A Phase 3, Randomized, Parallel-Group, Multicenter, Open-Label, Pharmacokinetic, Noninferiority Study of Ravulizumab Administered Subcutaneously Versus Intravenously in Adult Patients With Paroxysmal Nocturnal Hemoglobinuria Currently Treated With Eculizumab
Phase: PHASE3
Conditions: Paroxysmal Nocturnal Hemoglobinuria
Sponsor: Alexion Pharmaceuticals, Inc.

A Phase 3, Randomized, Parallel-Group, Multicenter, Open-
Label, Pharmacokinetic, Noninferiority Study of 
Ravulizumab Administered Subcutaneously Versus 
Intravenously in Adult Patients With Paroxysmal Nocturnal 
Hemoglobinuria Currently Treated With Eculizumab 
Unique Protocol ID: 
NCT Number 
EudraCT Number: 
Date of Protocol  
ALXN1210-PNH-303 
NCT03748823 
2017-002370-39 
08 July 2021 

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TITLE PAGE 
Protocol Title: A Phase 3, Randomized, Parallel-Group, Multicenter, Open-Label, 
Pharmacokinetic, Noninferiority Study of Ravulizumab Administered Subcutaneously Versus 
Intravenously in Adult Patients With Paroxysmal Nocturnal Hemoglobinuria Currently Treated 
With Eculizumab 
Protocol Number: ALXN1210-PNH-303 
Amendment Number: 5 
Compound Number: ALXN1210 
USAN/INN: Ravulizumab 
Short Title: PK Noninferiority Study of Ravulizumab SC Versus Ravulizumab IV 
Sponsor Name: 
Alexion Pharmaceuticals, Inc. 
Sponsor Address:  
121 Seaport Boulevard 
Boston MA 02210 
USA 
Regulatory Agency Identifying Number(s):  
EudraCT Number: 2017‐002370‐39 
IND Number: 128367 
Approval Date:  08 Jul 2021 

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Sponsor Signatory: 
Date 
Medical monitor contact information can be found in the study contact list distributed to 
study sites. 
24-hour Emergency Contact:
PPD
PPD
PPD

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INVESTIGATOR’S AGREEMENT 
 
 
I have read the ALXN1210-PNH-303 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 
Amendment 5 (08 Jul 2021) 
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of 
Directive 2001/20/EC of the European Parliament and the Council of the European Union. 
Overall Rationale for the Amendment 
The main rationale for this amendment is addition of secondary efficacy endpoints to align with 
endpoints indicated in the Statistical Analysis Plan v4.0 and HRQoL and treatment 
administration satisfaction endpoints to support assessment of patient preference. 
Other changes implemented through this protocol amendment constitute the addition of patient 
preference questionnaire, remote visit options in times of emergency, and COVID-19 risk 
assessment.  
Section/Table 
Description of Change 
Brief Rationale 
Section 1.1 
Synopsis, Section 3 
Objectives and 
Endpoints 
Patient Preference Questionnaire – Subcutaneous 
was included under HRQoL and treatment 
administration satisfaction endpoints. 
 
 
To support assessment of patient 
preference 
Section 1.1 
Synopsis, Section 3 
Objectives and 
Endpoints 
The efficacy endpoints of change in clinical 
manifestations of PNH over time, change in 
reticulocyte count over time, change in eGFR over 
time, and change in PNH RBC clone size over time 
were added in alignment with the endpoints indicated 
in the Statistical Analysis Plan v.4.0. 
To support assessments of disease 
manifestations and related 
laboratory parameters  
Section 1.1 
Synopsis, Section 
1.2 Study Schema, 
Section 4.1 Overall 
design 
Extension Period was corrected from 182 weeks to 
172 weeks 
To clarify the duration of the 
Extension Period 
Section 1.3 
Schedule of 
Activities, Table 4 
Assessment was added for FACIT-Fatigue and 
EORTC QLQ-C30 on Day 239, and for TASQ-SC 
on Days 183 and 239.  
To align with Statistical Analysis 
Plan v.4.0 and correct the 
assessments that were taken out 
inadvertently in Protocol 
Amendment 4. 
Section 1.3 
Schedule of 
Activities, Table 4 
and 5 
Years removed in table heading as they did not 
reflect the timeframe of the table. 
Correction 
Section 2.4.2 
Potential and 
Identified Risks, 
Section 10. 8 
COVID-19 Risk 
Assessment 
Added text referring reader to coronavirus disease 
2019 (COVID-19) considerations and noted that use 
of immunosuppressants by participants increases risk 
of serious infections 
To conform to EMA Guidance on 
the Management of Clinical Trials 
During the COVID-19 
(Coronavirus) Pandemic and FDA 
Guidance on Conduct of Clinical 
Trials of Medical Products during 
COVID-19 Public Health 
Emergency, and to advise 
regarding specific risks to this 
study population. 

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Section/Table 
Description of Change 
Brief Rationale 
Section 1.3 
Schedule of 
Activities, Table 5 
Patient preference questionnaire assessments were 
added to the Schedule of Activities and a 
corresponding footnote has been added 
To support assessment of patient 
preference 
Section 6.1 
Ravulizumab 
Table, 7 
The term “concentrated” was removed from the SC 
dosage form. Physical description of the Study Drug 
for SC administration was updated. 
Clarified to correctly reflect the 
physical description of the Study 
Drug 
Section 4.4 
Justification of 
Device Selected 
and Section 6.2 
On-body Delivery 
System 
The time for SC administration of ravulizumab was 
changed from “in less than” to “in approximately”. 
To clarify administration time for 
SC drug delivery and to align with 
the Instructions for Use for the 
OBDS. 
Section 4.4 
Justification of 
Device Selected 
and Section 6.3.1 
Ravulizumab IV 
and Ravulizumab 
SC – In-clinic 
Administration 
Text in Section 4.4 and numbered item 7 in Section 
6.3.1 were updated from “device” to “drug-device 
combination”.  
To correctly reflect that the OBDS 
is the drug-device combination. 
Section 8.1.6 
Quality of Life 
Questionnaires 
Description of the PNH Patient Preference 
Questionnaire – Subcutaneous was added 
To support assessment of patient 
preference 
Section 8.3.6.1 
Local and 
Systemic Reactions 
Clarification added for infusion-associated reactions 
“(infusion-related reactions)”. 
For clarification 
Section 9.4.2.2 
Quality of Life and 
Treatment 
Administration 
Satisfaction 
Planned analyses of the patient preference 
questionnaire were described 
To support assessment of patient 
preference 
Section 10.1.9 
Remote Visit 
Options in Times 
of Emergency 
Section detailing remote visit options in times of 
emergency (eg, COVID-19) was added. 
To ensure participant safety and 
treatment continuity. 
Section 10.6.4 
Patient Preference 
Questionnaire  
Section added to include Patient Preference 
Questionnaire – Subcutaneous 
To support assessment of patient 
preference 
Section 10.10 
Protocol 
Amendment 
History 
Updated to include details of Protocol Amendment 4 
To reflect the protocol amendment 
history 
Abbreviations: ADE = adverse device effect; COVID-19 = coronavirus disease 2019; CRF = case report form; 
eGFR = estimated glomerular filtration rate; EMA = European Medicines Agency; EORTC = European 
Organisation for Research and Treatment of Cancer ; FACIT = Functional Assessment of Chronic Illness Therapy; 
FDA = Food and Drug Administration; GDS = Global Drug Safety; HRQoL = health-related quality of life; 
IV = intravenous(ly); OBDS = on-body delivery system; PD = pharmacodynamic(s); PNH = paroxysmal nocturnal 
hemoglobinuria; PK = pharmacokinetic(s); QLQ C30 = Quality of Life Questionnaire-Core 30 Scale; 
QoL = quality of life; RBC = red blood cell; SC = subcutaneous(ly); TASQ = Treatment Administration 
Satisfaction Questionnaire. 

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TABLE OF CONTENTS 
INVESTIGATOR’S AGREEMENT ...............................................................................................3 
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE ............................................4 
TABLE OF CONTENTS .................................................................................................................6 
LIST OF TABLES .........................................................................................................................11 
LIST OF FIGURES .......................................................................................................................11 
1. 
PROTOCOL SUMMARY ..........................................................................................12 
1.1. 
Synopsis ......................................................................................................................12 
1.2. 
Study Schema .............................................................................................................18 
1.3. 
Schedule of Activities .................................................................................................18 
2. 
INTRODUCTION ......................................................................................................29 
2.1. 
Ravulizumab ...............................................................................................................29 
2.2. 
On-body Delivery System ..........................................................................................30 
2.3. 
Study Rationale ...........................................................................................................30 
2.4. 
Benefit/Risk Assessment ............................................................................................31 
2.4.1. 
Potential Benefits ........................................................................................................31 
2.4.2. 
Potential and Identified Risks .....................................................................................32 
2.4.2.1. 
Neisseria meningitidis Infections ...............................................................................32 
2.4.2.2. 
Immunogenicity ..........................................................................................................32 
2.4.2.3. 
Local and Systemic Reactions ....................................................................................32 
2.4.2.4. 
Pregnancy Exposure ...................................................................................................33 
2.4.2.5. 
Potential Device-Related Risks ..................................................................................33 
2.4.2.6. 
Considerations for Coronavirus Disease 2019 ...........................................................33 
2.4.3. 
Conclusion ..................................................................................................................33 
3. 
OBJECTIVES AND ENDPOINTS ............................................................................34 
4. 
STUDY DESIGN .......................................................................................................35 
4.1. 
Overall Design ............................................................................................................35 
4.2. 
Scientific Rationale for Study Design ........................................................................37 
4.3. 
Justification for Dose ..................................................................................................38 
4.4. 
Justification for Device Selected ................................................................................38 
4.5. 
Regulatory Status and Approval Strategy ...................................................................38 
4.6. 
End of Study Definition ..............................................................................................39 

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5. 
STUDY POPULATION .............................................................................................40 
5.1. 
Inclusion Criteria ........................................................................................................40 
5.2. 
Exclusion Criteria .......................................................................................................40 
5.3. 
Lifestyle Considerations .............................................................................................42 
5.4. 
Screen Failures ............................................................................................................42 
6. 
STUDY DRUG AND MEDICAL DEVICE ..............................................................43 
6.1. 
Ravulizumab ...............................................................................................................43 
6.1.1. 
Study Drug Preparation and Administration ..............................................................44 
6.1.1.1. 
Ravulizumab Subcutaneous ........................................................................................44 
6.1.1.2. 
Ravulizumab Intravenous ...........................................................................................45 
6.1.1.3. 
Special Treatment Considerations ..............................................................................45 
6.1.2. 
Packaging and Labeling ..............................................................................................45 
6.1.2.1. 
Ravulizumab SC .........................................................................................................45 
6.1.2.2. 
Ravulizumab Intravenous ...........................................................................................45 
6.2. 
On-body Delivery System ..........................................................................................45 
6.2.1. 
Packaging and Labeling ..............................................................................................46 
6.2.2. 
Anticipated Risks, Contraindications, Warnings ........................................................46 
6.3. 
Handling, Storage, Accountability, and Administration ............................................46 
6.3.1. 
Ravulizumab IV and Ravulizumab SC – In-clinic Administration ............................46 
6.3.2. 
Ravulizumab SC – At-home Administration ..............................................................47 
6.4. 
Measures to Minimize Bias: Randomization and Blinding ........................................48 
6.5. 
Study Drug Compliance .............................................................................................48 
6.6. 
Prior and Concomitant Therapy ..................................................................................48 
6.7. 
Dose or Treatment Group Modification .....................................................................49 
6.8. 
Treatments After the End of the Study .......................................................................49 
7. 
DISCONTINUATION OF STUDY DRUG AND PATIENT 
DISCONTINUATION/WITHDRAWAL ..................................................................50 
7.1. 
Patient Discontinuation/Withdrawal From the Study .................................................50 
7.2. 
Lost to Follow-Up.......................................................................................................51 
7.2.1. 
Discontinuation of Study/Site Termination by Sponsor or Health Authority ............51 
8. 
STUDY ASSESSMENTS AND PROCEDURES ......................................................52 
8.1. 
Efficacy Assessments .................................................................................................52 
8.1.1. 
Lactate Dehydrogenase and Other Disease-Related Laboratory Parameters .............52 

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8.1.2. 
Transfusion Avoidance ...............................................................................................52 
8.1.3. 
Breakthrough Hemolysis ............................................................................................52 
8.1.4. 
Stabilized Hemoglobin ...............................................................................................52 
8.1.5. 
Paroxysmal Nocturnal Hemoglobinuria Symptomatology .........................................52 
8.1.6. 
Quality of Life Questionnaires ...................................................................................52 
8.2. 
Safety Assessments .....................................................................................................54 
8.2.1. 
Major Adverse Vascular Events .................................................................................54 
8.2.2. 
Physical Examination .................................................................................................55 
8.2.3. 
Infusion Site Evaluation .............................................................................................55 
8.2.4. 
Vital Signs ..................................................................................................................55 
8.2.5. 
Electrocardiograms .....................................................................................................55 
8.2.6. 
Clinical Safety Laboratory Assessments ....................................................................55 
8.2.6.1. 
Urinalysis and Urine Chemistry .................................................................................56 
8.2.6.2. 
Virus Serology ............................................................................................................56 
8.2.6.3. 
Immunogenicity Assessments ....................................................................................56 
8.3. 
Adverse Events and Adverse Device Effects .............................................................56 
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 
8.3.3.1. 
Regulatory Reporting Requirements for Serious Adverse Events and Serious 
Adverse Device Effects ..............................................................................................57 
8.3.4. 
Pregnancy ...................................................................................................................58 
8.3.5. 
Vaccine and Antibiotic Prophylaxis ...........................................................................58 
8.3.6. 
Study Drug Administration Reactions ........................................................................59 
8.3.6.1. 
Local and Systemic Reactions ....................................................................................59 
8.3.6.2. 
Infusion-associated Reactions ....................................................................................59 
8.4. 
Device Performance Assessments ..............................................................................59 
8.5. 
Overdose .....................................................................................................................59 
8.6. 
Pharmacokinetic Assessments ....................................................................................60 
8.7. 
Pharmacodynamics .....................................................................................................60 
8.8. 
Genetics ......................................................................................................................60 
8.9. 
Biomarkers ..................................................................................................................60 

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8.10. 
Medical Resource Utilization and Health Economics ................................................60 
9. 
STATISTICAL METHODS AND PLANNED ANALYSES ...................................61 
9.1. 
Statistical Hypotheses .................................................................................................61 
9.2. 
Sample Size Determination ........................................................................................61 
9.3. 
Populations for Analyses ............................................................................................61 
9.4. 
Statistical Analyses .....................................................................................................62 
9.4.1. 
Primary Analysis ........................................................................................................62 
9.4.2. 
Secondary Analyses ....................................................................................................63 
9.4.2.1. 
Pharmacokinetic/Pharmacodynamic ...........................................................................63 
9.4.2.2. 
Quality of Life and Treatment Administration Satisfaction .......................................63 
9.4.3. 
Efficacy Analysis ........................................................................................................64 
9.4.4. 
Safety Analyses ..........................................................................................................64 
9.4.5. 
Device Performance Analyses ....................................................................................65 
9.4.6. 
Other Analyses ............................................................................................................65 
9.5. 
Interim Analysis for Futility and Sample Size Re-estimation ....................................65 
9.6. 
Other Statistical Issues ................................................................................................66 
9.6.1. 
Missing or Invalid Data ..............................................................................................66 
10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS ..................................................................................................67 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations ....................67 
10.1.1. 
Regulatory and Ethical Considerations ......................................................................67 
10.1.2. 
Informed Consent Process ..........................................................................................67 
10.1.3. 
Data Protection ...........................................................................................................68 
10.1.4. 
Source Documents ......................................................................................................68 
10.1.5. 
Dissemination of Clinical Study Data ........................................................................68 
10.1.6. 
Data Quality Assurance ..............................................................................................68 
10.1.7. 
Study and Site Closure................................................................................................69 
10.1.8. 
Publication Policy .......................................................................................................69 
10.1.9. 
Remote Visit Options in Times of Emergency ...........................................................70 
10.2. 
Appendix 2: Clinical Laboratory Tests .......................................................................71 
10.3. 
Appendix 3: Adverse Events and Adverse Device Effects: Definitions and 
Procedures for Recording, Evaluating, Follow-up, and Reporting ............................72 
10.4. 
Appendix 4: Investigational Medical Product or Device Complaints ........................79 

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10.5. 
Appendix 5: Contraceptive Guidance and Collection of Pregnancy 
Information .................................................................................................................80 
10.6. 
Appendix 6: Quality of Life Questionnaires ..............................................................82 
10.6.1. 
Functional Assessment of Chronic Illness Therapy--Fatigue Subscale 
Version 4 .....................................................................................................................82 
10.6.2. 
European Organisation for Research and Treatment of Cancer Quality of 
Life Questionnaire – Core 30 .....................................................................................83 
10.6.3. 
Treatment Administration Satisfaction Questionnaires ..............................................85 
10.6.3.1. 
Treatment Administration Satisfaction Questionnaire – Intravenous ........................85 
10.6.3.2. 
Treatment Administration Satisfaction Questionnaire – Subcutaneous .....................88 
10.6.4. 
Patient Preference Questionnaire ................................................................................91 
10.7. 
Appendix 7: Management of Potential Infusion-associated Adverse Events 
During Study Drug Administration ............................................................................93 
10.8. 
Appendix 8: COVID-19 Risk Assessment .................................................................94 
10.9. 
Appendix 9: Abbreviations .........................................................................................96 
10.10. 
PROTOCOL AMENDMENT HISTORY ..................................................................98 
11. 
REFERENCES ...........................................................................................................99 

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LIST OF TABLES 
Table 1: 
Study Drug Dosing .....................................................................................................14 
Table 2: 
Ravulizumab Subcutaneous Treatment Group: Schedule of Study Visits and 
Activities – Screening Through End of Randomized Treatment Period ....................20 
Table 3: 
Ravulizumab Intravenous Treatment Group: Schedule of Study Visits and 
Activities – Screening Through End of Randomized Treatment Period ....................23 
Table 4: 
Schedule of Study Visits and Activities – Extension Period Through Day 
365 ..............................................................................................................................25 
Table 5: 
Schedule of Study Visits and Activities – Extension Period, Day 421 
Through Day 1275 ......................................................................................................27 
Table 6: 
Dosing .........................................................................................................................36 
Table 7: 
Study Drug Administered ...........................................................................................43 
Table 8: 
Dosing Reference Chart for Ravulizumab Subcutaneous Group ...............................44 
Table 9: 
Dosing Reference Chart for Ravulizumab Intravenous Group ...................................44 
Table 10: Populations for Analyses ............................................................................................61 
Table 11: Dosing Window Requirements for Inclusion in the Pharmacokinetic 
Analysis Set ................................................................................................................62 
Table 12: Criteria for Futility Analysis and Sample Size Re-estimation....................................66 
Table 13: Protocol-Required Safety Laboratory Assessments ...................................................71 
Table 14: Potential Risks and Mitigation Measures due to COVID-19 .....................................94 
LIST OF FIGURES 
Figure 1: 
Diagram of the On-body Delivery System .................................................................30 

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1. 
PROTOCOL SUMMARY 
1.1. 
Synopsis 
Protocol Title: A Phase 3, Randomized, Parallel-Group, Multicenter, Open-Label 
Pharmacokinetic, Noninferiority Study of Ravulizumab Administered Subcutaneously Versus 
Intravenously in Adult Patients With Paroxysmal Nocturnal Hemoglobinuria Currently Treated 
With Eculizumab 
Short Title: PK Noninferiority Study of Ravulizumab SC Versus Ravulizumab IV 
Rationale: The purpose of this study is to compare the pharmacokinetics (PK) of ravulizumab 
subcutaneous (SC) administered via an on-body delivery system (OBDS) to ravulizumab 
intravenous (IV) in patients with paroxysmal nocturnal hemoglobinuria (PNH) who are clinically 
stable and have been previously treated with eculizumab for at least 3 months prior to study 
entry. Based on the established relationship between PK exposure and clinical efficacy of 
ravulizumab IV, the PK noninferiority of ravulizumab SC to ravulizumab IV will enable 
bridging of efficacy and safety data from ravulizumab IV to ravulizumab SC. The study 
hypothesis is that Day 71 ravulizumab SC serum Ctrough will be noninferior compared with 
Day 71 ravulizumab IV serum Ctrough. 
The study is also intended to demonstrate the safety and tolerability of ravulizumab SC and the 
ravulizumab OBDS, a drug-device combination product. 
Objectives and Endpoints  
Objectives 
Endpoints 
Primary 
Primary PK endpoint 
To evaluate PK noninferiority of ravulizumab SC 
versus ravulizumab IV in adult patients with PNH 
Day 71 serum ravulizumab Ctrough 
Secondary 
PK Endpoint 
To characterize PK of ravulizumab SC 
Ctrough over time 
 
PD Endpoint 
To characterize PD of ravulizumab SC 
Free serum C5 concentrations over time 
 
Immunogenicity Endpoint 
To characterize immunogenicity of ravulizumab SC 
Incidence of treatment-emergent ADAs over time 
 
HRQoL and Treatment Satisfaction Endpoints 
To evaluate HRQoL and treatment satisfaction on 
ravulizumab SC 
 
• 
Change in FACIT-Fatigue Scale, Version 4, from 
Baseline to Day 183 
• 
Change in EORTC QLQ-C30 Version 3.0, from 
Baseline to Day 183 
• 
Reported treatment administration satisfaction as 
measured by the TASQ score at Baseline and 
Day 183 
• 
Reported patient preference as measured by the 
PPQ-SC score at Day 1093 
 
Safety Endpoints 
To evaluate safety of ravulizumab SC and ravulizumab 
OBDS  
• 
Change in physical examinations, vital signs, 
electrocardiograms, and laboratory assessments 
over time  
• 
Incidence of adverse events and serious adverse 
events 

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Objectives 
Endpoints 
• 
Incidence of adverse device effects and serious 
adverse device effects 
 
Efficacy Endpoints 
To evaluate efficacy of ravulizumab SC  
• 
Change over time in LDH 
• 
Incidence of breakthrough hemolysis 
• 
Achievement of transfusion avoidance 
• 
Achievement of stabilized hemoglobin 
• 
Change in clinical manifestations of PNH over 
time 
• 
Change in reticulocyte count over time 
• 
Change in eGFR over time 
• 
Change in PNH RBC clone size over time 
 
Performance Endpoint  
To assess performance of ravulizumab OBDS  
• 
Reported outcome of attempted full-dose 
administration (including device 
failure/malfunction) 
Abbreviations: ADA = antidrug antibody; C5 = complement component 5; Ctrough = predose concentration; 
eGFR = estimated glomerular filtration rate; EORTC = European Organisation for Research and Treatment of 
Cancer; FACIT = Functional Assessment of Chronic Illness Therapy; HRQoL = health-related quality of life; 
IV = intravenous; LDH = lactate dehydrogenase; OBDS = on-body delivery system; PD = pharmacodynamic(s); 
PK = pharmacokinetic(s); PNH = paroxysmal nocturnal hemoglobinuria; PPQ-SC = Patient Preference 
Questionnaire – Subcutaneous; QLQ-C30 = Quality of Life Questionnaire-Core 30 Scale; RBC = red blood cell; 
SC = subcutaneous; TASQ = Treatment Administration Satisfaction Questionnaire. 
Study Drug Formulations 
Treatment 
Formulation 
Delivery Mechanism 
Ravulizumab IV 
10 mg/mL ravulizumab in 10 mM sodium 
phosphate containing 150 mM sodium 
chloride, 0.02% polysorbate 80, and water 
for injection, pH 7.0 
Intravenous infusion 
Ravulizumab SC 
70 mg/mL ravulizumab in 50 mM sodium 
phosphate containing 25 mM arginine, 5% 
sucrose, 0.05% polysorbate 80, and water 
for injection, pH 7.4 
Subcutaneous infusion via OBDS  
Abbreviations: OBDS = on-body delivery system. 
Overall Design:  
This is a Phase 3, randomized, open-label, parallel-group, multicenter study to evaluate PK 
noninferiority of ravulizumab SC administered via an OBDS compared with intravenously 
administered ravulizumab IV in adult patients with PNH who are clinically stable and have been 
previously treated with eculizumab for at least 3 months prior to study entry. 
The study will consist of an up to a 30-day Screening Period, a 10-week Randomized Treatment 
Period, and an Extension Period of up to 172 weeks or until the product is registered or approved 
(in accordance with country-specific regulations), whichever occurs first. The study duration for 
each patient will be up to 3.5 years. Patients will be stratified by weight group (≥ 40 kg to 
< 60 kg and ≥ 60 kg to < 100 kg) and then randomized in a 2:1 ratio to receive either 
ravulizumab SC or ravulizumab IV. 

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Ravulizumab IV dosing during the Randomized Treatment Period will be administered in the 
clinic by a trained member of the site study team. Day 1 of study treatment will occur 12 to 
16 days from the patient’s last dose of eculizumab. Timing for study drug administration and 
predose PK sample collection is critical to ensure adequate numbers of patients with evaluable 
PK data (Table 1 ). The time for the start of the dose administered on Day 1 is the nominal time 
for all subsequent doses and PK/PD sample collections. Specifically, all subsequent doses during 
the Randomized Treatment Period are expected to be administered at the same time of day that 
the dose was administered on Day 1. The PK samples are expected to be drawn as close as 
possible to the administration of the dose (or from the nominal time from the start of the Day 1 
dose on nondosing days). The PK analysis set population is defined in Section 9.3. 
Ravulizumab OBDS will be supplied in a kit, comprising 245 mg of ravulizumab SC in a sterile, 
single-use, prefilled cartridge assembly copackaged with a single-use injector. Two kits will be 
used to deliver the full 490 mg dose of ravulizumab SC. 
Ravulizumab IV loading and maintenance doses will be based on patient body weight prior to 
dosing at each dosing visit (Table 1 ). 
During the Randomized Treatment Period, patients assigned to the ravulizumab SC group will 
receive a loading dose of ravulizumab IV on Day 1, followed by maintenance doses of 
ravulizumab SC on Day 15 and every week (qw) thereafter through completion of the 
Randomized Treatment Period. Patients assigned to the ravulizumab IV group will receive a 
loading dose of ravulizumab IV on Day 1 followed by a maintenance dose of ravulizumab IV on 
Day 15 (Table 1 ).  
Table 1: 
Study Drug Dosing  
Treatment Group 
Randomized Treatment Period (10 weeks) 
Extension Period (up to 
172 weeks) 
Ravulizumab SC 
Loading Dose on Day 1: 
Ravulizumab IV 
2400 mga or 
Ravulizumab IV 
2700 mgb 
SC Doses on Days 15, 22, 29, 
36, 43, 50, 57, and 64: 
Ravulizumab SC 490 mgc  
(2 ravulizumab OBDS kits per 
weekly dose) 
Maintenance Doses on 
Day 71 and qw through 
Day 1275:  
Ravulizumab SC 490 mgd 
(2 ravulizumab OBDS kits 
per weekly dose) 
Ravulizumab IV 
Maintenance Dose on Day 15:  
Ravulizumab IV 3000 mga  
or 
Ravulizumab IV 3300 mgb  
a Weight group ≥ 40 to < 60 kg. 
b Weight group ≥ 60 to < 100 kg.  
c On Day 15, patients who randomized to the ravulizumab SC group will self-administer ravulizumab SC in the 
clinic with oversight by trained study site personnel as part of the required training program for at-home 
self-administration. On Days 29, 43, 57, and 64, ravulizumab SC will be self-administered by the patient in the 
clinic with oversight by trained study site personnel. On Days 22, 36, and 50, ravulizumab dosing can be 
self-administered by the patient at home. With approval from the Sponsor, the patient can self-administer 
ravulizumab SC at the clinic at these visits.  

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d Self-administered by the patient at home or self-administered in the clinic with oversight by trained study site 
personnel on scheduled visit days. With approval from the Sponsor, the patient can self-administer ravulizumab 
SC at the clinic on dosing days that are not scheduled in-clinic visits. On Day 71, patients who had been 
randomized to the ravulizumab IV group will self-administer ravulizumab SC in the clinic with oversight by 
trained study site personnel as part of the required training program for at-home self-administration. 
Abbreviations: IV = intravenous; OBDS = on-body delivery system; qw = every week; SC = subcutaneous. 
Day 71 is the end of the Randomized Treatment Period and the beginning of the Extension 
Period. All Day 71 assessments completed prior to dosing are considered part of the Randomized 
Treatment Period. Dosing on Day 71 is the start of the Extension Period. During the Extension 
Period: 
• Patients who had been randomized to the ravulizumab SC group will continue to 
receive 490 mg of ravulizumab SC using 2 OBDS kits on Day 71 and qw thereafter 
through the end of the Extension Period (up to Day 1275) 
• Patients who had been randomized to the ravulizumab IV group will switch to 
490 mg of ravulizumab SC using 2 OBDS kits on Day 71 and qw thereafter through 
the end of the Extension Period (up to Day 1275) 
Ravulizumab SC dosing during the Extension Period can be self-administered by the patient at 
home with the following exceptions where ravulizumab SC will be administered in the clinic: 
• For patients who had been randomized to the ravulizumab IV group, ravulizumab SC 
490 mg dose on Day 71 will be self-administered by the patient in the clinic with 
oversight by trained study site personnel as part of the required training program for 
at-home self-administration. 
• For all patients, doses that coincide with study visits specified in the Schedule of 
Activities (SoA, Section 1.3) will be self-administered by the patient in the clinic with 
oversight by trained study site personnel. 
• With approval from the Sponsor, the patient can self-administer ravulizumab SC at 
the clinic on dosing days that are not scheduled in-clinic visits (with oversight by 
trained study site personnel). 
The end of the study for each patient occurs when the safety follow-up is completed. The safety 
follow-up consists of a phone call 30 days after the last dose. Data collection during the safety 
follow-up is limited to reporting adverse events and concomitant medications. If a patient 
discontinues treatment, but does not discontinue from the study, the end of study for such a 
patient will be their last visit as long as that visit is more than 30 days from their last dose. The 
end of the study is defined as the date of the last patient visit or safety follow up, whichever 
occurs later. 
Number of Patients: 
Approximately 105 patients (70 patients in the ravulizumab SC group and 35 patients in the 
ravulizumab IV group) will be enrolled in the study. An interim analysis for sample size 
re-estimation will be conducted and the sample size may be increased to a maximum of 
144 patients Section 9.5). 

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Inclusion Criteria 
Patients must meet all inclusion and no exclusion criteria. Patients who fail study eligibility may 
be rescreened once based on discussion and agreement between the Investigator and the Medical 
Monitor. 
Patients are eligible to be included in the study only if they fulfill all of the following criteria: 
Age 
1. Patients must be at least 18 years of age at the time of signing the informed consent. 
Patient and Disease Characteristics 
2. Treated with eculizumab according to the labeled dosing recommendation for PNH 
(900 mg every 14 days ± 2 days) for at least 3 months prior to study entry with no missed 
doses within 2 months prior to study entry and no more than 2 doses outside of the visit 
window.  
3. Lactate dehydrogenase levels ≤ 1.5 × ULN (upper limit of normal), according to central 
laboratory, at Screening. Sample must be obtained within 24 hours of or immediately 
prior to a scheduled eculizumab dose administration (ie, at trough eculizumab level). 
4. Documented diagnosis of PNH confirmed by high-sensitivity flow cytometry evaluation 
(Borowitz, 2010).  
5. Vaccinated against meningococcal infections within 3 years prior to, or at the time of, 
initiating study drug to reduce the risk of meningococcal infection (N meningitidis). 
Weight 
6. Body weight ≥ 40 to < 100 kg, and in the opinion of the Investigator, are likely to remain 
within this body weight range for the duration of the study. 
Contraception 
7. Female patients of childbearing potential and male patients with female partners of 
childbearing potential must follow protocol-specified contraception guidance while on 
treatment and for at least 8 months after last dose of study drug. 
Informed Consent 
8. Patients must be willing and able to give written informed consent and to comply with all 
study visits and procedures, including self-administration of ravulizumab SC doses, and 
the use of any data collection device(s) to directly record patient data. 
Exclusion Criteria  
Patients are excluded from the study if any of the following criteria are met: 
Medical Conditions 
1. More than 1 LDH value > 2 × ULN within the 3 months prior to study entry. 
2. Major adverse vascular event (MAVE) in the 6 months prior to study entry. 
3. Platelet count < 30,000/mm3 (30 × 109/L) at Screening. 

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4. Absolute neutrophil count < 500/µL (0.5 × 109/L) at Screening. 
5. History of bone marrow transplantation. 
6. History of N meningitidis infection. 
7. History of unexplained infections. 
8. Active systemic bacterial, viral, or fungal infection within 14 days prior to study drug 
administration on Day 1. 
9. Presence of fever ≥ 38°C (100.4°F) within 7 days prior to study drug administration on 
Day 1. 
10. Human immunodeficiency virus (HIV) infection (evidenced by HIV-1 or HIV-2 antibody 
titer). 
11. History of malignancy within 5 years of Screening with the exception of nonmelanoma 
skin cancer or carcinoma in situ of the cervix that has been treated with no evidence of 
recurrence. 
12. History of or ongoing major cardiac, pulmonary, renal, endocrine, or hepatic disease (eg, 
active hepatitis) that, in the opinion of the Investigator or Sponsor, precludes the patient’s 
participation in an investigational clinical study. 
13. Unstable medical conditions (eg, myocardial ischemia, active gastrointestinal bleed, 
severe congestive heart failure, anticipated need for major surgery within 6 months of 
Day 1, coexisting chronic anemia unrelated to PNH) that would make patients unlikely to 
tolerate the requirements of the protocol). 
14. History of hypersensitivity to any ingredient contained in the study drug including 
hypersensitivity to murine proteins. 
15. Female patients who plan to become pregnant or are currently pregnant or breastfeeding. 
16. Female patients who have a positive pregnancy test result at screening or on Day 1. 
17. 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 an 
additional risk for the patient, or confound the outcome of the study. 
18. Known or suspected history of drug or alcohol abuse or dependence within 1 year prior to 
Screening. 
19. Inability to complete the requirements for SC self-administration. 
20. Inability to travel to the clinic for specified visits during the Randomized Treatment 
Period or fulfil the logistic requirements of study drug.  
Prior/Concomitant Therapy 
21. Concomitant use of anticoagulants is prohibited if not on a stable regimen for at least 
2 weeks prior to study entry. 

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Prior/Concurrent Clinical Study Experience 
22. Participation in another 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 that investigational 
product, whichever is greater (except for participation in observational studies [eg, PNH 
Registry]). 
23. Received any other experimental C5 antagonist at any time. 
1.2. 
Study Schema  
 
 
 
 
 
 
 
 
 
Ravulizumab SC dosage: Day 1 loading dose (IV) = 2400 mg for patients weighing ≥ 40 kg to < 60 kg and 2700 mg 
for patients weighing ≥ 60 kg to < 100 kg; Day 15 and all subsequent SC doses = 490 mg qw for all patients. 
Ravulizumab IV dosage: Day 1 loading dose (IV) = 2400 mg for patients weighing ≥ 40 mg to < 60 kg and 2700 mg 
for patients weighing ≥ 60 kg to < 100 kg; Day 15 maintenance dose (IV) = 3000 mg for patients weighing ≥ 40 kg 
to < 60 kg, 3300 mg for patients weighing ≥ 60 kg to < 100 kg.  
Extension Period maintenance doses (SC) = 490 mg qw for all patients. 
Abbreviations: IV = intravenous; OBDS = on-body delivery system; qw = every week; SC = subcutaneous. 
1.3. 
Schedule of Activities  
The SoA for Screening and the Randomized Treatment Period is provided for the ravulizumab 
SC group in Table 2 and for the ravulizumab IV group in Table 3 . Day 71 is the end of the 
Randomized Treatment Period. All assessments for Day 71 will be performed prior to dosing. On 
Day 15, a qualified member of the site study team will train patients randomized to ravulizumab 
SC on self-administration of ravulizumab SC using the OBDS kits prior to self-administration by 
the patient. The patient will self-administer the Day 15 dose of ravulizumab SC in the clinic with 
oversight by trained study site personnel. On Days 22, 36, and 50, ravulizumab SC can be 
self-administered by the patient at home. With approval from the Sponsor, the patient can 
self-administer ravulizumab SC at the clinic on these days (with oversight by trained study site 
Screening 
(up to 30 days) 
Randomized Treatment Period 
(10 weeks) 
Extension Period 
(172 weeks) 
Patients on 
eculizumab 
≥3 months 
(n=105) 
Randomization 
Ravulizumab IV (n=35 ) 
Weight based dosing 
Ravulizumab OBDS (n=70)
490 mg qw
Ravulizumab OBDS 
Maintenance dose – 490 mg qw
Day 71 
Primary Analysis 
Predose 
Day 1 
Ravulizumab IV loading dose 
(all patients)
First dose
Ravulizumab OBDS
Maintenance dose
Ravulizumab IV 
Day 15 

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personnel). On Days 29, 43, 57, and 64, ravulizumab SC will be self-administered by the patient 
in the clinic with oversight by trained study site personnel.  
The SoA for the Extension Period is provided in Table 4 and Table 5 . Dosing on Day 71 is the 
start of the Extension Period. The first dose of ravulizumab SC for patients who had been 
randomized to ravulizumab IV during the Randomized Treatment Period will be on Day 71. On 
Day 71, a qualified member of the site study team will train patients who had been randomized 
to ravulizumab IV on self-administration of ravulizumab SC using the OBDS kits prior to 
self-administration by the patient. The patient will self-administer the Day 71 dose of 
ravulizumab SC in the clinic with oversight by trained study site personnel. For patients who had 
been randomized to ravulizumab SC, dosing on Day 71 will be by self-administration during the 
in-clinic visit. For the remainder of the Extension Period, weekly dosing of ravulizumab SC for 
all patients can be by self-administration by the patient at home or in the clinic at visits specified 
in Table 4 and Table 5 . With approval from the Sponsor, the patient can self-administer 
ravulizumab SC at the clinic on dosing days that are not scheduled in-clinic visits (with oversight 
by trained study site personnel).  
Procedures conducted as part of the patient’s routine clinical management (eg, hematology 
assessments) and obtained before signing of the informed consent form (ICF) may be utilized for 
screening purposes provided the procedures meet protocol-specified criteria and were performed 
within the time frame specified in the SoA. 
Quality of life assessments will be administered and recorded on paper throughout the study. 
Data associated with ravulizumab SC dosing when it is administered in the home setting during 
the Extension Period will be recorded in a patient e-diary. 
The site will monitor self-administration of ravulizumab SC by the patient via telephone calls 
with the patient on scheduled at-home dosing days during the Randomized Treatment Period 
(patients randomized to ravulizumab SC) to ensure that the patient is queried about study drug 
dose administered and device condition. During the Extension Period, the site will contact 
patients by telephone on Day 78 to query the patient on study drug administration and 
completion of the patient e-diary. After Day 78, sites will monitor self-administration of 
ravulizumab SC via the patient e-diary. 
Laboratory specimen handling and processing instructions will be provided in the study 
laboratory manual. Blood samples should not be collected from a heparinized line. Post IV dose 
(Day 1 for both cohorts, and also Day 15 for the ravulizumab IV cohort) blood samples should 
be collected from the contralateral arm. 
Unscheduled visits that occur outside the protocol-specified visits are permitted at the discretion 
of the Investigator. Procedures, tests, and assessments conducted during unscheduled visits will 
be performed at the discretion of the Investigator.  
If breakthrough hemolysis is suspected, LDH, PK, PD, and antidrug antibody (ADA) samples 
must be collected for analysis at the central laboratory. If the suspected event of breakthrough 
hemolysis occurs outside of a scheduled visit, the patient is expected to return to the site for an 
Unscheduled Visit for evaluation and collection of the required LDH, PK, PD, and ADA 
samples. For purposes of defining breakthrough hemolysis, assessment of LDH must be based on 
a central laboratory value. 

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Table 2: 
Ravulizumab Subcutaneous Treatment Group: Schedule of Study Visits and Activities – Screening Through 
End of Randomized Treatment Period 
Study Day 
Screening
–30 to –1 
1 
15 
22 
29  
36 
43 
50  
57  
64  
71a 
Study Week 
 
 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Site visit (V) or at-home dosing of ravulizumab SC (H)  
 
V 
V 
H 
V 
H 
V 
H 
V 
V 
V 
Dose window (nominal time in hours from the start of the 
first dose on Day 1)b  
 
 
± 1 
± 6 
± 6 
± 6 
± 6 
± 6 
± 1 
± 1 
± 1 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
X 
X 
 
 
 
 
 
 
 
 
 
Medical history and demographics 
X 
 
 
 
 
 
 
 
 
 
Confirmation or administration of meningococcal vaccinationc 
X 
X 
 
 
 
 
 
 
 
 
 
HIV testing 
X 
 
 
 
 
 
 
 
 
 
PNH clone sized 
X 
X 
 
 
 
 
 
 
 
 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
X 
X 
 
X 
 
X 
 
X 
X 
X 
Pregnancy teste 
X 
X 
X 
 
 
 
 
 
 
 
X 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
Ravulizumab IV loading dose administrationf 
 
X 
 
 
 
 
 
 
 
 
 
Ravulizumab SC administrationg 
 
 
Xh 
Xi 
Xh 
Xi 
Xh 
Xi 
Xh 
Xh 
 
Patient training on dose administrationj 
 
 
X 
 
 
 
 
 
 
 
 
Scheduled telephone callk 
 
 
 
X 
 
X 
 
X 
 
 
 
Infusion site evaluationl 
 
X 
X 
 
X 
 
X 
 
X 
X 
 
PK/PD sampling (within 30 minutes predose)m 
 
X 
X 
 
 
 
 
 
X 
X 
X 
Postdose PK/PD sampling (within 30 minutes postdose) 
 
X 
 
 
 
 
 
 
 
 
 
Immunogenicity (ADA) (within 30 minutes predose)m 
 
X 
 
 
 
 
  
 
 
 
X 
PNH symptomatology 
X 
X 
X 
 
 
 
X 
 
 
 
X 
FACIT-Fatigue 
X 
X 
 
 
 
 
X 
 
 
 
X 
EORTC QLQ-C30 
X 
X 
 
 
 
 
X 
 
 
 
X 
TASQ-IVn 
X 
X 
X 
 
 
 
 
 
 
 
 
TASQ-SCo 
 
 
 
 
 
 
X 
 
 
 
X 
Vital signsp 
X 
X 
X 
 
X 
 
X 
 
X 
X 
X 
Safety 12-lead ECG 
X 
 
 
 
 
 
 
 
 
 
X 
Chemistry, including LDHq 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
Hematology, including coagulation 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
Urinalysis and urine chemistry 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
Physical examination 
X 
 
 
 
 
 
 
 
 
 
 
Abbreviated physical examinationr 
 
X 
X 
 
X 
 
X 
 
X 
 
X 

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Table 2: 
Ravulizumab Subcutaneous Treatment Group: Schedule of Study Visits and Activities – Screening Through 
End of Randomized Treatment Period 
Study Day 
Screening
–30 to –1 
1 
15 
22 
29  
36 
43 
50  
57  
64  
71a 
Study Week 
 
 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Site visit (V) or at-home dosing of ravulizumab SC (H)  
 
V 
V 
H 
V 
H 
V 
H 
V 
V 
V 
Dose window (nominal time in hours from the start of the 
first dose on Day 1)b  
 
 
± 1 
± 6 
± 6 
± 6 
± 6 
± 6 
± 1 
± 1 
± 1 
Review safety card 
 
X 
X 
 
X 
 
X 
 
X 
X 
X 
Breakthrough hemolysiss 
 
←Monitor continuously→ 
Adverse events/adverse device effects 
←Monitor continuously→ 
Concomitant medications 
←Monitor continuously→ 
Record transfusions and transfusion parameters 
←Monitor continuously→ 
a Day 71 assessments for the Randomized Treatment Period must be performed predose on Day 71. 
b Dosing must be administered on the visit day indicated during the Randomized Treatment Period. Doses after Day 1 are expected to be administered at the same nominal time as 
the dose on Day 1. 
c All patients must be vaccinated against meningococcal infections within 3 years prior to, or at the time of, initiating study drug.  
d White blood cell (granulocyte and monocyte) and red blood cell clone size measured by high-sensitivity flow cytometry at Screening and Day 1; red blood cell clone size only on 
Day 71. 
e Female patients of childbearing potential only: serum pregnancy test at Screening and Day 71; urine pregnancy test at all other required time points. A negative urine test result is 
required prior to administering ravulizumab to female patients of childbearing potential at the indicated visits. 
f Ravulizumab IV weight-based dosing on Day 1 (2400 mg for patients ≥ 40 to < 60 kg and 2700 mg for patients ≥ 60 to < 100 kg) is to be administered after Day 1 assessments 
are performed. 
g Ravulizumab SC 490 mg qw maintenance dose on Day 15 and thereafter. 
h Ravulizumab SC self-administered in the clinic.  
i Ravulizumab SC self-administered at home. With approval from the Sponsor, the patient can self-administer ravulizumab SC at the clinic on these days (with oversight by 
trained study site personnel). 
j A qualified member of the site study team will provide initial (and ongoing as appropriate) training on how to properly self-administer ravulizumab SC using the 2 required 
OBDS kits. 
k Site will contact patient via telephone at scheduled dosing times to ensure patient is queried about study drug dose administration and device condition.  
l New or worsening abnormalities should be reported as AEs 
m The timing for PK sample collection is critical to the primary endpoint for this study. Serum samples for PK/PD/ADA analyses are to be collected as close as possible, but no 
more than 30 minutes prior to dosing. Day 71 dosing is included in the Extension Period (Table 4 ). Samples should be collected from the contralateral arm used for IV dosing. 
Samples should not be collected from a heparinized line. 
n At screening, patients complete TASQ-IV within 24 hours of receiving their eculizumab dose. 
o Patients randomized to ravulizumab SC group complete TASQ-IV at Screening, Day 1 and Day 15 and then complete TASQ-SC at Day 43 and Day 71. 
p On dosing days, vital signs will be obtained before study drug administration. 
q Follicle stimulating hormone levels will be measured during Screening only in order to confirm postmenopausal status. 

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r Abbreviated physical examination consists of a body system relevant examination based upon Investigator (or designee) judgment and patient symptoms. At least 1 body system 
must be checked for an abbreviated physical examination. 
s If a suspected event of breakthrough hemolysis occurs, blood samples for LDH, PK, PD, and ADA parameters will be collected and sent to the central laboratory for analysis. If 
the suspected event of breakthrough does not occur at a scheduled visit, an unscheduled visit should occur for evaluation of the patient and collection of the required blood 
samples. 
Abbreviations: ADA = antidrug antibody; ECG = electrocardiogram; EORTC QLQ-C30 = European Organisation for Research and Treatment of Cancer, Quality of Life 
Questionnaire-Core 30 Scale; FACIT-Fatigue = Functional Assessment of Chronic Illness Therapy-Fatigue Scale; H = at-home dosing; HIV = human immunodeficiency virus; 
IV = intravenous; LDH = lactate dehydrogenase; PD = pharmacodynamic(s); PK = pharmacokinetic(s); PNH = paroxysmal nocturnal hemoglobinuria; qw = every week; 
SC = subcutaneous; TASQ = Treatment Administration Satisfaction Questionnaire; V = site visit. 

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Table 3: 
Ravulizumab Intravenous Treatment Group: Schedule of Study Visits and Activities – Screening Through 
End of Randomized Treatment Period 
Study Day 
Screening  
–30 to –1 
1 
15 
29 
43 
57 
71a  
Study Week 
 
 
2 
4 
6 
8 
10 
Site visit (V) 
 
V 
V 
V 
V 
V 
V 
Dose window (nominal time in hours from the start of first dose on 
Day 1)b 
 
 
± 1 
 
 
 
± 1 
Informed consent 
X 
 
 
 
 
 
 
Inclusion/Exclusion 
X 
X 
 
 
 
 
 
Medical history and demographics 
X 
 
 
 
 
 
Confirmation or administration of meningococcal vaccinationc 
X 
X 
 
 
 
 
 
HIV testing 
X 
 
 
 
 
 
PNH clone sized 
X 
X 
 
 
 
 
X 
Height 
X 
 
 
 
 
 
 
Weight 
X 
X 
X 
 
 
 
X 
Pregnancy teste 
X 
X 
X 
 
 
 
X 
Randomization 
 
X 
 
 
 
 
 
Ravulizumab IV loading dose administrationf 
 
X 
 
 
 
 
 
Ravulizumab IV administrationg 
 
 
X 
 
 
 
 
Infusion site evaluationh 
 
X 
X 
 
 
 
 
PK/PD sampling (within 30 minutes predose)i 
 
X 
X 
 
 
 
X 
Postdose PK/PD sampling (within 30 minutes postdose) 
 
X 
X 
 
 
Xj 
 
Immunogenicity (ADA) (within 30 minutes predose)i 
 
X 
 
 
  
 
X 
PNH symptomatology 
X 
X 
X 
 
X 
 
X 
FACIT-Fatigue 
X 
X 
 
 
X 
 
X 
EORTC QLQ-C30 
X 
X 
 
 
X 
 
X 
TASQ-IV 
Xk 
X 
 
 
X 
 
X 
Vital signsl 
X 
X 
X 
X 
X 
X 
X 
Safety 12-Lead ECG 
X 
 
 
 
 
 
X 
Chemistry, including LDHm 
X 
X 
X 
X 
X 
X 
X 
Hematology, including coagulation 
X 
X 
X 
X 
X 
X 
X 
Urinalysis and urine chemistry 
X 
X 
X 
X 
X 
X 
X 
Physical examination 
X 
 
 
 
 
 
 
Abbreviated physical examinationn 
 
X 
X 
X 
X 
X 
X 
Review safety card  
 
X 
X 
X 
X 
X 
X 
Breakthrough hemolysiso 
 
←Monitor continuously→ 
Adverse events 
←Monitor continuously→ 
Concomitant medications 
←Monitor continuously→ 
Record transfusions and transfusion parameters 
 
←Monitor continuously→ 

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a Day 71 assessments for the Randomized Treatment Period must be performed predose on Day 71. 
b Dosing must be administered on the visit day indicated during the Randomized Treatment Period. Doses after Day 1 are expected to be administered at the same nominal time as 
the dose on Day 1. 
c All patients must be vaccinated against meningococcal infections within 3 years prior to, or at the time of, initiating study drug.  
d White blood cell (granulocyte and monocyte) and red blood cell clone size measured by high-sensitivity flow cytometry at Screening and Day 1; red blood cell clone size only on 
Day 71. 
e Female patients of childbearing potential only. Serum pregnancy test at Screening and Day 71; urine pregnancy test at all other required time points. A negative urine test result 
is required prior to administering ravulizumab to female patients of childbearing potential at the indicated visits. 
f Ravulizumab IV weight-based loading dose on Day 1 (2400 mg for patients weighing ≥ 40 to < 60 kg and 2700 mg for patients weighing ≥ 60 to < 100 kg) is to be administered 
after Day 1 assessments are performed. 
g Ravulizumab weight-based maintenance dosing on Day 15 is: 3000 mg for patients weighing ≥ 40 to < 60 kg and 3300 mg for patients weighing ≥ 60 to < 100 kg. 
h New or worsening abnormalities should be reported as AEs 
i The timing for PK sample collection is critical to the primary endpoint for this study. Serum samples for PK/PD/ADA analyses are to be collected as close as possible but no 
more than 30 minutes prior to dosing. Day 71 dosing is included in the Extension Period (Table 4 ). Samples should be collected from the contralateral arm used for IV dosing. 
Samples must not be collected from a heparinized line. 
j There is no dose of ravulizumab administered on Day 57; sample to be collected anytime during the assessments on Day 57.  
k During Screening, patients complete TASQ-IV within 24 hours of receiving a dose of eculizumab. 
l On dosing days, vital signs will be obtained before study drug administration. 
m Follicle stimulating hormone levels will be measured during Screening only in order to confirm postmenopausal status.  
n Abbreviated physical examination consists of a body system relevant examination based upon Investigator (or designee) judgment and patient symptoms. At least 1 body system 
must be checked for an abbreviated physical examination.  
o If a suspected event of breakthrough hemolysis occurs, blood samples for LDH, PK, PD, and ADA parameters will be collected and sent to the central laboratory. If the 
suspected event of breakthrough does not occur at a scheduled visit, an Unscheduled Visit should occur for evaluation of the patient and collection of the required blood samples. 
Abbreviations: ADA = antidrug antibody; AE = adverse event; ECG = electrocardiogram; EORTC QLQ-C30 = European Organisation for Research and Treatment of Cancer, 
Quality of Life Questionnaire-Core 30 Scale; FACIT-Fatigue = Functional Assessment of Chronic Illness Therapy-Fatigue Scale; HIV = human immunodeficiency virus; 
IV = intravenous; LDH = lactate dehydrogenase; PD = pharmacodynamic(s); PK = pharmacokinetic(s); PNH = paroxysmal nocturnal hemoglobinuria; TASQ = Treatment 
Administration Satisfaction Questionnaire; V = site visit.  

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Table 4: 
Schedule of Study Visits and Activities – Extension Period Through Day 365 
 
Study Day 
71 
78 
85 
99 
127 
183 
239 
295 
365  
Study Week 
10 
 
12 
14 
18 
26 
34 
42 
52 
Site visit (V) or at-home dosing of 
ravulizumab SC (H) 
V 
H 
V 
V 
V 
V 
V 
V 
V 
Visit Window (± Day) 
NA 
 
1 
1 
1 
1 
1 
1 
1 
Dose window (nominal time in hours 
from the start of first dose on Day 1)a 
± 1 
 
 
 
 
 
 
 
 
Patient training on dose administrationb 
X 
 
 
 
 
 
 
 
 
Ravulizumab SC administration  
X 
X 
X 
X 
X 
X 
X 
X 
X 
Telephone call check 
 
Xc 
 
 
 
 
 
 
 
Infusion site evaluationd 
X 
 
X 
X 
X 
X 
X 
X 
X 
PK/PD samplinge 
X 
 
X 
X 
X 
X 
X 
X 
X 
Immunogenicity (ADA)e 
 
 
X 
X 
X 
X 
X 
X 
X 
PNH symptomatology 
 
 
 
X 
X 
X 
 
X 
X 
FACIT-Fatigue 
 
X 
 
X 
 
X 
X 
X 
X 
EORTC QLQ-C30 
 
X 
 
X 
 
X 
X 
X 
X 
TASQ-SC 
 
 
X 
 
 
X 
X 
 
X 
Vital signsf 
 
 
X 
X 
X 
X 
X 
X 
X 
Chemistry, including LDH 
 
 
X 
X 
X 
X 
X 
X 
X 
Hematology, including coagulation 
 
 
X 
X 
X 
X 
X 
X 
X 
Urinalysis and urine chemistry 
 
 
X 
X 
X 
X 
X 
X 
X 
Pregnancy testg 
 
 
X 
X 
X 
X 
X 
X 
X 
Weight 
 
 
X 
X 
X 
X 
X 
X 
X 
Abbreviated physical examinationh 
 
 
X 
X 
X 
X 
X 
X 
X 
Review safety card  
 
 
X 
X 
X 
X 
X 
X 
X 
Treatment adherence monitoring by e-diary 
 
←At every weekly dose→ 
Breakthrough hemolysisi 
←Monitor continuously→ 
Record transfusions and transfusion parameters  
←Monitor continuously→ 
Concomitant medications 
←Monitor continuously→ 
Adverse events  
←Monitor continuously→ 
a Day 71 dosing is the beginning of the Extension Period. The Day 71 dose is expected to be administered at the same nominal time as the dose on Day 1. The ravulizumab SC 
490 mg dose on Day 71 will be self-administered in the clinic. For patients who had been randomized to the ravulizumab IV group, this will be part of the required training 
program. 
b For patients who had been randomized to the ravulizumab IV group, a qualified member of the site study team will provide initial (and ongoing as appropriate) training on how 
to properly self-administer ravulizumab SC using the 2 required OBDS kits. For all patients, doses that coincide with study visit days will be self-administered in the clinic with 

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oversight by trained study site personnel. All other doses can be self-administered at home. With approval from the Sponsor, the patient can self-administer ravulizumab SC at 
the clinic on dosing days that are not scheduled in-clinic visits (with oversight by trained study site personnel). 
c Site will contact patients by telephone to query the patient on ravulizumab SC administration and completion of the patient e-diary.  
d New or worsening abnormalities should be reported as AEs. 
e Serum samples for PK/PD/ADA analyses will be collected predose (Day 71 included; see Table 2 and Table 3). Samples should not be collected from a heparinized line. 
f Vital signs will be obtained before study drug administration. 
g For female patients of childbearing potential only. A negative urine test result is required prior to administering ravulizumab to female patients of childbearing potential at the 
indicated visits. 
h Abbreviated physical examination consists of a body system relevant examination based upon Investigator (or designee) judgment and patient symptoms. At least 1 body system 
must be checked for an abbreviated physical examination. 
i If a suspected event of breakthrough hemolysis occurs, blood samples for LDH, PK, PD, and ADA parameters will be collected and sent to the central laboratory for analysis. If 
the suspected event of breakthrough does not occur at a scheduled visit, an unscheduled visit should occur for evaluation of the patient and collection of the required blood 
samples. 
Abbreviations: ADA = antidrug antibody; ECG = electrocardiogram; EORTC QLQ-C30 = European Organisation for Research and Treatment of Cancer, Quality of Life 
Questionnaire-Core 30 Scale; ET = early termination; FACIT-Fatigue = Functional Assessment of Chronic Illness Therapy-Fatigue Scale; H = at-home dosing; LDH = lactate 
dehydrogenase; NA = not applicable; OBDS = on-body delivery system; PD = pharmacodynamic(s); PK = pharmacokinetic(s); PNH = paroxysmal nocturnal hemoglobinuria; 
SC = subcutaneous; TASQ = Treatment Administration Satisfaction Questionnaire; V = site visit.  

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Table 5: 
Schedule of Study Visits and Activities – Extension Period, Day 421 Through Day 1275 
Study Day 
421 
477 
533 
589 
645 
701 
757 
813 
869 
925 
981 
1037 
1093 
1149 
1205 
1275/ 
ET 
Safety 
Follow-
up 
Study Week 
60 
68 
76 
84 
92 
100 
108 
116 
124 
132 
140 
148 
156 
164 
172 
182 
 
Site Visit Window  
(± Day) 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
 
Ravulizumab SC 
administrationa 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Telephone call check 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xb 
PK/PD samplingc 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Immunogenicity (ADA)c 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
FACIT-Fatigue 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
X 
 
EORTC QLQ-C30 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
X 
 
TASQ-SC 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
X 
 
PPQ-SC 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Xd 
 
Vital signse 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Safety 12-Lead ECG 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Chemistry, including 
LDH 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Hematology, including 
coagulation 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Urinalysis and urine 
chemistry 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Pregnancy testf 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Abbreviated physical 
examinationg 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Physical examination 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Review safety card  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Treatment adherence 
monitoring by e-diary 
←At every weekly dose→ 
 
Breakthrough hemolysish 
←Monitor continuously→ 
 
Record transfusions and 
transfusion parameters  
←Monitor continuously→ 
 
Concomitant medications 
←Monitor continuously→ 
Adverse events  
←Monitor continuously→ 

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a For all patients, doses that coincide with study visit days can be self-administered in the clinic with oversight by trained study site personnel. All other doses can be 
self-administered at home.  
b A follow-up phone call is to be conducted 30 days after the last dose of study drug and is limited to adverse event and concomitant medication monitoring. 
c Serum samples for PK/PD/ADA analyses will be collected predose. Samples should not be collected from a heparinized line. 
d PPQ-SC will be collected only once for each patient; at Day 1093 or at ET for patients who discontinue the study prior to Day 1093. PPQ-SC will not be collected at Day 1275.  
e Vital signs will be obtained before study drug administration. 
f For female patients of childbearing potential only. Serum pregnancy test at ET only; urine pregnancy test at all other time points. A negative urine test result is required prior to 
administering ravulizumab to female patients of childbearing potential at the indicated visits. 
g Abbreviated physical examination consists of a body system relevant examination based upon Investigator (or designee) judgment and patient symptoms. At least 1 body system 
must be checked for an abbreviated physical examination. 
h If a suspected event of breakthrough hemolysis occurs, blood samples for LDH, PK, PD, and ADA parameters will be collected and sent to the central laboratory for analysis. If 
the suspected event of breakthrough does not occur at a scheduled visit, an unscheduled visit should occur for evaluation of the patient and collection of the required blood 
samples. 
Abbreviations: ADA = antidrug antibody; ECG = electrocardiogram; EORTC QLQ-C30 = European Organisation for Research and Treatment of Cancer, Quality of Life 
Questionnaire-Core 30 Scale; ET = early termination; FACIT-Fatigue = Functional Assessment of Chronic Illness Therapy-Fatigue Scale; H = at-home dosing; LDH = lactate 
dehydrogenase; NA = not applicable; PD = pharmacodynamic(s); PK = pharmacokinetic(s); PNH = paroxysmal nocturnal hemoglobinuria; PPQ-SC = Patient Preference 
Questionnaire - Subcutaneous; SC = subcutaneous; TASQ = Treatment Administration Satisfaction Questionnaire; V = site visit.  

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2. 
INTRODUCTION 
Paroxysmal nocturnal hemoglobinuria (PNH) is an ultra-rare and life-threatening acquired 
hemolytic disorder caused by uncontrolled activation of the terminal complement pathway 
(Brodsky, 2014; Brodsky, 2015). Chronic, uncontrolled complement component 5 (C5) cleavage 
and release of C5a and C5b-9 lead to red blood cell (RBC) hemolysis. Hemolysis results in the 
release of intracellular free hemoglobin and lactate dehydrogenase (LDH) into circulation; 
irreversible binding to and inactivation of nitric oxide (NO) by hemoglobin and inhibition of NO 
synthesis; vasoconstriction and tissue-bed ischemia due to absence of vasodilatory NO as well as 
possible microthrombi manifesting as abdominal pain, dysphagia, and erectile dysfunction; 
platelet activation; and a proinflammatory and prothrombotic state (Brodsky, 2014; Hill, 2013). 
A substantial proportion of patients with PNH experience renal dysfunction and pulmonary 
hypertension (Brodsky, 2014; Hill, 2013; Hill, 2012; Hillmen, 2010). Patients also experience 
venous or arterial thrombosis in diverse sites, including the abdomen or central nervous system 
(Brodsky, 2014). Secondary effects in addition to the risk of major end organ damage from 
thrombosis include abdominal pain, extreme or unrelenting fatigue, difficulties in concentrating 
or thinking, and reduced activities of daily living (ADL). 
The main objective of effective PNH treatment with targeted therapy is to provide immediate, 
complete, and sustained inhibition of terminal complement activity to block intravascular 
hemolysis and thereby prevent thrombosis. Prior to ravulizumab, the only approved treatment for 
PNH that blocks terminal complement activity was eculizumab (Soliris®), a humanized 
monoclonal antibody (mAb) derived from the murine anti-human C5 antibody m5G1.1 and 
specifically binds to the complement protein C5 with high affinity. Eculizumab is administered 
by intravenous (IV) infusion every other week. 
2.1. 
Ravulizumab 
Ravulizumab (IV formulation; Ultomiris®) was approved by the FDA on 21 Dec 2018 for the 
treatment of PNH. Ravulizumab (ALXN1210) is a humanized mAb that binds to C5 and blocks 
its activation by complement pathway convertases, thereby preventing the release of the 
proinflammatory anaphylatoxin C5a and the formation of the terminal complement complex via 
C5b. Ravulizumab was designed through minimal targeted engineering to substitute 4 amino 
acids in the eculizumab heavy chain (Sheridan, 2018). These changes extend the half-life of 
ravulizumab relative to eculizumab, while preserving the high degree of specificity and 
selectivity for binding to C5 of eculizumab (Sahelijo, 2015).  
There is extensive clinical experience with ravulizumab administered IV in completed Phase 1 
studies and ongoing Phase 1b, 2, and 3 clinical studies. Detailed information about the 
pharmacokinetics (PK), mechanism of action, known and expected benefits, risks, and 
reasonably anticipated adverse events (AEs) with ravulizumab IV administration is provided in 
the Investigator’s Brochure (IB). 
A Phase 1 study of ravulizumab administered SC was conducted in healthy volunteers 
(Study ALXN1210-SC-101). This Phase 1 study evaluated the safety, tolerability, PK, 
pharmacodynamics (PD), and immunogenicity of a single 400-mg dose of ravulizumab SC 
compared with a single 400-mg dose of ravulizumab IV. In this study, ravulizumab was 

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administered subcutaneously by a trained member of the study team at clinical sites. 
Administration of ravulizumab 400 mg SC was generally safe and well tolerated. 
2.2. 
On-body Delivery System 
The ravulizumab on-body delivery system (OBDS) is a drug-device combination product 
comprised of a prefilled cartridge containing ravulizumab SC copackaged with an on-body 
injector. The device is a compact, sterile, single-use, disposable, electro-mechanical (battery 
powered, microprocessor controlled), investigational medical device with a 29-gauge integrated 
needle (manufactured by West Pharmaceuticals, Inc.) designed to be used together with a 
prefilled stoppered Crystal Zenith® cartridge with a piston and telescopic screw assembly (TSA) 
(Figure 1).  
The OBDS cartridge and on-body injector used in ravulizumab OBDS kits is the same platform 
currently approved for use with evolocumab (Repatha®) as a combination agent in the United 
States and CE marked in the European Union as a class IIa Medical Device. 
There is no clinical experience with the ravulizumab OBDS in patients with PNH. 
Figure 1: 
Diagram of the On-body Delivery System 
 
Abbreviation: CZ = Crystal Zenith. 
2.3. 
Study Rationale 
The purpose of this study is to compare the PK, specifically predose serum concentration 
(Ctrough), of ravulizumab SC administered via an OBDS versus ravulizumab IV administration in 
patients who are clinically stable and have been treated with eculizumab for at least 3 months 
prior to study entry. Based on the established relationship between PK exposure and clinical 
response in patients with PNH treated with IV ravulizumab that has shown maximal efficacy 
(terminal complement inhibition and LDH suppression effect) at the Ctrough achieved in the 
registration study, demonstration of noninferior Ctrough for ravulizumab SC compared with 
ravulizumab IV will enable bridging of the efficacy and tolerability data from ravulizumab IV 
registration studies.  
 

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The study hypothesis is that Day 71 Ctrough for ravulizumab SC will be noninferior to that for 
ravulizumab IV. A noninferiority, rather than a bioequivalence, design was selected for the 
comparison between treatments for the following reasons:  
• A noninferiority outcome on Day 71 Ctrough will ensure similar efficacy between SC 
and IV. 
• Ravulizumab is tolerated at higher PK exposures following IV administration than 
those expected in this study from either the SC group or the IV group, thus 
noninferior and higher SC ravulizumab Ctrough compared with IV ravulizumab Ctrough 
will represent similar tolerability. 
Following the clinical development of ravulizumab administered IV once every 8 weeks (q8w), 
the availability of treatment with ravulizumab SC every week (qw) provides an additional 
treatment option for patients that may reduce the burdens associated with chronic IV treatment 
regimens. To simplify self-administration for patients, the use of an OBDS to deliver 
ravulizumab SC has been selected, and is based on a “user friendly” drug-device combination 
product (Section 6.2).  
Subcutaneous administration will also provide patients the option to self-administer with 
increased flexibility that may improve their health-related quality of life (HRQoL). This study 
will assess safety and HRQoL relative to the current standard of care (eculizumab administered 
as a biweekly IV infusion). In addition, ravulizumab IV has a well-tolerated safety profile even 
at higher doses, thus PK parameters for ravulizumab SC that are higher than corresponding 
parameters for ravulizumab IV (ie, Ctrough) are expected to have similar tolerability. 
2.4. 
Benefit/Risk Assessment 
Please refer to the ravulizumab Investigator’s Brochure and the Ravulizumab OBDS Device 
Investigator’s Brochure for a complete description. 
2.4.1. 
Potential Benefits 
The main objective of effective PNH treatment with targeted therapy is to provide immediate, 
complete, and sustained inhibition of terminal complement activity to block hemolysis and 
prevent thrombosis.  
The recommended dosing of the currently approved therapy for patients with PNH (eculizumab, 
Soliris) administered by IV infusion, begins with an induction regimen of 600 mg administered 
IV once weekly for 4 weeks followed by maintenance dosing of 900 mg in the fifth week and 
every 2 weeks (q2w) (14 ± 2 days) thereafter. The requirement for biweekly IV infusions 
administered by a health care professional may significantly impact patients’ QoL, many of 
whom have to miss days of work, as well as may require travel to clinical sites to accommodate 
treatment.  
In the Phase 3 Study ALXN1210-PNH-302, ravulizumab IV (n = 97) was shown to be 
noninferior to eculizumab IV (n = 98) for the treatment of patients with PNH who were clinically 
stable and had received eculizumab for at least 3 months prior to study entry, based on the 
primary endpoint of percent change in LDH levels, a direct marker of complement-mediated 
hemolysis in PNH. All efficacy endpoints were consistently in favor of ravulizumab, with fewer 

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and less frequent breakthrough hemolysis events in patients treated with ravulizumab. A similar 
safety profile was observed for ravulizumab and eculizumab.  
Self-administered SC treatment for PNH offers the potential for increased independence over 
treatment by IV infusion and may reduce the burdens and risks associated with chronic IV 
treatment regimens while increasing patient adherence (Ingersoll, 2008).  
Therapies that can be delivered SC are desirable, particularly for patients with chronic diseases 
such as PNH who currently only have IV options available commercially. Therefore, it is 
important to evaluate the ravulizumab on-body injector as a potential option for 
self-administration at home through short-duration SC infusions, which could result in a more 
convenient way of dosing. 
2.4.2. 
Potential and Identified Risks  
2.4.2.1. 
Neisseria meningitidis Infections 
Increased susceptibility to infection with Neisseria meningitidis is a known risk associated with 
terminal complement inhibition. Similar to eculizumab, the main risk associated with 
ravulizumab is the risk of meningococcal infections.  
Specific risk mitigation measures are in place to address this risk (Section 8.3.5). 
2.4.2.2. 
Immunogenicity 
Administration of any therapeutic protein, including ravulizumab, may induce an immunogenic 
response potentially resulting in ADAs. The spectrum of potential clinical 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 SC and 1 healthy subject treated with 
ravulizumab IV in Study ALXN1210-SC-101, and in 4 healthy Japanese subjects 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.  
In studies of patients with atypical hemolytic uremic syndrome (aHUS), only 1 
treatment-emergent ADA has been reported with ravulizumab. 
Monitoring of immunogenicity for this study will be conducted as described in Section 1.3 and 
Section 8.2.6.3.  
2.4.2.3. 
Local and Systemic Reactions 
Protein therapies administered either SC or 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 SC or IV drug administration and may include 
reactions such as erythema, pruritus, and bruising. Infusion-associated reactions are those 
systemic in nature which may be immune or non immune-mediated generally occurring within 
hours of drug administration. Immune-mediated reactions may include allergic reactions (eg, 

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anaphylaxis), while non immune-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 8.3.6.1). 
2.4.2.4. 
Pregnancy Exposure 
No studies of ravulizumab have been conducted in pregnant women.  
Pregnant or nursing female 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 10.5 (Appendix 5). In the event of a pregnancy, the patient 
will be discontinued from study drug (Section 7.1).  
2.4.2.5. 
Potential Device-Related Risks 
There is no clinical experience with the ravulizumab OBDS. It is considered an investigational 
medical device and as such bears some potential risks resulting from device deficiencies or user 
error. Risk management activities (risk control and mitigation measures) have been conducted 
per ISO14971. Please refer to the Ravulizumab OBDS Investigator’s Brochure for a more 
complete description of the device and potential benefit/risk. 
Data supporting the development of the ravulizumab OBDS include the data from the healthy 
volunteer study using the SmartDose device, that showed the device was well tolerated and safe 
to use. A risk management study was performed on the ravulizumab OBDS by Alexion and West 
Pharmaceutical Services, Inc. and risk analyses were performed in accordance with EN ISO 
14971:2012. The results of these risk assessments show that all residual risks fall under the 
low/acceptable or medium/investigate risk category. Control strategies are in place to further 
mitigate the medium/investigate category risks. Therefore, it is considered that these potential 
risks are balanced by the opportunity to develop ravulizumab OBDS as an alternative and more 
convenient way of drug administration in patients requiring chronic treatment. 
2.4.2.6. 
Considerations for Coronavirus Disease 2019 
The coronavirus disease 2019 (COVID‑19) pandemic is active in many countries at the time of 
this protocol amendment. Given this unique circumstance, specific consideration has been given 
to the risks and benefits of the study as they relate to COVID‑19, and the global and local 
changes that exist as a result of the pandemic. This assessment is described in Section 10.8. 
2.4.3. 
Conclusion 
The efficacy of ravulizumab IV was shown to be noninferior to eculizumab in Phase 3 clinical 
studies in complement inhibitor-naïve patients and in patients who had previously received 
treatment with eculizumab. Ravulizumab (IV formulation; Ultomiris) was approved by the FDA 
on 21 Dec 2018 for the treatment of PNH. Ravulizumab SC may provide additional benefit by 
reducing the treatment burden associated with chronic IV dosing. The safety of ravulizumab SC 
via an OBDS in patients with PNH at the doses specified in this protocol is supported by data 
from clinical studies of ravulizumab IV and SC in healthy volunteers and clinical studies of 
ravulizumab IV in patients with PNH, in addition to postmarketing data on the West SmartDose 
Platform used with other approved therapies. The benefit/risk of ravulizumab SC administration 
to patients with PNH is anticipated to be favorable. 

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3. 
OBJECTIVES AND ENDPOINTS 
Objectives 
Endpoints 
Primary 
Primary PK endpoint 
To evaluate PK noninferiority of ravulizumab SC 
versus ravulizumab IV in adult patients with PNH  
Day 71 serum ravulizumab Ctrough 
Secondary  
PK Endpoint 
To characterize PK of ravulizumab SC 
Ctrough over time 
 
PD Endpoint 
To characterize PD of ravulizumab SC 
Free serum C5 concentrations over time 
 
Immunogenicity Endpoint 
To characterize immunogenicity of ravulizumab SC 
Incidence of treatment-emergent ADAs over time 
 
HRQoL and Treatment Satisfaction Endpoints 
To evaluate HRQoL and treatment satisfaction on 
ravulizumab SC 
• 
Change in FACIT-Fatigue Scale, Version 4, from 
Baseline to Day 183 
• 
Change in EORTC QLQ-C30 Version 3.0, from 
Baseline to Day 183 
• 
Reported treatment administration satisfaction as 
measured by the TASQ score at Baseline and 
Day 183 
• 
Reported patient preference as measured by the 
PPQ-SC score at Days 1093  
 
Safety Endpoints 
To evaluate safety of ravulizumab SC and ravulizumab 
OBDS  
• 
Change in physical examinations, vital signs, 
electrocardiograms, laboratory assessments over 
time  
• 
Incidence of adverse events and serious adverse 
events 
• 
Incidence of adverse device effects and serious 
adverse device effects 
 
Efficacy Endpoints 
To evaluate efficacy of ravulizumab SC  
• 
Change over time in LDH 
• 
Incidence of breakthrough hemolysis 
• 
Achievement of transfusion avoidance 
• 
Achievement of stabilized hemoglobin 
• 
Change in clinical manifestations of PNH over 
time 
• 
Change in reticulocyte count over time 
• 
Change in eGFR over time 
• 
Change in PNH RBC clone size over time  
 
Performance Endpoint  
To assess performance of ravulizumab OBDS  
• 
Reported outcome of attempted full-dose 
administration (including device 
failure/malfunction) 
Abbreviations: ADA = antidrug antibody; C5 = complement component 5; Ctrough = predose concentration; 
eGFR = estimated glomerular filtration rate; EORTC = European Organisation for Research and Treatment of 
Cancer; FACIT = Functional Assessment of Chronic Illness Therapy; HRQoL = health-related quality of life; 
IV = intravenous; LDH = lactate dehydrogenase; OBDS = on-body delivery system; PD = pharmacodynamic(s); 
PK = pharmacokinetic(s); PNH = paroxysmal nocturnal hemoglobinuria; PPQ-SC = Patient Preference 
Questionnaire – Subcutaneous; QLQ-C30 = Quality of Life Questionnaire-Core 30 Scale; RBC = red blood cell; 
SC = subcutaneous; TASQ = Treatment Administration Satisfaction Questionnaire. 

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4. 
STUDY DESIGN 
4.1. 
Overall Design  
This is a Phase 3, randomized, open-label, parallel-group, multicenter study to evaluate PK 
noninferiority of ravulizumab SC administered via an OBDS compared with intravenously 
administered ravulizumab IV in adult patients with PNH who are clinically stable and have been 
previously treated with eculizumab for at least 3 months prior to study entry. This study is 
planned to be conducted at up to 60 centers globally. 
The study will consist of an up to a 30-day Screening Period, a 10-week Randomized Treatment 
Period, and an Extension Period of up to 172 weeks or until the product is registered or approved 
(in accordance with country-specific regulations), whichever occurs first (Section 1.2). The study 
duration for each patient will be up to 3.5 years. Study entry is defined as the date when 
informed consent is provided. Patients will be stratified by weight groups (≥ 40 to < 60 kg and 
≥ 60 to < 100 kg) and then randomized in a 2:1 ratio to receive either ravulizumab SC or 
ravulizumab IV.  
All IV dosing during the Randomized Treatment Period will be administered in the clinic by a 
trained member of the site study team. Day 1 of study treatment will occur 12 to 16 days from 
the patient’s last dose of eculizumab. Timing for study drug administration and predose PK 
sample collection is critical to ensure adequate numbers of patients with evaluable PK data 
(Table 6 ). The time for the start of the dose administered on Day 1 is the nominal time for all 
subsequent doses and PK/PD sample collections. Specifically, all subsequent doses during the 
Randomized Treatment Period are expected to be administered at the same time of day that the 
dose was administered on Day 1. The PK samples are expected to be drawn as close as possible 
to the administration of the dose (or from the nominal time from the start of the Day 1 dose on 
nondosing days). The PK analysis set population is defined in Section 9.3. 
The study will enroll at least 105 patients (70 patients in the ravulizumab SC group; 35 patients 
in the ravulizumab IV group). An interim analysis for sample size re-estimation will be 
conducted and the sample size may be increased to a maximum of 144 patients (Section 9.5).  
Ravulizumab OBDS will be supplied in a kit, comprising 245 mg of ravulizumab SC in a sterile, 
single-use, prefilled cartridge assembly copackaged with a single-use injector. Two kits will be 
used to deliver the full 490 mg dose of ravulizumab SC. 
Ravulizumab IV loading and maintenance doses will be based on patient body weight at the last 
recorded study visit.  
Patients randomly assigned to the ravulizumab SC group will receive a loading dose of 
ravulizumab IV on Day 1 followed by maintenance doses of ravulizumab SC on Day 15 and qw 
thereafter for a total of 10 weeks of study treatment. Two ravulizumab OBDS kits will be used to 
deliver the full maintenance dose of ravulizumab SC. Patients randomly assigned to the 
ravulizumab IV group will receive a loading dose of ravulizumab IV on Day 1 followed by a 
maintenance dose of ravulizumab IV on Day 15 (Table 6 ).  
On Day 15, patients who randomized to the ravulizumab SC group will self-administer 
ravulizumab SC in the clinic with oversight by trained study site personnel as part of the required 
training program for at-home self-administration. Once training has been completed, the patient 

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will be able to self-administer ravulizumab SC. On Days 29, 43, 57, and 64, patients can 
self-administer ravulizumab SC in the clinic with oversight by trained study site personnel. On 
Days 22, 36, and 50, ravulizumab SC can be self-administered by the patient at home. With 
approval from the Sponsor, the patient can self-administer ravulizumab SC at the clinic on 
dosing days that are not scheduled in-clinic visits. On days that ravulizumab SC is 
self-administered at home, the site will contact the patient via telephone at scheduled times to 
ensure patient is queried about study drug dose administration and device condition. 
Table 6: 
Dosing  
Treatment Group 
Randomized Treatment Period (10 weeks) 
Extension Period (up to 
172 weeks) 
Ravulizumab SC 
Loading Dose on Day 1: 
Ravulizumab IV 
2400 mga or 
Ravulizumab IV 
2700 mgb 
 
SC Doses on Days 15, 22, 29, 
36, 43, 50, 57, and 64: 
Ravulizumab SC 490 mgc  
(2 ravulizumab OBDS kits per 
weekly dose) 
Maintenance Doses on 
Day 71 and qw through 
Day 1275:  
Ravulizumab SC 490 mgd 
(2 ravulizumab OBDS kits 
per weekly dose) 
Ravulizumab IV 
Maintenance Dose on Day 15:  
Ravulizumab IV 3000 mga  
or 
Ravulizumab IV 3300 mgb  
a Weight group ≥ 40 to < 60 kg. 
b Weight group ≥ 60 to < 100 kg.  
c On Day 15, patients who randomized to the ravulizumab SC group will self-administer ravulizumab SC in the 
clinic with oversight by trained study site personnel as part of the required training program for self-administration 
at home. On Days 29, 43, 57, and 64, ravulizumab SC will be self-administered by the patient in the clinic with 
oversight by trained study site personnel. On Days 22, 36, and 50, ravulizumab SC can be self-administered by the 
patient at home. With approval from the Sponsor, the patient can self-administer ravulizumab SC at the clinic on 
dosing days that are not scheduled in-clinic visits. 
d Self-administered by the patient at home or self-administered in the clinic with oversight by trained study site 
personnel on scheduled visit days. With approval from the Sponsor, the patient can self-administer ravulizumab 
SC at the clinic on dosing days that are not scheduled in-clinic visits. On Day 71, patients who had been 
randomized to the ravulizumab IV group will self-administer ravulizumab SC in the clinic with oversight by 
trained study site personnel as part of the required training program for at-home self-administration. 
Abbreviations: IV = intravenous; OBDS = on-body delivery system; qw = every week; SC = subcutaneous. 
Day 71 is the end of the Randomized Treatment Period and the beginning of the Extension 
Period. All Day 71 assessments completed prior to dosing are considered part of the Randomized 
Treatment Period. Dosing on Day 71 is the start of the Extension Period. During the Extension 
Period: 
• Patients who had been randomized to the ravulizumab SC group will continue to 
receive 490 mg of ravulizumab SC using 2 OBDS kits on Day 71 and qw thereafter 
through the end of the Extension Period (up to Day 1275) 
• Patients who had been randomized to the ravulizumab IV group will switch to 
490 mg of ravulizumab SC using 2 OBDS kits on Day 71 and qw thereafter through 
the end of the Extension Period (up to Day 1275) 
Ravulizumab SC dosing during the Extension Period will be self-administered by the patient at 
home with the following exceptions where ravulizumab SC must be administered in the clinic: 

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• For patients who had been randomized to the ravulizumab IV group, the ravulizumab 
SC 490-mg dose on Day 71 will be self-administered by the patient in the clinic with 
oversight by trained study site personnel as part of the required training program for 
at home self-administration 
• For all patients, doses that coincide with study visits specified in the SoA 
(Section 1.3) will be self-administered by the patient in the clinic with oversight by 
trained study site personnel. 
• With approval from the Sponsor, the patient can self-administer ravulizumab SC at 
the clinic on dosing days that are not scheduled in-clinic visits (with oversight by 
trained study site personnel).  
• An additional follow-up phone call will occur 30 days following the last dose of 
ravulizumab (SC or IV) and is limited to AE and concomitant medication monitoring. 
4.2. 
Scientific Rationale for Study Design 
The purpose of this study is to compare the PK, specifically serum Ctrough, of ravulizumab SC 
administered via an OBDS versus ravulizumab IV in patients with PNH who are clinically stable 
and have been treated with eculizumab for at least 3 months prior to study entry.  
This study is designed to bridge the efficacy data generated during the studies supporting 
registration of ravulizumab IV to ravulizumab SC on the basis of PK noninferiority principles. 
The scientific rationale for the use of PK noninferiority principles is as follows: 
1. There is an established relationship between PK exposure and clinical efficacy that 
underscores a direct link between drug concentration and complement inhibition. 
2. There is an established clinical relevance of a PK target concentration for efficacy. 
Specifically, clinical efficacy can be achieved by complete and sustained complement 
inhibition through ensuring serum ravulizumab Ctrough remains above the PK target 
concentration at all times. In the Phase 3 studies, steady state therapeutic serum 
concentrations were achieved immediately following the initial dose of ravulizumab and 
were sustained with q8w maintenance. 
3. To bridge the efficacy of the reference IV product to the follow-on SC product by 
establishing PK Ctrough noninferiority comparison, where the comparison is performed 
using the standard regulatory framework of demonstrating the lower bound of a 2-sided 
90% CI of the geometric mean ratio for Ctrough (SC/IV) being greater than the 
prespecified noninferiority boundary of 0.8. 
In the proposed study, the test (ravulizumab SC) and the reference (ravulizumab IV) groups are 
expected to maintain ravulizumab Ctrough concentrations above the PK target concentration for 
efficacy from the start of study treatment. The noninferiority PK assessment is planned on 
Day 71 (at the time of the Ctrough following the first maintenance IV dose) and the Sponsor plans 
to collect safety and tolerability data for up to 3.5 years) or until the product is registered or 
approved (in accordance with country-specific regulations), whichever occurs first. 
The safety parameters being evaluated are commonly used in clinical studies per International 
Council for Harmonisation (ICH) and Good Clinical Practice (GCP) guidelines. 

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4.3. 
Justification for Dose 
The doses of ravulizumab IV intended for administration in this study are standardized in the 
clinical development program of ravulizumab IV. Full details are available in the Ravulizumab 
OBDS Investigator’s Brochure. 
A single dose of ravulizumab SC 400 mg, administered consecutively as 4 separate 
100-mg injections, has been evaluated in a Phase 1 healthy volunteer study and preliminary data 
indicate ravulizumab SC 400 mg was generally well-tolerated and without any safety concerns.  
The proposed weekly dosing regimen of ravulizumab SC 490 mg to be evaluated in this study 
was identified by integrating the available Phase 1 PK data from Study ALXN1210-SC-101 and 
from the ravulizumab IV clinical development program using a modelling and simulation 
framework. A fixed SC maintenance dose of 490 mg for patients weighing ≥ 40 to < 100 kg 
starting 2 weeks following an IV loading dose is expected to maintain serum drug concentrations 
above the target concentration needed for complete inhibition of terminal complement in all 
adult patients weighing ≥ 40 to < 100 kg from the start of the treatment. 
4.4. 
Justification for Device Selected 
Ravulizumab SC is intended to be self-administered via SC infusion for maintenance dosing 
using the ravulizumab OBDS in the clinic or home setting. The ravulizumab OBDS kit consists 
of ravulizumab SC in a sterile, single-use, prefilled cartridge and is copackaged with a single-use 
on-body injector. 
The drivers for the SC device selection were dose volume capability, demonstrated reliability, 
and patient-centered usability requirements including ease of use with minimal steps, minimal 
discomfort, hidden needle, as well as the ability to move about and perform moderate physical 
activities during the infusion such as walking, reaching, and bending. The West SmartDose 
Gen 1 device platform meets these criteria. 
The ravulizumab OBDS is a disposable, single-use drug-device combination that is configured to 
deliver a fixed dose of ravulizumab via SC infusion in approximately 10 minutes (2 devices are 
required for each weekly dose). The device is designed to be easy to use, with a single button to 
initiate dosing, visual and auditory cues of the device readiness and dose completion, and a 
safety lock that prevents accidental initiation of dose delivery until the device is attached to the 
body via an adhesive patch. The small gauge needle in the device and route of administration 
may carry a reduced risk of systemic infection and other complications compared with IV 
infusions. Please refer to the Ravulizumab OBDS Investigator’s Brochure for a more complete 
description of the device. 
4.5. 
Regulatory Status and Approval Strategy 
Ravulizumab (IV formulation; Ultomiris®) has been approved in the US, Japan, and the EU for 
the treatment of PNH. Ravulizumab SC has not received marketing authorization in any country.  
The West SmartDose device platform is used for a currently marketed product (evolocumab 
420 mg). It is the first delivery system with a regulatory approval track record and proven 
performance compared with other delivery systems under development with similar functionality 

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and user interface profile. However, it is considered an investigational medical device for the 
intended use with ravulizumab. 
Following clinical evaluation in this study, the ravulizumab OBDS is planned to be registered for 
its intended use with ravulizumab according to local regulations. 
4.6. 
End of Study Definition 
The end of the study for each patient occurs when the safety follow-up is completed. The safety 
follow-up consists of a telephone call 30 days after the last dose. Data collection during the 
safety follow-up is limited to reporting adverse events and concomitant medications. If a patient 
discontinues treatment, but does not discontinue from the study, the end of study for such a 
patient will be their last visit as long as that visit is more than 30 days from their last dose. The 
end of the study is defined as the date of the last patient visit or safety follow up, whichever 
occurs later. 

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5. 
STUDY POPULATION 
5.1. 
Inclusion Criteria 
Patients must meet all inclusion and no exclusion criteria. Patients who fail any of the eligibility 
criteria may be rescreened once based on discussion and agreement between the Investigator and 
the Medical Monitor. 
Patients are eligible to be included in the study only if they fulfill all of the following criteria: 
Age 
1. Patients must be at least 18 years of age at the time of signing the informed consent. 
Patient and Disease Characteristics 
2. Treated with eculizumab according to the labeled dosing recommendation for PNH 
(900 mg every 14 days ± 2 days) for at least 3 months prior to study entry with no missed 
doses within 2 months prior to study entry and no more than 2 doses outside of the visit 
window.  
3. Lactate dehydrogenase levels ≤ 1.5 × ULN (upper limit of normal), according to central 
laboratory, at Screening. Sample must be obtained within 24 hours of or immediately 
prior to a scheduled eculizumab dose administration (ie, at trough eculizumab level). 
4. Documented diagnosis of PNH confirmed by high-sensitivity flow cytometry evaluation 
(Borowitz, 2010).  
5. Vaccinated against meningococcal infections within 3 years prior to, or at the time of, 
initiating study drug to reduce the risk of meningococcal infection (N meningitidis). 
Weight 
6. Body weight ≥ 40 to < 100 kg, and in the opinion of the Investigator, are likely to remain 
within this body weight range for the duration of the study. 
Contraception 
7. Female patients of childbearing potential and male patients with female partners of 
childbearing potential must follow protocol-specified contraception guidance 
(Section 10.5 [Appendix 5]) while on treatment and for at least 8 months after last dose 
of study drug. 
Informed Consent 
8. Patients must be willing and able to give written informed consent and to comply with all 
study visits and procedures, including self-administration of ravulizumab SC doses, and 
the use of any data collection device(s) to directly record patient data. 
5.2. 
Exclusion Criteria  
Patients are excluded from the study if any of the following criteria are met: 
Medical Conditions 
1. More than 1 LDH value > 2 × ULN within the 3 months prior to study entry. 

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2. Major adverse vascular event (MAVE) in the 6 months prior to study entry. 
3. Platelet count < 30,000/mm3 (30 × 109/L) at Screening. 
4. Absolute neutrophil count < 500/µL (0.5 × 109/L) at Screening. 
5. History of bone marrow transplantation. 
6. History of N meningitidis infection. 
7. History of unexplained infections. 
8. Active systemic bacterial, viral, or fungal infection within 14 days prior to study drug 
administration on Day 1. 
9. Presence of fever ≥ 38°C (100.4°F) within 7 days prior to study drug administration on 
Day 1. 
10. Human immunodeficiency virus (HIV) infection (evidenced by HIV-1 or HIV-2 antibody 
titer). 
11. History of malignancy within 5 years of Screening with the exception of nonmelanoma 
skin cancer or carcinoma in situ of the cervix that has been treated with no evidence of 
recurrence. 
12. History of or ongoing major cardiac, pulmonary, renal, endocrine, or hepatic disease (eg, 
active hepatitis) that, in the opinion of the Investigator or Sponsor, precludes the patient’s 
participation in an investigational clinical study. 
13. Unstable medical conditions (eg, myocardial ischemia, active gastrointestinal bleed, 
severe congestive heart failure, anticipated need for major surgery within 6 months of 
Day 1, coexisting chronic anemia unrelated to PNH) that would make patients unlikely to 
tolerate the requirements of the protocol). 
14. History of hypersensitivity to any ingredient contained in the study drug including 
hypersensitivity to murine proteins. 
15. Female patients who plan to become pregnant or are currently pregnant or breastfeeding. 
16. Female patients who have a positive pregnancy test result at screening or on Day 1. 
17. 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 an 
additional risk for the patient, or confound the outcome of the study. 
18. Known or suspected history of drug or alcohol abuse or dependence within 1 year prior to 
Screening. 
19. Inability to complete the requirements for SC self-administration. 
20. Inability to travel to the clinic for specified visits during the Randomized Treatment 
Period or fulfil the logistic requirements of study drug.  
Prior/Concomitant Therapy 
21. Concomitant use of anticoagulants is prohibited if not on a stable regimen for at least 
2 weeks prior to study entry. 

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Prior/Concurrent Clinical Study Experience 
22. Participation in another 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 that investigational 
product, whichever is greater (except for participation in observational studies [eg, PNH 
Registry]). 
23. Received any other experimental C5 antagonist at any time. 
5.3. 
Lifestyle Considerations 
Not applicable for this study.  
5.4. 
Screen Failures 
Screen failures are defined as patients who consent to participate in the clinical study but are not 
subsequently randomized to treatment. 
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. 

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6. 
STUDY DRUG AND MEDICAL DEVICE 
6.1. 
Ravulizumab 
Ravulizumab SC is formulated at pH 7.4 and is supplied in 3.5-mL single-use cartridges. Each 
cartridge of ravulizumab SC contains 245 mg of ravulizumab (70 mg/mL) in 50 mM sodium 
phosphate, 25 mM arginine, 5% sucrose, 0.05% polysorbate 80, and water for injection. 
Ravulizumab IV is formulated at pH 7.0 and is supplied in 30-mL single-use vials. Each vial of 
ravulizumab IV 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. 
Both ravulizumab SC and ravulizumab IV formulations are suitable for human use and 
manufactured under current Good Manufacturing Practices. 
Details regarding ravulizumab SC and ravulizumab IV formulations are presented in Table 7 . 
The dosing reference charts for ravulizumab SC and ravulizumab IV groups are presented in 
Table 8 and Table 9 , respectively. 
Table 7: 
Study Drug Administered 
 
Ravulizumab SC (Test Therapy) 
Ravulizumab IV (Reference Therapy) 
Dosage Form 
Sterile, preservative-free aqueous 
solution (70 mg/mL) in single-use, 
3.5-mL prefilled cartridge designed for 
use in a single-use on-body delivery 
system 
Concentrated sterile, preservative-free 
aqueous solution (10 mg/mL) in single-use 
30-mL vials 
Route of 
Administration  
SC infusion via the ravulizumab OBDS a 
IV infusion by diluting into commercially 
available saline (0.9% sodium chloride 
injection; country-specific pharmacopeia) 
Packaging and 
Supply 
Ravulizumab primary container closure is 
cyclic olefinic polymer crystal zenith 
cartridge stoppered with butyl rubber 
stopper and a telescopic screw assembly. 
The ravulizumab OBDS will be supplied 
in kits copackaged with the prefilled 
cartridge and device.  
The US Pharmacopeia/European 
Pharmacopeia Type 1 borosilicate 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 of 
Study Drug 
Translucent clear to yellowish color, 
practically free from particles 
Clear to translucent, slight whitish color, 
practically free from particles 
Manufacturer 
Alexion or contracted manufacturing 
organization 
Alexion or contracted manufacturing 
organization 
a The ravulizumab OBDS is a drug-device combination product of a prefilled cartridge containing ravulizumab and 
the West SmartDose device that will be copackaged for SC administration.  
Abbreviations: IV = intravenous; OBDS = on-body delivery system; SC = subcutaneous. 

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Table 8: 
Dosing Reference Chart for Ravulizumab Subcutaneous Group 
Dose Type 
Body 
Weight (kg)a 
Dose 
(mg) 
Ravulizumab 
Volume (mL) 
Saline 
Volume 
(mL) 
Total 
Volume 
(mL) 
Minimum 
Infusion 
Duration 
minutes 
(hours) 
Maximum 
Infusion 
Rate 
(mL/hour) 
Loading 
(IV) 
≥ 40 to < 60 
2400a 
240 
240 
480 
114 (1.9) 
253 
≥ 60 to < 100 
2700a 
270 
270 
540 
102 (1.7) 
318 
Maintenance 
(SC) 
≥ 40 to < 100 
490 
3.5 mL × 2 
NA 
7.0 mL 
9 minutes 
(0.15)b 
23.3 
Note: Additional dose preparation instructions are provided in the pharmacy manual. 
a Ravulizumab IV dose will be based on the body weight at the last recorded study visit. 
b The rate of the SC infusion is preprogrammed into the device. Nine minutes is an approximate based on the 
instructions for use. 
Abbreviations: IV = intravenous; NA = not applicable; SC = subcutaneous.  
Table 9: 
Dosing Reference Chart for Ravulizumab Intravenous Group 
Dose Type 
Body Weight 
(kg)a 
Dose 
(mg) 
Ravulizumab 
Volume (mL) 
Saline 
Volume 
(mL) 
Total 
Volume 
(mL) 
Minimum 
Infusion 
Duration 
minutes 
(hours) 
Maximum 
Infusion 
Rate 
(mL/hour) 
Loading (IV) 
≥ 40 to < 60 
2400 
240 
240 
480 
114 (1.9) 
253 
≥ 60 to < 100 
2700 
270 
270 
540 
102 (1.7) 
318 
Maintenance 
(IV) 
≥ 40 to < 60 
3000 
300 
300 
600 
140 (2.4) 
250 
≥ 60 to < 100 
3300 
330 
330 
660 
120 (2.0) 
330 
Extension (SC) 
≥ 40 to < 100 
490 
3.5 mL × 2 
NA 
7.0 mL 
9 minutes 
(0.15)b 
23.3 
Note: Additional dose preparation instructions are provided in the pharmacy manual. 
a Ravulizumab IV dose will be based on the body weight at the last recorded study visit.  
b The rate of the SC infusion is preprogrammed into the device. Nine minutes is an approximate based on the 
instructions for use.  
Abbreviations: IV = intravenous; NA = not applicable; SC = subcutaneous. 
6.1.1. 
Study Drug Preparation and Administration 
Ravulizumab IV will be prepared and administered by a trained member of the site study team. 
Ravulizumab SC can be self-administered by patients who have completed the required training 
for self-administration of ravulizumab SC. Study drug is to be dispensed only to enrolled patients 
who are confirmed eligible for participation.  
6.1.1.1. 
Ravulizumab Subcutaneous 
On Day 15 during the Randomized Treatment Period (for patients randomized to ravulizumab 
SC) and Day 71 during the Extension Period (for patients randomized to ravulizumab IV), a 
qualified member of the site study team will provide initial (and ongoing as appropriate) training 
on how to properly self-administer ravulizumab SC using the 2 required OBDS kits. Following 
completion of required training, all patients will self-administer their weekly SC infusions at 
home or in the clinic (with oversight by trained study site personnel), on days specified in the 

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SoA (Section 1.3). With approval from the Sponsor, the patient can self-administer ravulizumab 
SC at the clinic on dosing days that are not scheduled in-clinic visits. 
The patient is required to follow the instructions for use (IFU) as written. Detailed instructions 
regarding self-administration of the study drug are provided in the IFU. 
In the event of OBDS malfunction where no dose or a partial dose is delivered, the patient should 
use a new OBDS to ensure that the patient receives at least 490 mg of ravulizumab SC. Please 
refer to Section 10.4 (Appendix 4), Investigational Medical Product or Device Complaints. 
6.1.1.2. 
Ravulizumab Intravenous 
Ravulizumab IV must NOT be administered as an IV push or bolus injection.  
Infusions of ravulizumab IV should be prepared using aseptic technique. The patient’s required 
dose of ravulizumab will be further diluted as specified in Table 7 and Table 8 . Once the dosing 
solution is prepared for a patient, it can only be administered to that patient. Drug will be 
administered using an IV tubing set via an infusion pump. Use of a 0.2-micron filter is required 
during infusion of ravulizumab IV. Vials of study drug are for one time use only and any drug 
product remaining in the vial should not be used for another patient. 
The in-use shelf life of the dosing solution is 6 hours at ambient temperature. The expiration date 
and time of the dosing solution is calculated from breach of the first vial. The dose must be 
administered within the expiration date and time. 
Additional details on preparation and dose administration of study drug are provided in the 
pharmacy manual.  
6.1.1.3. 
Special Treatment Considerations 
Infusion of other MAbs has been associated with infusion reactions, with onset typically during 
or shortly after completion of the infusion. Refer to Section 10.7 (Appendix 7) for guidance on 
identifying and managing potential drug infusion reactions. 
6.1.2. 
Packaging and Labeling 
6.1.2.1. 
Ravulizumab SC 
Ravulizumab SC will be packaged as described in Section 6.2.1. 
6.1.2.2. 
Ravulizumab Intravenous 
The primary packaging of ravulizumab IV 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. 
6.2. 
On-body Delivery System 
The ravulizumab OBDS drug-device combination product consists of a prefilled cartridge 
containing ravulizumab SC and an on-body injector. The ravulizumab OBDS is a compact, 
sterile, single-use, electro-mechanical, wearable infusion device that administers a fixed dose of 
ravulizumab from a prefilled cartridge assembly into an SC tissue at a fixed rate via a stainless 

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steel 29-gauge needle. The device is a sterile, single use, surgically invasive active medical 
device for transient use as per definitions from Medical Device Directive 93/42/EEC. The device 
contains non removable batteries and includes a biocompatible adhesive patch. The device with 
adhesive is removed from the skin following completion of the dose. 
The primary container closure (cartridge) consists of a 5-mL CZ cartridge with a chlorobutyl 
elastomeric septum, a chlorobutyl elastomeric piston, and a TSA that is threaded into the piston. 
The prefilled CZ cartridge is copackaged with the on-body injector in a 2-compartment blister 
tray. The prefilled cartridge assembly is loaded into the device immediately prior to use by the 
patient. The device is designed for use only with the provided 3.5-mL prefilled cartridge. 
After loading the cartridge into the device, adhering the device to the skin, and device activation 
the 3.5-mL dose will be delivered in approximately 10 minutes. 
Following the completion of training on the use of the device by a qualified member of the site 
study team, all patients will self-administer ravulizumab SC doses as specified in the SoA. 
Additional instructions will be provided in the IFU. Additional details on the device are located 
in the Ravulizumab OBDS Investigator’s Brochure. 
6.2.1. 
Packaging and Labeling 
The ravulizumab OBDS drug-device combination consists of 2 parts: a prefilled cartridge 
containing ravulizumab and the on-body injector. The prefilled cartridge and device constituent 
parts are copackaged in a thermoformed blister pack with a Tyvek lid over the compartment 
containing the device to provide a sterile barrier. The secondary packaging consists of a blank 
carton containing the blister pack and a booklet label with relevant instructions. 
An identification trace label is attached to the Tyvek covered blister, a serial number label 
attached to the side of the device, and a single panel label is affixed to each cartridge. 
6.2.2. 
Anticipated Risks, Contraindications, Warnings 
Refer to the Ravulizumab OBDS Device Investigator’s Brochure for anticipated risks, 
contraindications, and warnings. 
6.3. 
Handling, Storage, Accountability, and Administration 
Details regarding preparation, handling, storage, accountability, and administration of the study 
drug (ravulizumab IV and ravulizumab SC as part of the ravulizumab OBDS kits), whether 
administered in the clinic or self-administered at home are discussed below. Additional guidance 
is provided in the pharmacy manual and the IFU.  
6.3.1. 
Ravulizumab IV and Ravulizumab SC – In-clinic Administration 
1. Study drug kits will be released to each site upon receipt of all required documentation 
based upon applicable regulations. 
2. Upon arrival of the study drug kits at the study site, the pharmacist or designee should 
promptly remove the study drug kits from the shipping cooler and store them in their 
original cartons under refrigerated conditions at 2°C to 8°C (35°F to 47°F) and protected 
from light.  

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3. Ravulizumab IV admixed drug product and ravulizumab OBDS kits should be at ambient 
temperature prior to administration. The material must not be heated (eg, by using a 
microwave or other heat source). 
4. Only authorized site staff may supply or administer study drug at times noted in 
Section 1.3. The patient will undergo training, by a qualified member of the site study 
team, to self-administer using the ravulizumab OBDS on Day 15 (patients randomized to 
ravulizumab SC) and on Day 71 during the Extension Period (patients who had been 
randomized to ravulizumab IV). After completion of training, ravulizumab SC can be 
self-administered by the patient at home or self-administered in the clinic with oversight 
by trained study site personnel at times noted in Section 1.3. All study drugs 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. 
5. The Investigator, institution, pharmacist, or the head of the medical institution (if 
applicable) is responsible for study drug accountability, reconciliation, and record 
maintenance (ie, receipt, reconciliation, and final disposition records).  
6. Unless institutional procedures require immediate destruction of used ravulizumab IV 
study drug, accountability will be performed on used and unused IV study drug vials.  
7. The ravulizumab OBDS is a single-use drug-device combination that will be immediately 
disposed in a biological waste container after drug administration. Accountability will be 
performed on used and unused cartridges and devices.  
8. At the end of the study, a final reconciliation must be performed between the amount of 
study drug kits supplied, dispensed, and subsequently destroyed or returned to Alexion.  
6.3.2. 
Ravulizumab SC – At-home Administration 
Ravulizumab OBDS kits for self-administration will be provided to patients in accordance with 
regional and local requirements. 
Upon receipt of the ravulizumab OBDS kits the patient is expected to promptly store them in 
accordance with the IFU.  
Patients are expected to follow the training instructions and IFU on each dosing day to ensure 
appropriate administration of their ravulizumab dose. The study site personnel will monitor 
self-administration of ravulizumab SC via telephone calls with the patient on scheduled at-home 
dosing days during the Randomized Treatment Period to ensure that the patient is queried about 
study drug dose administered and device condition. During the Extension Period, ravulizumab 
SC will be self-administered by the patient at home or self-administered in the clinic with 
oversight by trained study site personnel on scheduled visit days. With approval from the 
Sponsor, the patient can self-administer ravulizumab SC at the clinic on dosing days that are not 
scheduled in-clinic visits. On Day 71, patients who had been randomized to the ravulizumab IV 
group will self-administer ravulizumab SC in the clinic with oversight by trained study site 
personnel as part of the required training program for at-home self-administration. 
A biological waste container will be supplied to each patient for at-home disposal of used 
ravulizumab OBDS. Unused kits should be returned to the site. 

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6.4. 
Measures to Minimize Bias: Randomization and Blinding 
This is an open-label study. Measures implemented to reduce potential bias include stratification 
and randomization. Following stratification by weight (≥ 40 to < 60 kg or ≥ 60 to < 100 kg) each 
patient will be randomly assigned to a treatment group in a 2:1 ratio using a centralized 
interactive voice- or web response system.  
6.5. 
Study Drug Compliance 
At in-clinic visits, ravulizumab IV will be administered in a controlled setting under the 
oversight of the Investigator or designee, thereby ensuring compliance with study drug 
administration. At scheduled in-clinic visits, ravulizumab SC will be self-administered by the 
patient in a controlled setting with oversight by trained study site personnel, thereby ensuring 
compliance with study drug administration. Prior to self-administration, all patients are required 
to complete training for proper use of the ravulizumab OBDS kits by a qualified member of the 
site study team. When patients are self-administering the required ravulizumab SC doses at 
home, compliance will be monitored by the site via telephone calls with the patient on scheduled 
at-home dosing days during the Randomized Treatment Period to ensure that the patient is 
queried about study drug dose administered and device condition. During the Extension Period, 
the site will contact patients by telephone on Day 78 to query the patient on study drug 
administration and completion of the patient e-diary. After Day 78, sites will monitor 
self-administration of ravulizumab SC via the patient e-diary. 
6.6. 
Prior and 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 electronic 
case report forms (eCRF). In addition, history of meningococcal vaccination must be collected 
for the 3 years prior to first dose of study drug. 
Transfusions of packed red blood cells received within 1 year prior to first study drug 
administration will be recorded in the patient’s eCRF. 
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 current medications for PNH. 
Concomitant medications will be recorded from the first infusion of study drug through 30 days 
after the patient’s last dose of study drug, unless the patient transitions to an alternate treatment 
for PNH. 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 the 
allowed medications described below 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. 
Concomitant use of anticoagulants is prohibited if not on a stable dose regimen for at least 
2 weeks prior to study entry. 

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Use of complement inhibitors other than the patient’s assigned study treatment is prohibited. 
6.7. 
Dose or Treatment Group Modification 
Patients who received ravulizumab IV during the Randomized Treatment Period will switch to 
ravulizumab SC 490 mg qw at the start of the Extension Period and continue with this treatment 
for the duration of the study. 
During the Randomized Treatment Period, if any patient administered ravulizumab IV reaches a 
body weight ≥ 100 kg before Day 71, the patient’s data will be excluded from the primary 
endpoint analysis and the patient will be discontinued from the study as described in Section 7.1. 
If the patient’s body weight is ≥ 100 kg on Day 71, the patient’s data will be included in the 
primary analysis. The patient will be discontinued from the study following completion of 
Day 71 predose assessments. 
During the Randomized Treatment Period, if any patient administered ravulizumab SC reaches a 
body weight ≥100 kg, the patient will be discontinued from treatment. The patient’s data will not 
be included in the primary endpoint analysis, unless the first observation of such a weight for this 
patient was at the Day 71 assessment. The patient will be discontinued from the study as 
described in Section 7.1. 
If any patient administered ravulizumab SC reaches a body weight ≥ 100 kg, the patient will be 
discontinued from treatment.  
No other dose or treatment group modification is permitted in the study. 
6.8. 
Treatments After the End of the Study 
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7. 
DISCONTINUATION OF STUDY DRUG AND PATIENT 
DISCONTINUATION/WITHDRAWAL 
7.1. 
Patient Discontinuation/Withdrawal From the Study 
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 Early Termination (ET) 
Visit (SoA, Section 1.3). 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: 
• Serious hypersensitivity reactions (such as bronchospasm with wheezing or requiring 
ventilator support or symptomatic hypotension, refer to Section 10.7) or serum 
sickness-like reactions manifesting 1 to 14 days after drug administration; 
• Severe uncontrolled infection; 
• Patient body weight increase to ≥ 100 kg; 
• Pregnancy or planned pregnancy; or 
• If the Sponsor’s Medical Monitor or the Investigator deems it is in the best interest of 
the patient. 
It is expected that the Investigator will contact the Medical Monitor prior to discontinuing a 
patient’s study drug. If a patient is discontinued from study drug the patient may remain in the 
clinical study. In this case the patient should be encouraged to return for the remainder of his or 
her protocol-scheduled visits until starting a different complement-targeted therapy. 
The reason for the treatment discontinuation (patient discontinues study drug, but may continue 
to be present for protocol-required assessments) or study discontinuation (patient discontinues 
study drug and ends participation in the study) will be recorded in the eCRF. 
If a patient is withdrawn from the study with an ongoing AE or an unresolved laboratory 
abnormality that, in the opinion of the Investigator, is outside of the reference range and 
clinically significant (Section 8.2.6), the Investigator will attempt to provide follow-up until the 
laboratory abnormality or AE has resolved or stabilized. 
A patient whose body weight increases to 100 kg or more will be discontinued from the study 
and will return to the care of the patient’s treating physician. 
If a female patient is permanently discontinued from study drug due to pregnancy, the 
Investigator will attempt to follow up until the outcome of the pregnancy is known Section 10.5 
(Appendix 5). 
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. 

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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 fails to return for scheduled visits and 
is unable to be contacted by the study site.  
The following actions must be taken if a patient fails to return to the clinic for a required study 
visit or if the patient is unable to be contacted by telephone on days that are scheduled for 
at-home self-administration of ravulizumab SC: 
• The site must attempt to contact the patient and reschedule the missed visit/telephone 
call as soon as possible and counsel the patient on the importance of maintaining the 
assigned visit schedule and ascertain whether or not the patient wishes to and/or 
should continue in the study. 
• Before a patient is deemed lost to follow-up, the Investigator or designee must make 
every effort to regain contact with the patient (where possible, 3 telephone calls and, 
if necessary, a certified letter to the patient’s last known mailing address or local 
equivalent methods). These contact attempts should be documented in the patient’s 
medical record. 
• Should the patient continue to be unreachable the patient will be considered to have 
withdrawn consent and future missed visits will not be considered protocol 
deviations.  
7.2.1. 
Discontinuation of Study/Site Termination by Sponsor or Health Authority 
The Sponsor or health authority may terminate the study for reasonable cause. Conditions that 
may warrant termination of the study include, but are not limited to, 
• Discovery of an unexpected, serious, or unacceptable risk to patients enrolled in the 
study  
• Sponsor decision to suspend or discontinue testing, evaluation, or development of the 
study drug  
• Failure of the Investigator to comply with the approved protocol, pertinent guidelines, 
and/or regulations  
• Submission of knowingly false information from the Investigator to the Sponsor 
and/or health authorities  
Should the study be terminated early, the Sponsor or designee will notify the health authority and 
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) according to local 
requirements. Additionally, the Investigators and site monitors will be informed about study 
termination and applicable next steps. 

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8. 
STUDY ASSESSMENTS AND PROCEDURES 
Study procedures and their timing are summarized in the SoA (Section 1.3). Protocol waivers or 
exemptions are not allowed. However, under exceptional circumstances, the Investigator may 
also need to deviate from the protocol to eliminate an immediate hazard to a trial subject and this 
needs to be discussed as soon as possible with medical monitor.  
8.1. 
Efficacy Assessments 
8.1.1. 
Lactate Dehydrogenase and Other Disease-Related Laboratory Parameters 
Blood and urine samples will be collected at the time points indicated in the SoA (Section 1.3). 
The following disease-related laboratory parameters will be measured during the study: 
• Lactate dehydrogenase 
• Reticulocyte count 
• Paroxysmal nocturnal hemoglobinuria RBC clone size evaluated by high-sensitivity 
flow cytometry (Borowitz, 2010) 
• Estimated glomerular filtration rate (calculated using the Modification of Diet in 
Renal Disease formula) 
8.1.2. 
Transfusion Avoidance 
Achievement of transfusion avoidance is defined as patients who remained transfusion free and 
did not require a transfusion after the first dose of study drug. 
8.1.3. 
Breakthrough Hemolysis 
Breakthrough hemolysis is defined as at least 1 new or worsening symptom or sign of 
intravascular hemolysis (fatigue, hemoglobinuria, abdominal pain, shortness of breath [dyspnea], 
anemia [hemoglobin < 10 g/dL], MAVE including thrombosis, dysphagia, or erectile 
dysfunction) in the presence of elevated LDH ≥ 2 × ULN as assessed by the central laboratory.  
8.1.4. 
Stabilized Hemoglobin 
Stabilized hemoglobin is defined as the avoidance of a ≥ 2 g/dL decrease in hemoglobin level 
from Baseline in the absence of transfusion from Baseline to the end of the period of interest. 
8.1.5. 
Paroxysmal Nocturnal Hemoglobinuria Symptomatology 
The Investigator or designee will assess each patient for signs and symptoms of PNH, which may 
include the following: fatigue, chest pain, abdominal pain, dyspnea, dysphagia, erectile 
dysfunction, and red/dark urine or hemoglobinuria.  
8.1.6. 
Quality of Life Questionnaires 
Two validated HRQoL scales will be administered to patients before study drug administration 
and at the time points specified in the SoA (Section 1.3).  

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• The Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue scale, 
Version 4.0, is a collection of HRQoL questionnaires pertaining to the management 
of fatigue symptoms due to a chronic illness. The FACIT-Fatigue is a 13-item 
questionnaire that assesses self-reported fatigue and its impact upon daily activities 
and function over the preceding 7 days. Patients will score each item on a 5-point 
scale: 0 (not at all) to 4 (very much). Total scores range from 0 to 52 with higher 
score indicating better HRQoL. 
• The European Organisation for Research and Treatment of Cancer (EORTC) Quality 
of Life Questionnaire-Core 30 Scale (QLQ-C30), Version 3.0, is a questionnaire 
developed to assess the HRQoL of cancer patients. The questionnaire includes the 
following subscales: global health status, functional scales (physical functioning, role 
functioning, emotional functioning, cognitive functioning, and social activity), 
symptom scales (fatigue, nausea and vomiting, and pain), and single items (dyspnea, 
insomnia, appetite loss, constipation, diarrhea, and financial difficulties). Thirty 
questions are related to HRQoL, with the first 28 questions scored on a 4-point scale 
(1 = not at all to 4 = very much) and the final 2 questions that probe the patient’s 
overall health and HRQoL scored on a scale of 1 (very poor) to 7 (excellent). Each 
subscale has a range of 0% to 100%, with a high score representing a higher response 
level. Thus, a high score for a functional scale represents a high level of functioning, 
but a high score for a symptom scale represents a high level of 
symptomatology/problem.  
Treatment administration satisfaction and patient preference questionnaires will also be assessed 
at the time points specified in the SoA (Section 1.3).  
• The Treatment Administration Satisfaction Questionnaire (TASQ) is a validated 
questionnaire that will assess patients’ perceptions and satisfaction with prior 
eculizumab IV or ravulizumab SC treatment (Theodore-Oklota, 2016). The TASQ 
scores treatment administration satisfaction through 5 domains: physical impact, 
psychological impact, impact on ADL, convenience, and satisfaction. Each domain 
offers up to 5 response options with lower scores indicating a more positive response. 
Scoring is completed by summing each of the 5 domains. NOTE: Any safety data 
generated from this questionnaire will be documented as an AE on the AE eCRF as 
per the Investigator’s medical judgement. 
• The PNH Patient Preference Questionnaire-Subcutaneous (PNH-PPQ-SC [PPQ-SC]) 
was developed to evaluate patient preference for ravulizumab administered 
subcutaneously versus eculizumab administered intravenously. The questionnaire 
contains 13 questions, including 1 overall preference question; 1 question evaluating 
preference for eculizumab or ravulizumab according to 13 treatment characteristics 
(eg, “Frequency of treatment”, “Time required to receive treatment”) and 1 write-in 
option; 1 question asking patients to indicate which treatment characteristic was most 
important for their overall medication preference; 5 questions evaluating aspects of 
treatment with eculizumab; and 5 questions evaluating those same aspects of 
treatment with ravulizumab administered subcutaneously. The overall preference 
question asks patients to indicate which of the 2 medications they prefer based upon 
their experience with the 2 treatments. Patients may also select “I do not have a 

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preference”. Question 1 is scored such that “Soliris (eculizumab) via infusion” = -1, 
“Ultomiris SC (ravulizumab) via subcutaneous injection” = 1, and “I do not have a 
preference” = 0. Question 2, which assesses preference on 13 treatment 
characteristics, uses a 5-point scale (“Strongly Prefer Soliris (eculizumab)” = -2; 
“Somewhat Prefer Soliris (eculizumab)” = -1; “I do not have a Preference” = 0; 
“Somewhat Prefer Ultomiris SC (ravulizumab)” = 1; “Strongly Prefer Ultomiris SC 
(ravulizumab)” = 2). The 10 questions that elicit patient evaluation of each drug use a 
5-point scale (“Not at all” = 0; “A little bit” = 1; “Somewhat” = 2; “Quite a bit” = 3; 
“Very much” = 4). Of these 10 questions, 2 (Questions 6 and 11) will be reverse 
scored so that high scores in the patient evaluation section of the questionnaire 
represent a more favorable evaluation of the drug in consideration. 
The FACIT-Fatigue, EORTC QLQ-C30, TASQ-IV/TASQ-SC, and PPQ-SC will be 
administered and recorded on paper. Examples of these QoL assessment tools are provided in 
Appendix 6 (Section 10.6.1, Section 10.6.2, Section 10.6.3, and Section 10.6.4, respectively).  
8.2. 
Safety Assessments 
The Investigator or designee will meet with the patients to discuss the potential safety risks of 
ravulizumab SC, ravulizumab OBDS, and ravulizumab IV to give the Investigator the 
opportunity to address any of the patient’s safety concerns regarding the study. 
Investigators are instructed to follow up on any AEs through to their conclusion (resolution or 
stabilization) as described in Section 10.3 (Appendix 3).  
The time points for all safety assessments are provided in the SoA (Section 1.3). 
8.2.1. 
Major Adverse Vascular Events 
The description of the MAVE including the method of diagnosis (eg, magnetic resonance 
imaging, ultrasound, angiogram), date of diagnosis, and date resolved (or ongoing) will be 
collected on the eCRF as part of the patient’s medical history (prior to Baseline) and throughout 
the study. 
A MAVE is defined as follows: 
• Thrombophlebitis/deep vein thrombosis 
• Pulmonary embolus 
• Myocardial infarction 
• Transient ischemic attack 
• Unstable angina 
• Renal vein thrombosis 
• Acute peripheral vascular occlusion 
• Mesenteric/visceral vein thrombosis or infarction 
• Mesenteric/visceral arterial thrombosis or infarction 
• Hepatic/portal vein thrombosis (Budd-Chiari syndrome) 

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• Cerebral arterial occlusion/cerebrovascular accident 
• Cerebral venous occlusion 
• Renal arterial thrombosis 
• Gangrene (nontraumatic; nondiabetic) 
• Amputation (nontraumatic; nondiabetic) 
• Dermal thrombosis 
• Other (specify) 
8.2.2. 
Physical Examination 
A physical examination will include the following assessments: general appearance; skin; head, 
ear, eye, nose, and throat; neck; lymph nodes; chest; heart; abdominal cavity; limb; central 
nervous system; and musculoskeletal system. An abbreviated physical examination consists of a 
body system relevant examination based upon Investigator judgment and patient symptoms. 
8.2.3. 
Infusion Site Evaluation 
Subcutaneous or IV infusion site evaluations will be performed at the time points specified in the 
SoA (Section 1.3).  
8.2.4. 
Vital Signs 
Vital sign measurements will be taken after the patient has been resting for at least 5 minutes, 
and will include systolic and diastolic blood pressure (BP; mm Hg), heart rate (beats/minute), 
respiratory rate (breaths/minute), and temperature (°C or °F). 
8.2.5. 
Electrocardiograms 
Single 12-lead electrocardiogram (ECG) will be obtained as outlined in the SoA (Section 1.3) 
using an ECG machine that automatically calculates the heart rate and measures PR, QRS, QT, 
and QTc intervals. 
Patients must be supine for approximately 5 to 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.  
8.2.6. 
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). 

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If a suspected event of breakthrough hemolysis occurs, an Unscheduled Visit must take place at 
which time a sample is collected for analysis of LDH, PK, PD, and ADA by the central 
laboratory.  
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. 
If laboratory values from non protocol-specified laboratory assessments performed at the 
institution’s local laboratory require a change in patient management or are considered clinically 
significant by the Investigator (eg, serious AE [SAE] or AE or dose modification) then the 
results must be recorded in the eCRF. 
8.2.6.1. 
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. 
Urine samples will also be analyzed to measure protein and creatinine to calculate the urine 
protein:creatinine ratio. 
8.2.6.2. 
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. 
8.2.6.3. 
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 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. 
8.3. 
Adverse Events and Adverse Device Effects 
Adverse events and SAEs 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 

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representative). An adverse device effect (ADE) is an AE deemed related to the use of an 
investigational medical device. The ADEs and serious ADEs (SADEs) will be determined by the 
Investigator or qualified designee. 
The Investigator or qualified designees are responsible for detecting, documenting, and recording 
events that meet the definition of an AE, SAE, ADE, or SADE and remain responsible for 
following up events that are serious, considered related to the study drug, investigational medical 
device, 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, SAEs, 
ADEs, and SADEs 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 events will be collected from the signing of the ICF until the follow-up contact specified in 
the SoA (Section 1.3). 
Investigators are not obligated to actively seek AEs or SAEs after conclusion of the study 
participation. However, if the Investigator learns of an 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. 
Transfusions are treated as efficacy endpoints (Section 8.1.2). Transfusions administered in the 
inpatient or outpatient setting should not be captured as AEs or SAEs unless identified as such by 
the Investigator. 
The method of recording, evaluating, and assessing causality of AE and SAE and the procedures 
for completing and transmitting SAE reports are provided in Appendix 3 (Section 10.3). 
8.3.2. 
Method of Detecting Adverse Events and Serious Adverse Events 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the patient is the preferred method to inquire about 
AE occurrences.  
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). 
8.3.3.1. 
Regulatory Reporting Requirements for Serious Adverse Events and Serious 
Adverse Device Effects 
Prompt notification by the Investigator to the Sponsor of an SAE (eg, suspected unexpected 
serious adverse reaction [SUSAR], unanticipated serious adverse device effect [USADE]) is 
essential so that legal obligations and ethical responsibilities towards the safety of patients and 
the safety of a study drug or investigational medical device under clinical investigation are met.  

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The Sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study drug or medical device under clinical 
investigation. The Sponsor will comply with country-specific regulatory requirements relating to 
safety reporting to the regulatory authority, IRBs/ IECs, and Investigators. 
The Council for International Organizations of Medical Sciences (CIOMS) or MedWatch reports 
must be prepared for SUSAR or USADE (Section 10.3 [Appendix 3]) according to local 
regulatory requirements and Sponsor policy and forwarded to Investigators as necessary. 
An Investigator who receives an Investigator safety report describing an SAE or other specific 
safety information (eg, summary or listing of SAEs) from the Sponsor will review and notify the 
IRB/IEC, if appropriate according to local requirements. 
8.3.4. 
Pregnancy 
Contraception guidance that must be followed for the study is described in Section 10.5 
(Appendix 5). 
For females of childbearing potential, a serum or urine pregnancy test (ie, beta-human chorionic 
gonadotropin) will be performed according to the SoA (Section 1.3). 
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. 
8.3.5. 
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 have been 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. 
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 

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as described in the SoA (Section 1.3). Vaccination(s) for N meningitidis will be recorded in the 
patient’s eCRF. 
8.3.6. 
Study Drug Administration Reactions 
8.3.6.1. 
Local and Systemic Reactions 
Infusion-site reactions are those localized to the site of SC or IV drug administration and may 
include those such as erythema, pruritus, and bruising. Infusion-associated reactions 
(infusion-related reactions) are those systemic in nature which may be immune or 
nonimmune-mediated generally occurring within hours of drug administration. 
Immune-mediated reactions may include allergic reactions (eg, anaphylaxis), while non immune-
mediated reactions are nonspecific (eg, headache, dizziness, nausea). Monitoring for these 
reactions will be conducted as part of routine safety assessments for this study. 
8.3.6.2. 
Infusion-associated Reactions 
Infusion-associated reactions are defined as systemic AEs (eg, fever, chills, flushing, alterations 
in heart rate and BP, dyspnea, nausea, vomiting, diarrhea, and generalized skin rashes) occurring 
during or within 24 hours of the start of IV or SC infusion that are assessed by the Investigator to 
be related to the study drug. 
8.4. 
Device Performance Assessments 
Device performance will be assessed using the reported outcome of attempted full dose 
administration (including device failure/malfunction) per the requirements in the IFU.  
Investigators and patients must report all device deficiencies observed during the course of the 
study (Section 10.4, Appendix 4). Device deficiencies will be documented in the eCRF as 
appropriate. 
In the event of a device deficiency, whether or not associated with a missed dose, the 
ravulizumab OBDS may be sent to a core laboratory for analysis.  
8.5. 
Overdose 
For this study, any IV or SC dose of ravulizumab greater than that specified/required in the 
protocol will be considered an overdose medication error. Overdoses are medication errors 
which are not considered AEs or ADEs unless there is an untoward medical occurrence resulting 
from them. The Sponsor does not recommend specific treatment for an overdose unless there are 
associated laboratory abnormalities or clinical symptoms. 
Overdose associated with SC administration of ravulizumab via OBDS is defined as 
administration of ravulizumab SC greater than the dose contained in 2 full OBDS cartridges. The 
definition is developed for the practical considerations that a full dose ravulizumab SC 
administration entails the use of multiple OBDS units, each with a cartridge containing a fixed 
dose/volume of ravulizumab. The definition is based on the overdose definition for a study drug 
and the wide dose range of safety tolerance for ravulizumab previously clinically investigated 
(up to 5400 mg IV, equivalent to ≤ ravulizumab in ten full OBDS cartridges). 

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8.6. 
Pharmacokinetic Assessments  
The timing for collection of samples for PK is critical to the primary endpoint for this study. The 
time of the start of the dose administered on Day 1 is the nominal time for all subsequent doses 
and associated samples. A sample obtained outside of the allotted PK visit windows will be 
considered a protocol deviation. The timing for the next sample collection will remain relative to 
the nominal time of the start of dose administration on Day 1. 
Blood samples for determination of serum drug concentrations will be collected before 
administration of study drug at the time points and within the windows indicated in the SoA 
(Section 1.3). For Day 1 of the SC group and Days 1 and 15 of the IV group, a postdose blood 
sample will be collected within 30 minutes of the end of the infusion. For Day 57 of the IV 
group, a blood sample will be collected during the site visit; no dose is administered on Day 57. 
The date and time (24-hour clock time) of each sample acquisition will be recorded. 
In the event of breakthrough hemolysis an additional PK sample will be required. Unused 
samples may be retained for a period of up to 5 years to perform additional ravulizumab-related 
assessments as necessary. 
The laboratory manual will provide details on sample collection, including blood volume 
requirements. 
Serum ravulizumab concentration over time will be evaluated with primary endpoint (Ctrough at 
Day 71) as the main PK parameter of interest. Other PK parameters may be explored. 
8.7. 
Pharmacodynamics 
Free C5 concentrations will be evaluated over time. Blood samples will be collected before 
administration of study drug at the time points and within the windows indicated in the SoA 
(Section 1.3). For Day 1 of the SC group and Days 1 and 15 of the IV group, a postdose blood 
sample will be collected within 30 minutes of the end of the infusion. For Day 57 of the IV 
group, a blood sample will be collected during the site visit; no dose is administered on Day 57. 
Samples obtained outside of the allotted visit windows will be considered protocol deviations. In 
the event of breakthrough hemolysis, an additional PD sample will be required. 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. 
8.8. 
Genetics 
Genetics will not be evaluated in this study. 
8.9. 
Biomarkers 
Not applicable. 
8.10. 
Medical Resource Utilization and Health Economics 
Medical resource utilization and health economics data will not be evaluated in this study. 

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9. 
STATISTICAL METHODS AND PLANNED ANALYSES 
9.1. 
Statistical Hypotheses 
The statistical hypothesis is that the Day 71 Ctrough concentration of patients treated with 
ravulizumab SC via an OBDS is noninferior to that of patients treated with ravulizumab IV. 
9.2. 
Sample Size Determination  
Assuming the ratio of the geometric means of Ctrough (SC/IV) is 1.03 and the coefficient of 
variation is 0.4, 62 patients in the ravulizumab SC group and 31 patients in the ravulizumab IV 
comparison group will achieve 90% power to detect noninferiority using a one-sided test at an 
alpha level of 0.05 and a PK noninferiority boundary (NIB) of 0.8. The alpha level and NIB are 
based on recommendations in guidance documents “Standard Approaches to Establishing 
Bioequivalence” and “Guideline on the Investigation of Bioequivalence”, from the US Food and 
Drug Administration and European Medicines Agency, respectively. This sample size is 
increased to 105 patients (70 patients in the ravulizumab SC group and 35 patients in the 
ravulizumab IV group) to account for the possibility that up to 10% of patients may not meet the 
criteria for inclusion in the PK analysis set. An interim analysis to evaluate futility and perform a 
sample size re-estimation will be performed. More information on this interim analysis is 
provided in Section 9.5 and details will be presented in the Statistical Analysis Plan (SAP).This 
sample size re-estimation may lead to an increase of up to 144 patients (up to 96 patients in the 
ravulizumab SC group and 48 patients in the ravulizumab IV comparison group). 
9.3. 
Populations for Analyses 
The populations for analyses are defined in Table 10 . Dosing windows for inclusion in the PK 
analysis set are presented in Table 10 . 
Table 10: 
Populations for Analyses 
Population 
Description 
Enrolled  
All patients who sign the ICF and who are randomized. 
PD analysis set  
All patients who receive at least 1 dose of ravulizumab and who have 
evaluable PD data. 
PK analysis set 
All patients who have evaluable PK dataa and for whom: 
1. All doses up to Day 64 are compliant with the planned dose and the 
dosing time windows specified in Table 11 .  
2. The predose PK sample on Day 71 has been collected within ± 3 hours 
from the nominal time of the first dose on Day 1.  
Per protocol analysis set 
All patients in the PK analysis set who satisfied all key eligibility criteria for 
the study (inclusion criteria 2, 3, 4, 6, 8 and exclusion criteria 1 through 4; as 
described in Section 5). 
Full analysis set 
All patients who receive at least 1 dose of ravulizumab. 
Safety analysis set 
All patients who receive at least 1 dose of ravulizumab. Patients will be 
analyzed according to the study drug they actually received. 
Abbreviations: ICF = informed consent form; PD = pharmacodynamic; PK = pharmacokinetic. 
a Evaluable PK data are defined as non-missing results generated from samples that comply with sample integrity 
requirements during sample collection, storage, shipment, and bioanalysis. 

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Table 11: 
Dosing Window Requirements for Inclusion in the Pharmacokinetic 
Analysis Set  
Study Day 
15 
22 
29 
36 
43 
50 
57 
64 
Window for dosing to be compliant for inclusion 
in the PK analysis set (nominal time in hours 
from the start of the first dose on Day 1)  
± 3 
± 6 
± 6 
± 6 
± 6 
± 6 
± 3 
± 3 
a Refer to Table 2 and Table 3 in Section 1.3 for details on dosing and dosing windows. 
The PK analysis set will be used for the primary analysis (Section 9.4.1). 
9.4. 
Statistical Analyses 
All data and all outcomes derived from the data will be presented in detailed data listings or 
summary tabulations. Graphical displays may also be provided when appropriate. All analyses 
will be performed using SAS® release, version 9.4 or higher (SAS Institute Inc., Cary, NC, USA) 
or other validated statistical software. Continuous variables will be summarized using descriptive 
statistics, including number of observations and mean, standard deviation, median, minimum, 
and maximum values. Categorical variables will be summarized by frequency counts and 
percentage of patients. 
Details of the statistical analyses described below will be specified in a separate Statistical 
Analysis Plan (SAP) before database lock and analysis. Any change to the data analysis methods 
described in the protocol will require an amendment only if it changes the primary objective or 
the study conduct. Any other change to the data analysis methods described in the protocol or 
SAP, and the justification for making the change, will be described in the clinical study report. 
Additional exploratory analyses of the data may be conducted as deemed appropriate. 
9.4.1. 
Primary Analysis 
The primary analysis to evaluate noninferiority in serum Ctrough of ravulizumab SC compared 
with ravulizumab IV will be conducted after all patients have completed all protocol-required 
assessments in the Randomized Treatment Period. 
The primary analysis will be performed on the PK analysis set.  
The primary endpoint is the Day 71 serum ravulizumab Ctrough. The ratio of the geometric mean 
Ctrough from the ravulizumab SC group over the geometric mean Ctrough from ravulizumab IV 
group with a 2-sided 90% CI will be calculated. If the lower bound of the 90% CI for the ratio of 
the geometric means (ravulizumab SC/ravulizumab IV) is greater than the NIB of 80%, then the 
ravulizumab SC treatment will be concluded to be noninferior to the ravulizumab IV treatment. 
To obtain the above referenced 90% CI, the Ctrough data under consideration will be analyzed 
using analysis of variance. In addition to the formulation (SC or IV), the model for statistical 
analysis will take into account body weight. The data will be transformed prior to analysis using 
a logarithmic transformation. The point estimate and CIs will be calculated and constructed for 
the mean difference of log-transformed parameters. These will then be back-transformed to be 
presented on the ratio scale. 
Sensitivity analyses will be performed by repeating the primary analysis on the Full Analysis Set 
(FAS) patients with evaluable PK data and the Per Protocol Set (PPS). 

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9.4.2. 
Secondary Analyses 
Secondary analyses will be performed on the Full Analysis Set (FAS). When applicable, results 
from the Randomization Treatment Period will be presented in parallel by treatment group, but 
no formal comparisons will be performed. Summaries of data over time while patients are 
receiving SC administration of ravulizumab will be based on time since first exposure to 
ravulizumab SC. At the start of the Extension Period, it will have been 56 days since their first 
dose of ravulizumab SC for patients randomized to the SC group, while patients initially 
randomized to the IV group will be getting their first dose of ravulizumab SC. This exposure 
difference will be taken into account and, as an example, a summary for Day 183 (since first 
dose of ravulizumab SC) will use study Day 183 data from patients randomized to the SC group 
and study Day 239 data from patients randomized to the IV group. 
9.4.2.1. 
Pharmacokinetic/Pharmacodynamic 
Pharmacokinetic analyses will be performed for all patients from the FAS who have evaluable 
PK data, as described in PK analysis set in Section 9.3. Since this is a multicenter patient study 
censoring of PK or PD data may be considered when a sample collection or handling error is 
inferred. 
Graphs of mean serum ravulizumab concentrations versus time will be constructed. Graphs of 
serum concentrations versus time for individual patients may also be provided. Actual dose 
administration and sampling times will be used for all calculations. Descriptive statistics will be 
calculated for serum concentration data at each sampling time as appropriate.  
Pharmacodynamic analyses will be performed for all patients from the FAS who have evaluable 
PD data. The PD effects of ravulizumab will be evaluated by assessing the absolute values for 
free C5 serum concentrations over time. Descriptive statistics will be calculated for the PD data 
at each sampling time as appropriate. Additional assessments of serum free C5 concentration 
may be considered as appropriate. 
9.4.2.2. 
Quality of Life and Treatment Administration Satisfaction 
Quality of life will be evaluated using FACIT-Fatigue Version 4 Questionnaire as well as the 
EORTC QLQ-C30 Version 3.0 questionnaire. The data from these questionnaires will be 
summarized at Baseline and Day 183, as well as each applicable postbaseline time point using 
descriptive statistics for continuous variables for the observed value as well as the change from 
Baseline. 
Patient satisfaction with treatment administration will be evaluated using TASQ scores. These 
data will be summarized at Baseline and Day 183, as well as each applicable postbaseline time 
point using descriptive statistics for continuous variables for the observed value as well as the 
change from Baseline. NOTE: Any safety data generated from this questionnaire will be 
documented as an AE on the AE eCRF as per the Investigator’s medical judgement. 
Patient preference as assessed by the PPQ-SC will be summarized. Among patients who receive 
ravulizumab SC and have evaluable PPQ-SC data, the number and proportion of patients with a 
preference for ravulizumab SC, eculizumab, or no preference will be presented at the applicable 
postbaseline time point. 

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9.4.3. 
Efficacy Analysis 
Lactate dehydrogenase and other disease-related laboratory parameters will be summarized at 
Baseline and each applicable postbaseline time point using descriptive statistics for continuous 
variables for the observed value as well as the change from Baseline. 
The number and proportion of patients with breakthrough hemolysis (defined in Section 8.1.3) 
will be summarized over time by presenting the number and proportion of patients with a 
breakthrough along with a 2-sided 95% CI for each applicable postbaseline time point. The 
number and proportion of patients who do not require a transfusion and the number and 
proportion of patients with stabilized hemoglobin (defined in Section 8.1.4) will be summarized 
similarly. 
9.4.4. 
Safety Analyses 
All safety analyses will be conducted for the Safety Set, defined as all patients who receive at 
least 1 dose of ravulizumab.  
The following definitions will be used for AEs and ADEs: 
• Pretreatment AEs: Any AE that starts after providing informed consent, but before 
the first infusion of study drug 
• Treatment-emergent AE (TEAE): Any AE that starts during or after the first infusion 
of study drug. 
• All ADEs are by definition occurring during or after the start of the first infusion. 
The incidence of TEAEs will be summarized by System Organ Class (SOC) and Preferred Term 
overall, by severity, and by relationship to treatment. The incidence of SAEs will also be 
summarized. The incidence of ADEs and SADEs will be summarized similarly by SOC and 
Preferred Term and by severity. All AEs and ADEs will be coded using Medical Dictionary for 
Regulatory Activities, version 18 or higher. 
Adverse changes from Baseline in physical examination findings will be classified as AEs and 
analyzed accordingly. 
Observed values and changes from Baseline (last assessment prior to ravulizumab) in ECGs, 
vital signs, and laboratory assessments will be summarized for all applicable study visits. For 
laboratory results that can be classified as normal, low, or high based on normal range values, 
shifts from baseline in classification will be summarized for all applicable study visits. 
Changes from Baseline in ECG intervals (PR, RR, QT, and QTcF) will be summarized for all 
applicable study visits. The QT interval will be corrected for heart rate using Fridericia’s formula 
(QTcF). 
For the immunogenicity data the number and proportion of patients who develop ADAs to 
ravulizumab and the titer values will be summarized. The proportion of patients with at least 
1 positive ADA result over time (ever positive) and the proportion of patients always negative 
may be explored. 

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9.4.5. 
Device Performance Analyses 
Device performance will be evaluated by the number and proportion of doses that were 
completely administered successfully out of all attempted full-dose administration. The reasons 
for doses not being completely administered will be summarized. For reasons reported as 
“device-related technical failure” these technical failures will be further summarized by category. 
9.4.6. 
Other Analyses  
Additional exploration of PK, PD, ravulizumab OBDS performance data, and patient reported 
outcomes may be performed as considered necessary.  
9.5. 
Interim Analysis for Futility and Sample Size Re-estimation  
An interim analysis will be performed when 50% of the planned patients (n = 105) have been 
assessed for the primary endpoint (ie, 34 patients in the ravulizumab SC group and 17 patients in 
the ravulizumab IV comparison group). This is expected to yield at least 45 patients who meet 
the criteria for inclusion in the PK analysis set.  
The initial part of the analysis will be to assess futility in order to allow the Sponsor to stop the 
study early if it is unlikely to lead to a significant final result. This will conserve resources and 
not expose additional patients to the study drug in the event that noninferiority appears very 
unlikely. 
Following the futility assessment, but using the same set of patients and data, an interim sample 
size re-estimation analysis to reassess the required size of the study based on estimation of the 
primary endpoint will also be performed. 
Enrollment of patients will proceed without interruption while the analysis is ongoing. 
There are no plans to stop the study for demonstration of noninferiority at the interim analysis. 
Futility Analysis 
A nonbinding futility boundary based on conditional power for noninferiority (CPni) of 20% will 
be used so that if the Sponsor decides to continue the study, even if the futility boundary is 
crossed, there will be no impact to the primary analysis Type I error rate. 
Sample Size Re-estimation 
The sample size re-estimation (SSR) analysis will also be based on the CPni calculated using the 
results obtained at this interim analysis. The CPni will be calculated assuming the ‘observed 
effect’ values; ie, the population mean Ctrough equals the sample mean Ctrough at the time of the 
sample size re-estimation. The maximum total number of patients will be 144. The sample size 
will never be reduced from the planned sample size of 105 patients. If the CPni is at least 90% 
for the planned total sample size of 105 patients, then no increase in sample size will be made.  
The decision to be made based on this sample size re-estimation analysis will follow the 
following rule (Table 12 ): 
If CPmin ≤ CPni < 0.9, increase the sample size by just the right amount such that CPni is 
increased to 90%, subject to a cap of 144 patients. The range CPmin ≤ CPni < 0.9 is called the 
promising zone for noninferiority. Specifically, if CPni is in its promising zone, this decision rule 

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increases the sample size, to the smaller of 144 patients or the number needed to boost CPni to 
90%.  
Table 12: 
Criteria for Futility Analysis and Sample Size Re-estimation  
 
Decision  
CPni ≤ 20% 
Consider stopping for futility 
20% < CPni < CPmin% 
Continue to N = 105 
CPmin% ≤ CPni < 90% 
Increase to smaller of N = 144 or N needed for CPni = 90% 
90% ≤ CPni 
Continue to N = 105 
Abbreviations: CPmin = CPni = conditional power for noninferiority; N = number [of patients]. 
The lower bound of the promising zone, CPmin, will be determined following the approach 
explained in Mehta and Pocock (Mehta, 2011) and is not explicitly stated here to avoid potential 
study bias following any decision made based on this sample size re-estimation analysis. Further 
details will be provided in the SAP. 
9.6. 
Other Statistical Issues 
9.6.1. 
Missing or Invalid Data 
If a Day 1 assessment is missing the Screening assessment will be used as the Baseline 
assessment.  
Missing data for HRQoL instruments will be handled as specified in the instructions for each 
instrument. 

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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 and ISO guidelines 
− Applicable laws and regulations 
• The protocol, protocol amendments, ICF, IBs, and other relevant documents must be 
submitted to an IRB/IEC by the Investigator and/or by the Sponsor based on 
applicable local regulations. These documents must be reviewed and approved by the 
IRB/IEC before the study is initiated.  
• Any amendments to the protocol will require IRB/IEC approval before 
implementation of changes made to the study design except for changes necessary to 
eliminate an immediate hazard to study patients.  
• The Investigator will be responsible for the following: 
− Providing written summaries of the status of the study to the IRB/IEC 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, ICH guidelines, the IRB/IEC, 
European regulation 536/2014, ISO 14155 for clinical studies (if applicable), and all 
other applicable local regulations 
• The clinical investigation cannot begin until the required approval/favorable opinion 
from the IRB/IEC or regulatory authority has been obtained, if appropriate, as well as 
any additional requirements imposed by the IRB/IEC or regulatory authority to be 
followed. 
10.1.2. 
Informed Consent Process 
The Investigator or designee will explain the nature of the study to the patient and answer all 
questions regarding the study.  
Patients must be informed that their participation is voluntary. Patients will be required to sign a 
statement of informed consent that meets the requirements of 21 CFR 50, local regulations, ICH 

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guidelines, Health Insurance Portability and Accountability Act requirements, ISO 14155 for 
clinical studies, where applicable, and the IRB/IEC or study center.  
The medical record must include a statement that written informed consent was obtained before 
the patient was 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, if applicable.  
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. Patient records or datasets that are 
transferred to the Sponsor will contain the identifier only; patient names or other information that 
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, appropriate IRB/IEC 
members, and inspectors from regulatory authorities. 
10.1.4. 
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 Investigator’s site. 
The Investigator or designee will prepare and maintain adequate and accurate source documents 
(medical records, ECGs, AE and concomitant medication reporting, raw data collection forms) 
designed to record all observations and other pertinent data for each patient. Data reported on the 
CRF or entered in the eCRF that are transcribed from source documents must be consistent with 
the source documents or the discrepancies must be explained. The Investigator may need to 
request previous medical records or transfer records. Also, current medical records must be 
available. 
10.1.5. 
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 or EU website www.clinicaltrialsregister.eu/ or other 
publicly accessible websites as appropriate and in accordance with local regulations. 
10.1.6. 
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 

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responsible for verifying that data entries are accurate and correct by physically or electronically 
signing the CRF.  
The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.  
The Investigator must permit study-related monitoring, audits, IRB/IEC review, and regulatory 
agency inspections and provide direct access to source data documents.  
The Sponsor or designee is responsible for the data management of this study including quality 
checking of the data.  
Study monitors will perform ongoing risk-based monitoring to include source data review and 
verification to confirm that data entered into the eCRF 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.  
10.1.7. 
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. Study sites will be closed upon study completion. A study site is 
considered closed when all required documents and study supplies have been collected and a 
study-site closure visit has been performed. 
The Investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the Sponsor or Investigator may include but are 
not limited to: 
• Failure of the Investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the Sponsor’s procedures, or GCP guidelines 
• Inadequate recruitment of patients by the Investigator 
• Discontinuation of further 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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10.1.9. 
Remote Visit Options in Times of Emergency  
To ensure patient safety and treatment continuity in times of emergency (eg, COVID-19 
pandemic), the following will apply where patients are not able to reach the study sites, and until 
patients are able to resume study visits at the site. 
Alternative visit options, such as remote visits, may be at the Investigator’s discretion and 
oversight, in accordance with the local regulations. Remote visit options may include visits 
conducted at the patient’s home, an alternative qualified healthcare facility, or virtually through 
phone or video conference. All assessments that can be conducted remotely for the study visit 
day should be conducted according to the Schedule of Activities (Section 1.3) at the discretion of 
the Investigator by trained qualified staff and in accordance with all national, state, and local 
laws or regulations. Information about AEs and concomitant medications may be collected from 
the patient by telephone or other means of communication on the day of the remote visit. In case 
of any signs or symptoms indicating an SAE, the patient will need to be evaluated at the study 
site. 

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10.2. 
Appendix 2: Clinical Laboratory Tests  
The tests detailed in Table 13 will be performed by the central laboratory.  
Protocol-specific requirements for inclusion or exclusion of patients are detailed in Section 5. 
Additional tests may be performed at any time during the study as determined necessary by the 
Investigator or as required by local regulations. 
Table 13: 
Protocol-Required Safety Laboratory Assessments  
Laboratory 
Assessments 
Parameters 
Hematology 
Platelet Count  
Red blood cell (RBC) Count 
Hemoglobin 
Hematocrit 
RBC Indices: 
Distribution width 
Mean corpuscular volume 
Mean corpuscular 
hemoglobin 
% Reticulocytes 
White blood cell (WBC) 
count with Differential: 
Neutrophils 
Lymphocytes 
Monocytes 
Eosinophils 
Basophils 
Clinical 
Chemistry 
Blood urea nitrogen (BUN) 
C-reactive protein 
Creatinine 
Aspartate aminotransferase 
(AST)/serum glutamic 
oxaloacetic transaminase 
(SGOT) 
Total and direct bilirubin 
Chloride  
Potassium 
Bicarbonate  
Sodium  
Alanine aminotransferase 
(ALT)/serum glutamic 
pyruvic transaminase 
(SGPT) 
Total protein 
Glucose (nonfasting) 
Alkaline phosphatase, 
Gamma glutamyltransferase, 
Lactate dehydrogenase 
Albumin 
Uric acid 
Coagulation 
D-dimer, international normalized ratio, partial thromboplastin time, prothrombin time 
Routine urinalysis 
- Appearance, color, specific gravity, pH, glucose, protein, blood, ketones, bilirubin, 
urobilinogen, nitrite, creatinine and protein:creatinine ratio 
- Microscopic examination (if blood or protein is abnormal)  
Other Screening 
tests 
- Serum human chorionic gonadotropin (hCG) pregnancy test (as needed for women of  
 childbearing potential) 
- Follicle stimulating hormone testing  
- Human immunodeficiency virus (HIV)-1 and HIV-2 antibodies 
The results of each test must be entered into the eCRF. 
Complement 
activity 
Free C5, PNH clone size 
Abbreviations: C5 = complement component 5; eCRF = electronic case report form; PNH = paroxysmal nocturnal 
hemoglobinuria. 

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10.3. 
Appendix 3: Adverse Events and Adverse Device Effects: Definitions 
and Procedures for Recording, Evaluating, Follow-up, and 
Reporting 
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 drug administration even though it may have been present 
before the start of the study. 
• 
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
• 
“Lack of efficacy” or “failure of expected pharmacological action” per se will not be reported as an AE or 
SAE. Such instances will be captured in the efficacy assessments. However, the signs, symptoms, and/or 
clinical sequelae resulting from lack of efficacy will be reported as AE or SAE if they fulfil the definition of 
an AE or SAE.  
• 
The signs, symptoms, and/or clinical sequelae resulting from lack of efficacy will be reported as AE or SAE 
if they fulfil the definition of an AE or SAE.  
 
Events NOT Meeting the Adverse Event Definition  
• 
Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to the procedure is the 
AE. Situations in which an untoward medical occurrence did not occur (eg, hospitalization for elective 
surgery if planned before the signing the ICF, admissions for social reasons or for convenience). 
• 
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or detected at the start 
of the study that do not worsen. 
• 
Lack of drug effect is not an AE in clinical studies, because the purpose of the clinical study is to establish 
drug effect. 
• 
A medication error (including intentional misuse, abuse, and overdose of the product) or use other than what 
is defined in the protocol is not considered an AE unless there is an untoward medical occurrence as a result 
of a medication error. 
• 
Cases of pregnancy that occur during maternal or paternal exposure to investigational product 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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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). Transfusions administered in the inpatient or outpatient setting should 
not be captured as AEs or SAEs unless identified as such by the Investigator. 
A serious adverse event is defined as any untoward medical occurrence that, at any dose: 
1. Results in death 
2. Is life-threatening 
The term 'life-threatening' in the definition of 'serious' refers to an event in which the patient was at risk of death 
at the time of the event. It does not refer to an event, which hypothetically might have caused death, if it were 
more severe. 
3. Requires inpatient hospitalization or prolongation of existing hospitalization 
In general, hospitalization signifies that the patient has been detained (usually involving at least an overnight 
stay) at the hospital or emergency ward for observation and/or treatment that would not have been appropriate in 
the physician’s office or outpatient setting. Complications that occur during hospitalization are AEs. If a 
complication prolongs hospitalization or fulfills any other serious criteria, the event is serious. When in doubt as 
to whether “hospitalization” occurred or was necessary, the AE should be considered serious. 
Hospitalization for elective treatment of a pre-existing condition that did not worsen from baseline is not 
considered an AE. 
4. Results in persistent disability/incapacity 
• 
The term disability means a substantial disruption of a person’s ability to conduct normal life functions. 
• 
This definition is not intended to include experiences of relatively minor medical significance such as 
uncomplicated headache, nausea, vomiting, diarrhea, influenza, and accidental trauma (eg, sprained ankle) 
which may interfere with or prevent everyday life functions but do not constitute a substantial disruption. 
5. Is a congenital anomaly/birth defect 
6. Other situations: 
Medical or scientific judgment should be exercised in deciding whether SAE reporting is appropriate in other 
situations such as important medical events that may not be immediately life-threatening or result in death or 
hospitalization but based upon appropriate medical judgment may jeopardize the patient or may require medical 
or surgical intervention to prevent one of the other outcomes listed in the above definition. These events should 
usually be considered serious. 
Suspected Unexpected Serious Adverse Reactions 
Suspected Unexpected Serious Adverse Reactions 
Suspected unexpected serious adverse reactions (SUSARs) are serious events that are not listed in the IB and that 
the Investigator identifies as related to investigational product or procedure. The 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 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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Adverse Device Effect 
Adverse Device Effect Definition 
• 
An AE related to the use of an investigational medical device. This includes any AE resulting from 
insufficiencies or inadequacies in the instructions for use, the deployment, the installation, the operation, 
or any malfunction of the investigational medical device.  
• 
An ADE includes any event that is a result of use error or intentional misuse. Use error refers to an act 
or omission of an act which results in a different device response than intended by the manufacturer or 
the user. An unexpected physiological response of the subject does not in itself constitute a use error. 
• 
Missing dose (no dose) and partial dose (under dose) medication errors occurring with the use of the 
device are considered ADEs. Each ADE must be associated with 1 study device (ie, 1 OBDS kit in the 
current study).  
• 
Ravulizumab SC overdose involving multiple OBDS kits is a medication error pertaining to the SC drug 
administration route therefore will not be considered an ADE. Overdose medication errors from both IV 
and SC ravulizumab administration defined under Section 8.5. 
 
ADEs may arise from the following occasions (Note: These examples are strictly hypothetical and have no 
implications to the ravulizumab OBDS or any other devices): 
• 
Normal use example: injection site reactions not associated with any apparent device deficiency, use 
error or abnormal use of the device 
• 
Device deficiency example: A bent needle leading to injection site laceration 
• 
Use error example: With all the intentions to follow the IFU to complete the required dosing, a subject 
forgot to properly prepare the device application site skin by trimming the hairs leading to the device 
falling off in the middle of the dosing that led to a partial dosing 
• 
Misuse (abnormal use) example: A subject, against the device indications specified in the ravulizumab 
OBDS IB, used the device to administer a substance other than the investigational drug, resulting in 
toxicity stemming from the substance 
For this study, one ADE is associated with one investigational device (ie, one OBDS kit). The kit number 
associated with each ADE must be recorded in the CRF under the ADE. 
Medication Error Adverse Device Effects 
Two OBDS kits will be used to deliver the full 490 mg dose of ravulizumab SC. Missed dose (no dose) and 
partial dose (under dose) medication errors associated with study devices or the use of study devices are 
considered ADEs. 
• 
MISSING DOSE: Any missing dose or no dose delivered associated with ravulizumab SC 
administration using OBDS is to be considered an ADE. The kit number associated with the no dose 
ADE should be recorded together with the ADE. 
• 
PARTIAL DOSE: Following a partial dose there may be an ADE associated with one device. Therefore, 
one partial dose ADE is associated with one OBDS unit and one kit number is required in the recording 
of the partial dose ADE. 
Serious Adverse Device Effect 
Serious Adverse Device Effect Definition 
A serious adverse device effect (SADE) is an ADE that has resulted in any of the consequences characteristic of 
an SAE. 
Unanticipated Serious Adverse Device Effect 
Unanticipated Serious Adverse Device Effect Definition 
An unanticipated serious adverse device effect (USADE) is an SADE which by its nature, incidence, severity or 
outcome has not been identified in the current version of the ravulizumab OBDS IB as an expected event 
(21CFR803.3).  

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Device Deficiency 
Device Deficiency Definition 
A device deficiency is an inadequacy of an investigational medical device related to its identity, quality, 
durability, reliability, safety or performance. This may be due to malfunction, misuse, user error, inadequate 
labeling or insufficient information provided by the manufacturer. 
If a medication error is associated with a device deficiency/malfunction, it is considered an ADE. 

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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 or SAE information in the eCRF. 
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/SADE cover page to Alexion Global Drug Safety 
(GDS) via email: 
 or facsimile: 
 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 GDS. 
• 
The Investigator will attempt to establish a diagnosis of the event based on signs, symptoms, and/or 
other clinical information. Whenever possible, the diagnosis (not the individual signs/symptoms) will be 
documented as the AE/SAE. 
Assessment of Event Severity 
The Investigator will make an assessment of severity 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) v4.03, published 14 Jun 2010. Each CTCAE term is a Lowest Level Term (LLT) per the 
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 study drug and occurrence of each 
AE/SAE and between study device and occurrence of each ADE/SADE. An Investigator causality 
assessment must be provided for all AEs and ADEs (both nonserious and serious). This assessment must 
be recorded in the eCRF and on any additional forms, as appropriate. The definitions for the causality 
assessments are as follows: 
− 
Not related (unrelated): There is no evidence to suggest that there was a reasonable possibility 
that the drug caused the adverse event. 
− 
Related: There is evidence to suggest that there was a reasonable possibility that the drug 
caused the adverse event. 
• 
The Investigator will use clinical judgment to determine the relationship to the study drug or the 
investigational medical device. 
PPD
PPD

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Adverse Event and Serious Adverse Event Recording 
• 
Alternative causes, such as underlying disease(s), concomitant therapy, and other risk factors, as well as 
the temporal relationship of the event to study drug administration will be considered and investigated. 
• 
This protocol will use the current IB as the Reference Safety Document. The expectedness and reporting 
criteria of an SAE will be determined by the Sponsor, based on the Reference Safety Document. The 
Investigator will also consult the IB in his/her assessment. 
• 
There may be situations in which an SAE has occurred and the Investigator has minimal information to 
include in the initial report to Alexion or designee. However, it is very important that the Investigator 
always make an assessment of causality for every event before the initial transmission of the SAE 
data to Alexion GDS. 
• 
The Investigator may change his/her opinion of causality in light of follow-up information and send an 
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 post-mortem findings including 
histopathology if available. 
• The site will enter new or updated SAE data into the electronic system as soon as it becomes available, 
but no later than 24 hours. The Investigator will submit any updated SAE data to the GDS within 
24 hours of awareness of the information. 
 
Reporting of Serious Adverse Events and Serious Adverse Device Effects 
SAE and SADE Reporting to Alexion or Designee via the RAVE Safety Gateway 
All SAEs and SADEs must be reported to Alexion GDS within 24 hours of the Investigator or site staff 
awareness. These timelines for reporting SAE and SADE 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. 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 

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SAE and SADE Reporting to Alexion or Designee via the RAVE Safety Gateway 
• 
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/SADE reporting via fax or email. Facsimile 
transmission or email may be used in the event of electronic submission failure. 
Email: 
 
Facsimile: 
 
• 
When further information becomes available, the eCRF should be updated with the new information and 
an updated SAE report should be submitted to Alexion GDS via the RAVE Safety Gateway.  
• 
After the study is completed at a given site, the EDC will be taken offline to prevent the entry of new 
data or changes to existing data. 
• 
If a site receives a report of a new SAE from a study patient or receives updated data on a previously 
reported SAE after the electronic data collection tool has been taken offline, then the site can report this 
information on a paper SAE contingency form to Alexion GDS. 
 
 
SAE or SADE Reporting to Alexion or Designee via Paper Contingency CRF 
• 
If applicable, additional information such as relevant medical records should be submitted to Alexion 
GDS via the email address or fax 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. 
PPD
PPD

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10.4. 
Appendix 4: Investigational Medical Product or Device Complaints 
If the use of an investigational medical product or device led to an AE or ADE as defined in 
Section 10.3 (Appendix 3), the event will be evaluated by Alexion’s GDS and the recording and 
reporting procedures will be followed as described. 
Complaints are written, electronic, or oral communications that allege deficiencies about an 
investigational medical device’s identity, quality, durability, reliability, safety, or performance, 
Upon identification of a product complaint, on either ravulizumab IV dosing solution or 
ravulizumab OBDS, the site or patient must contact Medical Vigilance Solutions using the local 
phone number in the IFU document. The site must complete the Product Quality Complaints 
Form (See the Pharmacy Manual for details). 
The following includes potential issues that may warrant lodging a complaint: 
• Medical device failure: the ravulizumab OBDS drug-device combination product is 
used in compliance with the IFU, but does not perform as described (eg, incomplete 
dose or no dose delivered) 
• Labeling irregularity (eg, missing or illegible information on any part of the 
packaging or IFU) 
• Change in appearance of the study drug (eg, color change or presence of particulate 
matter in the cartridge) 
• Evidence of tampering or compromised packaging of the ravulizumab OBDS kit 
• Indicator light turns red during the infusion, and device beeps repeatedly 
• User error: The ravulizumab OBDS drug-device combination product is not used in 
compliance with the IFU. 
Additional details will be provided in the IFU. 
The Investigator is responsible for ensuring that all product complaints that occur after signing of 
the ICF through 30 days after the last dose of study drug or at the end of the study, whichever is 
later, are reported. 

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10.5. 
Appendix 5: Contraceptive Guidance and Collection of Pregnancy 
Information 
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). 
Female 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:  
1.  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.  
Male patients with a female spouse/partner of childbearing potential or a pregnant or 
breastfeeding spouse or partner must agree to use double barrier contraception (male condom 
plus appropriate barrier method for the female partner) while on treatment and for at least 
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 subjects must not donate ova while on treatment 
and for at least 8 months after the last dose of study drug. 
Pregnancy Testing 
Women of childbearing potential should only be included after a confirmed 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.  
Collection and Reporting of Pregnancy Data  
• 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. 
• If a female patient or a male patient’s female partner becomes pregnant during the 
conduct of this study, the Investigator must submit the “Pregnancy Reporting and 
Outcome/Breastfeeding” form to Alexion GDS via facsimile or email (Section 10.3 
[Appendix 3]). When the outcome of the pregnancy becomes known, the form should 
be updated and submitted to Alexion GDS. If additional follow-up is required, the 
Investigator will be 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”) and any 
AEs experienced by the infant must be reported to Alexion GDS or designee via 
email or facsimile (see Section 10.3 [Appendix 3]). 
• Pregnancy in itself is not regarded as an AE unless there is a suspicion that the study 
drug may have interfered with the effectiveness of a contraceptive medication. 
However, complications of pregnancy and abnormal outcomes of pregnancy are AEs 
and may meet the criteria for an SAE (eg, ectopic pregnancy, spontaneous abortion, 
intrauterine fetal demise, neonatal death, or congenital anomaly). Elective abortions 
without complications should not be reported as AEs (Section 8.2). 
• Any female patient who becomes pregnant while participating in the study will be 
discontinued from study drug. 

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10.6. 
Appendix 6: Quality of Life Questionnaires 
10.6.1. 
Functional Assessment of Chronic Illness Therapy--Fatigue Subscale Version 4 
FACIT-Fatigue will be administered and recorded on paper.  
 

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10.6.2. 
European Organisation for Research and Treatment of Cancer Quality of Life 
Questionnaire – Core 30 
EORTC QLQ-C30 will be administered and recorded on paper.  
 

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10.6.3. 
Treatment Administration Satisfaction Questionnaires  
The Treatment Administration Satisfaction Questionnaires (TASQ-IV and TASQ-SC) will be 
administered and recorded on paper. 
Used with permission from the developer, Genentech/Roche. 
10.6.3.1. Treatment Administration Satisfaction Questionnaire – Intravenous 
Instructions: Please complete the following questions based on your Soliris treatment. Your 
Soliris was given through a thin plastic tube and a needle that was put directly into a vein in your 
arm, called an intravenous or IV infusion. Please answer the questions based on your most 
recent Soliris IV infusion. 
1. Thinking about the IV infusion, how satisfied or dissatisfied are you with the IV infusion? 
Very satisfied 
Satisfied 
Neither satisfied 
nor dissatisfied 
Dissatisfied 
Very dissatisfied 
2. Thinking about the IV infusion, how do you rate the pain, swelling, or redness you 
experienced at the site of the drug injection? 
None 
Mild 
Moderate 
Severe 
Very Severe 
3. Thinking about the IV infusion, how do you rate the pain you experience with the IV 
infusion process? 
None 
Mild 
Moderate 
Severe 
Very Severe 
4. Thinking about the IV infusion, are the side effects of the IV infusion as you expected? 
Much better 
than expected 
Somewhat better 
than expected 
Met my 
expectations 
Somewhat worse 
than my 
expectations 
Much worse 
than my 
expectations 
5. Before you receive the IV infusion do you feel anxious about having the infusion? 
Not at all 
A little bit 
Somewhat 
Quite a bit 
Very much 
6. When you receive the IV infusion do you worry that your condition would get worse? 
Not at all 
A little bit 
Somewhat 
Quite a bit 
Very much 
7. When you receive the IV infusion do you feel anxious thinking about your disease? 
Not at all 
A little bit 
Somewhat 
Quite a bit 
Very much 

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8. Thinking about IV infusion, how confident are you that the IV infusion is treating your 
disease? 
Not at all 
A little bit 
Somewhat 
Quite a bit 
Very much 
9. When you receive the IV treatment do you feel restricted by the IV infusion? 
Not at all 
A little bit 
Somewhat 
Quite a bit 
Very much 
10. Thinking about the IV infusion, how convenient is it for you to get your IV infusion? 
Very convenient 
Convenient 
Neither 
convenient nor 
inconvenient 
Inconvenient 
Very 
inconvenient 
11. Thinking about the IV infusion, how do you feel about the amount of time it takes to get your 
IV infusion? 
 
Too short 
Just right 
Too long 
 
12. Thinking about the IV infusion, do you feel that the length of time to get your IV infusion 
was as you expected? 
Much shorter 
than expected 
Somewhat 
shorter than 
expected 
As expected 
Somewhat 
longer than 
expected 
Much longer 
than expected 
13. Thinking about the IV infusion, how bothered are you by the amount of time it takes to get 
the infusion? 
Not at all 
bothered 
A little bothered 
Moderately 
bothered 
Quite bothered 
Very bothered 
14. How much does the IV infusion: 
a. Interfere with your usual or daily activities? 
Not at all 
A little bit 
Somewhat 
Quite a bit 
Very much 
b. Limit your daily activities? 
Never 
Rarely 
Sometimes 
Most of the time 
Always 
15. Because of the length of time to apply the IV infusion do you feel that you have lost or 
gained time for other things? 
Lost a lot of 
time 
Lost some time 
Neither lost nor 
gained time 
Gained some 
time 
Gained a lot of 
time 

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16. When you receive the IV infusion treatment, are you able to talk to your nurse and/or doctor 
as much as you would like about your illness? (please only check ONE answer) 
⁮ 
Yes, I had more than enough time to talk to my nurse and/or doctor. 
⁮ 
Yes, but I would have liked more time to talk to my nurse and/or doctor. 
⁮ 
It does not matter to me if I have time to talk to my nurse and/or doctor during 
my treatment. 
⁮ 
No, I did not have enough time to talk to my nurse and/or doctor. 
⁮ 
No, I did not talk to my nurse and/or doctor at all. 
17. Does the IV infusion impact the amount of time you have to talk to your nurse and/or doctor 
about your illness and other concerns? 
 
Yes 
No 
 
18. Thinking about the IV infusion, if given the option, which would you prefer (both options 
treat your disease in the same way)? Please check one. 
 ⁮ 
Prefer intravenous (IV) injection given through a port or a thin plastic tube and a 
needle into your vein (IV drip). This treatment option usually takes 30 minutes to 2 
hours.  
⁮ 
Prefer subcutaneous (SC) injection, applied with a device on the thigh or abdomen 
(or belly). This treatment option usually takes 10 – 30 minutes. 
⁮ 
No preference for treatment option. 
19. Thinking about the IV infusion, would you recommend the way you received the treatment 
(IV infusion) to another patient? 
Definitely yes 
Probably yes 
I don’t know 
Probably not 
Definitely not 

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10.6.3.2. Treatment Administration Satisfaction Questionnaire – Subcutaneous 
Instructions: Please complete the following questions based on your ravulizumab treatment. 
Your ravulizumab was given through 2 devices placed onto your thigh or abdomen (or belly) 
area, called a subcutaneous or SC infusion. Please answer the questions based on your most 
recent ravulizumab SC infusion. 
1. Thinking about the SC infusion, how satisfied or dissatisfied are you with the SC infusion? 
Very satisfied 
Satisfied 
Neither satisfied 
nor dissatisfied 
Dissatisfied 
Very dissatisfied 
2. Thinking about the SC infusion, how do you rate the pain, swelling, or redness you 
experienced at the site of the drug infusion? 
None 
Mild 
Moderate 
Severe 
Very Severe 
3. Thinking about the SC infusion, how do you rate the pain you experience with the SC 
infusion process? 
None 
Mild 
Moderate 
Severe 
Very Severe 
4. Thinking about the SC infusion, are the side effects of the SC infusion as you expected? 
Much better 
than expected 
Somewhat better 
than expected 
Met my 
expectations 
Somewhat worse 
than my 
expectations 
Much worse 
than my 
expectations 
 
 
 
 
 
5. Before you receive the SC infusion do you feel anxious about having the infusion? 
Not at all 
A little bit 
Somewhat 
Quite a bit 
Very much 
6. When you receive the SC infusion do you worry that your condition would get worse? 
Not at all 
A little bit 
Somewhat 
Quite a bit 
Very much 
7. When you receive the SC infusion do you feel anxious thinking about your disease? 
Not at all 
A little bit 
Somewhat 
Quite a bit 
Very much 
8. Thinking about SC infusion, how confident are you that the SC infusion is treating your 
disease? 
Not at all 
A little bit 
Somewhat 
Quite a bit 
Very much 
 
 
 
 
 
9. When you receive the SC treatment do you feel restricted by the SC infusion? 

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Not at all 
A little bit 
Somewhat 
Quite a bit 
Very much 
10. Thinking about the SC infusion, how convenient is it for you to get your SC infusion? 
Very convenient 
Convenient 
Neither 
convenient nor 
inconvenient 
Inconvenient 
Very 
inconvenient 
11. Thinking about the SC infusion, how do you feel about the amount of time it takes to get 
your SC infusion? 
 
Too short 
Just right 
Too long 
 
12. Thinking about the SC infusion, do you feel that the length of time to get your SC infusion 
was as you expected? 
Much shorter 
than expected 
Somewhat 
shorter than 
expected 
As expected 
Somewhat 
longer than 
expected 
Much longer 
than expected 
13. Thinking about the SC infusion, how bothered are you by the amount of time it takes to get 
the infusion? 
Not at all 
bothered 
A little bothered 
Moderately 
bothered 
Quite bothered 
Very bothered 
14. How much does the SC infusion: 
a. Interfere with your usual or daily activities? 
Not at all 
A little bit 
Somewhat 
Quite a bit 
Very much 
b. Limit your daily activities? 
Never 
Rarely 
Sometimes 
Most of the time 
Always 
15. Because of the length of time to apply the SC infusion do you feel that you have lost or 
gained time for other things?  
Lost a lot of 
time 
Lost some time 
Neither lost nor 
gained time 
Gained some 
time 
Gained a lot of 
time 
16. When you receive the SC infusion treatment, are you able to talk to your nurse and/or doctor 
as much as you would like about your illness? (please only check ONE answer) 
⁮ 
Yes, I had more than enough time to talk to my nurse and/or doctor. 
⁮ 
Yes, but I would have liked more time to talk to my nurse and/or doctor. 

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⁮ 
It does not matter to me if I have time to talk to my nurse and/or doctor during 
my treatment. 
⁮ 
No, I did not have enough time to talk to my nurse and/or doctor. 
⁮ 
No, I did not talk to my nurse and/or doctor at all. 
17. Does the SC infusion impact the amount of time you have to talk to your nurse and/or doctor 
about your illness and other concerns? 
 
Yes 
No 
 
18. Thinking about the SC treatment, if given the option, which would you prefer (both options 
treat your disease in the same way)? Please check one. 
 ⁮ 
Prefer intravenous (IV) injection given through a port or a thin plastic tube and a 
needle into your vein (IV drip). This treatment option usually takes 35 minutes to 2 
hours.  
⁮ 
Prefer subcutaneous (SC) injection, applied with a device on the thigh or abdomen 
(or belly). This treatment option is usually takes 10 to 20 minutes. 
⁮ 
No preference for treatment option. 
19. Thinking about the SC treatment, would you recommend the way you received the treatment 
(SC infusion) to another patient? 
Definitely yes 
Probably yes 
I don’t know 
Probably not 
Definitely not 
 

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10.6.4. 
Patient Preference Questionnaire 
The PPQ will be administered and recorded on paper. 
 

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10.7. 
Appendix 7: Management of Potential Infusion-associated Adverse 
Events During Study Drug Administration  
Intravenous and SC infusion-associated reactions are a potential risk with the use of monoclonal 
antibodies; these reactions can be non-immune 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.  
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 v4.03 or higher. 
If anaphylaxis occurs according to the criteria listed below, then administration of subcutaneous 
epinephrine (1/1000, 0.3 mL to 0.5 mL, or equivalent) should be considered. In the case of 
bronchospasm, treatment with an inhaled beta agonist also should be considered. Patients 
administered an antihistamine for the treatment or prevention of an infusion reaction should be 
given appropriate warnings about drowsiness and impairment of driving ability before being 
discharged from the center.  
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 mm Hg or greater than 30% decrease from that patient’s baseline 
Source: (Sampson, 2006)  
 

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10.8. 
Appendix 8: COVID-19 Risk Assessment 
PNH can cause irreversible morbidity and even mortality, if untreated. As such, and due to the 
limited number of available treatment options, the benefit a participant may receive from joining 
an investigational study with a therapeutic treatment is potentially significant. In this particular 
case, the fact that the study is open-label and every participant is treated with the study 
intervention also contributes to the potential benefit a participant may derive from partaking in 
the study. Given that treatment for PNH does involve immunosuppression, there is a theoretical 
concern that the risk for infection may be higher than in participants not receiving 
immunosuppressants. However, there is no specific data to further inform this risk. Apart from 
the predictable risk of infection with Neisseria meningitidis, which is an important identified risk 
and directly related to the mechanism of action of ravulizumab (terminal C5 inhibitor [targeted 
immunosuppressant]), the mechanism that might lead to other serious infections, including viral 
infections in participants treated with ravulizumab, remains unclear. The site Investigator will 
therefore balance the risk/benefit considerations in the study participant, taking these factors into 
account.  
The potential risks identified and mitigation measures put in place in light of the COVID-19 
pandemic are provided in Table 14. 
Table 14: 
Potential Risks and Mitigation Measures due to COVID-19 
Risks category 
Summary of Data/ 
Rationale for Risk 
Mitigation Strategy 
Potential risks 
Healthcare institution 
availability for 
non-COVID-19 
related activities  
COVID-19 pandemic may impact the workload of 
healthcare institutions globally and may reduce staff 
availability to perform non-urgent activities and 
non-COVID-19 related activities. 
 
During the time that the 
COVID-19 pandemic is active, 
Alexion will not open study 
sites or enroll new participants 
at sites unless the sites have the 
resourcing and capabilities to 
implement the study per 
protocol. 
Data quality and 
integrity 
Lack of availability of site personnel to perform 
study assessments and capture study specific data in 
a timely manner and to maintain adequate quality 
standards. 
Lack of availability of site personnel to ensure 
adequate and continuous chain of custody, storage 
conditions, and monitoring for investigational 
product and biological samples. 
Inability of study monitors and quality personnel to 
conduct in-person visits to exercise adequate 
oversight of study execution at investigational sites. 
Missing data (COVID-19 pandemic may impact 
study visit schedules, and increase missed visits 
and/or participant study discontinuations 
inadvertently resulting in missing data [eg, for 
protocol-specified procedures]). 
During the time that the 
COVID-19 pandemic is active, 
Alexion will only open study 
sites that report enough 
personnel capacity to 
sufficiently conduct clinical 
study-related activities.  
During this timeframe, site 
capacity will be reviewed by the 
site Investigator and the study 
Medical Monitor prior to 
Screening. Each site is also 
evaluated for the capacity to 
perform remote monitoring 
visits and remote source data 
verification. 

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Risks category 
Summary of Data/ 
Rationale for Risk 
Mitigation Strategy 
During the time that the 
COVID-19 pandemic is active, 
it will be important to capture 
specific information in the 
eCRF that explains the reason 
the data is missing (eg, missed 
study visits or participant study 
discontinuations due to 
COVID-19). 
Abbreviation: COVID-19 = coronavirus disease 2019; eCRF = electronic case report form. 

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10.9. 
Appendix 9: Abbreviations 
 
Abbreviation 
Definition 
ADA 
antidrug antibody 
ADE 
adverse device effect 
ADL 
activities of daily living 
AE 
adverse event 
aHUS 
atypical hemolytic uremic syndrome 
BP 
blood pressure 
C5 
complement component 5 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
CIOMS 
Council for International Organizations of Medical Sciences 
CTCAE 
Common Terminology Criteria for Adverse Events 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EDC 
electronic data capture 
e-diary 
electronic diary 
EORTC 
European Organisation for Research and Treatment of Cancer 
ET 
early termination 
FACIT-Fatigue 
Functional Assessment of Chronic Illness Therapy-Fatigue scale 
FAS 
Full Analysis Set 
GCP 
good clinical practice 
GDS 
Global Drug Safety 
HIV 
human immunodeficiency virus 
HRQoL 
health-related quality of life 
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 
IFU 
instructions for use 
IRB 
Institutional Review Board 
IV 
intravenous(ly) 
LDH 
lactate dehydrogenase 
LLT 
lowest level term 
mAb 
monoclonal antibody 
MAVE 
major adverse vascular event 
NIB 
noninferiority boundary 
NO 
nitric oxide 
OBDS 
on-body delivery system 
PD 
pharmacodynamic(s) 
PEF 
peak expiratory flow 
PK 
pharmacokinetic(s) 
PNH 
paroxysmal nocturnal hemoglobinuria 
PPQ-SC 
Patient Preference Questionnaire - Subcutaneous 

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Abbreviation 
Definition 
qw 
every week 
q8w 
once every 8 weeks 
QoL 
quality of life 
QLQ-C30 
Quality of Life Questionnaire - Core 30 scale 
RBC 
red blood cell 
SADE 
serious adverse device effect 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SC 
subcutaneous(ly) 
SoA 
schedule of activities 
SOC 
System Organ Class 
SUSAR 
suspected unexpected serious adverse reactions 
TASQ 
Treatment Administration Satisfaction Questionnaire 
TEAE 
treatment-emergent adverse event 
TSA 
telescopic screw assembly 
USADE 
unanticipated serious adverse device effect 
ULN 
upper limit of normal 
 

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10.10. 
PROTOCOL AMENDMENT HISTORY 
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the Table of Contents (TOC). 
DOCUMENT HISTORY 
Document 
Type of 
Amendment 
(Global or 
Country-specific) 
Date 
Summary of Key Changes in the Amendment 
Amendment 4 
Global 
19 Nov 2019 
• To increase the Extension Period to up to 
3.5 years. All patients will enter an Extension 
Period and receive ravulizumab 
subcutaneous (SC) via the on-body delivery 
system (OBDS) for up to 3.5 years, or until 
the product is registered or approved (in 
accordance with country-specific 
regulations), whichever occurs first. 
• To update the definition for the 
pharmacokinetic (PK) analysis set based on 
an assessment of compliance with the dosing 
and PK sampling windows specified in the 
Schedule of Activities (SoA; Section 1.3) and 
on PK simulations conducted to confirm 
permitted dosing and sampling windows. 
Amendment 3 
Global 
17 May 2019 
• To reduce the patient burden by eliminating 
three in-clinic study visits for patients in the 
ravulizumab SC treatment group during the 
Randomized Treatment Period and replacing 
with self-administration of ravulizumab SC 
by the patient in the home setting 
• To provide additional information required 
by ISO guidelines for investigational devices 
Amendment 2 
Global 
20 Sep 2018 
• Modification of the criteria of the assessment 
of causality of adverse events by the 
Investigator 
• To capture medication errors occurring with 
the use of ravulizumab OBDS as adverse 
device effects (ADEs) 
• Administrative changes including 
introduction of the possibility of recording 
quality of life assessments data optionally on 
paper 
Amendment 1 
France 
01 Aug 2018 
To remove free hemoglobin testing, add 
restriction on ova donation for female subjects, 
and address minor inconsistencies. 
Original 
protocol 
Not applicable 
25 Jun 2018 
Not applicable 
 

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11. 
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