A Phase 3 Open-label, Randomized, Controlled Study to Evaluate the Efficacy and Safety of Intravenously Administered Ravulizumab Compared With Best Supportive Care in Patients With COVID-19 Severe Pneumonia, Acute Lung Injury, or Acute Respiratory Distress Syndrome
Phase: PHASE3
Conditions: COVID-19 Severe Pneumonia, Acute Lung Injury, Acute Respiratory Distress Syndrome, Pneumonia, Viral
Sponsor: Alexion Pharmaceuticals, Inc.

A Phase 3 Open-label, Randomized, Controlled Study to 
Evaluate the Efficacy and Safety of Intravenously 
Administered Ravulizumab Compared with Best Supportive 
Care in Patients with COVID-19 Severe Pneumonia, Acute 
Lung Injury, or Acute Respiratory Distress Syndrome 
 
Unique Protocol ID: 
ALXN1210-COV-305 
NCT Number: 
NCT04369469 
EudraCT Number:  
2020-001497-30 
Date of Protocol:  
09 June 2020 
 

Protocol Amendment 3 (Global) 
 
 
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Alexion Confidential 
TITLE PAGE 
Protocol Title: A Phase 3 Open-label, Randomized, Controlled Study to Evaluate the Efficacy 
and Safety of Intravenously Administered Ravulizumab Compared with Best Supportive Care in 
Patients with COVID-19 Severe Pneumonia, Acute Lung Injury, or Acute Respiratory Distress 
Syndrome 
Protocol Number: ALXN1210-COV-305 
Compound: Ravulizumab (ALXN1210) 
Study Phase: Phase 3 
Short Title: Efficacy and Safety Study of IV Ravulizumab in Patients with COVID-19 Severe 
Pneumonia 
Sponsor Name: Alexion Pharmaceuticals, Inc. 
Legal Registered Address: 
Alexion Pharmaceuticals, Inc. 
121 Seaport Boulevard 
Boston, MA 02210 
USA 
Regulatory Agency Identifier Number(s) 
IND: 149,271 
EudraCT: 2020-001497-30 
Original Protocol: 09 Apr 2020 
Protocol Amendment 1 (Global): 13 Apr 2020 
Protocol Amendment 2 (Global): 17 Apr 2020 
Protocol Amendment 2.1 (Germany): 08 May 2020 
Protocol Amendment 2.2 (France): 08 May 2020 
Protocol Amendment 2.3 (France): 13 May 2020 
Protocol Amendment 3 (Global): 09 Jun 2020 

PPD
PPD
PPD
PPD

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INVESTIGATOR’S AGREEMENT 
I have read the study protocol and agree to conduct the study in accordance with this protocol, all 
applicable government regulations, the principles of the International Council for Harmonisation 
of Technical Requirements for Pharmaceuticals for Human Use (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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TABLE OF CONTENTS 
TITLE PAGE ...................................................................................................................................1 
SPONSOR SIGNATORY ...............................................................................................................2 
INVESTIGATOR’S AGREEMENT ...............................................................................................3 
TABLE OF CONTENTS .................................................................................................................4 
LIST OF TABLES ...........................................................................................................................9 
LIST OF FIGURES .......................................................................................................................10 
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE ..........................................11 
1. 
PROTOCOL SUMMARY ..........................................................................................18 
1.1. 
Synopsis ......................................................................................................................18 
1.2. 
Schema ........................................................................................................................21 
1.3. 
Schedule of Activities .................................................................................................22 
2. 
INTRODUCTION ......................................................................................................26 
2.1. 
Study Rationale ...........................................................................................................26 
2.2. 
Background .................................................................................................................26 
2.2.1. 
Nonclinical Evidence Supporting the Role of Complement in COVID-19 ...............26 
2.2.2. 
Clinical Hypothesis Supporting Utility of Ravulizumab in COVID-19 .....................28 
2.3. 
Benefit/Risk Assessment ............................................................................................29 
2.3.1. 
Risk Assessment .........................................................................................................29 
2.3.2. 
Benefit Assessment .....................................................................................................30 
2.3.3. 
Overall Benefit: Risk Conclusion ...............................................................................30 
3. 
OBJECTIVES AND ENDPOINTS ............................................................................32 
4. 
STUDY DESIGN .......................................................................................................33 
4.1. 
Overall Design ............................................................................................................33 
4.2. 
Scientific Rationale for Study Design ........................................................................33 
4.3. 
Justification for Dose ..................................................................................................35 
4.4. 
End of Primary Evaluation Definition ........................................................................38 
4.5. 
End of Study Definition ..............................................................................................38 
5. 
STUDY POPULATION .............................................................................................39 
5.1. 
Inclusion Criteria ........................................................................................................39 
5.2. 
Exclusion Criteria .......................................................................................................39 
5.3. 
Lifestyle Considerations .............................................................................................40 

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5.4. 
Screen Failures ............................................................................................................40 
6. 
STUDY INTERVENTION ........................................................................................41 
6.1. 
Study Intervention(s) Administered ...........................................................................41 
6.1.1. 
Packaging and Labeling ..............................................................................................41 
6.2. 
Preparation/Handling/Storage/Accountability ............................................................42 
6.3. 
Measures to Minimize Bias: Randomization and Blinding ........................................43 
6.4. 
Study Intervention Compliance ..................................................................................43 
6.5. 
Concomitant Therapy .................................................................................................43 
6.5.1. 
Disallowed Medicine and Therapy .............................................................................43 
6.6. 
Dose Modification ......................................................................................................43 
6.7. 
Intervention After the End of the Study .....................................................................43 
7. 
DISCONTINUATION OF STUDY INTERVENTION AND PATIENT 
DISCONTINUATION/WITHDRAWAL ..................................................................44 
7.1. 
Discontinuation of Study Intervention ........................................................................44 
7.2. 
Patient Discontinuation/Withdrawal from the Study ..................................................44 
7.3. 
Lost to Follow-up .......................................................................................................44 
8. 
STUDY ASSESSMENTS AND PROCEDURES ......................................................46 
8.1. 
Eligibility and Administrative Assessments ...............................................................46 
8.1.1. 
Informed Consent .......................................................................................................46 
8.1.2. 
Inclusion and Exclusion Criteria ................................................................................46 
8.1.3. 
Medical History ..........................................................................................................46 
8.1.4. 
Demographics .............................................................................................................46 
8.1.5. 
Vaccination or Antibiotic Prophylaxis .......................................................................47 
8.2. 
Screening Assessments ...............................................................................................47 
8.2.1. 
SARS-COV-2 Testing ................................................................................................47 
8.2.2. 
Chest Computed Tomography or X-ray .....................................................................47 
8.2.3. 
Pregnancy Testing ......................................................................................................47 
8.3. 
Efficacy Assessments .................................................................................................47 
8.3.1. 
Primary Efficacy Assessments ...................................................................................47 
8.3.2. 
Secondary Efficacy Assessments ...............................................................................47 
8.3.2.1. 
Sequential Organ Failure Assessment Score ..............................................................48 
8.4. 
Safety Assessments .....................................................................................................48 
8.4.1. 
Physical Examinations ................................................................................................48 

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8.4.2. 
Vital Sign Measurements ............................................................................................49 
8.4.3. 
Electrocardiograms .....................................................................................................49 
8.4.4. 
Clinical Safety Laboratory Assessments ....................................................................49 
8.4.5. 
Immunogenicity ..........................................................................................................50 
8.4.6. 
Glasgow Coma Scale ..................................................................................................50 
8.4.7. 
Pregnancy ...................................................................................................................50 
8.4.8. 
Patient Safety Information Card .................................................................................51 
8.4.9. 
Vaccine and Antibiotic Prophylaxis ...........................................................................51 
8.4.10. 
Hospital Discharge ......................................................................................................51 
8.4.11. 
Follow-up Monitoring ................................................................................................52 
8.4.12. 
Early Termination .......................................................................................................52 
8.5. 
Exploratory Assessments ............................................................................................52 
8.5.1. 
Clinical Improvement at Day 29 .................................................................................52 
8.5.2. 
12-item Short Form at Days 29, 60, and 90 ................................................................52 
8.5.3. 
EuroQol-5 Dimension-5 Level at Days 29, 60, and 90 ..............................................53 
8.6. 
Adverse Events and Serious Adverse Events .............................................................53 
8.6.1. 
Time Period and Frequency for Collecting AE and SAE Information .......................54 
8.6.2. 
Method of Detecting AEs and SAEs ..........................................................................54 
8.6.3. 
Follow-up of AEs and SAEs .......................................................................................54 
8.6.4. 
Regulatory Reporting Requirements for SAEs ...........................................................54 
8.6.5. 
Adverse Events of Special Interest .............................................................................55 
8.7. 
Treatment of Overdose ...............................................................................................55 
8.8. 
Pharmacokinetics ........................................................................................................55 
8.9. 
Pharmacodynamics .....................................................................................................55 
8.10. 
Genetics ......................................................................................................................55 
8.11. 
Biomarkers ..................................................................................................................56 
8.12. 
Immunogenicity ..........................................................................................................56 
8.13. 
Health Economics Data or Medical Resource Utilization ..........................................56 
9. 
STATISTICAL CONSIDERATIONS .......................................................................57 
9.1. 
Statistical Hypotheses .................................................................................................57 
9.2. 
Sample Size Determination ........................................................................................57 
9.3. 
Populations for Analyses ............................................................................................58 
9.4. 
Statistical Analyses .....................................................................................................58 

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9.4.1. 
Efficacy Analyses .......................................................................................................59 
9.4.1.1. 
Analyses of Primary Efficacy Endpoint .....................................................................59 
9.4.1.2. 
Analyses of Secondary Efficacy Endpoints ................................................................59 
9.4.1.3. 
Multiplicity Adjustment ..............................................................................................60 
9.4.2. 
Safety Analyses ..........................................................................................................60 
9.4.3. 
Pharmacokinetic and Pharmacodynamic Analyses ....................................................61 
9.4.4. 
Biomarker Analyses ....................................................................................................61 
9.4.5. 
Immunogenicity Analyses ..........................................................................................61 
9.4.6. 
Analyses of Exploratory Endpoints ............................................................................61 
9.5. 
Interim Analyses .........................................................................................................61 
9.5.1. 
Data Monitoring Committee .......................................................................................62 
10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS ..................................................................................................63 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations ....................63 
10.1.1. 
Regulatory and Ethical Considerations ......................................................................63 
10.1.2. 
Financial Disclosure ...................................................................................................63 
10.1.3. 
Informed Consent Process ..........................................................................................64 
10.1.4. 
Data Protection ...........................................................................................................65 
10.1.5. 
Dissemination of Clinical Study Data ........................................................................65 
10.1.6. 
Data Quality Assurance ..............................................................................................65 
10.1.7. 
Source Documents ......................................................................................................66 
10.1.8. 
Study and Site Start and Closure ................................................................................66 
10.1.9. 
Publication Policy .......................................................................................................67 
10.2. 
Appendix 2: Clinical Laboratory Tests .......................................................................68 
10.3. 
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting ........................................................................70 
10.3.1. 
Definition of AE .........................................................................................................70 
10.3.2. 
Definition of SAE .......................................................................................................71 
10.3.3. 
Recording and Follow-Up of AE and/or SAE ............................................................71 
10.3.4. 
Reporting of SAEs ......................................................................................................72 
10.4. 
Appendix 4: Contraceptive Guidance and Collection of Pregnancy 
Information .................................................................................................................74 
10.4.1. 
Definitions ..................................................................................................................74 

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10.4.2. 
Contraception Guidance .............................................................................................74 
10.4.2.1. 
Guidance for Female Patients .....................................................................................74 
10.4.2.2. 
Guidance for Male Patients ........................................................................................76 
10.4.3. 
Collection of Pregnancy Information .........................................................................76 
10.4.3.1. 
Male Patients With Partners Who Become Pregnant .................................................77 
10.4.3.2. 
Female Patients Who Become Pregnant .....................................................................77 
10.5. 
Appendix 5: Biomarkers .............................................................................................78 
10.6. 
Appendix 6: Management of Potential Drug Infusion Reactions ...............................79 
10.7. 
Appendix 7: Protocol Amendment History ................................................................81 
10.8. 
Appendix 8: Abbreviations .........................................................................................82 
11. 
REFERENCES ...........................................................................................................84 
 

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LIST OF TABLES 
Table 1: 
Schedule of Activities .................................................................................................22 
Table 2: 
Potential Risks and Mitigation Strategies ...................................................................29 
Table 3: 
Objectives and Endpoints ...........................................................................................32 
Table 4: 
Study Design Rationale for Study ALXN1210-COV-305 .........................................33 
Table 5: 
Ravulizumab Dosage Regimen for COVID-19 Severe Pneumonia, Acute 
Lung Injury, or Acute Respiratory Distress Syndrome ..............................................41 
Table 6: 
Ravulizumab Dosage Form and Strength ...................................................................42 
Table 7: 
Sequential Organ Failure Assessment Scoring ...........................................................48 
Table 8: 
Glasgow Coma Scale ..................................................................................................50 
Table 9: 
Protocol-required Laboratory Assessments ................................................................68 
Table 10: Clinical Criteria for Diagnosing Anaphylaxis ............................................................80 

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LIST OF FIGURES 
Figure 1: 
Study ALXN1210-COV-305 Schematic ....................................................................21 
Figure 2: 
Eculizumab Clearance Changes Over Time in Pediatric Patients With 
Thrombotic Microangiopathy Following Hematopoietic Stem-cell 
Transplant ...................................................................................................................35 
Figure 3: 
Simulations Comparing “With” and “Without” the Faster Clearance 
Assumption of Ravulizumab in Adult Patients With Thrombotic 
Microangiopathy Following Hematopoietic Stem-cell Transplant ............................37 

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PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE 
Amendment 3 (Global) 
Overall Rationale for the Amendment: 
This global amendment was initiated to update the inclusion and exclusion criteria, study 
endpoints and objectives, and the schedule of activities. Patient-reported outcomes (SF-12 and 
EQ-5D-5L) were added and changes were also implemented to align content in Section 9 
(Statistical Considerations) with version 1and version 2 of the statistical analysis plan. 
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. 
Substantive changes are documented in the table below.

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Section # and Title 
Description of Change 
Brief Rationale 
1.1 – Synopsis,  
3 – Objectives and Endpoints 
8.3.2 – Secondary Efficacy 
Assessments 
 
• 
Reordered secondary endpoints 
The ordering of testing for the secondary 
endpoints has been changed to align with 
the order of interest from a clinical and 
patient perspective. This reordering 
reduces the risk of a type II error if a 
more clinically important endpoint is set 
below another endpoint in the hierarchy 
for which the null hypothesis is not 
rejected. 
 
The secondary endpoint of survival at 
Day 60 and Day 90 has been removed 
from the testing procedure when all 
patients have completed the Primary 
Evaluation Period, which is Day 29, as 
sufficient information for this endpoint 
may not be available. 
1.1 – Synopsis,  
3 – Objectives and Endpoints 
8.3.2 – Secondary Efficacy 
Assessments 
9.4 – Statistical Analyses 
• 
Revised biomarker endpoint 
 
 
• 
Added 3 exploratory objectives 
to evaluate: the effect of 
ravulizumab + BSC or 
BSC alone on clinical 
improvement, and health-related 
quality of life (SF-12 PCS and 
MCS, and EQ-5D-5L scores) 
 
 
• 
Redefined baseline 
• 
To include an evaluation of 
prothrombic activity 
 
• 
Clinical improvement as measured 
via a 6-point ordinal scale is 
included to evaluate the severity of 
the underlying disease over time; the 
SF-12 and EQ-5D-5L are 
patient-reported outcome 
questionnaires that are included to 
assess health-related quality of life  
 
• 
To align with revised definition in 
version 1 of the SAP 
1.1 – Synopsis (Intervention 
Groups and Duration) 
6.1 – Study Interventions 
Administered 
Added dosing units to the header 
columns of Table s1 and Table 5 
Correction of a typographical error 
1.2 – Schema 
• 
Revised schema to add all study 
timepoints for both treatment 
groups 
• 
Revised footnotes 
For clarity and parallel construction 
1.3 – Schedule of Activities 
8.13 – Health Economics Data or 
Medical Resource Utilization 
Added SF-12 and EQ-5D-5L 
questionnaires 
For internal document consistency as 
questionnaires were added as exploratory 
endpoints 
1.3 – Schedule of Activities 
Added timepoints at Screening for 
“Mechanical ventilation status” and 
“Adverse event review and 
evaluation” 
To ensure AEs are collected after signing 
of the informed consent form 
 
To ensure that mechanical ventilation 
status is assessed during screening 
1.3 – Schedule of Activities 
Added timepoint at Day 60 and 
Day 90 for assessment of concomitant 
medications and nonpharmacologic 
treatments and therapies 
For clarity 

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1.3 – Schedule of Activities 
Footnote #4: Added sentence that 
patients who are discontinued from 
the study will be contacted by 
telephone on Day 29 to assess their 
health status  
To determine health status (including 
survival) at Day 29 
1.3 – Schedule of Activities 
• 
Updated SoA to indicate that 
FiO2, SpO2, PaO2 will be 
assessed daily 
 
• 
Footnote #9: Added sentence that 
SpO2, PaO2 (if available), and 
FiO2 should be measured 
predose for patients randomized 
to ravulizumab + BSC 
• 
For clarity  
 
 
 
• 
To establish baseline values for these 
parameters 
1.3 – Schedule of Activities 
Footnote #14: Revised to ensure that 
immunogenicity sampling is not 
collected postdose 
For clarity 
Footnote #14 and #15: Expanded the 
predose (within 4 hours of the start of 
infusion) and postdose (within 
4 hours after the end of infusion) 
sampling windows 
Given the half-life of the molecule, these 
expanded windows allow the 
investigational site staff to collect 
protocol-specified laboratory samples 
within a reasonable timeframe. 
1.3 – Schedule of Activities 
Footnote #16: Revised to indicate that 
biomarker samples will be collected 
for all patients; however, for patients 
randomized to the 
ravulizumab + BSC treatment group 
biomarker samples will be collected 
any time before the start of infusion 
For clarity 
1.3 – Schedule of Activities 
Footnote #19: Added statement to 
indicate that medical history should 
include the date of first onset of signs 
and symptoms of SARS-CoV-2 
infection. 
For clarity 
5 – Study Population 
Added a clarifying statement that the 
3-day Screening Period is allowed to 
evaluate patients for eligibility. If the 
Screening and Day 1 Visits are 
combined, the patient has to meet all 
inclusion/no exclusion criteria prior to 
randomization. 
To clarify that patients may be evaluated 
for eligibility at any time during the 
3-day Screening Period. 
5.1 – Inclusion Criteria 
8.2.1 - SARS-COV-2 Testing 
Revised criterion #2 – Confirmed 
diagnosis of SARS-CoV-2 infection 
can be via PCR and/or antibody test 
For clarity 
5.1 – Inclusion Criteria 
Revised criterion #4 – Target 
population is required to be in 
respiratory distress with either 
invasive or noninvasive mechanical 
ventilation (also defined) 
For clarity and to ensure investigational 
sites are supplied with a clear definition 
of invasive and noninvasive mechanical 
ventilation 

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5.2 – Exclusion Criteria,  
6.5.1 – Disallowed Medicine and 
Therapy 
Removed rituximab and mitoxantrone 
as prohibited medications (criteria 5b 
and 5c) 
These medications have been historically 
disallowed in the Sponsor’s neurology 
studies due to a potential drug-drug 
interaction that could lower rituximab 
levels, and due to a potential 
confounding effect for efficacy with 
mitoxantrone. However, there is a very 
low likelihood that patients with severe 
COVID-19 will be receiving these 
therapies in an acute setting, and the 
potential interactions are less important 
in this acute setting. Therefore, the 
Sponsor has elected to remove these 
medications from the list of excluded 
concomitant medications. 
5.2 – Exclusion Criteria 
6.5.1 – Disallowed Medicine and 
Therapy 
Revised washout period for IVIg 
(criterion 5d) 
For clarity 
5.2 – Exclusion Criteria 
Revised criterion to indicate that 1) 
patients who receive medications as 
part of BSC at the hospital due to 
emergency authorization under a 
compassionate use or expanded 
access program and 2) patients who 
receive antivirals (such as remdesivir) 
as part of a clinical study are eligible 
for participation in the study (criterion 
6) 
To allow for enrollment of patients who 
may receive antivirals as part of a clinical 
study and receive treatment with 
investigational therapies under a 
compassionate use (emergency approval) 
or expanded access program 
5.2 – Exclusion Criteria 
Removed verbiage indicating female 
patients will be evaluated for 
breastfeeding status or pregnancy at 
Day 1 (criterion 7). 
Correction of a typographical error 
5.2 – Exclusion Criteria 
Added criterion #9 – Allows 
enrollment of patients not currently 
vaccinated against Neisseria 
meningitidis but who will receive 
prophylactic antibiotic treatment for 
at least 8 months after last infusion of 
study drug or until at least 2 weeks 
after they receive vaccination against 
N. meningitidis 
Per Health Authority request 
5.4 – Screen Failures  
Revised definition 
For clarity 
6.2 – Preparation/Handling/ 
Storage/Accountability 
Revised instructions to consult the 
pharmacy manuals 
To ensure that investigational sites 
consult the study Pharmacy Manual for 
additional details on preparation, 
handling, storage, and/or accountability 
6.4 – Study Intervention 
Compliance 
Removed instructions to consult the 
pharmacy manual 
Patient compliance instructions are not 
expected to be included in the study 
Pharmacy Manual 

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6.5 – Concomitant Therapy 
• 
Added statement that antivirals 
may be administered as a part of 
BSC 
• 
Added vaccines to the list of 
examples of concomitant 
medications that are anticipated 
to be recorded in the CRF/eCRF 
• 
Per Health Authority request  
 
 
• 
For clarity 
8.3.2.1 – Sequential Organ 
Failure Assessment Score 
• 
Added statement that the 
assessment of PaO2 is optional 
and that the SpO2 will serve as 
the surrogate for respiratory 
status 
• 
SpO2/FiO2 and the associated 
cutoff values were added to 
Table 7 
• 
Added footnote to Table 7 
To allow for an alternate assessment of 
the respiratory system to help inform 
SOFA scoring and for clarity 
8.4.1 – Physical Examinations 
Revised to indicate that body weight 
has to be measured, but should be 
estimated using best judgement if it 
cannot be measured. 
For clarity 
8.4.4 – Clinical Safety 
Laboratory Assessments 
Revised to indicate that 
non-protocol-specified laboratory 
results that are considered clinically 
significant are not required to be 
entered in the CRF/eCRF; however, 
the Investigator is still required to 
report (and record in the AE 
CRF/eCRF) the laboratory 
abnormality if deemed clinically 
significant 
The study is being implemented in an 
acute inpatient setting and 
non-protocol-specified laboratory results 
may not be readily accessible to sponsor 
staff for verification. 
8.4.8 – Patient Safety 
Information Card 
8.4.9 – Vaccine and Antibiotic 
Prophylaxis 
Updated to indicate that the guidance 
is specific to patients randomized to 
ravulizumab + BSC  
For clarity 
8.4.12. Early Termination 
Added section 
To ensure that patients who are 
discontinued from the study before 
Day 29 present for the Early Termination 
Visit. The patient will also be contacted 
via telephone on Day 29 to assess health 
status.  
8.5.1 – Clinical Improvement at 
Day 29 
Added section 
To better characterize response to 
treatment 
8.5.2 – 12-item Short Form at 
Days 29, 60, and 90 
Added section 
To assess impact on health economics 
8.5.3 – EuroQol-5 Dimension-
5 Level at Days 29, 60, and 90 
Added section 
To assess impact on health economics 
8.8 – Pharmacokinetics 
8.12 – Immunogenicity 
10.2 – Appendix 2 (Clinical 
Laboratory Tests) 
Table 9 – Revised to indicate that PK 
and immunogenicity samples will 
only be collected from patients 
randomized to ravulizumab + BSC 
To align with the SoA and for clarity 
8.9 – Pharmacodynamics 
Revised to indicate that PD samples 
will be collected from all patients 
For clarity  

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8.11 – Biomarkers 
10.2 – Appendix 2 (Clinical 
Laboratory Tests) 
• 
Revised to indicate that 
biomarker samples will be 
collected from all patients 
• 
Revised list of inflammatory and 
complement pathway 
biomarkers, and added a 
coagulation biomarker 
• 
Added that biomarkers may also 
be analyzed by specialty 
laboratories 
For clarity and to ensure the most 
appropriate samples are collected given 
the target population and potential 
underlying diseases 
9.1 – Statistical Hypotheses 
Reordered list of alternate hypotheses. 
To align with the SAP, version 1 
9.2 – Sample Size Determination 
9.5 – Interim Analyses 
Revised to indicate that futility was 
nonbinding 
To align with the SAP, version 1 
9.4 – Statistical Analyses 
9.5 – Interim Analyses 
 
Revised to indicate that Primary 
Evaluation Period and interim 
analyses will include “available” 
PK/PD/immunogenicity data 
Due to the COVID-19 pandemic, there 
have been processing delays in collected 
laboratory samples. Therefore results 
may not be available in order to perform 
prespecified statistical analyses. 
9.4.1.1 – Analyses of Primary 
Efficacy Endpoint 
• 
Added process for imputation of 
missing survival data and specific 
sensitivity analyses to be 
conducted for the primary 
efficacy endpoint (survival 
[based on all-cause mortality] at 
Day 29) 
• 
Revised the test used for 
sensitivity analysis of the primary 
endpoint 
To align with the SAP, version 2 
9.4.1.2 – Analyses of Primary 
Efficacy Endpoint 
• 
Revised analyses for the 
evaluation of selected secondary 
efficacy endpoints (ie, number of 
days free of mechanical 
ventilation at Day 29, duration of 
ICU stay at Day 29, and SOFA 
score). Analyses to be conducted 
for these secondary efficacy 
endpoints will include a multiple 
imputation approach using 
missing at random data. 
Sensitivity analyses will include 
the following scenarios: best, 
worst, and all available. 
Circumstances under which the 
analyses will be conducted have 
also been clarified. 
• 
Removed statement that duration 
of ICU stay will be summarized 
for nonsurvivors 
• 
Revised study day covariate to 
specify Days 5, 10, 15, 22, and 
29 (for SOFA and SpO2/FiO2) 
• 
To align with the SAP, version 2  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
• 
To align with the SAP, version 2  
 
 
• 
To align with the SAP, version 1 

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9.4.1.3 – Multiplicity 
Adjustments 
Revised closed testing order for 
secondary endpoints. Survival at 
Day 60 and Day 90 is now excluded 
from the closed testing procedure, but 
will be analyzed separately 
To align with the SAP, version 1 
9.4.2 - Safety Analyses 
ECG data was added to the list of 
safety analyses to be summarized 
over time. 
To align with the SAP, version 1 
9.4.3 – Analyses of 
Pharmacokinetic and 
Pharmacodynamic 
Revised PK and PD analyses 
To align with the SAP, version 1 
9.4.4 – Analyses of Biomarker 
Added that biomarker data will only 
be summarized for the final study 
report 
To align with the SAP, version 1 
9.4.6 – Analyses of Exploratory 
Endpoint 
• 
Added analyses to be conducted 
for the new exploratory endpoints 
of time to clinical improvement 
 
• 
Added analyses for the 
evaluation of PROs SF-12 and 
EQ-5D-5L at Days 29, 60, and 90 
• 
To align with the SAP, version 1 
 
 
 
• 
PROs were added to evaluate 
health-related quality of life of 
patients enrolled in this study 
9.5 – Interim Analyses 
Revised tests that will be used in the 
analyses of efficacy and futility.  
To align with the SAP, version 2 
10.1.6 – Data Quality Assurance 
Added clarification that remote 
source data verification may be 
employed in the study 
Per emerging regulatory guidances 
10.2 – Appendix 2 (Clinical 
Laboratory Tests) 
Table 9 – For safety labs to be 
collected locally; clarified that arterial 
blood gas to be obtained when 
available.  
 
Added coagulation marker (Factor II); 
added inflammatory biomarkers 
(IL-2R, Pentatraxin-3, and 
Citrullinated histone H3); removed 
complement pathway biomarkers 
(C5a, C3a, total C3, Factor B, and 
Factor Ba) 
For clarity and to ensure that the most 
appropriate biomarker samples relative to 
the target population are obtained 
Throughout 
Editorial changes 
For clarity, correction of typographical 
errors, and/or internal document 
consistency 
Abbreviations: AE = adverse event; BSC = best supportive care; C = complement component; 
COVID-19 = Coronavirus Disease 2019; CRF = case report form; eCRF = electronic case report form; 
ECG = electrocardiogram; EQ-5D-5L = EuroQol 5-Dimension 5-Level; FiO2 = fraction of inspired oxygen; 
ICU = intensive care unit; IL = interleukin; IVIg = intravenous immunoglobulin; MCS = Mental Component 
Summary; PaO2 = partial pressure of oxygen; PCR = polymerase chain reaction; PCS = Physical Component 
Summary; PD = pharmacodynamic; PK = pharmacokinetic; PRO = patient reported outcomes; SAP = Statistical 
Analysis Plan; SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2; SF-12 = Short-Form 12; 
SoA = Schedule of Activities; SOFA = Sequential Organ Failure Assessment; SpO2 = peripheral capillary oxygen 
saturation.  
 
 
 

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1. 
PROTOCOL SUMMARY 
1.1. 
Synopsis 
Protocol Title: 
A Phase 3 Open-label, Randomized, Controlled Study to Evaluate the Efficacy and Safety of 
Intravenously Administered Ravulizumab Compared with Best Supportive Care in Patients with 
COVID-19 Severe Pneumonia, Acute Lung Injury, or Acute Respiratory Distress Syndrome 
Short Title: 
Efficacy and Safety Study of IV Ravulizumab in Patients with COVID-19 Severe Pneumonia 
Rationale: 
ULTOMIRIS® (ravulizumab), an effective and widely studied terminal complement inhibitor 
with a well-established safety profile, is proposed for the treatment of patients who have a 
confirmed diagnosis of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) 
infection with a clinical presentation consistent with Coronavirus Disease 2019 (COVID-19) 
severe pneumonia, acute lung injury, or acute respiratory distress syndrome (ARDS). 
Ravulizumab produces immediate, complete, and sustained inhibition of complement 
component 5-mediated terminal complement activity. Treatment with ravulizumab could 
decrease COVID-19-induced lung injury (ie, improve clinical outcomes in patients with 
COVID-19 severe pneumonia, acute lung injury, or ARDS). 
Objectives and Endpoints 
Objective  
Endpoints 
Primary 
To evaluate the effect of ravulizumab + BSC compared 
with BSC alone on the survival of patients with 
COVID-19 
• 
Survival (based on all-cause mortality) at Day 29 
Secondary 
To evaluate the efficacy of ravulizumab + BSC 
compared with BSC alone on outcomes in patients with 
COVID-19 
• 
Number of days free of mechanical ventilation at 
Day 29 
• 
Duration of intensive care unit stay at Day 29 
• 
Change from baseline in SOFA score at Day 29 
• 
Change from baseline in SpO2/FiO2 at Day 29 
• 
Duration of hospitalization at Day 29 
• 
Survival (based on all-cause mortality) at Day 60 
and Day 90 
Safety 
To characterize the overall safety of ravulizumab + BSC 
compared with BSC alone in patients with COVID-19 
• 
Incidence of TEAEs and TESAEs 
PK/PD/Immunogenicity 
To characterize the PK/PD and immunogenicity of 
ravulizumab in patients with COVID-19 
• 
Change in serum ravulizumab concentrations over 
time 
• 
Change in serum free and total C5 concentrations 
over time 
• 
Incidence and titer of anti-ALXN1210 antibodies 

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Biomarkers 
To assess the effect of C5 inhibition on systemic 
activation of complement, inflammation, and 
prothrombic activity in patients with COVID-19 
• 
Change in absolute levels of soluble biomarkers in 
blood associated with complement activation, 
inflammatory processes, and hypercoagulable states 
over time 
Exploratory 
To evaluate the effect of ravulizumab + BSC compared 
with BSC alone on progression to renal failure requiring 
dialysis in patients with COVID-19 
• 
Incidence of progression to renal failure requiring 
dialysis at Day 29 
To evaluate the effect of ravulizumab + BSC compared 
with BSC alone on clinical improvement in patients with 
COVID-19 
• 
Time to clinical improvement (based on a modified 
6-category ordinal scale) over 29 days 
To evaluate the effect of ravulizumab + BSC compared 
with BSC alone on the health-related quality of life of 
patients with COVID-19 
• 
SF-12 PCS and MCS scores at Day 29 (or 
discharge), Day 60, and Day 90 
• 
EQ-5D-5L scores at Day 29 (or discharge), Day 60, 
and Day 90 
Baseline is defined as the last available assessment on or before Day 1 for all patients. Day 1 will be defined as the 
date of the first infusion of ravulizumab for patients randomized and dosed with ravulizumab and as the date of 
randomization for patients randomized but not dosed with ravulizumab. 
Abbreviations: BSC = best supportive care; C5 = complement component 5; COVID-19 = Coronavirus 
Disease 2019; EQ-5D-5L = EuroQol 5-dimension 5-level; FiO2 = fraction of inspired oxygen; MCS = Mental 
Component Summary; PCS = Physical Component Summary; PD = pharmacodynamic; PK = pharmacokinetic; 
SF-12 = 12-item Short Form; SOFA = Sequential Organ Failure Assessment; SPO2 = peripheral capillary oxygen 
saturation; TEAE = treatment-emergent adverse event; TESAE = treatment-emergent serious adverse event. 
Overall Design 
Study ALXN1210-COV-305 is a multicenter Phase 3, open-label, randomized, controlled study 
designed to evaluate the safety and efficacy of intravenous (IV) ravulizumab + best supportive 
care (BSC), compared with BSC alone in patients with a confirmed diagnosis of SARS-CoV-2 
infection, and a clinical presentation consistent with COVID-19 severe pneumonia, acute lung 
injury, or ARDS. Patients at least 18 years of age, weighing ≥ 40 kg, and admitted to a 
designated hospital facility for treatment will be screened for eligibility in this study. Accounting 
for a 10% nonevaluable rate, approximately 270 patients will be randomized in a 2:1 ratio 
(180 patients to receive ravulizumab + BSC, 90 patients to BSC alone). 
Patients randomized to ravulizumab + BSC will receive a weight-based dose of ravulizumab on 
Day 1 (Table s1). On Day 5 and Day 10, doses of 600 mg or 900 mg ravulizumab will be 
administered (according to weight category) and on Day 15 patients will receive 
900 mg ravulizumab. Patients in both treatment groups will continue to receive medications, 
therapies, and interventions per standard hospital treatment protocols for the duration of the 
study. 
Screening and the Day 1 visits can occur on the same day if the patient has met all inclusion and 
no exclusion criteria. 

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Disclosure Statement: 
This is an open-label parallel-treatment study. 
Number of Patients: 
Approximately 270 patients (180 ravulizumab + BSC, 90 BSC alone) will be randomly assigned 
to 1 of 2 treatment groups. 
Intervention Groups and Duration: 
The study consists of a Screening Period of up to 3 days, a Primary Evaluation Period of 
4 weeks, a final assessment at Day 29, and a Follow-up Period of 8 weeks. The 2 follow-up visits 
will be conducted 4 weeks apart as a telephone call if the patient is discharged from the hospital 
or an in-person visit if the patient is still hospitalized. The total duration of each patient’s 
participation is anticipated to be approximately 3 months. 
The dosage regimen to be administered during this study is provided in Table s1. No additional 
doses are allowed during the Primary Evaluation Period (ie, from Day 1 to Day 29). 
Table s1: Ravulizumab Dosage Regimen for COVID-19 Severe Pneumonia, Acute Lung 
Injury, or Acute Respiratory Distress Syndrome 
Patient Body 
Weight (kg)1 
Day 1 Dose (mg) 
Day 5 Dose (mg) 
Day 10 Dose (mg) 
Day 15 Dose (mg) 
40 to < 60 
2400 
600 
600 
900 
60 to < 100 
2700 
900 
900 
900 
≥ 100 
3000 
900 
900 
900 
1. The patient’s body weight will be recorded on the day of the infusion visit. If the weight at the day of the infusion 
cannot be obtained, the weight recorded during the previous study visit may be used. 
Abbreviation: COVID-19 = Coronavirus Disease 2019. 
Data Monitoring Committee: Yes 
 
 

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1.2. 
Schema 
Figure 1: 
Study ALXN1210-COV-305 Schematic 
 
 
A weight-based dose of ravulizumab will be administered on Day 1 as follows: Patients weighing ≥ 40 to < 60 kg: 
2400 mg; ≥ 60 to < 100 kg: 2700 mg; or ≥ 100 kg: 3000 mg. 
A weight-based dose of ravulizumab will be administered on Day 5 and Day 10 as follows: Patients weighing ≥ 40 
to < 60 kg: 600 mg; ≥ 60 to < 100 kg: 900 mg; or ≥ 100 kg: 900 mg. 
On Day 15, patients will receive 900 mg ravulizumab. 
**Day 29 represents the end of the Primary Evaluation Period.  
Abbreviations: BSC = best supportive care; D = day; EOS = end-of-study; N = number of patients. 
 

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1.3. 
Schedule of Activities  
Table 1: 
Schedule of Activities 
Period 
Screening 
Period 
 
Primary Evaluation Period 
Follow-up Period5 
Study Day (D) 
D -3  
to D -1 
D11,2 
D52 
D102 
D152 
D22 
D29/ 
Discharge 3 
Early 
Termination4 
D60 
D90 
Study Window (days) 
NA 
NA 
±1 
±1 
±1 
±1 
±1 
 
±7 
Eligibility 
 
 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
X 
 
 
 
 
 
 
 
 
Medical history19 
X 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
Study Administrative 
 
 
 
 
 
 
 
 
 
Confirmation of vaccination or appropriate antibiotic 
prophylaxis against N. meningitidis6 
X 
 
 
 
 
 
 
 
X 
Screening Laboratory Tests 
 
 
 
 
 
 
 
 
 
Confirmed positive SARS-CoV-2 test 
X 
 
 
 
 
 
 
 
 
Chest CT or X-ray7 
X 
 
 
 
 
 
 
 
 
Pregnancy test8 
X 
 
 
 
 
 
X 
X 
 
Randomization 
 
 
 
 
 
 
 
 
 
Randomized to study drug + BSC or BSC alone 
 
X 
 
 
 
 
 
 
 
Administration of Study Drug 
 
 
 
 
 
 
 
 
 
Ravulizumab2 
 
X 
X 
X 
X 
 
 
 
 
Efficacy Assessments 
 
 
 
 
 
 
 
 
 
Survival status 
 
<<monitor continuously>>18 
X 
Mechanical ventilation status 
X 
<<monitor continuously>>18 
 
Hospitalization status 
 
<<monitor continuously>>18 
 
Intensive care unit status 
 
<<monitor continuously>>18 
 
Dialysis status 
 
<<monitor continuously>>18 
 
FiO2, SpO2, PaO29 
 
<<monitor daily>>9 
 
Sequential Organ Failure Assessment score 
X 
X 
X 
X 
X 
X 
X 
X 
 
Safety Assessments 
 
 
 
 
 
 
 
 
 
Electrocardiogram 
X 
 
 
 
 
 
X 
X 
 
Complete physical examination10 
X 
 
 
 
 
 
X 
X 
 
Abbreviated physical examination10 
 
X 
X 
X 
X 
X 
 
 
 
Glasgow Coma Scale 
X 
X 
X 
X 
X 
X 
X 
X 
 

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Period 
Screening 
Period 
 
Primary Evaluation Period 
Follow-up Period5 
Study Day (D) 
D -3  
to D -1 
D11,2 
D52 
D102 
D152 
D22 
D29/ 
Discharge 3 
Early 
Termination4 
D60 
D90 
Study Window (days) 
NA 
NA 
±1 
±1 
±1 
±1 
±1 
 
±7 
Body weight 
X 
X 
X 
X 
X 
 
 
 
 
Vital sign measurements (predose)11 
X 
X 
X 
X 
X 
X 
X 
X 
 
Adverse event review and evaluation 
X 
<<monitor continuously>> 
 
X 
Review safety card12 
 
X12 
 
 
 
 
X12 
X12 
X12 
Safety Laboratory Tests (Predose)13 
 
 
 
 
 
 
 
 
 
Clinical chemistry 
X 
X 
X 
X 
X 
X 
X 
X 
 
Hematology 
X 
X 
X 
X 
X 
X 
X 
X 
 
Coagulation panel and D-dimer 
X 
X 
X 
X 
X 
X 
X 
X 
 
Urinalysis 
X 
X 
X 
X 
X 
X 
X 
X 
 
Direct Coombs test 
X 
 
 
 
 
 
 
 
 
PK/PD/Immunogenicity Tests 
 
 
 
 
 
 
 
 
 
PK14 
 
X 
X 
X 
X 
X 
X 
X 
 
Total and free C515 
 
X 
X 
X 
X 
X 
X 
X 
 
Immunogenicity (predose)14 
 
X 
 
 
 
 
X 
X 
 
Biomarker Tests 
 
 
 
 
 
 
 
 
 
Serum and plasma biomarkers (predose)16 
X 
X 
X 
X 
X 
X 
X 
X 
 
Other 
 
 
 
 
 
 
 
 
 
Concomitant medication17 
X 
<<monitor continuously>> 
X 
Nonpharmacologic treatments and therapies18 
X 
<<monitor continuously>> 
X 
Patient-reported Outcomes 
 
 
 
 
 
 
 
 
 
SF-12 
 
 
 
 
 
 
X 
 
X 
EQ-5D-5L 
 
 
 
 
 
 
X 
 
X 
1. The Day 1 visit may occur on the same day as Screening. 
2. Patients randomized to ravulizumab + BSC will receive a weight-based dose of ravulizumab on Day 1 (Table 5). On Day 5 and Day 10, additional doses of 
600 mg or 900 mg ravulizumab will be administered (according to weight category) and on Day 15 patients will receive 900 mg of ravulizumab. 
3. If a patient is discharged before the end of the Primary Evaluation Period (Day 29), the patient will undergo the early discharge assessments. In addition, the 
patient will be contacted via telephone on Day 29 to assess health status (eg, survival, mechanical ventilation, hospitalization, intensive care unit, and 
dialysis). Follow-up telephone calls should be performed as planned unless the patient withdraws consent. 
4. The Early Termination Visit is to be conducted when the patient discontinues from the study during the Primary Evaluation Period. In addition, the patient will 
be contacted via telephone on Day 29 to assess health status (eg, survival, mechanical ventilation, hospitalization, intensive care unit, and dialysis). 
5. Additional monitoring will be performed during the 2 follow-up visits to review patient status, including survival and pregnancy, and to obtain information 
about new or worsening TESAEs. The follow-up will be conducted as a telephone call if the patient is discharged from the hospital or an in-person visit if 
the patient is still hospitalized.  

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6. Confirmation of meningococcal vaccination within the past 5 years prior to dosing for patients randomized to ravulizumab + BSC. If vaccination cannot be 
confirmed, the patient should receive prophylactic antibiotics prior to initiating ravulizumab treatment and for at least 8 months from the last infusion of 
ravulizumab. When patients are vaccinated less than 2 weeks prior to treatment with ravulizumab or after initiation of ravulizumab, they should continue 
antibiotic prophylaxis for at least 2 weeks after meningococcal vaccination. 
7. Can be performed within the 3 days prior to Screening or at Screening. Imaging performed as part of the patient’s routine clinical care is expected and 
acceptable for inclusion in this study. 
8. Urine or serum pregnancy tests (beta human chorionic gonadotropin) to be performed in all female patients. A negative pregnancy test result is required before 
administration of ravulizumab.  
9. SpO2 to be measured by pulse oximetry. PaO2 to be measured by arterial blood gas, if available. FiO2 to be measured by supplemental oxygen. For patients 
treated with ravulizumab, SpO2, PaO2 (if available), and FiO2 should be measured predose on Day 1. The highest daily measurement of oxygen pressure or 
saturation on the lowest inspired supplemental oxygen level will be recorded in the CRF/eCRF. 
10. Complete or abbreviated physical examination is to be performed at the timepoints indicated in the SoA. A complete physical examination will include, at a 
minimum, assessments of the following organs/body systems: skin, head, ears, eyes, nose, throat, neck, lymph nodes, chest, heart, abdomen, extremities, and 
musculoskeletal. An abbreviated physical examination consists of at least an evaluation of the respiratory and cardiovascular systems. Clinically significant 
abnormalities or findings will be recorded in the AE CRF/eCRF. 
11. Vital sign measurements should include systolic and diastolic BP (millimeters of mercury [mm Hg]), heart rate (beats/minute), respiratory rate 
(breaths/minute), and temperature (degrees Celsius [°C] or degrees Fahrenheit [°F]). These measurements will be taken predose on dosing days. 
12. When the patient is responsive and capable of understanding, review the Patient Safety Information Card (including discussion of the risks of meningococcal 
infections) during the hospitalization and at discharge. Upon discharge, patients who received ravulizumab, must carry the Patient Safety Information Card 
at all times and for at least 8 months after the last infusion of ravulizumab. 
13. Clinical safety laboratory measurements will be collected predose on dosing days. 
14. Serum samples for PK and immunogenicity analyses will be collected at the timepoints indicated in the SoA for patients randomized to ravulizumab + BSC. 
On Day 1/dosing days, immunogenicity and PK samples will be collected within 4 hours before the administration of ravulizumab (predose) and PK samples 
will be collected within 4 hours after the end-of-infusion (postdose). Postdose PK samples must be collected from a separate line or needle stick to the 
noninfused arm, not from the infusion line. Pharmacokinetic and immunogenicity samples can be collected at any time on nondosing days during the 
Primary Evaluation Period. 
15. Serum samples for total and free C5 analyses will be collected at the timepoints indicated in the SoA for all patients. For patients randomized to 
ravulizumab + BSC, samples will be collected within 4 hours before the administration of ravulizumab (predose) and within 4 hours after the end-of-infusion 
(postdose) on dosing days. Postdose samples must be collected from a separate line or needle stick to the noninfused arm, not from the infusion line. 
Samples can be collected at any time on nondosing days during the Primary Evaluation Period. 
16. Serum and plasma biomarker samples for biomarker analyses will be collected for all patients at the timepoints indicated in the SoA and stored at the 
investigational site prior to analysis by Alexion or designee. Samples will be collected predose (any time before infusion start) for patients who are 
randomized to the ravulizumab + BSC treatment group. 
17. Concomitant medications and nonpharmacologic therapies considered relevant to the treatment of COVID-19 (BSC) or ravulizumab treatment (eg, 
antimicrobials, antimalarials, antivirals, steroids, and vasopressors) that the patient is receiving, at the time of Screening and for treating TEAEs/TESAEs, 
will be recorded in the AE CRF/eCRF. 
18. Will be assessed via a telephone call at Day 29 for all patients who are discharged before the end of the Primary Evaluation Period (Day 29).  
19. Medical history should also include date of first onset of signs and symptoms of SARS-CoV-2 infection. 
Abbreviations: AE = adverse event; BSC = best supportive care; BP = blood pressure; C = complement component/protein; COVID-19 = Coronavirus 
Disease 2019; CT = computed tomography; D = day; eCRF = electronic case report form; EQ-5D-5L = EuroQol 5-dimension 5-level [questionnaire] 

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FiO2 = fraction of inspired oxygen; NA = not applicable; PaO2 = partial pressure of oxygen; PD = pharmacodynamics; PK = pharmacokinetics; 
SARS-COV-2 = severe acute respiratory syndrome coronavirus-2; SF-12 = 12-item Short Form; SoA = Schedule of Activities; SpO2 = peripheral capillary 
oxygen saturation; TESAE = treatment emergent serious adverse event. 
 

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2. 
INTRODUCTION 
2.1. 
Study Rationale 
ULTOMIRIS® (ravulizumab), an effective and widely studied terminal complement inhibitor 
with a well-established safety profile, is proposed for the treatment of patients who have a 
confirmed diagnosis of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) 
infection with a clinical presentation consistent with Coronavirus Disease 2019 (COVID-19) 
severe pneumonia, acute lung injury, or acute respiratory distress syndrome (ARDS). 
Ravulizumab produces immediate, complete, and sustained inhibition of complement 
component 5 (C5)-mediated terminal complement activity. Treatment with ravulizumab could 
decrease COVID-19 induced lung injury (ie, improve clinical outcomes in patients with 
COVID-19 severe pneumonia, acute lung injury, or ARDS). 
2.2. 
Background 
The novel SARS-CoV-2 is a beta-coronavirus identified as the causative agent in COVID-19 
(CDC, COVID 19 Situation Summary). Clinical manifestations of COVID-19 range from mild 
flu-like symptoms (eg, low grade fever, cough, fatigue) to ARDS, respiratory failure, multiple 
organ failure, and eventual death. An accelerating incidence of SARS-CoV-2 infections have 
been reported for patients who present with severe pneumonia, acute lung injury, or ARDS. 
Emerging epidemiologic data indicate that approximately 30 - 50% of patients with COVID-19 
may require hospitalization, approximately 10% may be admitted to critical care units, and 2.5% 
or more may die of multiorgan failure, especially those individuals who are older or have other 
comorbidities. For hospitalized patients, the World Health Organization (WHO) has issued 
recommendations on disease management and therapeutic regimens (WHO, 2020). Aside from 
supportive care, no therapeutic regimens have been proven effective in reducing either the 
human-to-human transmission of the infection or its associated fatalities. Mortality in those with 
critical illness has been reported as > 50%; therefore, implementation of proven critical care 
interventions such as lung protective ventilation is recommended by WHO. 
2.2.1. 
Nonclinical Evidence Supporting the Role of Complement in COVID-19 
Acute respiratory distress syndrome is a constellation of immune-mediated pathologies that are 
observed in severe cases of coronavirus infection (Hammerschmidt, 1980). This pattern was 
observed in 2002 with the emergence of severe acute respiratory syndrome-coronavirus 
(SARS-CoV), and in 2012 when a related coronavirus, Middle East respiratory syndrome 
coronavirus (MERS-CoV) was identified (Rota, 2003, Zaki, 2012). Complement activation and 
complement component 5a (C5a; the proinflammatory anaphylatoxin) are involved in multiple 
mechanisms in the development of acute lung disease induced by pathogenic viruses  
(Wang, 2015). Emerging evidence suggests that activation of the complement system is involved 
in the pathogenesis of coronavirus (CoV)-related ARDS, and that a C5 inhibitor may be an 
effective therapeutic in CoV-mediated disease (Gralinski, 2018). 
The complement system is a part of the immune system that enhances the ability of antibodies 
and phagocytic cells to clear pathogens and damaged cells. It is made up of more than 30 plasma 

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proteins that opsonize pathogens and induce a series of inflammatory responses to help fight 
infection. The complement system has key roles in innate and adaptive immune responses, but 
when hyperactivated can lead to tissue injury. Within the complement system there are 
3 pathways (classical, lectin, and alternative) that lead to cleavage of C5 and formation of the 
membrane attack complex, or terminal complement pathway. 
Preclinical data have demonstrated a role for complement activation in CoV-mediated disease. 
Gralinski evaluated activation of the complement system in a mouse model of CoV. The 
C57BL/6J mice were infected with mouse-adapted SARS-CoV which resulted in high-titer virus 
replication within the lung, induction of inflammatory cytokines and chemokines, and immune 
cell infiltration within the lung. Complement activation was measured by detection of 
complement pathway component cleavage products. Complement protein 3 activation products 
were detected in SARS-CoV MA15-infected mice, but not in control mice, as early as 1 day 
post-infection. Complement protein 3 deposition was observed in the lungs of infected wildtype 
mice on Day 2 and Day 4 post-infection. Transgenic animals lacking complement component 3 
(C3) were protected from SARS-CoV-induced weight loss, had reduced pathology 
(inflammatory cells in the large airway and parenchyma, perivascular cuffing, thickening of the 
interstitial membrane, and low levels of intra-alveolar edema), had improved respiratory 
function, and exhibited lower levels of inflammatory cytokines or chemokines in the lung and 
periphery. Notably, the kinetics of viral replication were unaltered in the C3-deficient mice 
relative to wildtype controls, suggesting that the observed effects were due to control of 
complement-mediated inflammatory processes and not reduction of viral titer. Complement 
protein 3 is a central hub in the complement cascade and acts as a relay for activation from the 
alternative pathway. However transgenic mice lacking alternative pathway proteins Factor B or 
C4 did not have the same protection from CoV-mediated weight loss as compared with 
C3-deficient mice, suggesting that inhibition of the complement alternative pathway alone is 
insufficient. This implies that inhibition of a key relay point such as C3 or potentially C5, may be 
required. 
A second model of viral-mediated lung infection also points to a role for complement  
(Jiang, 2018). A MERS-CoV infection in mice causes severe acute respiratory failure and high 
mortality accompanied by elevated secretion of cytokines and chemokines. In these infected 
mice, excessive complement activation was detected. Increased concentrations of C5a and 
terminal complement complex (C5b-9), activation products resulting from cleavage of C5, were 
detected in sera and lung tissue, respectively. Blocking C5a with a specific antibody to the C5a 
receptor (C5aR) reduced alveolar macrophage infiltration and interferon (IFN)-gamma receptor 
expression in lung, resulting in less tissue damage. Decreased spleen tissue damage was also 
observed. Interestingly, anti-C5aR treatment led to decreased viral replication in lung tissues. 
Patients infected by avian influenza virus H5N1 can also present with severe pneumonia, acute 
lung injury, or ARDS. The histopathological changes in the lungs are like those observed in 
severe acute respiratory syndrome (SARS) (Ng, 2006). In a mouse model of H5N1, complement 
activates immune effector cells and drives lung inflammation. Complement proteins C3a and 
C5a can increase vascular permeability, recruit and activate leukocytes, activate endothelial cells, 
upregulate adhesion molecule and cytokine expression, and induce goblet cell secretion of 
mucus, exacerbating disease through multiple mechanisms. In these mice, deposition of C3, 
C5b-9, and mannose-binding lectin (MBL)-C was observed in lung tissue. Upregulation of 
MBL-associated serine protease-2 (MASP-2) and complement receptors C3aR and C5aR was 

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also detected. Specific inhibition of either C3aR or C5a in the infected mice was effective in 
reducing lung damage, attenuating inflammation and neutrophil infiltration in the lung, and 
improving survival (Sun, 2013). 
2.2.2. 
Clinical Hypothesis Supporting Utility of Ravulizumab in COVID-19 
Clinical evidence suggests that complement is activated during SARS infection and that the 
progression of severe pneumonia, acute lung injury, or ARDS in these patients is strongly 
associated with complement activation. The C3c fragment is present in the sera of patients with 
SARS and is a strong indicator of disease severity (Pang, 2006). Consistent with this finding, the 
complement activation product C5a is associated with the inflammatory response and severe 
lung damage that occurs in patients infected with the 2009 H1N1 influenza virus (Ohta, 2011). It 
has also been shown that SARS-CoV can directly activate complement via the lectin pathway 
(Ip, 2005). Patients with SARS develop autoantibodies against human epithelial cells and 
endothelial cells that mediate complement-dependent cytotoxicity (Yang, 2005). 
Multiple lines of evidence support the hypothesis that complement is a key mediator of 
virally-induced lung damage and that acute lung injury associated with CoV infection is partially 
mediated by complement (Wong, 2004). Therefore, it is plausible to hypothesize that 
COVID-19-related injuries and multiorgan failures are mediated, at least in part, by complement 
activation. The existing data point to the role of C3 and the terminal complement complex, but 
not the alternative pathway alone. Inhibition of complement, specifically at the terminal 
complement node through inhibition of C5, may control the inflammatory processes which drive 
ARDS. 
At present, there are no therapies that have received global approval by regulatory authorities for 
the prevention and/or treatment of COVID-19. China’s National Health Commission recently 
updated treatment guidelines for COVID-19 recommending the use of tocilizumab 
(anti-interleukin [IL] 6R monoclonal antibody [mAb]) to treat Chinese patients infected with 
SARS-CoV-2 who have developed serious lung damage and have elevated levels of IL-6 in the 
blood. A variety of supportive therapies are being used in an attempt to improve prognosis in 
critically ill patients with confirmed COVID-19 presenting with severe pneumonia, acute lung 
injury, or potentially life-threatening ARDS. Despite the use of these supportive agents, patients 
have continued to experience deterioration of respiratory function, a critical contributor to fatal 
outcomes. 
Ravulizumab is a mAb that specifically binds to the complement protein C5 with high affinity, 
thereby inhibiting its cleavage to C5a and C5b (the initiating subunit of C5b-9) and preventing 
the generation of the terminal complement complex C5b-9. This mechanism of action provides a 
therapeutic rationale for the use of ravulizumab in diseases in which complement activation is 
involved. In addition, the selective blockade of complement cascade at C5 by ravulizumab 
preserves the activity of upstream components of the complement cascade that are known to be 
essential for opsonization of microorganisms and prevention of immune complex disorders 
(Prodinger, 1999). Importantly, C5 blockade preserves the immunoprotective and 
immunoregulatory functions of early complement components. 
Complement inhibition has been shown to be an effective therapeutic target in hematological and 
neuroinflammatory diseases. Ravulizumab is proposed for the treatment of patients with 
confirmed SARS-CoV-2 infection with a clinical presentation consistent with COVID-19 severe 

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pneumonia, acute lung injury, or ARDS. Treatment with ravulizumab produces complete and 
sustained inhibition of C5-mediated terminal complement activity. Treatment with ravulizumab 
could improve outcomes in patients with COVID-19 severe pneumonia, acute lung injury, or 
ARDS. 
2.3. 
Benefit/Risk Assessment 
2.3.1. 
Risk Assessment 
Potential risks associated with participation in this study and risk mitigation measures are 
enumerated in Table 2. 
Table 2: 
Potential Risks and Mitigation Strategies 
Risks of Clinical Significance 
Summary of Data/ 
Rationale for Risk 
Mitigation Strategy 
Identified risk 
Meningococcal infection 
Patients who have not received a 
meningococcal vaccination within the 
past 5 years may be unable to receive 
meningococcal vaccinations prior to 
initiating treatment with ravulizumab 
during this study. 
If vaccination cannot be confirmed, 
the patient should receive 
prophylactic antibiotics against 
meningococcal infection prior to 
initiating ravulizumab treatment and 
for at least 8 months from the final 
infusion of ravulizumab (only 
applicable to patients exposed to 
study drug). 
 
When patients are vaccinated less 
than 2 weeks prior to treatment with 
ravulizumab or after initiation of 
ravulizumab, they should continue 
antibiotic prophylaxis for at least 
2 weeks after meningococcal 
vaccination. 
Potential risks 
Serious infections 
Ravulizumab could increase the risk 
of infection in this patient population. 
This potential risk is based on the 
mode of action of ravulizumab and 
experience with the use of 
eculizumab. Since the relevance of 
serious infection with ravulizumab 
therapy has not been confirmed in 
clinical studies, this remains a 
potential risk. 
Training healthcare professionals and 
patients about the potential risk of 
additional serious infection. 
Monitoring for signs and symptoms 
of serious infections will be 
conducted as part of routine safety 
assessments for this study. In 
addition to appropriate antibiotic 
coverage versus infection and 
opportunistic infections, guidelines 
for immune reconstitution and 
revaccination will be followed, as 
applicable. 
Immunogenicity  
Treatment with any therapeutic 
protein has the potential to induce an 
immune response. Potential clinical 
consequences may include severe 
hypersensitivity type reactions, 
Across 350 patients enrolled in 
ravulizumab, Phase 3 clinical studies, 
2 patients were reported with 
treatment-emergent ADAs. 
 

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Risks of Clinical Significance 
Summary of Data/ 
Rationale for Risk 
Mitigation Strategy 
decrease in efficacy and induction of 
autoimmunity, including antibodies to 
the endogenous form of the protein 
(Li, 2002; Casadevall, 2002). 
Presence of anti-ALXN1210 
antibodies will be assessed.  
Infusion site or 
infusion-associated reactions 
Protein therapies administered 
intravenously have the potential risk 
of causing local (infusion-site) 
reactions and systemic reactions 
(infusion-associated reactions). 
Monitoring for infusion reactions 
will be conducted as part of routine 
safety assessments for this study. 
Management of potential infusion 
reactions is detailed in Section 10.6.  
Pregnancy exposure/lactation 
No studies of ravulizumab have been 
conducted in pregnant women. There 
are no data available on excretion of 
ravulizumab in breast milk. 
Pregnant or nursing female patients 
will be excluded from participating 
in this clinical study. Patients and 
their spouses/partners must use a 
highly effective or acceptable 
method of contraception for a period 
of 8 months following the final 
infusion of ravulizumab. 
Breastfeeding should be discontinued 
during treatment and up to 8 months 
after the final infusion of 
ravulizumab. 
Abbreviations: ADA = antidrug antibody. 
2.3.2. 
Benefit Assessment 
Potential benefits of study participation include: 
• Improve survival rate of patients with SARS-CoV-2 infection who are receiving 
ravulizumab + best supportive care (BSC) compared with BSC alone 
• Decrease lung injury in patients with SARS-CoV-2 infection while on supportive 
medical care 
• Improve clinical outcomes in patients with SARS-CoV-2 infection while on 
supportive medical care 
2.3.3. 
Overall Benefit: Risk Conclusion 
Although the efficacy of ravulizumab has not been previously studied in patients with severe 
pneumonia, acute lung injury, or ARDS, the emerging evidence for the scientific rationale, the 
predicted drug concentrations and pharmacodynamic (PD) effects after administration of the 
recommended dose (Section 4.3), and its established safety profile indicate that ravulizumab is 
an appropriate candidate for clinical investigation, and that the potential for clinical benefit 
outweighs the risk of treatment with ravulizumab for patients participating in 
Study ALXN1210-COV-305. 
The safety profile of ravulizumab is well characterized in the current clinical development 
programs, including approved indications in paroxysmal nocturnal hemoglobinuria (PNH) and 

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atypical hemolytic uremic syndrome (aHUS). Known and potential risks can be effectively 
managed with the risk mitigation strategies currently in place for ravulizumab. 
More detailed information about the known and expected benefits and risks and reasonably 
expected adverse events (AEs) of ravulizumab may be found in the Investigator’s Brochure (IB). 

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3. 
OBJECTIVES AND ENDPOINTS 
Table 3: 
Objectives and Endpoints 
Objective  
Endpoints 
Primary 
To evaluate the effect of ravulizumab + BSC compared 
with BSC alone on the survival of patients with 
COVID-19 
• 
Survival (based on all-cause mortality) at Day 29 
Secondary 
To evaluate the efficacy of ravulizumab + BSC 
compared with BSC alone on outcomes in patients with 
COVID-19 
• 
Number of days free of mechanical ventilation at 
Day 29 
• 
Duration of intensive care unit stay at Day 29 
• 
Change from baseline in SOFA score at Day 29 
• 
Change from baseline in SpO2/FiO2 at Day 29 
• 
Duration of hospitalization at Day 29 
• 
Survival (based on all-cause mortality) at Day 60 
and Day 90 
Safety 
To characterize the overall safety of ravulizumab + BSC 
compared with BSC alone in patients with COVID-19 
• 
Incidence of TEAEs and TESAEs 
PK/PD/Immunogenicity 
To characterize the PK/PD and immunogenicity of 
ravulizumab in patients with COVID-19 
• 
Change in serum ravulizumab concentrations over 
time 
• 
Change in serum free and total C5 concentrations 
over time 
• 
Incidence and titer of anti-ALXN1210 antibodies 
Biomarkers 
To assess the effect of C5 inhibition on systemic 
activation of complement, inflammation, and 
prothrombic activity in patients with COVID-19 
• 
Change in absolute levels of soluble biomarkers in 
blood associated with complement activation, 
inflammatory processes, and hypercoagulable states 
over time 
Exploratory 
To evaluate the effect of ravulizumab + BSC compared 
with BSC alone on progression to renal failure requiring 
dialysis in patients with COVID-19 
• 
Incidence of progression to renal failure requiring 
dialysis at Day 29 
To evaluate the effect of ravulizumab + BSC compared 
with BSC alone on clinical improvement in patients with 
COVID-19 
• 
Time to clinical improvement (based on a modified 
6-point ordinal scale) over 29 days 
To evaluate the effect of ravulizumab + BSC compared 
with BSC alone on the health-related quality of life of 
patients with COVID-19 
• 
SF-12 PCS and MCS scores at Day 29 (or 
discharge), Day 60, and Day 90 
• 
EQ-5D-5L scores at Day 29 (or discharge), Day 60, 
and Day 90 
Baseline is defined as the last available assessment on or before Day 1 for all patients. Day 1 will be defined as the 
date of the first infusion of ravulizumab for patients randomized and dosed with ravulizumab and as the date of 
randomization for patients randomized but not dosed with ravulizumab. 
Abbreviations: BSC = best supportive care; C5 = complement component 5; COVID-19 = Coronavirus 
Disease 2019; EQ-5D-5L = EuroQol-5 Dimension-5 level; FiO2 = fraction of inspired oxygen; MCS = Mental 
Component Summary; PCS = Physical Component Summary; PD = pharmacodynamic; PK = pharmacokinetic; 
SF-12 = 12-item Short Form; SOFA = Sequential Organ Failure Assessment; SpO2 = peripheral capillary oxygen 
saturation; TEAE = treatment-emergent adverse event; TESAE = treatment-emergent serious adverse event. 

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4. 
STUDY DESIGN 
4.1. 
Overall Design 
Study ALXN1210-COV-305 is a multicenter Phase 3, open-label, randomized, controlled study 
designed to evaluate the safety and efficacy of intravenous (IV) ravulizumab + BSC, compared 
with BSC alone, in patients with a confirmed diagnosis of SARS-CoV-2 infection, and a clinical 
presentation consistent with COVID-19 severe pneumonia, acute lung injury, or ARDS. Patients 
at least 18 years of age, weighing ≥ 40 kg, and admitted to a designated hospital facility for 
treatment will be screened for eligibility in this study. Accounting for a 10% nonevaluable rate, 
approximately 270 patients will be randomized in a 2:1 ratio (180 patients to receive 
ravulizumab + BSC, 90 patients to receive BSC alone). 
Patients randomized to ravulizumab + BSC will receive a weight-based dose of ravulizumab on 
Day 1 (Table s1). On Day 5 and Day 10, doses of 600 mg or 900 mg ravulizumab will be 
administered (according to weight category) and on Day 15 patients will receive 
900 mg ravulizumab. Patients in both treatment groups will continue to receive medications, 
therapies, and interventions per standard hospital treatment protocols for the duration of the 
study. 
The study consists of a Screening Period of up to 3 days, a Primary Evaluation Period 
of 4 weeks, a final assessment at Day 29, and a Follow-up Period of 8 weeks. The 2 follow-up 
visits will be conducted 4 weeks apart as a telephone call if the patient is discharged from the 
hospital or an in-person visit if the patient is still hospitalized. The total duration of each 
patient’s participation is anticipated to be approximately 3 months (Figure 1). 
Screening and the Day 1 visits can occur on the same day if the patient has met all inclusion and 
no exclusion criteria. 
4.2. 
Scientific Rationale for Study Design 
Table 4: 
Study Design Rationale for Study ALXN1210-COV-305 
Design Element 
Rationale 
This is an open-label, 2:1 randomized, controlled study. 
o 
A randomized, controlled study design minimizes bias 
to selection or treatment allocation. This design will 
ensure identification of an effective treatment that may 
improve survival in patients with COVID-19 severe 
pneumonia, acute lung injury, or ARDS. 
o 
The 2:1 randomization will ensure that approximately 
two-thirds of patients are exposed to treatment and 
provides more safety information in this patient 
population for benefit-risk assessment. 
Study ALXN1210-COV-305 is being conducted in patients 
with SARS-CoV-2 infection with a clinical presentation 
consistent with COVID-19 severe pneumonia, acute lung 
injury, or ARDS. 
o 
There is no approved treatment for patients with the 
severe form of COVID-19. 
o 
Clinical evidence suggests that complement is 
activated during SARS infection and that the 
progression of disease is also associated with 
complement activation. 

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Design Element 
Rationale 
o 
Treatment with ravulizumab could 1) decrease lung 
injury and improve clinical outcomes in patients with 
SARS-CoV-2 infection while on supportive medical 
care and 2) provide additional time for patients to 
recover. 
For patients randomized to ravulizumab + BSC, a 
weight-based dose of ravulizumab will be administered on 
Day 1. On Day 5 and Day 10, additional doses of 600 mg 
or 900 mg ravulizumab will be administered (according to 
weight category) and on Day 15 patients will receive 
900 mg ravulizumab. 
o 
Preliminary PK/PD data suggest that the complement 
system is amplified in patients with COVID-19 severe 
pneumonia, acute lung injury, or ARDS beyond what 
has been observed in patients with aHUS and that 
additional doses of ravulizumab are needed to provide 
complete and sustained complement inhibition. 
o 
Due to the rapid activation of complement associated 
with the severe form of COVID-19 (ie, 
hyperinflammatory response known as cytokine storm 
syndrome [Mehta, 2020]), this ravulizumab dosage 
regimen is expected to improve survival and clinically 
relevant endpoints in these patients. 
Duration of study 
o 
The Primary Evaluation Period was chosen in 
consideration of the critical status of patients who are 
admitted to the ICU due to COVID-19 associated lung 
injury and typical duration of their stay in the ICU. 
o 
A Follow-up Period, consisting of 2 follow-up visits 
conducted approximately 4 weeks apart on Day 60 and 
Day 90, will be implemented to determine survival, 
monitor for pregnancy, and obtain information about 
new or worsening TESAEs. This duration is 
appropriate given the clinical presentation of 
COVID-19 patients with lung injury. 
Primary endpoint of survival (all-cause mortality) at 
Day 29 
o 
The mortality rate of patients with COVID-19 
associated severe pneumonia, acute lung injury, or 
ARDS is staggeringly high (upwards of 50%). Often 
patients die within a very short time from initial onset 
of symptoms. 
o 
The chosen primary endpoint is anticipated to reflect a 
ravulizumab treatment effect over 4 weeks and thus an 
immediate impact on survival. 
Secondary endpoints 
o 
Most secondary endpoints were selected based on 
Society of Critical Care Medicine recommendations 
for standardized endpoints in clinical studies using an 
intervention to reduce the duration of mechanical 
ventilation (Blackwood, 2019). 
o 
The SOFA score is a validated endpoint used in the 
critical care setting to determine clinical outcomes (eg, 
multiorgan failure) (Lambden, 2019). 
Abbreviations: aHUS = atypical hemolytic uremic syndrome; ARDS = acute respiratory distress syndrome; 
BSC = best supportive care; COVID-19 = Coronavirus Disease 2019; ICU = intensive care unit; 
PD = pharmacodynamic; PK = pharmacokinetic; SARS = severe acute respiratory syndrome; 
SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2; SOFA = sequential organ failure assessment; 
TESAE = treatment-emergent serious adverse event. 

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4.3. 
Justification for Dose 
The proposed dosage regimen for patients with COVID-19 severe pneumonia, acute lung injury, 
or ARDS is based on ravulizumab use in aHUS clinical studies, eculizumab and ravulizumab use 
in patients with thrombotic microangiopathy following hematopoietic stem-cell transplant 
(HSCT-TMA), and emerging data from patients with COVID-19 treated with eculizumab under 
compassionate use. 
Preliminary unpublished pharmacokinetic (PK) and PD data suggest that the complement system 
in patients with COVID-19 severe pneumonia, acute lung injury, or ARDS is amplified beyond 
that observed in patients with aHUS, and that additional and increased doses of ravulizumab are 
needed to provide complete and sustained complement inhibition. Increased complement 
activation (or complement amplification) is noted in other clinical settings, also necessitating 
more frequent dosing to maintain terminal complement inhibition (Jodele, 2016). 
Patients who developed HSCT-TMA were initially treated with eculizumab at the regimen 
approved for treatment of patients with aHUS, with additional doses administered as needed to 
maintain total complement activity. Changes in eculizumab clearance were noted during the first 
several weeks of treatment in the HSCT-TMA study (Figure 2). Mean drug clearance normalized 
for weight during the first week of therapy was 3.5-fold higher than during the fifth week 
(86.0 mL/hr/70 kg patient versus 24.4 mL/hr/70 kg patient, respectively).  
Figure 2: 
Eculizumab Clearance Changes Over Time in Pediatric Patients With 
Thrombotic Microangiopathy Following Hematopoietic Stem-cell Transplant 
 
Note: Apparent systemic clearances were normalized by allometrically scaled body weight to account for body size 
differences and to allow comparison across the range of patients’ age. 
Source: Jodele, 2016 

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The effect on eculizumab clearance is thought to be driven by an increase in complement 
activation, due to endothelial damage that may result from the HSCT and/or myeloablative 
treatment pretransplant. Higher concentrations of circulating complement complexes are 
expected to bind more of the anti-C5 drug, thereby leading to a faster clearance of eculizumab 
relative to other indications (aHUS or PNH) (Jodele, 2016). 
The learnings from Jodele in the use of eculizumab in this amplified complement setting were 
used to inform ravulizumab dosing in this study. To account for the increased drug clearance 
noted soon after treatment initiation, 2 additional weight-based doses are proposed on Day 5 and 
Day 10 on top of the approved ravulizumab weight-based dose on Day 1 (CPR-0024.00). 
Simulations were conducted to determine the expected exposure differences following the 
proposed more frequent early dosing, with and without the increased clearance assumption, to 
assess expected differences in ravulizumab exposure (Figure 3; CPR-0025.00). These 
simulations support the expected relative safety of these additional early doses, with exposures 
expected not to exceed ravulizumab exposures that have been safely achieved following 
approved ravulizumab dosing. 

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Figure 3: 
Simulations Comparing “With” and “Without” the Faster Clearance 
Assumption of Ravulizumab in Adult Patients With Thrombotic 
Microangiopathy Following Hematopoietic Stem-cell Transplant 
 
Note: Gray region represents the 95% prediction interval; ie, 2.5% to 97.5% range; black solid line is the median of 
the simulated concentration-time profiles; horizontal dashed line represents the threshold concentration of 
175 μg/mL (based on dose rationale document), above which complete and sustained terminal complement 
inhibition is maintained.  
Abbreviations: D = day; q8w = dosing every 8 weeks. 
Source: Report CPR-0025.00, Figure 8 
The proposed ravulizumab dosage regimen for treating patients with COVID-19 (Table 5) relies 
on this earlier work in support of dosing patients with HSCT-TMA, with a slight modification of 
the Day 15 dose (since chronic dosing is not needed in the treatment of patients with 
COVID-19). 
Based on the importance of complete terminal complement inhibition to ameliorate 
COVID-19-induced lung injury, more frequent early ravulizumab dosing is expected to address 

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the increased drug clearance resulting from complement amplification, particularly within the 
first 2 weeks of treatment when complement would be expected to be most amplified. 
This is the basis of the therapeutic strategy to achieve complete complement inhibition in 
patients with COVID-19 infection who present with severe pneumonia, acute lung injury, and/or 
ARDS. 
4.4. 
End of Primary Evaluation Definition 
The end of the Primary Evaluation Period is defined as the date when the last surviving patient 
completes the Day 29/early termination (ET) visit. 
4.5. 
End of Study Definition 
The end of the study is defined as the last patient’s last visit, which may be the final safety 
follow-up telephone call or in-person visit. 

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5. 
STUDY POPULATION 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, are not permitted. 
The Sponsor allows a 3-day Screening Period to evaluate patients for eligibility. If the Screening 
and Day 1 Visits are combined, the patient must meet all inclusion criteria and not meet any 
exclusion criteria prior to randomization. 
5.1. 
Inclusion Criteria 
Patients are eligible to be included in the study only if all the following criteria apply: 
Age 
1. Patient must be ≥ 18 years of age at the time of providing informed consent. 
Type of Patient and Disease Characteristics 
2. Confirmed diagnosis of SARS-CoV-2 infection (eg, via polymerase chain reaction [PCR] 
and/or antibody test) presenting as severe COVID-19 requiring hospitalization. 
3. Severe pneumonia, acute lung injury, or ARDS confirmed by computed tomography 
(CT) or X-ray at Screening or within the 3 days prior to Screening, as part of the patient’s 
routine clinical care. 
4. Respiratory distress requiring mechanical ventilation, which can be either invasive 
(requiring endotracheal intubation) or noninvasive (with continuous positive airway 
pressure [CPAP] or bilevel positive airway pressure [BiPAP]). 
Weight 
5. Body weight ≥ 40 kg at the time of providing informed consent. 
Sex 
6. Male or female. 
7. Female patients of childbearing potential and male patients with female partners of 
childbearing potential must follow protocol-specified contraception guidance for 
avoiding pregnancy for 8 months after treatment with the study drug (as described in 
Section 10.4 [Appendix 4]). 
5.2. 
Exclusion Criteria  
Patients are excluded from the study if any of the following criteria apply: 
Medical Conditions 
1. Patient is not expected to survive for more than 24 hours. 
2. Patient is on invasive mechanical ventilation with intubation for more than 48 hours prior 
to Screening. 
3. Severe pre-existing cardiac disease (ie, New York Heart Association Class 3 or Class 4, 
acute coronary syndrome, or persistent ventricular tachyarrhythmias). 

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4. Patient has an unresolved Neisseria meningitidis infection. 
Prior/Concomitant Therapy 
5. Use of the following medications and therapies: 
a. Current treatment with a complement inhibitor or 
b. Intravenous immunoglobulin (IVIg) within 4 weeks prior to randomization on Day 1. 
Prior/Concurrent Clinical Study Experience 
6. Treatment with investigational therapy in a clinical study within 30 days before 
randomization, or within 5 half-lives of that investigational therapy, whichever is greater 
Exceptions: 
a. Investigational therapies will be allowed if received as part of best supportive care 
through an expanded access protocol or emergency approval for the treatment of 
COVID-19. 
b. Investigational antiviral therapies (such as remdesivir) will be allowed even if 
received as part of a clinical study. 
Diagnostic Assessments 
7. Female patients who are breastfeeding or who have a positive pregnancy test result at 
Screening. 
Other Exclusions 
8. History of hypersensitivity to any ingredient contained in the study drug, including 
hypersensitivity to murine proteins. 
9. Patient who is not currently vaccinated against N. meningitidis, unless the patient agrees 
to receive prophylactic treatment with appropriate antibiotics for at least 8 months after 
the last infusion of study drug or until at least 2 weeks after the patient receives 
vaccination against N. meningitidis. 
5.3. 
Lifestyle Considerations 
No lifestyle considerations are applicable for this study. 
5.4. 
Screen Failures 
Screen failures are defined as patients who provide informed consent, did not meet any 
inclusion/exclusion criteria, and are not randomly assigned to treatment. 
A minimal set of screen failure information is required to ensure transparent reporting of screen 
failure patients to meet the Consolidated Standards of Reporting Trials (CONSORT) publishing 
requirements. Minimal information includes demography (if allowable per local regulations), 
screen failure details (eg, failed eligibility criteria), and any AEs, including any serious adverse 
events (SAEs) and any relevant concomitant medication use during the Screening Period. 
Individuals who do not meet the criteria for participation in this study (screen failure) due to a 
reason that is expected to resolve or has resolved may be rescreened based on discussion and 
agreement between the Investigator and the Medical Monitor. 

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6. 
STUDY INTERVENTION 
Ravulizumab, a recombinant humanized anti-C5 mAb composed of two 448 amino acid heavy 
chains and two 214 amino acid light chains, is an IgG2/4 kappa immunoglobulin consisting of 
human constant regions, and murine complementarity-determining regions grafted onto human 
framework light- and heavy-chain variable regions. Ravulizumab is produced in Chinese hamster 
ovarian cell lines and was designed through minimal targeted engineering of eculizumab by 
introducing 4 unique amino acid substitutions to its heavy chain to extend antibody half-life. 
Ravulizumab drug product is supplied for clinical studies as a sterile, preservative-free 
10 mg/mL solution in single-use vials and designed for infusion by diluting into commercially 
available saline (0.9% sodium chloride injection; country-specific pharmacopeia) for 
administration via IV infusion. 
6.1. 
Study Intervention(s) Administered 
The proposed dosage regimen for the treatment of patients with COVID-19 who are ≥ 18 years 
and ≥ 40 kg and are randomized to ravulizumab + BSC is presented in Table 5. 
Table 5: 
Ravulizumab Dosage Regimen for COVID-19 Severe Pneumonia, Acute 
Lung Injury, or Acute Respiratory Distress Syndrome 
Patient Body 
Weight (kg)1 
Day 1 Dose (mg) 
Day 5 Dose (mg) 
Day 10 Dose (mg) 
Day 15 Dose (mg) 
40 to < 60 
2400 
600 
600 
900 
60 to < 100 
2700 
900 
900 
900 
≥ 100 
3000 
900 
900 
900 
1. 
The patient’s body weight will be recorded on the day of the infusion visit. If the weight at the day of the 
infusion cannot be obtained, the weight recorded during the previous study visit may be used. 
Abbreviations: COVID-19 = Coronavirus Disease 2019. 
Ravulizumab drug product is formulated at pH 7.0 and each 30 mL vial contains 300 mg of 
ravulizumab, 0.02% polysorbate 80, 150 mM sodium chloride, 6.63 mM sodium phosphate 
dibasic, 3.34 mM sodium phosphate monobasic, and Water for Injection, United States 
Pharmacopeia. 
The ravulizumab admixture will be administered to the patient using an IV tubing set via an 
infusion pump followed by an IV flush. Use of a 0.2 micron filter is required during the infusion. 
The IV flush is infused at the same rate of the infusion and end of flush is considered the end of 
infusion. The IV flush volume is not to be included in the total volume of study drug 
administered. Additional details are provided in the Pharmacy Manual. 
6.1.1. 
Packaging and Labeling 
Ravulizumab will be manufactured and supplied by Alexion in single 30 mL vials as a solution 
concentration of 10 mg/mL (Table 6). Each vial contains 300 mg of ravulizumab for 
IV administration. 

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Table 6: 
Ravulizumab Dosage Form and Strength 
Product Name 
Ravulizumab 
Dosage Form 
Concentrate solution for infusion 
Type 
Biologic 
Dose 
300 mg 
NIMP and IMP 
IMP 
Route of Administration 
Intravenous infusion 
Physical Description 
30 mL vial of 10 mg/mL sterile, preservative-free 
Sourcing 
Provided centrally by Alexion or locally by the study site, subsidiary, or 
designee 
Packaging and Labeling 
Single-use, United States Pharmacopeia/European Pharmacopeia Type 1 clear 
and colorless glass vial, stoppered with a gray butyl rubber stopper, and sealed 
with aluminum seal with a polypropylene flip-off cap 
Abbreviations: IMP = investigational medicinal product; NIMP = non-investigational medicinal product. 
6.2. 
Preparation/Handling/Storage/Accountability 
Stability studies of the diluted admixture of ravulizumab (10 mg/mL) in 0.9% sodium chloride 
injection support an in-use stability of 6 hours at room temperature at 23°C – 27°C (73°F – 80°F) 
and 24 hours when refrigerated at 2°C – 8°C (36°F – 46°F). 
Ravulizumab vials should not be frozen or shaken. 
The Investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received and any discrepancies are reported 
and resolved before use of the study intervention. 
Only patients enrolled in the study and randomized to the ravulizumab + BSC group may receive 
the study intervention and only authorized site staff may supply or administer the study 
intervention. All study intervention must be stored in a secure, environmentally controlled, and 
monitored (manual or automated) area in accordance with the labeled storage conditions with 
access limited to the Investigator and authorized site staff. 
The Investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance (ie, 
receipt, reconciliation, and final disposition records). 
This responsibility includes the reporting of any product complaints* to 
 within 1 business day of awareness. 
*A product complaint is defined as any written, electronic, or oral communication that alleges 
deficiencies related to the identity, quality, durability, reliability, usability, safety, effectiveness, 
or performance of a product or clinical study material and/or its packaging components after it 
is has been released for distribution to an end customer that affects the performance of such 
product. 
Further guidance and information are provided in the Pharmacy Manual. 
PPD

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6.3. 
Measures to Minimize Bias: Randomization and Blinding 
This is an open-label study. Eligible patients who meet all inclusion and no exclusion criteria 
will be randomized in a 2:1 ratio to receive either ravulizumab + BSC or BSC alone. 
Randomization will be stratified by intubated or not intubated on Day 1. A randomization 
schedule will be developed by a centralized third party. 
6.4. 
Study Intervention Compliance 
When patients are dosed at the investigational site, they will receive ravulizumab directly from 
the Investigator or designee, under medical supervision, thereby minimizing noncompliance. The 
date and time of the dose administered will be recorded in the source documents and recorded in 
the case report form (CRF)/electronic case report form (eCRF). The dose of ravulizumab and 
study patient identification will be confirmed at the time of dosing by a member of the 
investigational site staff. 
6.5. 
Concomitant Therapy 
Patients may receive appropriate concomitant medications, including antivirals, as part of BSC 
during this clinical study, unless prohibited per exclusion criterion 5. 
Concomitant medications considered relevant to treatment of COVID-19 or ravulizumab 
treatment (eg, vaccines, antimicrobials, antimalarials, antivirals, steroids, and vasopressors) that 
the patient is receiving at the time of enrollment or receives during the study must be recorded in 
the CRF/eCRF along with: 
• Reason for use, 
• Dates of administration, including start and end dates, and 
• Dosage information including dose and frequency. 
The Medical Monitor should be contacted if there are any questions regarding concomitant 
therapy. 
6.5.1. 
Disallowed Medicine and Therapy 
Use of the following medications and therapies is prohibited for the specified duration prior to 
Screening and for the duration of the study: 
• Current treatment with a complement inhibitor, and 
• Intravenous immunoglobulin (IVIg) within 4 weeks prior to randomization on Day 1. 
6.6. 
Dose Modification 
Additional doses are not allowed during the study. 
6.7. 
Intervention After the End of the Study 
The dosage regimen to be administered during this study is provided in Table 5. Patients will 
continue to be under the care of their treating physician after the study has concluded. 

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7. 
DISCONTINUATION OF STUDY INTERVENTION AND 
PATIENT DISCONTINUATION/WITHDRAWAL 
7.1. 
Discontinuation of Study Intervention 
This is an open-label study. Study drug discontinuation is only applicable for patients who are 
randomized to ravulizumab + BSC. In rare instances, it may be necessary for a patient to 
permanently discontinue (definitive discontinuation) the study drug. If the study drug is 
definitively discontinued, the patient should remain in the study to be evaluated for safety. 
Patients should be considered for discontinuation from study drug if any of the following occur: 
• Serious hypersensitivity reaction; 
• Severe uncontrolled infection; 
• Use of disallowed medication as defined in Section 6.5; 
• Pregnancy or planned pregnancy; or 
• Alexion or the Investigator deems it is necessary for the participant. 
Data to be collected at the time of discontinuation of study drug, including follow-up for any 
further evaluations that need to be completed is provided in the Schedule of Activities (SoA, 
Table 1). 
7.2. 
Patient Discontinuation/Withdrawal from the Study 
• When applicable, all efforts should be made to ensure patients are willing to comply 
with study participation prior to conducting the screening procedures. The study staff 
should notify Alexion and their site monitor of all study withdrawals as soon as 
possible. The reason for patient discontinuation must be recorded in the source 
documents and CRF/eCRF. 
• 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. This is expected to be uncommon. 
• At the time of discontinuing from the study, if possible, an ET visit should be 
conducted. Refer to the SoA (Table 1) for assessments to be collected at the time of 
study discontinuation and follow-up. 
• If the patient withdraws consent for disclosure of future information, Alexion may 
retain and continue to use any data collected before such a withdrawal of consent. 
• If a patient withdraws from the study, he/she may request destruction of any samples 
taken and not tested, and the Investigator must document this in the site study records. 
7.3. 
Lost to Follow-up 
If a patient is unreachable for a scheduled visit within the acceptable visit window (SoA, 
Table 1), the site study staff must make a reasonable attempt to contact the patient to determine 

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the reason for missing the visit. If the patient continues to be unreachable, he/she will be 
considered as lost to follow-up. 
Discontinuation of specific sites or of the study as a whole is handled as part of Section 10.1.8. 

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8. 
STUDY ASSESSMENTS AND PROCEDURES 
• Study procedures and their timing are summarized in the SoA (Table 1). The list of 
clinical laboratory tests to be performed is provided in Section 10.2. 
• Immediate safety concerns should be discussed with Alexion immediately upon 
occurrence or awareness to determine if the patient should continue or discontinue 
study intervention. 
• Adherence to the study design requirements, including those specified in the SoA 
(Table 1), is essential and required for study conduct. 
• All screening evaluations must be completed and reviewed to confirm that potential 
patients meet all eligibility criteria. The Investigator will maintain a screening log to 
record details of all patients screened and to confirm eligibility or record reasons for 
screening failure, as applicable. 
• Procedures conducted as part of the patient’s routine clinical management (eg, blood 
count) and obtained before signing of the informed consent form (ICF) may be 
utilized for screening or baseline purposes provided the procedures met the 
protocol-specified criteria and were performed within the time frame defined in the 
SoA (Section 1.3). 
8.1. 
Eligibility and Administrative Assessments 
8.1.1. 
Informed Consent 
Patients or their legally acceptable representative must be consented per the informed consent 
process outlined in Section 10.1.3. If allowable per local regulations, exceptions may be granted 
in cases where the patient is unable to provide informed consent. 
8.1.2. 
Inclusion and Exclusion Criteria 
All inclusion (Section 5.1) and exclusion (Section 5.2) criteria must be reviewed by the 
Investigator or qualified designee to ensure the patient qualifies for study participation. 
8.1.3. 
Medical History 
The patient’s relevant medical history, including prior and concomitant conditions/disorders, 
treatment history, and history of medical conditions (ie, cardiovascular and respiratory, including 
smoking status) will be evaluated by the Investigator and documented in the source documents 
and CRF/eCRF. Medical history should also include date of first onset of signs and symptoms of 
SARS-CoV-2 infection. 
8.1.4. 
Demographics 
A review of demographic parameters, including age, gender, race, and ethnicity will be 
performed, if allowable per local regulations. 

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8.1.5. 
Vaccination or Antibiotic Prophylaxis 
Confirmation of meningococcal vaccination within the past 5 years prior to dosing for patients 
randomized to ravulizumab + BSC. If vaccination cannot be confirmed, the patient should 
receive prophylactic antibiotics prior to initiating ravulizumab treatment and for at least 
8 months from the last infusion of ravulizumab. When patients are vaccinated less than 2 weeks 
prior to treatment with ravulizumab or after initiation of ravulizumab, they should continue 
antibiotic prophylaxis for at least 2 weeks after meningococcal vaccination. 
Additional guidance is provided in Section 8.4.9. 
8.2. 
Screening Assessments 
8.2.1. 
SARS-COV-2 Testing 
The SARS-CoV-2 infection will be evaluated at the designated hospital. A confirmed positive 
result (eg, via PCR and/or antibody test) is required before randomization. 
8.2.2. 
Chest Computed Tomography or X-ray 
Chest CT or X-ray scans will be performed during the Screening Period to confirm findings 
consistent with severe pneumonia, acute lung injury, or ARDS in patients with COVID-19. 
Scans performed during the course of the patient’s clinical care are accepted and expected to 
fulfil this diagnostic inclusion criterion for Study ALXN1210-COV-305. 
8.2.3. 
Pregnancy Testing 
Urine or serum pregnancy tests (beta human chorionic gonadotropin) will performed in all 
female patients. A negative pregnancy test result is required before administration of 
ravulizumab. 
8.3. 
Efficacy Assessments 
8.3.1. 
Primary Efficacy Assessments 
Survival at Day 29 will be determined. 
8.3.2. 
Secondary Efficacy Assessments 
The following secondary efficacy parameters will also be measured through Day 29: 
• Mechanical ventilation status, 
• Time in the intensive care unit (ICU), 
• Sequential Organ Failure Assessment (SOFA) score, 
• Oxygen saturation levels (peripheral capillary oxygen saturation [SpO2]), 
• Supplemental oxygen status (fraction of inspired oxygen [FiO2]), and 
• Duration of hospitalization.  
The following secondary efficacy parameter will be measured at Day 60 and Day 90: 

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• Survival (based on all-cause mortality) 
8.3.2.1. 
Sequential Organ Failure Assessment Score 
Multiple organ failure is a significant indicator of mortality in patients admitted to the ICU. In 
this study, patients will be evaluated using the SOFA score, an assessment tool that includes a 
review of 6 organ systems: respiratory, renal, hepatic, cardiac, coagulation, and central nervous 
system (Vincent, 1998). Each organ system is scored from 0 to 4 points using the worst value 
observed within the previous 24 hours (Table 7). 
Arterial blood gas may not be drawn on a protocol-specified visit day; therefore, the assessment 
of partial pressure of oxygen (PaO2) is optional and the highly correlated SpO2 will be a 
surrogate for the respiratory system assessment. 
Table 7: 
Sequential Organ Failure Assessment Scoring 
Organ System 
Variable 
(Units) 
Score Allocation 
0 
1 
2 
3 
4 
Respiratory 
PaO2/FiO2 
(mmHg)1 
 
 
 
 
SpO2/FiO2 
≥ 400 
 
 
 
 
 
≥ 302 
< 400 
 
 
 
 
 
< 302 
< 300 
 
 
 
 
 
< 221 
< 200 AND 
respiratory 
support (eg, 
mechanical 
ventilation) 
 
< 142 AND 
respiratory 
support (eg, 
mechanical 
ventilation) 
< 100 AND 
respiratory support 
(eg, mechanical 
ventilation) 
 
 
< 67 AND 
respiratory support 
(eg, mechanical 
ventilation) 
Renal 
Creatinine 
(μmol/L) 
< 110 
110 - 170 
171 - 299 
300 - 400 
> 440 
Hepatic 
Bilirubin 
(μmol/L) 
< 20 
20 - 32 
33 - 101 
102 - 204 
> 204 
Cardiac 
Inotropes 
(μg/kg/min) 
Mean 
arterial 
pressure 
> 70 mm
Hg 
Mean 
arterial 
pressure 
< 70 mm
Hg 
Dopamine 
≤ 5 
or 
Dobutamine 
any dose 
Dopamine > 5 
or 
Epinephrine 
≤ 0.1 
or 
Norepinephrine 
≤ 0.1 
Dopamine > 15 
or 
Epinephrine > 0.1 
or 
Norepinephrine 
> 0.1 
Coagulation 
Platelets 
(× 103/mm3) 
≥ 150 
< 150 
< 100 
< 50 
< 20 
CNS 
GCS 
15 
13 - 14 
10 - 12 
6 - 9 
< 6 
1.As arterial blood gas may not be drawn on a protocol-specified visit day, the PaO2 assessment is optional. 
Abbreviations: CNS = central nervous system; GCS = Glasgow Coma Scale; FiO2 = fraction of inspired oxygen; 
PaO2 = partial pressure of oxygen; SpO2 = peripheral capillary oxygen saturation. 
Source: Vincent, 1998; Pandharipande, 2006 
8.4. 
Safety Assessments 
8.4.1. 
Physical Examinations 
The following safety-related parameters will be measured through Day 29. 

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• Complete or abbreviated physical examinations will be assessed by the Investigator 
or designee. A complete physical examination will include, at a minimum, 
assessments of the skin, head, ears, eyes, nose, throat, neck, lymph nodes, chest, 
heart, abdomen, extremities, and musculoskeletal. An abbreviated physical 
examination will include at a minimum, assessment of the respiratory system and 
cardiovascular systems. 
• Body weight should be measured, but if the site does not have the capacity to measure 
the patient’s body weight it should be estimated using best judgement. 
Investigators or designees should pay special attention to clinical signs related to previous 
serious illnesses. Clinically significant abnormalities or findings will be recorded on the AE 
CRF/eCRF. 
8.4.2. 
Vital Sign Measurements 
Vital sign measurements will include systolic and diastolic blood pressure (millimeters of 
mercury [mm Hg]), heart rate (HR, beats/minute), respiratory rate (RR, breaths/minute), and 
temperature (degrees Celsius [°C] or degrees Fahrenheit [°F]). Vital sign measurements will be 
taken predose on dosing days. 
8.4.3. 
Electrocardiograms 
• A single 12-lead electrocardiogram (ECG) will be conducted to obtain HR, pulse rate 
(PR) interval, combination of the Q wave, R wave and S wave (QRS) interval, 
interval between the start of the Q wave and the end of the T wave (QT), and the 
corrected QT (QTc) interval(s). 
8.4.4. 
Clinical Safety Laboratory Assessments 
• The Investigator must review the laboratory report, document this review, and record 
any clinically relevant changes occurring during the study in the AE CRF/eCRF. The 
laboratory reports must be filed with the source documents. Clinically significant 
abnormal laboratory findings are those that are not associated with the underlying 
disease, unless judged by the Investigator or designee to be more severe than 
expected for the patient’s condition. 
• All laboratory tests with values considered clinically significantly abnormal during 
participation in the study should be repeated until the values return to normal or 
baseline or are no longer considered clinically significant by the Investigator or the 
Medical Monitor. 
− 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 Alexion 
notified. 
− All protocol-required laboratory assessments, as defined in Section 10.2, must be 
conducted in accordance with the Laboratory Manual and the SoA (Table 1). 
− Laboratory assessments performed at the institution’s local laboratory that require 
a change in patient management or are considered clinically significant by the 

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Investigator (eg, reported as an SAE or AE), must be recorded in the AE 
CRF/eCRF. 
8.4.5. 
Immunogenicity 
Details of immunogenicity assessments are presented in Section 8.12. 
8.4.6. 
Glasgow Coma Scale 
The Glasgow Coma Scale (GCS) is a validated prognostic tool used in the clinical assessment of 
unconsciousness (eg, patients who are comatose) (Sternbach, 2000).The GCS is comprised of 
3 domains – eye response, verbal response, and motor response and within each domain contains 
a subset of responses that are separately assigned a score (Table 8). The GCS has also been used 
in the critical care setting as an aid in managing respiratory support. A total GCS score of < 8 is 
indicative of a patient’s need for endotracheal intubation. The GCS will be measured to enable 
calculation of the secondary efficacy endpoint, SOFA score. 
Table 8: 
Glasgow Coma Scale 
Response 
Score 
Eye opening 
 
Spontaneous 
4 
To speech 
3 
To pain 
2 
None 
1 
Best verbal response 
 
Oriented 
5 
Confused conversation 
4 
Inappropriate words 
3 
Incomprehensible sounds 
2 
None 
1 
Best motor response 
 
Obeys commands 
6 
Localizes pain 
5 
Withdrawal (normal flexion) 
4 
Abnormal flexion (decorticate) 
3 
Extension (decerebrate) 
2 
None 
1 
Source: Sternbach, 2000 
8.4.7. 
Pregnancy 
• Pregnancy data from all female patients and female spouses/partners of male patients will 
be collected from the signing of the ICF until the conclusion of the study participation. If 
a pregnancy is reported, the Investigator must immediately inform Alexion within 
24 hours of awareness of the pregnancy and follow the procedures outlined in 
Section 10.4. 
• For all Alexion products, both in development or post-approval, exposure during 
pregnancy must be recorded and the pregnancy followed, until the outcome of the 
pregnancy is known (ie, spontaneous miscarriage, elective termination, normal birth, or 

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congenital abnormality), even if the patient discontinues the study intervention or 
withdraws from the study. The corresponding infant must be followed-up with for 
3 months postpartum. 
• Pregnancy is not considered as an AE (Section 10.4.3) unless there is a suspicion that 
ravulizumab 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) (Section 8.6). Elective 
abortions without complications should not be reported as AEs. 
8.4.8. 
Patient Safety Information Card 
When patients randomized to ravulizumab + BSC are able to understand, a Patient Safety 
Information Card will be provided to carry with them at all times. The card is provided to 
increase patient awareness of the risk of meningococcal infections, and promote quick 
recognition and disclosure of any potential signs or symptoms of infection experienced during 
the course of the study and to inform patients on what actions must be taken if they are 
experiencing signs or symptoms of infection. 
At each visit throughout the study, the study staff will ensure that the patient has the Patient 
Safety Information Card. Patients are required to carry the Patient Safety Information Card for 
8 months after the last infusion of ravulizumab. 
8.4.9. 
Vaccine and Antibiotic Prophylaxis 
It is anticipated that patients randomized to ravulizumab + BSC who have not received a 
meningococcal vaccination within the past 5 years may be unable to receive meningococcal 
vaccinations prior to initiating treatment with ravulizumab during this study. If vaccination 
cannot be confirmed, the patient should receive prophylactic antibiotics against meningococcal 
infection prior to initiating ravulizumab treatment and for at least 8 months from the last infusion 
of ravulizumab. 
When patients can be vaccinated, vaccines against meningococcal 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 the current national vaccination 
guidelines or local practice for vaccination use with complement inhibitors (eg, ravulizumab). 
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. 
When patients are vaccinated after initiation of ravulizumab, they should continue antibiotic 
prophylaxis for at least 2 weeks after meningococcal vaccination. 
8.4.10. 
Hospital Discharge 
If a patient is discharged before the end of the Primary Evaluation Period, the patient will be 
contacted via telephone on Day 29 to assess health status (survival, mechanical ventilation, 
hospitalization, intensive care unit, and dialysis). 

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8.4.11. 
Follow-up Monitoring 
Follow-up visits will be conducted as indicated in the SoA (Table 1) to review patient status; 
including survival, monitoring for pregnancy, and to obtain information about new or worsening 
treatment-emergent SAEs (TESAEs). The follow-up visits will be conducted as a telephone call 
if the patient is discharged from the hospital or an in person visit if the patient is still 
hospitalized. 
8.4.12. 
Early Termination 
If a patient is discontinued from the study during the Primary Evaluation Period (ie, from Day 1 
through Day 29), the patient should present for the Early Termination visit, to be conducted as 
specified in the SoA (Table 1). The patient will be contacted via telephone on Day 29 to assess 
health status (eg, survival, mechanical ventilation, hospitalization, intensive care unit, and 
dialysis). 
8.5. 
Exploratory Assessments 
The following exploratory parameters will also be measured: 
• Progression to renal failure requiring dialysis at Day 29 
8.5.1. 
Clinical Improvement at Day 29 
A reduction in the time to clinical improvement, especially when the patient is treated within a 
short timeframe from symptom onset has been reported in studies comparing antivirals to 
placebo (Wang, 2020). Time to clinical improvement will be evaluated during this study and is 
defined as a live discharge, a decrease from of least 2 points (ie, #5 to #3) from baseline, or both. 
A modified 6-category ordinal scale (itemized below) will be used to evaluated clinical 
improvement. 
1. Discharged 
2. Hospitalized, not requiring supplemental oxygen 
3. Hospitalized, requiring supplemental oxygen 
4. Hospitalized, requiring noninvasive mechanical ventilation 
5. Hospitalized, requiring invasive mechanical ventilation 
6. Death 
8.5.2. 
12-item Short Form at Days 29, 60, and 90 
The Short-Form (SF)-12 is a validated health-related quality of life (HR-QoL) instrument that is 
widely used across a broad spectrum of disease indications. Adapted from the 36 -item SF survey 
that was designed to evaluate physical and mental health status, the SF-12 survey contains only 
12 questions but covers the same 8 domains. There is a further stratification into 2 summary 
measures (Physical Component Summary [PCS-12] and Mental Component Summary 
[MCS-12]) as specified below. 
• PCS-12 

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− General health (1 item) 
− Physical functioning (2 items) 
− Role physical (2 items) 
− Body pain (1 item) 
• MCS-12 
− Vitality (1 item) 
− Social Functioning (1 item) 
− Role Emotional (2 items) 
− Mental Health (2 items) 
The PCS-12 and MCS-12 summary measures are scored using a norm-based method (ie, 
mean = 50, SD = 10) (Jenkinson, 1997). A PCS-12 or MCS-12 score of 50 indicates an average 
score with respect to a healthy population. Scores lower than 50 reflect less than average health 
and scores greater than 50 reflect better than average health (Ware, 1995). 
The SF-12 assumes a recall of 1 week before responding to questions. The survey is anticipated 
to be completed in several minutes and can be completed by the patient or via an interviewer 
(in-person or over the telephone). 
8.5.3. 
EuroQol-5 Dimension-5 Level at Days 29, 60, and 90 
The EuroQol 5-dimension, 5 severity level (EQ-5D-5L) questionnaire is a brief, validated, 
HR-QoL instrument that is intended to assess the patient’s health status at the time of 
administration. The questionnaire contains 5 dimensions (mobility, self-care, usual activities, 
pain/discomfort, and anxiety/depression), each of which includes 5 response variables (no 
problems, slight problems, moderate problems, severe problems, and extreme problems)  
(EQ - 5D, 2019) There is no summary score generated upon completion, but rather a 5-digit 
profile (termed “health state”) based on each of the dimensions that can be further converted to a 
single numerical score (index value).Value sets (a collection of index values) have been derived 
for multiple countries/regions. 
A vertical visual analogue scale (VAS) is included for patients to indicate a self-rated estimate of 
their health. The VAS ranges from 100 (best health you can imagine) to 0 (worst health you can 
imagine). 
The EQ-5D-5L questionnaire and VAS are anticipated to be completed in several minutes and 
can be completed by the patient, via an interviewer (in-person or over the telephone); or via 
proxy. 
8.6. 
Adverse Events and Serious Adverse Events  
The definitions of AEs and SAEs can be found in Section 10.3. 
All AEs will be reported to the Investigator or qualified designee by the patient (or, when 
appropriate, by a caregiver, surrogate, or the patient’s legally acceptable representative). 

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The Investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible for following 
up AEs that are serious, considered related to the study intervention or study procedures, or that 
caused the patient to discontinue the study intervention (see Section 7). 
Procedures for recording, evaluating, follow-up, and reporting AEs and SAEs are outlined in 
Section 10.3 (Appendix 3). 
8.6.1. 
Time Period and Frequency for Collecting AE and SAE Information 
All AEs and SAEs will be collected from the time of informed consent until through the 
timepoints specified in the SoA (Table 1). 
All SAEs will be recorded and reported to Alexion or the designee immediately and under no 
circumstance should this exceed 24 hours, as indicated in Section 10.3 (Appendix 3). The 
Investigator will submit any updated SAE data to Alexion within 24 hours of it being available. 
Investigators are not obligated to actively seek AE or SAE data after conclusion of the study 
participation. However, if the Investigator learns of any SAE, including a death, at any time after 
a patient has been discharged from the study, and he/she considers the event to be reasonably 
related to the study intervention or study participation, the Investigator must promptly notify 
Alexion. 
8.6.2. 
Method of Detecting AEs and SAEs  
The method of recording, evaluating, and assessing causality of AE and SAE and the procedures 
for completing and transmitting SAE reports are provided in Section 10.3. 
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. 
8.6.3. 
Follow-up of AEs and SAEs  
After the initial AE/SAE report, the Investigator is required to proactively follow-up on each 
patient at subsequent visits/contacts. All SAEs will be followed-up until resolution, stabilization, 
the event is otherwise explained, or the patient is lost to follow-up (as defined in Section 7.3). 
Further information on follow-up procedures is provided in Section 10.3. 
8.6.4. 
Regulatory Reporting Requirements for SAEs  
• Prompt notification of an SAE by the Investigator to Alexion is essential so that legal 
obligations and ethical responsibilities towards the safety of patients and the safety of 
a study intervention under clinical investigation are met. 
• Alexion has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study intervention under clinical 
investigation. Alexion will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, Institutional Review 
Board/Independent Ethics Committee (IRBs/IEC), and Investigators. 

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• Suspected unexpected serious adverse reactions (SUSARs) must be reported 
according to local regulatory requirements and Alexion 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 Alexion will 
review and then file it along with the IB and will notify the (IRB/IEC), if appropriate 
according to local requirements. 
8.6.5. 
Adverse Events of Special Interest 
Adverse events of special interest that will be monitored during this study are meningococcal 
infections. 
8.7. 
Treatment of Overdose 
No cases of ravulizumab overdose have been reported during clinical studies. Any dose of 
ravulizumab greater than that specified in the protocol will be considered an overdose. 
Overdoses are medication errors that are not considered TEAEs unless there is an untoward 
medical occurrence resulting from the overdose. 
In the event of an overdose, the Investigator or designee should: 
1. Contact the Medical Monitor immediately. 
2. Closely monitor the patient for any SAE. 
3. Obtain a plasma sample for PK analysis if requested by the Medical Monitor (determined 
on a case-by-case basis). 
4. Document the quantity of the excess dose as well as the duration of the overdose in the 
CRF/eCRF. 
8.8. 
Pharmacokinetics 
Samples will be collected from patients randomized to ravulizumab + BSC as specified in the 
SoA (Table 1) to determine serum concentrations of ravulizumab. The actual date and time 
(24-hour clock time) of each sample will be recorded. 
8.9. 
Pharmacodynamics 
Samples will be collected from all patients as specified in the SoA (Table 1) to assess the effect 
of ravulizumab on total and free C5 (for patients randomized to ravulizumab + BSC) and 
determine complement activation in patients randomized to BSC alone. The actual date and time 
(24-hour clock time) of each sample will be recorded. 
8.10. 
Genetics 
Genetics will not be evaluated in this study. 

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8.11. 
Biomarkers 
Serum and plasma samples will be collected from all patients for biomarker analysis to evaluate 
complement activation and related pathways and cardiovascular health, and their clinical 
response to ravulizumab. These biomarkers include complement pathway proteins (eg, total and 
free C5, soluble C5b-9 [sC5b-9]), cytokines associated with inflammation and disease (eg, IL-1, 
IL-2R, IL-6, IL-8, IL-21, tumor necrosis factor [TNF]-b, Pentraxin-3, Citrullinated histone H3, 
and monocyte chemoattractant protein [MCP]-1), Factor II, and markers associated with 
cardiovascular disease (procalcitonin, myoglobin, high sensitivity troponin I [hs-TnI] and 
N-terminal pro-b-type natriuretic peptide [NT-proBNP]). 
8.12. 
Immunogenicity  
Antibodies to ALXN1210 (ie, antidrug antibody [ADA]) will be evaluated in serum samples 
collected from patients randomized to ravulizumab + BSC according to the SoA (Table 1). 
Additionally, serum samples should also be collected at the final visit from patients who 
discontinued ravulizumab or were withdrawn from the study. These samples will be tested by 
Alexion or Alexion’s designee. 
Serum samples will be screened for antibodies binding to ravulizumab and the titer of confirmed 
positive samples will be reported. Other analyses may be performed to further characterize the 
immunogenicity of ravulizumab. 
The detection and characterization of antibodies to ravulizumab will be performed using a 
validated assay method. Samples collected for detection of antibodies to ravulizumab will also be 
evaluated for study intervention serum concentration to enable interpretation of the antibody 
data. Confirmed antibody positive samples will be further evaluated for antibody titer and the 
presence of neutralizing antibodies. 
8.13. 
Health Economics Data or Medical Resource Utilization 
Data collected during this study that may be used to conduct economic analyses include: 
• Duration of hospitalization (total days or length of stay), 
• Duration of ICU stay (including total days), and 
• Patient reported outcomes (eg, SF-12, version 2 and EQ-5D-5L). 

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9. 
STATISTICAL CONSIDERATIONS 
9.1. 
Statistical Hypotheses 
The primary null hypothesis is that there is no difference in survival between ravulizumab + BSC 
and BSC alone as measured by the difference in the proportions surviving at Day 29 between the 
2 treatment groups. The alternative hypothesis is that ravulizumab + BSC will improve survival 
at Day 29 compared with BSC alone. 
The null hypotheses associated with the secondary objectives are that ravulizumab + BSC is no 
different than BSC alone for the respective endpoints; the alternative hypotheses are described 
below: 
1. Number of days free of mechanical ventilation: The alternative hypothesis is that 
treatment with ravulizumab + BSC will increase the number days free of mechanical 
ventilation at Day 29 compared with BSC alone. 
2. Duration of ICU stay: The alternative hypothesis is that treatment with 
ravulizumab + BSC will reduce the number days in the ICU at Day 29 compared with 
BSC alone. 
3. Change in SOFA score: The alternative hypothesis is that treatment with 
ravulizumab + BSC will improve changes in SOFA score at Day 29 compared with 
BSC alone. 
4. Change in SpO2/FiO2: The alternative hypothesis is that treatment with 
ravulizumab + BSC will improve changes in SpO2/FiO2 at Day 29 compared with 
BSC alone. 
5. Duration of hospitalization: The alternative hypothesis is that treatment with 
ravulizumab + BSC will reduce the number days in the hospital at Day 29 compared with 
BSC alone. 
6. Survival (based on all-cause mortality) at Day 60 and Day 90: The alternative hypothesis 
is that ravulizumab + BSC will improve survival at Day 60 and Day 90 compared with 
BSC alone. 
9.2. 
Sample Size Determination 
A sample size of 243 patients (162 ravulizumab + BSC, 81 BSC alone) is required to ensure at 
least 90% power and detect an improvement in survival from 60% in the BSC alone group to 
80% in the ravulizumab + BSC group at Day 29. 
This sample size calculation assumes: 
• 1-sided Z-test of the difference in 2 proportions, 
• Type I error = 0.025, 
• Pooled variance, 
• 2:1 randomization on the 2 treatment groups, 

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• One interim analysis at 50% information which will be after collecting primary efficacy 
data on approximately 122 patients. The early stopping boundaries for efficacy and 
futility (nonbinding) will be constructed using α-spending function as Lan-DeMets 
spending function with O’Brien-Fleming flavor and β-spending function as Gamma(-4) 
(Lan, 1983; Hwang, 1990). 
Considering a nonevaluable rate of 10%, this study is planned to randomize approximately 
270 patients (180 ravulizumab + BSC, 90 BSC alone). 
9.3. 
Populations for Analyses 
The population sets used for analysis sets are defined in the following: 
Analysis Set 
Description 
Intent to Treat (ITT) 
The ITT consists of all randomized patients and participants will be analyzed 
as randomized. 
 
The ITT will be used for the analysis of efficacy data and is considered the 
primary analysis population. 
Per-Protocol Set (PPS) 
The PPS is a subset of the ITT without any important protocol deviations that 
could impact efficacy analyses. Determination of applicable important 
protocol deviations for this purpose will be made prior to database lock. 
 
The PPS will be used for sensitivity analyses of the primary and secondary 
efficacy endpoints. 
Safety Set (SS) 
The SS consists of all randomized patients who receive at least 1 dose of 
ravulizumab for patients randomized to ravulizumab + BSC or who were 
randomized to BSC alone. The SS will be used for the analysis of safety data. 
Abbreviation: BSC = best supportive care.  
9.4. 
Statistical Analyses 
The primary analysis will be conducted when all patients have completed the Primary Evaluation 
Period. This analysis will include all efficacy, safety, and available PK/PD/immunogenicity 
study data for regulatory submission purposes and will be the final analysis of the Primary 
Evaluation Period. 
Summary statistics will be presented by treatment group and by visit, where applicable. 
Descriptive statistics for continuous variables will minimally include the number of patients, 
mean, standard deviation, median, minimum, and maximum. For categorical variables, 
frequencies and percentages will be presented. Graphical displays will be provided as 
appropriate. All statistical analyses will be performed based on a 2-sided Type I error of 5%, 
unless otherwise noted. 
Baseline is defined as the last available assessment on or before Day 1 for all patients. Day 1 will 
be defined as the date of the first infusion of ravulizumab for patients randomized and dosed with 
ravulizumab and as the date of randomization for patients randomized but not dosed with 
ravulizumab. 
Analyses will be performed using SAS® software Version 9.4 or higher. 

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9.4.1. 
Efficacy Analyses 
9.4.1.1. 
Analyses of Primary Efficacy Endpoint 
The primary efficacy endpoint is survival (based on all-cause mortality) at Day 29 and will be 
compared between the 2 treatment groups using a 1-sided Mantel-Haenszel (MH) test of the 
difference in 2 proportions stratified by intubated or not intubated on Day 1 and a Type I error of 
0.025. The estimated MH risk difference will be summarized along with the 95% confidence 
interval using Mantel-Haenszel stratum weights (Mantel, 1959) and the Sato variance estimator 
(Sato, 1989). Missing survival data for the primary analysis will be imputed using a multiple 
imputation approach assuming the data are missing at random (MAR) using a logistic regression 
model with covariates for treatment group, the randomization stratification factor, age, sex, and 
presence of a pre-existing condition at baseline. Sensitivity analyses will include the worst-case, 
all available, and best-case scenarios. 
Survival will also be analyzed using the method of Kaplan and Meier (KM) and compared using 
a log-rank test stratified by intubated or not intubated on Day 1 as a sensitivity analysis. Hazard 
ratio and risk reduction will be summarized from a Cox proportional hazards model stratified by 
intubated or not intubated on Day 1. Confidence intervals (95%) will be presented for the 
survival estimate at Day 29 based on the complementary log-log transformation. Kaplan-Meier 
curves for both treatment groups will be produced. 
A sensitivity analysis of the primary endpoint will also be performed using a 3-level categorical 
outcome of 3) alive and discharged from the ICU; 2) alive and in the ICU or 1) death. The 
2 treatment groups will be compared using an ordinal logistic regression with covariates for 
treatment group and the randomization stratification factor. 
Additional sensitivity analyses will include statistical models adjusting for age, randomization 
stratification factor, and other important baseline covariates. Subgroup analyses will also be 
performed by age group, randomization stratification factor, and other important baseline 
covariates. The Statistical Analysis Plan (SAP) will describe the sensitivity and subgroup 
analyses in greater detail. 
An interim analysis of the primary endpoint will also be conducted as described in Section 9.5. 
9.4.1.2. 
Analyses of Secondary Efficacy Endpoints 
Number of days free of mechanical ventilation at Day 29 will be compared between treatment 
groups using an analysis of covariance (ANCOVA), adjusting for age, and randomization 
stratification factor, among survivors. Missing data will be imputed using a multiple imputation 
approach assuming the data are MAR. Sensitivity analyses will include the worst-case, all 
available, and best-case scenarios. 
Duration of ICU stay at Day 29 will be compared between treatment groups using an ANCOVA, 
adjusting for age and randomization stratification factor, among survivors. Missing data will be 
imputed using a multiple imputation approach assuming the data are MAR. Sensitivity analyses 
will include the worst-case, all available, and best-case scenarios. 
Changes in SOFA score from Day 1 to Day 29 will be summarized by treatment group and study 
visit for all patients and will be analyzed using a mixed model for repeated measures (MMRM) 
with baseline SOFA score, age, randomization stratification factor, treatment group indicator, 

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study day (Days 5, 10, 15, 22, and 29), and study day by treatment group interaction as 
covariates. Sensitivity analyses will include imputations for missing data. 
Change from baseline in SpO2/FiO2 at Day 29 will be analyzed using a MMRM with baseline 
SpO2/FiO2, age, randomization stratification factor, treatment group indicator, study day 
(Days 5, 10, 15, 22, and 29), and study day by treatment group interaction as covariates. All 
patients will be included in the model. Sensitivity analyses will include imputations for missing 
data. Change from baseline in PaO2/FiO2 at Day 29 will also be analyzed using a MMRM with 
baseline PaO2/FiO2, age, randomization stratification factor, treatment group indicator, study 
day, and study day by treatment group interaction as fixed covariates. All patients will be 
included in the model. Sensitivity analyses will include imputations for missing data.  
Duration of hospitalization at Day 29 will be analyzed in a similar manner as duration of ICU 
stay. 
Survival (based on all-cause mortality) at Day 60 and Day 90 will be estimated using the KM 
method and compared using a log-rank test stratified by intubated or not intubated on Day 1. 
Hazard ratio and risk reduction will be summarized from a Cox proportional hazards model 
stratified by intubated or not intubated on Day 1. Confidence intervals (95%) will be presented 
for the survival estimates at Day 60 and Day 90 based on the complementary loglog 
transformation. Kaplan and Meier curves for both treatment groups will be produced. 
9.4.1.3. 
Multiplicity Adjustment 
A closed testing procedure will be applied to control the type I error for the analyses of the 
primary and secondary endpoints. If the primary endpoint is statistically significant in favor of 
ravulizumab, the secondary endpoints will be evaluated according to the following rank order: 
1. Number of days free of mechanical ventilation at Day 29, 
2. Duration of ICU stay at Day 29, 
3. Change from baseline in SOFA score at Day 29, 
4. Change from baseline in SpO2/FiO2 at Day 29, 
5. Duration of hospitalization at Day 29. 
The hypothesis testing will proceed from highest rank (#1) the number of days free of 
mechanical ventilation at Day 29 to the lowest rank (#5) duration of hospitalization at Day 29, 
and if statistical significance is not achieved at an endpoint (p≥0.05), then endpoints of lower 
rank will not be considered to be statistically significant. Confidence intervals and p-values will 
be presented for all secondary efficacy endpoints for descriptive purposes, regardless of the 
outcome of the closed testing procedure. 
An additional secondary endpoint will be assessed beyond Day 29 regardless of the results of the 
closed testing procedure: Survival (based on all-cause mortality) at Day 60 and Day 90. 
9.4.2. 
Safety Analyses 
All safety analyses will be made on the Safety Set (SS). Safety results will be reported by 
treatment group. 

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The analysis and reporting of AEs and SAEs will be based on TEAEs and TESAEs, defined as 
AEs and SAEs with onset during or after treatment with ravulizumab. The incidence of TEAEs 
and TESAEs will be summarized by System Organ Class and Preferred Term, with additional 
summaries showing relationship to ravulizumab, severity, TEAEs or TESAEs leading to 
ravulizumab discontinuation, and TESAEs resulting in death. 
Laboratory measurements as well as their changes from baseline at each visit and shift from 
baseline, if applicable, will be summarized. Vital sign measurements, physical examination 
findings, and ECG data will also be summarized over time. 
9.4.3. 
Pharmacokinetic and Pharmacodynamic Analyses 
All patients who have evaluable PK/PD data will be used to summarize PK/PD parameters for 
ravulizumab. Descriptive statistics of ravulizumab concentration data will be presented for 
patients randomized and treated with ravulizumab for each scheduled sampling timepoint. 
Total and free C5 concentrations will be evaluated by assessing the absolute values and changes 
and percentage changes from baseline, as appropriate. Descriptive statistics will be presented by 
treatment group and for each scheduled sampling timepoint. 
9.4.4. 
Biomarker Analyses 
Serum and plasma biomarkers’ actual values, and changes from baseline, and their association 
with observed clinical responses to ravulizumab will be summarized over time, as appropriate. 
Biomarker data will only be summarized at the final analysis at the end of the study. 
9.4.5. 
Immunogenicity Analyses 
The incidence and titers for ADAs to ravulizumab will be summarized in tabular format by 
treatment group. The proportion of patients ever positive and the proportion of patients always 
negative may be explored. Confirmed ADA positive samples will be evaluated for the presence 
of neutralizing antibodies. 
9.4.6. 
Analyses of Exploratory Endpoints 
Incidence of and time to progression to renal failure requiring dialysis at Day 29 will be analyzed 
in a similar manner as the primary endpoint. 
Time to clinical improvement will be analyzed using the KM method and compared using a 
log-rank test stratified by intubated or not intubated on Day 1. 
The SF-12 PCS and MCS scores and EQ-5D-5L index and VAS scores will be analyzed using an 
ANCOVA, adjusting for age and the randomization stratification factor. 
9.5. 
Interim Analyses  
An interim analysis for efficacy and futility will be conducted when approximately 122 patients 
have completed Day 29. If the stopping criteria are met, the study may be terminated early for 
efficacy or futility depending on which stopping boundary is crossed. The early stopping 
boundaries for efficacy and futility (nonbinding) will be constructed using α-spending function 
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1-sided t-test based on the results from combining all imputed datasets for overall inference will 
be used with an overall Type I error of 0.025. 
The SAP will describe the planned interim analyses in greater detail. 
Provided the study was not stopped early for efficacy or futility, the final primary analysis will 
be conducted when all patients have completed the Primary Evaluation Period. This analysis will 
include all efficacy, safety, and available PK/PD/immunogenicity study data for regulatory 
submission purposes. This analysis will not be considered an interim analysis. 
9.5.1. 
Data Monitoring Committee 
An independent Data Monitoring Committee (DMC), comprising experts in relevant fields with 
no direct relationship to the study, will be appointed by Alexion. A minimum of 3 experts 
(including 1 biostatistician) will be selected. The DMC will review and evaluate cumulative 
safety data and key efficacy data at prespecified intervals. The DMC’s purview will include 
recommendations to continue or terminate the study. 
Final decisions regarding study conduct will be made by Alexion. Substantive decisions will be 
communicated to Investigators, IRBs/IECs, and appropriate regulatory authorities. 
The specific responsibilities of the DMC including frequency of meetings will be described in 
the DMC Charter. 

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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 Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines 
− Applicable International Council for Harmonisation of Technical Requirements 
for Pharmaceuticals for Human Use (ICH) Good Clinical Practice (GCP) 
Guidelines 
− Applicable laws and regulations 
• The protocol, protocol amendments, ICF, IB, and other relevant documents (eg, 
advertisements) must be submitted to an IRB/IEC by the Investigator and reviewed 
and approved by the IRB/IEC before the study is initiated. 
• 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. 
• For studies to be approved by Medicines and Healthcare products Regulatory 
Agency: The Investigator will notify the IRB/IEC of deviations from the study 
protocol or GCP as defined by UK legislation as a serious breach or as required by 
IRB/IEC procedures. 
• The Investigator will be responsible for the following: 
− Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC 
− Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures 
− Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC, European regulation 
536/2014 for clinical studies (if applicable), and all other applicable local 
regulations 
10.1.2. 
Financial Disclosure 
Investigators or designees and Sub-Investigators will provide Alexion with sufficient, accurate 
financial information as requested to allow Alexion to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators are 

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responsible for providing information on financial interests during the course of the study and for 
1 year after completion of the study. 
10.1.3. 
Informed Consent Process 
• It is the responsibility of the Investigator or designee to obtain informed consent from 
all patients or their legally acceptable representative as defined per local and country 
regulations where the study is taking place, and answer all questions regarding the 
study, prior to any study related procedures including screening assessments. 
• Where applicable by national laws and allowed by local regulations, and following 
IRB/IEC approval, patients who are unable to provide informed consent, and whose 
legally acceptable representative is unavailable, can be enrolled per the judgement of 
the Investigator or designee. 
• In the exceptional circumstance where informed consent cannot be obtained because 
of an inability to communicate with, or obtain legally effective consent from the 
patient and time is not sufficient to obtain consent from the patient's legally 
acceptable representative, the following procedure should be followed: 
− Written certification from the Investigator and a physician who is not involved 
with the research must be submitted to the IRB/IEC within 5 working days after 
administration of the initial dose. 
− If the patient is enrolled without their consent or that of their legally acceptable 
representative, all reasonable attempts should be made to inform the patient or 
their legally acceptable representative and/or family of the patient’s enrollment in 
the study as soon as possible. 
− Document efforts to contact the legally acceptable representative in the study 
records. 
• The Investigator or designee will explain the nature of the study (including but not 
limited to the objectives, potential benefits and risks, inconveniences, and the 
patient’s rights and responsibilities) to the patient or his/her legally acceptable 
representative, defined according to local and country regulations where the study is 
taking place, and answer all questions regarding the study. 
• Patients must be informed that their participation is voluntary. Patients or their legally 
acceptable representative will be required to sign a statement of informed consent or a 
certified translation if applicable, that meets the requirements of 21 CFR 50, local 
regulations, EU General Data Protection Regulation, ICH guidelines, Health 
Insurance Portability and Accountability Act requirements, where applicable, and the 
IRB/IEC or study center. 
• The patient’s medical record must include a statement that informed consent was 
obtained before the patient was screened in the study (or as soon as feasible in the 
case of emergency enrollment by the Investigator or designee) and date the written 
consent was obtained. The authorized person obtaining the informed consent must 
also sign the ICF(s). 

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• Patients must be reconsented to the most current version of the ICFs during their 
participation in the study. 
• A copy of the ICF must be provided to the patient or the patient’s legally acceptable 
representative, as applicable. This document may require translation into the local 
language. Documentation of ICFs must remain in each patient’s study file and must 
be available for verification at any time. 
10.1.4. 
Data Protection 
• Patients will be assigned a unique identifier by Alexion. Any patient records or 
datasets that are transferred to Alexion will contain the identifier only; patient names 
or any information which would make the patient identifiable will not be transferred. 
• Patients or their legally acceptable representative must be informed that their personal 
study-related data will be used by Alexion in accordance with local data protection 
law. The level of disclosure must also be explained to the patients who will be 
required to give consent for their data to be used as described in the informed consent. 
• Patients or their legally acceptable representative must be informed that their medical 
records may be examined by Clinical Quality Assurance auditors or other authorized 
personnel appointed by Alexion, by appropriate IRB/IEC members, and by inspectors 
from regulatory authorities. 
10.1.5. 
Dissemination of Clinical Study Data 
Study-related information and study results may be posted on publicly accessible clinical study 
databases (eg, the US website www.clinicaltrials.gov or the EU website 
www.clinicaltrialsregister.eu), as appropriate, and in accordance with national, regional, and 
local regulations. 
10.1.6. 
Data Quality Assurance 
• All patient data relating to the study will be recorded on printed or eCRF unless 
transmitted to Alexion or designee electronically (eg, laboratory data). The 
Investigator is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the eCRF. 
• The Investigator must maintain accurate documentation (source data) that supports 
the information entered in the CRF/eCRF. 
• The Investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents. 
• Alexion or designee is responsible for the data management of this study including 
quality checking of the data. 
• Study monitors will perform ongoing source data verification to confirm that data 
entered into the CRF/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 

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approved protocol and any other study agreements, ICH GCP, and all applicable 
regulatory requirements. 
− Due to the COVID-19 pandemic, remote source data verification may be 
employed where permitted by local regulations.  
− The scope of the source data verification will be described in detail in the 
Monitoring Plan. 
• Records and documents, including signed ICFs, pertaining to the conduct of this 
study must be retained by the Investigator for 2 years after the last marketing 
application approval, or if not approved, 2 years following the discontinuance of the 
study intervention, 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 Alexion. No records may be transferred to another location or 
party without written notification to Alexion. 
10.1.7. 
Source Documents 
Source documents provide evidence for the existence of the patient and substantiate the integrity 
of the data collected. The Investigator or designee will prepare and maintain adequate and 
accurate source documents (eg, 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/eCRF that are transcribed from source documents must be consistent 
with the source documents or the discrepancies must be explained. The Investigator may need to 
request previous medical records or transfer records, depending on the study. Also, current 
medical records must be available. Source documents are filed at the Investigator’s site. 
10.1.8. 
Study and Site Start and Closure 
The study start date is the date on which the first patient is consented. 
Alexion reserves the right to close the study site or terminate the study at any time for any reason 
at the sole discretion of Alexion. Study sites will be closed after the study is completed or 
following the decision to close or terminate the study. A study site is considered closed when all 
patients have completed the end of study or ET visit, all data have been collected and entered 
into electronic data capture (EDC) system, 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 Alexion 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, Alexion’s procedures, or GCP guidelines 
• Inadequate recruitment of patients by the Investigator 
• Discontinuation of further study intervention development 

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If the study is prematurely terminated or suspended, Alexion shall promptly inform the 
Investigators, the IRBs/IECs, the regulatory authorities, and any contract research 
organization(s) used in the study of the reason for termination or suspension, as specified by the 
applicable regulatory requirements. The Investigator shall promptly inform the patient and 
should assure appropriate patient therapy and/or follow-up. 
10.1.9. 
Publication Policy 
• Where possible, primary manuscripts reporting results of the primary efficacy 
endpoint or the final results will be submitted for publication within 12 to 18 months 
of the primary evaluation date or end of study, whichever is earlier. 
• Investigators who participate as authors in manuscripts derived from 
Alexion-sponsored studies will agree to the prerequisites as outlined in the Alexion 
author engagement agreement prior to engaging in manuscript development. 
• The Investigator agrees to submit proposals for new manuscripts (whether or not the 
proposed analyses are derived from protocol-specified endpoints) to Alexion for 
review and consideration. All manuscripts or abstracts emanating from approved 
proposals are to be submitted to Alexion for review before submission to the 
journal/society. This allows Alexion to protect proprietary information and to provide 
comments. 
− The proprietary nature of some development work may preclude publication. In 
some cases, it may be necessary to delay a publication to allow Alexion to ensure 
protection of intellectual property. 
• In general, primary publications, including congress and journal publications, 
containing the protocol-specified results of a study should occur prior to the 
publication of individual study site results or case reports. Alexion’s policy prohibits 
duplicate publication, whereby the same results must not be published in multiple 
peer-reviewed journal manuscripts. 
− Encore congress publications may be appropriate to allow communication of 
research findings to relevant audience and geographical regions. 
• Alexion will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, Alexion will generally 
support publication of multicenter studies only in their entirety and not as individual 
site data. In this case, a Coordinating Investigator will be designated by mutual 
agreement. 
• Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements and per the Alexion 
Publication Policy. 

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10.2. 
Appendix 2: Clinical Laboratory Tests 
• The tests listed in Table 9 may be performed by the local or central laboratory, as 
appropriate for all patients unless otherwise noted. 
• Protocol-specific requirements for inclusion or exclusion of patients are detailed in 
Section 5 of the protocol. 
• Additional tests may be performed at any time during the study as determined 
necessary by the Investigator or required by local regulations. 
• Women of childbearing potential should only be enrolled after a negative serum or 
urine pregnancy test result at Screening. Additional serum or urine pregnancy testing 
will be employed as required by site policies, local regulations, or per the 
requirements of the IRB/IEC and should be performed per the timepoints specified in 
the SoA (Table 1). 
• Investigators must document their review of each laboratory safety report. Clinically 
significant findings resulting in an assessment of a TESAE should be recorded on the 
AE CRF/eCRF. 
Table 9: 
Protocol-required Laboratory Assessments 
The following parameters may be analyzed by the local laboratory: 
Hematology Panel 
Haptoglobin 
Hematocrit 
Hemoglobin 
Platelet count  
WBC count  
WBC differential 
 
Coagulation Panel 
D-dimer 
International normalized ratio 
Partial thromboplastin time 
Prothrombin time 
Fibrinogen 
 
 
Urinalysis 
Albumin 
Creatinine 
Protein 
Clinical Chemistry Panel 
Alanine aminotransferase 
Aspartate aminotransferase 
Blood urea nitrogen 
C-reactive protein 
Creatinine 
Lactate dehydrogenase 
Sodium 
Total bilirubin (direct and indirect) 
Ferritin 
 
Other 
Arterial blood gas (when available) 
Beta human chorionic gonadotropin (all females of 
childbearing potential only; optional if urine pregnancy 
test is negative) 
Direct Coombs test 
 
The following parameters may be analyzed by the central laboratory or specialty laboratories: 

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Inflammatory Biomarkers 
IL1, IL-2R, IL-6, IL-8,IL-21, Pentraxin-3, and 
Citrullinated histone H3  
 
Complement Pathway Biomarkers 
Total and free C5 and sC5b-9 
 
Cardiac Biomarkers 
Procalcitonin  
Myoglobin 
NT-proBNP 
hs-TnI 
Other Biomarkers 
MCP-1 
TNF-b 
 
Immunogenicity assay 
(only collect from patients randomized to 
ravulizumab + BSC) 
 
Pharmacokinetic assay 
(only collect from patients randomized to 
ravulizumab + BSC) 
 
Coagulation Biomarker  
Factor II 
Abbreviations: BSC = best supportive care; C = complement protein; hs-TnI = high sensitivity troponin I; 
IL = interleukin, MCP = monocyte chemoattractant protein; NT-proBNP = N-terminal pro b-type natriuretic 
peptide; sC5b-9 = soluble C5b-9; TNF = tumor necrosis factor; WBC = white blood cell. 

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10.3. 
Appendix 3: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting 
10.3.1. 
Definition of AE 
AE Definition 
• 
An AE is any untoward medical occurrence in a patient, temporally associated with the use of study 
intervention, whether or not considered related to the study intervention. 
• 
Note: An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease (new or exacerbated) temporally associated with the use of study intervention. 
Events Meeting the AE Definition  
• 
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or other safety 
assessments (eg, ECG, radiological scans, vital signs measurements), including those that worsen from 
baseline, considered clinically significant in the medical and scientific judgment of the Investigator (ie, not 
related to progression of underlying disease). 
• 
Exacerbation of a chronic or intermittent pre-existing condition including either an increase in frequency 
and/or intensity of the condition. 
• 
New conditions detected or diagnosed after study intervention administration even though it may have been 
present before the start of the study. 
• 
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
• 
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study intervention or a 
concomitant medication. Overdose per se will not be reported as an AE/SAE unless it is an intentional 
overdose taken with possible suicidal/self-harming intent. Such overdoses should be reported regardless of 
sequelae. 
• 
 “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 fulfill the definition of 
an AE or SAE. 
 
Events Not Meeting the AE 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. 
• 
A medication error (including intentional misuse, abuse, and overdose of the product) or use other than what 
is defined in the protocol is not considered an AE unless there is an untoward medical occurrence as a result 
of a medication error. 
• 
Cases of pregnancy that occur during maternal or paternal exposure to study intervention 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. 
• 
Any clinically significant abnormal laboratory findings or other abnormal safety assessments which are 
associated with the underlying disease, unless judged by the Investigator to be more severe than expected for 
the patient’s condition. 
• 
The disease/disorder being studied or expected progression, signs, or symptoms of the disease/disorder being 
studied, unless more severe than expected for the patient’s condition. 
• 
Situations in which an untoward medical occurrence did not occur (social and/or convenience admission to a 
hospital). 

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10.3.2. 
Definition of SAE 
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). 
An SAE 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 
was 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 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. 
• 
Examples of such events include invasive or malignant cancers, intensive treatment in an emergency room 
or at home for allergic bronchospasm, blood dyscrasias or convulsions that do not result in hospitalization, 
or development of drug dependency or drug abuse. 
10.3.3. 
Recording and Follow-Up of AE and/or SAE 
Recording of AE and/or SAE 
• 
When an AE/SAE occurs, it is the responsibility of the Investigator to review all documentation (eg, hospital 
progress notes, laboratory reports, and diagnostics reports) related to the event. 
• 
The Investigator will then record all relevant AE/SAE information in the CRF/eCRF. 
• 
It is not acceptable for the Investigator to send photocopies of the patient’s medical records to Alexion in 
lieu of completion of the Alexion/AE/SAE CRF/eCRF page. 
• 
There may be instances when copies of medical records for certain cases are requested by Alexion. In this 
case, all patient identifiers, with the exception of the patient number, will be redacted on the copies of the 
medical records before submission to Alexion. 
• 
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 Intensity 
The Investigator will make an assessment of intensity for each AE and SAE reported during the study and assign 
it to one of the following categories from National Cancer Institute CTCAE v5.0, published 27 Nov 2017: 
• 
Grade 1: Mild (awareness of sign or symptom, but easily tolerated) 
• 
Grade 2: Moderate (discomfort sufficient to cause interference with normal activities) 

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• 
Grade 3: Severe (incapacitating, with inability to perform normal activities) 
• 
Grade 4: Life-threatening 
• 
Grade 5: Fatal 
• 
An event is defined as “serious” when it meets at least one of the predefined outcomes as described in the 
definition of an SAE, not when it is rated as severe. 
Assessment of Causality 
• 
The Investigator is obligated to assess the relationship between the study intervention and each occurrence 
of each AE or SAE. An Investigator causality assessment must be provided for all AEs (both nonserious and 
serious). This assessment must be recorded in the CRF/eCRF and on any additional forms, as appropriate. 
The definitions for the causality assessments are as follows: 
− 
Not related: There is no reasonable possibility the study intervention caused the AE. 
 
The AE has a more likely alternative etiology; it may be due to underlying or 
concurrent illness, complications, concurrent treatments, or effects of another 
concurrent drug. 
 
The event does not follow a reasonable temporal relationship to administration of the 
study intervention. 
− 
Related: There is a reasonable possibility the study intervention caused the AE. 
 
The AE has a temporal relationship to the administration of the study intervention. 
 
The event does not have a likely alternative etiology.  
 
The event corresponds with the known pharmaceutical profile of the study 
intervention. 
 
There is improvement on discontinuation and/or reappearance on rechallenge. 
• 
The Investigator will use clinical judgment to determine the relationship. 
• 
Alternative causes, such as underlying disease(s), concomitant therapy, and other risk factors, as well as the 
temporal relationship of the event to study intervention administration will be considered and investigated. 
• 
The Investigator will also consult the IB and/or Product Information, for marketed products, in his/her 
assessment. 
• 
For each AE/SAE, the Investigator must document in the medical notes that he/she has reviewed the 
AE/SAE and has provided an assessment of causality. 
• 
There may be situations in which an SAE has occurred, and the Investigator has minimal information to 
include in the initial report to Alexion. 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. 
• 
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 AEs and SAEs 
• 
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 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. 
• 
New or updated information will be recorded in the originally completed CRF/eCRF. 
• 
The Investigator will submit any updated SAE data to Alexion within 24 hours of receipt of the 
information. 
10.3.4. 
Reporting of SAEs  
SAE Reporting to Alexion via an Electronic Data Collection Tool 
• 
All SAEs will be recorded and reported to Alexion or designee immediately and within 24 hours of 
awareness. 
• 
The primary mechanism for reporting an SAE to Alexion will be the electronic data collection tool. 
• 
If the electronic system is unavailable at the time that the Investigator or site becomes aware of an SAE, the 
site will use the paper Contingency Form for SAE reporting via fax or email. Facsimile transmission or 
email may be used in the event of electronic submission failure. 
− 
Email: 
 or Fax: 
 
• 
The site will enter the SAE data into the EDC system as soon as it becomes available. 
PPD
PPD

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• 
When further information becomes available, the EDC should be updated within 24 hours with the new 
information and an updated SAE report should be submitted to Alexion global drug safety (GDS). 
• 
After the study is completed at a given site, the electronic data collection tool will be taken off-line 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 off-line, then the site can report this 
information on a paper SAE form (see next section) or to the Alexion/Medical Monitor/SAE Coordinator 
by telephone. 
SAE Reporting to Alexion via Paper Safety Reporting Form 
• 
All SAEs will be recorded and reported to Alexion or designee immediately and within 24 hours 
awareness. 
• 
SAEs will be reported using the Safety Reporting Form and submitted to Alexion GDS. The Investigator 
must complete, sign, and date the SAE pages, verify the accuracy of the information recorded on the SAE 
pages with the corresponding source documents, and send a copy via email or facsimile to the contact 
information provided below: 
− 
Email: 
 or Fax: 
 
• 
Additional follow-up information, if required or available, should be entered into the CRF/eCRF and sent 
to Alexion GDS within 24 hours of the Investigator or study site staff becoming aware of this additional 
information via the reporting process outlined above. 
• 
For all SAEs, the Investigator must provide the following: 
− 
Appropriate and requested follow-up information in the time frame detailed above 
− 
Causality of the SAE(s) 
− 
Treatment of/intervention for the SAE(s) 
− 
Outcome of the SAE(s) 
− 
Medical records and laboratory/diagnostic information 
• 
All paper forms and follow-up information submitted to Alexion GDS must be accompanied by a cover 
page signed by the Investigator. 
• 
Paper source documents and/or reports should be kept in the appropriate section of the study file. 
PPD
PPD

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10.4. 
Appendix 4: Contraceptive Guidance and Collection of Pregnancy 
Information 
10.4.1. 
Definitions 
Woman of Childbearing Potential (WOCBP) 
A woman is considered fertile following menarche and until becoming postmenopausal unless 
permanently sterile (see below). 
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot be 
confirmed before administering the dose of study intervention, additional evaluation should be 
considered. 
Women in the following categories are not considered WOCBP 
1. Premenarchal 
2. Premenopausal female with one of the following: 
• Documented hysterectomy 
• Documented bilateral salpingectomy 
• Documented bilateral oophorectomy 
• For individuals with permanent infertility due to an alternate medical cause other than 
the above, (eg, Mullerian agenesis, androgen insensitivity), Investigator discretion 
should be applied to determining study entry. 
• Note: Documentation can come from the site personnel’s: review of the patient’s 
medical records, medical examination, or medical history interview. 
3. Postmenopausal female 
• A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. 
− A high follicle stimulating hormone (FSH) level in the postmenopausal range may 
be used to confirm a postmenopausal state in women not using hormonal 
contraception or hormonal replacement therapy (HRT). However, in the absence 
of 12 months of amenorrhea, confirmation with more than 1 FSH measurement is 
required. 
• Females on HRT and whose menopausal status is in doubt will be required to use one 
of the non-estrogen hormonal highly effective contraception methods if they wish to 
continue their HRT during the study. Otherwise, they must discontinue HRT to allow 
confirmation of postmenopausal status before study enrollment. 
10.4.2. 
Contraception Guidance 
10.4.2.1. Guidance for Female Patients 
Female patients of non-childbearing potential are exempt from contraception requirements. Non-
childbearing potential for female patients is defined as any of the following: 

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1. Prior to first menses 
2. Postmenopausal, as documented by amenorrhea for at least 1 year prior to the Day 1 visit 
and FSH serum levels consistent with postmenopausal status 
3. Permanent sterilization at least 6 weeks prior to the Day 1 visit: 
4. Hysteroscopic sterilization 
5. Bilateral tubal ligation or bilateral salpingectomy 
6. Hysterectomy 
7. Bilateral oophorectomy 
Female patients of childbearing potential must use a highly effective method of contraception, 
including at least one of the following: 
1. Intrauterine device (without copper) in place for at least 6 weeks. 
2. Progestogen-only hormonal contraception (either oral, injectable, or implantable) for at 
least 6 weeks. 
3. Intrauterine progestogen releasing system for at least 6 weeks. 
4. Bilateral tubal occlusion for at least 6 weeks. 
5. Combined (estrogen- and progestogen-containing) hormonal contraception (either oral, 
intravaginal, or transdermal) for at least 6 weeks. Estrogen-containing hormonal 
contraception is acceptable only if it has been used for at least 6 weeks immediately prior 
to the Day 1 visit. Estrogen-containing hormonal contraception may not be initiated 
during the study period. 
6.  Surgical sterilization of the male partner (medical assessment of azoospermia is required 
if vasectomy was performed within the prior 6 months). 
7. Sexual abstinence for female patients:  
a. Sexual abstinence is considered a highly effective method only if defined as 
refraining from heterosexual intercourse. In this study, abstinence is only acceptable 
if consistent with the patient’s preferred and usual lifestyle. Abstinent female patients 
who wish to initiate a highly effective method of contraception during the study must 
refrain from heterosexual intercourse for at least 1 menstrual cycle. 
b. Periodic abstinence (eg, calendar, symptothermal, or post-ovulation methods) is not 
considered a highly effective method of contraception for female patients. 
Other methods of contraception that are not considered highly effective for female patients: 
1. Barrier methods, such as male or female condoms, diaphragm, or cervical cap, used alone 
or in combination, are not acceptable. 
2. Spermicides or spermicidal sponges, used alone or in combination with barrier methods, 
are not acceptable. 
Withdrawal (coitus interruptus) is not acceptable. 
Lactational amenorrhea is not acceptable. 

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Female patients randomized to ravulizumab + BSC must not donate ova from the Day 1 visit 
until 8 months after treatment with the last infusion of study drug. 
10.4.2.2. Guidance for Male Patients 
Contraception is the responsibility of the heterosexually active male patients, regardless of his 
female partner’s method of contraception. 
Male patients who have had a vasectomy > 6 months prior must use a condom during 
heterosexual intercourse. Male patients who have had a vasectomy < 6 months prior must use a 
condom and spermicide during heterosexual intercourse. 
Male patients who have not had a vasectomy must use a condom and spermicide during 
heterosexual intercourse from the Day 1 visit until 8 months after treatment with the last infusion 
of study drug. 
10.4.2.2.1. Sexual Abstinence for Male Patients 
Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse. In this study, abstinence is only acceptable if consistent with the 
patients’ s preferred and usual lifestyle. Abstinent male patients who become heterosexually 
active must use a condom and spermicide during intercourse. 
Periodic abstinence (eg, calendar, symptothermal, or post-ovulation methods for a female 
partner) is not considered a highly effective method of contraception for male patients. 
Male patients randomized to ravulizumab + BSC must not donate sperm from the Day 1 visit 
until 8 months after treatment with the last infusion of study drug. 
10.4.3. 
Collection of Pregnancy Information 
Pregnancy data will be collected during this study for all female patients and female 
spouses/partners of male patients. Exposure during pregnancy (also referred to as exposure in 
utero) can be the result of either maternal exposure or transmission of study intervention 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. 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 study intervention 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. 
Pregnancy is not regarded as an AE unless there is a suspicion that the study intervention 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. 

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Any female patient who becomes pregnant while participating in the study will be discontinued 
from study intervention. 
10.4.3.1. Male Patients With Partners Who Become Pregnant 
• The Investigator will attempt to collect pregnancy information on any male patient’s 
female partner who becomes pregnant while the male patient is in this study. This 
applies only to male patients who receive ravulizumab. 
• After obtaining the necessary signed informed consent from the pregnant female 
partner directly, the Investigator will record pregnancy information on the appropriate 
Pregnancy Outcome/Breastfeeding form and submit it to Alexion within 24 hours of 
learning of the partner’s pregnancy. The female partner will also be followed to 
determine the outcome of the pregnancy. Information on the status of the mother and 
child will be forwarded to Alexion. Generally, the follow-up will be no longer than 6 
to 8 weeks following the estimated delivery date. Any termination of the pregnancy 
will be reported regardless of fetal status (presence or absence of anomalies) or 
indication for the procedure. 
10.4.3.2. Female Patients Who Become Pregnant 
• The Investigator will collect pregnancy information on any female patient who 
becomes pregnant while participating in this study. The initial Information will be 
recorded on the appropriate form and submitted to Alexion within 24 hours of 
learning of a patient’s pregnancy. 
• The patient will be followed-up to determine the outcome of the pregnancy. The 
Investigator will collect follow-up information on the patient and the neonate and the 
information will be forwarded to Alexion. Generally, follow-up will not be required 
for longer than 3 months beyond the estimated delivery date. Any termination of 
pregnancy will be reported, regardless of fetal status (presence or absence of 
anomalies) or indication for the procedure. 
• While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy for medical reasons will be 
reported as an AE or SAE. A spontaneous abortion (occurring at < 22 weeks 
gestational age) or still birth (occurring at > 22 weeks gestational age) is always 
considered to be an SAE and will be reported as such. Any post-study pregnancy 
related SAE considered reasonably related to the study intervention by the 
Investigator will be reported to Alexion as described in Section 8.6.4. While the 
Investigator is not obligated to actively seek this information in former study patients, 
he or she may learn of an SAE through spontaneous reporting. 

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10.5. 
Appendix 5: Biomarkers 
• Blood samples will be collected for biomarker analyses and the data may be used for 
future exploratory research related to complement activation and inflammatory 
processes. The samples may also be used to develop tests/assays including diagnostic 
tests related to C5 inhibitors and COVID-19 with clinical presentation of severe 
pneumonia, acute lung injury, or ARDS. 
• The samples may be analyzed as part of a multistudy assessment of biomarkers in the 
response to ravulizumab to understand COVID-19 or related conditions. 
• The results of biomarker analyses may be reported in a final clinical study report or in 
a separate summary report. 
• Alexion or designee will store the samples obtained for biomarker analyses in a 
secure storage space with adequate measures to protect confidentiality. 

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10.6. 
Appendix 6: Management of Potential Drug Infusion Reactions 
Intravenous and infusion-associated reactions are a potential risk with the use of monoclonal 
antibodies; these reactions can be nonimmune or immune mediated (eg, hypersensitivity 
reactions). Signs and symptoms may include headache, fever, facial flushing, pruritus, myalgia, 
nausea, chest tightness, dyspnea, vomiting, erythema, abdominal discomfort, diaphoresis, 
shivers, hypertension, lightheadedness, hypotension, palpitations, and somnolence. Signs and 
symptoms of hypersensitivity or allergic reactions may include hives, swollen face, eyelids, lips, 
or tongue, or trouble with breathing. 
All administration-, IV-, and infusion-associated reactions will be reported to the Investigator 
and qualified designee. The Investigator and qualified designee are responsible for detecting, 
documenting, and recording events that meet the definition of AE or SAE and remain 
responsible for following up events that are serious, considered related to the study drug, or 
study procedures; or that caused the participant to discontinue ravulizumab (Section 7). 
Definitions and procedures for recording, evaluating, follow-up, and reporting AEs and SAEs are 
outlined in Section 10.3. 
Before any infusion is started, the treating physician and other appropriate personnel must make 
certain that medication (ie, adrenaline, inhaled beta agonists, antihistamines, corticosteroids) and 
other equipment to treat anaphylaxis are readily available. The infusion must be stopped 
immediately if Grade ≥ 2 allergic/hypersensitivity reactions (including drug fever) or Grade ≥ 3 
cytokine release syndrome/acute infusion reaction occurs. The Sponsor must be notified within 
24 hours of any infusion reaction requiring interruption or discontinuation of study drug. 
Patients who experience a reaction during the administration of study drug should be treated 
according to institutional guidelines. For a Grade 1 or Grade 2 infusion reaction, the infusion 
should be temporarily stopped and treatment with an antihistamine (eg, diphenhydramine 25 to 
50 mg orally or equivalent) and acetaminophen (650 mg orally or equivalent) may be considered. 
If the patient’s signs and symptoms have resolved (with or without administration of the above 
medication), the infusion may be restarted. However, the patients should be infused at a slower 
rate and be monitored closely for any signs and symptoms of infusion reactions during the 
remainder of the infusion. Patients experiencing an infusion reaction should be observed in the 
clinic until resolution of the reaction, or until the Investigator determines the patient is no longer 
at risk. 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. 
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. 

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Table 10: 
Clinical Criteria for Diagnosing Anaphylaxis 
Anaphylaxis is highly likely when any 1 of the following 3 criteria is fulfilled: 
• 
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: 
o 
Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, reduced peak expiratory flow, 
hypoxemia) 
o 
Reduced blood pressure or associated symptoms of end-organ dysfunction (eg, hypotonia [collapse], 
syncope, incontinence)  
• 
Two or more of the following that occur rapidly after exposure to a likely allergen for that participant 
(minutes to several hours): 
o 
Involvement of the skin-mucosal tissue (eg, generalized hives, itch-flush, swollen lips/tongue/uvula) 
o 
Respiratory compromise (eg, dyspnea, wheeze/bronchospasm, stridor, reduced peak expiratory flow, 
hypoxemia) 
o 
Reduced blood pressure or associated symptoms (eg, hypotonia [collapse], syncope, incontinence) 
o 
Persistent gastrointestinal symptoms (eg, crampy abdominal pain, vomiting)  
• 
Reduced blood pressure after exposure to known allergen for that participant (minutes to several hours): 
o 
Systolic blood pressure of less than 90 mmHg or greater than 30% decrease from that participant’s 
baseline 
Source: (Sampson, 2006) 

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10.7. 
Appendix 7: Protocol Amendment History  
The Protocol Amendment Summary of Changes table for the current amendment is located 
directly before the Table of Contents. 
DOCUMENT HISTORY 
Document 
Date 
Summary of Key Changes in the Amendment 
Amendment 2.3 (France) 
08 May 2020 
• 
Updates implemented in this protocol amendment were 
based on Ethics Committee feedback. 
o 
Added specific informed consent measures to be 
instituted for patients enrolled in France. 
Amendment 2.2 (France) 
08 May 2020 
• 
Updates implemented in this protocol amendment were 
based on Health Authority feedback. 
o 
Removed 2 prohibited medications (ie, rituximab 
and mitoxantrone) as their use is not 
contraindicated in the treatment of patients with 
Coronavirus Disease 2019 severe pneumonia, acute 
lung injury, or acute respiratory distress syndrome. 
Amendment 2.1 (Germany) 
08 May 2020 
• 
Updates implemented in this protocol amendment were 
based on Health Authority feedback. High-level changes 
were incorporated as follows. 
o 
To allow enrollment of patients not currently 
vaccinated against Neisseria meningitidis but who 
will receive prophylactic antibiotic treatment for at 
least 8 months after last infusion of study drug or 
until 2 weeks after they receive vaccination against 
N. meningitidis 
o 
Added statement that antivirals may be 
administered as a part of best supportive care 
Amendment 2 (Global) 
17 Apr 2020 
• 
Updates implemented in this protocol amendment were 
based on Health Authority feedback. High-level changes 
were incorporated as follows. 
o 
To relocate “Survival (based on all-cause mortality) 
at Day 60 and Day 90” from the list of exploratory 
endpoints to the list of secondary endpoints 
o 
To clarify that patients discharged from the hospital 
before the end of the Primary Evaluation Period 
will be contacted via telephone on Day 29 to 
determine health status (eg, survival, mechanical 
ventilation, hospitalization, intensive care unit, and 
dialysis) 
o 
To remove the definition of Full Analysis Set and 
add definition of Intent to Treat 
o 
To revise analyses of selected endpoints 
Amendment 1 (Global) 
13 Apr 2020 
• 
To clarify the informed consent process for patients who are 
unconscious and whose legally acceptable representative is 
not immediately available 
• 
To append Investigator guidance regarding the management 
of potential drug infusion reactions during ravulizumab 
administration. 
Original Protocol (Global) 
09 Apr 2020 
Not applicable 
 

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10.8. 
Appendix 8: Abbreviations 
Abbreviated or Specialist Term 
Explanation 
ADA 
antidrug antibody 
AE 
adverse event 
aHUS 
atypical hemolytic uremic syndrome 
ANCOVA 
analysis of covariance 
ARDS 
acute respiratory distress syndrome 
BiPAP 
bilevel positive airway pressure 
BSC 
best supportive care 
C3 
complement component 3 
C5 
complement component 5 
C5a 
complement component 5a 
C5aR 
C5a receptor 
C5b-9 
terminal complement complex 
CIOMS 
Council for International Organizations of Medical Sciences 
CONSORT 
Consolidated Standards of Reporting Trials 
CoV 
coronavirus 
COVID-19 
Coronavirus Disease 2019 
CPAP 
continuous positive airway pressure 
CRF 
case report form 
CT 
computed tomography 
DMC 
Data Monitoring Committee 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EDC 
electronic data capture 
EQ-5D-5L 
EuroQol-5 Dimension-5 Level 
ET 
early terminated/termination 
FiO2 
fraction of inspired oxygen 
FSH 
follicle stimulating hormone 
GCP 
Good Clinical Practice 
GCS 
Glasgow Coma Scale 
GDS 
global drug safety 
HR 
heart rate 
HRT 
hormonal replacement therapy 
hs-TnI 
high sensitivity troponin I 
HSCT-TMA 
thrombotic microangiopathy following hematopoietic stem-cell transplant 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
ICU 
intensive care unit 
ITT 
intent-to-treat 
IEC 
Independent Ethics Committee 
IFN 
interferon 
IL 
interleukin 
IRB 
Institutional Review Board 
IV 
intravenous 
IVIg 
intravenous immunoglobulin 
KM 
Kaplan-Meier 
mAb 
monoclonal antibody 
MAR 
missing at random 
MASP-2 
MBL-associated serine protease-2 
MBL 
mannose-binding lectin 

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Abbreviated or Specialist Term 
Explanation 
MCP 
monocyte chemoattractant protein 
MCS 
Mental Component Summary 
MERS-CoV 
Middle East respiratory syndrome coronavirus 
MH 
Mantel-Haenszel 
MMRM 
mixed model for repeated measures 
NT-proBNP 
N-terminal pro b-type natriuretic peptide 
PaO2 
partial pressure of oxygen 
PCR 
polymerase chain reaction 
PCS 
Physical Component Summary 
PD 
pharmacodynamic 
PK 
pharmacokinetic 
PNH 
paroxysmal nocturnal hemoglobinuria 
PPS 
Per Protocol Set 
PR 
pulse rate 
QRS 
combination of the Q wave, R wave and S wave 
QT 
interval between the start of the Q wave and the end of the T wave 
QTc 
corrected QT interval 
RR 
respiratory rate 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SARS 
severe acute respiratory syndrome 
SARS-CoV-2 
severe acute respiratory syndrome coronavirus 2 
SARS-CoV 
severe acute respiratory syndrome coronavirus 
sC5b-9 
soluble C5b-9 
SF-12 
12-item Short Form 
SoA 
Schedule of Activities 
SOFA 
Sequential Organ Failure Assessment 
SpO2 
peripheral capillary oxygen saturation 
SS 
Safety Set 
SUSAR 
suspected unexpected serious adverse reaction 
TNF 
tumor necrosis factor 
TEAE 
treatment-emergent adverse event 
TESAE 
treatment-emergent serious adverse event 
VAS 
Visual Analogue Scale 
WHO 
World Health Organization 
WOCBP 
Woman of childbearing potential 

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11. 
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