Conditions: Generalized Myasthenia Gravis
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 175
Healthy volunteers: no

Brief summary:
The primary purpose of this study is to evaluate the safety and efficacy of ravulizumab for the treatment of participants with generalized myasthenia gravis (gMG).

Detailed description:

Arms:
arm 1: Participants will receive ravulizumab for the duration of the study. arm 2: Participants will receive placebo during the 26-week randomized-controlled period of the study, after which they will enter the open-label extension period of the study and receive ravulizumab.

Interventions: intervention 1: Ravulizumab intervention 2: Placebo
Intervention descriptions: intervention 1: Concentrated sterile, preservative-free aqueous solution (10 milligrams \[mg\]/milliliter \[mL\]) in single-use, 30-mL vial for intravenous (IV) infusion. Single loading dose on Day 1, followed by regular maintenance dosing beginning on Day 15, based on weight. intervention 2: Matching, sterile, preservative-free aqueous solution in single-use, 30-mL vial for IV infusion. Single loading dose on Day 1, followed by regular maintenance dosing beginning on Day 15, based on weight.

Protocol document:
Prot_000.pdf: 
Protocol 
ALXN1210-MG-306 Amendment 2 
Page 1 of 109 
Alexion Confidential 
TITLE PAGE 
Protocol Title: 
A Phase 3, Randomized, Double-Blind, Placebo-Controlled, 
Multicenter Study to Evaluate the Safety and Efficacy of 
Ravulizumab in Complement-Inhibitor-Naïve Adult Patients 
With Generalized Myasthenia Gravis  
Protocol Number: 
ALXN1210-MG-306 
Compound Number: 
ALXN1210 
USAN/INN: 
Ravulizumab 
Amendment Number: 
2 
Short Title: 
Safety and Efficacy Study of Ravulizumab in Adults With 
Generalized Myasthenia Gravis 
Sponsor Name 
Alexion Pharmaceuticals, Inc. (Alexion) 
Legal Registered 
Address: 
121 Seaport Boulevard 
Boston, MA 02210 
USA 
Regulatory Agency 
Identifying Number: 
IND: 140,115 
EUDRACT: 2018-003243-39 
Approval Date: 
25 Oct 2019 
NCT #NCT03920293


Protocol 
Sponsor Signatory: 
ALXN1210-MG-306 Amendment 2 
/L? /tJ3fa-011
Date 
Medical Monitor Name and Contact Information can be found in the Study Contact list 
distributed to Study Sites. 
24-hour Emergency Contact: 
Page 2 of 109 
Alexion Confidential 
PPD
PPD


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Alexion Confidential 
INVESTIGATOR’S AGREEMENT 
 
I have read the ALXN1210-MG-306 study protocol and agree to conduct the study in accordance 
with this protocol, all applicable government regulations, the principles of the ICH E6 
Guidelines for Good Clinical Practice, and the principles of the World Medical Association 
Declaration of Helsinki. I also agree to maintain the confidentiality of all information received or 
developed in connection with this protocol.  
 
 
 
 
 
____________________________________ 
Printed Name of Investigator 
 
_____________________________________ 
Signature of Investigator 
 
_______________ 
Date 


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PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE 
 
DOCUMENT HISTORY 
Document 
Date 
Amendment 2 
25 Oct 2019 
Amendment 1.2 (France) 
14 Oct 2019 
Amendment 1.1 (Germany) 
27 Jun 2019 
Amendment 1 
11 Dec 2018 
Original Protocol 
16 Nov 2018 
 
Amendment 2 (25 Oct 2019) 
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of 
Directive 2001/20/EC of the European Parliament and the Council of the European Union. 
Overall Rationale for the Amendment 
To revise secondary and exploratory endpoints, to decrease burden to patients by reduction in 
assessment and visit frequency, to provide additional guidance for supplemental dosing, and to 
clarify minor operational aspects of the protocol.   
Section # and Name 
Description of Change 
Brief Rationale 
Title page 
Updated legal registered address. 
 
Sponsor Signatory 
Removed sponsor signatory’s personal contact 
information. 
Contact information is 
provided in the study contact 
list provided to sites. 
Section 1.1 and Section 3 
Objectives and Endpoints 
Moved change from baseline in MG-QOL15r 
and Neuro-QOL Fatigue scores and MG-ADL 
and QMG responder from exploratory to 
secondary endpoints. PK/PD/ADA endpoints 
moved from under exploratory to new 
independent subheading. Expanded 
exploratory endpoints to include change from 
baseline in MG-ADL and QMG 
subcomponent scores as well as incidence of 
hospitalizations/MG-related hospitalizations 
and Clinical Deterioration/MG crisis. Clarified 
that endpoints will be evaluated throughout 
study. 
To better characterize disease 
parameters associated with 
gMG and yield a clearer 
assessment of the impact of 
study intervention. 
Section 1.3 Schedule of 
Activities 
Removed evaluation of Myasthenia Gravis 
Foundation of America-Post-Interventional 
Status (MGFAPIS) on Day 1. 
Post-intervention status 
cannot be evaluated before 
patients receive study 
intervention.  
Added serum pregnancy test at Day 183/ET. 
To ensure patient safety. 
Removed visits at Weeks 3, 8, 14, 22, and 40; 
reduced number of visits at which MG-
QOL15r, Neuro-QOL Fatigue, and EQ-5D-5L 
are collected, including removal from Clinical 
Deterioration visits; expanded visit window 
and reduced/moved PK/Free C5 and ADA 
collections during extension.  
To reduce burden on patient. 


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Section # and Name 
Description of Change 
Brief Rationale 
Added body weight collection at all visits. 
Needed to ensure that proper 
dosage is administered. 
Revised footnotes to specify data collected for 
MG history and C-SSRS, assessments needed 
at Clinical Deterioration visits, and 
requirement for Properly Trained Clinical 
Evaluator to perform QMC and MGC 
assessments. 
Clarifications 
Section 2.3 Study Rationale 
Added approval of eculizumab for the 
treatment of neuromyelitis optica spectrum 
disorder. 
Update. 
Section 4.1.1 Screening Period 
Clarified MG history data collection, 
including 2-year hospitalization history. 
 
Removed incorrect statement about retaining a 
patient who experiences Clinical 
Deterioration/MG crisis during the Screening 
Period (inconsistent with Section 5.4). 
To enable assessment of pre-
study hospitalizations. 
 
Correction. 
 
Section 4.2.4 Responsibilities 
for Myasthenia Gravis 
Assessments 
Noted that MG-ADL must be performed first, 
QMG second. 
Clarification. 
Section 4.4 Justification for 
Dose 
Revised to reflect that the ravulizumab dosing 
regimen used in this study is approved for 
adult patients with PNH. 
To inform on labeled dosing 
recommendation. 
Section 5.1 Inclusion Criteria 
Revised IC#2 and IC#3 to clarify that MG 
diagnosis must occur at least 6 months prior to 
screening, and that eligibility is confirmed by 
positive anti-AChR Ab test result at screening 
and by abnormal neuromuscular transmission 
test and/or improvement in MG signs with 
oral cholinesterase inhibitor treatment either 
historically or during screening. 
To further clarify entry 
criteria for the investigator.  
Section 5.2 Exclusion Criteria 
Revised EC#1 to permit treated patients with 
stage 1 or 2 thymoma other than thymic 
carcinoma and EC#2 to exclude 
thymomectomy or any thymic surgery. 
To clarify entry criteria for 
patients with thymoma. 
Added 3 new exclusion criteria for history of 
unexplained infections, active infections 
within 14 days of study drug administration, 
or fever within 7 days of study drug 
administration. 
To exclude enrollment of 
patients with active systemic 
infections. 
Section 6.1 Study Drug 
Administration 
Added instruction for action to be taken if a 
patient’s body weight drops below 40 kg 
during treatment. 
Clarification. 
Section 6.4 Concomitant 
Therapy 
Added that MG-specific medication or therapy 
(eg, thymectomy, ISTs including 
corticosteroids, IVIg, and PE/PP) within 2 
years prior to screening will be recorded. 
Clarification regarding data 
collection. 


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Section # and Name 
Description of Change 
Brief Rationale 
Section 6.5.1.4 PE/PP/IVIg 
In Table 7 and Table 8, applicable 
supplemental dosing day range has been 
added, and doses and corresponding diluent 
and total volumes have been corrected in the 
Placebo group Open Label Extension 
associated with the Blinded ravulizumab 
loading dose administered on Day 183. Details 
in text on supplemental dose timing. 
To clarify timing of 
supplemental dosing and to 
maintain blind on Day 183. 
Section 6.5.1.5 Disallowed 
Medications and Therapies 
Added chronic PE/PP and IVIg therapies. 
To clarify that only acute 
treatment is permitted. 
Section 8.1.1 Hospitalization 
Reduced information to be collected to 
include only that required for meaningful 
assessment. 
To reduce burden on patients. 
Section 8.1.2 Clinical 
Deterioration 
Replaced text description of PK/PD sampling 
during Clinical Deterioration with a figure that 
provides instructions more clearly. Changed 
numbering to bullets.  
Clarification. Specific order 
of procedures is not required. 
Section 8.1.9 MGFA Clinical 
Classification 
Added new section describing Day 1 
assessment of MGFA Clinical Classification. 
Correction. 
Section 8.1.10 MGFA Post-
Intervention Status 
Noted that modified version of MGFA-PIS 
does not include categories of Exacerbation or 
Died of MG. 
Clarification. 
Section 8.2.3 
Electrocardiogram 
Indicated that QT interval will be corrected for 
heart rate using Fridericia’s formula. 
Clarification. 
Section 8.2.4.1 Urinalysis and 
Urine Chemistry 
Removed statement regarding 
protein:creatinine ratio, which will not be 
performed in this study. 
Correction. 
Section 8.2.5.1 Columbia-
Suicidal Severity Rating Scale 
Added timepoints (lifetime and past 1 year [12 
months]) for assessing suicidal ideation and 
behaviors  
To provide specific time 
points for data collection that 
have been implemented in the 
eCRF. 
Section 8.3.1 Time Period and 
Frequency for Collecting 
Adverse Event and Serious 
Adverse Event Information 
All adverse events that occur after the 
informed consent form (ICF) is signed must 
be recorded in the adverse event case report 
form, not in the medical history form.   
To ensure appropriate 
collection of pretreatment 
adverse events. 
Section 8.8 Biomarkers 
Noted that unused PK/PD/ADA/AChR 
samples may be stored for future biomarker 
research. 
To allow for future studies to 
understand drug/disease 
mechanisms. 
Section 8.9 Healthcare 
Resource Utilization  
Data collected will be the type of facility 
(hospital, rehabilitation center, or hospice), 
whether the primary reason for admission was 
related to MG, and the duration of 
hospitalization. 
To reduce data collection to 
only those elements needed 
for analysis. 
Section 9 Statistical 
Considerations 
Added description of plans for CSR 
preparation. 
Clarification. 
Section 9.1 Statistical 
Hypotheses 
Re-ordered secondary and exploratory 
hypotheses and estimation of treatment effect 
to align with changes made in Section 1.1 and 
Section 3 Objectives and Endpoints. 
To better characterize disease 
parameters associated with 
gMG and yield a clearer 
assessment of the impact of 
study intervention. 
Section 9.4.5.4 Multiplicity 
Adjustment for Primary and 
Secondary Endpoints 
Added description of secondary hypothesis 
testing. 
To inform on statistical 
methods. 


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Section # and Name 
Description of Change 
Brief Rationale 
Section 9.4.6.4 Analysis of PK 
and PD 
Revised description of analyses to be 
performed. 
To inform on statistical 
methods. 
Section 10.1.3 Data Protection 
Described storage of anonymized data. 
To inform on data protection. 
Section 10.2 Appendix 2: 
Clinical Laboratory Tests 
Deleted creatinine and added leukocyte 
esterase, ADA, and AChR Ab. 
Correction. 
Section 10.8 Appendix 8 
Myasthenia Gravis Composite 
Scale  
Replaced with updated image. 
Correction. 
Section 10.11 Appendix 11: 
Neurology Quality of Life 
Fatigue 
The last 3 questions of the Neurology Quality 
of Life Fatigue questionnaire were added to 
Appendix 11. 
Page 2 of the sample 
document was missing in 
prior versions of the protocol. 
Section 10.12 Appendix 12: 
Myasthenia Gravis Foundation 
of America Clinical 
Classification 
MGFA clinical classification is added as 
Appendix 12.  
In this trial, MGFA 
classification is utilized to 
assess the MG clinical state 
of patients. It was missing in 
prior versions of the protocol. 
Section 10.16 Appendix 16: 
Statistical Considerations 
Expanded description of sample size 
determination. 
To inform on statistical 
methods. 
 
 


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TABLE OF CONTENTS 
TITLE PAGE ...................................................................................................................................1 
INVESTIGATOR’S AGREEMENT ...............................................................................................3 
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE ............................................4 
TABLE OF CONTENTS .................................................................................................................8 
1. 
PROTOCOL SUMMARY ..........................................................................................15 
1.1. 
Synopsis ......................................................................................................................15 
1.2. 
Schema ........................................................................................................................19 
1.3. 
Schedule of Activities .................................................................................................20 
2. 
INTRODUCTION ......................................................................................................26 
2.1. 
Generalized Myasthenia Gravis ..................................................................................26 
2.2. 
Background .................................................................................................................26 
2.2.1. 
Unmet Medical Need in Patients With Generalized Myasthenia Gravis ...................26 
2.2.2. 
Role of Complement in Myasthenia Gravis ...............................................................26 
2.3. 
Study Rationale ...........................................................................................................27 
2.4. 
Benefit/Risk Assessment ............................................................................................28 
2.4.1. 
Identified and Potential Risks .....................................................................................28 
2.4.1.1. 
Identified Risk ............................................................................................................28 
2.4.1.2. 
Potential Risks ............................................................................................................28 
3. 
OBJECTIVES AND ENDPOINTS ............................................................................30 
4. 
STUDY DESIGN .......................................................................................................31 
4.1. 
Overall Design ............................................................................................................31 
4.1.1. 
Screening Period (2 - 4 Weeks Prior to Day 1) ..........................................................32 
4.1.2. 
Randomization ............................................................................................................32 
4.1.3. 
Randomized Controlled Period (26 Weeks) ...............................................................32 
4.1.4. 
Open-Label Extension Period .....................................................................................33 
4.2. 
Standard Protocol Definitions .....................................................................................33 
4.2.1. 
Clinical Deterioration .................................................................................................33 
4.2.2. 
Unscheduled Visits .....................................................................................................33 
4.2.3. 
Properly Trained Clinical Evaluator ...........................................................................33 
4.2.4. 
Responsibilities for Myasthenia Gravis Assessments ................................................34 
4.3. 
Scientific Rationale for Study Design ........................................................................34 


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4.4. 
Justification for Dose ..................................................................................................35 
4.5. 
End of Study Definition ..............................................................................................36 
5. 
STUDY POPULATION .............................................................................................37 
5.1. 
Inclusion Criteria ........................................................................................................37 
5.2. 
Exclusion Criteria .......................................................................................................38 
5.3. 
Lifestyle Considerations .............................................................................................39 
5.4. 
Screen Failures ............................................................................................................39 
6. 
STUDY DRUG ...........................................................................................................40 
6.1. 
Study Drugs Administered .........................................................................................40 
6.2. 
Preparation/Handling/Storage/Accountability ............................................................42 
6.2.1. 
Study Drug Preparation ..............................................................................................42 
6.2.2. 
Storage ........................................................................................................................42 
6.2.3. 
Packaging and Labeling ..............................................................................................43 
6.2.4. 
Accountability .............................................................................................................43 
6.2.5. 
Handling and Disposal ................................................................................................43 
6.3. 
Measures to Minimize Bias: Randomization and Blinding ........................................44 
6.3.1. 
Randomization ............................................................................................................44 
6.3.2. 
Blinding ......................................................................................................................44 
6.4. 
Concomitant Therapy .................................................................................................45 
6.5. 
Study Drug Compliance .............................................................................................45 
6.5.1. 
Allowed Medications ..................................................................................................45 
6.5.1.1. 
Palliative and Supportive Care ...................................................................................45 
6.5.1.2. 
Cholinesterase Inhibitors ............................................................................................45 
6.5.1.3. 
Immunosuppressive Agents ........................................................................................46 
6.5.1.4. 
Plasma Exchange/Plasmapheresis/Intravenous Immunoglobulin ..............................46 
6.5.1.5. 
Disallowed Medications and Therapies ......................................................................49 
6.5.2. 
Rescue Therapy ..........................................................................................................49 
6.6. 
Intervention After the End of the Study .....................................................................49 
7. 
DISCONTINUATION OF STUDY INTERVENTION AND PATIENT 
DISCONTINUATION/WITHDRAWAL ..................................................................50 
7.1. 
Discontinuation of Study Intervention ........................................................................50 
7.2. 
Lost to Follow Up .......................................................................................................50 
8. 
STUDY ASSESSMENTS AND PROCEDURES ......................................................52 


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8.1. 
Efficacy Assessments .................................................................................................52 
8.1.1. 
Hospitalization ............................................................................................................52 
8.1.2. 
Clinical Deterioration .................................................................................................52 
8.1.3. 
Myasthenia Gravis Activities of Daily Living Profile ................................................54 
8.1.4. 
Quantitative Myasthenia Gravis Score .......................................................................54 
8.1.5. 
Myasthenia Gravis Composite Score ..........................................................................54 
8.1.6. 
Euro Quality of Life 5D-5L ........................................................................................54 
8.1.7. 
Revised Myasthenia Gravis Qualify of Life-15 Scale ................................................54 
8.1.8. 
Neurological Quality of Life Fatigue .........................................................................55 
8.1.9. 
Myasthenia Gravis Foundation of America Clinical Classification ...........................55 
8.1.10. 
Myasthenia Gravis Foundation of America Post-Intervention Status ........................55 
8.2. 
Safety Assessments .....................................................................................................55 
8.2.1. 
Physical Examination .................................................................................................55 
8.2.2. 
Vital Signs and Pulse Oximetry ..................................................................................55 
8.2.3. 
Electrocardiogram .......................................................................................................55 
8.2.4. 
Clinical Safety Laboratory Assessments ....................................................................56 
8.2.4.1. 
Urinalysis and Urine Chemistry .................................................................................56 
8.2.4.2. 
Virus Serology ............................................................................................................56 
8.2.4.3. 
Immunogenicity Assessments ....................................................................................56 
8.2.5. 
Suicidal Risk Monitoring ............................................................................................56 
8.2.5.1. 
Columbia-Suicidal Severity Rating Scale ..................................................................56 
8.3. 
Adverse Events and Serious Adverse Events .............................................................57 
8.3.1. 
Time Period and Frequency for Collecting Adverse Event and Serious 
Adverse Event Information .........................................................................................57 
8.3.2. 
Method of Detecting Adverse Events and Serious Adverse Events ...........................57 
8.3.3. 
Follow-up of Adverse Events and Serious Adverse Events .......................................57 
8.3.4. 
Regulatory Reporting Requirements for Serious Adverse Events .............................58 
8.3.5. 
Pregnancy ...................................................................................................................58 
8.3.6. 
Vaccine and Antibiotic Prophylaxis ...........................................................................58 
8.3.7. 
Study Drug Administration Reactions ........................................................................59 
8.3.7.1. 
Local and Systemic Reactions ....................................................................................59 
8.3.7.2. 
Infusion-Associated Reactions ...................................................................................59 
8.4. 
Adverse Events of Special Interest .............................................................................59 


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8.5. 
Pharmacokinetics ........................................................................................................59 
8.6. 
Pharmacodynamics .....................................................................................................60 
8.7. 
Genetics ......................................................................................................................60 
8.8. 
Biomarkers ..................................................................................................................60 
8.9. 
Healthcare Resource Utilization .................................................................................60 
9. 
STATISTICAL CONSIDERATIONS .......................................................................61 
9.1. 
Statistical Hypotheses .................................................................................................61 
9.1.1. 
Primary Hypothesis ....................................................................................................61 
9.1.2. 
Secondary Hypotheses ................................................................................................61 
9.1.3. 
Hypotheses Related to Exploratory Efficacy Objectives ............................................62 
9.1.4. 
Estimation of Treatment Effect for Secondary and Exploratory Hypotheses ............62 
9.2. 
Sample Size Determination ........................................................................................63 
9.3. 
Populations for Analyses ............................................................................................63 
9.4. 
Statistical Analyses .....................................................................................................63 
9.4.1. 
Enrollment and Disposition ........................................................................................63 
9.4.2. 
Demographics, Baseline Characteristics, Inclusion and Exclusion Criteria, 
and Protocol Deviations ..............................................................................................64 
9.4.3. 
Medical/Surgical History, Physical Examination, and Myasthenia Gravis 
History ........................................................................................................................64 
9.4.4. 
Prior and Concomitant Medications ...........................................................................64 
9.4.5. 
Efficacy Analyses .......................................................................................................64 
9.4.5.1. 
Primary Efficacy Analysis ..........................................................................................64 
9.4.5.2. 
Sensitivity Analyses for Primary Endpoint ................................................................65 
9.4.5.3. 
Analyses of Secondary and Exploratory Endpoints ...................................................65 
9.4.5.4. 
Multiplicity Adjustment for Primary and Secondary Endpoints ................................65 
9.4.5.5. 
Per Protocol Analyses for Primary and Secondary Endpoints ...................................66 
9.4.6. 
Safety Analyses ..........................................................................................................66 
9.4.6.1. 
Analysis of Adverse Events ........................................................................................66 
9.4.6.2. 
Analysis of Clinical Laboratory Parameters, Vital Sign Measurements and 
Electrocardiogram Parameters ....................................................................................66 
9.4.6.3. 
Other Safety Analyses ................................................................................................66 
9.4.6.4. 
Analysis of Pharmacokinetics and Pharmacodynamics .............................................66 
9.4.6.5. 
Analysis of Immunogenicity .......................................................................................67 


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9.4.6.6. 
Analysis of Exploratory Biomarkers ..........................................................................67 
9.5. 
Interim Analyses .........................................................................................................67 
9.6. 
Data Monitoring Committee .......................................................................................67 
10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS ..................................................................................................68 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations ....................68 
10.1.1. 
Regulatory and Ethical Considerations ......................................................................68 
10.1.2. 
Informed Consent Process ..........................................................................................68 
10.1.3. 
Data Protection ...........................................................................................................69 
10.1.4. 
Dissemination of Clinical Study Data ........................................................................69 
10.1.5. 
Data Quality Assurance ..............................................................................................69 
10.1.6. 
Source Documents ......................................................................................................70 
10.1.7. 
Study and Site Closure ................................................................................................70 
10.1.8. 
Publication Policy .......................................................................................................71 
10.2. 
Appendix 2: Clinical Laboratory Tests .......................................................................72 
10.3. 
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting ........................................................................73 
10.3.1. 
Adverse Event .............................................................................................................73 
10.3.2. 
Serious Adverse Event ................................................................................................74 
10.3.3. 
Suspected Unexpected Serious Adverse Reactions ....................................................74 
10.3.4. 
Recording and Follow-Up of Adverse Event and/or Serious Adverse Event ............75 
10.3.5. 
Reporting of Serious Adverse Events .........................................................................76 
10.4. 
Appendix 4: Contraceptive Guidance and Collection of Pregnancy 
Information .................................................................................................................78 
10.4.1. 
Contraception Guidance .............................................................................................78 
10.4.2. 
Pregnancy Testing ......................................................................................................78 
10.4.3. 
Collection and Reporting of Pregnancy Information ..................................................79 
10.5. 
Appendix 5: Management of Potential Infusion-Associated Adverse Events 
During Study Drug Administration ............................................................................80 
10.6. 
Appendix 6: Myasthenia Gravis Activities of Daily Living Profile ...........................82 
10.7. 
Appendix 7: Quantitative Myasthenia Gravis Score for Disease Severity .................83 
10.8. 
Appendix 8: Myasthenia Gravis Composite Scale .....................................................84 
10.9. 
Appendix 9: Euro Quality of Life Questionnaire .......................................................85 
10.10. 
Appendix 10: Myasthenia Gravis Quality-of-Life 15r Scale .....................................88 


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10.11. 
Appendix 11: Neurology Quality of Life Fatigue ......................................................89 
10.12. 
Appendix 12: Myasthenia Gravis Foundation of America Clinical 
Classification ..............................................................................................................91 
10.13. 
Appendix 13: Myasthenia Gravis Foundation of America Post-Interventional 
Status ...........................................................................................................................92 
10.14. 
Appendix 14: Columbia-Suicide Severity Rating Scale – Baseline/Screening 
(Version 1/14/09) ........................................................................................................93 
10.15. 
Appendix 15: Columbia-Suicide Severity Rating Scale - Since Last Visit 
(Version 1/14/09) ........................................................................................................96 
10.16. 
Appendix 16: Statistical Considerations .....................................................................99 
10.16.1. 
Additional Details on Sample Size Determination .....................................................99 
10.16.2. 
Additional Details on Sensitivity Analysis for Primary Endpoint ..............................99 
10.16.2.1. Placebo-based Sensitivity Analysis ............................................................................99 
10.16.2.2. Tipping Point Sensitivity Analysis .............................................................................99 
10.17. 
Appendix 17: Abbreviations .....................................................................................101 
10.18. 
Appendix 18: Protocol Amendment History ............................................................104 
11. 
REFERENCES .........................................................................................................107 
 
LIST OF TABLES 
Table 1: 
Schedule of Activities: Screening Through End of the Randomized-
Controlled Period ........................................................................................................20 
Table 2: 
Schedule of Activities: Extension Period ...................................................................23 
Table 3: 
Myasthenia Gravis Assessments and Responsibilities ...............................................34 
Table 4: 
Ravulizumab Weight-Based Dosing ...........................................................................35 
Table 5: 
Study Drug Administered ...........................................................................................40 
Table 6: 
Reference Chart for Weight-Based Dosing ................................................................41 
Table 7: 
Supplemental Dose When Plasmapheresis/Plasma Exchange is Administered 
as Rescue Therapy on Nonscheduled Dosing Visits ..................................................47 
Table 8: 
Supplemental Dose When Intravenous Immunoglobulin is Administered as 
Rescue Therapy on Nonscheduled Dosing Visits .......................................................48 
Table 9: 
Study ALXN1210-MG-306: Analysis Sets ................................................................63 
Table 10: Protocol-Required Safety Laboratory Assessments ...................................................72 
Table 11: List of Abbreviations and Definitions of Terms .......................................................101 
 


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LIST OF FIGURES 
Figure 1: 
Ravulizumab Every 8 Weeks Dosage Regimen Versus Eculizumab Every 
2 Weeks Dosage Regimen ..........................................................................................28 
Figure 2: 
PK/PD/ADA Sampling for Clinical Deterioration .....................................................53 
 


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1. 
PROTOCOL SUMMARY 
1.1. 
Synopsis 
Protocol Title: A Phase 3, Randomized, Double-Blind, Placebo-Controlled, Multicenter Study 
to Evaluate the Safety and Efficacy of Ravulizumab in 
Complement-Inhibitor-Naïve Adult Patients With Generalized Myasthenia 
Gravis 
Short Title: Safety and Efficacy Study of Ravulizumab in Adults With Generalized Myasthenia 
Gravis 
Rationale: Ravulizumab (ALXN1210) was engineered from eculizumab (h5G1.1-mAb), 
humanized monoclonal antibody that specifically binds with high affinity to the human terminal 
complement component (C5), inhibiting C5 enzymatic cleavage and thereby preventing the 
generation of the proinflammatory/prothrombotic complement activation products, C5a, and the 
cytolytic and proinflammatory/prothrombotic membrane attack complex, C5b-9, which are 
responsible for the antibody-mediated destruction of the neuromuscular junction (NMJ), loss of 
acetylcholine receptors, and failure of neuromuscular transmission associated with generalized 
myasthenia gravis (gMG). Eculizumab is approved for the treatment of gMG, paroxysmal 
nocturnal hemoglobinuria, and atypical hemolytic uremic syndrome in many countries 
worldwide, including Japan, the USA, and countries in the European Union under the trade name 
Soliris®. 
Ravulizumab preserves immediate and complete C5 inhibition while providing sustained 
complement inhibition throughout a prolonged dosing interval; it was specifically designed (and 
has subsequently been proven) to have an increased half-life relative to eculizumab. Therefore, 
ravulizumab requires less frequent (once every 8 weeks [q8w]) infusions than eculizumab (once 
every 2 weeks [q2w] infusions). Given that gMG is a chronic disease with a significant treatment 
burden, the relative convenience of the ravulizumab dosing regimen may increase patient 
satisfaction and treatment adherence, and ultimately, lead to improved health outcomes. 
Ravulizumab was designed based on comprehensive modelling and simulation analyses to 
maintain efficacious concentrations across an extended dosing interval. The enhanced 
pharmacokinetic (PK)/pharmacodynamic profile of ravulizumab, with fewer PK troughs than 
eculizumab, has the potential to improve therapeutic efficacy while maintaining a safety profile 
similar to that of eculizumab. Furthermore, the q8w dosing regimen minimizes the risk of 
incomplete complement inhibition. 


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Study ALXN1210-MG-306 Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
To assess the efficacy of ravulizumab compared with 
placebo in the treatment of gMG based on the 
improvement in the Myasthenia Gravis-Activities of 
Daily Living (MG-ADL) profile.  
Change from Baseline in MG-ADL total score at 
Week 26 of the Randomized-Controlled Period. 
Secondary 
• 
To assess the efficacy of ravulizumab compared 
with placebo in the treatment of gMG based on 
the improvement in the Quantitative Myasthenia 
Gravis (QMG) total score. 
• 
Change from Baseline in QMG total score at 
Week 26. 
• 
To assess the efficacy of ravulizumab compared 
with placebo in the treatment of gMG based on 
the improvement in quality of life measures. 
• 
Change from Baseline in the Revised 
15-Component Myasthenia Gravis Quality of Life 
(MG-QOL15r) score at Week 26. 
• 
Change from Baseline in Neuro-QOL Fatigue 
score at Week 26. 
• 
To assess the efficacy of ravulizumab compared 
with placebo in the treatment of gMG based on 
other efficacy endpoints. 
• 
Improvement of at least 3 points in the MG-ADL 
total score from Baseline at Week 26. 
• 
Improvement of at least 5 points in the QMG total 
score from Baseline at Week 26. 
Exploratory 
• 
To assess the efficacy of ravulizumab in the 
treatment of gMG based on other efficacy 
endpoints throughout the study. 
• 
Change from Baseline in the Myasthenia Gravis 
Composite (MGC) score at Week 26. 
• 
Myasthenia Gravis Foundation of America 
(MGFA) Post-Intervention Status (PIS) at 
Week 26. 
• 
Change from Baseline in Euro Quality of Life 
(EQ-5D-5L) at Week 26. 
• 
Change from baseline in MG-ADL subcomponent 
scores (bulbar, limbs, respiratory, and ocular) at 
Week 26. 
• 
Change from baseline in QMG subcomponent 
scores (bulbar, limbs, respiratory, and ocular) at 
Week 26. 
• 
Incidence of hospitalizations/MG-related 
hospitalizations. 
• 
Incidence of Clinical Deterioration/MG crisis. 
PK/PD/Immunogenicity 
 
• 
To evaluate the PK/PD and immunogenicity of 
ravulizumab in the treatment of gMG throughout 
the study. 
• 
Change in serum ravulizumab concentration over 
time. 
• 
Change in serum free C5 concentration over time. 
• 
Incidence of treatment-emergent antidrug 
antibodies over time. 
Safety 
 
To characterize the overall safety of ravulizumab in 
the treatment of gMG. 
• 
Incidence of adverse events and serious adverse 
events over time. 
• 
Changes from Baseline in vital signs and 
laboratory assessments. 
The above endpoints will be evaluated over time throughout the study. 


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Overall Design: 
This is a Phase 3, randomized, double-blind, parallel-group, placebo-controlled, multicenter 
study to evaluate the safety and efficacy of ravulizumab for the treatment of patients with gMG. 
Approximately 160 eligible patients will be stratified by region (North America, Europe, 
Asia-Pacific, and Japan) and randomized 1:1 to 1 of 2 treatment groups: (1) ravulizumab 
infusion or (2) placebo infusion. There will be 3 periods in this study: Screening Period, 
Randomized-Controlled Period, and an Open-Label Extension (OLE) Period. 
Eight weeks after the final dose of study drug is administered, all enrolled patients will return for 
an End of Study (EOS) Visit (Visit 25) at Week 132, during which final study assessments will 
be conducted. If a patient withdraws from the study or completes the study early because 
ravulizumab has become registered or approved (in accordance with country-specific 
regulations) prior to Visit 24, the patient will be encouraged to return for an Early Termination 
Visit, 8 weeks after the last dose of study drug was administered, during which final planned 
safety assessments will be conducted. Attempts should be made to follow all patients for safety 
for 8 weeks following the patient’s last dose of study drug. 
Patients being treated with an immunosuppressive therapy (IST) at the time of the Screening 
Visit may continue to receive ISTs throughout the Randomized-Controlled and OLE Periods. 
However, the dosage of IST must not be changed and no new ISTs may be added during the 
Randomized-Controlled Period of the study, unless deemed by the Investigator to be medically 
necessary.  
Throughout the study, rescue therapy (eg, high-dose corticosteroids, plasmapheresis/plasma 
exchange, or intravenous immunoglobulin) will be allowed if a patient experiences Clinical 
Deterioration, as defined by the study protocol. The rescue therapy used for a particular patient 
will be at the discretion of the Investigator.  
The primary endpoint for this study will be measured at Week 26. Endpoints will be measured 
and analyzed irrespective of rescue therapy. For those patients who complete the study, as 
defined in the protocol, the EOS Visit is defined as patient’s last visit in the (up to) 2-year OLE 
Period. Including the 8-week safety follow-up, which begins after the patient’s last dose of study 
drug is administered, the overall study-duration for an individual patient is estimated to take up 
to 132 weeks (from enrollment through the end of the Safety Follow-up). The period of active 
patient-participation is estimated to take up to 132 weeks (from enrollment through the EOS 
Visit).  
Number of Patients: 
Patients will be screened until enough patients have been enrolled to achieve an estimated total 
of 160 patients, with approximately 80 patients per group. 
Intervention Groups and Duration: 
At the time of randomization, all patients will be reassessed for eligibility based on the study 
inclusion and exclusion criteria. All patients who meet the inclusion criteria and none of the 
exclusion criteria, have been vaccinated against Neisseria meningitidis, within the timeframe 
specified in the inclusion criteria, and have been cleared for randomization by the Investigator 
will be randomized 1:1 to 1 of 2 treatment groups: (1) ravulizumab infusion or (2) placebo 


Protocol 
 
ALXN1210-MG-306 Amendment 2 
Page 18 of 109 
Alexion Confidential 
infusion. Patients will be centrally randomized using interactive response technology. The 
randomization will be stratified by region (North America, Europe, Asia-Pacific, and Japan).  
Patients randomized to the ravulizumab group will receive a blinded loading dose of 
ravulizumab on Day 1, followed by blinded maintenance doses of ravulizumab on Day 15 
(Week 2) and q8w thereafter, for a total of 18 weeks of treatment. Patients randomized to 
placebo will receive a blinded dose of placebo on Day 1, followed by blinded doses of placebo 
on Day 15 (Week 2) and q8w thereafter, for a total of 18 weeks. Both ravulizumab and placebo 
will be administered by intravenous infusion. 
After the 26-Week Randomized-Controlled Period and assessments on Day 183 (Week 26), 
patients in the placebo group will receive a blinded loading dose of ravulizumab and patients in 
the ravulizumab group will receive a blinded ravulizumab dose of 900 mg; the 900-mg dose was 
chosen to ensure maintenance of complete C5 inhibition until the next scheduled maintenance 
dose at Week 28 (Day 197). Starting at Week 28, all patients will begin open-label ravulizumab 
maintenance doses q8w.  
The OLE Period for each patient will commence when the patient receives a dose of ravulizumab 
on Week 26 (Day 183) and will continue for up to 2 years or until the product is registered or 
approved (in accordance with country-specific regulations), whichever occurs first. 
Data Monitoring Committee: No. 


Protocol 
 
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1.2. 
Schema 
Study ALXN1210-MG-306 Schematic 
 
1 Ravulizumab dosage regimen:   
LOADING DOSE (Day 1) =  
2400 mg for patients weighing ≥ 40 kg to < 60 kg 
2700 mg for patients weighing ≥ 60 kg to < 100 kg 
3000 mg for patients weighing ≥ 100 kg 
MAINTENANCE DOSE (Day 15 and every 8 weeks [q8w] thereafter) =  
3000 mg for patients weighing ≥ 40 kg to < 60 kg 
3300 mg for patients weighing ≥ 60 kg to < 100 kg 
3600 mg for patients weighing ≥ 100 kg 
2 Standard of care treatment to remain stable throughout the Randomized-Controlled Period 
Abbreviations: IV = intravenous; N = number [of patients] 
 


Protocol 
 
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Page 20 of 109 
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1.3. 
Schedule of Activities  
Table 1: 
Schedule of Activities: Screening Through End of the Randomized-Controlled Period 
Period/Phase 
Screening 
Randomized-Controlled Period 
Clinical 
Deterioration1 
Study Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9/ET2 
 
Study Day 
 
D1 
D8 
D15 
D29 
D71 
D85 
D127 
D183 
Window (day) 
 
 
± 2 
± 2 
± 2 
± 2 
± 2 
± 2 
± 2 
 
Weeks 
-4 to -2 W 
 
W1 
W2 
W4 
W10 
W12 
W18 
W26 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
Assessment of Inclusion/ 
Exclusion Criteria 
X 
X 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
MG History3 
X 
 
 
 
 
 
 
 
 
 
MGFA Clinical Classification4 
X 
X 
 
 
 
 
 
 
 
 
Weight 
X 
 
X 
 
X 
X 
X 
X 
X 
 
Height 
X 
 
 
 
 
 
 
 
 
 
HIV-(1 and 2) testing 
X 
 
 
 
 
 
 
 
 
 
Vital Signs & Pulse Oximetry5 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical Examination 
X 
 
 
 
 
 
 
 
X 
X 
Abbreviated Physical 
Examination6 
 
X 
X 
X 
X 
X 
X 
X 
 
 
Concomitant Medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Non-Drug Therapy 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
MG Therapy Status 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hospitalization Status 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Event 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
MG-ADL4,7 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
QMG4,8 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
MG-QOL15r 
X 
X 
 
 
X 
 
X 
X 
X 
 
Neuro-QOL Fatigue 
X 
X 
 
 
X 
 
X 
X 
X 
 
EQ-5D-5L 
X 
X 
 
 
X 
 
X 
X 
X 
 
MGC4,8 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
MGFA-PIS4 
 
 
 
 
X 
 
X 
X 
X 
 
C-SSRS Baseline/Screening 
Version9 
 
X 
 
 
 
 
 
 
 
 
C-SSRS Since Last Visit 
Version 
 
 
 
 
 
 
X 
 
X 
 
ECG 
X 
 
 
 
 
 
 
 
X 
 
AChR Ab 
X 
 
 
 
 
 
X 
 
X 
X 


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ALXN1210-MG-306 Amendment 2 
 
Page 21 of 109 
Alexion Confidential 
Table 1: 
Schedule of Activities: Screening Through End of the Randomized-Controlled Period (Continued) 
Period/Phase 
Screening 
Randomized-Controlled Period 
Clinical 
Deterioration1 
Study Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9/ET2 
 
Study Day 
 
D1 
D8 
D15 
D29 
D71 
D85 
D127 
D183 
Window (day) 
 
 
± 2 
± 2 
± 2 
± 2 
± 2 
± 2 
± 2 
 
Weeks 
-4 to -2 W 
 
W1 
W2 
W4 
W10 
W12 
W18 
W26 
 
Clinical Lab Tests10 
X 
X 
 
X 
 
X 
 
X 
X 
X 
Pregnancy Test 11 
X 
X 
 
X 
 
X 
 
X 
X 
 
PK, Free C512 
 
B/P 
 
T/P 
 
T/P 
 
T/P 
T 
X 
ADA13 
 
X 
 
 
 
X 
 
X 
X 
X 
N meningitidis Vaccine13 
X 
 
 
 
 
 
 
 
 
 
Patient Safety Information 
Card14 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Randomization15 
 
X 
 
 
 
 
 
 
 
 
Study Drug Infusion16 
 
X 
 
X 
 
X 
 
X 
 
 
1  Evaluation of Clinical Deterioration must be performed as soon as possible, within 48 hours of notification to the Investigator of symptom onset. If Clinical 
Deterioration occurs between scheduled visits, only the assessments for the Clinical Deterioration visit are needed. If Clinical Deterioration occurs on a 
scheduled visit, all scheduled assessments should be performed for that visit as well as for the evaluation of Clinical Deterioration. Additional evaluation visits 
may be scheduled at the discretion of the Investigator. 
2 If a patient withdraws early from the study during the Randomized-Controlled Period, an Early Termination Visit will be performed. 
3 MG history will include diagnosis date; initial MG clinical presentation (oMG or gMG); time to gMG, if initial clinical presentation was oMG; maximum 
MGFA classification since diagnosis; ventilatory support since diagnosis; dates of MG exacerbation or crisis since diagnosis and prior to Day 1; and any MG-
related hospitalizations in 2 years prior to screening. MG-specific medication or therapy taken within 2 years prior to screening will be recorded. 
4 Refer to Section 4.2.4. 
5 Vital signs and pulse oximetry will include systolic and diastolic blood pressure (millimeters of mercury [mmHg]), pulse oximetry (oxygen saturation [SO2]), 
heart rate (beats/minute), and temperature (degrees Celsius [°C] or degrees Fahrenheit [°F]). On dosing days, vital signs will be taken before study drug 
administration and after the patient has been resting for at least 5 minutes. 
6 To be performed, if necessary, on the basis of the patient’s health status and the clinical judgment of the Investigator. 
7 The MG-ADL is required to be performed first, followed by the QMG. The MG-activities of daily living (MG-ADL) assessment should be performed by a 
Properly Trained Clinical Evaluator (as defined in the study protocol), preferably the same evaluator, throughout the study. The recall period for MG-ADL is 
the preceding 7 days or since the last visit if the visit interval is less than 7 days. 
8 The QMG and MGC assessments should be performed by a Properly Trained Clinical Evaluator (as defined in the study protocol), preferably the same 
evaluator, throughout the study. If a patient is taking a cholinesterase inhibitor, the dose must be withheld for at least 10 hours prior to the assessment.  
9 C-SSRS will be assessed for both lifetime and past 1 year (12 months). 
10 Clinical laboratory tests will be performed at the central laboratory.  


Protocol 
 
ALXN1210-MG-306 Amendment 2 
 
Page 22 of 109 
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Table 1: 
Schedule of Activities: Screening Through End of the Randomized-Controlled Period (Continued) 
11 Pregnancy tests must be performed on all patients of child-bearing potential at the specified time points. Serum pregnancy test will be performed at Screening 
and Day 183/ET; urine pregnancy tests will be performed locally at all other required time points. A negative urine test result performed locally is required 
prior to administering ravulizumab to patients of childbearing potential at the indicated visits. Additional pregnancy tests (urine or serum) may also be 
performed at any visit at the Investigator’s discretion. 
12 Baseline (B) and trough (T) blood samples for serum PK, free C5 (PD), and ADA will be collected predose (within 30 minutes prior to the start of infusion of 
study drug). Peak (P) blood samples for serum PK/PD samples are to be taken within the 30 minutes following completion of study drug infusion. The T 
samples may be drawn through the venous access created for the dose infusion, prior to administration of the dose. The P samples will be drawn from the 
patient’s opposite, noninfused arm. On Day 183 (Week 26), the T sample is considered a Randomized-Controlled Period assessment and the P sample is 
considered an Extension Period assessment. All collection times will be recorded in eCRF. In the event of Clinical Deterioration, blood samples for serum 
PK/PD and ADA analyses will be collected if supplemental dosing is provided (see Section 8.1.2). 
13 To reduce the risk of meningococcal infection (N meningitidis), all patients must be vaccinated against meningococcal infections within 3 years prior to, or at 
the time of, initiating study drug. Patients who initiate study drug treatment less than 2 weeks after receiving a meningococcal vaccine must receive treatment 
with appropriate prophylactic antibiotics until 2 weeks after vaccination. 
14 Patients will be given a Patient Safety Information Card prior to the first dose of study drug. At each visit throughout the study, the study staff will ensure that 
the patient has the Patient Safety Information Card. 
15 All patients that continue to meet all inclusion criteria and none of the exclusion criteria and have been cleared for randomization by the Investigator will be 
centrally randomized through interactive response technology (IRT). 
16 Study drug will be administered intravenously via infusion after completion of all other tests and procedures, excluding the peak blood sampling for PK/PD, 
free C5, and ADA. 
Abbreviations: AChR Ab = acetylcholine receptor antibody; ADA = antidrug antibody; B = baseline sample; C5 = complement component 5; 
C-SSRS = Columbia-Suicide Severity Rating Scale; D = day; ECG = electrocardiogram; EQ-5D-5L=Euro Quality of Life; ET = Early Termination; 
HIV = Human Immunodeficiency Virus; MG = Myasthenia Gravis; MG-ADL = Myasthenia gravis Activities of Daily Living profile; MGC = Myasthenia gravis 
Composite score; MGFA = Myasthenia Gravis Foundation of America; MGFA-PIS = MGFA-Post-Intervention Status; N meningitidis = Neisseria meningitidis; 
P = peak sample; PK/PD = pharmacokinetic(s)/pharmacodynamic(s); QMG = Quantitative Myasthenia Gravis score for disease severity; QoL = quality of life; 
T = trough sample; W = week(s). 
 


Protocol 
 
ALXN1210-MG-306 Amendment 2 
 
Page 23 of 109 
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Table 2: 
Schedule of Activities: Extension Period 
Period 
Open-Label Extension  
Clinical  
Deterioration1 
Study Visit 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
21 
22 
23 
24 
25 
 
Study Days2 
D183 
D197 
D211 
D253 
D267 
D309 
D365 
D421 
D477 
D533 
D589 
D645 
D701 
D757 
D813 
D869 
D925/
ET3/ 
EOS 
 
Weeks 
W26 
W28 
W30 
W36 
W38 
W44 
W52 
W60 
W68 
W76 
W84 
W92 
W100 W108 W116 W124 
W 
132 
 
Window (day) 
 
± 3 
± 7 
± 7 
± 7 
± 7 
± 7 
± 7 
± 7 
± 7 
± 7 
± 7 
± 7 
± 7 
± 7 
± 7 
± 7 
 
Weight 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Vital Signs & 
Pulse Oximetry4 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical 
Examination 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Abbreviated 
Physical 
Examination5 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Concomitant 
Medication 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Non-Drug 
Therapy 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
MG Therapy 
Status 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hospitalization 
Status 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Events 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
MG-ADL6, 7 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
QMG6, 8 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
MG-QOL15r 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Neuro-QOL 
Fatigue 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
EQ-5D-5L 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
MGC6, 8 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
MGFA-PIS6 
 
 
 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
 
C-SSRS Since 
Last Visit 
Version 
 
 
 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
 
ECG 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
AChR Ab 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
Clinical Lab 
Tests9 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


Protocol 
 
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Page 24 of 109 
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Table 2: 
Schedule of Activities: Extension Period (Continued) 
Period 
Open-Label Extension  
Clinical  
Deterioration1 
Study Visit 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
21 
22 
23 
24 
25 
 
Study Days2 
D183 
D197 
D211 
D253 
D267 
D309 
D365 
D421 
D477 
D533 
D589 
D645 
D701 
D757 
D813 
D869 
D925/
ET3/ 
EOS 
 
Weeks 
W26 
W28 
W30 
W36 
W38 
W44 
W52 
W60 
W68 
W76 
W84 
W92 
W100 W108 W116 W124 
W 
132 
 
Window (day) 
 
± 3 
± 7 
± 7 
± 7 
± 7 
± 7 
± 7 
± 7 
± 7 
± 7 
± 7 
± 7 
± 7 
± 7 
± 7 
± 7 
 
Pregnancy 
Test10 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
PK, Free C511 
P 
T/P 
 
T/P 
 
T/P 
T/P 
 
T/P 
 
T/P 
 
T/P 
 
T/P 
 
T 
X 
ADA11 
 
 
 
X 
 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
Patient Safety 
Information 
Card12 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Ravulizumab 
Infusion13 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
1 Evaluation of Clinical Deterioration must be performed as soon as possible, within 48 hours of notification to the Investigator of symptom onset. If Clinical 
Deterioration occurs between scheduled visits, only the assessments for the Clinical Deterioration visit are needed. If Clinical Deterioration occurs on a 
scheduled visit, all scheduled assessments should be performed for that visit as well as for the evaluation of Clinical Deterioration. Additional evaluation visits 
can be scheduled at the discretion of the Investigator. 
2 Extension Period begins at the start of Day 183 (Week 26) dosing. 
3 If a patient withdraws early from the study during the Extension Period an Early Termination Visit will be performed. 
4 Vital signs and pulse oximetry will include systolic and diastolic blood pressure (millimeters of mercury [mmHg]), pulse oximetry (oxygen saturation [SO2]), 
heart rate (beats/minute), and temperature (degrees Celsius [°C] or degrees Fahrenheit [°F]). On dosing days, vital signs will be taken before study drug 
administration and after the patient has been resting for at least 5 minutes. 
5 To be performed, if necessary, on the basis of the patient’s health status and the clinical judgment of the Investigator. 
6 Refer to Section 4.2.4. 
7 The MG-ADL is required to be performed first, followed by the QMG. The MG-ADL should be performed by a Properly Trained Clinical Evaluator (as 
defined in the study protocol), preferably the same evaluator, throughout the study. The recall period for MG-ADL is the preceding 7 days or since the last visit 
if the visit interval is less than 7 days. 
8 The QMG and MGC assessments should be performed by a Properly Trained Clinical Evaluator (as defined in the study protocol), preferably the same 
evaluator, throughout the study. If a patient is taking a cholinesterase inhibitor, the dose must be withheld for at least 10 hours prior to the assessment. 
9 Clinical laboratory tests will be performed at the central laboratory.  
10 Pregnancy tests must be performed on all patients of child-bearing potential at the specified time points. Serum pregnancy tests will be performed at 
Day 925/ET/EOS; urine pregnancy tests will be performed locally at all other required time points. A negative urine test result performed locally is required 
prior to administering ravulizumab to patients of childbearing potential at the indicated visits. Additional pregnancy tests (urine or serum) may also be 
performed at any visit at the Investigator’s discretion. 


Protocol 
 
ALXN1210-MG-306 Amendment 2 
 
Page 25 of 109 
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Table 2: 
Schedule of Activities: Extension Period (Continued) 
11Trough (T) blood samples for serum PK, free C5 (PD), and ADA will be collected predose (within 30 minutes prior to the start of infusion of study drug). Peak 
(P) blood samples for serum PK/PD are to be taken within the 30 minutes following completion of study drug infusion. The T samples may be drawn through 
the venous access created for the dose infusion, prior to administration of the dose. The P samples will be drawn from the patient’s opposite, noninfused arm. 
On Day 183 (Week 26), the T sample is considered a Randomized-Controlled Period assessment and the P sample is considered an Extension Period 
assessment. All collection times will be recorded in eCRF. In the event of Clinical Deterioration, a blood sample for serum PK/PD and ADA analyses will be 
collected if supplemental dosing is provided (see Section 8.1.2). 
12Patients will be given a Patient Safety Information Card prior to the first dose of study drug. At each visit throughout the study, staff will ensure that the patient 
has the Patient Safety Information Card. 
13Ravulizumab will be administered intravenously via infusion after completion of all other tests and procedures, excluding the peak blood sampling for PK, 
free C5, and ADA. 
Abbreviations: AChR Ab = Acetylcholine receptor antibody; ADA = Antidrug antibody B = Baseline sample; C5 = Complement component 5; 
C-SSRS = Columbia-Suicide Severity Rating Scale; ECG = electrocardiogram; EOS=End of Study; EQ-5D-5L = Euro Quality of Life; ET = Early Termination; 
ICU = Intensive Care Unit; MG = Myasthenia Gravis; MG-ADL = MG Activity of Daily Living profile; MGC = Myasthenia Gravis Composite score; 
MGFA = Myasthenia Gravis Foundation of America; MGFA-PIS = MGFA-Post-Intervention Status; N meningitidis = Neisseria meningitidis; P = peak sample; 
PK/PD = pharmacokinetics/pharmacodynamics; QMG = Quantitative Myasthenia Gravis score for disease severity; QoL = quality of life; T = trough sample. 


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2. 
INTRODUCTION 
2.1. 
Generalized Myasthenia Gravis 
Generalized myasthenia gravis (gMG) is a rare disorder, which based on studies conducted in 
Europe, has an estimated prevalence between 145 to 278 per million inhabitants (Cetin, 2012; 
Fang, 2015; Heldal, 2009). Patients with gMG suffer from a devastating inflammatory 
neuromuscular disorder with limited therapeutic options. 
Generalized myasthenia gravis patients differ from the ocular myasthenia gravis (MG) 
population in that neuromuscular inflammation and the resultant clinical findings are not just 
limited to the ocular muscles, but involve all voluntary muscle groups: the bulbar, respiratory, 
head, neck, trunk, or peripheral muscles with or without involvement of the eyes. Profound 
weakness and devastating consequences, including slurred speech, dysarthria, dysphagia, 
disorienting vision, shortness of breath (both with activity and at rest), weakness of the upper and 
lower extremities, impaired mobility, marked reductions in the ability to perform activities of 
daily living (ADLs), extreme fatigue, and episodes of pulmonary failure requiring mechanical 
ventilation are hallmarks of gMG. Compared with patients with isolated ocular MG, patients 
with gMG have a greater incidence of morbidities and a higher burden of disease (Engel-Nitz, 
2018).  
Hospitalizations for gMG exacerbations are common, with the need for respiratory support, 
including mechanical ventilation secondary to respiratory failure (eg, myasthenic crisis) and 
gastrointestinal tube placement for nutritional support and prevention of dysphagia-associated 
aspiration. Patients with more advanced gMG have been reported to experience increased 
mortality of up to 40% at 10 years following diagnosis (Christensen, 1998). 
2.2. 
Background 
2.2.1. 
Unmet Medical Need in Patients With Generalized Myasthenia Gravis 
In difficult-to-control cases, patients with gMG experience unrelenting inflammation, tissue 
destruction, and consequent severe morbidities including profound muscle weakness, impaired 
mobility, shortness of breath, pulmonary failure, extreme fatigue, risk for aspiration, and 
markedly impaired ADLs (Sahashi, 1978; Silvestri, 2014; Suh, 2013). These patients are 
typically diagnosed in the prime of their adult lives, with a median age of onset ranging from 
36 to 60 years (Suh, 2013). As a result of the morbidities associated with gMG, many patients 
cannot work or have diminished work-capacity, experience difficultly caring for themselves and 
others, and require assistance speaking, eating, ambulating, breathing, and performing ADLs. 
2.2.2. 
Role of Complement in Myasthenia Gravis 
Uncontrolled terminal complement activation has been implicated in animal models of 
experimental autoimmune gMG (Sahashi, 1978; Fitch, 1999; Dalakas, 2004; Keshavjee, 2005; 
Patel, 2005) as well as in other forms of autoimmune neuropathy in humans. Autoantibodies 
recognize targeted neural or muscle tissues, including the acetylcholine receptor (AChR), leading 
to uncontrolled terminal complement activation at the neural or muscle surface (Ha, 2015).  


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Autoantibody-driven uncontrolled terminal complement activation with membrane attack 
complex (MAC)-dependent lysis and activation, and C5a-dependent inflammation at the 
neuromuscular junction (NMJ) causes AChR loss and failure of neuromuscular transmission. 
Consistent with this model, both complement component (C) 3 (C3a and C3b) fragments and the 
MAC C5b-9 have been found in NMJs of MG patients (Sahashi, 1978). 
Taken together, the data support that uncontrolled terminal complement activation at the NMJ 
plays a role in the destruction of post-synaptic structure. Rapid, complete, and sustained 
inhibition of terminal complement activation is a biologically rational approach to prevent the 
damage caused in patients with gMG. 
2.3. 
Study Rationale 
Ravulizumab (ALXN1210) was engineered from eculizumab (h5G1.1-mAb), a humanized 
monoclonal Ab (mAb) that specifically binds with high affinity to the human terminal C5, 
inhibiting C5 enzymatic cleavage and thereby preventing the generation of the 
proinflammatory/prothrombotic mediators, such as MAC C5b-9, which are responsible for the 
inflammatory consequences of terminal complement activation. Eculizumab is approved for the 
treatment of gMG, paroxysmal nocturnal hemoglobinuria (PNH), atypical hemolytic uremic 
syndrome (aHUS), and neuromyelitis optica spectrum disorder (NMOSD) in many countries 
worldwide under the trade name Soliris®. 
Ravulizumab preserves immediate and complete C5 inhibition while providing sustained 
complement inhibition throughout a prolonged dosing interval; it was specifically designed (and 
has subsequently been proven) to have an increased half-life relative to eculizumab. Therefore, 
ravulizumab requires less frequent (once every 8 weeks [q8w]) infusions relative to eculizumab 
(once every 2 weeks [q2w] infusions). Given that gMG is a chronic disease with a significant 
treatment burden, the relative convenience of the ravulizumab dosing regimen may increase 
patient satisfaction, increase treatment adherence, and ultimately, lead to improved health 
outcomes. 
Ravulizumab was designed based on comprehensive modelling and simulation analyses to 
maintain efficacious concentrations across a longer dosing interval. The enhanced 
pharmacokinetic (PK)/pharmacodynamic (PD) profile of ravulizumab, with fewer PK troughs, 
than eculizumab, has the potential to improve therapeutic efficacy while maintaining a safety 
profile similar to that of eculizumab. Furthermore, the q8w dosing regimen minimizes the risk of 
incomplete complement inhibition. The infusion frequency is relatively low (6 infusions per 
year) (Figure 1), which offers the potential for improved quality of life (QoL) through fewer 
missed days of work or school, better treatment adherence, and improved accessibility. 


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Figure 1: 
Ravulizumab Every 8 Weeks Dosage Regimen Versus Eculizumab Every 
2 Weeks Dosage Regimen 
 
 
Ravulizumab offers a convenient dosing and immediate onset of action with effective and 
complete terminal complement inhibition at the end of the first infusion. Additionally, the dose 
regimen of ravulizumab has been optimized to reduce the exposure differences across the adult 
body-weight range by utilizing a weight-based dosing paradigm that provides immediate, 
complete, and sustained C5 inhibition over the entire dosing interval. Therefore, ravulizumab 
minimizes the risk of inflammation, including C5a recruitment and activation of inflammatory 
cells as well as direct MAC-complex induced damage of the motor neural endplate (Kusner, 
2008).  
The proposed rationale for the ravulizumab posology for the gMG indication is highly consistent 
with the approach used in dose-selection for eculizumab in the aHUS and gMG indications. 
2.4. 
Benefit/Risk Assessment 
Ravulizumab provides patients and physicians with an option for less frequent dosing, which 
allows greater access to care for those patients who may not initiate treatment on eculizumab, 
may discontinue eculizumab due to frequency of dosing, or who are currently receiving 
eculizumab every 2 weeks. 
2.4.1. 
Identified and Potential Risks 
2.4.1.1. 
Identified Risk 
2.4.1.1.1. Neisseria meningitidis 
Increased susceptibility to infection caused by Neisseria meningitidis (N meningitidis) is a 
known risk associated with complement inhibition. The main risk associated with ravulizumab is 
the risk of meningococcal infections. Specific risk mitigation measures are in place to address 
this risk, as described in Section 8.3.6. 
2.4.1.2. 
Potential Risks 
2.4.1.2.1. Immunogenicity 
Administration of any therapeutic protein, including ravulizumab, may induce an immunogenic 
response potentially resulting in antidrug antibodies (ADA). The spectrum of potential clinical 


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consequences may include severe hypersensitivity-type reactions and decrease in efficacy (PK 
and/or PD neutralization) due to development of neutralizing ADA (Casadevall, 2002; Li, 2001).  
Of the 261 patients with PNH who were treated with ravulizumab in the ravulizumab IV clinical 
studies, 1 patient developed a treatment-emergent ADA. Treatment-emergent ADAs have been 
observed in 3 healthy subjects treated with ravulizumab subcutaneous (SC) and 1 healthy subject 
treated with ravulizumab IV in Study ALXN1210-HV-104. All ADA positive titer values were 
low and negative for eculizumab cross-reactivity. There was no apparent impact of 
immunogenicity on the PK or PD of ravulizumab. More information about the immunogenicity 
of ravulizumab may be found in the current edition of the Investigator’s Brochure (IB). 
Monitoring of immunogenicity for this study will be conducted as described in Section 1.3 and 
Section 8.2.4.3. 
2.4.1.2.2. Local and Systemic Reactions 
Protein therapies administered IV have the potential risk of causing local (infusion-site reactions) 
and systemic reactions (infusion-associated reactions). Infusion-site reactions are those localized 
to the site of IV drug administration and may include reactions such as erythema, pruritus, and 
bruising. Infusion-associated reactions are those which are systemic in nature and which may be 
immune or nonimmune-mediated, generally occurring within hours of drug administration. 
Immune-mediated reactions may include allergic reactions (eg, anaphylaxis), while 
nonimmune-mediated reactions are nonspecific (eg, headache, dizziness, nausea). Monitoring for 
these reactions will be conducted as part of routine safety assessments for this study 
(Section 8.3.7). 
2.4.1.2.3. Pregnancy Exposure 
No studies of ravulizumab have been conducted in pregnant women. Pregnant or nursing patients 
will be excluded from the clinical study. Patients enrolled in the study, and their 
spouses/partners, will use a highly effective or acceptable method of contraception as required in 
Section 10.4 (Appendix 4). In the event of a pregnancy, the patient will be discontinued from 
study drug (Section 7). 
More detailed information about the known and expected benefits and risks and reasonably 
expected adverse events of ravulizumab may be found in the IB. 


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3. 
OBJECTIVES AND ENDPOINTS 
Objectives 
Endpoints 
Primary 
To assess the efficacy of ravulizumab compared with 
placebo in the treatment of gMG based on the 
improvement in the Myasthenia Gravis-Activities of 
Daily Living (MG-ADL) profile.  
Change from Baseline in MG-ADL total score at 
Week 26 of the Randomized-Controlled Period. 
Secondary 
• 
To assess the efficacy of ravulizumab compared 
with placebo in the treatment of gMG based on 
the improvement in the Quantitative Myasthenia 
Gravis (QMG) total score. 
• 
Change from Baseline in QMG total score at 
Week 26. 
• 
To assess the efficacy of ravulizumab compared 
with placebo in the treatment of gMG based on 
the improvement in quality of life measures. 
• 
Change from Baseline in the Revised 
15-Component Myasthenia Gravis Quality of Life 
(MG-QOL15r) score at Week 26. 
• 
Change from Baseline in Neuro-QOL Fatigue 
score at Week 26. 
• 
To assess the efficacy of ravulizumab compared 
with placebo in the treatment of gMG based on 
other efficacy endpoints. 
• 
Improvement of at least 3 points in the MG-ADL 
total score from Baseline at Week 26. 
• 
Improvement of at least 5 points in the QMG total 
score from Baseline at Week 26. 
Exploratory 
• 
To assess the efficacy of ravulizumab in the 
treatment of gMG based on other efficacy 
endpoints throughout the study. 
• 
Change from Baseline in the Myasthenia Gravis 
Composite (MGC) score at Week 26. 
• 
Myasthenia Gravis Foundation of America 
(MGFA) Post-Intervention Status (PIS) at 
Week 26. 
• 
Change from Baseline in Euro Quality of Life 
(EQ-5D-5L) at Week 26. 
• 
Change from baseline in MG-ADL subcomponent 
scores (bulbar, limbs, respiratory, and ocular) at 
Week 26. 
• 
Change from baseline in QMG subcomponent 
scores (bulbar, limbs, respiratory, and ocular) at 
Week 26. 
• 
Incidence of hospitalizations/MG-related 
hospitalizations. 
• 
Incidence of Clinical Deterioration/MG crisis. 
PK/PD/Immunogenicity 
 
• 
To evaluate the PK/PD and immunogenicity of 
ravulizumab in the treatment of gMG throughout 
the study. 
• 
Change in serum ravulizumab concentration over 
time. 
• 
Change in serum free C5 concentration over time. 
• 
Incidence of treatment-emergent antidrug 
antibodies over time. 
Safety 
 
To characterize the overall safety of ravulizumab in 
the treatment of gMG. 
• 
Incidence of adverse events and serious adverse 
events over time. 
• 
Changes from Baseline in vital signs and 
laboratory assessments. 
The above endpoints will be evaluated over time throughout the study. 


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4. 
STUDY DESIGN 
4.1. 
Overall Design 
This is a Phase 3, randomized, double-blind, parallel-group, placebo-controlled, multicenter 
study to evaluate the safety and efficacy of ravulizumab for the treatment in patients with gMG. 
Approximately 160 eligible patients will be stratified by region (North America, Europe, 
Asia-Pacific, and Japan) and randomized 1:1 to 1 of 2 treatment groups: (1) ravulizumab 
infusion or (2) placebo infusion. There will be 3 periods in this study: Screening Period, 
Randomized-Controlled Period, and an Open-Label Extension (OLE) Period. 
After the 26-Week Randomized-Controlled Period and assessments on Day 183 (Week 26), 
patients in the placebo group will receive a blinded loading dose of ravulizumab and patients in 
the ravulizumab group will receive a blinded ravulizumab dose of 900 mg. Starting Week 28, all 
patients will begin open-label ravulizumab maintenance doses q8w. For patients in the 
ravulizumab group, a blinded ravulizumab dose of 900 mg was chosen to ensure maintenance of 
complete C5 inhibition until the next scheduled maintenance dose at Week 28 (Day 197). 
Eight weeks after the final dose of study drug is administered, all enrolled patients will return for 
an End of Study (EOS) Visit (Visit 25) at Week 132 during which final study assessments will 
be conducted. If a patient withdraws from the study, or completes the study early (prior to 
Visit 24; Week 124), the patient will be encouraged to return for an Early Termination (ET)/EOS 
Visit, 8 weeks after the day the last dose of study drug was administered, during which final 
planned safety assessments will be conducted (see Section 4.5 for further details regarding end of 
study and study completion). Attempts should be made to follow all patients for safety for 
8 weeks from the day the last dose of study drug is administered.  
Patients who are being treated with an immunosuppressive therapy (IST) at the time of the 
Screening Visit may continue taking their baseline ISTs throughout the Randomized-Controlled 
and OLE Periods. However, the dosage of IST must not be changed and no new ISTs may be 
added or discontinued during the Randomized-Controlled Period of the study, unless deemed by 
the Investigator to be medically necessary.  
Throughout the study, rescue therapy (eg, high-dose corticosteroid, plasmapheresis (PP)/plasma 
exchange (PE), or intravenous immunoglobulin [IVIg]) will be allowed if a patient experiences 
Clinical Deterioration as defined in this protocol (Section 4.2.1). The rescue therapy used for a 
particular patient will be at the discretion of the Investigator.  
The primary endpoint for this study will be measured at Week 26 (Day 183), irrespective of 
rescue therapy.  
Including the 8-week safety follow-up, which begins after the last dose of study drug is 
administered, the overall study duration for an individual patient is estimated to take up to 
132 weeks (from enrollment through the end of the Safety Follow-up). The period of active 
patient-participation is estimated to take up to 132 weeks (from enrollment through the EOS 
Visit). Schedules of Activities (SOA) for the Randomized-Controlled Period and the OLE Period 
are provided in Table 1 and Table 2, respectively. 


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4.1.1. 
Screening Period (2 - 4 Weeks Prior to Day 1) 
At the screening visit, after obtaining informed consent, the patient will be screened for study 
eligibility through medical history review, demographic data, and laboratory assessments. The 
medical history review will include MG diagnosis date; initial MG clinical presentation (ocular 
MG [oMG] or gMG); time to gMG, if initial clinical presentation was oMG; maximum MGFA 
classification since diagnosis; ventilatory support since diagnosis; dates of MG exacerbation or 
crisis since diagnosis and prior to Day 1; and any MG-related hospitalizations in 2 years prior to 
screening. MG-specific medication or therapy (eg, thymectomy, ISTs including corticosteroids, 
IVIg, and PE/PP) within 2 years prior to screening will be recorded. 
If all inclusion criteria and none of the exclusion criteria are met, patients will be vaccinated 
against N meningitidis, if not already vaccinated within the 3 years prior to their enrollment in 
the study. Patients who initiate study drug treatment less than 2 weeks after receiving a 
meningococcal vaccine must receive treatment with appropriate prophylactic antibiotics until 
2 weeks after vaccination.  
If a patient experiences a Clinical Deterioration or MG Crisis during the Screening Period, the 
Sponsor must be notified.  
4.1.2. 
Randomization 
At the time of randomization, all patients will be reassessed for eligibility based on the study 
inclusion and exclusion criteria. All patients who are vaccinated, continue to meet all of the 
inclusion criteria and none of the exclusion criteria at Randomization [Day 1]), and have been 
cleared for randomization by the Investigator, will be randomized 1:1 to the ravulizumab group 
or the placebo group. Patients will be centrally randomized using interactive response technology 
(IRT). The randomization will be stratified by region (North America, Europe, Asia-Pacific, and 
Japan). 
4.1.3. 
Randomized Controlled Period (26 Weeks) 
Throughout the study, rescue therapy (eg, high-dose corticosteroid, PE/PP, or IVIg) will be 
allowed when a patient’s health would be in jeopardy if rescue therapy was not administered (eg, 
emergent situations), or if a patient experiences Clinical Deterioration as defined in this protocol. 
The rescue therapy used for a particular patient will be at the discretion of the Investigator.  
Patients must be informed of potential signs and symptoms of Clinical Deterioration or MG 
Crisis and instructed to contact the Investigator to be evaluated within 48 hours of notification of 
the Investigator of the symptom onset. At the evaluation visit, the Investigator or the 
Investigator’s designee will perform the assessments as specified by this protocol. The 
Investigator or designee will determine whether or not the patient meets the definition of Clinical 
Deterioration as defined by this protocol in Section 4.2.1 and treat the patient accordingly.  
The primary endpoint for this study will be measured at Week 26 (Day 183), irrespective of 
rescue therapy. 
See the SOA for further details regarding visit procedures throughout the study (Section 1.3). 


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4.1.4. 
Open-Label Extension Period 
After the 26-Week Randomized-Controlled Period and assessments on Day 183 (Week 26), 
patients in the placebo group will receive a blinded loading dose of ravulizumab and patients in 
the ravulizumab group will receive a blinded ravulizumab dose of 900 mg; the 900-mg dose was 
chosen to ensure maintenance of complete C5 inhibition until the next scheduled maintenance 
dose at Week 28 (Day 197). Starting at Week 28, all patients will begin open-label ravulizumab 
maintenance doses q8w.  
The OLE Period for each patient will commence when the patient receives a dose of ravulizumab 
on Week 26 (Day 183) and will continue for up to 2 years or until the product is registered or 
approved (in accordance with country-specific regulations), whichever occurs first. 
4.2. 
Standard Protocol Definitions 
4.2.1. 
Clinical Deterioration 
For this protocol, Clinical Deterioration is defined as any of the following: 
1. Patients who experience an MG Crisis, which is defined as weakness from MG that is severe 
enough to necessitate intubation or to delay extubation following surgery. The respiratory 
failure is due to weakness of respiratory muscles. Severe bulbar (oropharyngeal) muscle 
weakness often accompanies the respiratory muscle weakness, or may be the predominant 
feature in some patients; or, 
2. Significant symptomatic worsening to a score of 3 or a 2-point worsening from Baseline on 
any one of the individual MG-Activities of Daily Living (MG-ADL) items other than double 
vision or eyelid droop; or,  
3. Administration of rescue therapy to a patient whose, in the opinion of the Investigator or 
Investigator-designated physician, health would be in jeopardy, if rescue therapy were not 
given (eg, emergent situations). 
4.2.2. 
Unscheduled Visits 
Under exceptional circumstances, additional (unscheduled) visits outside the specified visits are 
permitted at the discretion of the Investigator. Procedures, tests, and assessments will be 
performed at the discretion of the Investigator and efforts will be made to map the corresponding 
data to the appropriate visit as described in the electronic case report form (eCRF) completion 
guidelines and training materials.  
4.2.3. 
Properly Trained Clinical Evaluator 
Properly Trained Clinical Evaluators are study staff that have been certified in administering the 
MG-ADL, QMG, and Myasthenia Gravis Composite (MGC) assessments. Only Properly 
Trained Clinical Evaluators may administer these assessments. A Properly Trained Clinical 
Evaluator may be a neurologist, physical therapist, or other study team member delegated by the 
Investigator. Only the Investigator or a neurologist may perform the manual muscle test (MMT), 
components of the MGC, the Myasthenia Gravis Foundation of America-Post-Interventional 
Status (MGFA-PIS), and Myasthenia Gravis Foundation of America (MGFA) Classification. 


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Clinical Evaluator training and certification for this protocol will take place either at the 
Investigator’s Meeting or via the Sponsor’s designated on-line training portal. 
4.2.4. 
Responsibilities for Myasthenia Gravis Assessments 
Responsibilities for MG assessments are listed in Table 3. Throughout the study, MG 
assessments should be performed at approximately the same time of day by a Properly Trained 
Clinical Evaluator, and preferably the same evaluator. The MG-ADL should always be 
performed first, followed by the QMG. 
Table 3: 
Myasthenia Gravis Assessments and Responsibilities 
Assessment 
Evaluator 
MG-ADL 
Properly Trained Clinical Evaluator 
QMG  
Properly Trained Clinical Evaluator  
MGC 
Properly Trained Clinical Evaluator 
MGC (MMT Components) 
Investigator or Neurologist 
MGFA-PIS (modified version) 
Investigator or Neurologist 
MGFA Classification 
Investigator or Neurologist 
Abbreviations: MG-ADL = Myasthenia Gravis Activities of Daily Living Profile; MGC = Myasthenia Gravis 
Composite scale; MGFA = Myasthenia Gravis Foundation of America; MGFA-PIS = Myasthenia Gravis 
Foundation of America Post-Intervention Status; MMT = manual muscle test; QMG = Quantitative Myasthenia 
Gravis score for disease severity. 
4.3. 
Scientific Rationale for Study Design 
Published data support the MG-ADL profile as an established, sensitive, and objective 
assessment of treatment response over time in patients with gMG (Howard, 2017). 
The safety parameters being evaluated are commonly used in clinical studies per International 
Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use 
(ICH) and Good Clinical Practice (GCP) guidance. 
Placebo was selected as the control and patients will be allowed to continue stable therapy with 
standard of care therapy (ie, ISTs) throughout the course of the study, which thereby allows for 
comparison of the safety and efficacy of ravulizumab when administered in addition to the 
patient’s standard of care treatment to current standard of care therapies in patients with gMG.  
Given the heterogeneity of the disease and fluctuation in the severity of symptoms, there is no 
1 international standard of care accepted, and targeted treatment with complement-inhibitor 
drugs, such as the recently introduced eculizumab, is not yet widely available to patients 
worldwide and is not yet considered standard of care for all patients with gMG. A 
placebo-controlled study allows for the evaluation of treatment effect and allows for a 
double-blind design; an important study condition to be maintained when considering endpoints 
that includes neurological scales, which are known to be especially prone to placebo effects. The 
placebo-controlled part of the study will be limited to 26 weeks, after which time all patients will 
transition to open-label treatment with ravulizumab for up to 2 years during the OLE Period. At 
all points throughout the study, physicians will be encouraged to prioritize patient safety, and if 
patients experience Clinical Deterioration, the full range of rescue therapies will be permitted. 


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4.4. 
Justification for Dose 
The ravulizumab dosage regimen for this study (Table 4) was approved for the treatment of adult 
patients with PNH based on comprehensive modelling and simulation analyses of Phase 1 and 2 
PK/PD data in healthy volunteers and PK/PD/efficacy (lactate dehydrogenase) and safety data in 
patients with PNH. This regimen is considered optimal for achieving immediate, complete, 
sustained inhibition of terminal complement activity within each dosing interval and for the 
entire treatment course in adult patients.  
Table 4: 
Ravulizumab Weight-Based Dosing 
Weight (kg) 
Loading Dose (mg) 
Maintenance Dose (mg) 
(administered q8w) 
≥ 40 to < 60 
2400 
3000 
≥ 60 to < 100 
2700 
3300 
≥ 100 
3000 
3600 
Abbreviation: q8w = every 8 weeks. 
Consistent with approved eculizumab labeling for treating adult and pediatric patients with 
aHUS and adult patients with gMG, supplemental dosing of ravulizumab in the amount of 50% 
(rounded up if not in integral of 300 mg due to vial configuration) will be given in the setting of 
concomitant PE/PP rescue therapy. For adult patients with gMG, supplemental dosing of 
ravulizumab (in the amount of 600 mg) will be given in the setting of concomitant IVIg rescue 
therapy. The 600 mg supplemental ravulizumab dose has been selected based on PK simulations 
considering the published data describing the impact of co-administration of IVIg on eculizumab 
PK/PD (Fitzpatrick, 2011) (see Table 7 and Table 8).  
Supplemental study drug (or placebo) dosing is required if PE/PP or IVIg rescue therapy is 
provided on non-dosing days; no supplemental study drug (or placebo) dosing is required if 
PE/PP or IVIg infusion is provided on a dosing day, but it must occur prior to study drug 
administration. If PE/PP or IVIg is administered on scheduled dosing visits, regular dosing will 
be started within 60 minutes after the completion of PE/PP or IVIg. If PE/PP or IVIg is 
administered on non-scheduled dosing visits, for patients receiving PE/PP: supplemental dose 
administration will be started within 4 hours after the PE/PP session is completed; for patients 
receiving IVIg: supplemental dose administration will be started within 4 hours after the last 
continuous session(s) of IVIg is completed (see Section 6.5.1.4). 
The favorable benefit/risk profiles of ravulizumab from the Phase 3 studies in patients with PNH 
have confirmed immediate (after the first dose or loading dose), complete (free C5 < 0.5 µg/mL) 
and sustained (throughout entire active treatment course) terminal complement inhibition under 
the above investigated dosage regimen. Based on the totality of PK, PD, ADA, efficacy, and 
safety data obtained from the ravulizumab development program, the above body weight-based 
dosage regimen for treating adult patients with PNH may also be beneficial in treating patients 
with gMG. 
After the 26-Week Randomized-Controlled Period and assessments on Day 183 (Week 26), 
patients in the placebo group will receive a blinded loading dose of ravulizumab and patients in 
the ravulizumab group will receive a blinded ravulizumab dose of 900 mg; the 900-mg dose was 
chosen to ensure maintenance of complete C5 inhibition until the next scheduled maintenance 


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dose at Week 28 (Day 197). Starting at Week 28 (Day 197), all patients will begin open-label 
ravulizumab maintenance doses q8w.  
The proposed q8w dosage regimen will facilitate studying a range of PK drug exposures useful 
in assessing ravulizumab exposure-response relationships in patients with gMG. Safety and 
tolerability of ravulizumab have been established over a wide range of PK exposures, including 
those expected under the proposed gMG dosage regimens, in healthy volunteers and patients. 
4.5. 
End of Study Definition 
A patient is considered to have completed the study if: 
• The patient has completed all periods of the study including the last visit of the OLE 
Period, or  
• In the event the study is completed early, the patient has completed all applicable 
periods of the study including the EOS visit 
• The patient completes the study early (and completes the EOS Visit) because the 
study drug has become registered or approved (in accordance with country-specific 
regulations) 
Measurement of the primary endpoints will be complete after the last visit of the last patient in 
the Randomized-Controlled Period. The EOS is defined as the date of the last visit of the last 
patient in the study or last scheduled procedure shown in the SoA (Section 1.3) for the last 
patient in the study globally. The study completion date corresponds to the last visit when the 
final patient in the study is examined or received an intervention for the primary or secondary 
endpoints and AEs.  


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5. 
STUDY POPULATION 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers are not allowed. 
5.1. 
Inclusion Criteria 
Patients are eligible to be included in the study only if all of the following criteria apply: 
Age 
1. Male and female patients must be aged ≥ 18 years of age at the time of signing the 
informed consent 
Type of Patient and Disease Characteristics 
2. Diagnosed with MG at least 6 months (180 days) prior to the date of the Screening Visit 
3. Confirmation of eligibility by: 
a. Positive serologic test for anti-AChR Abs as confirmed at screening, and 
b. One of the following (either historical or during screening): 
• 
Abnormal neuromuscular transmission test demonstrated by single-fiber 
electromyography or repetitive nerve stimulation 
• 
Positive anticholinesterase test (eg, edrophonium chloride test) 
• 
Demonstrated improvement in MG signs on oral cholinesterase inhibitors, as 
assessed by the treating physician 
4. Myasthenia Gravis Foundation of America Clinical Classification Class II to IV at 
screening 
5. MG-ADL profile must be ≥ 6 at screening and randomization (Day 1) 
6. Patients receiving treatment with any of the following must have been receiving 
treatment and on a stable dose for the time periods specified below prior to the date of the 
Screening Visit: 
• Azathioprine (AZA): Must have been on AZA for ≥ 6 months (180 days) and 
have been on a stable dose for ≥ 2 months (60 days)  
• Immunosuppressive therapies (ie, mycophenolate mofetil [MMF], methotrexate 
[MTX], cyclosporine [CYC], tacrolimus [TAC], or cyclophosphamide [CY]), 
must have been on the IST for ≥ 3 months (90 days) and have been on a stable 
dose for ≥ 1 month (30 days) 
• Oral corticosteroids, must have been on a stable dose for ≥ 4 weeks (28 days)  
• A cholinesterase inhibitor, at the time of the Screening Visit, must have been on 
a stable dose for ≥ 2 weeks (14 days)  
7. To reduce the risk of meningococcal infection (N meningitidis), all patients must be 
vaccinated against meningococcal infections within the 3 years prior to, or at the time of, 
initiating study drug. Patients who initiate study drug treatment less than 2 weeks after 


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receiving a meningococcal vaccine must receive treatment with appropriate prophylactic 
antibiotics until 2 weeks after vaccination 
Weight 
8. Body weight ≥ 40 kg at the time of screening 
Pregnancy and Contraception 
9. Patients of childbearing potential and patients with partners of childbearing potential must 
follow protocol-specified contraception guidance (Section 10.4, Appendix 4) for avoiding 
pregnancy while on treatment and for 8 months after last dose of study drug 
Informed Consent 
10. Capable of giving signed informed consent as described in Section 10.1, Appendix 1, 
which includes compliance with the requirements and restrictions listed in the informed 
consent form (ICF) and in this protocol 
5.2. 
Exclusion Criteria  
Patients are excluded from the study if any of the following criteria apply: 
Medical Conditions 
1. Any active or untreated thymoma or history of thymic carcinoma or thymic malignancy  
Note: Treated patients with history thymoma other than thymic carcinoma corresponding 
to clinical stage 1 and 2 with no evidence of recurrence as defined by a recent negative 
imaging study (CT scan with IV contrast or MRI scan within 6 months of randomization) 
are eligible for enrollment. 
2. History of thymectomy, thymomectomy, or any thymic surgery within the 12 months 
prior to screening 
3. History of hypersensitivity to any ingredient contained in the study drug, including 
hypersensitivity to murine proteins 
4.  History of N meningitidis infection 
5. Human immunodeficiency virus (HIV) infection (evidenced by HIV-1 or HIV-2 antibody 
titer) 
6. Known medical or psychological condition(s) or risk factor that, in the opinion of the 
Investigator, might interfere with the patient’s full participation in the study, pose any 
additional risk for the patient, or confound the assessment of the patient or outcome of the 
study 
7. History of hospitalization for ≥ 24 hours, for any reason, within the 4 weeks (28 days) 
prior to screening 
8. Clinical features that, in the opinion of the Investigator, consistent with MG 
crisis/exacerbation or Clinical Deterioration, at the time of the Screening Visit or at any 
time prior to randomization 
9. Female patients who plan to become pregnant or are currently pregnant or breastfeeding 


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10.  Female patients who have a positive pregnancy test result at screening or on Day 1 
Prior/Concomitant Therapy 
11. Use of the following within the time period specified below: 
• 
IVIg within the 4 weeks (28 days) prior to randomization (Day 1) 
• 
Use of PE within the 4 weeks (28 days) prior to randomization (Day 1) 
• 
Use of rituximab within the 6 months (180 days) prior to screening 
12. Patients who have received previous treatment with complement-inhibitors 
(eg, eculizumab) 
Prior/Concurrent Clinical Study Experience 
13. Participation in another interventional treatment study or use of any experimental therapy 
within 30 days before initiation of study drug on Day 1 in this study or within 5 half-lives 
of the study drug, whichever is greater 
Additional Medical Conditions 
14. History of unexplained infections 
15. Active systemic bacterial, viral, or fungal infection within 14 days prior to study drug 
administration on Day 1 
16. Presence of fever ≥ 38°C (100.4°F) within 7 days prior to study drug administration on 
Day 1 
5.3. 
Lifestyle Considerations 
No restrictions are required in this study. 
5.4. 
Screen Failures 
Screen failures are defined as patients who consent to participate in the clinical study but are not 
subsequently randomized to a treatment group. A minimal set of screen failure information is 
required to ensure transparent reporting of screen failure patients to meet the Consolidated 
Standards of Reporting Trials publishing requirements and to respond to queries from regulatory 
authorities. Minimal information includes demography, screen failure details, eligibility criteria, 
and any serious adverse event (SAE). 
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened once based on discussion and agreement between the Investigator and the Medical 
Monitor. 
A patient who experiences a gMG Clinical Deterioration or exacerbation/crisis during the 
Screening Period will be considered a screening failure. Such patients may be rescreened with 
Sponsor approval once they are treated and medically stable, in the opinion of the Investigator. 
At least 28 days of clinical stability must exist prior to enrollment. The patient must meet all of 
the inclusion criteria and none of the exclusion criteria at the time of rescreening in order to enter 
the study. 


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6. 
STUDY DRUG 
6.1. 
Study Drugs Administered 
Ravulizumab is formulated at pH 7.0 and is supplied in 30 mL single-use vials. Each vial of 
ravulizumab contains 300 mg of ravulizumab (10 mg/mL) in 10 mM sodium phosphate, 150 mM 
sodium chloride, 0.02% polysorbate 80, and water for injection. The comparator product is 
formulated as a matching sterile, clear, colorless solution with the same buffer components, but 
without active ingredient. Additional details are presented in Table 5.  
Table 5: 
Study Drug Administered 
Product Name 
Ravulizumab  
Placebo 
Dosage Form 
Concentrated sterile, preservative-free 
aqueous solution (10 mg/mL) in 
single-use 30 mL vials 
Sterile, preservative-free aqueous 
solution in single-use 30 mL vials 
Route of Administration 
Intravenous infusion 
Intravenous infusion 
Dosing Instructions 
Refer to pharmacy manual for dosing 
instructions 
Refer to pharmacy manual for dosing 
instructions 
Packaging and Labeling 
Glass vials and stoppered with a butyl 
rubber stopper with an aluminum 
overseal and a flip-off cap. Study drug 
will be supplied in kits.  
Glass vials and stoppered with a butyl 
rubber stopper with an aluminum 
overseal and a flip-off cap. Study drug 
will be supplied in kits.  
Physical Description 
Liquid solution practically free from 
particles 
Liquid solution practically free from 
particles  
Manufacturer 
Alexion Pharmaceuticals, Inc. or 
Contracted Manufacturing 
Organization 
Alexion Pharmaceuticals, Inc. or 
Contracted Manufacturing 
Organization 
Source: product specifications 
Study drug will be administered as indicated in Table 6.  
During the Randomized-Controlled Period, patients in the ravulizumab or placebo treatment 
groups will receive a weight-based loading dose of ravulizumab or placebo, respectively, on 
Day 1 (Visit 2). At Visit 4 (Week 2), patients in the ravulizumab or placebo treatment groups 
will receive weight-based maintenance doses or ravulizumab or placebo, respectively, q8w 
through the completion of the Randomized-Controlled Period. After the completion of the 
Randomized-Controlled Period, patients will enter the OLE Period.  
After the 26-Week Randomized-Controlled Period and assessments on Day 183 (Week 26), 
patients in the placebo group will receive a blinded loading dose of ravulizumab and patients in 
the ravulizumab group will receive a blinded ravulizumab dose of 900 mg; the 900-mg dose was 
chosen to ensure maintenance of complete C5 inhibition until the next scheduled maintenance 
dose at Week 28 (Day 197). Starting at Week 28, all patients will begin open-label ravulizumab 
maintenance doses q8w.  


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Table 6: 
Reference Chart for Weight-Based Dosing 
Study Period 
Ravulizumab or Placebo 
Dosing 
Body Weight 
(kg)1 
Ravulizumab 
Dose  
(mg) 
Ravulizumab 
Volume (mL) 
Placebo 
Volume 
(mL) 
Diluent (0.9% 
Sodium 
Chloride) 
Volume 
(mL) 
Total 
Volume  
(mL) 
Ravulizumab Group 
 
Randomized-Controlled 
Loading dose 
(Day 1) 
 
≥ 40 to < 60 
2400 
240 
0 
240 
480 
≥ 60 to < 100 
2700 
270 
0 
270 
540 
≥ 100 
3000 
300 
0 
300 
600 
Maintenance dose 
(Days 15, 71, 127) 
 
≥ 40 to < 60 
3000 
300 
0 
300 
600 
≥ 60 to < 100 
3300 
330 
0 
330 
660 
≥ 100 
3600 
360 
0 
360 
720 
Open-Label Extension 
Blinded dose2 
(Day 183) 
≥ 40 to < 60 
900 
90 
150 
240 
480 
≥ 60 to < 100 
900 
90 
180 
270 
540 
≥ 100 
900 
90 
210 
300 
600 
Open-label maintenance dose 
(Days 197 to 869 q8w) 
≥ 40 to < 60 
3000 
300 
0 
300 
600 
≥ 60 to < 100 
3300 
330 
0 
330 
660 
≥ 100 
3600 
360 
0 
360 
720 
Placebo Group 
 
Randomized-Controlled 
Loading dose 
(Day 1) 
 
≥ 40 to < 60 
0 
0 
240 
240 
480 
≥ 60 to < 100 
0 
0 
270 
270 
540 
≥ 100 
0 
0 
300 
300 
600 
Maintenance dose 
(Days 15, 71, 127) 
 
≥ 40 to < 60 
0 
0 
300 
300 
600 
≥ 60 to < 100 
0 
0 
330 
330 
660 
≥ 100 
0 
0 
360 
360 
720 
Open-Label Extension 
Blinded loading dose3 
(Day 183) 
≥ 40 to < 60 
2400 
240 
0 
240 
480 
≥ 60 to < 100 
2700 
270 
0 
270 
540 
≥ 100 
3000 
300 
0 
300 
600 
Open-label maintenance dose 
(Days 197 to 869, q8w) 
≥ 40 to < 60 
3000 
300 
0 
300 
600 
≥ 60 to < 100 
3300 
330 
0 
330 
660 
≥ 100 
3600 
360 
0 
360 
720 
1 Dose regimen will be based on the patient’s most recently recorded body weight from a previous study/screening visit. Contact the Alexion medical monitor if a 
patient’s weight drops below 40 kg during the treatment period. 
2 Blinded dose on Day 183 (Week 26) for patients who were randomized to the ravulizumab group and are entering into the Open-Label Extension Period. 
3 Blinded loading dose on Day 183 (Week 26) for patients who were randomized to the placebo group and are entering into the Open-Label Extension Period. 


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6.2. 
Preparation/Handling/Storage/Accountability 
Study drug will be released to the site upon receipt of all required essential documents based 
upon federal, state, and local regulations.  
Only patients enrolled in the study may receive study drug and only authorized site staff may 
supply or administer study drug. All study drug must be stored in a secure, environmentally 
controlled, and monitored (manual or automated) area in accordance with the labeled storage 
conditions with access limited to the Investigator and authorized site staff. 
The Investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance (ie, 
receipt, reconciliation, and final disposition records). 
6.2.1. 
Study Drug Preparation  
Study drug will be prepared and administered by a trained member of the site study team. Study 
drug is to be administered only to enrolled patients who are confirmed eligible for participation.  
Preparation of ravulizumab and placebo doses must be performed in accordance with study 
center-specific local standards by qualified and study-trained pharmacy personnel. 
The handling and preparation of materials used to prepare and administer the study drug must be 
carried out using aseptic techniques for sterile products.  
All study patients, investigative-site personnel, Sponsor staff, Sponsor designees, and all staff 
directly associated with the conduct of the study will be blinded to patient treatment assignments. 
Further details on preparation and dose administration of study drug, as well as disposal of study 
drug, can be found in the pharmacy manual.  
6.2.2. 
Storage 
The Investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study drugs received and that any discrepancies are reported and 
resolved before use of the study drug. 
Upon arrival at the investigative site, the study drug should be promptly removed from the 
shipping cooler and stored in refrigerated conditions at 2°C to 8°C (36°F to 46°F). The 
pharmacist should immediately record the receipt of the study drug and notify the distributor if 
vials are damaged and/or if temperature excursions have occurred during transportation. Study 
drug must be stored in a secure, limited-access storage area and temperature must be monitored 
daily.  
Diluted solutions of study drug may be stored at 2°C to 8°C (36°F to 46°F) for up to 24 hours 
prior to administration. The solution should be allowed to warm to room temperature prior to 
administration.  
The admixed drug product should be at room temperature prior to administration. The material 
must not be heated (eg, by using a microwave or other heat source) other than by ambient air 
temperature. 


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Please consult the pharmacy manual for further information regarding the storage conditions of 
reconstituted ravulizumab. 
6.2.3. 
Packaging and Labeling 
The primary packaging of ravulizumab consists of a 30-mL vial (Type I borosilicate glass) with 
a stopper and a seal. The secondary packaging consists of a single vial carton. Both primary 
(vial) and secondary (carton) packaging include a booklet label with relevant information. 
Additional details are presented in Table 5 and in the Pharmacy Manual. The placebo will have 
an identical appearance to that of ravulizumab.  
6.2.4. 
Accountability 
When a drug shipment is received at the site, the pharmacist should verify the contents, sign the 
packing invoice provided with the shipment, and maintain the original copy for review by the 
site monitor in the pharmacy binder. Additionally, study drug receipt (as well as condition of the 
study drug at the time of receipt) must be reported to the IRT system to allow drug 
randomization, resupply, estimations, and drug expiration control. 
Unless notified otherwise, empty vials and vials with residual materials should be kept for 
inspection and accountability by the study monitor prior to their destruction or handled per local 
pharmacy standard operating procedures for clinical study drugs. Destruction of used and unused 
vials, either locally or centrally, must be properly documented. Drug accountability will be 
managed through the IRT system and detailed instructions on managing the IRT drug 
accountability module will be included in the IRT User Guide. The IRT module will perform 
accountability in two stages, where site personnel will complete an initial accountability entry in 
the system followed by confirmation by the Study Monitor that the site has correctly entered the 
appropriate status for all study drug. The pharmacist or designee must maintain accurate records 
demonstrating dates and amount of study drug received, to whom dispensed (patient-by-patient 
accounting), and accounts of any study drug accidentally or deliberately destroyed. These drug 
accountability records must be readily available upon request, and will be reviewed throughout 
the study. 
Each kit will have a label and a place for the pharmacist to record the patient number and initials.  
The study monitor will examine the inventory during the study. Additionally, the inventory 
records must be readily available to regulatory authorities, the local regulatory agency, or an 
independent auditor’s inspection at any time. 
Refer to the Pharmacy Manual for additional information. 
6.2.5. 
Handling and Disposal 
 All clinical study material provided to the Investigator will be stored in a secure place, and 
allocated and dispensed by appropriately trained personnel. Detailed records of the amounts of 
the study drug received, dispensed, and destroyed will be maintained. 
To satisfy regulatory requirements regarding drug accountability, all remaining ravulizumab 
inventory will be reconciled and destroyed or returned to Alexion at the end of the study 
according to applicable regulations. 


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Refer to the Pharmacy Manual for further information. 
6.3. 
Measures to Minimize Bias: Randomization and Blinding 
6.3.1. 
Randomization 
Patients will be randomized on Day 1 after the Investigator has verified that they are eligible. 
Patients will be stratified by region (North America, Europe, Asia-Pacific, and Japan) and 
randomized 1:1 either to ravulizumab IV infusion or to placebo IV infusion. Patients will be 
centrally randomized using IRT. 
6.3.2. 
Blinding 
All investigative site personnel, Sponsor staff, Sponsor designees, staff directly associated with 
the conduct of the study, and all patients will be blinded to patient treatment assignments. The 
double-blind will be maintained by using identical study drug kits and labels for ravulizumab and 
placebo. The placebo will have an identical appearance to that of ravulizumab. The 
randomization code will be maintained by the IRT provider. After the 26-Week Randomized-
Controlled Period and assessments on Day 183 (Week 26), patients in the placebo group will 
receive a blinded loading dose of ravulizumab and patients in the ravulizumab group will receive 
a blinded ravulizumab dose of 900 mg. Starting at Week 28, all patients will begin open-label 
ravulizumab maintenance doses q8w. For patients in the ravulizumab group, a blinded 
ravulizumab dose of 900 mg was chosen to ensure maintenance of complete C5 inhibition until 
the next scheduled maintenance dose at Week 28 (Day 197). 
Unblinding should only be considered for the safety of the patient. If unblinding is deemed 
necessary by the Investigator, the Investigator should make a reasonable attempt to contact the 
Sponsor to discuss possible unblinding. After a reasonable attempt has been made, the 
Investigator can unblind the patient’s treatment allocation using an IRT. The Investigator must 
note the date, time, and reason for unblinding. The Investigator should also inform the Medical 
Monitor that the patient was unblinded; however, they should not reveal to the Medical Monitor 
the patients’ treatment allocation.  
When an adverse event (AE) is an unexpected or related and serious, the blind will be broken for 
that specific patient only. The blind will be maintained for persons responsible for the ongoing 
conduct of the study (such as the management, monitors, Investigators, etc.) and those 
responsible for data analysis and interpretation of results, such as biometrics personnel.  
Unblinded information will only be accessible to those who need to be involved in the safety 
reporting to Health Authorities, Independent Ethics Committees (IECs), and/or Institutional 
Review Boards (IRBs). 
Any patient who is unblinded during the Randomized-Controlled Period will be discontinued 
from the study. 
Investigators will receive only blinded information unless unblinded information is judged 
necessary for safety reasons. 


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6.4. 
Concomitant Therapy 
Prior medications (including vitamins and herbal preparations), including those discussed in the 
exclusion criteria (Section 5.2) and procedures (any therapeutic intervention, such as 
surgery/biopsy or physical therapy) the patient takes or undergoes within 28 days prior to the 
start of screening until the first dose of study drug, will be recorded in the patient’s eCRF. In 
addition, history of meningococcal vaccination must be collected for the 3 years prior to first 
dose of study drug. MG-specific medication or therapy (eg, thymectomy, ISTs including 
corticosteroids, IVIg, and PE/PP) within 2 years prior to screening will be recorded. 
All medication use and procedures undertaken during the study will be recorded in the patient’s 
source document/medical chart and eCRF. This record will include all prescription drugs, herbal 
products, vitamins, minerals, over-the-counter medications, and any other current medications. 
Concomitant medications will be recorded from the first infusion of study drug through 8 weeks 
after the patient’s last dose of study drug. Any changes in concomitant medications also will be 
recorded in the patient’s source document/medical chart and eCRF. Any concomitant medication 
deemed necessary for the patient’s standard of care during the study, or for the treatment of any 
AE, along with any other medications, other than those listed as prohibited medications in 
Section 6.5.1.5 may be given at the discretion of the Investigator. However, it is the 
responsibility of the Investigator to ensure that details regarding all medications are recorded in 
full in the patient’s source document/medical chart and eCRF. 
6.5. 
Study Drug Compliance 
Study drug will be administered in a controlled setting under the supervision of the Investigator 
or designee, thereby ensuring compliance with study drug administration. 
6.5.1. 
Allowed Medications 
6.5.1.1. 
Palliative and Supportive Care 
Palliative and supportive care is permitted during the course of the study for underlying 
conditions.  
The medications described in the following sections are allowed under certain circumstances and 
restrictions. 
6.5.1.2. 
Cholinesterase Inhibitors 
For patients who enter the study receiving a cholinesterase inhibitor at screening, the dose and 
schedule of their cholinesterase inhibitor should be maintained stable throughout the entire 
Randomized-Controlled and OLE Periods, unless there is compelling medical need. Increases in 
cholinesterase therapy that are required as a result of intercurrent illness or other medical cause 
of deterioration are permitted, but dosing should be returned to dosing levels at study entry as 
soon as feasible and the Sponsor should be notified of the change.  
1. Cholinesterase inhibitor treatment must be withheld for at least 10 hours prior to 
administration of the QMG and MGC tests.  
2. If a decrease in cholinesterase inhibitor is considered based on clinical evaluation, 
Sponsor approval must be obtained prior to the change in dose.  


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6.5.1.3. 
Immunosuppressive Agents 
The following immunosuppressive agents are allowed during the study: corticosteroid, AZA, 
MMF, MTX, TAC, CYC, or CY. The immunosuppressive agent(s) and its appropriate dose level 
to be used for an individual patient will be at the discretion of the treating physician/Investigator. 
1. Corticosteroid: for patients who enter the study receiving oral corticosteroid, eg, 
prednisone, the dose/schedule may not be changed during the entire double-blind study 
period (ie, the Randomized-Controlled Period). If a decrease or taper in steroid dose is 
considered during the Randomized-Controlled Period based on clinical evaluation, 
Sponsor approval must be obtained prior to the change in order for the patient to remain 
on study. If the dose level subsequently must be increased, the dose level increase cannot 
be above the dose level reported at the baseline (at the start of randomized treatment).  
2. High-dose steroid should be reserved for patients that experience Clinical Deterioration 
as defined by this protocol. Every effort should be made to notify the Sponsor within 
24 hours of administration should a patient require rescue therapy for Clinical 
Deterioration.  
3. AZA, MMF, MTX, TAC, CYC, or CY: for patients who enter the study receiving above 
mentioned immunosuppressive agents, the dosing regimen of the immunosuppressive 
agent may not be changed during the entire Randomized-Controlled Period. If a change 
in the dosing regimen is considered due to known toxicity or side effects associated with 
the given immunosuppressive agent, Sponsor approval must be obtained prior to the dose 
change. A different immunosuppressive agent cannot be added or substituted during the 
26-week Randomized-Controlled Period. 
6.5.1.4. 
Plasma Exchange/Plasmapheresis/Intravenous Immunoglobulin 
Use of PE/PP or IVIg (acute use only) will be allowed for patients who experience a Clinical 
Deterioration as defined by this protocol. The rescue therapy used for a particular patient will be 
at the discretion of the Investigator. Every effort should be made to notify the Sponsor within 
24 hours should a patient require rescue therapy.  
Supplemental study drug (or placebo) dosing is required if PE/PP or IVIg rescue therapy is 
provided on nondosing days; if PE/PP or IVIg infusion is provided on a dosing day, it must occur 
prior to study drug administration.  
1. If PE/PP or IVIg is administered on nonscheduled dosing visits: 
a. Patients receiving PE/PP: supplemental dose administration will be started within 
4 hours after the PE/PP session is completed (Table 7) 
b. Patients receiving IVIg: supplemental dose administration will be started within 
4 hours after the last continuous session(s) of IVIg is completed (Table 8) 
2. If PE/PP or IVIg is administered on scheduled dosing visits: 
a. Regular dosing will be started within 4 hours after the completion of PE/PP or IVIg 
3. No gap is required between a supplemental dose and the regular scheduled dose. 


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Table 7: 
Supplemental Dose When Plasmapheresis/Plasma Exchange is Administered as Rescue Therapy on 
Nonscheduled Dosing Visits 
Study Period 
Previous 
Ravulizumab or 
Placebo Scheduled 
Dosing Visit 
Next Applicable 
Supplemental 
Dosing Day 
Range 
Body Weight 
Used for Most 
Recent 
Scheduled 
Dose (kg)1 
Ravulizumab 
Dose  
(mg) 
Volume (mL) 
Ravulizumab 
Placebo 
Diluent 
(0.9% 
sodium 
chloride) 
Total 
Ravulizumab Group 
Randomized-
Controlled 
Loading dose 
(Day 1) 
 
Days 2 to 14 
≥ 40 to < 60 
1200 
120 
0 
120 
240 
≥ 60 to < 100 
1500 
150 
0 
150 
300 
≥ 100 
1500 
150 
0 
150 
300 
Maintenance dose 
(Days 15, 71, 127) 
 
Days 16 to 70, 
Days 72 to 126, 
Days 128 to 182 
≥ 40 to < 60 
1500 
150 
0 
150 
300 
≥ 60 to < 100 
1800 
180 
0 
180 
360 
≥ 100 
1800 
180 
0 
180 
360 
Open-Label 
Extension 
Blinded dose2 
(Day 183) 
Days 184 to 196 
≥ 40 to < 60 
600 
60 
60 
120 
240 
≥ 60 to < 100 
600 
60 
90 
150 
300 
≥ 100 
600 
60 
90 
150 
300 
Open-label 
maintenance dose 
(Days 197 to 869 q8w) 
On intervals 
between 
scheduled visits 
≥ 40 to < 60 
1500 
150 
0 
150 
300 
≥ 60 to < 100 
1800 
180 
0 
180 
360 
≥ 100 
1800 
180 
0 
180 
360 
Placebo Group 
Randomized-
Controlled 
Loading dose 
(Day 1) 
 
Days 2 to 14 
≥ 40 to < 60 
0 
0 
120 
120 
240 
≥ 60 to < 100 
0 
0 
150 
150 
300 
≥ 100 
0 
0 
150 
150 
300 
Maintenance dose 
(Days 15, 71, 127) 
 
Days 16 to 70, 
Days 72 to 126, 
Days 128 to 182 
≥ 40 to < 60 
0 
0 
150 
150 
300 
≥ 60 to < 100 
0 
0 
180 
180 
360 
≥ 100 
0 
0 
180 
180 
360 
Open-Label 
Extension 
Blinded loading dose3 
(Day 183) 
Days 184 to 196 
≥ 40 to < 60 
1200 
120 
0 
120 
240 
≥ 60 to < 100 
1500 
150 
0 
150 
300 
≥ 100 
1500 
150 
0 
150 
300 
Open-label 
maintenance dose 
(Days 197 to 869, 
q8w) 
On intervals 
between 
scheduled visits 
≥ 40 to < 60 
1500 
150 
0 
150 
300 
≥ 60 to < 100 
1800 
180 
0 
180 
360 
≥ 100 
1800 
180 
0 
180 
360 
1 Supplemental dose will be based on the patient’s body weight used to determine the most recently administered scheduled dose. 
2 Blinded dose on Day 183 (Week 26) for patients who were randomized to the ravulizumab group and are entering into the Open-Label Extension Period. 
3 Blinded loading dose on Day 183 (Week 26) for patients who were randomized to the placebo group and are entering into the Open-Label Extension Period. 


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Table 8: 
Supplemental Dose When Intravenous Immunoglobulin is Administered as Rescue Therapy on Nonscheduled 
Dosing Visits 
Study Period 
Previous 
Ravulizumab or 
Placebo Scheduled 
Dosing Visit 
Next Applicable 
Supplemental 
Dosing Day 
Range 
Body Weight 
Used for Most 
Recent 
Scheduled Dose 
(kg)1 
Ravulizumab 
Dose  
(mg) 
Volume (mL) 
Ravulizumab 
Placebo 
Diluent 
(0.9% 
sodium 
chloride) 
Total 
Ravulizumab Group 
Randomized-
Controlled 
Loading dose 
(Day 1) 
 
Days 2 to 14 
≥ 40 to < 60 
600 
60 
0 
60 
120 
≥ 60 to < 100 
600 
60 
0 
60 
120 
≥ 100 
600 
60 
0 
60 
120 
Maintenance dose 
(Days 15, 71, 127) 
 
Days 16 to 70, 
Days 72 to 126, 
Days 128 to 182 
≥ 40 to < 60 
600 
60 
0 
60 
120 
≥ 60 to < 100 
600 
60 
0 
60 
120 
≥ 100 
600 
60 
0 
60 
120 
Open-Label 
Extension 
Blinded dose2 
(Day 183) 
Days 184 to 196 
≥ 40 to < 60 
600 
60 
0 
60 
120 
≥ 60 to < 100 
600 
60 
0 
60 
120 
≥ 100 
600 
60 
0 
60 
120 
Open-label 
maintenance dose 
(Days 197 to 869 
q8w) 
On intervals 
between 
scheduled visits 
≥ 40 to < 60 
600 
60 
0 
60 
120 
≥ 60 to < 100 
600 
60 
0 
60 
120 
≥ 100 
600 
60 
0 
60 
120 
Placebo Group 
Randomized-
Controlled 
Loading dose 
(Day 1) 
 
Days 2 to 14 
 
≥ 40 to < 60 
0 
0 
60 
60 
120 
≥ 60 to < 100 
0 
0 
60 
60 
120 
≥ 100 
0 
0 
60 
60 
120 
Maintenance dose 
(Days 15, 71, 127) 
 
Days 16 to 70, 
Days 72 to 126, 
Days 128 to 182 
≥ 40 to < 60 
0 
0 
60 
60 
120 
≥ 60 to < 100 
0 
0 
60 
60 
120 
≥ 100 
0 
0 
60 
60 
120 
Open-Label 
Extension 
Blinded loading dose3 
(Day 183) 
Days 184 to 196 
 
≥ 40 to < 60 
600 
60 
0 
60 
120 
≥ 60 to < 100 
600 
60 
0 
60 
120 
≥ 100 
600 
60 
0 
60 
120 
Open-label 
maintenance dose 
(Days 197 to 869, 
q8w) 
On intervals 
between 
scheduled visits 
≥ 40 to < 60 
600 
60 
0 
60 
120 
≥ 60 to < 100 
600 
60 
0 
60 
120 
≥ 100 
600 
60 
0 
60 
120 
1 Supplemental dose will be based on the patient’s body weight used to determine the most recently administered scheduled dose. 
2 Blinded dose on Day 183 (Week 26) for patients who were randomized to the ravulizumab group and are entering into the Open-Label Extension Period. 
3 Blinded loading dose on Day 183 (Week 26) for patients who were randomized to the placebo group and are entering into the Open-Label Extension Period. 


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6.5.1.5. 
Disallowed Medications and Therapies 
The following concurrent medications are prohibited during the study: 
• 
Rituximab 
• 
Chronic PE/PP therapy  
• 
Chronic IVIg therapy 
• 
Eculizumab (or other complement-inhibitors) 
Patient-use of rituximab or eculizumab (or other complement inhibitors) at any point during the 
study will result in the patient being discontinued from the study. 
6.5.2. 
Rescue Therapy 
Rescue therapy (eg, high-dose corticosteroid, PE/PP, or IVIg) will be allowed when a patient’s 
health would be in jeopardy if rescue therapy was not administered (eg, emergent situations) or, 
if a patient experiences Clinical Deterioration as defined in this protocol. The rescue therapy 
used for a particular patient will be at the discretion of the Investigator. The date and time of 
rescue medication administration as well as the name and dosage regimen of the rescue 
medication will be recorded. 
Should a patient require rescue therapy, every effort should be made to notify the Sponsor within 
24 hours. 
6.6. 
Intervention After the End of the Study 
Patients will return to the care of their treating physician at the completion of study participation. 


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7. 
DISCONTINUATION OF STUDY INTERVENTION AND 
PATIENT DISCONTINUATION/WITHDRAWAL 
7.1. 
Discontinuation of Study Intervention 
A patient may withdraw from the study at any time at his/her own request, or may be withdrawn 
at any time at the discretion of the Investigator for safety, behavioral, compliance, or 
administrative reasons. If a patient discontinues treatment from the study, the Investigator will 
attempt to perform (if the patient agrees) assessments specified for the ET Visit, or if not 
possible, a follow-up phone call to be conducted 8 weeks after the last dose of study drug has 
been administered (SoA, Section 1.3). Attempts should also be made to follow all patients for 
safety for a total of 8 weeks from the day the last dose of study drug is administered. The 
Sponsor and site monitor will be notified as soon as possible. If a patient is withdrawn from the 
study or withdraws consent no further data will be collected. Patients who withdraw from the 
study will not be replaced. 
Patients should be discontinued from study drug if any of the following occur during the study: 
1. Serious hypersensitivity reaction (such as bronchospasm with wheezing or requiring 
ventilator support or symptomatic hypotension, refer to Section 10.5 [Appendix 5]) or 
serum sickness-like reactions manifesting 1 to 14 days after study drug administration; 
2. Severe uncontrolled infection; 
3. Pregnancy or planned pregnancy; or 
4. Sponsor or Investigator deems it is in the best interest of the patient. 
5. Use of rituximab, eculizumab (or other complement-inhibitors) 
The Investigator should contact the Medical Monitor prior to discontinuing a patient from study 
drug. If a patient discontinues from treatment, the patient should be encouraged to return for the 
ET Visit (SoA, Section 1.3) 8 weeks after the patient’s last dose of study drug. 
The reason for the treatment discontinuation (ie, patient withdraws consent, patient withdrawal 
from procedures, physician decision, AE, or other reason specified in eCRF) will be recorded in 
the eCRF. 
If a female patient is permanently discontinued from study drug due to pregnancy, the 
Investigator will make a reasonable attempt to follow-up, in accordance with local laws and 
regulations, until the outcome of the pregnancy is known (Section 10.4 [Appendix 4]).  
If the patient withdraws consent for disclosure of future information, the Sponsor may retain and 
continue to use all data collected before such a withdrawal of consent. 
If a patient withdraws from the study, the patient may request destruction of any samples taken 
and not tested, and the Investigator must document this in the site study records as well as inform 
the site monitor and Sponsor. 
7.2. 
Lost to Follow Up 
A patient will be considered lost to follow-up if the patient repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site.  


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The following actions must be taken if a patient fails to return to the clinic for a required study 
visit: 
1. The site must attempt to contact the patient and reschedule the missed visit as soon as 
possible and counsel the patient on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the patient wishes to and/or should continue in the 
study. 
2. Before a patient is deemed lost to follow up, the Investigator or designee must make 
every effort to regain contact with the patient (where possible, 3 telephone calls and, if 
necessary, a certified letter to the patient’s last known mailing address or local equivalent 
methods). These contact attempts should be documented in the patient’s medical record. 
3. Should the patient continue to be unreachable, the patient will be considered to have 
withdrawn consent and future missed visits will not be considered protocol deviations.  


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8. 
STUDY ASSESSMENTS AND PROCEDURES 
8.1. 
Efficacy Assessments  
8.1.1. 
Hospitalization 
Information related to all-cause hospitalization, including those that occurred within the last 
2 years prior to screening, will be collected through the OLE Period. Hospitalizations are defined 
as all admissions to a healthcare facility (hospital, rehabilitation center, or hospice), irrespective 
of the underlying relation to MG. Dates of admission/discharge, reasons for hospitalization, 
relationship to MG, and other relevant information will be collected on the eCRF. 
8.1.2. 
Clinical Deterioration 
Information related to Clinical Deterioration, as defined in Section 4.2.1, will be collected from 
patient signing of the ICF through the OLE Period. The evaluation visit for a Clinical 
Deterioration must be performed as soon as possible, within 48 hours of notification to the 
Investigator of the symptom onset. Additional Unscheduled Visits (Section 4.2.2) can be 
scheduled at the discretion of the Investigator. The following tests and procedures will be 
completed at this visit: 
• Measure vital signs and pulse oximetry, including assessments of systolic and blood 
pressure (BP), temperature (°C or °F), oxygen saturation (SO2), and heart rate (HR). 
• Record any new medications or changes to concomitant medications, including all 
treatments for MG. 
• Evaluate and record any new AEs or changes in AEs since the previous visit. 
• Administer MG-ADL by a properly trained evaluator, preferably the same evaluator, 
throughout the study. The recall period is the preceding 7 days or since the last visit 
whichever occurs earlier.  
• Administer clinical assessments QMG and MGC; these should be performed at 
approximately the same time of day by a properly trained evaluator, preferably the 
same evaluator, throughout the study.  
• Collect blood sample for the AChR auto-Abs test. 
• Collect blood samples for clinical laboratory tests (see Section 10.2 [Appendix 2]). 
• If medically indicated for evaluation of Clinical Deterioration, additional tests may be 
performed at the discretion of the Investigator.  
• PK/PD/ADA sampling at or during Clinical Deterioration Visit is described in 
Figure 2.  
 


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Figure 2: 
PK/PD/ADA Sampling for Clinical Deterioration 
 
Abbreviations: ADA = antidrug antibody; IVIg = intravenous immunoglobulin; PD = pharmacodynamic(s); PE = plasma exchange; PK = pharmacokinetic(s); 
PP = plasmapheresis 
 
 


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8.1.3. 
Myasthenia Gravis Activities of Daily Living Profile  
The MG-ADL is an 8-point questionnaire that focuses on relevant symptoms and functional 
performance of ADL in patients with MG (Section 10.6 [Appendix 6]). The 8 items of the 
MG-ADL questionnaire were derived from symptom-based components of the original 13-item 
QMG scale to assess disability secondary to ocular (2 items), bulbar (3 items), respiratory 
(1 item), and gross motor or limb (2 items) impairment related to effects from MG. In this 
functional status instrument, each response is graded 0 (normal) to 3 (most severe). The range of 
total MG-ADL score is 0 - 24. The recall period for MG-ADL is the preceding 7 days. The MG-
ADL profile should be administered by a properly trained evaluator. For consistency, the same 
evaluator should administer the questionnaire throughout the study. 
8.1.4. 
Quantitative Myasthenia Gravis Score 
The QMG scoring system consists of 13 items: ocular (2 items), facial (1 item), bulbar (2 items), 
gross motor (6 items), axial (1 item), and respiratory (1 item); each graded 0 to 3, with 3 being 
the most severe (Section 10.7 [Appendix 7]). The range of total QMG score is 0 - 39. The QMG 
scoring system is considered to be an objective evaluation of therapy for MG and is based on 
quantitative testing of sentinel muscle groups. The MGFA task force has recommended that the 
QMG score be used in prospective studies of therapy for MG (Benatar, 2012).  
8.1.5. 
Myasthenia Gravis Composite Score 
The MGC is a validated assessment tool for measuring clinical status of patients with MG. The 
range of total MGC score is 0 - 50. The MGC assesses 10 important functional areas most 
frequently affected by MG and the scales are weighted for clinical significance that incorporates 
patient-reported outcomes (Burns, 2010) (Section 10.8 [Appendix 8]). 
8.1.6. 
Euro Quality of Life 5D-5L 
The Euro Quality of Life-5L (EQ-5D-5L) (Section 10.9 [Appendix 9]) is a self-assessed, 
health-related QoL questionnaire. The scale measures QoL on a 5-component scale including 
mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each level is rated 
on a scale that describes the degree of problems in that area (ie, I have no problems walking 
about, slight problems, moderate problems, severe problems, or unable to walk). This tool also 
has an overall health scale where the rater selects a number between 1 - 100 to describe the 
condition of their health, 100 being the best imaginable. Convergent validity was demonstrated 
by a correlation between EQ-5D-5L and the dimensions of World Health Organization 5 Well 
Being questionnaires, (r = 0.43, p < 0.001) (Janssen, 2013). The EQ-5D-5L approach is reliable, 
average test-retest reliability using interclass coefficients with mean of 0.78 and 0.73 (Brooks, 
1996; Chaudhury, 2006). 
8.1.7. 
Revised Myasthenia Gravis Qualify of Life-15 Scale 
The revised Myasthenia Gravis Qualify of Life 15-item scale (MG-QOL15r) (Section 10.10  
[Appendix 10]) is a health-related QoL evaluative instrument specific to patients with MG. The 
MG-QOL15r was designed to provide information about patients’ perception of impairment and 
disability, determine the degree to which disease manifestations are tolerated, and to be 


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administered and interpreted easily (Burns, 2016). The MG-QOL15r will be completed by the 
patient. Higher scores indicate greater extent of and dissatisfaction with MG-related dysfunction. 
8.1.8. 
Neurological Quality of Life Fatigue 
The Neuro-QOL Fatigue is a reliable and validated brief 19-item survey of fatigue, completed by 
the patient (Cella, 2010). Higher scores indicate greater fatigue and greater impact of MG on 
activities (Section 10.11 [Appendix 11]).  
8.1.9. 
Myasthenia Gravis Foundation of America Clinical Classification 
The MGFA Clinical Classification will be assessed on Day 1 (Section 10.12 [Appendix 12]).  
8.1.10. 
Myasthenia Gravis Foundation of America Post-Intervention Status 
The MG clinical state will be assessed using a modified version of the MGFA-PIS 
(Section 10.13 [Appendix 13]). Change in status categories of Improved, Unchanged, or Worse, 
as well as the minimal manifestation (MM) will be assessed and recorded at the time points 
indicated in the SoA (Section 1.3) by the Investigator or the same neurologist skilled in the 
evaluation of patients with MG throughout the study. The subscores of MM, ie, MM-0, MM-1, 
and MM-3, will not be used in this protocol.  
8.2. 
Safety Assessments 
8.2.1. 
Physical Examination 
A physical examination will include assessments of the following body systems: general 
appearance; skin; head, ear, eye, nose, throat; neck; lymph node; chest; heart; abdominal cavity; 
limb; central nervous system; and musculoskeletal. An abbreviated physical examination 
consists of a body-system relevant examination based upon Investigator judgment and patient 
symptoms. For consistency, all efforts should be made to have the physical examination 
performed by the same qualified study staff.  
8.2.2. 
Vital Signs and Pulse Oximetry 
Vital signs and pulse oximetry will be measured at every visit and will include assessments of 
systolic and diastolic BP (mmHg), temperature (°C or °F), SO2, and HR (beats per minute). Vital 
signs will be obtained after the patient has been supine or seated for at least 5 minutes. Ideally, 
each patient’s BP should be measured using the same arm.  
8.2.3. 
Electrocardiogram 
Single 12-lead electrocardiogram (ECG) will be obtained as outlined in the SoA (Section 1.3) 
using an ECG machine to obtain HR and measures of PR, QRS, QT, and QTc intervals. QT 
interval will be corrected for heart rate using Fridericia’s formula (QTcF). Patients must be 
supine for approximately 5 - 10 minutes before ECG collection and remain supine but awake 
during ECG collection. 
The Investigator or designee will be responsible for reviewing the ECG to assess whether the 
ECG is within normal limits and determine the clinical significance of the results. These 
assessments will be indicated on the eCRF. 


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8.2.4. 
Clinical Safety Laboratory Assessments 
Laboratory assessments will be tested at a central laboratory facility. Any clinically significant 
abnormal results should be followed until resolution or stabilization. 
All protocol-required laboratory assessments, as defined in Section 10.2 (Appendix 2), must be 
conducted in accordance with the laboratory manual and the SoA (Section 1.3). 
The Investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the study in the AE section of the eCRF. The 
laboratory reports must be filed with the source documents.  
Clinically significant abnormal laboratory findings associated with the underlying disease are not 
considered AEs unless they are judged by the Investigator to be more severe than expected for 
the patient’s condition. 
If such values do not return to normal/baseline within a period of time judged reasonable by the 
Investigator, the etiology should be identified and the Sponsor notified. 
8.2.4.1. 
Urinalysis and Urine Chemistry 
Urine samples will be analyzed for the parameters listed in Section 10.2 (Appendix 2). A 
microscopic examination of urine samples will be performed if the results of the macroscopic 
analysis are abnormal. 
8.2.4.2. 
Virus Serology 
Human immunodeficiency virus testing for HIV-1 and HIV-2 is required of all patients prior to 
enrollment. Patients who are HIV positive will not be enrolled. 
8.2.4.3. 
Immunogenicity Assessments 
Blood samples will be collected to test for presence of ADAs to ravulizumab in serum prior to 
study drug administration. Further characterization of antibody responses may be conducted as 
appropriate, including ADA titer, binding and neutralizing antibodies, PK/PD, safety, and 
activity of ravulizumab. Antibodies to ravulizumab will be evaluated in serum samples collected 
from all patients according to the SoA (Section 1.3). Serum samples will be screened for 
antibodies binding to ravulizumab and the titer of confirmed positive samples will be reported. 
The detection and characterization of antibodies to ravulizumab will be performed using a 
validated assay by or under the supervision of the Sponsor.  
Detailed instructions on the procedure for collecting, processing, storing, and shipping serum 
samples for immunogenicity analysis will be provided in the laboratory manual. 
8.2.5. 
Suicidal Risk Monitoring 
8.2.5.1. 
Columbia-Suicidal Severity Rating Scale 
The Columbia-Suicide Severity Rating Scale (C-SSRS; Section 10.14 [Appendix 14] and 
Section 10.15 [Appendix 15]) is a validated questionnaire used extensively across primary care, 
clinical practice, surveillance, research, and institutional settings to assess suicidal ideation and 
behavior (Posner, 2011). The C-SSRS will be administered by the Investigator or a properly 


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trained designee. The C-SSRS will be assessed for both lifetime and past 1 year (12 months) as 
specified in the SoA (Section 1.3). The C-SSRS is being implemented to ensure that patients 
who are experiencing suicidal ideation or behavior are properly recognized and adequately 
managed.  
8.3. 
Adverse Events and Serious Adverse Events 
Adverse events will be reported to the Investigator or qualified designee by the patient (or when 
appropriate, by a caregiver, surrogate, or the patient’s legally authorized representative). 
The Investigator or qualified designees are responsible for detecting, documenting, and recording 
events that meet the definition of an AE or SAE, and remain responsible for following up events 
that are serious, considered related to the study drug or study procedures; or that caused the 
patient to discontinue the study drug (Section 7).  
Definitions and procedures for recording, evaluating, follow-up, and reporting AEs and SAEs are 
outlined in Section 10.3 (Appendix 3). 
8.3.1. 
Time Period and Frequency for Collecting Adverse Event and Serious Adverse 
Event Information  
All AEs will be collected from the signing of the ICF until 8 weeks after the last dose of study 
drug is administered. 
Medical occurrences that begin before the start of study drug but after obtaining informed 
consent must be recorded in the AE case report form (CRF) as AEs and not in the Medical 
History/Current Medical Conditions CRF. 
All SAEs will be recorded and reported to the Sponsor or designee within 24 hours, as indicated 
in Section 10.3 (Appendix 3). The investigator will submit any updated SAE data to the Sponsor 
within 24 hours of awareness. 
Investigators are not obligated to actively seek AEs or SAEs after the conclusion of study 
participation. However, if the Investigator learns of any SAE, including a death, at any time after 
a patient has been discharged from the study, regardless of whether or not the event is related to 
the study drug, the Investigator must promptly notify the Sponsor. 
The method of recording, evaluating, and assessing causality of AE and SAE and the procedures 
for completing and transmitting SAE reports are provided in Section 10.3 (Appendix 3). 
8.3.2. 
Method of Detecting Adverse Events and Serious Adverse Events 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
nonleading verbal questioning of the patient is the preferred method to inquire about 
AE occurrences.  
8.3.3. 
Follow-up of Adverse Events and Serious Adverse Events 
After the initial AE/SAE report, the Investigator is required to proactively follow each patient at 
subsequent visits/contacts. All SAEs will be followed until resolution, stabilization, the event is 
otherwise explained, or the patient is lost to follow-up (as defined in Section 7.2). Further 
information on follow-up procedures is given in Section 10.3 (Appendix 3). 


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8.3.4. 
Regulatory Reporting Requirements for Serious Adverse Events 
• The Investigator must notify the Sponsor of an SAE within 24 hours of the first awareness of 
the event.  
• The Sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study drug under clinical investigation. The Sponsor 
will comply with country-specific regulatory requirements relating to safety reporting to the 
regulatory authority, IRB/IEC, and Investigators. 
• The Council for International Organizations of Medical Sciences (CIOMS) or MedWatch 
reports must be prepared for suspected unexpected serious adverse reactions (SUSARs) 
(Section 10.3 [Appendix 3]) according to local regulatory requirements and Sponsor policy 
and forwarded to Investigators as necessary. Alexion procedures for the reporting of 
SUSARs are in accordance with United States Title 21 Code of Federal Regulations (CFR) 
312.32 and European Union Clinical Trial Directive 2001/20/EC and the associated detailed 
guidance documents or national regulatory requirements in participating countries, as well as 
IRBs/IECs where applicable. 
• An Investigator who receives an Investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAEs) from the Sponsor will review 
and acknowledge the report and notify the IRB/IEC, if appropriate, according to local 
requirements. 
8.3.5. 
Pregnancy 
Contraception guidance that must be followed for the study duration is detailed in 
Section 10.4 (Appendix 4). 
For patients of childbearing potential, a serum pregnancy test (ie, beta-human chorionic 
gonadotropin) will be performed at Screening and at the EOS/ET. Urine pregnancy tests will be 
performed at all other required time points, as indicated in the SoA (Section 1.3). A negative 
pregnancy test is required prior to administering ravulizumab to patients of childbearing 
potential. 
If a pregnancy is reported, the Investigator should inform the Sponsor within 24 hours of 
learning of the pregnancy and should follow the procedures outlined in 
Section 10.4 (Appendix 4). 
Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, and ectopic pregnancy) are considered SAEs and should be reported as described in 
Section 10.3 (Appendix 3). 
8.3.6. 
Vaccine and Antibiotic Prophylaxis 
As with any terminal complement antagonist, the use of ravulizumab increases the patient’s 
susceptibility to meningococcal infection (N meningitidis). To reduce the risk of meningococcal 
infection, all patients must be vaccinated against meningococcal infections within the 3 years 
prior to, or at the time of, initiating study drug. Patients who initiate study drug treatment less 
than 2 weeks after receiving a meningococcal vaccine must receive treatment with appropriate 
prophylactic antibiotics until 2 weeks after vaccination. 


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Vaccines against serotypes A, C, Y, W135, and B, where available, are recommended to prevent 
common pathogenic meningococcal serotypes. Patients must be vaccinated or revaccinated 
according to current national vaccination guidelines or local practice for vaccination use with 
complement-inhibitors (eg, eculizumab). 
Vaccination may not be sufficient to prevent meningococcal infection. Consideration should be 
given per official guidance and local practice on the appropriate use of antibacterial agents. All 
patients should be monitored for early signs of meningococcal infection, evaluated immediately 
if infection is suspected, and treated with appropriate antibiotics, if necessary. 
To increase risk awareness and promote quick disclosure of any potential signs or symptoms of 
infection experienced by the patients during the course of the study, patients will be provided a 
safety card to carry with them at all times. Additional discussion and explanation of the potential 
risks, signs, and symptoms will occur at each visit as part of the review of the patient safety card 
as described in the SoA (Section 1.3). Vaccination(s) for N meningitidis will be recorded on the 
patient’s eCRF. 
8.3.7. 
Study Drug Administration Reactions 
8.3.7.1. 
Local and Systemic Reactions 
Infusion-site reactions are those localized to the site of IV study drug administration and may 
include those such as erythema, pruritus, and bruising. Infusion-associated reactions are those 
which are systemic in nature and which may be immune or nonimmune-mediated generally 
occurring within hours of study drug administration. Immune-mediated reactions may include 
allergic reactions (eg, anaphylaxis), while nonimmune-mediated reactions are nonspecific (eg, 
headache, dizziness, nausea). Monitoring for these reactions will be conducted as part of routine 
safety assessments for this study. 
8.3.7.2. 
Infusion-Associated Reactions 
Infusion-associated reactions are defined as systemic AEs (eg, fever, chills, flushing, alterations 
in HR and BP, dyspnea, nausea, vomiting, diarrhea, and generalized skin rashes) occurring 
during or within 24 hours of the start of IV infusion that are assessed by the Investigator to be 
possibly, probably, or definitely related to the study drug. 
8.4. 
Adverse Events of Special Interest 
Meningococcal infections will be collected as adverse events of special interest (AESI) for this 
study.  
8.5. 
Pharmacokinetics 
Blood samples will be obtained to assess pre- and post-treatment serum ravulizumab 
concentrations at the time points and within the windows indicated in the SoA (Section 1.3). 
Samples obtained outside of the allotted windows will be considered protocol deviations. Unused 
samples may be retained for a period of up to 5 years to perform additional assessments as 
necessary. 


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Additional details on sample collection, including blood volume requirements, are provided in 
the laboratory manual. 
8.6. 
Pharmacodynamics 
Blood samples will be obtained to assess pre- and post-treatment serum free C5 at the time points 
and within the windows indicated in the SoA Section 1.3). Samples obtained outside of the 
allotted windows will be considered protocol deviations. Unused samples may be retained for a 
period of up to 5 years to perform additional assessments as necessary. 
Additional details on sample collection, including blood volume requirements, are provided in 
the laboratory manual. 
8.7. 
Genetics 
Genetics will not be evaluated in this study. 
8.8. 
Biomarkers 
Blood samples for the assessment of AChR auto-Abs will be obtained at the time points 
indicated in the SoA (Section 1.3). 
Additional details on sample collection, including blood volume requirements, are provided in 
the laboratory manual. 
Remaining samples from PK, PD, immunogenicity, and biomarker testing may be stored for 
future biomarker research. Analyses may be performed on biomarker variants thought to play a 
role in gMG activity/progression or treatment response to ravulizumab. These samples may also 
be used to develop methods, assays, prognostics, and/or companion diagnostics related to the 
study drug target, disease process, pathways associated with disease state, and/or mechanism of 
action of the study drug. 
Samples may be stored for a maximum duration according to local regulations following the last 
patient’s last visit for the study, at a facility selected by the sponsor, to enable further analyses. 
8.9. 
Healthcare Resource Utilization  
Healthcare resource utilization data, associated with medical encounters, will be collected by the 
Investigator or designee for all patients throughout the study. Data will be recorded in the eCRF.  
The data collected may be used to conduct exploratory economic analyses and will include: 
• Whether patients were admitted to a hospital, rehabilitation center, or hospice 
• Whether the primary reason for admission was related to MG (yes/no) 
• Duration of hospitalization (admission and discharge dates) 


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9. 
STATISTICAL CONSIDERATIONS 
Statistical methods described in this section will be further elaborated in a separate SAP. The 
SAP will be developed and finalized before database lock. The analyses will be performed using 
the SAS® statistical software system Version 9.4 or later. Statistical analyses will include 
tabulations of summary data, inferential analyses, by-patient listings and figures. Inference from 
efficacy analyses will be based on 2-sided Type I error (α) = 5%. Summary statistics for 
continuous variables will minimally include n, mean, standard deviation, minimum, median, and 
maximum. For categorical variables, frequencies and percentages will be presented. 
The baseline value for analysis and reporting will be based on the last nonmissing measurement 
on or prior to the first dose of study drug. The treatment groups for analysis and reporting will be 
based on the conventions outlined in Table 9. A ‘Total’ group will be formed to report 
demographics, baseline characteristics and other prestudy information such as prestudy SAEs, 
medical history, or prior medications. Details for imputation of efficacy data will be described in 
the SAP. Missing safety data will not be imputed. 
A clinical study report (CSR) will be produced based on efficacy, safety, PK, PD, and 
immunogenicity data collected though the end of the 26-week Randomized-Controlled Period. A 
final CSR to summarize long-term efficacy, safety, PK, PD, and immunogenicity parameters will 
be produced at study completion. 
9.1. 
Statistical Hypotheses 
9.1.1. 
Primary Hypothesis 
The primary hypothesis for this study is that ravulizumab is superior to placebo in improvement 
of MG-ADL total score at Week 26. 
The treatment effect based on the primary endpoint will be estimated by the difference in means 
between the ravulizumab group and placebo group in the change from Baseline in MG-ADL 
total score at Week 26 irrespective of rescue therapy1. A lower value of the corresponding 
estimate will indicate a beneficial treatment effect. 
9.1.2. 
Secondary Hypotheses 
The following secondary hypotheses will be included in study-wise multiplicity adjustment 
(provided the null hypothesis for primary endpoint is rejected) (Section 9.4.5.4): 
1. Ravulizumab is superior to placebo in improvement of QMG total score at Week 26. 
2. Ravulizumab is superior to placebo in QMG 5-point response (≥ 5 point improvement 
from baseline in QMG total score) at Week 26. 
 
 
 
 
1 Rescue therapy includes high-dose corticosteroids, PE/PP or IVIg. It will be allowed when a patient’s health is in 
jeopardy, if rescue therapy was not administered (eg, emergent situations), or if a patient experiences Clinical 
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3. Ravulizumab is superior to placebo in improvement of the MG-QOL15r total score at 
Week 26. 
4. Ravulizumab is superior to placebo in improvement of Neuro-QOL Fatigue total 
score at Week 26. 
5. Ravulizumab is superior to placebo in MG-ADL 3-point response 
(≥3 point improvement from baseline in MG-ADL total score) at Week 26. 
 
9.1.3. 
Hypotheses Related to Exploratory Efficacy Objectives 
1. Ravulizumab is superior to placebo in improvement of MGC total score at Week 26. 
2. Ravulizumab is superior to placebo in MGFA-PIS at Week 26. 
3. Ravulizumab is superior to placebo in improvement of EQ-5D-5L index score at 
Week 26. 
4. Ravulizumab is superior to placebo in improvement of MG-ADL subcomponent scores 
(bulbar, limbs, respiratory, and ocular) at Week 26. 
5. Ravulizumab is superior to placebo in improvement of QMG subcomponent scores 
(bulbar, limbs, respiratory, and ocular) at Week 26. 
6. Ravulizumab is superior to placebo in reducing incidence of hospitalizations/MG-related 
hospitalizations. 
7. Ravulizumab is superior to placebo in reducing incidence of Clinical Deterioration/MG 
crisis. 
9.1.4. 
Estimation of Treatment Effect for Secondary and Exploratory Hypotheses 
The treatment effect corresponding to the change from Baseline continuous endpoints will be 
estimated similarly as the primary endpoint. 
The treatment effect corresponding to the following dichotomous endpoints will be estimated by 
the odds ratio (OR) of the proportions of the corresponding endpoint in the ravulizumab group 
compared with the placebo group:  
a. MG-ADL 3-point response at Week 26 irrespective of rescue therapy  
b. QMG 5-point response at Week 26 irrespective of rescue therapy 
c. Incidence of hospitalization/MG-related hospitalizations irrespective of rescue 
therapy 
d. Incidence of Clinical Deterioration/MG crisis over 26 weeks irrespective of rescue 
therapy 
An estimate of OR < 1 corresponding to the hospitalization and Clinical Deterioration endpoint 
will indicate a beneficial treatment effect, likewise an estimate of OR > 1 corresponding 
responder endpoints will indicate a beneficial treatment effect.  


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The treatment effect corresponding to the MGFA-PIS endpoint will be estimated by the 
proportional OR of the cumulative proportions over the ordinal categories (starting from the best 
outcome) of this endpoint in the ravulizumab group compared with the placebo group at 
Week 26, irrespective of rescue therapy. An estimate of OR > 1 will indicate a beneficial 
treatment effect.  
9.2. 
Sample Size Determination 
Approximately 160 patients will be randomly assigned to ravulizumab and placebo in a 1:1 ratio 
(ravulizumab:placebo) stratified by region (North America, Europe, Asia-Pacific, and Japan) to 
ensure at least 90% nominal power to reject the null hypotheses of no treatment difference for 
the primary and secondary endpoints based on 2-sided Type I error (α) = 5%. Assumptions 
related to statistical power calculations are based on Study ECU-MG-301. Details are provided 
in Section 10.16 (Appendix 16).  
9.3. 
Populations for Analyses 
For purposes of analysis, the following analysis sets are defined in Table 9. 
Table 9: 
Study ALXN1210-MG-306: Analysis Sets 
Population 
Description 
Randomized set  
All randomized patients grouped by randomized treatment group (for 
reporting disposition, demographics, and baseline characteristics). 
PK Analysis Set (PKAS) 
All ravulizumab treated patients with at least1 post-baseline PK concentration 
available. 
Full analysis set (FAS) 
All randomized patients who received at least 1 dose of study drug grouped by 
randomized treatment group (for reporting efficacy data). 
Per protocol set (PPS)  
Subset of FAS without any major protocol deviations1 during 
Randomized-Controlled Period grouped by randomized treatment group (for 
reporting key efficacy data). 
Safety set (SS) 
All patients who received at least 1 dose of study drug grouped by treatment 
actually received (for reporting exposure and safety data). For a patient to be 
analyzed according to the treatment they actually received and not according 
to the randomization schedule, they would have to receive that treatment for 
the entire duration of Randomized-Controlled Period. 
Open-label extension set 
All patients who received at least 1 dose of ravulizumab starting from 
Week 26 onward (for reporting all data from the OLE Period). 
1 Determination of applicable major protocol deviations for this purpose will be made prior to database lock and 
study unblinding. 
9.4. 
Statistical Analyses 
9.4.1. 
Enrollment and Disposition 
The number of patients screened, screen failures, and randomized patients will be presented. 
Enrollment information will be presented grouped by stratification factor and treatment group. 
Number of patients discontinued along with reasons from Randomized-Controlled Period, OLE 
Period, and the overall study will be summarized. 


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9.4.2. 
Demographics, Baseline Characteristics, Inclusion and Exclusion Criteria, and 
Protocol Deviations 
All demographic information and baseline characteristics will be reported by treatment group 
and overall. No statistical test will be performed for homogeneity among treatment groups. 
The number and percentage of patients not meeting specific inclusion or exclusion criterion will 
be summarized. Similar summary will be provided for major protocol deviations based on 
prespecified categories. 
9.4.3. 
Medical/Surgical History, Physical Examination, and Myasthenia Gravis 
History 
The medical and surgical history will be summarized by the Medical Dictionary for Regulatory 
(MedDRA) Activities, Version 20.1, or later by System Organ Class (SOC) and Preferred Term. 
Myasthenia gravis and abnormal physical examination will also be summarized. 
9.4.4. 
Prior and Concomitant Medications 
For analysis and reporting purpose, any medication started prior to first dose of study drug will 
be considered as prior medication; and medications that started on or after the first dose of study 
drug will be considered as concomitant medications. All prior and concomitant medications 
including MG-specific medications and rescue therapy during the study, if any, will be 
summarized.  
9.4.5. 
Efficacy Analyses 
9.4.5.1. 
Primary Efficacy Analysis 
The Mixed-effects Model with Repeated Measures (MMRM) will be used for the primary 
efficacy endpoint (change from Baseline in MG-ADL total score at Week 26) using all available 
longitudinal data (either complete or partial) regardless of whether patients received a rescue 
therapy2. Missing data will not be imputed for the primary analysis. The model will include the 
MG-ADL change from Baseline score at each prespecified time point as the response variable, 
fixed categorical effects of treatment, study visit and treatment-by-study visit interaction, region; 
as well as fixed covariate of baseline MG-ADL total score. The treatment effect will be 
evaluated via contrast for the treatment-by-visit term at Week 26. An unstructured covariance 
matrix will be used to model the correlations among repeated measurements within each patient. 
Other covariance structures will be implemented if a convergence issue occurs (details to be 
provided in SAP). The Kenward-Rogers method will be used to estimate the denominator 
degrees of freedom. 
 
 
 
 
2 Rescue therapy includes high-dose corticosteroids, PE/PP or IVIg. It will be allowed when a patient’s health is in 
jeopardy, if rescue therapy was not administered (eg, emergent situations), or if a patient experiences Clinical 
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9.4.5.2. 
Sensitivity Analyses for Primary Endpoint 
Two sensitivity analyses will be performed for the primary efficacy endpoint to explore the 
robustness of the MMRM results for the primary efficacy analysis: 
1. Placebo-based sensitivity analysis: 
The placebo-based sensitivity analysis will consider the Missing Not At Random 
(MNAR) mechanism for the missing data, where it will be assumed that patients who 
discontinue early from ravulizumab will follow the trajectory of outcomes similar to the 
one in the placebo group after discontinuation of ravulizumab, taking into account 
observed values prior to discontinuation. 
2. Tipping point sensitivity analysis: 
This approach assumes that patients who discontinue from ravulizumab treatment 
experience worsening defined by a prespecified adjustment in the primary efficacy 
endpoint. 
9.4.5.3. 
Analyses of Secondary and Exploratory Endpoints 
All continuous secondary and exploratory endpoints related to change from Baseline will be 
analyzed similarly as the primary endpoint.  
The QMG 5-point and MG-ADL 3-point responder endpoints will be analyzed using a mixed 
effect repeated measures model. The model will include response variable at each pre-specified 
time point as the dependent variable, fixed categorical effects of treatment, study visit and 
treatment-by-study visit interaction, and region; as well as fixed covariate of baseline QMG or 
MG-ADL total score (depending on the response variable). The treatment effect will be 
evaluated via contrast for the treatment-by-visit term at Week 26. An unstructured covariance 
matrix will be used to model the correlations among repeated measurements within each patient. 
Other covariance structures will be implemented if a convergence issue occurs (details to be 
provided in SAP). 
Clinical Deterioration/MG crisis and hospitalizations/MG-related hospitalizations will be 
analyzed using a logistic regression model with treatment group, region.  
The MGFA-PIS endpoint at Week 26 will be considered as an ordinal scale. A logistic regression 
of the cumulative odds (cumulated over the categories starting from best outcome) will be 
performed using treatment as fixed categorical effect and adjusting for region. 
Long-term efficacy data will be summarized descriptively based on OLE set. 
9.4.5.4. 
Multiplicity Adjustment for Primary and Secondary Endpoints 
The study is designed to strongly control the overall 2-sided Type I error of α = 0.05. The 
primary null hypothesis will be tested first at α = 0.05. If statistically significant, 5 secondary 
hypotheses will be tested for superiority using a closed-testing procedure with the following 
order: 
1. Change from Baseline in QMG total score at Week 26 


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2. Proportion of patients with improvement of at least 5 points in the QMG total score from 
Baseline at Week 26 
3. Change from Baseline in MG-QOL15r at Week 26 
4. Change from Baseline in Neuro-QOL Fatigue at Week 26 
5. Proportion of patients with improvement of at least 3 points in the MG-ADL total score 
from Baseline at Week 26 
The testing will proceed from (#1) to (#5) and if statistical significance is not achieved (p≤0.05), 
then subsequent endpoints will not be considered to be statistically significant. Estimates and 
confidence intervals will be computed for all these secondary endpoints regardless of the 
outcome of the closed testing procedure. 
9.4.5.5. 
Per Protocol Analyses for Primary and Secondary Endpoints 
Supplemental per protocol analyses for primary and secondary endpoints will be performed 
based on per protocol set (PPS) in the same manner as done for FAS. 
9.4.6. 
Safety Analyses 
The safety and tolerability of ravulizumab will be assessed based on adverse events, clinical 
laboratory findings, vital sign findings, and ECG abnormalities. Safety analyses will be 
performed on the Safety Population and OLE set based on the study period under consideration.  
9.4.6.1. 
Analysis of Adverse Events 
Analysis and reporting for AEs will be based on treatment-emergent adverse events (TEAEs), 
including treatment-emergent serious adverse events (TESAEs) defined as an AE with onset on 
or after first dose of ravulizumab in the Randomized-Controlled Period. Treatment-emergent 
AEs and TESAEs will be summarized by MedDRA SOC and Preferred Term, by severity, and 
by relationship to the study drug. Patient-years adjusted event rates will be generated to 
characterize long-term safety profile. 
9.4.6.2. 
Analysis of Clinical Laboratory Parameters, Vital Sign Measurements and 
Electrocardiogram Parameters 
Laboratory measurements as well as their changes from Baseline at each visit and shift from 
baseline, if applicable, will be summarized descriptively. ECG, vital sign, and pulse oximetry 
findings will also be summarized using descriptive analyses. 
9.4.6.3. 
Other Safety Analyses 
The number and percentage of patients in each of the C-SSRS categories and shift analyses will 
be produced. Results from pregnancy tests will be summarized. 
9.4.6.4. 
Analysis of Pharmacokinetics and Pharmacodynamics 
Individual serum concentration data for all patients who receive at least 1 dose of ravulizumab 
and who have evaluable PK data will be used to derive PK parameters for ravulizumab. 


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Pharmacokinetic parameters such as peak and trough serum ravulizumab concentrations will be 
reported and summarized.  
Graphs of mean serum concentration-time profiles will be constructed. Graphs of serum 
concentration-time profiles for individual patients may also be provided. Descriptive statistics 
will be calculated for serum concentration data at each sampling time, as appropriate. 
Population-PK will be performed with this data but will be described in a separate report. 
Pharmacodynamic analyses will be performed for all patients who receive at least 1 dose of 
ravulizumab and who have evaluable PD data.  
Descriptive statistics will be presented for all ravulizumab PD endpoints at each sampling time 
(Section 1.3). The PD effects of ravulizumab administered IV will be evaluated by assessing the 
absolute values and changes from baseline in free C5 serum concentrations over time, as 
appropriate. Assessments of ravulizumab PK/PD relationships may be explored using data from 
this study or in combination with data from other studies.  
9.4.6.5. 
Analysis of Immunogenicity  
The presence of ADAs in serum ravulizumab will be assessed over the duration of the study. 
Immunogenicity results will be analyzed by summarizing the number and percentage of patients 
who develop detectable ADA. The association of ADA with ravulizumab concentration, PD 
parameters, efficacy, and TEAEs may be evaluated. 
9.4.6.6. 
Analysis of Exploratory Biomarkers  
Acetylcholine receptor antibody titer levels as well as their changes from Baseline at each visit 
will be summarized descriptively. 
9.5. 
Interim Analyses  
No interim analysis is planned for Study ALXN1210-MG-306 during the 
Randomized-Controlled Period. The primary analysis will be conducted when the last patient 
completes the Randomized-Controlled Period, the database is locked, and the study 
randomization schedule is unblinded. Periodic analysis and reporting will be performed during 
the OLE Period based on regulatory requirement. Final analysis and reporting will be conducted 
at the conclusion of the study. 
9.6. 
Data Monitoring Committee 
No independent Data Monitoring Committee is planned for Study ALXN1210-MG-306. 


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10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations 
10.1.1. 
Regulatory and Ethical Considerations 
• This study will be conducted in accordance with the protocol and with the following: 
− Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and CIOMS International Ethical Guidelines 
− Applicable ICH-GCP Guidelines 
− Applicable laws and regulations 
• The protocol, protocol amendments, ICF, IB, and other relevant documents (eg, 
advertisements) must be submitted to an IRB/IEC by the Investigator and reviewed and 
approved by the IRB/IEC before the study is initiated.  
• The IRB/IEC and relevant regulatory authority must be notified of any significant 
amendment to the protocol, as applicable. Necessary approvals must be given before changes 
are implemented.  
• The Investigator will be responsible for the following: 
− Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC 
− Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures 
− Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 Code of Federal Regulations (CFR), ICH guidelines, the IRB/IEC, 
European regulation 536/2014 for clinical studies (if applicable), and all other 
applicable local regulations 
10.1.2. 
Informed Consent Process 
• The Investigator or his/her representative will explain the nature of the study to the patient or 
his/her legally authorized representative and answer all questions regarding the study.  
• Patients must be informed that their participation is voluntary. Patients or their legally 
authorized representative will be required to sign a statement of informed consent that meets 
the requirements of 21 CFR 50, local regulations, ICH guidelines, Health Insurance 
Portability and Accountability Act requirements, where applicable, and the IRB/IEC or study 
center.  


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• The medical record must include a statement that written informed consent was obtained 
before the patient was enrolled in the study and the date the written consent was obtained. 
The authorized person obtaining the informed consent must also sign the ICF. 
• Patients must be reconsented to the most current version of the ICF(s) during their 
participation in the study. A copy of the ICF(s) must be provided to the patient. 
• The Investigator must retain the original version of the signed ICF(s). A copy of the signed 
ICF(s) must be provided to the patient.  
• A patient who is rescreened is not required to sign another ICF unless an updated ICF is 
available. 
10.1.3. 
Data Protection 
• Patients will be assigned a unique identifier by the Sponsor. Any patient records or datasets 
that are transferred to the Sponsor will contain the identifier only; patient names or any 
information which would make the patient identifiable will not be transferred.  
• The patient must be informed that his/her personal study-related data will be used by the 
Sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the patient.  
• The patient must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the Sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities. 
• Alexion will store anonymized data [ie, data that has been anonymized through removal of 
elements that will identify the individual directly so that the individual is no longer uniquely 
identifiable] in the study databases for no less than 15 years after the completion of the study 
or until the purposes of collection and use are attained, after which data will be destroyed. 
Health authorities and regulatory authorities may retain and utilize such information for the 
period set forth in applicable law or as duly determined at the relevant regulatory authority’s 
discretion. 
10.1.4. 
Dissemination of Clinical Study Data 
Study-related information and study results may be posted on the US National Institutes of 
Health website www.clinicaltrials.gov, the EU website www.clinicaltrialsregister.eu/, or other 
publicly accessible websites as appropriate and in accordance with local regulations. 
10.1.5. 
Data Quality Assurance 
• All patient data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the Sponsor or designee electronically (eg, laboratory data). The Investigator is 
responsible for verifying that data entries are accurate and correct by physically or 
electronically signing the CRF.  
• The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.  


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• The Investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.  
• The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data.  
• Study monitors will perform ongoing source data verification to confirm that data entered 
into the CRF by authorized site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of patients are being protected; and that the study is 
being conducted in accordance with the currently approved protocol and any other study 
agreements, ICH-GCP, and all applicable regulatory requirements. Study monitors will 
communicate with investigative sites on a regular basis regarding the study and all protocol 
deviations will be appropriately documented by the Investigator or designee, and study 
monitors. 
• Records and documents, including signed ICFs, pertaining to the conduct of this study must 
be retained by the investigator for 5 years after study completion unless local regulations or 
institutional policies require a longer retention period. No records may be destroyed during 
the retention period without the written approval of the Sponsor. No records may be 
transferred to another location or party without written notification to the Sponsor.  
10.1.6. 
Source Documents 
• Source documents provide evidence for the existence of the patient and substantiate the 
integrity of the data collected. Source documents are filed at the investigative site. 
• The Investigator or designee will prepare and maintain adequate and accurate source 
documents (medical records, ECGs, AE and concomitant medication reporting, and raw data 
collection forms) designed to record all observations and other pertinent data for each patient. 
• Data entered in the eCRF that are transcribed from source documents must be consistent with 
the source documents or the discrepancies must be explained. The Investigator may need to 
request previous medical records or transfer records, depending on the study. Also, current 
medical records must be available. 
10.1.7. 
Study and Site Closure 
The Sponsor reserves the right to close the study site or terminate the study at any time for any 
reason at their sole discretion. A study site is considered closed when all required documents and 
study supplies have been collected and a study-site closure visit has been performed. 
The Investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the Sponsor or Investigator may include but are 
not limited to: 
• Failure of the Investigator to comply with the protocol, the requirements of the IRB/IEC or 
local health authorities, the Sponsor’s procedures, or GCP guidelines 
• Inadequate recruitment of patients by the Investigator 


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• Discontinuation of further ravulizumab development 
10.1.8. 
Publication Policy 
The full terms regarding publication of the results of this study are outlined in the applicable 
Clinical Study Agreement. 


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10.2. 
Appendix 2: Clinical Laboratory Tests  
The tests detailed in Table 10 will be performed by the central laboratory.  
Protocol-specific requirements for inclusion or exclusion of patients are detailed in Section 5 of 
the protocol. 
Additional tests may be performed at any time during the study as determined necessary by the 
Investigator or required by local regulations. 
Table 10: 
Protocol-Required Safety Laboratory Assessments 
Laboratory 
Assessments 
Parameters 
Hematology 
Platelet count  
RBC count 
Hemoglobin 
Hematocrit 
RBC indices: 
Distribution width 
Mean corpuscular volume 
Mean corpuscular 
hemoglobin 
% Reticulocytes 
WBC count with 
differential: 
Neutrophils 
Lymphocytes 
Monocytes 
Eosinophils 
Basophils 
Clinical 
Chemistry 
BUN 
C-reactive protein 
Creatinine 
Chloride  
Potassium 
Bicarbonate  
Sodium  
Glucose (nonfasting) 
AST/SGOT 
ALT/SGPT 
Alkaline phosphatase, 
Gamma glutamyltransferase 
Total and direct bilirubin 
Total protein 
Albumin 
Uric acid 
Coagulation 
international normalized ratio, partial thromboplastin time, prothrombin time 
Urine 
Appearance, color, specific gravity, pH, glucose, protein, leukocyte esterase, blood, ketones, 
bilirubin, urobilinogen, nitrite, microscopic examination (if blood or protein is abnormal)  
Other Screening 
tests 
Serum/urine beta-hCG pregnancy test (as needed for patients of child-bearing potential) 
Serum follicle-stimulating hormone test (as needed for patients who consider themselves 
postmenopausal)  
HIV-1 and HIV-2 antibodies 
 
The results of each test must be entered into the eCRF. 
Complement 
activity 
Free C5 
Other 
Antidrug antibodies, AChR antibody 
Abbreviations: AChR = acetylcholine receptor; ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
BUN = blood urea nitrogen; C5 = complement component 5; eCRF = electronic case report form; hCG = human 
chorionic gonadotropin; HIV-1 = human immunodeficiency virus type 1; HIV-2 = human immunodeficiency virus 
type 2; RBC = red blood cells; SGOT = serum glutamic oxaloacetic transaminase; SGPT = serum glutamic 
pyruvic transaminase; WBC = white blood cells. 
 


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


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10.3.2. 
Serious Adverse Event 
If an event is not an AE per definition above, then it cannot be an SAE even if serious conditions 
are met (eg, hospitalization for signs/symptoms of the disease under study, death due to 
progression of disease). 
A serious adverse event is defined as any untoward medical occurrence that, at any dose: 
• 
Results in death 
• 
Is life-threatening 
The term ‘life-threatening’ in the definition of ‘serious’ refers to an event in which the participant was at 
risk of death at the time of the event. It does not refer to an event, which hypothetically might have caused 
death, if it were more severe. 
• 
Requires inpatient hospitalization or prolongation of existing hospitalization 
In general, hospitalization signifies that the patient has been detained (usually involving at least an 
overnight stay) at the hospital or emergency ward for observation and/or treatment that would not have 
been appropriate in the physician’s office or outpatient setting. Complications that occur during 
hospitalization are AEs. If a complication prolongs hospitalization or fulfills any other serious criteria, the 
event is serious. When in doubt as to whether “hospitalization” occurred or was necessary, the AE should 
be considered serious. 
Hospitalization for elective treatment of a pre-existing condition that did not worsen from baseline is not 
considered an AE. 
• 
Results in persistent disability/incapacity 
The term disability means a substantial disruption of a person’s ability to conduct normal life functions. 
 
This definition is not intended to include experiences of relatively minor medical significance such as 
uncomplicated headache, nausea, vomiting, diarrhea, influenza, and accidental trauma (eg, sprained ankle) 
which may interfere with or prevent everyday life functions but do not constitute a substantial disruption. 
1. Is a congenital anomaly/birth defect 
2. Other situations: 
Medical or scientific judgment should be exercised in deciding whether SAE reporting is appropriate in 
other situations such as important medical events that may not be immediately life-threatening or result in 
death or hospitalization but may jeopardize the participant or may require medical or surgical intervention 
to prevent one of the other outcomes listed in the above definition. These events should usually be 
considered serious. 
10.3.3. 
Suspected Unexpected Serious Adverse Reactions 
Suspected Unexpected Serious Adverse Reactions Definition 
Suspected unexpected serious adverse reactions (SUSARs) are serious events that are not listed in the IB 
and that the Investigator identifies as related to study drug or procedure. The US 21CFR312.32 and EU 
Clinical Trial Directive 2001/20/EC and the associated detailed guidance documents or national 
regulatory requirements in participating countries require the reporting of SUSARs. Alexion has 
procedures that will be followed for the recording and expedited reporting of SUSARs that are consistent 
with global regulations and the associated detailed guidance documents. Suspected unexpected serious 
adverse reactions will be reported to the national competent authority and IRBs/IECs where applicable. 


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10.3.4. 
Recording and Follow-Up of Adverse Event and/or Serious Adverse Event 
Adverse Event and Serious Adverse Event Recording 
• 
When an AE or SAE occurs, it is the responsibility of the Investigator to review all documentation 
(eg, hospital progress notes, laboratory reports, and diagnostics reports) related to the event. The 
Investigator will then record all relevant AE/SAE information in the CRF. 
• 
It is not acceptable for the Investigator to send photocopies of the patient’s medical records to Alexion 
or designee in lieu of completion of the AE/SAE report. If applicable, additional information such as 
relevant medical records, should be submitted with a signed SAE cover page to Alexion Global 
Pharmacovigilance (GPV) via ClinicalSAE@alexion.com or via Facsimile: + 1.203.439.9347. In this 
case, all patient identifiers, with the exception of the patient number, will be redacted on the copies of 
the medical records before sending to GPV. 
• 
The Investigator will attempt to establish a diagnosis of the event based on signs, symptoms, and/or 
other clinical information. Whenever possible, the diagnosis (not the individual signs/symptoms) will 
be documented as the AE or SAE. 
Assessment of Event Severity 
The Investigator will make an assessment of intensity for each AE and SAE reported during the study and 
assign it to 1 of the following categories from National Cancer Institute Common Terminology Criteria for 
Adverse Events (CTCAE) v5.0, published 27 Nov 2017. Each CTCAE term is a Lowest Level Term (LLT) 
per MedDRA. Each LLT will be coded to a MedDRA Preferred Term:  
• 
Grade 1: Mild (asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated) 
• 
Grade 2: Moderate (minimal, local or noninvasive intervention indicated; limiting age-appropriate 
instrumental ADL) 
• 
Grade 3: Severe (severe or medically significant, but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care ADL) 
• 
Grade 4: Life-threatening (urgent intervention indicated) 
• 
Grade 5: Fatal (death related to AE) 
Any change in the severity of an AE should be documented based on specific guidelines in the eCRF 
Completion Guidelines. 
Severity and seriousness must be differentiated: severity describes the intensity of an AE, while the term 
seriousness refers to an AE that has met specific criteria for an SAE as described above. 
Assessment of Causality 
• 
The Investigator is obligated to assess the relationship between the study drug and each occurrence 
of each AE or SAE. An Investigator causality assessment must be provided for all AEs (both 
nonserious and serious). This assessment must be recorded in the eCRF and on any additional 
forms, as appropriate. The definitions for the causality assessments are as follows:  
o 
Not related (unrelated)  
o Related: Temporal relationship to the study drug. Other conditions (concurrent illness, 
concurrent medication reaction, or progression/expression of disease state) do not appear 
to explain the event; the event corresponds with the known pharmaceutical profile; 
improvement on discontinuation; reappearance on rechallenge. 
Adverse Event Recording 
• 
The Investigator will use clinical judgment to determine the relationship to the study drug. 
• 
Alternative causes, such as underlying disease(s), concomitant therapy, and other risk factors, as 
well as the temporal relationship of the event to study drug administration will be considered and 
investigated. 


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Adverse Event and Serious Adverse Event Recording 
• 
The expectedness and reporting criteria of an SAE will be determined by the Sponsor, based on 
the Reference Safety Document. The Investigator will also consult the IB in his/her assessment. 
• 
There may be situations in which an SAE has occurred and the Investigator has minimal 
information to include in the initial report to Alexion or designee. However, it is very important 
that the Investigator always makes an assessment of causality for every event before the 
initial transmission of the SAE data to Alexion GPV. 
• 
The Investigator may change his/her opinion of causality in light of follow-up information and 
send a SAE follow-up report with the updated causality assessment. 
The causality assessment is one of the criteria used when determining regulatory reporting 
requirements. 
Follow-up of Adverse Events and Serious Adverse Events 
• 
The Investigator is obligated to perform or arrange for the conduct of supplemental measurements 
and/or evaluations as medically indicated or as requested by Alexion or designee to elucidate the 
nature and/or causality of the AE or SAE as fully as possible. This may include additional laboratory 
tests or investigations, histopathological examinations, or consultation with other health care 
professionals. 
• 
If a patient dies during participation in the study or during a recognized follow-up period, the 
Investigator will provide Alexion or designee with a copy of any postmortem findings including 
histopathology, if available. 
• 
The site will enter new or updated SAE data into the electronic system as soon as it becomes 
available, but no later than 24 hours. The Investigator will submit any updated SAE data to the GPV 
within 24 hours of awareness of the information. 
10.3.5. 
Reporting of Serious Adverse Events 
Serious Adverse Event Reporting to Alexion or Designee via the RAVE Safety Gateway 
All SAEs must be reported to Alexion GPV within 24 hours of the Investigator or site staff awareness. 
These timelines for reporting SAE information to the Sponsor need to be followed for the initial SAE report 
and for all follow-up SAE information. 
The Investigator or designee must record the SAE data in the eCRF and verify the accuracy of the 
information with corresponding source documents. The SAE report should be submitted electronically via 
the RAVE Safety Gateway.  
In the event that either the electronic data capture (EDC) or the RAVE Safety Gateway is unavailable at the 
site(s), the SAE must be reported on the paper SAE Contingency Form accompanied by an Investigator 
signed cover page. Facsimile transmission or email may be used in the event of electronic submission 
failure. 
For all SAEs, the Investigator must provide the following: 
• 
Appropriate and requested follow-up information in the time frame detailed below 
• 
Causality of the SAE(s) 
• 
Treatment of/intervention for the SAE(s) 
• 
Outcome of the SAE(s) 
• 
Supporting medical records and laboratory/diagnostic information 
• 
The primary mechanism for reporting an SAE to Alexion or designee will be the RAVE Safety 
Gateway. 
• 
If the electronic system is unavailable at the time that the Investigator or site becomes aware of an 
SAE, the site will use the paper Contingency Form for SAE reporting via facsimile or email. 
Facsimile transmission or email may be used in the event of electronic submission failure. 
Email: clinicalsae@alexion.com  
Facsimile: + 1.203.439.9347 


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Serious Adverse Event Reporting to Alexion or Designee via the RAVE Safety Gateway 
• 
As soon as the EDC becomes available, the data should be entered in the eCRF and forwarded to 
Alexion GPV via the RAVE Safety Gateway. 
• 
When further information becomes available, the eCRF should be updated with the new 
information and an updated SAE report should be submitted to Alexion GPV via the RAVE Safety 
Gateway.  
• 
After the study is completed at a given site, the EDC will be taken offline to prevent the entry of 
new data or changes to existing data. 
• 
If a site identifies a new SAE from a study patient or receives updated data on a previously 
reported SAE after the electronic data collection tool has been taken offline, then the site can 
report this information on a paper SAE form to Alexion GPV. 
SAE Reporting to Alexion or Designee via Paper Contingency Case Report Form 
• 
If applicable, additional information such as relevant medical records should be submitted to 
Alexion GPV via the email address or facsimile number noted above.  
• 
All paper forms and follow-up information submitted to the Sponsor outside of the RAVE Safety 
Gateway (eg, discharge summary) should be kept in the appropriate section of the study file. 
 


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10.4. 
Appendix 4: Contraceptive Guidance and Collection of Pregnancy 
Information 
10.4.1. 
Contraception Guidance 
Before receiving study drug, female patients who consider themselves to be postmenopausal 
must provide evidence of menopause based on a combination of amenorrhea for at least 1 year 
and increased serum follicle-stimulating hormone level (> 30 IU/L). 
Patients of childbearing potential must use a highly effective or acceptable method of 
contraception (as defined below) starting at Screening and continuing for at least 8 months after 
the last dose of study drug. 
Highly effective contraceptive methods include:  
1. Hormonal contraception associated with inhibition of ovulation 
2. Intrauterine device 
3. Intrauterine hormone-releasing system 
4. Bilateral tubal occlusion 
5. Vasectomized partner provided that the partner is the patient’s sole sexual partner 
6. Sexual abstinence defined as refraining from heterosexual intercourse during the entire 
period of risk associated with the study drug treatment; reliability of sexual abstinence 
needs to be evaluated in relation to the duration of the clinical study and the preferred and 
usual lifestyle of the patient 
Acceptable contraceptive methods include:  
7. A combination of male condom with either cap, diaphragm, or sponge with spermicide 
(double barrier methods) 
The above-listed method(s) of contraception chosen for an individual patient can be determined 
by the Investigator with consideration for the patient’s medical history and concomitant 
medications.  
Patients with a spouse/partner of childbearing potential or a pregnant or breastfeeding spouse or 
partner must agree to use double barrier contraception (male condom plus appropriate barrier 
method for the female partner) while on treatment and for at least 8 months after the last dose of 
study drug. Double barrier contraception is required even with documented medical assessment 
of surgical success of a vasectomy.  
Male patients must not donate sperm and female patients must not donate ova while on treatment 
and for at least 8 months after the last dose of study drug. 
10.4.2. 
Pregnancy Testing 
Patients of childbearing potential should only be included after a menstrual period and a negative 
highly sensitive serum pregnancy test. 
Additional pregnancy testing should be performed per the time points specified in the SoA 
(Section 1.3). 


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Pregnancy testing will be performed whenever a menstrual cycle is missed or when pregnancy is 
otherwise suspected. 
10.4.3. 
Collection and Reporting of Pregnancy Information  
No studies of ALXN1210 have been conducted in pregnant women. Pregnant or nursing female 
patients are excluded from the study. Patients enrolled in the study, and a spouse or partner, will 
use a highly effective or acceptable method of contraception. 
In the event of a pregnancy event, pregnancy data will be collected during this study for all 
patients and a female spouse/partner of male patients. Exposure during pregnancy (also referred 
to as exposure in utero) can be the result of either maternal exposure or transmission of drug 
product via semen following paternal exposure. For all Alexion products, both in development or 
postapproval, exposure during pregnancy must be recorded and the pregnancy followed until the 
outcome of the pregnancy is known (ie, spontaneous miscarriage, elective termination, normal 
birth, or congenital abnormality), even if the patient discontinues study drug or withdraws from 
the study.  
If a female patient or a patient’s female partner becomes pregnant during the conduct of this 
study, the Investigator must submit the “Pregnancy Reporting and Outcome/Breastfeeding” form 
to Alexion GPV via facsimile or email (Section 10.3). When the outcome of the pregnancy 
becomes known, the form should be updated and submitted to Alexion GPV. If additional 
follow-up is required, the Investigator will be requested to provide the information. 
Exposure of an infant to an Alexion product during breastfeeding must also be reported (via the 
“Pregnancy Reporting and Outcome Form/Breastfeeding” form) and any AEs experienced by the 
infant must be reported to Alexion GPV or designee via email or facsimile (Section 10.3). 
Pregnancy in itself is not regarded as an AE unless there is a suspicion that the investigational 
product may have interfered with the effectiveness of a contraceptive medication. However, 
complications of pregnancy and abnormal outcomes of pregnancy are AEs and may meet the 
criteria for an SAE (eg, ectopic pregnancy, spontaneous abortion, intrauterine fetal demise, 
neonatal death, or congenital anomaly). Elective abortions without complications should not be 
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10.5. 
Appendix 5: Management of Potential Infusion-Associated Adverse 
Events During Study Drug Administration 
Intravenous and infusion-associated reactions are a potential risk with the use of mAbs; these 
reactions can be nonimmune or immune-mediated (eg, hypersensitivity reactions). Signs and 
symptoms may include headache, fever, facial flushing, pruritus, myalgia, nausea, chest 
tightness, dyspnea, vomiting, erythema, abdominal discomfort, diaphoresis, shivers, 
hypertension, lightheadedness, hypotension, palpitations, and somnolence. Signs and symptoms 
of hypersensitivity or allergic reactions may include hives, swollen face, eyelids, lips, or tongue, 
or trouble with breathing.  
All administration-, IV-, and infusion-associated reactions will be reported to the Investigator or 
qualified designee (Section 8.3). The Investigator or qualified designee are responsible for 
detecting, documenting, and recording events that meet the definition of AE or SAE and remain 
responsible for following up events that are serious, considered related to the study drug, or 
study procedures; or that caused the patient to discontinue the study drug (Section 7).  
Definitions and procedures for recording, evaluating, follow-up, and reporting AEs and SAEs are 
outlined in Section 10.3 (Appendix 3). 
Patients who experience a reaction during the administration of study drug should be treated 
according to institutional guidelines.  
Patients who experience a severe reaction during administration of study drug resulting in 
discontinuation of study drug should undergo all scheduled safety, PK, and PD evaluations 
required by the protocol. The Sponsor must be notified within 24 hours of any infusion reaction 
requiring interruption or discontinuation of study drug. All AEs that may indicate an 
infusion-related response will be graded according to the CTCAE v5.0 or higher. 
If anaphylaxis occurs according to the criteria listed below, then administration of SC 
epinephrine (1/1000, 0.3 mL to 0.5 mL, or equivalent) should be considered. In the case of 
bronchospasm, treatment with an inhaled beta agonist also should be considered. Patients 
administered an antihistamine for the treatment or prevention of an infusion reaction should be 
given appropriate warnings about drowsiness and impairment of driving ability before being 
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Clinical Criteria for Diagnosing Anaphylaxis: 
Anaphylaxis is highly likely when any 1 of the following 3 criteria is fulfilled: 
(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 1 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. 
Systolic BP of less than 90 mmHg or greater than 30% decrease from that patient’s baseline 
Abbreviations: BP = blood pressure; PEF = peak expiratory flow. 
Source: Sampson, 2006 


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10.6. 
Appendix 6: Myasthenia Gravis Activities of Daily Living Profile 
 


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10.7. 
Appendix 7: Quantitative Myasthenia Gravis Score for Disease 
Severity 
 


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10.8. 
Appendix 8: Myasthenia Gravis Composite Scale 
 


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10.9. 
Appendix 9: Euro Quality of Life Questionnaire  
 
 


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Appendix 9: Euro Quality of Life Questionnaire (Continued)
 
 


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Appendix 9: Euro Quality of Life Questionnaire (Continued) 
 


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10.10. 
Appendix 10: Myasthenia Gravis Quality-of-Life 15r Scale 
 


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10.11. 
Appendix 11: Neurology Quality of Life Fatigue 
 
 


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Appendix 11: Neurology Quality of Life Fatigue (Continued) 
 


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10.12. 
Appendix 12: Myasthenia Gravis Foundation of America Clinical 
Classification 
 


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10.13. 
Appendix 13: Myasthenia Gravis Foundation of America Post-
Interventional Status 
Note that a modified version of Change in Status (excludes “Exacerbation” and “Died of MG”) 
is used in this protocol (see Section 8.1.9). 
 


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10.14. 
Appendix 14: Columbia-Suicide Severity Rating Scale – 
Baseline/Screening (Version 1/14/09) 
 
 


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Appendix 14: Columbia-Suicide Severity Rating Scale – Baseline/Screening (Continued) 
 
 


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Appendix 14: Columbia-Suicide Severity Rating Scale – Baseline/Screening (Continued) 
  


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10.15. 
Appendix 15: Columbia-Suicide Severity Rating Scale - Since Last 
Visit (Version 1/14/09) 
 
 
 


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Appendix 15: Columbia-Suicide Severity Rating Scale - Since Last Visit (Continued) 
 
 


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Appendix 15: Columbia-Suicide Severity Rating Scale - Since Last Visit (Continued) 
 


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10.16. 
Appendix 16: Statistical Considerations 
10.16.1. 
Additional Details on Sample Size Determination 
The power calculations were based on the longitudinal change from baseline in MG-ADL total 
score observed in REGAIN (Study ECU-MG-301). The treatment effect (difference between 
the eculizumab and the placebo arms in mean change (95% CI) from baseline to Week 6 for 
MG-ADL) was estimated to be -1.9 (-3.27, -0.55) and the estimated common standard 
deviation was 3.7. Based on these parameter estimates and the assumption that ALXN1210-
MG-306 study will provide similar results, a total of N = 160 patients is required to ensure at 
least 90% power to reject the null hypothesis of no treatment effect for MG-ADL at the 
Type I error rate = 5% (2-sided) based on a t-statistic for two independent samples. A 
simulation-based approach was also adopted to independently verify the sample size calculation 
in which a large number of virtual datasets were generated with a total of 160 patients 
(equally distributed between two arms) each having a longitudinal profile of change in MG-
ADL and baseline MG-ADL score generated according to the treatment-specific variance-
covariance structure obtained from REGAIN database. The empirical power was calculated 
by the proportion of times these virtual trials rejected the null hypothesis based on the 
MMRM model described above. 
10.16.2. 
Additional Details on Sensitivity Analysis for Primary Endpoint 
To assess the credibility of the primary analysis, the following sensitivity analyses are planned, 
based on assumptions that are unfavorable enough to the ravulizumab group to constitute a 
convincing stress test of the primary analysis. 
10.16.2.1. Placebo-based Sensitivity Analysis 
The placebo-based sensitivity analysis will consider the MNAR mechanism for the missing data, 
where it will be assumed that patients who discontinue early from the ravulizumab group will 
follow the trajectory of outcomes similar to the one in the placebo group after discontinuation of 
ravulizumab, taking into account observed values prior to discontinuation (Little, 1996); 
(Ratitch, 2013). Patients discontinuing early from placebo will be assumed to have unobserved 
outcomes similar to placebo patients who remain on their randomized treatment. The assumption 
that the efficacy profiles of dropouts after discontinuation of ravulizumab are similar to those of 
patients in the placebo group provides an estimand of efficacy attributable to patients in the 
ravulizumab group if received through the time point of interest, while limiting efficacy after 
early discontinuation to that of the placebo group.  
10.16.2.2. Tipping Point Sensitivity Analysis 
An additional sensitivity analysis will be performed based on the delta-adjusted stress testing 
method (tipping point analysis). This approach assumes that patients who discontinue from the 
active treatment experience worsening defined by a prespecified adjustment (delta) in the 
primary efficacy endpoint compared with the observed efficacy score of patients that continue 
the study to next visit (O'Kelley, 2014). Since a negative change in QMG total score indicates 
improvement, the prespecified value of delta will be a non-negative fixed quantity. For each 
value of delta, the treatment effect will be determined and the value of delta for which the 


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nominal 2-sided p-value crosses 0.05, will be considered as the ‘tipping point’ in the sense that 
the positive conclusion drawn from the primary analysis is reversed when patients who drop out 
are assumed to experience this fixed worsening after the discontinuation visit. After such a 
tipping point is determined, clinical judgment will be applied as to the plausibility of the 
assumptions underlying this tipping point. This methodology is expected to inform of what it 
would take to overturn study conclusions based on varying assumptions about missing data. A 
value of delta as zero will be considered equivalent to the primary analysis.  
 


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10.17. 
Appendix 17: Abbreviations 
Table 11: 
List of Abbreviations and Definitions of Terms 
AChR 
acetylcholine receptor 
AChR Ab 
acetylcholine receptor antibody 
ADA 
antidrug antibody 
ADL 
activities of daily living 
AE 
adverse event 
AESI 
adverse event of special interest 
aHUS 
atypical hemolytic uremic syndrome 
Alexion 
Alexion Pharmaceuticals, Inc.; the Sponsor 
AST 
aspartate aminotransferase 
AZA 
azathioprine 
BP 
blood pressure 
BUN 
blood urea nitrogen 
C5 
complement component 5 
C5b-9 
terminal complement complex 
CFR 
Code of Federal Regulations 
CIOMS 
Council for International Organizations of Medical Sciences 
CRF 
case report form 
CFR 
Code of Federal Regulations 
C-SSRS 
Columbia Suicide Severity Rating Scale 
CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse 
Events 
CY 
cyclophosphamide 
CYC 
cyclosporine 
EC 
Ethics Committee 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EOS 
End of Study 
EQ-5D-5L 
Euro Quality of Life 
ET 
Early Termination 
EU 
European Union 
FDA 
(US) Food and Drug Administration 


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Table 11: 
List of Abbreviations and Definitions of Terms (Continued) 
GCP 
Good Clinical Practice 
gMG 
generalized myasthenia gravis 
GPV 
Global Pharmacovigilance 
HIV 
human immunodeficiency virus 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use  
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
IRT 
interactive response technology 
IST 
immunosuppressant therapy 
IV 
intravenous(ly) 
IVIg 
intravenous immunoglobulin 
mAb 
monoclonal antibody 
MAC 
membrane attack complex 
MedDRA 
Medical Dictionary for Regulatory Activities 
MG 
myasthenia gravis 
MG-ADL 
Myasthenia Gravis Activities of Daily Living profile 
MGC 
Myasthenia Gravis Composite score 
MGFA 
Myasthenia Gravis Foundation of America 
MGFA-PIS 
Myasthenia Gravis Foundation of America Post-Intervention Status 
MG-QoL15r 
Revised Myasthenia Gravis Quality of Life 15-item scale 
MM 
minimal manifestation 
MMF 
mycophenolate mofetil 
MMRM 
Mixed-effects Model with Repeated Measures 
MNAR 
Missing Not At Random 
MTX 
methotrexate 
N meningitidis 
Neisseria meningitidis 
NCI-CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse 
Events 
Neuro-QOL  
Neurological Quality of Life 
NMJ 
neuromuscular junction 


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Table 11: 
List of Abbreviations and Definitions of Terms (Continued) 
OLE 
Open-Label Extension 
oMG 
ocular myasthenia gravis 
PD 
pharmacodynamic(s) 
PE 
plasma exchange 
PIS 
post-intervention status 
PP 
plasmapheresis  
PK 
pharmacokinetic(s) 
PNH 
paroxysmal nocturnal hemoglobinuria 
PPS 
Per protocol set 
Q2W 
every 2 weeks 
Q8W 
every 8 weeks 
QMG 
Quantitative Myasthenia Gravis score for disease severity 
QoL 
quality of life 
QT 
interval between the start of the Q wave and the end of the T wave in 
an ECG 
QTc 
corrected QT interval 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SC 
subcutaneous 
SO2 
oxygen saturation 
SoA 
Schedule of Activities 
SOC 
system organ class 
SUSAR 
suspected unexpected serious adverse reaction 
TAC 
tacrolimus 
TEAE 
treatment-emergent adverse event 
TESAE 
treatment-emergent serious adverse event 
 
 


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10.18. 
Appendix 18: Protocol Amendment History  
Amendment 1 (11 Dec 2018) 
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of 
Directive 2001/20/EC of the European Parliament and the Council of the European Union. 
Overall Rationale for the Amendment 
To change duration of safety follow-up after last dose; add additional details on assessments, 
align pregnancy and clinical laboratory testing frequency with infusions; change supplemental 
dosing recommendations and sample collection when rescue therapy is provided; and update 
adverse event and pregnancy/contraception language. 
Section # and Name 
Description of Change 
Brief Rationale 
Section 1.1: Synopsis; Section 4.1: 
Overall Design; Section 7.1: 
Discontinuation of Study 
Intervention; Section 8.3.1: Time 
Period and Frequency for Collecting 
Adverse Event and SAE Information 
Patients will be followed for safety for 
8 weeks after last dose of study drug. 
A 24-week follow-up in 
patients is not feasible as 
safety data would likely be 
confounded by new 
treatments. 
 
To align with duration of 
safety follow-up for other 
ravulizumab programs. 
Section 1.3: Schedule of Activities 
Changed terminology of targeted 
physical examination to abbreviated 
physical examination throughout 
protocol. 
 
Clarification that C-SSRS 
Baseline/Screening Version assessment 
will occur on Day 1 and C-SSRS Since 
Last Visit Version assessment will 
occur on subsequent indicated visits. 
 
Added reference to section detailing 
assigned evaluator for assessment 
instruments. 
 
Frequency of Clinical Lab Test and 
Pregnancy Test assessments reduced 
and aligned with infusion visits. 
 
Clarified PK/PD and ADA sample 
collection should occur in the event of 
Clinical Deterioration.  
To align with terminology 
for physical examination. 
 
 
To ensure appropriate C-
SSRS versions are 
administered. 
 
 
 
 
To precisely specify 
appropriate evaluator for 
each assessment instrument.  
 
To align with infusion visits 
and reduce burden on 
patients. 
 
To ensure PK/PD and ADA 
analyses are performed 
consistently across events if 
Clinical Deterioration occurs. 
Section 4.2.2: Unscheduled Visits 
Specified that efforts will be made to 
map unscheduled visit data with the 
appropriate visit in the eCRF. 
To ensure data is associated 
with the appropriate visit. 
Section 4.2.3: Properly Trained 
Clinical Evaluator 
Removed EQ-5D-5L and MG-QOL15r 
from section as these instruments are 
completed by patients. 
To clarify as these 
assessments are completed 
by patients. 
Section 4.2.4: Responsibilities for 
Myasthenia Gravis Assessments 
Removed EQ-5D-5L and MG-QOL15r 
from Myasthenia Gravis Assessments 
and Responsibilities table. 
To clarify as assessments are 
completed by the patient. 


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Section # and Name 
Description of Change 
Brief Rationale 
Section 6.1: Study Drugs 
Administered 
Updated Table 6 to indicate volumes 
needed for ravulizumab, placebo, and 
diluent. 
To ensure proper preparation 
of placebo and ravulizumab 
doses. 
Section 6.2.4: Accountability 
Updated details for study drug 
accountability to reflect use of 
interactive response technology (IRT) 
and study monitors. 
To ensure proper 
accountability of study drug 
while using IRT. 
Section 6.2.5: Handling and Disposal 
Provided details for study drug handling 
and disposal. 
To provide additional details 
on proper handling and 
disposal of study drug. 
Section 6.5.1.4: Plasma 
Exchange/Plasmapheresis/Intravenous 
Immunoglobulin 
Updated timing and dosing levels for 
supplemental study drug administration 
when PE/PP or IVIg rescue therapy is 
provided. 
To ensure proper and 
consistent dosing of 
supplemental study drug 
following PE/PP or IVIg. 
Section 8.1.1: Hospitalization 
Updated definition of hospitalization. 
To ensure admission to 
facility overnight is collected 
as hospitalization. 
Section 8.1.2: Clinical Deterioration 
Section 10.2 (Appendix 2) referenced in 
clinical laboratory tests. 
 
MG Crisis or Clinical Deterioration 
Visit changed to Clinical Deterioration 
Visit. 
To align with Section 10.2 
(Appendix 2): Clinical 
laboratory tests. 
 
To provide consistency with 
Clinical Deterioration 
criteria. 
Section 8.2.5.1: Columbia-Suicidal 
Severity Rating Scale 
Updated to detail the C-SSRS will be 
administered by the Investigator or a 
properly trained designee.  
To align with other sections 
of the protocol indicating the 
Investigator or a properly 
trained designee will 
administer the assessment. 
Section 8.3.1: Time Period and 
Frequency for Collecting Adverse 
Event and SAE Information 
Updated language on submission of 
SAE data. 
To align with current 
practices. 
Section 8.3.4: Regulatory Reporting 
Requirements for Serious Adverse 
Events 
Added language on reporting of 
SUSARs. 
To align with regulatory 
feedback on ravulizumab 
program. 
Section 8.3.5: Pregnancy; Section 1.3: 
Schedule of Activities 
Updated to indicate that serum 
pregnancy testing will occur at 
Screening and at the End of Study. 
To align with Table 1 and 
Table 2 of Schedule of 
Activities. 
Section 10.2 (Appendix 2): Clinical 
Laboratory Tests 
Added serum follicle stimulating 
hormone and urine creatinine testing. 
Removed D-dimer and free hemoglobin 
testing. 
To fix inconsistencies 
between protocol sections 
and remove D-dimer and free 
hemoglobin assessment. 
Section 10.3.4 (Appendix 3): 
Recording and Follow-Up of Adverse 
Event and/or Serious Adverse Event  
Updated to clarify that the expectedness 
and reporting criteria of an SAE will be 
based on the Reference Safety 
Document. 
To ensure Reference Safety 
Document is used when 
recording an AE. 
Section 10.4.1 (Appendix 4): 
Contraception Guidance 
Updated to indicate that male patients 
must not donate sperm and female 
patients must not donate ova while on 
treatment and for at least 8 months after 
the last dose of study drug. 
To align with current 
Alexion language. 
Section 10.4.3 (Appendix 4): 
Collection and Reporting of 
Pregnancy Information 
Updated language on collection and 
reporting of pregnancy information. 
To align with current 
Alexion language. 


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Section # and Name 
Description of Change 
Brief Rationale 
Section 10.5 (Appendix 5): 
Management of Potential Infusion-
Associated Adverse Events During 
Study Drug Administration 
Updated to indicate CTCAE v5.0 or 
higher will be used to grade an infusion-
related response. 
To align with proper CTCAE 
version planned for use. 
Throughout 
Minor editorial and document 
formatting revisions have been made 
throughout the document. 
As these changes are minor, 
they have not been 
summarized. 
Abbreviations: ADA = antidrug antibody; AE = adverse event; C-SSRS = Columbia Suicide Severity Rating Scale; 
CTCAE = National Cancer Institute Common Terminology Criteria for Adverse Events; eCRF = electronic case 
report file; EQ-5D-5L = Euro Quality of Life; IRT = interactive response technology; IVIg = intravenous 
immunoglobulin; MG = myasthenia gravis; MG-QoL15r = Revised Myasthenia Gravis Quality of Life 15-item 
scale; PD = pharmacodynamic; PE = plasma exchange; PK = pharmacokinetic; PP = plasmapheresis; SAE = serious 
adverse event; SUSAR = suspected unexpected serious adverse reaction 
 


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11. 
REFERENCES 
Benatar M, Sanders DB, Burns TM, et al. Recommendations for myasthenia gravis clinical trials. 
Muscle Nerve. 2012;45(6):909-917. 
Brooks R. EuroQol: the current state of play. Health Policy. 1996;37(1):53-72. 
Burns TM, Conaway M, Sanders DB. The MG Composite: A valid and reliable outcome 
measure for myasthenia gravis. Neurology. 2010;74(18):1434-1440. 
Burns TM, Sadjadi R, Utsugisawa K, et al. International clinimetric evaluation of the MG-
QOL15, resulting in slight revision and subsequent validation of the MG-QOL15r. Muscle & 
Nerve. 2016;54(6):1015-1022. 
Casadevall N, Nataf J, Viron B, et al. Pure red-cell aplasia and antierythropoietin antibodies in 
patients treated with recombinant erythropoietin. N Engl J Med. 2002;346(7):469-475. 
Cella D. Measuring Quality of Life in Neurological Disorders; Final Report of the Neuro-QOL 
Study September 2010. 2010 2010. Report No. 
Cetin H, Fulop G, Zach H, Auff E, Zimprich F. Epidemiology of myasthenia gravis in Austria: 
rising prevalence in an ageing society. Wien Klin Wochenschr. 2012;124(21-22):763-768. 
Chaudhury C, Brooks CL, Carter DC, Robinson JM, Anderson CL. Albumin binding to FcRn: 
distinct from the FcRn-IgG interaction. Biochemistry. 2006;45(15):4983-4990. 
Christensen PB, Jensen TS, Tsiropoulos I, et al. Mortality and survival in myasthenia gravis: a 
Danish population based study. Journal of Neurology, Neurosurgery &amp; Psychiatry. 
1998;64(1):78-83. 
Dalakas MC. Intravenous Immunoglobulin in Autoimmune Neuromuscular Diseases. JAMA. 
2004;291:2367-2375. 
Engel-Nitz NM, Boscoe A, Wolbeck R, Johnson J, Silvestri NJ. Burden of illness in patients 
with treatment refractory myasthenia gravis. Muscle & Nerve. 2018;58(1):99-105. 
Fang F, Sveinsson O, Thormar G, et al. The autoimmune spectrum of myasthenia gravis: a 
Swedish population-based study. Journal of internal medicine. 2015;277(5):594-604. 
Fitch JC, Rollins S, Matis L, et al. Pharmacology and biological efficacy of a recombinant, 
humanized, single-chain antibody C5 complement inhibitor in patients undergoing coronary 
artery bypass graft surgery with cardiopulmonary bypass. Circulation. 1999;100(25):2499-2506. 
Fitzpatrick AM, Mann CA, Barry S, Brennan K, Overell JR, Willison HJ. An open label clinical 
trial of complement inhibition in multifocal motor neuropathy. J Peripher Nerv Syst. 
2011;16(2):84-91. 


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Ha JC, Richman DP. Myasthenia gravis and related disorders: Pathology and molecular 
pathogenesis. Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease. 
2015;1852(4):651-657. 
Heldal AT, Owe JF, Gilhus NE, Romi F. Seropositive myasthenia gravis: a nationwide 
epidemiologic study. Neurology. 2009;73(2):150-151. 
Howard JF, Freimer M, O'Brien F, Wang JJ, Collins SR, Kissel JT. QMG and MG-ADL 
correlations: Study of eculizumab treatment of myasthenia gravis. Muscle & Nerve. 
2017;56(2):328-330. 
Janssen MF, Pickard AS, Golicki D, et al. Measurement properties of the EQ-5D-5L compared 
to the EQ-5D-3L across eight patient groups: a multi-country study. Quality of Life Research. 
2013;22(7):1717-1727. 
Keshavjee S, Davis RD, Zamora MR, de PM, Patterson GA. A randomized, placebo-controlled 
trial of complement inhibition in ischemia-reperfusion injury after lung transplantation in human 
beings. J Thorac Cardiovasc Surg. 2005;129(2):423-428. 
Kusner LL, Kaminski HJ, Soltys J. Effect of complement and its regulation on myasthenia gravis 
pathogenesis. Expert Rev Clin Immunol. 2008;4(1):43-52. 
Li J, Yang C, Xia Y, et al. Thrombocytopenia caused by the development of antibodies to 
thrombopoietin. Blood. 2001;98(12):3241-3248. 
Little R, Yau L. Intent-to-Treat Analysis for Longitudinal Studies with Drop-Outs. Biometrics. 
1996;52(4):1324-1333. 
O'Kelley M RB. Clinical trials with missing data: a guide for practitioners.  Statistics in Practice. 
Statistics in Practice. 1 ed. Chichester, West Sussex, UK: John Wiley & Sons, Ltd; 2014. p. 257-
368. 
Patel MR, Granger CB. Pexelizumab: a novel therapy for myocardial ischemia-reperfusion. 
Drugs Today (Barc ). 2005;41(3):165-170. 
Posner K, Brown GK, Stanley B, et al. The Columbia-Suicide Severity Rating Scale: initial 
validity and internal consistency findings from three multisite studies with adolescents and 
adults. Am J Psychiatry. 2011;168(12):1266-1277. 
Ratitch B, O'Kelly M, Tosiello R. Missing data in clinical trials: from clinical assumptions to 
statistical analysis using pattern mixture models. Pharmaceutical Statistics. 2013;12(6):337-347. 
Sahashi K, Engel AG, Linstrom JM, Lambert EH, Lennon VA. Ultrastructural localization of 
immune complexes (IgG and C3) at the end-plate in experimental autoimmune myasthenia 
gravis. J Neuropathol Exp Neurol. 1978;37(2):212-223. 
Sampson HA, Munoz-Furlong A, Campbell RL, et al. Second symposium on the definition and 
management of anaphylaxis: summary report--Second National Institute of Allergy and 


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Infectious Disease/Food Allergy and Anaphylaxis Network symposium. J Allergy Clin Immunol. 
2006;117(2):391-397. 
Silvestri NJ, Wolfe GI. Treatment-refractory myasthenia gravis. J Clin Neuromuscul Dis. 
2014;15(4):167-178. 
Suh J, Goldstein JM, Nowak RJ. Clinical characteristics of refractory myasthenia gravis patients. 
Yale J Biol Med. 2013;86(2):255-260. 

SAP_001.pdf: 
NCT #NCT03920293 
Statistical Analysis Plan 
 
A Phase 3, Randomized, Double-Blind, Placebo- 
Controlled, Multicenter Study to Evaluate the Safety and 
Efficacy of Ravulizumab in Complement-Inhibitor-Naïve 
Adult Patients With Generalized Myasthenia Gravis 
 
 
 
Version 
Date 
SAP V1.0 
06 April 2020 
SAP Addendum  03 December 2020 
SAP Addendum 2 10 June 2021 


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Alexion Pharmaceuticals, Inc. 
 
 
 
 
 
 
 
 
 
STATISTICAL ANALYSIS PLAN 
 
 
 
PROTOCOL NUMBER: ALXN1210-MG-306 
 
 
A Phase 3, Randomized, Double-Blind, Placebo-Controlled, Multicenter Study to Evaluate the 
Safety and Efficacy of Ravulizumab in Complement-Inhibitor-Naïve Adult Patients With 
Generalized Myasthenia Gravis 
 
 
 
 
 
 
 
 
 
Author: PPD 
Date: 6 April 2020 
Version: 1.0 


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1. 
APPROVAL SIGNATURES 
 
 
 
 
 
08-Apr-2020 | 09:57:57 EDT 
 
 
Date dd Mmm yyyy 
 
 
 
 
08-Apr-2020 | 09:57:57 EDT 
 
Date dd Mmm yyyy 
 
 
 
 
 
08-Apr-2020 | 09:57:57 EDT 
 
Date dd Mmm yyyy 
PPD 


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2. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF 
FIGURES 
TABLE OF CONTENTS 
1. 
APPROVAL SIGNATURES ........................................................................................ 2 
2. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES ................. 3 
TABLE OF CONTENTS ................................................................................................................. 3 
LIST OF TABLES ........................................................................................................................... 6 
LIST OF FIGURES .......................................................................................................................... 7 
3. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ............................... 8 
4. 
DESCRIPTION OF THE PROTOCOL ...................................................................... 10 
4.1. 
Planned Analyses ........................................................................................................ 11 
4.2. 
Changes From Analyses Specified in the Protocol ..................................................... 11 
4.3. 
Changes From Analyses Specified in the Previous Version of the SAP .................... 11 
5. 
DEFINITIONS ............................................................................................................ 12 
5.1. 
Efficacy ....................................................................................................................... 12 
5.1.1. 
Primary Endpoint(s) .................................................................................................... 12 
5.1.2. 
Secondary Endpoints ................................................................................................... 12 
5.1.2.1. 
Quantitative Myasthenia Gravis Total Score .............................................................. 12 
5.1.2.2. 
Revised Myasthenia Gravis Qualify of Life-15 Scale ................................................. 13 
5.1.2.3. 
Neuro-QOL Fatigue Scale ........................................................................................... 13 
5.1.3. 
Exploratory Endpoints ................................................................................................ 13 
5.1.3.1. 
Myasthenia Gravis Composite Scale .......................................................................... 13 
5.1.3.2. 
Myasthenia Gravis Foundation of America Post-Intervention Status ......................... 14 
5.1.3.3. 
European Quality of Life 5-Dimension-5-Level ......................................................... 14 
5.1.3.4. 
Myasthenia Gravis-Activities of Daily Living Subcomponent Scores ....................... 14 
5.1.3.5. 
Quantitative Myasthenia Gravis Subcomponent Scores ............................................. 14 
5.1.3.6. 
Clinical Deterioration .................................................................................................. 14 
5.2. 
Safety .......................................................................................................................... 15 
5.2.1. 
Adverse Events (AEs) ................................................................................................. 15 
5.2.1.1. 
Adverse Events of Special Interest ............................................................................. 15 
5.2.2. 
Vital Signs and Pulse Oximetry .................................................................................. 15 
5.2.3. 
Laboratory Assessments .............................................................................................. 16 


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5.2.4. 
Electrocardiograms (ECGs) ........................................................................................ 16 
5.2.5. 
Physical Examination .................................................................................................. 16 
5.2.6. 
Suicidal Risk Monitoring ............................................................................................ 16 
5.3. 
Pharmacokinetic/Pharmacodynamic/Immunogenicity ................................................. 16 
5.4. 
Exploratory Biomarkers .............................................................................................. 16 
6. 
DATA SETS ANALYZED (STUDY POPULATIONS) ........................................... 17 
6.1. 
Full Analysis Set (FAS) .............................................................................................. 17 
6.2. 
Per Protocol Set (PPS) ................................................................................................ 17 
6.3. 
Safety Set .................................................................................................................... 18 
6.4. 
Other Sets .................................................................................................................... 18 
7. 
STATISTICAL ANALYSIS ....................................................................................... 19 
7.1. 
Study Patients .............................................................................................................. 19 
7.1.1. 
Disposition of Patients ................................................................................................ 19 
7.1.2. 
Protocol Deviations ..................................................................................................... 20 
7.1.3. 
Demographics, Disease Characteristics, and History ................................................. 20 
7.1.3.1. 
Demographics ............................................................................................................. 20 
7.1.3.2. 
Disease Characteristics ................................................................................................ 21 
7.1.3.3. 
Medical/Surgical History and Baseline Physical Examination ................................... 21 
7.1.4. 
Prior and Concomitant Medications / Therapies ......................................................... 21 
7.2. 
Efficacy Analyses ....................................................................................................... 23 
7.2.1. 
Primary Analysis ......................................................................................................... 23 
7.2.1.1. 
Handling of Dropouts or Missing Data ....................................................................... 23 
7.2.1.2. 
Subgroup Analysis ...................................................................................................... 24 
7.2.1.3. 
Multicenter Studies ...................................................................................................... 24 
7.2.1.4. 
Hypothesis Testing and Significance Level ................................................................ 24 
7.2.1.5. 
Sensitivity Analyses .................................................................................................... 25 
7.2.2. 
Secondary Analyses .................................................................................................... 26 
7.2.3. 
Exploratory Analyses .................................................................................................. 27 
7.2.4. 
Other Efficacy Analyses .............................................................................................. 28 
7.2.5. 
Pharmacokinetic and Pharmacodynamic Analyses ..................................................... 28 
7.2.6. 
Exploratory Biomarker Analyses ................................................................................ 29 
7.3. 
Safety Analyses ........................................................................................................... 29 
7.3.1. 
Study Duration, Treatment Compliance, and Exposure .............................................. 29 


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7.3.2. 
Adverse Events (AEs) .................................................................................................30 
7.3.2.1. 
Overall Summary of Adverse Events ..........................................................................31 
7.3.2.2. 
Adverse Events and Serious Adverse Events by System Organ Class and 
Preferred Term ............................................................................................................32 
7.3.2.3. 
Adverse Events and Serious Adverse Events by System Organ Class, 
Preferred Term, and Relationship ...............................................................................32 
7.3.2.4. 
Adverse Events and Serious Adverse Events by System Organ Class, 
Preferred Term, and Severity ......................................................................................32 
7.3.2.5. 
Deaths, Other Serious Adverse Events, and Other Significant Adverse 
Events ..........................................................................................................................32 
7.3.3. 
Other Safety ................................................................................................................32 
7.3.3.1. 
Analyses for Laboratory Tests ....................................................................................32 
7.3.3.2. 
Vital Signs, Pulse Oximetry, and Physical Examination ............................................33 
7.3.3.3. 
Electrocardiogram (ECG) ...........................................................................................33 
7.3.3.4. 
Immunogenicity ..........................................................................................................34 
7.3.3.5. 
Columbia-Suicide Severity Rating Scale (C-SSRS) ...................................................34 
8. 
REFERENCES............................................................................................................35 
9. 
APPENDICES ............................................................................................................36 
9.1. 
Protocol Schedule of events ........................................................................................36 
9.2. 
Sample Size, Power, and Randomization....................................................................36 
9.3. 
Technical Specifications for Derived Variables .........................................................36 
9.4. 
Additional Details on Statistical Methods ..................................................................38 
9.4.1. 
Myasthenia Gravis-Activities of Daily Living Subcomponent Scores .......................38 
9.4.2. 
Quantitative Myasthenia Gravis Score for Disease Severity Subcomponent 
Scores ..........................................................................................................................38 
9.4.3. 
European Quality of Life 5 dimension-5-level Health State Index 
Calculations .................................................................................................................38 
9.4.4. 
SAS Code for Repeated Measures Mixed Model Analysis ........................................39 
9.4.5. 
SAS Code for Placebo-based Sensitivity Analysis .....................................................40 
9.4.6. 
SAS Code for Tipping Point Sensitivity Analysis ......................................................41 
9.4.7. 
SAS Code for Mixed Effect Repeated Measures Model ............................................41 
9.4.8. 
SAS Code for Proportional Odds Model ....................................................................42 
9.4.9. 
SAS Code for Poisson Regression ..............................................................................42 


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LIST OF TABLES 
Table 1: 
Abbreviations and Acronyms ........................................................................................8 
Table 2: 
Analysis Periods From Day 1 Through the Data Cutoff Date ....................................19 
Table 3: 
Age and Reference Date..............................................................................................36 
Table 4: 
EQ-5D-5L US Composite Time Trade-off (cTTO) Value Set ...................................39 


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LIST OF FIGURES 
No table of figures entries found. 


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3. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
The following abbreviations and acronyms are used in this Statistical Analysis Plan (SAP). 
Table 1:   Abbreviations and Acronyms 
Abbreviation or Acronym 
Explanation 
AChR Ab 
acetylcholine receptor antibody 
ADA 
antidrug antibody 
ADL 
activities of daily living 
AE 
adverse event 
AESI 
adverse events of special interest 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
AZA 
azathioprine 
bpm 
beats per minute 
C5 
complement component 5 
CI 
confidence interval 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CSR 
clinical study report 
CTCAE 
Common Terminology Criteria for Adverse Events 
cTTO 
composite time trade-off 
EC 
exclusion criteria 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EQ-5D-5L 
European Quality of Life 5 dimension-5-level 
FAS 
full analysis set 
FDA 
Food and Drug Administration 
gMG 
generalized myasthenia gravis 
HR 
heart rate 
IC 
inclusion criteria 
IST 
immunosuppressive therapy 
LLT 
Lowest Level Term 
MAR 
missing at random 
MedDRA 
Medical Dictionary for Regulatory Activities 
MCMC 
Markov Chain Monte Carlo 
MG 
myasthenia gravis 
MG-ADL 
Myasthenia Gravis-Activities of Daily Living 
MGC 
Myasthenia Gravis Composite scale 
MGFA 
Myasthenia Gravis Foundation of America 
MGFA-PIS 
Myasthenia Gravis Foundation of America Post-Intervention Status 
MG-QOL15r 
Revised 15 Component Myasthenia Gravis Quality of Life 
MM 
minimal manifestation 
MMF 
mycophenolate mofetil 
MMRM 
mixed-effect model for repeated measures 
MNAR 
missing not at random 
Neuro-QOL 
Neurological Quality of Life 
oMG 
ocular myasthenia gravis 
OLE 
Open-label Extension 
OLES 
Open-label Extension Set 


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Abbreviation or Acronym 
Explanation 
OLEES 
Open-label Efficacy Extension Set 
OR 
Odds ratio 
PY 
patient years 
PD 
pharmacodynamic(s) 
PK 
pharmacokinetic(s) 
PKAS 
PK analysis set 
PPS 
Per Protocol set 
PTAE 
pre-treatment adverse event 
q8w 
every 8 weeks 
QMG 
Quantitative Myasthenia Gravis score for disease severity 
QoL 
quality of life 
QT 
interval between the start of the Q-wave and the end of the T-wave in an 
ECG 
QTc 
corrected QT interval 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SAS 
statistical analysis software® 
SD 
Standard deviation 
SOC 
System Organ Class 
SS 
Safety Set 
TEAE 
treatment-emergent adverse event 
VAS 
visual analogue scale 
WHO-DD 
World Health Organization Drug Dictionary 


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4. 
DESCRIPTION OF THE PROTOCOL 
ALXN1210-MG-306 is a Phase 3, randomized, double-blind, parallel-group, placebo-controlled, 
multicenter study to evaluate the safety and efficacy of ravulizumab for the treatment of adult 
patients with generalized myasthenia gravis (gMG). Approximately 160 eligible patients will be 
randomized 1:1 to 1 of 2 treatment groups: (1) ravulizumab infusion or (2) placebo infusion; 
randomization will be stratified by region (North America, Europe, Asia-Pacific, and Japan). 
There will be 3 periods in this study: a 4-week Screening Period, a 26-week 
Randomized-Controlled Period, and an Open-label Extension (OLE) Period of up to 2 years. 
Patients being treated with an immunosuppressive therapy (IST) at the time of the Screening 
Visit may continue to receive ISTs throughout the Randomized-Controlled and OLE Periods. 
However, the dosage of IST must not be changed, and no new ISTs may be added during the 
Randomized-Controlled Period of the study, unless deemed by the Investigator to be medically 
necessary. 
Throughout the study, rescue therapy (eg, high-dose corticosteroids, acute 
plasmapheresis/plasma exchange, or acute intravenous immunoglobulin) will be allowed if a 
patient experiences Clinical Deterioration, as defined by the study protocol. The rescue therapy 
for a particular patient will be at the discretion of the Investigator. 
During the Randomized-Controlled Period, patients in the ravulizumab or placebo treatment 
groups will receive a weight-based loading dose of ravulizumab or placebo, respectively, on 
Day 1. At Week 2, patients will receive weight-based maintenance doses of ravulizumab or 
placebo, respectively, every 8 weeks (q8w) through the completion of the 
Randomized-Controlled Period. 
After the 26-week Randomized-Controlled Period and assessments on Week 26 (Day 183), 
patients randomized to the placebo group will receive a blinded weight-based loading dose of 
ravulizumab and patients randomized to the ravulizumab group will receive a blinded flat dose of 
ravulizumab 900 mg to ensure maintenance of complete complement component (C5) inhibition 
until the next scheduled maintenance dose at Week 28 (Day 197). Starting at Week 28, all 
patients will begin open-label ravulizumab maintenance doses q8w. 
The primary objective of this study is to assess the efficacy of ravulizumab compared with 
placebo in the treatment of gMG based on the improvement in the Myasthenia Gravis-Activities 
of Daily Living (MG-ADL) profile. 
The secondary objectives of the study are the following: 
• 
To assess the efficacy of ravulizumab compared with placebo in the treatment of 
gMG based on the improvement in the Quantitative Myasthenia Gravis (QMG) total 
score. 
• 
To assess the efficacy of ravulizumab compared with placebo in the treatment of 
gMG based on the improvement in quality of life measures. 
• 
To assess the efficacy of ravulizumab compared with placebo in the treatment of 
gMG based on other efficacy endpoints. 


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4.1. 
Planned Analyses 
A clinical study report (CSR) will be produced based on efficacy, safety, pharmacokinetic(s) 
(PK), pharmacodynamic(s) (PD), and immunogenicity data collected through the end of the 
26-week Randomized-Controlled Period. For patients in the OLE at the time of database lock, 
long-term data will be included up to a data cutoff date which will occur when the last patient 
enrolled completes the Randomized-Controlled Period. Assessments to be included are: primary, 
and secondary endpoints, and clinical laboratory assessments up to Week 52 as well as adverse 
events (AEs), serious adverse events (SAEs), and concomitant medications up to the data cutoff. 
This SAP outlines only the analyses that are to be included in the CSR. 
A final SAP/CSR to summarize long-term efficacy, safety, PK, PD, and immunogenicity 
parameters will be produced at study completion. 
 
4.2. 
Changes From Analyses Specified in the Protocol 
None. 
 
4.3. 
Changes From Analyses Specified in the Previous Version of the SAP 
Not applicable. 


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5. 
DEFINITIONS 
5.1. 
Efficacy 
5.1.1. 
Primary Endpoint(s) 
The primary endpoint of the study is change from Baseline in MG-ADL total score at Week 26 
of the Randomized-Controlled Period. 
The MG-ADL is an 8-point questionnaire that focuses on relevant symptoms and functional 
performance of ADL in patients with myasthenia gravis (MG) (refer to Section 10.6 
[Appendix 6] of the protocol). The 8 items of the MG-ADL questionnaire are derived from 
symptom-based components of the original 13-item QMG scale to assess disability secondary to 
ocular (2 items), bulbar (3 items), respiratory (1 item), and gross motor or limb (2 items) 
impairment related to effects from MG. In this functional status instrument, each response is 
graded 0 (normal) to 3 (most severe). The range of total MG-ADL score is between 0 to 24 
(inclusive). Higher scores indicate worse symptoms. The recall period for MG-ADL is the 
preceding 7 days. 
A 2-point reduction in MG-ADL total score is considered a clinically meaningful improvement 
(Muppidi, 2011). A ≥ 3-point improvement in MG-ADL total score from Baseline at Week 26 
was selected as a robust clinically significant threshold for the secondary endpoint. 
 
5.1.2. 
Secondary Endpoints 
The secondary efficacy endpoints of the study (to be tested in a hierarchical manner) are: 
1. Change from Baseline in QMG total score at Week 26. 
2. Improvement of at least 5 points in the QMG total score from Baseline at Week 26. 
3. Change from Baseline in the Revised 15 Component Myasthenia Gravis Quality of Life 
(MG-QOL15r) score at Week 26. 
4. Change from Baseline in Neurological Quality of Life (Neuro-QOL) Fatigue score at 
Week 26. 
5. Improvement of at least 3 points in the MG-ADL total score from Baseline at Week 26. 
 
5.1.2.1. 
Quantitative Myasthenia Gravis Total Score 
The QMG scoring system for disease severity provides an objective evaluation of muscle 
strength in MG based on quantitative testing of sentinel muscle groups. The scoring system 
consists of 13 items: ocular (2 items), facial (1 item), bulbar (2 items), gross motor (6 items), 
axial (1 item), and respiratory (1 item); each graded 0 to 3 (0 = None, 1 = Mild, 2 = Moderate, 
and 3 = Severe) (refer to Section 10.7 [Appendix 7] of the protocol). The range of total QMG 
score is between 0 to 39 (inclusive), with higher scores indicating more severe disease. For 
patients taking cholinesterase inhibitors, the dose of the cholinesterase inhibitor will be withheld 
for at least 10 hours prior to the QMG evaluation. 
A 3.5-point difference has been shown to correlate with clinically meaningful change 
(Zinman, 2007; Barth, 2011). A ≥ 5-point improvement in QMG total score from Baseline at 
Week 26 was selected as a robust clinically significant threshold for the secondary endpoint. 


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5.1.2.2. 
Revised Myasthenia Gravis Qualify of Life-15 Scale 
The revised 15 Component Myasthenia Gravis Qualify of Life (MG-QOL15r) (refer to Section 
10.10 [Appendix 10] of the protocol) is a health-related quality of life (QoL) evaluative 
instrument specific to patients with MG. The MG-QOL15r is designed to provide information 
about patients’ perception of impairment and disability, determine the degree to which disease 
manifestations are tolerated, and to be administered and interpreted easily. The MG-QOL15r will 
be completed by the patient. The scoring system for each of the 15 items are: 0 = Not at all, 
1 = Somewhat, and 2 = Very much. The MG-QOL15r total score ranges from 0 to 30 (inclusive). 
Higher scores indicate greater dissatisfaction with MG-related dysfunction. 
5.1.2.3. 
Neuro-QOL Fatigue Scale 
The Neuro-QOL Fatigue is a reliable and validated brief 19-item survey of fatigue, completed by 
the patient. The scoring system for each of the 19 items are: 1 = Never, 2 = Rarely, 
3 = Sometimes, 4 = Often, and 5 = Always. The Neuro-QOL Fatigue total score ranges from 
19 to 95 (inclusive). Higher scores indicate greater fatigue and greater impact of MG on 
activities (refer to Section 10.11 [Appendix 11] of the protocol). 
 
5.1.3. 
Exploratory Endpoints 
The exploratory endpoints are: 
• Change from Baseline in the Myasthenia Gravis Composite (MGC) score at Week 26. 
• Myasthenia Gravis Foundation of America Post-Intervention Status (MGFA-PIS) at 
Week 26. 
• Change from Baseline in European Quality of Life 5-dimension-5-level (EQ-5D-5L) 
at Week 26. 
• Change from Baseline in MG-ADL subcomponent scores for the bulbar, limbs, 
respiratory, and ocular at Week 26. 
• Change from Baseline in QMG subcomponent scores for the bulbar, limbs, 
respiratory, and ocular at Week 26. 
• Incidence of hospitalizations/MG-related hospitalizations. 
• Incidence of Clinical Deterioration/MG crisis. 
5.1.3.1. 
Myasthenia Gravis Composite Scale 
The Myasthenia Gravis Composite (MGC) scale is a validated assessment tool for measuring 
clinical status of patients with MG. The MGC assesses 10 important functional areas most 
frequently affected by MG and the scales are weighted for clinical significance that incorporates 
patient-reported outcomes (refer to Section 10.8 [Appendix 8] of the protocol). The range of total 
MGC score is 0 to 50 (inclusive), with lower scores indicating less disability and higher scores 
indicating greater disability. For patients taking cholinesterase inhibitors, the dose of the 
cholinesterase inhibitor will be withheld for at least 10 hours prior to the MGC evaluation. 


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5.1.3.2. 
Myasthenia Gravis Foundation of America Post-Intervention Status 
The MG clinical state will be assessed using a modified version of the Myasthenia Gravis 
Foundation of America Post-Intervention Status (MGFA-PIS) (Refer Section 10.13 
[Appendix 13] of the protocol). Change in status categories of Improved, Unchanged, or Worse, 
as well as the minimal manifestation (MM) will be assessed by the Investigator or the same 
neurologist skilled in the evaluation of patients with MG throughout the study. The subscores of 
MM, ie, MM-0, MM-1, and MM-3, will not be used. 
 
5.1.3.3. 
European Quality of Life 5-Dimension-5-Level 
The EQ-5D-5L (refer to Section 10.9 [Appendix 9] of the protocol) is a self-assessed, 
health-related QoL questionnaire. It is a measure of health status consisting of two parts. The 
first part assesses health in five dimensions including mobility, self-care, usual activities, 
pain/discomfort, and anxiety/depression. Each level is rated on a scale that describes the degree 
of problems in that area (ie, I have no problems walking about, slight problems walking, 
moderate problems walking, severe problems walking, or unable to walk). This part of the EQ- 
5D-5L questionnaire provides a descriptive profile that can be used to generate a health state 
profile. For example, a patient in health state 12345 would have no problems with mobility, 
slight problems with self-care (washing or dressing), moderate problems with doing usual 
activities, severe pain or discomfort and extreme anxiety or depression. The EQ-5D-5L health 
states can be represented by a single summary number (index value), which reflects how good or 
bad a health state is according to the preferences of the general population of a country/region. A 
health state index score will be calculated using US specific value set (Pickard, 2019). Refer to 
Section 9.4.3 for additional description and method of calculation. 
The second part of the questionnaire consists of a visual analogue scale (VAS) on which the 
patient rates their perceived health from 0 (the worst imaginable health) to 100 (the best 
imaginable health). 
 
5.1.3.4. 
Myasthenia Gravis-Activities of Daily Living Subcomponent Scores 
MG-ADL subcomponent scores for bulbar, limb, respiratory, and ocular function are derived 
from the MG-ADL items. Refer to Section 9.4.1 for the scoring method. 
 
5.1.3.5. 
Quantitative Myasthenia Gravis Subcomponent Scores 
Quantitative Myasthenia Gravis subcomponent scores for bulbar, limb, respiratory, and ocular 
muscle strength are derived from the QMG items. Refer to Section 9.4.2 for the scoring method. 
 
5.1.3.6. 
Clinical Deterioration 
Clinical Deterioration is defined as any of the following: 
1. Patients who experience an MG Crisis, which is defined as weakness from MG that is 
severe enough to necessitate intubation or to delay extubation following surgery. The 
respiratory failure is due to weakness of respiratory muscles. Severe bulbar 
(oropharyngeal) muscle weakness often accompanies the respiratory muscle weakness, or 
may be the predominant feature in some patients; or, 


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2. Change to a score of 3 or a 2-point worsening from Baseline on any 1 of the individual 
MG-ADL items other than double vision or eyelid droop, that in the investigator’s 
assessment is associated with significant symptomatic worsening; or, 
3. Administration of rescue therapy to a patient whose, in the opinion of the Investigator or 
Investigator-designated physician, health would be in jeopardy, if rescue therapy were 
not given (eg, emergent situations). 
 
5.2. 
Safety 
The safety and tolerability of ravulizumab compared with placebo will be evaluated by physical 
examinations, vital signs, electrocardiograms (ECGs), clinical laboratory assessments, the 
Columbia-Suicide Severity Rating Scale (C-SSRS) and incidence of AEs and SAEs. 
5.2.1. 
Adverse Events (AEs) 
An AE is defined as untoward medical occurrence in a patient administered a pharmaceutical 
product and which does not necessarily have a causal relationship with this treatment. An AE can 
therefore be any unfavorable or unintended sign (eg, an abnormal laboratory finding), symptom, 
or disease temporally associated with the use of a medicinal product, whether or not considered 
related to the medicinal product. 
The severity of AEs will be graded using Common Terminology Criteria for Adverse Events 
(CTCAE) v 5.0. Each CTCAE term is a Lowest Level Term (LLT) per Medical Dictionary for 
Regulatory Activities (MedDRA). Each LLT will be coded to a MedDRA Preferred Term: 
• Grade 1: Mild (asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated) 
• Grade 2: Moderate (minimal, local or noninvasive intervention indicated; limiting 
age-appropriate instrumental ADL) 
• Grade 3: Severe (severe or medically significant, but not immediately 
life-threatening; hospitalization or prolongation of hospitalization indicated; 
disabling; limiting self-care ADL) 
• Grade 4: Life-threatening (urgent intervention indicated) 
• Grade 5: Fatal (death related to AE) 
Adverse events are further defined in Protocol Section 10.3. 
 
5.2.1.1. 
Adverse Events of Special Interest 
Meningococcal infections will be collected as adverse events of special interest (AESI) for this 
Study. 
 
5.2.2. 
Vital Signs and Pulse Oximetry 
Vital signs and pulse oximetry will be measured at every visit and will include assessments of 
systolic and diastolic blood pressure (mmHg), temperature (°C or °F), oxygen saturation, and 
heart rate (HR) in beats per minute (bpm). 


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5.2.3. 
Laboratory Assessments 
A central laboratory will be used to evaluate all laboratory assessments. Samples for analysis of 
serum pregnancy, hematology, clinical chemistry, coagulation, and urinalysis will be collected 
(Refer Appendix 2 of the protocol for a listing of all protocol required safety laboratory 
parameters). 
 
5.2.4. 
Electrocardiograms (ECGs) 
A single 12-lead ECG will be used to obtain HR and measures of PR, QRS, QT, and corrected 
QT (QTc) intervals. The QT interval will be corrected for HR using Fridericia’s formula (QTcF). 
 
5.2.5. 
Physical Examination 
A physical examination will be performed assessing general appearance; skin; head, ear, eye, 
nose, throat; neck; lymph node; chest; heart; abdominal cavity; limb; central nervous system; and 
musculoskeletal. An abbreviated physical examination will be performed consisting of a body 
system relevant examination based upon Investigator judgment and patient symptoms. 
 
5.2.6. 
Suicidal Risk Monitoring 
The Columbia-Suicide Severity Rating Scale (refer to Section 10.14 [Appendix 14] and Section 
10.15 [Appendix 15] of the protocol) is a validated questionnaire used extensively across 
primary care, clinical practice, surveillance, research, and institutional settings to assess suicidal 
ideation and behavior. The C-SSRS will be administered and assessed at screening for both 
lifetime and past 1 year (12 months) and at study visits as outlined in the protocol schedule of 
assessments. 
5.3. 
Pharmacokinetic/Pharmacodynamic/Immunogenicity 
Assessments for PK/PD/immunogenicity are as follows: 
• 
Change in serum ravulizumab concentration over time. 
• 
Change in serum free C5 concentration over time. 
• 
Incidence of antidrug antibodies (ADAs) over time. 
 
5.4. 
Exploratory Biomarkers 
Blood samples for acetylcholine receptor antibody (AChR Ab) will be collected at specified time 
points. The AChR Ab analysis will be conducted at a central laboratory. 
Remaining samples from PK, PD, immunogenicity, and biomarker testing may be stored for 
future biomarker research. Analyses may be performed on biomarker variants thought to play a 
role in gMG activity/progression or treatment response to ravulizumab. These samples may also 
be used to develop methods, assays, prognostics, and/or companion diagnostics related to the 
study drug target, disease process, pathways associated with disease state, and/or mechanism of 
action of the study drug. 
 
Samples may be stored for a maximum duration according to local regulations following the last 
patient’s last visit for the study, at a facility selected by the sponsor, to enable further analyses. 


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6. 
DATA SETS ANALYZED (STUDY POPULATIONS) 
 
6.1. 
Full Analysis Set (FAS) 
The Full Analysis Set (FAS) will consist of all randomized patients who received at least 1 dose 
of study drug. The primary population for assessment of efficacy during the Randomized- 
Controlled Period is the FAS. Patients will be compared for efficacy according to the treatment 
they were randomized to receive, regardless of the treatment received. 
 
6.2. 
Per Protocol Set (PPS) 
The Per Protocol Set (PPS) will consist of a subset of the FAS without any major protocol 
deviations during the Randomized-Controlled Period. The PPS will include all patients who meet 
all the following criteria: 
• Missed 0 doses (scheduled and supplemental) of study drug during the 26 weeks of 
Randomized-Controlled Period 
• Have no major protocol deviations or inclusion/exclusion criteria deviations that 
might potentially affect efficacy. Specifically, 
o Met following inclusion criteria (IC) 
 IC#2: Diagnosed with MG at least 6 months prior to the date of the 
Screening Visit 
 IC#3: Confirmed MG diagnosis as required per protocol 
 IC#4: MGFA Class II to IV 
 IC#6: Stable dose of MG treatment received per time periods specified by 
the protocol 
o Did not meet exclusion criteria (EC): 
 EC#1: Any active or untreated thymoma or history of thymic carcinoma or 
thymic malignancy 
 EC#2: History of thymectomy, thymomectomy, or any thymic surgery 
within the 12 months prior to screening 
 EC#8: Clinical features consistent with MG crisis/exacerbation or Clinical 
Deterioration during the screening period 
 EC#11: Prohibited medications within the time period specified in 
exclusion #11 
 EC#12: Previous treatment with a complement inhibitor 
 EC#13: Participation in another interventional treatment study or use of 
any experimental therapy within the time specified in exclusion #13 


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• Did not receive incorrect randomized treatment (ie, all patients who received their 
correctly assigned treatment) 
• Did not take a cholinesterase inhibitor within 10 hours prior to the QMG and MGC 
tests at baseline and Week 26. 
• Did not receive rescue medication on Day 1 
• Did not have changes in background MG medication in accordance with Section 6.5.1 
of the protocol 
• Did not have unblinding of treatment allocation by the Investigator 
Determination of any other applicable major protocol deviations potentially affecting efficacy 
will be made prior to database lock and study unblinding. 
The primary and secondary endpoint analyses for the Randomized-Controlled Period will be 
performed on the PPS. 
 
6.3. 
Safety Set 
The Safety Set (SS) will consist of all patients who received at least 1 dose of study drug 
(ravulizumab or placebo). Patients will be compared for safety according to the treatment they 
actually received. For a patient to be analyzed according to the treatment they actually received 
and not according to the randomization schedule, they would have to receive that treatment for 
the entire duration of the Randomized-Controlled Period. Safety analyses for the 
Randomized-Controlled Period will be performed on the SS. 
 
6.4. 
Other Sets 
The randomized set will consist of all randomized patients grouped by randomized treatment 
group. 
The PK Analysis Set (PKAS) will consist of all ravulizumab treated patients with at least 1 post- 
baseline PK concentration available. 
The Ravulizumab Treated Set will consist of all patients who received at least 1 dose of 
ravulizumab either in the Randomized-Controlled Period or the OLE. 
The Open-label Extension Set (OLES) will consist of all patients who received at least 1 dose of 
ravulizumab starting from Week 26 onward and prior to the data cutoff date. 
The Open-label Efficacy Extension Set (OLEES) will consist of a subset of the OLES who have 
completed Week 52 study visit or withdrew from the study prior to Week 52. 


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7. 
STATISTICAL ANALYSIS 
All data collected in this study will be presented using summary tables, figures, and data listings. 
Summaries for the Randomized-Controlled Period will be presented by treatment group (ie, 
“Ravulizumab” and “Placebo”) and overall. Additionally, efficacy and safety summaries for 
patients in the Ravulizumab Treatment Period up to the data cutoff date will be presented as 
detailed in the following sections by treatment sequence (ie, “Ravulizumab to Ravulizumab” and 
“Placebo to Ravulizumab”). For continuous variables, summary statistics will include number of 
observations (n), mean, SD, median, minimum, and maximum values. Frequencies and 
percentages will be calculated for categorical variables. For table and figure summaries, all data 
will be tabulated and analyzed per the evaluation visit as recorded on the electronic case report 
forms (eCRF) even if the assessment is outside of visit window. 
Unless otherwise specified, data collected at an unscheduled visit will be included in by patient 
listings, but no assignment of the scheduled visit will be made for the purposes of summary 
tabulations. However, unscheduled study visits will be used in the calculation of baseline values. 
All analyses will be performed using Statistical Analysis Software® (SAS®) release, version 
4.7.3 or higher (SAS Institute Inc., Cary, NC, USA) or other validated statistical software. 
The following table displays the analysis periods utilized in this SAP. 
Table 2: 
Analysis Periods From Day 1 Through the Data Cutoff Date 
 
Period 
Time Window 
Study Assessment 
Exposure to Study Drug in Treatment 
Group 
Ravulizumab to 
Ravulizumab 
Group 
Placebo to 
Ravulizumab 
Group 
1 
First study drug administration 
until the Week 26 dose 
Randomized- 
Controlled Period 
Ravulizumab 
Placebo 
2 
On/after the ravulizumab dose 
date/time at Week 26 to cutoff 
date 
Open-label 
Extension Period 
Ravulizumab 
Ravulizumab 
3 
First ravulizumab infusion to 
cutoff date 
Ravulizumab 
Treatment Period 
Ravulizumab 
Ravulizumab 
 
7.1. 
Study Patients 
7.1.1. 
Disposition of Patients 
A summary of patient disposition will be presented by treatment group and overall and will 
include a summary of the number and percentage of patients screened, screen failed, randomized, 
and treated. The number and percentage of patients who completed the study through the end of 
the Randomized-Controlled Period or discontinued/withdrew from the study in the 
Randomized-Controlled Period, along with primary reason for discontinuation/withdrawal, will 
be summarized. 
A table summarizing the above information by the stratification factor ‘region’ will be provided. 
The regions will be: North America, Europe, Asia-Pacific, and Japan. 


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The number and percentage of patients in each analysis set will be tabulated. The number and 
percentage of patients not meeting specific inclusion or exclusion criterion will be summarized. 
An additional summary of patient disposition for patients who entered the OLE Period prior to 
the data cutoff date will be presented by treatment sequence and overall. This summary will be 
performed on the OLES and will include the number and percentage of patients who entered the 
OLE Period and are continuing at the time of the data cutoff. The number and percentage of 
patients who discontinued/withdrew from the study along with the reasons for discontinuation 
from OLE period will be summarized. A similar summary will be performed for the OLEES. 
A listing of disposition data by patient will be provided. A listing of patients who did not meet 
the inclusion criteria or met the exclusion criteria will also be provided. 
 
7.1.2. 
Protocol Deviations 
All important protocol deviations will be listed for all patients in the FAS. The number and 
percentage of patients with important protocol deviations will be summarized by treatment group 
and overall using the FAS. A by-patient listing of important protocol deviations will be provided. 
 
7.1.3. 
Demographics, Disease Characteristics, and History 
All demographic and baseline characteristics information will be summarized using the FAS, SS, 
OLES, and OLEES. No statistical test will be performed for homogeneity among treatment 
groups. Summary statistics will be presented by treatment group and overall. Demographic and 
baseline characteristics including MG disease characteristics will also be summarized by 
treatment group and region. By-patient listings of demographic information, MG disease 
characteristics, MG medical history, and medical/surgical history will be provided. 
7.1.3.1. 
Demographics 
The following demographic variables will be summarized: 
• Sex 
• Race and Ethnicity utilizing designations for race (American Indian or Alaska Native, 
Asian, Black or African American, Native Hawaiian or Other Pacific Islander, White, 
and Other) and two designations for ethnicity (Hispanic or Latino; and Not Hispanic 
or Latino) as characterized in Section IV of the Food and Drug Administration (FDA) 
guidance titled ‘Collection of Race and ethnicity data in clinical trials’ 
• Age (years) at First Infusion: descriptive statistics (n, mean, SD, minimum, and 
maximum) and frequency of patients in the following categories: ≤65 years, > 65 
years 
• Baseline Weight: descriptive statistics (n, mean, median, SD, minimum, and 
maximum) and frequency of patients in the following categories: ≥ 40 to < 60 kg, 
≥ 60 to < 100 kg, and ≥ 100 kg 
• Baseline Height 
• Baseline Body Mass Index 
• Region randomization stratification 


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7.1.3.2. 
Disease Characteristics 
The following disease characteristics will be summarized. 
• Age (years) at MG diagnosis 
• Years from MG diagnosis to informed consent 
• Type of first MG clinical presentation: ocular MG (oMG) or generalized MG (gMG) 
• Time to gMG, if the first presentation was oMG (months) 
• Maximum MGFA clinical classification prior to screening 
• Baseline MGFA clinical classification 
• Ventilator support at any time prior to Screening 
• History of MG exacerbation and MG crisis (number of patients with exacerbations or 
crisis, and total number of exacerbations or crisis overall and per 100 patient-years) 
and whether any MG medication was taken. 
• All cause hospitalization and hospitalizations due to MG in the 2 years prior to 
screening and per 100 patient-years; duration and need for ventilator support during 
the hospitalization. 
7.1.3.3. 
Medical/Surgical History and Baseline Physical Examination 
Medical history will be classified by System Organ Class (SOC) and Preferred Term using the 
latest available version of MedDRA and will be reported by treatment group and overall for the 
SS. Likewise, baseline physical examination information will be summarized for the SS. 
7.1.4. 
Prior and Concomitant Medications / Therapies 
Prior and concomitant MG and non-MG medications during the Randomized-Controlled Period 
as well as all meningococcal vaccinations, will be summarized separately using the SS. In 
addition, concomitant MG and non-MG medications during the OLE Period will be summarized 
using the OLES, and OLEES. Prior non-MG medications include all medications taken within 
28 days prior to informed consent and up to the first dose of study drug administration. Prior MG 
medications include all medications taken within 2 years prior to informed consent and up to the 
first dose of study drug administration. The MG medications taken more than 2 years prior to 
informed consent will be presented in by-patient listings along with all other MG medications. 
Prior meningococcal vaccinations include all vaccinations administered within 3 years of the first 
dose study drug administration. Concomitant medications during the Randomized-Controlled 
Period are defined as medications received by the patients on/after first study infusion through 
Week 26 (ie, prior to the first study infusion in the OLE Period). Concomitant medications 
during the OLE Period are defined as medications received by the patients on/after first study 
infusion in the OLE Period. 
Medications will be coded using the World Health Organization Drug Dictionary (WHO-DD) 
version in use by Alexion at the time of the analysis. Medication summaries by treatment group 
and overall (ie, number [%] of patients using prior and concomitant medications), will be 
presented by WHO-DRUG Anatomical Therapeutic Chemical (ATC) Level 3 and by WHO- 
DRUG generic name. Medications will be ordered by most prevalent WHO ATC based on total 


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patients reporting any medication in that drug class. Then, by most prevalent generic name based 
on total patients reporting any medication in that drug class/generic name. Similar summaries 
will be provided for patients experiencing clinical deterioration. 
Concomitant non-MG medications used by 5% of patients or more will be provided. 
Immunosuppressive therapy use (0, 1, 2, etc.) within 2 years prior to informed consent and up to 
the first dose of study drug administration as well as at baseline will be presented by treatment 
group. Any IST dose at baseline will be presented by treatment group for the following ISTs: 
Corticosteroid, azathioprine (AZA), and mycophenolate mofetil (MMF). 
Changes in concomitant MG medications during the Randomized-Controlled Period as well as 
the reason, will be summarized by treatment group and for patients experiencing clinical 
deterioration. Concomitant prohibited medication summaries by treatment group will be 
presented. 
The MG therapy status during the Randomized-Controlled Period will be summarized by 
treatment group and visit. Similar summaries will be provided for patients experiencing clinical 
deterioration during the Randomized-Controlled Period. 
Non-pharmacologic therapies and procedures will be classified by SOC and Preferred Term and 
will be reported by treatment group and overall for the SS. 


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7.2. 
Efficacy Analyses 
The FAS will be the primary population used for the analyses of all efficacy endpoints for the 
Randomized-Controlled Period. Sensitivity analyses of the primary and secondary efficacy 
endpoints will also be conducted using the PPS. The Randomized-Controlled Period Baseline is 
defined as the last available assessment value prior to first study drug infusion. In general, the 
baseline assessment will be the Day 1 assessment. For QMG and MGC, in the event that 
cholinesterase inhibitor was not withheld for at least 10 hours prior to administration of the 
QMG and MGC tests, the Screening Visit assessment will be used as Baseline. If cholinesterase 
inhibitor was not withheld for at least 10 hours for these visits, the Day 1 assessment will be used 
as Baseline. 
Efficacy analyses of MG-ADL and QMG total scores will be performed on the OLEES as 
specified in Section 7.2.4. The OLE Baseline is defined as the last available assessment prior to 
first study drug administered in the OLE Period. In general, the OLE Baseline assessment will be 
the Day 183 assessment. In the event that cholinesterase inhibitor was not withheld for at least 
10 hours prior to administration of the QMG test, the prior visit assessment will be used as 
baseline. 
7.2.1. 
Primary Analysis 
The primary endpoint is change from Baseline in MG-ADL total score at Week 26 of the 
Randomized-Controlled Period. 
Change from Baseline in MG-ADL total score at Week 26 will be analyzed using a mixed-effect 
model for repeated measures (MMRM; [Mallinckrodt 2001, 2004]). The model will include the 
MG-ADL change from Baseline score at each prespecified time point (Weeks 1, 2, 4, 10, 12, 18, 
and 26) as the response variable, fixed categorical effects of treatment, study visit and 
treatment-by-study visit interaction, the randomization stratification variable region; as well as 
fixed covariate of baseline MG-ADL total score. An unstructured covariance matrix will be used 
to model the correlations among repeated measurements within each patient. If this analysis fails 
to converge, the following structures will be tested and the final covariance structure will be 
determined by Akaike’s information criterion: first order autoregressive, compound symmetry, 
and Toeplitz method. A difference in treatment effect between the ravulizumab and placebo 
treatment groups along with a 2-sided 95% confidence interval (CI) and p-value will be 
calculated. The Kenward-Rogers method will be used to estimate the denominator degrees of 
freedom. Missing data will not be imputed for the primary analysis. Similar summaries will be 
presented for the other Randomized-Controlled Period study visits. 
Absolute levels and the change in MG-ADL total score will be summarized by treatment group 
and visit. 
7.2.1.1. 
Handling of Dropouts or Missing Data 
Missing data for primary, secondary, and tertiary endpoints at Week 26 analyses will be handled 
as indicated for the specific analyses. 
Baseline is defined as the last available assessment prior to first study drug infusion for all 
patients. If the Day 1 assessment is missing, the last Screening assessment will be used as the 
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7.2.1.2. 
Subgroup Analysis 
Summaries of primary and secondary endpoints during the Randomized-Controlled Period will 
be produced for the following subgroups by treatment group: Region, gender, race, age at first 
study drug infusion (18 to 65 years and > 65 years), IST use at baseline (corticosteroid, 
corticosteroid + IST, none), years from diagnosis to informed consent (≤ median, >median), 
MGFA (II, III, and IV), and baseline body weight categories (≥ 40 to < 60 kg, ≥ 60 to < 100 kg, 
and ≥ 100 kg). If the number of patients for a given subgroup category is less than 10, then the 
category maybe collapsed with another category. 
 
7.2.1.3. 
Multicenter Studies 
Based on the small number of randomized patients expected at each study site in this 
multinational study, center will not be used as an explanatory factor in the efficacy analyses. 
7.2.1.4. 
Hypothesis Testing and Significance Level 
Primary Hypothesis 
The primary hypothesis for this study is that ravulizumab is superior to placebo in improving 
MG-ADL total score at Week 26. 
The treatment effect based on the primary endpoint will be estimated by the difference in means 
between the ravulizumab group and the placebo group in the change from Baseline in MG-ADL 
total score at Week 26 irrespective of rescue therapy. A lower value of the corresponding 
estimate will indicate a beneficial treatment effect. 
Secondary Hypotheses 
The following secondary hypotheses will be included in step-wise multiplicity adjustment 
(provided the null hypothesis for primary endpoint is rejected) 
1. Ravulizumab is superior to placebo in improvement of QMG total score at Week 26. 
2. Ravulizumab is superior to placebo in QMG 5-point response (≥ 5-point 
improvement from baseline in QMG total score) at Week 26. 
3. Ravulizumab is superior to placebo in improvement of the MG-QOL15r total score at 
Week 26. 
4. Ravulizumab is superior to placebo in improvement of Neuro-QOL Fatigue total 
score at Week 26. 
5. Ravulizumab is superior to placebo in MG-ADL 3-point response (≥ 3-point 
improvement from baseline in MG-ADL total score) at Week 26. 
The study is designed to control the overall 2-sided Type I error of α = 0.05. The primary null 
hypothesis will be tested first at α=0.05. If statistically significant, 5 secondary hypotheses will 
be tested for superiority using a closed-testing procedure with the following order: 
1. Change from Baseline in QMG total score at Week 26 
2. Proportion of patients with improvement of at least 5 points in the QMG total score 
from baseline at Week 26 
3. Change from Baseline in MG-QOL15r at Week 26 


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4. Change from Baseline in Neuro-QOL Fatigue at Week 26 
5. Proportion of patients with improvement of at least 3 points in the MG-ADL total 
score from baseline at Week 26 
The testing will proceed from (#1) to (#5), and if statistical significance is not achieved (p-value 
>0.05), then subsequent endpoints will not be considered statistically significant. Estimates and 
CIs will be computed for all these secondary endpoints regardless of the outcome of the closed 
testing procedure. 
Under this prespecified closed testing procedure, no adjustment of the Type I error is required. 
Hypotheses Related to Exploratory Efficacy Objectives 
The exploratory hypotheses are as follows: 
1. Ravulizumab is superior to placebo in improvement of MGC total score at Week 26. 
2. Ravulizumab is superior to placebo in MGFA-PIS at Week 26. 
3. Ravulizumab is superior to placebo in improvement of EQ-5D-5L index score at 
Week 26. 
4. Ravulizumab is superior to placebo in improvement of MG-ADL subcomponent 
scores (bulbar, limbs, respiratory, and ocular) at Week 26. 
5. Ravulizumab is superior to placebo in improvement of QMG subcomponent scores 
(bulbar, limbs, respiratory, and ocular) at Week 26. 
6. Ravulizumab is superior to placebo in reducing incidence of 
hospitalizations/MG-related hospitalizations. 
7. Ravulizumab is superior to placebo in reducing incidence of Clinical 
Deterioration/MG crisis. 
 
7.2.1.5. 
Sensitivity Analyses 
The following sensitivity analyses will be produced for the primary endpoint of change in 
MG-ADL to Week 26: 
• Placebo-based sensitivity analysis: 
The placebo-based sensitivity analysis will consider the missing not at random (MNAR) 
mechanism for the missing data, where it will be assumed that unobserved outcomes for 
patients who discontinue early from ravulizumab will follow the trajectory of outcomes 
similar to the one in the placebo group, taking into account observed values prior to 
discontinuation (Ratitch, 2014). Patients discontinuing early from placebo will be 
assumed to have unobserved outcomes similar to placebo patients who remain on their 
randomized treatment. The assumption that the efficacy profiles of dropouts after 
discontinuation of ravulizumab are similar to those of patients in the placebo group 
provides an estimate of efficacy attributable to patients in the ravulizumab group if 
received through the time point of interest, while limiting efficacy after early 
discontinuation to that of the placebo group. Refer to Section 9.4.5 for additional 
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• Tipping point sensitivity analysis: 
An additional sensitivity analysis will be performed based on the delta-adjusted stress 
testing method (tipping point analysis). This approach assumes that patients who 
discontinue from ravulizumab treatment experience worsening, defined by a prespecified 
adjustment (delta) in the primary efficacy endpoint compared with the observed efficacy 
score of patients that continue the study to next visit (Ratitch, 2014). Since a negative 
change in MG-ADL total score indicates improvement, the prespecified value of delta 
will be a non-negative quantity. For each value of delta, the treatment effect will be 
determined, and the value of delta for which the nominal 2-sided p-value crosses 0.05, 
will be considered as the ‘tipping point’ in the sense that the positive conclusion drawn 
from the primary analysis is reversed when patients who drop out are assumed to 
experience this fixed worsening after the discontinuation visit. After such a tipping point 
is determined, clinical judgment will be applied as to the plausibility of the assumptions 
underlying this tipping point. This methodology is expected to inform what it would take 
to overturn study conclusions based on varying assumptions about missing data. A value 
of delta as zero will be considered equivalent to the primary analysis. Refer to 
Section 9.4.6 for additional description. 
• The primary endpoint analyses ignoring the randomization strata will be performed. 
• The primary endpoint analyses will be performed including rescue received during the 
Randomized-Controlled Period (Yes/No) in the model. 
 
7.2.2. 
Secondary Analyses 
Secondary endpoints will be tested in a hierarchical manner for superiority following the order 
described in Section 7.2.1.4 
Point estimates and CIs will be computed for all secondary efficacy endpoints for descriptive 
purposes, regardless of whether a lack of significance of a test precludes assessment of 
subsequent tests. 
Change from Baseline to Week 26 in QMG total score, MG-QOL15r score, and Neuro-QOL 
Fatigue score will be analyzed using MMRM as described for the primary endpoint in 
Section 7.2.1. 
The secondary endpoints of at least 3-point improvement in MG-ADL from baseline to Week 26 
irrespective of rescue therapy (and at least 5-point improvement in QMG total score) will be 
analyzed using a mixed effect repeated measures model. The MG-ADL 3-point (and QMG 
5-point) response at post dosing visits during the Randomized-Controlled Period will be used as 
the response variable and fixed categorical effects of treatment, study visit and 
treatment-by-study visit interaction, and the randomization stratification variable region, as well 
as fixed covariate of baseline MG-ADL total score as a continuous variable (and QMG total 
score) will be included in the model as explanatory variables. The treatment effect will be 
evaluated via contrast for the treatment-by-visit term at Week 26. An unstructured covariance 
matrix will be used to model the correlations among repeated measurements within each patient. 
If this analysis fails to converge, a first-order autoregressive structure in which the highest 
correlation assumed between visits that are closest in time will be used. Odds ratios (ORs) of 


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treatment effect (ravulizumab group compared to placebo) along with a 2-sided 95% CIs and p- 
values will be calculated. An estimate of OR > 1 will indicate a beneficial treatment effect. 
Similar summaries will be presented for the other Randomized-Controlled Period study visits 
and for various point reductions in MG-ADL (eg, at least 2, 3, etc.) and in QMG (eg, at least 3, 
4, etc.). 
Additional summaries of the proportion of patients with various point reductions in the MG- 
ADL total score from baseline to Week 26 irrespective of rescue therapy will be produced by 
treatment group. Similarly, summaries of the proportion of patients with various point reductions 
in the QMG total score from baseline to Week 26 will be produced by treatment group. These 
summaries will additionally be generated for patients who received any rescue therapy during the 
Randomized-Controlled Period, those who did not receive any rescue therapy, and classifying 
patients who received rescue as non-responders from the time rescue therapy was administered. 
 
7.2.3. 
Exploratory Analyses 
Absolute scores and changes from Baseline in MGC, EQ-5D-5L VAS and health state index 
scores, and MG-ADL and QMG subcomponent scores, will be summarized by treatment group 
and visit. The MG-ADL and QMG subcomponent scores will be analyzed for all patients and for 
patients with abnormal subcomponent scores at baseline. The same approach using MMRM as 
described for the primary analysis of MG-ADL will be employed. 
A summary of the MGFA-PIS will be presented by treatment group and visit showing the 
number and percentage of patients in each category (ie, improved and achieved minimal 
manifestation, improved and did not achieve minimal manifestation, unchanged, and worsened). 
The treatment effect corresponding to the MGFA-PIS endpoint will be estimated by the 
proportional OR of the cumulative proportions over the ordinal categories (starting from the best 
outcome) of this endpoint in the ravulizumab group compared with the placebo group at 
Week 26, irrespective of rescue therapy. An estimate of OR > 1 will indicate a beneficial 
treatment effect. A logistic regression of the cumulative odds (cumulated over the categories 
starting from best outcome) will be performed using treatment as fixed categorical effect and 
adjusting for region. Note: the above categories might be collapsed if the model does not 
converge. If the assumption of proportional odds is rejected, a different approach will be 
considered. 
The number of patients hospitalized, reason for admission, and duration will be summarized by 
treatment group. Hospitalization/MG-related hospitalizations (yes/no) maybe be analyzed using a 
logistic regression model with treatment group and the randomization stratification variable 
region, provided there are enough hospitalizations/MG-related hospitalizations to perform the 
analysis. The treatment effect will be estimated by the OR in the ravulizumab group compared 
with the placebo group. An estimate of OR < 1 will indicate a beneficial treatment effect. 
Additionally, the number of hospitalizations/MG-related hospitalization (0, 1, 2, and ≥ 3) 
irrespective of rescue therapy will be summarized. The incidence of hospitalization/MG-related 
hospitalization per 100-patient years (PY) of exposure irrespective of rescue therapy, may be 
analyzed using a Poisson regression repeated measures model if there are enough 
hospitalizations/MG-related hospitalization to perform this analysis. The model will include the 
following terms: treatment group and the randomization stratification variable region. The log of 


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time in the study will be used as the offset variable. The treatment effect will be estimated by the 
Incidence rate ratio in the ravulizumab group compared to the placebo group. 
The number of patients with clinical deterioration/MG crisis over 26 weeks irrespective of rescue 
therapy, will be summarized by treatment group. The same approaches as described for 
hospitalization/MG-related hospitalization will be employed for clinical deterioration/MG crisis. 
The number of patients admitted to a rehabilitation center or hospice and duration during the 
Randomized-Controlled Period will be summarized by treatment group. 
 
7.2.4. 
Other Efficacy Analyses 
The following describes the analyses to be performed for patients in the OLEES. 
Change from Randomized-Controlled Period Baseline in MG-ADL total score through Week 52 
for patients in the “Ravulizumab to Ravulizumab” will be performed on the OLEES and 
analyzed using MMRM. The model will include MG-ADL total score change from Baseline as 
the response variable, fixed categorical effects of study visit and the randomization stratification 
variable region; as well as fixed covariate of baseline MG-ADL total score. An unstructured 
covariance matrix will be used to model the correlations among repeated measurements within 
each patient. If this analysis fails to converge, the following structures will be tested and the final 
covariance structure will be determined by Akaike’s information criterion: first order 
autoregressive, compound symmetry, and Toeplitz method. A 2-sided 95% CI will be calculated. 
Similarly, change from the OLE Period Baseline in MG-ADL total score through Week 52 will 
be performed on the OLEES and analyzed using MMRM for each treatment sequence. A similar 
analysis will be conducted for the other secondary endpoints QMG total score, MG-QOL15r, and 
Neuro-QOL Fatigue score. 
Absolute levels and change from Randomized-Controlled Period Baseline and OLE Period 
Baseline in MG-ADL and QMG total scores will be summarized by visit for each treatment 
sequence. 
The proportion of patients with various point reductions (eg at least 2, 3, etc.) in the MG-ADL 
total score from Randomized-Controlled Period Baseline through Week 52 for patients in the 
“Ravulizumab to Ravulizumab” arm will be produced. Two-sided 95% CIs will be calculated. 
Similarly, the proportion of patients with various point reductions in the MG-ADL total score 
from the OLE Period Baseline through Week 52 will be produced by treatment sequence. Similar 
summaries will be provided for QMG with various point reductions (eg, at least 3, 4, etc.). 
 
7.2.5. 
Pharmacokinetic and Pharmacodynamic Analyses 
Graphs of mean serum concentration-time profiles during the Randomized-Controlled Period 
will be constructed. Graphs of serum concentration-time profiles for individual patients may also 
be provided. Descriptive statistics will be calculated for serum concentration data at each 
sampling time during the Randomized-Controlled Period, as appropriate. 
Pharmacodynamic analyses during the Randomized-Controlled Period will be performed for all 
patients who receive at least 1 dose of ravulizumab and who have evaluable PD data. 


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Descriptive statistics will be presented for all ravulizumab PD endpoints at each sampling time 
during the Randomized-Controlled Period. The PD effects of ravulizumab administered 
intravenously will be evaluated by assessing the absolute values, changes and percentage 
changes from baseline in free C5 serum concentrations over time, as appropriate. 
 
7.2.6. 
Exploratory Biomarker Analyses 
Exploratory biomarker analyses will be included in a separate standalone report. A listing of 
AChR Ab will be provided. 
 
 
7.3. 
Safety Analyses 
All safety analysis through the Randomized-Controlled Period will be conducted on the SS. All 
safety analyses for patients during the Ravulizumab Treated Period will be conducted on the 
ravulizumab treated set. Baseline is defined as the last available assessment prior to first study 
drug infusion. 
 
7.3.1. 
Study Duration, Treatment Compliance, and Exposure 
Summary statistics (mean, standard deviation [SD], median, minimum, and maximum) through 
the Randomized-Controlled Period will be produced by treatment group for the following using 
the FAS and SS: 
• Duration of study participation calculated as the time in days from the signing of informed 
consent until the date of completion/discontinuation (or death) from the 
Randomized-Controlled Period/Week 26 (ie, study duration = date of completion of 
Randomized-Controlled Period/discontinuation [or death]-date of informed consent + 1) 
• Total time on study treatment (days) calculated as the time in days from first study drug 
infusion date until the date of completion/discontinuation (or death) from the 
Randomized-Controlled Period (ie, treatment duration = date of completion of 
Randomized-Controlled Period /discontinuation [or death] - first study drug infusion 
date + 1). 
• Total dose administered and total infusion volume 
• Number of infusions 
• Number of loading doses and maintenance doses per patient 
• Number of supplemental doses per patient 
• Total number of patients with an infusion interruption and total number of infusions 
interrupted. Similar summaries of infusion interruptions will be provided for loading, 
maintenance, and supplemental infusions. 
• Total number of patients with an infusion interruption due to an AE and total number of 
infusions interrupted. Similar summaries of infusion interruptions will be provided for 
loading, maintenance, and supplemental infusions. 


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The frequency and percentage of patients who had a percentage of drug compliance range by 
increments of 10% (ie, ≥ 90% to ≤ 100%, ≥ 80% to < 90%, etc) during the Randomized- 
Controlled-Period will also be included. This will be calculated as follows: 
Percent compliance = Total number of infusions taken from Day 1 to end of 
Randomized-Controlled Period (excluding Day 183 infusion) / Total number of expected 
infusions to end of Randomized-Controlled Period (excluding Day 183 infusion) 
Additionally, the following summaries by treatment sequence will be presented for patients in 
Ravulizumab Treatment Period using the ravulizumab treated set. The exposure to placebo will 
not be re-summarized. Only exposure to ravulizumab up to data cutoff date will be summarized: 
• Duration of study participation calculated as the time in days from the signing of informed 
consent until the date of data cutoff date/discontinuation (or death) from the OLE period (ie, 
study duration = date of data cutoff date/discontinuation [or death] -date of informed consent 
+ 1) 
• Total time on ravulizumab (days) calculated as the time in days from first ravulizumab 
infusion date until data cutoff date/discontinuation (or death) (ie, treatment duration = data 
cutoff date/discontinuation - first ravulizumab infusion date + 1). 
• Total patient-years of exposure (years) to ravulizumab 
• Number of ravulizumab infusions from first ravulizumab infusion to data cutoff date 
• Total number of patients with ravulizumab infusion interruption from first ravulizumab 
infusion to data cutoff date as well as total number of ravulizumab infusions interrupted. 
• Total number of patients with ravulizumab infusion interruption due to an AE from first 
ravulizumab infusion to data cutoff date as well as total number of ravulizumab infusions 
interrupted. 
The frequency and percentage of patients who had a percentage of drug compliance range by 
increments of 10% (ie, ≥ 90% to ≤ 100%, ≥ 80% to < 90%, etc) through data cutoff will also be 
included. This will be calculated as follows: 
Percent compliance = Total number of ravulizumab infusions taken from first ravulizumab 
infusion to data cutoff date / Total number of expected ravulizumab infusions to data cutoff date 
By-patient listings will be produced for study duration, treatment compliance, and exposure. 
 
7.3.2. 
Adverse Events (AEs) 
Adverse Events through the Randomized-Controlled Period will be classified by SOC and 
Preferred Term using the latest available version of MedDRA and will be reported by treatment 
group and overall. The AEs will be determined as occurring prior to treatment (pre-treatment) or 
as on or after first treatment (treatment-emergent) as described in Section 9.3. Analyses of 
pre-treatment adverse events (PTAEs) and treatment-emergent adverse events (TEAEs) through 
the Randomized-Controlled Period (Week 26/Day 183) will be tabulated and presented 
separately. Patients having multiple AEs within a category (eg, overall, SOC, Preferred Term) 
will be counted once in that category. For severity/relationship tables, the patient’s highest 
grade/most related event within a category will be counted. Percentages will be based on the 
number of treated patients in the SS within a treatment group and overall. Tables will be sorted 


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by descending frequency of SOC and by descending frequency of Preferred Term within SOC 
based on the ravulizumab arm. The rate of TEAE adjusted by patient-year (PY) of exposure, 
defined in Section 9.3 will be displayed together with the number of events. 
All TEAEs during the Ravulizumab Treatment Period will be tabulated and presented by 
treatment sequence and overall using the ravulizumab treated set. Percentages will be based on 
the number of treated patients in the ravulizumab treated set within a treatment sequence and 
overall. 
Listings will be provided for all TEAEs and PTAEs for the SS. 
AEs will include the displays described in the following sub-sections. 
 
7.3.2.1. 
Overall Summary of Adverse Events 
Overall summary tables of TEAEs during the Randomized-Controlled Period and for patients in 
the Ravulizumab Treatment period will be presented using summary statistics (n, %). The 
number of events and rate per 100 PY (n, rate) and number of patients with events (n, %) will be 
displayed for the following events subcategories: 
• Total number of TEAEs and patients with TEAEs 
• Related TEAEs 
• Not related TEAEs 
• Grade 1 TEAEs 
• Grade 2 TEAEs 
• Grade 3 TEAEs 
• Grade 4 TEAEs 
• Grade 5 TEAEs 
The number and percentage of patients who have any TEAE leading to study treatment 
discontinuation or who died on study will be presented. 
These statistics will be prepared separately for SAEs with the exception of severity grading. 
Additional summary tables stratifying AEs occurring throughout the Randomized-Controlled 
Period by gender, race, region, age at first study drug infusion (18 to 65 years and > 65 years), 
IST use at baseline (corticosteroid, corticosteroid + IST, none), MGFA (II, III, and IV), and 
baseline body weight categories (≥ 40 to < 60 kg, ≥ 60 to < 100 kg, and ≥ 100 kg) will be 
provided. 
For patients in the ravulizumab treated set, the above overall summaries of TEAEs will be 
presented by treatment sequence and time intervals during the Ravulizumab Treatment Period (0 
to 6 months (ie, first ravulizumab dose to Week 26 ravulizumab dose), >6 to 12 months; > 12 to 
18 months, and 0 to cutoff). 


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7.3.2.2. 
Adverse Events and Serious Adverse Events by System Organ Class and 
Preferred Term 
The number of AEs and the number and percentage of patients with events during the 
Randomized-Controlled Period will be presented by SOC and Preferred Term. Patients are 
counted once in each SOC and Preferred Term. Percentages will be based on the total number of 
treated patients in the treatment group. Additional summary tables of TEAEs by SOC and 
Preferred Term occurring in 2% or more of patients as well as stratifying AEs by gender, race, 
region, age at first study drug infusion, IST use at baseline, MGFA, and baseline body weight 
categories will also be provided. All SAEs will be summarized similarly. 
In addition, for patients in the ravulizumab treated set, TEAEs by SOC and Preferred Term will 
be presented by treatment sequence and time intervals during the Ravulizumab Treatment 
Period. 
 
7.3.2.3. 
Adverse Events and Serious Adverse Events by System Organ Class, Preferred 
Term, and Relationship 
The number of AEs and the number and percentage of patients with events will be presented by 
SOC and Preferred Term as described above by relationship (related, not related). If a patient has 
more than one occurrence of an AE, the strongest relationship to study treatment will be used in 
the summary table. All SAEs will be summarized similarly. 
In addition, for patients in the ravulizumab treated set, TEAEs by SOC and Preferred Term by 
relationship will be presented by treatment sequence during the Ravulizumab Treatment Period. 
 
7.3.2.4. 
Adverse Events and Serious Adverse Events by System Organ Class, Preferred 
Term, and Severity 
The number of AEs and the number and percentage of patients with events will be presented by 
SOC and Preferred Term as described above by severity (Grade 1-5). If a patient has more than 
1 occurrence of an AE, the most severe occurrence will be used in the summary table. 
In addition, for patients in the ravulizumab treated set, TEAEs by SOC and Preferred Term by 
severity will be presented by treatment sequence during the Ravulizumab Treatment Period. 
 
7.3.2.5. 
Deaths, Other Serious Adverse Events, and Other Significant Adverse Events 
A listing of patient deaths will be produced. Meningococcal infections, the AESIs, will be 
included in the TEAE summaries by SOC and Preferred Term. 
 
7.3.3. 
Other Safety 
 
7.3.3.1. 
Analyses for Laboratory Tests 
Absolute values and changes from baseline in central laboratory parameter (continuous 
variables) will be summarized descriptively at each visit, by treatment group. Baseline is defined 
as the last available assessment value prior to the first study drug infusion. Shift tables over time 
will be presented for all central laboratory values, where applicable, using normal, low, or high 
based on normal range values. For purposes of analyses, laboratory results based upon 
standardized units will be used. Box plots will be presented for the following central laboratory 


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parameters by visit: aspartate aminotransferase (AST), alanine aminotransferase (ALT), 
creatinine, glucose, hematocrit, hemoglobin, lymphocytes neutrophils, leukocytes, and platelets. 
For patients in the ravulizumab treated set, absolute values and changes from baseline in central 
laboratory parameter (continuous variables) will be summarized descriptively at each visit, by 
treatment sequence. Baseline is defined as the last assessment prior to first dose of ravulizumab. 
All central laboratory data will be presented in by-patient listings. 
 
7.3.3.2. 
Vital Signs, Pulse Oximetry, and Physical Examination 
Absolute values and changes from baseline in vital signs (blood pressure [systolic and diastolic], 
HR, respiratory rate, and temperature) and pulse oximetry will be summarized descriptively at 
each visit during the Randomized-Controlled Period, by treatment group. Baseline is defined as 
the last available assessment value prior to the first study drug infusion. A listing of vital signs 
will be presented. 
Absolutes values and changes from baseline in weight will be summarized by visit and treatment 
group. A listing of weight will be produced. 
The number and percentage of patients with at least 1 post-treatment vital sign measurement 
meeting any of the following criteria will be summarized by treatment group: 
• Systolic blood pressure: <90 mmHg, >140 mmHg, >160 mmHg 
• Diastolic blood pressure: <50 mmHg, >90 mmHg, >100 mmHg 
• Heart rate: <60 bpm, >100 bpm 
• Body weight: decrease of ≥7% from baseline and increase of ≥7% from baseline 
• Temperature: >38.0°C, <36.0°C 
• Respiratory rate: <12 breaths/min, > 20 breaths/min 
Adverse changes from baseline in physical examination findings will be classified as AEs and 
analyzed accordingly. 
 
7.3.3.3. 
Electrocardiogram (ECG) 
Descriptive statistics by visit and treatment group will be presented for each ECG parameter 
(including PR, QRS, QT, and QTcF) values and for change from baseline values. An outlier 
analysis will be performed that will summarize the frequency and percentage of patients who 
meet any of the following outlier criteria: 
• QT, QTcF interval >450 msec 
• QT, QTcF interval >480 msec 
• QT, QTcF interval >500 msec 
• QT, QTcF interval increases from baseline >30 msec 
• QT, QTcF interval increases from baseline > 60 msec 
A listing of ECG results will be presented. 


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7.3.3.4. 
Immunogenicity 
The number and percentage of patients developing confirmed positive ADAs, and anti-drug 
neutralizing antibodies, where applicable, will be summarized by treatment group and visit. 
 
7.3.3.5. 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
The following categories are C-SSRS categories and have binary responses (yes/no): 
1. Wish to be Dead 
2. Non-specific active suicidal thoughts 
3. Active suicidal ideation with any methods (not plan) without intent to act 
4. Active suicidal ideation with some intent to act, without specific plan 
5. Active suicidal ideation with specific plan and intent 
6. Preparatory acts or behavior 
7. Aborted attempt 
8. Interrupted attempt 
9. Non-fatal suicide attempt 
10. Completed suicide 
Self-injurious behavior without suicidal intent is also a C-SSRS outcome (although not 
suicide-related) and has a binary response (yes/no). 
Composite endpoints based on the above categories are defined as follows: 
Suicidal Ideation (1-5): A yes answer to any one of the five suicidal ideation questions 
(categories 1-5) on the C-SSRS 
Suicidal Behavior (6-10): A yes answer to any one of the five suicidal behavior questions 
(categories 6-10) on the C-SSRS 
Suicidal ideation or behavior: A yes answer to any one of the ten suicidal ideation and 
behavior questions (Categories 1-10) on the C-SSRS. 
For each of the 3 composite endpoints as well as the self-injurious behavior without suicidal 
intent, the number and percentage of patients who experience an event at baseline and at least 
once during the treatment period will be summarized by treatment group. The Baseline C-SSRS 
assessment includes both (A) Lifetime assessment (for both the suicidal ideation and for the 
suicidal behavior categories) and (B) 1 year prior to treatment. 
A shift tabulation from baseline will be produced by treatment group during the 
randomized-controlled period. A separate shift tabulation will be produced using each of these 
2 baselines against the 3 composite endpoints. The 3 groupings for the shift tables are: (a) No 
suicidal ideation or behavior, (b) composite endpoint of Suicidal Ideation, and (c) composite 
endpoint of Suicidal Behavior. Each patient is counted in one cell only for each of the 
2 tabulations. Patients with both Suicidal Ideation and Suicidal Behavior are included in the 
Suicidal Behavior category for the particular tabulation. 


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8. 
REFERENCES 
Simon Pickard, United States Valuation of EQ-5D-5L Health States Using and International 
Protocol; Value in Health 2019; 22(8):931–941. 
 
Barth D, Nabavi NM, Ng E, Nwe P, Bril V. Comparison of IVIg and PLEX in patients with 
myasthenia gravis. Neurology. 2011;76(23):2017-2023. 
 
Mallinckrodt CH, Clark WS, David SR. Accounting for dropout bias using mixed-effects 
models. J Biopharm Stat 2001; 11(1&2):9-21. 
 
Mallinckrodt CH, Kaiser CJ, Watkin JG, Molenberghs G, Carroll RJ. The effect of correlation 
structure on treatment contrasts estimated from incomplete clinical trial data with 
likelihood-based repeated measures compared with last observation carried forward ANOVA. 
Clin Trials 2004; 1(6):477-489. 
 
Muppidi S, Wolfe GI, Conaway M, Burns TM; and The MG Composite and MG-QoL15 Study 
Group. MG-ADL: still a relevant outcome measure. Muscle Nerve. 2011;44(5):727-731. 
 
Ratitch B, O’Kelly M et al. Clinical trials with missing data (2014).1st ed: John Wiley & Sons 
Guidance for Industry and Food and Drug Administration Staff; October 2016. Collection of 
Race and Ethnicity Data in Clinical Trials. 
 
Zinman L, Ng E, Bril V. IV immunoglobulin in patients with myasthenia gravis: a randomized 
controlled trial. Neurology. 2007;68(11):837-841. 


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9. 
APPENDICES 
9.1. 
Protocol Schedule of events 
Refer to the protocol for a schedule of events. 
 
9.2. 
Sample Size, Power, and Randomization 
Approximately 160 patients will be randomly assigned to ravulizumab and placebo in a 1:1 ratio 
(ravulizumab:placebo) stratified by region (North America, Europe, Asia-Pacific, and Japan) to 
ensure at least 90% nominal power to reject the null hypotheses of no treatment difference for 
the primary and secondary endpoints based on 2-sided Type I error (α) = 5%. The power 
calculations were based on the longitudinal change from baseline in MG-ADL total score 
observed in REGAIN (Study ECU-MG-301). The treatment effect (difference between the 
eculizumab and the placebo arms in mean change (95% CI) from baseline to Week 6 for 
MG-ADL) was estimated to be -1.9 (-3.27, -0.55) and the estimated common SD was 3.7. Based 
on these parameter estimates and the assumption that Study ALXN1210-MG-306 will provide 
similar results, a total of N = 160 patients is required to ensure at least 90% power to reject the 
null hypothesis of no treatment effect for MG-ADL at the Type I error rate = 5% (2-sided) based 
on a t-statistic for 2 independent samples. A simulation-based approach was also adopted to 
independently verify the sample size calculation in which a large number of virtual datasets were 
generated with a total of 160 patients (equally distributed between 2 arms) each having a 
longitudinal profile of change in MG-ADL and baseline MG-ADL score generated according to 
the treatment-specific variance-covariance structure obtained from REGAIN database. The 
empirical power was calculated by the proportion of times these virtual trials rejected the null 
hypothesis based on the MMRM model described above. 
9.3. 
Technical Specifications for Derived Variables 
The following derived data will be calculated prior to analysis. 
 
Age 
Age will be presented as the number of years between date of birth and the reference date. The 
following ages (in years) may be computed using the formula (reference date – date of 
birth) + 1/365.25, with reference dates indicated as follows: 
Table 3: 
Age and Reference Date 
 
AGE 
REFERENCE DATE 
• 
Age at enrollment 
• 
Date of signing ICF 
• 
Age at MG diagnosis 
• 
Date of MG diagnosis 
• 
Age at first infusion 
• 
Date of first infusion 
Abbreviations: ICF = informed consent form; MG = myasthenia gravis 
For all dates, in cases where only the month and year are provided for a date, the day for the date 
will be imputed as 15. Missing month will be imputed as June. In cases where the day is 
observed but the month is missing, the date will be imputed as June 15. 


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Disease Duration 
The MG disease duration will be presented as the number of years between the date of first 
infusion and the date of the first MG diagnosis (ie, INT [(Date of first infusion – Date of MG 
diagnosis + 1)/365.25] or a similar formula using months and years or years only in the event of 
partial dates for first symptoms) 
 
Definition of Baseline Values 
The Randomized-Controlled Period Baseline The Randomized-Controlled Period Baseline is 
defined as the last available assessment value prior to first study drug infusion. In general, the 
baseline assessment will be the Day 1 assessment. For QMG and MGC, in the event that 
cholinesterase inhibitor was not withheld for at least 10 hours prior to administration of the 
QMG and MGC tests, the Screening Visit assessment will be used as Baseline. If cholinesterase 
inhibitor was not withheld for at least 10 hours for these visits, the Day 1 assessment will be used 
as Baseline. 
The OLE Baseline is defined as the last available assessment prior to first study drug 
administered in the OLE Period. In general, the OLE Baseline assessment will be the Day 183 
assessment. In the event that cholinesterase inhibitor was not withheld for at least 10 hours prior 
to administration of the QMG test, the prior visit assessment will be used as baseline. 
 
Change From Baseline 
Change in values from baseline will be calculated as follows. 
Change in Value = (subsequent value – baseline value), given that both the baseline value and 
subsequent value are non-missing. 
Adverse Events 
Treatment-emergent adverse events (TEAEs) are events with start dates and start times on or 
after first dose of study drug administration. If the start date of an AE is partially or completely 
missing and the end (stop) date and time of the AE does not indicate that it occurred prior to first 
dose, then the determination of treatment-emergent status will be based on the following: 
• If the start year is after the year of the first study drug dose, then the AE is 
treatment-emergent; else, 
• If the start year is the same as the year of the first study drug dose and 
o the start month is missing, then the AE is treatment-emergent; else if 
o the start month is present and is the same or after the month of the first study drug 
dose, then the AE is treatment-emergent; else. 
• If the start date is completely missing, then the AE is treatment-emergent. 
All other AEs are considered PTAEs. 
Patient percentages are based on the total number of treated patients in the particular treatment 
group. 


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The rate of AEs adjusted by PY of exposure is defined as “number of events per 100 
patient-years.” Total PY will be summed across all individual PY of exposure. The PY of 
exposure is calculated as (Week 26 completion date or discontinuation/death date)-(first study 
drug infusion date) + 1 for the Randomized-Controlled Period and as (Data cutoff date or 
discontinuation/death date)-(first ravulizumab infusion date) + 1 for the Ravulizumab Treated 
Period. 
 
9.4. 
Additional Details on Statistical Methods 
9.4.1. 
Myasthenia Gravis-Activities of Daily Living Subcomponent Scores 
The MG-ADL subcomponent scores for the bulbar, limbs, respiratory, and ocular are derived 
from the MG-ADL items. The following illustrates the scoring procedure: 
 
MG-ADL Subcomponent 
Score 
Bulbar 
Sum of talking, chewing, swallowing 
Limbs 
Sum of impairment of ability to brush teeth or comb hair 
and impairment of ability to arise from a chair 
Respiratory 
Breathing 
Ocular 
Sum of double vision and eyelid droop 
 
9.4.2. 
Quantitative Myasthenia Gravis Score for Disease Severity Subcomponent 
Scores 
The QMG subcomponent scores for the bulbar, limbs, respiratory, and ocular are derived from 
the QMG items. The following illustrates the scoring procedure: 
 
QMG Subcomponent 
Score 
Bulbar 
Sum of the items of swallowing and speech 
Limbs 
Sum of right arm outstretched, left arm outstretched, 
right hand grip, left hand grip, head lift, right leg 
outstretched, and left leg outstretched 
Respiratory 
Forced vital capacity 
Ocular 
Sum of the items of double vision, ptosis, and facial 
muscles 
 
9.4.3. 
European Quality of Life 5 dimension-5-level Health State Index Calculations 
The responses to the five EQ-5D dimensions can be converted into a single number called an 
index value. The EQ-5D-5L health state index scores is derived by applying a formula that 
attaches values (also called weights) to each of the levels in each dimension. The index can be 
calculated by subtracting the appropriate weights for each dimension level of health state from 1. 
The EQ- 5D-5L index scores for this study will be obtained using the US composite time trade- 
off (cTTO) method. The calculation is illustrated in Table 4 below: 


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Table 4:    EQ-5D-5L US Composite Time Trade-off (cTTO) Value Set 
 
US TTO 
Example: the value for 
health state 21354 
Full health (11111) 
Full Health=1 
Mobility level 2 
-0.096 
-0.096 
Mobility level 3 
-0.122 
Mobility level 4 
-0.237 
Mobility level 5 
-0.322 
Self-Care level 2 
-0.089 
0 
Self-Care level 3 
-0.107 
Self-Care level 4 
-0.220 
Self-Care level 5 
-0.261 
Usual Activity level 2 
-0.068 
Usual Activity level 3 
-0.101 
-0.101 
Usual Activity level 4 
-0.255 
Usual Activity level 5 
-0.255 
Pain/Discomfort level 2 
-0.06 
Pain/Discomfort level 3 
-0.098 
Pain/Discomfort level 4 
-0.318 
Pain/Discomfort level 5 
-0.414 
-0.414 
Anxiety/Depression level 2 
-0.057 
Anxiety/Depression level 3 
-0.123 
Anxiety/Depression level 4 
-0.299 
-0.299 
Anxiety/Depression level 5 
-0.321 
Health State Index Score 
=1-0.096+0-0.101-0.414- 
0.299=0.090 
 
 
9.4.4. 
SAS Code for Repeated Measures Mixed Model Analysis 
The main analysis method for the primary endpoint of change from baseline to Week 26 in 
MG-ADL and many of the secondary and tertiary endpoints involve mixed model repeated 
measures analysis. The basic SAS® code for change in MG-ADL is given by: 
proc mixed data=ADEFF method=reml; 
class subjid trt01pn avisitn region; 
model chg= trt01pn avisitn trt01pn*avisitn base region/ddfm=kr solution; 
repeated avisitn/type=un subject=subjid; 
lsmeans trt01pn *avisitn/cl diff; 
where subjid is the patient identifier variable, trt01pn is the randomized treatment group, avisitn 
is the visit variable, base is the MG-ADL value at baseline, chg is the change from baseline in 
MG-ADL, and region is the randomization stratification variable. 


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9.4.5. 
SAS Code for Placebo-based Sensitivity Analysis 
A sensitivity analysis for the change from baseline in MG-ADL at Week 26 will be analyzed 
using the MMRM model as specified for the primary analysis. For patients who discontinued 
treatment, responses after treatment discontinuation, for both groups, will be imputed with 
multiple imputation methodology (SAS PROC MI) based on the response for placebo treated 
patients. Markov Chain Monte Carlo (MCMC) imputation method will be used to fill in the 
intermittent missing values under the assumption of missing at random (MAR) and generate a 
monotone pattern (1000 imputations will be generated). Subsequently, multiple imputation will 
be performed at each visit sequentially, using a regression method obtained only from placebo 
treated patients with terms for baseline MG-ADL total score at baseline and the randomization 
stratification variable region. After obtaining complete data sets for each visit, these complete 
data sets will be analyzed using MMRM analysis, and inferences from each complete data set 
will be combined to obtain an overall test statistic for treatment effect. Below is some sample 
code: 
Markov Chain Monte Carlo (MCMC) imputation method: 
proc mi data=ADEFF out=monotone seed=123 nimpute=1000; 
by trt01pn; 
mcmc impute=monotone; 
var base region1 region2 region3 Week1 - Week26; 
where trt01pn is the randomized treatment group, base is the MG-ADL value at baseline, Week 1 
– Week 26 are the change from baseline in MG-ADL at the particular visit, and region1,2,3 are 3 
dummy variables based on the randomization stratification region. 
The following is a partial SAS code for the placebo-based pattern imputation at Week X: 
proc mi data=monotone out=outmi seed=123 nimpute=1; 
by _imputation_; 
class trt01pn region; 
var base region Week1 - Week26; 
monotone reg(/details); 
mnar model (Week X/modelobs=(trt01pn=”0”)) 
run; 
Once multiple completed data sets are generated, the same method, MMRM, used for the 
primary analysis, is then used to analyze each imputed data set separately (Refer to Section 9.4.4 
for SAS code), and inferences from each complete dataset will be combined to obtain an overall 
test statistic using proc mianalyze: 
proc mianalyze data=diff2; 
by avisitn; 
modeleffects estimate; 


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stderr stderr; 
 
9.4.6. 
SAS Code for Tipping Point Sensitivity Analysis 
The following illustrates the sensitivity analysis for the primary endpoint of change from 
Baseline to Week 26 in MG-ADL with the tipping-point approach where a search is conducted 
for a tipping point that reverses the study conclusion from being favorable to ravulizumab to 
being unfavorable. For the tipping point sensitivity analysis, the missing data mechanism for the 
missing change from baseline values at Week 26 will be considered to be MNAR. Markov Chain 
Monte Carlo (MCMC) imputation method will be used to fill in the intermittent missing values 
under the assumption of MAR and generate a monotone pattern (1000 imputations will be 
generated). Subsequently imputations are performed for missing change observations at every 
visit sequentially for the ravulizumab treated patients assuming not the full treatment effect, but 
the treatment effect minus a shift parameter delta. The adjustment will be applied to the first 
unobserved outcome from ravulizumab. After obtaining complete data sets for multiple shift 
parameters, the complete data sets will be used in the MMRM analysis, and inferences from each 
complete dataset will be combined using SAS PROC MIANALYZE to obtain an overall test 
statistic for each shift value. Multiple shift parameters will be tested until the inference concludes 
that statistical significance disappears. The following is a partial SAS code for the multiple 
imputation analysis for a specified shift parameter at Week X: 
proc mi data=monotone out=outmi seed=123 nimpute=1; 
by _imputation_; 
class trt01pn Region; 
monotone method=reg ; 
var trt01pn region base Week 1 - Week26; 
mnar adjust (Week X /shift=delta adjustobs=(trt01pn='Ravulizumab')); 
where trt01pn is the randomized treatment group, base is the MG-ADL value at baseline, 
Week 1 – Week 26 are the change from baseline in MG-ADL at the particular visit, and region is 
the randomization stratification. 
The 1000 imputed data sets are then analyzed using MMRM (Refer Section 9.4.4 for SAS code) 
and PROC MIANALYZE procedure will be used to generate valid statistical inferences about 
these parameters. 
 
9.4.7. 
SAS Code for Mixed Effect Repeated Measures Model 
The analysis of secondary endpoints of at least 3-point improvement in MG-ADL and at least 5- 
point improvement in QMG will involve fitting a mixed effect repeated measures model. The 
basic SAS code for that analysis is given by: 
proc glimmix data=adeff method = rmpl; 
class usubjid trt01pn avisitn region ; 
model crit2fn = trt01pn avisitn trt01pn*avisitn region/ dist = binomial link = logit; 
random avisitn / subject = usubjid residual type = un; 


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lsmeans trt01pn*avisitn/ilink diffs oddsratio cl; 
 
 
9.4.8. 
SAS Code for Proportional Odds Model 
The analysis of MGFA-PIS at Week 26 will involve fitting the proportional Odds model with 
proc logistic. The basic SAS code for that analysis is given by: 
proc logistic data=adeff descending; 
class trt01pn region; 
model aval=trt01pn region; 
oddsratio trt01pn; 
 
9.4.9. 
SAS Code for Poisson Regression 
The analysis of incidence of hospitalization/MG-related hospitalization and clinical 
deterioration/MG crisis will involve Poisson regression analysis. The basic SAS code for that 
analysis is given by: 
proc genmod; 
class tr01pg1n region; 
model count = tr01pg1n region/ type3 dist=poisson scale=pearson offset=logpy; 
estimate "log Ravuvs Placebo" trt01pn 1 -1 /exp; 
lsmeans trt01pn/ilink exp cl; 
run; 
where trt01pn is the randomized treatment group, count is the number of hospitalization (or MG 
hospitalization/Clinical deterioration/MG crisis), region is the randomization stratification 
variable. 


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Alexion Pharmaceuticals, Inc. 
 
 
 
 
 
 
 
 
 
STATISTICAL ANALYSIS PLAN ADDENDUM 
 
 
 
PROTOCOL NUMBER: ALXN1210-MG-306 
 
 
A Phase 3, Randomized, Double-Blind, Placebo-Controlled, Multicenter Study to Evaluate the 
Safety and Efficacy of Ravulizumab in Complement-Inhibitor-Naïve Adult Patients With 
Generalized Myasthenia Gravis 
 
 
 
 
 
 
 
 
 
Author:PPD 
Date: 3 December 2020 
Version: V1.0, Final 


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1. 
APPROVAL SIGNATURES 
 
 
 
 
 
 
 
 
Date dd Mmm yyyy 
Date dd Mmm yyyy 
Date dd Mmm yyyy 
PPD 
PPD 
PPD 


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2. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF 
FIGURES 
TABLE OF CONTENTS 
1. 
APPROVAL SIGNATURES ....................................................................................... 2 
2. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES ................. 3 
TABLE OF CONTENTS ................................................................................................................ 3 
LIST OF TABLES .......................................................................................................................... 3 
3. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS .............................. 4 
4. 
STATISTICAL ANALYSIS PLAN ADDENDUM .................................................... 5 
4.1. 
Changes From Analyses Specified in the Protocol ...................................................... 5 
4.2. 
Changes From Analyses Specified in the Previous Version of the SAP ..................... 5 
LIST OF TABLES 
Table 1: 
Abbreviations and Acronyms ....................................................................................... 4 
Table 2: 
Non-Compliance Calculations for Patients in the Randomized-Controlled 
Period ........................................................................................................................... 7 
Table 3: 
Non-Compliance Calculations for Patients in the Ravulizumab Treatment 
Period ........................................................................................................................... 7 


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3. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
The following abbreviations and acronyms are used in this Addendum to the Statistical Analysis 
Plan (SAP). 
Table 1: 
Abbreviations and Acronyms 
 
Abbreviation or Acronym 
Explanation 
AE 
Adverse event 
C5 
Complement component 5 
COVID-19 
Coronavirus Disease 2019 
eCRF 
Electronic case report form 
FAS 
Full analysis set 
FVC 
Force vital capacity 
IVIg 
Intravenous immunoglobulin 
MAR 
Missing at random 
MedDRA 
Medical Dictionary for Regulatory Activities 
mFAS 
Modified full analysis set 
MG 
Myasthenia gravis 
MG-ADL 
Myasthenia Gravis-Activities of Daily Living 
MMRM 
Mixed-effect model for repeated measures 
MNAR 
Missing not at random 
OLE 
Open-label Extension 
OLES 
Open-label Extension Set 
PD 
Pharmacodynamic(s) 
PE 
Plasma exchange 
PK 
Pharmacokinetic(s) 
PP 
Plasmapheresis 
PPS 
Per Protocol set 
PT 
Preferred term 
QMG 
Quantitative Myasthenia Gravis score for disease severity 
RCP 
Randomized-Controlled Period 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SOC 
System Organ Class 
SS 
Safety Set 


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4. 
STATISTICAL ANALYSIS PLAN ADDENDUM 
The Statistical Analysis Plan (SAP) Addendum details the changes and/or additional analyses 
required to address the impact of Coronavirus Disease 2019 (COVID-19) on the planned 
analyses as described in the Final SAP Version 1.0 dated 6 April 2020. In general, the study 
objectives for this study have not changed and the interest remains in a treatment effect that is 
not confounded by pandemic-related disruptions. Additionally, the originally planned statistical 
methodology as specified in Section 7.2 of SAP V1.0 has not changed. Section 4.2 below details 
the changes from the analyses specified in SAP V1.0. 
 
4.1. 
Changes From Analyses Specified in the Protocol 
None. 
 
4.2. 
Changes From Analyses Specified in the Previous Version of the SAP 
Changes from analyses specified in the final SAP Version 1.0 dated 6 April 2020 include the 
following: 
1. The planned analyses of long-term safety and efficacy data for patients in the Open-Label 
Extension (OLE) at the time of database lock is updated from Section 4.1 of SAP V1.0 to 
restrict the scope of safety analyses in the OLE to patients who completed or would have 
completed Week 52 assessments as of the data cutoff date, which is based on when the 
last patient enrolled completes the Randomized Controlled Period. This will align the 
follow up time for both safety and efficacy. Details of the assessments to be summarized 
up to Week 52 for these patients as well as for discontinued patients who would have 
reached Week 52 by the data cutoff date had they remained on study are provided in 
Version 1.0 of the SAP and include at a minimum the following: disposition, study drug 
exposure, primary and secondary endpoints, and clinical laboratory assessments as well 
as adverse events (AEs), serious adverse events (SAEs), and concomitant medications. 
 
Based on this, the definition of the Open-Label Extension Set (OLES) will be updated 
from Section 6.4 of SAP V1.0 to consist of all patients who received at least 1 dose of 
ravulizumab starting from Week 26 and who have completed Week 52 study visit or who 
would have completed Week 52 by the data cutoff date but withdrew from the study. 
This analysis set will also replace the Open-Label Efficacy Extension Set for all analyses 
specified in SAP V1.0. 
 
2. A modified Full Analysis Set (mFAS) will be added and will consist of a subset of the 
Full Analysis Set (FAS) excluding patients who were impacted by COVID-19 during the 
Randomized-Controlled Period (RCP) as follows: 
a. Patients who had a COVID-19 related adverse event during the RCP 
b. Patients who missed 2 consecutive scheduled doses of study drug during the RCP 
due to COVID-19-related disruptions 


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c. Patients who terminated early during the RCP due to COVID-19 related 
disruptions 
d. Patients who received concomitant treatments for COVID-19 during the RCP that 
could be used as MG medication 
3. The originally planned statistical analyses as specified in Section 7.2 of SAP V1.0 will be 
utilized for statistical inference of all primary and secondary endpoints as well as the 
exploratory endpoints that are analyzed using mixed-effect model for repeated measure 
(MMRM). Patients impacted by the following pandemic related intercurrent events will 
be handled using the hypothetical strategy as follows: 
a. Efficacy assessments for patients who had COVID-19 related SAE will be excluded 
from the planned analysis from date of the event up to 2 weeks from resolution of the 
SAE. 
b. Efficacy assessments for patients who had a change in their MG concomitant treatment 
due to COVID-19 will be excluded from the planned analysis until the dose returns to 
baseline levels. 
c. Efficacy assessments for patients who missed 1 dose of study drug due to COVID-19- 
related disruptions will not be excluded from the planned analysis with the following 
exceptions: 
• If the efficacy assessment took place more than 16 weeks from the last 
administration of study drug, then it will be excluded. 
• For patients randomized to placebo who missed the loading dose at Week 26, 
efficacy assessments will be excluded up to 7 days from reinitiating study 
drug administration. 
d. Efficacy assessments for patients who missed 2 or more sequential doses of study drug 
due to COVID-19 will be excluded from the planned analysis up to 2 weeks from 
reinitiating study drug administration. 
e. The tipping point sensitivity analyses specified in Section 7.2.1.5 of SAP V1.0 will tip 
missing data due to pandemic-unrelated missing data but will use standard missing at 
random (MAR) imputations for pandemic-related missing data. Similarly, the placebo- 
based sensitivity analysis will limit efficacy after early discontinuation due to pandemic- 
unrelated missing data in the ravulizumab group to that of the placebo group but will use 
standard MAR imputations for pandemic-related missing data. 
4. Calculation of drug compliance during the RCP as specified in Section 7.3.1 of the SAP 
will be modified from being based on number of scheduled doses given out of number of 
expected scheduled doses, to reflecting percentage of time during the RCP that the patient 
is considered to have complete terminal complement inhibition ie 100%-sum (percentage 
of time non-compliant with scheduled doses). Non-compliance time will be calculated 
for any consecutively missed scheduled dose(s) as shown in Table 2. Negative non- 
compliance, which might occur for discontinued patients, will be set to 0. 


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Table 2: 
Non-Compliance Calculations for Patients in the Randomized-Controlled 
Period 
 
First Scheduled Dose Missed 
Non-Compliance Calculationsa 
Any except Day 15 
[(Minimum (Day of dose re-initiation relative to Day 1 or 183b or Day of 
discontinuation) – (target day of last dose given relative to Day 
1+56+14))/183]*100 
Day 15 
[(Minimum (Day of dose re-initiation relative to Day 1 or 183b or day of 
discontinuation) – (target day of last dose given relative to Day 1 + 14 + 14=29) 
)/183]*100 
a The initial 56 and 14 days in the calculations reference the dose coverage of the last dose given. The second 14 
days is added to take into account the potential for dosing visits occurring within 2 weeks of an expected visit to be 
entered under the regularly scheduled visit. 
b 183 days is used for patients who did not reinitiate study drug in the randomized-controlled period by data cutoff 
date 
 
5. Calculation of ravulizumab drug compliance for patients in the ravulizumab treatment 
Period (including OLE) using the ravulizumab treated set, will be modified from being 
based on the number of scheduled ravulizumab doses given out of the number of 
expected scheduled ravulizumab doses to reflecting percentage of time during the 
ravulizumab treatment period that the patient is therapeutically dosed ie 100%-sum 
(percentage of time non-compliant with scheduled ravulizumab doses). Non-compliance 
time will be calculated for any consecutively missed scheduled dose(s) as shown in Table 
3. Negative non-compliance, which might occur for discontinued patients, will be set to 
0: 
 
Table 3: 
Non-Compliance Calculations for Patients in the Ravulizumab Treatment 
Period 
 
First Scheduled Ravulizumab Dose 
Missed 
Non-Compliance Calculationsa 
Ravulizumab to Ravulizumab 
Any except Day 15 or Day 197 
[(Minimum (Day of dose re-initiation relative to Day 1 or 365b or day 
of discontinuation) – (target day of last dose given relative to Day 
1+56+14))/365]*100 
Day 15 or Day 197 
[(Minimum (Day of dose re-initiation relative to Day 1 or 365c or day 
of discontinuation) – (target day of last dose given relative to Day 1 
+ 14 + 14))/365]*100 
Placebo to Ravulizumab 


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First Scheduled Ravulizumab Dose 
Missed 
Non-Compliance Calculationsa 
Any except Day 183 or Day 197 
[(Minimum (Day of dose re-initiation relative to Day 1 or 365d or day 
of discontinuation) – ( target day of last ravu dose given relative to 
Day 1) )+56+14)/183]*100 
Day 183 
[(Minimum (Day of dose re-initiation relative to Day 1 or 365e or day 
of discontinuation) – 183)/183]*100 
Day 197 
[(Minimum (Day of dose re-initiation relative to Day 1 or 365f or day 
of discontinuation) – (target day of last ravu dose 
given)+14+14))/183]*100 
a The initial 56 and 14 days in the calculations reference the dose coverage of the last dose given. The second 14 
days is added to take into account the potential for dosing visits occurring within 2 weeks of an expected visit to be 
entered under the regularly scheduled visit. 
b 365 days is used for patients who did not reinitiate study drug in the OLE by data cutoff date 
6. Section 7 of the SAP V1.0 specifies that data collected at an unscheduled visit will be 
included in by-patient listings, but assignment of the scheduled visit will not be made for 
the purposes of summary tabulations with the exception of calculation of baseline values. 
This is updated to utilize the window algorithm specified below to allow the use of 
unscheduled postbaseline visits, if available, to replace missing scheduled visits, and this 
update is not intended to reassign all visits. Assessments collected for clinical 
deterioration will not be utilized. Assessments conducted at early termination visits will 
be similarly assigned. 
For all postbaseline by-visit assessments, the number of days from baseline will be 
calculated using the following formula: (date of assessment) - (date of first study 
treatment) + 1. This number of days will be used to assign analysis visit for a missed 
visit/assessment. This may not always correspond to the electronic case report form 
(eCRF) visit. 
For all visits, the lower bound and the upper bound for the analysis visit windows are 
defined as the midpoints of the target date of scheduled visits. If the date of assessment 
falls in between the lower bound and the upper bound for a visit as defined in the 
protocol schedule of assessment, then it will be assigned to that visit. If the interval 
separating 2 scheduled visits is an even number of days, that middle day will be included 
in the lower bound of the next visit window. For example, for an assessment with a 
scheduled visit Day 127, and a prior scheduled visit Day of 85 and subsequent scheduled 
visit Day of 183, the window will start at 106 days from baseline and will go to 154 days 
from baseline. 
If only one record is within an analysis visit window, the data from that record will be 
used for the missed visit/ assessment in the analysis. If more than one record is within the 
same analysis visit window, the record closest to the midpoint of the interval will be used 


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for the missed visit/assessment. If two records are “tied” before and after the middle of 
the interval, the earlier record will be used in the analysis. 
The following additional sensitivity and supplementary analyses will be included to assess the 
impact of the pandemic disruption on the trial and to address pandemic-related data missingness: 
1. The summary of patient disposition specified in Section 7.1.1 of the SAP V1.0 will 
include COVID-19 related screen failure reasons and COVID-19 related 
discontinuations/withdrawals from both the Randomized-Controlled Period and the OLE 
Period. 
2. Descriptive statistics of demographic, baseline disease characteristics as specified in 
Section 7.1.3 of the SAP V1.0, and the change from baseline in Myasthenia Gravis- 
Activities of Daily Living (MG-ADL) during the RCP, will be provided by enrollment 
period as follows: before March 2020, March 2020-August 2020, and after September 
2020. Similarly, a summary table of treatment emergent adverse events during the RCP 
by System Organ Class (SOC) and Preferred Term (PT) stratified by enrollment period 
will be provided. 
3. A summary of the number and percentage of patients with pre-treatment and treatment 
emergent known Exposure to COVID-19 during the RCP will be provided by treatment 
group using the Safety Set (SS). 
4. A summary of COVID-19 related important protocol deviations during the RCP will be 
provided. A by-patient listing of all protocol deviations will be provided. 
5. A summary of the number and percentage of patients who missed a study visit and/or 
who had a modified study visit during the RCP along with the reasons (COVID-19 
related/not), will be provided by treatment group and by visit using the FAS. For patients 
who had a modified study visit, the method for the different assessments will be 
summarized. Similar summaries will be provided for patients in the OLES. 
6. For the secondary endpoint change from baseline to Week 26 in Quantitative Myasthenia 
Gravis (QMG), an additional analysis will be performed after using a multiple imputation 
approach and using a regression method to impute Forced Vital Capacity (FVC) for 
patients whose other sentinel muscle groups were evaluated. This will be followed by 
calculating QMG total scores and analyzed using MMRM. In addition, an analysis of the 
5-point improvement in the recalculated QMG total score from Baseline to Week 26 will 
be performed utilizing mixed effect repeated measures model. 
7. The primary and secondary endpoint analyses will be repeated using the mFAS. 
Similarly, a summary table of treatment emergent adverse events (TEAE) by SOC and 
PT will be conducted on the mFAS. 
8. To assess the impact of change in endpoint ascertainment, descriptive statistics of the 
primary endpoint of change from baseline in MG-ADL by visits during the RCP and by 
method of assessment (in clinic versus alternative method), will be provided by pooled 
treatment arms using the FAS. 
9. A summary table of TEAEs during the RCP by SOC and Preferred Term will be provided 
for patients who were diagnosed with COVID-19 using the SS. 


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10. The following summaries will be added to the summaries specified in Section 7.3.1 of the 
SAP V1.0 using the FAS and SS: the total number and percentage of patients with any 
missed doses per schedule of assessment during the RCP, the reason and the total number 
of missed doses (1, 2, 3, 4 or more), will be provided. Similarly, the total number of 
patients with any unscheduled infusions during the RCP, the reason and the total number 
of unscheduled doses (1, 2, 3, 4 or more) will be provided. Similar summaries will be 
provided for patients in the ravulizumab Treatment Period using the ravulizumab treated 
set. 
The following include additional clarifications and analyses to SAP V1.0. 
• 
The first criterion for inclusion into the PPS in Section 6.2 of SAP V1.0 is clarified as 
follows: 
During the RCP, missed 0 doses per protocol schedule of assessment. Patients with a 
clinical deterioration per protocol during the RCP who receive rescue therapy 
(IVIg/PP/PE) should have received at least 1 supplemental dose at the conclusion of 
rescue therapy. 
• 
The summary of actual values, change from baseline, and percentage change from 
baseline in serum free C5 concentrations as detailed in Section 7.2.5 of the SAP V1.0 will 
be modified to exclude Day 1 free C5 samples considered biologically implausible. The 
exclusions will be corroborated with the paired PK data. 
• 
A summary of infusion reactions during the RCP will be summarized by preferred term 
and by treatment group using the SS. 
• 
The proportion of patients with a ≥ 2-point reduction in MG-ADL regardless of rescue 
therapy for at least 4 consecutive visits during the first 10 weeks, will be summarized by 
treatment group. The same summary classifying patients who received rescue therapy as 
non-responders will be produced. 


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Alexion Pharmaceuticals, Inc. 
 
 
 
 
 
STATISTICAL ANALYSIS PLAN ADDENDUM 2 
 
 
 
PROTOCOL NUMBER: ALXN1210-MG-306 
 
 
A Phase 3, Randomized, Double-Blind, Placebo-Controlled, Multicenter Study to Evaluate the 
Safety and Efficacy of Ravulizumab in Complement-Inhibitor-Naïve Adult Patients With 
Generalized Myasthenia Gravis 
 
 
 
 
 
 
 
 
 
Author: PPD 
Date: 10 June 2021 
Version: V1.0, Final 


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1. 
APPROVAL SIGNATURES 
 
 
 
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Date dd Mmm yyyy 
 
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2. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF 
FIGURES 
TABLE OF CONTENTS 
1. 
APPROVAL SIGNATURES ........................................................................................ 2 
2. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES .................. 3 
TABLE OF CONTENTS .................................................................................................................. 3 
LIST OF TABLES ........................................................................................................................... 3 
3. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ............................... 4 
4. 
STATISTICAL ANALYSIS PLAN ADDENDUM ..................................................... 5 
4.1. 
Changes from Analyses Specified in the Protocol ........................................................ 5 
4.2. 
Changes from Analyses Specified in the Previous Version of the SAP ....................... 5 
LIST OF TABLES 
Table 1: 
Abbreviations and Acronyms ........................................................................................ 4 


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3. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
The following abbreviations and acronyms are used in this Addendum to the Statistical Analysis 
Plan (SAP). 
Table 1: 
Abbreviations and Acronyms 
 
Abbreviation or Acronym 
Explanation 
FAS 
Full analysis set 
IST 
immunosuppressant therapy 
IVIg 
intravenous immunoglobulin 
MedDRA 
Medical Dictionary for Regulatory Activities 
MG 
myasthenia gravis 
MG-ADL 
Myasthenia Gravis-Activities of Daily Living 
PE 
plasma exchange 
PP 
plasmapheresis 
QMG 
Quantitative Myasthenia Gravis score for disease severity 
SAP 
statistical analysis plan 
SMQ (N) 
standard MedDRA queries (narrow) 
SS 
safety set 


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4. 
STATISTICAL ANALYSIS PLAN ADDENDUM 
This Statistical Analysis Plan (SAP) Addendum 2 V1.0 details in Section 4.2 the changes and/or 
additional analyses from the SAP V1.0 dated 06 April 2020 and the SAP addendum V1.0 dated 
03 December 2020. 
 
4.1. 
Changes from Analyses Specified in the Protocol 
None. 
 
4.2. 
Changes from Analyses Specified in the Previous Version of the SAP 
Changes and/or additional analyses from those specified in the final SAP V1.0 dated 6 April 
2020 and the SAP addendum V1.0 dated 03 December 2020 include the following: 
 
1. Additional summaries of myasthenia gravis (MG) therapies will be provided using the 
safety set (SS) as follows: 
 
a. Number and percentage of patients with 0, 1, 2 or more of immunosuppressant 
therapy (IST) or intravenous immunoglobulin (IVIg)/ Plasmapheresis (PP)/ 
Plasma exchange (PE) within 2 years prior to Screening visit will be provided. 
ISTs include corticosteroids, azathioprine, cyclophosphamide, cyclosporine, 
methotrexate, mycophenolate mofetil, tacrolimus, or rituximab. 
 
b. Number and percentage of patients with 0, 1, 2 or more ISTs within 2 years prior 
to Screening visit will be provided. 
 
c.  Number and percentage of patients with 0, 1, 2 or more ISTs at first dose of study 
drug will be provided. Please note that use of rituximab is not allowed within 6 
months prior to Screening. 
 
2. The additional MG therapy categories in # 1 will be added to the list of subgroups for 
primary and secondary endpoint table analyses using the FAS as specified in the final 
SAP V1.0 dated 6 April 2020 Section 7.2.1.2. 
 
3. For the secondary endpoints of at least 3-point improvement in Myasthenia 
Gravis-Activities of Daily Living (MG-ADL) and at least 5-point improvement in 
Quantitative Myasthenia Gravis score for disease severity (QMG) from baseline to Week 
26, the following other covariance structures may be utilized in the mixed-effect model 
for repeated measures if a convergence issue occurs with the proposed unstructured 
covariance and first auto-regressive structures: compound symmetry and Toeplitz 
method. 
 
4. A summary of treatment emergent adverse events during the Randomized-Controlled 
Period utilizing standard Medical Dictionary for Regulatory Activities (MedDRA) query 


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(narrow) (SMQ[N]) of hypersensitivity will be summarized by preferred term and by 
treatment group using the SS. This summary will replace the infusion related reaction 
summary described in SAP addendum V1.0. 


 
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