A Phase 3, Randomized, Double-blind, Placebo-Controlled, Multicenter Study to Evaluate the Efficacy and Safety of Ravulizumab in Adult Participants Who Have Thrombotic Microangiopathy Associated With a Trigger
Phase: PHASE3
Conditions: Thrombotic Microangiopathy
Sponsor: Alexion Pharmaceuticals, Inc.

Protocol Amendment 2 
10 Nov 2021 
ALXN1210-TMA-315 
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Alexion Confidential 
TITLE PAGE 
Protocol Title: A Phase 3, Randomized, Double-blind, Placebo-Controlled, Multicenter Study to 
Evaluate the Efficacy and Safety of Ravulizumab in Adult Participants Who Have Thrombotic 
Microangiopathy Associated With a Trigger 
Protocol Number: ALXN1210-TMA-315 
Amendment Number: Protocol Amendment 2 (Global) 
Compound: Ravulizumab (ALXN1210) 
Study Phase: 3 
Short Title: Phase 3 Study of Ravulizumab in Thrombotic Microangiopathy Associated With a 
Trigger 
Sponsor Name: Alexion Pharmaceuticals Inc. 
Legal Registered Address: 121 Seaport Boulevard, Boston, MA 02210, USA 
Regulatory Agency Identifier Number(s) 
IND: 128367 
EudraCT: 2020-005328-13 
Release Date: 10 Nov 2021 
Sponsor Signatory: 
11-Nov-2021 | 13:20:40 EST
Alexion Pharmaceuticals Inc. 
Date 
Medical Monitor Contact Information can be found in the Study Reference Manual 
distributed to study sites. 

Protocol Amendment 2 
ALXN1210-TMA-315 
10 Nov 2021 
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Alexion Confidential 
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 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 
 
 

Protocol Amendment 2 
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10 Nov 2021 
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PROTOCOL AMENDMENT SUMMARY OF CHANGES  
Amendment 2 (Global) (10 Nov 2021) 
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of 
Directive 2001/20/EC of the European Parliament and the Council of the European Union. 
Overall Rationale for the Amendment: 
The primary driver for this amendment is to allow for participants to be randomized based on 
local laboratory assessments (with the exception of the ST-HUS screen and ADAMTS13 activity 
tests which must be performed at the central laboratory) and allow for participants to be 
randomized prior to the availability of the ST-HUS screen and ADAMTS13 activity tests to align 
with current practice patterns for management of TMA patients. Additional changes update and 
clarify the TMA eligibility criteria, expand the window to assess eligibility for laboratory 
assessments to include ≤ 14 days prior to the Screening Period, define the estimands 
corresponding to the primary and key secondary endpoints according to ICH E9 (R1) addendum 
on estimands and sensitivity analysis in clinical trials, add additional endpoints to assess loss of 
TMA response, changes in hematological and renal response parameters, and survival, elevate 
changes in patient-reported outcomes as measured by FACIT-Fatigue to a secondary endpoint, 
update the efficacy analyses to be based on the modified Intent-to-Treat analysis set, and add 
COVID-19 risk assessment language. Minor typographical clarifications and corrections were 
also made. 
 
Section # and Name 
Description of Change 
Brief Rationale 
Section 1.1, Synopsis; Section 
3.1, Overview of Objectives 
and Endpoints 
Revised the primary endpoint to 
“Complete TMA Response during the 
26-week randomized Treatment 
Period.” 
Editorial revision to align with the 
description of the primary efficacy 
endpoint in the statistical 
methodology section of the protocol; 
this endpoint was prespecified as 
“during the 26-week randomized 
Treatment Period” from study 
initiation but was written 
inconsistently throughout the original 
protocol. 
Added a key secondary endpoint to the 
table of endpoints for “on dialysis at 
Week 26”.  
To align with the efficacy endpoints 
described in the statistical 
methodology section of the protocol; 
endpoint was prespecified in the 
original protocol but omitted from 
the table of endpoints in error. 
Added an additional secondary 
endpoint to the protocol assess Loss of 
TMA Response  
To assess the subsequent loss of 
TMA response in participants who 
achieved TMA response during the 
Treatment Period 
Added additional secondary endpoints 
to the protocol to assess changes from 
baseline in hematologic parameters at 
all scheduled assessments 
To assess trends in hematologic 
parameters 

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Section # and Name 
Description of Change 
Brief Rationale 
Added an additional secondary 
endpoint to the table of endpoints to 
assess changes from baseline in eGFR 
at all scheduled assessments; Revised 
the endpoints for response in at least 1 
TMA parameter, and renal response 
and hematologic response, separately, 
to be assessed at all scheduled 
assessments 
To align with the efficacy endpoints 
described in the statistical 
methodology section of the protocol; 
endpoint was prespecified in the 
original protocol but omitted from 
the table of endpoints in error. 
Added an additional secondary 
endpoint to the protocol to assess 
increases in hemoglobin ≥ 1 gram/dL  
To allow for evaluation of increases 
in hemoglobin at 2 separate cutoffs 
given that varying degrees of 
improvement are expected based on 
the heterogenicity of the population 
Elevated “change in patient-reported 
outcomes as measured by FACIT-
Fatigue” to a secondary endpoint 
To allow for patient-reported 
outcomes to support the value of the 
primary endpoint 
Added a safety endpoint to assess 
changes from baseline in vital signs 
and laboratory parameters  
To further characterize participant 
safety  
Editorial revisions and clarifications 
were made to the key secondary 
endpoints.  
Editorial revision to align with the 
estimands corresponding to the key 
secondary efficacy objectives in 
accordance with ICH E9 (R1) 
addendum on estimands and 
sensitivity analysis in clinical trials  
Section 1.1, Synopsis; Section 
1.2, Schema; Section 4.1, 
Overall Design 
Updated the description of the 
participant population to reflect that 
participants must have met protocol 
defined criteria during the Screening 
Period instead of randomization; added 
“and/or ≤ 14 days prior to the 
Screening Period” to eligibility 
window.  
Correction; To align the window for 
screening labs (IC #5) with the 
window for clinical diagnosis of 
TMA (IC #4) 
Section 1.2, Schema; Section 
1.3, Schedule of Activities  
Added language to specify local or 
central laboratory results may be used 
to determine eligibility, with the 
exception of the ST-HUS screen and 
ADAMTS13 activity tests which must 
be performed at the central laboratory. 
With the exceptions of the ST-HUS 
screen and ADAMTS13 activity tests, 
if local labs are used to establish 
eligibility, central laboratory tests are 
not required at the Screening visit. 
To allow use of local labs to 
determine eligibility to align with 
current practice patterns for 
management of TMA patients. 
Section 3.1, Overview of 
Objectives and Endpoints 
Added an exploratory objective and 
endpoint to assess overall survival by 
Week 26 and Week 52  
To assess the impact of ravulizumab 
on overall survival 

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Section # and Name 
Description of Change 
Brief Rationale 
Section 3.2.1, Complete TMA 
Response 
Clarified that first laboratory value for 
the assessment of response parameters 
will be based on central laboratory 
results; the second value will be 
assessed based on the earliest value 
obtained ≥ 24 hours after the first value 
and may be based on central or local 
laboratory results 
Clarification  
Section 3.2.4, Loss of TMA 
Response 
Added section to define ‘Loss of TMA 
Response”   
Definition of new endpoint 
Section 3.2.5, TMA Relapse 
Revised the definition of TMA Relapse 
to “evidence of worsening hematologic 
and renal dysfunction due to TMA 
during the post-treatment follow-up 
period and requires treatment 
intervention, as determined by the 
Investigator.” 
The revised criterion is more 
clinically relevant, incorporating 
whether the patient requires 
treatment. An Investigator’s decision 
to treat a patient for relapse depends 
on a number of clinical and 
histological factors such as renal 
reserve and the patient’s overall 
functional status. The revised 
criterion removes thresholds for 
laboratory criteria and instead allows 
for clinical judgement, taking into 
account aforementioned factors to 
determine if a participant has 
experienced a relapse. 
Section 4.4, Remote Visit 
Options in Times of 
Emergency 
Revised language to remove home 
health services and specify that remote 
visits include virtual phone or video 
conference visits; Added language to 
specify the minimum assessments 
collected during remote visits which 
must be recorded in the source 
documents; Added language to specify 
that the Investigator should contact the 
Medical Monitor to determine next 
appropriate steps if a participant is not 
able to complete a visit where study 
drug is administered 
To operationally simplify the 
processes associated with a remote 
visit when required during times of 
emergency 
Section 5, Study Population 
Updated language to specify that the 
eligibility window for laboratory 
assessments may include “≤ 14 days 
prior to the Screening Period”; Added 
language to specify local or central 
laboratory results may be used to 
determine eligibility, with the 
exception of the ST-HUS screen and 
ADAMTS13 activity tests which must 
be performed at the central laboratory; 
Added language to specify that 
participants may be randomized prior 
to availability of the central laboratory 
results from the ST-HUS screen and 
ADAMTS13.  
To allow use of local labs to 
determine eligibility to align with 
current practice patterns for 
management of TMA patients. 

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Section # and Name 
Description of Change 
Brief Rationale 
Section 5.1, Inclusion Criteria 
Revised IC #4c to specify examples of 
solid organ transplants; Removed 
“Diagnosis of” from the requirement of 
TMA 
Clarification 
Revised IC #5 to specify that the 
laboratory finding criteria can be 
confirmed during Screening or ≤ 14 
days prior to the start of the Screening 
Period. Removed that central 
laboratory results were required. 
To align the window for screening 
labs (IC #5) with the window for 
clinical diagnosis of TMA (IC #4) 
and to allow use of local labs to align 
with current practice patterns for 
management of TMA patients 
Revised IC #5c to clarify the criterion 
of acute kidney injury for kidney 
transplant recipients. 
Clarification to allow for post-kidney 
transplant recipients to be evaluated 
for eligibility; the previous criterion 
was inadvertently worded as 
exclusionary towards all kidney 
transplant recipients 
Removed the requirement for 
vaccination against Haemophilus 
influenzae type b (Hib) and 
Streptococcus pneumoniae from the 
inclusion criteria (IC #7) 
Vaccination against Hib and S. 
pneumoniae is only based on local 
requirements and is reflected in 
Section 8.1.5 Vaccination and 
Antibiotic Prophylaxis.  
Section 5.2, Exclusion Criteria 
Revised EC #3 to separate the 
requirements for participants with 
native kidneys and kidney transplant 
recipients; Added “ongoing acute 
kidney injury requiring dialysis 
treatment lasting for > 14 days prior to 
Screening” to the requirement for 
participants with native kidneys 
To allow for the enrollment of kidney 
transplant patients; to ensure 
exclusion of participants with native 
kidneys who are on dialysis for more 
than 14 days 
Revised EC #7 to “Known Shiga toxin-
producing Escherichia coli 
infections…”  
To exclude patients known to have 
hemolytic uremic syndrome due to 
Shiga toxin-producing infections 
Revised EC #9 to “Positive direct 
Coombs test which in the judgement of 
the Investigator is indicative of a 
clinically significant immune-mediated 
hemolysis not due to TMA.” 
A positive Coombs test can result 
from a variety of factors and may not 
always be clinically significant. New 
criteria will allow Investigator 
judgment to determine the clinical 
significance of the Coombs test 
result. 
Revised EC #10 to “Clinical diagnosis 
of DIC in the judgement of the 
Investigator, utilizing the ISTH scoring 
criteria 
Diagnosis of DIC requires clinical 
interpretation of lab values. This 
change allows the investigator to 
review lab values within the 
appropriate clinical context to 
confirm DIC. 
Revised EC #11 to “Presence of sepsis 
requiring vasopressors”  
Clarification of criterion intended to 
exclude patients with sepsis who are 
on vasopressors; the previous 
language inadvertently excluded all 
patients with infection  

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Section # and Name 
Description of Change 
Brief Rationale 
Revised EC #14 to “Kidney biopsy (if 
available) showing the presence of any 
of the following in glomeruli: 
≥ 50% interstitial fibrosis and tubular 
atrophy; ≥ 50% glomerular sclerosis; 
≥ 50% active crescent formation” 
Clarification of the requirement to 
specify that the ≥ 50% requirement 
applies to each condition individually 
Revised EC #18 to “Human 
immunodeficiency virus (HIV) 
infection (evidenced by a positive HIV-
1 or HIV-2 antibody titer). A 
documented negative HIV-1/HIV-2 test 
within 6 months prior to Screening is 
acceptable to confirm eligibility.” 
Clarification that patients are 
excluded if they are HIV positive; 
due to inadequate punctuation, this 
criterion was previously written in a 
way that could be perceived as 
contradictory 
Added EC #22: “Respiratory failure 
from any cause requiring mechanical 
ventilation (including intubation, 
bilevel positive airway pressure 
[BiPAP], or continuous positive airway 
pressure [CPAP]) within 72 hours prior 
to randomization” 
To exclude participants with a high 
risk of mortality from respiratory 
failure in order to mitigate 
confounding impact of respiratory 
failure on study endpoints  
Revised EC #24 to clarify participants 
will be excluded from study eligibility 
if they participate in an interventional 
treatment study for TMA or in any 
interventional treatment study with an 
unapproved therapy for any indication 
during the wash-out period  
Clarification of the types of studies 
resulting in exclusion 
Section 6.1, Study Drug 
Administered 
Revised the description of dose 
schedule to specify that participants in 
the ravulizumab group will receive a 
blinded maintenance dose at Day 15 
instead of Week 2 
Clarification of the specific study 
time point so that the terminology is 
consistent throughout the protocol 
Section 6.3.1, Randomization 
Removed “after the Investigator has 
verified that they are eligible” from the 
timing of randomization 
Allowance of randomization prior to 
ST-HUS or ADAMTS13 results may 
result in determination of ineligibility 
after randomization  
Section 6.3.2, Blinding 
Updated the description of unblinding 
at the time of the primary analysis to 
indicate that sites and participants will 
be unblinded at the same time as the 
sponsor 
Clarification of the time of 
unblinding for all parties 
Section 6.6.1, Allowed 
Medicine and Therapy 
Added note that guidance on the use of 
COVID-19 vaccines is provided in 
Section 10.9 of protocol 
To guide reader on additional 
information relevant to allowed 
medicine and therapy 
Section 6.6.2, Disallowed 
Medicine and Therapy 
Added text to specify that participants 
are prohibited from receiving 
therapeutic plasma exchange/plasma 
infusion following randomization 
during the Treatment Period 
Clarification that therapeutic plasma 
exchange/plasma infusion is 
permitted during the screening period 
and Follow-up Period which is 
consistent with current practice 
patterns for TMA patients 

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Section # and Name 
Description of Change 
Brief Rationale 
Section 6.6.2, Disallowed 
Medicine and Therapy; 
Section 7.1, Discontinuation 
of Study Drug 
Revised text to specify that study drug 
may be permanently discontinued 
following using of disallowed 
medication following consultation with 
the Medical Monitor  
To allow for Investigator’s to consult 
with the Medical Monitor in cases of 
participant receipt of prohibited 
medications and/or therapies 
Section 8.5.2, Concomitant 
Medications and Procedures 
Clarified that concomitant dosage 
information including dose and 
frequency is not required on the CRF 
Clarification 
Section 8.9.3, Real Time 
Complement Activity; Section 
10.3, Clinical Laboratory 
Tests; Section 1.3, Schedule 
of Activities 
Added text to specify that RTCA 
plasma and urine are to be collected 
and frozen from all sites, and that only 
select sites will perform additional on-
site fresh sample testing 
Clarification 
Section 9.3, Populations for 
Analyses; Section 9.4.1, 
Efficacy Analyses 
Removed the Enrolled Set. Added the 
Modified Intent to Treat (mITT) 
Analysis Set as the primary analysis set 
Patients are allowed to be 
randomized while results from ST-
HUS and/or ADAMTS13 screen are 
pending. Following randomization, 
receipt of positive aforementioned 
results will exclude patients from 
mITT. 
Section 9.4.1.1, Analyses of 
the Primary Efficacy Endpoint 
Added descriptions on handling of 
missing data and intercurrent events 
under the estimand framework; 
Updated the definition of baseline 
value for eGFR 
To align to ICH E9 (R1) addendum 
on estimands and sensitivity analysis 
in clinical trials; To account for the 
effect of dialysis on eGFR results at 
baseline 
Section 9.4.1.2, Analyses of 
Secondary Efficacy Endpoints 
Revised analysis description of the key 
secondary endpoints 
To add clarity on the planned 
analyses and add descriptions on 
handling of missing data and 
intercurrent events under the 
estimand framework 
Clarified the description of additional 
secondary endpoints; Added definition 
of baseline values for all parameters 
other than eGFR 
Clarification 
Section 9.4.1.3, Multiplicity 
Adjustment 
Editorial revisions to the list of key 
secondary endpoints 
To align with the revisions made 
within Section 1.1 and Section 3.1 
Section 10.2, Mapping of 
Objectives to Estimands 
Added a table that maps the objectives 
to the study estimands. 
To align to ICH E9 (R1) addendum 
on estimands and sensitivity analysis 
in clinical trials 
Section 10.3, Clinical 
Laboratory Tests 
Added language to specify local or 
central laboratory results may be used 
to determine eligibility, with the 
exceptions of the ST-HUS screen and 
ADAMTS13 activity tests which must 
be performed at the central laboratory. 
With the exceptions of the ST-HUS 
screen and ADAMTS13 activity tests, 
if local labs are used to establish 
eligibility, central laboratory tests are 
not required at the Screening visit. 
To allow use of local labs to 
determine eligibility to align with 
current practice patterns for 
management of TMA patients.  

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Section # and Name 
Description of Change 
Brief Rationale 
Added language to allow for the 
Investigator to assess the presence of 
Shiga toxin-producing E. coli infection 
based on clinical judgement in 
participants who cannot produce a stool 
sample for the ST-HUS screen during 
the Screening Period 
To allow Investigator to proceed with 
enrollment if stool specimen for ST-
HUS is not available but collect it 
when stool is available. 
Revised description of the timing of 
serum pregnancy testing and clinical 
complement tests 
Clarification 
Added absolute reticulocyte count and 
urine protein creatinine ratio to the 
protocol-required laboratory 
assessments 
Correction 
Removal of RBC morphology, urea, 
and ST-HUS rectal swab from the list 
of protocol-required laboratory 
assessments 
Assessments not needed for the 
assessment of safety or efficacy. 
Section 10.10, COVID-19 
Vaccine Risk Assessment 
COVID-19 vaccine risk assessment 
language included.  
Section newly added to provide 
potential risks identified and 
mitigation measures put in place in 
light of the COVID-19 pandemic and 
COVID-19 vaccination rollout. 
Section 10.13, International 
Society on Thrombosis and 
Haemostasis (ISTH) Criteria 
for Disseminated Intravascular 
Coagulation (DIC) 
Removed ‘central laboratory’ from the 
requirement for laboratory cutoff 
values.  
To allow the use of local labs to 
determine eligibility to align with 
current practice patterns for 
management of TMA patients 

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TABLE OF CONTENTS 
TITLE PAGE ...................................................................................................................................1 
INVESTIGATOR’S AGREEMENT ...............................................................................................2 
PROTOCOL AMENDMENT SUMMARY OF CHANGES ..........................................................3 
TABLE OF CONTENTS ...............................................................................................................10 
LIST OF FIGURES .......................................................................................................................15 
1. 
PROTOCOL SUMMARY ..........................................................................................16 
1.1. 
Synopsis ......................................................................................................................16 
1.2. 
Schema ........................................................................................................................20 
1.3. 
Schedule of Activities .................................................................................................20 
2. 
INTRODUCTION ......................................................................................................26 
2.1. 
Study Rationale ...........................................................................................................26 
2.2. 
Background .................................................................................................................26 
2.3. 
Benefit/Risk Assessment ............................................................................................27 
2.3.1. 
Risk Assessment .........................................................................................................27 
2.3.2. 
Benefit Assessment .....................................................................................................29 
2.3.3. 
Overall Benefit: Risk Conclusion ...............................................................................29 
3. 
OBJECTIVES AND ENDPOINTS ............................................................................30 
3.1. 
Overview of Objectives and Endpoints ......................................................................30 
3.2. 
Definitions of Endpoints .............................................................................................31 
3.2.1. 
Complete TMA Response ...........................................................................................31 
3.2.2. 
Hematologic Response ...............................................................................................32 
3.2.3. 
Renal Response ...........................................................................................................32 
3.2.4. 
Loss of TMA Response ..............................................................................................32 
3.2.5. 
TMA Relapse ..............................................................................................................32 
4. 
STUDY DESIGN .......................................................................................................33 
4.1. 
Overall Design ............................................................................................................33 
4.2. 
Scientific Rationale for Study Design ........................................................................33 
4.2.1. 
Rationale for the Primary Endpoint ............................................................................34 
4.2.2. 
Rationale for the Secondary Endpoints ......................................................................35 
4.3. 
Justification for Dose ..................................................................................................35 
4.4. 
Remote Visit Options in Times of Emergency ...........................................................35 

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4.5. 
End of Study Definition ..............................................................................................35 
5. 
STUDY POPULATION .............................................................................................36 
5.1. 
Inclusion Criteria ........................................................................................................36 
5.2. 
Exclusion Criteria .......................................................................................................37 
5.3. 
Lifestyle Considerations .............................................................................................39 
5.4. 
Screen Failures ............................................................................................................39 
6. 
STUDY INTERVENTION ........................................................................................40 
6.1. 
Study Drug Administered ...........................................................................................40 
6.2. 
Preparation/Handling/Storage/Accountability ............................................................41 
6.3. 
Measures to Minimize Bias: Randomization and Blinding ........................................42 
6.3.1. 
Randomization ............................................................................................................42 
6.3.2. 
Blinding ......................................................................................................................42 
6.4. 
Study Intervention Compliance ..................................................................................42 
6.5. 
Best Supportive Care ..................................................................................................43 
6.6. 
Concomitant Therapy .................................................................................................43 
6.6.1. 
Allowed Medicine and Therapy .................................................................................43 
6.6.2. 
Disallowed Medicine and Therapy .............................................................................43 
6.7. 
Dose Modification ......................................................................................................43 
6.8. 
Intervention After the End of the Study .....................................................................44 
7. 
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL .......................................45 
7.1. 
Discontinuation of Study Drug ...................................................................................45 
7.2. 
Participant Withdrawal from the Study ......................................................................46 
7.3. 
Lost to Follow-up .......................................................................................................46 
8. 
STUDY ASSESSMENTS AND PROCEDURES ......................................................48 
8.1. 
General Assessments and Procedures .........................................................................48 
8.1.1. 
Informed Consent .......................................................................................................48 
8.1.2. 
Inclusion/Exclusion Criteria .......................................................................................48 
8.1.3. 
Demographics .............................................................................................................48 
8.1.4. 
Medical History ..........................................................................................................48 
8.1.5. 
Vaccination and Antibiotic Prophylaxis .....................................................................49 
8.2. 
Efficacy Assessments .................................................................................................49 
8.2.1. 
Laboratory Assessments for Efficacy Endpoints ........................................................49 

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8.2.2. 
Dialysis Status ............................................................................................................50 
8.2.3. 
Transfusion History and Transfusion Requirement Status During the Study ............50 
8.2.4. 
Survival Status ............................................................................................................50 
8.3. 
Safety Assessments .....................................................................................................50 
8.3.1. 
Participant Safety Card ...............................................................................................50 
8.3.2. 
Physical Examinations ................................................................................................50 
8.3.3. 
Vital Signs ..................................................................................................................51 
8.3.4. 
Electrocardiograms .....................................................................................................51 
8.3.5. 
Clinical Safety Laboratory Assessments ....................................................................51 
8.3.5.1. 
Virus Serology ............................................................................................................52 
8.3.6. 
Pregnancy ...................................................................................................................52 
8.4. 
Adverse Events and Serious Adverse Events .............................................................52 
8.4.1. 
Time Period and Frequency for Collecting AE and SAE Information .......................52 
8.4.2. 
Method of Detecting AEs and SAEs ..........................................................................53 
8.4.3. 
Follow-up of AEs and SAEs .......................................................................................53 
8.4.4. 
Regulatory Reporting Requirements for SAEs ...........................................................53 
8.4.5. 
Major Adverse Cardiovascular Events .......................................................................53 
8.4.6. 
Adverse Events of Special Interest .............................................................................54 
8.5. 
Review of Prior and Concomitant Medications and Procedures ................................54 
8.5.1. 
Prior Medications and Procedures ..............................................................................54 
8.5.2. 
Concomitant Medications and Procedures .................................................................54 
8.6. 
Treatment of Overdose ...............................................................................................55 
8.7. 
Pharmacokinetics and Pharmacodynamics .................................................................55 
8.8. 
Immunogenicity Assessments ....................................................................................56 
8.9. 
Biomarkers ..................................................................................................................56 
8.9.1. 
Blood Biomarkers .......................................................................................................56 
8.9.2. 
Urine Biomarkers ........................................................................................................56 
8.9.3. 
Real Time Complement Activity ................................................................................57 
8.9.4. 
Additional Biomarker Research .................................................................................57 
8.10. 
Genetics ......................................................................................................................57 
8.11. 
Other Assessments ......................................................................................................57 
8.11.1. 
Patient-Reported Outcome Measures .........................................................................57 
8.11.2. 
Medical Resource Utilization .....................................................................................58 

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9. 
STATISTICAL CONSIDERATIONS .......................................................................59 
9.1. 
Statistical Hypotheses .................................................................................................59 
9.2. 
Sample Size Determination ........................................................................................59 
9.3. 
Populations for Analyses ............................................................................................59 
9.4. 
Statistical Analyses .....................................................................................................59 
9.4.1. 
Efficacy Analyses .......................................................................................................60 
9.4.1.1. 
Analyses of Primary Efficacy Endpoint .....................................................................60 
9.4.1.2. 
Analyses of Secondary Efficacy Endpoints ................................................................61 
9.4.1.3. 
Multiplicity Adjustment..............................................................................................62 
9.4.2. 
Safety Analyses ..........................................................................................................62 
9.4.2.1. 
Adverse Events ...........................................................................................................62 
9.4.2.2. 
Physical Examination and Vital Signs ........................................................................63 
9.4.2.3. 
Clinical Laboratory Tests ...........................................................................................63 
9.4.2.4. 
Electrocardiograms .....................................................................................................63 
9.4.2.5. 
MACE .........................................................................................................................63 
9.4.3. 
Pharmacokinetic/Pharmacodynamic Analysis ............................................................63 
9.4.4. 
Immunogenicity Analyses ..........................................................................................64 
9.4.5. 
Exploratory Analyses ..................................................................................................64 
9.4.5.1. 
Quality of Life ............................................................................................................64 
9.4.5.2. 
Other Exploratory Endpoints ......................................................................................64 
9.5. 
Planned Analyses ........................................................................................................64 
9.5.1. 
Interim Analysis ..........................................................................................................64 
9.5.2. 
Primary Efficacy Analysis ..........................................................................................65 
9.5.3. 
Final Analysis .............................................................................................................65 
9.6. 
Data Monitoring Committee .......................................................................................65 
10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS ..................................................................................................66 
10.1. 
Regulatory, Ethical, and Study Oversight Considerations .........................................66 
10.1.1. 
Regulatory and Ethical Considerations ......................................................................66 
10.1.2. 
Financial Disclosure ...................................................................................................67 
10.1.3. 
Informed Consent Process ..........................................................................................67 
10.1.4. 
Data Protection ...........................................................................................................68 
10.1.5. 
Dissemination of Clinical Study Data ........................................................................68 

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10.1.6. 
Data Quality Assurance ..............................................................................................68 
10.1.7. 
Source Documents ......................................................................................................69 
10.1.8. 
Study and Site Start and Closure ................................................................................69 
10.1.9. 
Publication Policy .......................................................................................................70 
10.1.10. 
Good Clinical Practice Compliance............................................................................71 
10.2. 
Mapping Objectives to Estimands ..............................................................................72 
10.3. 
Clinical Laboratory Tests ...........................................................................................73 
10.4. 
Adverse Events: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting ...........................................................................................76 
10.4.1. 
Definition of AE .........................................................................................................76 
10.4.2. 
Definition of SAE .......................................................................................................77 
10.4.3. 
Recording and Follow-Up of AE and/or SAE ............................................................78 
10.4.4. 
Reporting of SAEs ......................................................................................................79 
10.5. 
Management of Potential Infusion-related Adverse Events During 
Ravulizumab Administration ......................................................................................80 
10.6. 
Contraceptive Guidance and Collection of Pregnancy Information ...........................82 
10.6.1. 
Definitions ..................................................................................................................82 
10.6.2. 
Contraception Guidance .............................................................................................82 
10.6.2.1. 
Guidance for Female Participants ...............................................................................83 
10.6.2.2. 
Guidance for Male Participants ..................................................................................84 
10.6.3. 
Collection of Pregnancy Information .........................................................................84 
10.6.3.1. 
Male Participants With Partners Who Become Pregnant ...........................................85 
10.6.3.2. 
Female Participants Who Become Pregnant ...............................................................85 
10.7. 
Biomarkers ..................................................................................................................87 
10.8. 
Genetics ......................................................................................................................88 
10.9. 
COVID-19 Risk Assessment ......................................................................................89 
10.10. 
COVID-19 Vaccine Risk Assessment ........................................................................91 
10.11. 
Patient-Reported Outcome Instruments ......................................................................92 
10.11.1. 
Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) .........92 
10.11.2. 
EuroQoL 5-Dimensions 5-Level (EQ-5D-5L) ...........................................................93 
10.11.3. 
Kidney Disease Quality of Life instrument™–36 items (KDQOL-36) .....................96 
10.12. 
Gene Mutations That Cause aHUS ...........................................................................102 

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10.13. 
The International Society on Thrombosis and Haemostasis (ISTH) Criteria 
for Disseminated Intravascular Coagulation (DIC) ..................................................103 
10.14. 
Abbreviations ............................................................................................................104 
10.15. 
Protocol Amendment History ...................................................................................106 
11. 
REFERENCES .........................................................................................................107 
LIST OF TABLES 
Table 1: 
Schedule of Activities for Screening and 26-Week Treatment Period .......................21 
Table 2: 
Schedule of Activities During the Post-treatment Follow-up Period .........................25 
Table 3: 
Potential Risks and Mitigation Strategies ...................................................................28 
Table 4: 
Mapping Objectives to Endpoints ..............................................................................30 
Table 5: 
Overview of Complete Thrombotic Microangiopathy Response ...............................32 
Table 6: 
Study Drug ..................................................................................................................40 
Table 7: 
Weight-based Doses of Ravulizumab .........................................................................41 
Table 8: 
Mapping Objectives to Estimands ..............................................................................72 
Table 9: 
Protocol-Required Laboratory Assessments...............................................................74 
Table 10: Clinical Criteria for Diagnosing Anaphylaxis ............................................................81 
Table 11: Potential Risks and Mitigation Measures due to COVID-19 .....................................89 
Table 12: Potential Risks and Mitigation Measures due to COVID 19 Vaccine........................91 
 
LIST OF FIGURES 
Figure 1: 
Study Design Schematic .............................................................................................20 
 

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1. 
PROTOCOL SUMMARY 
1.1. 
Synopsis 
Protocol Title: A Phase 3, Randomized, Double-blind, Placebo-Controlled, Multicenter Study to 
Evaluate the Efficacy and Safety of Ravulizumab in Adult Participants Who Have Thrombotic 
Microangiopathy Associated With a Trigger 
Short Title: Phase 3 Study of Ravulizumab in Thrombotic Microangiopathy Associated With a 
Trigger 
Rationale: The development of thrombotic microangiopathy (TMA) often follows activation of 
complement by a trigger. Such triggers include, but are not limited to, infection, drug exposure, 
autoimmune disease, transplant (solid organ or bone marrow), malignant hypertension, and 
pregnancy. The presence of one or more of these triggers is a consideration for the diagnosis of 
atypical hemolytic uremic syndrome (aHUS), a type of complement-mediated TMA. The first 
approved complement component 5 (C5) inhibitor, eculizumab, demonstrated efficacy in aHUS 
in clinical studies and in TMAs triggered by renal transplant in real-world data from the global 
aHUS registry. Multiple single-center studies have demonstrated the efficacy of eculizumab in 
treating a wide array of triggers. However, most studies assessing efficacy in this population are 
retrospective, single-arm/single-center experience, or fail to control for presentation severity or 
time to treatment. Thus, a randomized, controlled study is needed to assess C5 inhibition in TMA 
associated with a trigger. 
Phase 3 studies with ravulizumab demonstrated efficacy in the treatment of TMA due to aHUS 
in adult and pediatric patients. In these studies, ravulizumab treatment achieved complete 
terminal complement inhibition resulting in Complete TMA Response, defined by normalization 
of hematologic parameters and improvement in renal function in the majority of patients. The 
study population included patients who presented with TMA after renal transplant or pregnancy, 
but excluded other triggers such as infection, drug exposure, and autoimmune disease.  
The objective of this study is to investigate the efficacy and safety of ravulizumab administered 
by intravenous (IV) infusion compared to placebo in adult participants with TMA associated 
with a range of triggers. 
 

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Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
To assess the efficacy of ravulizumab in 
the treatment of participants with TMA 
Complete TMA Response during the 26-week randomized 
Treatment Period  
Secondary 
To characterize TMA response 
Time to Complete TMA Response during the 26-week randomized 
Treatment Period a 
 
Time to response for each TMA parameter during the 26-week 
Treatment Period  
 
Achievement of hematologic response at Week 26 a  
 
Achievement of hematologic response at all scheduled assessments  
Achievement of renal response at all scheduled assessments 
Achievement of response in at least 1 TMA parameter at all 
scheduled assessments 
Changes from baseline in hematologic response parameters at all 
scheduled assessments: 
 
Platelets 
 
LDH 
 
Hemoglobin 
To assess impact on hemoglobin levels 
Increases in hemoglobin at Week 26 of: 
 
≥ 1 gram/dL  
 
≥ 2 grams/dL  
To evaluate change in kidney function  
Change from baseline in eGFR at Week 26 a 
On dialysis at Week 26 a 
Change from baseline in eGFR at all scheduled assessments 
Change from baseline in dialysis requirement at Week 26 and 
Week 52 
 
Duration of dialysis  
To assess duration of Complete TMA 
Response and TMA Relapse  
Complete TMA Response at Week 52 among participants who 
achieved Complete TMA Response during the 26-week Treatment 
Period  
Loss of TMA Response during the 26-week Treatment Period (for 
participants who achieved Complete TMA Response during the 26-
week randomized Treatment Period) 
TMA Relapse during post treatment follow-up period (for 
participants who achieved Complete TMA response during the 26-
week randomized Treatment Period) 
To assess improvement in 
patient-reported QoL outcomes  
Change in patient-reported outcomes as measured by FACIT-Fatigue 
at all scheduled assessments 
PK/PD/Immunogenicity 
To assess PK/PD of ravulizumab in 
participants with TMA 
Serum ravulizumab concentrations over time 
Absolute values, change from baseline, and percentage change from 
baseline in serum free C5 concentrations over time 
 
Absolute values, change from baseline, and percentage change from 
baseline in serum total C5 concentrations over time 
To characterize the potential for 
immunogenicity of ravulizumab in 
participants with TMA 
Incidence and titers of ADAs over time 
Safety 
To characterize the safety profile of 
ravulizumab in participants with TMA 
Incidence of AEs and SAEs by Week 26 and Week 52 
Incidence of MACEs by Week 26 and Week 52 

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Objectives 
Endpoints 
Changes from baseline in vital signs and laboratory parameters at 
scheduled assessments 
a Key secondary endpoints. The primary and key secondary efficacy analyses will use a hierarchical stepdown 
closed-testing procedure.  
Abbreviations: ADA = antidrug antibody; AE = adverse event; C5 = complement component 5; eGFR = estimated 
glomerular filtration rate; LDH = lactate dehydrogenase; MACE = major adverse cardiovascular event; 
PD = pharmacodynamic(s); PK = pharmacokinetic(s); QoL = quality of life; SAE = serious adverse event; 
TMA = thrombotic microangiopathy. 
 

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Overall Design 
This is a Phase 3, randomized, double-blind, placebo-controlled study of ravulizumab in addition 
to best supportive care (BSC) in adult participants (≥ 18 years of age) with TMA following a 
defined trigger. All participants must have severe acute kidney injury and a diagnosis of TMA 
based on protocol-defined criteria (ie, thrombocytopenia, microangiopathic hemolytic anemia, 
elevated lactate dehydrogenase [LDH]), which is associated with at least 1 trigger, such as 
autoimmune disease, infection, solid organ transplant, drugs, or malignant hypertension, 
occurring during the Screening Period and/or ≤ 14 days prior to start of the Screening Period.  
The study consists of an up to 2-week Screening Period, a 26-week randomized Treatment 
Period, and a 26-week Post-treatment Follow-up Period. Thus, the total treatment duration is 
26 weeks and the total study duration is up to 54 weeks. 
Participants will be screened for eligibility for up to 2 weeks during the Screening Period (and/or 
≤ 14 days prior to start of the Screening Period for laboratory parameters). Approximately 100 
adult participants will be randomized in a 1:1 ratio to receive either ravulizumab or placebo. 
Randomization will be stratified by baseline dialysis status and by primary trigger type. 
During the 26-week Treatment Period, all participants will receive a weight-based loading dose 
of ravulizumab or placebo on Day 1, followed by weight-based maintenance doses of 
ravulizumab or placebo on Day 15 and then once every 8 weeks (q8w) thereafter. All 
participants will receive BSC throughout the study. 
During the 26-week Post-Treatment Follow-up Period, participants will continue to receive BSC, 
at the discretion of the Investigator and will be monitored for safety, TMA response, and clinical 
events of interest. 
The end of the study is defined as the last participant’s last visit in the Post-treatment Follow-up 
Period. 
Disclosure Statement: This is a parallel group treatment study with 2 arms that is participant, 
Investigator, and outcomes assessor blinded. 
Number of Participants: Approximately 100 participants will be enrolled in the study. 
Intervention Groups and Duration: 
Eligible participants will be enrolled into the study and will be randomized in a 1:1 ratio to 
receive either ravulizumab IV infusion or placebo IV infusion in combination with BSC.  
Ravulizumab will be supplied as a sterile, preservative-free 10 mg/mL solution in single-use 
vials, designed for administration via IV infusion by diluting into commercially available saline 
(0.9% sodium chloride injection). Placebo will have an identical appearance to that of 
ravulizumab. 
Ravulizumab has been shown to achieve immediate, complete, and sustained inhibition of 
terminal complement in adult patients with paroxysmal nocturnal hemoglobinuria (PNH) and in 
pediatric and adult patients with aHUS. It is expected that the same dosing regimen will also 
achieve comparable inhibition of complement-mediated damage in patients with TMA. 
Data Monitoring Committee: No 

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1.2. 
Schema 
Figure 1: 
Study Design Schematic 
 
Note: Randomized participants will receive a weight-based loading dose on Day 1, followed by weight-based 
maintenance dosing on Day 15 and then q8w. Weight-based dosing regimen will be based on the last recorded 
study visit body weight. 
Note: Eligibility evaluation may be based on laboratory results obtained during the Screening Period or ≤ 14 days 
prior to the start of the Screening Period. Local or central laboratory results may be used to determine eligibility, 
with the exceptions of the ST-HUS screen and ADAMTS13 activity tests which must be performed at the central 
laboratory. With the exceptions of the ST-HUS screen and ADAMTS13 activity tests, if local labs are used to 
establish eligibility, central laboratory tests are not required at the Screening visit. 
Abbreviations: ADAMTS13 = a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13; 
BSC = best supportive care; q8w = every 8 weeks; ST-HUS = Shiga toxin-related hemolytic uremic syndrome; 
TMA = thrombotic microangiopathy. 
1.3. 
Schedule of Activities 
Schedules of activities are provided as follows: 
 Screening and 26-week Treatment Period provided in Table 1 
 26-week Post-treatment Follow-up Period provided in Table 2 

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Table 1: 
Schedule of Activities for Screening and 26-Week Treatment Period 
Period 
Screen-
ing 
Treatment Period 
Notes 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
Week 
Up to  
2 W 
 
W1 
W2 
W3 
W4 
W6 
W8 
W10 W12 W14 W18 W22 W26/ 
EDa 
Days and Window 
D -14 
to -1 
D1 
D8 
± 2 
D15 
± 2 
D22 
± 2 
D29 
± 2 
D43 
± 2 
D57 
±2 
D71 
± 3 
D85 
± 3 
D99 
± 3 
D127 
± 3 
D155 
± 3 
D183 
± 3 
General Assessments/Procedures 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Confirm 
inclusion/exclusion 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Confirm eligibility prior to first dose 
of ravulizumab; participants may be 
rescreened once  
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
TMA diagnosis/history  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Transfusion/dialysis history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Section 8.2.2 and Section 8.2.3  
Prior medications and 
procedures 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Meningococcal vaccination 
X 
Completion of vaccination series and re-vaccination according to national and local guidelines 
Section 8.1.5  
Hib and S pneumoniae 
vaccination 
X 
Completion of vaccination series and re-vaccination according to national and local guidelines 
Only required if indicated according 
to current national/local vaccination 
guidelines for participants with lupus 
nephritis, systemic sclerosis, or solid 
organ transplant (Section 8.1.5) 
Full physical examination 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Abbreviated physical 
examination 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Weight and heightb 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height only at Screening 
Vital signsc 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Serology  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Section 10.2 
Specialty screening labs 
Xd 
 
 
 
 
 
 
 
 
 
 
 
 
 
ADAMTS13, Coombs test, and 
ST-HUS 
Pregnancy test (WOCBP 
only) 
X 
X 
 
X 
X 
X 
 
 
X 
 
 
X 
 
X 
Serum test required at Screening, 
Day 183 and EOS/ED; urine test all 
other visits 
ECGe 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 

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Table 1: 
Schedule of Activities for Screening and 26-Week Treatment Period 
Period 
Screen-
ing 
Treatment Period 
Notes 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
Week 
Up to  
2 W 
 
W1 
W2 
W3 
W4 
W6 
W8 
W10 W12 W14 W18 W22 W26/ 
EDa 
Days and Window 
D -14 
to -1 
D1 
D8 
± 2 
D15 
± 2 
D22 
± 2 
D29 
± 2 
D43 
± 2 
D57 
±2 
D71 
± 3 
D85 
± 3 
D99 
± 3 
D127 
± 3 
D155 
± 3 
D183 
± 3 
Dispense participant safety 
card 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Instruct participants to carry safety 
card at all times and bring it to 
scheduled visits 
Patient Reported Outcome 
Questionnaires 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
X 
FACIT-Fatigue, EQ-5D-5L, and 
KDQOL-36  
Blood sample and spot 
urine collection for clinical 
laboratory tests 
Xd 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Includes hematology, coagulation 
(screening only), clinical chemistry 
panels, as well as clinical complement 
tests and spot urine samples 
(Section 10.2) 
Concomitant medications, 
nonpharmacologic 
therapies, and procedures 
 
Continuous monitoring 
 
Adverse events 
X 
Continuous monitoring 
 
Participant safety card 
review 
 
Continuous monitoring 
 
Medical resource utilization 
X 
Continuous monitoring 
 
Transfusion requirements 
 
Continuous monitoring 
 
Dialysis requirements 
 
Continuous monitoring 
 
Survival status 
 
Continuous monitoring 
 
PK/PD/Immunogenicity Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
Predose blood samples for 
PK/PDf 
 
X 
 
X 
 
 
 
 
X 
 
 
X 
 
X 
Collected anytime at Week 26 and 
ED Visit 
Postdose blood samples for 
PK/PDg 
 
X 
 
X 
 
 
 
 
X 
 
 
X 
 
 
 
Predose blood sample for 
ADA 
 
X 
 
 
 
 
 
 
X 
 
 
X 
 
X 
Collected anytime at Week 26 and 
ED Visit 
Exploratory Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood and urine samples 
for exploratory biomarkers 
Xh 
X 
 
X 
 
 
X  
 
 
X 
 
X 
 
X 
Section 8.9 

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Table 1: 
Schedule of Activities for Screening and 26-Week Treatment Period 
Period 
Screen-
ing 
Treatment Period 
Notes 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
Week 
Up to  
2 W 
 
W1 
W2 
W3 
W4 
W6 
W8 
W10 W12 W14 W18 W22 W26/ 
EDa 
Days and Window 
D -14 
to -1 
D1 
D8 
± 2 
D15 
± 2 
D22 
± 2 
D29 
± 2 
D43 
± 2 
D57 
±2 
D71 
± 3 
D85 
± 3 
D99 
± 3 
D127 
± 3 
D155 
± 3 
D183 
± 3 
Blood and urine samples 
for RTCA 
Xh 
X 
 
X 
 
 
X  
 
 
X 
 
X 
 
X 
All sites are to collect and ship frozen 
RTCA plasma and urine samples to 
the central laboratory. Only selected 
sites will perform additional on-site 
testing of freshly collected blood, 
plasma and urine using a dedicated 
RTCA reader and specific 
instructions provided by the Sponsor 
and as defined in the laboratory 
manual. See Section 8.9.3  
Blood sample for genetic 
testingi 
 
Xi 
 
 
 
 
 
 
 
 
 
 
 
  
May be collected anytime during 
study 
Study Intervention 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ravulizumab or placebo 
 
X 
 
X 
 
 
 
 
X 
 
 
X 
 
 
Administer after all other required 
tests/procedures. 
Note: All assessments should be performed prior to administration of study drug on dosing days, unless otherwise specified. For participants on dialysis, study visits should be 
conducted on non-dialysis days, whenever possible. However, if this is not feasible, then all study-related procedures and study drug administration should be performed prior to 
the participant receiving dialysis. 
a  For participants who discontinue study drug prior to the end of the Treatment Period, the ED visit should be completed as soon as possible. In addition, a Follow-up Phone Call 
will be performed 8 weeks (56 days) ± 5 days following the participant’s last dose of study drug to collect concomitant medications, nonpharmacologic therapies and procedures, 
and AEs.  
b Weight should be obtained at every visit and measured predose on dosing visits. The dose regimen is based on the last recorded study visit body weight. If the study drug is 
prepared the day before a visit, the weight from the previous study visit may be used. 
c Vital sign measurements include systolic and diastolic BP, pulse oximetry, heart rate, respiratory rate, and body temperature. On dosing days, vital signs will be taken predose. 
d Eligibility evaluation may be based on laboratory results obtained during the Screening Period or ≤ 14 days prior to the start of the Screening Period. Local or central laboratory 
results may be used to determine eligibility, with the exceptions of the ST-HUS screen and ADAMTS13 activity tests which must be performed at the central laboratory. With 
the exceptions of the ST-HUS screen and ADAMTS13 activity tests, if local labs are used to establish eligibility, central laboratory tests are not required at the Screening visit. 
e Participants must be supine during ECG collection. 
f The baseline predose sample on Day 1 will be collected within 90 minutes prior to the start of infusion. For all subsequent visits falling on dosing days, predose samples will be 
collected within 0.5 hours prior to the start of infusion. In order to minimize needle sticks to the participant, the predose sample may be drawn through the venous access created 
for the dose infusion, prior to administration of the dose.  
g Samples will be collected postdose at EOI (within 0.5 hours after the EOI from the participant’s opposite, noninfused arm).  

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h  Collect blood and urine samples for exploratory biomarker and RTCA prior to therapeutic plasma exchange/plasma infusion, if applicable. Participants are prohibited from 
receiving therapeutic plasma exchange / plasma infusion at any time following randomization during the Treatment Period. 
i For participants that provide additional informed consent for genetic testing. 
Abbreviations: ADA = antidrug antibody; ADAMTS13 = a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13; AE = adverse event; BP = blood 
pressure; D = day; ECG = electrocardiogram; ED = early discontinuation; EQ-5D-5L = EuroQoL 5 Dimension 5 Level; FACIT = Functional Assessment of Chronic Illness 
Therapy; KDQOL-36 = Kidney Disease Quality of Life instrument – 36 items; PD = pharmacodynamics; PK = pharmacokinetics; RTCA = Real Time Complement Activity; 
ST-HUS = Shiga toxin-related hemolytic uremic syndrome; TMA = thrombotic microangiopathy; W = Week; WOCBP = woman of childbearing potential. 
 
 

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Table 2: 
Schedule of Activities During the Post-treatment Follow-up Period 
Period 
Post-treatment Follow-up Period 
Notes 
Visit 
14 
15 
16 
Week 
W34 
W43 
W52/EOS 
Days and window 
D239 ± 7  
D302 ± 7 
D365 ± 7 
General Procedures/Assessments 
 
 
 
 
Pregnancy test (WOCBP only) 
X 
 
X 
Serum test required at Screening, Day 183 and EOS/ED; urine test all other visits 
Abbreviated physical examination 
X 
X 
X 
 
Vital signsa 
X 
X 
X 
 
Blood samples and spot urine collection for 
clinical laboratory tests 
 
 
X 
Includes hematology, clinical chemistry panels, as well as clinical complement 
tests and spot urine samples (Section 10.2) 
Patient Reported Outcome Questionnaires 
X 
 
X 
FACIT-Fatigue, EQ-5D-5L, and KDQOL-36  
Concomitant medications, nonpharmacologic 
therapies, and procedures 
Continuous monitoring 
 
Adverse events 
Continuous monitoring 
 
Participant safety card review 
Continuous monitoring 
Participants are to carry the card with them at all times until 8 months after the last 
dose of study drug  
Medical resource utilization 
Continuous monitoring 
 
Transfusion requirements 
Continuous monitoring 
 
Dialysis requirements 
Continuous monitoring 
 
Survival status 
Continuous monitoring 
 
PK/PD/Immunogenicity Assessments 
 
 
 
 
 
Blood samples for PK/PD 
X 
 
X 
Samples collected anytime  
Blood sample for ADA 
X 
  
X 
Samples collected anytime  
Exploratory Assessments 
 
 
 
 
 
Blood and urine samples for exploratory 
biomarkers   
X 
X 
X 
Section 8.9  
a Vital sign measurements include systolic and diastolic BP, pulse oximetry, heart rate, respiratory rate, and body temperature. 
Abbreviations: ADA = antidrug antibody; D = day; EOS = end of study; EQ-5D-5L = EuroQoL 5 Dimension 5 Level; FACIT = Functional Assessment of Chronic Illness 
Therapy; KDQOL-36 = Kidney Disease Quality of Life instrument – 36 items; PD = pharmacodynamics; PK = pharmacokinetics; W = Week; WOCBP = woman of childbearing 
potential. 
 
 

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2. 
INTRODUCTION 
2.1. 
Study Rationale 
The development of TMA often follows activation of complement by a trigger. Such triggers 
include, but are not limited to, autoimmune disease, infection, drug exposure, transplant (solid 
organ or bone marrow), malignant hypertension, and pregnancy (Goodship, 2017). Ravulizumab 
is a humanized monoclonal antibody that binds to C5 and blocks its activation by complement 
pathway convertases, thereby preventing the release of the proinflammatory anaphylatoxin 
complement component 5a (C5a) and the formation of the terminal complement complex via 
C5b. Phase 3 studies of C5 inhibition with ravulizumab demonstrated efficacy in the treatment of 
TMA due to aHUS in adult and pediatric patients. In these studies, ravulizumab treatment 
achieved complete terminal complement inhibition resulting in Complete TMA Response, 
defined by normalization of hematologic parameters and improvement in renal function in the 
majority of patients (Rondeau, 2020). The study population included patients who presented with 
TMA after renal transplant or pregnancy, but excluded other triggers such as infection, drug 
exposure, and autoimmune disease. 
The objective of this study is to evaluate the efficacy and safety of ravulizumab administered by 
IV infusion compared to placebo in adult participants with TMA associated with a range of 
triggers. 
2.2. 
Background 
Thrombotic microangiopathy is a rare, life-threatening disease often caused by complement 
activation that results in endothelial damage. In some patients, complement-mediated TMA may 
result from a trigger that injures the endothelium, such as post-partum, malignant hypertension 
(sometimes termed hypertensive emergency), infection, transplant (solid organ or bone marrow), 
autoimmune disease, and certain drugs (Aigner, 2019; Go, 2016; Goodship, 2017; Park, 2018). 
Many patients present in critical condition, require management in an intensive care unit, and 
often need dialysis. Once multiorgan dysfunction develops, patients have a poor prognosis (Le 
Clech, 2019).  
Two complement C5 inhibitors, ravulizumab and eculizumab, are approved for the treatment of 
patients with aHUS, a type of complement-mediated TMA. There are currently no approved 
therapies for the broader complement-mediated TMA population. Treatment typically consists of 
corticosteroids and/or therapeutic plasma exchange (TPE) or plasma infusion. The underlying 
trigger may also be treated, along with other supportive measures (eg, transfusion, dialysis), as 
appropriate. While TPE/plasma infusion will improve hematologic parameters in 
complement-mediated TMA, neither corticosteroids nor TPE/plasma infusion will address the 
underlying complement dysregulation and the TMA process is likely to persist (Azoulay, 2017; 
Kavanagh, 2006; Laurence, 2013). Removal of the trigger and supportive care are sometimes 
sufficient to reverse TMA symptoms; however, in patients with severe renal manifestations, 
outcomes are not greatly improved after removing/treating the trigger and providing supportive 
care. 
In patients with aHUS, ravulizumab achieved immediate, complete, and sustained inhibition of 
terminal complement and improved renal function (Rondeau, 2020). It is hypothesized that 

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ravulizumab will be similarly effective in the treatment of complement-mediated TMA at the 
approved aHUS dosing regimen.  
A detailed description of the chemistry, pharmacology, efficacy, and safety of ravulizumab is 
provided in the Investigator’s Brochure (IB). 
2.3. 
Benefit/Risk Assessment 
Detailed information about the known and expected benefits and risks of ravulizumab is 
provided in the IB. 
2.3.1. 
Risk Assessment 
Based on clinical experience and cumulative safety data from clinical studies of ravulizumab in 
PNH and aHUS, ravulizumab has been demonstrated to be generally well tolerated, and exposure 
to ravulizumab in humans has not raised any unexpected safety concerns. 
Ravulizumab functions by blocking terminal complement; therefore, participants have increased 
susceptibility to serious infections, in particular Neisseria meningitidis. Specific risk mitigation 
measures available to support the safe use of ravulizumab in participants in this study are 
described in Table 3. 
As with any therapeutic protein, administration of ravulizumab may lead to the development of 
antidrug antibodies (ADAs). Monitoring of immunogenicity is planned during this study, as 
described in Section 8.8. Intravenous administration of any investigational product may result in 
infusion reactions. Management of potential infusion reactions is described in Section 10.5. 
The coronavirus disease 2019 (COVID‑ 19) pandemic is active in many countries at the time of 
this protocol development. Given this unique circumstance, specific consideration has been 
given to the risks and benefits of the study as they relate to COVID‑ 19, and the global and local 
changes that exist as a result of the pandemic. This assessment is described in Section 10.9. 
More detailed information about the known and expected benefits and risks and reasonably 
expected adverse events (AEs) of ravulizumab may be found in the IB or local product labeling. 

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Table 3: 
Potential Risks and Mitigation Strategies 
Risks of Clinical 
Significance 
Summary of Data/Rationale for 
Risk 
Mitigation Strategy 
 
Identified risk 
 
 
Meningococcal infection 
Complement C5 inhibition is known 
to increase the susceptibility to 
infections caused by N meningitidis. 
Participants must be vaccinated against all 
available serotypes of N meningitidis (A, 
C, Y, W 135, and B) where available. If 
participants cannot be vaccinated, they 
should be administered prophylactic 
antibiotics for the entire period they are 
treated with ravulizumab and for 8 months 
following their last dose of ravulizumab. 
Once the participant is able to be 
vaccinated, antibiotic prophylaxis for 
meningococcal infections should be 
maintained for at least 2 weeks after 
vaccination. However, vaccination may 
not be sufficient to prevent meningococcal 
infection.  
Potential risks 
 
 
Serious infection 
Apart from the predictable risk of 
infection with Neisseria species, 
which is well-known and directly 
related to the mechanism of action of 
ravulizumab, the mechanism that 
may lead to other serious infections 
in patients treated with ravulizumab 
remains unclear. 
Since the relevance of serious 
infection with ravulizumab therapy 
has not been confirmed in clinical 
trials, this remains a potential risk. 
Increased awareness of healthcare 
professionals and participants about the 
potential risk of serious infection. 
Monitoring for signs and symptoms of 
serious infections will be conducted as part 
of routine safety assessments for this 
study. 
Immunogenicity 
Treatment with any therapeutic 
protein has the potential to induce an 
immune response. Potential clinical 
consequences may include 
hypersensitivity type reactions, 
decrease in efficacy, and induction of 
autoimmunity, including antibodies 
to the endogenous form of the protein 
(Casadevall, 2002; Li, 2001). 
Protein therapies administered 
intravenously have the potential risk 
of causing local (infusion-site) 
reactions and systemic reactions 
(infusion-associated reactions).  
In Studies ALXN1210-PNH-103 and 
ALXN1210-PNH-201, no participant had a 
positive ADA sample. In Phase 3 studies 
in PNH (N = 261) and aHUS (N = 89) 
patients, there were 2 (0.57%) cases of 
treatment-emergent ADAs reported with 
ravulizumab. 
Presence of ADA will be assessed. 
Monitoring for infusion reactions will be 
conducted as part of routine safety 
assessments for this study. 
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 participants are 
excluded from the clinical study. 
Participants enrolled in the study, and their 
spouses/partners, must use a highly 
effective or acceptable method of 
contraception for a period of 8 months 

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Table 3: 
Potential Risks and Mitigation Strategies 
Risks of Clinical 
Significance 
Summary of Data/Rationale for 
Risk 
Mitigation Strategy 
 
following the final dose of ravulizumab. 
Breastfeeding should be discontinued 
during treatment and for up to 8 months 
after treatment with ravulizumab. 
Abbreviations: ADA = antidrug antibody; aHUS = atypical hemolytic uremic syndrome; C5 = complement 
component 5; PNH = paroxysmal nocturnal hemoglobinuria. 
2.3.2. 
Benefit Assessment 
Complement-mediated TMA is a rare and potentially fatal disease with limited treatment 
options, and severe renal injury is often irreversible, therefore development of new therapies is 
important to address unmet medical needs. 
Ravulizumab represents an appropriate candidate for investigation due to demonstrated efficacy 
and safety in treatment of aHUS and other disorders of complement, including PNH.  
2.3.3. 
Overall Benefit: Risk Conclusion 
Taking into account the high unmet need for effective therapies for complement-mediated TMA, 
the outcomes of this patient population with currently available care, along with the measures 
taken to minimize risk to participants in this study, the potential risks of ravulizumab are justified 
by the anticipated benefits. 

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3. 
OBJECTIVES AND ENDPOINTS 
The objectives and endpoints for Study ALXN1210-TMA-315 are provided in Table 4. A 
mapping of objectives to estimands is provided in Section 10.2.  
3.1. 
Overview of Objectives and Endpoints 
Table 4: 
Mapping Objectives to Endpoints 
Objectives 
Endpoints 
Primary 
To assess the efficacy of ravulizumab in 
the treatment of participants with TMA 
Complete TMA Response during the 26-week randomized 
Treatment Period (Section 3.2.1) 
Secondary 
To characterize TMA response 
 
Time to Complete TMA Response during the 26-week randomized 
Treatment Period a 
 
Time to response for each TMA parameter during the 26-week 
Treatment Period  
 
Achievement of hematologic response (Section 3.2.2) at Week 26 a  
 
Achievement of hematologic response at all scheduled assessments 
 
Achievement of renal response (Section 3.2.3) at all scheduled 
assessments 
 
Achievement of response in at least 1 TMA parameter at all 
scheduled assessments 
 
Changes from baseline in hematologic response parameters at all 
scheduled assessments: 
 
Platelets 
 
LDH 
 
Hemoglobin 
To assess impact on hemoglobin levels 
Increases in hemoglobin at Week 26 of: 
 
≥ 1 gram/dL  
 
≥ 2 grams/dL 
To evaluate change in kidney function 
Change from baseline in eGFR at Week 26 a 
 
On dialysis at Week 26 a 
 
Change from baseline in eGFR at all scheduled assessments 
 
Change from baseline in dialysis requirement at Week 26 and 
Week 52 
 
Duration of dialysis 
To assess duration of Complete TMA 
Response and TMA Relapse  
Complete TMA Response at Week 52 among participants who 
achieved Complete TMA Response during the 26-week Treatment 
Period  
Loss of TMA Response (Section 3.2.4) during the 26-week 
Treatment Period (for participants who achieved Complete TMA 
Response during the 26-week randomized Treatment Period) 
TMA Relapse (Section 3.2.4) during post treatment follow-up period 
(for participants who achieved Complete TMA response during the 
26-week randomized Treatment Period) 
To assess improvement in patient-reported 
QoL outcomes  
Change in patient-reported outcomes as measured by FACIT-Fatigue 
at all scheduled assessments 
PK/PD/Immunogenicity 
To assess PK/PD of ravulizumab in 
participants with TMA 
Serum ravulizumab concentrations over time 
Absolute values, change from baseline, and percentage change from 
baseline in serum free C5 concentrations over time 

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Objectives 
Endpoints 
 
Absolute values, change from baseline, and percentage change from 
baseline in serum total C5 concentrations over time 
To characterize the potential for 
immunogenicity of ravulizumab in 
participants with TMA 
Incidence and titers of ADAs over time 
Safety 
To characterize the safety profile of 
ravulizumab in participants with TMA 
Incidence of AEs and SAEs by Week 26 and Week 52 
Incidence of MACEs (Section 8.4.5) by Week 26 and Week 52 
Changes from baseline in vital signs and laboratory parameters at 
scheduled assessments 
Exploratory 
To assess improvement in extrarenal 
manifestations 
Extrarenal manifestations by Week 26 and Week 52 
To assess impact of treatment on 
resolution of hemolysis 
RBC transfusions by Week 26 and Week 52 
To assess improvement in patient-reported 
QoL outcomes  
Change in patient-reported outcomes as measured by EQ-5D-5L and 
KDQOL-36 
To assess biomarkers and autoantibodies in 
participants with TMA 
Exploratory biomarkers will be assessed in blood and urine for 
change from baseline and may include but are not limited to, 
markers of vascular damage, renal injury and complement 
dysregulation (eg, sC5b-9, factor Ba). 
To assess complement pathway genetic 
mutations in participants with TMA 
associated with a trigger 
Incidence of complement dysregulation-related mutations 
To assess health resource utilization during 
the study  
Number and duration of hospitalizations (including stays in intensive 
care unit, if applicable) 
 
Number of outpatient visits (including physician and emergency 
room visits) 
To assess impact on overall survival  
Overall survival by Week 26 and Week 52  
a Key secondary endpoints. The primary and key secondary efficacy analyses will use a hierarchical stepdown 
closed-testing procedure as described in Section 9.4.1.3. 
Abbreviations: ADA = antidrug antibody; AE = adverse event; Ba = complement factor Ba; C5 = complement 
component 5; eGFR = estimated glomerular filtration rate; EQ-5D-5L = EuroQoL 5 Dimension 5 Level; 
FACIT = Functional Assessment of Chronic Illness Therapy; GI = gastrointestinal; KDQOL-36 = Kidney Disease 
Quality of Life instrument – 36 items; LDH = lactate dehydrogenase; MACE = major adverse cardiovascular 
event; PD = pharmacodynamic(s); PK = pharmacokinetic(s); PLT = platelet; QoL = quality of life; SAE = serious 
adverse event; sC5b-9 = soluble terminal complement complex C5b-9 (membrane attack complex); 
TMA = thrombotic microangiopathy. 
3.2. 
Definitions of Endpoints 
3.2.1. 
Complete TMA Response 
Complete TMA Response is defined as the normalization of hematologic parameters (platelet 
count and LDH) and ≥ 30% improvement in estimated glomerular filtration rate (eGFR) from 
baseline (Table 5).  
For Complete TMA Response, participants must have met all 3 TMA response parameters, with 
each parameter meeting the requirement at 2 separate assessments obtained at least 24 hours 
apart, and any measurement in between. The first laboratory value will be assessed based on 
central laboratory results; the second laboratory value will be assessed based on the earliest value 
obtained ≥ 24 hours after the first value and may be based on central or local laboratory results.    

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Table 5: 
Overview of Complete Thrombotic Microangiopathy Response 
 
 
TMA Response Parameter 
Complete TMA Response 
Hematologic Response 
 
Normalization of platelet count without 
transfusion support during the prior 7 days 
 
Normalization of LDH 
Renal Response 
 
Improvement in eGFR of ≥ 30% compared 
to baseline 
Abbreviations: eGFR = estimated glomerular filtration rate; LDH = lactate dehydrogenase; TMA = thrombotic 
microangiopathy. 
3.2.2. 
Hematologic Response 
Hematologic Response is defined as the normalization of platelets without transfusion support 
during the prior 7 days and the normalization of LDH. 
3.2.3. 
Renal Response 
Renal Response is defined as an improvement in eGFR of ≥ 30% compared to baseline. 
3.2.4. 
Loss of TMA Response 
For participants that meet the criteria for Complete TMA Response during the 26-week 
Treatment Period, Loss of TMA Response is defined as when the participant fails to meet the 
criteria for one or more components of TMA response at a subsequent visit during the 26-week 
Treatment Period. At least one parameter must fail to meet the response criteria at 2 separate 
assessments obtained at least 24 hours apart, and any measurement in between. The first 
laboratory value will be assessed based on central laboratory results; the second laboratory value 
will be assessed based on the earliest value obtained ≥ 24 hours after the first value and may be 
based on central or local laboratory results. 
3.2.5. 
TMA Relapse 
For participants that meet the criteria for Complete TMA Response during the 26-week 
Treatment Period, TMA Relapse is defined as evidence of worsening hematologic and renal 
dysfunction due to TMA during the post-treatment follow-up period and requires treatment 
intervention, as determined by the Investigator. 

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4. 
STUDY DESIGN 
4.1. 
Overall Design 
This is a Phase 3, randomized, double-blind, placebo-controlled study of ravulizumab in addition 
to BSC in adult participants (≥ 18 years of age) with TMA following a defined trigger. All 
participants must have acute kidney injury and a diagnosis of TMA, based on the 
protocol-defined criteria (ie, thrombocytopenia, microangiopathic hemolytic anemia, elevated 
LDH) occurring during the Screening Period and/or ≤ 14 days prior to start of the Screening 
Period, and which is associated with at least 1 trigger, such as autoimmune disease, infection, 
solid organ transplant, drugs, or malignant hypertension. 
The study consists of an up to 2-week Screening Period, a 26-week randomized Treatment 
Period, and a 26-week Post-treatment Follow-up Period (Figure 1). Thus, the total treatment 
duration is 26 weeks and the total study duration is up to 54 weeks. 
Participants will be screened for eligibility for up to 2 weeks during the Screening Period (and/or 
≤ 14 days prior to start of the Screening Period for laboratory parameters). Approximately 100 
adult participants will be randomized in a 1:1 ratio to receive either ravulizumab or placebo. 
Randomization will be stratified by baseline dialysis status and by primary trigger type. 
During the Treatment Period, all participants will receive a weight-based loading dose of 
ravulizumab or placebo on Day 1, followed by weight-based maintenance doses of ravulizumab 
or placebo on Day 15 and then q8w thereafter (Table 7). All participants will receive BSC 
throughout the study as defined in Section 6.5. 
During the Post-treatment Follow-up Period, participants may continue to receive BSC, at the 
discretion of the Investigator, and will be monitored for safety, TMA response, and clinical 
events of interest. If a participant meets criteria for TMA Relapse (Section 3.2.5) during the 
Post-Treatment Follow-up Period, the participant may be treated with BCS at the discretion of 
the Investigator. 
The end of the study is defined as the last participant’s last visit in the Post-treatment Follow-up 
Period. 
4.2. 
Scientific Rationale for Study Design 
A randomized, double-blind, placebo-controlled study design is selected to provide the most 
robust evidence of the efficacy of ravulizumab on TMA response, disease progression, and 
safety. Randomization minimizes the effects of baseline differences and confounding factors on 
the study endpoints. The use of a placebo comparator allows for a more accurate assessment of 
the true effects of treatment with ravulizumab. 
Randomization will be stratified by baseline dialysis status and by primary trigger type using a 
dynamic allocation procedure. This dynamic randomization improves treatment balance when 
the number of strata is large compared to the total number of participants enrolled in the study. 
The 26-week treatment duration was chosen to provide adequate time to assess safety, TMA 
response, and other efficacy endpoints after treatment with ravulizumab. 

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The study will limit the time between TMA presentation and treatment initiation, as well as the 
duration of dialysis prior to treatment initiation, to 2 weeks to assess the benefit of early 
intervention with ravulizumab on recovery of renal function. Because this study aims to establish 
efficacy with ravulizumab as an early therapeutic option for participants with 
complement-mediated TMA, in combination with removal of the trigger, the targeted study 
population will be participants who meet TMA criteria, but have more severe renal 
manifestations. 
4.2.1. 
Rationale for the Primary Endpoint 
The primary endpoint is Complete TMA Response during the 26-week randomized Treatment 
Period.  
The renal component of the primary endpoint, improvement of ≥ 30% in eGFR, closely 
approximate with a ≥ 25% improvement in serum creatinine, which was a component of the 
primary endpoint in clinical studies of ravulizumab in treating patients with aHUS (Rondeau, 
2020). 
Measuring GFR through renal clearance of infused exogenous agents (eg, inulin) is the gold 
standard technique for assessing kidney function. Serum creatinine has been the most widely 
used surrogate for measured GFR, however, is confounded by endogenous factors including sex, 
ethnicity and age and exogenous factors such as creatinine assay variability and certain classes of 
medications that modulate renal handling of creatinine.  This makes serum creatinine a poor 
surrogate for kidney function.  The Chronic Kidney Disease Epidemiology Collaboration 
(CKD-EPI) equation for eGFR calculation is widely used for diagnosis and monitoring of kidney 
disease and was introduced because of known limitations of serum creatinine measurement 
(Florkowski, 2011). The CKD-EPI has been validated against measured GFR. The eGFR 
calculation uses sex, ethnicity, and age of the patient, some of the sources of variation when 
using the serum creatinine alone. However, as creatinine is effectively the only measured 
parameter in the eGFR equation, errors in the serum creatinine will produce errors in the eGFR. 
Serum creatinine has a low intra-individual coefficient of variation (CV) compared with the 
between individual CV. Thus, serum creatinine is not very sensitive as a marker of deteriorating 
renal function when an individual is compared to the population reference range. Indeed, it has 
been shown that the serum creatinine can remain within the population reference interval when 
the individual’s GFR has decreased by 50% (Shemesh, 1985).  
The renal component of the primary endpoint, improvement of ≥ 30% in eGFR, rather than 
complete recovery, is selected because renal repair after an insult is often maladaptive with 
inflammation, fibrosis, and vascular rarefaction leading to persistent cell and tissue malfunction 
and eventually chronic kidney disease (CKD). The frequency, severity, type, and duration of 
injury as well as the premorbid renal reserve seem to be risk factors for maladaptive repair 
(Venkatachalam, 2015). It is likely that maladaptive repair mechanisms will hinder complete 
recovery of renal function. In addition, patients with renal dysfunction are often continued on 
renal-protective medications, such as angiotensin-converting enzyme (ACE) inhibitors or 
angiotensin II receptor blockers (ARBs), which are known to reduce eGFR. Moreover, post-
transplant patients are maintained on calcineurin inhibitors (CNIs), which are also known to 
reduce eGFR. 

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4.2.2. 
Rationale for the Secondary Endpoints 
Time to achieve Complete TMA Response during the 26-week Treatment Period will provide 
prescribers with additional guidance to evaluate and characterize efficacy of ravulizumab 
treatment. In addition, given the fact that the resolution of the different TMA components may 
occur at different time points after treatment initiation, and that some participants may 
experience partial response, additional key secondary endpoints including the proportion of 
participants that achieve the individual components of the Complete TMA Response definition, 
as well as the time to achieve each of them, will be evaluated to fully characterize the potential 
benefit of ravulizumab treatment. The proportion of participants that achieve an increase of 
≥ 1 gram/dL and ≥ 2 grams/dL in hemoglobin will also be assessed. 
Complement-mediated TMA is a multisystem complication with prominent kidney involvement. 
Literature shows that up to 40% or more of patients with complement-mediated TMA are on 
dialysis at presentation (Le Clech, 2019). Therefore, secondary endpoints to assess change in 
dialysis status as well as change in eGFR have been chosen. 
4.3. 
Justification for Dose 
Ravulizumab has been shown to achieve immediate, complete, and sustained inhibition of 
terminal complement in adult patients with PNH and in pediatric and adult patients with aHUS. 
It is expected that the same dosing regimen will also achieve comparable inhibition of 
complement-mediated damage in patients with TMA. 
4.4. 
Remote Visit Options in Times of Emergency 
To ensure participant safety and treatment continuity in times of emergency (eg, COVID-19 
pandemic), the following will apply where participants are not able to reach the study sites, and 
until participants are able to resume study visits at the site. If a participant is not able to complete 
a visit where study drug is administered, the Investigator should contact the Medical Monitor to 
determine next appropriate steps. 
Remote visit options may be at the Investigator’s discretion and oversight, in accordance with 
the local regulations. Remote visit options include visits conducted virtually through phone or 
video conference. All assessments for the study visit day should be conducted according to the 
Schedule of Activities (Section 1.3), whenever possible. At minimum, information about AEs, 
concomitant medications, background therapies, and disease-related signs or symptomatology 
must be collected by the Investigator for evaluation on the day of the remote visit and recorded 
in the source documents. In case of any signs or symptoms indicating a serious adverse event 
(SAE), the participant will need to be evaluated at the study site. 
4.5. 
End of Study Definition 
A participant is considered to have completed the study if he/she has completed all phases of the 
study including the last scheduled procedure shown in the Schedule of Activities (Section 1.3). 
The end of the study is defined as the date the last participant completes the last visit shown in 
the Schedule of Activities for the Post-treatment Follow-up Period. 

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5. 
STUDY POPULATION 
 Eligibility evaluation may be based on laboratory results obtained during the 
Screening Period or ≤ 14 days prior to the start of the Screening Period. 
 Local or central laboratory results may be used to determine eligibility, with the 
exceptions of the ST-HUS screen and ADAMTS13 activity tests which must be 
performed at the central laboratory. With the exceptions of the ST-HUS screen and 
ADAMTS13 activity tests, if local labs are used to establish eligibility, central 
laboratory tests are not required at the Screening visit. 
 Participants may be randomized prior to availability of central laboratory results from 
the ST-HUS screen and ADAMTS13 test.  
 If a participant is found not to meet eligibility based on central laboratory results 
for the ST-HUS screen and ADAMTS13 activity tests following randomization, 
the participant must be discontinued and will be replaced. Participants 
discontinued following randomization based on ST-HUS screen and ADAMTS13 
test results will not be counted towards the total sample size as described in 
Section 9.2. Analyses in this study are planned to be based on results from the 
central laboratory.  
 Prospective approval of protocol deviations to recruitment and enrollment criteria, 
also known as protocol waivers or exemptions, is not permitted.  
5.1. 
Inclusion Criteria 
To be eligible to participate in the study, participants must meet all of the below criteria: 
Age 
1. Must be ≥ 18 years of age at the time of signing the informed consent 
Weight 
2. Body weight ≥ 30 kg at Screening  
Sex 
3. Male and female  
Female participants of childbearing potential and male participants must follow 
protocol-specified contraception guidance as described in Section 10.6. 
Disease Characteristics 
4. TMA within ≤ 14 days prior to Screening is associated with at least 1 of the following 
triggers: 
a. Autoimmune (lupus nephritis, systemic sclerosis associated TMA [SSc-TMA]) 
b. Infection 
c. Solid organ transplant (eg, kidney, pancreas, liver, heart, small bowel) 
d. Drugs 
e. Malignant hypertension  

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5. Confirmation of all of the following laboratory findings during the Screening Period 
and/or ≤ 14 days prior to the start of the Screening Period:  
a. Platelet count < 150,000/μL 
b. Lactate dehydrogenase ≥ 1.5 × ULN and hemoglobin ≤ LLN (based on age and sex) 
c. Acute kidney injury as defined by meeting 1 or more of the following criteria (for 
kidney transplant recipients, the pre-TMA value is based on post-transplant eGFR):  
 Acute decline in eGFR ≥ 50% from pre-TMA value (pre-TMA value must be 
≤ 12 months prior to Screening) 
 New acute kidney injury with an eGFR ≤ 30 mL/min/1.73 m2 
 New initiation of dialysis due to TMA requiring > 1 session and for no more than 
14 days prior to Screening 
Vaccinations and Antibiotics 
6. Vaccinated against meningococcal infection (N meningitidis), within 3 years prior to, or 
at the time of, randomization. Participants who initiate study drug treatment less than 
2 weeks after receiving a meningococcal vaccine must receive appropriate prophylactic 
antibiotics for at least 2 weeks after the vaccination. If participant cannot receive the 
meningococcal vaccine, then participant must be willing to receive antibiotic prophylaxis 
coverage against N meningitidis during the entire Treatment Period and for 8 months 
following the final dose of study drug. 
Informed Consent 
7. Capable of giving signed informed consent as described in Section 10.1.3 which includes 
compliance with the requirements and restrictions listed in the informed consent form 
(ICF) and in this protocol. 
5.2. 
Exclusion Criteria 
Participants are excluded from the study if any of the following criteria apply: 
Medical Conditions  
1. Any known gene mutation that causes aHUS (Section 10.12)   
2. Post-partum aHUS  
3. Known CKD: 
 In participants with native kidneys: eGFR ≤ 45 mL/min/1.73 m2 by CKD-EPI 
equation (Levey, 2009) due to any cause or ongoing acute kidney injury requiring 
dialysis treatment lasting for > 14 days prior to Screening.  
 In kidney transplant recipients: determination of CKD threshold will be based on 
Investigator judgment. 
4. TMA due to hematopoietic stem cell transplantation ≤ 12 months of Screening 
5. Primary and secondary glomerular diseases other than lupus 
6. Diagnosis of primary antiphospholipid antibody syndrome 

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7. Known Shiga toxin-producing Escherichia coli infections including but not limited to 
Shiga toxin-related hemolytic uremic syndrome 
8. Known familial or acquired ‘a disintegrin and metalloproteinase with a thrombospondin 
type 1 motif, member 13’ (ADAMTS13) deficiency (activity < 5%) 
9. Positive direct Coombs test which in the judgement of the Investigator is indicative of a 
clinically significant immune-mediated hemolysis not due to TMA 
10. Clinical diagnosis of disseminated intravascular coagulation (DIC) in the judgement of 
the Investigator, utilizing the International Society on Thrombosis and Haemostasis 
(ISTH) scoring criteria (Section 10.13) 
11. Presence of sepsis requiring vasopressors within 7 days prior to or during Screening 
12. Presence of monoclonal gammopathy including but not limited to multiple myeloma 
13. Known bone marrow insufficiency or failure evidenced by cytopenias 
14. Kidney biopsy (if available) showing any of the following in glomeruli:  
 ≥ 50% interstitial fibrosis tubular atrophy; 
 ≥ 50% glomerulosclerosis; 
 ≥ 50% crescent formation.  
15. Among transplant recipients, presence of confirmed cellular or antibody-mediated graft 
rejection 
16. Life expectancy < 6 months, hospice, or palliative care 
17. Unresolved N meningitidis infection 
18. Human immunodeficiency virus (HIV) infection evidenced by a positive HIV-1 or HIV-2 
antibody titer. A documented negative HIV-1/HIV-2 test within 6 months prior to 
Screening is acceptable to confirm eligibility 
19. History of malignancy within 5 years of Screening with the exception of nonmelanoma 
skin cancer or carcinoma in situ of the cervix that has been treated with no evidence of 
recurrence 
20. Known medical or psychological condition(s) or risk factor that, in the opinion of the 
Investigator, might interfere with the participant’s full participation in the study, pose any 
additional risk for the participant, or confound the assessment of the participant or 
outcome of the study 
21. Hypersensitivity to any ingredient contained in the study drug, including hypersensitivity 
to murine proteins 
22. Respiratory failure from any cause requiring mechanical ventilation (including 
intubation, bilevel positive airway pressure (BiPAP), or continuous positive airway 
pressure [CPAP]) within 72 hours prior to randomization 
Prior/Concomitant Therapy 
23. Use of any complement inhibitors within the past 3 years  

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Prior/Concurrent Clinical Study Experience 
24. Participation in the following types of interventional treatment studies within 30 days 
before Day 1 in this study or within 5 half-lives of that interventional treatment, 
whichever is greater: 
 Interventional treatment study of any unapproved therapy regardless of indication 
 Interventional treatment study of any therapy (approved or unapproved) being 
evaluated for TMA intervention 
Other Exclusions 
25. Pregnant, breastfeeding, or intending to conceive during the course of the study  
5.3. 
Lifestyle Considerations 
There are no lifestyle restrictions for this study. 
5.4. 
Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently randomized to either treatment group (ravulizumab or placebo). A minimal set 
of screen failure information is required to ensure transparent reporting of screen failure 
participants to meet the Consolidated Standards of Reporting Trials (CONSORT) publishing 
requirements and to respond to queries from regulatory authorities. Minimal information 
includes demography, screen failure details (eg, failed eligibility criteria), and any AEs, 
including any SAEs and any related concomitant medication, occurring during the Screening 
Period. 
During the Screening Period, potential participants who fail to meet laboratory eligibility criteria 
(eg, LDH, platelet count, and creatinine) will be allowed to repeat the laboratory test once 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.   

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6. 
STUDY INTERVENTION 
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according to the 
study protocol. 
For this study, the study intervention will include the administration of study drug (ravulizumab 
or placebo) in addition to BSC. 
6.1. 
Study Drug Administered 
Ravulizumab is formulated at pH 7.0 and is supplied in 30 mL single-use vials. Each vial of 
ravulizumab contains 300 mg of ravulizumab (10 mg/mL) in 10 mM sodium phosphate, 150 mM 
sodium chloride, 0.02% polysorbate 80, and water for injection. The comparator product 
(placebo) is formulated as a matching sterile, clear, colorless solution with the same buffer 
components, but without active ingredient. Additional details are presented in Table 6. 
Table 6: 
Study Drug 
Intervention Name 
Ravulizumab  
Placebo 
Dose Formulation 
Vial 
Vial 
Physical description 
Liquid solution practically free from 
particles 
Liquid solution practically free from 
particles 
Unit Dose Strength 
300 mg (10 mg/mL concentrated 
solution) 
Placebo 
Route of Administration 
IV infusion 
IV infusion 
Use 
Experimental 
Placebo comparator 
Sourcing 
Provided centrally by Alexion or 
contracted manufacturing organization 
Provided centrally by Alexion or 
contracted manufacturing organization 
Packaging and Labeling 
Ravulizumab will be provided in glass 
vials and stoppered with a butyl rubber 
stopper with aluminum overseal and 
flip-off cap. Ravulizumab will be 
supplied in kits and labeled as required 
per country requirement. 
Placebo will be provided in glass vials 
and stoppered with a butyl rubber 
stopper with aluminum overseal and 
flip-off cap. Placebo will be supplied in 
kits and labeled as required per country 
requirement. 
Abbreviations: IV = intravenous. 
 
The dosing regimen consists of a loading dose followed by maintenance dosing administered 
q8w. The maintenance dosing will be initiated 2 weeks after the loading dose administration. 
Weight-based dosing (Table 7) will be based on the participant’s body weight recorded at the 
day of the infusion visit. If the study intervention must be prepared the day prior to the visit, the 
weight from the prior visit may be used to determine the dose. 

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Table 7: 
Weight-based Doses of Ravulizumab 
Body Weight Rangea 
Loading Dose (Day 1) 
Maintenance Doses (Days 15, 71, and 127) 
≥ 30 to < 40 kg 
1200 mg  
2700 mg 
≥ 40 to < 60 kg 
2400 mg 
3000 mg 
≥ 60 to < 100 kg 
2700 mg 
3300 mg 
≥ 100 kg 
3000 mg 
3600 mg 
a  Dose will be based on the last recorded study visit body weight. If the study drug is prepared the day before a 
visit, the weight from the most recent study visit should be used. 
At the scheduled dosing visits (Section 1.3), study drug should be administered after all other 
tests and procedures have been completed, excluding the postdose sample collections 
(pharmacokinetic [PK]/pharmacodynamic [PD]/biomarkers). 
During the Treatment Period, participants will be randomized 1:1 to receive blinded doses of 
ravulizumab or placebo: 
 Participants in the ravulizumab group will receive a blinded loading dose of 
ravulizumab via IV infusion on Day 1, followed by a blinded maintenance dose at 
Day 15 then q8w thereafter through the end of the Treatment Period. 
 Participants in the placebo group will receive a blinded matching placebo dose via IV 
infusion on Day 1, followed by a blinded matching placebo dose at Day 15, then q8w 
thereafter through the end of the Treatment Period. 
6.2. 
Preparation/Handling/Storage/Accountability 
 The Investigator, or designee, must confirm appropriate temperature conditions have 
been maintained during transit for all study drug received and any discrepancies are 
reported and resolved before use of the study drug. 
 Only participants enrolled in the study may receive the study drug and only 
authorized site staff may supply or administer the study drug. All study drug must be 
stored in a secure, environmentally controlled, and monitored (manual or automated) 
area in accordance with the labeled storage conditions with access limited to the 
Investigator and authorized site staff. 
 The Investigator, institution, or the head of the medical institution (where applicable) 
is responsible for study drug accountability, reconciliation, and record maintenance 
(ie, receipt, reconciliation, and final disposition records). 
 This responsibility includes the reporting of any product complaints to 
productcomplaints@alexion.com within 1 business day. 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 regarding preparation, handling, storage, accountability, and final 
disposition of unused study drug is provided in the Pharmacy Manual. 

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6.3. 
Measures to Minimize Bias: Randomization and Blinding 
6.3.1. 
Randomization  
Participants will be randomized on Day 1. Participants will be randomized 1:1 either to 
the ravulizumab treatment group or to the placebo treatment group. Randomization will be 
performed centrally using Interactive Response Technology (IRT).  
To balance the effects of potential confounding factors between the ravulizumab and placebo 
arms, randomization will be stratified by baseline dialysis status (Yes versus No) and primary 
trigger type (autoimmune, infection, solid organ transplant, drugs, or malignant hypertension) 
using a dynamic allocation procedure (Pocock, 1975). 
6.3.2. 
Blinding  
Participants, all investigative site personnel, and any Alexion employee, or designee, directly 
associated with the conduct of the study will be blinded to participant treatment assignments. 
The blinding will be maintained by using identical study drug kits and labels for ravulizumab 
and placebo. The placebo will have an identical appearance to that of ravulizumab. 
The randomization code will be maintained by the IRT provider. 
The primary analysis will occur after all participants complete the Week 26 Visit or withdraw 
from the study prior to Week 26. Alexion will be unblinded at the time of the primary analysis 
and the treatment assignment for each patient will be communicated to the investigative site 
personnel at that time.  
In case of an emergency, the Investigator has the sole responsibility for determining if 
unblinding of a participant’s intervention assignment is warranted. Participant safety must 
always be the first consideration in making such a determination. The date and reason that the 
blind was broken must be recorded in the source documentation and case report form (CRF), as 
applicable. If the Investigator decides that unblinding is warranted, the Investigator will be able 
to unblind the patient’s treatment allocation directly using the IRT. If a patient’s intervention 
assignment is unblinded, the Investigator should make every effort to ensure that the intervention 
assignment is not revealed to other individuals (eg, other clinical research site staff, study team 
including the Alexion Medical Monitor), unless necessary for the best clinical care of the patient. 
When an AE is unexpected or related and serious, the blind will be broken for that specific 
participant only. The blind will be maintained for persons responsible for the ongoing conduct of 
the study (such as the study site, monitors, and Investigators) and those responsible for data 
analysis and interpretation of results, such as biometrics personnel.  
Unblinded information will only be accessible to those who need to be involved in the 
safety reporting to Health Authorities, Independent Ethics Committees (IECs), and/or 
Institutional Review Boards (IRBs). 
6.4. 
Study Intervention Compliance 
During this study, participants will receive dosing with study drug under the supervision of the 
Investigator or designee. 

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The date and time of each dose administered will be recorded in the source documents and in the 
CRF. 
6.5. 
Best Supportive Care 
In this study, participants in both treatment groups will receive BSC as background therapy, 
which will be determined by the Investigator according to institutional practices and participant 
characteristics. Best supportive care measures include but are not limited to: 
 Transfusion support, which should be provided as required per institutional guidelines 
and based on the participant’s clinical condition 
 Anti-infectives (antibiotics, antivirals, and antifungals) 
 Renal replacement therapy (dialysis) 
 Antihypertensive medications 
 Therapy for TMA associated with lupus nephritis or SSc-TMA 
 Withdrawal or dose adjustment of the suspected agent for drug-induced TMA 
6.6. 
Concomitant Therapy 
6.6.1. 
Allowed Medicine and Therapy 
Any medication or therapy (including over-the-counter or prescription medicines, vaccines, 
vitamins, and/or herbal supplements) deemed necessary for the participant’s care during the 
study, or for the treatment of any AE, along with any other medications, other than those listed as 
disallowed medications in Section 6.6.2, may be given at the discretion of the Investigator. 
However, it is the responsibility of the Investigator to ensure that details regarding the 
medication are recorded on the CRF. Please note that guidance on the use of COVID-19 vaccines 
is provided in Section 10.10. Guidance on required vaccinations and antibiotic prophylaxis is 
provided in Section 8.1.5.  
6.6.2. 
Disallowed Medicine and Therapy 
Participants are prohibited from receiving therapeutic plasma exchange/plasma infusion at any 
time following randomization during the Treatment Period. Participants are prohibited from 
receiving any of the following medications and therapies during the entire duration of study 
participation: 
 Experimental interventions or therapies 
 Eculizumab or other agents that act on the complement pathway 
In the event that a participant receives a prohibited medication and/or therapy, the Investigator 
must confer with the Medical Monitor to determine if the participant should discontinue study 
drug (Section 7.1). 
6.7. 
Dose Modification 
Dose modification of the study drug for an individual participant is not permitted for this study. 

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6.8. 
Intervention After the End of the Study 
After a participant completes the Treatment Period or withdraws from the study, study drug will 
not be administered. 
Upon completion of the last study visit, participants will return to the care of their treating 
physician. 

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7. 
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL 
7.1. 
Discontinuation of Study Drug 
A participant has the right to discontinue study drug at any time.  
Participants must permanently discontinue the study drug for any of the following reasons: 
 Hypersensitivity reaction meeting criteria for SAE 
 Severe uncontrolled infection 
 Pregnancy or planned pregnancy 
 Participant is unblinded during the Treatment Period 
In addition, the study drug may be permanently discontinued for any of the following reasons: 
 Adverse event that would, in the opinion of the Investigator, make continued 
participation in the study an unacceptable risk 
 Use of disallowed medication (as defined in Section 6.6.2) 
 Deviation(s) from the protocol 
 Significant non-compliance 
 Alexion or the Investigator deems it is necessary for the participant 
 Termination of the study 
The reason for discontinuation of study drug will be recorded in the source documents and CRF. 
If the study drug is definitively discontinued, every effort should be made to have the participant 
continue in the study as per the Schedule of Activities (Section 1.3) through the Week 52/End of 
Study (EOS) Visit (for safety follow up and collection of other data). If a participant discontinues 
study drug due to an AE, including SAEs, the event should be followed as described in 
Section 10.4.3. 
Participants who discontinue study drug and remain on study may receive treatment consistent 
with local standard practice for their disease per the Investigator’s judgment, as applicable.  
If the participant does not agree to continue with the study visits, the following activities should 
be completed: 
 Early Discontinuation (ED) Visit should be performed as outlined in the Schedule of 
Activities (Section 1.3). 
 A Follow-up Phone Call will be performed 8 weeks following the participant’s last 
dose of study drug to collect information on concomitant medications, 
nonpharmacologic therapies and procedures, and AEs. 

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7.2. 
Participant Withdrawal from the Study 
 All efforts should be made to ensure participants 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 participant discontinuation must be recorded in the 
source documents and CRF. 
 A participant 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. 
 For participants who withdraw from the study prior to Week 26, an ED Visit should 
be conducted, whenever possible, per the Schedule of Activities (Section 1.3). A 
Safety Follow-up Phone Call should be conducted at least 8 weeks after the final dose 
of study drug to collect information on concomitant medications, nonpharmacologic 
therapies and procedures, and AEs. 
 For participants who withdraw from the study during the Follow-up Period, an EOS 
Visit should be conducted, whenever possible, per the Schedule of Activities 
(Section 1.3). 
 The participant will be permanently discontinued from the study drug at the time of 
study withdrawal. 
 If the participant withdraws consent for disclosure of future information, Alexion may 
retain and continue to use any data collected before such a withdrawal of consent, if 
permitted by local requirements. 
 If a participant withdraws from the study, the participant may request destruction of 
any samples taken and not tested, and the Investigator, or designee, must document 
this in the site study records. 
 Information about survival status at time of discontinuation and at Week 52 should be 
collected, whenever possible. If a participant's survival status is not available at the 
time of discontinuation, sites should attempt to collect the status (eg, via public 
records or telephone call). 
7.3. 
Lost to Follow-up 
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. 
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit: 
 The site must attempt to contact the participant and reschedule the missed visit as 
soon as possible and counsel the participant on the importance of maintaining the 
assigned visit schedule and ascertain whether or not the participant wishes to and/or 
should continue in the study. 

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 Before a participant is deemed lost to follow up, the Investigator, or designee, must 
make every effort to regain contact with the participant (where possible, 3 telephone 
calls and, if necessary, a certified letter to the participant’s last known mailing 
address or local equivalent methods). These contact attempts should be documented 
in the participant’s medical record. 
 Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study. 
 If a participant is deemed lost to follow-up, information about survival status at time 
of discontinuation and at Week 52 should be collected, whenever possible. If a 
participant's survival status is not available at the time, sites should attempt to collect 
the status (eg, via public records or telephone call). 
Discontinuation of specific sites or of the study as a whole are 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 Schedules of Activities 
(Section 1.3). Protocol waivers or exemptions are not allowed. 
 Immediate safety concerns should be discussed with Alexion immediately upon 
occurrence or awareness to determine if the participant should continue or 
discontinue study intervention. 
 Adherence to the study design requirements, including those specified in the 
Schedules of Activities (Section 1.3), is essential and required for study conduct. 
 All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The Investigator will maintain a screening log 
to record details of all participants screened and to confirm eligibility or record 
reasons for screening failure, as applicable. 
 Procedures conducted as part of the participant’s routine clinical management (eg, 
blood count) and obtained before signing of the ICF may be utilized for screening or 
baseline purposes provided the procedures met the protocol-specified criteria as 
described in Section 5. 
 The Investigator may delegate activities as permissible and documented in site 
delegation log. 
8.1. 
General Assessments and Procedures 
8.1.1. 
Informed Consent 
The Investigator or qualified designee must obtain a signed and dated ICF for each participant 
and/or their legally authorized representative prior to conducting any study procedures. The 
process for informed consent is outlined in Section 10.1.3. All efforts should be made to ensure 
participants are willing to comply with study participation prior to conducting the Screening 
procedures. 
8.1.2. 
Inclusion/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 participant qualifies for study participation. 
8.1.3. 
Demographics  
Demographic parameters, including age, sex, race, and ethnicity will be documented in the CRF. 
8.1.4. 
Medical History 
The participant’s relevant medical history, including prior and concomitant conditions/disorders 
(including TMA diagnosis), treatment history, and family history of relevant diseases will be 
evaluated at Screening by the Investigator, or qualified designee, and documented in the source 
documents and CRF. Any changes to medical history occurring during the Screening Period and 
prior to first dose of study drug on Day 1 will be documented prior to study drug administration. 

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8.1.5. 
Vaccination and Antibiotic Prophylaxis 
Due to its mechanism of action, the use of ravulizumab increases a participant’s susceptibility to 
meningococcal infection due to N meningitidis. To reduce the risk of infection, all participants 
must be vaccinated within 3 years prior to or at the time of the first infusion of study drug. 
Participants who have not been vaccinated prior to starting study drug for any reason, should 
receive appropriate prophylactic antibiotics prior to and for at least 2 weeks after vaccination. 
Vaccines against serotypes A, C, Y, W135, and B where available, are recommended in 
preventing the commonly pathogenic meningococcal serotypes. Participants must receive the 
complete primary vaccination series and be revaccinated if indicated according to current 
national vaccination guidelines. Vaccination may not be sufficient to prevent meningococcal 
infection. 
Participants should be administered prophylactic antibiotics for meningococcal infection until at 
least 2 weeks after vaccination if randomization occurs < 2 weeks after initial vaccination. 
Consideration should be given per official guidance and local practice on the appropriate use of 
prophylactic antibacterial agents. All participants should be monitored for early signs of 
meningococcal infection, evaluated immediately if infection is suspected, and treated with 
appropriate antibiotics, if necessary. Participants who cannot receive meningococcal vaccine 
should receive antibiotic prophylaxis coverage against N meningitis during the entire Treatment 
Period and for 8 months following the final dose of study drug. 
To increase risk awareness and promote quick disclosure of any potential signs or symptoms of 
infection experienced by the participants during the course of the study, participants will be 
provided a Participant Safety Card to carry with them at all times (Section 8.3.1). Additional 
discussion and explanation of the potential risks, signs, and symptoms will occur at specific time 
points as part of the review of the Participant Safety Card and throughout the study as described 
in the Schedule of Activities. 
Meningococcal serogroups ACWY and B vaccinations are required during screening for 
participants who do not meet criteria for previous vaccination. The vaccination series will be 
completed during the study according to national and local vaccination schedule guidelines. 
Participants who have TMA associated with triggers of lupus nephritis, systemic sclerosis, or 
solid organ transplant must also be vaccinated against Hib and S pneumoniae prior to 
randomization, unless previously vaccinated, if indicated according to current national/local 
vaccination guidelines. 
Vaccination status and administration of any vaccines, including those for N meningitidis, will be 
recorded on the CRF. 
8.2. 
Efficacy Assessments 
8.2.1. 
Laboratory Assessments for Efficacy Endpoints 
Laboratory assessments (platelets, LDH, and eGFR) to determine Complete TMA Response, 
Hematologic Response, and Renal Response will be performed according to the Schedule of 
Activities (Section 1.3) and will assessed based on the predetermined criteria for TMA response 
as defined in Section 3.2. 

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The eGFR calculation will be based on the CKD-EPI formula for all participants using serum 
creatinine collected prior to study drug administration, if applicable. 
8.2.2. 
Dialysis Status   
Participant dialysis status ≤ 14 days prior to Screening, during the Screening Period, and during 
the study will be documented on the CRF. 
8.2.3. 
Transfusion History and Transfusion Requirement Status During the Study 
The number and volume of transfusions ≤ 14 days prior to Screening, during the Screening 
Period, and during the study will be documented on the CRF. The information to be collected 
includes date of the transfusion, number of units, and volume of each blood component given. 
8.2.4. 
Survival Status 
Participant survival status will be assessed throughout the duration of the study. 
8.3. 
Safety Assessments 
8.3.1. 
Participant Safety Card 
Before the first dose of the study drug, a Participant Safety Card will be provided to participants 
to carry with them at all times until 8 months after the final dose of study treatment. The card is 
provided to increase participant awareness of the risk of meningococcal infection and promote 
quick recognition and disclosure of any potential signs or symptoms of infection experienced 
during the course of the study and to inform participants 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 participant has the 
Participant Safety Card. 
8.3.2. 
Physical Examinations 
 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, musculoskeletal, and neurological state 
(with emphasis on presence/degree of edema). 
 An abbreviated physical examination will include, at a minimum, a body-system 
relevant examination based upon the Investigator’s judgment and participant 
symptoms. 
 Investigators should pay special attention to clinical signs related to previous serious 
illnesses. 
 Additional physical examinations can be performed as medically indicated during the 
study at the Investigator’s discretion. 
 Weight and height (Screening only) will also be measured and recorded. 

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8.3.3. 
Vital Signs 
 Body temperature (°C or °F), heart rate, respiratory rate, systolic and diastolic blood 
pressure (mm Hg), and pulse oximetry will be assessed. 
 Blood pressure and heart rate measurements will be assessed with the participant in a 
seated or supine position using a completely automated device. Manual techniques 
will be used only if an automated device is not available. 
 Blood pressure and heart rate measurements should be preceded by at least 5 minutes 
of rest for the participant in a quiet setting without distractions (eg, television, cell 
phones). Ideally, the same arm for each participant should be used for measurements. 
 Vital signs will be collected predose at ravulizumab dosing visits. 
8.3.4. 
Electrocardiograms 
 Single 12-lead electrocardiogram (ECGs) will be conducted locally to obtain heart 
rate, PR, QRS, interval between the start of the Q wave and the end of the T wave in 
an ECG (QT), and corrected QT (QTc) intervals. QT interval will be corrected for 
heart rate using Fridericia’s formula (QTcF). 
 Single 12-lead ECG will be performed at Screening and at the end of the Treatment 
Period (Day 183). For participants that discontinue study drug prior to Week 26, an 
ECG should be performed at the ED Visit. 
 Participants must be supine during ECG collection. 
 The Investigator will be responsible for reviewing the ECG to assess whether the 
ECG is within normal limits and determine the clinical significance of the results. 
8.3.5. 
Clinical Safety Laboratory Assessments 
 All protocol-required laboratory assessments, as outlined in Section 10.2, must be 
conducted in accordance with the Laboratory Manual and the Schedule of Activities 
(Section 1.3).  
 The Investigator must review the laboratory report, document this review, and record 
any clinically relevant changes occurring during the study in the AE section of the 
CRF. The laboratory reports must be filed with the source documents. Clinically 
significant abnormal laboratory findings are those which are not associated with the 
underlying disease, unless judged by the Investigator to be more severe than expected 
for the participant’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. 
Note: For participants that withdraw from the study, all laboratory tests with values 
considered clinically significantly abnormal within 8 weeks after the last dose of 
study drug should be repeated until the values return to normal or baseline or are no 
longer considered clinically significant by the Investigator. 

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8.3.5.1. 
Virus Serology 
Human immunodeficiency virus testing for HIV-1 and HIV-2 is required for all participants prior 
to randomization. 
8.3.6. 
Pregnancy 
 Pregnancy testing must be performed on all women of childbearing potential 
(WOCBP) at protocol-specified time points in the Schedule of Activities 
(Section 1.3). Pregnancy tests (urine or serum) may also be performed at any time 
during the study at the Investigator’s discretion. 
 A negative pregnancy test is required for WOCBP before study drug administration. 
 Pregnancy data from female participants and female spouses/partners of male 
participants will be collected from the first dose of study drug through the EOS Visit. 
Any female participant who becomes pregnant while participating in the study will be 
discontinued from study drug. If a pregnancy is reported, the Investigator, or 
designee, must immediately inform Alexion within 24 hours of awareness of the 
pregnancy and follow the procedures outlined in Section 10.6.3. 
8.4. 
Adverse Events and Serious Adverse Events 
The definitions of AEs and SAEs can be found in Section 10.4 
All AEs will be reported to the Investigator or qualified designee by the participant (or, when 
appropriate, by a caregiver, surrogate, or the participant’s legally authorized representative). 
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 drug or study procedures, or that caused 
the participant to discontinue the study drug (see Section 7). 
Procedures for recording, evaluating, follow-up, and reporting AEs and SAEs are outlined in 
Section 10.4. 
8.4.1. 
Time Period and Frequency for Collecting AE and SAE Information 
All AEs and SAEs will be collected from the signing of the ICF until the EOS Visit. For 
participants who withdraw from the study during the Treatment Period, all AEs and SAEs should 
be collected through 8 weeks after last dose of study drug. For participants who discontinue 
study drug, but remain in the Follow-up Period, all AEs and SAEs will be collected through the 
EOS Visit. 
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 10.4. The Investigator, or 
designee, will submit any updated SAE data to Alexion within 24 hours of the date the study site 
became aware of the event. 
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 participant has concluded participation in the study, and he/she considers the event to be 

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reasonably related to the study drug or study participation, the Investigator must promptly notify 
Alexion. 
8.4.2. 
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 10.4. 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about AE 
occurrences. 
8.4.3. 
Follow-up of AEs and SAEs 
After the initial AE/SAE report, the Investigator is required to proactively follow-up on each 
participant at subsequent visits/contacts. All SAEs will be followed up until resolution, 
stabilization, the event is otherwise explained, or the participant is lost to follow-up (as defined 
in Section 7.3). Further information on follow-up procedures is provided in Section 10.4. 
8.4.4. 
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 participants 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, IRBs/IECs, and Investigators. 
 Alexion is required to submit individual suspected unexpected serious adverse 
reaction (SUSAR) reports (defined in Section 10.4.2) in the format of 
MedWatch 3500 or Council for International Organizations of Medical Sciences 
(CIOMS) I Form to health authorities and Investigators as required. Forms submitted 
to Investigators will be blinded to treatment assignment. In limited circumstances, the 
blind may be broken in the case of urgent safety issues that could compromise 
participant safety. 
 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. 
8.4.5. 
Major Adverse Cardiovascular Events 
Major adverse cardiovascular events (MACEs) will be assessed as part of the planned evaluation 
of AEs. A MACE is defined as any of the following: 
 Non-fatal myocardial infarction 
 Non-fatal stroke 

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 Death from cardiovascular disease 
The description of the MACE including the method of the diagnosis, date of diagnosis, and the 
date resolved (or ongoing) will be collected on the CRF as part of the participant’s medical 
history (prior to baseline) and throughout the study. 
8.4.6. 
Adverse Events of Special Interest 
Meningococcal infections will be considered to be adverse events of special interest. 
8.5. 
Review of Prior and Concomitant Medications and Procedures 
It is important for the Investigator or designee to review each medication the participant is taking 
before starting the study and at each study visit (Section 1.3) and record relevant changes in the 
CRF. 
8.5.1. 
Prior Medications and Procedures 
Prior medications and/or vaccines (including vitamins, herbal preparations, and those discussed 
in the eligibility criteria [Section 5]) and procedures (any therapeutic drug, such as mechanical 
ventilation, renal replacement therapy, surgery/biopsy or physical therapy) that the participant 
receives or undergoes ≤ 14 days prior to Screening or during the Screening Period, as well as any 
meningococcal vaccine administered within the last 3 years, will be recorded in the participant’s 
CRF. 
Information regarding the BSC treatment for the participant’s current complement-mediated 
TMA will be recorded in the participant’s CRF. 
8.5.2. 
Concomitant Medications and Procedures 
Concomitant medications (including any medication, vitamin, herbal preparation or supplement) 
and procedures (defined in Section 6.6) are those received on or after the first study drug date 
(Day 1), including those started before Day 1 and continued after Day 1. At each study visit, 
participants should be questioned about any new medication or nonpharmacologic therapies or 
changes to concomitant medications and nonpharmacologic therapies since the last visit. 
Concomitant medications and nonpharmacologic therapies should be recorded in the source 
documents and the participant’s CRF (unless otherwise noted) including: 
 Reason for use 
 Dates of administration including start and end dates 
 Dosage information including dose and frequency (this information is recorded in the 
source documents but not required on the CRF) 
Any concomitant medication deemed necessary for the participant’s care during the study, or for 
the treatment of any AE, along with any other medications, other than those listed as disallowed 
medications in Section 6.6.2, may be given at the discretion of the Investigator. However, it is 
the responsibility of the Investigator to ensure that details regarding all medications are recorded 
as described above, in the participant’s source documents and CRF. 

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Information regarding the use of BSC (Section 6.5) and disease-specific treatment received 
during the course of the study will be recorded in the source documents and the participant’s 
CRF, including treatment(s) for new thrombotic events. 
Vaccination and antibiotics administered for prophylaxis of meningococcal infection (if 
applicable) during the study will also be recorded. 
The Medical Monitor should be contacted if there are any questions regarding concomitant 
medications or procedures. 
8.6. 
Treatment of Overdose 
For this study, any dose of ravulizumab greater than that specified in the protocol will be 
considered an overdose. Any blinded dose greater than that specified in the protocol will be 
considered a suspected overdose. 
Alexion does not recommend specific treatment for an overdose. 
Overdoses are medication errors that are not considered AEs unless there is an untoward medical 
occurrence resulting from the overdose. 
In the event of an overdose or suspected overdose, the Investigator/treating physician should: 
1. Contact the Medical Monitor immediately. 
2. Closely monitor the participant for any AE/SAE. 
3. Obtain a plasma sample for PK analysis if requested by the Medical Monitor (determined 
on a case-by-case basis). 
4. For unblinded participants, document the quantity of the excess dose as well as the 
duration of the overdose in the CRF. 
Decisions regarding dose interruptions or modifications will be made by the Investigator in 
consultation with the Medical Monitor based on the clinical evaluation of the participant. 
8.7. 
Pharmacokinetics and Pharmacodynamics 
 Blood samples for determination of serum drug concentrations and PD assessments 
(free and total C5) will be collected before and after administration of study drug at 
the time points specified in the Schedule of Activities (Section 1.3). 
 Instructions for the collection and handling of biological samples, including blood 
volume requirements, are provided in the Laboratory Manual. The actual date and 
time (24-hour clock time) of each sample will be recorded. 
 The Day 1 baseline PK and PD blood samples will be collected at predose, within 
90 minutes before administering study drug (Section 1.3). The predose blood sample 
may be drawn through the venous access created for the dose infusion, prior to 
administration of the dose. 
 All subsequent predose samples will be collected within 0.5 hours prior to the start of 
infusion. In order to minimize needle sticks to the participant, the predose sample 

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may be drawn through the venous access created for the dose infusion, prior to 
administration of the dose. 
 Postdose PK and PD blood samples will be collected within 0.5 hours after 
completion of the study drug infusion. The postdose blood samples will be drawn 
from the participant’s opposite, noninfused arm. 
 For indicated visits not falling on dosing days, samples may be collected at any time 
that visit day. 
 In the event of an unscheduled visit, PK and PD blood sample will be collected as 
soon as possible. 
Study drug concentration information that may/would unblind the study will not be reported to 
investigative sites or blinded personnel until the study has been unblinded. 
8.8. 
Immunogenicity Assessments 
Antidrug antibodies to ravulizumab (ie, antidrug antibody) will be evaluated in serum samples 
collected from all participants according to the Schedule of Activities (Section 1.3). 
The detection and characterization of antibodies to ravulizumab will be performed using a 
validated assay method. Confirmed antibody positive samples will be further evaluated for 
antibody titer and the presence of neutralizing antibodies. 
8.9. 
Biomarkers 
Please refer to the Laboratory Manual for details on sample collection, including blood volume 
requirements. Biomarker samples may be analyzed after study completion. 
8.9.1. 
Blood Biomarkers 
Blood (whole blood, serum, and plasma) samples for biomarker research will be collected from 
all participants at the time points specified in the Schedule of Activities (Section 1.3). 
Biomarkers to be measured may include, but are not limited to, assessments of the following: 
 Vascular inflammation (eg, shed tumor necrosis factor receptor I [sTNF-RI])  
 Endothelial damage and/or activation (eg, thrombomodulin and shed vascular cell 
adhesion molecule 1 [sVCAM-1])  
 Complement pathway dysregulation (eg, soluble C5b-9 [sC5b-9] and factor Ba) 
8.9.2. 
Urine Biomarkers 
Urine samples for biomarker research will be collected from all participants during Screening 
and at the time points specified in the Schedule of Activities (Section 1.3). 
Biomarkers to be measured may include, but are not limited to, assessments of the following: 
 Complement pathway dysregulation (eg, sC5b-9 and factor Ba) 
 Renal injury biomarkers (eg, neutrophil gelatinase-associated lipocalin [NGAL]) 

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8.9.3. 
Real Time Complement Activity 
Blood and urine samples will be collected by all sites for exploratory Real Time Complement 
Activity (RTCA) during Screening and at the time points specified in the Schedule of Activities 
(Section 1.3) through the end of the Treatment Period (Day 183). Samples are to be collected, 
frozen, and shipped to the central laboratory.   
Selected sites will perform additional RTCA testing using freshly collected whole blood 
dipotassium ethylenediaminetetraacetic acid (K2EDTA), plasma, and urine samples with same 
day, on-site testing using a dedicated reader and specific instructions provided by the Sponsor 
and as instructed in the laboratory manual; the reader output will be masked such that all site 
personnel will be blinded from the RTCA results. 
8.9.4. 
Additional Biomarker Research 
Residual blood and urine samples from exploratory biomarkers, PK, PD, and immunogenicity, 
will be stored for additional method developments of assays (eg, prognostic and/or diagnostic 
tests related to the study drug target, disease process, pathways associated with disease state, 
other TMA or complement-related diseases, and/or mechanism of action of ravulizumab). 
Samples will be retained to enable further analysis on ravulizumab but for no longer than 5 years 
after termination of the study or other period as per local requirements. 
8.10. 
Genetics 
For participants who sign an additional optional consent, whole blood for exploratory genetics 
may/will be collected at the time point specified in the Schedules of Activities 
(Section 1.3). Exploratory genetics may be performed to investigate genetic variants in genes 
that may be associated with complement dysregulation or metabolism or efficacy of 
ravulizumab. Please refer to the Laboratory Manual for details on sample collection, including 
sample requirements. 
Participation is optional. Participants who do not wish to participate in the genetic research may 
still participate in the study. 
In the event of DNA extraction failure, a replacement genetic blood sample may be requested 
from the participant. Signed informed consent will be required to obtain a replacement sample 
unless it was included in the original consent. 
See Section 10.8 for information regarding DNA sample retention and future genetics research. 
8.11. 
Other Assessments 
8.11.1. 
Patient-Reported Outcome Measures 
Quality of life scales will be administered electronically by the Investigator or a qualified site 
staff member prior to other study procedures at visits specified in the Schedule of Activities 
(Section 1.3). 
All assessments should be administered in a quiet room and should be administered 
electronically by the Investigator or a qualified site staff member prior to other study procedures 
at visits specified in the Schedules of Activities (Section 1.3). These assessments may be 

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recorded on paper if electronic devices are unavailable or cannot be used. If the Investigator 
deems that the participant is not able to self-report using any of these instruments at a particular 
time point, then they will not be administered to the participant. 
The following quality of life scales will be administered: 
 The Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue scale 
(Section 10.11.1), Version 4.0, is a 13-item questionnaire that assesses self-reported 
fatigue and its impact upon daily activities and function over the preceding 7 days 
(Cella, 2002; Webster, 2003; Yellen SB, 1997) 
 The EuroQoL 5-Dimensions 5-Level (EQ-5D-5L) (Section 10.11.2) is a self-assessed, 
standardized instrument to measure health-related quality of life and has been used in 
a wide range of health conditions. The EQ-5D-5L comprises 5 dimensions, each 
describing a different aspect of health: mobility, self-care, usual activities, 
pain/discomfort, and anxiety/depression.  
 The Kidney Disease Quality of Life instrument-36 items (KDQOL-36™) 
(Section 10.11.3) is a 36-item kidney-specific health-related quality of life measure 
including Short-Form Health Survey 12 Item (SF-12) as generic core plus the burden 
of kidney disease, symptoms/problems of kidney disease, and effects of kidney 
disease scales. 
8.11.2. 
Medical Resource Utilization 
Medical resource utilization and health economics data associated with medical encounters, 
concomitant medication use, and other indicators of health resource utilization will be collected. 
Protocol-mandated procedures, tests, and encounters are excluded. 
The data collected may be used to conduct descriptive exploratory analyses and will include, but 
are not limited to: 
 Number, reason, and duration of hospitalizations (including stays in intensive care 
unit, if applicable) 
 Number of outpatient medical encounters (including physician or emergency room 
visits) and the underlying reason 

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9. 
STATISTICAL CONSIDERATIONS 
9.1. 
Statistical Hypotheses 
The primary efficacy analysis will test the hypothesis that ravulizumab is superior to placebo 
based on the proportion of participants achieving Complete TMA Response during the 26-week 
Treatment Period. The estimand corresponding to the primary efficacy analysis is described in 
Section 10.2. Hypothesis testing will be 2-sided and performed at the 0.05 level of significance. 
The null and alternative hypotheses for the primary analysis are as follows: 
H0: Prav = Pplacebo vs. HA: Prav ≠ Pplacebo  
where Prav is the proportion of participants achieving Complete TMA Response in the 
ravulizumab + BSC group and Pplacebo is the proportion of participants achieving Complete TMA 
Response in the placebo + BSC group.  
9.2. 
Sample Size Determination 
The sample size determination was based on a 2-sided Fisher’s exact test performed at a 2-sided 
significance level of 0.05, comparing the proportion of participants achieving Complete TMA 
Response during the 26-week randomized Treatment Period in participants randomized to 
ravulizumab versus placebo. A sample size of 100 (50 participants per treatment group) has 
approximately 90% power to detect a statistically significant (p ≤ 0.05) treatment difference of 
35% in the proportion of responders at a 2-sided significance level of 0.05, assuming the 
responder rate is 35% with placebo plus BSC and 70% with ravulizumab plus BSC and an 
anticipated 10% drop-out rate (Caires, 2012; Humphreys, 2004; Lee, 2012; Schwarz, 2010; 
Song, 2013; Waters, 2007; Wu, 2013). 
9.3. 
Populations for Analyses 
The population sets used for analysis are defined in the following: 
Population 
Description 
Intent to Treat 
All randomized participants 
Modified Intent to Treat (mITT) 
All randomized participants, excluding participants who enroll prior to 
availability of ST-HUS and ADAMTS13 central laboratory results and are 
subsequently found to be ineligible after randomization 
Safety Set 
All participants who receive at least 1 dose of study drug. Participants will 
be analyzed according to the study drug they actually received for 
reporting exposure and safety data 
Pharmacokinetic/Pharmacodynamic 
(PK/PD) Analysis Set 
All participants who receive at least 1 dose of study drug and who have 
evaluable PK/PD data 
Per Protocol (PP) Set  
To be defined in the Statistical Analysis Plan  
Abbreviations: ADAMTS13 = a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13; 
ST-HUS = Shiga toxin-related hemolytic uremic syndrome  
9.4. 
Statistical Analyses 
Statistical methods described in this section will be further elaborated in a separate Statistical 
Analysis Plan (SAP). Summary statistics will be computed and displayed by treatment group and 
by visit, where applicable. Descriptive statistics for continuous variables will minimally include 

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the number of participants, mean, standard deviation (SD), minimum, median, and maximum. 
For categorical variables, frequencies and percentages will be presented. Graphical displays will 
be provided as appropriate. 
Analyses will be performed using the SAS® software Version 9.4 or higher.  
9.4.1. 
Efficacy Analyses 
Efficacy analyses will be performed using the mITT Set, which will exclude participants who 
enrolled prior to availability of ST-HUS and ADAMTS13 central laboratory results and were 
subsequently found to be ineligible after randomization. The mITT was selected as the primary 
efficacy population to ensure the exclusion of participants with thrombotic thrombocytopenic 
purpura (TTP) or Shiga toxin E. coli related hemolytic uremic syndrome (ST-HUS) as potential 
confounders in the efficacy analyses, as these conditions present similarly to the target 
population but have distinct clinical prognosis and management. 
The primary analysis and selected secondary efficacy analyses will be performed on the ITT Set 
and PP Set as sensitivity analyses as necessary.  
9.4.1.1. 
Analyses of Primary Efficacy Endpoint 
The estimand corresponding to the primary endpoint is defined as the difference in the 
proportion of participants with Complete TMA Response during the 26-week Treatment Period 
between treatment groups in participants in the mITT analysis set. A composite strategy will be 
applied where participants will be classified as nonresponders if they do not have any TMA 
response observed before the intercurrent events: premature discontinuation of study treatment or 
initiation of disallowed therapy or medicine, regardless whether the TMA response is observed 
after these intercurrent events (refer to Section 10.2). For other participants without the above 
intercurrent events, Complete TMA Response by Week 26 will be assessed using all available 
assessments within the 26-week randomized Treatment Period.  
The primary efficacy analysis will test the hypothesis that ravulizumab is superior to placebo 
based on the proportion of participants achieving Complete TMA Response (Section 8.2.1) 
during the 26-week randomized Treatment Period. Participants must meet each TMA Response 
criterion at 2 separate assessments at least 24 hours apart, and any measurement in between.  
The primary efficacy analysis will be performed at the end of the 26-week Treatment Period 
after all participants have completed 26 weeks or withdrawn early from the 26-week Treatment 
Period.  
The primary analysis will be based on a Cochran-Mantel-Haenszel test stratified by 
randomization stratification factors at a 5% significance level, comparing the proportion of 
participants achieving Complete TMA Response during the 26-week randomized Treatment 
Period between the 2 treatment groups in the mITT Set. The analysis will be performed 
according to the randomized treatment assignment.  Non-Responder Imputation (NRI) method 
will be used to handle missing data. 
If a participant is not on dialysis at baseline, baseline eGFR will be defined as the last non-
missing assessment prior to the start of study treatment. If a participant is on dialysis on Day 1, 
baseline eGFR will be imputed as described in the SAP. If the participant is on dialysis for the 

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entire 26-week Treatment Period, or through early discontinuation of study drug, then the change 
in eGFR will not be calculated.  
As a sensitivity analysis, a 2-sided Fisher's exact test on the primary endpoint will be performed. 
A re-randomization test to calculate the p-value will also be explored. The p-values from 
sensitivity analyses for efficacy endpoints are for descriptive purpose only and not adjusted for 
multiplicity. Details on sensitivity analyses will be provided in the SAP. 
9.4.1.2. 
Analyses of Secondary Efficacy Endpoints 
9.4.1.2.1. Analyses of Key Secondary Endpoints 
Key secondary endpoints (defined in Table 4) and corresponding estimands (defined in 
Section 10.2) will be analyzed as follows: 
For time to Complete TMA Response (Section 3.2.1), participants will be assigned as responders 
at the time of their response and will be censored at the earliest of their discontinuation time or at 
the end of available follow-up if they have not responded by then. The corresponding estimand is 
the hazard ratio of time to Complete TMA Response between treatment groups in participants in 
the mITT. A hypothetical strategy will be applied where all data after intercurrent events of 
premature discontinuation of study treatment or initiation of disallowed therapy or medicine will 
be censored. Kaplan-Meier cumulative distribution curves will be generated for each treatment 
group, and a log-rank test comparing the curves will be performed. A corresponding summary 
table will present by treatment group the cumulative distribution function estimate, the number 
of participants at risk, the number of participants responding, and the number of participants 
censored at each post-baseline time point. The table will also present the first quartile, median, 
and third quartile, along with the corresponding 2-sided 95% CI, of time to response.  
For hematologic response at Week 26 and on dialysis at Week 26, the corresponding estimand is 
the difference in the proportion of participants achieving hematologic response at Week 26 or 
difference in the proportion of participants on dialysis at Week 26 respectively, between 
treatment groups in participants in the mITT. Analyses will be based on a composite strategy 
where participants will be considered as nonresponders after intercurrent events of premature 
discontinuation of treatment or initiation of disallowed therapy or medicine. Following a similar 
approach as for the analyses of the primary estimand, a Cochran-Mantel-Haenszel test will be 
applied and NRI method will be used to handle missing data.  
For change from baseline in eGFR at Week 26, the corresponding estimand is the difference in 
the mean of change from baseline in eGFR at Week 26 between treatment groups in participants 
in the mITT, if participants do not prematurely discontinue study treatment or initiate disallowed 
therapy or medicine. Analyses will be based on hypothetical strategy where data collected after 
the intercurrent events of treatment discontinuation or initiation of disallowed therapy or 
medicine will become irrelevant. The treatment comparison will be conducted based on a Mixed-
Effect Model Repeated Measures (MMRM) method using a mixed model including observed 
measurement at all visits prior to treatment discontinuation or initiation of disallowed therapy or 
medicine. The model includes the categorical fixed effects of treatment, study visit, and study 
visit by treatment interaction, stratification factor, and the continuous fixed covariate of baseline 
measurement. An unstructured covariance matrix will be used to model the within-participant 

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errors. The specified MMRM analysis can produce valid statistical inference under the missing-
at-random (MAR) missing data mechanism assumption. 
9.4.1.2.2. Analyses of Additional Secondary Endpoints 
Additional secondary endpoints defined in Table 4 will be analyzed as follows: 
Time to response for each individual TMA parameter during the 26-week Treatment Period will 
be assessed in a similar manner as time to Complete TMA Response. 
The binary additional secondary endpoints will be summarized by randomized treatment group 
by calculating the point estimate and 2-sided 95% CI for the response rate, based on exact 
confidence limits using the Clopper Pearson method. Treatment comparison of the response rate 
at all scheduled assessments during the 26-week randomized Treatment Period will be based on 
Cochran-Mantel-Haenszel test stratified by randomization stratification factors.  
For continuous additional secondary endpoints, MMRM model will be used and similar statistics 
will be provided as described above. 
For all parameters summarized during the Randomized Treatment Period other than eGFR, 
baseline is defined as the last non-missing assessment value prior to the start of study treatment 
(data from Screening or Day 1, prior to date of randomization). 
For participants who require dialysis, change from baseline in dialysis requirements will be 
summarized.  
9.4.1.3. 
Multiplicity Adjustment  
The primary and key secondary efficacy analyses will use a hierarchical stepdown closed-testing 
procedure. If the null hypothesis for the primary efficacy estimand is rejected, the key secondary 
efficacy estimands will be tested in the following order until a non-significant test is observed, at 
which point no further testing of subsequent estimand will occur: 
1. Time to Complete TMA Response during the 26-week randomized Treatment Period 
2. Achievement of hematologic response at Week 26 
3. Change from baseline in eGFR at Week 26 
4. On dialysis at Week 26 
9.4.2. 
Safety Analyses 
All safety analyses will be performed on the Safety Set. Participants will be analyzed according 
to the study treatment they actually received. 
9.4.2.1. 
Adverse Events 
The following definitions will be used for AEs: 
 Pretreatment AEs: Any AE that starts after providing informed consent, but before 
the first infusion of study drug 
 Treatment-emergent adverse event (TEAE): Any AE that starts between the start of 
the first infusion of study drug and up to 8 months after the last infusion of study drug 

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 Treatment-emergent SAE (TESAE): A TEAE that meets the criteria for serious 
(Section 10.4.2) 
 Post-treatment AEs: Any AE that starts 8 months or later after the last infusion of 
study drug 
The incidence of TEAEs, TEAEs leading to withdrawal from the study, TEAEs leading to study 
drug discontinuation, and TESAEs will be summarized by treatment group. All AEs will be 
coded using the Medical Dictionary for Regulatory Activities (MedDRA), version 23.0 or 
higher, and will be summarized by System Organ Class and Preferred Term overall, by severity, 
and by relationship to study drug. 
Detailed by-participant listings of TEAEs, TESAEs, related TEAEs, TEAEs leading to 
withdrawal from the study, and TEAEs leading to study drug discontinuation will be provided. 
9.4.2.2. 
Physical Examination and Vital Signs 
Adverse changes from baseline in physical examination findings will be classified as AEs and 
analyzed accordingly. 
Vital signs will be summarized descriptively by treatment group at baseline and post-baseline 
time points and for changes from baseline. 
9.4.2.3. 
Clinical Laboratory Tests 
Observed values and changes from baseline in clinical chemistry, hematology, and spot urine 
collection will be summarized descriptively by treatment group at baseline and at each 
post-baseline time point. For laboratory results that can be classified as normal, low, or high 
based on normal range values, shifts from baseline in classification will be summarized for all 
study visits. 
9.4.2.4. 
Electrocardiograms 
By-participant data listings of ECG parameters will be provided separately for each disease 
cohort. Electrocardiograms will be evaluated and summarized as normal, abnormal not clinically 
significant, or abnormal clinically significant. A shift from baseline to worst on-study ECG table 
will be presented for ECG results. Observed values and change from baseline in ECG intervals 
(PR, RR, QT, and QTc) will be summarized descriptively at baseline and each postbaseline time 
point. The QT interval will be corrected for heart rate using Fridericia’s formula (QTcF). 
9.4.2.5. 
MACE 
Descriptive statistics for number and percentage of participants with MACEs will be presented 
by treatment group. Pre-treatment and treatment-emergent MACE rates through Day 183 
(Week 26) (number per 100 participant-years) along with participant-years of follow up and total 
number of MACEs will be displayed by treatment group. MACE is defined in Section 8.4.5. 
9.4.3. 
Pharmacokinetic/Pharmacodynamic Analysis 
Individual PK/PD data will be collected for all participants. 

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Graphs of mean serum ravulizumab concentration-time profiles will be constructed. Graphs of 
serum concentration-time profiles for individual participants may also be provided. Descriptive 
statistics will be calculated for serum concentration data at each sampling time, as appropriate. 
The PD effects of ravulizumab will be evaluated by assessing the absolute values and changes 
and percentage changes from Baseline in serum free C5 concentrations over time, as appropriate. 
Descriptive statistics will be calculated for the PD data at each sampling time, as appropriate. 
9.4.4. 
Immunogenicity Analyses  
The incidence of ADAs to ravulizumab will be presented at each postbaseline time point in 
tabular format. Additionally, any confirmed ADA-positive samples will be tested for titer and the 
presence of neutralizing antibodies to ravulizumab. 
9.4.5. 
Exploratory Analyses 
The exploratory efficacy analyses will be descriptive in nature and will be based on the mITT 
Set. Full details regarding the exploratory analyses will be described in the SAP.  
9.4.5.1. 
Quality of Life 
The following quality of life assessments will be summarized by treatment group at baseline and 
each postbaseline time point using descriptive statistics for the observed value as well as the 
change from baseline: 
 EQ-5D-5L 
 KDQOL-36 
9.4.5.2. 
Other Exploratory Endpoints 
Analyses of exploratory biomarkers and genetic testing will be described in separate SAPs and 
may be summarized after study completion.  
9.5. 
Planned Analyses 
9.5.1. 
Interim Analysis 
An interim analysis to assess sample size re-estimation will be performed when 50% of the 
planned participants (n = 100) have been assessed for the primary estimand. This interim 
analysis will be performed by an unblinded independent statistical center that is not involved 
with study conduct or final analysis of study data. Enrollment of participants will proceed 
without interruption while the analysis is ongoing. There are no plans to stop the study for 
demonstration of efficacy or futility at the interim analysis. 
The sample size re-estimation analysis will be based on the conditional power calculated using 
the results obtained at this interim analysis. If the conditional power falls within the promising 
zone based on the estimated treatment effect, the sample size will be increased up to a maximum 
of 150 participants. Because the total sample size could potentially be increased in a data-
dependent manner following the interim analysis, the final primary analysis for the primary 
estimand will be tested using the Cui, Hung, Wang method for controlling the type 1 error (Cui, 
1999). Full details will be provided in a separate interim SAP.  

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9.5.2. 
Primary Efficacy Analysis 
The primary efficacy analysis will be performed at the end of the 26-Week Treatment Period 
after all participants have completed or withdrawn from the 26-Week Treatment Period. This 
analysis will allow for evaluation of the primary estimand. 
9.5.3. 
Final Analysis  
The final study analysis will be conducted at the end of the study (Section 4.5). The SAP will 
describe the planned analysis in greater detail. 
9.6. 
Data Monitoring Committee  
This study will not include a Data Monitoring Committee. 

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10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
10.1. 
Regulatory, Ethical, and Study Oversight Considerations 
10.1.1. 
Regulatory and Ethical Considerations 
 This study will be conducted in accordance with the protocol and the following: 
 Consensus ethical principles derived from international guidelines including 
the Declaration of Helsinki and 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, substantial protocol amendments, ICF, IB, and other relevant 
documents (eg, advertisements) must be submitted to an IRB/IEC by the 
Investigator/Alexion and reviewed and approved by the IRB/IEC before the study 
is initiated. 
 If any of these documents require regulatory/health authority approval per 
local regulations, Alexion will also obtain such approval before the study is 
initiated. 
 Any substantial amendments to the protocol will require IRB/IEC and 
regulatory/health authority approval before implementation of changes made to 
the study design, except for changes necessary to eliminate an immediate hazard 
to study participants.  
 The Investigator will notify the IRB/IEC of deviations from the study protocol or 
GCP as defined by applicable law 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, Directive 2001/20/EC, 
European regulation 536/2014 for clinical studies (if applicable), and all other 
applicable local regulations 

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10.1.2. 
Financial Disclosure 
The Principal Investigator and all 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 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 signed (written or 
electronic signature) informed consent from all study participants, or the participant’s 
legally authorized representative, prior to performing any study-related procedures 
including screening assessments. 
 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 
participant’s rights and responsibilities) to the participant or his/her legally authorized 
representative, defined according to local and country regulations where the study is 
taking place, and answer all questions regarding the study. 
 Participants must be informed that their participation is voluntary. Participants or 
their legally authorized 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 GCP 
guidelines, Health Insurance Portability and Accountability Act requirements, where 
applicable, and the IRB/IEC or study center. 
 The participant’s medical record must include a statement that signed (written or 
electronic) informed consent was obtained before any screening procedures were 
performed with a participant, and the date the written consent was obtained. The 
authorized person obtaining the informed consent must also sign the ICF(s). 
 Participants must be reconsented to the most current version of the ICF(s) during their 
participation in the study, as applicable. 
 A copy of the signed (written or electronic) informed consent documentation (ie, a 
complete set of participant information sheets and fully executed signature pages) 
must be provided to the participant or the participant’s legally authorized 
representative, as applicable. This document may require translation into the local 
language. Original signed (written or electronic) consent forms must remain in each 
participant’s study file and must be available for verification at any time. 
Participants who are rescreened outside of the Screening window (Section 1.3) are required to 
sign a new ICF (see Section 5.4). 
The ICF will contain a separate section that addresses the use of remaining mandatory samples 
for optional exploratory research. The Investigator or authorized designee will explain to each 
participant or their legally authorized representative the objectives of the exploratory research. 
Participants or their legally authorized representative will be told that they are free to refuse to 
participate and may withdraw their consent at any time and for any reason during the storage 

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period. A separate signature will be required to document a participant’s agreement to allow any 
remaining specimens to be used for exploratory research. Participants who decline to participate 
in this optional research will not provide this separate signature. 
10.1.4. 
Data Protection 
 Participants will be assigned a unique identifier by Alexion. Any participant 
records or datasets that are transferred to Alexion will contain the identifier only; 
participant names, initials, or any information which would make the participant 
identifiable will not be transferred. 
 Participants must be informed that their personal study-related data will be used in 
accordance with applicable data protection law, and participants must also be 
informed of any individuals rights they may have with regard to their personal 
data. Participants will be informed about how their personal study-related data 
will be disclosed, and will be required to agree to the information contained in the 
informed consent and provide consent to the processing of their personal data, if 
required by applicable data protection law. 
 Participants must be informed that their medical records may be examined by 
Clinical Quality Assurance auditors or other authorized personnel appointed by 
Alexion, appropriate IRB/IEC members, and inspectors from regulatory 
authorities. 
 Alexion as a data controller has implemented privacy and security controls 
designed to help protect participant personal data; including information security 
controls, firewalls, incident detection, and secure transfer measures. 
 In the event of any accidental or unlawful destruction, loss, alteration, 
unauthorized disclosure of, or access to, personal data (“breach”), the controller 
has implemented procedures and measures to promptly address and mitigate any 
risk to the data participant. In the event of a breach, the controller will notify the 
appropriate regulatory authorities and/or the data participant in accordance with 
applicable data protection law. 
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 participant data relating to the study will be recorded on printed CRF or electronic 
case report form (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 CRF. 

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 The Investigator must maintain accurate documentation (source data) that supports 
the information entered in the CRF. 
 The Investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents. 
 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 by authorized site personnel are accurate, complete, and 
verifiable from source documents; that the safety and rights of participants are being 
protected; and that the study is being conducted in accordance with the currently 
approved protocol and any other study agreements, ICH GCP, and all applicable 
regulatory requirements. 
 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 Clinical 
Monitoring Plan. 
 Records and documents, including signed ICFs, pertaining to the conduct of this 
study must be retained by the Investigator after study completion per local regulations 
or institutional policies. No records may be destroyed 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 participant 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 participant. 
Data reported on the CRF that are transcribed from source documents must be consistent with 
the source documents or the discrepancies must be explained. Case report forms must be 
completed by the Investigator or designee as indicated in the site delegation log. The Investigator 
may need to request previous medical records or transfer records, depending on the study. Also, 
current medical records must be available to Alexion, Alexion delegates, and health authorities, 
as requested. Source documents are filed at the study site. 
Per ICH E6 (R2) guidelines and good documentation practice requirements, source documents 
and study records in all media (eg, paper, electronic) must be Attributable, Legible, 
Contemporaneous, Original, Accurate, and Complete. 
10.1.8. 
Study and Site Start and Closure 
The study start date is the date on which the first participant is consented. 

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Alexion reserves the right to close the study site or terminate the study at any time for any reason 
at its sole discretion. 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 participants 
have completed the EOS or ED Visit, all data have been collected and entered into the electronic 
data capture (EDC) system, all required documents and study supplies have been collected and 
reconciled, 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 ICH/GCP guidelines 
 Inadequate recruitment of participants by the Investigator 
 Discontinuation of further study intervention development 
 Alexion or a health authority may terminate the study for reasonable cause. 
Conditions that may warrant termination of the study include, but are not limited to: 
 Discovery of an unexpected, serious, or unacceptable risk of the study drug to 
participants enrolled or continuing in the study  
 Alexion decision to suspend or discontinue testing, evaluation, or development of 
the study drug for the indication of TMA associated with trigger(s) 
If the study is prematurely terminated or suspended, Alexion shall promptly inform the 
Investigators, the IECs/IRBs, 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 participant and 
should assure appropriate participant 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. 

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 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. 
 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 as 
defined by the Pharmaceutical Research and Manufacturers of America and the 
International Committee of Medical Journal Editors and per the Alexion 
Publication Policy. 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. 
 Alexion will Publish Patient Lay Summaries and include participants and/or 
caregivers as reviewers for readability and understanding of lay person language. 
10.1.10. 
Good Clinical Practice Compliance 
Alexion and any third party to whom aspects of the study management or monitoring have been 
delegated will undertake their assigned roles for this study in compliance with all applicable 
industry regulations, ICH GCP Guideline E6 R2, EU Directive 2001/20/EC, as well as all 
applicable national and local laws and regulations. 
Visits to sites are conducted by representatives of Alexion and/or the company 
organizing/managing the research on behalf of Alexion to inspect study data, participants’ 
medical records, and CRFs in accordance with current GCP and respective local and 
(inter)national government regulations and guidelines. Records and data may additionally be 
reviewed by auditors or by regulatory authorities. 
Alexion ensures that local regulatory authority requirements are met before the start of the study. 
Alexion (or designee) is responsible for the preparation, submission, and confirmation of receipt 
of any regulatory authority approvals required prior to release of study drug for shipment to the 
site. 

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10.2. 
Mapping Objectives to Estimands 
Table 8: 
Mapping Objectives to Estimands 
Objectives 
Estimands  
Primary 
To assess the efficacy of ravulizumab in 
the treatment of participants with TMA 
 
 
Population: Participants with TMA due to a trigger who are 
included in the mITT (defined in Section 9.3). 
 
Variable: Complete TMA Response during the 26-week 
randomized Treatment Period (Section 3.2.1). 
 
Treatments: Ravulizumab vs. placebo  
 
IE:  
o 
IE1: premature discontinuation of study treatment; 
o 
IE2: initiation of disallowed therapy or medicine 
All participants who meet response criteria after IE1 or IE2 
will be considered as nonresponders thereafter. 
Summary measure: Difference between treatment groups in the 
proportion of participants with Complete TMA response 
Key Secondary 
To characterize TMA response 
 
 
Population: Participants with TMA due to a trigger who are 
included in the mITT. 
 
Variable: Time to Complete TMA Response during the 26-week 
randomized Treatment Period. 
 
Treatments: Ravulizumab vs. placebo  
 
IE:  
o 
IE1: premature discontinuation of study treatment; 
o 
IE2: initiation of disallowed therapy or medicine 
All data after IE1 or IE2 will be censored. 
Summary measure: Hazard ratio between treatment groups 
To characterize TMA response 
 
 
Population: Participants with TMA due to a trigger who are 
included in the mITT. 
 
Variable: Achievement of hematologic response at Week 26 
(Section 3.2.2). 
 
Treatments: Ravulizumab vs. placebo  
 
IE:  
o 
IE1: premature discontinuation of study treatment; 
o 
IE2: initiation of disallowed therapy or medicine 
All participants who meet response criteria after IE1 or IE2 
will be considered as nonresponders thereafter. 
Summary measure: Difference between treatment groups in the 
proportion of participants with hematologic response at Week 26. 
To evaluate change in kidney function 
 
 
Population: Participants with TMA due to a trigger who are 
included in the mITT (defined in Section 9.3). 
 
Variable: Change from baseline in eGFR at Week 26. 
 
Treatments: Ravulizumab vs. placebo  
 
IE:  
o 
IE1: premature discontinuation of study treatment; 
o 
IE2: initiation of disallowed therapy or medicine 
All data after IE1 or IE2 will not be used. 
Summary measure: Difference between treatment groups in the 
mean of change from baseline in eGFR at Week 26. 

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Table 8: 
Mapping Objectives to Estimands 
Objectives 
Estimands  
To evaluate change in kidney function 
 
 
Population: Participants with TMA due to a trigger who are 
included in the mITT (defined in Section 9.3). 
 
Variable: On dialysis at Week 26. 
 
Treatments: Ravulizumab vs. placebo  
 
IE:  
o 
IE1: premature discontinuation of study treatment; 
o 
IE2: initiation of disallowed therapy or medicine 
All participants will be considered as nonresponders after 
IE1 or IE2. 
Summary measure: Difference between treatment groups in the 
proportion of participants on dialysis at Week 26. 
Abbreviations: eGFR = estimated glomerular filtration rate; IE = intercurrent event; mITT = Modified Intent-to-
Treat; TMA = thrombotic microangiopathy 
10.3. 
Clinical Laboratory Tests 
 The tests detailed in Table 9 will be performed by the central laboratory or designated 
ancillary laboratories unless otherwise noted.  
 As described in Section 5, local or central laboratory results may be utilized for the 
assessment of eligibility, with the exceptions of the ST-HUS screen and ADAMTS13 
activity tests which must be performed at the central laboratory. With the exceptions 
of the ST-HUS screen and ADAMTS13 activity tests, if local labs are used to 
establish eligibility, central laboratory tests are not required at the Screening visit. 
 For participants who experience constipation and cannot produce a stool sample 
for the ST-HUS screen during the Screening period, an assessment of the 
presence of Shiga toxin-producing E. coli infection can be evaluated by the 
Investigator based on the clinical presentation of the participant. If a stool sample 
for the ST-HUS screen cannot be obtained during the Screening period, laboratory 
evaluation for the ST-HUS screen will be made from the first available stool 
sample, which may include samples obtained post randomization.  
 After the Screening Period, local laboratory results are only required in the event 
the central laboratory results are not available in time for either study drug 
administration and/or response evaluation. Additionally, if the local laboratory 
results are used to make either a study intervention decision or response 
evaluation, the results must be entered into the CRF. If a local sample is obtained, 
it is important that the sample for central analysis is obtained at the same time. 
 Protocol-specific requirements for inclusion or exclusion of participants 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. 
 Pregnancy testing: WOCBP should only be enrolled after a negative serum pregnancy 
test result at Screening (serum pregnancy test to be collected at Screening, Day 183, 
and EOS/ED). Urine pregnancy testing will be performed at all other timepoints as 

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specified in the Schedule of Activities (Section 1.3) unless serum testing is required 
by site policies, local regulation, or IRB/IEC. 
 Investigators must document their review of each laboratory safety report. 
 
Table 9: 
Protocol-Required Laboratory Assessments 
Laboratory Assessments 
Parameters 
Hematology 
 Platelet count  
 Immature platelet fraction 
 Hematocrit 
 Red blood cell count 
 RBC indices 
o Mean corpuscular volume 
o Mean corpuscular hemoglobin 
o Absolute count and percentage of reticulocytes 
 White blood cell count with differential (including early progenitors): 
o Neutrophils, segmented 
o Lymphocytes 
o Monocytes 
o Eosinophils 
o Basophils  
 Hemoglobin  
 Haptoglobin 
Coagulation panel (performed 
at Screening only)  
 INR 
 PT 
 APTT 
 D-dimer 
 Fibrinogen 
Clinical chemistry 
 Lactate dehydrogenase 
 Liver function tests:  
o ALT 
o AST  
o ALP 
o Albumin  
o Total protein 
o Total bilirubin (direct and indirect)  
o GGT 
 Glucose (nonfasting) 
 C-reactive protein 
 Renal function:  
o Blood urea nitrogen 
o Calcium  
o Chloride 
o Creatinine  
o Magnesium 
o Phosphate 
o Potassium 
o Sodium  
o Total carbon dioxide 
Spot urine studies 
 Protein 
 Creatinine 

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Table 9: 
Protocol-Required Laboratory Assessments 
Laboratory Assessments 
Parameters 
 Urine protein creatinine ratio 
Clinical complement testsb 
Serum samples will include, but are not limited to, assessments of the following: 
 C3 and C4 
PK/PD  
 Serum PK  
 Serum PD (free and total C5) 
Immunogenicity 
 ADA  
Biomarkers 
Exploratory blood samples may include, but are not limited to, assessments of 
the following: 
 Vascular inflammation (eg, sTNF-RI)  
 Endothelial damage and/or activation (eg, thrombomodulin and sVCAM-1)  
 Complement pathway dysregulation (eg, sC5b-9, C5a, and factor Ba) 
Exploratory urine biomarkers may include, but are not limited to, assessments 
of the following: 
 Complement pathway dysregulation (eg, sC5b-9 and factor Ba) 
 Renal injury biomarkers (eg, neutrophil gelatinase-associated lipocalin 
[NGAL]) 
Freshly collected whole blood K2EDTA, plasma and urine samples, and frozen 
plasma and urine samples for RTCA 
Other screening tests 
 ADAMTS13 activity  
 ST-HUS screen (eg, Shiga toxin enzyme immunoassay/PCR in stool/stool 
culture)  
 Coombs test, direct 
 HIV-1 and HIV-2 antibody  
 Serum follicle-stimulating hormone and estradiol (as needed in WOCBP 
only) 
 Serum or urine human chorionic gonadotropin pregnancy test (as needed 
for WOCBP)a  
Other study-specific tests 
 Blood sample for genetics analysis (optional; additional consent required) 
a  Serum pregnancy test at Screening, Day 183, and EOS/ED. Urine pregnancy test at all other timepoints as 
specified in Schedule of Activities (Section 1.3). Additional urine pregnancy testing when deemed necessary by 
the Investigator. 
b Clinical complement tests to occur together with the clinical laboratory tests as specified in Schedule of Activities 
(Section 1.3). 
 
Abbreviations: ADA = antidrug antibody(ies); ADAMTS13 = a disintegrin and metalloproteinase with a 
thrombospondin type 1 motif, member 13; ALP = alkaline phosphatase; ALT = alanine aminotransferase; 
APTT =activated partial thromboplastin time; AST = aspartate aminotransferase; C3, C4, C5, and 
C5a = complement components 3, 4, 5, and 5a; ED = early discontinuation; EOS = end of study; GGT = gamma-
glutamyltransferase; HIV = human immunodeficiency virus; INR = international normalized ratio; 
K2EDTA = dipotassium ethylenediaminetetraacetic acid; PCR = polymerase chain reaction; 
PD = pharmacodynamic; PK = pharmacokinetic; PT = prothrombin time; RBC = red blood cell; RTCA = Real Time 
Complement Activity; sC5b-9 = soluble terminal complement complex C5b-9 (membrane attack complex); 
ST-HUS = Shiga toxin-related hemolytic uremic syndrome; sTNF-R1 = shed tumor necrosis factor receptor 1; 
sVCAM-1 = shed vascular cell adhesion molecule 1; WOCBP = woman of childbearing potential. 
 

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10.4. 
Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting 
10.4.1. 
Definition of AE 
AE Definition 
 
 An AE is any untoward medical occurrence in a participant or clinical investigation participant administered 
a pharmaceutical product and which does not necessarily have to have a causal relationship with this 
treatment (ICH E2A). 
 
 
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 the study drug, 
whether or not considered related to the 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. 
 
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 participant’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 participant’s condition. 
 
Situations in which an untoward medical occurrence did not occur (social and/or convenience admission to a 
hospital). 

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Events Not Meeting the AE Definition  
 
“Lack of efficacy” or “failure of expected pharmacological action” per se will not be reported as an AE or 
SAE. Such instances will be captured in the efficacy assessments. However, the signs, symptoms, and/or 
clinical sequelae resulting from lack of efficacy will be reported as AE or SAE if they fulfil the definition of 
an AE or SAE. 
10.4.2. 
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 participant was at risk of 
death at the time of the event. It does not refer to an event, which hypothetically might have caused death, if it 
was more severe. 
3.  Requires inpatient hospitalization or prolongation of existing hospitalization 
In general, hospitalization signifies that the participant 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 participant or may require medical or surgical intervention to prevent 
one of the other outcomes listed in the above definition. These events should usually be considered serious. 
 
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. 
 
A suspected unexpected serious adverse reaction (SUSAR) is defined as: 
An event that is assessed as serious by the Investigator and/or Alexion that is not listed in the appropriate 
Reference Safety Information (IB) and has been assessed that there is at least a reasonable possibility that the 
event is related to the investigational medicinal product by the Investigator and/or Alexion. 
Alexion has procedures that will be followed for the recording, medical assessment, and expedited reporting of 
SUSARs that are consistent with global regulations, legislation, and guidance documents. 
 
Suspected unexpected serious adverse reactions will undergo expedited reporting to the national regulatory 
authorities, IRBs/IECs, and Investigators following local regulatory reporting requirements where applicable. 

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10.4.3. 
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. 
 
It is not acceptable for the Investigator to send photocopies of the participant’s medical records to Alexion in 
lieu of completion of the AE/SAE CRF page. 
 
There may be instances when copies of medical records for certain cases are requested by Alexion. In this 
case, all participant identifiers, with the exception of the participant 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 Common Terminology Criteria for Adverse 
Events (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) 
 
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 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. 

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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. 
 
If a participant dies during participation in the study or during a recognized follow-up period, the Investigator 
will provide Alexion with a copy of any post-mortem findings including histopathology. 
 
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. 
10.4.4. 
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 EDC system. 
 
If the electronic system is unavailable or site staff are unable to process the SAE via the EDC system 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: clinicalsae@alexion.com or Fax: + 1.203.439.9347 
 
The site will enter the SAE data into the EDC system as soon as it becomes available. 
 
When further information becomes available, the EDC should be updated immediately with the new 
information and an updated SAE report should be submitted to Alexion global drug safety (GDS) within 
24 hours of Investigator/site awareness.  
 
After the participant has completed the study, no new data or changes to existing data are expected to be 
entered in the EDC system. 
o 
If a site receives a report of a new SAE from a study participant which the Investigator considers to 
be related to the study intervention, or the site receives updated data on a previously reported SAE 
after the EDC system has been taken offline, then the site can report this information on a paper 
Contingency Form for SAE Reporting via facsimile or email. 
 
 

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10.5. 
Management of Potential Infusion-related Adverse Events During 
Ravulizumab Administration 
Intravenous and infusion-related 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-related 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 10.4. 
Participants who experience a reaction during the administration of ravulizumab should be 
treated according to institutional guidelines. 
Participants who experience a severe reaction during administration of ravulizumab resulting in 
discontinuation of ravulizumab should undergo all scheduled safety, PK, and PD evaluations 
required by the protocol. Alexion must be notified within 24 hours of any infusion-related 
reaction requiring interruption or discontinuation of ravulizumab. All AEs that may indicate an 
infusion-related response will be graded according to the Common Terminology Criteria for 
Adverse Events CTCAE v5.0 or higher.  
If anaphylaxis occurs according to the criteria listed in Table 10 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. 
Participants administered an antihistamine for the treatment or prevention of an infusion-related 
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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10.6. 
Contraceptive Guidance and Collection of Pregnancy Information 
10.6.1. 
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 first dose of study drug, 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 tubal ligation or 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 participant’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 prior to the Day 1 Visit. 
 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 
may be required. In the absence of 12 months of amenorrhea, the reason for not 
obtaining FSH levels should be documented by the Investigator at the time of 
Screening.  
 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. 
4. Permanent sterilization at least 6 weeks prior to the Day 1 Visit. 
10.6.2. 
Contraception Guidance 
Contraceptive use by male or female participants should be consistent with local regulations 
regarding the methods of contraception utilized for those participating in clinical studies. If 

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teratogenic effects are suspected to be transferred to a fetus/embryo from a female spouse/partner 
of a male participant, pregnancy follow-up information will be obtained for the partner who 
becomes pregnant (refer to Section 10.6.3.1). In these cases, follow-up will be conducted on the 
pregnant partner in the same manner as a female participant who becomes pregnant during the 
study. 
10.6.2.1. Guidance for Female Participants 
Female participants of childbearing potential must have a negative serum pregnancy test as 
required by local regulations within 2 weeks prior to the first dose of study drug and have a 
negative urine pregnancy test prior to the first dose of study drug on Day 1. Additional 
requirements for pregnancy testing during and after dosing with study drug are indicated in the 
Schedule of Activities (Section 1.3). 
The Investigator is responsible for the review of medical history, menstrual history, and recent 
sexual activity to decrease the risk for inclusion of a woman with an early undetected pregnancy. 
The Investigator should evaluate the potential for contraceptive method in relationship to the first 
dose of study drug. 
Female participants of childbearing potential must use a highly effective or acceptable method of 
contraception, including at least 1 of the following until at least 8 months (generally 5.5 terminal 
half-lives) after the final dose of study drug. Highly effective methods are: 
1. Intrauterine device in place for at least 6 weeks prior to first dose of study drug.  
2. Progestogen-only hormonal contraception associated with inhibition of ovulation (either 
oral, injectable, or implantable) for at least 6 weeks prior to first dose of study drug.  
3. Intrauterine progestogen releasing system for at least 6 weeks prior to first dose of study 
drug. 
4. Bilateral tubal occlusion for at least 6 weeks prior to first dose of study drug.  
5. Combined (estrogen- and progestogen-containing) hormonal contraception (either oral, 
intravaginal, or transdermal) for at least 6 weeks prior to first dose of study drug.  
6. Surgical sterilization of the male partner (medical assessment of azoospermia is required 
if vasectomy was performed within the prior 6 months prior to the first dose of study 
drug). Male partner is still required to use condom during sexual intercourse. 
7. Sexual abstinence for female participants: 
 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 participant’s preferred and usual lifestyle. Abstinent female 
participants must refrain from heterosexual intercourse for at least 8 months after the 
final dose of study drug. 
Other methods of contraception that are not considered highly effective for female participants 
but are acceptable birth control methods that result in a failure rate of more than 1% per year 
include: 

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 Progestogen-only oral hormonal contraception, where inhibition of ovulation is not 
the primary mode of action 
 Male or female condom with or without spermicide 
 Cap, diaphragm, or sponge with spermicide 
 A combination of male condom with cap, diaphragm, or sponge with spermicide 
(double-barrier methods) 
Female participants must not donate ova from the Day 1 Visit at least until 8 months after their 
final dose of study drug. 
The following methods of contraception are considered unacceptable in this study: 
 Periodic abstinence (calendar, symptothermal or post ovulation methods 
 Withdrawal (coitus interruptus) 
 Spermicides only 
 Lactational amenorrhea method 
 Female condom and male condom should not be used together. 
10.6.2.2. Guidance for Male Participants  
Contraception is the responsibility of the heterosexually active male participants, regardless of 
his female partner’s method of contraception. 
Male participants who have had a vasectomy > 6 months prior to the dose of study drug must use 
a condom during heterosexual intercourse. Male participants who have had a vasectomy 
< 6 months prior to the first dose of study drug and those who have not had a vasectomy must 
use a condom and spermicide during heterosexual intercourse for at least 8 months after their 
final dose of study drug. 
10.6.2.2.1. Sexual Abstinence for Male Participants  
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 
participant’s preferred and usual lifestyle. Abstinent male participants 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 participants. 
Male participants must not donate sperm from the Day 1 visit until 8 months after the last dose of 
study drug. 
10.6.3. 
Collection of Pregnancy Information 
Pregnancy data will be collected during this study for all female participants and female 
spouses/partners of male participants from the first dose of study drug until the EOS Visit. Any 
female participant who becomes pregnant during the study will be discontinued from the study 
drug. Exposure during pregnancy (also referred to as exposure in utero) can be the result of 

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either maternal exposure or transmission of study drug via semen following paternal exposure. If 
a female participant or a male participant’s female spouse/partner becomes pregnant during the 
conduct of this study, the Investigator must submit the “Pregnancy/Breastfeeding Reporting and 
Outcome 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 drug during breastfeeding must also be reported (via the 
“Pregnancy/Breastfeeding Reporting and Outcome Form”) and any AEs experienced by the 
infant must be reported to Alexion GDS via email or facsimile. 
Pregnancy is not regarded as an AE unless there is a suspicion that the study drug may have 
interfered with the effectiveness of a contraceptive medication. However, complications of 
pregnancy and abnormal outcomes of pregnancy are AEs and may meet the criteria for an SAE 
(eg, ectopic pregnancy, spontaneous abortion, intrauterine fetal demise, neonatal death, or 
congenital anomaly). Elective abortions without complications should not be reported as AEs. 
10.6.3.1. Male Participants With Partners Who Become Pregnant 
 The Investigator will attempt to collect pregnancy information on any male 
participant’s female partner who becomes pregnant while the male participant is in 
this study. After the study is unblinded, this applies only to male participants who 
received ravulizumab. 
 After obtaining the necessary signed informed consent from the pregnant female 
partner directly, the Investigator will record pregnancy information on the appropriate 
“Pregnancy/Breastfeeding Reporting and Outcome 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 3 months following the delivery date. Any termination of the 
pregnancy will be reported regardless of fetal status (presence or absence of 
anomalies) or indication for the procedure. 
10.6.3.2. Female Participants Who Become Pregnant 
 The Investigator will collect pregnancy information on any female participant 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 participant’s pregnancy. 
 For all Alexion products, both in development or postapproval, exposure during 
pregnancy must be recorded and the pregnancy followed, until the outcome of the 
pregnancy is known (ie, spontaneous miscarriage, elective termination, normal birth, 
or congenital abnormality), even if the participant discontinues the study intervention 
or withdraws from the study. The Investigator will collect follow-up information on 
the participant 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 

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estimated delivery date. Any termination of pregnancy will be reported, regardless of 
fetal status (presence or absence of anomalies) or indication for the procedure. 
 Pregnancy is not considered as an AE unless there is a suspicion that the study 
intervention may have interfered with the effectiveness of a contraceptive medication. 
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 poststudy 
pregnancy-related SAE considered reasonably related to the study intervention by the 
Investigator will be reported to Alexion. While the Investigator is not obligated to 
actively seek this information in former study participants, he or she may learn of an 
SAE through spontaneous reporting. 
 Any female participant who becomes pregnant while participating in the study will 
discontinue study drug. 
 
 

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10.7. 
Biomarkers 
 Blood and urine samples will be collected for biomarker analyses and the data will be 
used for research (eg, exploratory) related to ravulizumab or complement-mediated 
TMA and related diseases. The samples may also be used to develop methods 
including prognostic and/or diagnostic tests related to the study drug target, disease 
process, pathways associated with complement-mediated TMA, and/or mechanism of 
action of ravulizumab. 
 The samples may be analyzed as part of a multistudy assessment of biomarkers in the 
response to ravulizumab to understand study disease or related conditions. 
 The results of biomarker analyses may be reported in the clinical study report (CSR) 
or in a separate study summary. 
 Alexion or designee will store the samples obtained for biomarker analyses in a 
secure storage space with adequate measures to protect confidentiality. 
 The samples will be retained while research on ravulizumab continues but no longer 
than 5 years after termination of the study or other period/time point per local 
requirements. 
 
 

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10.8. 
Genetics 
Use/Analysis of DNA 
 Genetic variation may impact a participant’s response to study drug, susceptibility to, 
and severity and progression of disease. Variable response to study intervention may 
be due to genetic determinants that impact study intervention absorption, distribution, 
metabolism, and excretion; mechanism of action of the study intervention; disease 
etiology; and/or molecular subtype of the disease being treated. Therefore, where 
local regulations and IRB/IEC allow, blood samples will be collected for DNA 
analysis from consenting participants. 
 DNA samples will be used for research related to ravulizumab or 
complement-mediated TMA and related diseases. They may also be used to develop 
tests/assays including diagnostic tests related to ravulizumab and 
complement-mediated TMA. Genetic research may consist of the analysis of one or 
more candidate genes or the analysis of genetic markers throughout the genome (as 
appropriate). 
 The samples may be analyzed as part of a multistudy assessment of genetic factors 
involved in the response to ravulizumab or study interventions of this class to 
understand study disease or related conditions. 
 The results of genetic analyses may be reported in the CSR or in a separate study 
summary. 
 Alexion or designee will store the DNA samples in a secure storage space with 
adequate measures to protect confidentiality. 
 The samples will be retained while research on ravulizumab continues but no longer 
than 15 years or other period as per local requirements. 
 
 

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10.9. 
COVID-19 Risk Assessment 
Complement-mediated TMA can cause irreversible morbidity and even mortality, if untreated. 
As such, and due to the limited number of available treatment options, the benefit a participant 
may receive from joining an investigational study with a therapeutic treatment is potentially 
significant. Given that treatment for complement-mediated TMA does involve 
immunosuppression, there is a theoretical concern that the risk for infection may be higher than 
in participants not receiving immunosuppressants. However, there is no specific data to further 
inform this risk. Apart from the predictable risk of infection with Neisseria species, which is 
well-known and directly related to the mechanism of action of ravulizumab, the mechanism 
which might lead to other serious infections including viral infections in patients treated with 
ravulizumab remains unclear. The Investigator will therefore balance the risk/benefit 
considerations in the study participant taking these factors into account. 
The potential risks identified and mitigation measures put in place in light of the COVID-19 
pandemic are provided in Table 11. 
Table 11: 
Potential Risks and Mitigation Measures due to COVID-19 
Risks Category 
Summary of Data/ 
Rationale for Risk 
Mitigation Strategy 
Potential risks 
Potentially higher risk 
population for COVID 
-19 infection 
Participants in this study will receive background 
therapy that may include immunosuppressants 
Participants in this study may receive 
meningococcal vaccination and prophylactic 
antibiotics prior to treatment with a C5 inhibitor.  
It is unknown how this may impact their risk for 
COVID-19 infection. 
During the time that the 
COVID-19 pandemic is active, 
Alexion will recommend that 
sites in a position to start the 
study and enroll participants 
follow the national and 
institutional guidances 
regarding prevention of 
COVID-19 infection. 
Additionally, during that time 
period, it is expected that 
Investigators and their staff will 
take all possible precautions in 
order to minimize a 
participant’s potential exposure 
to COVID-19 infection. 
Depending on the site, this will 
consist of measures such as 
social distancing, temperature 
screening, enhanced cleaning, 
and use of personal protective 
equipment for participants, 
staff, and caregivers as 
necessary. 

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Table 11: 
Potential Risks and Mitigation Measures due to COVID-19 
Risks Category 
Summary of Data/ 
Rationale for Risk 
Mitigation Strategy 
Healthcare institution 
availability for 
non-COVID-19 
related activities  
COVID-19 pandemic may impact the workload of 
healthcare institutions globally and may reduce staff 
availability to perform non-urgent activities and 
non-COVID-19 related activities. 
 
During the time that the 
COVID-19 pandemic is active, 
Alexion will not open study 
sites or enroll new participants 
at sites unless the sites have the 
resourcing and capabilities to 
implement the study per 
protocol. 
Data quality and 
integrity 
Lack of availability of site personnel to perform 
study assessments and capture study specific data in 
a timely manner and to maintain adequate quality 
standards. 
Lack of availability of site personnel to ensure 
adequate and continuous chain of custody, storage 
conditions, and monitoring for investigational 
product and biological samples. 
Inability of study monitors and quality personnel to 
conduct in-person visits to exercise adequate 
oversight of study execution at investigational sites. 
Missing data (COVID-19 pandemic may impact 
study visit schedules and increase missed visits 
and/or participant study discontinuations 
inadvertently resulting in missing data [eg, for 
protocol-specified procedures]). 
During the time that the 
COVID-19 pandemic is active, 
Alexion will only open study 
sites that report enough 
personnel capacity to 
sufficiently conduct clinical 
study-related activities. 
During this timeframe, 
participants eligibility as well as 
site capacity will be reviewed 
by the site Investigator and the 
study Medical Monitor prior to 
Screening. Each site is also 
evaluated for the capacity to 
perform remote monitoring 
visits and remote source data 
verification. 
During the time that the 
COVID-19 pandemic is active, 
it will be important to capture 
specific information in the 
eCRF that explains the reason 
the data is missing (eg, missed 
study visits or participant study 
discontinuations due to 
COVID-19). 
Abbreviations: C5 = complement component 5; COVID-19 = coronavirus disease 2019; eCRF = electronic case 
report form. 
 

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10.10. 
COVID-19 Vaccine Risk Assessment 
Following a review of the available COVID-19 vaccine data (eg, Pfizer/BioNTech, Moderna, 
AstraZeneca, Johnson & Johnson), it is unlikely that the immune response to a COVID-19 
vaccine (and therefore the efficacy of the vaccination) would be diminished with concomitant 
ravulizumab administration, based on ravulizumab’s mechanism of action. There is currently no 
information available evaluating the safety and efficacy of COVID-19 vaccines in participants 
treated with ravulizumab. 
Vaccination may further activate complement. As a result, patients with complement-mediated 
diseases may experience increased signs and symptoms of their underlying disease. Therefore, 
patients should be closely monitored for disease symptoms after recommended vaccination. 
Because vaccines may activate complement, if possible, consider vaccination when the 
underlying complement mediated disease is clinically controlled and when systemic C5 inhibitor 
concentration (and subsequent complement blockade) is relatively high, shortly after 
administration. 
Local and national guidelines should be consulted for recommendations related to COVID-19 
vaccination. The potential risks identified and mitigation measures put in place in light of the 
COVID-19 vaccination rollout are provided in Table 12. 
Table 12: 
Potential Risks and Mitigation Measures due to COVID 19 Vaccine 
Risks Category 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
Potential risks 
Data quality and 
integrity 
Missing data due to appointments for COVID-19 
vaccination or side effects of COVID-19 vaccine 
may impact study visit schedules, and increase 
missed visits and/or participant study 
discontinuations, inadvertently resulting in 
missing data (eg, for protocol-specified 
procedures). 
Capture specific information in the 
eCRF that explains the reason for 
missing data (eg, missed study 
visits due to appointments for 
COVID-19 vaccination or side 
effects of COVID-19 vaccine). 
Abbreviations: COVID-19 = coronavirus disease 2019; eCRF = electronic case report form 
 
 

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10.11. 
Patient-Reported Outcome Instruments 
10.11.1. 
Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) 
 

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10.11.2. 
EuroQoL 5-Dimensions 5-Level (EQ-5D-5L)  
 
 
 

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EQ-5D-5L (Continued, Page 2)  
 
 
 

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EQ-5D-5L (Continued, Page 3)  
 

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10.11.3. 
Kidney Disease Quality of Life instrument™–36 items (KDQOL-36) 
 
 
 
 

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KDQOL-36 (Continued, Page 2) 
 

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KDQOL-36 (Continued, Page 3) 
 

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KDQOL-36 (Continued, Page 4) 
 

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KDQOL-36 (Continued, Page 5) 
 

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KDQOL-36 (Continued, Page 6) 
 
 
 

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10.12. 
Gene Mutations That Cause aHUS 
Known gene mutations that cause aHUS may include, but are not limited to the following 
mutations or antibodies:  
 Complement factor H (CFH) 
 Complement factor I (CFI) 
 Membrane cofactor protein (CD46) 
 Complement component 3 (C3) 
 Complement factor B (CFB) 
 Thrombomodulin (THBD) 
 Complement factor H-related protein 1 (CFHR1) 
 Complement factor H-related protein 5 (CFHR5) 
 Diacylglycerol kinase epsilon (DGKE) 
 
 
 

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10.13. 
The International Society on Thrombosis and Haemostasis (ISTH) 
Criteria for Disseminated Intravascular Coagulation (DIC) 
The ISTH Criteria for DIC (Taylor, 2001) will be used for DIC diagnosis in this study. 
INSTRUCTIONS: Use only in participants with clinical suspicion for DIC (eg, excessive 
bleeding in the setting of malignancy, severe infection or sepsis, obstetric complications, 
trauma). 
Diagnostic criteria for overt DIC (participant has to have an underlying disorder known to be 
associated with overt DIC to use this algorithm): 
Variable 
Points 
Platelet count, cells × 109/L 
≥ 100 
0 
50 to < 100 
1 
< 50 
2 
Elevated levels of a fibrin-related marker a (eg, D-dimer, fibrin 
degradation products) 
No increase 
0 
Moderate increase 
2 
Severe increase 
3 
Prolonged prothrombin time, seconds 
< 3 
0 
3 to < 6 
1 
≥ 6 
2 
Fibrinogen level, g/L 
≥ 1 
0 
< 1 
1 
a Use laboratory-specific cutoff values. 
Interpretation 
Score 
Diagnosis 
< 5 
Not suggestive of overt DIC, may be non-overt DIC; repeat within next 1 to 2 days and 
manage clinically as appropriate 
≥ 5 
Compatible with overt DIC; treat for DIC as appropriate and repeat scoring daily 
 
 

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10.14. 
Abbreviations 
Abbreviation 
Definition 
ADA 
antidrug antibodies 
ADAMTS13 
a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 
AE 
adverse event 
aHUS 
atypical hemolytic uremic syndrome 
BSC 
best supportive care 
C5 
complement component 5 
C5a 
complement component 5a 
CI 
confidence interval 
CIOMS 
Council for International Organizations of Medical Sciences 
CKD 
chronic kidney disease 
CKD-EPI 
Chronic Kidney Disease Epidemiology Collaboration 
CNI 
calcineurin inhibitor 
CONSORT 
Consolidated Standards of Reporting Trials  
COVID-19 
coronavirus disease 2019 
CRF 
case report form 
CSR 
clinical study report 
CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events 
CV 
coefficient of variation 
DIC 
disseminated intravascular coagulation 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
ED 
early discontinuation 
EDC 
electronic data capture 
eGFR 
estimated glomerular filtration rate 
EOS 
end of study 
EQ-5D-5L 
EuroQol 5-Dimension 5-Level 
FACIT 
Functional Assessment of Chronic Illness Therapy 
FSH 
follicle stimulating hormone 
GCP 
Good Clinical Practice 
GDS 
global drug safety 
Hib 
haemophilus influenzae type b 
HIV 
human immunodeficiency virus 
HRT 
hormonal replacement therapy 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
ISTH 
International Society of Thrombosis and Haemostasis  
ITT 
Intent to Treat 
IV 
intravenous(ly) 
KDQOL-36 
Kidney Disease Quality of Life instrument – 36 items 
LDH 
lactate dehydrogenase 
LLN 
lower limit of normal 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
Modified Intent to treat 
MMRM 
Mixed-Effect Model Repeated Measures 
PD 
pharmacodynamic(s) 
PK 
pharmacokinetic(s) 

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Abbreviation 
Definition 
PNH 
paroxysmal nocturnal hemoglobinuria 
q8w 
every 8 weeks 
QTcF 
QT interval corrected for heart rate using Fridericia’s formula 
RTCA 
Real Time Complement Activity 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
sC5b-9 
soluble terminal complement complex C5b-9 (membrane attack complex) 
SSc-TMA 
systemic sclerosis associated thrombotic microangiopathy 
ST-HUS 
Shiga toxin-related hemolytic uremic syndrome 
sTNF-R1 
shed tumor necrosis factor receptor 1 
SUSAR 
suspected unexpected serious adverse reaction 
sVCAM-1 
shed vascular cell adhesion molecule 1 
TEAE 
treatment-emergent adverse event 
TESAE 
treatment-emergent serious adverse event 
TMA 
thrombotic microangiopathy 
TPE 
therapeutic plasma exchange 
ULN 
upper limit of normal 
WOCBP 
woman of childbearing potential 
 
 
 

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10.15. 
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 
Type of 
Amendment 
(Global or 
Country-specific) 
Date 
Summary of Key Changes in the 
Amendment 
Amendment 1 
UK 
03 Jun 2021 
To add COVID 19 vaccine risk assessment 
language 
Original 
protocol 
Not applicable 
16 Dec 2020 
Not applicable 
 

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11. 
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