secretion; Popescu et al, 2011), and some 
encephalitic presentations but are unified by the detection of AQP4-IgG in serum or 
cerebrospinal fluid (Jacob et al, 2012).  
Treatment for NMO/NMOSD includes management of acute attacks, prevention of attacks, 
monitoring adverse events (AEs), and evaluating changes in therapy for breakthrough disease 
or lack of tolerability. Currently, there are no approved treatments in any country indicated for 
the treatment of NMO/NMOSD, and to date, there have been no controlled clinical studies for 
this disease. Patients with NMO/NMOSD are typically treated prophylactically with off-label 
immunosuppressants such as azathioprine (AZA), mycophenolate mofetil (MMF), daily 
prednisone, or rituximab to prevent relapses. High-dose steroids and plasma exchange are 
generally used for the acute management of relapses. Results of uncontrolled studies with 
rituximab, a chimeric monoclonal antibody (mAb) against the human CD20 molecule 
(Browning, 2006), provide evidence for the therapeutic effect of B-cell depletion 
in NMO/NMOSD (Cree et al, 2005; Jacob et al, 2008; Bedi et al, 2011; Kim et al, Nov 2011; 
Ip et al, 2013). B-cell analysis of rituximab failures revealed the presence of CD19+/CD20- 
plasmablasts (Dr Larry Steinman, Professor, Stanford University, personal communication), 
which support the need for a more effective B-cell depleting mAb than rituximab in the 
treatment of this disease. Therefore, it is conceivable that direct suppression of CD19+ B cells 
could be more effective in mitigating the impact of plasmablasts on NMO/NMOSD attacks 
than suppression of CD20+ B cells. Anti-CD20 mAbs may work by starving CD19+ 
plasmablast generation (ie, by targeting CD19+ and CD positive (CD20+) memory B cells 
rather than CD19+ plasmablasts directly). This suggests that targeting CD19+ B cells has a 
potential advantage over targeting CD20+ B cells as a therapeutic intervention for treating 
NMO and NMOSD.  
1.2 
MEDI-551 Background 
MEDI-551 is briefly described below. Refer to the current Investigator’s Brochure (IB) for 
details.  
MEDI-551 is a humanized, affinity-optimized, afucosylated immunoglobulin G1 kappa 
(IgG1κ) mAb that binds to the B-cell specific surface antigen CD19 resulting in the depletion 
of B cells. MEDI-551 is glycoengineered by expression of mAb 16C4 in a fucosyltransferase-
deficient Chinese hamster ovary producer cell line (BioWa Potelligent® Technology), which 
generates a homogenously afucosylated antibody. The removal of fucose from the mAb Fc 
results in approximately 10-fold increased affinity for the activating FcJ receptor IIIA and 
significantly enhances ADCC. The antigen-binding properties of MEDI-551 (high affinity, 
slow internalization, and slow off-rate) are favorable for an ADCC-dependent mechanism of 


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action. MEDI-551 is composed of 2 light chains and 2 heavy chains, with an overall molecular 
weight of approximately 149 kilodalton (kDa). MEDI-551 does not mediate complement-
dependent cytotoxicity (CDC). 
1.3 
Summary of Nonclinical Experience 
Nonclinical evaluation demonstrated that MEDI-551 specifically recognizes human CD19 and 
has poor or no cross-reactivity to CD19 expressed on cells from nonhuman primates, rodents, 
or rabbits. Therefore, the human CD19 transgenic (huCD19 TG) mouse was selected as the 
relevant animal model for testing the pharmacodynamics (PD) and toxicology of MEDI-551. 
In huCD19 TG mice, MEDI-551 effectively depleted B cells in blood and tissue. The duration 
of B-cell depletion was dose-dependent and was sustained for more than 10 weeks after 
treatment with a single 250 μg injection of MEDI-551. An additional 4-6 weeks were required 
for the B cells to recover to levels and maturities similar to those in immunoglobulin (Ig) G 
control-treated animals. The effect of treatment with MEDI-551 was limited to B cells and did 
not have an impact on other immune cells in circulation, as assessed by flow cytometry. Thus, 
MEDI-551 selectively targets and depletes B cells. Furthermore, during the course of the 
study, the levels of Ig in serum increased in control animals. These increases in serum Ig were 
blocked in groups treated with MEDI-551, suggesting that MEDI-551 inhibits antibody 
production. In a murine model of experimental systemic sclerosis (SSc), where production of 
pathogenic autoantibodies requires CD19+ B cells, MEDI-551 was highly effective at 
reducing circulating and target tissue infiltrating B cells. Total serum Ig, autoantibodies, and 
deposition of complement proteins in target tissues were also reduced by MEDI-551. These 
findings demonstrate that treatment with MEDI-551 may result in clinical benefit in 
autoimmune diseases in which B-cell-dependent T-cell activation and autoantibodies are 
thought to have pathogenic roles. 
Completed nonclinical toxicology studies with the huCD19 TG mouse model demonstrated 
that there were no adverse effects after a single intravenous (IV) dose (up to 50 mg/kg), 
5 weekly IV doses (up to 36.6 mg/kg), or 13 or 26 weekly IV doses (up to 30 mg/kg). The 
only findings from these toxicology studies were related to the pharmacologic action of B-cell 
depletion. The no observed adverse effect level (NOAEL) for MEDI-551 as a single IV agent 
is at least 36.6 mg/kg/week for up to 1 month and 30 mg/kg/week for multiple IV doses up to 
6 months. Results of a fertility and embryo-fetal development (EFD) study showed no adverse 
findings in the study, other than a treatment-related reduction in fertility index and the number 
of mice that were pregnant/number of mice in cohabitation. Importantly, there was no MEDI-
551 impact on EFD. Treatment with MEDI-551 resulted in the expected pharmacological 
depletion of total B lymphocytes in peripheral blood of adult mice. 
An additional 13-week repeat-dose study to evaluate the toxicity of weekly subcutaneous (SC) 
administration of MEDI-551 (3 or 30 mg/kg SC; 30 mg/kg IV comparator) has been 


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completed. While the findings during the dosing phase were similar to those identified in the 
previous repeat dose toxicology studies, during the recovery phase an increased incidence of 
background bronchiolo-alveolar adenomas (benign) was noted in the 30 mg/kg IV group only. 
Given that this finding is isolated to this study and was not observed in the longer duration, 
26-week chronic toxicity study (which also included a 30 mg/kg IV group), the relevance to 
overall risk assessment for patients is unknown. 
For detailed descriptions of nonclinical studies and results refer to the MEDI-551 IB.  
1.4 
Summary of Clinical Experience 
The current clinical program for MEDI-551 consists of two completed Phase 1 studies, one in 
adults with SSc (Study MI-CP200) and one in adults with relapsing forms of MS (Study CD-
IA-MEDI-551-1102), and 6 ongoing Phase 1 and Phase 2 studies in adults with B-cell 
malignancies (Studies MI-CP204, CD-ON-MEDI-551-1088, CD-ON-MEDI-551-1019, 
D2852C00004, J1340, and D2850C00001).  
Across these studies, MEDI-551 has been and is being administered as an IV infusion at 
single doses up to 10 mg/kg, at multiple doses up to 12 mg/kg. For Study MI-CP204, the 
maximum tolerated dose (MTD) of MEDI-551 was not observed. The highest planned doses 
were 10 mg/kg (median exposure of 675 mg [480-1,034 mg]) in Study MI-CP200 and 
12 mg/kg (maximum median average monthly exposure and duration of 1218.2 mg 
[618.7-2152 mg] and 6.0 months [1.0-24.1 months]) in Study MI-CP204. 
Study CD-IA-MEDI-551-1102 in relapsing forms of MS evaluated the safety and tolerability 
of a single course of IV MEDI-551 (30, 100, or 600 mg) or placebo administered twice as a 
fixed IV dose on Day 1 and Day 15, or a single dose of SC MEDI-551 (60 or 300 mg) or 
placebo over a 24-week period with long-term follow up for all subjects for B-cell recovery. 
The most frequently reported treatment-emergent adverse events (TEAEs) in studies of 
MEDI-551 in subjects with SSc or relapsing forms of MS include infusion-related reaction, 
nausea, fatigue, pain in extremity, arthralgia, and cough. The most frequently reported TEAEs 
in studies of MEDI-551 in subjects with advanced B-cell malignancies include infusion-
related reaction, anemia, fatigue, chills, cough, diarrhea, nausea, vomiting, neutropenia, 
thrombocytopenia, pyrexia, hypocalcemia, hypomagnesemia, hypertriglyceridemia, and 
hypokalemia.  
Infusion-related reaction is the only identified risk of IV MEDI-551 to date, and has occurred 
in both oncology and nononcology studies with MEDI-551. Although the exact mechanism of 
the MEDI-551-associated infusion-related reaction is unknown, such events can occur with 
the administration of foreign proteins such as other types of mAbs. The risk of 
infusion-related reaction is mitigated by premedicating subjects prior to administration of IV 
MEDI-551. While premedication may reduce infusion-related reactions, it may not completely 


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eliminate the risk. To date, no serious infusion-related reactions have been reported in subjects 
who received protocol-defined premedication prior to administration of IV MEDI-551.  
Progressive multifocal leukoencephalopathy (PML) has been reported in the setting of B-cell 
depleting therapies and other immunosuppressive regimens (Calabrese et al, 2015) and is a 
potential risk of treatment with MEDI-551. A subject in Study CD-IA-MEDI-551-1155 
developed altered mental state, seizures, and new brain lesions that on brain MRI raised 
suspicion of PML. Cerebrospinal fluid (CSF) testing for the John Cunningham virus (JCV) 
was performed, with inconclusive results (two negative results in reference laboratories and 
one positive result in a local laboratory). Brain tissue was not available for examination. The 
subject died from cardiopulmonary complications. Based on all available data, the differential 
diagnosis included acute disseminated encephalomyelitis (ADEM), atypical NMOSD attack, 
and PML. No conclusive diagnosis could be made. 
Details of all clinical studies with MEDI-551 are provided in the IB. 
1.5 
Rationale for Study 
MEDI-551 is a humanized, affinity-optimized, afucosylated IgG1κ mAb that binds to the 
B-cell specific surface antigen CD19 resulting in the depletion of B cells. It is currently in 
clinical development in diseases such as B-cell malignancies and relapsing forms of MS, 
where B-cell depletion may have or has been shown to have a therapeutic effect.  
Neuromyelitis optica/NMOSD is a rare, chronic, relapsing disorder with debilitating effects. 
There are currently no medicinal products approved for the prevention of NMO/NMOSD 
relapses or the treatment of acute relapses.  Off-label medications are currently being used for 
the prevention and treatment of NMO/NMOSD relapse based on low-level evidence and 
unproven efficacy. There is a high unmet medical need for more effective therapies in this 
patient population. Furthermore, to date, no randomized-controlled clinical trials have been 
conducted in this patient population. 
Available research shows NMO/NMOSD to be an autoantibody-mediated, plasmablast-driven 
disease, and that depleting B cells may have an impact on delaying or preventing relapse and 
disease progression. Since the results of small, uncontrolled studies of the anti-CD20 mAb 
rituximab have provided evidence for the therapeutic effect of B-cell depletion in 
NMO/NMOSD (Cree et al, 2005; Jacob et al, 2008; Bedi et al, 2011; Kim et al, Nov 2011; 
Ip et al, 2013) and that a CD19+ B-cell depleting agent may be more effective than a CD20+ 
B-cell depleting agent in the treatment of this disease, this study is being conducted to 
evaluate the efficacy of MEDI-551 in this target population. 
Results of preclinical and clinical studies with MEDI-551 demonstrate that MEDI-551 
provides an acceptable risk-benefit ratio for patients with NMO/NMOSD and support the 
initiation of a registration study.  


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Further information regarding the rationales for the study design and dose-level selection are 
provided in Section 3.2.  
1.6 
Research Hypotheses 
1.6.1 
Primary Hypothesis 
The primary hypothesis for this study is that by depleting CD19+ B cells including 
plasmablasts and plasma cells, MEDI-551 is effective in reducing the risk of NMO/NMOSD 
attack compared to placebo, thus effectively reducing the risk of irreversible disability caused 
by such attacks.  
1.6.2 
Secondary Hypotheses 
The secondary hypotheses are:  
x 
Depletion of CD19+ B cells by MEDI-551 reduces worsening in Kurtzke Expanded 
Disability Severity Scale (EDSS) and decreases the loss of low-contrast visual acuity in 
adult subjects with NMO/NMOSD. 
x 
Depletion of CD19+ B cells by MEDI-551 reduces NMO/NMOSD-related in-patient 
hospitalizations. 
x 
Depletion of CD19+ B cells by MEDI-551 reduces the cumulative number of active 
lesions found on MRI. 
 
2 
OBJECTIVES 
2.1 
Objectives 
2.1.1 
Primary Objective 
To compare the efficacy of MEDI-551 versus placebo in reducing the risk of an 
NMO/NMOSD attack in subjects with NMO/NMOSD.   
2.1.2 
Secondary Objectives 
1 
To compare the efficacy of MEDI-551 versus placebo on the reduction of EDSS 
worsening in subjects with NMO/NMOSD. 
2 
To compare the efficacy of MEDI-551 versus placebo on the change from baseline of 
low-contrast visual acuity score in subjects with NMO/NMOSD. 
3 
To compare the efficacy of MEDI-551 versus placebo in reducing the cumulative active 
MRI lesion count (new gadolinium [Gd]-enhancing or new/enlarging T2). 
4 
To compare the efficacy of MEDI-551 versus placebo in reducing NMO/NMOSD-
related in-patient hospitalizations in subjects with NMO/NMOSD. 
5 
To characterize the long-term efficacy of MEDI-551 by means of annualized attack rate. 


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6 
To evaluate the safety and tolerability of a single course of MEDI-551 in subjects with 
NMO/NMOSD in the Randomized-controlled Period (RCP) and repeated doses of 
MEDI-551 in the Open-label- Period (OLP). 
7 
To characterize the pharmacokinetic (PK) profile and immunogenicity of MEDI-551 in 
NMO/NMOSD subjects. 
 
2.1.3 
Exploratory Objectives 
1 
To compare the effect of MEDI-551 versus placebo on health-related quality of life 
(HRQoL) as measured by the 4-week recall SF-36 Health Survey (SF-36) physical 
component score (PCS) and mental component score (MCS) in NMO/NMOSD subjects. 
2 
To compare the effect of MEDI-551 versus placebo on pain as measured using the pain 
numeric rating scale (NRS). 
3 
To characterize the PD profile (B cells and plasma cell signature) of MEDI-551 in 
NMO/NMOSD subjects. 
4 
To compare the effect of MEDI-551 versus placebo on AQP4-IgG titer. 
5 
To compare the effect of MEDI-551 versus placebo on soluble biomarkers (eg, 
cytokines, chemokines, and immunoglobulins) and genomic (ribonucleic acid [RNA; 
microRNA]) biomarkers and other relevant cells (eg, T cells, astrocytes) in 
NMO/NMOSD subjects. 
 
2.2 
Study Endpoints 
2.2.1 
Primary Endpoint 
The primary endpoint is the time (days) from Day 1 to onset of an Adjudication Committee 
(AC)-determined NMO/NMOSD attack on or before Day 197. The definition of an 
NMO/NMOSD attack is the presence of a new symptom(s) or worsening of an existing 
symptom(s) related to NMO/NMOSD that meets at least ONE of the protocol-defined criteria 
for an NMO/NMOSD attack provided in Table 11.  
2.2.2 
Secondary Endpoints  
Endpoints 1, 2, 3, and 4 are key secondary endpoints to be considered for studywise Type I 
error control. 
1 
Worsening from baseline in EDSS at last visit during the RCP.  
2 
Change from baseline in low-contrast visual acuity binocular score measured by low-
contrast Landolt C Broken Rings Chart, at last visit during the RCP. 
3 
Cumulative total active MRI lesions (new Gd-enhancing or new/enlarging T2) during the 
RCP. 


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4 
Number of NMO/NMOSD-related in-patient hospitalizations. In-patient hospitalization 
is defined as more than an overnight stay (see Section 4.3.1.6). 
5 
Annualized attack rate (total number of AC-determined NMO/NMOSD attacks 
normalized by person-years) during any exposure to MEDI-551. 
6 
Treatment-emergent adverse events, including treatment-emergent serious adverse 
events (TESAEs). Laboratory measurements as well as their changes or shift from 
baseline over time. 
7 
Pharmacokinetic profile of MEDI-551. 
8 
Incidence of anti-drug antibodies (ADAs) directed against MEDI-551 for the duration of 
the study, both predose and postdose for each subject. 
 
2.2.3 
Exploratory Endpoint(s) 
1 
Change from baseline in the 4-week recall SF-36 PCS and MCS at the last visit during 
the RCP.  
2 
Change from baseline in pain NRS in 5 locations at the last visit during the RCP. 
3 
B-cell counts (total and subsets).  
4 
Change from baseline in plasma cell gene signature.  
5 
Serum AQP4-IgG titers. 
 
3 
STUDY DESIGN 
3.1 
Description of the Study 
3.1.1 
Overview
 
This is a multicenter, multinational, randomized, double-masked, placebo-controlled- study 
with an open-label extension period to evaluate the efficacy and safety of IV MEDI-551 in 
adult subjects with AQP4-IgG seropositive and seronegative NMO and NMOSD. Following a 
screening period of up to 28 days, a maximum of 252 subjects with NMO/NMOSD will be 
randomized and dosed, in a 3:1 ratio [IV MEDI-551 (300 mg at Day 1 and 300 mg at Day 15) 
or placebo] for a period of 197 days (RCP). 
Enrollment of subjects into the study will stop when a total of 67 AC-determined NMOSD 
attacks occur, when 252 subjects have been randomized and dosed, or following a 
recommendation by the independent DMC to stop enrollment, whichever occurs first. 
Subjects who complete the RCP without experiencing an NMO/NMOSD attack will be given 
the option to enroll into an OLP and will initiate or continue treatment with MEDI-551. 
Subjects who experience an NMO/NMOSD attack during the RCP, and for whom the attack is 
determined by the AC, will be given the option to enroll into the OLP following rescue 


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therapy. Subjects for whom the NMO/NMOSD attack is not determined by the AC will 
continue in the RCP until Day 197 (or until another attack occurs that is determined by the 
AC). Subjects who are in the RCP when enrollment is discontinued upon recommendation of 
the independent DMC based on evidence of efficacy and safety, will discontinue the RCP as 
soon as possible, preferably within 14 days, and be given the option to enter the OLP. 
The OLP will continue for a minimum of 1 year and a maximum of 3 years after the last 
subject enters, or until regulatory approval for MEDI-551 as treatment for NMO in the 
participating country, or until the Sponsor discontinues development of MEDI-551 in this 
indication, whichever occurs first as described in Figure 1. Subjects can choose to exit the 
OLP at any time for any reason, including seeking alternative treatment options, at which 
point they will enter the Safety Follow-up Period (SFP; unless consent is withdrawn). 
All subjects will continue in the SFP for a total of 12 months from last dose to evaluate the 
long-term safety of the investigational product. 
 


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Figure 1 
Study Flow Diagram 
 
AC = Adjudication Committee; AQP4-IgG = aquaporin-4 immunoglobulin G; FU = follow-up; IV = intravenous; max = maximum; min = minimum; 
NMO/NMOSD = neuromyelitis optica/neuromyelitis optica spectrum disorders; OLP = Open-label Period; RCP = Randomized-controlled Period; Q26W = 
every 26 weeks; SFP = Safety Follow-up Period; yr = year.  


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The endpoints to be measured in this study are described in Section 2.2. 
3.1.1.1 
Screening Period 
Subjects with the diagnosis of NMO/NMOSD will be screened over a 28-day period to 
establish their eligibility to participate in the study based on the inclusion and exclusion 
criteria in Section 4.1.2 and Section 4.1.3, respectively. AQP4-IgG serostatus will be 
determined by a central laboratory. For subjects who are found to be AQP4-IgG negative in 
the screening period, relevant data documenting their NMO disease will be assessed by an 
independent Eligibility Committee (see Section 4.2.1.1) to ensure that the data are consistent 
with the diagnosis of NMO. All subjects who fulfill eligibility criteria will then be randomized 
into the study. Subjects undergoing screening at the time when the 252nd subject is 
randomized and dosed, subjects in screening at the time the 67th AC-determined attack is 
confirmed, and subjects undergoing screening at the time enrollment is terminated for any 
other reason, will not be randomized. 
3.1.1.2 
Randomization (Day 1) 
Two hundred and fifty-two subjects will be randomized into the study in a 3:1 ratio to receive 
IV MEDI-551 (300 mg) or placebo as described in Table 1. Randomization will occur on Day 
1 (within 28 days of the start of screening) and will be stratified by AQP4-IgG serostatus (in a 
ratio of approximately 80:20 seropositive and seronegative subjects, respectively) and by 
region (Japan vs non-Japan). 
3.1.1.3 
Randomized-controlled Period (Day 1 to Day 197) 
Following randomization on Day 1, subjects will be treated with MEDI-551 or placebo on 
Day 1 and Day 15. An oral corticosteroid course will be initiated on Day 1 (prednisone 
20 mg/day or equivalent oral glucocorticoid) and continue until Day 14. Tapering of the oral 
corticosteroids will occur from Day 15 to Day 21. By Day 21, tapering must be completed. 
During the RCP, subjects will be followed at scheduled study visits and by telephone 
interview as described in Table 6. The planned duration of the RCP for each subject will be 
197 days. All subjects who complete the RCP without experiencing an NMO/NMOSD attack 
will be given the option to enter the OLP. Subjects who are in the RCP when a total of 67 
AC-determined NMOSD attacks have occurred, or when enrollment is discontinued upon 
recommendation of the independent DMC based on evidence of efficacy and safety, will 
discontinue the RCP as soon as possible, preferably within 14 days, and be given the option to 
enroll into the OLP. . 
The process for the diagnosis of an NMO/NMOSD attack is outlined in Figure 3. Subjects will 
be monitored for new or worsening symptoms related to NMO/NMOSD during study visits 
and with follow-up phone calls every 2 weeks between study visits (or if a scheduled visit is 
missed).  


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When a possible new or worsening symptom(s) related to NMO/NMOSD is identified, 
subjects will be required to inform the site. If an Assessment Visit is deemed necessary, this 
must be scheduled as soon as possible but within 72 hours of reporting of the symptom to the 
site. At the Assessment Visit, subjects will initially undergo evaluations to determine if the 
symptoms are related to NMO/NMOSD; if related, the subjects will undergo further 
evaluations to determine if the symptoms meet at least ONE of the protocol-defined criteria 
for an NMO/NMOSD attack outlined in Table 11. In cases where a new or worsening 
symptom(s) does not meet at least one of the protocol-defined criteria for an NMO/NMOSD 
attack, the subject will continue in the RCP. The data related to the assessment of the 
symptoms that were determined by the investigator as not related to NMO/NMOSD will be 
sent to the AC for review. 
Assessment of new symptoms or worsening of existing symptoms should be completed within 
5 days to determine if an attack has occurred. Treatment of an attack should preferably be 
initiated after completion of the attack assessment and the determination that the protocol 
attack criteria have been met. However, the Principal Investigator can initiate rescue therapy 
at any time before full assessment is completed. Rescue therapy will be given as directed by 
the investigator. This may include IV corticosteroids, intravenous immunoglobulin (IVIG), 
and/or plasma exchange (PLEX). 
Upon completion of the Assessment Visit, the complete set of data generated from the 
assessments will be sent to the AC regardless of whether an NMO/NMOSD attack was 
diagnosed according to the protocol criteria by the Principal Investigator. The adjudication 
process will be completed within 14 days (+ 3 days) from initiation of the Assessment Visit 
and the AC determination will be communicated to the Principal Investigator.  
The procedures for identifying and adjudicating an NMO/NMOSD attack are described in 
Section 4.3.1.1. 
Subjects for whom the diagnosis of an NMO/NMOSD attack is not determined by the AC will 
be given the option to continue in the RCP until Day 197. Subjects for whom the diagnosis of 
an NMO/NMOSD attack is determined by the AC will be given the option to enter the OLP. 
In addition, subjects who experience an NMO/NMOSD attack that requires rescue treatment 
and meets the protocol-defined criteria, regardless of the outcome of the AC review, will 
undergo an Attack Follow-up Visit 28 days from Day 1 of the Assessment Visit. This visit 
may correspond with an OLP or SFP visit or may be scheduled separately. 
If subjects do not wish to enter the OLP or wish to leave the RCP at any point, they will 
continue to the SFP (unless consent is withdrawn). 


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3.1.1.4 
Open-label Period 
Subjects will be given the option to enter the OLP if they: 
1 
Complete 197 days of the RCP, or 
2 
Experience an AC-determined NMO/NMOSD attack during the RCP, or 
3 
Are in the RCP at the time when 67 AC-determined attacks have occurred  
4 
Are in the RCP when enrollment is discontinued upon recommendation of the DMC 
based on evidence of efficacy and safety (see Section 4.4). 
 
Subjects who discontinue from the RCP for reasons other than one of the reasons above will 
not be eligible for the OLP. Reasons for subjects not entering the OLP will be captured. These 
subjects will be followed for safety in the SFP. 
The first day of the OLP will be Day 1 (OLP Day 1). Upon entering the OLP for one of the 
three reasons outlined above, subjects will receive MEDI-551 as described in Table 2. During 
the OLP, subjects will be followed at scheduled study visits and will initiate or continue on 
MEDI-551 therapy per Table 7. The OLP will continue for a maximum of 3 years (after the 
last subject enters), until regulatory approval for MEDI-551 in each participating country or 
until the Sponsor discontinues development of MEDI-551 in this indication, whichever occurs 
first. Subjects can choose to exit the OLP at any time for any reason, including seeking 
alternative treatment options, at which point they will enter the SFP (unless consent is 
withdrawn).  
Subjects will be followed for NMO/NMOSD attacks in the same fashion as in the RCP and 
events will be centrally adjudicated.  
3.1.1.5 
Safety Follow-up Period 
The SFP will start when a subject prematurely discontinues from the RCP or OLP. The length 
of the SFP will be determined by the time elapsed from the time of the last dose of the 
investigational product to the time of the premature discontinuation, to complete a total of 
52 weeks. During the SFP, the subject will be monitored for AEs/serious adverse events 
(SAEs), B-cell levels, ADAs, and immunoglobulin levels.  
During the SFP, a subject may receive standard treatment for their NMO/NMOSD at the 
discretion of the investigator. 
3.1.2 
Treatment Regimen 
Randomized-controlled Period 
Subjects will be randomized in a 3:1 ratio to receive MEDI-551 or placebo during the 
197 days of the RCP as described in Table 1. 


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Table 1 
Randomized-controlled Period Treatment Regimen 
Treatment Arm 
Treatment Regimen 
1 
300 mg IV MEDI-551 on Day 1 and Day 15 
2 
IV Placebo on Day 1 and Day 15 
IV = intravenous 
 
Investigational product will be administered as a 90-minute IV infusion via an infusion pump. 
All subjects in the placebo and MEDI-551 arms will be premedicated on Day 1 and Day 15 
with IV methylprednisolone (80-125 mg or equivalent glucocorticoid), oral (PO) 
diphenhydramine (25-50 mg or equivalent antihistamine), and PO paracetamol 
(acetaminophen; 500-650 mg) prophylactically to prevent infusion reactions. Sites should 
utilize local supplies of the premedications where possible. The Sponsor will provide 
reimbursement during the study.  
Additionally, all subjects entering the RCP will be treated for 2 weeks (Day 1 to Day 14) with 
oral corticosteroids (prednisone 20 mg/day or equivalent oral glucocorticoid). A tapering 
schedule will be implemented from Day 15 to Day 21 (see Section 4.5.2).  
Open-label Period 
All subjects who enter the OLP will receive open-label MEDI-551. In order to provide 
subjects who were receiving placebo during the RCP with 2 doses of MEDI-551 (OLP Day 1 
and OLP Day 15) and to ensure maintaining the masking of the study, subjects who were in 
Treatment Arm 1 (MEDI-551) or Treatment Arm 2 (placebo) will be dosed as described in 
Table 2. 
Table 2 
Open-label Period Treatment Regimen 
Treatment Arm in 
RCP 
Treatment Regimen 
1 
300 mg IV MEDI-551 on OLP Day 1, masked IV placebo OLP Day 15, then 300 mg 
IV MEDI-551 Q26W thereafter a  
2 
300 mg IV MEDI-551 on OLP Day 1, masked 300 mg IV MEDI-551 on OLP Day 15, 
then 300 mg IV MEDI-551 Q26W thereafter a 
IV = intravenous; OLP = Open-label Period; Q26W = every 26 weeks; RCP = Randomized-controlled Period; 
SFP = Safety Follow-up Period.  
a 
The OLP will continue for a minimum of 1 year after the last subject enters and a maximum of 3 years 
(after the last subject enters), or until regulatory approval for MEDI-551 in the participating country, or 
until the Sponsor discontinues development of MEDI-551 in this indication, whichever occurs first. 
Subjects can choose to exit the OLP at any time for any reason, including seeking alternative treatment 
options, at which point they will enter the SFP (unless consent is withdrawn). 
 
Dosing of subjects enrolling into the OLP following an adjudicated NMO/NMOSD attack, 
following the occurrence of the 67th adjudicated NMO/NMOSD attack, or following 


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discontinuation of enrollment upon recommendation of the independent DMC based on 
evidence of efficacy and safety, will follow the OLP dosing regimen as detailed above in 
Table 2. 
Investigational product will be administered as a 90-minute IV infusion via an infusion pump. 
All subjects will be premedicated on OLP Day 1 and OLP Day 15 and at subsequent dosing 
visits with IV methylprednisolone (80-125 mg or equivalent glucocorticoid), 
PO diphenhydramine (25-50 mg or equivalent antihistamine), and PO paracetamol 
(acetaminophen; 500-650 mg) prophylactically to prevent infusion reactions. Sites should 
utilize local supplies of the premedications where possible. The Sponsor will provide 
reimbursement during the study.  
3.1.3 
Management of Study Medication Related Toxicities 
Infusion-related reaction is the only identified risk of IV MEDI-551 to date and has occurred 
in both MEDI-551 oncology and non-oncology studies. For subjects experiencing an infusion-
related reaction, an approach to these reactions based on severity of symptoms is presented in 
Table 3 and Appendix 2 (National Institute of Allergy and Infectious Diseases [NIAID] and 
Food Allergy and Anaphylaxis Network [FAAN] Guidance for Anaphylaxis Diagnosis), with 
suggested treatment options. Final treatment is at the discretion of the investigator and should 
reflect local standard of care. 


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Table 3 
An Approach to Management of Anaphylactic, Hypersensitivity, and Infusion Reactions 
Severity of Symptoms 
Treatment 
Investigational Product 
Mild reactions (infusion and 
hypersensitivity) 
Mild infusion reactions such as 
headache, nausea, nonpruritic 
rash, or mild hypersensitivity 
reactions including localized 
cutaneous reactions such as mild 
pruritus, flushing, rash, 
dizziness, headache, ≤ 20 mmHg 
change in systolic BP from pre-
infusion measurement 
• 
Evaluate subject, including close monitoring of vital 
signs  
• 
At the discretion of the investigator, treat subject, for 
example, with: 
• 
Normal saline (~500-1000 mL/hour IV) and/or 
• 
Diphenhydramine 50 mg IV or equivalent and/or 
• 
Acetaminophen 500-650 mg or equivalent dose of 
paracetamol and/or 
• 
Topical antihistamines and/or low-potency topical 
corticosteroid preparations and/or 
• 
Anti-nausea medication, as needed 
• 
Stop IP infusion immediately 
• 
Once the event has resolved, resume current IP 
infusion under observation and complete IP infusion at 
no more than half the planned infusion rate 
Moderate reactions (infusion) 
Infusion reaction such as those 
listed above under mild 
reactions but excluding 
moderate hypersensitivity 
reactions (see below) 
• 
Evaluate subject, including close monitoring of vital 
signs 
• 
Treat subject, for example, with: 
• 
Normal saline (~500-1000 mL/hour IV) and/or 
• 
Diphenhydramine 50 mg IV or equivalent and/or 
• 
Acetaminophen 500-650 mg or equivalent dose of 
paracetamol and/or 
• 
Anti-nausea and/or antiemetic intramuscular, as needed 
• 
Stop the infusion immediately 
• 
Once the event has resolved, resume current IP 
infusion under observation and at no more than half 
the planned infusion rate after treatment of current 
signs and symptoms as suggested 
Moderate hypersensitivity 
reactions 
Infusion reactions which may 
include generalized rash or 
urticaria, palpitations, chest 
discomfort, shortness of breath, 
hypo- or hypertension with 
> 20 mmHg change in systolic 
BP from pre-infusion 
measurement 
• 
Evaluate subject, including close monitoring of vital 
signs 
• 
Treat subject, for example, with: 
• 
Normal saline (~500-1000 mL/hour IV) and/or 
• 
Diphenhydramine 50 mg IV or equivalent and/or 
• 
Acetaminophen 500-650 mg or equivalent dose of 
paracetamol and/or 
• 
IV corticosteroids, such as hydrocortisone 100 mg or 
methylprednisolone 20-40 mg 
• 
Stop the infusion immediately 
• 
Once the event has resolved, resume current IP 
infusion under observation and at no more than half 
the planned infusion rate after treatment of current 
signs and symptoms as suggested 


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Table 3 
An Approach to Management of Anaphylactic, Hypersensitivity, and Infusion Reactions 
Severity of Symptoms 
Treatment 
Investigational Product 
Severe 
Above plus fever with rigors, 
hypo- or hypertension with 
≥ 40 mmHg change in systolic 
BP, signs of end organ 
dysfunction (eg, symptomatic 
hypotension such as hypotonia, 
syncope, incontinence, seizure) 
from pre-infusion measurement, 
or wheezing, angioedema, or 
stridor 
• 
Evaluate subject, including close monitoring of vital 
signs  
• 
Treat subject, for example, with: 
• 
Normal saline (~500-1000 mL/hour IV) and/or 
• 
Diphenhydramine 50 mg IV or equivalent and/or 
• 
Acetaminophen 500-650 mg or equivalent dose of 
paracetamol and/or 
• 
IV corticosteroids, such as hydrocortisone 100 mg or 
methylprednisolone 20-40 mg 
• 
Stop the infusion immediately 
• 
Once all symptoms have disappeared, resume current 
IP infusion under observation and at no more than half 
the planned infusion rate after treatment of current 
signs and symptoms as suggested 
• 
If severe event recurs in the same subject, discontinue 
further IP administration 
Life threatening 
Defined as a reaction that is life 
threatening and requires pressor 
and/or ventilator support or 
shock associated with acidemia 
and impairing vital organ 
function due to tissue 
hypoperfusion 
• 
Evaluate subject, including close monitoring of vital 
signs 
• 
Maintain airway, oxygen if available 
• 
Treat subject immediately, for example with: 
• 
Normal saline (~500-1000 mL/hour IV) 
• 
Epinephrine for bronchospasm, hypotension 
unresponsive to IV fluids, or angioedema. Dose and 
route as per local standard of care, example, epinephrine 
1:1000, 0.5-1.0 mL administered SC for mild cases and 
intramuscular for more severe cases 
• 
IV corticosteroids, such as hydrocortisone 100 mg or 
methylprednisolone 20-40 mg 
• 
Diphenhydramine 50 mg IV or equivalent 
• 
Acetaminophen 500-650 mg or equivalent dose of 
paracetamol 
• 
Call emergency medical transport for transport to 
emergency hospital based on judgment of the 
investigator 
• 
Stop IP infusion immediately 
• 
Do not resume current infusion 
• 
Permanently discontinue IP administration 
• 
Consider need for additional oral antihistamine 
administration or oral corticosteroid administration to 
prevent reoccurrence of symptoms over subsequent 
2-3 days 
BP = blood pressure; IP = investigational product; IV = intravenous; mmHg = millimeters mercury; SC = subcutaneous.  


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3.2 
Study Design and Dose Rationale 
3.2.1 
Study Design Rationale 
This study design was developed to provide balance between scientific considerations and 
patient safety. A placebo-comparator treatment arm was chosen because there are no currently 
approved medications for the treatment of NMO/NMOSD. While there is anecdotal evidence 
for using various immunosuppressants in NMO/NMOSD, the efficacy and safety profiles of 
these agents are not well characterized because there have been no controlled clinical studies 
using these agents in this disease indication. The use of a placebo arm will allow for a clear 
and robust evaluation of MEDI-551 and provide for the highest sensitivity to detect efficacy. 
The therapeutic estimation of the potential effect of MEDI-551 is based on published 
literature, albeit uncontrolled data, showing that B-cell depletion may have a positive effect in 
preventing NMO/NMOSD attacks. The Sponsor expects that MEDI-551 will share the same 
class effects that have been seen with other B-cell depleting agents in subjects with 
NMO/NMOSD.  
A 3:1 randomization scheme was chosen for this study. According to Dumville et al (2006), 
unequal randomization is particularly useful when the experimental group is expected to 
benefit greatly from a new treatment that would not have been otherwise available and can 
provide the clinician with a reduced learning curve by allowing treatment in a higher 
percentage of subjects (Dumville et al, 2006). The 3:1 randomization ratio is an effective and 
efficient approach to build an enriched safety database for MEDI-551 while keeping the 
number of required events or subjects in the placebo arm at a minimum acceptable level. This 
randomization ratio also addresses, to a certain degree, the serious ethical/safety concerns of 
investigators and patients regarding enrollment of subjects to a placebo arm. In addition to 
limiting the number of subjects who receive placebo, the study has been designed to limit the 
actual duration of placebo exposure to a maximum of 197 days or time to onset of an 
AC-determined NMO/NMOSD attack, whichever occurs earlier, after which all subjects will 
have the option to enter the OLP and receive MEDI-551.  
Due to the potential severity of NMO/NMOSD attacks and their debilitating nature, the study 
is further designed to ensure safety in this subject population through careful monitoring and 
early evaluation of signs and symptoms of NMO/NMOSD attacks, scheduled study visits and 
study assessments, follow-up telephone contact every 2 weeks with study subjects by study 
site staff, a liberal “escape clause” (ie, immediate access to rescue therapy following 
identification of an NMO/NMOSD attack), and monitoring by an independent Data 
Monitoring Committee (DMC).  
Also, the informed consent form (ICF), which will include detailed explanation and 
risk:benefit expectations, will provide subjects and investigators the opportunity to discuss 


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appropriate risk estimation and to fully understand the risks and potential benefits of this 
study. 
The rationale for the use of oral corticosteroids (prednisone 20 mg/day or equivalent oral 
glucocorticoid) for the first 14 days, with a 1-week taper, is to provide prophylaxis against an 
NMO/NMOSD attack for the period wherein the PD effect of MEDI-551 is not expected. 
Based on our PK/PD data, a period of approximately 2-4 weeks is required for maximal B-cell 
depletion to occur.  
In addition, studies with rituximab have reported a few attacks in the first month of therapy 
possibly related to increased B-cell activating factor (BAFF; Bar-Or et al, 2010) and therefore 
an increase of AQP4-IgG titers. Feedback from external experts has suggested that providing 
such prophylaxis is viewed as particularly important in a setting where existing 
immunosuppressive regimens will be withdrawn at randomization. 
3.2.2 
Dose Rationale 
The 300 mg dose of MEDI-551 was selected to achieve complete peripheral B-cell depletion. 
Based on existing PK and B-cell PD data from Study MI-CP200, a fixed dose of 300 mg 
MEDI-551 given on Day 1 and Day 15 is predicted to fully deplete peripheral blood B cells to 
undetectable levels and maintain B-cell suppression for 28 weeks, therefore sustaining B-cell 
depletion for the duration of the RCP. In theory, an initial dose of MEDI-551 will deplete the 
peripheral blood B cells; however, additional B cells will then recirculate out of the lymphoid 
tissues. The second dose of MEDI-551 on Day 15 is timed to deplete the newly recirculated 
B cells from the peripheral blood. 
This dose regimen is supported by clinical data from other B-cell depleting mAbs, where 
IV dosing on Day 1 and Day 15 will provide optimal B-cell depletion in both blood and 
tissues (Huffstutter et al, 2011; Hauser et al, 2008; Bar-Or et al, 2008; Kappos et al, 2011).  
A fixed dose of 300 mg MEDI-551 administered on OLP Day 1 (and OLP Day 15 for subjects 
who received placebo in the RCP) and then every 26 weeks is predicted to fully deplete 
peripheral blood B cells to undetectable levels and maintain B-cell suppression for the dose 
interval of the OLP (Figure 2).  


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Figure 2 
PD Model Simulation Supporting Dosing Regimen 
 
PD = pharmacodynamic; Q26W = every 26 weeks 
 
3.2.3 
Rationale for Study Population 
This clinical study is designed to study the efficacy and safety of MEDI-551 as a maintenance 
treatment of subjects with established NMO/NMOSD aimed to reduce the risk of 
NMO/NMOSD attacks. Therefore, the inclusion/exclusion criteria define a group of adult 
subjects (women and men aged 18 years and above) who must have a diagnosis of 
NMO/NMOSD at the time of screening and a documented history of 1 or more 
NMO/NMOSD acute relapses that required rescue therapy within the last year, or 2 or more 
NMO/NMOSD acute relapses that required rescue therapy within the 2 years prior to 
screening.  
Both AQP4-IgG seropositive and seronegative subjects will be enrolled in the study to fully 
capture the entire spectrum of this potentially fatal and rare demyelinating neurological 
disease. There is a series of clinical studies showing that AQP4-IgG is involved in the 
pathogenesis of NMO and that AQP4-IgG may be predictive of relapse and/or later 
conversion to definite NMO (Weinshenker et al, 2006; Matiello et al, 2008). In a multicenter 
study of 175 Caucasian patients, bilateral ON at onset was more common in AQP4-IgG 
seronegative patients as was simultaneous ON and myelitis, and the time to diagnosis was 
shorter in the AQP4-IgG seronegative group. Additionally, the disease course was more often 
monophasic in AQP4-IgG seronegative patients (Jarius et al, 2012).  


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There is strong evidence to support the hypothesis that NMO is a pathologically 
heterogeneous disease, as even using the most reliable of recombinant assays, there are 
subsets of subjects who do not test seropositive for AQP4-IgG that may still present with 
NMO and conditions that may cause myelitis and ON by other mechanisms. It has been 
speculated that different etiological mechanisms are involved in AQP4-IgG seronegative 
NMO/NMOSD. Recent studies have identified a subset of AQP4-IgG seronegative NMO 
patients who are positive for antibodies against myelin-oligodendrocyte glycoprotein (MOG), 
a protein expressed on the outer surface of the myelin sheath and oligodendrocytes 
(Kitley, Woodhall et al, 2012; Mader et al, 2011), and for antibodies against CV2/CRMP5 
(Jarius et al, 2012). Since an anti-CD19 B-cell depleting mAb will remove the source of 
AQP4-IgG, it should also remove the source of these antibodies. The clinical presentation of 
an attack is considered by NMO experts to be indistinguishable between seropositive and 
seronegative NMO patients. 
Several assays have shown to be able to detect AQP4-IgG even in samples taken from 
subjects during remission and treatment with strong immunosuppressants such as rituximab, 
AZA, mitoxantrone, and/or cyclophosphamide, plausibly ruling out the likelihood that 
seronegativity is generally the result of insufficient assay sensitivity.  
In addition, evidence for the therapeutic effect of B-cell depletion with rituximab in NMO 
seropositive and seronegative subjects is supported by a number of uncontrolled studies 
comparing relapse rates and EDSS scores before and after treatment (Jacob et al, 2008; 
Bedi et al, 2011; Kim SH et al, 2011; Ip et al, 2013). 
The AQP4-IgG status was available in all subjects in the previously described rituximab 
studies, with seronegative status occurring in nearly 20% to 30% of NMO/NMOSD patients 
tested. 
Thus, this study population will include approximately 80% subjects who are AQP4-IgG 
seropositive and 20% of subjects who are AQP4-IgG seronegative. In subjects who are AQP4-
IgG seronegative, the diagnosis of NMO is less clear; therefore, these subjects must meet the 
clinical criteria for NMO according to Wingerchuk et al, 2006 and not have brain MRI lesions 
consistent with MS. In addition, screening data of these subjects will be reviewed by an 
independent Eligibility Committee to confirm the diagnosis of NMO in the absence of AQP4-
IgG seropositive status. 
The study allows for inclusion of a wide age range of subjects as recent international research 
has shown under-representation of older participants in clinical studies. It is both unhelpful for 
optimal healthcare as well as fundamentally unjust to exclude participants from clinical 
research based solely on an arbitrary age limit (Briggs et al, 2012). 


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3.2.4 
Rationale for Endpoints 
3.2.4.1 
Primary Endpoint 
The primary endpoint of time (days) from Day 1 to onset of an AC-determined 
NMO/NMOSD attack on or before Day 197 is based on the natural history of the disease, 
which is characterized by a stepwise deterioration of motor, sensory, visual, and 
bowel/bladder function (Sellner et al, 2010), and recurrent attacks that can result in blindness, 
paralysis, and even death. Attacks of NMO/NMOSD are more severe than MS and usually 
result in incomplete recovery and permanent deficits. Thus, establishing a primary endpoint 
using an annualized relapse rate as usually utilized in MS studies where subjects typically 
have mild attacks and exacerbations followed by varying degrees of recovery, would expose 
subjects to a longer study period with an increased risk to the placebo subjects. Utilizing time 
to attack as the primary endpoint limits subject exposure but still provides a robust endpoint.  
3.2.4.2 
Secondary Endpoints 
Worsening from Baseline in EDSS at Last Visit During the Randomized-controlled 
Period 
A subject will be considered to have a worsening in overall EDSS score if one of the 
following criteria is met:  
(a) Worsening of 2 or more points in EDSS score for patients with baseline score of 0. 
(b) Worsening of 1 or more points in EDSS score for patients with baseline score of 
1 to 5. 
(c) Worsening of 0.5 points or more in EDSS score for patients with baseline score of 
5.5 or more. 
 
Myelitis attacks in NMO/NMOSD patients are severe and may lead to permanent disability. 
Measurement of disease progression in NMO/NMOSD patients is critically important since 
the potential for recovery depends on the severity of the attacks. The EDSS is a commonly 
used measure of disability in MS, and given the lack of any validated scales for NMO, is 
widely considered appropriate for measuring the level of disability in patients with 
NMO/NMOSD. Because the time to achieve these EDSS scores is often long, a short-term 
indicator of disease progression can be applied to the disease course by using an increase in 
EDSS score sustained over several months called “sustained disease progression.” Several 
definitions of sustained disease progression for clinical trials and observational studies have 
been proposed, including a 2- or more point increase in EDSS score for patients with a 
baseline score of 0; an increase in 1 point or more in EDSS score for patients with a baseline 
score of 1-5; or an increase of 0.5 points or more in EDSS score for patients with a baseline 
score of 5.5 or more has been used in the literature. 


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Change from Baseline in Low-contrast Visual Acuity ScoreMeasured by Low-contrast 
Landolt C Broken Rings Chart at Last Visit During the Randomized-controlled Period 
Visual loss and dysfunction are recognized disabling clinical manifestations in patients with 
NMO/NMOSD. In MS clinical trials, low-contrast visual acuity emerged as the leading 
candidate to measure visual disability in MS. Subsequent studies found that low contrast 
acuity testing correlated well with brain MRI lesion burden, visual evoked potentials and 
retinal nerve fiber layer (RNFL) loss as measured by optical coherence tomography (OCT). 
Worsening of visual function by a clinically significant > 7 letters or approximately 1.5 lines 
for low-contrast acuity is associated with approximately 4.5 μm reduction in RNFL thickness 
in MS. Additional longitudinal studies have shown RNFL axonal loss over time that occurs 
even in the absence of an acute ON attack and correlates with clinical meaningful worsening 
of vision and quality of life in patients with MS. The low-contrast visual acuity test is used to 
determine the number of letters that can be read on a standardized low-contrast Landolt C 
Broken Rings Chart held at a distance of 3 meters. Due to lack of standard visual function 
measures specific to NMO/NMOSD, and the fact that both MS and NMO/NMOSD patients 
can experience ON, and this endpoint has been previously used widely in MS studies, there is 
good rationale for using this endpoint in this NMO/NMOSD study. This secondary endpoint 
will evaluate whether MEDI-551 will have an effect on improving vision sensitivity. 
Reduction in the Cumulative Total Active MRI Lesions (New Gd-enhancing or 
New/Enlarging T2) 
In clinical practice there is wide use of MRI in the diagnosis and management of NMO; 
however, the role of MRI in this setting is not well established and studied. The actual 
interpretation of MRI related to the diagnosis and the follow up of patients with 
NMO/NMOSD are not consistently established. Therefore, this study aims to collect 
longitudinal MRI data during both study periods including at the time of an attack, to 
investigate the characteristics and evolution of spinal and brain lesions in NMO/NMOSD. 
Number of NMO/NMOSD-related In-patient Hospitalizations During the Randomized-
controlled Period 
Patients with relapsing NMO/NMOSD have recurrent attacks that can be severe and result in 
blindness, paralysis, and even death (Oh and Levy, 2012). Consequently, such attacks 
frequently result in in-patient hospitalizations. Less severe attacks can be managed without the 
need for hospitalization. Post initial acute phase of an attack, the patient will often require 
ongoing care and rehabilitation in the recovery phase post an attack. Therefore, this secondary 
endpoint will evaluate whether MEDI-551 will be effective in reducing NMO/NMOSD-
related hospitalizations compared to placebo. All hospitalizations recorded during the RCP 
will be included in the analysis.  
In-patient hospitalization, for the purposes of analysis of the secondary endpoint, is defined as 
a stay in hospital that goes beyond midnight of the first day of admission. Any duration of stay 


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(calculated as the difference between discharge date and admission date) of more than 1 day 
will contribute to this endpoint. This includes the time a subject may enter an emergency 
department plus subsequent admission to a ward. Hospitalizations for the administration of 
NMO-related medications or procedures only (ie, the administration or procedure was isolated 
and not provided during a subject’s hospitalization due to NMO for another reason) will not 
be included in the secondary endpoint analysis. 
Annualized Attack Rate (Total Number of Adjudication Committee-determined 
NMO/NMOSD Attacks Normalized by Total Person-years) During any Exposure to 
MEDI-551 
This endpoint will be evaluated in all subjects who receive at least one dose of MEDI-551.  
This secondary endpoint will be an important marker for assessing frequency of AC-
determined NMO/NMOSD attacks during long-term treatment with MEDI-551. Although no 
comparator is available for long-term comparison, a descriptive summary of AC-determined 
NMO/NMOSD attack rate over various lengths of exposure to MEDI-551 will provide a sense 
of constancy of attack rate. 
Safety and Tolerability of MEDI-551 
The safety and tolerability endpoints are designed to evaluate the safety and tolerability of 
administration of MEDI-551 in subjects with NMO/NMOSD for this study population. These 
endpoints will be assessed primarily by summarizing TEAEs and TESAEs, and changes from 
baseline in laboratory measurements (including ADA status and titers and vaccine titers [see 
below]), significant physical examination findings, and vital sign measurements. 
Vaccine Titers 
Vaccination results in immunological memory by expansion of antigen specific CD4+ 
T-helper and CD8- cytotoxic cells as well as through induction of antigen-specific B–cell cell 
maturation and antibody secretion (Siegrist, 2013). Given the depletion effect of MEDI-551 
on B cells, it is mechanistically relevant to investigate whether immunization responses are 
diminished by following vaccine-generated antibody titers, including tetanus.  
3.2.4.3 
Exploratory Endpoints 
Change from Baseline in the Short Form-36 Physical and Mental Component Scores (4-
week Recall Version) 
The literature provides evidence of the strong impact NMO has on HRQoL 
(Chanson et al, 2011; Kanamori et al, 2011). In one study, the main impact was on PCS 
(Chanson et al, 2011); however, both PCS and MCS scores on the SF-36 Health Survey were 
significantly lower in NMO than for the general population, even in the cohort of patients 
outside an NMO attack period and with relatively low EDSS (mean score: 3.5), indicating the 
importance of the HRQoL evaluation in NMO. 


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Change from Baseline in Pain Numeric Rating Scale 
A number of recent publications have indicated that patients with NMO/NMOSD experience 
pain throughout the course of their disease. Pain in demyelinating and inflammatory CNS 
diseases can be disabling and may contribute to a lower quality of life and overall increased 
health care burden. Neuromyelitis optica is associated with extensive spinal cord injury, 
brainstem disorders, ON, and sometimes a combination of these (Qian et al, 2012) and pain in 
five different locations (eyes, legs, arms, upper back and lower back, respectively) will be 
measured at baseline and monthly thereafter throughout the study. 
B-cell Counts (Total and Subsets) 
As MEDI-551 binds to and depletes CD19+ B cells, the depletion is a direct measure of PD 
effect. Additionally, CD19+ plasmablasts are increased in the peripheral blood on 
NMO/NMOSD patients and produce anti-AQP4 antibodies. Since AQP4-IgG titers correlate 
with disease activity (Jarius et al, 2008; Kim et al, Sept 2011), the extent and/or duration of 
B-cell/plasma-cell depletion may correlate with response to MEDI-551 in these subjects.  
Plasma Cell Gene Signature 
Production of pathogenic autoantibodies by plasma cells is a hallmark of autoimmune 
diseases; thus, plasma cell levels may be associated with the efficacy of B-cell depleting 
therapies like MEDI-551. Flow cytometry methods commonly used to enumerate and describe 
plasma cells are difficult to implement routinely in large clinical studies because of the 
insufficient stability of plasma cells. For this reason, whole genome microarray analysis of 
sorted cellular fractions was used to develop a highly sensitive and specific gene expression 
signature comprised of multiple plasma cell-enriched genes. In Study MI-CP200, MEDI-551 
caused a statistically significant, dose-dependent depletion of the plasma cell gene signature. 
Thus, it would be relevant to characterize the effect of MEDI-551 on plasma gene signature in 
patients with NMO/NMOSD. 
Subpopulations of CD19+ and CD20- B cells showing properties of plasmablasts are 
increased selectively in the peripheral blood of NMO/NMOSD patients and anti-AQP4 
antibodies are produced by these cells. These B-cell subsets have been shown to expand 
2 weeks prior to and during NMO/NMOSD attacks. Measuring the depletion of plasma 
cells/plasmablasts will provide key PD information as MEDI-551 should deplete this cell 
population. The levels of the plasma cell signature prior to and following MEDI-551 treatment 
may provide information about which patients are more likely to respond to this therapy 
and/or predict an attack.  
Serum AQP4-IgG Titers 
Several previous studies determined that AQP4 antibody levels correlated with clinical disease 
activity, with relapses associated with up to a 3-fold increase in AQP4 antibody titers (Jarius 


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et al, 2008). Since CD19+ plasmablasts produce pathogenic anti-AQP4 antibodies, it will be 
important to characterize the time course and extent of the effect of MEDI-551 on AQP4-IgG 
titers.  
3.2.4.4 
Exploratory Investigations 
Levels of Soluble and Genomic Biomarkers (eg, Cytokines, Chemokines, 
Immunoglobulins, and mRNA/Micro-RNA), and Relevant Cell Counts 
A number of biomarkers that may provide additional insights into the mechanism of action of 
MEDI-551 in NMO/NMOSD or potentially predict response to MEDI-551 will be explored. 
An example of a relevant biomarker is BAFF, which is a cytokine that acts as a potent 
activator of B cells and plays an important role in the proliferation and differentiation of B 
cells. As the primary receptor for BAFF is expressed on mature B cells, it has been 
demonstrated that circulating BAFF is inversely correlated with B-cell depletion. Other serum 
biomarkers such as CCL19 and CXCL13 are also related to B-cell dynamics and may predict 
responses to B-cell depleting therapies. 
T-cell Responses 
There is increasing evidence for the involvement of effector T cells in the pathogenesis of 
NMO (reviewed in Mitsdoerffer et al, 2013). AQP4-specific antibodies in NMO serum are 
immunoglobulin G1 (IgG1), a subclass of mature IgG that requires help from T cells. T cells 
from NMO patients demonstrated greater proliferation to AQP4 and AQP4 peptide fragments 
than those from healthy controls (Varrin-Doyer et al, 2012). Therefore, antigen-specific T 
cells may contribute to the generation of AQP4-IgG in the peripheral immune compartment 
and to the development of NMO lesions in the CNS.   
B-cell depletion, both ex vivo and in vivo, resulted in diminished 
proliferative and proinflammatory cytokine responses of both CD4 and CD8 T cells of MS 
patients (Bar-Or et al, 2010). It is mechanistically relevant to investigate whether T-cell 
responses are also diminished following B-cell depletion in NMO patients. 
4 
MATERIALS AND METHODS 
4.1 
Subjects 
4.1.1 
Number of Subjects 
A maximum of 252 subjects will be randomized and dosed in this study. Because this study is 
event-driven where the primary objective is based on a total of 67 AC-determined 
NMO/NMOSD attacks, and the rate of NMO/NMOSD attacks is not established in the 
literature, this number of subjects was determined by analyzing masked data of the actual 
attack rate from the first 78 subjects who completed the RCP in this study. The attack status 
(attack/no attack) of the 78 subjects was randomly sampled with different attack rate, which 
gave an estimate of the number of attacks for the total sample size. This simulation process 


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was repeated 10,000 times to give a distribution of the number of attacks for the total sample 
size, from which the probability of observing at least 67 attacks could be estimated. Based on 
the 78 completed subjects, this procedure showed that with 252 subjects there is a 90% 
probability of reaching the required 67 AC-determined attacks. 
Of the total number of subjects enrolled, approximately 80% will be AQP4-IgG seropositive 
and 20% will be AQP4-IgG seronegative.  
4.1.2 
Inclusion Criteria 
Subjects must meet all of the following criteria: 
1 
Age 18 years or above at the time of screening.  
2 
Written informed consent and any locally required authorization (eg, Health Insurance 
Portability and Accountability Act [HIPAA] in the United States of America (USA), 
European Union [EU] Data Privacy Directive in the EU) obtained from the subject/legal 
representative prior to performing any protocol-related procedures, including screening 
evaluations 
3 
One of the following: 
(a) Positive serum anti-AQP4-IgG result at screening (verified by the allocated central 
laboratory) and a documented history of one or more NMO/NMOSD acute relapses 
that required rescue therapy within the last year, or 2 or more NMO/NMOSD acute 
relapses that required rescue therapy within 2 years prior to screening; OR  
(b) Negative serum anti-AQP4-IgG result at screening (verified by the allocated central 
laboratory) without evidence of brain lesion consistent with MS and meets the 
clinical criteria for NMO according to Wingerchuk et al, 2006 and a documented 
history of one or more NMO acute relapses that required rescue therapy within the 
last year, or 2 or more NMO acute relapses that required rescue therapy within 
2 years prior to screening. Note that data from AQP4-IgG seronegative subjects will 
be reviewed by an independent eligibility committee (see Section 4.2.1.1) to confirm 
eligibility.  
In the event that a subject has not received rescue therapy for a relapse due to a 
misdiagnosis or mismanagement of symptoms at a practice or medical center outside 
of the investigator’s control, the subject may still be eligible for the study if, 
following a review of the relapse data, the medical monitor and investigator are 
satisfied that the subject experienced a genuine relapse. 
4 
Subjects who have had a relapse immediately prior to screening must have at least 4 
weeks in which their relapse symptoms are stable or improving prior to randomization.  
5 
Expanded Disability Status Scale score at randomization less than or equal to 7.5. A 
score of 8.0 may be eligible if the investigator and medical monitor assess that the 
subject is reasonably able to participate in the study 


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6 
Females of childbearing potential who are sexually active with a nonsterilized male 
partner must use a highly effective method of contraception (subjects in the Czech 
Republic only must use 1 additional method of contraception) from screening, and must 
agree to continue using such precautions for 6 months after the final dose of 
investigational product; cessation of contraception after this point should be discussed 
with a responsible physician. Periodic abstinence, the rhythm method, and the 
withdrawal method are not acceptable methods of contraception.  
(a) Females of childbearing potential are defined as those who are not surgically sterile 
(ie, bilateral tubal ligation, bilateral oophorectomy, or complete hysterectomy) or 
those who are not postmenopausal (per International Council for Harmonisation 
[ICH] M3(R2) 11.2: defined as 12 months with no menses without an alternative 
medical cause) 
(b) A highly effective method of contraception is defined as one that results in a low 
failure rate (ie, less than 1% per year) when used consistently and correctly. The 
acceptable highly effective methods of contraception are described in Table 4. 
7 
Nonsterilized males who are sexually active with a female partner of childbearing 
potential must use a male condom plus spermicide (subjects in the Czech Republic only 
must use 1 additional method of contraception) (see Table 4) from Day 1 for 3 months 
after receipt of the final dose of investigational product. Because male condom and 
spermicide is not a highly effective contraception method, it is strongly recommended 
that female partners of male subjects to also use a highly effective method of 
contraception throughout this period.  
8 
Sterilized males, without the appropriate post-vasectomy documentation on the absence 
of sperm in the ejaculate, who are sexually active with a female partner of childbearing 
potential must use a condom and spermicide from Day 1 for 3 months after receipt of the 
final dose of investigational product.  
 
Table 4 
Highly Effective Methods of Contraception   
Barrier Methods 
Hormonal Methods 
• 
Intrauterine device 
• 
Intrauterine hormone-releasing system a 
• 
Bilateral tubal occlusion 
• 
Vasectomized partner b 
• 
Sexual abstinence c 
• 
Combined (estrogen and progestogen containing 
hormonal contraception) 
• 
Oral (combined pill) 
• 
Injectable 
• 
Transdermal (patch) 
• 
Progestogen-only hormonal contraception 
associated with inhibition of ovulation d 
• 
Implantable 
• 
Intravaginal 
a 
This is also considered a hormonal method. 
b 
With appropriate post-vasectomy documentation of surgical success (absence of sperm in ejaculate). 


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Table 4 
Highly Effective Methods of Contraception   
Barrier Methods 
Hormonal Methods 
c 
Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual 
intercourse during the entire period of the study and if it is the preferred and usual lifestyle of the subject. 
d 
Progestogen-only hormonal contraception, where inhibition of ovulation is not the primary mode of action 
(eg, minipill), is not accepted as a highly effective method). 
 
9 
Willing to forego other forms of investigational treatment for NMO/NMOSD during the 
study 
10 Ability and willingness to complete the study 
 
4.1.3 
Exclusion Criteria 
Any of the following would exclude the subject from participation in the study: 
General Exclusion Criteria 
1 
Any condition that, in the opinion of the investigator, would interfere with the evaluation 
or administration of the investigational product or interpretation of subject safety or 
study results 
2 
Concurrent/previous enrollment in another clinical study involving an investigational 
treatment within 4 weeks or 5 published half-lives of the investigational treatment, 
whichever is the longer, prior to randomization 
3 
An estimated glomerular filtration rate (GFR) of < 60 mL/minute  
4 
Lactating or pregnant females or females who intend to become pregnant anytime from 
signing the ICF through the study plus 6 months following last dose of investigational 
product 
5 
Known history of allergy or reaction to any component of the investigational product 
formulation or history of anaphylaxis following any biologic therapy 
6 
Evidence of alcohol, drug, or chemical abuse, or a recent history of such abuse < 1 year 
prior to randomization 
7 
Major surgery within 8 weeks prior to signing the ICF, or elective surgery planned from 
screening through the duration of the RCP of the study 
8 
Spontaneous or induced abortion, still or live birth, or pregnancy ≤ 4 weeks prior to 
signing the ICF 
9 
Subjects who are unable to undergo an MRI scan (eg, hypersensitivity to Gd-containing 
MRI contrast agents, implanted pacemakers, defibrillators, or other metallic objects on or 
inside the body that limit performing MRI scans) 
10 At screening (one repeat test may be conducted to confirm results prior to randomization 
within the same screening period), any of the following: 


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(a) Aspartate transaminase (AST) > 2.5 × upper limit of normal (ULN) 
(b) Alanine transaminase (ALT) > 2.5 × ULN 
(c) Total bilirubin > 1.5 × ULN (unless due to Gilbert’s syndrome) 
(d) Platelet count < 75,000/μL (or < 75 × 109/L) 
(e) Hemoglobin < 8 g/dL (or < 80 g/L) 
(f) Glycosylated hemoglobin (HbA1c) > 8% at screening (subjects with diabetes only) 
(g) CD19+ B cell counts below the lower limit of normal (LLN) according to the central 
laboratory 
 
Exclusion Criteria Related to Concomitant Medications 
11 Receipt of the following at any time prior to randomization: 
(a) Alemtuzumab 
(b) Total lymphoid irradiation 
(c) Bone marrow transplant 
(d) T-cell vaccination therapy 
12 Receipt of rituximab or any experimental B-cell depleting agent within the 6 months 
prior to screening, unless the subject has B-cell counts above the LLN according to the 
central laboratory 
13 Receipt of IVIG within 1 month prior to randomization 
14 Receipt of any of the following within 3 months prior to randomization: 
(a) Natalizumab (Tysabri®) 
(b) Cyclosporin 
(c) Methotrexate 
(d) Mitoxantrone 
(e) Cyclophosphamide 
(f) Tocilizumab 
(g) Eculizumab 
 
15 Severe drug allergic history or anaphylaxis to two or more food products or medicine 
(including known sensitivity to acetaminophen/paracetamol, diphenhydramine or 
equivalent antihistamine, and methylprednisolone or equivalent glucocorticoid) 
Exclusion Criteria Related to NMO and Other Diseases 
16 AQP4-IgG seronegative subjects with a brain MRI abnormality that meets the diagnostic 
criteria for MS (MRIs taken at screening will be assessed centrally) 


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17 Uncontrolled hypertension as indicated by the treating physician and/or principal 
investigator 
18 Any concomitant disease other than NMO that required treatment with oral or IV 
steroids at doses > 20 mg/day for > 21 days within the 6 months prior to screening 
19 Any subjects diagnosed with a concurrent autoimmune disease that is either uncontrolled 
or requires the use of disease-modifying agents or immunosuppressive agents 
 
Exclusion Criteria Related to Infection and Malignancy Risk Factors 
20 Receipt of any of the following: 
(a) Any live or attenuated vaccine within 3 weeks prior to Day 1 (administration of 
killed vaccines is acceptable, the Sponsor recommends that investigators ensure all 
subjects are up to date on required vaccinations prior to study entry) 
(b) Bacillus of Calmette and Guérin (BCG) vaccine within 1 year of signing the ICF 
(c) Blood transfusion within 4 weeks prior to signing the ICF 
21 Clinically significant serious active or chronic viral or bacterial infection that requires; 
treatment with anti-infectives, hospitalization, or, in the investigator’s opinion, 
represents an additional risk to the subject, within 60 days prior to randomization 
22 Known history of a primary immunodeficiency (congenital or acquired) or an underlying 
condition such as human immunodeficiency virus (HIV) infection or splenectomy that 
predisposes the subject to infection 
23 At screening (one repeat test may be conducted to confirm results prior to randomization 
within the same screening period), any of the following: 
(a) Total Ig < 600 mg/dL 
(b) Absolute neutrophil count < 1200 cells/μL 
(c) CD4 T lymphocyte count < 300 cells/μL 
24 Confirmed positive test for hepatitis B/hepatitis C serology at screening: 
(a) Hepatitis B surface antigen positive,  
(b)  Hepatitis B core antibody positive with negative hepatitis B surface antibody  
(c) Hepatitis C antibody positive 
25 Subjects with a positive QuantiFERON®-TB Gold test, unless an appropriate course of 
anti-tuberculosis (TB) treatment has been documented. Subjects with an indeterminate 
result may be eligible if a chest x-ray shows no evidence of TB and there is no evidence 
of latent TB 
26 History of cancer, apart from squamous cell or basal cell carcinoma of the skin treated 
with documented success of curative therapy > 3 months prior to randomization 
 


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4.1.4 
Subject Enrollment and Randomization 
4.1.4.1 
Enrollment 
Study participation begins (ie, a subject is “enrolled”) once written informed consent is 
obtained and a subject identification (SID) number is assigned by a central system (eg, an 
interactive voice/web response system, IVRS/IWRS). Thereafter, the screening evaluations 
may begin to assess study eligibility (inclusion/exclusion) criteria. The SID number will be 
used to identify the subject during the screening process and throughout study participation, if 
applicable.  
A master log of all consented subjects will be maintained at the site and will document all 
screening failures (ie, subjects who are consented but do not meet study eligibility criteria 
and/or are not randomized), including the reason(s) for screening failure. 
Subjects who fail to meet the inclusion/exclusion criteria (ie, screening failures) should not, 
under any circumstances, be randomized (if applicable) or receive investigational product. 
There can be no exceptions to this rule. Subjects who are screening failures should be 
withdrawn from the study; however, they may be re-screened once in the event that the 
investigator believes that the subject will subsequently meet all eligibility criteria. Subjects 
who are rescreened will be assigned a new SID number.  
Enrollment into the study will stop when one of the following occurs: 
1 
A total of 67 AC-determined NMOSD attacks have occurred 
2 
252 subjects have been randomized and dosed 
3 
Recommendation by the independent DMC to cease enrollment 
 
Informed Consent Requirements 
Before enrolling into the study, all subjects must review, understand, and sign the ICF. The 
ICF will include detailed explanations and risk:benefit expectations from the study and will 
provide subjects and investigators the opportunity to discuss appropriate risk estimation and to 
fully understand the risks and potential benefits of this study. Study procedures may only be 
performed after written informed consent is obtained. Reconsent will only be required if a 
subject fails screening and is subsequently rescreened. Subjects may be rescreened only once.  
In addition, subjects will also be required to consent to the use of their medical data and 
biological samples. 
All subjects who enter the OLP will be required to review and sign a specific ICF that 
highlights the risks and potential benefits of participating in the OLP.  


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Subjects may give optional consent for collection of a deoxyribonucleic acid (DNA) sample 
for genetic and future research (see Section 4.1.8). 
4.1.4.2 
Randomization Process 
An IVRS/IWRS will be used for randomization to a treatment group and assignment of 
masked investigational product kit numbers. A subject is considered randomized into the 
study when the investigator notifies the IVRS/IVWS that a subject meets eligibility criteria 
and the IVRS/IVWS provides the assignment of masked investigational product kit numbers 
for the subject.  
4.1.5 
Withdrawal from the Study 
Subjects are at any time free to withdraw from the study (investigational product and 
assessments), without prejudice to further treatment (withdrawal of consent). Such subjects 
will always be asked about the reason(s) and the presence of any AEs.  
Subjects in the RCP who express a wish to prematurely discontinue from the study will be 
followed for protocol-specified assessments until Day 197, unless consent is withdrawn 
specifically for further study participation. In this case the subject will complete the SFP 
unless the subject is lost to follow up, or the subject is enrolled in another clinical study. 
Subjects who discontinue from the OLP will enter the SFP, if possible. 
In the Czech Republic only, subjects may discontinue from the investigational product and, 
following an Early Discontinuation Visit (EDV), subjects will enter the SFP if they agree to 
this safety follow up; unless the subject is lost to follow up, or the subject is enrolled in 
another clinical study. 
Diaries and all study medications should be returned by the subject. If a subject withdraws 
consent from further participation in the study, then no further study visits or data collection 
should take place. 
A subject’s decision to withdraw from treatment must be documented in the source 
documents.  
4.1.6 
Discontinuation of Investigational Product 
An individual subject will not receive any further investigational product if any of the 
following occur in the subject in question: 
1 
Withdrawal of consent for further treatment with investigational product or the subject is 
lost to follow-up 
2 
An AE that, in the opinion of the investigator or the Sponsor, contraindicates further 
dosing 


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3 
Subject is determined to have met one or more of the exclusion criteria or failed to meet 
all of the inclusion criteria for study participation and there is a potential safety risk 
associated with continuation identified upon consultation with the medical monitor 
4 
Pregnancy 
5 
Any of the following liver function abnormalities: 
(a) ALT or AST > 8 × ULN 
(b) ALT or AST > 5 × ULN for more than 2 weeks (in absence of elevated bilirubin 
and/or other symptoms listed in item ‘d’) 
(c) ALT or AST > 3 × ULN and total bilirubin > 2 × ULN or international normalized 
ratio [INR] > 1.5; see Section 5.6.2 for additional details regarding reporting of 
subjects with ALT or AST > 3 × ULN and total bilirubin > 2 × ULN with unknown 
etiology (ie, Hy’s law cases) 
(d) ALT or AST > 3 × ULN with the appearance of fatigue, nausea, vomiting, right 
upper quadrant pain or tenderness, fever, rash, and/or eosinophilia (> 5%) 
6 
Any life-threatening (Grade 4) clinical event including anaphylaxis related to the 
investigational product as agreed upon consultation with the medical monitor 
7 
Recurrent severe (Grade 3) hypersensitivity reaction related to the investigational 
product as agreed upon consultation with the medical monitor 
8 
Recurrent severe (Grade 3) infusion reaction related to investigational product as agreed 
upon consultation with the medical monitor 
9 
Grade 3 or higher neutropenia that does not improve to at least Grade 2 within 5 days as 
agreed upon consultation with the medical monitor  
10 Receipt of a prohibited medication in the RCP prior to Day 15 or during the OLP 
following consultation with the medical monitor (see Section 4.7.2).  
11 Noncompliance to the study protocol as judged by the investigator and/or the Sponsor 
 
Subjects who are permanently discontinued from receiving investigational product will be 
followed for protocol-specified assessments including follow-up of any AEs unless consent is 
withdrawn specifically for further study participation (Section 4.1.5), the subject is lost to 
follow-up, or the subject is enrolled in another clinical study. 
4.1.7 
Replacement of Subjects 
Dropout in the RCP will not be adjusted by replacing subjects.  
4.1.8 
Withdrawal of Informed Consent for Donated Biological Samples 
Biological Samples Obtained for the Main Study 
Study data are protected by the use of an SID number, which is a number specific to the 
subject. The investigator is in control of the information that is needed to connect a study 


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sample to a subject. A subject’s consent to the use of data does not have a specific expiration 
date, but the subject may withdraw consent at any time by notifying the investigator. If 
consent is withdrawn, any samples collected prior to that time may still be given to and used 
by the Sponsor but no new data or samples will be collected unless specifically required to 
monitor safety of the subject. 
Samples Obtained for Genetic Research and Future Research 
Samples obtained for genetic research and future research will be labeled with a sample 
identification number but will not be labeled with personal identifiers such as the subject’s 
name. A file linking this sample identification number with the SID number will be kept in a 
secure place at the Sponsor with restricted access. If the subject withdraws consent for 
participating in genetic research and future research, this link will allow the Sponsor to locate 
the subject’s sample and destroy it. The coding of samples and results is to ensure that these 
research results are kept confidential by keeping the subject’s identity and these results 
separate.  
If the subject consents to have his/her samples used for genetic research and future research, 
this additional research may not start immediately and may start at any time during the storage 
period. The subject’s sample(s) including any specimens of extracted DNA will be stored by 
the Sponsor with similar samples from other subjects at a secure central laboratory. The 
subject’s samples will not be kept for more than 25 years after the end of the study in which 
they were collected. If the subject chooses not to allow his/her study samples to be used for 
genetic research and future research, the samples will be destroyed by the Sponsor once they 
are no longer required for the main study. 
If consent is withdrawn after a sample has been taken but before the subject’s sample is sent to 
the Sponsor for genetic research and future research, the investigator will arrange to have it 
destroyed. If consent is withdrawn after the subject’s sample(s) have been sent to the Sponsor 
for genetic research and future research, the Sponsor and the investigator will ensure that these 
sample(s) are destroyed unless the sample identification number has been removed and the 
subject can no longer be linked to any sample(s). However, if the subject’s samples have 
already been used for research, the Sponsor is not required to destroy results of this research. 
In this case only the remaining sample(s) will be destroyed. 
4.2 
Schedule of Study Procedures 
4.2.1 
Enrollment/Screening Period 
Table 5 shows all procedures to be conducted at the screening visit. The screening period will 
be up to 28 days, unless otherwise noted below, and all screening procedures must be 
completed within this time period. Screening assessments are presented in Table 5 and may be 
performed in any order following the signing of the informed consent. 


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Any subject who has an AQP4-IgG seronegative status at screening will have their medical 
history and MRI data reviewed by an independent Eligibilty Committee (see Section 4.2.1.1) 
to ensure that the subject meets the Wingerchuk et al, 2006 diagnostic criteria for NMO.  
If any screening hematology/chemistry blood draws, or urine tests are performed within 
10 days of Day 1 that are also required at Day 1, these do not need to be repeated.  
The screening period may be extended by up to 28 days to allow for repeat procedures and to 
allow results for protocol-specified procedures and processes (including the eligibility review) 
to be obtained. However, if the subject cannot be assessed within the defined screening period, 
the subject must be withdrawn and screen failed. In addition, any subject who experiences an 
NMO/NMOSD relapse in screening up to and prior to randomization, should be screen failed 
to allow appropriate management of the relapse. Such subjects cannot be rescreened for at 
least 28 days from the completion of the treatment for the NMO/NMOSD relapse. 
In the event a subject is re-screened a full neuroaxis MRI need not be repeated if the previous 
study neuroaxis MRI was conducted within the 3 months prior to the rescreening visit. 
Any subject who is a screen failure may be rescreened once, unless the need to maintain the 
80:20 ratio of AQP4-IgG seropositive subjects to AQP4-IgG seronegative subjects prevents 
them from being randomized. In exceptional circumstances an additional re-screening may be 
permitted, this must be documented by the Principal Investigator and is subject to approval by 
the medical monitor.  
In the event screening is extended, blood samples for serum chemistry and hematology must 
be redrawn within the 28 days prior to randomization.  
Written informed consent and any locally required privacy act document authorization must 
be obtained prior to performing any protocol-specific procedures, including screening 
evaluations.  
Subjects undergoing screening at the time when the 252nd subject is randomized and dosed, 
subjects undergoing screening at the time the 67th AC determined attack occurs, and subjects 
undergoing screening at the time enrollment is terminated for any other reason, will not be 
randomized. 
Table 5 
Schedule of Screening Procedures  
Study Period 
Screening 
Week  
-4 to -1 
Day 
Day -28 to Day -1 
Procedure / Visit Number 
1 
Written informed consent/ assignment of SID number 
X 


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Table 5 
Schedule of Screening Procedures  
Study Period 
Screening 
Week  
-4 to -1 
Day 
Day -28 to Day -1 
Procedure / Visit Number 
1 
Verify eligibility criteria 
X 
Medical and disease history (including smoking and alcohol history) 
X 
C-SSRS (“Baseline/Screening” version) a 
X 
Physical/neurological examination 
X 
Body weight and height 
X 
Vital signs 
X 
ECG 
X 
Chest x-ray b 
X 
Collect blood for: c 
Serum chemistry and hematology  
X 
TB assessment (QuantiFERON®-TB Gold) 
X 
Hepatitis B, C; HIV-1, -2; virology, JCV antibody titers 
X 
Hemoglobin A1c (subjects with diabetes only) 
X 
Serum βHCG (females with childbearing potential only) 
X 
Whole blood for flow cytometry (B-cell count and cell subsets) 
X 
Serum for AQP4-IgG serostatus assay and titers 
X 
Total Ig, IgM, IgG, IgA, IgE 
X 
Collect urine for urinalysis 
X 
Neuroaxis MRI scan (including optic nerve) 
X 
Independent EDSS/FSS administration a 
X 
Independent ophthalmology examination (high-/low-contrast visual acuity 
test, RAPD assessment) 
X 
Assessment of AEs/SAEs and concomitant medications 
X 
Distribute subject HCRU diary and provide instructions d 
X 
AE = adverse event; AQP4-IgG = autoantibodies against aquaporin-4; βHCG = beta human chorionic 
gonadotropin; C-SSRS = Columbia-Suicide Severity Rating Scale; ECG = electrocardiogram; EDSS = 
Expanded Disability Status Scale; FSS = Functional Systems Scores; HCRU = Healthcare Resource 
Utilization; HIV = human immunodeficiency virus; JCV = polyomavirus John Cunningham; MRI = magnetic 
resonance imaging; RAPD = relative afferent pupillary defect; SAE = serious adverse event; SID = subject 
identification; TB = tuberculosis 
a 
If the EDSS and the C-SSRS are performed by the same person, the EDSS must be done first. 
b 
Chest x-ray is not mandatory unless meets the conditions described in Section 4.3.3.6. 
c 
Blood draws should be fasting.  


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Table 5 
Schedule of Screening Procedures  
Study Period 
Screening 
Week  
-4 to -1 
Day 
Day -28 to Day -1 
Procedure / Visit Number 
1 
d 
Subject diaries will be distributed to aid in subject recollection of HCRU events. 
 
 
4.2.1.1 
Eligibility Committee 
Three experts in NMO/NMOSD disease will constitute the independent Eligibility Committee. 
This committee has the mandate to evaluate the screening visit and medical history data from 
all subjects who have an AQP4-IgG seronegative result from the central lab and determine 
whether the subject meets the Wingerchuk et al, 2006 criteria for NMO. The committee will 
use its judgement and clinical experience to make its determination based on the data 
provided. The committee’s role, function, and procedures are governed by a separate charter.  
4.2.2 
Treatment Period 
4.2.2.1 
Randomized-controlled Treatment Period 
Randomization will occur on Day 1 (within 28 days of the start of screening, unless screening 
is extended as noted above). Table 6 shows all procedures to be conducted during the 
Randomized-controlled treatment period. Patient-reported outcomes should be done first 
followed by all other assessments/procedures in an order determined by the site. All 
procedures must be completed prior to administration of investigational product. If necessary, 
the randomization visit may be split over 2 days, in this case randomization and 
investigational product administration must occur on the second day. If a subject discontinues 
from the study early during the RCP, all procedures should be conducted as presented in 
Table 6 for the Day 197/ EDV. If a subject withdraws from the study, every attempt should be 
made to have the subject come to the site to conduct EDV assessments.  
If a subject withdraws during a scheduled study visit, that visit will change to an EDV and 
procedures should be conducted according to those presented for Day 197/EDV. Following an 
EDV, all subjects should continue into the SFP.  
At the time 67 AC-determined attacks have occurred or when enrollment is discontinued upon 
recommendation of the independent DMC based on evidence of efficacy and safety, the 
sponsor will notify all sites and the sites will notify all subjects who are in the RCP that these 
subjects must discontinue the RCP as soon as possible, preferably within 14 days, and should 
be given the option to enroll into the OLP. Procedures should be conducted as presented in 
Table 6 for the Day 197/ EDV; however, subjects who have had an MRI in the last 3 months 
need NOT repeat the MRI. Subjects who decide to enroll into the OLP will follow the 
procedures of the OLP presented in Table 7. 


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Table 6 
Schedule of Randomized-controlled Treatment Period Study Procedures 
Study Period 
Randomized-controlled Period 
Week 
0 
1 
2 
4 
8 
12 
16 
22 
28/EDV  
Day 
1 h 
8 
15  
29 
57 
85 
113 
155 
197 
Visit Window 
 
r 1d 
r 3d 
r 3d 
r 3d 
r 3d 
r 3d 
r 3d 
r 7d 
Procedure / Visit Number 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Verify eligibility criteria 
X 
 
 
 
 
 
 
 
 
SF-36v2 Health Survey a 
X 
 
 
 
 
X 
 
 
X 
Pain NRS 
X 
 
 
X 
X 
X 
X 
X 
X 
Modified Rankin Scale 
X 
 
 
X 
X 
X 
X 
X 
X 
Medical and disease history (including smoking and alcohol history) 
X 
 
 
 
 
 
 
 
 
C-SSRS (“Since Last Visit” version) g 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical/neurological examination 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Body weight  
X 
 
 
 
 
X 
 
 
X 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECG 
X 
 
 
 
 
 
 
 
X 
Collect blood for: 
 
Hematology and serum chemistry 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
MEDI-551 concentration (PK)  
X b 
X 
X b 
X 
X 
X 
X 
X 
X 
MEDI-551 ADA 
X 
 
 
X 
 
X 
 
 
X 
Total Ig, IgM, IgG, IgA, IgE 
- 
 
 
 
 
X 
 
 
X 
Whole blood for flow cytometry (B-cell count and cell subsets) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum for AQP4-IgG assay (titers) 
X 
 
X 
X 
X 
X 
 
 
X 
Whole blood for gene expression 
X 
 
X 
X 
X 
X 
X 
 
X 
Whole blood for DNA sample (optional) 
X 
 
 
 
 
 
 
 
 


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Table 6 
Schedule of Randomized-controlled Treatment Period Study Procedures 
Study Period 
Randomized-controlled Period 
Week 
0 
1 
2 
4 
8 
12 
16 
22 
28/EDV  
Day 
1 h 
8 
15  
29 
57 
85 
113 
155 
197 
Visit Window 
 
r 1d 
r 3d 
r 3d 
r 3d 
r 3d 
r 3d 
r 3d 
r 7d 
Procedure / Visit Number 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Serum for exploratory biomarkers 
X 
 
X 
X 
X 
X 
X 
X 
X 
Vaccination titers (tetanus)  i 
X 
 
 
 
 
 
 
 
X 
Collect urine for: 
 
Urine HCG (females with childbearing potential only)  
(pre-IV dose only) c 
X 
 
X 
 
 
 
 
 
X 
Urinalysis 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Assess subject for new/worsening symptoms related to NMO/NMOSD d, e 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Independent EDSS/FSS administration g 
X 
 
 
 
 
X 
 
 
X 
Independent ophthalmology examination (high-/low-contrast visual acuity test, 
RAPD assessment)  
X 
 
 
 
 
X 
 
 
X 
Neuroaxis MRI (including optic nerve) 
 
 
 
 
 
 
 
 
X 
Randomize subjects in IVRS 
X 
 
 
 
 
 
 
 
 
Investigational product administration 
X 
 
X j 
 
 
 
 
 
 
Dispense/monitor low-dose steroids 
X 
X 
X 
X 
 
 
 
 
 
Assessment of AEs/SAEs (including infusion reactions) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Dispense and review subject HCRU diaries f 
X 
X 
X 
X 
X 
X 
X 
X 
X 


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Table 6 
Schedule of Randomized-controlled Treatment Period Study Procedures 
Study Period 
Randomized-controlled Period 
Week 
0 
1 
2 
4 
8 
12 
16 
22 
28/EDV  
Day 
1 h 
8 
15  
29 
57 
85 
113 
155 
197 
Visit Window 
 
r 1d 
r 3d 
r 3d 
r 3d 
r 3d 
r 3d 
r 3d 
r 7d 
Procedure / Visit Number 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Follow-up telephone call 
Telephone calls every 2 weeks will commence from Day 43 and continue for 
the duration of the RCP, except for study visit weeks 
ADA = anti-drug antibody; AE = adverse event; AQP4-IgG = autoantibodies against aquaporin-4; C-SSRS = Columbia-Suicide Severity Rating Scale; d = day(s) 
D/C = discontinuation; ECG = electrocardiogram; EDSS = Expanded Disability Status Scale; EDV = Early Discontinuation Visit; FSS = Functional Systems 
Scores; HCG = human chorionic gonadotropin; HCRU = Healthcare Resource Utilization; Ig A/E/G/M = immunoglobulin A/E/G/M; IV = intravenous; IVRS = 
interactive voice response system; MRI = magnetic resonance imaging; NMO/NMOSD = neuromyelitis optica/neuromyelitis optica spectrum disorders; NRS = 
numeric rating scale; PK = pharmacokinetic; RAPD = relative afferent pupillary defect; RCP = Randomized-controlled Period; SAE = serious adverse event; SF-
36v2 = Short Form-36 Health Survey, version 2 
Note: All procedures to be performed prior to randomization. 
a 
SF-36v2 Health Survey 4-week recall to be used at all time points. The 1-week recall version will also be used for an attack.  
b 
Pharmacokinetic blood samples to be collected predose and approximately 15 minutes postdose (± 5 minutes) after completion of MEDI-551 or placebo 
administration.  
c 
Urine HCG to be followed up to 26 weeks following discontinuation.  
d 
If a subject has an NMO/NMOSD attack prior to Day 1, and the subject has not been randomized, the visit should not continue. The subject should be 
treated for the attack as required, screen failed, and then reassessed for eligibility once the subject’s condition is stable.  
e 
In the event that an NMO/NMOSD attack is suspected, procedures in Section 4.2.3 should be followed.  
f 
Subject diaries will be distributed to aid in subject recollection of HCRU events.  
g 
If the EDSS and the C-SSRS are performed by the same person, the EDSS must be done first. 
h 
If necessary, the randomization visit may be split over 2 days, in this case randomization and investigational product administration must occur on the 
second day.  
i 
Tetanus vaccine titers will be tested at Day 1 for all subjects. Subjects with a negative result will not continue to be tested. Subjects who test positive will 
continue to be tested at all specificed vaccination titer timepoints.  
j 
In the event that the second dose of investigational product is delayed due to medical/safety reasons, dosing must be discussed with the medical monitor 
prior to administration of investigational product. 
 


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4.2.2.2 
Open-label Period  
Table 7 shows all procedures to be conducted during the OLP. Patient-reported outcomes 
should be done first followed by all other assessments/procedures in an order determined by 
the site. For subjects completing Day 197 of the RCP, Day 1 of the OLP should be the same 
day; however, it may be delayed for up to 14 days (procedures do not need to be repeated). 
Subjects are not permitted to enter the OLP after 14 days, unless there is a compelling reason 
that is discussed with, and agreed to by the medical monitor, in which case a short extension 
may be granted.  
Subjects who experience an AC-determined NMO/NMOSD attack during the RCP must enter 
the OLP within 28 days of the site receiving confirmation of the attack from the AC. Entering 
subjects into the OLP beyond the 28 days from the AC confirmation should be discussed with 
the medical monitor. Procedures that were done during the last visit can be used for Day 1 of 
the OLP if this occurs within 14 days from the Assessment Visit. Otherwise, procedures 
required for OLP Day 1 should be performed. 
Subjects who are in the RCP at the time the 67th AC-determined attack occurs, or when 
enrollment is discontinued upon recommendation of the independent DMC based on evidence 
of efficacy and safety, and wish to enroll in the OLP, should do so as soon as possible, 
preferably within 14 days. Consulation with the medical monitor is advised in cases where the 
transition to the OLP is not completed within 14 days. 
Administration of MEDI-551 will start on OLP Day 1. 
The OLP will continue for a minimum of 1 year after the last subject enters and a maximum 
of 3 years (after the last subject enters), or until regulatory approval for MEDI-551 in the 
participating country, or until the Sponsor discontinues development of MEDI-551 in this 
indication, whichever occurs first. All subjects entering the OLP will be required to reconsent 
prior to receiving MEDI-551. Subjects can choose to exit the OLP at any time, for any reason, 
including seeking alternative treatment options, at which point they will enter the SFP (unless 
consent is withdrawn). 
If a subject discontinues from the OLP, all procedures should be conducted as presented in 
Table 7 for the Day 365/EDV. If a subject withdraws from the study, every attempt should be 
made to have the subject come to the site to conduct EDV assessments. Following the EDV, 
the subject will enter the SFP (Section 4.2.4).  
If a subject withdraws during a scheduled study visit, that visit will change to an EDV and 
procedures should be conducted according to those presented for Day 365/EDV for the OLP.  


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At the point the Sponsor decides to terminate the OLP, the next visit for all ongoing subjects 
in that period will be an EDV to capture all assessments; this would also represent the first 
visit of the SFP. 


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Table 7 
Schedule of Open-label Period Study Procedures 
Study Period 
Open-label Period 
Week 
0 
2 
4 
13 
26 
39, then 
Q26W 
52, then 
Q26W/EDV 
Day 
1 
15 
29 
92 
183 
274+ 
365+ 
Visit Window 
(+ 14d from 
Day 197 RCP 
or +28d AC 
Determination) 
r 3d 
r 3d 
r 14d 
± 7d 
± 14d 
r 7d 
Procedure/Visit Number 
1 
2 
3 
4 
5 
6, 8,10, etc 
7, 9, 11, etc 
Written informed consent 
X 
 
 
 
 
 
 
SF-36v2 Health Survey 
 
 
 
X 
X 
X 
X 
Pain NRS 
 
 
X 
X 
X 
X 
X 
Modified Rankin Scale 
 
 
X 
X 
X 
X 
X 
Physical/neurological examination 
X a 
X 
X 
X 
X 
X 
X 
C-SSRS (“Since Last Visit” version) h 
X a 
X 
X 
X 
X 
X 
X 
Vital signs 
X a 
X 
X 
X 
X 
X 
X 
Collect blood for: 
Hematology and serum chemistry 
X a 
X 
X 
X 
X 
X 
X 
MEDI-551 ADA 
X a 
 
 
X 
X 
X 
X 
Total Ig, IgM, IgG, IgA, IgE 
X a 
 
 
X 
X 
X 
X 
Whole blood for flow cytometry (B-cell count and 
cell subsets)  
 
X 
X 
X 
X 
X 
X 
Serum for AQP4-IgG assay (titers) 
X a 
 
X 
X 
X 
 
X 
Whole blood for gene expression 
 
 
X 
X 
X 
 
X 
Serum for exploratory biomarkers 
 
X 
X 
X 
X 
X 
X 
Vaccination titers (tetanus) j 
 
 
 
X 
X 
 
X 


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Table 7 
Schedule of Open-label Period Study Procedures 
Study Period 
Open-label Period 
Week 
0 
2 
4 
13 
26 
39, then 
Q26W 
52, then 
Q26W/EDV 
Day 
1 
15 
29 
92 
183 
274+ 
365+ 
Visit Window 
(+ 14d from 
Day 197 RCP 
or +28d AC 
Determination) 
r 3d 
r 3d 
r 14d 
± 7d 
± 14d 
r 7d 
Procedure/Visit Number 
1 
2 
3 
4 
5 
6, 8,10, etc 
7, 9, 11, etc 
Collect urine for: 
Urine HCG (females with childbearing potential 
only; pre-IV dose only) 
X b 
X 
 
 
X 
 
X 
Urinalysis 
X a 
X 
X 
X 
X 
X 
X 
Assess subject for new/worsening symptoms related to 
NMO/NMOSD c 
X b 
X 
X 
X 
X 
X 
X 
Independent EDSS/FSS administration h 
- 
 
 
X 
X 
X 
X 
Independent ophthalmology examination (high-/low-
contrast visual acuity test, RAPD assessment)  
 
 
 
X 
X 
X 
X 
Neuroaxis MRI (including optic nerve)  
(X) d 
 
 
 
 
 
X e 
Investigational product administration 
X b 
X i 
 
 
X 
 
X g 
Assessment of AEs/SAEs (including infusion 
reactions) 
X b 
X 
X 
X 
X 
X 
X 
Concomitant medications 
X b 
X 
X 
X 
X 
X 
X 
Dispense and review subject HCRU diary entries f 
X b 
X 
X 
X 
X 
X 
X 


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Table 7 
Schedule of Open-label Period Study Procedures 
Study Period 
Open-label Period 
Week 
0 
2 
4 
13 
26 
39, then 
Q26W 
52, then 
Q26W/EDV 
Day 
1 
15 
29 
92 
183 
274+ 
365+ 
Visit Window 
(+ 14d from 
Day 197 RCP 
or +28d AC 
Determination) 
r 3d 
r 3d 
r 14d 
± 7d 
± 14d 
r 7d 
Procedure/Visit Number 
1 
2 
3 
4 
5 
6, 8,10, etc 
7, 9, 11, etc 
AC = Adjudication Committee; ADA = anti-drug antibody; AE = adverse event; AQP4-IgG = autoantibodies against aquaporin-4; C-SSRS = Columbia-
Suicide Severity Rating Scale; d = day(s); EDSS = Expanded Disability Status Scale; EDV = Early Discontinuation Visit; FSS = Functional Systems Scores; 
HCG = human chorionic gonadotropin; HCRU = Healthcare Resource Utilization; Ig A/E/G/M = immunoglobulin A/E/G/M; IV = intravenous; MRI = 
magnetic resonance imaging; NMO/NMOSD = neuromyelitis optica/neuromyelitis optica spectrum disorders; NRS = numeric rating scale; OLP = Open-label 
Period; Q26W = every 26 weeks; RAPD = relative afferent pupillary defect; RCP = Randomized-controlled Period; SAE = serious adverse event; SF-36v2 = 
Short Form-36 Health Survey, version 2 
a 
For subjects who enter the OLP prior to Day 197 of the RCP due to an AC-determined NMO/NMOSD attack and 14 days have elapsed since the 
Assessment Visit, all procedures listed for Day 1 should be repeated. For subjects completing Day 197 of the RCP, Day 1 of the OLP should be the same 
day; however, it may be delayed for up to 14 days and procedures do not need to be repeated.    
b 
Conduct for all subjects.  
c 
In the event that an NMO/NMOSD attack is suspected, procedures in Section 4.2.3 should be followed.  
d 
If the subject experienced an NMO/NMOSD attack during the RCP, any part of the neuroaxis MRI that was not done at the time of the Assessment Visit 
should be conducted at Day 1 of the OLP, otherwise it is not required.   
e 
An MRI will be conducted yearly.   
f 
Subject diaries will be distributed to aid in subject recollection of HCRU events.  
g 
If an EDV is being conducted, investigational product will not be given. 
h 
If the EDSS and the C-SSRS are performed by the same person, the EDSS must be done first. 
i 
In the event that the second dose of investigational product is delayed due to a medical/safety reason, dosing must be discussed with the medical monitor 
prior to administration of investigational product.  
j 
Tetanus vaccine titers will only be tested in the OLP for subjects who tested positive at Day 1 of the RCP.  
 


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4.2.3 
Study Procedures for Assessment Visit 
Table 8 shows all study procedures to be conducted at Assessment Visits for subjects 
experiencing new or worsening symptom(s) potentially related to NMO/NMOSD. An 
Assessment Visit should be scheduled as soon as possible and within 72 hours of symptom 
report. Procedures to determine whether symptoms are related to NMO/NMOSD should be 
conducted first, followed by procedures for determination of an NMO/NMOSD attack. All 
clinical assessments need to be documented with time and date, and the order of the 
assessments should be determined by the nature of the suspected attack (eg, EDSS before 
Independent ophthalmology in case of myelitis symptoms). An MRI of all domains should be 
performed as part of an Assessment Visit and can be done at any time during the Assessment 
Visit. The order of the MRI domains performed can be determined by the nature of the 
suspected attack. MRI images/study report should not be reviewed by the Principal 
Investigator unless a specific criterion for an attack requires review of the MRI. In such cases 
review of the MRI image MUST be done AFTER the review of all relevant clinical 
assessment data (eg, EDSS in the case of myelitis/brainstem/brain symptoms or 
ophthalmology in the case of optic neuritis symptoms) is completed. Assessments should be 
concluded as soon as possible, but should not extend beyond 4 days from Day 1 of the 
Assessment Visit. 
If the investigator determines that the new or worsening symptom(s) are not related to 
NMO/NMOSD, then the independent assessments (EDSS, Independent ophthalmology, and 
MRI) are not required. 
 


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Table 8 
Schedule of Study Procedures for the Assessment Visit
Procedure 
Assessment Visit a 
Pain NRS 
X 
Vital signs 
X 
Modified Rankin Scale 
X 
Physical/neurological examination 
X 
Collect blood for: 
Hematology and serum chemistry 
X 
MEDI-551 ADA 
X 
Total Ig, IgM, IgG, IgA, IgE 
X 
Whole blood for flow cytometry (B-cell count and cell subsets) 
X 
Serum for AQP4-IgG assay (titers) 
X 
Whole blood for gene expression 
X 
Serum for exploratory biomarkers 
X 
Collect urine for urinalysis 
X 
Procedures for determination of an NMO/NMOSD attack: 
Independent ophthalmology examination (high-/low-contrast visual acuity test, RAPD 
assessment) 
X 
Independent EDSS/FSS administration c 
X 
Neuroaxis MRI scan b 
X 
SF-36 (1-week recall version) 
X 
C-SSRS (“Since Last Visit” version) c 
X 
ECG 
X 
Review data generated against protocol defined attack criteria and create a narrative of 
the Assessment Visit findings 
X 


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Table 8 
Schedule of Study Procedures for the Assessment Visit
Procedure 
Assessment Visit a 
Assessment of AEs and SAEs 
X 
Concomitant medications 
X 
Review subject diary entries 
X 
ADA = anti-drug antibody; AE = adverse event; AQP4-IgG = autoantibodies against aquaporin-4; C-SSRS = Columbia Suicide Severity Rating Scale; ECG = 
electrocardiogram; EDSS = Expanded Disability Status Scale; FSS = Functional Systems Scores; Ig A/E/G/M = immunoglobulin A/E/G/M; MRI = magnetic 
resonance imaging; NMO/NMOSD = neuromyelitis optica/ neuromyelitis spectrum disorders; NRS = numeric rating scale; RAPD = relative afferent pupillary 
defect; SAE = serious adverse event; SF-36 = Short Form-36 Health Survey 
a 
Visit to be conducted within 72 hours of onset of report to site of new symptom(s) or worsening of an existing symptom(s) potentially related to 
NMO/NMOSD; visit may be conducted over 5 days.  
b 
The MRI image/report is only reviewed by the Principal Investigator in the event it is required by the protocol-defined attack criteria.  
c 
If the EDSS and the C-SSRS are performed by the same person, the EDSS must be done first.  
 


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4.2.4 
Managing Subjects With Worsening Attacks 
Following the diagnosis of an attack by the Principal Investigator, the attack symptoms and 
findings may get worse. In this case, the assessments and management will be done in 
accordance with the standard of care at the site. The change in symptoms/findings, 
assessments completed, and treatments administered should all be recorded in the electronic 
case report form (eCRF).  
4.2.5 
Study Procedures for Attack Follow-up Visit 
Subjects who experience an NMO/NMOSD attack that meets the protocol-defined criteria and 
requires rescue treatment, regardless of the outcome of the AC review, will undergo an Attack 
Follow-up Visit. Table 9 shows procedures to be conducted for the Attack Follow-up Visit. 
Patient reported outcomes should be done first followed by all other assessments/procedures 
in an order determined by the site. An Attack Follow-up Visit should be conducted 28 days 
from Day 1 of the Assessment Visit. This visit may correspond with an OLP or SFP visit or 
may be scheduled separately. 
Table 9 
Schedule of Study Procedures for the Attack Follow-up Visit 
Procedure 
Follow-up Assessment Visit a 
Visit Window 
28 days (± 7 days) After Assessment Visit 
Pain NRS 
X 
Vital signs 
X 
Modified Rankin Scale 
X 
SF-36 Health Survey (1-week recall version) 
X 
C-SSRS (“Since Last Visit” version) c 
X 
Physical/neurological examination 
X 
Collect blood for: 
Hematology and serum chemistry 
X 
Whole blood for flow cytometry (B-cell count and cell 
subsets) 
X 
Serum for AQP4-IgG assay (titers) 
X 
Collect urine for urinalysis 
X 
Independent ophthalmology examination (high-/low-
contrast visual acuity test, RAPD assessment) 
X b 
Independent EDSS/FSS administration 
X b, c 
Assessment of AEs and SAEs 
X 
Concomitant medications 
X 




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4.3 
Description of Study Procedures 
4.3.1 
Efficacy
 
4.3.1.1 
Identification, Assessment, and Adjudication of an NMO/NMOSD Attack  
Overview 
The process for identification, assessment, and adjudication of an NMO/NMOSD attack is 
presented in Figure 3 and requires that subjects reporting a new or worsening symptom(s) of a 
potential NMO/NMOSD attack must be evaluated at an Assessment Visit at the clinical site 
by the investigator as soon as possible, but within 72 hours of the report. Following the start of 
the Assessment Visit, the procedures required to diagnose an NMO/NMOSD attack per the 
protocol-defined attack criteria must be completed within a total of 5 days following the start 
of the Assessment Visit.  
Figure 3 
Flow Chart of Assessment and Diagnosis of an NMO/NMOSD Attack 
 
AC = Adjudication Committee; AE = adverse event; EDSS = Expanded Disability Status Scale; FSS = 
Functional Systems Scores; MRI = magnetic resonance imaging; NMO/NMOSD = neuromyelitis 
optica/neuromyelitis optica spectrum disorders; OLP = Open-label Period; RCP = Randomized-controlled 
Period.  
 
The Assessment Visit is designed to determine if an attack per the protocol criteria has 
occurred. There are two main outcomes of the Assessment Visit: 


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1 
The investigator determines that the symptoms ARE related to NMO/NMOSD and 
completes the full attack assessment. In this case specified data generated at the 
Assessment Visit, regardless of whether or not the investigator determined that a 
protocol-defined NMO/NMOSD attack has occurred, will be submitted to the AC for a 
real-time review.  
2 
The investigator determines that the symptoms ARE NOT related to NMO/NMOSD. In 
this case the data related to the assessment of the symptoms will also be sent to the AC 
for review (not in real time).  
 
The adjudication process requires that adjudication will be completed within a total of 14 days 
(+ 3 days) of the start of the Assessment Visit. The determination of the AC as to whether an 
NMO/NMOSD attack has occurred will be communicated to the clinical site. Only subjects 
where their attack was determined by the AC will be eligible to enroll into the OLP. 
Rescue therapy for an NMO/NMOSD attack will be given by the investigator according to the 
investigator’s clinical judgment that the subject is experiencing an NMO/NMOSD attack. 
Rescue therapy will not be affected by the AC decision as to whether the NMO/NMOSD 
attack has or has not been determined. Subjects who receive rescue therapy for an 
NMO/NMOSD attack that was determined by the AC will have the option to enroll into the 
OLP. Subjects whose attack was not determined by the AC will have the option to continue in 
the RCP.  
There may be an interval of a few days between the completion of the rescue therapy and the 
completion of the adjudication process. This period probably does not present a safety concern 
(possible NMO/NMOSD attack) as the rescue therapy would have only just concluded, and 
the effects of the rescue therapy will cover the period before the OLP starts. 
Detailed Procedures 
Identification 
There are 3 possibilities for identifying new or worsening symptoms that may relate to an 
NMO/NMOSD attack: 
x 
The subject reports the symptom directly to the site 
x 
A symptom is identified during a study visit 
x 
A symptom is identified during the telephone call every 2 weeks to the subject 
 
Telephone Calls to Subjects 
The investigator or designee will contact all subjects by telephone every 2 weeks, 
commencing from Day 43 of the RCP through the end of the subject’s participation in the 
RCP (except where timing coincides with study visit weeks).  


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The purpose of these calls is to assess for any signs and/or symptoms of an NMO/NMOSD 
attack (examples of possible symptoms are presented in Table 11). The calls will follow a 
prespecified script.  
If the investigator suspects an NMO/NMOSD attack or impending attack, an Assessment Visit 
will be scheduled within 72 hours. 
Recording Symptoms of NMO/NMOSD 
Details of any symptoms of NMO/NMOSD that occur or worsen during the study will be 
recorded at the Assessment Visit. Any symptom determined as not related to NMO/NMOSD 
should be reported as an AE.  
Information regarding new or worsening symptoms may be provided during study visits 
(including follow-up by the site owing to a missed study visit), during scheduled bi-weekly 
telephone calls, or from spontaneous reporting from the subject at any time during the study.  
In any of the above situations, information will be elicited from the subjects as to whether they 
have had any changes in their NMO/NMOSD status since the last contact with the site. A 
standardized worksheet will be used by all sites in order to elicit consistent information in the 
same manner. 
If the investigator suspects an NMO/NMOSD attack or impending attack, an Assessment Visit 
will be scheduled within 72 hours.  
Information to be recorded at the Assessment Visit includes the following: date of contact, 
each symptom, date and time of onset, date of resolution, treatment administered, date of 
assessment visit scheduled, and whether the symptom was not related to NMO/NMOSD but to 
an AE, or an SAE (see Section 5.5, Reporting of Serious Adverse Events). 
Assessment Visit 
The investigator initially conducts a physical and neurological examination as described in 
Section 4.3.3.2. If the symptom(s) is assessed by the investigator as not related to 
NMO/NMOSD, an AE must be reported (see Section 5.4) and the subject will continue in the 
RCP or the OLP, as applicable, without further action. The data related to the assessment of 
the symptoms that were determined by the investigator as not related to NMO/NMOSD will 
be sent to the AC for non-real-time review. 
If the symptom(s) is assessed as related to NMO/NMOSD, full assessment of the potential 
NMO/NMOSD attack will be conducted and the investigator will determine if an attack 
fulfilling the protocol-defined criteria for an NMO/NMOSD attack has occurred (Table 11). 
The date and time of all clinical assessments, conducted by the independent assessors, must be 
documented, and the order of the assessments should be driven by the nature of the suspected 


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attack (eg, EDSS before Independent ophthalmology in case of myelitis symptoms). MRI of 
all domains should be performed as part of an Assessment Visit and can be done at any time 
during the Assessment Visit. The order of the MRI domains performed can be determined by 
the nature of the suspected attack. MRI images/study report should not be reviewed by the 
Principal Investigator unless a specific criterion for an attack requires review of the MRI.  
Following completion of the independent clinical assessment, the Principal Investigator 
should decide if any of the CLINICAL (without MRI) criteria (numbers 1 to 8, 12 and 13) are 
met. Within one domain (optic nerve, spinal cord, brain or brainstem), the clinical criterion 
with the most significant change should be selected. Only in cases where none of the 
CLINICAL criteria are met, criteria that include MRI review can be selected (numbers 9 to 
11, 14 to 18). Only in this situation is MRI review of the relevant domain allowed.  
If the attack presents in more than one domain (optic nerve, spinal cord, brain or brainstem), 
more than one criterion can be selected.  


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Table 11 
Protocol-defined Criteria for an NMO/NMOSD Attack 
Example Symptoms of an 
NMO/NMOSD Attack a 
Attack Type b 
Protocol-defined Attack Criteria  
Blurred vision 
Loss of vision 
Eye pain 
ON 
1. 
Greater than 15-character drop in high-contrast Landolt C Broken Rings Chart from last visit as 
measured in a previously affected eye and no other ophthalmological explanation 
2. 
At least 2-step drop c in CF to NLP from last visit as measured in a previously affected eye and no 
other ophthalmological explanation 
3. 
At least 7 or more character drop in low-contrast Landolt C Broken Rings Chart from last visit as 
measured in either eye alone (monocular) AND a new RAPD in affected eye 
4. 
At least 7 or more character drop in low-contrast Landolt C Broken Rings Chart from last visit as 
measured in either eye alone (monocular) AND loss of a previously documented RAPD in fellow eye 
5. 
At least 5 or more character drop in high-contrast Landolt C Broken Rings Chart from last visit as 
measured in either eye alone (monocular) AND a new RAPD in affected eye 
6. 
At least 5 or more character drop in high-contrast Landolt C Broken Rings Chart from last visit as 
measured in either eye alone (monocular) AND loss of a previously documented RAPD in fellow eye 
7. 
At least 1-step drop d in CF to NLP from last visit as measured in a previously affected eye AND a new 
RAPD in affected eye 
8. 
At least 1-step drop d in CF to NLP from last visit as measured in a previously affected eye AND loss 
of a previously documented RAPD in fellow eye 
9. 
At least 7 or more character drop in low-contrast Landolt C Broken Rings Chart from last visit as 
measured in either eye alone (monocular) AND a new Gd-enhancing or new/enlarging T2 MRI lesion 
in the corresponding optic nerve f 
10. At least 5 or more character drop in high-contrast Landolt C Broken Rings Chart from last visit as 
measured in either eye alone (monocular) AND a new Gd-enhancing or new/enlarging T2 MRI lesion 
in the corresponding optic nerve f 
11. At least 1-step drop d in CF to NLP from last visit as measured in a previously affected eye AND a new 
Gd-enhancing or new/enlarging T2 MRI lesion in the corresponding optic nerve f 
Deep or radicular pain 
Extremity paraesthesia 
Weakness 
Sphincter dysfunction 
Myelitis e 
12. At least 2-point worsening in 1 or more of the relevant (pyramidal, bladder/bowel, sensory) FSS 
compared to last visit 
13. At least 1-point worsening in EDSS score compared to last visit if previous EDSS score is 5.5 or more 


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Table 11 
Protocol-defined Criteria for an NMO/NMOSD Attack 
Example Symptoms of an 
NMO/NMOSD Attack a 
Attack Type b 
Protocol-defined Attack Criteria  
Lhermitte’s sign (not in 
isolation) 
14. At least 1-point worsening in 2 or more of the relevant (pyramidal, bladder/bowel, sensory) FSS 
compared to last visit when the last visit score was 1 or greater AND a new Gd-enhancing or 
new/enlarging T2 MRI lesion in the spinal cord 
15. At least 0.5-point worsening in EDSS score compared to last visit if previous EDSS score is 5.5 or 
more AND a new GD-enhancing or new/enlarging T2 MRI lesion in the spinal cord 
Nausea 
Intractable vomiting 
Intractable hiccups 
Other neurological signs (eg, 
double vision, dysarthria, 
dysphagia, vertigo, 
oculomotor palsy, weakness, 
nystagmus, other cranial 
nerve abnormality) 
Brainstem 
16. Isolated (not present at last visit) intractable nausea, vomiting, and/or hiccups lasting for greater than 
48 hours AND a new Gd-enhancing or new/enlarging T2 MRI lesion in the brainstem 
17. At least 2-point worsening in 1 or more of the relevant (brainstem, cerebellar) FSS compared to last 
visit AND a new Gd-enhancing or new/enlarging T2 MRI lesion in the brainstem 
Encephalopathy 
Hypothalamic dysfunction 
Brain 
18. At least 2-point worsening in 1 or more of the relevant (cerebral, sensory, pyramidal) FSS (with a score 
of 3 or more at the current visit) compared to last visit AND a new Gd-enhancing or new/enlarging T2 
MRI lesion in the brain consistent with the clinical presentation 
CF = counting fingers; EDSS = Expanded Disability Severity Score; FSS = Functional System Scores; Gd = gadolinium; HM = hand motion; LP = light 
perception; MRI = magnetic resonance imaging; NLP = no light perception; NMO/NMOSD = neuromyelitis optica/neuromyelitis optica spectrum disorders; 
ON = optic neuritis; RAPD = relative afferent pupillary defect. 
a 
The symptoms listed are examples and are not inclusive of all NMO/NMOSD symptoms. 
b 
Four major areas of the body may be affected by an attack: the optic nerve, resulting in ON; the spinal cord, resulting in myelitis; the brainstem, resulting 
in a number of outcomes; and the brain.  
c 
At least 2-step drop can be any of the following worsening: on Landolt C Broken Rings Chart to HM, LP, or NLP; CF to LP or NLP; HM to NLP. 
d 
At least 1-step drop can be any of the following worsening: on Landolt C Broken Rings Chart to CF, HM, LP, or NLP; CF to HM or LP or NLP; HM to 
LP or NLP; LP to NLP.  
e 
Note: A 1-point change in a single FSS without a change in the EDSS, with or without a new Gd-enhancing or new/enlarging T2 MRI lesion in the spinal 
cord, is not considered a clinically significant change and will not count as an attack per this protocol. 
f 
Lesions seen in the optic chiasm also count towards these criteria.  


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Evaluations of the symptom(s) assessed as related to NMO/NMOSD to identify an 
NMO/NMOSD attack in accordance with the protocol-defined criteria will include the 
following: 
x 
Refer for ophthalmology examinations (see Section 4.3.1.3) 
x 
An independent EDSS/Functional Systems Scores (FSS) assessment (see Section 4.3.1.4) 
x 
Conduct an MRI (MRI images/study report should not be reviewed by the Principal 
Investigator unless a specific criterion for an attack requires review of the MRI. In such 
cases, review of the MRI image MUST be done AFTER the review of all relevant clinical 
assessment data is complete).  
 
The following flow diagrams illustrate the processes for evaluating symptoms affecting the 
eye (Figure 4), symptoms affecting the spinal cord (Figure 5), and symptoms affecting the 
brain or brainstem (Figure 6). 
Figure 4 
Process for Assessing Symptoms Affecting the Eye 
 
AE = adverse event; MRI = magnetic resonance imaging; NMO = neuromyelitis optica; RAPD = relative 
afferent pupillary defect.  
 


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Figure 5 
Process for Assessing Symptoms Affecting the Spinal Cord 
 
AE = adverse event; EDSS = Expanded Disability Severity Score; FSS = Functional Systems Scores; MRI = 
magnetic resonance imaging; NMO/NMOSD = neuromyelitis optica/neuromyelitis optica spectrum disorders.  
 


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Figure 6 
Process for Assessing Symptoms Affecting the Brain or Brainstem 
 
AE = adverse event; EDSS = Expanded Disability Severity Score; FSS = Functional Systems Scores; MRI = 
magnetic resonance imaging; NMO/NMOSD = neuromyelitis optica/neuromyelitis optica spectrum disorders; 
RCP = Randomized-controlled Period. 
 
Every effort should be made to initiate rescue therapy only after full assessment is conducted 
and the NMO/NMOSD attack has been diagnosed in accordance with the protocol-defined 
criteria. However, the investigators can at any time decide to initiate rescue therapy if, in their 
clinical judgment, the subject will be at unacceptable risk if such therapy is not immediately 
initiated. 
Adjudication Process (For Attacks Occurring During the RCP) 
The entire data generated during the Assessment Visit of the potential attack will be provided 
to the AC upon completion of the assessment. The adjudication process will be completed 
when the AC makes their final decision, which will occur in a total of 14 days (+ 3 days) from 
the start of the Assessment Visit.  


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The data set that will be delivered to the AC will be identical to the data set generated and 
used by the Principal Investigator to make the diagnosis of NMO/NMOSD attack and will 
include the following:  
x 
Description of the new or worsening symptom 
x 
Findings of physical and neurological examination 
x 
Relevant laboratory test results 
x 
Relevant x-ray studies, if performed in relation to the assessment 
x 
Expanded Disability Status Scale score as determined by the independent assessor 
x 
Ophthalmology examination results done by an independent ophthalmologist 
x 
Magnetic resonance imaging scans if done as required by certain protocol attack criteria 
x 
Short narrative written by the Principal Investigator to summarize the assessment 
WITHOUT disclosing if an NMO/NMOSD attack was diagnosed (narrative template will 
be provided by the Sponsor)  
 
The data set will be provided to the independent AC by the vendor according to the 
Adjudication Committee Charter (see Section 4.3.1.5). 
The AC will not be provided with the Principal Investigator’s opinion of whether an 
NMO/NMOSD attack has occurred, nor will the AC receive information about which protocol 
attack criterion was met or whether a rescue medication was provided. 
The decision by the AC will be communicated to the Principal Investigator at the clinical site. 
At this point the following scenarios will be possible: 
1 
Subjects for whom the NMO/NMOSD attack was determined by the AC will have the 
option to enter the OLP. If the subject decides not to enter the OLP, the subject will then 
enter the SFP. 
2 
Subjects for whom the NMO/NMOSD attack was not determined by the AC will 
continue in the RCP.  
 
In addition, the dataset that was generated and used by the Principal Investigator to assess the 
symptom(s) that were determined not to be related to NMO/NMOSD will be delivered to the 
AC for review and will include the following: 
x 
Description of the new or worsening symptom 
x 
Findings of physical and neurological examinations 
x 
Relevant laboratory test results 
x 
Relevant x-ray studies, if performed in relation to the assessment 
x 
Any other work-up that was performed to assess the symptom(s) 


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Adjudication Process (For Attacks Occurring During the OLP) 
The data generated during the Assessment Visit and the full assessment of the potential attack 
will be provided to the AC and follow the same process as described above for the RCP.  
The data to be adjudicated will be provided to the independent AC by the vendor according to 
the Adjudication Committee Charter (see Section 4.3.1.5).  
Regardless of the decision made by the AC, the subject may choose to continue in the OLP or 
withdraw from the OLP and enter the SFP.  
4.3.1.2 
Neuroaxis Magnetic Resonance Imaging Scan 
MRI for All Subjects 
All subjects will have a full neuroaxis MRI scan, including optic nerve, spinal cord, and brain 
performed at screening to determine eligibility and establish a baseline (see Section 4.2.1). In 
the event a subject is re-screened a full neuroaxis MRI need not be repeated if the previous 
study neuroaxis MRI was conducted within the 3 months prior to the rescreening visit. A 
neuroaxis MRI scan will be repeated at 28 weeks in subjects who complete the RCP without 
having experienced an NMO/NMOSD attack. Subjects who discontinue the RCP due to the 
occurrence of the 67th AC-determined attack who have had an MRI in the last 3 months need 
NOT repeat the MRI. During the OLP, neuroaxis MRI scans will be performed every 52 
weeks. All MRI scans will be centrally read and data collected for analysis at the end of the 
study. 
The Principal Investigator at the site should not use these MRIs for any clinical decision 
making, but review of the brain MRI is acceptable if there is a safety alert from the central 
MRI reader indicating the presence of a new lesion(s). 
MRI for NMO/NMOSD Attacks 
In addition to the scheduled MRIs, at the time of any Assessment Visit, a full neuroaxis MRI 
scan will be performed of all domains. These scans will be sent for a central reading and data 
will be collected for analysis at the end of the study. MRI images/study report obtained during 
an Assessment Visit should not be reviewed by the Principal Investigator unless a specific 
criterion for an attack requires review of the MRI (Table 11). In such cases review of the MRI 
image and local report MUST be done AFTER the review of all relevant clinical assessment 
data is complete.   
The Principal Investigator at the site should not use these MRIs for any clinical decision 
making. Additionally, the Principal Investigator should NOT use the MRI to make any 
decisions regarding the potential severity of an NMO/NMOSD attack; rather it should only be 
used to confirm the clinical presentation. The MRI scan will also be read centrally, and the 


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central report and image will be used by the AC for the adjudication of the NMO/NMOSD 
attack.  
Neuroaxis MRI Documentation and Assessment 
All MRI scans are to be performed at the study site. To ensure that MRI scans are of 
acceptable quality for viewing the optic nerve, spinal cord, and brain, the settings and 
procedures (specified by the central reader) to be used for the MRI scanners are mandated at a 
minimum standard and defined in the MRI Imaging Manual (provided separately). The site 
will be required to perform a qualification MRI scan to send to the central reading site to 
ensure compliance with the requirements for the study. Qualification MRI scans may require 
consenting a volunteer subject from the investigative site, depending on local Institutional 
Review Board/Ethics Committee (IRB/EC) requirements. 
All MRI images from the site will be date and time stamped and sent to the central imaging 
vendor that is independent of the study sites. The images will be read by 2 independent neuro-
radiologists at the central reading site for a consensus read and central reporting.  The MRI 
reports and scans produced as part of the protocol-defined criteria for an NMO/NMOSD 
attack will be sent from the central reading site to the AC as part of the assessment data to be 
adjudicated.  
4.3.1.3 
Independent Ophthalmology Assessments 
The protocol-defined ophthalmology assessment will consist of a high- and low-contrast 
visual acuity test, and assessment for relative afferent pupillary defect (RAPD).  
All examinations must be conducted by an ophthalmologist or another site member with 
appropriate training and experience who is independent of the investigator and the subject. If 
possible, the same person should review a single subject through every ophthalmology 
assessment. The data generated from the ophthalmology assessments will be entered directly 
into an electronic data capture device provided to the site with a date and time stamp. In order 
to minimize bias, the ophthalmology examiner will not have access to prior visual acuity 
scores or RAPD findings at the time of a new evaluation. The ophthalmology examiner will 
be instructed NOT to elicit or discuss the subjects’ experiences or AEs on the study.  
Ophthalmology assessments will be completed at screening, Day 1, at scheduled study visits, 
and Assessment Visits, according to the schedule of procedures in Table 5, Table 6, Table 7, 
Table 8, and Table 9.  
In the event that a subject has new or worsening symptoms related to NMO/NMOSD, all 
ophthalmology assessments will also be performed at an Assessment Visit.  
The ophthalmology examiner will provide a full report of the examination findings, in 
accordance with protocol-defined parameters, to the investigator to review against a subject’s 


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previous reports and to determine if the findings meet 1 or more of the protocol-defined 
criteria for ON attack. 
Visual Acuity Assessments 
For the purposes of this study, visual acuity will be measured using Landolt C Broken Ring 
Chart (both high and low contrast). Best-corrected monocular and binocular vision will be 
tested. 
Visual acuity tests are used to determine the smallest characters that can be read on a 
standardized chart. The Landolt C Broken Ring Chart has a standardized format designed to 
be equally detectable for normal observers consisting of an incomplete ring resembling the 
letter “C.” The width of the break and the ring are each one-fifth of its overall diameter. The 
subject must indicate where the break is located, the break being positioned in any direction. 
Each line has 5 rings and the spacing between the rings and the lines is proportional to the ring 
size. The change in visual acuity from one line to the next occurs in equal logarithmic steps. 
To standardize the method of assessment, the charts must be used in a retro-illuminated Early 
Treatment Diabetic Retinopathy Study (ETDRS) cabinet to eliminate the need for 
standardization of height and room lighting.  
Charts and wheeled light cabinets will be supplied to all sites.  
To ensure consistency of visual acuity testing across subjects and study sites, the following 
set-up and procedures are required: 
Low-contrast Visual Acuity 
x 
Charts must be used with a retro-illuminated ETDRS cabinet 
x 
Use a well-lit room, but one not exposed to full sunlight to not distract from the subject’s 
normal eyesight 
x 
Use overhead lights to provide an even distribution of light across the room 
x 
Prevent distractions and limit movement in the room 
x 
Position the subject at a distance of 3 meters from the chart 
x 
Test best-corrected monocular and binocular vision 
x 
Ask the subject to describe the top line of the chart from left to right. Record the number 
of rings that the subject successfully describes as the subject describes them. If subject 
cannot easily read the rings, ask the subject to guess.  
x 
Ask the subject to continue reading each subsequent line below the top line until the 
subject reaches a line where all the rings cannot be made out. Record the number of rings 
that the subject successfully describes as the subject reads them  
x 
Compare the subject’s results against the actual rings on each line of the chart 
x 
The last line the subject is able to see and read correctly determines the score 


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High-contrast Visual Acuity 
x 
Use a well-lit room, but one not exposed to full sunlight to not distract from the subject’s 
normal eyesight 
x 
Use overhead lights to provide an even distribution of light across the room 
x 
Prevent distractions and limit movement in the room 
x 
Position the subject at a distance of 3 meters from the chart 
x 
Test best-corrected monocular and binocular vision 
x 
Ask the subject to describe the top line of the chart from left to right. Record the number 
of rings that the subject successfully describes as the subject views them. If subject cannot 
easily read the rings, ask the subject to guess.  
x 
Ask the subject to continue describing each subsequent line below the top line until the 
subject reaches a line where all the rings cannot be made out. Record the number of rings 
that the subject successfully describes as the subject reads them 
x 
Compare the subject’s results against the actual rings on each line of the chart 
x 
The last line the subject is able to see and read correctly determines the score 
 
The following visual acuity data are to be reported by the ophthalmology examiner: 
x 
Low-contrast visual acuity score for each eye separately and both eyes together 
x 
High-contrast visual acuity score for each eye separately and both eyes together 
x 
If a subject cannot read any lines on the chart, visual acuity will be tested by counting 
fingers (CF), hand movement (HM), or light perception (LP) at 1 meter, or no light 
perception (NLP)/total blindness. 
 
Assessment of Relative Afferent Pupillary Defect 
For the purposes of this study, RAPD will be assessed by the “swinging light test,” a method 
of detecting differences between the two eyes in how the pupils respond to light shone in one 
eye at a time. This test must be administered by an ophthalmologist or another site member 
with appropriate training and experience (ie, not the investigator) and in accordance with 
standard of care at the institution. If possible, the same ophthalmology examiner should 
review a single subject through every assessment. 
The RAPD test can be useful in detecting unilateral or asymmetric disease of the retina or 
optic nerve. The physiological basis of the test is that in healthy eyes the reaction of the pupils 
in the left and right eyes are linked; that is, a bright light shone in one eye will lead to equal 
constriction of both pupils. A RAPD is present if the initial consensual pupillary constriction 
is greater than the initial direct pupillary constriction. 


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The following procedures are recommended: 
x 
Perform the test in a semi-darkened room. If the room is too dark it will be difficult to 
observe pupil responses, particularly in heavy pigmented eyes 
x 
Use a bright torch such as a small flashlight that can be focused to provide a narrow, even 
beam of light 
x 
Ask the subject to focus on a distant object and keep looking at it – use a chart or picture 
as an object of focus 
x 
Move the flashlight from side to side so the beam of light shines directly into each eye. 
Do not swing the beam from side to side around a central axis (eg, by holding it in front 
of the subject’s nose) as this can stimulate the near response 
x 
Keep the light source at the same distance from each eye to ensure the light stimulus is 
equally bright in both 
x 
Keep the beam of light steadily on the first eye for at least 3 seconds to allow the pupil 
size to stabilize. Note whether the pupil of the eye being illuminated reacts briskly and 
constricts fully to the light. Also note the response in the other eye – does it also constrict 
briskly? 
x 
Move the light quickly to shine in the opposite eye. Hold the light steady for at least 
3 seconds. Note whether the pupil of the eye being illuminated stays the same size, or 
whether it gets bigger. Note the response in the opposite eye.  
x 
Repeat the test, observing the response of the pupils of both eyes when one and then the 
other is illuminated. 
 
The RAPD results will be reported as follows: 
x 
Date and time of examination 
x 
Presence or absence or loss of RAPD in either eye 
x 
If RAPD is present, record pupillary responses on a scale of 1+ to 5+ for each eye 
according to the criteria in Table 12. 
 
Table 12 
Pupil Response Scoring Criteria for Relative Afferent Pupillary 
Defect  
Score 
Definition 
1 + 
Weak initial constriction and greater re-dilatation 
2 + 
Initial stall and greater re-dilatation 
3 + 
Immediate pupillary dilatation 
4 + 
Immediate pupillary dilatation following prolonged illumination of the good eye for 6 seconds 
5 + 
Immediate pupillary dilatation with no secondary constriction 
Source: Bell et al, 1993.  
 


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On receipt of the full examination results from the ophthalmology examiner, the investigator 
must compare the results against the last assessment.  
4.3.1.4 
Expanded Disability Status Scale and Functional Systems Scores 
The EDSS and its associated FSS provide a system for quantifying disability and monitoring 
changes in the level of disability over time. The EDSS scores and FSS will be captured and 
date and time stamped using electronic data capture. Standardized guidance for the assessment 
of the EDSS and FSS has been developed, including a set of definitions for the EDSS and 
FSS. The latest version of the EDSS/FSS is version 04/10.2, which will be used in this study 
(Kappos et al, 2015; Kurtzke, 1983; D’Souza et al, 2016). 
The EDSS ranges from 0 (normal neurological exam) to 10 (death from MS), with half steps 
from 1.0 to 9.5. Increasing values represent a higher grade of impairment and disability. The 
EDSS steps 1.0 to 5.0 refer to patients with MS who are able to walk without any aid and are 
defined more by the results of the 7 Functional Systems (FS; Visual FS, Brainstem FS, 
Pyramidal FS, Cerebellar FS, Sensory FS, Bowel and Bladder FS, and Cerebral FS). Each FS 
is structured in grades from 0 to 5 or 6 (only the Visual FS has a maximal grade 4 after 
conversion). The EDSS steps Ӌ 5.5 are exclusively defined by the ability to ambulate, the 
assistance required, or the use of a wheelchair. The EDSS and FSS are provided in    
Appendix 4. 
The EDSS assessment will be completed at screening, Day 1 of the RCP, at scheduled study 
visits, and Assessment Visits, according to the schedule of procedures in Table 5, Table 6, 
Table 7, Table 8, and Table 9. The assessment must be conducted by a trained and certified 
neurologist (so called EDSS examiner) who is independent of the treating physician (so called 
investigator) and the subject. A back-up EDSS examiner must be available so that EDSS 
assessments can be made at the time of an NMO/NMOSD attack. The same EDSS examiner 
should perform the assessment for individual subjects for the duration of the study to ensure 
consistency with assessment, if possible. MedImmune will provide training to all EDSS 
examining investigators and collect documented evidence of training prior to allowing 
administration of the EDSS for the purposes of the study. The data generated from the 
examination will be captured electronically. In order to minimize bias, the EDSS examiner 
will not have access to prior EDSS/FSS at the time of a new evaluation. The EDSS examiner 
will be instructed NOT to elicit or discuss the subject’s experiences or AEs on the study.  
4.3.1.5 
Independent Adjudication Committee 
Three experts in NMO/NMOSD disease will constitute the independent AC. This committee 
has the mandate to evaluate each data set that is generated during the Assessment Visit and 
determine if an NMO/NMOSD attack occurred based on the clinical presentation, 
assessments, and the protocol-defined criteria for an NMO/NMOSD attack. The committee is 
completely independent and blinded to treatment assignments and/or to pertinent treatment 


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unmasking information (eg, B-cell counts, AQP4-IgG titers post-randomization) of study 
subjects, and to any decision made by the Principal Investigator regarding an NMO/NMOSD 
attack. The committee will use its judgement and clinical experience to make its determination 
based on the data provided. The committee will review the same data that are available to the 
Principal Investigator when he/she makes his/her determination about the attack. In 
exceptional cases, determined and justified by the committee as such, the committee can 
request to review additional data that is essential to make a determination. The committee’s 
role, function and procedures are governed by a separate charter.  
The data from all subjects who are assessed at an Assessment Visit due to a new symptom(s) 
or worsening of an existing symptom(s) related to NMO/NMOSD will be sent for adjudication 
by the AC regardless of whether the Principal Investigator has determined that an 
NMO/NMOSD attack has occurred. Furthermore, the AC will not receive information about 
which protocol attack criterion was met and the rescue medication utilized.  
Determination of an NMO/NMOSD attack by the AC is for the purpose of determining which 
events will be included in the primary analysis. It will NOT affect the rescue therapy that a 
subject may receive.   
Only subjects in whom the attack was determined by the AC will be given the option to enter 
the OLP.  
In addition, the data set that was generated and used by the Principal Investigator to assess the 
symptom(s) that were determined not to be related to NMO/NMOSD in the RCP, will be 
delivered to the AC for a non-real-time review. 
4.3.1.6 
Healthcare Resource Utilization 
The Healthcare Resource Utilization (HCRU) information is collected to quantify the impact 
of disease and treatment on the subject’s scheduled and medical facility visits. The HCRU 
information related to NMO/NMOSD will be elicited using a subject diary.  
At each scheduled study visit, all subjects will be provided with a paper diary and asked to 
complete these for the duration of their participation in the study. At each visit, the diary will 
be returned to the site and the data will be reviewed by the investigator. The diary will 
constitute source data and will be retained by the site. 
In-patient hospitalization, for the purposes of analysis of the secondary endpoint, is defined as 
a stay in a hospital that goes beyond midnight of the first day of admission. Any duration of 
stay (calculated as the difference between discharge date and admission date) of more than 1 
day will contribute to this endpoint. This includes the time a subject may enter an emergency 
department plus subsequent admission to a ward. Hospitalizations for the administration of 
NMO-related medications or procedures only (ie, the administration or procedure was isolated 


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and not provided during a subject’s hospitalization due to NMO for another reason) will not 
be included in the secondary endpoint analysis. 
Information will be collected throughout the RCP and the OLP on all NMO/NMOSD-related 
HCRU visits as presented in Table 13. 
Table 13 
Healthcare Resource Utilization Information to be Collected and 
Frequency 
Parameter 
Frequency 
Ambulance transport 
Total number of times since the last visit 
Visits to primary healthcare physician 
Total number of times since the last visit 
Emergency Room/Department visits 
Total number of times since the last visit 
Hospitalization (general care) 
Total number of days since the last visit 
Hospitalization (intensive care) 
Total number of days since the last visit 
Other healthcare visits (eg, physiotherapist) 
Total number of times since the last visit 
Home visit from a physician 
Total number of times since the last visit 
Home visit from a nurse 
Total number of times since the last visit 
 
Subjects will also be asked to record any medical procedures they undergo for their 
NMO/NMOSD (outside of scheduled study procedures) in the diary. 
4.3.2 
Patient-reported Outcomes 
Patient-reported outcome (PRO) is an umbrella term referring to all outcomes and symptoms 
that are directly reported by a subject. Patient-reported outcomes, including HRQoL, have 
become significant endpoints when evaluating effectiveness of treatments in clinical trials. 
Five separate pain NRS and the Short Form 36 Health Survey version 2 (SF-36v2) have been 
selected for this study and will be administered at time points indicated in Table 6 and 
Table 8. 
4.3.2.1 
Pain NRS 
Eleven-point pain NRS will be used to capture a subject’s worst pain levels experienced in the 
eyes, upper back, lower back, arms, and legs, where 0 = no pain and 10 = worst pain 
imaginable. The subject will be asked to rate the pain he/she has experienced in each of the 5 
locations over the past 24 hours. 
The pain NRS will be completed according to the schedule of procedures in Table 5, Table 6, 
Table 7, Table 8, and Table 9. 


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4.3.2.2 
Short Form-36 Health Survey 
The SF-36v2 is a validated, generic health survey that captures information about functional 
health and well-being from the patient’s perspective. The SF-36v2 is for adults aged 18 years 
and older and it can be used across all diseases. The SF-36v2 consists of 36 items and 
measures eight domains (see Appendix 6). These are Physical Functioning, Role Physical, 
Bodily Pain, General Health, Vitality, Social Functioning, Role Emotional, and Mental 
Health. The standard recall period of the SF-36v2 is 4 weeks with response options for each of 
the 36 items ranging from 1-3 (10 items), or 1-5 (26 items). The SF-36v2 is a self-completed 
paper-based survey, available in multiple modes of administration and can be completed in 
5 to 10 minutes. Translations are available for multiple countries and languages.  
As well as a profile of the eight domain scores, the SF-36v2 provides psychometrically-based 
PCS and MCS scores. The scores range from 0-100, with a higher score indicting better health 
and well-being. The scores are calibrated so that 50 is the average score or norm with a 
standard deviation of 10. 
The SF-36v2 with a 4-week recall period will be used at 3-monthly intervals throughout the 
study to evaluate HRQoL for the duration of the subject’s participation in the study. 
If a subject has an Assessment Visit, the subject will be asked to complete the SF-36 acute 
version (1-week recall) to capture the impact of the attack on HRQoL. These data will be used 
primarily for health economic purposes with the generation of an attack utility profile.  
4.3.2.3 
Collection of PRO Endpoints 
Standard procedures for minimizing bias and enhancing PRO compliance will be followed 
throughout the study. Site assessments of PROs should be made prior to any other site 
activities and encounters with physician, with exception of an Assessment Visit wherein 
procedures to identify an NMO/NMOSD attack will take precedence. The subjects will be 
instructed to complete the PROs independently. The site will have a designated quiet space for 
subjects to use when completing the assessments. Dedicated investigational staff at the site 
will be responsible for ensuring that the PRO administration will be followed according to the 
specific instructions from the clinical study team. The site staff will be required to monitor 
that the subjects have completed the appropriate PRO instruments in their entirety during the 
site visits.  
4.3.3 
Medical History and Physical Examination, Electrocardiogram, 
Weight, Vital Signs, and Chest X-ray 
4.3.3.1 
Medical History 
A complete medical history will be completed during screening. The subject’s full 
NMO/NMOSD disease history will also be captured, including date of original diagnosis of 
NMO/NMOSD, historical AQP4-IgG status, relapse dates and type of relapse (eg, ON, 


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myelitis, brain and brainstem), and treatment for the relapse. Information related to other 
autoimmune diseases (eg, rheumatoid arthritis, Hashimoto’s thyroiditis, systemic lupus 
erythematosus, Sjogren’s syndrome, diabetes, myasthenia gravis, and pernicious anemia) will 
also be captured.  
On Day 1 of the RCP, the medical and disease history will be reviewed and any changes since 
screening will be documented, if applicable.  
4.3.3.2 
Physical and Neurological Examination 
Complete physical and neurological examinations will be performed at intervals designated in 
the schedules of study procedures (see Table 5, Table 6, Table 7, Table 8, and Table 9) and 
include the following examinations: head, eyes, ears, nose and throat, lungs heart, abdomen, 
joints, muscles and soft tissues, nervous system, skin, lymph nodes, mental status, cranial 
nerves, nystagmus, motor system - muscle strength,  sensory system - sensation, bowel and 
bladder function, deep tendon reflexes, gait, station, coordination, and other. Additional 
neurological exams may be conducted according to local practice. 
In the event that a new abnormality is identified, the investigator should perform further 
investigations according to clinical judgment.  
Any abnormalities should be reported as AEs or signs/symptoms of NMO as applicable. 
4.3.3.3 
Body Weight and Height 
Height will be measured at screening. Body weight will be measured at screening and at Days 
1, 85, and 197 of the RCP. 
Any abnormalities should be reported as AEs or signs/symptoms of NMO/NMOSD as 
applicable. 
4.3.3.4 
Electrocardiogram 
Electrocardiogram (ECG) recordings will be evaluated at screening, Day 1, Day 197, and at 
the Assessment Visit as presented in Table 5, Table 6, and Table 8. These will be performed 
as per local investigative site procedures. The principal investigator or qualified designee will 
review and indicate if the ECG is normal, abnormal (clinically significant), or abnormal (not 
clinically significant). Any medically significant changes from the screening ECG will be 
recorded as an AE or SAE. The QTc interval measurements will be recorded for all subjects.  
Any abnormalities should be reported as AEs or signs/symptoms of NMO as applicable. 


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4.3.3.5 
Vital Signs 
Vital signs (body temperature, blood pressure [BP], pulse rate, and respiratory rate) will 
be evaluated at screening, and at various time points as outlined in Table 5, Table 6, Table 7, 
Table 8, Table 9, and Table 10.  
Vital signs should be within 60 minutes prior to investigational product administration, every 
15 minutes (± 5 minutes) during the infusion, immediately (+ 5 minutes) after the end of the 
infusion, and then every 30 minutes (± 5 minutes) for 2 hours after dosing or until stable, 
whichever is later.  
Any abnormalities should be reported as AEs or signs/symptoms of NMO/NMOSD as 
applicable. 
It is important that body temperature is assessed in order to evaluate the subjects of any signs 
of infection or infusion reaction, especially when assessing for potential attacks.  
4.3.3.6 
Chest X-ray 
A screening chest x-ray (anterior/posterior and lateral) will be mandatory if, in the opinion of 
the investigator, the subject has a previous history of or a suspected pulmonary infection or 
disease. The chest x-ray will be performed during the screening period. The chest x-ray may 
be substituted with documentation of a previous chest x-ray performed within the previous 
3 months that meets the inclusion criteria. A previous computerized tomography evaluation of 
the lungs may be substituted for the chest x-ray if performed within the last 3 months. 
4.3.4 
Columbia-Suicide Severity Rating Scale 
In 2012, the United States Food and Drug Administration/Center for Drug Evaluation 
(US FDA/CDER) mandated that prospective suicidal ideation and behavioral assessments be 
conducted in clinical trials using investigational products that may be used for or appear to 
have an effect on the CNS.  
The Center for Suicide Risk Assessment and Columbia University Department of Psychiatry 
developed the Columbia-Suicide Severity Rating Scale (C-SSRS) to assess suicide risk. The 
C-SSRS is unique in that it assesses both suicidal behavior and predicts future attempts. The 
C-SSRS is used extensively across primary care, clinical practice, surveillance, research, and 
institutional settings.  
The C-SSRS involves a series of probing questions that inquire about possible suicidal 
thinking and behavior, and classifies these events of interest into 11 categories of interest as 
part of the assessment process. The terminology considered important includes 5 levels of 
suicidal ideation, 5 levels of suicidal behavior, and the category “self-injurious behavior, no 
suicidal intent.” A different version of the C-SSRS is administered at different visits during 
the study. The Sponsor will be responsible for ensuring the relevant site staff are appropriately 


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trained in the C-SSRS. Documented evidence of training of the sites will be required prior to 
C-SSRS administration to subjects in the study.  
The “Baseline/Screening” questionnaire will be administered at screening (Appendix 7). This 
version of the scale combines the “Baseline” and “Screening” versions to assess suicidality in 
a patient’s lifetime and over the 6 months prior to screening. This version can assess a 
subject’s lifetime suicidality for data collection purposes. Although the C-SSRS is a detailed 
interview, the full questionnaire is needed only if the initial screening questions regarding 
suicidal ideation and behavior are positive. Typically, the assessment takes approximately 1 to 
2 minutes for those who have no positive findings and no more than 10 minutes for subjects 
who may have a number of positive findings requiring further probing questions.  
The “Since Last Visit” version of the C-SSRS will be administered at all scheduled visits and 
Assessment Visits during the RCP, all visits during the OLP, and every visit during the SFP 
for all subjects randomized into the study. The “Since Last Visit” version assesses suicidality 
since the subject’s last visit. This version is used to assess subjects who have completed at 
least one initial C-SSRS assessment and should be used during the RCP and the OLP. The 
“Since Last Visit” version assesses any suicidal thoughts or behaviors that the subject may 
have had since the last time they were administered the C-SSRS (Appendix 8). 
In the event that a subject is considered to be at risk based on the outcome of the C-SSRS, the 
investigator should treat the subject according to their clinical judgment and report the AE 
according to AE/SAE definitions and reporting requirements outlined in this protocol (see 
Section 5.1, Section 5.2, and Section 5.4.  
4.3.5 
Modified Rankin Scale 
The modified Rankin Scale (mRS) is a commonly used scale for measuring the degree of 
disability or dependence in the daily activities of people who have suffered a stroke or other 
causes of neurological disability (Farrell et al, 1991; van Swieten et al, 1988).  
The mRS ranges from 0 to 6, ranging from perfect health without symptoms to death as 
follows:  
x 
0 - No symptoms 
x 
1 - No significant disability. Able to carry out all usual activities, despite some symptoms 
x 
2 - Slight disability. Able to look after own affairs without assistance, but unable to carry 
out all previous activities 
x 
3 - Moderate disability. Requires some help, but able to walk unassisted 
x 
4 - Moderately severe disability. Unable to attend to own bodily needs without assistance, 
and unable to walk unassisted 
x 
5 - Severe disability. Requires constant nursing care and attention, bedridden, incontinent 


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x 
6 - Dead 
 
4.3.6 
Clinical Laboratory Tests 
A Laboratory Manual will be provided to the sites that specifies the procedures for collection, 
processing, storage, and shipment of samples, as well as laboratory contact information, 
specific to this clinical research study.  
Clinical laboratory safety tests, including serum pregnancy tests, will be performed in a 
central clinical laboratory. Urine pregnancy tests may be performed at the site using a licensed 
test (dipstick); TB test will be performed at the site. Abnormal laboratory results should be 
repeated as soon as possible (preferably within 24 to 48 hours). Blood samples should be 
collected with subject in a fasting state. In addition, abnormal laboratory results may be 
graded according to National Cancer Institute (NCI) Common Terminology Criteria for 
Adverse Events V4.0 (NCI, 2009). 
The following clinical laboratory tests will be performed (see Table 5, Table 6, Table 7, 
Table 8, and Table 10 for the schedule of tests):  
Serum Chemistry 
• 
Calcium 
• 
Gamma glutamyl transferase (GGT)
• 
Chloride 
• 
Lactic dehydrogenase (LDH)
• 
Magnesium 
• 
Uric acid
• 
Potassium 
• 
Creatinine
• 
Sodium 
• 
Blood urea nitrogen (BUN)
• 
Bicarbonate 
• 
Glucose
• 
Aspartate transaminase (AST) 
• 
Albumin
• 
Alanine transaminase (ALT) 
• 
Total protein
• 
Alkaline phosphatase (ALP) 
• 
Triglycerides
• 
Total bilirubin 
• 
Cholesterol
Note for serum chemistries: Tests for AST, ALT, ALP, and total bilirubin must be conducted concurrently and 
assessed concurrently.  
 
Hematology 
• 
White blood cell (WBC) count with differential 
• 
Platelet count 
• 
Red blood cell (RBC) count 
• 
Mean corpuscular volume (MCV) 
• 
Hematocrit 
• 
Mean corpuscular hemoglobin concentration 
(MCHC) 
• 
Hemoglobin 
• 
Hemoglobin A1c (subjects with diabetes only) 
• 
Coagulation: prothrombin time (PT), activated 
partial thromboplastin time (aPTT), 
international normalized ratio (INR) 
 
 


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Urinalysis 
• 
Color 
• 
Glucose 
• 
Appearance 
• 
Ketones 
• 
Specific gravity 
• 
Blood 
• 
pH 
• 
Bilirubin 
• 
Protein 
• 
Microscopy including WBC/high power field 
(HPF), RBC/HPF 
 
Pregnancy Test (females of childbearing potential only) 
• 
Urine human chorionic gonadotropin (HCG) 
• 
Serum beta-HCG (at screening only) 
 
Other Safety Tests 
• 
Hepatitis B surface antigen, hepatitis B core antibody (anti-HBc), hepatitis B surface antibody, hepatitis C 
antibody 
• 
Tuberculosis (TB) test (eg, QuantiFERON-TB Gold test) if applicable, as per local standard of care 
guidelines, at screening only) 
• 
Human immunodeficiency virus (HIV)-1,-2 antibody (screening only) 
• 
Polyomavirus JCV antibody titers (serum to be collected at screening only and frozen for future testing, if 
required).  
• 
In a case of suspected PML, a CSF sample for JCV DNA polymerase chain reaction (PCR) will be 
collected and frozen immediately. 
• 
Tetanus vaccination titers 
• 
Total Ig, IgM, IgG, IgA, IgE 
 
Other Tests 
• 
Serum autoantibodies 
 
Estimated Glomerular Filtration Rate 
The estimated GFR must be ≥ 60 mL/minute for study eligibility to minimize the risk of 
developing nephrogenic systemic fibrosis upon receiving Gd-containing contrast agents. The 
estimated GFR will be calculated by the central laboratory based on the plasma and urine 
creatinine samples provided using the Modification of Diet in Renal Disease formula. 
Glomerular filtration rate eligibility must be confirmed by the site on receipt of the central 
laboratory report and prior to randomization.  
Vaccination Titers 
Serum samples for anti-tetanus vaccine antibody titers will be collected from all subjects 
according to the schedules of procedures in Table 6 and Table 7. The assay will be conducted 
by the central laboratory and further details will be provided in the Laboratory Manual.  


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Because MEDI-551 may reduce vaccine titers, the levels reported for this study by the central 
laboratory will not be made available to the sites or to the sponsor at any point during the 
study prior to unmasking of the study. 
4.3.7 
Pharmacokinetic Evaluation and Methods 
Samples for MEDI-551 serum concentration will be collected according to the schedules of 
procedures in Table 6. 
Serum samples will be measured for MEDI-551 levels by MedImmune using a validated 
immunoassay. Detailed procedures for sample collection, processing, storage, and shipment 
are presented in the Laboratory Manual provided to each study site. 
4.3.8 
Immunogenicity Evaluation and Methods 
Serum samples for ADA will be collected from all subjects according to the schedules of 
procedures in Table 6, Table 7, Table 8, and Table 10. 
Samples will be measured for the presence of ADA by MedImmune using a validated, 
drug-tolerant solution phase bridging assay. Tiered analyses will be performed to include 
screening, confirmatory, and titer assay components and positive-negative cut points will be 
employed that were statistically determined from drug naive validation. Evaluations will be 
performed at baseline prior to administration of investigational product and at routine time 
points during the treatment and follow-up phase of the study or at discontinuation.  
4.3.9 
Biomarker Evaluations and Methods 
Samples for measurement of biomarkers listed below will be collected according to the 
schedules of procedures in Table 6, Table 7, and Table 8. Detailed procedures for sample 
collection, processing, storage, and shipment are presented in the Laboratory Manual provided 
to the study site 
Serum for AQP4-IgG Serostatus Assay 
The AQP4-IgG serostatus assay will be used to determine AQP4-IgG serostatus for 
stratification purposes. The assay will be conducted by a central laboratory using a 
commercially available visual fluorescence-observation cell binding assay (EUROIMMUN) 
that has been validated to Clinical Laboratory Improvement Amendment/College of American 
Pathologists standards. The method involves detection of IgG binding to cells expressing 
recombinant AQP4. The serostatus of each subject will be provided to the site prior to 
randomization.  
The screening, baseline, and study visit assays used to determine AQP4-IgG titer will be 
conducted by a central laboratory using a quantitative flow cytometry assay based on binding 
of IgG to cells transfected with AQP4. Serum will be collected for the measurement of serum 


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AQP4-IgG by flow cytometry at visits specified in Table 5, Table 6, Table 7, Table 8, and 
Table 9.  
Because MEDI-551 is hypothesized to reduce AQP4-IgG titers the AQP4-IgG titer levels 
reported for this study by the central laboratory will not be made available to the sites or the 
sponsor at any point during the study prior to unmasking of the study. 
Whole Blood for Flow Cytometry 
Whole blood samples for quantification of relevant immune cells will be collected 
according to the schedules of procedures in Table 5, Table 6, Table 7, Table 8, Table 9, and 
Table 10. Flow cytometry performed at a central laboratory will be used to enumerate B-cell, 
T-cell, and natural killer (NK)-cell levels and to conduct immunophenotyping analyses of 
various B-cell subsets. 
MEDI-551 is known to deplete CD19+ B cells. Therefore, in this study, the results of flow 
cytometry for B-cell counts could potentially be unmasking. For this reason, these data will 
not be made available to the sites or the sponsor from post-randomization through the 
remainder of the study prior to unmasking of the study. 
Whole Blood for Gene Expression  
Whole blood samples will be used to isolate messenger ribonucleic acid (mRNA) and assess 
the effect of MEDI-551 on a specific plasma cell gene signature. In addition, the effects of 
MEDI-551 on the expression of mRNA in pathways thought to be involved in NMO or related 
to treatment response will be explored. These analyses will be performed using Affymetrix 
whole genome expression array and/or TaqMan®-based assays on selected gene panels. Whole 
Blood will be collected at visits specified in Table 6, Table 7, Table 8, and Table 10. Specific 
procedures for sample collection, processing, storage, and shipment can be found in a separate 
laboratory manual provided to the sites. MEDI-551 is known to reduce the plasma cell gene 
signature. Because the results of the the plasma cell gene signature could potentially be 
unmasking, these samples will not be tested prior to unmasking of the study. 
4.3.9.1 
Exploratory Investigations 
Serum for Exploratory Biomarker Studies 
Serum will be collected for the measurement of exploratory biomarkers at visits specified in 
Table 6, Table 7 and Table 8. The effect of MEDI-551 on relevant protein biomarkers will be 
explored. These studies may include immunoglobulins, specific autoantibodies or 
autoantibody arrays, inflammatory proteins (eg, cytokines and chemokines), or other 
biomarkers and cell-based bioassays that are related to disease mechanisms or the mechanism 
of action of MEDI-551. The presence of autoantibodies to antigens other than AQP4 may be 
explored throughout the study.  


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Whole Blood for DNA Analysis (Optional) 
To investigate genetic characteristics that may be associated with subjects’ clinical responses 
to MEDI-551, the following may be evaluated: polymorphisms in B-cell related genes, 
NK cell-related genes, Fc receptor genes, and changes in antibody or T-cell receptor gene 
sequences.  
The collection of blood for DNA analysis is optional. The completion of a separate ICF 
(Informed Consent Form for Collection of Blood Samples for DNA Analysis) must be signed 
by the subject if blood is to be used for DNA analysis (see Section 4.1.4). Subjects who do not 
wish to have the DNA test will still be eligible for the study. Subjects who elect to have the 
DNA analysis done may, at any time prior to the end of the study, request that the blood 
collected for DNA analysis be destroyed. However, this will only be possible prior to samples 
being de-identified as described below (also see Section 4.1.8).  
All specimen and subject identifiers must be removed from the DNA blood samples such that 
under no circumstances can the DNA blood samples be linked back to a specific subject. In 
most cases, this will require that DNA blood samples have current labeling removed and the 
tubes relabeled. Special labeling capable of adhering to frozen tubes must be used. If it is not 
possible to remove the original labeling, then it must be determined whether the DNA blood 
samples can go through a freeze thaw and be realiquoted in order to maintain confidentiality. 
All re-labeled DNA blood samples must be cross referenced to the original demographics in a 
secure database to ensure that only designated and approved laboratory personnel have access 
to these data. A special release must be obtained prior to use of specified DNA blood samples. 
4.3.10 
Estimate of Volume of Blood to Be Collected 
The estimated volume of blood to be collected from each subject at each visit (and across all 
visits) from screening through the SFP is presented in Table 14. If repeats of any blood tests 
are required, the volume of blood collection will increase accordingly. 
Table 14 
Estimate of Blood Volume to Be Collected 
Visit Day 
Estimated Blood Volume (mL) 
Screening (Day -28 to Day -1) 
31 
Randomized-controlled Period 
Day 1 
37  
Day 8 
16 
Day 15 
30.5 
Day 29 
29.75 
Day 57 
27.5 
Day 85 
34.75  


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Table 14 
Estimate of Blood Volume to Be Collected 
Visit Day 
Estimated Blood Volume (mL) 
Day 113 
25 
Day 155 
20 
Day 197 
37  
Open-label Period 
Open-label Day 1 
19.75 b 
Open-label Day 15 
19 
Open-label Day 29 
26.5 
Open-label Day 92 
36 
Open-label Day 183 
36 
Open-label Day 274, then Q26W 
26.25 
Open-label Day 365, then Q26W 
36 
Assessment Visit 
33.75 
Attack Follow-up Visit 
13.3 
Safety Follow-up Period 
Every 3 months 
12.25 
Total 
547.3 a 
Q26W = every 26 weeks. 
a 
Minimum total volume; maximum volume dependent upon subject duration in the study.  
b 
Only applicable for subjects where Open-label Day 1 is required.  
 
4.4 
Study Suspension or Termination 
The Sponsor reserves the right to temporarily suspend or terminate enrollment, RCP, OLP or 
the entire study at any time for the following reasons:  
1 
The incidence or severity of AEs in this or other studies indicates a potential health 
hazard to subjects 
2 
Subject enrollment is unsatisfactory 
3 
Non-compliance that might significantly jeopardize the validity or integrity of the trial  
4 
Sponsor decision to terminate development 
5 
Sponsor decision to terminate the trial based on a planned futility analysis 
6 
Recommendation of the independent DMC to discontinue enrollment and transition 
subjects from the RCP to the OLP due to evidence of efficacy and safety  
7 
Any other reason which justify this action/actions. 
 


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If MedImmune determines that temporary suspension or termination of the study is required, 
MedImmune will discuss the reasons for taking such action with all participating investigators 
(or head of the medical institution, where applicable). When feasible, MedImmune will 
provide advance notice to all participating investigators (or head of the medical institution, 
where applicable) of the impending action. In the case of the Sponsor discontinuting 
enrollment upon recommendation of the independent DMC based on evidence of efficacy and 
safety, subjects in the RCP at the time enrollment is terminated will be given the option to 
enter the OLP. The rationale for such a decision will be shared and discussed with 
investigators, IRBs, ethic committees, and regulatory agencies where appropriate. In addition, 
detailed procedures for transition of patients from the RCP to the OLP will be provided to the 
investigators in such a case.  
If the study or any part of it is suspended or terminated for safety or efficacy reasons, 
MedImmune will promptly inform all investigators, heads of the medical institutions (where 
applicable), and/or institutions conducting the study. MedImmune will also promptly inform 
the relevant regulatory authorities of the suspension/termination along with the reasons for 
such action. Where required by applicable regulations, the investigator or head of the medical 
institution must inform the IRB/IEC promptly and provide the reason(s) for the 
suspension/termination. If the study is suspended for safety reasons and it is deemed 
appropriate by the Sponsor to resume the study, approval from the relevant regulatory 
authorities (and IRBs/IECs when applicable) will be obtained prior to resuming the study. 
4.5 
Investigational Products 
4.5.1 
Identity of Investigational Product(s) 
MedImmune will provide the investigator(s) with investigational product (Table 15) using 
designated distribution centers.  




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new dose must be prepared using a new vial. The dose preparation must be documented in the 
investigational product accountability log. The same line may be used to administer 
investigational product (MEDI-551 or placebo) as used to administer premedication.  
Investigational Product Inspection 
Each vial selected for dose preparation should be inspected. MEDI-551 is supplied as a clear 
to opalescent, colorless to yellow liquid; free from or practically free from visible particles. 
The placebo is supplied as a clear to opalescent, colorless to yellow liquid; free from or 
practically free from visible particles. MEDI-551 is supplied at a concentration of 10 mg/mL 
for IV infusion after dilution into a 0.9% (weight per volume [w/v]) NaCl IV infusion bag.  
If there are any defects noted with the investigational product, the Investigator and Site 
Monitor should be notified immediately. Refer to the Product Complaint section for further 
instructions. 
Dose Preparation Steps 
Preparation of MEDI-551 or placebo into the IV infusion bag is to be performed aseptically. 
The investigational product manager should remove the tab portion of the vial cap and clean 
the rubber stopper with 70% ethyl alcohol or equivalent. To avoid foaming, the vial should not 
be shaken. A vial should only be used one time to prepare a single dose. 
MEDI-551 and placebo vials do not contain preservatives and any unused portion must be 
discarded. 
MEDI-551 and placebo have been shown to be compatible when diluted into a polyvinyl 
chloride (PVC)-free, di(2-ethylhexyl)phthalate (DEHP)-free, and latex-free infusion bag 
containing a total volume of 250 mL of 0.9% (w/v) NaCl for injection. A single 250 mL 
infusion bag will be prepared for each subject on each dosing day. To prepare each dose, a 
30 mL volume of NaCl must first be removed aseptically from the infusion bag and discarded 
before either MEDI-551 or placebo is added to the bag. Next, a total of 30 mL of 
investigational product must be withdrawn aseptically from the 3 supplied investigational 
product vials in the kit (10 mL per vial) using a syringe and needle and added into the infusion 
bag using aseptic technique. After the investigational product is added to the infusion bag, the 
contents of the bag should be gently mixed to ensure homogeneity of the solution within the 
bag. Do not shake or vigorously agitate the infusion bag.  
MEDI-551 and placebo will be identical in appearance and will be clear to opalescent, 
colorless to yellow liquid, and free from or practically free from particles. The placebo is 
supplied as a clear to opalescent, colorless to yellow liquid, free from or practically free from 
particles. MEDI-551 and placebo doses will not be distinguishable during dose preparation, 
handling, and infusion.  


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Total in-use storage time from needle puncture of the MEDI-551 or placebo vials to start of 
administration should not exceed 4 hours at room temperature or 24 hours at 2°C to 8°C (36°F 
to 46°F). If storage time exceeds these limits, a new dose must be prepared from new vials.  
4.5.1.2 
Treatment Administration 
Randomized-controlled Period 
The first day of dosing is considered Day 1. 
During the RCP, doses of investigational product must be administered according to the study 
schedule (Day 1 and Day 15). In the event that a subject or investigative site is unable to 
adhere to this schedule, a window of r 3 days is permitted at Day 15. In the event that the 
second dose of investigational product (scheduled to be given on Day 15 post randomization) 
is delayed due to a medical/safety reason, dosing must be discussed with the medical monitor 
prior to administration of investigational product.  
If the subject is not dosed within this window they may remain in the RCP. 
Open-label Period 
For subjects completing Day 197 of the RCP, Day 1 of the OLP should be the same day; 
however, it may be delayed for up to 14 days (procedures do not need to be repeated). 
Subjects are not permitted to enter the OLP after 14 days, unless there is a compelling reason 
discussed with, and agreed to by, the medical monitor, in which case a short extension may be 
granted. 
Subjects in the RCP at the time the 67th AC-determined attack occurs or when enrollment is 
discontinued upon recommendation of the independent DMC based on evidence of efficacy 
and safety who wish to enroll in the OLP need to do so as soon as possible, preferably within 
14 days. Consulation with the medical monitor is advised in cases where the transition to the 
OLP is not completed within 14 days.  
The first day of dosing of the OLP is considered OLP Day 1. 
During the OLP, the same schedule as the RCP applies for OLP Day 1 and Day 15. In the 
event that the second dose of investigational product (scheduled to be given on Day 15 of the 
OLP) is delayed due to a medical/safety reason, dosing must be discussed with the medical 
monitor prior to administration of investigational product. For the 6 monthly dosing visits, a 
dosing window of r 7 days will be permitted. If the subject has not returned within the 7-day 
window in the OLP, the investigator must contact the subject and discuss subsequent subject 
management with the medical monitor. Subjects may be withdrawn from study medication 
and enter the SFP at the discretion of the medical monitor. 


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During both the RCP and the OLP, MEDI-551 (300 mg) or placebo will be administered as an 
IV infusion using the following guidelines: 
1 
Women of childbearing potential must have a negative urine pregnancy test prior to 
receiving MEDI-551 or placebo  
2 
Subjects with signs or symptoms of clinically significant infections at the time of 
planned infusion of MEDI-551 or placebo should not be retreated until the infection has 
resolved.  
3 
MEDI-551 or placebo must be administered at room temperature by controlled infusion 
via an infusion pump into a peripheral vein at a rate of 42 mL/hr for the first 30 minutes, 
with the rate escalated in accordance with Table 16, unless an infusion reaction occurs 
necessitating the modulation or stopping of the infusion.  
4 
MEDI-551 or placebo must not be administered via IV push or bolus but as a slow IV 
infusion. The entire content of the IV bag will be infused using an infusion pump using a 
0.22 or 0.2 micron filter. 
 


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Table 16 
Infusion Times for IV Administration of MEDI-551 300 mg or 
Placebo 
Number of IV 
Bags 
Cumulative Time 
(minutes) 
Infusion Rate 
(mL/hour) 
Infusion Rate 
(mg/hour) 
Total mg Infused 
1 
0-30 
42 
50 
25 
31-60 
125 
150 
75 
61-90 
333 
400 
200 
IV = intravenous 
 
5 
A physician must be present at the site or immediately available to respond to 
emergencies during all administrations of MEDI-551 or placebo. Fully functional 
resuscitation facilities should be available. 
6 
At Day 1 and Day 15 of the RCP and OLP Day 1 and OLP Day 15 and at subsequent 
dosing visits in the OLP, all study subjects will be premedicated with IV 
methylprednisolone (80-125 mg or equivalent glucocorticoid), PO acetaminophen 
(500-650 mg) or equivalent dose of paracetamol, and PO diphenhydramine (25-50 mg) 
or equivalent antihistamine, 30 to 60 minutes prior to MEDI-551 or placebo 
administration to mitigate infusion reactions.  
7 
Prior to the start of the infusion, please be sure that the bag content is at room 
temperature to avoid an infusion reaction due to the administration of the solution at low 
temperatures. 
8 
Because of the possible need to vary infusion rates depending on tolerance of the 
infusion, the total infusion time may exceed the time stated in Table 16. UNLESS AN 
INFUSION REACTION OCCURS RESULTING IN DISCONTINUATION, THE 
ENTIRE INFUSION BAG CONTENTS MUST BE ADMINISTERED. 
9 
If there are no requirements to slow, interrupt or permanently stop the infusion, the 
anticipated infusion time to deliver each dose is anticipated to be 
90 minutes ± 15 minutes. 
10 After IV administration, up to an additional 25 mL of saline will be given via infusion 
pump at the same pump speed utilized at the completion of the initial dosing. 
 
The duration of investigational product infusion and duration of investigational product 
administration will be calculated as follows: 
Duration of Infusion Time: The amount of time elapsed from the infusion start time to the 
infusion stop time. Infusion start time is defined as the time point wherein investigational 
product is first infused into the subject. Infusion stop time is defined as the time point where 
the infusion pump completes infusion of the investigational product, not including the slow 
clearing of the infusion line. Beware not to rapidly clear the infusion line containing the 
residual investigational product as it may trigger an infusion reaction. 


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Duration of Administration: The amount of time elapsed from the infusion pump start time 
to the infusion pump stop time PLUS the time required to clear the infusion line of residual 
investigational product. The duration of administration will always be greater than the 
duration of infusion and will always include the slow clearing of the infusion line. 
Both the duration of the investigational product infusion and the duration of investigational 
product administration will be recorded. 
Pharmacokinetic laboratory samples will be collected on Day 1 and Day 15 predose and 
approximately 15 minutes (± 5 minutes) after the completion of MEDI-551 or placebo 
administration.  
If a subject experiences an AE in the OLP that the investigator assesses as related to 
investigational product, the subsequent dose may be delayed up to 14 days from the date of 
the next scheduled dose.  
4.5.1.3 
Monitoring of Dose Administration  
Vital signs (body temperature, BP, pulse rate, and respiratory rate) must be taken with the 
subject in a semi-supine position as follows:  
x 
Within 60 minutes prior to investigational product administration 
x 
Every 15 minutes (± 5 minutes) during the infusion 
x 
Immediately (± 5 minutes) after the end of the infusion 
x 
Every 30 minutes (± 5 minutes) for 2 hours after dosing or until stable, whichever is later  
 
If a hypersensitivity reaction occurs during the infusion, vital signs will be taken more 
frequently, as warranted by the severity of the reaction.  
As with any antibody, allergic reactions to dose administration are possible. Therefore, 
appropriate drugs and medical equipment to treat acute anaphylactic reactions must be 
immediately available, and study personnel must be trained to recognize and treat 
anaphylaxis.  
For Japanese subjects only, the initial dose on Day 1 of the RCP should be administered as a 
patient in-hospital procedure. The subject can be discharged the next day (Day 2) if no 
abnormal findings are observed. 
4.5.1.4 
Reporting Product Complaints 
Any defects with the investigational product must be reported immediately to the MedImmune 
Product Complaint Department by the site with further notification to the site monitor. All 
defects will be communicated to MedImmune and investigated further with the Product 


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Complaint Department. During the investigation of the product complaint, all investigational 
products must be stored at labeled conditions unless otherwise instructed. 
MedImmune contact information for reporting product complaints: 
Email: 
 
Phone: 
 
 
 
 
Fax: 
 
 
Mail: 
MedImmune, LLC 
 
 
Attn: Product Complaint Department 
 
 
One MedImmune Way, 
 
 
Gaithersburg, MD USA 20878 
 
4.5.2 
Additional Study Medications 
4.5.2.1 
Oral Corticosteroid Use 
Subjects will receive 2 weeks of oral corticosteroids (prednisone 20 mg/day or equivalent oral 
glucocorticoid) from Day 1 to Day 14. The following tapering schedule will be implemented 
from Day 15: 
 
15 mg prednisone PO on Day 15 
 
10 mg prednisone PO on Day 16 
 
7.5 mg prednisone PO on Day 17 
 
5 mg prednisone PO on Days 18 and 19 
 
2.5 mg prednisone PO on Days 20 and 21 
 
Sites should utilize local supplies of oral corticosteroids, where possible, and monitor 
compliance. The Sponsor will provide reimbursement during the study. 
4.5.2.2 
Rescue Medications 
Assessment of new symptoms or worsening of existing symptoms should be completed within 
5 days to determine if an attack has occurred. Treatment of an attack should preferably be 
initiated after completion of the attack assessment and the determination that the protocol 
attack criteria have been met. However, the Principal Investigator can initiate rescue therapy 
at any time before full assessment is completed. Rescue therapy will be given as directed by 
the investigator and may include IV corticosteroids, IVIG, and/or PLEX. 
PPD
PPD
PPD
PPD


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Sites should utilize local supplies of IV steroids, where possible, and the Sponsor will provide 
reimbursement during the study.  
All medications provided to the subject during the study will be recorded on the source 
document and include the dose, start and stop dates, frequency, and route of administration 
and reason for product administration. 
4.5.3 
Dose Adjustments and Missed Doses 
Dose adjustments are not permitted in this study. If, in the clinical judgment of the 
investigator, a subject is not well enough to receive investigational product, the dose should be 
omitted. In the event that a dose of investigational product is delayed due to medical/safety 
reasons, dosing and subject management must be discussed with the medical monitor prior to 
administration of further investigational product.   
A dosing window of r 7 days will be permitted at the 6 monthly visits. 
4.5.4 
Labeling
 
Labels will be prepared in accordance with Good Manufacturing Practice (GMP) and local 
regulatory guidelines. The label will fulfill GMP Annex 13 requirements for labeling. Label 
text will be translated into local languages, as required. 
4.5.5 
Storage
 
MEDI-551 or placebo is to be stored at 2°C to 8°C (36°F to 46°F).  
4.5.6 
Treatment Compliance 
Investigational product will be administered by study site personnel, who will monitor 
compliance. 
4.5.7 
Accountability 
The investigator’s or site’s designated investigational product manager is required to maintain 
accurate investigational product accountability records. The MedImmune representative who 
visits the study site to monitor the data will regularly review these records to ensure 
completion and compliance. Upon completion of the study, copies of investigational product 
accountability records will be returned to MedImmune. All unused investigational product 
will be returned to a MedImmune-authorized depot or disposed of upon authorization by 
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4.6 
Treatment Assignment and Masking 
4.6.1 
Methods for Assigning Treatment Groups 
An IVRS/IWRS will be used for randomization to a treatment group and assignment of 
masked investigational product kit numbers. A subject is considered randomized into the 
study when the investigator notifies the IVRS/IWRS that the subject meets eligibility criteria 
and the IVRS/IWRS provides the assignment of masked investigational product kit numbers 
to the subject. 
Subjects will be randomized at a 3:1 ratio with a permuted block randomization scheme to 
receive either MEDI-551 or placebo within each AQP4-IgG stratum determined at screening 
(seropositive versus seronegative). Enrollment will be further stratified by Japan versus non-
Japan region.  
4.6.2 
Methods for Ensuring Masking 
This is a double-masked study in which MEDI-551 and placebo are identically labeled and 
indistinguishable in appearance. As such, neither the subject/legal representative nor any of 
the investigator or Sponsor staff who are involved in the treatment or clinical evaluation of the 
subjects will be aware of the treatment received (ICH E9) (see Section 4.6.4.2 for unmasking 
related to interim analysis). In the event that treatment allocation for a subject becomes known 
to the investigator or other study staff involved in the management of study subjects, the 
Sponsor must be notified immediately. If the treatment allocation for a subject needs to be 
known to treat an individual subject for an AE, the investigator must notify the Sponsor 
immediately and, if possible, before unmasking the treatment allocation.  
Administration of the masked dose of MEDI-551 or placebo on OLP Day 15 is necessary to 
correctly administer the loading dose of 600 mg IV MEDI-551 to subjects previously 
randomized to the placebo group during the RCP, or to ensure that subjects previously 
randomized to MEDI-551 do not receive an extra treatment dose. This masking mechanism 
will be implemented through the IVRS to ensure that treatment during the RCP is not revealed 
to the sites.  
4.6.3 
Methods for Reducing Bias 
The following steps are being planned to mitigate/reduce bias towards the assessment of an 
NMO/NMOSD attack: 
1 
Study subjects will be instructed not to discuss AEs or NMO/NMOSD-related 
symptoms/medications with any of the independent assessors. 
2 
The EDSS rater will not have access to prior EDSS scores/FSS at the time of a new 
evaluation and will perform the evaluation of the subject without any knowledge of the 
subject’s AE history or management of symptoms or findings from physical/neurological 


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examinations. The EDSS rater will be instructed NOT to elicit or discuss the subjects’ 
experiences or AEs on the study. The EDSS rater must not manage the subject outside of 
the protocol for routine care or any other purpose. The EDSS scores will be captured 
electronically and transmitted to the investigator who will have access to the scores to 
compare against the protocol-defined criteria for an NMO/NMOSD attack. The EDSS 
scores/FSS will be monitored centrally by an independent expert. 
3 
The ophthalmology examiner will not have access to prior visual acuity and RAPD at the 
time of a new evaluation and perform the evaluation of the subject without any 
knowledge of the subject’s AE history or management of symptoms or findings from 
physical/neurological examination. The ophthalmology examiner will be instructed NOT 
to elicit or discuss the subjects’ experiences or AEs on the study. The ophthalmology 
examiner must not manage the subject outside of the protocol for routine care or any 
other purpose. The visual acuity scores and RAPD findings will be captured 
electronically and transmitted to the investigator who will have access to the score to 
compare against the protocol-defined criteria for an NMO/NMOSD attack. 
4 
The neuro-radiologist will not have access to the subject’s AE history or management of 
symptoms or findings from physical/neurological examination. 
5 
To minimize the potential influence of MRI findings on clinical assessment of possible 
attacks, MRI images/study report should not be reviewed by the Principal Investigator 
unless a specific criterion for an attack requires review of the MRI. In such cases, review 
of the MRI image and local study report MUST be done AFTER all relevant clinical 
assessments are completed. The time sequence of all procedures and reviews required for 
assessment will be documented to demonstrate compliance. 
6 
To further minimize the potential influence of MRI findings on the adjudication of 
possible attacks, the AC will not be given access to the MRIs (where required) until after 
their evaluation of the clinical data is complete.  
7 
To minimize the potential influence of the Principal Investigator’s review on the AC, the 
AC will not be provided with the Principal Investigator’s opinion as to whether an attack 
has occurred or not, nor will the AC receive information about which protocol attack 
criterion was met and the rescue medication utilized. 
8 
To assess for a potential bias in the investigator’s assessment of new symptoms, the data 
generated from this assessment, which determined that the symptoms were not related to 
NMO/NMOSD, will be sent to review by the AC. The level of agreement between the 
investigator and the AC will be assessed. 
 
4.6.4 
Methods for Unmasking  
The treatment code should not be broken except in medical emergencies when the appropriate 
management of the subject requires knowledge of the treatment randomization. The 


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investigator documents and reports the action to MedImmune, without revealing the treatment 
given to subject to the MedImmune staff. 
MedImmune retains the right to break the code for SAEs that are unexpected and are 
suspected to be causally related to an investigational product and that potentially require 
expedited reporting to regulatory authorities.  
4.6.4.1 
Unmasking in the Event of a Medical Emergency 
In the event of a medical emergency, the investigator must first attempt to contact the medical 
monitor to discuss the medical emergency and the reason for wanting to unmask the subject’s 
investigational product allocation prior to proceeding with unmasking. (Czech Republic only: 
in the event of a medical emergency that may be related to investigational product, the 
investigator may unmask an individual subject’s investigational product allocation if he/she 
feels it is required without prior contact to the medical monitor/sponsor.) Unmasking should 
occur only if the subject’s medical emergency would be managed differently as a result of the 
subject’s having received investigational product. In most cases, management of the medical 
emergency would be the same whether or not the subject received investigational product. If 
this is the case, the investigational product allocation should not be unmasked. 
In exceptional circumstances, where in the clinical judgment of the investigator the medical 
emergency necessitates that the subject’s investigational product allocation be immediately 
unmasked, the investigator may proceed with unmasking without prior discussion with the 
medical monitor. 
Instructions for unmasking an individual subject’s investigational product allocation are 
contained in the IVRS/IWRS manual.  
4.6.4.2 
Unmasking for Interim Analysis Purposes 
An unmasked interim analysis is planned for this study as described in Section 4.8.10. The 
interim analysis to determine futility will be conducted by the DMC; Sponsor, and sites will 
remain masked to the treatment assignment post-interim analysis.  
4.6.4.3 
Unmasking due to Known or Hypothesized Effects of MEDI-551 
MEDI-551 is known to deplete CD19+ B-cells; therefore, the results of flow cytometry to 
count B-cells are potentially unmasking. These data will not be made available to 
investigation sites post randomization through the remainder of the study. 
Data from early phase development in non-oncology subject populations receiving MEDI-551 
suggest that MEDI-551 administration may be associated with potential unspecified mild 
reduction in total Ig in individual subjects. Since this reduction may be potentially unmasking, 
these data will not be made available to investigational sites post randomization through the 
remainder of the study. 


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MEDI-551 is hypothesized to reduce titers of AQP4-IgG. AQP4-IgG titers from the central 
laboratory will not be made available to investigational sites at any point in the study.  
MEDI-551 is known to reduce the plasma cell gene signature. Because the results of the 
plasma cell gene signature assay could potentially be unmasking, these samples will not be 
tested prior to un-masking of the study. 
MEDI-551 may also reduce tetanus vaccine titers; therefore, the results of the vaccine titer 
assay will not be mabe available to the sites at any point during the study. 
Any potentially unmasking data from the protocol will not be available to the sponsor until the 
study has been unmasked following completion of the RCP. 
Investigators must not request any potentially unmasking laboratory results at a local or other 
central laboratory. 
4.7 
Restrictions During the Study and Concomitant Treatment(s) 
The investigator must be informed as soon as possible about any medication taken from the 
time of screening until the end of the study (final study visit). Any concomitant medication(s), 
including herbal preparations, taken during the study will be recorded.  
4.7.1 
Permitted Concomitant Medications 
Investigators may prescribe concomitant medications or treatments deemed necessary to 
provide adequate supportive care except for those medications identified as “excluded” as 
listed in Section 4.7.2. Specifically, subjects should receive full supportive care during the 
study, including transfusions of blood and blood products, and treatment with antibiotics, anti-
emetics, anti-diarrheals, and analgesics, and other care as deemed appropriate, and in 
accordance with their institutional guidelines. 
Subjects who experience an NMO/NMOSD attack should be given rescue therapy according 
to the judgment of the investigator as described in Section 4.5.2.2.  
All concomitant and rescue therapy given to the subject during the study will be recorded on 
the source document and includes, but is not limited to, the dose, start and stop dates, 
frequency, route of administration, and reason for administration.  
4.7.1.1 
Immunosuppressive Medications During the Screening Period 
Subjects that have previously been taking immunosuppressive medications (including but not 
limited to, AZA and MMF) and steroids not specifically excluded in Section 4.1.3 for the 
prevention or treatment of NMO/NMOSD relapses may continue to take those medications 
during the screening period as long as the dose remains stable or decreases. 


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Immunosuppressive medications must be stopped prior to dosing on Day 1. Steroids must 
continue according to the protocol (see Section 4.5.2.2). 
4.7.2 
Prohibited Concomitant Medications 
The following medications (and procedure) are prohibited from the day of dosing on Day 1 
through the end of the subjects’ participation in the OLP:  
x 
Any immunosuppressant for the prevention of NMO/NMOSD attacks (this includes but is 
not limited to AZA, MMF, rituximab, etc) 
x 
High-dose steroids, with the exception of those required to treat an NMO/NMOSD attack 
x 
Low-dose steroids, unless discussed and agreed with the medical monitor, with the 
exception of those specified by the protocol in the RCP and topical steroids 
x 
PLEX, unless used to treat an NMO/NMOSD attack.  
x 
Alemtuzumab 
x 
Eculizumab 
x 
Total lymphoid irradiation 
x 
Bone marrow transplant 
x 
T-cell vaccination therapy 
x 
Natalizumab 
x 
Cyclosporin 
x 
Methotrexate 
x 
Mitoxantrone  
x 
Cyclophosphamide 
x 
Tocilizumab 
x 
Any other immunosuppressant medication, unless discussed and approved by the medical 
monitor 
 
In addition to the medications described above, subjects must be instructed not to take any 
medications, including over-the-counter products, without first consulting with the 
investigator. 
Subjects may exit the OLP at any time for any reason, including seeking alternative treatment 
options, at which point they will enter the SFP. 
There are no prohibited medications during the SFP. During the SFP, a subject may receive 
standard treatment for their NMO/NMOSD at the discretion of the investigator and in 
compliance with established clinical practice. 


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4.8 
Statistical Evaluation 
4.8.1 
General Considerations 
Tabular summaries will be presented by treatment group. Categorical data will be summarized 
by the number and percentage of subjects in each category. Continuous variables will be 
summarized by descriptive statistics. Additional details of statistical analyses will be 
described in the statistical analysis plan.  
The primary and key secondary endpoints will be analyzed and reported based on both AQP4-
IgG seropositive and Intent-to-Treat (ITT) population, defined as all subjects who are 
randomized into the study and receive at least one dose of investigational product. Additional 
efficacy analyses will be performed in both seropositive and ITT populations. Treatment 
groups will be analyzed according to the initial randomization, regardless of whether subjects 
receive an investigational product different from that to which they were randomized. 
The safety data will be presented using the as-treated population, which will include all 
subjects who receive any investigational product. Specifically, subjects who received all 
placebo doses will be included in the placebo group for safety analyses; conversely, subjects 
who received at least one dose of MEDI-551 will be included in the active treatment group for 
safety analyses.  
Efficacy and safety data from the OLP will be presented based on subjects who receive at 
least one dose during the OLP. 
Unless otherwise specified, all statistical inference will be done at a significance level of 
two-sided α = 0.05.  
4.8.2 
Sample Size and Power Calculations 
The current study is being planned to detect a target relative reduction of 60% in risk for time 
from Day 1 to onset of an AC-determined NMO/NMOSD attack on or before Day 197 with 
90% power and α = 0.05 (two-sided). Details are provided in Appendix 9. A total of 67 AC-
determined NMO/NMOSD attacks are required for the ITT population. Subjects will be 
randomized in a 3:1 ratio to receive either MEDI-551 or placebo within both AQP4-IgG 
seropositive and seronegative strata. The stratification ratio is anticipated to be approximately 
80:20 with higher allocation to the seropositive cohort. If the seropositive cohort has 80% of 
the attacks, the study will have approximately 82% power to detect the target relative 
reduction of 60%. 
A maximum of 252 subjects will be randomized and dosed in this study. Because this study is 
event-driven where the primary objective is based on a total of 67 AC-determined 
NMO/NMOSD attacks, and the rate of NMO/NMOSD attacks is not established in the 
literature, this number of subjects was determined by analyzing masked data of the actual 


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attack rate from the first 78 subjects who completed the RCP in this study. The attack status 
(attack/no attack) of the 78 subjects was randomly sampled with different attack rate which 
gave an estimate of the number of attacks for the total sample size. This simulation process 
was repeated 10,000 times to give a distribution of the number of attacks for the total sample 
size, from which the probability of observing at least 67 attacks could be estimated. Based on 
the 78 completed subjects, this procedure showed that with 252 subjects there is a 90% 
probability of reaching the required 67 AC-determined attacks. 
Within each AQP4-IgG stratum, randomization will also be stratified by region (Japan vs non-
Japan). The number of Japanese subjects will be determined primarily by feasibility and will 
not depend on a minimum number of NMO/NMOSD attacks to be observed from Japanese 
subjects.  
4.8.3 
Efficacy 
4.8.3.1 
Primary Efficacy Analysis 
The following are the null and alternative hypotheses associated with the primary endpoint: 
ܪ଴ଵǣ ܪܴାൌͳ vs ܪଵଵǣ ܪܴା്ͳ, 
ܪ଴ଶǣ ܪܴ஺௅௅ൌͳ vs ܪଵଶǣ ܪܴ஺௅௅്ͳ, 
where ܪܴା indicates the hazard ratio of AC-determined NMO/NMOSD attack for MEDI-551 
relative to placebo in AQP4-IgG seropositive subjects. ܪܴ஺௅௅ denotes the same quantity for 
the ITT population. The treatment effect in the seropositive cohort will be defined as the 
relative reduction in ܪܴା; ie, 100 × (1-ܪܴା)A value of ܪܴା < 1 or a positive value of 
relative reduction will indicate the efficacy of MEDI-551 compared to placebo in the 
seropositive cohort. Similar interpretations will hold for ܪܴ஺௅௅Ǥ For the current study, the 
target treatment effect of 60% implies a hazard ratio (HR) of 0.4.  
For the AQP4-IgG seropositive cohort, the treatment effect will be assessed using the 
Cox proportional hazards model with treatment indicator (MEDI-551 or placebo) as an 
explanatory factor; whereas for the ITT population, the model will also include serostatus as 
an additional explanatory factor. The HR of MEDI-551 versus placebo will be estimated 
together with its associated 95% confidence interval (CI). The SAS PROC PHREG will be 
used for fitting this model. Subjects who complete Day 197 of the RCP or discontinue the 
study before Day 197 for reasons other than an AC-determined NMO/NMOSD attack will be 
censored in this model at the time of the Day 197/discontinuation visit. See Section 4.8.9 for 
details regarding Type I error control. 
An indicator variable for Japan versus non-Japan region will not be included in the Cox 
regression model due to the low number of anticipated Japanese subjects. An evaluation of 


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consistency of treatment effect in Japanese subjects with that observed in the global study will 
be determined. 
The data cutoff date for the primary analysis will be when the last subject completes the 
discontinuation visit following the 67th AC-determined attack, after all subjects complete the 
RCP if 67 AC-determined attacks do not occur, or after all subjects complete the EDV 
following discontinuation of enrollment upon recommendation of the independent DMC 
based on evidence of efficacy and safety. Subjects who are in the RCP when a total of 67 AC-
determined NMOSD attacks have occurred or when enrollment is discontinued upon 
recommendation of the DMC based on evidence of efficacy and safety will discontinue the 
RCP as outlined in Section 4.5.1.2. 
Since some AC-determined attacks may not be assessed within the assessment windows, a 
broader window will be used for primary analysis. Only AC-determined attacks with an 
assessment visit scheduled within 120 hours (5 days) of reporting symptoms and all 
assessments done within 10 days of an Assessment Visit will be included in the primary 
analysis. AC-determined attacks not included in primary analysis will be included in other 
supportive analyses. Sensitivity analysis will be conducted to assess the impact of the loss of 
any AC-determined attacks outside of the identified assessment window. 
4.8.3.2 
Additional Analyses of the Primary Endpoint 
An estimate of the cumulative event rates through the end of the RCP will be calculated using 
the Kaplan-Meier (KM) method. Graphical displays of KM estimates and cumulative 
incidence estimates will be presented by treatment group. 
The following sensitivity analyses of the primary endpoint will be performed:  
1 
Analysis using the Cox regression model and the following baseline characteristics and 
treatment as exploratory variables: 
x 
Number of NMO/NMOSD relapses prior to randomization 
x 
Baseline EDSS score 
2 
Analysis similar to primary analysis but considering only unanimous AC-determined 
NMO/NMOSD attacks (all 3 adjudicators agree) as events, remaining subjects will be 
considered as censored. 
3 
Analysis similar to primary analysis but also considering subjects who prematurely 
discontinue the RCP without experiencing an AC-determined NMO/NMOSD attack as 
treatment failures (events); remaining subjects will be considered as censored. 
4 
Sensitivity analysis will be conducted to assess the impact of the loss of any 
AC-determined attacks outside of the identified assessment window in the primary 
analysis. 
 


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4.8.3.3 
Secondary Efficacy Analyses 
Secondary endpoints 1 through 4 presented in Section 2.2.2 for AQP4-IgG seropositive cohort 
will be analyzed as follows:  
x 
Treatment effect for secondary efficacy endpoints based on EDSS worsening will be 
assessed using a logistic regression model with treatment and baseline EDSS as 
explanatory variables. The percentage of subjects meeting the endpoints, odds ratios, 
p-value, and 95% CIs of the odds ratios will be presented.  
x 
The treatment effect for the low-contrast visual acuity measured by change from baseline 
in low-contrast Landolt C Broken Rings Chart binocular scores will be assessed using an 
analysis of covariance model using treatment and baseline Landolt C Broken Rings Chart 
binocular score as explanatory variables. 
x 
The treatment effect for the secondary efficacy endpoints based on the cumulative 
number of active MRI lesions and number of NMO/NMOSD-related in-patient 
hospitalizations will be tested using Negative Binomial regression with treatment as an 
explanatory variable. 
 
Similar analyses will be performed for the ITT population by extending the above mentioned 
models to include an indicator variable for serostatus as well. 
See Section 4.8.9 for details regarding Type I error control. 
Annualized attack rate (total number of AC-determined NMO/NMOSD attacks normalized by 
person-years) during any exposure to MEDI-551 will be summarized descriptively. 
4.8.3.4 
Subgroup Analyses 
Consistency of treatment effect measured by primary and key secondary efficacy endpoints in 
the following subgroups will be investigated as follows: 
x 
Sex (male vs female) 
x 
Baseline EDSS (< 5 vs ≥ 5) 
x 
Number of prior NMO/NMOSD relapses (< 2 vs ≥ 2) 
x 
Disease duration category (< 5 years vs ≥ 5 years) 
x 
AQP4-IgG serostatus (positive vs negative) as determined at screening 
 
The nominal p-value and 95% CIs of treatment effect will be provided for each subgroup 
analysis. 
4.8.4 
Safety
 
4.8.4.1 
Analysis of Adverse Events 
The safety and tolerability of MEDI-551 will be assessed at completion of the study primarily 
by summarizing TEAEs including TESAEs. The occurrence of TEAEs will be collected and 


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summarized from the commencement of infusion of investigational product through the end of 
study. Treatment-emergent AEs and SAEs will be summarized by system organ class and 
preferred terms, by severity, and by relationship to the investigational product. For the OLP, 
the rate of AEs normalized by patient-years may be provided.  
4.8.4.2 
Analysis of Clinical Laboratory Parameters, Physical Examination Findings, 
and Vital Sign Measurements 
Laboratory measurements as well as their changes from baseline at each collection time point 
and shift from baseline if applicable will be summarized descriptively. Significant physical 
examination findings and vital sign measurements will also be summarized using descriptive 
analyses. 
4.8.5 
Patient-reported Outcomes 
4.8.5.1 
Short Form-36 Health Survey 
Treatment effect for the PRO endpoint based on SF-36 PCS (4-week recall) change from 
baseline at the last visit of the RCP will be tested using an analysis of covariance model using 
treatment and baseline SF-36 PCS score as explanatory variables. Similar analysis will be 
done for SF-36 MCS. 
For the 8 remaining domains, summaries of change from baseline will be presented. 
4.8.5.2 
Pain NRS 
Treatment effect for pain in 5 locations (eyes, legs, arms, upper back, and lower back) based 
on separate NRS change from baseline at the last visit of the RCP will be tested using analyses 
of covariance models using treatment and baseline pain NRS scores as explanatory variables. 
4.8.6 
Analysis of Immunogenicity, Pharmacokinetics, and Exploratory 
Biomarkers 
4.8.6.1 
Analysis of Immunogenicity 
The presence of ADAs to MEDI-551 in serum will be assessed over the duration of the study. 
Immunogenicity results will be analysed by summarizing the number and percentage of 
subjects who develop detectable ADA by treatment group. The association of ADA with 
MEDI-551 concentration, blood B-cell levels, attack rate, and TEAEs may be evaluated. 
4.8.6.2 
Analysis of Pharmacokinetics 
MEDI-551 concentration will be summarized descriptively over visits separated by 
AQP4-IgG seropositive and seronegative NMO/NMOSD subjects. Individual and mean 
MEDI-551 concentration versus time data will be plotted by AQP4-IgG seropositive and 
seronegative subjects. Pharmacokinetic parameters will be estimated using noncompartmental 
methods. Pharmacokinetic parameters will be listed by subjects and separated by AQP4-IgG 
seropositive and seronegative NMO/NMOSD subjects and summarized descriptively. 


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Population PK or PK/PD analysis may be conducted to include the exploratory analysis to 
identify the covariates that affect MEDI-551 PK in this subject population, or to investigate 
the relationship between MEDI-551 PK, PD, and response as appropriate. 
4.8.6.3 
Analysis of Exploratory Biomarkers 
AQP4-IgG titer, plasma gene signature change from baseline, and B-cell absolute counts and 
relative percentage based on baseline will be summarized descriptively by treatment groups. 
Additional research data and associated exploratory analyses may be reported separately from 
the main clinical study report.  
4.8.7 
Additional Analyses 
An exploratory analysis of time to AC-determined NMO/NMOSD attack or rescue therapy 
without an AC-determined NMO/NMOSD attack during the RCP will be conducted by 
considering rescue therapy as events of interest as well. Subjects who never experience any 
AC-determined NMO/NMOSD attack nor receive rescue therapy will be censored for this 
analysis. 
The agreement between site-determined NMO/NMOSD attack and AC- determined 
NMO/NMOSD attacks will be assessed by Kappa statistic.  
An inter- and intra-rater reliability assessment will be performed based on a random selection 
of all events contributing to the primary analysis. 
A shift analysis of the scores from the mRS will be performed.  
4.8.8 
Data Monitoring Committee 
An unmasked independent DMC will perform evaluations of safety and clinical outcome data 
at specified regular intervals throughout the study and make recommendations to the sponsor 
regarding further conduct of the study. The DMC will conduct an interim analysis for futility 
as described in the description of the interim analysis in Section 4.8.10.  
The DMC will monitor drop-out and missing primary and secondary outcome data on a case 
by case basis. In addition, the DMC will assess the thoroughness of the screening for possible 
NMO/NMOSD attacks and the effectiveness of the masking.  
The DMC will receive ‘real time’ reports of new NMO/NMOSD attacks and will review the 
adherence of the investigators and AC to the process of attack diagnosis and adjudication.  
Additional details will be provided in a separate DMC charter. 


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4.8.9 
Control of Type I Error 
The study is designed to strongly control the overall Type I error rate of α = 0.05 based on the 
Bonferroni-based chain procedure (Bretz et al, 2009; Millen and Dmitrienko, 2011). The 
primary null hypothesis will be hierarchically tested first at α = 0.05 in the AQP4-IgG 
seropositive cohort, and, if significant, it will be further tested in the ITT population at 
α = 0.05. If and only if the treatment group comparison is statistically significant within the 
ITT population, secondary hypotheses will be tested. Null hypotheses for the 4 key secondary 
endpoints will follow the same sequential testing strategy as the primary analysis (testing 
within seropositive subjects first, followed by the ITT population if the comparison within 
seropositive subjects is statistically significant). Each secondary hypothesis will be initially 
tested based on the Bonferroni method at α = 0.05/4 = 0.0125. If the null hypothesis for a 
particular secondary endpoint is rejected across both the seropositive and the ITT populations, 
the Type I error saved will be propagated equally to other non-rejected sets of secondary null 
hypotheses. The testing procedure will be repeated until all null hypotheses are rejected or no 
further null hypothesis can be rejected. Details are described in Appendix 11. 
4.8.10 
Interim Analysis for Futility 
An unmasked interim analysis will be conducted for futility assessment by an independent 
DMC when approximately 50% of the total planned AC-determined NMO/NMOSD attacks 
occur in this study. The information fraction will be determined by the ratio of the number of 
observed cases of AC-determined NMO/NMOSD attacks and the planned number of 
AC-determined NMO/NMOSD attacks. The predictive power will be calculated for the 
primary efficacy endpoint in the AQP4-IgG seropositive cohort as well as the ITT population 
based on the empirical trend observed at the interim analysis (Lan et al, 2009). The study may 
be declared as “futile” if calculated predictive power at interim is < 20% in both AQP4-IgG 
seropositive cohort and the ITT population. Details are provided in Appendix 10. 
5 
ASSESSMENT OF SAFETY 
5.1 
Definition of Adverse Events 
The ICH Guideline for Good Clinical Practice (GCP) E6(R1) defines an AE as: 
Any untoward medical occurrence in a patient or clinical investigation subject administered a 
pharmaceutical product and which does not necessarily have a causal relationship with this 
treatment. An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease temporally associated with the use of a 
medicinal product, whether or not considered related to the medicinal product. 
An AE includes but is not limited to any clinically significant worsening of a subject’s pre-
existing condition. An abnormal laboratory finding (including ECG finding) that requires 
medical intervention by the investigator, or a finding judged by the investigator as medically 


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significant should be reported as an AE. If clinical sequelae are associated with a laboratory 
abnormality, the diagnosis or medical condition should be reported (eg, renal failure, 
hematuria) not the laboratory abnormality (eg, elevated creatinine, urine red blood cells 
increased). Abnormal laboratory values that are not, in the investigator’s opinion, medically 
significant and do not require intervention should not be reported as AEs.  
Adverse events may be treatment emergent (eg, occurring after initial receipt of 
investigational product) or nontreatment emergent. A nontreatment-emergent AE is any new 
sign or symptom, disease, or other untoward medical event that begins after written informed 
consent has been obtained but before the subject has received investigational product.  
Elective treatment or surgery or preplanned treatment or surgery (that was scheduled prior to 
the subject being enrolled into the study) for a documented pre-existing condition that did not 
worsen from baseline is not considered an AE (serious or nonserious). An untoward medical 
event occurring during the prescheduled elective procedure or routinely scheduled treatment 
should be recorded as an AE or SAE. 
For the purposes of this protocol, NMO/NMOSD attacks will not be recorded as an AE during 
either the RCP or the OLP. Symptoms that are subsequently diagnosed due to another 
underlying cause will be recorded as AEs.  
5.2 
Definition of Serious Adverse Events 
An SAE is any AE that: 
x 
Results in death (for the purposes of this protocol, this includes NMO/NMOSD disease 
progression or attack) 
x 
Is immediately life-threatening 
x 
Requires inpatient hospitalization or prolongation of existing hospitalization  
x 
Results in persistent or significant disability/incapacity  
x 
Is a congenital anomaly/birth defect in offspring of the subject 
x 
Is an important medical event that may jeopardize the subject or may require medical 
intervention to prevent one of the outcomes listed above 
 
Medical or scientific judgment should be exercised in deciding whether expedited reporting is 
appropriate in this situation. Examples of medically important events are intensive treatment 
in an emergency room or at home for allergic bronchospasm, blood dyscrasias, or convulsions 
that do not result in hospitalizations; infection that requires treatment with IV antibiotics; or 
development of drug dependency or drug abuse.  


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For the purposes of this protocol, NMO/NMOSD disease progression or attack that do not 
result in death, but meet any of the other above listed SAE criteria, will not be reported as an 
SAE unless it occurs during the screening period or in the SFP. 
NMO/NMOSD disease progression or attacks that result in death will be reported as 
SAEs. 
All occurrences of NMO/NMOSD attacks will be carefully monitored by the site staff and the 
Sponsor to ensure these are identified in the required reporting timeline.  
Additionally, hospitalization for any procedure resulting from an NMO/NMOSD attack will 
not be reported as an SAE (eg, PLEX that could result in hospitalization).  
5.3 
Definition of Adverse Events of Special Interest 
An adverse event of special interest (AESI) is one of scientific and medical interest specific to 
understanding of the Investigational Product and requires close monitoring and rapid 
communication by the investigator to the Sponsor. An AESI may be serious or non-serious. 
The rapid reporting of AESIs allows ongoing analysis of these events in order to characterize 
and understand them in association with the use of this investigational product. 
Two adverse events are considered AESIs for this study: 1) hepatic function abnormality 
meeting the definition of Hy’s law; and 2) PML. See Section 5.6.2 and Section 5.6.3 for the 
definition and reporting of AESIs of hepatic function abnormality and PML, respectively.  
5.4 
Recording of Adverse Events 
Adverse events will be recorded on the eCRF using a recognized medical term or diagnosis 
that accurately reflects the event. Adverse events will be assessed by the investigator for 
severity, relationship to the investigational product, possible etiologies, and whether the event 
meets criteria of an SAE and therefore requires immediate notification to the Sponsor’s 
Patient Safety designee as described in Section 5.5. See Section 5.2 for the definition of SAEs 
and Appendix 3 and Appendix 12 for guidelines for assessment of severity and relationship. If 
an AE evolves into a condition that meets the regulatory definition of “serious,” it will be 
reported on the SAE Report Form. 
Infusion of biological products is commonly associated with infusion related reactions. 
Anaphylaxis and infusion related reactions have some common manifestations and may be 
difficult to distinguish from each other. Infusion related reactions are commonly observed 
during or shortly after the first time exposure to therapeutic monoclonal antibodies delivered 
through intravenous infusion. These reactions are less common following subsequent 
exposures. Unlike infusion related reactions, anaphylaxis is a rare event, usually occurring 
after subsequent exposure to an antigen, and it is most commonly accompanied by severe 








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followed for outcome of the mother and child (including any premature terminations) and 
should be reported to the Sponsor/designee after outcome. 
Should the investigator become aware of a pregnancy in the partner of a male study subject 
who has received investigational product, this should be reported within 24 hours of 
knowledge of the event to Sponsor/designee as above.  The Sponsor will endeavor to collect 
follow-up information on such pregnancies provided the partner of the study subject provides 
consent. 
6 
STUDY AND DATA MANAGEMENT 
6.1 
Training of Study Site Personnel 
Before the first subject is entered into the study, a MedImmune representative will review and 
discuss the requirements of the Clinical Study Protocol and related documents with the 
investigational staff and also train them in any study-specific procedures and system(s) 
utilized. This will include use of all assessment scales to be used in the study, and the 
appropriate set-up and use of any study-specific equipment required for evaluation of study-
related endpoints. 
Attendance at an Investigator Meeting is a requirement wherein key training for assessment of 
NMO/NMOSD attacks and other study-specific evaluations and assessments will be provided. 
In the event that study site staff are not able to attend the Investigator Meeting, alternative 
forums for training will be arranged and documented.  
The Principal Investigator will ensure that appropriate training relevant to the study is given to 
all of these staff, and that any new information relevant to the performance of this study is 
forwarded to the staff involved. 
The Principal Investigator will maintain a record of all individuals involved in the study 
(medical, nursing and other staff). 
6.2 
Monitoring of the Study 
During the study, a MedImmune representative will have regular contacts with the study site, 
including visits to: 
x 
Provide information and support to the investigator(s) 
x 
Confirm that facilities remain acceptable, including verification of MRI settings and 
assessment of environment for ophthalmology examinations 
x 
Confirm that the investigational team is adhering to the protocol, that data are being 
accurately and timely recorded in the eCRFs, that biological samples are handled in 
accordance with the Laboratory Manual and that study drug accountability checks are 
being performed 


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x 
Perform source data verification (a comparison of the data in the eCRFs with the subject’s 
medical records at the hospital or practice, and other records relevant to the study) 
including verification of informed consent of participating subjects. This will require 
direct access to all original records for each subject (eg, clinic charts) 
x 
Ensure withdrawal of informed consent to the use of the subject’s biological samples is 
reported and biological samples are identified and disposed of/destroyed accordingly, and 
the action is documented, and reported to the subject. 
 
The MedImmune representative will be available between visits if the investigator(s) or other 
staff at the patient site needs information and advice about the study conduct. 
6.2.1 
Source Data 
Refer to the Clinical Study Agreement for location of source data. 
6.2.1.1 
Direct Access to Source Data 
The head of the study site and the Principal Investigator/investigator will be expected to 
cooperate with all monitoring and auditing conducted by the Sponsor as well as inspections by 
the IRB/IEC or regulatory authorities. All study documents, such as raw data, will be open for 
direct access to source data at the request of the monitor and the auditor of the Sponsor, the 
IRB/IEC, or regulatory authorities.  
To ensure accuracy and completeness of documentation and to assure that the Principal 
Investigator has submitted the eCRFs to the Sponsor, the monitor(s) will verify data from the 
eCRFs against source data before the Principal Investigator signs the eCRFs. If the 
investigator wishes to amend the submitted eCRFs, the electronic system will document all 
changes in an electronic audit trail, which will be verified by the study monitor. 
6.2.2 
Study Agreements 
The Principal Investigator at each center should comply with all the terms, conditions, and 
obligations of the Clinical Study Agreement, or equivalent, for this study. In the event of any 
inconsistency between this Clinical Study Protocol and the Clinical Study Agreement, the 
terms of Clinical Study Protocol shall prevail with respect to the conduct of the study and the 
treatment of subjects and in all other respects, not relating to study conduct or treatment of 
subjects, the terms of the Clinical Study Agreement shall prevail. 
Agreements between MedImmune and the Principal Investigator must be in place before any 
study-related procedures can take place, or subjects are enrolled. 
6.2.3 
Archiving of Study Documents 
The investigator follows the principles outlined in the Clinical Study Agreement. 


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Study Files 
The Sponsor will provide the Principal Investigator with a file for the organization and 
retention of all study-related documents. All study documents, including letters from the 
Sponsor, should be retained in this file by the Principal Investigator. The study monitor will 
regularly check the file to ensure that all relevant documents have been retained. The contents 
of this file may be audited/inspected by the Sponsor’s auditor, regulatory authorities, or 
IRB/IEC. 
Period of Record Retention 
The study site and the Principal Investigator will retain essential documents specified in the 
ICH GCP (eg, source documents such as medical records, contract, signed consent form). 
Essential documents should be retained at the study site for at least 15 years following 
completion of the study, or in accordance with regulatory obligations if longer, and thereafter 
destroyed only after agreement with the Sponsor. In the event of any inconsistency between 
the above-mentioned contents and the contract with the study site, the contract shall prevail. If 
the Sponsor requires the documents to be retained for a longer period, the specific period and 
method of retention will be separately discussed between the study site and the Sponsor. The 
Sponsor should notify the head of the study site in writing when the study-related records are 
no longer needed. The records should be managed by a specific person designated by the head 
of the study site. 
6.3 
Study Timetable and End of Study 
The end of the study (“study completion”) is defined as the date of the last protocol-specified 
visit/assessment (including telephone contact) for the last subject in the study. This will occur 
when the last subject completes the 52-week SFP.  
An individual subject will be considered to have completed the RCP if the subject was 
followed through Day 197 or experienced an NMO/NMOSD attack as determined by the AC, 
regardless of the number of doses the subject received. Additionally, all subjects enrolled in 
the RCP at time that the 67th AC-determined attack is confirmed, or at the time the Sponsor 
discontinues enrollment upon recommendation of the independent DMC based on evidence of 
efficacy and safety, will also be considered as completers, regardless of the number of doses 
the subject received, provided the subject completes the Day 197/EDV visit. A subject will be 
considered to have completed the OLP if the subject participated for the duration of the OLP 
as per Section 3.1.1.4. A subject will be considered to have completed the SFP if the subject 
was followed for 52 weeks (12 months) after the last dose of investigational product. Subjects 
will be considered not to have completed a study period if consent was withdrawn, death 
occurred, or the subject was lost to follow up.  


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6.3.1 
Discontinuation or Suspension of the Study Program 
If the Sponsor decides to prematurely terminate or suspend the study, the Principal 
Investigator/investigator, head of the study site, and regulatory authorities should be given 
written notification of the reason(s) for the premature termination or suspension of the study. 
The Principal Investigator/investigator will immediately notify the subjects of this decision, 
provide appropriate medical treatment and take necessary measures, and record the treatment 
or measures taken on the source documents. 
6.3.2 
Completion of the Study 
Upon completion of the study, the Principal Investigator/investigator will notify the head of 
the study site in writing about the completion of the study as well as the summary of the 
results in accordance with the rule of the study site. Written notification of the results will be 
provided to the IRB and the Sponsor. 
6.4 
Data Management 
Data management will be performed by MedImmune Data Management staff according to the 
Data Management Plan. 
Adverse events will be classified according to the terminology of the latest version the 
Medical Dictionary for Regulatory Activities (MedDRA). Medications will be classified 
according to the AstraZeneca Drug Dictionary. All coding will be performed by the Medical 
Coding Team at the MedImmune Data Management Center. 
A Web-Based Data Capture system will be used for data collection and query handling. The 
investigator will ensure that data are recorded on the eCRFs as specified in the study protocol 
and in accordance with the instructions provided. 
The investigator ensures the accuracy, completeness, and timeliness of the data recorded and 
of the provision of answers to data queries according to the Clinical Study Agreement. The 
investigator will sign the completed eCRFs. A copy of the completed eCRFs will be archived 
at the study site. 
6.5 
Medical Monitor Coverage 
Each subject will be provided with contact information for the principal investigator. In 
addition, each subject will receive a toll-free number intended to provide the subject’s 
physician access to a medical monitor 24 hours a day, 7 days a week in the event of an 
emergent situation where the subject’s health is deemed to be at risk. In this situation, when a 
subject presents to a medical facility where the treating physician or health care provider 
requires access to a physician who has knowledge of the investigational product and the 
clinical study protocol and the Principal Investigator is not available, the treating physician or 


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health care provider can contact a medical monitor through this system, which is managed by 
a third party vendor. 
7 
ETHICAL AND REGULATORY REQUIREMENTS 
7.1 
Ethical Conduct of the Study 
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with ICH/ GCP, and applicable regulatory 
requirements. The applicable regulatory requirements in Japan are “Good Clinical Practice for 
Trials on Drugs (Ministry of Health, Labour, and Welfare [MHLW] Ordinance No. 28, 27 
March 1997, partially revised by MHLW Ordinance and their related notifications.”  
7.2 
Subject Data Protection 
The ICF will incorporate (or, in some cases, be accompanied by a separate document 
incorporating) wording that complies with relevant data protection and privacy legislation. 
MedImmune will not provide individual genotype results to subjects, any insurance company, 
any employer, their family members, general physician or any other third party, unless 
required to do so by law. 
Extra precautions are taken to preserve confidentiality and prevent genetic data being linked to 
the identity of the subject. In exceptional circumstances, however, certain individuals might 
see both the genetic data and the personal identifiers of a subject. For example, in the case of a 
medical emergency, a MedImmune Medical Monitor or an investigator might know a 
subject’s identity and also have access to his or her genetic data. Also Regulatory authorities 
may require access to the relevant files, though the subject’s medical information and the 
genetic files would remain physically separate.  
7.3 
Ethics and Regulatory Review 
An IRB/IEC should approve the final study protocol, including the final version of the ICF 
and any other written information and/or materials to be provided to the subjects. The 
investigator will ensure the distribution of these documents to the applicable IRB/IEC, and to 
the study site staff. 
The opinion of the IRB/IEC should be given in writing. The investigator should submit the 
written approval to MedImmune before enrollment of any subject into the study.  
The IRB/IEC should approve all advertising used to recruit subjects for the study. 
MedImmune should approve any modifications to the ICF that are needed to meet local 
requirements. 


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If required by local regulations, the protocol should be re-approved by the IRB/IEC annually. 
Before enrollment of any subject into the study, the final study protocol, including the final 
version of the ICF, is approved by the national regulatory authority or a notification to the 
national regulatory authority is done, according to local regulations. 
MedImmune (or local country representative) will handle the distribution of any of these 
documents to the national regulatory authorities. 
MedImmune (or local country representative) will provide Regulatory Authorities, IRB/IEC 
and Principal Investigators with safety updates/reports according to local requirements, 
including suspected unexpected serious adverse reactions (SUSARs), where relevant. 
Each Principal Investigator is responsible for providing the IRB/IEC with reports of any 
serious and unexpected adverse drug reactions from any other study conducted with the 
investigational product. MedImmune (or local country representative) will provide this 
information to the Principal Investigator so that he/she can meet these reporting requirements.  
The Principal Investigator is responsible for ensuring that the opinion is sought from the 
IRB/IEC, with respect to the appropriateness of continuing the study at the study site as per 
the local IRB/IEC requirements.  
A valid contract between the study site and the Sponsor should be signed before the 
investigator can enroll any subject into the study.  
7.3.1 
Ethics and Regulatory Review in Japan 
In addition, in Japan the head of the study site should submit a notification of 
direction/determination as well as IRB written approval to the Sponsor and the Principal 
Investigator before enrollment of any subject into the study.  
The Principal Investigator should submit progress reports to the IRB via the head of the study 
site at the time of any protocol reapproval.  
7.4 
Informed Consent 
The Principal Investigator(s) at each center will: 
x 
Ensure each subject is given full and adequate oral and written information about the 
nature, purpose, possible risk and benefit of the study 
x 
Ensure each subject is notified that they are free to discontinue from the study at any time 
x 
Ensure that each subject is given the opportunity to ask questions and allowed time to 
consider the information provided 


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x 
Ensure each subject provides signed and dated informed consent before conducting any 
procedure specifically for the study 
x 
Ensure the original, signed ICF(s) is/are stored in the Investigator’s Study File 
x 
Ensure a copy of the signed ICF is given to the subject 
x 
Ensure that any incentives for subjects who participate in the study as well as any 
provisions for subjects harmed as a consequence of study participation are described in 
the ICF that is approved by an IRB/IEC. 
 
If any new information about the investigational product becomes available that may 
influence the subject’s decision to continue in the study, the investigator(s) should 
immediately inform the subject of such information, record this in written form, and confirm 
with the subject if he/she wishes to continue participating in the study. In addition, if the 
investigator(s) deems it necessary to revise the ICF, it should be revised immediately (see 
Section 7.5) and the updated ICF should be explained to the subject, even if the subject(s) has 
been informed verbally about the new ICF. Written informed consent for the subject to 
continue participating in the study should be provided separately. 
7.5 
Changes to the Protocol and Informed Consent Form 
Study procedures will not be changed without the mutual agreement of the medical monitor, 
Principal Investigator, and MedImmune. 
If there are any substantial changes to the study protocol, then these changes will be 
documented in a study protocol amendment and where required in a new version of the study 
protocol. The amendment is to be approved by the relevant IRB/IEC and if applicable, also the 
national regulatory authority approval, before implementation. Local requirements are to be 
followed for revised protocols. 
MedImmune will distribute any subsequent amendments and new versions of the protocol to 
each Principal Investigator(s). For distribution to IRB/IEC see Section 7.3. 
If a protocol amendment requires a change to a site’s ICF, MedImmune and the site’s 
IRB/IEC are to approve the revised ICF before the revised form is used.  
If local regulations require, any administrative change will be communicated to or approved 
by each IRB/IEC. 
7.5.1 
Deviation From the Clinical Study Protocol 
The investigator(s) must not deviate from or make any changes to the protocol without 
documented agreement between the Principal Investigator and the Sponsor or IRB/IEC 
approval, based on deliberations. This shall not apply to cases where the deviation or change 
is necessary to avoid an immediate hazard to the subjects, for other compelling medical 


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reasons, or where the changes involve only logistical or administrative aspects of the clinical 
study (eg, changes to the organization/structure of MedImmune, the name/department of the 
study site, the address or phone number of the study site or Sponsor, and the job title of the 
investigator or medical monitor).  
The investigator(s) should document any and all deviations from the protocol regardless of the 
reason(s). Unless the deviation occurred to avoid an immediate hazard to the subjects or for 
other medically compelling reason(s), the investigator should prepare and submit the records 
explaining the reason(s) for the deviation(s) to MedImmune and the head of the study site and 
retain a copy of the records.  
The investigator(s) may deviate from or make a change to the protocol without documented 
agreement between the Principal Investigator and MedImmune or IRB approval only in the 
event of a medical emergency (eg, to avoid an immediate hazard to the subjects). In such 
cases, the Principal Investigator must notify MedImmune, the head of the study site, and the 
IRB as soon as possible about the details of the deviation or change, the reason for the 
deviation, and a proposed revision in the protocol, if required, to obtain their approval. For 
study sites in Japan, a certificate of approval by the head of the study site as well as the 
Sponsor should be obtained via the head of the study site. 
7.6 
Audits and Inspections 
All study data may be subject to a reliability review and onsite GCP inspection by the 
regulatory authorities.  
Authorized representatives of MedImmune, a regulatory authority, or an IRB/IEC may 
perform audits or inspections at the center, including source data verification. The purpose of 
an audit or inspection is to systematically and independently examine all study-related 
activities and documents, to determine whether these activities were conducted, and data were 
recorded, analyzed, and accurately reported according to the protocol, GCP, ICH guidelines, 
and any applicable regulatory requirements. The investigator will contact MedImmune 
immediately if contacted by a regulatory agency about an inspection at the site. 


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8 
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Jacob A, McKeon A, Nakashima I, Sato DK, Elsone L, Fujihara K, de Seze J. Current concept 
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Jarius S, Paul F, Franciotta D, Waters P, Zipp F, Hohlfeld R, et al. Mechanisms of disease: 
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Jarius S, Ruprecht K, Wildemann B, Kuempfel T, Ringelstein M, Geis C, et al. Contrasting 
disease patterns in seropositive and seronegative neuromyletis optica: A multicenter study of 
175 patients. J Neuroinflammation. 2012 Jan 19;9:14. 
Jarius S, Wildemann B. The history of neuromyelitis optica. J Neuroinflammation. 2013 Jan 
15;10:8.  
Kanamori Y, Nakashima I, Takai Y, Nishiyama S, Kuroda H, Takahashi T, et al. Pain in 
neuromyelitis optica and its effect on quality of life. Neurology. 2011 Aug:77:652-58. 
Kappos L, Li D, Calabresi PA, O'Connor P, Bar-Or A, Barkhof F, et al. Ocrelizumab in 
relapsing-remitting multiple sclerosis: a phase 2, randomised, placebo-controlled, multicentre 
trial. Lancet. 2011 Nov 19;378(9805):1779-87. 
Kappos L, D'Souza M, Lechner-Scott J, Lienert C. Mult Scler Relat Disord. 2015 
May;4(3):182-5.  
Kim W, Kim SH, Kim HJ. New insights into neuromyelitis optica. J Clin Neurol. 2011 
Sep;7(3):115-27. 
Kim SH, Kim W, Li XF, Jung IJ, Kim HJ. Repeated treatment with rituximab based on the 
assessment of peripheral circulating memory B cells in patients with relapsing neuromyelitis 
optica over 2 years. Arch Neurol. 2011 Nov;68(11):1412-20.  
Kitley J, Leite NI, Nakashima I, Waters P, McNeillis B, Brown R, et al. Prognostic factors and 
disease course in aquaporin-4 antibody-positive patients with neuromyelitis optica spectrum 
disorder from the United Kingdom and Japan. Brain. 2012;135:1834-49.  
Kitley J, Woodhall M, Waters P, Leite MI, Devenny E, Craig J, et al. Myelin-oligodendrocyte 
glycoprotein antibodies in adults with a neuromyelitis optica phenotype. Neurology. 2012 Sep 
18;79(12):1273-7. 
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scale (EDSS). Neurology. 1983;33(11):1444-52. 
Lan GKK, Hu P, and Proschan MAA. Conditional Power Approach to the Evaluation of 
Predictive Power. Statistics in Biopharmaceutical Research May 2009, Vol. 1, No. 2. 
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Matiello M, Lennon VA, Jacob A, Pittock SJ, Lucchinetti CF, Wingerchuk DM, et al. NMO-
IgG predicts the outcome of recurrent optic neuritis. Neurology. 2008;70:2197-2200. 
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clinical trial applications. Stat Biopharm Res. 2011;3:14-30. 
Misu T, Fujihara K, Nakashima I, Sato S, Itoyama Y. Intractable hiccup and nausea with 
periaqueductal lesions in neuromyelitis optica. Neurology. 2005 Nov 8;65(9):1479-82. 
Mitsdoerffer M, Kuchroo V, Korn T. Immunology of neuromyelitis optica: a T cell-B cell 
collaboration. Ann N Y Acad Sci. 2013 Apr;1283:57-66.  
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Oh J, Levy M. Neuromyelitis optica: an antibody-mediated disorder of the central nervous 
system. Neurol Res Int. 2012;2012:460825. 
Pittock SJ, Lennon VA, McKeon A, Mandrekar J, Weinshenker BG, Lucchinetti CF, O'Toole 
O, Wingerchuk DM. Eculizumab in AQP4-IgG-positive relapsing neuromyelitis optica 
spectrum disorders: an open-label pilot study. Lancet Neurol. 2013 Jun;12(6):554-62. 
Pittock SJ, Weinshenker BG, Lucchinetti CF, Wingerchuk DM, Corboy JR, Lennon VA. 
Neuromyelitis optica brain lesions localized at sites of high aquaporin 4 expression. Arch 
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Popescu BF, Lennon VA, Parisi JE, Howe CL, Weigand SD, Cabrera-Gomez JA, et al. 
Neuromyelitis optica unique area postrema lesions: nausea, vomiting, and pathogenic 
implications. Neurology. 2011 Apr 5;76(14):1229-37.  
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Qian P, Lancia S, Alvarez E, Klawiter C, Cross AH, Naismith RT. Association of 
neuromyelitis optica with severe and intractable pain. Arch Neurology. 2012;69(11):1482-7. 
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Network symposium. J Allergy Clin Immunol. 2006; 1175(3):391-7. 


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Sellner J, Boggild M, Clanet M, Hintzen RQ, Illes Z, Montalban X, et al. EFNS guidelines on 
diagnosis and management of neuromyelitis optica. Eur J Neurol. 2010 Aug;17(8):1019-32.  
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van Swieten J, Koudstaal P, Visser M, Schouten H, et al. Interobserver agreement for the 
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Zamvil SS. Aquaporin 4-specific T cells in neuromyelitis optica exhibit a Th17 bias and 
recognize clostridium ABC transporter. Ann Neurol. 2012 Jul;72(1):53-64. 
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neuromyelitis optica (Devic’s syndrome). Neurology 1999 Sep 22;53(5):1107-14. 
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9 
CHANGES TO THE PROTOCOL 
All changes described below have been incorporated into the current version of the protocol. 
Protocol Amendment 6; 11Oct2018 
The primary purpose of this amendment was to introduce language related to changes in the 
study resulting from the Sponsor’s decision to accept recommendations from the independent 
DMC, based on evidence of efficacy and safety, to stop study enrollment and allow subjects in 
the RCP at that time the option to enter the OLP. In addition, minor copy-editing and 
formatting issues were corrected throughout the document. Changes to the protocol reflecting 
the change above were made throughout the protocol (Synopsis, Sections 3.1, 4.2, 4.4, 4.5, 
4.8, and 6.3, and Table 2).  
Protocol Amendment 5; 16Jul2018 
Text revisions resulting from this amendment are incorporated in the body of Protocol 
Amendment 5. This amendment incorporates numerous administrative and personnel changes, 
corrects existing errors, and updates definitions and processes for safety reporting. Table and 
figure numbering was changed to sequential numbering to align with the new in-house 
authoring style. Minor copy editing and formatting were corrected throughout the document. 
Major changes to the protocol were as follows:  
1 
Title Page: The medical monitor was changed from 
, 
 to 
 
, 
, along with contact information. 
2 
Synopsis and Section 3.1.1 (Overview), Section 3.1.1.1 (Screening Period), Section 4.1.1 
(Number of Subjects), Section 4.2.1 (Enrollment/Screening Period), and Section 4.8.2 
(Sample Size and Power Calculations): Text was added to these sections to clarify that 
enrollment of subjects into the study will stop when a total of 67 AC-determined NMOSD 
attacks have occurred or when 252 subjects have been randomized and dosed, whichever 
occurs first, to account for subjects that are randomized but do not receive investigational 
product. 
3 
Section 4.1.2 (Inclusion Criteria), Table 4 (Highly Effective Methods of Contraception): 
Removed incorrect abbreviation for intrauterine hormone-releasing system and 
duplication of “injectable”. 
4 
Section 4.1.3 (Exclusion Criteria): Exclusion Criterion 12 was revised to add the 
stipulation that rituximab treatment with 6 months prior to screening is not exclusionary 
if a subject has B-cell counts above the LLN, since the reason for excluding rituximab 
within the prior 6 months is the possibility of low B cells. Exclusion Criterion19 was 
revised to read, “or” instead of “and” with reference to therapies for concurrent 
autoimmune disease. 
PPD
PPD
PPD
PPD
PPD


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5 
Section 4.2.1 (Enrollment/Screening Period), Table 5 (Schedule of Screening 
Procedures): Order of footnote references was corrected.  
6 
Section 4.2.2.1 (Randomized-controlled Treatment Period), Table 6 (Schedule of 
Randomized-controlled Treatment Period Study Procedures); Section 4.2.2.2 (Open-
label Period), Table 7 (Schedule of Open-label Period Study Procedures); and Section 
4.5.1.2 (Treatment Administration), Randomized-controlled Period: The window for the 
Day 15 visit (for both RCP and OLP) was changed from + 3 days to r  days, which 
provides scheduling flexibility to the sites and is anticipated to have no consequence on 
the pharmacodynamic effect or safety of the drug. 
7 
Section 4.2.2.2 (Open-label Period), Table 7 (Schedule of Open-label Period Study 
Procedures): Urine pregnancy tests for Weeks 13 and 39/then Q26W visits were 
removed as these are not required because the subjects are not dosed at these visits.  
8 
Section 4.3.1.2 (Neuroaxis Magnetic Resonance Imaging Scan), MRI for All Subjects: 
Text was added to stipulate that brain MRI review by the Principal Investigator is 
acceptable in the event of a safety alert of new brain lesion(s) from the central MRI 
reader. 
9 
Section 4.3.1.4 (Expanded Disability Status Scale and Functional Systems Scores): Text 
was revised to remove “face-to-face” as not all training is conducted person-to-person. 
10 Section 4.7.2 (Prohibited Concomitant Medications): Text was added that low-dose 
steroid may be permissible if discussed and agreed with the medical monitor, as in some 
situations low-dose steroid administration will have no impact on the NMO disease 
course. Also added prohibition of any other immunosuppressant medication (beyond 
those already named) unless discussed and approved by the medical monitor.  
11 Section 5.5 (Reporting of Serious Adverse Events): Information for SAE reporting was 
updated following a change of service provider. 
12 Section 5.6.1 (Overdose): The definition of overdose was expanded to include receipt of 
investigational product at a time/visit not specified in the protocol; information for 
overdose reporting was updated. 
13 Section 5.6.2 (Hepatic Function Abnormality): Text was revised to specify that all 
occurrences of Hy’s Law are to be considered SAEs and are to be reported to the 
Sponsor according to SAE reporting procedures. 
14 Section 5.6.3 (Progressive Multifocal Leukoencephalopathy): Process and information 
for reporting possible cases of PML were updated. 
15 Section 5.6.4 (Pregnancy): Information for pregnancy reporting was updated. 
16 Appendix 1 (Signatures): Text was updated to remove Jorn Drappa, MD and replace 
with Eliezer Katz, MD FACS for sponsor signature.  
 


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Protocol Amendment 4; 08Mar2017 
Text revisions resulting from this amendment are incorporated in the body of Protocol 
Amendment 4. The primary reasons for changes included in Amendment 4 are the removal of 
the sample size reassessment and the inclusion of clear guidance that stopping enrollment is 
based on the occurrence of 67 AC-determined NMOSD attacks or when 252 subjects have 
been enrolled. Minor edits were also addressed.   
1 
Protocol Synopsis: Revisions were made to the synopsis to reflect changes in the body of 
the protocol amendment.  
2 
Section 1.4 (Summary of Clinical Experience): Text was updated that Study CD-IA-
MEDI-551-1102 has now been completed. Additionally, text was added that PML has 
been reported in the setting of B-cell depleting therapies and other immunosuppressive 
regimens and is a potential risk of treatment with MEDI-551. A subject in Study CD-IA-
MEDI-551-1155 developed altered mental state, seizures, and new brain lesions that on 
brain MRI raised suspicion of PML. CSF testing for JCV was performed, with 
inconclusive results (two negative results in reference laboratories and one positive result 
in a local labarotory). Brain tissue was not available for examination. The subject died 
from cardiopulmonary complications. Based on all available data, the differential 
diagnosis included ADEM, atypical NMOSD attack, and PML. No conclusive diagnosis 
could be made. This text was added to provide investigators and others with the latest 
and most complete information regarding this potential safety risk.  
3 
Section 3.1.1 (Overview): Text was changed to a maximum of 252 subjects with 
NMO/NMOSD will be randomized in a 3:1 ratio to receive IV MEDI-551 (300 mg at 
Day 1 and 300 mg at Day 15) or placebo for a period of 197 days (RCP). Text was added 
that enrollment of subjects into the study will stop when a total of 67 AC-determined 
NMOSD attacks occur or when 252 subjects have been randomized, whichever occurs 
first. For this and all related changes in this amendment, the removal of the interim 
sample size reassessment resulted from discussion with the FDA regarding the timing of 
the sample size reassessment as related to the futility analysis. As the study progresses it 
becomes possible that the futility analysis will occur prior to the sample size 
reassessment, which would not allow for the performing of the sample size reassessment. 
Therefore an agreement was reached with the FDA for the removal of the sample size 
reassessment from the protocol and increasing the sample size to 252 subjects (or until 
67 AC-determined NMOSD attacks have occurred).  
4 
Section 3.1.1.1 (Screening Period): Text was added that subjects who are in screening at 
the time that 252 subjects are randomized will not be randomized into the study. This 
condition was added to prevent additional subject exposure to potential risks of the study 
beyond that required by the protocol objectives.  
5 
Figure 3.1.1-1 (Study Flow Diagram): The study flow diagram was revised to update the 
sample size to 252 subjects. 


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6 
Section 3.1.1.2 (Randomization [Day 1]): The maximum number of subjects to be 
randomized was changed from 212 to 252. 
7 
Section 3.1.1.3 (Randomized-controlled Period [Day 1 to Day 197]): New text was 
added to clarify that subjects who are in the RCP when a total of 67 AC-determined 
NMOSD attacks have occurred will discontinue the RCP within 14 days and be given 
the option to enroll into the OLP. Management of subjects who do not discontinue within 
14 days should be discussed with the medical monitor. This condition was added to 
prevent additional subject exposure to the potential risks of the study beyond that 
required by the protocol objectives. 
8 
Section 3.1.1.4 (Open-label Period): Text was minimally revised for Criterion #2 and 
Criterion #3 was added that subjects will be given the option to enter the OLP if they are 
in the RCP at the time 67 AC-determined attacks have occurred. Text was revised to 
clarify that subjects who discontinue from the RCP for reasons other than an 
NMO/NMOSD attack or the occurrence of 67 AC-determined attacks will not be eligible 
for the OLP. 
9 
Section 3.1.2 (Treatment Regimen) / Open-label Period: Text was added to clarify that 
dosing of subjects enrolling into the OLP following an adjudicated NMO/NMOSD 
attack, and following the occurrence of the 67th adjudicated NMO/NMOSD attack, will 
be identical to the OLP dosing regimen.  
10 Section 4.1.1 (Number of Subjects): New text was added that the study is event driven 
where the primary objective is based on a total of 67 AC-determined NMO/NMOSD 
attacks. Because the sample size reassessment was removed from the protocol a 
calculated assessment was performed to determine the number of patients needed to be 
randomized to reach 67 AC-adjudicated NMOSD attacks. As the rate of NMO/NMOSD 
attacks is not established in the literature, the attack rate was analyzed based on masked 
data from the first 78 subjects who completed the RCP in this study. The attack status 
(attack/no attack) of the 78 subjects was randomly sampled with different attack rates, 
which gave an estimate of the number of attacks for the total sample size. This 
simulation process was repeated 10,000 times to give a distribution of the number of 
attacks for the total sample size, from which the probability of observing at least 67 
attacks could be estimated. Based on the 78 completed subjects, this procedure showed 
that with a sample size of 227 there is a 50% probability of reaching the required 67 AC-
determined attacks and with 252 subjects there is a 90% probability of reaching the 
required 67 AC-determined attacks. The sample size of 252 subjects was selected to give 
a high degree of confidence that 67 attacks will be observed in this study. Enrollment of 
subjects into the study will stop when a total of 67 AC-determined NMOSD attacks 
occur or when 252 subjects have been randomized, whichever occurs first. 
11 Section 4.1.2 (Inclusion Criteria): Criteria #6b, 7, and 8 were revised to add text and new 
table (Table 4.1.2-1, Highly Effective Methods of Contraception) to emphasize that 
nonsterilized sexually active males with female partners of childbearing potential and 


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sterilized males must use a condom plus spermicide. It is strongly recommended that 
female partners of male subjects to also use a highly effective method of contraception 
throughout this period. 
12 Section 4.1.7 (Replacement of Subjects): Text mentioning sample size reassessment was 
removed as this will not be conducted. 
13 Section 4.2.1 (Enrollment/Screening Period): Text was added for clarification and 
consistency with other sections that subjects undergoing screening at the time 252 
subjects are randomized may not be randomized into the study and the management of 
these subjects should be discussed with the medical monitor. Similarly, subjects in 
screening at the time of the 67th AC-determined attack will not be randomized. The 
screening period may be extended to allow for repeat procedures.  
14 Section 4.2.2.1 (Randomized-controlled Treatment Period): Text was added to clarify 
that at the time 67 AC-determined attacks have occurred, the sponsor will notify all sites 
and the sites will notify subjects ongoing in the RCP that they must discontinue within 
14 days and should be given the option to enroll into the OLP. Procedures should be 
conducted as presented in the Schedule of Randomized-controlled Treatment Period 
Procedures for the Day 197/ EDV; however, subjects who have had an MRI in the last 
3 months need NOT repeat the MRI to reduce the burden on the subjects. Subjects who 
decide to enroll into the OLP will follow procedures of the OLP as presented in 
Table 4.2.2.2-1 (Schedule of Open-label Period Study Procedures). This time limit on 
discontinuation of the RCP is to ensure the timely completion of the study and to prevent 
any delay in continued receipt of study medication in the OLP, if subjects choose to 
enroll. 
15 Section 4.2.2.2 (Open-label Period): Text was added to clarify that subjects who are in 
the RCP at the time of the 67th AC-determined attack and want to enroll in the OLP must 
do so within 2 weeks of the occurrence of the 67th attack. This time limit on 
discontinuation of the RCP is to ensure the timely completion of the study and to prevent 
any delay in continued receipt of study medication in the OLP, if subjects choose to 
enroll. 
16 Table 4.2.2.2-1 (Schedule of Open-label Period Study Procedures): Text relating to the 
follow-up telephone calls has been removed as these calls are not necessary. The purpose 
of these calls was to mitigate against the risks of placebo use. As there is no placebo in 
the OLP these calls place an unnecessary burden on sites and subjects. Footnote “b” was 
updated to delete text that PK samples would be collected at selected sites only. 
17 Section 4.3.1.1 (Identification, Assessment, and Adjudication of an NMO/NMOSD 
Attack): Text amended to remove the need for follow-up telephone calls to subjects 
during the OLP. 
18 Section 4.3.1.2 (Neuroaxis Magnetic Resonance Imaging Scan): Text added to state that 
subjects who discontinue the RCP at the time of the 67th AC-determined attack need not 


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have an MRI repeated if the last one was done within 3 months to reduce the burden on 
the subjects 
19 Section 4.3.3.2 (Physical and Neurological Examination): Text was added for 
clarification that additional neurological exams may be conducted according to local 
practice. 
20 Section 4.3.5 (Modified Rankin Scale): Text indicating that the Principal Investigator 
will evaluate the mRS was removed as this assessment may be done by any trained and 
designated member of the site team. 
21 Section 4.3.6 (Clinical Laboratory Tests) / Other Safety Tests: Bullet point and text were 
added to further clarify that only in cases of suspected PML, a CSF sample for JCV 
DNA PCR will be collected and frozen immediately. 
22 Section 4.3.9.1 (Exploratory Investigations) / Serum for Exploratory Biomarker Studies: 
The last sentence in the subsection was revised to correct that the presence of 
autoantibodies to antigens other than AQP4 may be explored throughout the study. 
Additionally, the subsection, Blood for Peripheral Blood Mononuclear Cell Isolation for 
T-cell Evaluation was removed as it is not feasible to manage these samples within the 
required stability window. 
23 Table 4.3.10-1 (Estimate of Blood Volume to be Collected): Blood volumes for PBMC 
sample collection was removed from table and footnotes as PBMC will not be collected. 
24 Section 4.5.1.2 (Treatment Administration) / Open-label Period: Text was revised for 
consistency with other sections that subjects who are in the RCP at the time of 67th AC-
determined attack is achieved must enter the OLP within two weeks of the occurrence of 
the 67th attack, unless there is a compelling reason that is discussed and agreed with the 
medical monitor, in which case a short extension may be granted. 
25 Section 4.7.1.1 (Immunosuppressive Medications During the Screening Period): Text 
was removed regarding the treatment of an NMO/NMOSD attack in screening as this is 
no longer consistent with Section 4.2.1, which requires that subjects experiencing an 
attack in the screening period be screen failures. 
26 Section 4.8.2 (Sample Size and Power Calculations): Text revised for consistency with 
other sections that a maximum number of 252 subjects will be randomized. The sample 
size is based on a masked calculation of the attack rate for the first 78 subjects to 
complete the RCP and a simulation based on this attack rate that indicates a > 90% 
probability of achieving the required 67 AC-determined attacks with 252 subjects. Text 
mentioning masked sample size reassessment was removed as this will not be done.  
27 Section 4.8.3.1 (Primary Efficacy Analysis): Text was revised to clarify and for 
consistency with other sections that the data cutoff date for the primary analysis will be  
when the last subject completes the discontinuation visit following the 67th 
AC-determined attack, or after all subjects complete the RCP if 67 AC-determined 


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attacks do not occur. Subjects who are in the RCP when a total of 67 AC-determined 
NMOSD attacks have occurred will discontinue the RCP within 14 days.  
28 Section 4.8.10.1 (Masked Sample Size Reassessment): This section was removed as the 
reassessment will not be conducted.  
29 Section 5.3 (Definition of Adverse Events of Special Interest): Text was added and 
revised to clarify that 2 AEs will be considered AESIs for this study: 1) hepatic function 
abnormality meeting the definition of Hy’s Law, and 2) PML.  
30 Section 5.6.3 (Progressive Multifocal Leukoencephalopathy): Section and text were 
added indicating that PML is an AESI and a potential risk for MEDI-551 and that 
confirmation for PML diagnosis requires the presence of JVC in CSF or brain tissue 
biopsy sample, any suspected case of PML should be immediately reported to the 
sponsor and discussed with the medical monitor, and the medical monitor should be 
contacted for instruction on proper handling of subject samples and analysis in the case 
of potential PML. Sample transfer procedures are critical to ensure accurate test results, 
and the sponsor wishes to be involved in these processes to ensure appropriate 
procedures are followed. 
31 Section 6.3 (Study Timetable and End of Study): Text was added to clarify subject 
completion of the RCP. Any subject in the RCP at the time of the 67th AC-determined 
attack will be considered as having completed the RCP regardless of the doses the 
subject received.  
32 Appendix 9 (Sample Size Calculation): Text was added to align with changes in 
Section 4.8.2 and provide explanation that the originally planned masked interim sample 
size reassessment was removed from the protocol as a result of a discussion with the 
FDA regarding the timing of the sample size reassessment as related to the futility 
analysis. As the study progresses it becomes possible that the futility analysis will occur 
prior to the sample size reassessment, which would not allow the sample size 
reassessment to be performed. Therefore an agreement was reached with the FDA that 
the sample size reassessment would be removed from the protocol. The sample size was 
also increased to a maximum number of 252 randomized subjects to provide a high 
degree of confidence that 67 NMO/NMOSD attacks will be observed in the study.  
33 Appendix 11 (Details of Masked Sample Size Reassessment): Text and table (Table 9-5, 
Masked Sample Size Reassessment Examples [60% Treatment Effect]) were removed as 
this reassessment will not be conducted. 
 
Protocol Amendment 3; 18Oct2016 
Text revisions resulting from this amendment are incorporated in the body of Protocol 
Amendment 3. These changes were primarily made to provide additional clarification.  


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1 
Section 4.1.3 (Exclusion Criteria), Criterion 10g: Text was clarified to make it clear that 
the criterion refers to CD19+ B cell counts.  
2 
Section 4.2.1 (Enrollment/Screening Period) and Section 4.3.1.2 (Neuroaxis Magnetic 
Resonance Imaging Scan): Text added to allow the use of a previous MRI scan as part of 
the screening assessment for subjects that are being re-screened to prevent those subjects 
having to go through a lengthy and uncomfortable procedure if the previous MRI was 
done in the last 3 months. The sponsor has consulted with an expert on the matter and 
confirmed that MRI can be used for up to 3 months as the basis for the evaluation of 
eligibility, therefore this change which will only apply to a minimal number of subjects, 
will have not impact on the integrity of the protocol. 
3 
Section 4.2.1 (Enrollment/Screening Period): The opportunity for a subject to undergo 
one additional re-sceen has been introduced to ensure that a subject is not unreasonably 
excluded for reasons that would not prevent the subject from safely participating in the 
study or that would not impact the integrity of the study. This will not include subjects 
that have failed to meet entry criteria twice rather subjects that have not been able to 
enter for logistical reasons such as lab results not reported in the screening window. As 
such there is no impact on the subject population. 
4 
Section 4.3.1.3 (Independent Ophthalmology Assessments): wording related to the order 
of assessments has been removed to ensure consistency with changes made in protocol 
amendment 2 as the deletion of this text was overlooked in error when amendment 2 was 
created. 
Low and High Contrast Visual Acuity: following advice from expert ophthalmologists, 
clarification on when the high and low contrast visual acuity assessments should stop has 
been added to the protocol. The clarification is consistent with standard ophthalmology 
practice. 
5 
Section 4.3.1.4 (Expanded Disability Status Scale and Functional Systems Scores): 
Neurostatus as the name of the EDSS vendor was removed from the text as this group is 
no longer engaged with this study.  
Wording related to the order of assessments ha sbeen removed to ensure consistency with 
changes made in protocol amendment 2 as deletion of this text was overlooked in error 
when the amendment was created. 
6 
Section 4.3.6 (Clinical Laboratory Tests): Coagulation parameters were added to the 
hematology panel as these are currently being evaluated as part of this panel and were 
omitted in error. 
7 
Table 4.3.10.1 (Estimate of Blood Volume to be Collected): blood volumes for the 
Attack Follow-up Visit and total blood volume were corrected.  
8 
Table 4.5.1-1 (Identification of Investigational Products): The amount of polysorbate 80 
in the investigational product was corrected to 0.01% (w/v). 


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9 
Section 4.8.3.1 (Primary Analyses) and Section 4.8.3.2 (Additional Analyses of the 
Primary Endpoint): During discussions with the FDA the window in which attacks are 
assessed was discussed. It is essential for the quality of the data and patient safety that 
potential attacks are assessed as quickly as possible. The protocol therefore specifies a 3 
day window for subjects to come into the site and a further 5 days for assessments to be 
completed. However the sponsor and the FDA agreed that a wider window will apply for 
the statisticial analysis of the primary endpoint analysis to prevent valid attacks being 
excluded from the analysis. A sensitivity analysis to assess the impact of the loss of 
events outside of the identified assessment window was also added. The operational 
windows for management of subjects with potential attacks has not changed and there is 
no impact on the management of the subjects.  
10 Section 4.8.10.2 (Futility Assessment) and Appendix 10 (Details of Futility Analysis): 
Text was clarified to provide further information on how the futility assessment will be 
performed. 
11 Section 8 (References) additional references included in this amendment have been 
added. 
 
Protocol Amendment 2; 10Dec2015 
Text revisions resulting from this amendment are incorporated in the body of Protocol 
Amendment 2. The majority of these changes were primarily made for clarification to text and 
tables.  
1 
Protocol Synopsis and Section 3.1.1.1 (Screening Period), Section 3.2.3 (Rationale for 
Study Population), Section 4.1.2 (Inclusion Criteria), Criterion #3b, and Section 4.2.1 
(Enrollment/Screening Period): Text was amended to clarify that eligibility of AQP4-
IgG seronegative subjects will be determined by an independent eligibility committee to 
reflect actual practice. 
2 
Protocol Synopsis, Section 3.1.1 (Overview), 3.1.1.4 (Open-label Period), 4.2.2.2 
(Open-label Period), and Table 3.1.2-2 (Open-label Period Treatment Regimen), 
footnote “a”: Text was added or revised to clarify that subjects may exit the OLP at any 
time for any reason, including seeking alternative treatment options; this text 
modification was made in response to European Medicines Agency scientific advice. 
3 
Protocol Synopsis and Section 3.1.1.1 (Randomized-controlled Period (Day 1 to 
Day 197): Text was revised to clarify tht assessment of new symptoms or worsening of 
exisiting symptoms should be completed within 5 days to determine if an attack has 
occurred.  
4 
Protocol Synopsis and Section 4.1.1 (Number of Subjects), Section 4.1.7 (Replacement 
of Subjects), and Section 4.8.2 (Sample Size and Power Calculations): Text was revised 
to clarify that the study is event driven and enrollment of subjects will stop when a total 


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of 67 AC-determined NMO/NMOSD attacks occur. The planned number of subjects to 
be enrolled is 212; however, based on sample size reassessment the number maybe 
increased to a maximum of 252 subjects. 
5 
Protocol Synopis, Section 4.8.10.1 (Masked Sample Size Reassessment), and Appendix 
11 (Details of Masked Sample Size Reassessment ): Text was added for clarification that 
the study population may be increased up to 252 subjects if the ratio of the cumulative 
number of AC-determined NMO/NMOSD attacks to subject ratio is approximately 27% 
or less.  
6 
Section 1.4 (Summary of Clinical Experience): Text was revised to update the current 
statuses of clinical studies to align with the updated IB. 
7 
Section 3.1.1.2 (Randomization [Day 1]): Text was added to clarify that Day 1 is to 
occur within 28 days of the start of the screening period.  
8 
Section 3.1.1.5 (Safety Follow-Up Period): Text was added to align with the Czech 
Republic Local Protocol Amendment 1 as this is applicable globally; “During the SFP, a 
subject may receive standard treatment for their NMO/NMOSD at the discretion of the 
investigator.” 
9 
Section 3.2.4.2 (Secondary Endpoints): Subsection for Vaccine Titers and reference were 
added to provide the rationale for measuring anti-tetanus vaccine titers as one of the 
laboratory measures for the safety and tolerability of MEDI-551. 
10 Section 4.1.2 (Inclusion Criteria), Criteria #3b, #4, #6, #7 and #8: Criterion #3b was 
revised to clarify that data from AQP4-IgG subjects will be reviewed by an independent 
eligibility committee to confirm eligibility. Criterion #4 was revised to remove wording 
related to relapses in the screening period since these subjects should now be screen 
failed. Also, the time that subjects must be stable or improving prior to randomization 
was changed from at least  2 weeks to at least 4 weeks to ensure that the subject is 
appropriately managed and ensure there is less chance of an attack continuing. Criteria 
#6 and #7 were added to align with local requirements for the Czech Republic. Criterion 
#8 spelling was corrected to clarify that the criterion applies to males without appropriate 
post-vasectomy documentation. 
11 Section 4.1.3 (Exclusion Criteria), Criteria #3, #10g, #12, #23a, and #24: The text for 
Criterion #3 was revised to remove “at risk of developing nephrogenic systemic fibrosis 
after receiving gadolinium (Gd)-containing contrast agents” as all subjects with a score 
of less than 60 mL/minute may be at risk for developing nephrogenic systemic fibrosis 
and will be excluded. Criterion #10g was added to clarify that all subjects with B cells 
below the LLN are excluded as Criterion #12 applies only to subjects on rituximab; 
however, the same safety concerns apply regardless of prior medications. Criterion #12 
was modified to add text to exclude subjects using rituximab in the 6 months prior to 
screening as experience to date shows that B cells have not usually recovered to the LLN 
within this time frame. The text reference to B cells was removed as this is now covered 


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by Criterion #10g. Criterion #23a was modified to lower the total Ig value that is 
exclusionary as it was unnecessarily restrictive. The LLNs of the most abundant Igs (A, 
G, M) total to approximately 665 mg/dL, a further 10% under this does not constitute 
hypoglobulinemia. Criterion #24 text was added to clarify how hepatitis B and hepatitis 
C serology will be managed. In cases where the surface antigen is negative and the core 
antibody is positive, the presence of surface antibody will permit entry as it signifies that 
the subject is immune to hepatitis B, where the absence of surface antibody signifies that 
the subject is at risk of having hepatitis B. 
12 Section 4.1.4.1 (Enrollment): Text was revised to clarify that re-screened subjects will 
receive a new SID number to reflect actual practice with the INRS/IWRS. 
13 Section 4.1.5 (Withdrawal from the Study): Text was added to clarify that subjects at 
sites in the Czech Republic may discontinue investigational product following an EDV 
and enter the SFP if the subject agrees to enter the SFP, unless they are lost to follow up 
or enrolled in another clinical study.  
14 Section 4.2.1 (Enrollment/Screening Period): Text in this section was revised for the 
following reasons: 1) to allow procedures after consent is signed to be conducted in any 
order to give greater flexibility in scheduling the large number of study procedures; 2) to 
remove text to extend the screening period in the event that a subject has an NMO attack 
to ensure that subjects are appropriately stabilized prior to entry to the study; 3) to clarify 
that any subject who cannot be assessed in the 28-day screening period or experiences an 
NMO/NMOSD relapse, must be withdrawn and screen failed, and that any subject who 
is screen failed may be rescreened one further time, unless their participation would 
exceed the 80:20 ration; 4) to clarify that blood samples for serum chemistry and 
hematology must be redrawn in the event that screening is extended to ensure that safety 
laboratory results are up-to-date in the 28 days prior to randomization. 
15 Table 4.2.1-1 (Schedule of Screening Procedures): The table was modified for the 
following reasons: 1) blood samples for Total Ig, IgM, IgG, IgA, and IgE were added to 
the assessments to align with Administrative Change 1; 2) the ophthalmology assessment 
was revised to clarify that this should be an independent assessment; and 3) Footnote “d” 
was added to clarify that if the EDSS and C-SSRS are conducted by the same person that 
the EDSS should be performed first. This is the case at some sites and conducting the 
assessments in this same order will eliminate potential EDSS rater bias resulting from 
information gathered during the C-SSRS assessment. 
16 Section 4.2.1.1 (Eligibility Committee): New section was added to clarify that an 
independent Eligibility Committee will determine if subjects who are AQP4-IgG 
negative meet the Wingerchuk et al, 2006 criteria for NMO.  
17 Section 4.2.2.1 (Randomized-controlled Treatment Period): Text was revised for the 
following reasons: 1) to clarify that the randomization on Day 1 must occur within 
28 days of the start of the screening period, unless screening is extended; 2) to explain 


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the principle for ordering procedures to facilitate efficient conduct of the visit, including 
the conduct of the visit over 2 days; and 3) to remove text regarding an NMO attack at 
the randomization visit as it is now covered in the previous section. 
18 Table 4.2.2.1-1 (Schedule of Randomized-controlled Treatment Period Study 
Procedures): The table was modified for the following reasons: 1) Ig samples were 
removed for Day 1, Week 0 assessments to align with Administrative Change 1; 2) the 
ophthalmology assessment was revised to clarify that this should be an independent 
assessment; 3) footnote “e” was revised to claify that the subject should be treated for the 
attack as required, screen failed, and then reassessed; 4) footnote ‘h’ was added to clarify 
that if the EDSS and C-SSRS are conducted by the same person the EDSS should be 
done first to eliminate the possibility of bias; 5) footnote “i” was added to clarify that the 
randomization visit may be split over 2 days to accommodate the number of study 
procedures; and 6) footnote “j”was added to clarify that tetanus vaccine titers will be 
tested at Day 1 for all subjects and that with negative results will not continue to be 
tested but those who test positive will continue to be tested at specified titer time points; 
and 7) footnote “k” was added to clarify that if the second dose of investigational 
product is delayed due to medical/safety reasons, dosing must be discussed with the 
medical monitor prior to administration of investigational product to ensure all subjects 
have the same opportunity to receive investigational product.  
19 Section 4.2.2.2 (Open-label Period): Text was revised or added for the following 
reasons: 1) explain the principle for ordering procedures to facilitate efficient conduct of 
the visit; 2) to allow some flexibility in the time for subjects completing the RCP without 
an NMO/NMOSD attack to enter the OLP in the event that there is a safety issue; and 3) 
to increase the time period in which subjects who experience an AC-determined 
NMO/NMOSD attack have to enter the OLP to ensure that subjects are not unfairly 
excluded in the event that it may require a number of weeks for stabilization with rescue 
medication. Managing acute attacks with rescue medications is expected to prevent 
further NMO/NMOSD attacks. 
20 Table 4.2.2.2-1 (Schedule of Open-label Period Study Procedures): The table was 
modified for the following reasons: 1) footnote “d” was revised to clarify that if any part 
of the neuroaxis MRI was not done at the time of the Assessment Visit, it should be 
conducted at Day 1 of the OLP, otherwise it is not required; 2) footnote “g” was added to 
clarify that investigational product will not be given if the subject is undergoing an EDV; 
3) footnote “h” was added to clarify that if the EDSS and C-SSRS are conducted by the 
same person the EDSS should be performed first to eliminate potential bias; 4) footnote 
“i” was added to clarify that in the event that the second dose of investigational product 
is delayed due to medical/safety reasons, dosing must be discussed with the medical 
monitor prior to administration of investigational product to ensure that all subjects have 
the same opportunity to receive investigational product; 5) footnote ‘j’was added to 
clarify that tetanus vaccine titers will only be tested in the OLP for subjects who tested 


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positive at Day 1 of the RCP; and 6) to add +28 days to AC determination to the Day 1 
visit window for clarification. 
21 Section 4.2.3 (Study Procedures for Assessment Visit): Text was revised or added for the 
following reasons: 1) to clarify that procedures to determine whether symptoms are 
related to NMO/NMOSD should be conducted first, followed by procedures for 
determination of an NMO/NMOSD attack; 2) to clarify that all assessments are to be 
documented with time and date and that the order of the assessments should be 
determined by the nature of the suspected attack (eg, EDSS before Independent 
ophthalmology in the case of myelitis symptoms; 3) to clarify that an MRI of all domains 
may be performed as part of the Assessment Visit and can be done at any time during the 
Assessment Visit, and that the order of the MRI domains can be determined by the 
nature of the suspected attack; 4) to clarify that MRI images/study report should not be 
reviewed by the Principal Investigator unless a specific criterion for an attack requires 
review of the MRI and in such cases the review of the MRI image must be done after the 
review of all relevant clinical assessment data is complete; 5) to clarify that assessments 
should be concluded as soon as possible, but should not extend beyond 4 days from Day 
1 of the Assessment Visit; and 6) to clarify that if the investigator determines that new or 
worsening symptoms are not related to NMO, then the independent assessments will not 
be required. 
22 Table 4.2.3-1 (Schedule of Study Procedures for the Assessment Visit): The following 
modifications were made to the table: 1) assessments for procedures to determine an 
NMO/NMOSD attack were moved below the laboratory assessments and neuroaxis MRI 
scan was moved to be included in these assessments; 2) a new assessment was added to 
review data generated against protocol-defined attack criteria and create a narrative of 
the Assessment Visit findings; 3) footnote “b” was revised to change the original text to 
“the MRIimage/report is only reviewed by the Principal Investigator in the event it is 
required by the protocol-defined attack criteria; 4) footnote “c” was added to clarify that 
if the EDSS and C-SSRS are conducted by the same person that the EDSS must be 
performed first to eliminate the potential for bias; 3) former footnote “c” was removed to 
avoid confusion; as a full MRI will be performed regardless of the attack criteria.  
23 Section 4.2.4 (Managing Subjects With Worsening Attacks): New section was added to 
describe how to manage and capture data from subjects who experience worsening of an 
investigator-diagnosed attack. These unscheduled data will provide a narrative of the 
subject’s attacks if they worsen after diagnosis. 
24 Section 4.2.5 (Study Procedures for Attack Follow-up Visit): Text in this section was 
revised or added for the following reasons: 1) to move text to beginning of the paragraph 
for purpose of highlighing that subjects who experience an NMO/NMOSD attack 
requiring rescue treatment regardless of the outcome of the AC review will undergo an 
Attack Follow-up Visit; and 2) text was added to clarify the patient-reported outcomes 


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should be done first followed by all othr assessments/procedures in an order to be 
determined by the sites. 
25 Table 4.2.5-1 (Schedule of Study Procedures for the Attack Follow-up Visit): The 
following modifications were made to the table: 1) The order of assessments for SF-36 
Health Survey, C-SSRS, indpendent ophthalmology examination, and independent 
EDSS/FSS were rearranged; 2) footnote “c” was added to clarify that if the EDSS and 
C-SSRS are conducted by the same person that the EDSS must be performed first to 
eliminate the potential for bias. 
26 Section 4.2.6 (Safety Follow-up Period): Text was revised to remove reference to the 
order in which study assessments are to be performed as the order has no impact on any 
of the assessments in the SFP. 
27 Section 4.3.1.1 (Identification, Assessment, and Adjudication of an NMO/NMOSD 
Attack), Overview: Text was revised to clarify that following the start of the Assessment 
Visit, the procedures required to diagnose an NMO/NMOSD attack must be completed 
within a total of 5 days and to add greater clarity that there are 2 main outcomes to the 
Assessment Visit, which are outlined. 
28 Figure 4.3.1.1-1 (Flow Chart of Assessment and Diagnosis of an NMO/NMOSD 
Attack): The flow diagram was updated to better reflect required process; ie, that an MRI 
is always required at an Assessment Visit; however, review of the images is criterion 
dependent. 
29 Section 4.3.1.1 (Identification, Assessment, and Adjudication of an NMO/NMOSD 
Attack), Telephone Calls to Subjects: Text was modified to clarify that the telephone 
calls made to subjects will be every 2 weeks and not twice a week (bi-weekly). 
30 Section 4.3.1.1 (Identification, Assessment, and Adjudication of an NMO/NMOSD 
Attack), Assessment Visit: Text was revised for the following reasons: 1) to clarify that 
data for the assessment of symptoms that were determined as not related to 
NMO/NMOSD will be sent to the AC for non-real-time review; 2) to clarify the the date 
and time of clinical assessments conducted by independent assessors must be 
documented and the order of the assessments may be driven by the nature of the 
suspected attack; 3) to clarify that an MRI of all domains should be performed as part of 
an Assessment Visit and can be done at any time during the Assessment Visit, and that 
the order of the MRI domains can be determined by the suspected NMO/NMOSD attack; 
4) to clarify that MRI images/study report should not be reviewed by the Principal 
Investigator unless a specific criterion for an attack requires review of the MRI; 5) to 
clarify that following the independent clinical assessment, the Principal Investigator 
should decide if any of the clinical criteria have been met and that the criterion with the 
most significant change should be selected; and 6) if an attack presents in more than one 
domain, more than one criterion can be selected. These revisions were made to clarify 
that symptom(s) must meet at least one of the objective criteria for an NMO/NMOSD 


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attack and that the criteria with the most significant clinical change that the symptoms 
meet should be selected, subsequent criteria with a lesser clinical change that require 
MRI review should not be considered. However, the symptom(s) may meet more than 
one criterion for an NMO/NMOSD attack across a different body system. This is to 
ensure that MRI images and reports are not reviewed when a significant change meets 
criteria 1-8, 12, and 13.  
31 Section 4.3.1.1 (Identification, Assessment, and Adjudication of an NMO/NMOSD 
Attack), Adjudication Process (For Attacks Occurring During the RCP): Text was 
revised to clarify that the AC process will completed when the AC makes their final 
decision and that this will occur within a total of 14 days (+ 3 days) from the start of the 
Assessment Visit and that the data set will be provided to the independent AC by the 
vendor. 
32 Table 4.3.1.1-1 (Protocol-defined Criteria for an NMO/NMOSD Attack): The following 
modifications were made to the table: 1) footnote “c” was removed (re: “Symptoms must 
meet at least 1 of the objective criteria for NMO/NMOSD attack”) because this is 
explained in the text; 2) footnote “e” (newly designated footnote “d”) was modified to 
add “HM to LP or NLP” to 1-step drop in worsening missing from previous version and 
to align with Administrative Change 1; and 3) footnote “f” was added to clarify that 
lesions seen in the optic chiasm also count towards the ON criteria when evaluating 
Criteria 9, 10, and 11. 
33 Figure 4.3.1.1-2 (Process for Assessing Symptoms Affecting the Eye): The flow diagram 
was updated to better reflect required process; ie, that an MRI is always required at an 
Assessment Visit; however, review of the images is criterion dependent. 
34 Figure 4.3.1.1-3 (Process for Assessing Symptoms Affecting the Spinal Cord): The flow 
diagram was updated to better reflect required process; ie, that an MRI is always 
required at an Assessment Visit; however, review of the images is criterion dependent. 
35 Figure 4.3.1.1-4 (Process for Assessing Symptoms Affecting the Brain or Brainstem): 
The flow diagram was updated to better reflect required process; ie, that an MRI is 
always required at an Assessment Visit; however, review of the images is criterion 
dependent. 
36 Section 4.3.1.2 (Neuroaxis Magnetic Resonance Imaging Scan), MRI for NMO/NMOSD 
Attacks, and Neuroaxis MRI Documentation and Assessment: The text in these 
subsections was added or revised for the following reasons: 1) to clarify that a full 
neuroaxis MRI will be performed of all domains in addition to the scheduled MRI at the 
time of any Assessment Visit and that the MRI scans will be sent for a central reading 
and data will be collected for analysis at the end of the study; 2) to clarify the MRI 
images/study report obtained during an Assessment Visit should not be reviewed by the 
Principal Investigator unless required for a specific criterion; however, should it become 
necessary, review of MRI image and local report must be done after the review of all 


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relevant clinical assessment data is complete. As long as the MRIs are not reviewed by 
the Principal Investigator prior to review of the clinical assessments no bias will be 
introduced; 3) to clarify that the Principal Investigator should not use these MRIs for any 
clinical decision making; and 4) to clarify that qualification MRI scans may require 
consenting a volunteer subject from the investigative site, depending upon local IRB/EC 
requirements. 
37 Section 4.3.1.3 (Ophthalmology Assessments) and Visual Acuity Assessments: The 
following text in these subsections was added or revised: 1) text was added to clarify that 
the ophthalmology examiner is also independent and not otherwise involved in 
evaluating or examining the subject outside of the protocol to reduce the potential for 
bias; and 2) text referring to light meters was removed as these are not required. 
38 Section 4.3.1.4 (Expanded Disability Status Scale and Functional System Scores): Text 
was revised to clarify that the EDSS assessment must be conducted by a trained and 
certified neurologist who is also independent of the treating physician and the subject to 
reduce the potential for bias. 
39 Section 4.3.1.5 (Independent Adjudication Committee): Text was revised following the 
review of the first few attacks that occurred in the study, and input from the AC 
necessitated clarifications of the AC role and process. This is outlined in the new text 
and will be reflected also in an amended charter for the AC. The committee is 
completely independent and blinded to treatment assignments and/or to pertinent 
treatment unmasking information of study subjects. Clarified that events not related to 
NMO/NMOSD that occur in the RCP will be sent to the AC for non-real-time 
adjudication.  
40 Section 4.3.3.4 (Electrocardiogram): Text was revised to add ECG recording to Day 1, 
which was missing from previous text. 
41 Section 4.3.4 (Columbia-Suicide Severity Rating Scale): Text was revised to clarify that 
the Baseline/Screening questionnaire will be used to assess suicidality in a subject’s 
lifetime and over the 6 months prior to screening. 
42 Section 4.3.6 (Clinical Laboratory Tests): Text was modified or added for the following 
reasons: 1) hepatitis B surface antibody was added to Other Safety Tests for consistency 
with Exclusion Criterion #24; 2) text was added to clarify that the estimated GFR would 
be calculated and the GFR must be ≥ 60 mL/minute for study eligibility and for 
consistency with Exclusion Criterion #3. The estimated GFR would be calculated by the 
central laboratory based on the plasma and urine creatinine samples provided using the 
Modification of Diet in Renal Disease formula; 3) tetanus vaccination titers was added to 
Other Safety Tests; and 4) subsection for Vaccination Titers was added to specify which 
vaccine titers will be analyzed for the samples already specified in the protocol.  
43 Section 4.3.9 (Biomarker Evaluations and Methods): Text was added to explain that 
plasma cell gene signature data can be considered potentially unmasking and that the 


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sponsor will not see any potentially unmasking data until after the study has been 
unmasked for the primary analysis. 
44 Table 4.3.10-1 (Estimate of Blood Volume to Be Collected): The total blood volume for 
Screening was changed from 30 mL to 31 mL to add Ig samples to screening. Total 
blood volume for Day 1 changed from 38 mL to 37 mL to account for removal of Ig 
samples at Day 1 and to align with Administrative Change 1. 
45 Section 4.5.1.2 (Treatment Administration), Randomized-controlled Period, and 
Open-label Period: Text in these subsections was revised for the following reasons: 1) to 
allow some flexibility in the time for subjects completing the RCP without and 
NMO/NMOSD attack to enter the OLP in the events there is a safety issue; and 2) to 
clarify that in the event that the second dose of investigational products is delayed due to 
medical or safety reasons, subsequent dosing must be discussed with the medical 
monitor prior to administration of investigational product. Additionally, subjects are not 
permitted to enter the OLP after 14 days, unless there is a safety reason and the medical 
monitor agrees, in which case a short extension may be granted.  
46 Section 4.5.1.3 (Monitoring of Dose Administration): Text was added to state that 
Japanese subjects must receive their RCP Day 1 dose as in-patients per local 
Pharmaceuticals and Medical Devices Agency requirements. 
47 Section 4.5.2.2 (Rescue Medications): Text was revised to clarify that assessment of new 
symptoms or worsening of exisiting symptoms should be completed within 5 days to 
determine if an attack has occurred and that the Principal Investigator can initiate rescue 
therapy at any time before full assessment is completed and that rescue therapy may 
include IV corticosteroids, IVIG, and/or PLEX.  
48 Section 4.5.3 (Dose Adjustments and Missed Doses): Text was simplified to note that if 
any dose of investigational product is missed, subsequent dosing and subject 
management must be discussed with the medical monitor prior to any further dosing. 
49 Section 4.6.3 (Methods for Reducing Bias): Text was added or revised for the following 
reasons: 1) to clarify that the EDSS rater and the ophthalmology examiner must remain 
independent of the subject during the study to eliminate the potential for bias; and 2) to 
clarify that the MRI scans should not be reviewed by the Principal Investigator until 
review of the clinical data for the clinical assessments for an suspected attack type is 
complete. 
50 Section 4.6.4.1 (Unmasking in the Event of a Medical Emergency): Text was added for 
unmasking in a medical emergency for sites in the Czech Republic to align with the local 
amendment.  
51 Section 4.6.4.3 (Unmasking due to Known or Hypothesized Effects of MEDI-551): Text 
was added to inform that data from early phase development in non-oncology subject 
populations receiving MEDI-551 suggest that MEDI-551 administration may be 
associated with potential unspecified mild reduction in total Ig in individual subjects and 


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these data will not be made available to investigational sites post randomization through 
the remainder of the study as this reduction may be potentially unmasking. This addition 
was made to align with Administrative Change 1. Additionally, text was added to 
indicate that plasma cell gene signature data and tetanus vaccine titers are potentially 
unmasking and will not be made available to the sites and plasma cell gene signature 
samples will not be tested prior to unmasking, and a summary statement that all 
potentially unmasking data will not be available to the sponsor prior to unmasking of the 
study at the end of the RCP. 
52 Section 4.7.1.1 (Immunosuppressive Medications During the Screening Period): Text 
was revised to clarify that immunosuppressive medications must be stopped prior to 
dosing on Day 1, but steroids must continue according to the protocol. 
53 Section 4.7.2 (Prohibited Concomitant Medications): Text was added or revised for the 
following reasons: 1) to clarify that subjects may exit the OLP at any time for any 
reason, including to seek alternative treatment options as per EMA scientific advice; 2) 
to clarify that low-dose steroids prohibited by the protocol do not include topical steroids 
because they are not applied at immunosuppressive doses; and 3) to clarify that there are 
no prohibited medications during the SFP. 
54 Section 4.8.2 (Sample Size and Power Calculations): Text was modified to clarify that 
the study is event driven and enrollment of subjects will stop when a total of 67 
AC-determined NMO/NMOSD attacks occur. The planned number of subjects to be 
enrolled is 212; however, based on sample size reassessment the number maybe 
increased to a maximum of 252 subjects. All active randomized subjects at the time that 
67 events have occurred will continue in the study to complete the RCP. If eligible, these 
subjects will be able to roll over to the OLP. Therefore, the sample size will depend on 
achieving this goal and sample size reassessment. 
55 Section 5.2 (Definition of Serious Adverse Events): Text revised for the following 
reasons: 1) to clarify that for the purposes of this protocol an SAE of death will include 
NMO/NMOSD disease progression or attack; 2) to clarify that NMO/NMOSD disease 
progression or attacks that meet the SAE criteria, with the exception of death, do not 
need to be reported as SAEs in the RCP and OLP since they are study endpoints and to 
further clarify that NMO/NMOSD attacks that meet the SAE criteria during the 
screening period or SFP will be reported as SAEs as they are not considered study 
endpoints during these periods and data would otherwise be lost if not reported; and 3) to 
reinforce that NMO/NMOSD disease progression or attacks that result in death will be 
reported as SAEs; and 4) hospitalization for any procedure resulting from an 
NMO/NMOSD attack will not be reported as an SAE.  
56 Section 8 (References): Reference for Siegrist, 2013 was added to the reference list.  


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57 Appendix 5 (Pain NRS): The NRS form was updated to include a check box for the 
Attack Follow-up Visit as this was missing from the previous version and was 
inconsistent with the protocol. 
 


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Administrative Change 1; 18Feb2015 
Administrative changes were made primarily for consistency and to correct typographical 
errors. Administrative changes to the protocol are summarized below: 
1 
Table 4.2.1-1 (Schedule of Screening Procedures): Blood collection for total Ig, IgM, 
IgG, IgA, and IgE was added for consistency with Exclusion Criterion 23a in 
Section 4.1.3 (Exclusion Criteria), which states that subjects with a total Ig level of 
d 900 mg/dL at screening are not eligible for the study. 
2 
Table 4.2.2.1-1 (Schedule of Randomized-controlled Treatment Period Study 
Procedures): Blood collection for total Ig, IgM, IgG, IgA, and IgE was removed at Day 1 
for consistency with Exclusion Criterion 23a in Section 4.1.3 (Exclusion Criteria), which 
states that subjects with a total Ig level of d 900 mg/dL at screening are not eligible for 
the study. 
3 
Table 4.3.1.1-1 (Protocol-defined Criteria for an NMO/NMOSD Attack): Criterion 8 
under ON attack type was corrected to change the word “affected” to “fellow” for 
consistency with the wording in Criteria 4 and 6 of the same ON attack type as well as in 
the description of the RAPD assessment in Section 4.3.1.3 
(OphthalmologyAssessments). 
4 
Table 4.3.1.1-1 (Protocol-defined Criteria for an NMO/NMOSD Attack: A fourth 
example of a 1-step drop in visual acuity was added to Footnote “e,” which described a 
change in hand motion (HM) to light perception (LP) or no light perception (NLP); this 
example was omitted in error. 
5 
Table 4.3.10-1 (Estimate of Blood Volume to Be Collected): The estimated volume of 
blood to be collected from each subject at Screening was increased 1 mL and the blood 
to be collected from each subject at Day 1 was decreased by the same amount to account 
for the transition of Ig testing from Day 1 to Screening. 
6 
Section 4.6.4.3 (Unmasking due to Known or Hypothesized Effects of MEDI-551): 
Added that results of Ig testing (total Ig, IgM, IgG, IgA, and IgE) would not be made 
available to investigation sites post randomization through the remainder of the study. 
 
Protocol Amendment 1; 01Jul2014 
Text revisions resulting from this amendment are incorporated in the body of Protocol 
Amendment 1. The majority of these changes were made in response to feedback from the US 
FDA Special Protocol Assessment requested by MedImmune. Major changes to the protocol 
are summarized below. 
1 
Study Abstract: Updated to be consistent with the changes made to the body of the 
protocol. 


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2 
Section 1.1 (Disease Background) and Section 1.5 (Rationale for Study): Simplified the 
description of NMO and its associated characteristics for clarity. 
3 
Section 1.6.2 (Secondary Hypotheses): The following changes were made: 1) Added 
MRI lesion hypothesis; and 2) Removed secondary hypotheses pertaining to safety and 
PK to simplify the section and focus it on the efficacy outcomes. 
4 
Section 2.1.1 (Primary Objective) and Section 1.6.1 (Primary Hypothesis): Revised the 
subject population for the primary analysis to include both AQP4-IgG seropositive and 
seronegative subjects. 
5 
Section 2.1.2 (Secondary Objectives): Added secondary objective comparing the 
efficacy of MEDI-551 versus placebo in reducing the cumulative active MRI lesion 
count (new Gd-enhancing or new/enlarging T2). This study aims to collect longitudinal 
MRI data during both study periods, including at the time of an attack, to investigate the 
characteristics and evolution of spinal and brain lesions in NMO/NMOSD. 
6 
Section 2.1.3 (Exploratory Objectives): Added exploratory objective comparing the 
effect of MEDI-551 versus placebo on pain as measured using the pain NRS. A number 
of recent publications have indicated that patients with NMO/NMOSD experience pain 
throughout the course of their disease. Pain in demyelinating and inflammatory CNS 
diseases can be disabling and may contribute to a lower quality of life and overall 
increased health care burden.  
7 
Section 2.2.1 (Primary Endpoint): The following changes were made: 1) Revised the 
timeframe of the primary endpoint definition from Day 183 to Day 197 to coincide with 
the increased length of the RCP, which will be extended by 2 weeks to account for the 
2-week oral corticosteroid use between Day 1 and Day 14; 2) Removed the restriction 
that the primary analysis will be based on AQP4-IgG seropositive subjects. The primary 
analysis will first be tested in AQP4-IgG seropositive subjects, and if statistically 
significant, it will be further tested in all subjects; and 3) Removed Table 2.2.1-1 from 
this section and moved it to Section 4.3.1.1 (Identification, Assessment, and 
Adjudication of an NMO/NMOSD Attack).  
8 
Section 2.2.2 (Secondary Endpoints): The following changes were made: 1) Revised the 
visual acuity endpoint to change the measurement tool from the Sloan Letters Low 
Contrast Chart to the Landolt C Broken Rings Chart as recommended by MedImmune’s 
NMO Steering Committee; 2) Added an MRI lesion endpoint to coincide with the 
addition of a secondary objective; and 3) Revised the definition of in-patient 
hospitalization from hospital stay greater than 24 hours to more than an overnight stay. 
9 
Section 2.2.3 (Exploratory Endpoint[s]): The following changes were made: 1) Added an 
endpoint for the pain NRS objective; and 2) Removed the biomarker exploratory 
endpoint (this endpoint will be analyzed as part of an exploratory investigation. 
10 Section 3.1.1 (Overview): The following changes were made: 1) Changed the sample 
size of the study from 252 to 212 subjects due to the addition of the AQP4-IgG 


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seronegative subjects as part of the primary endpoints, with the potential to increase the 
number of subjects to 252 if the sample size needs to be reassessed; 2) Extended the 
RCP to 197 days to account for the 2-week oral corticosteroid use between Day 1 and 
Day 14; 3) Revised text for the enrollment of subjects into the OLP and continuation of 
subjects in the RCP if an NMO/NMOSD attack was not determined by the AC based on 
comments received from the Agency regarding the identification, assessment, and 
adjudication of NMO/NMOSD attacks; 4) Revised the time period for the OLP to add a 
maximum time length of 3 years (after the last subject enters) if regulatory approval or 
MEDI-551 development is halted after 3 years; 5) Renamed the Long-term Follow-up 
Period the SFP to evaluate the long-term safety of the investigational product; 6) Added 
subsections 3.1.1.1 (Screening Period), 3.1.1.2 (Randomization [Day 1]), 3.1.1.3 
(Randomized-controlled Period [Day 1 to Day 197]), 3.1.1.4 (Open-label Period), and 
3.1.1.5 (Safety Follow-up Period) to clarify existing text (Sections 3.1.1.1 and 3.1.1.2) 
and to summarize changes made to the design of the study based on the Agency’s 
comments to better define the identification, assessment, and adjudication of 
NMO/NMOSD attacks and the process of enrolling subjects into the OLP 
(Sections 3.1.1.3, 3.1.1.4, and 3.1.1.5); 7) Replaced previous Figure 3.1.1-1 (Study Flow 
Diagram) with new figure. 
11 Section 3.1.2 (Treatment Regimen): The following changes were made: 1) Clarified that 
equivalent antihistamines to diphenhydramine can be used as part of the MEDI-551 
premedication regimen; 2) Changed the 2-week tapering reduction schedule to 1 week; 
and 3) Clarified the text for dosing of subjects in the OLP. 
12 Section 3.2.1 (Study Design Rationale): Revised the study design rationale for clarity 
and for changes made to previous sections of the protocol. 
13 Section 3.2.2 (Dose Rationale): Revised the dose rationale for clarity. 
14 Section 3.2.3 (Rationale for Study Population): Revised the rationale for study 
population for clarity, to reflect changes in study design, and to add supporting 
information. 
15 Section 3.2.4 (Rationale for Endpoints): The following changes were made: 1) Revised 
the rationale for the primary, secondary, and exploratory endpoints for clarity and for 
consistency with changes made in Sections 2.2.1 (Primary Endpoint), 2.2.2 (Secondary 
Endpoints), and 2.2.3 (Exploratory Endpoint[s]); and 2) Added Section 3.2.4.4 
(Exploratory Investigations) to summarize the rationale for the biomarker endpoint 
(previously an exploratory endpoint) and added a rationale for investigating T-cell 
responses since there is increasing evidence for the involvement of effector T cells in the 
pathogenesis of NMO. 
16 Section 3.2.4.1 (Primary Endpoint): The following changes were made: 1) Revised text 
for primary endpoint to onset of an AC-determined NMO/NMOSD attack on or before 


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Day 197; 2) Revised text to support limiting subject exposure to placebo by utilizing 
time to attack as the primary endpoint.  
17 Section 3.2.4.2 (Secondary Endpoints): The following changes were made: 1) Changed 
low contrast visual acuity charts from Sloan Letters Chart to Landolt C Broken Rings 
Chart; 2) Added MRI-related endpoint rationale and supporting information for 
collecting longitudinal MRI data during both study periods and at time of attack to 
investigate the characteristics and evolution of spinal and brain lesions in 
NMO/NMOSD; 3) Redefined in-patient hospitalization for the purposes of analysis of 
the secondary endpoint and added supporting information.  
18 Section 4.1.1 (Number of Subjects): Clarified the number of subjects planned for the 
study based on both AQP4-IgG seropositive and seronegative subjects and the addition 
of subjects for the purposes of reassessing the sample size based on the NMO/NMOSD 
attack rate. 
19 Section 4.1.2 (Inclusion Criteria): The following changes were made: 1) Added to 
Inclusion Criterion 3b, data from AQP4-IgG seronegative subjects will be reviewed by 
an independent expert to confirm eligibility; 2) Added to Inclusion Criterion 7 that 
female partners who are unable to comply with any required contraception method (such 
as male condom plus spermicide) must use one of the other recommended highly 
effective contraceptive methods; 3) Changed Inclusion Criterion 7 to state that 
nonsterilized males must use contraception from Day 1 for 3 months if they are sexually 
active with a female partner of childbearing potential; and 4) Added Criterion 8, 
sterilized males, with the appropriate post-vasectomy documentation on the absence of 
sperm in the ejaculate, who are sexually active with a female partner of childbearing 
potential, must use a highly effective method of contraception from Day 1 for 3 months 
after receipt of the final dose of investigational product. Criterion was added to 
accommodate contraception requirements in the United Kingdom.  
20 Section 4.1.3 (Exclusion Criteria): The following changes were made: 1) Clarified 
Exclusion Criterion 11 to state prior to randomization; 2) Revised Exclusion Criterion 12 
to state prior to randomization rather than at the time of screening; and 3) Added 
Exclusion Criterion 13 excluding subjects who received IVIG within 1 month prior to 
randomization as it might affect subject outcomes. 
21 Section 4.1.4 (Subject Enrollment and Randomization): Added subsection headers 
(Sections 4.1.4.1 [Enrollment] and 4.1.4.2 [Randomization Process]) for clarity and 
revised the subsection on Informed Consent Requirements for clarity. 
22 Section 4.1.5 (Withdrawal from the Study): Added instructions for subjects who want to 
discontinue participation in the study during the RCP to consider following 
protocol-specified assessments until Day 197 and for subjects who want to discontinue 
the study during the OLP to enter the SFP in order to capture more data on these 
subjects. 


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23 Section 4.1.7 (Replacement of Subjects): The following changes were made: 1) Changed 
adjudicated to AC-determined NMO/NMOSD attacks; and 2) Removed reference to 
AQP4-IgG serostatus.  
24 Section 4.2.1 (Enrollment/Screening Period): The following changes were made: 
1) Added that any subject who has an AQP4-IgG seronegative status at screening will 
have their medical history and MRI data reviewed by an independent NMO expert to 
ensure that the subject meets the Wingerchuk et al, 2006 diagnostic criteria for NMO; 
2) Removed language regarding the definition of NMO/NMOSD relapse as the 
identification, assessment, and adjudication processes have been updated per comments 
made by the Agency; 3) Added assessment of JCV antibody titers at screening; 4) 
Clarified that whole blood for flow cytometry includes B-cell count and cell subsets; 
5) Clarified that serum for AQP4-IgG includes serostatus and titer assessments; and 
6) Changed APD assessment to RAPD assessment for the ophthalmology examination. 
25 Section 4.2.2.1 (Randomized-controlled Treatment Period): The following changes were 
made: 1) Extended the RCP to Day 197 due to the 2-week oral corticosteroid use 
between Day 1 and Day 14; this resulted in changing the Day 141 visit to Day 155; 2) 
Added that subjects should continue in the SFP if they undergo the EDV to follow 
subjects for safety. 
26 Table 4.2.2.1-1 (Schedule of Randomized-controlled Treatment Period Study 
Procedures): The following changes were made: 1) Changed Study Weeks 20 (Day 141) 
and 26/EDV (Day 183) to Study Weeks 22 (Day 155) and 28/EDV (Day 197); 2) 
Changed Pain scale to Pain NRS and deleted assessment at Day 15; 3) Added sample for 
whole blood for PBMC isolation to be collected a selected sites after the PBMC was 
added as an exploratory analysis at Days 1, 85, and 197/EDV; 4) Removed 
ophthalmology examinations for visual fields, OCT, and fundoscopy; and 5) Added mRS 
to assessments.  
27 Section 4.2.2.2 (Open-label Period): The following changes were made: 1) Revised text 
to clarify that subjects completing Day 197 of the RCP, Day 1 of the OLP should be the 
same day, but may be delayed up to 14 days without repeating procedures; subjects will 
not be permitted to enter the OLP after 14 days. The 14 days window was added to give 
the subject reasonable time to make the decision to enter the OLP without putting the 
subject at potential increased risk for an attack as he/she will not be treated until entering 
the OLP or deciding to discontinue from the study and getting another treatment; 2) 
Added that subjects who have an AC-determined NMO/NMOSD attack during the RCP 
must enter the OLP within 14 days of AC determination. If more than 14 days elapse 
since the Assessment Visit, Day 1 procedures should be repeated; 3) Added that MEDI-
551 will be administered on OLP Day 1; 4) Revised OLP duration as a minimum of 1 
year after the last subject enters and a maximum of 3 years after the last subject enters; 
5) Added that subjects entering the OLP will need to reconsent prior to receiving 
MEDI-551; 6) Changed Day 183+/EDV to Day 365+/EDV for early discontinuation; 7) 


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Changed Day 183+/EDV to Day 197+/EDV for procedures to be conducted for subjects 
who withdraw during a scheduled study visit. 
28 Table 4.2.2.2-1 (Schedule of Open-label Period Study Procedures): The following 
changes were made: 1) Added +14 days from Day 197 of the RCP or AC determination 
to visit window for Day 1 of the OLP; 2) Changed every 12 weeks (Q12W; Day 85) to 
Week 13 (Day 92), added Week 26 (Day 183) and Week 39, then every 26 weeks 
(Q26W; Day 274+), changed Q26W/EDV to Week 52, then Q26W/EDV (Day 365+); 3) 
Added written informed consent to procedures as subjects will require reconsent to enter 
the OLP; 4) Changed Pain scale to Pain NRS; 5) Removed ophthalmology examinations 
for visual fields, OCT, and fundoscopy; 6) Added footnotes for procedures to be 
conducted for clarification. 
29 Section 4.2.3 (Study Procedures for Assessment Visits): The following changes were 
made: 1) Changed Attack Visit to Assessment Visit; 2) Revised that Assessment Visit 
should be scheduled as soon as possible and within 72 hours of symptom report; 3) 
Revised to assessments should be concluded as soon as possible, but should not extend 
beyond 5 days from Day 1 of the Assessment Visit. 
30 Table 4.2.3-1 (Schedule of Study Procedures for the Assessment Visit): The following 
changes were made: 1) Changed Attack Visit to Assessment Visit; 2) Changed Pain scale 
to Pain NRS; 3) Removed ophthalmology examinations for visual fields, OCT, and 
fundoscopy; and 4) Added ECG to assessments.  
31 Section 4.2.5 (formerly Section 4.2.4, Safety Follow-up Period): The following changes 
were made: 1) Changed Long-term Follow-up Period to SFP; 2) Added that the SFP will 
start when a subject discontinues early from the RCP or the OLP, and the length of the 
SFP will be determined by the time elapsed from time of last dose of investigational 
product to time of early discontinuation to complete a total of 52 weeks; subjects who 
discontinue during the RCP will continue with study assessments until Day 197, unless 
consent is withdrawn; 3) Revised that the SFP will last 52 weeks from the last dose of 
study drug. The SFP is introduced to follow subjects who prematurely discontinue from 
the study for safety only as it is not reasonable to request subjects who do not wish to 
continue in the study to continue with the study procedures.  
32 Table 4.2.5-1 (formerly Table 4.2.4-1, Schedule of Procedures for Safety Follow-up 
Period): The following changes were made: 1) Changed Long-term Follow-up Period to 
SFP; 2) Removed assessments for assessing new and/or worsening NMO/NMOSD 
symptoms, whole blood for gene expression, concomitant medications, ophthalmology 
examinations for visual acuity, low-contrast visual acuity, afferent pupillary defect, and 
independent EDSS/FSS administration.  
33 Section 4.3.1.1 (Identification, Assessment, and Adjudication of an NMO/NMOSD 
Attack): The following changes were made: 1) Added overview section to explain the 
process for identification, assessment, and adjudication of an NMO/NMOSD attack; 


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2) Added revised flow chart; 3) Added process for rescue treatment for an 
NMO/NMOSD attack and that rescue treatment is to be given at clinical judgment of the 
investigator; 4) Added subsection, Detailed Procedures, for identifying new or 
worsening symptoms that may be related to an NMO/NMOSD attack; 5) Updated 
Table 4.3.1.1-1 (Protocol-defined Criteria for an NMO/NMOSD Attack) and moved to 
this section from Section 2.2.1; 6) Added 3 flow diagrams for assessing symptoms 
affecting the eye, spinal cord, and brain or brainstem; 7) Deleted Figure 4.3.1.1-2 
(NMO/NMOSD Attack Flow Diagram) as this was replaced by updated Figure 3.1.1-1 
(Study Flow Diagram); 8) Added Figures 4.3.1.1-2, 4.3.1.1-3, and 4.4.1.1-4.  
34 Section 4.3.1.1 (formerly Section 4.3.1.2), Recording Symptoms of NMO/NMOSD: The 
following changes were made: 1) Revised that details of NMO/NMOSD symptoms that 
occur or worsen during the study will be recorded at the Assessment Visit; 2) Added that 
information regarding new or worsening symptoms may be provided during the study 
visits, follow-up visit by the site, during bi-weekly telephone calls, or from spontaneous 
reporting by the subject; 3) Added that a standardized worksheet will be used by the sites 
to elicit consistent information; 4) Revised that information to be recorded includes date 
of contact, if symptom(s) was not related to NMO/NMOSD but to an AE, and date of 
scheduled Assessment Visit. 
35 Section 4.3.1.1 (formerly Section 4.3.1.3), Telephone Calls to Subjects Every 2 Weeks: 
The following changes were made: 1) Added section to define process for telephone 
contact with subjects and study periods and durations; 2) Added that calls will follow a 
pre-specified script; 3) Added that if the investigator suspects an NMO/NMOSD attack 
or impending attack, an Assessment Visit must be scheduled within 72 hours. These 
changes were made to clarify the telephone call process.  
36 Section 4.3.1.2 (formerly Section 4.3.1.4, Neuroaxis Magnetic Resonance Imaging 
Scan): The following changes were made: 1) Revised that MRI scan will be repeated at 
28 weeks instead of at 6 months, and the Principal Investigator should not use these 
MRIs for any clinical decision making; 2)  Added subsection for MRI process for all 
subjects; 3) Added subsection for process for MRI for NMO/NMOSD attacks; 4) 
Revised subsection for MRI imaging documentation and assessment; MRI reports and 
scans will be sent to the AC from the central reading site as part of the assessment data 
to be used for adjudication.  
37 Section 4.3.1.3 (formerly Section 4.3.1.5, Ophthalmology Assessments): The following 
changes were made: 1) Changed APD to RAPD; 2) Removed examination of visual 
fields, OCT, and fundoscopy; 3) Added that ophthalmology examiner will not have 
access to previous visual acuity scores or RAPD findings at the time of a new evaluation 
to minimize bias, and the ophthalmology assessments should be conducted as specified 
at the study visit, but prior to MRIs; 4) Changed ophthalmology assessments repeated at 
Day 183 to Day 197 for both the RCP and OLP; 5) Revised text that ophthalmology 
examiner provide a full report to the investigator to determine if the findings meet 1 or 


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more of the protocol-defined criteria for ON attack; 6) Revised subsection to Landolt C 
Broken Rings Chart and directions for use and conducting the assessments for 
low-contrast visual acuity and high-contrast visual acuity assessments; 7) Added that the 
investigator must compare the full examination results received from the ophthalmology 
examiner against the subject’s last assessment.  
38 Section 4.3.1.4 (formerly Section 4.3.1.6, Expanded Disability Status Scale and 
Functional Systems Scores): The following changes were made: 1) Updated text to 
reflect the latest version of the EDSS/FSS provided by Neurostatus (version 04/10.2) and 
reference; 2) Revised to inform about process and requirements for the EDSS examiner; 
3) Revised text to inform that data generated from the EDSS examination will be entered 
into an electronic data capture device provided to the site.  
39 Section 4.3.1.5 (formerly Section 4.3.1.7, Independent Adjudication Committee): The 
following changes were made: 1) Revised text to inform that data from all subjects who 
are assessed at an Assessment Visit will be sent for adjudication by the AC regardless of 
whether the Principal Investigator has determined that an NMO/NMOSD attack has 
occurred; 2) Revised text to reflect real-time adjudication, changes to OLP entry, and 
study design changes. 
40 Section 4.3.1.6 (formerly Section 4.3.1.6, Healthcare Resource Utilization): The 
following changes were made: 1) Added text to define in-patient hospitalization; 2) 
Revised Table 4.3.1.8-1 (Healthcare Resource Utilization Information to be Collected 
and Frequency) to change order of parameters; 3) Added text that subjects will be asked 
to record any medical procedures for NMO/NMOSD in the subject diary. 
41 Section 4.3.2 (Patient-reported Outcomes): The following changes were made: 1) Added 
5 separate pain NRS to PROs; 2) Revised text for clarity.  
42 Section 4.3.2.1 (Pain NRS): The following changes were made: 1) Changed Pain Scale 
to 11-point pain NRS; 2) Changed text to explain pain NRS.  
43 Section 4.3.2.2 (Short Form-36 Health Survey): Removed text that SF-36v2 should be 
completed prior to any study procedure or information is communicated to the patient 
and without assistance.  
44 Section 4.3.2.3 (Collection of PRO Endpoints): Section heading was added to separate 
process for collecting PRO endpoints from the SF-36 Healthy Survey.  
45 Section 4.3.3.1 (Medical History): The following changes were made: 1) Added date of 
original diagnosis for NMO/NMOSD is to be collected for subject’s disease history; 
2) Added diabetes, myasthenia gravis, and pernicious anemia to example of autoimmune 
diseases to be collected for the subject’s medical history. 
46 Section 4.3.3.4 (Electrocardiogram): The following changes were made: 1) Changed 
Day 183 to Day 197 for conducting ECG assessments and added Assessment Visit; 
2) Added “abnormal clinically significant” and “abnormal not clinically significant” to 
ECG review; 3) Removed respiratory rate as a measurement for the ECG. 


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47 Section 4.3.4 (formerly Section 4.3.3.7, Columbia-Suicide Severity Rating Scale): The 
following changes were made: 1) Changed administration of the “Since Last Visit” 
version from 3 and 6 months to all scheduled visits and Assessment Visits; 2) Changed 
Long-term Follow-up Period to SFP. 
48 Section 4.3.6 (formerly Section 4.3.4, Clinical Laboratory Tests): The following changes 
were made: 1) Removed exogenous corticosteroids from serum chemistry; 2) Added 
HIV-1 and -2 testing to be done only at screening; 3) Added polyomavius JC antibody 
titers to be collected only at screening and frozen for future testing, if required; 4) 
Revised GFR to be calculated by central laboratory based on plasma and urine creatinine 
samples and that the GFR must be confirmed by the site upon receipt of central 
laboratory report and prior to randomization.  
49 Section 4.3.9 (formerly Section 4.3.7, Biomarker Evaluations and Methods); subsection, 
Serum for AQP4-IgG Assay: Added screening to baseline and that study visit assays will 
be used to determine AQP4-IgG serostatus.  
50 Section 4.3.9.1 (formerly Section 4.3.7.1, Exploratory Investigations): The following 
changes were made: 1) Added new section heading to separate exploratory assessments 
from other study assessments; 2) Added subsection, Blood for Peripheral Blood 
Mononuclear Cell Isolation for T-cell Evaluation, and text for collection of PBMC. 
51 Section 4.3.10 (formerly, Section 4.3.8, Estimate of Volume of Blood to Be Collected): 
The following changes were made: 1) Changed Long-term Follow-up Period to SFP; 2) 
Revised Table 4.3.10-1 (Estimate of Blood Volume to Be Collected) and added visit 
days to the OLP with corresponding blood volumes and adjusted total blood volume; 3) 
Changed Attack Visit to Assessment Visit; 4) Added footnote for PBMC to be collected 
at specified sites and adjusted total blood volume for this blood collection. 
52 Section 4.5.1.1 (Investigational Product Dose Preparation): The following changes were 
made: 1) Added that MEDI-551 and placebo are supplied as a clear to opalescent, 
colorless to yellow liquid and free from or practically free from visible particles to 
Investigational Product Inspection; 2) Added “to opalescent” and “to yellow liquid” and 
“free from or practically free from particles” to the description of the appearance of 
MEDI-551 and placebo.  
53 Section 4.5.1.2 (Treatment Administration): The following changes were made: 
1) Revised the Open-label Period subsection and added that for subjects completing 
Day 197 of the RCP, Day 1 of the OLP should be the same day, although it may be 
delayed for up to 14 days and procedures will not need to be repeated.  
54 Section 4.5.2.1 (Oral Corticosteroid Use): The following changes were made: 1) 
Changed the last day of oral corticosteroid use to Day 14; 2) Modified the tapering 
schedule to be completed on Day 21.  
55 Section 4.5.2.2 (Rescue Medications): The following changes were made: 1) Changed 
investigator-identified NMO/NMOSD to NMO/NMOSD attack that meets the 


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protocol-defined criteria; 2) Removed reference to IV corticosteroids; 3) Revised text 
that all medications given to the subject during the study will be recorded, not only other 
study medications. 
56 Section 4.5.3 (Dose Adjustments and Missed Doses): Revised to extend the length of the 
RCP by 2 weeks, from Day 183 to Day 197. The RCP was extended for 2 weeks to 
accommodate the PD of MEDI-551. Full depletion of B cells occurs at least 2 weeks 
after the investigational product administration. These first 2 weeks will be covered by 
oral steroid treatment.  
57 Section 4.6.3 (Methods for Reducing Bias): Section was added to present steps for 
mitigating/reducing bias when assessing an NMO/NMOSD attack.  
58 Section 4.7.2 (Prohibited Concomitant Medications): The following changes were made: 
1) Revised wording for immunosuppressants from the treatment of NMO/NMOSD 
attacks to the prevention of NMO/NMOSD attacks; 2) Added RCP to low-dose steroids 
for clarification. 
59 Section 4.8.1 (General Considerations): The following changes were made: 1) Revised 
text for clarity that the primary endpoint and key secondary endpoints will be analyzed 
and reported; 2) Removed AQP4-IgG seropositive subjects from analysis of major 
secondary endpoints.  
60 Section 4.8.2 (Sample Size and Power Calculations): The following changes were made: 
1) Changed adjudicated NMO/NMOSD attack to AC-determined attack and Day 183 to 
Day 197; 2) Added stratification ratio of approximately 80:20 AQP4-IgG seropositive to 
seronegative strata; 3) Added hazard rate of 1.0/year for seronegative subjects receiving 
placebo. 
61 Section 4.8.3.1 (Primary Efficacy Analysis): The following changes were made: 
1) Updated null and alternative hypotheses associated with the primary endpoint; 
2) Revised text regarding treatment effect for the AQP4-IgG seropositive cohort; 
3) Revised text that primary analysis will be based on 67 AC-determined NMO/NMOSD 
attacks observed and analysis will be conducted once all ongoing subjects have been 
dosed and completed the RCP. 
62 Section 4.8.3.2 (Additional Analyses of the Primary Endpoint): Changes were made to 
the sensitivity analyses to be performed for the primary endpoint. The primary endpoint 
is determined in this study by the AC, which is composed of 3 adjudicators who review 
and assess the data related to the diagnosis of an attack. The sensitivity analysis will 
assess the consistency and objectivity of the AC members in making the diagnosis of an 
attack.  
63 Section 4.8.3.3 (Secondary Efficacy Analyses): The following changes were made: 
1) Changed Sloan Letters Low Contrast Chart to Landolt C Broken Rings Chart as an 
assessment tool for measuring low-contrast visual acuity; 2) Revised text regarding 


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treatment effect for secondary efficacy endpoints to be based on the cumulative number 
of active MRI lesions. 
64 Section 4.8.3.4 (Exploratory Analyses): Section was moved to new Subsection 4.8.6.3 
(Analysis of Exploratory Biomarkers). 
65 Section 4.8.3.4 (Subgroup Analyses): A new analysis, AQP4-IgG serostatus (positive vs 
negative) as determined at screening, was added to the subgroup analyses. 
66 Section 4.8.5.2 (Pain NRS): Pain NRS was added as a PRO.  
67 Section 4.8.6 (formerly Analysis of Immunogenicity) was changed to Analysis of 
Immunogenicity, Pharmacokinetics, and Exploratory Biomarkers, and Subsections 
4.8.6.1 (Analysis of Immunogenicity), 4.8.6.2 (Analysis of Pharmacokinetics), and 
4.8.6.3 (Analysis of Exploratory Biomarkers) were added.  
68 Section 4.8.7 (Additional Analyses): The following changes were made: 1) Changed 
adjudicated to AC-determined NMO/NMOSD attack; 2) Added agreement between 
site-determined and AC-determined attack will be assessed by Kappa statistic; 3) Added 
an inter- and intra-rater reliability assessment will be performed based on random 
selection of all events contributing to the primary endpoint and a shift analysis of scores 
from the mRS will be performed. 
69 Section 4.8.9 (Control of Type I Error): Section changed to “Control of Type I Error” 
and previous text was deleted. New text was added to present methods of testing for the 
primary and secondary null hypotheses. 
70 Section 4.8.10.1 (Masked Sample Size Reassessment): The following changes were 
made: 1) Changed threshold for sample size reassessment from 25% to when 
104 (approximately 50%) subjects complete the RCP; 2) Changed the ratio of 
cumulative number of AC-determined NMO/NMOSD attacks to subject ratio to 
approximately 27% to increase the sample size up to 252 subjects; 3) Added that 
reassessment will only be performed prior to the futility assessment. The increase in 
sample size will be necessary only if the number of attacks required (67) cannot be 
reached with the planned number of subjects. To keep this decision independent from the 
outcome of the unblinded interim analysis, the reassessment of sample size must be done 
before the futility assessment.  
71 Section 6.2.1.1 (Direct Access to Source Data): Subsection was added to ensure 
compliance with Japan regulatory authorities regarding monitoring, auditing, and access 
to study documents for study sites in Japan.  
72 Section 6.3 (Study Timetable and End of Study): The following changes were made: 1) 
Subsection 6.3.1 (Discontinuation or Suspension of the Study Program) and Subsection 
6.3.2 (Completion of the Study) were added for clarification and to ensure compliance 
with Japan regulatory authorities regarding discontinuation or suspension of the study by 
the Sponsor and to clarify the Principal Investigator’s responsibility for notifying the 
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73 Section 7.1 (Ethical Conduct of the Study): Subsection was revised to add text for 
regulatory requirements regarding ethical conduct of the study in Japan.  
74 Section 7.3.1 (Ethics and Regulatory Review in Japan): Subsection was added to ensure 
compliance with Japan regulatory authorities regarding IRB approval for study sites in 
Japan. 
75 Section 7.4 (Informed Consent): The following changes were made: 1) Added text for 
clarification for communicating new information about the investigational product to the 
subject; 2) Added text for instructing the subject if changes are made to the ICF.  
76 Section 7.5.1 (Deviation From the Clinical Study Protocol): Subsection was added for 
clarification regarding deviations to the study protocol and documentation of deviations.  
77 Section 7.6 (Audits and Inspections): Text was added to this section for clarification that 
all study data may be subject to reliability review and onsite GCP inspection by 
regulatory authorities.  
78 Section 8 (References): Section was updated to reflect reference changes throughout the 
protocol.  
79 Appendix 4 (Expanded Disability Status Scale and Functional Systems Scores): The 
previous version of the EDSS was replaced with the current version. 
80 Appendix 5 (Pain NRS): The appendix was changed to Pain NRS and sample assessment 
was replaced with the Pain NRS. 
81 Appendix 9 (Sample Size Calculation): Text was revised to address changes to the 
sample size calculations and hazard rates. 
82 Appendix 10 (Details of Futility Analysis): Title changed from “Futility Criterion” to 
“Futility Analysis.” 
83 Appendix 11 (Details of Masked Sample Size Re-assessment): The following changes 
were made: 1) Revised text to reflect changes in sample size re-assessment; 2) Updated 
Table 9-5 (Masked Sample Size Reassessment Examples [60% Treatment Effect]) to 
reflect changes in text.  
84 Appendix 12 (Type I Error Control): Appendix was added to add Type I error control 
and add Table 9-6 (List of Null Hypotheses Considered Under Multiplicity Adjustment 
Procedure), Figure 9-7 (Multiplicity Adjustment Strategy), Table 9-7 (Alpha Allocation 
Rule), and Table 9-8 (Alpha Propagation Rule).  
85 Appendix 13 (Assessment and Collection of Adverse Events): This appendix was added 
to provide AE and SAE variables to be collected during the study and to further explain 
methods for assessment and collection of AEs and SAEs.  


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Appendix 1 
Signatures 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Sponsor Signature(s) 
A Double-masked, Placebo-controlled Study with Open-label Period to Evaluate the Efficacy 
and Safety of MEDI-551 in Adult Subjects with Neuromyelitis Optica and Neuromyelitis 
Optica Spectrum Disorders 
I agree to the terms of this protocol amendment. 
 
Signature and date:   
Eliezer Katz, MD FACS  
Vice President  
Clinical Development Lead  
Viela Bio, Inc 
One MedImmune Way, Gaithersburg MD, 20878, USA 
Telephone number: 
 
 
 
 
 
 
 
 
 
 
 
PPD


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Signature of Principal or Coordinating Investigator 
A Double-masked, Placebo-controlled Study with Open-label Period to Evaluate the Efficacy 
and Safety of MEDI-551 in Adult Subjects with Neuromyelitis Optica and Neuromyelitis 
Optica Spectrum Disorders 
I, the undersigned, have reviewed this protocol amendment, and I agree to conduct this 
protocol in accordance with ethical principles that have their origin in the Declaration of 
Helsinki and are consistent with the International Council for Harmonisation (ICH) guidelines 
on Good Clinical Practice (GCP), any applicable laws and requirements, and any conditions 
required by a regulatory authority and/or Institutional Review Board/Independent Ethics 
Committee (IRB/IEC).  
I understand that the protocol amendment may not be modified without written approval of 
the Sponsor. All changes to the protocol amendment must be submitted to the applicable 
regulatory authority and IRB/IEC, and must be approved by the IRB/IEC prior to 
implementation except when necessary to eliminate immediate hazards to the subjects or 
when the change(s), as deemed by the Sponsor, involves only logistical or administrative 
changes. Documentation of IRB/IEC approval must be sent to the Sponsor immediately upon 
receipt. 
Signature and date:   
 
 
 
 
 
 
 
 
 
Name and title:    
 
 
 
 
 
 
 
 
 
Address including postal code:  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
Telephone number:   
 
 
 
 
 
 
 
 
 
Site/Center Number (if available)  
 
 
 
This document contains confidential information, which should not be copied, referred to, released, or published 
without written approval from MedImmune or AstraZeneca. Investigators are cautioned that the information in 
this protocol may be subject to change and revision. 
 


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Appendix 2 
National Institute of Allergy and Infectious Diseases and 
Food Allergy and Anaphylaxis Network Guidance for 
Anaphylaxis Diagnosis 
Sampson HA, Muñoz-Furlong A, Campbell RL, Adkinson FN Jr, Bock SA, Branum A, et al. 
Second symposium on the definition and management of anaphylaxis: Summary report -- 
Second National Institute of Allergy and Infectious Diseases/Food Allergy and Anaphylaxis 
Network symposium. J Allergy Clin Immunol. 2006;1175(3):391-7. 
The National Institute of Allergy and Infectious Diseases and Food Allergy and Anaphylaxis 
Network define anaphylaxis as a serious allergic reaction that is rapid in onset and may cause 
death. They recognize 3 categories of anaphylaxis, with criteria designated to capture from 
80% of cases (category 1) to > 95% of all cases of anaphylaxis (for all 3 categories).   
1 
Acute onset of an illness (minutes to several hours) with involvement of the skin, 
mucosal tissue, or both (eg, generalized hives, pruritus or flushing, swollen lips-tongue-
uvula) 
 
AND AT LEAST ONE OF THE FOLLOWING 
(a) Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, reduced peak 
expiratory flow [PEF], hypoxemia) 
(b) Reduced BP or associated symptoms of end-organ dysfunction (eg, hypotonia 
[collapse], syncope, incontinence) 
2 
Two or more of the following that occur rapidly after exposure to a likely allergen for 
that patient (minutes to several hours): 
(a) Involvement of the skin-mucosal tissue (eg, generalized hives, itch-flush, swollen 
lips-tongue-uvula) 
(b) Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, reduced PEF, 
hypoxemia) 
(c) Reduced BP or associated symptoms (eg, hypotonia [collapse], syncope, 
incontinence) 
(d) Persistent gastrointestinal symptoms (eg, crampy abdominal pain, vomiting) 
3 
Reduced BP after exposure to known allergen for that patient (minutes to several hours): 
(a) Infants and children: low systolic BP (age specific) or greater than 30% decrease in 
systolic BP 
(b) Adults: systolic BP of less than 90 mm Hg or greater than 30% decrease from that 
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Appendix 3 
Additional Safety Guidance 
Assessment of Severity 
Assessment of severity is one of the responsibilities of the investigator in the evaluation of 
AEs and SAEs. The determination of severity should be made by the investigator based upon 
medical judgment and the severity categories of Grade 1 to 5 as defined below. 
Grade 1 (mild) 
An event that is usually transient and may require only minimal 
treatment or therapeutic intervention. The event does not generally 
interfere with usual activities of daily living. 
Grade 2 (moderate) 
An event that is usually alleviated with additional specific 
therapeutic intervention. The event interferes with usual activities of 
daily living, causing discomfort but poses no significant or 
permanent risk of harm to the subject. 
Grade 3 (severe) 
An event that requires intensive therapeutic intervention. The event 
interrupts usual activities of daily living, or significantly affects the 
clinical status of the subject. 
Grade 4 (life threatening) An event, and/or its immediate sequelae, that is associated with an 
imminent risk of death or with physical or mental disabilities that 
affect or limit the ability of the subject to perform activities of daily 
living (eating, ambulation, toileting, etc). 
Grade 5 (fatal) 
Death (loss of life) as a result of an event. 
 
It is important to distinguish between serious criteria and severity of an AE. Severity is a 
measure of intensity whereas seriousness is defined by the criteria in Section 5.2. A Grade 3 
AE need not necessarily be considered an SAE. For example, a Grade 3 headache that persists 
for several hours may not meet the regulatory definition of an SAE and would be considered a 
nonserious event, whereas a Grade 2 seizure resulting in a hospital admission would be 
considered an SAE. 
Abnormal laboratory results may be graded according to NCI Common Terminology Criteria 
for Adverse Events V4.0 (NCI, 2009).  
Assessment of Relationship 
Relationship to Investigational Product 
The investigator is required to provide an assessment of relationship of AEs and SAEs to the 
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An event will be considered “not related” to use of the investigational product if any of the 
following tests are met: 
x 
An unreasonable temporal relationship between administration of the investigational 
product and the onset of the event (eg, the event occurred either before, or too long after, 
administration of the investigational product for it to be considered product-related) 
x 
A causal relationship between the investigational product and the event is biologically 
implausible (eg, death as a passenger in an automobile accident) 
x 
A clearly more likely alternative explanation for the event is present (eg, typical adverse 
reaction to a concomitant drug and/or typical disease-related event) 
 
Individual AE/SAE reports will be considered “related” to use of the investigational product if 
the “not related” criteria are not met.  
“Related” implies that the event is considered to be “associated with the use of the drug” 
meaning that there is “a reasonable possibility” that the event may have been caused by the 
product under investigation (ie, there are facts, evidence, or arguments to suggest possible 
causation). 
Relationship to Protocol Procedures 
The investigator is also required to provide an assessment of relationship of SAEs to protocol 
procedures on the SAE Report Form. This includes nontreatment-emergent SAEs (ie, SAEs 
that occur prior to the administration of investigational product) as well as treatment-emergent 
SAEs. A protocol-related SAE may occur as a result of a procedure or intervention required 
during the study (eg, blood collection, washout of an existing medication). The following 
guidelines should be used by investigators to assess the relationship of SAEs to the protocol: 
Protocol related: The event occurred due to a procedure/intervention that was described in the 
protocol for which there is no alternative etiology present in the subject’s medical record. 
Not protocol related: The event is related to an etiology other than the procedure/ intervention 
that was described in the protocol (the alternative etiology must be documented in the study 
subject’s medical record). 
 
 


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Appendix 4 
Kurtzke Expanded Disability Status Scale and Functional 
Systems Scores 
 


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Appendix 5 
Pain NRS 
 
 


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Appendix 6 
Short Form-36v2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Appendix 7 
Columbia-Suicide Severity Rating Scale:  
Baseline/Screening Version 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Appendix 8 
Columbia-Suicide Severity Rating Scale: Since Last Visit 
Version 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Appendix 9 
Sample Size Calculation 
The proposed study is being planned to detect a target relative reduction of 60% in risk for 
time (days) from Day 1 to onset of an AC-determined NMO/NMOSD attack on or before 
Day 197 with 90% power and D = 0.05 (two-sided), assuming an unequal randomization ratio 
of 3:1 to MEDI-551 versus placebo. Using the following formula, a total of 67 AC-determined 
NMO/NMOSD attacks will be required: 
ܧൌ൤ݖଵିఈଶ
Τ ൅ݖଵିఉ
݈݊ሺܪܴሻ
൨
ଶ
ൈሺݎ൅ͳሻଶ
ݎ
ǡ 
where ଵି஑ଶ
Τ and ଵିஒ are 100(  α ) th and 100 (1  β) th percentile of a standard normal 
distribution, r = 3 is the randomization ratio and HR = hazard ratio = 0.4. 
Assuming hazard rates of 1.5/year and 1.0/year for an NMO/NMOSD attack in the placebo 
arm for seropositive and seronegative groups, respectively, and using the following formula: 
ܰൌ
ܧ
ሺܨ݈ܽ݅ሻǡ 
a total of 212 (with an upward adjustment) subjects are expected to be enrolled in this study 
where 
ሺ	ሻൌݏଵܲଵ൅ݏଶܲଶ
is the weighted average of the failure probabilities ܲଵand  ܲଶin seropositive and seronegative 
cohorts, respectively, with associated stratum specific weights ݏଵൌͲǤͺ and ݏଶ= 0.2. Recall 
that subjects will be enrolled to seropositive and seronegative cohorts in an 80:20 ratio. 
Furthermore, the probability of an attack within ith cohort (i = 1, 2) is given by 
ܲ௜ൌሺͳ െݓሻ݌௜଴൅ݓ݌௜ଵ 
the weighted average of the failure probabilities ݌௜଴ and ݌௜ଵfor placebo and MEDI-551 groups, 
respectively; ݌௜଴ൌͳ െ݁ିఒ೔బி, ݌௜ଵൌͳ െ݁ିఒ೔భிǢ F = 197/365 = 0.54 to indicate the 197 days 
(28 weeks) duration of the controlled portion of the study; note that based on the assumptions 
for this study, ߣଵ଴ൌͳǤͷǡ ߣଵଵൌͲǤ͸ǡ ߣଶ଴ൌͳand ߣଶଵൌͲǤͶ and ݓ = 
௥
ଵା௥.= 0.75. 
Since the primary endpoint will be tested using the Cox proportional model, a simulation 
approach was used to investigate the power under alternative hypotheses mentioned above. 
Based on 5,000 simulations, the power for the overall and seropositive populations were 
observed as 94% and 91%, respectively. Moreover, the total required 67 events (212 subjects) 
were, on an average, distributed in seropostive and seronegative cohorts as 57 (168 subjects) 
and 10 (44 subjects) respectively. 
The underlying hazard rate of time to an NMO/NMOSD attack in the seropositive placebo 
group is estimated based on a meta-analytic approach from several open-label cohort studies 
(see Table 17) in the absence of any placebo-controlled study in this population to date. These 


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studies consisted of both seropositive and seronegative subjects and hence any finding related 
to hazard rate derived from these studies can be considered as an underestimation when 
applied for seropositive subgroup in the current study. Following are the 5 open-label studies 
considered with a total of 161 subjects: 
Table 17 
Open-label Cohort Studies in Neuromyelitis Optica 
Author 
Title 
Bedi et al 
Impact of rituximab on relapse rate and disability in neuromyelitis optica. 
Mult Scler. 2011 Oct;17(10):1225-30 
Costanzi et al 
Costanzi C, Matiello M, Lucchinetti CF, Weinshenker BG, Pittock SJ, 
Mandrekar J, et al. Azathioprine: tolerability, efficacy, and predictors of 
benefit in neuromyelitis optica. Neurology. August 16, 2011;77(7):659-66. 
Jacob et al 
Treatment of neuromyelitis optica with rituximab: retrospective analysis of 
25 patients. Muscle Nerve. 2008 Jan;39(1):87-90 
Kim et al 
Kim SH, Kim W, Li XF, Jung IJ, Kim HJ. Repeated treatment with 
rituximab based on the assessment of peripheral circulating memory B 
cells in patients with relapsing neuromyelitis optica over 2 years. Arch 
Neurol. 2011 Nov;68(11):1412-20. 
Pittock et al 
Pittock SJ, Lennon VA, McKeon A, Mandrekar J, Weinshenker BG, 
Lucchinetti CF, O'Toole O, Wingerchuk DM. Eculizumab in AQP4-IgG-
positive relapsing neuromyelitis optica spectrum disorders: an open-label 
pilot study. Lancet Neurol. 2013 Jun;12(6):554-62.  
 
The approximate time (months) between the first 2 pretreatment relapses was visually 
enumerated from the published figures for each study (Figure 7, Figure 8, Figure 9, Figure 10, 
and Figure 11). Subjects with second pretreatment relapses occurring within 12 months of the 
first relapse were considered failures. Hazard rate (assuming exponential distribution) was 
calculated from each study based on this failure rate. Overall hazard rate for time to second 
pretreatment relapse was calculated based on the weighted average of individual hazard rates 
(weight was based on number of failures from each study). The findings from this analysis are 
summarized in Table 18.  
Table 18 
Estimated Pretreatment Hazard Rate for Time to Relapse 
Study 
Number of 
Subjects 
No. of Subjects with 
Relapse by 1st Year 
Percentage of Subjects 
Relapse Free by 1st Year 
Hazard Rate
(per year) 
Bedi et al, 2011 
23 
14 
39% 
0.94 
Costanzi et al, 2011 
69 
48 
30.4% 
1.2 
Jacob et al, 2008 
25 
21 
16% 
1.83 
Kim et al, Nov 2011 
30 
19 
37% 
0.99 


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Table 18 
Estimated Pretreatment Hazard Rate for Time to Relapse 
Study 
Number of 
Subjects 
No. of Subjects with 
Relapse by 1st Year 
Percentage of Subjects 
Relapse Free by 1st Year 
Hazard Rate
(per year) 
Pittock et al, 2006 
14 
12 
14.3% 
1.94 
Overall 
161 
114 
29.2% 
1.23 
 
The weighted average of the hazard rates was determined as 1.33/year. As none of the cohorts 
in these studies received pure placebo treatment, the hazard rate for the placebo treatment for 
the seropositive subgroup in the current study is estimated to be 1.5/year. Conservatively, the 
hazard rate for the placebo treatment in seronegative subgroup is chosen as 1.0/year.  
 
Figure 7 
Neuromyelitis Optica Spectrum of Disorders Relapses Before and After 
Treatment with Azathioprine for 70 Patients with More Than 12 
Months Follow Up 
 
 
NMO = neuromyelitis optica.  
Source: Constanzi et al, 2011.  
 


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Figure 8 
Attack Frequency Before, During, and After Eculizumab Treatment 
 
Source: Pittock et al, 2006. 
 
Figure 9 
Relapses in Patients with Neuromyelitis Optica Before and After 
Treatment with Rituximab 
 
mo = months.  
Source: Jacob et al, 2008. 


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Figure 10 
Disease Course of Patients Treated with Rituximab 
 
Note: Disease course is depicted longitudinally, with each bar representing one patient. Each bar represents the 
type of treatment administered at a given time, a light gray bar representing no treatment, a dark gray 
representing other treatment (immunomodulatory, immunosuppressant) and black representing rituximab 
treatment. Each relapse is marked along the patient’s course by a solid black or white mark. Time 0 on the X axis 
marks the initiation of rituximab treatment and divides pre- and post-rituximab treatment phases. Numbers on the 
X and Y axes represent months before/after rituximab initiation and patient number respectively. Most (17 of 23) 
patients had no recorded clinical relapses, and the remaining six had reduction in relapse frequency with 
rituximab treatment. 
Source: Bedi et al, 2011. 
 


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Figure 11 
Relapses in Patients with Neuromyelitis Optica Before and After 
Treatment with Rituximab 
 
mo = months. 
Note: On the x-axis, 0 indicates start date of treatment. Each interrupted line on the y-axis represents a patient. 
Source: Kim et al, Nov 2011. 
 
The target treatment effect of 60% has been estimated by comparing similar empirical 
evidence from Costanzi et al, 2011 (treatment with AZA) and 3 articles from rituximab 
treatment (Bedi et al, 2011, Jacob et al, 2008, and Kim et al, Nov 2011). For each of these 
studies, the subjects who were relapse free within the first 12 months of respective treatment 
were visually identified (Table 19). Based on the survival rate thus obtained, the yearly 
constant hazard rate was calculated and the weighted average was determined. 
Table 19 
Calculated Yearly Constant Hazard Rate Based on Relapse-free 
Subjects in First 12 Months of Treatment 
Study 
N 
No. of Subjects with 
Relapse by 1st Year 
Percentage of Subjects 
Relapse-free by 1st Year 
Hazard Rate
(per year) 
Bedi et al, 2011 
23 
4 
83% 
0.19 
Jacob et al, 2008 
25 
7 
72% 
0.33 
Kim et al, Nov 2011 
30 
6 
80% 
0.22 
Overall 
78 
17 
78% 
0.25 




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sample size of 227 there is a 50% probability of reaching the required 67 AC-determined 
attacks and with 252 subjects there is a 90% probability of reaching the required 67 AC-
determined attacks. The sample size of 252 subjects was selected to give a high degree of 
confidence that 67 attacks will be observed in this study. 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Appendix 10 Details of Futility Analysis 
An unmasked interim analysis will be conducted for futility assessment by the DMC when 
approximately 50% of the total planned AC-determined NMO/NMOSD attacks occur in this 
study. This will be triggered when approximately 34 AC-determined NMO/NMOSD attacks 
occur in the ITT population. The assessment of futility will be based on predictive power, 
which is based on the average conditional power calculated at the observed treatment effect at 
the time of the interim analysis. The study will be considered futile if the predictive power is 
< 20% in both the ITT population and the AQP4-IgG seropositive cohort. Figure 12 provides 
estimated predictive power when observed treatment effect varies from 0 to 90% in relative 
reduction in risk of an AC-determined NMO/NMOSD attack in the ITT population. The 20% 
predictive power translates into a treatment effect of approximately 27%. A value of 50% and 
90% predictive power will result in 43% and 60% treatment effects, respectively, which are 
minimally detectable treatment effect and target treatment effect for this study. The actual 
predictive power will be calculated based on observed data.  
Figure 12 
Estimated Predictive Power Against Observed Interim Treatment 
Effect When 50% of AC-determined NMO/NMOSD Attacks are 
Available 
 
AC = Adjudication Committee; HR = hazard rate; NMO/NMOSD = neuromyelitis optica/neuromyelitis optica 
spectrum disorders 
 


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Appendix 11 Type I Error Control 
To establish Type I error control, the primary endpoint, and the 4 secondary endpoints will be 
denoted by E1 through E5, respectively, as follows: 
x 
E1: Time to AC-determined NMO/NMOSD attack 
x 
E2: Worsening from baseline in EDSS at last visit during the RCP 
x 
E3: Change from baseline in low-contrast visual acuity binocular score measured by low-
contrast Landolt C Broken Rings Chart, at last visit during RCP 
x 
E4: Cumulative total active MRI lesions (new Gd-enhancing or new/enlarging T2) during 
the RCP 
x 
E5: Number of NMO/NMOSD-related in-patient hospitalizations 
 
Based on 2 populations of interest (seropositive and ITT populations), this will result in 
testing 10 null hypotheses of no treatment effect labeled as follows (Table 21): 
Table 21 
List of Null Hypotheses Considered Under Multiplicity Adjustment 
Procedure 
Hypothesis 
Test 
S1 
Test E1 in seropositive subjects 
S2 
Test E2 in seropositive subjects 
S3 
Test E3 in seropositive subjects 
S4 
Test E4 in seropositive subjects 
S5 
Test E5 in seropositive subjects 
O1 
Test E1 in ITT population 
O2 
Test E2 in ITT population 
O3 
Test E3 in ITT population 
O4 
Test E4 in ITT population 
O5 
Test E5 in ITT population 
 
The multiplicity adjustment strategy based on Bonferroni-based chain procedure 
(Bretz et al, 2009; Millen and Dmitrienko, 2011) for testing these 10 hypotheses is defined in 
Figure 13. Each hypothesis is represented by a rectangular box. The connections among the 
hypotheses are visualized using arrows. A solid arrow is used to define the decision path after 
a hypothesis is rejected, eg, the hypothesis O1 is tested if and only if the hypothesis S1 is 
rejected. The Bonferroni-based chain procedures are characterized by 2 rules: 
x 
The alpha allocation rule specifies the initial distribution of the Type I error rate among 
the null hypotheses according to the relative importance of the null hypotheses 
x 
The alpha propagation rule determines the process of re-distributing the available Type I 
error rate among the non-rejected null hypotheses after each rejection 


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Figure 13 
Multiplicity Adjustment Strategy 
 
 
The alpha allocation rule is specified in Table 22. Specifically, the null hypothesis S1 receives 
the initial weight of 1 (ie, it is tested at the full D = 0.05) and the other null hypotheses receive 
zero weights. The alpha propagation rule is specified in Table 23. The alpha propagation rules 
are defined using transition parameters, eg, the first row in Table 23 shows that the fraction of 
the Type I error rate used in testing the null hypothesis S1 will be transferred to the null 
hypothesis O1 if the null hypothesis S1 is rejected. Similarly, if the null hypothesis O1 is 
rejected, the available Type I error rate will be split equally among the null hypotheses S2, S3, 
S4, and S5 (a quarter of the available Type I error rate will be allocated to each null 
hypothesis). The alpha allocation and alpha propagation rule uniquely define the Bonferroni-
based chain procedure and the associated multiplicity-adjusted p-values can be computed 
using Algorithm 2 given in Bretz et al (2009). 
 


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Table 22 
Alpha Allocation Rule 
Hypothesis 
Initial Alpha Allocation 
S1 
α 
S2 
0 
S3 
0 
S4 
0 
S5 
0 
O1 
0 
O2 
0 
O3 
0 
O4 
0 
O5 
0 
 
Table 23 
Alpha Propagation Rule 
Hypothesis 
S1 
S2 
S3 
S4 
S5 
O1 
O2 
O3 
O4 
O5 
S1 
0 
0 
0 
0 
0 
1 
0 
0 
0 
0 
S2 
0 
0 
0 
0 
0 
0 
1 
0 
0 
0 
S3 
0 
0 
0 
0 
0 
0 
0 
1 
0 
0 
S4 
0 
0 
0 
0 
0 
0 
0 
0 
1 
0 
S5 
0 
0 
0 
0 
0 
0 
0 
0 
0 
1 
O1 
0 
1/4 
1/4 
1/4 
1/4 
0 
0 
0 
0 
0 
O2 
0 
0 
1/3 
1/3 
1/3 
0 
0 
0 
0 
0 
O3 
0 
1/3 
0 
1/3 
1/3 
0 
0 
0 
0 
0 
O4 
0 
1/3 
1/3 
0 
1/3 
0 
0 
0 
0 
0 
O5 
0 
1/3 
1/3 
1/3 
0 
0 
0 
0 
0 
0 
 
 
 
 
 


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Appendix 12 Assessment and Collection of Adverse Events 
If an investigator learns of any SAEs, including death, at any time after a subject has 
completed the study and he/she considers there is a reasonable possibility that the event is 
related to MEDI-551, the investigator should notify the Sponsor.  
Variables to be Collected for AEs and SAEs 
AEs 
The following variables will be collected for each AE: 
x 
AE (verbatim) 
x 
Date when the AE started and stopped 
x 
Whether the AE is serious 
x 
Investigator causality rating against the investigational product (yes or no) 
x 
Action taken with regard to investigational product 
x 
If AE caused the subject to be withdrawn from the study (yes or no) 
x 
Outcome 
 
SAEs 
For SAEs, other variables will be collected, including treatment given for the event. 
It is important to distinguish between serious and severe AEs. Severity is a measure of 
intensity, whereas, seriousness is defined by the criteria presented in Section 5.2. An AE of 
severe intensity need not necessarily be considered serious. For example, nausea that persists 
for several hours may be considered severe nausea, but not an SAE. On the other hand, a 
stroke that results in only a limited degree of disability may be considered a mild stroke, but it 
would become an SAE when it satisfies the criteria.  
Causality 
The investigator will assess the causal relationship between the investigational product and 
each AE, and answer ‘yes’ or ‘no’ to the question, ‘Do you consider there is a reasonable 
possibility that the event may have been caused by the investigational product?’ 
For SAEs, the causal relationship will also be assessed for other medication and study 
procedures. For SAEs that could be associated with any study procedure, the causal 
relationship is implied as ‘yes.’  
AEs Based on Signs and Symptoms 
All AEs spontaneously reported by the subject or care provider, or reported in response to the 
question, ‘Have you had any health problems since the previous visit/you were last asked?’, or 


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any AEs that were observed, will be collected and recorded in the eCRF. When collecting 
AEs, recording the diagnosis is preferred to a listing of signs and symptoms. However, if a 
diagnosis is known and there are other signs or symptoms that are not generally considered 
part of the diagnosis, the diagnosis and each sign or symptom should be recorded separately. 
AEs Based on Examinations and Tests 
The results of protocol-mandated laboratory tests and vital signs will be summarized in the 
clinical study report. Deterioration in protocol-mandated laboratory test values or vital signs 
compared to baseline should only be reported as AEs if they fulfill any of the SAE criteria, or 
are a reason for the discontinuation of treatment with the investigational product. 
If deterioration in a laboratory test value or vital sign is associated with clinical signs and 
symptoms, the clinical sign or symptom should be reported as an AE and the associated 
laboratory test result or vital sign will be considered additional information. Wherever 
possible, the reporting investigator should use the clinical term rather than the laboratory term 
(eg, “anemia” versus “low hemoglobin value”). In the absence of clinical signs or symptoms, 
clinically-relevant deteriorations in nonmandated parameters should be reported as AE(s). 
Any new or aggravated clinically-relevant abnormal medical finding at a physical examination 
as compared with the baseline assessment will be reported as an AE (baseline data are 
collected at Visit 2).  
 
 

SAP_001.pdf: 
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Statistical Analysis Plan

A Double-masked, Placebo-controlled Study with Open-
label Period to Evaluate the Efficacy and Safety of MEDI-
551 in Adult Subjects with Neuromyelitis Optica and 
Neuromyelitis Optica Spectrum Disorders

Protocol Number: CD-IA-MEDI-551-1155
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TABLE OF CONTENTS
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6WXG\'HVLJQ 
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6FUHHQLQJ3HULRG 
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5DQGRPL]HGFRQWUROOHG3HULRG'D\WR'D\ 
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2SHQODEHO3HULRG 
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6DIHW\)ROORZXS3HULRG 
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7UHDWPHQW$VVLJQPHQWDQG0DVNLQJ 
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$QDO\VLV:LQGRZV 
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