Conditions: Coronavirus Disease 2019 (COVID-19)
Keywords: Prevention of respiratory failure
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 124
Healthy volunteers: no

Brief summary:
This is a prospective, phase 2, multicenter, randomized, double blind, placebo controlled, parallel group study to assess the safety and efficacy of CSL312 administered intravenously, in combination with standard of care (SOC) treatment, in patients with Coronavirus disease 2019 (COVID 19)

Detailed description:

Arms:
arm 1: Garadacimab, Factor XIIa Antagonist Monoclonal Antibody administered intravenously arm 2: CSL312 diluent administered intravenously

Interventions: intervention 1: Garadacimab, Factor XIIa Antagonist Monoclonal Antibody intervention 2: Placebo
Intervention descriptions: intervention 1: Garadacimab, Factor XIIa Antagonist Monoclonal Antibody administered intravenously intervention 2: CSL312 diluent administered intravenously

Protocol document:
Prot_000.pdf: 
C S L Be hri n g – C o nfi de ntial  
Te m plate: C S -S O P -0 4 -G 0 1 -T 0 1  
Versi o n N u m ber: 1. 0  
Effecti ve Date: Wee k c o m me nci n g 3 0 -A pr -2 0 1 8  
Pa ge 1 of 8 3  
C LI NI C A L S T U D Y P R O T O C O L  
 
A P h ase 2, M ultice nter, D o u ble -bli n d, R a n d o mize d, Pl ace b o -c o ntr olle d St u d y t o 
E v al u ate C S L 3 1 2 i n C or o n a vir us Dise ase 2 0 1 9 ( C O VI D- 1 9) 
 
St u d y N u m ber:  
C S L 3 1 2 _ C O VI D -1 9  
St u d y Pr o d uct:  
C S L 3 1 2 ( Gara daci ma b, Fact or XIIa A nta g o nist M o n ocl o nal 
A nti b o d y) 
De vel o p m e nt P h ase:  
P hase  2  
S h ort Title:  
C S L 3 1 2 i n C O VI D -1 9  
S p o ns or:  
C S L  Be hri n g L L C  
1 0 2 0 First A ve n ue 
Ki n g of Pr ussia, Pe n ns yl va nia 1 9 4 0 6 
U nite d States of A merica  
Pr ot oc ol V ersi o n:  
A me n d me nt  3  
Pr ot oc ol D at e:  
1 6  Se pte m ber  2 0 2 0  
I N D N u m ber: 
 
C o m pli a nce:  
T his st u d y will be c o n d ucte d i n acc or da n ce wit h sta n dar ds of G o o d 
Cli nical Practice (as d efi ne d b y t he I nter n ati o nal C o u ncil f or 
Har m o nisati o n) a n d all a p plica ble nati o nal a n d l o cal re g ulati o ns. 
 
C o m m erci al i n C o nfi de nce. T his d oc u me nt a n d t he i nf or mati o n c o ntai ne d herei n are pr o prietar y a n d 
c o nfi de ntial. T his d oc u me nt a n d t he c o ntai ne d i nf or mati o n are i nte n de d f or discl os ure t o a n d use b y t h ose 
pers o n nel w h o are u n der a n o bli gati o n of c o nfi de ntialit y b y a si g ne d a gree me nt wit h S p o ns or (“ C S L  Be hri n g”). 
T his d oc u me nt a n d t he c o ntai ne d i nf or mati o n ma y be discl ose d a n d use d o nl y t o t he e xte nt necessar y t o 
c o n d uct t he cli nical st u d y. Re pr o d ucti o n or discl os ure of t his d oc u me nt or its c o ntai ne d i nf or mati o n is 
f or bi d de n u nless at t he e x press re q uest or wit h t he writte n c o nse nt of C S L Be hri n g.  
 
C CI


CSL Behring 
Study Protocol: CSL312_COVID-19, Version: Amendment 3 (16 September 2020) 
CSL312 (Garadacimab) 
CSL Behring – Confidential 
Template: CS-SOP-04-G01-T01 
Version Number: 1.0 
Effective Date: Week commencing 30-Apr-2018 
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LIST OF PERSONNEL AND ORGANIZATIONS RESPONSIBLE FOR 
CONDUCT OF THE STUDY 
A list of personnel and organizations responsible for the conduct of the study will be supplied 
to study sites as part of the Investigator’s Study File. This list will be updated by 
CSL Behring (or delegate) and provided to the study sites as needed. 
 


CSL Behring 
Study Protocol: CSL312_COVID-19, Version: Amendment 3 (16 September 2020) 
CSL312 (Garadacimab) 
CSL Behring – Confidential 
Template: CS-SOP-04-G01-T01 
Version Number: 1.0 
Effective Date: Week commencing 30-Apr-2018 
Page 3 of 83 
REVISION HISTORY 
Date 
Version  
Summary of Changes 
19 May 2020 
Original 
Not applicable 
11 July 2020 
Amendment 1 1. Revised wording for indication to be studied. 
2. Revised pharmacokinetic (PK) secondary 
endpoints to include area under the plasma 
concentration-time curve from time zero to the 
time of the last measureable concentration 
(AUC0-last) rather than AUC from time zero up to 
a definite time (AUC0-t) and add terminal 
half-life (T1/2) 
3. Revised prohibited therapies section to indicate 
that the use of any investigational product (IP) or 
investigational device according to a formal 
protocol for another clinical study is 
PROHIBITED during this study. 
4. Revised study design, exclusion criteria, and 
prohibited/permitted therapies sections to 
indicate that off-label use of approved products 
(eg, antibodies against IL-6 
[anti-IL-6]/antibodies against IL-6 receptors 
[anti-IL-6R]), administration of investigational 
product (IP) for which emergency use 
authorization has been granted (eg, remdesivir). 
Additionally, the use of IP for which expanded 
access for treatment use (“compassionate use”) 
has been authorized (eg, convalescent plasma) is 
permitted during study participation. 
5. Revised planned number and location of study 
sites to indicate the possibility of adding study 
sites in Latin America. 
6. Revised inclusion criterion # 6 to specify that ≥ 1 
of the respiratory parameters for severe 
COVID-19 disease must be met at Screening 
including within 24 hours before Screening. 


CSL Behring 
Study Protocol: CSL312_COVID-19, Version: Amendment 3 (16 September 2020) 
CSL312 (Garadacimab) 
CSL Behring – Confidential 
Template: CS-SOP-04-G01-T01 
Version Number: 1.0 
Effective Date: Week commencing 30-Apr-2018 
Page 4 of 83 
7. Revised the definition for the Pharmacokinetic 
Analysis Set to indicate the requirement for 
≥ 1 blood sample available for CSL312 
concentration measurement after administration 
of CSL312. Also, revised the definition to 
indicate that the PK analyses will only be 
performed for subjects treated with CSL312 and 
not for those treated with placebo. 
8. Revised the definition of treatment effect of 
interest from “odds ratio of CSL312 + standard 
of care (SOC) versus placebo + SOC” to 
“proportion difference of CSL312 + SOC minus 
placebo + SOC”, updated the primary efficacy 
analysis, and added citation and reference to 
support this evaluation. 
9. Added details on Baseline comorbidities to be 
used as covariates in the statistical model. 
10. Added details on analysis of secondary efficacy 
endpoints. 
11. Added details on planned analysis of Sequential 
Organ Failure Assessment (SOFA) scores. 
12. Added sensitivity analyses to assess the effect of 
missing data. 
13. Added the definition of Baseline to be used in 
statistical analyses. 
14. Minor corrections and clarifications, including 
word modifications and administrative changes. 
25 August 2020 
Amendment 2 1. Increased the number of potential sites from 
approximately 20 sites to approximately 25 sites 
(≥ 15 sites in the United States of America 
(USA) and up to 10 sites in Brazil). 
2. Revised the temporary halting schedule for 
Independent Data Review Committee (IDMC) 
review such that enrollment will only be 
temporarily halted for review of safety data for 
the first 20 subjects. During subsequent IDMC 
reviews, enrollment will continue without pause. 
3. Revised eligibility criteria to indicate that 
eligibility may be assessed at the time of hospital 
admission provided that the subject is 
randomized within 24 hours of Screening. 


CSL Behring 
Study Protocol: CSL312_COVID-19, Version: Amendment 3 (16 September 2020) 
CSL312 (Garadacimab) 
CSL Behring – Confidential 
Template: CS-SOP-04-G01-T01 
Version Number: 1.0 
Effective Date: Week commencing 30-Apr-2018 
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4. Revised inclusion criteria to indicate that the 
SARS-CoV-2 infection must be determined using 
a molecular diagnostic test (reverse transcription 
polymerase chain reaction [RT-PCR] or 
equivalent) approved by regulatory authorities. 
5. Revised inclusion criteria to indicate that the 
SARS-CoV-2 test may be repeated within the 
Screening Period if a false negative result is 
suspected. 
6. Revised text regarding early hospital discharge to 
indicate the data to be obtained via weekly 
telephone call and by whom. 
7. Defined the minimum laboratory results that are 
required to initiate randomization. 
8. Revised study product administration to indicate 
that the intravenous infusion should be a slow 
injection, (ie, push of about 3 minutes). 
9. Added assessment of outcome measures before 
dosing on Day 1, including the subject’s use of 
supplemental oxygen; use of CPAP or BiPAP; 
use of HFNC; use of ECMO; intubation; and 
intensive care unit admission. 
10. Revised Schedule of Assessments to indicate that 
pre-existing laboratory results may be used in 
lieu of repeating the assessments for Screening 
provided that the assessments were performed 
with 48 hours of randomization and the subject 
agrees to the use of those data in the inform 
consent form. 
11. Added stratification by country variable (USA or 
Brazil) to the planned statistical analyses. 
16 September 2020 Amendment 3 1. Revised the required duration of the use of 
acceptable forms of contraception to ≥ 90 days 
after the last administration of study drug. 
2. Added the use a non-contact infrared 
thermometer to the methods of measuring body 
temperature. 
 


CSL Behring 
Study Protocol: CSL312_COVID-19, Version: Amendment 3 (16 September 2020) 
CSL312 (Garadacimab) 
CSL Behring – Confidential 
Template: CS-SOP-04-G01-T01 
Version Number: 1.0 
Effective Date: Week commencing 30-Apr-2018 
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Clinical Study Protocol Synopsis 
Title 
A Phase 2, Multicenter, Double-blind, Randomized, 
Placebo-controlled Study to Evaluate CSL312 in Coronavirus 
Disease 2019 (COVID-19) 
Study Number 
CSL312_COVID-19 
Sponsor 
CSL Behring LLC 
1020 First Avenue 
King of Prussia, Pennsylvania 19406 
United States of America 
Development 
Phase 
Phase 2 
Study Product 
CSL312 (Garadacimab, Factor XIIa Antagonist Monoclonal 
Antibody) 
Indication 
For the prevention of respiratory failure in patients with COVID-19 
Study Summary 
and Overview 
This is a prospective, phase 2, multicenter, randomized, 
double-blind, placebo-controlled, parallel-group study to assess the 
safety, PK, and efficacy of CSL312 administered intravenously, in 
combination with standard-of-care (SOC) treatment, in patients with 
Coronavirus disease 2019 (COVID-19). 


CSL Behring 
Study Protocol: CSL312_COVID-19, Version: Amendment 3 (16 September 2020) 
CSL312 (Garadacimab) 
CSL Behring – Confidential 
Template: CS-SOP-04-G01-T01 
Version Number: 1.0 
Effective Date: Week commencing 30-Apr-2018 
Page 7 of 83 
SOC treatment is defined as any written or established treatment 
protocol followed at the study site for patients with severe 
COVID-19 or complications associated with COVID-19, including 
off-label use of approved drugs (eg, antibodies against interleukin-6 
[anti-IL-6]/antibodies against IL-6 receptors [anti-IL-6R]) or an 
investigational product (IP) for which administration under an 
emergency use authorization has been granted (eg, remdesivir). 
Administration of IP for which expanded access for treatment use 
(“compassionate use”) has been authorized (eg, convalescent 
plasma) is also permitted during study participation. 
The study consists of a Screening Period of up to 2 days, and a 
Treatment Period of up to 28 days. 
Aggregate data from groups of subjects will be reviewed by an 
Independent Data Monitoring Committee (IDMC), both early and at 
predetermined intervals during the conduct of the study. 
For futility monitoring and sample size re-estimation, an interim 
analysis of unblinded primary endpoint data is planned after 
62 subjects (50% of the target sample size) have completed primary 
endpoint assessment. 
Primary Objective 
The primary objective of the study is to assess the treatment benefit 
of CSL312 after intravenous (IV) infusion in patients with 
COVID-19. 
Primary Endpoint 
The primary endpoint is the incidence of tracheal intubation or death 
prior to tracheal intubation from randomization to Day 28. 
Secondary 
Objectives 
The secondary objectives of the study are: 
• To further assess the efficacy of CSL312 
• To assess the safety of CSL312 
• To assess the pharmacokinetics (PK) of CSL312 


CSL Behring 
Study Protocol: CSL312_COVID-19, Version: Amendment 3 (16 September 2020) 
CSL312 (Garadacimab) 
CSL Behring – Confidential 
Template: CS-SOP-04-G01-T01 
Version Number: 1.0 
Effective Date: Week commencing 30-Apr-2018 
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Secondary 
Endpoints 
The secondary endpoints are: 
• All-cause mortality 
• Incidence of tracheal intubation 
• Clinical status as assessed on an 8-point National Institute of 
Allergy and Infectious Diseases (NIAID) ordinal scale 
• Use of continuous positive airway pressure (CPAP) or bi-level 
positive airway pressure (BiPAP) 
• Use of high-flow nasal cannula (HFNC) 
• Use of extracorporeal membrane oxygenation (ECMO) 
• Change in Sequential Organ Failure Assessment (SOFA) score 
• Length of hospital stay 
• Subjects experiencing the following safety events: 
o Adverse events (AEs) 
o Serious adverse events 
o Adverse events of special interest 
o CSL312-induced anti-drug antibodies 
o Clinically significant abnormalities in laboratory 
assessments reported as AEs 
• CSL312 PK in plasma: 
o Maximum plasma concentration (Cmax) 
o Time to maximum plasma concentration (Tmax) 
o Area under the plasma concentration-time curve from time 
zero to the time of the last measurable concentration 
(AUC0-last) 
o Terminal half-life (T1/2) 
Study Duration 
The duration of an individual subject’s study participation is 
expected to be up to 30 days. This estimate is based on: 
• A Screening Period of up to 2 days. 
• A Treatment Period of up to 28 days. 
The overall study duration (ie, first subject’s Screening Visit to last 
subject’s last study visit) will be approximately 6 months. 
Number of 
Subjects 
This study will enroll a total of approximately 124 subjects; 
62 subjects in the CSL312 + SOC group and 62 subjects in the 
placebo + SOC group. 
After the first 62 subjects have completed the primary endpoint 
assessment, an interim analysis will be performed for futility 
monitoring and sample size re-estimation, which may result in an 
increase in the target sample size. 


CSL Behring 
Study Protocol: CSL312_COVID-19, Version: Amendment 3 (16 September 2020) 
CSL312 (Garadacimab) 
CSL Behring – Confidential 
Template: CS-SOP-04-G01-T01 
Version Number: 1.0 
Effective Date: Week commencing 30-Apr-2018 
Page 9 of 83 
Study Population 
and Main Criteria 
for Eligibility 
Inclusion criteria: 
1. Capable of providing written informed consent. An individual 
legally permitted to make medical decisions on the subject’s 
behalf can provide written informed consent. 
2. Willing and able to adhere to all protocol requirements 
3. Age ≥ 18 years at the time that informed consent is obtained 
4. Positive for severe acute respiratory syndrome coronavirus-2 
(SARS-CoV-2) infection as determined using a molecular 
diagnostic test (reverse transcription polymerase chain reaction 
[RT-PCR] or equivalent) approved by regulatory authorities 
(including Food and Drug Administration or Brazilian Health 
Regulatory Agency) or allowed under an emergency use 
authorization within 14 days before Screening. If a false 
negative result is suspected, the SARS-CoV-2 test may be 
repeated within the Screening Period. 
5. Chest computed tomography (CT) scan or X-ray results 
confirming interstitial pneumonia 
6. Severe COVID-19 disease as evidenced by ≥ 1 of the following 
criteria at Screening including within 24 hours before Screening: 
• Respiratory frequency > 30 breaths per minute 
• Saturation of peripheral (capillary) oxygen (SpO2) ≤ 93% on 
room air 
• Ratio of partial pressure of arterial oxygen to fraction of 
inspired oxygen (PaO2/FiO2) < 300 
• Arterial oxygen saturation (SaO2)/FiO2 ratio < 218 (if 
PaO2/FiO2 ratio is not available) 
• Radiographic lung infiltrates > 50% 
 
Exclusion criteria: 
1. Currently enrolled, planning to enroll, or participated, within the 
last 30 days, in a clinical study requiring administration of an IP, 
including expanded access or compassionate use with the only 
exception being administration of convalescent plasma. 
Administration of IP is permitted only if an emergency use 
authorization has been granted (eg, remdesivir). Additionally, 
off-label use of approved drugs (eg, anti-IL-6/anti-IL-6R) is also 
permitted. 
2. Pregnant or breastfeeding (female subjects) 
3. Intubated or requires mechanical ventilation (including ECMO) 
at the time of randomization 
4. In the opinion of the investigator, the subject is expected to be 
intubated within the first 24 hours after IP administration 


CSL Behring 
Study Protocol: CSL312_COVID-19, Version: Amendment 3 (16 September 2020) 
CSL312 (Garadacimab) 
CSL Behring – Confidential 
Template: CS-SOP-04-G01-T01 
Version Number: 1.0 
Effective Date: Week commencing 30-Apr-2018 
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5. Active Do-Not-Intubate (DNI) or Do-Not-Resuscitate (DNR) 
order 
6. In the opinion of the investigator, the subject is not expected to 
survive for > 48 hours 
7. Any of the following comorbid conditions prior to 
randomization and prior to SARS-CoV-2 infection: 
• Severe heart failure (New York Heart Association Class IV) 
• End-stage renal disease (Stage ≥ 4) or need for renal 
replacement therapy 
• Biopsy-confirmed cirrhosis, portal hypertension, or hepatic 
encephalopathy 
• Malignancy (Stage IV) 
• Chronic lung disease requiring the use of oxygen at home 
• Active tuberculosis disease 
8. Active bleeding or current clinically significant coagulopathy 
(eg, international normalized ratio [INR] > 1.5) or clinically 
significant risk for bleeding (eg, recent intracranial hemorrhage 
or bleeding peptic ulcer within the last 4 weeks) 
9. History of venous thrombosis, myocardial infarction, or 
cerebrovascular event within the last 3 months, or a 
prothrombotic disorder (eg, antithrombin III, protein C, or 
protein S deficiency) 
10. Known or suspected Grade 3 or 4 infusion-related reaction or 
hypersensitivity (per Common Terminology Criteria for Adverse 
Events) to monoclonal antibody therapy, or hypersensitivity to 
the IP or any excipients of the IP [National Cancer Institute, 
2009] 
11. Currently receiving a therapy not permitted during the study 
12. Female subject of childbearing potential or fertile male subject 
either not using or not willing to use an acceptable method of 
contraception to avoid pregnancy during the study and for 
90 days after administration of IP 
13. Any clinical or laboratory abnormality or other underlying 
conditions (eg, psychological disorders, substance abuse) that 
would render the subject unsuitable for participation in the study, 
in the opinion of the investigator 
Study Product 
Dose, Dosing 
Regimen and 
Administration  
CSL312 will be supplied as a sterile solution for injection 
containing 100 mg/mL of CSL312 in 2-mL vials. A single dose of 
700 mg will be administered once, in an infusion volume of 7 mL, 
by slow IV injection (ie, push of about 3 minutes). 


C S L  Be hri n g  
St u d y Pr ot oc ol: C S L 3 1 2 _ C O VI D -1 9, Versi o n: A me n d me nt  3 ( 1 6 Se pte m ber  2 0 2 0)  
C S L 3 1 2 ( Gara daci ma b)  
C S L Be hri n g – C o nfi de ntial  
Te m plate: C S -S O P -0 4 -G 0 1 -T 0 1  
Versi o n N u m ber: 1. 0  
Effecti ve Date: Wee k c o m me nci n g 3 0 -A pr -2 0 1 8  
Pa ge 1 1  of 8 3  
C o m p ar at or 
Pr o d uct, D ose, 
D osi n g Re gi me n 
a n d 
A d mi nistr ati o n  
Place b o will be s u p plie d as a sterile preser v ati ve -free s ol uti o n f or 
i njecti o n i n 1 0- m L vials. T he place b o is t he s a me as t he C S L 3 1 2 
f or m ulati o n b uffer, b ut d oes n ot c o ntai n t he acti ve s u bsta nce 
(ie, C S L 3 1 2). Place b o will be a d mi nistere d o nce, i n a n i nf usi o n 
v ol u me of 7 m L, b y sl o w I V i njecti o n (ie, p us h of a b o ut 3 mi n utes ). 
Effic ac y 
Assess me nts  
O utc o me assess me nts will i ncl u de t he s u bject’s use of s u p ple me ntal 
o x y ge n; use of C P A P or Bi P A P; use of H F N C; use of E C M O; 
i nt u bati o n; e xt u bati o n; cli nical stat us o n sta n dar di ze d scal es; 
i nte nsi ve care u nit (I C U) a d missi o n a n d disc har ge; a n d h os pital 
disc har ge or deat h.  
S afet y Ass ess me nts  Safet y will be assesse d t hr o u g h d oc u me ntati o n of 
treat me nt-e mer ge nt a d verse e ve nts, vital si g ns, p h ysical 
e xa mi nati o ns, res pirat or y para meters, cli nical  la b orat or y 
assess me nts, a n d a nti - dr u g a nti b o dies. 
P h ar m ac o ki netics  
Bl o o d sa m ples will be c ollecte d f or assess me nt of C S L 3 1 2 P K i n 
plas ma.  
 
 
 
 
 
 
St atistic al A n al yses  S a m ple Size  
T here are li mite d data a v aila ble o n t he rat es of s u bjects wit h 
C O VI D - 1 9 w h o pr o gress t o trac heal i nt u bati o n or deat h pri or t o 
trac heal i nt u bati o n wit hi n 2 8 da ys. F or sa m ple size calc ul ati o n, a 
rate of 30 % i n t he c o ntr ol gr o u p a n d a rate of 1 0 % i n t he C S L 3 1 2 
gr o u p ha ve bee n ass u me d. Wit h a 2-si de d α = 0. 0 5 a n d 1: 1 
ra n d o mizati o n rati o f or C S L 3 1 2 + S O C vers us place b o  + S O C, a 
t otal of 1 2 4 s u bjects nee d t o be ra n d o mize d ( 6 2 s u bjects t o 
C S L 3 1 2 + S O C, 6 2 s u bjects t o place b o + S O C) i n or der t o ac hie ve 
8 0 % p o wer t o det ect a treat me nt differe n ce usi n g a 2 - gr o u p 
c hi-s q uare t est. 
F or t he f utilit y m o nit ori n g a n d sa m ple size re -esti mati o n, a n i nteri m 
a nal ysis of u n bli n de d pri mar y e n d p oi nt data is pla n ne d after 
6 2 s u bjects ( 5 0 % of t he t ar get sa m ple size) h a ve c o m plete d pri mar y 
e n d p oi nt assess me nt. A d diti o nal details o n t he i nteri m a nal ysis are 
pr o vi de d i n t he b o d y of t he pr ot oc ol. 
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C S L  Be hri n g  
St u d y Pr ot oc ol: C S L 3 1 2 _ C O VI D -1 9, Versi o n: A me n d me nt  3 ( 1 6 Se pte m ber  2 0 2 0)  
C S L 3 1 2 ( Gara daci ma b)  
C S L Be hri n g – C o nfi de ntial  
Te m plate: C S -S O P -0 4 -G 0 1 -T 0 1  
Versi o n N u m ber: 1. 0  
Effecti ve Date: Wee k c o m me nci n g 3 0 -A pr -2 0 1 8  
Pa ge 1 2  of 8 3  
 
A n al yses of Pri m ar y Effic ac y  
T he pri mar y e n d p oi nt f or t his st u d y is t he i nci de nce of trac heal 
i nt u bati o n or deat h pri or t o trac heal i nt u bati o n fr o m ra n d o mizati o n 
t o Da y 2 8. T he pr o p orti o n will be calc ulate d as t he n u m ber of 
s u bjects wit h trac heal i nt u bati o n or deat h pri or t o trac heal i nt u bati o n 
di vi de d b y t he t otal n u m ber of s u bjects f or eac h treat me nt gr o u p. 
Treat me nt effect of i nterest (ie,  esti ma n d) is defi ne d as t he 
pr o p orti o n differe nce of trac heal i nt u bati o n or deat h pri or t o trac heal 
i nt u bati o n ( C S L 3 1 2 + S O C mi n us place b o  + S O C)  i n t he tar get 
p o p ulati o n re gar dless of w het her a d diti o nal treat me nt is use d or 
i nitial S O C has c ha n ge d. T he I nte nt-t o-treat A nal ysis Set will be 
use d f or t he pri mar y efficac y a n al yses.  
Firt h l o gistic re gressi o n m o del i ncl u di n g treat me nt gr o u p; a ge gr o u p 
as a c o nti n u o us c o variate ; ge n der ( mal e or fe male); c o u ntr y ( U S A or 
Brazil);  a n d Baseli ne c o m or bi dities ( yes or n o) as cate g orical 
c o variates will be use d t o c o m pare t he rates b et wee n t he 2  treat me nt 
gr o u ps. C o m or bi dities i ncl u de h y perte nsi o n, dia b etes, a n d o besit y 
( defi ne d as b o d y mass i n de x ≥ 3 0 k g/ m 2). A 2-si de d p-val ue w ill be 
esti mate d fr o m t he m o del. T he pr o p orti o n differe n ce a n d ass ociate d 
9 5 % c o nfi de n ce i nter v al ( CI) will be esti mate d usi n g  t he met h o d 
descri be d b y G e at  al [2 0 1 1 ]. T he mI T T A n al ysis Set will be use d 
f or pri mar y effi cac y e n d p oi nt se nsiti vit y a nal ysis. 
Se nsiti vit y a nal yses t o assess t he effect of missi n g data will be 
c o n d ucte d, f or e xa m ple, b y perf or mi n g ti p pi n g p oi nt a nal yses t hat 
var y ass u m pti o ns a b o ut t he missi n g o utc o mes i n b ot h st u d y 
treat me nt gr o u ps. 
Ot her A n al yses  
Details of t he a n al yses of sec o n dar y efficac y, safet y, P K,  
 are 
pr o vi de d i n t he f ull cli nical st u d y pr ot oc ol. 
 
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C S L  Be hri n g  
St u d y Pr ot oc ol: C S L 3 1 2 _ C O VI D -1 9, Versi o n: A me n d me nt  3 ( 1 6 Se pte m ber  2 0 2 0)  
C S L 3 1 2 ( Gara daci ma b)  
C S L Be hri n g – C o nfi de ntial  
Te m plate: C S -S O P -0 4 -G 0 1 -T 0 1  
Versi o n N u m ber: 1. 0  
Effecti ve Date: Wee k c o m me nci n g 3 0 -A pr -2 0 1 8  
 
Pa ge 1 3  of 8 3  
Sc he d ule of Assess me nts  
St u d y Peri o d  
Scree ni n g  
Tre at m e nt Peri o d  
St u d y Wee k  
Wee k  -1  
Wee k 1  
Wee k 2  
Wee k 3  
Wee k 4  
St u d y D a y  
Scree ni n g 
Visit a 
D- 2 t o 
D 1 b  
D 1  
D 2  
D 3 t o 
D 6  
D 7  
D 8 t o 
D 1 3  
D 1 4  
D 1 5 t o 
D 2 0  
D 2 1  
D 2 2 t o 
D 2 7  
D 2 8  
E O S d, e 
B ef o re 
D osi n g  
D osi n g  
After D osi n g c 
3 0  mi n  
6  h  
Visit Wi n d o w  
N A  
 
 
±  1 5  mi n  
±  2  h  
N A  
N A  
N A  
N A  
N A  
N A  
N A  
N A  
±  2 d  
Writte n i nf or me d c o nse nt
f 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
I ncl usi o n/e xcl usi o n criteria 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
C o nfir m S A R S -C o V -2 p ositi v e g 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
C hest C T sca n or X -ra yh 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
Me dical hist or y/ d e m o gra p hics  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
P h ysical e xa mi n ati o n i 
X  
 
 
 
 
 
 
 
 
 
 
 
 
X  
Hei g ht a n d b o d y wei g ht j 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital si g ns k 
X 
X 
 
 
Res pirat or y para meters l 
X u 
X 
 
 
G C S f or S O F A sc ore  
X  
X  
 
 
 
X  
 
X  
 
X  
 
X  
 
X  
Arterial bl o o d g as/ Pa O 2 f or S O F A 
sc orem  
X 
X 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
NI AI D 8 -p oi nt or di n al scale  
 
X  
 
 
 
X  
 
X  
 
X  
 
X  
 
X  
Uri ne c ollecti o n f or uri n al ysis n 
X  
X  
 
 
 
 
 
 
 
 
 
 
 
X  
P re g na nc y testn , o 
X  
 
 
 
 
 
 
 
 
 
 
 
 
X  
He mat ol o g y, bi o c h e mistr y, 
c oa g ulati o n n, p 
X 
X 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
Ra n d o mizati o n  
 
X  
 
 
 
 
 
 
 
 
 
 
 
 
Assi g n me nt t o I P q 
 
X  
 
 
 
 
 
 
 
 
 
 
 
 
Bl o o d sa m ples f or P K a n d  
 
assess me nts r,s 
 
X 
 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
O utc o me assess m e nts t 
 
X 
 
 
A d mi nistrati o n of I P q 
 
 
X  
 
 
 
 
 
 
 
 
 
 
 
C
CI
C CI


C S L  Be hri n g  
St u d y Pr ot oc ol: C S L 3 1 2 _ C O VI D -1 9, Versi o n: A me n d me nt  3 ( 1 6 Se pte m ber  2 0 2 0)  
C S L 3 1 2 ( Gara daci ma b)  
C S L Be hri n g – C o nfi de ntial  
Te m plate: C S -S O P -0 4 -G 0 1 -T 0 1  
Versi o n N u m ber: 1. 0  
Effecti ve Date: Wee k c o m me nci n g 3 0 -A pr -2 0 1 8  
 
Pa ge 1 4  of 8 3  
St u d y Peri o d  
Scree ni n g  
Tre at m e nt Peri o d  
St u d y Wee k  
Wee k  -1  
Wee k 1  
Wee k 2  
Wee k 3  
Wee k 4  
St u d y D a y  
Scree ni n g 
Visit a 
D- 2 t o 
D 1 b  
D 1  
D 2  
D 3 t o 
D 6  
D 7  
D 8 t o 
D 1 3  
D 1 4  
D 1 5 t o 
D 2 0  
D 2 1  
D 2 2 t o 
D 2 7  
D 2 8  
E O S d, e 
B ef o re 
D osi n g  
D osi n g  
After D osi n g c 
3 0  mi n  
6  h  
Visit Wi n d o w  
N A  
 
 
±  1 5  mi n  
±  2  h  
N A  
N A  
N A  
N A  
N A  
N A  
N A  
N A  
±  2 d  
A Es  
 
 
Pre vi o us/c o nc o mita nt me dicati o n 
a n d t hera pies 
X 
 
; AE  = a d v erse e v e nt; A N VI S A = Brazilia n Healt h Re g ulat or y A g e n c y ; Bi P A P  = bi -le v el p ositi ve air wa y press ure; C 1-I N H = C 1 esterase i n hi bit or; 
C P A P  = c o nti n u o us p ositi v e air wa y press ure: C T  = c o m p ute d t o m o gra p h y; β - h C G = b eta h u ma n c h ori o nic g o n a d otr o pi n; e C R F  = electr o nic case re p ort f or m; 
E C M O = e xtrac or p oreal me m bra n e o x y g e n ati o n; E O S  = En d of S t u d y; F D A  = F o o d a n d Dr u g A d mi nistrati o n; Fi O 2 = fracti o n of i ns pire d o x y ge n; G C S = Glas g o w C o ma Scale; 
H F N C  = hi g h -fl o w n asal ca n n ula; I C U = i nte nsi v e care u nit; I C F = i nf or me d c o nse nt f or m; I P = i n v esti g ati o n al pr o d u ct; I N R = i nter nati o nal n or malize d rati o; I V = i ntra ve n o us; 
F XII  = c oa g ulati o n fact or  XII; N A  = n ot a p plica ble; NI AI D  = Nati o n al I nstit ute of Aller g y a n d I nfecti o us Diseases; Pa O 2 = partial press ure of arterial o x y ge n; 
; P K = p h ar mac o ki n etic; P T  = pr ot hr o m bi n ti me; R T- P C R = re v erse tra nscri pti o n p ol y merase c h ai n reacti o n; Sa O 2  = arterial o x y ge n sat urati o n; 
S A R S - C o- V- 2 = se v ere ac ute res pirat or y s y n dr o me c or o n a vir us-2; S O C  = sta n d ar d of care; S O F A = Se q u e ntial Or g a n Fail ure Assess me nt; S p O 2 = sat urati o n of peri p heral 
(ca pillar y) o x y g e n; Tma x  = ti me t o ma xi m u m plas ma c o n ce ntrati o n; T T = t hr o m bi n ti me. 
N otes  f or Sc he d ule of Assess m e nts: 
a. 
If Scree ni n g o cc urs o n Da y 1, t h e assess m e nts sc h e d ule d t o o cc ur at b ot h Scree ni n g a n d b ef ore d osi n g o n Da y  1 ma y be perf or me d o nl y o nce (ie, d o n ot nee d t o be re peate d).  
b.  
Pre- e xisti n g la b orat or y res ults fr o m assess me nts p erf orme d d uri n g t h e Scree ni n g Peri o d, b ut b ef ore o btai ni n g i nf or me d c o nse nt, ma y be use d i n lie u of perf or mi n g t he 
assess me nt at Scree ni n g (t h e sa me assess me nt d o es n ot n ee d t o b e re p eate d/ p erf or me d at Scree ni n g), if t h e s u bject a grees t o t he use of t h ose data i n t he I C F. H o we ver, t he 
assess me nts m ust h a v e b ee n p erf or me d wit h 4 8  h o urs of ra n d o mizati o n.  
c. 
Assess me nts t o b e p erf or me d after d osi n g will b e d o n e after t h e e n d of t h e i nf usi o n of I P ( C S L 3 1 2 or place b o) , w hic h s h o ul d be d o ne as a sl o w i njecti o n, (ie, p us h of a b o ut 
3 mi n utes) . 
d.  
F or s u bjects w h o are disc h ar g e d fr o m t h e h os pital b ef ore Da y  2 8, t h e E O S assess me nts will b e p erf or me d o n t h e d a y of disc har ge a n d s u bjects will be e nc o ura ge d t o ret ur n t o 
t he st u d y site t o c o m plete t h e E O S Visit assess me nts o n Day 2 8, b ut if a s u bject is n ot a ble t o p artici p ate i n t h e Da y  2 8 ( E O S) Visit i n pers o n, t he n t he s u bject will be 
c o ntacte d b y tele p h o n e t o assess cli nical stat us, A Es, a n d c o n c o mita nt me dicati o ns. F or a n y s u bject w h o wit h dra ws fr o m t he st u d y bef ore Da y  2 8, atte m pts will be ma de t o 
c o m plete a n d d o c u me nt t h e Da y  2 8 Visit ( E O S) assess me nts.  
e. 
F or s u bjects w h o are disc h ar g e d fr o m t h e h os pital b ef ore Da y  2 8, a wee kl y tele p h o n e call will b e ma d e t o assess cli nical stat us, A Es, a n d c o nc o mita nt me dicati o ns. T hese 
s u bjects will b e e n c o ura g e d t o ret ur n f or t h e Da y  2 8 ( E O S) Visit.  
f. 
Writte n i nf or me d c o nse nt m ust be o btai n e d b ef ore a n y st u d y -s p ecific assess me nts or pr o ce d ures are p erf or me d. A n i n di vi d ual le gall y per mitte d t o ma ke me dical decisi o ns o n 
t he s u bject’s b e h alf ma y pr o vi d e writte n i nf or me d c o nse nt f or st u d y p artici p ati o n.  
g.  
P ositi ve f or S A R S - C o V-2 i nfecti o n as d eter mi n e d usi n g  a m olec ular dia g n ostic test ( R T-P C R or e q ui v ale nt) a p pr o v e d b y re g ulat or y a ut h orities (i ncl u di n g t he F D A a n d 
A N VI S A) or all o we d u n d er a n e mer g e n c y use a ut h orizati o n wit hi n 1 4 d a ys b ef ore Scree ni n g. If a false n e g ati v e res ult is s us pecte d, t he S A R S - C o V-2 test ma y be re peate d 
wit hi n t he Scree ni n g Peri o d.  
h.  
T o be eli gi ble f or st u d y p artici p ati o n, t h e s u bject’s t h oracic C T  sca n or X-ra y ( p erf or me d wit hi n t h e 2 4 h o urs pri or t o Scree ni n g) m ust s h o w si g ns of i nterstitial p ne u m o nia.  
C CI
C CI


C S L  Be hri n g  
St u d y Pr ot oc ol: C S L 3 1 2 _ C O VI D -1 9, Versi o n: A me n d me nt  3 ( 1 6 Se pte m ber  2 0 2 0)  
C S L 3 1 2 ( Gara daci ma b)  
C S L Be hri n g – C o nfi de ntial  
Te m plate: C S -S O P -0 4 -G 0 1 -T 0 1  
Versi o n N u m ber: 1. 0  
Effecti ve Date: Wee k c o m me nci n g 3 0 -A pr -2 0 1 8  
 
Pa ge 1 5  of 8 3  
i. 
A p h ysical e x a mi n ati o n will b e c o n d u cte d p er t h e st u d y site’s sta n d ar d pr o ce d ure.  
j. 
T he s u bject’s h ei g ht a n d b o d y wei g ht will o nl y b e meas ure d at Scree ni n g.  
k.  
Vital s i g n assess me nts, i n cl u di n g bl o o d press ure (s yst olic a n d diast olic), h eart rate, a n d b o d y te m p erat ure, s h o ul d b e assesse d a n d rec or de d i n t he e C R F at a p pr o xi matel y t he 
sa me ti me e ac h d a y d uri n g st u d y p artici p ati o n. Bl o o d press ure a n d h eart rate will b e measure d wit h t h e s u bject i n a s u pi ne or seate d p ositi o n after resti n g f or ≥ 5 mi n utes. 
B o d y te m perat ure will b e meas ure d eit h er s u bli n g u all y or t y m p a nicall y; b o d y te m p erat ure ma y als o b e meas ure d usi n g a n o n -c o ntact i nfrare d t her m o meter . The met h o d of 
meas ure m e nt s h o ul d b e c o nsiste nt t hr o u g h o ut t h e st u d y f or a gi v e n s u bject.  
l. 
Res pirat or y p ara meters: res pirat or y rate ( breat hs p er mi n ute), S p O 2 ( %), a n d Fi O 2 ( n at ural air i n cl u des 2 1 % o x y g e n, w hic h is e q ui vale nt t o Fi O₂ of 0. 2 1). Res pirat or y 
para meters s h o ul d b e meas ure d o n ce d ail y, i d eall y p erf or me d t o g et h er wit h vital si g ns at t h e sa me ti me of t h e d a y . 
m.  Pa O 2 s h o ul d b e meas ure d o nl y o n d a ys w h e n t h e S O F A sc ore is assesse d. A n i n d welli n g arterial cat heter s h o ul d n ot be place d j ust t o c ollect t hese sa m ples. Alt h o u g h t he 
Pa O 2/ Fi O2 rati o is prefera ble t o calc ulate t h e S O F A sc ore, if Pa O2 is n ot a v aila ble, t h e Sa O 2/ Fi O2 rati o ma y b e use d i nstea d. 
n.  
T hese assess me nts will b e p erf or me d at t h e l o cal la b orat or y.  
o.  
A uri ne test f or β -h C G will b e p erf or me d at t h e l o cal la b orat or y f or all fe male s u bjects of c hil d b eari n g p ote ntial t o r ule o ut pre g na nc y d uri n g Scree ni n g a n d at t he e n d of t he 
Treat me nt Peri o d. A ser u m pre g na n c y te st will b e p erf or me d b y t he site if uri n e res ult is i n c o n cl usi ve. 
p.  
Bl o o d sa m ples will b e a n al y ze d f or t h e la b orat or y p ara meters s p ecifie d i n Ta ble  3. 
q.  
I P will be eit h er I V C S L 3 1 2 + S O C or I V place b o  + S O C.  
r. 
Bl o o d sa m ples will b e a n al y ze d at t h e ce ntral la b orat or y f or t h e P K p ara meters s p ecifie d i n Secti o n  7. 4  
 
A nal ysis of t h e P K d ata will b e perf or me d b y C S L ( or d ele g ate).  
s. 
O n Da y  1, bl o o d  sa m ples will b e c ollecte d at 3 0 mi n utes a n d 6  h o urs after t h e e n d of t h e i nf usi o n of I P t o p erf or m P K assess me nts.  
t. 
O utc o me assess m e nts i n cl u d e t h e s u bject’s use of s u p ple me ntal o x y g e n; use of C P A P or Bi P A P; use of H F N C; use of E C M O; i nt u bat i o n; e xt u bati o n; I C U a d missi o n a n d 
disc har ge; a n d h os pital disc h ar g e or d eat h.  
u.  
Res ults fr o m res pirat or y p ara meter  assess m e nts  p erf or me d at t h e ti me of h os pital a d missi o n ma y b e use d, wit h o ut t h e re q uire me nt t o re peat t hese assess me nts f or t he 
Scree ni n g Visit pr o vi d e d t h a t t h e assess me nts were p erf or me d wit hi n 2 4 h o urs b ef ore Scree ni n g f or t his st u d y.  
 
C CI


C S L  Be hri n g  
St u d y Pr ot oc ol: C S L 3 1 2 _ C O VI D -1 9, Versi o n: A me n d me nt  3 ( 1 6  Se pte m ber  2 0 2 0)  
C S L 3 1 2 ( Gara daci ma b)  
C S L Be hri n g – C o nfi de ntial  
Te m plate: C S -S O P -0 4 -G 0 1 -T 0 1  
Versi o n N u m ber: 1. 0  
Effecti ve Date: Wee k c o m me nci n g 3 0 -A pr -2 0 1 8  
Pa ge 1 6  of 8 3  
Ta ble of C o nte nts  
LI S T O F P E R S O N N E L A N D O R G A NI Z A TI O N S R E S P O N SI B L E F O R C O N D U C T O F 
T H E S T U D Y  ....................................................................................................................... 2 
R E VI SI O N HI S T O R Y  ............................................................................................................... 3 
Cli nical St u d y Pr ot oc ol S y n o psis .............................................................................................. 6 
Sc he d ule of Assess me nts  ......................................................................................................... 1 3 
Ta ble of C o nte nts ..................................................................................................................... 1 6  
List of Ta bles ............................................................................................................................ 2 0  
List of Fi g ures .......................................................................................................................... 2 0  
List of A b bre viati o ns  ............................................................................................................... 2 1 
1  I ntr o d ucti o n ....................................................................................................................... 2 4 
1. 1  
Bac k gr o u n d ................................................................................................................... 2 4  
1. 2  
I nf or mati o n o n C S L 3 1 2................................................................................................. 2 7 
1. 3  
St u d y O ver vie w ............................................................................................................. 2 7  
1. 4  
P ote ntial Ris ks a n d Be nefits .......................................................................................... 2 7  
2  St u d y O bjecti ves a n d E n d p oi nts ........................................................................................ 3 0  
2. 1  
Pri mar y O bjecti ve a n d E n d p oi nts.................................................................................. 3 0  
2. 1. 1  
Pri mar y O bjecti ve  ...................................................................................................... 3 0 
2. 1. 2  
Pri mar y E n d p oi nt ...................................................................................................... 3 0  
2. 2  
Sec o n dar y O bj ecti ves a n d E n d p oi nts ............................................................................ 3 0  
2. 2. 1  
Sec o n dar y O bj ecti ves  ................................................................................................ 3 0 
2. 2. 2  
Sec o n dar y E n d p oi nts ................................................................................................. 3 0  
2. 3  
2. 3. 1  
2. 3. 2  
3  St u d y Desi g n ..................................................................................................................... 3 3  
3. 1  
Pla n ne d N u m ber of S u bj ects ......................................................................................... 3 5  
3. 2  
Pla n ne d St u d y D urati o n................................................................................................. 3 5  
3. 3  
Pl a n ne d C o u ntries a n d Esti mate d N u m ber of Sites....................................................... 3 6  
4  St u d y I nter ve nti o ns ............................................................................................................ 3 6  
4. 1  
Descri pti o n of I n v esti gati o nal Pr o d uct .......................................................................... 3 6  
C CI


C S L  Be hri n g  
St u d y Pr ot oc ol: C S L 3 1 2 _ C O VI D -1 9, Versi o n: A me n d me nt  3 ( 1 6 Se pte m ber  2 0 2 0)  
C S L 3 1 2 ( Gara daci ma b)  
C S L Be hri n g – C o nfi de ntial  
Te m plate: C S -S O P -0 4 -G 0 1 -T 0 1  
Versi o n N u m ber: 1. 0  
Effecti ve Date: Wee k c o m me nci n g 3 0 -A pr -2 0 1 8  
 
Pa ge 1 7  of 8 3  
4. 1. 1  
C S L 3 1 2 ...................................................................................................................... 3 6  
4. 1. 2  
Place b o ( C S L 3 1 2 Dil ue nt) ........................................................................................ 3 7  
4. 1. 3  
Acc o u nta bilit y a n d Destr ucti o n ................................................................................. 3 8  
4. 1. 4  
D ose M o dificati o n ..................................................................................................... 3 8  
5  All ocati o n, D osi n g, a n d A d mi nistrati o n ............................................................................ 3 9  
5. 1  
All ocati o n t o Treat me nt  ................................................................................................. 3 9 
5. 1. 1  
S u bject Assi g n me nt  ................................................................................................... 3 9 
5. 1. 2  
Ra n d o mizati o n Pr oce d ur es ........................................................................................ 3 9  
5. 1. 3  
Bli n di n g Pr oce d ures .................................................................................................. 3 9  
5. 1. 3. 1  
Bli n di n g Met h o d .................................................................................................... 3 9  
5. 1. 3. 2  
Brea ki n g t he Bli n d f or a n E mer ge n c y ................................................................... 4 0  
5. 1. 3. 3  
Pla n ne d U n bli n di n g Pr oce d ures ............................................................................ 4 0  
5. 1. 3. 4  
A d - h oc Saf et y U n bli n di n g ..................................................................................... 4 1 
6  St u d y P o p ulati o n a n d Mai n Criteria f or Eli gi bilit y  ........................................................... 4 1 
6. 1  
Eli gi bilit y Criteria .......................................................................................................... 4 1  
6. 2  
I nclusi o n Criteria  ........................................................................................................... 4 1 
6. 3  
E xcl usi o n Criteria  .......................................................................................................... 4 2 
6. 4  
Disc o nti n uati o n of St u d y Treat me nt a n d S u bject Wit h dra wal ...................................... 4 4  
6. 4. 1  
Earl y Disc har ge fr o m t he H os pital ............................................................................ 4 4  
6. 4. 2  
Disc o nti n uati o n of St u d y Treat me nt.......................................................................... 4 4  
6. 4. 3  
S u bject Wit h dra wal  ................................................................................................... 4 5 
6. 4. 4  
Pr oce d ures f or H a n dli n g Wit h dra wals  ...................................................................... 4 5 
6. 4. 5  
Re place me nt P olic y  ................................................................................................... 4 5 
7  St u d y Assess me nts  ............................................................................................................. 4 5 
7. 1  
U nsc he d ule d St u d y Assess me nts a n d A d diti o nal Me dical Data ................................... 4 5  
7. 2  
Efficac y Assess me nts  .................................................................................................... 4 6 
7. 3  
De m o gra p hics a n d Safet y Assess me nts  ........................................................................ 4 6 
7. 4  
P har mac o ki netic Assess me nts  ....................................................................................... 4 9 
7. 5  
 
8  St u d y O versi g ht ................................................................................................................. 4 9  
8. 1  
O versi g ht a n d M o nit ori n g C o m mittees ......................................................................... 4 9  
8. 2  
St u d y Halti n g Criteria  ................................................................................................... 5 0 
8. 3  
Tr eat me nt C o m plia nce  .................................................................................................. 5 1 
C CI


C S L  Be hri n g  
St u d y Pr ot oc ol: C S L 3 1 2 _ C O VI D -1 9, Versi o n: A me n d me nt  3 ( 1 6 Se pte m ber  2 0 2 0)  
C S L 3 1 2 ( Gara daci ma b)  
C S L Be hri n g – C o nfi de ntial  
Te m plate: C S -S O P -0 4 -G 0 1 -T 0 1  
Versi o n N u m ber: 1. 0  
Effecti ve Date: Wee k c o m me nci n g 3 0 -A pr -2 0 1 8  
 
Pa ge 1 8  of 8 3  
9  Pr o hi bite d a n d Per mitte d T hera pies .................................................................................. 5 2  
9. 1  
Pr o hi bite d T hera pies  ...................................................................................................... 5 2 
9. 2  
Per mitte d Me dicati o ns/ T hera pies  .................................................................................. 5 2 
9. 3  
Lifest yle Restricti o ns  ..................................................................................................... 5 3 
9. 4  
O ver d ose ........................................................................................................................ 5 3  
1 0  A d verse E v e nts  .................................................................................................................. 5 4 
1 0. 1  Defi niti o ns  ..................................................................................................................... 5 4 
1 0. 1. 1  
A d verse E v e nt  ........................................................................................................... 5 4 
1 0. 1. 2  
Seri o us A d vers e E ve nt  ............................................................................................... 5 5 
1 0. 1. 3  
A d verse E v e nt of S pecial I nterest  ............................................................................. 5 6 
1 0. 2  Se verit y of A d v erse E v e nts ........................................................................................... 5 7  
1 0. 3  Ca usalit y of A d vers e E ve nts.......................................................................................... 5 7  
1 0. 4  O bser vati o n Peri o d f or A d verse E ve nts ........................................................................ 5 8  
1 0. 5  F oll o w- u p of A d vers e E v e nts ........................................................................................ 5 8  
1 0. 6  A d verse E v e nt Re p orti n g .............................................................................................. 5 8  
1 0. 6. 1  
A d verse E v e nts  .......................................................................................................... 5 8 
1 0. 6. 2  
Seri o us A d vers e E ve nts  ............................................................................................. 5 8 
1 0. 6. 3  
A d verse E v e nts of S peci al I nterest  ............................................................................ 6 0 
1 0. 6. 4  
Ot her Si g nifica nt E ve nts ........................................................................................... 6 0  
1 0. 6. 5  
O ver d ose .................................................................................................................... 6 0  
1 0. 6. 6  
Pre g na nc y a n d Breastf ee di n g  .................................................................................... 6 0 
1 0. 7  I nstit uti o nal Re vie w B oar d/I n de pe n d e nt Et hics C o m mittee Re p orti n g Re q uire me nts . 6 1 
1 1  Statistical A nal yses  ............................................................................................................ 6 1 
1 1. 1  Sa m ple Size  ................................................................................................................... 6 1 
1 1. 2  Descri pti o n  of St u d y A nal ysis Sets ............................................................................... 6 2 
1 1. 2. 1  
Scree ne d A n al ysis Set  ............................................................................................... 6 2 
1 1. 2. 2  
I nte nt-t o-Treat A nal ysis Set  ....................................................................................... 6 2 
1 1. 2. 3  
M o difie d I nte nt- t o-Treat A nal ysis Set  ....................................................................... 6 2 
1 1. 2. 4  
Safet y A n al ysis Set  .................................................................................................... 6 2 
1 1. 2. 5  
P har mac o ki netic A nal ysis Set  ................................................................................... 6 2 
1 1. 2. 6  
 
1 1. 3  A nal yses of Pri mar y Effi cac y  ........................................................................................ 6 3 
1 1. 4  A nal yses of Sec o n d ar y Efficac y  .................................................................................... 6 3 
C CI


C S L  Be hri n g  
St u d y Pr ot oc ol: C S L 3 1 2 _ C O VI D -1 9, Versi o n: A me n d me nt  3 ( 1 6 Se pte m ber  2 0 2 0)  
C S L 3 1 2 ( Gara daci ma b)  
C S L Be hri n g – C o nfi de ntial  
Te m plate: C S -S O P -0 4 -G 0 1 -T 0 1  
Versi o n N u m ber: 1. 0  
Effecti ve Date: Wee k c o m me nci n g 3 0 -A pr -2 0 1 8  
 
Pa ge 1 9  of 8 3  
1 1. 5  A nal ysis of Safet y  ......................................................................................................... 6 5 
1 1. 6  A nal yses of P har mac o ki netics ....................................................................................... 6 6  
1 1. 7  
 
1 1. 8  I nteri m A nal ysis ............................................................................................................ 6 8 
1 2  Re g ulat or y a n d Et hics C o nsi derati o ns ............................................................................... 6 9  
1 2. 1  Re g ulat or y C o nsi derati o ns ............................................................................................ 6 9  
1 2. 2  I nstit uti o nal Re vie w B oar d/I n de pe n d e nt Et hics C o m mittee ......................................... 6 9 
1 2. 3  S u bject I nf or mati o n a n d I nf or me d C o nse nt .................................................................. 6 9  
1 2. 4  S u bject C o nfi de ntialit y  .................................................................................................. 7 0 
1 2. 5  I n de m nit y a n d C o m pe nsati o n ........................................................................................ 7 0 
1 3  A d mi nistrati ve C o nsi derati o ns  .......................................................................................... 7 0 
1 3. 1  Cli nical Trial Researc h A gree me nt ................................................................................ 7 0  
1 3. 2  Cli nical St u d y Re gistrati o n a n d Res ults Discl os ure ...................................................... 7 1  
1 3. 3  I m ple me ntati o n of t he Cli nical St u d y Pr ot oc ol a n d A me n d me nts ................................ 7 1 
1 3. 4  Pr ot oc ol De viati o ns ....................................................................................................... 7 1  
1 3. 5  D oc u me ntati o n a n d Rec or d Kee pi n g ............................................................................ 7 2  
1 3. 5. 1  
Data C ollecti o n  .......................................................................................................... 7 2 
1 3. 5. 2  
Data Q ualit y Ass ura nce  ............................................................................................. 7 2 
1 3. 5. 3  
M o nit ori n g ................................................................................................................. 7 2  
1 3. 5. 4  
Rec or d Re te nti o n ....................................................................................................... 7 3 
1 3. 6  St u d y a n d Site Cl os ure .................................................................................................. 7 3  
1 3. 7  Cli nical St u d y Re p ort .................................................................................................... 7 3  
1 3. 8  Use of Dat a a n d P u blicati o ns ........................................................................................ 7 4  
1 4  Refere n ces  ......................................................................................................................... 7 5 
1 5  A p pe n dices ........................................................................................................................ 7 8  
 
C CI


C S L  Be hri n g  
St u d y Pr ot oc ol: C S L 3 1 2 _ C O VI D -1 9, Versi o n: A me n d me nt  3 ( 1 6 Se pte m ber  2 0 2 0)  
C S L 3 1 2 ( Gara daci ma b)  
C S L Be hri n g – C o nfi de ntial  
Te m plate: C S -S O P -0 4 -G 0 1 -T 0 1  
Versi o n N u m ber: 1. 0  
Effecti ve Date: Wee k c o m me nci n g 3 0 -A pr -2 0 1 8  
 
Pa ge 2 0  of 8 3  
List of Ta bles  
Ta ble  1 
Descri pti o n of C S L 3 1 2 .................................................................................... 3 7  
Ta ble  2 
Descri pti o n of Place b o  ..................................................................................... 3 8 
Ta ble  3 
De m o gra p hics a n d Safet y Assess me nts  ........................................................... 4 6 
Ta ble  4 
 
 
List of Fi g ures  
Fi g ure 1  
St u d y Desi g n  .................................................................................................... 3 3 
Fi g ure 2  
Pre dicte d ( Me dia n + 9 5 % PI) F XII -me di ate d Kalli krei n Acti vit y After S i n gle 
I ntra ve n o us D os es of C S L 3 1 2 (I ncl u di n g 1 0 m g/ k g) ...................................... 3 5 
 
 
C CI


C S L  Be hri n g  
St u d y Pr ot oc ol: C S L 3 1 2 _ C O VI D -1 9, Versi o n: A me n d me nt  3 ( 1 6 Se pte m ber  2 0 2 0)  
C S L 3 1 2 ( Gara daci ma b)  
C S L Be hri n g – C o nfi de ntial  
Te m plate: C S -S O P -0 4 -G 0 1 -T 0 1  
Versi o n N u m ber: 1. 0  
Effecti ve Date: Wee k c o m me nci n g 3 0 -A pr -2 0 1 8  
 
Pa ge 2 1  of 8 3  
List of A b bre vi ati o ns  
A b bre vi ati o n  
Ter m  
3 F 7  
Pare ntal a nti b o d y t o C S L 3 1 2  
A C E -2  
A n gi ote nsi n -c o n verti n g e nz y me  2  
 
 
A E  
A d v erse e ve nt  
A E SI  
A d verse e ve nt of s pecial i nterest  
A nti -I L-6  
A nti b o dies a gai nst i nterle u ki n-6  
A nti -I L- 6 R 
A nti b o dies a gai nst i nterle u ki n- 6 rece pt ors 
A N VI S A  
Brazilia n Healt h Re g ulat or y A ge n c y  
A R D S  
Ac ute res pirat or y distress s y n dr o me 
a P T T 
Acti vate d partial t hr o m b o plasti n ti me  
A U C 0- last 
Area u n d er t he plas ma c o nce ntrati o n -ti me c ur ve fr o m ti me zer o t o 
t he ti me of t he last meas ura ble c o n ce ntrati o n 
β F XIIa  
Acti vate d c o a g ulati o n fact or XII b eta  
Bi P A P  
Bi -le vel p ositi ve air wa y press ure 
B K  
Bra d y ki ni n 
CI  
C o nfi de nce i nter v al  
C ma x  
Ma xi m u m plas ma c o nce ntrati o n  
C o V 
C or o na vir us 
C O VI D - 1 9 
C or o na vir us Disease 2 0 1 9 
C P  
C o n diti o nal p o wer 
C P A P  
C o nti n u o us p ositi ve air wa y press ure  
C S L  
C S L Be hri n g  
C S L 3 1 2 
Fact or  XIIa a nta g o nist m o n ocl o nal a nti b o d y 
C S P  
Cli nical st u d y pr ot oc ol 
C S R  
Cli nical st u d y re p ort 
C T  
C o m p ute d t o m o gra p h y  
C T C A E  
C o m m o n Ter mi n ol o g y Criteria f or A d verse E v e nts  
C T R A  
Cli nical Trial Researc h A gree me nt  
C V %  
Perce nt c o effi cie nt of varia nce  
D A B K  
des -Ar g 9 bra d y ki ni n 
DI C  
Disse mi nate d i ntra vasc ul ar c oa g ul ati o n  
D NI  
D o - n ot-i nt u bate 
D N R  
D o - n ot-res us citate 
C CI


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Abbreviation 
Term 
eCRF 
Electronic case report form 
ECMO 
Extracorporeal membrane oxygenation 
EOS 
End of Study 
FDA 
Food and Drug Administration 
FiO2 
Fraction of inspired oxygen 
FXII 
Coagulation factor XII 
FXIIa 
Activated coagulation factor XII 
GCP 
Good Clinical Practice 
G-CSF 
Granulocyte colony-stimulating factor 
GMP 
Good Manufacturing Practice 
HAE 
Hereditary angioedema 
HFNC 
High-flow nasal cannula 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation of Technical 
Requirements for Pharmaceuticals for Human Use 
ICU 
Intensive care unit 
IDMC 
Independent Data Monitoring Committee 
IEC 
Independent Ethics Committee 
Ig 
Immunoglobulin 
IL 
Interleukin 
IP 
Investigational product 
INR 
International normalized ratio 
IP-10 
Interferon gamma-induced protein 10 
IRB 
Institutional Review Board 
IRT 
Interactive response technology 
ITT 
Intent-to-treat 
IV 
Intravenous 
KKS 
Kallikrein-kinin system 
KM 
Kaplan-Meier 
LMWH 
Low molecular-weight heparin 
LOS 
Length of stay 
MCP-1 
Monocyte chemoattractant protein-1 
MedDRA 
Medical Dictionary for Regulatory Activities 
MERS 
Middle East respiratory syndrome 


C S L  Be hri n g  
St u d y Pr ot oc ol: C S L 3 1 2 _ C O VI D -1 9, Versi o n: A me n d me nt  3 ( 1 6 Se pte m ber  2 0 2 0)  
C S L 3 1 2 ( Gara daci ma b)  
C S L Be hri n g – C o nfi de ntial  
Te m plate: C S -S O P -0 4 -G 0 1 -T 0 1  
Versi o n N u m ber: 1. 0  
Effecti ve Date: Wee k c o m me nci n g 3 0 -A pr -2 0 1 8  
 
Pa ge 2 3  of 8 3  
A b bre vi ati o n 
Ter m  
MI P - 1 α 
Macr o p ha g e i nfla m mat or y pr otei n 1-al p ha 
mI T T  
M o difie d i nte nt- t o-treat 
N C P E R E  
N o vel C or o na vir us P ne u m o nia E mer ge n c y Res p o nse 
E pi de mi ol o g y 
NI AI D  
Nati o nal I nstit ute of Aller g y a n d I nfecti o us Diseas es  
NI V  
N o n -i n vasi ve ve ntilati o n 
Pa O 2 
Partial press ure of arterial o x y ge n  
 
 
P K  
P har mac o ki netic  
P T  
Pr ot hr o m bi n ti me  
R T -P C R  
Re verse tra nscri pti o n p ol y merase c hai n reacti o n  
S A E  
Seri o us a d verse e ve nt  
Sa O 2 
A rterial o x y ge n s at urati o n 
S A R S  
Se vere ac ute res pirat or y s y n dr o me  
S A R S - C o V- 2 
Se vere ac ute res pirat or y s y n dr o me c or o n a vir us- 2 
S M T  
Safet y Ma na g e me nt Tea m  
S O C  
Sta n dar d - of-care  
S O F A  
Se q ue ntial Or ga n Fail ure Assess me nt  
S p O 2 
Sat urati o n of peri p heral (ca pillar y) o x y g e n 
T 1/ 2 
Ter mi nal half -life 
T E A E  
Treat me nt -e mer ge nt a d v erse e v e nt  
T E E  
T hr o m b oe m b olic e ve nt 
T ma x  
Ti me t o ma xi m u m plas ma c o nce ntrati o n  
T N F -α  
T u m or necr osis fact or -al p ha 
U S A  
U nite d States of A merica  
W H O  
Worl d Healt h Or ga nizati o n 
 
C CI


CSL Behring 
Study Protocol: CSL312_COVID-19, Version: Amendment 3 (16 September 2020) 
CSL312 (Garadacimab) 
CSL Behring – Confidential 
Template: CS-SOP-04-G01-T01 
Version Number: 1.0 
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1 Introduction 
1.1 Background 
Coronavirus disease 2019 (COVID-19) is caused by a new coronavirus strain of severe acute 
respiratory syndrome coronavirus-2 (SARS-CoV-2). According to the World Health 
Organization (WHO), the virus emerged in Wuhan, China [WHO Disease Outbreak News, 
2020]. Since the first reports in December 2019, SARS-CoV-2 has spread rapidly with 
soaring numbers of confirmed cases globally [WHO COVID-19 Situation Report 65, 2020]. 
Symptoms elicited by SARS-CoV-2 include fever, dry cough, dyspnea, and fatigue. While 
most patients display a mild form of illness, a subset of infected individuals (~14%) develop 
severe disease, viral pneumonia, leading to hospitalization and the need for oxygen support, 
with approximately 5% of these patients requiring intensive care unit (ICU) admission 
[Novel Coronavirus Pneumonia Emergency Response Epidemiology Team (NCPERE Team), 
2020]. In severe cases, COVID-19 may be complicated by acute respiratory distress 
syndrome (ARDS), sepsis and septic shock, multi-organ failure, and even death [Yang et al, 
2020]. Risk factors associated with severe disease are age > 65 years and underlying 
comorbidities, such as obesity, diabetes mellitus, and other chronic disorders. 
Emerging radiological evidence suggests that patients with COVID-19 pneumonia present 
with thoracic computed tomography (CT) imaging abnormalities [Shi et al, 2020]. The 
predominant pattern reported is ground-glass opacity, with ill-defined margins, air 
bronchograms, smooth or irregular interlobular or septal thickening, and thickening of the 
adjacent pleura. CT scan abnormalities appear to evolve from focal unilateral to diffuse 
bilateral ground-glass opacities and may progress to or co-exist with consolidations within 
1 to 3 weeks. Evidence suggests that CT abnormalities are observed even in patients with 
mild symptoms. Overall, the reported imaging characteristics bear resemblance to those 
observed for other coronavirus infections, such as severe acute respiratory syndrome (SARS) 
and Middle East respiratory syndrome (MERS), and are suggestive of vascular leakage and 
fluid accumulation in the lung tissue. 


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In a study by Huang et al, patients with COVID-19 had CT scan abnormalities that were 
associated with leukocytopenia and lymphopenia [Huang et al, 2020]. At the time of hospital 
admission, increased prothrombin time (PT) and D-dimer levels have been observed in 
patients that are eventually admitted to the ICU. Preliminary evidence further suggests that 
the non-survivors, at the time of admission, had higher levels of D-dimer and fibrin 
degradation product, longer PT, and activated partial thromboplastin time (aPTT) compared 
with survivors [Tang et al, 2020] During their hospital stays, 71.4% of non-survivors and 
0.6% of survivors met the criteria for disseminated intravascular coagulation (DIC). Together, 
these data suggest that severe COVID-19 is associated with activation of the coagulation 
cascade. While DIC was initially thought to be a consequence of extrinsic activation of the 
coagulation system, more recent findings suggest that intrinsic activation may also play a 
role. Lastly, analysis of immune mediators in plasma showed increased concentrations of 
interleukin (IL)-2, IL-7, IL-10, granulocyte colony-stimulating factor (G-CSF), interferon 
gamma-induced protein 10 (IP-10), monocyte chemoattractant protein-1 (MCP-1), 
macrophage inflammatory protein 1-alpha (MIP-1α), and tumor necrosis factor-alpha 
(TNF-α) in ICU patients compared with non-ICU patients [Huang et al, 2020]. 
Similar to SARS-CoV, the functional ligand of SARS-CoV-2 is angiotensin-converting 
enzyme-2 (ACE-2). Binding of SARS-CoV to ACE-2 has been reported to downmodulate 
ACE-2 expression. In addition to its role in the renin–angiotensin system, ACE-2 inactivates 
des-Arg9 bradykinin (DABK), a potent vasodilative, vascular leakage, and proinflammatory 
mediator. Hence, we postulate that dysregulated ACE-2-dependent inactivation of DABK 
contributes to vascular leakage, fluid accumulation, and excessive tissue inflammation in 
COVID-19. 
Coagulation factor XII (FXII) is the principal initiator of the plasma contact phase system. 
Upon contact with negatively-charged surfaces, FXII is converted to activated coagulation 
factor XII (FXIIa), leading to the production of bradykinin (BK) through the kallikrein-kinin 
pathway. Binding of BK to BK receptor type 2 and DABK to BK receptor type 1 activates 
various intracellular signaling pathways that dilate vessels, induce chemotaxis of neutrophils, 
and increase vascular permeability and fluid efflux. Further cleavage of FXIIa releases the 
light chain containing activated beta coagulation factor XII (βFXIIa), which can activate the 
classical complement pathway. Independent of kallikrein-kinin system (KKS) and 
complement activation, FXII induces expression of inflammatory mediators, including IL-8, 
IL-1β, and IL-6 on human fibroblasts and precision cut lung slices. 


CSL Behring 
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FXII activation to FXIIa also initiates the intrinsic coagulation pathway through cleavage and 
subsequent activation of coagulation factor XI. This pathway supports the formation of a 
stable thrombus but appears to have no critical function for fibrin formation during “normal” 
hemostasis at a site of injury. Specifically, patients with congenital deficiency of FXII do not 
exhibit a bleeding phenotype. Similarly, FXII knockout mice and rats maintain normal 
hemostasis despite FXII deficiency. Taken together, these findings show that FXII has potent 
proinflammatory and procoagulant activities. 
To date, no targeted treatment for the COVID-19 associated pulmonary edema has been 
identified. Multiple potential therapeutic options, including immune modulation and antiviral 
combined with adjuvant therapies are currently under investigation. While the role of FXII in 
COVID-19 is currently not understood, indirect evidence, such as excessive fluid 
accumulation, DIC, and the observed cytokine storm may implicate this molecule in 
COVID-19. Of note, endothelial cell permeability during Hantavirus infection involved 
FXII-dependent activation of the KKS, implicating FXII in the pathobiology of viral 
infections [Taylor et al, 2013]. 
We hypothesize that FXII inhibition attenuates progression of SARS-CoV-2-related 
respiratory disease toward severe pneumonia and ARDS. Specifically, we hypothesize that 
FXII-targeted interventions will attenuate vascular leakage and expression of inflammatory 
mediators through inhibition of KKS-dependent BK generation. We further postulate that 
FXII inhibition will have a beneficial effect on DIC through attenuation of intrinsic 
coagulation-driven thrombosis. 
According to feedback from treating physicians, in patients with disease progression, the time 
period from symptoms onset to development of dyspnea is reported to be between 
5 to 10 days, and progression to severe leukocytopenic or lymphocytopenic pneumonia with 
or without ARDS occurs within 10 to 14 days. An estimated 15% to 18% of these patients 
will need mechanical ventilation, despite the use of non-invasive ventilation (NIV) support in 
the earliest phases of the disease. The probability of progression to end-stage disease is 
unpredictable, with the majority of these patients dying from multi-organ failure. Preventing 
disease progression to avoid the need for mechanical ventilation in patients with severe 
COVID-19 pneumonia should reduce morbidity and mortality and result in a decrease in the 
use of healthcare resources, ie, the need for mechanical ventilation and prolonged ICU stay. 


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1.2 Information on CSL312 
CSL312 is a fully human immunoglobulin G4 (IgG4)/lambda, FXIIa antagonist, recombinant 
monoclonal antibody. CSL312 binds to the catalytic domain of FXIIa and potently inhibits 
the intrinsic coagulation cascade and BK production via inhibition of KKS [Cao et al, 2018]. 
Based on available nonclinical data, CSL312 may offer a novel therapeutic approach to 
prevent disease progression in patients with COVID-19. 
CSL312 is a potent antithrombotic antibody in both mouse and rabbit thrombosis models 
involving FXII activation (without bleeding risk in either thrombosis or bleeding models). 
Pharmacologically, CSL312 treatment is accompanied by an expected increase in aPTT but 
without any increase in PT [Larsson et al, 2014]. CSL312 inhibits BK production in vitro and 
attenuates edema formation in vivo in BK-mediated edema models (ACE-inhibitor induced 
edema and acute anaphylaxis mouse models) [Cao et al, 2018]. CSL312 attenuates 
expression of inflammatory mediators. The parental antibody to CSL312, 3F7, attenuates 
bleomycin-induced lung fibrosis, renal fibrosis in a unilateral ureteral obstruction model, and 
liver fibrosis in mice. Based on available nonclinical data, CSL312 might offer a novel 
therapeutic approach to prevent disease progression in patients with COVID-19. 
1.3 Study Overview 
Study CSL312_COVID-19 is a prospective, phase 2, multicenter, randomized, double-blind, 
placebo-controlled, parallel-group study to assess the safety and efficacy of CSL312 
administered intravenously in combination with standard-of-care (SOC) treatment in patients 
with COVID-19. The study will consist of a Screening Period of up to 2 days and a 
Treatment Period of up to 28 days. Eligible subjects will be randomly assigned to receive a 
single intravenous (IV) dose of either CSL312 or placebo in addition to SOC treatment 
(CSL312 + SOC or placebo + SOC) on Day 1. The primary endpoint for this study is the 
incidence of tracheal intubation or death prior to tracheal intubation from randomization to 
Day 28. A more detailed overview of the study is provided in Section 3. 
1.4 Potential Risks and Benefits 
CSL312 is a fully human monoclonal antibody that inhibits FXIIa activity. CSL312 is 
currently being developed for routine prophylaxis to prevent angioedema attacks in patients 
with hereditary angioedema (HAE). In the current study, CSL312 will be administered for the 
first time to subjects with COVID-19 with the aim of preventing disease progression (ie, the 
need for tracheal intubation or death). 


CSL Behring 
Study Protocol: CSL312_COVID-19, Version: Amendment 3 (16 September 2020) 
CSL312 (Garadacimab) 
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Version Number: 1.0 
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CSL312 is currently only administered in the clinical study setting in accordance with the 
clinical study protocol (CSP). The maximum dose and the predicted corresponding maximum 
plasma concentration (Cmax) in this study is equal to the highest administered dose and its 
corresponding Cmax observed in the phase 1 study (CSL312_1001). Each subject who 
participated in Study CSL312_1001 received a single dose of CSL312; each subject who 
participates in the current study will receive a single dose of either CSL312 in addition to 
SOC treatment (CSL312 + SOC) or placebo in addition to SOC treatment (placebo + SOC). 
Benefits 
The benefits of CSL312, when provided in addition to SOC treatment, in patients with 
COVID-19 are unknown. Potential benefits are based on the mechanism of action of 
CSL312, ie, inhibition of FXIIa. The potential benefit is the prevention of disease progression 
in patients with COVID-19. Subjects randomly assigned to the placebo + SOC group, which 
is included for scientific rigor, are not expected to receive any additional benefits from 
placebo beyond the expected response to SOC treatment. 
Risks 
The following risks were not observed in the phase 1 study (CSL312_1001) but are potential 
risks based on the drug class and mechanism of action of CSL312: 
• Severe Hypersensitivity/Anaphylactic-type Reactions: Administration of 
therapeutic proteins including monoclonal antibodies such as CSL312 is associated 
with the risk of hypersensitivity and anaphylactic reactions, some of which can be 
serious and life-threatening. Appropriate precautions will be taken when CSL312 is 
administered at the study site, with constant monitoring for potential anaphylactic 
reactions. The administration of CSL312 will be performed under medical supervision 
with immediate access to emergency equipment and medication for the treatment of 
severe hypersensitivity and anaphylaxis. 
• Exacerbation of Cytokine Release Syndrome: Cytokine release syndrome is a 
symptom complex caused by the rapid release of pro-inflammatory cytokines from 
target immune cells which can be life-threatening [Stebbings et al, 2007; Stebbings 
et al, 2013]. Patients with severe COVID-19 are known to have an evolving cytokine 
release syndrome at the time of ICU admission. The administration of CSL312 will be 
performed under constant medical supervision and cytokine levels will be tested 
before and after dosing. 


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• Bleeding and Thromboembolic Events: By blocking FXIIa with CSL312, there may 
be a potential risk of bleeding or thromboembolic events (TEEs) due to altered 
hemostasis, unstable clot formation, or impaired clot breakdown. In addition, because 
of the pharmacological action of CSL312, a prolongation of aPTT is expected to be 
observed in a concentration-dependent manner. Clinical experience with CSL312 in 
healthy volunteers in the phase 1 study (CSL312_1001) and patients with HAE in the 
ongoing phase 2 study (CSL312_2001) did not show an effect on PT. This is 
consistent with the observation that patients who have congenital deficiency of FXII 
do not exhibit a bleeding phenotype, despite having a prolonged aPTT [Lammle et al, 
1991; Ratnoff and Colopy, 1955]. In addition, nonclinical studies in mice and rabbits 
showed no impairment in hemostasis after inhibition of FXIIa [Larsson et al, 2014]. 
Currently, there is also no human experience with the administration of CSL312 in 
combination with other anticoagulant drugs. Coagulation parameters will be 
monitored throughout the study and subjects will be monitored carefully for any signs 
of bleeding or thrombosis. 
• Immunogenicity (Anti-drug Antibodies): All protein therapeutics are potentially 
immunogenic. Because CSL312 is a protein, it has the potential to cause the 
development of neutralizing and non-neutralizing anti-drug antibodies (ADAs). 
Subjects will be monitored for the development of immunogenicity throughout the 
study. 
Given the potential benefit of CSL312 in patients with COVID-19, the favorable safety data 
from the phase 1 study (CSL312_1001) and the ongoing phase 2 study (CSL312_2001), and 
the implementation of procedures in the current study to closely monitor subject safety, the 
associated benefit-risk assessment is considered acceptable. Additional information on 
CSL312 can be found in the CSL312 Investigator’s Brochure. 


CSL Behring 
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2 Study Objectives and Endpoints 
2.1 Primary Objective and Endpoints 
2.1.1 
Primary Objective 
The primary objective of the study is to assess the treatment benefit of CSL312 after IV 
infusion in patients with COVID-19. 
2.1.2 
Primary Endpoint 
Endpoint 
Summary Measure 
Incidence of tracheal intubation or death 
prior to tracheal intubation 
Proportion of subjects progressing to 
tracheal intubation or dying prior to tracheal 
intubation from randomization to Day 28 
 
2.2 Secondary Objectives and Endpoints 
2.2.1 
Secondary Objectives 
The secondary objectives of the study are: 
1. To further assess the efficacy of CSL312 
2. To assess the safety of CSL312 
3. To assess the pharmacokinetics (PK) of CSL312 
2.2.2 
Secondary Endpoints 
Secondary 
Objectives 
Endpoints 
Summary Measures 
1 
All-cause mortality 
Proportion of deaths from all 
causes occurring from 
randomization to Day 28 
1 
Incidence of tracheal intubation 
Proportion of subjects intubated 
from randomization to Day 28 


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Secondary 
Objectives 
Endpoints 
Summary Measures 
1 
Clinical status as assessed on an 
8-point National Institute of Allergy 
and Infectious Diseases (NIAID) 
ordinal scale (Appendix 3) 
• Number and proportion of 
subjects with ≥ 2-point 
improvement in the ordinal scale 
• Number and proportion of 
subjects within each of the 
categories of the ordinal scale 
1 
Use of continuous positive airway 
pressure (CPAP) or bi-level 
positive airway pressure (BiPAP) 
Proportion of subjects using CPAP 
or BiPAP 
1 
Use of high-flow nasal cannula 
(HFNC) 
Proportion of subjects using HFNC 
1 
Use of extracorporeal membrane 
oxygenation (ECMO) 
Proportion of subjects requiring 
ECMO 
1 
Change in Sequential Organ Failure 
Assessment (SOFA) score 
(Appendix 2) 
• Median of maximum change 
from Baseline in SOFA score  
• Change from Baseline in SOFA 
score and in the individual 
components of SOFA score 
1 
Hospital length of stay (LOS) 
• Median LOS in hospital stay 


C S L  Be hri n g  
St u d y Pr ot oc ol: C S L 3 1 2 _ C O VI D -1 9, Versi o n: A me n d me nt  3 ( 1 6 Se pte m ber  2 0 2 0)  
C S L 3 1 2 ( Gara daci ma b)  
C S L Be hri n g – C o nfi de ntial  
Te m plate: C S -S O P -0 4 -G 0 1 -T 0 1  
Versi o n N u m ber: 1. 0  
Effecti ve Date: Wee k c o m me nci n g 3 0 -A pr -2 0 1 8  
 
Pa ge 3 2  of 8 3  
Sec o n d ar y 
O bjecti ves  
E n d p oi nts  
S u m m ar y Me as ures  
2 
S u bjects e x perie n ci n g t he f oll o wi n g 
safet y e v e nts: 
•  A d verse e ve nts ( A Es)  
•  Seri o us a d verse e ve nts ( S A Es)  
•  A d verse e ve nts of s pecial i nterest 
( A E SIs) 
•  C S L 3 1 2-i n d uce d a nti- C S L 3 1 2 
a nti b o dies 
•  Cli nicall y si g nifica nt 
a b n or malities i n la b orat or y 
assess me nt t hat are re p orte d as 
A Es  
N u m ber a n d pr o p orti o n of s u bjects 
e x perie n ci n g t he s pecifi e d safet y 
e ve nts after treat me nt wit h C S L 3 1 2 
or place b o  
3  
C S L 3 1 2 P K i n plas ma:  
•  Ma xi m u m plas ma c o nce ntrati o n 
( Cma x ) 
•  Ti me t o ma xi m u m plas ma 
c o nce ntr ati o n ( T ma x ) 
•  Ar ea u n d er t he plas ma 
c o nce ntr ati o n -ti me c ur ve fr o m 
ti me zer o t o t he ti me of t he last 
meas ura ble c o nce ntrati o n 
( A U C0- last) 
•  Ter mi nal half -life ( T1/ 2) 
•  Mea n ( ±  S D) a n d g e o metric mea n 
( ge o metric c oefficie nt of 
variati o n perce nta ge [ C V %]) f or 
all P K para meters e xce pt T ma x . 
•  Me dia n ( mi ni m u m, ma xi m u m) 
f or Tma x  
 
2. 3  
 
2. 3. 1  
 
C CI
C CI
C CI


C S L  Be hri n g  
St u d y Pr ot oc ol: C S L 3 1 2 _ C O VI D -1 9, Versi o n: A me n d me nt  3 ( 1 6 Se pte m ber  2 0 2 0)  
C S L 3 1 2 ( Gara daci ma b)  
C S L Be hri n g – C o nfi de ntial  
Te m plate: C S -S O P -0 4 -G 0 1 -T 0 1  
Versi o n N u m ber: 1. 0  
Effecti ve Date: Wee k c o m me nci n g 3 0 -A pr -2 0 1 8  
 
Pa ge 3 3  of 8 3  
2. 3. 2  
 
3  St u d y Desi g n  
T his is a pr os pecti ve, p hase 2, m ultice nter, ra n d o mize d, d o u ble- bli n d, place b o-c o ntr olle d, 
parallel - gr o u p st u d y t o assess t he safet y, P K, a n d efficac y of I V a d mi nistrati o n of C S L 3 1 2, 
a d mi nistere d i n c o m bi nati o n wit h S O C treat me nt, i n patie nts wit h C O VI D - 1 9 (Fi g ure 1 ). 
S O C treat me nt is defi ne d as a n y writte n or esta blis he d treat me nt pr ot o c ol f oll o we d at t he 
st u dy site f or patie nts wit h se vere C O VI D - 1 9 or c o m plicati o ns ass ociate d wit h C O VI D- 1 9, 
i ncl u di n g off-la bel us e of a p pr o ve d dr u gs (a nti b odies a gai nst I L - 6 [a nti-I L-6]/ a nti b o dies 
a gai nst I L-6 r ece pt ors [a nti -I L-6 R]) or a n I P f or w hic h a d mi nistrati o n u n der a n e m er g e nc y 
use a ut h orizati o n has b ee n gra nte d ( e g, re m desi vir). A d mi nistrati o n of I P f or w hic h e x pa n de d 
access f or treat me nt use ( “c o m passi o nate use”) h as bee n a ut h orize d (e g, c o n valesce nt 
plas ma) is als o per mitte d d uri n g st u d y partici pati o n.  
Fi g ure  1 
St u d y  Desi g n  
 
I C F = i nf or me d c o nse nt f or m; P B O = place b o; S O C  = sta n dar d-of -care. 
If Scree ni n g occ urs o n D a y 1, t he assess me nts sc h e d ule d t o occ ur at b ot h Scree ni n g a n d 
bef ore d osi n g o n D a y 1 ma y be perf or me d o nl y o nce (ie, d o n ot nee d t o be re peat e d).  
C CI
C CI


C S L  Be hri n g  
St u d y Pr ot oc ol: C S L 3 1 2 _ C O VI D -1 9, Versi o n: A me n d me nt  3 ( 1 6 Se pte m ber  2 0 2 0)  
C S L 3 1 2 ( Gara daci ma b)  
C S L Be hri n g – C o nfi de ntial  
Te m plate: C S -S O P -0 4 -G 0 1 -T 0 1  
Versi o n N u m ber: 1. 0  
Effecti ve Date: Wee k c o m me nci n g 3 0 -A pr -2 0 1 8  
 
Pa ge 3 4  of 8 3  
St u d y Ty pe  
Pr os pecti ve/I nter v e nti o nal 
St u d y Peri o ds  
T he st u d y will c o nsist of a Scree ni n g Peri o d of u p t o 
2 da ys a n d a 2 8- d a y Treat me nt Peri o d  
Bli n di n g Ty pe  
T he st u d y will be c o n d ucte d i n a n d o u ble- bli n d ma n ner 
St u d y C o nfi g ur ati o n  
Parallel gr o u p  
Met h o d of Assi g n me nt t o 
Tre at me nt  
Eli gi ble s u bjects will be ra n d o mize d ( 1: 1) o n D a y  1 of t he 
Treat me nt Peri o d t o recei ve treat me nt wit h eit her 
C S L 3 1 2 + S O C or place b o + S O C  
S O C  = sta n dar d-of -care treat me nt. 
A g gre gate d ata fr o m gr o u ps of s u bjects will be re vie we d b y a n I n de pe n d e nt Data M o nit ori n g 
C o m mittee (I D M C), b ot h earl y a n d at pre d eter mi ne d i nter vals d uri n g t he c o n d uct of t he 
st u d y. T he first 2 0 s u bjects will be e nr olle d, ra n d o ml y assi g ne d t o treat me nt, a n d recei ve 
i n vesti gati o nal pr o d uct (I P). T he 1st I D M C meeti n g will occ ur a p pr o xi mat el y 1 0 da ys after 
all 2 0 s u bjects ha ve c o m plete d Da y 3. T h e data f or t hese s u bjects will be re vie we d b y a n 
I D M C t o deter mi ne w het her t her e are a n y safet y c o ncer ns bef ore e nr olli n g t he ne xt 
2 0 s u bjects. T he n t he 2 n d I D M C meeti n g will occ ur a p pr o xi matel y 7 da ys after a t otal of 
4 0 s u bjects ha ve c o m plet e d Da y 3. T h e 3r d meeti n g will occ ur a p pr o xi mat el y 7 da ys after a 
t otal of 6 0 s u bjects ha ve c o m plete d Da y 3 a n d t he 4t h meeti n g will occ ur after a  t otal of 
8 0 s u bjects ha ve c o m plet e d Da y 3. A d diti o nal details o n t he I D M C are pr o vi de d i n Secti o n  8 . 
D ose R ati o n ale 
T he d ose of C S L 3 1 2 t o be use d i n t his st u d y was selecte d b ase d o n t he o bser ve d safet y, P K, 
 data o btai ne d fr o m t he p hase 1 si n gle-as ce n di n g d ose st u d y ( C S L 3 1 2 _ 1 0 0 1) after 
a d mi nistrati o n of si n gle I V a n d s u bc uta n e o us d oses of C S L 3 1 2 ra n gi n g fr o m 0. 1 t o 1 0 m g/ k g 
( 7. 7 5 t o 1 0 1 5 m g) i n healt h y v ol u nteers. A p o p ulati o n P K/ 
 m o del was de vel o pe d t o 
descri be t he ti me c o urse of i n hi biti o n of F XIIa- me diate d acti vit y base d o n t he o bser ve d d ata 
fr o m t he first i n h u ma n st u d y after si n gle I V a n d S C d oses of C S L 3 1 2. Base d o n t his P K/ 
 
m o del, 7 0 0 m g (e q ui vale nt t o 1 0 m g/ k g f or a s u bject wit h a b o d y wei g ht of 7 0 k g) of 
C S L 3 1 2 is pre dicte d t o res ult i n ≥ 9 0 % i n hi biti o n of F XIIa- m e diate d kalli krei n acti vit y o ver 
2 8 da ys. T he si m ulate d F XIIa- me diate d kalli krei n acti vit y pr ofiles at differe nt d oses 
(i ncl u di n g 1 0 m g/ k g) is prese nte d i n Fi g ure 2 . 
C CI
C C
I
C C
I


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Figure 2 
Predicted (Median + 95% PI) FXII-mediated Kallikrein Activity 
After Single Intravenous Doses of CSL312 (Including 10 mg/kg) 
 
FXIIa = activated factor XII; PI = prediction interval. 
Solid line = median; shaded region = 95% PI. 
3.1 Planned Number of Subjects 
This study will enroll a total of approximately 124 subjects; 62 subjects in the 
CSL312 + SOC group and 62 subjects in the placebo + SOC group. 
After the first 62 subjects have completed the primary endpoint assessment, an interim 
analysis will be performed for futility monitoring and sample size re-estimation, which may 
result in an increase in the target sample size of up to 248 subjects. Additional details on the 
interim analysis are provided in Section 11.8. 
3.2 Planned Study Duration 
The duration of an individual subject’s study participation is expected to be up to 30 days. 
This estimate is based on: 
• A Screening Period of up to 2 days 
• A Treatment Period of up to 28 days 
The overall study duration (ie, first subject’s Screening Visit to last subject’s last study visit) 
will be approximately 6 months. 


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3.3 Planned Countries and Estimated Number of Sites 
This study will be conducted at approximately 25 investigational sites; at least 15 sites in the 
United States of America (USA) and up to 10 sites in Brazil. 
4 Study Interventions 
4.1 Description of Investigational Product 
4.1.1 
CSL312 
CSL312 will be supplied (2 mL per vial) as a sterile, preservative-free solution for injection, 
at pH 6.1 (Table 1). CSL312 is formulated in buffer containing 20 MM L-histidine, 150 nM 
arginine monohydrochloride, 140 nM L-proline, 0.02% w/v polysorbate 80, and hydrochloric 
acid. Each vial contains CSL312 at a concentration of 100 mg per 1 mL. 


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Table 1 
Description of CSL312 
Substance name 
CSL312 
Active substance 
Fully human IgG4/lambda recombinant monoclonal 
antibody which specifically binds to the catalytic 
domain of FXIIa 
INN 
Garadacimab 
Dosage form 
Sterile solution for injection containing 100 mg/mL of 
CSL312 in 2-ml vials 
Dose 
700 mg 
Dosing regimen 
Single dose of CSL312 will be administered once 
during the Treatment Period as a slow IV injection, (ie, 
push of about 3 minutes 
Infusion volume 
7 mL (100 mg/mL) 
Route of administration 
Intravenous infusion 
Anatomic location of 
administration 
Peripheral vein 
FXIIa = activated coagulation factor XII; IgG = immunoglobulin G; INN = international nonproprietary name; 
IV = intravenous. 
CSL312 will be manufactured in accordance with International Council for Harmonisation of 
Technical Requirements for Pharmaceuticals for Human Use (ICH) Good Manufacturing 
Practice (GMP) guidelines and local regulatory requirements. 
Additional details related to the dosing and administration of the IP (ie, CSL312 or placebo), 
as well as the procedure used to prepare the study treatment before administration will be 
described in the IMP manual. 
4.1.2 
Placebo (CSL312 Diluent) 
The placebo will be supplied (10 mL per vial) as a sterile, preservative-free solution for 
injection (Table 2). The placebo is the same as the CSL312 formulation buffer, but does not 
contain the active substance (ie, FXIIa antagonist monoclonal antibody). 


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Table 2 
Description of Placebo 
Substance name 
Placebo 
Active substance 
Not applicable 
Trade name 
Not applicable 
Dosage form 
Sterile solution for injection in10-mL vial 
Route of administration 
Intravenous infusion 
 
The placebo will be manufactured in accordance with ICH GMP guidelines and local 
regulatory requirements. 
Additional details related to the dosing and administration of the IP (ie, CSL312 or placebo), 
as well as the procedure used to prepare the study treatment before administration will be 
described in the IMP manual. 
4.1.3 
Accountability and Destruction 
All supplies of IP must be accounted for throughout the study. Records for the delivery of IP 
to the study site, inventory at the study site, the use by each subject, and the destruction or 
return of IP to CSL Behring (CSL; or delegate) must be maintained by the investigator (or 
delegate) using the interactive response technology (IRT) system. The investigator (or 
delegate) must provide reasons for any discrepancies in drug accountability using the IRT 
system. 
Further details regarding accountability and destruction of IP are provided in the IMP 
manual. 
4.1.4 
Dose Modification 
No modification of dose is planned for this study because subjects are only expected to 
receive 1 dose of IP (CSL312 + SOC or placebo + SOC) on Day 1 of the Treatment Period. 


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5 Allocation, Dosing, and Administration 
5.1 Allocation to Treatment 
5.1.1 
Subject Assignment 
After informed consent has been obtained, subjects will be assigned a study-level unique 
subject identification number, via an IRT system, which will be used to identify the subject 
for the duration of the study. Subject identification numbers will not be reassigned or reused. 
5.1.2 
Randomization Procedures 
Randomization will be conducted using an IRT. The investigator will be supplied with a user 
guide for the IRT. Subjects will be randomly assigned to treatment with either 
CSL312 + SOC or placebo + SOC using a 1:1 randomization ratio and stratified by country 
(USA or Brazil). 
A centralized randomization schedule will be used. The randomization list will be generated 
according to the approved randomization specifications. The IRT service provider will keep 
the randomization code on file. 
5.1.3 
Blinding Procedures 
5.1.3.1 
Blinding Method 
Investigational site staff, including the investigators, will be blinded to treatment allocation. 
Subjects and CSL staff (or delegates) participating in the conduct of the study will also be 
blinded to treatment allocation (double-blind). 
Unblinded study site personnel delegated by the investigator will prepare the IP, as assigned 
by the IRT. Unblinded study site personnel are not to administer the IP and will not be 
involved in conducting or recording any study assessment procedures (ie, in the care of the 
subject). Study site staff who will be conducting safety assessments, including the 
investigator, and subjects will be blinded to treatment allocation, the contents of the syringe 
and to kit number assignment (double-blind). Sponsor staff will also be blinded to treatment 
allocation, the contents of the syringe and kit number assignment, except as stated below. 


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A study-independent bioanalyst, statistician, and programming support responsible for the 
sample analysis and IDMC operations will be unblinded as well as a representative from 
Clinical Trial Supply and from IRT. Additionally, unblinded monitors may be assigned to 
sites. Designated unblinded personnel agree not to disclose the contents of the randomization 
list, the contents of the kit list or any subject kit number assignment. The safety-related data 
provided to the IDMC during the course of the study will be unblinded. All individuals will 
be placed under strict confidentiality to protect the integrity of the study. 
All blood samples analyzed by the central laboratory will remain blinded until database lock. 
Blood samples analyzed by the local laboratory will be interpreted by personnel appointed by 
the investigator and defined in the site-specific blinding plan. 
Study unblinding will take place following the locking of the database except in situations as 
outlined in Sections 5.1.3.2, 5.1.3.3, and 5.1.3.4. 
Adequate procedures are in place to ensure the integrity of the blinded data within CSL. 
Study data will be provided to the IDMC as unblinded data, as requested. 
5.1.3.2 
Breaking the Blind for an Emergency 
The randomization code for individual subjects may be unblinded to a site during the study in 
emergency situations for reasons of subject safety, if knowing treatment assignment will 
change subject management. In case of an emergency situation for the reason of subject 
safety, the investigator should use the IRT to identify the treatment allocation for a subject. 
Whenever possible, the investigator should consult with CSL before unblinding the 
randomization code. The reason for unblinding the randomization code must be fully 
recorded in the subject’s source documents, and the investigator must follow the defined 
procedures provided in the study reference manuals. The subject’s treatment allocation 
should not be recorded in the subject’s source document. 
5.1.3.3 
Planned Unblinding Procedures 
Periodic unblinding safety reviews are planned for this study for the purposes of safety 
monitoring activities by the IDMC. With authorization by CSL, the IRT will provide the 
unblinded statistician performing analysis for the IDMC or the unblinded statistician with the 
randomization code or an IRT user account access to obtain the required information directly 
from the IRT. 


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An unblinded interim futility and sample size re-estimation analysis will also be performed 
by an IDMC. With authorization by CSL, the IRT will provide the unblinded statistician 
performing the analysis for the IDMC with the randomization code or an IRT user account 
access to obtain the required information directly from the IRT. 
At the end of the study, CSL will authorize that the study be unblinded after database lock. 
The randomization codes will be provided to the study statistician (or delegate). 
5.1.3.4 
Ad-hoc Safety Unblinding 
CSL Global Clinical Safety Pharmacovigilance personnel may, on an ad-hoc basis, unblind 
the randomization code directly in the IRT at any time during the study because of a safety 
concern. The purpose of the unblinded data review is to determine whether there is a risk to 
subject safety that would require further action either for the individual management of a 
study subject or for the ongoing conduct of the study. The need to unblind a subject or group 
of subjects may not necessarily arise because of an SAE. The need to unblind on an ad-hoc 
basis will be determined by CSL’s Global Clinical Safety and Pharmacovigilance senior 
leadership. 
6 Study Population and Main Criteria for Eligibility 
6.1 Eligibility Criteria 
The study population will be selected on the basis of the inclusion and exclusion criteria 
described in the sections below. Subject eligibility should be reviewed and documented by an 
appropriately medically qualified member of the investigator’s study team before subjects are 
included in the study. Eligibility may be assessed at the time of hospital admission provided 
that the subject is randomized within 24 hours. 
6.2 Inclusion Criteria 
To be enrolled and randomized into the study, subjects must meet all of the following 
inclusion criteria: 
1. Capable of providing written informed consent. An individual legally permitted to 
make medical decisions on the subject’s behalf can provide written informed consent 
2. Willing and able to adhere to all protocol requirements 
3. Age ≥ 18 years at the time that informed consent is obtained 


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4. Positive for SARS-CoV-2 infection as determined using a molecular diagnostic test 
(reverse transcription polymerase chain reaction [RT-PCR] or equivalent) approved 
by regulatory authorities (including Food and Drug Administration [FDA] or 
Brazilian Health Regulatory Agency [ANVISA]) or allowed under an emergency use 
authorization within 14 days before Screening. If a false negative result is suspected, 
the SARS-CoV-2 test may be repeated within the Screening Period. 
5. Chest computed tomography (CT) scan or X-ray results confirming interstitial 
pneumonia 
6. Severe COVID-19 disease as evidence by ≥ 1 of the following criteria at Screening 
including within 24 hours before Screening: 
• Respiratory frequency > 30 breaths per minute 
• Saturation of peripheral (capillary) oxygen (SpO2) ≤ 93% on room air 
• Ratio of partial pressure of arterial oxygen to fraction of inspired oxygen 
(PaO2/FiO2 ratio) < 300 
• Ratio of arterial oxygen saturation to fraction of inspired oxygen (SaO2/FiO2 
ratio) < 218 (if PaO2/FiO2 ratio is not available) 
• Radiographic lung infiltrates > 50% 
6.3 Exclusion Criteria 
Subjects must not be enrolled into the study or randomly assigned to treatment if they meet 
any of the following exclusion criteria: 
1. Currently enrolled, planning to enroll, or participated, within the last 30 days, in a 
clinical study requiring administration of an IP, including expanded access or 
compassionate use with the only exception being the administration of convalescent 
plasma. Administration of IP is permitted only if an emergency use authorization has 
been granted (eg, remdesivir). Additionally, off-label use of approved drugs (eg, 
anti-IL-6/anti-IL-6R) is also permitted. 
2. Pregnant or breastfeeding (female subjects) 
3. Intubated and require mechanical ventilation (including ECMO) at the time of 
randomization 


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4. In the opinion of the investigator, the subject is expected to be intubated in the first 
24 hours after IP administration 
5. Active Do-Not-Intubate (DNI) or Do-Not-Resuscitate (DNR) order 
6. In the opinion of the investigator, not expected to survive for > 48 hours after 
admission 
7. Presence of any of the following comorbid conditions prior to randomization and 
prior to SARS-CoV-2 infection: 
• Severe heart failure (New York Heart Association Class IV) 
• End-stage renal disease (Stage ≥ 4) or need for renal replacement therapy 
• Biopsy-confirmed cirrhosis, portal hypertension, or hepatic encephalopathy 
• Malignancy (Stage IV) 
• Chronic lung disease requiring the use of oxygen at home 
• Active tuberculosis disease 
8. Active bleeding or a current clinically significant coagulopathy (eg, international 
normalized ratio [INR] > 1.5) or clinically significant risk for bleeding (eg, recent 
intracranial hemorrhage or bleeding peptic ulcer within the last 4 weeks) 
9. History of venous thrombosis, myocardial infarction, or cerebrovascular event within 
3 months, or a prothrombotic disorder (eg, antithrombin III, protein C, or protein S 
deficiency) 
10. Known or suspected Grade 3 or 4 infusion-related reaction or hypersensitivity (per 
Common Terminology Criteria for Adverse Events [CTCAE]) to monoclonal 
antibody therapy, or hypersensitivity to the IP or any excipients of the IP [National 
Cancer Institute, 2009] 
11. Currently receiving a therapy not permitted during the study (see Section 9.1) 
12. Female subject of childbearing potential or fertile male subject either not using or not 
willing to use an acceptable method of contraception to avoid pregnancy during the 
study and for 90 days after receipt of the last dose of IP. Note: Acceptable methods of 
contraception are defined in Section 9.3 


C S L  Be hri n g  
St u d y Pr ot oc ol: C S L 3 1 2 _ C O VI D -1 9, Versi o n: A me n d me nt  3 ( 1 6 Se pte m ber  2 0 2 0)  
C S L 3 1 2 ( Gara daci ma b)  
C S L Be hri n g – C o nfi de ntial  
Te m plate: C S -S O P -0 4 -G 0 1 -T 0 1  
Versi o n N u m ber: 1. 0  
Effecti ve Date: Wee k c o m me nci n g 3 0 -A pr -2 0 1 8  
 
Pa ge 4 4  of 8 3  
1 3.  A n y cli nical or la b or at or y a b n or malit y or ot her u n derl yi n g c o n diti o ns (e g, 
ps yc h ol o gical dis or ders, s u bsta nce a b us e) t hat w o ul d re n der t he s u bject u ns uita ble f or 
partici pati o n i n t he st u d y, i n t he o pi ni o n of t he i n vesti gat or 
6. 4  Disc o nti n u ati o n of St u d y Tre at me nt a n d S u bject Wit h dr a w al  
6. 4. 1  E arl y Disc h ar ge fr o m t he H os pit al  
All s u bjects w h o mai ntai n  c o nse nt will re mai n i n t he st u d y t hr o u g h Da y 2 8 f or all i m p orta nt 
safet y a n d effi cac y assess me nts. All Da y 2 8 assess me nts will be c o n d ucte d o n t he da y of 
disc har ge fr o m t he h os pital. F or su bjects w h o are disc har ge d b ef ore Da y  2 8 , t he i n vesti gat or 
( or dele g ate) will c o ntact t he m via wee kl y tele p h o ne calls. If t he t ele p h o ne call is perf or m e d 
b y n o n- me dical st u d y pers o n nel, t he i nf or mati o n o n cli nical stat us, A Es, a n d  c ha n ges i n 
co nc o mita nt me dicati o ns  nee d t o be re vie we d b y t he i n vesti gat or or a me di call y trai ne d 
dele gate . T h ese s u bjects will be sc he d ule d f or a n i n- pers o n visit o n Da y 2 8 t o perf or m t he 
E n d of St u d y ( E O S) Visit assess me nts i ncl u di n g 
 a n d ot her la b orat or y 
para meters.  
E ver y eff ort will be ma d e t o e nc o ur a ge b ot h s u bject a n d i n vesti gat ors t o c o nti n ue st u d y 
assess me nts via tele p h o n e f oll o wi n g h os pital disc har ge, u nless t he s u bj ect wit h dra ws 
c o nse nt. 
6. 4. 2  Disc o nti n u ati o n of St u d y Tre at me nt  
S u bjects ma y disc o nti n ue st u d y treat me nt wit h t he I P at a n y ti me at t heir o w n r e q uest, or at 
t he discreti o n of t he i n vesti gat or or C S L f or safet y, be ha vi oral, or a d mi nistrati ve reas o ns. 
S u bjects w h o disc o nti n ue treat me nt wit h t he I P b ut re mai n i n t he st u d y, will be as ke d t o 
c o m plete a d diti o nal f oll o w -u p assess me nts or all o w data c ollecti o n as detaile d i n t he 
Sc he d ule of Assess me nts . If a s u bject disc o nti n ues I P a n d decli nes f urt her st u d y 
pr oce d ur es/ visit partici pati o n, t he s u bject will be wit h dra w n fr o m t he st u d y, a n d atte m pts will 
be ma de t o c o m plete a n d d oc u me nt t he E O S Visit assess me nts.  
C CI


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6.4.3 
Subject Withdrawal 
Subjects may withdraw from the study at any time either at their own request or at the 
discretion of the investigator or CSL for safety, behavioral, or administrative reasons 
(eg, because of an AE, protocol deviation, subject noncompliance, or study termination). The 
investigator should record in the electronic case report form (eCRF) and in the subject's 
medical records the reason for and date of subject withdrawal. 
In accordance with the ICH principles of Good Clinical Practice (GCP), the investigator 
always has the option to advise a subject to withdraw from the study if the subject's safety or 
well-being is compromised by his or her further participation in the study. Concern for the 
interests of the subject must always prevail over the interests of the study. 
6.4.4 
Procedures for Handling Withdrawals 
If a subject is withdrawn from the study, attempts will be made to complete and document the 
Day 28 (EOS) Visit assessments. If the subject is withdrawn from the study after receiving IP, 
every effort will be made to ensure that the relevant safety assessments are completed. The 
subject may also be asked by the investigator to complete other study assessments. 
If the subject withdraws from the study, and also withdraws consent for disclosure of future 
information, CSL may retain and continue to use any data collected before such withdrawal 
of consent. 
6.4.5 
Replacement Policy 
Subjects withdrawn from the study will not be replaced. 
7 Study Assessments 
7.1 Unscheduled Study Assessments and Additional Medical Data 
Unscheduled study assessments are possible and can be documented in the unscheduled visit 
in the eCRF. 
Additional data given to CSL may include any medical information from hospital records 
required by the study but not outlined in the study protocol. This information may be required 
to help scientific understanding of study data and might be collected even the completion of 
the study. 


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7.2 Efficacy Assessments 
Outcome assessments will include the following: 
• Use of supplemental oxygen 
• Use of CPAP or BiPAP 
• Use of HFNC 
• Use of ECMO 
• Intubation 
• Extubation 
• Clinical status on standardized scales (SOFA score and NIAID 8-point ordinal scale 
score) 
• ICU admission and discharge 
• Hospital discharge or death 
7.3 Demographics and Safety Assessments 
The clinical procedures to be conducted during this study related to the evaluation of safety 
are provided in Table 3. Some laboratory assessments may also be used for Screening. 
Clinical laboratory assessments are to be performed at time points as detailed in the Schedule 
of Assessments. 
Table 3 
Demographics and Safety Assessments 
Assessment 
Description 
Demographics 
• Year of birth/age 
• Sex 
• Race and ethnicity 
Medical History 
• Relevant medical history 
• Contraception method (if relevant) 
• Previous and concomitant medications and therapies 
• Smoking history 
Pregnancy Test 
(local laboratory) 
• Urine test for β-hCG will be performed for all female subjects of childbearing 
potential to rule out pregnancy at Screening and the end of the Treatment Period. A 
serum pregnancy test will be performed by the site if urine result is inconclusive. 
Physical 
Examination 
• As per the study site’s standard procedure 
Chest CT scan or 
X-ray 
• Chest CT scan or X-ray results must show signs of interstitial pneumonia to confirm 
eligibility criteria at Screening. 


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Assessment 
Description 
Adverse Events 
• Evaluation of all AEs (eg, causality/relatedness, severity, seriousness) 
• AESIs: 
o Abnormal bleeding events 
o TEEs 
o Severe hypersensitivity including anaphylaxis 
Vital Signs 
• Blood pressure (systolic and 
diastolic) 
• Body temperature 
• Heart rate 
• Height and weight 
Respiratory 
Parameters 
• Respiratory rate 
• SpO2 
• FiO2 
• PaO2 
Urinalysis (dipstick) 
(test kits provided 
for local laboratory) 
Mandatory review of all parameters indicated by * is required before 
randomization. 
• Specific gravity 
• Ketones 
• pH 
• Bilirubin 
• Leukocyte esterase* 
• Urobilinogen 
• Occult blood* 
• Protein* 
• Nitrite 
• Glucose* 
Hematology 
(local laboratory) 
Mandatory review of all parameters indicated by * is required before 
randomization. 
• Hemoglobin* 
• Hematocrit* 
• Erythrocytes (RBC count)* 
• RBC indices: mean corpuscular volume; mean corpuscular hemoglobin; 
mean corpuscular hemoglobin concentration; erythrocyte distribution width 
• Platelets* 
• Leukocytes (WBC count)* 
• WBC differential (percentage or absolute): neutrophils; neutrophil band forms; 
lymphocytes; monocytes; eosinophils; basophils 
• Reticulocytes 


C S L  Be hri n g  
St u d y Pr ot oc ol: C S L 3 1 2 _ C O VI D -1 9, Versi o n: A me n d me nt  3 ( 1 6 Se pte m ber  2 0 2 0)  
C S L 3 1 2 ( Gara daci ma b)  
C S L Be hri n g – C o nfi de ntial  
Te m plate: C S -S O P -0 4 -G 0 1 -T 0 1  
Versi o n N u m ber: 1. 0  
Effecti ve Date: Wee k c o m me nci n g 3 0 -A pr -2 0 1 8  
 
Pa ge 4 8  of 8 3  
Assess me nt  
Descri pti o n  
Bi oc he mistr y  
(l ocal la b orat or y) 
M a n d at or y re vie w of all p ar a m eters i n dic ate d b y * is re q uire d bef ore 
r a n d o miz ati o n . 
•  S o di u m *  
•  G G T *  
•  P otassi u m *  
•  L D H *  
•  C hl ori de *  
•  T otal bilir u bi n *  
•  Bicar b o nate  
•  Direct bilir u bi n *  
•  Car b o n di o xi de  
•  Ma g nesi u m *  
•  Calci u m  
•  P h os p hate  
•  Bl o o d urea nitr o ge n * 
•  C R P * 
•  Urea *  
•  T otal c h olester ol  
•  Creati ni ne *  
•  Tri gl yceri des  
•  Gl uc ose *  
•  H D L c h olester ol  
•  T otal pr otei n  
•  L D L c h olester ol  
•  Al b u mi n  
•  Uric aci d  
•  Al kali ne p h os p hatase *  
•  C K, C P K *  
•  A L T *  
•  Ferriti n  
•  A S T *  
 
C oa g ulati o n  
(ce ntral la b orat or y) 
•  
 
•  
  
•  
 
•  
 
C oa g ulati o n  
(l ocal la b orat or y) 
•  
 
•  
 
P K assess me nts  
(ce ntral la b orat or y ) 
•  C ma x  
•  A U C 0 -last 
•  T ma x  
•  T 1/ 2 
C yt o ki ne Pr ofile  
(ce ntral la b orat or y) 
•  I nfla m mat or y c yt o ki ne pa nel 
 
 
(ce ntral la b orat or y) 
•  
 
 
; AE SI  = a d verse e ve nts of s pecial i nterest; A L T  = ala ni ne a mi n otra nsferase; 
; A S T = as partate a mi n otra nsferase; A U C 0-last = area u n der t he 
plas ma c o nce ntrati o n -ti me c ur ve fr o m ti me zer o t o t he ti me of t he last meas urea ble c o nce ntrati o n; 
β- h C g  = beta -h u ma n c h ori o nic g o na d otr o pi n; B U N  = bl o o d urea nitr o ge n; C K/ C P K  = creati ne ki nase; 
C ma x  = ma xi m u m plas ma c o nce ntrati o n; C R P  = C-reacti ve pr otei n; Fi O2 = fracti o n of ins pire d o x y ge n; 
G G T  = ga m ma -gl uta m yl tra nsferase; H D L  = hi g h -de nsit y li p o pr otei n; I N R  = i nter nati o nal n or malize d rati o; 
L D H  = lactate de h y dr o ge nase; L D L = l o w-de nsit y li p o pr otei n; Pa O 2 = partial press ure of arterial o x y ge n; 
P T  = pr ot hr o m bi n ti me; R B C  = re d bl o o d cell; S p O 2 = sat urati o n of peri p heral (ca pillar y) o x y ge n; 
T 1/ 2 = ter mi nal half-life; T E E = t hr o m b oe m b olic e ve nt; W B C = w hite bl o o d cell.  
C CI
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C S L  Be hri n g  
St u d y Pr ot oc ol: C S L 3 1 2 _ C O VI D -1 9, Versi o n: A me n d me nt  3 ( 1 6 Se pte m ber  2 0 2 0)  
C S L 3 1 2 ( Gara daci ma b)  
C S L Be hri n g – C o nfi de ntial  
Te m plate: C S -S O P -0 4 -G 0 1 -T 0 1  
Versi o n N u m ber: 1. 0  
Effecti ve Date: Wee k c o m me nci n g 3 0 -A pr -2 0 1 8  
 
Pa ge 4 9  of 8 3  
7. 4  P h ar m ac o ki netic Assess me nts  
Bl o o d sa m ples will be c ollecte d bef ore d osi n g a n d o n Da y 1 at 3 0 mi n utes a n d 6 h o urs aft er 
t he e n d of t he i nf usi o n of I P, Da y 2, Da y 7, D a y 1 4, Da y 2 1, a n d D a y 2 8 f or assess me nt of 
C S L 3 1 2 P K i n plas ma. P K assess me nts will i ncl u de C ma x , Tma x , A U C 0- last, a n d T1/ 2. 
Details relate d t o t he c ollecti o n, pre parati o n, a n d tra nsfer of P K sa m ples will be pr o vi de d i n 
t he la b orat or y ma n u al. 
7. 5  
 
 
 
 
 
 
 
 
 
 
8  St u d y O versi g ht  
8. 1  O versi g ht a n d M o n it ori n g C o m mittees 
A n I D M C will be esta blis he d t o m o nit or t he critical safet y dat a ge nerate d d uri n g t he st u d y. 
T he I D M C will c o nsist of i n de pe n de nt cli nical s pecialists i n i nter nal me dici ne, p ul m o n ol o g y, 
i nte nsi ve car e, a n d statistics, w h o als o ha ve e x perie nce i n cli nical st u dies. T he I D M C will 
re vie w acc u m ulati n g dat a fr o m t he o n g oi n g st u d y i n a n u n bli n de d ma n ner. Base d o n t hese 
re vie ws, t he I D M C will a d vise o n t he f urt her c o n d uct of t he st u d y. C S L will c o nti n ue t he 
st u d y u nless a safet y iss u e is c o nfir me d t hat w arra nts st u d y ter mi nati o n. 
C CI
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Review schedule for IDMC: 
• 1st meeting after the initial 20 subjects (10 CSL312, 10 placebo) 
• 2nd meeting after 40 subjects (20 CSL312, 20 placebo) 
• 3rd meeting after 60 subjects (30 CSL312, 30 placebo) 
• 4th meeting after 80 subjects (40 CSL312, 40 placebo) 
The IDMC will also review the accumulating data in an unblinded manner to assess futility 
and the need for sample size increase based on an interim analysis. This committee will also 
review the data to make any necessary decisions on future drug supply and other investments. 
Details on the composition, responsibilities, activities, timing of meetings, data required for 
each review, analyses, and the review and decision making processes for the IDMC will be 
described in detail in the IDMC charter. 
8.2 Study Halting Criteria 
The study will be halted (no recruitment or further dosing), pending review, if any of the 
following criteria are met: 
• One subject develops an SAE that results in death and is considered by the 
investigator and/or CSL to be related to the administration of CSL312 
• One subject develops any other serious event that is deemed to pose an unacceptable 
risk to other subjects in the study, and this event is considered by the investigator 
and/or CSL to be related to the administration of CSL312 
• An overall pattern of symptomatic, clinical, or laboratory events that the medical 
monitor, CSL or IDMC consider associated with CSL312 and that may appear minor 
in terms of individual events but that collectively may represent a serious potential 
concern for safety 
• Three subjects with severe toxicity for the same parameter associated with study 
product 


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If any study halting rules are triggered, it will result in a TEMPORARY halt: 
• CSL’s Safety Management Team (SMT) will make a recommendation 
• The SMT will conduct a safety assessment of the relevant safety observation to 
establish whether the study should be resumed or whether the temporary halt should 
continue and will further escalate to the Global Safety Committee 
• If additional risk-benefit measures are warranted and modifications to the protocol are 
required to resume the study (including the addition of new risk mitigation measures), 
then a substantial protocol amendment will be submitted 
• Regulatory authorities and Institutional Review Boards (IRBs)/Independent Ethics 
Committees (IECs) will be informed of a study halt and then its resumption 
If safety concerns warrant a PERMANENT stop to the study: 
• The SMT will conduct a risk assessment 
• The SMT and Global Safety Committee are involved in recommending a stop, if it is 
has concluded that continued dosing poses an unacceptable risk to subjects and no 
further risk mitigation steps can be applied 
• CSL’s Global Benefit Risk Committee will ratify the decision to stop the study 
• In case decision to stop study is not ratified, GBRC could recommend study 
continuation with implementation of additional risk-benefit measures (including 
addition of new risk mitigation measures); substantial protocol amendment will be 
submitted if modifications are required to continue the study 
Regulatory authorities and IRBs/IECs will be notified in the case of a study stop. 
8.3 Treatment Compliance 
All doses of IP will be administered by IV infusion at the study site. Treatment compliance 
will be assessed using the administration details entered into the eCRF. A subject will be 
regarded as compliant with regard to IP administration if the subject received between ≥ 80% 
and ≤ 120% of the planned dose of IP. 


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9 Prohibited and Permitted Therapies 
9.1 Prohibited Therapies 
Because of the severity of the COVID-19 pneumonia pandemic, it is difficult to define in 
advance any contraindications to concomitant treatments (including antiviral drugs). Any 
medication that the subject is receiving at the time of study enrollment or that the subject 
receives during study participation will be recorded in the subject’s eCRF along with the 
dates of administration (start date and end date), dosing information (dose and frequency), 
and reason for use. 
The use of any IP or investigational device according to a clinical study protocol for another 
clinical study is PROHIBITED during this study and within ≤ 30 days before Screening or 
within 5 half-lives of the final dose of IP administered during the previous interventional 
study, whichever is longer. However, use of an IP with emergency use authorization is 
permitted (see Section 9.2). 
Use of the following mediations is also PROHIBITED during this study: 
• any therapeutic antibody other than CSL312 
• anticoagulant therapy except low-molecular-weight heparin (LMWH) 
9.2 Permitted Medications/Therapies 
The following medications and therapies are PERMITTED at any time during the study: 
• Prescribed medications required for the management of acute or chronic medical 
conditions including COVID-19, except those described in Section 9.1. 
• Treatment considered SOC for COVID-19, defined as any written or established 
treatment protocol followed at the study site for the treatment of patients with severe 
COVID-19 or complications associated with COVID-19, including off-label use of 
approved drugs (eg, anti-IL-6/anti-IL-6R), an IP for which administration under an 
emergency use authorization has been granted (eg, remdesivir). Administration of IP 
for which expanded access for treatment use (“compassionate use”) has been 
authorized (eg, convalescent plasma) is also permitted during study participation. 
• Therapies to treat any AEs that the subject experiences during the study, including 
non-prophylactic aspirin (eg, to treat a headache). 
• LMWH 


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9.3 Lifestyle Restrictions 
Female subjects of childbearing potential and fertile male subjects must use a medically 
reliable form of contraception until 90 days after the last administration of study drug. 
Childbearing potential is assumed in all female subjects except: 
• Female subjects ages > 45 years with amenorrhea for ≥ 12 months without an 
alternative medical cause. 
• Female subjects who are surgically sterile for ≥ 3 months before providing informed 
consent. 
Acceptable methods of contraception are: 
• Abstinence, where abstinence is the preferred and usual lifestyle of the subject, 
including refraining from heterosexual intercourse during the entire period of risk 
associated with the IP. Periodic abstinence (calendar, symptothermal, and 
post-ovulation methods), withdrawal (coitus interruptus), spermicides only, and 
lactational amenorrhea method are not acceptable definitions of abstinence. 
• Hormonal methods associated with inhibition of ovulation, if used at a stable dose 
during the 3 months before Screening with no plans to change dose during the study. 
Acceptable hormonal methods include: oral contraceptives, contraceptive medication 
patch, contraceptive medication injection, estrogen/progestin vaginal ring, or 
contraceptive medication implant. 
• Use of intrauterine device (placed > 3 months before providing informed consent). 
• Surgical sterilization (> 3 months before providing informed consent) of subject or 
subject's partner. 
9.4 Overdose 
Overdose is defined as the infusion or ingestion of any dose (single or cumulative) of a 
product that is considered excessive. In this study, excessive is defined as any dose greater 
than the planned dose. The effects of any potential overdose with CSL312 have not been 
studied. In case of overdose, the subject should be closely monitored, and supportive 
treatment should be administered, as needed. 


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10 Adverse Events 
10.1 Definitions 
10.1.1 Adverse Event 
As per ICH E2A (Clinical Safety Data Management: Definitions and Standards for Expedited 
Reporting), an AE is any untoward medical occurrence in a patient or clinical investigation 
subject administered a pharmaceutical product and which does not necessarily have a causal 
relationship with this treatment. An AE can, therefore, be any unfavorable and unintended 
sign (including an abnormal, clinically significant laboratory finding), symptom, or disease 
temporally associated with the use of a medicinal (investigational) product, whether or not 
considered related to the medicinal (investigational) product. 
The period of observation for AEs extends from the time that informed consent is obtained 
until the EOS Visit (see Section 10.4 for further details). 
Adverse events may include: 
• Exacerbation (ie, an increase in the frequency or severity) of a pre-existing condition. 
Illness present before study entry should be recorded in the medical history section of 
the eCRF and only be reported as an AE if there is an increase in the frequency or 
severity of the condition during the study. 
• A clinical event occurring after consent but before IP administration. 
• Intercurrent illnesses with an onset after administration of IP. 
Adverse events do not include: 
• Events identified at Screening that meet exclusion criteria. 
• Medical or surgical procedures (the condition that leads to the procedure is the AE). 
• Situations where an untoward medical occurrence has not taken place. For example: 
o Planned hospitalizations due to pre-existing conditions, which have not worsened. 
o Hospitalizations that occur for procedures not due to an AE (eg, cosmetic 
surgery). 
o Hospitalizations for a diagnostic procedure where the hospital stay is less than 
24 hours in duration or for normal management procedures (eg, chemotherapy). 


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• Overdose of IP or any concomitant therapy that does not result in any adverse signs or 
symptoms. 
For laboratory safety parameters, any instances of absolute values being outside the reference 
range or changes at any visit after study start that are considered by the investigator as 
clinically significant must recorded in the eCRF as AEs. In addition, at the investigator’s 
discretion, any changes or trends over time in laboratory parameters can be recorded in the 
eCRF as AEs if such changes or trends are considered to be clinically relevant, even if the 
absolute values are within the reference range. 
Laboratory findings do not need to be reported as AEs in the following cases: 
• Increases in aPTT will not be classified as AEs because CSL312 is expected to cause 
increase in these parameters. 
• Laboratory parameters already beyond the reference range at Screening, unless a 
further increase/decrease can be considered an exacerbation of a pre-existing 
condition.  
• Abnormal laboratory parameters caused by mechanical or physical influences on the 
blood sample (eg, in vitro hemolysis) and flagged as such by the laboratory in the 
laboratory report. 
• Abnormal parameters that are obviously biologically implausible (eg, values that are 
incompatible with life or outside the measuring range). 
• An abnormal laboratory value that cannot be confirmed after repeat analysis, 
preferably in the same laboratory (ie, the previous result could be marked as not valid 
and should not necessarily be reported as an AE). 
10.1.2 Serious Adverse Event 
An SAE is defined as any untoward medical occurrence that at any dose: 
• Results in death – The event must be the cause of death for the SAE to meet this 
serious criterion. 
• Is life-threatening – The term “life-threatening” refers to an event in which the 
subject was at risk of death at the time of the event; it does not refer to an event that 
hypothetically might have caused death if it had been more severe. 


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• Requires in-patient hospitalization or prolongation of existing hospitalization – 
CSL considers “hospitalization or prolongation of existing hospitalization” for 
≥ 24 hours as the defining criterion for an SAE. Hospital admissions for planned 
surgery or for normal disease management procedures (eg, chemotherapy) are not 
considered as defining criteria for SAEs. 
• Results in persistent or significant disability or incapacity. 
• Is a congenital anomaly or birth defect. 
• Is medically significant – A medically significant event is defined as an event that 
does not necessarily meet any of the SAE criteria, but which is judged by a physician 
to potentially jeopardize the subject or require medical or surgical intervention to 
prevent one of the above outcomes listed as an SAE criterion. 
Adverse events that do not fall into the above categories are defined as nonserious AEs. 
10.1.3 Adverse Event of Special Interest 
There are several AEs that will be monitored closely as AESIs to enable an adequate 
risk-benefit evaluation of CSL312 during the study and additional data may be requested for 
these events. The AESIs will be: 
• Bleeding events that are abnormal in the opinion of the investigator 
• TEEs 
o Non-systemic thrombosis (eg, localized thrombosis associated with vascular 
access) is not considered an AESI 
• Severe hypersensitivity including anaphylaxis 
The reporting requirements for AESIs are detailed in Section 10.6.1. 


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10.2 Severity of Adverse Events 
The severity of each AE (ie, nonserious and serious AEs) is to be assessed by the investigator 
as follows: 
Severity 
Definition 
Mild 
A type of AE that is usually transient and may require only minimal 
treatment or therapeutic intervention. The event does not generally interfere 
with usual activities of daily living. 
Moderate 
A type of AE that is usually alleviated with additional specific therapeutic 
intervention. The event interferes with usual activities of daily living, 
causing discomfort but poses no significant or permanent risk of harm to the 
subject. 
Severe 
A type of AE that interrupts usual activities of daily living, or significantly 
affects clinical status, or may require intensive therapeutic intervention. 
Clinical Data Interchange Standards Consortium (CDISC) Study Data Tabulation Model (SDTM) Severity 
Intensity Scale for Adverse Event Terminology. 
10.3 Causality of Adverse Events 
The causal relationship of an AE to IP must always be assessed by the investigator. All AEs 
will be classified as either related or not related to IP. If a causality assessment is not 
provided for an AE (including an SAE), that AE will be considered related to the IP. 
The degree of certainty with which an AE is attributed to the IP or an alternative cause 
(eg, natural history of the underlying disease, concomitant therapy) will be determined by 
how well the event can be understood in terms of: 
• Known pharmacology of the IP. 
• Clinically and/or pathophysiologically plausible context. 
• Reaction of a similar nature previously observed with similar products, or reported in 
the literature for similar products as being product related (eg, headache, facial 
flushing, pallor). 
• Plausibility supported by the temporal relationship (eg, the event being related by 
time to administration or termination of treatment with the IP, drug withdrawal or 
reproduced on rechallenge). 


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10.4 Observation Period for Adverse Events 
The observation period for the reporting of AEs (and SAEs) for an individual subject will 
start at the time that informed consent is obtained for participation in the current study and 
end at the subject’s final site visit. 
If the investigator becomes aware of an SAE that has started after the EOS Visit and is 
considered by the investigator causally related to the IP, the event must be reported to CSL 
following the same timelines and procedures described for SAEs occurring during the study 
(see Section 10.6.1). 
Such events are not entered into the eCRF. 
10.5 Follow-up of Adverse Events 
Every effort should be made to follow AEs until resolution or stabilization. Ongoing, 
nonserious AEs that have not resolved or stabilized will be followed until the subject 
completes the study. SAEs will be followed until the AE resolves, stabilizes, or the subject is 
lost to follow-up. 
10.6 Adverse Event Reporting 
10.6.1 Adverse Events 
At each clinical evaluation, the investigator (or delegate) will determine whether any AEs 
have occurred. All AEs are to be recorded in the eCRF. If known, the medical diagnosis of an 
AE should be recorded in preference to the listing of individual signs and symptoms. The 
investigator must follow up on the course of an AE until resolution or stabilization. If an SAE 
is ongoing after the final study visit, the SAE will continue to be followed up until resolution, 
stabilization, or the subject is lost to follow-up. 
If, during study participation, a subject presents with a pre-existing condition that was not 
noted at the time of study entry, the condition should be retrospectively recorded in the 
Medical History eCRF. 
10.6.2 Serious Adverse Events 
This study will comply with all applicable regulatory requirements and adhere to the full 
requirements of ICH E2A (Clinical Safety Data Management: Definitions and Standards for 
Expedited Reporting). Foreign cross reporting will be ensured. 


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For SAEs occurring during the study, the investigator or delegate will enter all relevant 
information in the eCRF. 
All SAEs that occur during the course of the study, whether or not causally related to 
the IP, must be entered into the eCRF immediately (within 24 hours of the investigator 
becoming aware of the event). An assessment of causality to the IP must be included. 
AEs occurring in the period between the time that informed consent is obtained and the time 
of the first exposure to the IP that meets 1 or more of the seriousness criteria must be entered 
into the eCRF in the same manner as other SAEs and will be included in the clinical study 
database. 
Any SAE that occurs after the final study visit and is considered by the investigator as 
causally related to the IP must be reported following the same timelines and reporting 
procedures described for SAEs occurring during the study. Such events are not entered into 
the eCRF. 
The minimum reporting requirements for reporting of SAEs include: 
• Subject identification number 
• Suspected medicinal product and/or procedure 
• Event term 
• Reporting source identification 
If the minimum requirements for reporting are fulfilled, the investigator should not wait to 
receive additional information to fully document the event. 
In addition, the investigator must: 
• Report all SAEs to the relevant IRB/IEC within the timeframe specified by the IRB/IEC. 
• If the subject is an active participant in the study: 
o Enter follow-up information in the eCRF until the SAE has resolved, or, in the 
case of permanent impairment, until stabilized. 
o Ensure that the causality assessment for all SAEs is entered in the eCRF 
• If the subject is no longer participating in the study, report the follow-up information to 
CSL. 


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In cases of death, the investigator should supply CSL and the IRB/IEC (as applicable) with 
any additional information as it becomes available (eg, autopsy reports and detailed medical 
reports). 
10.6.3 Adverse Events of Special Interest 
AESIs must be reported as AEs in the subject’s eCRF. Additional data might be requested in 
the eCRF for these events. Serious and nonserious AESIs must be reported following 
expedited reporting procedures, as described for SAEs (see Section 10.6.2). 
10.6.4 Other Significant Events 
Not applicable. 
10.6.5 Overdose 
Any overdose that occurs in association with an adverse sign or symptom must be entered 
into the eCRF as an AE; if the AE meets any seriousness criteria, the event must be reported 
as an SAE (see Section 10.6.2). 
Details (ie, volume infused, location of infusion, infusion start and stop times, and infusion 
rate) of overdose of IP (defined in Section 9.4) must be recorded in the Study Treatment 
Administration eCRF. Details of an overdose of any concomitant therapy must be recorded in 
the Concomitant Medication eCRF. 
10.6.6 Pregnancy and Breastfeeding 
A female subject or female partner of a male subject who becomes pregnant while 
participating in the study, or up to and including 90 days after the last dose of IP, must notify 
the investigator immediately. 
If a female subject becomes pregnant during study participation, she may continue study 
procedures at the discretion of the investigator. If the subject withdraws from study 
participation, the procedure for discontinuation of a subject will be followed, as described in 
Section 6.4.3). 
CSL must be notified within 5 days of the investigator becoming aware of the pregnancy. 


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Whenever possible, a pregnancy in a subject or in a female partner of a male subject exposed 
to the IP should be followed to term so as to assess any potential occurrence of congenital 
anomalies or birth defects. Any follow-up information, including premature termination and 
the status of the mother and child after delivery, should be reported by the investigator to 
CSL using a Pregnancy Reporting/Outcome Form. 
10.7 Institutional Review Board/Independent Ethics Committee Reporting 
Requirements 
The time frame within which an IRB/IEC must be notified of deaths and IP-related 
unexpected SAEs is stipulated by each IRB/IEC. It is the investigator’s responsibility to 
comply with the requirements for IRB/IEC notification. CSL will provide investigators with 
all details of all SAEs reported to regulatory authorities. 
11 Statistical Analyses 
11.1 Sample Size 
There are limited data on the rates of subjects with COVID-19 who progress to tracheal 
intubation or death prior to tracheal intubation within 28 days. For sample size calculation, a 
rate of 30% in the control group and a rate of 10% in the CSL312 group have been assumed. 
With a 2-sided α = 0.05 and 1:1 randomization ratio for CSL312 + SOC versus 
placebo + SOC, a total of 124 subjects need to be randomized (62 subjects to CSL312 + SOC 
and 62 subjects to placebo + SOC) in order to achieve 80% power to detect a treatment 
difference using a 2 group chi-square test. For the sample size calculation, it is further 
confirmed using simulations performed in East® 6.5 software (Cytel, Inc.: Waltham, MA) 
that 80% power is maintained, accounting for the interim analysis for futility and sample size 
re-estimation. 


C S L  Be hri n g  
St u d y Pr ot oc ol: C S L 3 1 2 _ C O VI D -1 9, Versi o n: A me n d me nt  3 ( 1 6 Se pte m ber  2 0 2 0)  
C S L 3 1 2 ( Gara daci ma b)  
C S L Be hri n g – C o nfi de ntial  
Te m plate: C S -S O P -0 4 -G 0 1 -T 0 1  
Versi o n N u m ber: 1. 0  
Effecti ve Date: Wee k c o m me nci n g 3 0 -A pr -2 0 1 8  
 
Pa ge 6 2  of 8 3  
1 1. 2  Descri pti o n of St u d y A n al ysis Sets  
1 1. 2. 1  Scree ne d  A n al ysis Set  
T he Scree ne d A nal ysis Set c o m prises all s u bjects w h o pr o vi de writte n i nf or me d c o nse nt a n d 
w h o c o m plete all of t he Scree ni n g pr o ce d ures. 
1 1. 2. 2  I nte nt-t o-Tre at A n al ysis Set  
T he I nte nt- t o-tr eat (I T T) A nal ysis Set c o m prises all s u bjects i n t he Scree ne d A nal ysis Set 
w h o wer e ra n d o ml y assi g ne d t o treat me nt. T he I T T A nal ysis Set will be a n al yze d usi n g t he 
treat me nt t o w hic h t he s u bject was ra n d o mize d, re gar dless of t he treat me nt act uall y recei ve d. 
A n y s u bject w h o recei ves a treat me nt ra n d o mizati o n n u m ber w ill be c o nsi d ere d t o ha v e bee n 
ra n d o ml y assi g ne d t o treat me nt. 
1 1. 2. 3  M o difie d I nte nt -t o-Tre at A n al ysis Set  
T he M o difie d I nte nt- t o-tr eat ( mI T T) A n al ysis Set c o m prises all s u bjects i n t he I T T A nal ysis 
Set w h o were ra n d o mize d, a n d recei ve d a n y a m o u nt of st u d y treat me nt ( C S L 3 1 2 + S O C or 
place b o  + S O C). I n t he mI T T A n al ysis Set, a nal yses will be base d o n t he treat me nt t o w hic h 
s u bjects were ra n d o ml y assi g ne d, re gar dl ess of w hic h treat me nt t he y act uall y recei v e d.  
1 1. 2. 4  S afet y A n al ysis Set  
T he Safet y A nal ysis Set c o m prises all s u bjects i n t he I T T A nal ysis Set w h o recei v e a n y 
a m o u nt of I P ( C S L 3 1 2 + S O C or place b o  + S O C), a n d will be base d o n t he act ual treat me nt 
recei v e d. 
1 1. 2. 5  P h ar m ac o ki netic A n al ysis Set  
T he P K A nal ysis Set will c o m prise all s u bjects i n t he Safet y A nal ysis Set w h o recei v e d a n y 
a m o u nt of C S L 3 1 2 + S O C a n d ha ve ≥ 1 bl o o d sa m ple a vaila ble after a d mi nistrati o n of 
C S L 3 1 2 f or C S L 3 1 2 c o nce ntrati o n meas ure me nt. P K a nal yses will n ot be perf or me d f or 
s u bjects w h o ar e treat e d wit h place b o + S O C.  
1 1. 2. 6  
 
 
 
 
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11.3 Analyses of Primary Efficacy 
The primary endpoint for this study is the incidence of tracheal intubation or death prior to 
tracheal intubation from randomization to Day 28. The proportion will be calculated as the 
number of subjects with tracheal intubation or death divided by the total number of subjects 
for each treatment group. Treatment effect of interest (ie, estimand) is defined as the 
proportion difference of tracheal intubation or death prior to tracheal intubation 
(CSL312 + SOC minus placebo + SOC) in the target population regardless of whether 
additional treatment is used or initial SOC has changed. The ITT Analysis Set will be used 
for the primary efficacy analyses. 
Firth logistic regression model including treatment group; age group as a continuous 
covariate; gender (male or female); country (USA or Brazil); and Baseline comorbidities (yes 
or no) as categorical covariates will be used to compare the rates between the 2 treatment 
groups. Comorbidities include hypertension, diabetes, and obesity (defined as body mass 
index ≥ 30 [kg/m2]). A 2-sided p-value will be estimated from the model. The proportion 
difference and associated 95% confidence interval (CI) will be estimated using the method 
described by Ge at al [2011]. The mITT Analysis Set will be used for primary efficacy 
endpoint sensitivity analysis. 
Sensitivity analyses to assess the effect of missing data will be conducted, for example, by 
performing tipping point analyses that vary assumptions about the missing outcomes in both 
study treatment groups. 
11.4 Analyses of Secondary Efficacy 
The following secondary efficacy endpoints will be summarized by treatment group using 
subject count and percentage: 
• All-cause mortality 
• Incidence of tracheal intubation from randomization to Day 28 


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• Proportions of subjects using CPAP or BiPAP 
• Proportion of subjects using HFNC 
• Proportion of subjects using ECMO 
The same testing method used for the primary efficacy variable will also be used to compare 
the above secondary efficacy endpoints between the 2 treatment groups. The proportion 
differences, associated 95% CIs, and 2-sided p-values will be reported. 
Clinical Status Assessed on an 8-Point NIAID Ordinal Scale 
Frequency and proportion of subjects within each category of the 8-point NIAID ordinal 
scale will be summarized along with graphical displays for each treatment group. Frequency 
and proportion of subjects with an improvement from Baseline of ≥ 2 points will be analyzed 
using descriptive statistics. 
Hospital Length of Stay 
Hospital LOS is defined as the time interval from randomization to hospital discharge alive. 
In this analysis, for subjects who did not have hospital discharge (ie, no recorded date of 
hospital discharge) and did not die, the time to hospital discharge will be censored at the last 
known in-hospital date if the subject did not complete the 28-day Treatment Period. For 
subjects who do not have a hospital discharge event or censoring time within the 28 days 
after randomization or for subjects who have died, an administrative censoring will be 
applied at 28 days. 
Hospital LOS will be analyzed using Cox model including treatment group; age as a 
continuous covariate; gender (male or female), country (USA or Brazil); and comorbidities 
(yes or no) as categorical covariates in the model. Hazard ratio, its 95% CI and 2-sided Wald 
p-value for hypothesis-testing will be estimated from the model. Cumulative event rates will 
be calculated using the Kaplan-Meier (KM) method. The effect over time will be illustrated 
with a plot of the complement (1 – KM) of KM estimates. Event counts and percentages will 
be summarized. If ties occur, Efron’s method will be used to adjust for ties. 


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Sequential Organ Failure Assessment 
Maximum SOFA score, maximum change from Baseline in SOFA score, and mean SOFA 
score during the study will be calculated for each subject and summarized by treatment 
group. Descriptive statistics for continuous variables will be reported. Median differences 
between treatment groups and 95% CIs using Hodges-Lehmann’s method will be reported. 
Nonparametric Wilcoxon rank-sum test will be used to compare the 2 treatment groups. 
SOFA score components will also be summarized by treatment and visit using descriptive 
statistics. 
The ITT Analysis Set and mITT Analysis Set will be used for the secondary efficacy endpoint 
analyses. 
Baseline is defined as the most recent, non-missing value before randomization, if applicable, 
otherwise, the most recent non-missing value before administration of IP. 
11.5 Analysis of Safety 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) version 21.1 (or higher). A treatment-emergent adverse event (TEAE) is defined 
as an AE reported at or after the start of the first administration of study treatment. Only 
TEAEs will be summarized. 
An overview summary of TEAEs, including counts and percentages of subjects with any 
TEAE; TEAEs related to study treatment; TEAEs leading to permanent discontinuation of 
study treatment; TEAE leading to dose modifications; serious TEAEs; serious TEAEs related 
to study treatment; fatal TEAEs; fatal TEAEs related to study treatment, TEAEs by severity, 
and TEAEs of special interest will be produced. 
TEAEs will be summarized by system organ class and preferred term. TEAEs will also be 
summarized by causality and severity. All TEAE summaries will be provided for each 
treatment and overall. 
Number and percentage of subjects with plasma anti-CSL312 antibodies will be summarized 
by treatment group and overall. 
Laboratory evaluations (hematology, biochemistry, and urinalysis) will be summarized 
descriptively by treatment group. 


C S L  Be hri n g  
St u d y Pr ot oc ol: C S L 3 1 2 _ C O VI D -1 9, Versi o n: A me n d me nt  3 ( 1 6 Se pte m ber  2 0 2 0)  
C S L 3 1 2 ( Gara daci ma b)  
C S L Be hri n g – C o nfi de ntial  
Te m plate: C S -S O P -0 4 -G 0 1 -T 0 1  
Versi o n N u m ber: 1. 0  
Effecti ve Date: Wee k c o m me nci n g 3 0 -A pr -2 0 1 8  
 
Pa ge 6 6  of 8 3  
Vital si g n fi n di n gs a n d res pirat or y para meters will be liste d b y s u bject a n d ti me p oi nt. T he 
val ues a n d c h a n ge fr o m Baseli ne at eac h visit will be d escri pti vel y s u m marize d b y treat me nt 
gr o u p. 
T he Safet y A nal ysis Set will be use d f or all safet y a nal yses.  
1 1. 6  A n al yses of P h ar m ac o ki netics  
T he P K data f or C S L 3 1 2 plas ma c o nce ntrati o n will be s u m marize d b y n o mi nal ti me p oi nt f or 
eac h tr eat me nt gr o u p. T h e f oll o w i n g descri pti ve st atistics will be prese nte d f or plas ma 
c o nce ntr ati o n s u m maries: n, arit h metic mea n, S D, C V %, me dia n, ge o metri c mea n, mi ni m u m, 
a n d ma xi m u m. 
T he P K para m eters f or C S L 3 1 2, deri ve d usi n g a n o nc o m part me ntal met h o d, will be 
s u m marize d descri pti vel y b y treat me nt gr o u p. 
T he f oll o wi n g P K para m eters will be deri v e d a n d s u m marize d: 
•  C ma x  
•  A U C 0- last 
•  T ma x  
•  T 1/ 2 
T he f oll o wi n g descri pti v e statistics will be prese nte d f or all P K para meters, e xce pt f or T ma x , 
n, arit h metic mea n, S D, C V %, me dia n, ge o metric mea n, mi ni m u m, a n d ma xi m u m. F or T ma x , 
n, me dia n, mi ni m u m a n d ma xi m u m will be s u m marize d.  
T he P K A nal ysis Set will be use d f or all P K a nal yses.  
1 1. 7  
 
C CI
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C S L  Be hri n g  
St u d y Pr ot oc ol: C S L 3 1 2 _ C O VI D -1 9, Versi o n: A me n d me nt  3 ( 1 6 Se pte m ber  2 0 2 0)  
C S L 3 1 2 ( Gara daci ma b)  
C S L Be hri n g – C o nfi de ntial  
Te m plate: C S -S O P -0 4 -G 0 1 -T 0 1  
Versi o n N u m ber: 1. 0  
Effecti ve Date: Wee k c o m me nci n g 3 0 -A pr -2 0 1 8  
 
Pa ge 6 7  of 8 3  
C CI


C S L  Be hri n g  
St u d y Pr ot oc ol: C S L 3 1 2 _ C O VI D -1 9, Versi o n: A me n d me nt  3 ( 1 6 Se pte m ber  2 0 2 0)  
C S L 3 1 2 ( Gara daci ma b)  
C S L Be hri n g – C o nfi de ntial  
Te m plate: C S -S O P -0 4 -G 0 1 -T 0 1  
Versi o n N u m ber: 1. 0  
Effecti ve Date: Wee k c o m me nci n g 3 0 -A pr -2 0 1 8  
 
Pa ge 6 8  of 8 3  
1 1. 8  I nteri m A n al ysis 
A n i nteri m a nal ysis of u n bli n de d pri mar y e n d p oi nt data is pla n ne d after 6 2 s u bjects ( 5 0 % of 
t he tar get sa m ple size) ha ve c o m plete d pri mar y e n d p oi nt assess me nt. T he i nteri m a nal ysis 
will be perf or me d f or t he p ur p ose of f utilit y m o nit ori n g a n d sa m ple size re- esti mati o n. 
At t he i nteri m a nal ysis, t he c o n diti o nal p o wer ( C P) will be calc ulate d ass u mi n g t he data yet 
t o be o bser ve d f oll o w t he c urre nt tr e n d o bser v e d i n t he data a v aila ble f or t h e i nteri m a nal ysis. 
C he n et al  [2 0 0 4 ] s h o w e d t hat st o p pi n g a st u d y earl y f or f utilit y or i ncreasi n g t he sa m ple size 
w he n t he i nteri m res ult is pr o misi n g will n ot i nflate t he Ty pe  I err or rate. T h us, a statistical 
a dj ust me nt f or m ulti plicit y i s n ot necessar y t o c o ntr ol t he o verall Ty p e I err or of t he st u d y. 
Me hta a n d P oc oc k  [2 0 1 1 ] ha ve s h o w n t hat t he b o u n dar y f or t he pr o misi n g i nteri m res ult ma y 
b e l o were d t o 0. 3 6, if t h e ma xi m u m all o wa ble sa m ple size is restricte d t o 2  ti mes t he ori gi nal 
sa m ple size. 
Base d o n t he re vie w of t he i nteri m a nal ysis, earl y st o p pi n g f or f utilit y or sa m ple size 
re-esti mati o n ma y be rec o m me n de d f or i m ple me ntati o n f oll o wi n g  t hese g ui deli nes: 
•  St o p f or f utilit y if C P  < 0. 1 0 (f utilit y z o ne) 
•  C o nti n ue t o t he pla n ne d c o m pleti o n if 0. 1 0 ≤ C P < 0. 3 6 ( u nfa v ora ble z o ne) 
•  I ncrease t he s a m ple size u p t o 2 0 0 if 0. 3 6 ≤ C P  < 0. 8 0 ( pr o misi n g z o ne) 
•  C o nti n ue t o t he pla n ne d c o m pleti o n if C P ≥ 0. 8 0 (fa v ora bl e z o ne) 
F ull details of t he i nteri m a nal ysis, i ncl u di n g t he f or m ula t o calc ulate t h e C P will be s pecifie d 
i n t he I D M C statistical a nal ysis pla n. Alt h o u g h t he statistical g ui deli nes will be pre-s pecifie d, 
a n u m ber of f act ors m ust be c o nsi dere d t h or o u g hl y as part of t he d ecisi o n t o m o dif y or st o p 
t he st u d y earl y. A rec o m me n dati o n t o m o dif y or ter mi nate t he st u d y will n ot be base d s olel y 
o n statistical gr o u n ds. 
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12 Regulatory and Ethics Considerations 
12.1 Regulatory Considerations 
CSL or its agents will submit the appropriate documents to the local regulatory agencies and 
will await approval before commencement of the study. 
This study will be conducted and documented in accordance with the applicable regulatory 
guidelines and requirements. 
The procedures set out in this CSP are designed to ensure that CSL and the investigator abide 
by the principles of the current ICH GCP guidelines on the conduct, evaluation, and 
documentation of this study, as described in ICH E6 (Guideline for GCP). The study will also 
be carried out according to all applicable international and national regulatory requirements. 
12.2 Institutional Review Board/Independent Ethics Committee 
The investigator must submit the CSP and informed consent forms (ICFs) for review by an 
authorized and properly constituted (according to local guidelines) IRB/IEC. Written 
approval must be received from the IRB/IEC before commencement of the study. 
12.3 Subject Information and Informed Consent 
Informed consent of study subjects according to the standards of GCP must be implemented 
in this clinical study before protocol-specified procedures are carried out. Information should 
be given in both oral and written form and should be deemed appropriate by the IRB/IEC. 
Subjects, their relatives (or if necessary, legally acceptable representatives) must be given 
ample opportunity to inquire about the details of the study. 
The subject (or if necessary, legally acceptable representatives) must be provided with a copy 
of the signed ICF. 
Should there be any amendments to the CSP that would directly affect the subject’s 
participation in the study (eg, a change in any procedures), then the ICF must be amended to 
incorporate this modification. Subjects must be informed of the change and they must sign 
the amended ICF indicating that they re-consent to participate in the study. 


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12.4 Subject Confidentiality 
All subject names and contact details will be kept confidential. Subjects will be identified 
throughout documentation and evaluation by the subject number assigned to them during the 
study. Each subject will be told that all study findings will be handled in the strictest 
confidence. 
The investigator at the study site will be responsible for retaining sufficient information about 
each subject (eg, name, address, phone number, and identity in the study) so that regulatory 
agencies or CSL may access this information should the need arise. These records should be 
retained in a confidential manner as long as legally mandated according to local 
requirements. 
Subject medical records pertaining to the study may be inspected/audited at any time by CSL 
employees or their duly authorized representatives, a health authority or the IRB/IEC. All 
records accessed will be strictly confidential. Consent to participate in the study includes 
consent to these inspections/audits  
12.5 Indemnity and Compensation 
CSL has taken out insurance to cover its obligations under both the Indemnity and the 
Compensation guidelines for injury to subjects involved in the study. 
Other details regarding compensation and the obligations of the investigator/CSL are 
provided in the Clinical Trial Research Agreement (CTRA) for the study (Section 13.1). 
13 Administrative Considerations 
13.1 Clinical Trial Research Agreement 
This study will be conducted under a CTRA between CSL (“Sponsor”) and the institutions 
representing the investigational study sites (“Authority”). Financial support to the 
investigational sites will be detailed in the CTRA. The CTRA will clearly delineate the 
responsibilities and obligations of the investigators and CSL, and will form the contractual 
basis under which the clinical study will be conducted. The CTRA may be executed by 
electronic signature (current provider DocuSign) in compliance with 21 Code of Federal 
Regulations Part 11 and simple or advanced electronic signature according to European 
Union Regulation No. 910/2014 – eIDAS. 


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13.2 Clinical Study Registration and Results Disclosure 
CSL will provide the relevant CSP information in public databases before or at 
commencement of the study. CSL may also provide study information for inclusion in 
national registries according to local regulatory requirements. 
Results of this study will be disclosed according to the relevant regulatory requirements. All 
publications in peer-reviewed medical journals resulting from this study will be listed in the 
original CSP registration record. 
13.3 Implementation of the Clinical Study Protocol and Amendments 
With the exception of medical emergencies, no changes or deviations in the conduct of the 
signed CSP will be permitted without documented approval of the CSL Medical Monitor or 
designee and the IRB/IEC. In the event of a medical emergency, the investigator at the study 
site will institute any medical procedures deemed appropriate. However, all such procedures 
must be promptly reported to the CSL Medical Monitor and the IRB/IEC. 
Modifications to the CSP that may affect subject safety or the way the study is to be 
conducted will be documented in a protocol amendment, which must be approved by the 
IRB/IEC. 
Administrative changes to the CSP, defined as minor corrections and/or clarifications that 
have no effect on the way that the study is to be conducted, will not require IRB/IEC 
approval, but will be submitted to the IRB/IEC for their information. 
13.4 Protocol Deviations 
All instances where the requirements of the CSP were not complied with will be tracked. 
Corresponding subjects may be withdrawn from the study at the discretion of the investigator 
and/or CSL. CSP deviations arise when either subjects who have been entered in the study 
and/or the study sites deviate from the IRB/IEC-approved study protocol. 
If a major protocol deviation (ie, a deviation that could have a significant effect on the 
subject’s safety, rights, or welfare and/or on the integrity of the study data) occurs, the 
investigator must notify CSL and the appropriate IRB/IEC as soon as possible or as per local 
requirements. 


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13.5 Documentation and Record Keeping 
13.5.1 Data Collection 
The investigator (or delegate) will maintain individual records for each subject. These records 
should include dates when a subject visited the study site, records of vital signs, medical 
history, or physical examinations, administration of IP or concomitant therapy, any AEs 
experienced, and other notes as appropriate. These records (electronic or paper) constitute 
source data. 
An eCRF will be provided by CSL (or delegate) for each subject enrolled into the study. The 
investigator is responsible for ensuring accurate and proper completion of the eCRF in a 
timely manner so that it always reflects the latest observations on the subjects enrolled in the 
study. All entries on the eCRF must be backed up by source data unless the eCRF is 
considered source data. All source data will be kept according to all applicable regulatory 
requirements. Source data must be completed legibly for each subject enrolled into the study 
and signed by the investigator (or delegate). 
13.5.2 Data Quality Assurance 
Data generated throughout the study will be monitored and the eCRFs checked against the 
subject records for completeness and accuracy. The investigator must provide direct access to 
source data documents. CSL’s study monitor will perform this function. 
Following completion of eCRF pages and entry of the data into a database, the data will be 
checked electronically and manually for consistency and plausibility. Queries will be 
generated for questionable data and clarification sought from the investigator. These data 
queries must be resolved in a timely manner by the investigator (or delegate). 
13.5.3 Monitoring 
The monitoring activities during the current COVID-19 pandemic will be primarily or 
exclusively be performed without peripheral visits. Remote monitoring will be performed 
through periodic, comprehensive connections through the internet or telephone with all 
participating study sites by CSL personnel or representatives. 


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13.5.4 Record Retention 
The investigator must follow the principles for record retention outlined in the CTRA. An 
investigator study file prepared by CSL (or delegate), containing all applicable documents for 
use at the study site, will be made available to the investigator before the start of the study. 
All study documentation and materials maintained in the investigator study file must be kept 
in conformance with applicable national laws and regulations. 
All study documentation and materials maintained in the investigator study file at the study 
site must be available for inspection by CSL’s study monitor (or delegate) to determine that 
all required documentation is present and correct. 
The study may be audited or inspected by qualified delegates from CSL or a competent 
health authority. 
Following completion of the study, the investigator is responsible for archiving the 
investigator’s study file, the subject’s records and the source data according to applicable 
regulatory requirements. 
13.6 Study and Site Closure 
CSL reserves the right to prematurely discontinue or suspend the study either at a particular 
site or at all study sites at any time and for any reason. If such action is taken, the CSL Study 
Monitor (or delegate) will discuss this with the investigator at each study site at that time and 
notify the investigators in writing. If the study is suspended or terminated for safety reasons, 
all investigators and the relevant regulatory agencies will be immediately notified of the 
action as well as the reason for the suspension/termination. The investigator at each study site 
will advise their IRB/IEC overseeing the study of the suspension/termination. 
13.7 Clinical Study Report 
A clinical study report (CSR) will be written after the completion of the study. CSL or its 
agent will write the CSR in consultation with the investigator or, if applicable, a nominated 
coordinating investigator (or delegate). CSL requires that the coordinating investigator will 
sign the CSR. 
Progress reports may be provided to the relevant regulatory bodies in accordance with their 
requirements. 


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13.8 Use of Data and Publications 
The rights and obligations of investigators and CSL concerning any formal presentation or 
publication of data collected as a direct or indirect result of this study will be addressed 
specifically in the CTRA for the study. 


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14 References 
Cao H, Biondo M, Lioe H, Busfield S, Rayzman V, Nieswandt B, et al. Antibody-mediated 
inhibition of FXIIa blocks downstream bradykinin generation. J Allergy Clin Immunol. 
2018;142(4):1355-1358. 
Chen YH, DeMets DL, Lan KK. Increasing the sample size when the unblinded interim result 
is promising. Stat Med. 2004;23(7) :1023-1038. 
Ge M, Durham LK, Meyer RD, Xie W, Thomas N. Covariate-adjusted difference in 
proportions from clinical trials using logistic regression and weighted risk differences. Drug 
Information Journal. 2011;45:481-493. 
Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, et al. Clinical features of patients infected with 
2019 novel coronavirus in Wuhan, China. Lancet. 2020;395(10223):497-506. 
doi: 10.1016/S0140-6736(20)30183-5. Epub 24 January 2020. Erratum in: Lancet. 
30 January 2020. 
Jones AE, Trzeciak S, Kline JA. The Sequential Organ Failure Assessments score for 
predicting outcome in patients with severe sepsis and evidence of hypoperfusion at the time 
of emergent department presentation. Crit Care Med. 2009;37(5):1649-1654. 
Lammle B, Wuillemin WA, Huber I, Krauskopf M, Zürcher C, Pflugshaupt R, et al. 
Thromboembolism and bleeding tendency in congenital factor XII deficiency – a study on 
74 subjects from 14 Swiss families. Thromb Haemost. 1991;65(2):117-121. 
Larsson M, Rayzman V, Nolte MW, Nickel KF, Björkqvist J, Jämsä A, et al. A factor XIIa 
inhibitory antibody provides thromboprotection in extracorporeal circulation without 
increasing bleeding risk. Sci Transl Med. 2014;6(222):222. 
Mehta CR, Pocock SJ. Adaptive increase in sample size when interim results are promising: a 
practical guide with examples. Stat Med. 2011;30(28):3267-3284. 
National Cancer Institute, National Institutes of Health, United States Department of Health 
and Human Services (DHHS). Common Terminology Criteria for Adverse Events (CTCAE) 
version 4.0. NIH Publication No. 03-5410. Revised May 2009. Available at: 
https://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03/Archive/CTCAE_4.0_2009-05-29_Quick
Reference_8.5x11.pdf. Accessed on May 08, 2020. 


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National Institute of Allergy and Infectious Diseases (NIAID). ClinicalTrials.gov. Adaptive 
COVID-19 Treatment Trial (ACTT). Available at: 
https://clinicaltrials.gov/ct2/show/NCT04280705. Accessed: May 05, 2020. 
Newcombe RG. Confidence intervals for an effect size measure based on the Mann-Whitney 
statistic. Part 2: asymptomatic methods and evaluation. Statist. Med. 2006;25(4):559-573. 
Novack V, Beitler JR, Yitshak-Sade M, Thompson BT, Schoenfeld DA, Rubenfeld G, et al. 
Alive and ventilator free: a hierarchical, composite outcome for clinical trials in the acute 
respiratory distress syndrome. Crit Care Med. 2020;48(2):158-166. 
Novel Coronavirus Pneumonia Emergency Response Epidemiology Team (NCPERE Team). 
Vital surveillances: the epidemiological characteristics of an outbreak of 2019 novel 
coronavirus diseases (COVID-19) – China, 2020. China CDC Weekly. 2020;2(8):113-122. 
Ratnoff OD, Colopy JE. A familial haemorrhagic trait associated with a deficiency of a 
clot-promoting fraction of plasma. J Clin Invest. 1955;34(4):602–613. 
Shi H, Han X, Jiang N, Cao Y, Alwalid O, Gu J, et al. Radiological findings from 81 patients 
with COVID-19 pneumonia in Wuhan, China: a descriptive study. Lancet Infect Dis. 
2020 Feb 24. doi: 10.1016/S1473-3099(20)30086-4. [Epub ahead of print]. 
Stebbings R, Findlay L, Edwards C, Eastwood D, Bird C, North D, et al. “Cytokine storm” in 
the phase I trial of monoclonal antibody TGN1412: better understanding the causes to 
improve preclinical testing of immunotherapeutics. J Immunol. 2007;179(5):3325-3331. 
Stebbings R, Eastwood D, Poole S, Thorpe R. After TGN1412: recent developments in 
cytokine release assays. J Immunotoxicol. 2013;10(1):75-82. 
doi: 10.3109/1547691X.2012.711783. Epub 11 September 2012. 
Tang N, Li D, Wang X, Sun Z. Abnormal coagulation parameters are associated with poor 
prognosis in patients with novel coronavirus pneumonia. J Thromb Haemost. 
19 February 2020. doi: 10.1111/jth.14768. [Epub ahead of print] 
Taylor SL, Wahl-Jensen V, Copeland AM, Jahrling PB, Schmaljohn CS. Endothelial cell 
permeability during hantavirus infection involves factor XII-dependent increased activation 
of the kallikrein-kinin system. PLoS Pathog. 2013;9(7):e1003470. 
doi: 10.1371/journal.ppat.1003470. Epub 18 July 2013. 


CSL Behring 
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Teasdale G, Maas A, Lecky F, Manley G, Stocchetti N, Murray G. The Glasgow Coma Scale 
at 40 years: standing the test of time. Lancet Neurol. 2014;13(8):844-854. 
World Health Organization (WHO). COVID-19 Situation Report 65. WHO website. 
Published: 25 March 2020. Accessed: 26 March 2020. Available from: 
https://www.who.int/docs/default-source/coronaviruse/situation-reports/20200325-sitrep-65-c
ovid-19.pdf. 
World Health Organization (WHO). Emergencies preparedness, response: Novel Coronavirus 
– China. Disease outbreak news. Update: 12 January 2020 [cited 18 March 2020]. Available 
from: https://www.who.int/csr/don/12-january-2020-novel-coronavirus-china/en/. 
Yang X, Yu Y, Xu J, Shu H, Xia J, Liu H, et al. Clinical course and outcomes of critically ill 
patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, 
observational study. Lancet Respir Med. 2020 Feb 24. doi: 10.1016/S2213-2600(20)30079-5. 
[Epub ahead of print] Erratrum in Lancet Respir Med. 2020 Feb 28. 
 


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15 Appendices 
Appendix 1 
Signatures 
Appendix 2 
Sequential Organ Failure Assessment (SOFA) Scale 
Appendix 3 
National Institute of Allergy and Infectious Diseases (NIAID) 8-point 
Ordinal Scale 
Appendix 4 
Glasgow Coma Scale 
 


C S L B e hri n g 
St u d y Pr ot o c ol: C S L 3 1 2 _ C O VI D- 1 9, Versi o n: A m e n d m e nt 3 ( 1 6 S e pt e m b er 2 0 2 0) 
C S L 3 12 ( G ar a d a ci m a b) 
A p p e n di x 1 
Si g n at u r es 
Si g n at u r e o n B e h alf of S p o ns o r 
St u d y Titl e: 
A P h as e 2, M ulti c e nt er , D o u bl e- bli n d , R a n d o mi z e d , 
Pl a c e b o- c o ntr oll e d St u d y t o E v al u at e C S L 3 l 2 i n C or o n a vir us 
Dis e as e 2 0 1 9 ( C O VI D- 1 9) 
P r ot o c ol N u m b e r: 
C S L 3 1 2 C O VI D- 1 9 
I h a v e r e a d t h e Cli ni c al St u d y Pr ot o c ol , d at e d 1 6 S e pt e m b er 2 0 2 0, titl e d " A P h as e 2, 
M ulti c e nt er, D o u bl e -bli n d , R a n d o mi z e d, Pl a c e b o- c o ntr oll e d St u d y t o E v al u at e C S L 3 1 2 i n 
C or o n a vir us Dis e as e 2 0 1 9 ( C O VI D- 1 9)" a n d c o nfir m t h at, t o t h e b est of m y k n o wl e d g e, t h e 
pr ot o c ol a c c ur at el y d es cri b es t h e d esi g n a n d c o n d u ct of t h e st u d y. 
 
 
C S L B e hri n g - C o nfi d e nti al 
T e m pl at e: C S -S O P -0 4- G O I-T O I 
Versi o n N u m b er: 1.0 
Eff e cti v e D at e: W e e k c o m m e n ci n g 3 0- A pr- 2 0 1 8 
• 
D at e 
P a g e 7 9 of 8 3 
P P D
P P D
P P D


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Signature of Principal Investigator 
 
Study Title: 
A Phase 2, Multicenter, Double-blind, Randomized, 
Placebo-controlled Study to Evaluate CSL312 in Coronavirus 
Disease 2019 (COVID-19) 
Protocol Number: 
CSL312_COVID-19 
Site Number: 
 
I have read the Clinical Study Protocol, dated 16 September 2020, titled “A Phase 2, 
Multicenter, Double-blind, Randomized, Placebo-controlled Study to Evaluate CSL312 in 
Coronavirus Disease 2019 (COVID-19)”. 
By signing this Clinical Study Protocol, I agree to conduct the clinical study, after approval 
by an Institutional Review Board or Independent Ethics Committee (as appropriate), in 
accordance with the Clinical Study Protocol, the standards of Good Clinical Practice (as 
defined by the International Council on Harmonisation) and applicable regulatory 
requirements. 
Changes to the Clinical Study Protocol will only be implemented after written approval is 
received from CSL Behring and the Institutional Review Board or Independent Ethics 
Committee (as appropriate) with the exception of medical emergencies. 
I will ensure that study staff fully understand and follow the Clinical Study Protocol. 
 
 
 
(Signature) 
 
 
Date (DD MMM YYYY) 
(Printed name) 
 
 
 
(Title) 
 
 
 


CSL Behring 
Study Protocol: CSL312_COVID-19, Version: Amendment 3 (16 September 2020) 
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Appendix 2 
Sequential Organ Failure Assessment (SOFA) Scale 
 
SOFA Score 
1 
2 
3 
4 
Respirationa 
PaO2/FiO2 ratio 
(mmHg) 
< 400 
< 300 
< 220 
< 100 
SaO2/FiO2 ratio 
(mmHg) 
221-301 
142-220 
67-141 
< 67 
Coagulation 
Platelets × 103/mm3 
< 150 
< 100 
< 50 
< 20 
Liver 
Bilirubin (mg/dL) 
1.2-1.9 
2.0-5.9 
6.0-11.9 
> 12.0 
Cardiovascularb 
Hypotension 
MAP < 70 
Dopamine ≤ 5 
or dobutamine 
(any) 
Dopamine > 5 
or 
norepinephrine 
≤ 0.1 
Dopamine > 15 
or 
norepinephrine 
> 0.1 
Central Nervous System 
Glasgow Coma Score 
13-14 
10-12 
6-9 
< 6 
Renal 
Creatinine (mg/dL) 
or urine output (mL/d) 
1.2-1.9 
2.0-3.4 
3.5-4.9 
or < 500 
> 5.0 
or < 200 
FiO2 = fraction of inspired oxygen; MAP = mean arterial pressure; PaO2 = partial pressure of arterial oxygen; 
SaO2 = arterial oxygen saturation. 
a. 
PaO2/FiO2 ratio is preferable. If not available, the SaO2/FiO2 ratio may be used. 
b. Vasoactive medications administered for ≥ 1 hour (dopamine and norepinephrine µg/kg/min). 
Source: Jones et al, 2009. 


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Appendix 3 
National Institute of Allergy and Infectious Diseases (NIAID) 
8-point Ordinal Scale 
The ordinal scale is an assessment of the clinical status at the first assessment of a given 
study day. 
NIAID 
Score 
Description 
1 
Death 
2 
Hospitalized, on invasive mechanical ventilation or ECMO 
3 
Hospitalized, on NIV or high-flow oxygen devices 
4 
Hospitalized, requiring supplemental oxygen 
5 
Hospitalized, not requiring supplemental oxygen – requiring ongoing medical 
care (COVID-19 related or otherwise) 
6 
Hospitalized, not requiring supplemental oxygen – no longer requires ongoing 
medical care 
7 
Not hospitalized, limitation on activities and/or requiring home oxygen 
8 
Not hospitalized, no limitations on activities 
COVID-19 = Coronavirus 2019; ECMO = extracorporeal membrane oxygenation; NIAID = National Institute 
of Allergy and Infectious Diseases; NIV = non-invasive ventilation. 
Source: NIAID, 2020. 
 


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Appendix 4 
Glasgow Coma Scale 
 
Feature 
Scale Responses 
Score 
Eye opening (E) 
Spontaneous 
4 
To speech 
3 
To pain 
2 
None 
1 
Best verbal response (V) 
Oriented 
5 
Sounds 
4 
Words 
3 
Confused 
2 
None 
1 
Best motor response (M) 
Obeying commands 
6 
Localizing 
5 
Normal flexion (withdrawal) 
4 
Abnormal flexion 
3 
Extension 
2 
None 
1 
Total comma score 
3-15 
Source: Teasdale et al, 2014. 


V er si o n: 1. 0
Si g n at ur e P a g e 1  of 1
--- D o N ot D et a c h T hi s Si g n at ur e P a g e ---
gl b d ct m p
Pri nt D at e: 1 8- A u g- 2 0 2 1 0 9: 4 7: 5 3 G M T- 0 4: 0 0
Si g n at ur e P a g e
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Si g n e d B y
D at e ( G M T)
A p pr o v e d-
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1 7- S e p- 2 0 2 0 1 9: 4 9: 4 8
A p pr o v e d- Cli ni c al S af et y P h y si ci a n A p pr o v al
1 8- S e p- 2 0 2 0 0 6: 5 8: 5 4
A p pr o v e d-
 A p pr o v al
1 8- S e p- 2 0 2 0 1 2: 0 8: 0 3
P P D
P P D
P P D
P P D
P P D

SAP_001.pdf: 
SAP version: 1.0 
 
Page 1 of 49 
Date: 28 Aug 2020 
Confidential 
CS-SOP-01-F01 Version 2.0 
Effective Date: Week commencing 25-June-2018 
 
STATISTICAL ANALYSIS PLAN 
 
Study Title: A Phase 2, Multicenter, Double-blind, Randomized, Placebo-controlled 
Study to Evaluate CSL312 in Coronavirus Disease 2019 (COVID-19) 
Study Number: 
CSL312_COVID-19 
Study Product: 
CSL312 (Garadacimab, Factor XIIa Antagonist Monoclonal 
Antibody) 
Development Phase: 
Phase 2 
Sponsor: 
CSL Behring LLC 
1020 First Avenue 
King of Prussia, PA 19406 
United States of America 
Version: 
1.0 
Version Date: 
28 Aug 2020 
Compliance: 
This study will be conducted in accordance with standards of 
Good Clinical Practice (as defined by the International Council 
for Harmonisation) and all applicable national and local 
regulations.  
 
COMMERCIAL IN CONFIDENCE 
This document and the information contained herein are proprietary and confidential. This document 
and the contained information are intended for disclosure to and use by those personnel who are under 
an obligation of confidentiality by a signed agreement with the Sponsor (CSL Behring LLC). This 
document and the contained information may be disclosed and used only to the extent necessary to 
conduct the clinical study. Reproduction or disclosure of this document or its contained information is 
forbidden unless at the express request or with the written consent of CSL Behring LLC. 
 


 
C S L Be hri n g  
St u d y N u m ber:  C S L 3 1 2 _ C O VI D -1 9  
 
St u d y Pr o d uct:  C S L 3 1 2  
 
S A P versi o n: 1. 0 
 
Pa ge 2 of 4 9  
Date: 2 8 A u g  2 0 2 0  
C o nfi de ntial  
C S -S O P -0 1 -F 0 1 Versi o n 2. 0  
Effecti ve Date: Wee k c o m me nci n g 2 5 -J u ne-2 0 1 8  
Ta ble of C o nte nts  
Ta ble of C o nte nts ....................................................................................................................... 2 
 M o dificati o n Hist or y  ........................................................................................................... 6 
 List of A b bre viati o ns ........................................................................................................... 7 
 P ur p ose .............................................................................................................................. 1 0  
 St u d y Desi g n ...................................................................................................................... 1 0  
4. 1  
O bjecti ves a n d  E n d p oi nts .............................................................................................. 1 1  
 
Pri mar y O bjecti ve  ...................................................................................................... 1 1  
 
Pri mar y St u d y H y p ot heses ........................................................................................ 1 1  
 
Sec o n dar y O bj ecti ves  ................................................................................................ 1 2 
 
 
4. 2  
St u d y Treat me nts  ........................................................................................................... 1 4 
4. 3  
Ra n d o mizati o n Pr oce d ur es a n d Bli n di n g ...................................................................... 1 4  
4. 4  
Deter mi nati o n  of t he I nitial Sa m ple Size  ...................................................................... 1 4 
4. 5  
Pla n ne d I nteri m A n al yses a n d Re vie ws. ....................................................................... 1 5  
 
I D M C Re vie w Meeti n gs f or Safet y M o nit ori n g ....................................................... 1 5 
 
I D M C Re vie w Meeti n g f or F utilit y a n d Sa m ple Size Re -esti mati o n ........................ 1 5 
 C ha n ges fr o m t he Pr ot oc ol Pla n ne d A nal yses ................................................................... 1 5  
 St u d y A nal ysis Sets  ........................................................................................................... 1 5 
6. 1  
Scree ne d A n al ysis Set .................................................................................................... 1 5  
6. 2  
I nte nt-t o-treat A nal ysis Set ............................................................................................ 1 5 
6. 3  
M o difie d I nte nt- t o-Treat A nal ysis Set  ........................................................................... 1 6 
6. 4  
Safet y A n al ysis Set  ........................................................................................................ 1 6 
6. 5  
P har mac o ki netic A nal ysis Set  ....................................................................................... 1 6 
6. 6  
 
 Ge ner al C o nsi derati o ns ...................................................................................................... 1 7  
C CI
C CI


 
CSL Behring  
Study Number: 
CSL312_COVID-19 
 
Study Product: 
CSL312 
 
SAP version: 1.0 
 
Page 3 of 49 
Date: 28 Aug 2020 
Confidential 
CS-SOP-01-F01 Version 2.0 
Effective Date: Week commencing 25-June-2018 
 
Data Handling Conventions ............................................................................................... 17 
8.1 
Missing Data .................................................................................................................. 17 
8.2 
General Derived Variables ............................................................................................. 17 
 
Reference Dates and Study Day ................................................................................ 17 
 
Durations and Time to Event Data ............................................................................ 18 
 
Baseline Definition .................................................................................................... 19 
 
Change from Baseline ............................................................................................... 19 
 
Multiple Assessments ................................................................................................ 19 
 
Actual Treatment ....................................................................................................... 20 
 
Derived Variables ...................................................................................................... 20 
8.2.7.1 
Subgroup: Sex ........................................................................................................ 20 
8.2.7.2 
Subgroup: Age Group ............................................................................................ 20 
8.2.7.3 
Subgroup: Comorbidity ......................................................................................... 20 
8.2.7.4 
Subgroup: Use of Approved / Emergency-authorization Usage of Anti-COVID-19 
Drugs ...................................................................................................................... 21 
8.2.7.5 
Subgroup: Country ................................................................................................. 21 
8.3 
Study Periods Relative to Treatment ............................................................................. 21 
 
Study Population ................................................................................................................ 21 
9.1 
Subject Disposition ........................................................................................................ 21 
9.2 
Protocol Deviations / Reasons for Exclusion From Analysis Sets ................................ 22 
9.3 
Demographic and Baseline Characteristics ................................................................... 23 
9.4 
Prior/Concomitant Medications and Procedures ........................................................... 25 
 Efficacy .............................................................................................................................. 25 
10.1 Progression to Tracheal Intubation or Death Prior to Tracheal Intubation .................... 26 
 
Primary Estimand ...................................................................................................... 26 
 
Primary Efficacy Analysis ......................................................................................... 27 
 
Sensitivity Analyses for Progression to Tracheal Intubation or Death Prior to 
Tracheal Intubation .................................................................................................... 27 
10.1.3.1 
Tipping Point Analysis ........................................................................................... 28 


 
C S L Be hri n g  
St u d y N u m ber:  C S L 3 1 2 _ C O VI D -1 9  
 
St u d y Pr o d uct:  C S L 3 1 2  
 
S A P versi o n: 1. 0 
 
Pa ge 4 of 4 9  
Date: 2 8 A u g  2 0 2 0  
C o nfi de ntial  
C S -S O P -0 1 -F 0 1 Versi o n 2. 0  
Effecti ve Date: Wee k c o m me nci n g 2 5 -J u ne-2 0 1 8  
 
S u b gr o u p A nal yses f or Pr o gressi o n t o Trac h eal I nt u bati o n or Deat h Pri or t o Trac heal 
I nt u bati o n ................................................................................................................... 3 0 
1 0. 2  A nal ysis of Sec o n dar y E n d p oi nts .................................................................................. 3 0  
 
Sec o n dar y Efficac y A nal ysis  ..................................................................................... 3 1 
 
S u b gr o u p A nal yses f or Sec o n dar y Effi cac y E n d p oi nts ............................................. 3 3  
 
 
1 0. 3  M ulti ple C o m paris o ns a n d M ulti plicit y  ........................................................................ 3 5 
1 0. 4  Missi n g Data a n d I m p utati o n ........................................................................................ 3 5  
1 0. 5  Treat me nt C o m plia nce  .................................................................................................. 3 5 
 Safet y A n al yses  .................................................................................................................. 3 5 
1 1. 1  E xte nt of E x p os ure ........................................................................................................ 3 5  
1 1. 2  A d ver se E v e nts .............................................................................................................. 3 6 
1 1. 3  Cli nical La b orat or y E val uati o ns .................................................................................... 3 8  
1 1. 4  Ot her Safet y M eas ur es  .................................................................................................. 3 9 
 
Vital Si g ns  ................................................................................................................. 3 9 
 
Res pirat or y Tests  ....................................................................................................... 4 0 
 
Glas g o w C o ma Scale ( S O F A Sc ore C o m p o ne nt)...................................................... 4 0  
 
P h ysical E xa mi nati o n  ................................................................................................ 4 0 
 P har mac o ki netic A nal yses  ................................................................................................. 4 0 
1 2. 1  Dr u g C o nce ntr ati o n Meas ures ....................................................................................... 4 1  
1 2. 2  Deri vi n g a n d S u m marizi n g P har mac o ki netic Para meters  ............................................. 4 2 
 
 
1 3. 1  
 
 Refere n ces .......................................................................................................................... 4 5  
 A p pe n dices ........................................................................................................................ 4 6  
1 5. 1  P K Para meters  ............................................................................................................... 4 6 
1 5. 2  Se q ue ntial Or ga n Fail ur e Assess me nt ( S O F A) Scale  .................................................... 4 7 
C CI
C CI
C CI


 
CSL Behring  
Study Number: 
CSL312_COVID-19 
 
Study Product: 
CSL312 
 
SAP version: 1.0 
 
Page 5 of 49 
Date: 28 Aug 2020 
Confidential 
CS-SOP-01-F01 Version 2.0 
Effective Date: Week commencing 25-June-2018 
15.3 National Institute of Allergy and Infectious Diseases (NIAID) 8-point Ordinal Scale . 48 
15.4 Glasgow Coma Scale ..................................................................................................... 49 
 
 
 


 
CSL Behring  
Study Number: 
CSL312_COVID-19 
 
Study Product: 
CSL312 
 
SAP version: 1.0 
 
Page 6 of 49 
Date: 28 Aug 2020 
Confidential 
CS-SOP-01-F01 Version 2.0 
Effective Date: Week commencing 25-June-2018 
 Modification History 
Version 
Effective Date  
Author of 
Modification 
Reason for Change 
1.0 
28/AUG/2020 
 
N/A – First Version 
 
 
 
 
 
 
 


 
C S L Be hri n g  
St u d y N u m ber:  C S L 3 1 2 _ C O VI D -1 9  
 
St u d y Pr o d uct:  C S L 3 1 2  
 
S A P versi o n: 1. 0 
 
Pa ge 7 of 4 9  
Date: 2 8 A u g  2 0 2 0  
C o nfi de ntial  
C S -S O P -0 1 -F 0 1 Versi o n 2. 0  
Effecti ve Date: Wee k c o m me nci n g 2 5 -J u ne-2 0 1 8  
 List of A b bre vi ati o ns  
A b bre vi ati o n  
Defi niti o n  
 
 
A Da M  
A nal ysis D ata M o del 
A E  
A d verse e ve nt 
A E SI  
A d verse e ve nt of s pecial interest  
 
 
A T C  
A nat o mical T hera pe utic C he mical  
A U C 0- last 
Area u n d er t he plas ma c o nce ntrati o n -ti me c ur ve fr o m ti me zer o t o t he 
ti me of t he last meas ura ble c o nce ntrati o n 
 
 
Bi P A P  
Bi -le vel p ositi ve air wa y press ure 
B L Q  
Bel o w li mit of q ua ntificati o n  
B MI  
B o d y mass i n de x  
C DI S C  
Cli nical D ata Interc ha n g e Sta n dar ds C o ns orti u m 
CI  
C o nfi de nce i nter v al  
C ma x  
Ma xi m u m plas ma co nce ntrati o n  
C o V 
C or o na vir us 
C O VI D - 1 9 
C or o na vir us Disease  2 0 1 9 
C P A P  
C o nti n u o us p ositi ve air wa y press ure 
C R F  
Case Re p ort F or m  
C T C A E  
C o m m o n ter mi n ol o g y criteria f or a d vers e e ve nts 
C V %  
C oefficie nt of v ariati o n p erce nt a ge  
E C M O  
E xtrac or p oreal me m bra n e o x y ge nati o n  
E O S  
E n d of St u d y 
Fi O 2 
Fracti o n of i ns pire d o x y g e n 
H F N C  
Hi g h -fl o w nasal ca n n ula 
I C F 
I nf or me d c o ns e nt f or m 
 
 
I D M C 
I n de pe n de nt Data M o nit ori n g C o m mittee 
I F N 
I nterfer o n 
I L 
I nterle u ki n 
I N R 
I nter nati o nal n or malize d rati o 
C CI
C CI
C CI
C CI
C CI
C CI


 
C S L Be hri n g  
St u d y N u m ber:  C S L 3 1 2 _ C O VI D -1 9  
 
St u d y Pr o d uct:  C S L 3 1 2  
 
S A P versi o n: 1. 0 
 
Pa ge 8 of 4 9  
Date: 2 8 A u g  2 0 2 0  
C o nfi de ntial  
C S -S O P -0 1 -F 0 1 Versi o n 2. 0  
Effecti ve Date: Wee k c o m me nci n g 2 5 -J u ne-2 0 1 8  
A b bre vi ati o n 
Defi niti o n  
I P 
I n vesti gati o nal pr o d uct 
I R T 
I nteracti ve res p o nse t ec h n ol o g y 
I T T 
I nte nt-t o-treat 
I V 
I ntra ve n o us 
K M  
Ka pla n -Mei er  
L O S  
Le n gt h of sta y 
M A P  
Mea n art erial pr ess ure  
Me d D R A  
Me dical Dicti o nar y f or R e g ulat or y A cti vities  
mI T T  
M o difie d I nte nt- t o-treat 
n 
N u m ber of o bser vati o ns 
NI AI D  
Nati o nal I nstit ute of Aller g y a n d I nfecti o us Diseas es  
Pa O 2 
Partial press ure o x y g e n  
 
 
P K  
P har mac o ki netic  
P T  
Pr ot hr o m bi n ti me  
Sa O 2 
Peri p heral arterial o x y g e n sat urati o n 
S A E  
Seri o us a d verse e ve nt  
S A P  
Statistical a nal ysis pla n  
S A R S - C o V- 2 
Se vere ac ute r es pirat or y s y n dr o me c or o n a vir us- 2 
S A S  
Statistical A nal ysis S yste m  
S D  
Sta n dar d de viati o n  
S D T M  
St u d y Data Ta b ulati o n M o del 
S E  
Sta n dar d err or  
S M Q  
Sta n dar dize d Me d D R A Q uer y  
S O C  
Sta n dar d -of -car e  
S O F A  
Se q ue ntial Or ga n F ail ure A ssess me nt 
S p O 2 
Peri p heral o x y ge n s at urati o n 
T 1/ 2 
Ter mi nal half -lif e 
T E A E  
Treat me nt -e mer ge nt a d v erse e v e nt  
T E E  
T hr o m b oe m b olic e ve nt 
T F L  
Ta ble, fi g ure, a n d listi n g  
T N F  
T u m or necr osis fact or  
C CI


 
CSL Behring  
Study Number: 
CSL312_COVID-19 
 
Study Product: 
CSL312 
 
SAP version: 1.0 
 
Page 9 of 49 
Date: 28 Aug 2020 
Confidential 
CS-SOP-01-F01 Version 2.0 
Effective Date: Week commencing 25-June-2018 
Abbreviation 
Definition 
Tmax 
Time to maximum plasma concentration 
USA 
United States of America 
 
 


 
CSL Behring  
Study Number: 
CSL312_COVID-19 
 
Study Product: 
CSL312 
 
SAP version: 1.0 
 
Page 10 of 49 
Date: 28 Aug 2020 
Confidential 
CS-SOP-01-F01 Version 2.0 
Effective Date: Week commencing 25-June-2018 
 Purpose 
This statistical analysis plan (SAP) provides a detailed and complete description of the 
planned final analysis for the study CSL312_COVID-19. Mock table, figure, and listing 
(TFL) shells will be provided in a separate supporting document along with details for the 
practical implementation of the analyses. 
This SAP complies with the International Council for Harmonisation E9 ‘Statistical 
Principles for Clinical Trials’ and E9 (R1) ‘Statistical Principles for Clinical Trials: 
Addendum: Estimands and Sensitivity Analysis in Clinical Trials’. It is based upon the 
following study documents: 
• Study Protocol Amendment 2 (dated 25 Aug 2020) 
• Case Report Form (CRF), Version 1.0 (dated 03 Jun 2020) 
• Independent Data Monitoring Committee (IDMC) SAP 1.0 (dated 28 Aug 2020) 
• CSL Behring’s response to comments from the Federal Drug Agency (1.11.3 Clinical 
Information Amendment)  
All decisions regarding the analysis of the study results, as defined in this version of the SAP, 
have been made before first unblinding for the IDMC analyses. 
 Study Design 
This is a prospective, phase 2, multicenter, randomized, double-blind, placebo-controlled, 
parallel-group study to assess the safety, pharmacokinetic (PK), and efficacy of intravenous 
(IV) administration of CSL312, administered in combination with standard-of-care (SOC) 
treatment, in subjects with COVID-19 (Figure 1). 
This study will enroll a total of approximately 124 subjects and will be conducted at 
approximately 25 investigational sites; at least 15 sites in the United States of America (USA) 
and up to 10 sites in Brazil. Eligible subjects will be randomized to receive CSL312+SOC or 
placebo+SOC in a 1:1 ratio before dosing on Day 1. 
After the first 62 subjects have completed the primary endpoint assessment or discontinued 
from the study prematurely, an interim analysis will be performed for futility monitoring and 
sample size re-estimation, which may result in an increase in the target sample size of up to 
248 subjects. 


 
CSL Behring  
Study Number: 
CSL312_COVID-19 
 
Study Product: 
CSL312 
 
SAP version: 1.0 
 
Page 11 of 49 
Date: 28 Aug 2020 
Confidential 
CS-SOP-01-F01 Version 2.0 
Effective Date: Week commencing 25-June-2018 
The study consists of a Screening Period (up to 2 days) and a 28-days Treatment Period. If 
Screening occurs on Day 1, the assessments scheduled to occur at both on Screening and 
before dosing on Day 1 may be performed only once (i.e., do not need to be repeated). 
During the Treatment Period, CSL312+SOC or placebo+SOC will be administered once on 
Day 1. 
Figure 1 
Study Design 
 
ICF = informed consent form; PBO = placebo; SOC = standard-of-care. 
The schedule of assessments can be found in the protocol. 
4.1 
Objectives and Endpoints 
 Primary Objective 
The primary objective of the study is to assess the treatment benefit of CSL312 after IV 
infusion in patients with COVID-19. 
 Primary Study Hypotheses 
The study is designed to test the null (H0) and the alternative (HA) hypotheses for the risk 
difference as defined below: 
H0: πCSL312 – πplacebo ≥ 0 
HA: πCSL312 – πplacebo < 0 
Where πCSL312 is the risk to progress to tracheal intubation or die before tracheal intubation in 
the CSL312 group and πplacebo is the risk to progress to tracheal intubation or die before 
tracheal intubation in the placebo group. Under the null hypothesis, the assumption is that no 
beneficial effect is afforded by CSL312, while the alternative hypothesis states that 


 
C S L Be hri n g  
St u d y N u m ber:  C S L 3 1 2 _ C O VI D -1 9  
 
St u d y Pr o d uct:  C S L 3 1 2  
 
S A P versi o n: 1. 0 
 
Pa ge 1 2  of 4 9  
Date: 2 8 A u g  2 0 2 0  
C o nfi de ntial  
C S -S O P -0 1 -F 0 1 Versi o n 2. 0  
Effecti ve Date: Wee k c o m me nci n g 2 5 -J u ne-2 0 1 8  
C S L 3 1 2 + S O C is effecti ve i n re d uci n g t he ris k t o pr o gress t o trac heal i nt u b ati o n or die 
bef ore tr ac h eal i nt u bati o n c o m pare d t o t he place b o  + S O C gr o u p. 
 Sec o n d ar y O bjecti ves  
T he sec o n d ar y o bjecti ves of t he st u d y are: 
1.  To f urt her assess t he effi cac y of C S L 3 1 2 
2.  To assess t he saf et y of C S L 3 1 2 
3.  To assess t he P K of C S L 3 1 2 
 
 
Ta ble  1 
St u d y O bjecti ves a n d E n d p oi nts  
O bjecti ves  
E n d p oi nts  
S u m m ar y Me as ure(s)  
Pri m ar y  
I nci de nce of trac heal 
i nt u bati o n or deat h pri or t o 
trac heal i nt u bati o n 
Pr o p orti o n of s u bjects pr o gressi n g t o 
trac heal i nt u bati o n or d yi n g pri or t o trac heal 
i nt u bati o n fr o m ra n d o mizati o n t o Da y 2 8 
Sec o n d ar y  
1  
All -ca use m ortalit y  
Pr o p orti o n of deat hs fr o m all ca uses 
occ urri n g fr o m ra n d o mizati o n t o Da y 2 8 
1  
I nci de nce of trac heal i nt u bati o n 
Pr o p orti o n of s u bjects i nt u bate d fr o m 
ra n d o mizati o n t o Da y 2 8 
1  
Cli nical stat us as assesse d o n a n 8 -p oi nt 
Nati o nal I nstit ute of Aller g y a n d 
I nfecti o us Diseases ( NI AI D) or di nal 
scale 
•  N u m ber a n d pr o p orti o n of s u bjects wit h 
≥ 2- p oi nt i m pr o ve me nt i n t he or di nal 
scale 
•  N u m ber a n d pr o p orti o n of s u bjects wit hi n 
eac h of t h e cat e g ories of t he or di nal scale  
1  
Use of c o nti n u o us p ositi ve air wa y 
press ure ( C P A P) or bi -le vel p ositi ve 
air wa y pr ess ure ( Bi P A P)  
Pr o p orti o n of s u bjects usi n g C P A P or 
Bi P A P  
C CI
C
C
I
C CI


 
C S L Be hri n g  
St u d y N u m ber:  C S L 3 1 2 _ C O VI D -1 9  
 
St u d y Pr o d uct:  C S L 3 1 2  
 
S A P versi o n: 1. 0 
 
Pa ge 1 3  of 4 9  
Date: 2 8 A u g  2 0 2 0  
C o nfi de ntial  
C S -S O P -0 1 -F 0 1 Versi o n 2. 0  
Effecti ve Date: Wee k c o m me nci n g 2 5 -J u ne-2 0 1 8  
O bjecti ves  
E n d p oi nts  
S u m m ar y Me as ure(s)  
1  
Use of hi g h -fl o w n asal ca n n ula ( H F N C) 
Pr o p orti o n of s u bjects usi n g H F N C 
1  
Use of e xtr ac or p oreal me m bra ne 
o x y ge nati o n ( E C M O) 
Pr o p orti o n of s u bjects re q uiri n g E C M O 
1  
C ha n ge i n Se q ue ntial Or ga n Fail ure 
Assess me nt ( S O F A) sc or e  
•  Me dia n of ma xi m u m c ha n ge fr o m 
b aseli ne i n S O F A sc ore  
•  C ha n ge fr o m b as eli ne i n S O F A sc ore a n d 
i n t he i n di vi d ual c o m p o ne nts of S O F A 
sc ore 
1  
H os pital le n gt h of sta y ( L O S)  
•  Me dia n L O S i n h os pital sta y 
2  
S u bjects e x perie n ci n g t he f oll o wi n g 
safet y e v e nts: 
•  A d verse e ve nts ( A Es)  
•  Seri o us a d verse e ve nts ( S A Es)  
•  A d verse e ve nts of s pecial i nterest 
( A E SIs) 
•  C S L 3 1 2-i n d uce d a nti- C S L 3 1 2 
a nti b o dies 
•  Cli nicall y si g nifica nt a b n or malities i n 
la b orat or y ass ess me nt t hat are 
re p orte d as A Es 
N u m ber a n d pr o p orti o n of s u bjects 
e x perie n ci n g t he s pecifi e d safet y e v e nts 
after treat me nt wit h C S L 3 1 2 or place b o  
3  
C S L 3 1 2 P K i n plas ma:  
•  Ma xi m u m plas ma c o nce ntrati o n 
( Cma x ) 
•  Ti me t o ma xi m u m plas ma 
c o nce ntr ati o n ( T ma x ) 
•  Area u n d er t he plas ma 
c o nce ntr ati o n -ti me c ur ve fr o m ti me 
zer o t o t he ti me of t he last meas ura ble 
c o nce ntr ati o n ( A U C 0- last) 
•  Ter mi nal half -lif e ( T1/ 2) 
•  Mea n ( ± sta n dar d de viati o n [ S D]) a n d 
ge o metric mea n ( ge o metric c oefficie nt of 
variati o n perce nta ge [ C V %]) f or all P K 
para meters e xce pt T ma x . 
•  Me dia n ( mi ni m u m, ma xi m u m) f or T
ma x  
C CI


 
CSL Behring  
Study Number: 
CSL312_COVID-19 
 
Study Product: 
CSL312 
 
SAP version: 1.0 
 
Page 14 of 49 
Date: 28 Aug 2020 
Confidential 
CS-SOP-01-F01 Version 2.0 
Effective Date: Week commencing 25-June-2018 
4.2 
Study Treatments 
Subjects will be randomized to receive a single dose of CSL312 or placebo along with SOC. 
4.3 
Randomization Procedures and Blinding  
Randomization and blinding procedures are described in the protocol. Randomization will be 
conducted using an interactive response technology (IRT). Subjects will be randomly 
assigned to treatment with either CSL312 + SOC or placebo + SOC using a 1:1 
randomization ratio and stratified by country (USA or Brazil). A centralized randomization 
schedule will be used. The randomization list will be generated according to the approved 
randomization specifications. The IRT service provider will keep the randomization code on 
file. 
Study unblinding will take place after database lock, except in the situations as outlined in 
protocol sections 5.1.3.2, 5.1.3.3, and 5.1.3.4 related to emergency unblinding and unblinding 
for safety reasons. 
Adequate procedures are in place to ensure the integrity of the blinded data within CSL. 
Study data will be provided to the IDMC as unblinded data. 
The analyses planned for the IDMCs are described in a separate IDMC SAP. 
4.4 
Determination of the Initial Sample Size 
There are limited data on the rates of subjects with COVID-19 who progress to tracheal 
intubation or death prior to tracheal intubation within 28 days. For sample size calculation, a 
rate of 30% in the control group and a rate of 10% in the CSL312 group have been assumed. 
With a 1-sided α = 0.025 (which is equivalent to a 2-sided α = 0.05) and 1:1 randomization 
ratio for CSL312 + SOC versus placebo + SOC, a total of 124 subjects need to be 
randomized (62 subjects to CSL312 + SOC and 62 subjects to placebo + SOC) to achieve 
80% power to show superiority using a 2 group chi-square test. For the sample size 
calculation, it is further confirmed using simulations performed in East 6.5 that 80% power is 
maintained, accounting for the interim analysis for futility and sample size re-estimation. 
Depending on the results after the interim analysis, the sample size may by increased up to 
248 subjects (124 subjects in CSL312 + SOC and 124 subjects in placebo + SOC). 


 
CSL Behring  
Study Number: 
CSL312_COVID-19 
 
Study Product: 
CSL312 
 
SAP version: 1.0 
 
Page 15 of 49 
Date: 28 Aug 2020 
Confidential 
CS-SOP-01-F01 Version 2.0 
Effective Date: Week commencing 25-June-2018 
4.5 
Planned Interim Analyses and Reviews. 
 IDMC Review Meetings for Safety Monitoring 
Four IDMC review meetings are planned to monitor the critical safety data. Ad-hoc meetings 
are possible. Details are specified in the IDMC SAP.  
 IDMC Review Meeting for Futility and Sample Size Re-estimation 
The IDMC will convene for an interim analysis meeting when the unblinded analysis of the 
key efficacy data (primary endpoint assessment plus premature study discontinuations) from 
the first 62 subjects (50% of the target sample size) is available to assess futility and the need 
for a sample size re-estimation. Details are specified in the IDMC SAP. 
The analyses to be provided for the IDMC meetings are specified in the IDMC SAP. 
 Changes from the Protocol Planned Analyses 
There are no changes to the analyses planned as specified in the study protocol. 
 Study Analysis Sets 
6.1 
Screened Analysis Set 
The Screened Analysis Set comprises all subjects who provide written informed consent and 
who complete all of the Screening procedures. 
Technical Note: Subjects with informed consent date and an eligibility assessment available 
will be included. 
6.2 
Intent-to-treat Analysis Set 
The Intent-to-treat (ITT) Analysis Set comprises all subjects in the Screened Analysis Set 
who were randomly assigned to treatment. The ITT Analysis Set will be analyzed using the 
treatment to which the subject was randomized, regardless of the treatment actually received. 
Any subject who receives a treatment randomization number will be considered to have been 
randomly assigned to treatment. 
Technical Note: Subjects in the Screened Analysis Set who have a randomization number will 
be included. 


 
C S L Be hri n g  
St u d y N u m ber:  C S L 3 1 2 _ C O VI D -1 9  
 
St u d y Pr o d uct:  C S L 3 1 2  
 
S A P versi o n: 1. 0 
 
Pa ge 1 6  of 4 9  
Date: 2 8 A u g  2 0 2 0  
C o nfi de ntial  
C S -S O P -0 1 -F 0 1 Versi o n 2. 0  
Effecti ve Date: Wee k c o m me nci n g 2 5 -J u ne-2 0 1 8  
6. 3  
M o difie d Inte nt -t o- Tre at A n al ysis Set 
T he M o difie d I nte nt- t o-tr eat ( mI T T) A n al ysis Set c o m prises all s u bjects i n t he I T T A nal ysis 
Set w h o were ra n d o mize d  a n d recei ve d a n y a m o u nt of st u d y treat me nt ( C S L 3 1 2 + S O C or 
place b o  + S O C). I n t he mI T T A n al ysis Set, a nal yses will be base d o n t he treat me nt t o w hic h 
s u bjects were ra n d o ml y assi g ne d, re gar dl ess of w hic h treat me nt t he y act uall y recei v e d.  
Tec h nical N ote:  S u bjects i n t he I T T A nal ysis Set w h o recei ve  a n y a m o u nt of i n vesti gati o nal 
pr o d uct ( I P) e nt ere d i n t h e C R F will be i ncl u de d. 
6. 4  
S afet y A n al ysis Set 
T he Safet y A nal ysis Set c o m prises all s u bjects i n t he I T T A nal ysis Set w h o recei v e a n y 
a m o u nt of I P ( C S L 3 1 2 + S O C or place b o  + S O C ) a n d a nal yses  will be b a se d o n t he act ual 
treat me nt recei ve d. 
Tec h nical N ote:  S u bjects i n t he I T T A n al ysis Set  w h o  recei ve a n y a m o u nt of I P  e ntere d i n t he 
C R F will be i ncl u de d. 
6. 5  
P h ar m ac o ki netic A n al ysis Set  
T he P K A nal ysis Set c o m prise s all s u bjects i n t he Safet y A nal ysis Set w h o recei v e d a n y 
a m o u nt of C S L 3 1 2 + S O C a n d ha ve ≥ 1 bl o o d sa m ple a vaila ble after a d mi nistrati o n of 
C S L 3 1 2 f or C S L 3 1 2 c o nce ntrati o n meas ure me nt. P K a nal yses will n ot be perf or me d f or 
s u bjects w h o ar e treat e d wit h place b o + S O C.  
Tec h nical N ote:  S u bjects i ncl u de d i n t he Safet y A nal ysis Set  w h o recei ve d C S L 3 1 2 a n d w h o 
ha ve at least 1 bl o o d sa m ple f or C S L 3 1 2 c o nce ntrati o n meas ure me nt  after a d mi nistrati o n of 
C S L 3 1 2 a vaila ble will be i ncl u de d.  
6. 6  
 
 
 
 
 
 
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 General Considerations 
Datasets submitted to regulatory agencies will be created according to Clinical Data 
Interchange Standards Consortium (CDISC) standards. Submission data will be provided in 
Study Data Tabulation Model (SDTM) format. Analysis data will be provided in Analysis 
Data Model (ADaM) format. 
Statistical Analysis System (SAS) version 9.4 or higher will be used to perform all data 
analyses. 
Continuous variables will be summarized in terms of the number of observations (n), mean, 
SD, median, first quartile, third quartile, minimum and maximum. Other descriptive statistics 
(e.g., standard error [SE], CV%) may be reported when appropriate. For repeated assessments 
of continuous variables, the change from baseline will also be summarized. Categorical 
variables will be summarized using frequency counts and percentages. Analyses that use 
other descriptive statistics will have the specific descriptive statistics identified with the 
analysis in the applicable SAP section. 
Statistical tests will be 1-sided and will be performed at an alpha level of 0.025 unless 
otherwise stated. 
 Data Handling Conventions 
8.1 
Missing Data 
Missing data occurs when any requested data is not provided, leading to blank fields on the 
collection instrument. These data will be indicated using a “blank” in subject listing displays. 
Answers such as “Not applicable” and “Not evaluable” are not considered to be missing data 
and should be displayed as such. 
The details of handling missing data are presented in the corresponding SAP sections (e.g., 
primary and secondary efficacy analyses, safety analyses). 
8.2 
General Derived Variables 
The following sections provide a general description of the derived variables for data 
analyses. 
 Reference Dates and Study Day 
Reference dates are used to assign study periods relative to IP.  


 
C S L Be hri n g  
St u d y N u m ber:  C S L 3 1 2 _ C O VI D -1 9  
 
St u d y Pr o d uct:  C S L 3 1 2  
 
S A P versi o n: 1. 0 
 
Pa ge 1 8  of 4 9  
Date: 2 8 A u g  2 0 2 0  
C o nfi de ntial  
C S -S O P -0 1 -F 0 1 Versi o n 2. 0  
Effecti ve Date: Wee k c o m me nci n g 2 5 -J u ne-2 0 1 8  
•  T he ref er e nce d ate  f or safet y, 
 a n d P K is t he start date  (a n d ti me) of treat me nt  (i.e., t he 
date  [a n d ti me] of t he a d mi nistrati o n of I P) a n d will be use d t o calc ulate t h e st u d y da y a n d 
t o assess t he baseli ne val ue t o calc ulate c ha n g es fr o m baseli ne or s hifts t o baseli ne. 
•  T he ref er e nce d ate f or efficac y is t he date (a n d ti me) of ra n d o mizati o n a n d will be use d t o 
calc ulate t he ti me i nter val f or t he efficac y ti me -t o-e ve nt e n d p oi nts a n d t o assess t he 
baseli ne val ue t o calc ulat e c ha n g es fr o m bas eli ne or s hifts t o baseli ne . 
If t he date of i nterest occ urs o n or after t he refere n ce date, t h e n t he st u d y da y will be 
calc ulate d as ( date of i nterest - refer e nce date) + 1. If t he date of i nterest occ urs bef ore t he 
refere nce date, t h e n t he st u d y da y will be calc ulat e d as ( dat e of i nterest - refere n ce d ate). 
T here is n o st u d y da y 0. 
 D ur ati o ns a n d Ti m e t o E ve nt D at a 
D urati o ns (e. g., t he d urati o n of a n A E ) cal c ulate d i n f ull da ys (if ti me is n ot a vaila ble) or i n 
partial  da ys (if ti me is a v aila ble ) a re defi ne d as  
•  e ve nt e n d dat e - e v e nt start date + 1 , if ti me is n ot a vaila ble; 
•  e ve nt e n d dat e a n d ti me - e ve nt start date a n d ti me, if b ot h e n d ti me a n d start ti me are 
a vaila ble. I n t his case, t h e d urati o n nee ds t o b e tra nsf or me d t o da ys. 
T h us, t here will be n o d urati o n of 0  if t he ti me is n ot a vaila ble. If a n e ve nt h as missi n g or 
partiall y missi n g start or e n d date n o d urati o n will be calc ul ate d. F or d urati o ns w hic h us uall y 
last less t ha n a da y ( e. g., t he d urati o n of a n i nf usi o n), t he d urati o n will o nl y be calc ul ate d if 
start a n d e n d ti me ar e a v aila ble. 
F or ela pse d ti me ( e. g., t h e ti me t o e ve nt), use  
•  e ve nt date - ref er e nce d ate, if ti me is n ot a vaila ble; 
•  e ve nt date a n d ti me - refere nce d ate a n d ti me, if b ot h e ve nt a n d refere nce ti me are 
a vaila ble. T his will  re q uire tra nsf or mati o n t o t he desire d u nit (e. g., da ys). 
T h us, a n e ve nt w hic h h a p pe ns o n t he sa me dat e as t he refere n ce dat e will ha ve a n ela pse d 
ti me of 0, if e ve nt ti me or ref ere n ce ti me are n ot a vaila ble. F or t he a nal ysis of ti me -t o-e ve nt 
o bser vati o ns t hat ar e e q u al t o 0, t hese val ues will be set t o a ver y s mall val ue ( 0. 0 0 0 0 0 0 1) t o 
a v oi d t hat t he o bser vati o n is e xcl u de d fr o m t he a n al ysis i n s o me S A S pr oce d ures. 
To tra nsf or m d ur ati o ns or ela pse d ti me  w hic h are calc ulate d i n da ys i nt o wee ks , di vi de t he 
n u m ber of da ys b y 7; t o r e p ort i n m o nt hs di vi de t he n u m ber of d a ys b y 3 0. 4 3 7 5; t o re p ort i n 
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years divide the number of days by 365.25. These algorithms return decimal numbers and 
ignore the actual numbers of days in the months or years between start date and stop date 
(i.e., the calendar days are ignored). The "year" used in these algorithms is 365.25 days long, 
and the "month" is one twelfth of that year. 
 Baseline Definition 
For efficacy endpoints, baseline is defined as the most recent, non-missing value before 
randomization (including unscheduled visits) unless otherwise stated. If no value before 
randomization exists, the most recent, non-missing value before IP administration will be 
used as baseline value. 
For safety, baseline is defined as the most recent, non-missing value before IP administration 
(including unscheduled visits) unless otherwise stated. 
 Change from Baseline 
Change from baseline is calculated as: 
• visit value - baseline value. 
Percentage change from baseline is calculated as: 
• (change from baseline / baseline value) * 100. 
If either the baseline or visit value is missing, the change from baseline and percentage 
change from baseline will also be missing. 
 Multiple Assessments 
All data will be reported according to the nominal visit date for which it was assessed (i.e., no 
visit windows will be applied during dataset creation and the visit will not be re-allocated if 
the actual visit date deviates from the planned date according to the visit schedule in the 
protocol). Unscheduled data will not be included in by-visit summaries, but may contribute to 
the Baseline value, the End of Study (EOS) value, or best/worst case value (e.g., shift tables) 
and will be displayed in the listings. 
If multiple assessments on the same day or on different days are reported for the same 
scheduled visit, then the assessment for that scheduled visit will be analyzed according to the 
following rules: 
• if an assessment was repeated as safety follow-up (e.g., laboratory value out of normal 
range) use the initial, abnormal assessment for that scheduled visit; 


 
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• in all other cases, use the last valid assessment for that scheduled visit; rationale: the 
assessment was repeated either because the initial assessment was missing or invalid 
(e.g., due to technical issues, loss of sample, clotting of sample or other reasons of this 
type) or the assessment was repeated but the reasons were not collected or unknown. 
Data from all assessments (scheduled and unscheduled), including multiple assessments, will 
be included in the listings. 
 Actual Treatment 
The subject’s actual treatment will be derived from the exposure data (kit number from drug 
administration). If a subject receives a study treatment different from the randomized 
treatment, the actual treatment is the treatment received. 
 Derived Variables 
The derived variables used for the analysis will be defined and specified in detail in the 
respective section of the SAP. 
8.2.7.1 
Subgroup: Sex 
• Male; 
• Female. 
8.2.7.2 
Subgroup: Age Group 
• < 65 years; 
• ≥ 65 years of age. 
For the demography table, additional categories for subjects < 65 years of age will be 
displayed: 
o < 18 to 29 years; 
o 30 to 39 years; 
o 40 to 49 years; 
o 50 to 64 years. 
These categories will not be used in the subgroup analyses for efficacy. 
8.2.7.3 
Subgroup: Comorbidity 
• Any comorbidity factor present: yes (including hypertension; diabetes; obesity, defined as 
body mass index [BMI] ≥ 30); 


 
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• Any comorbidity factor present: no. 
For assignment of comorbidity see Section 9.3. 
8.2.7.4 
Subgroup: Use of Approved / Emergency-authorization Usage of Anti-
COVID-19 Drugs 
• Any concomitant usage of anti-COVID-19 drugs during the trial: yes; 
• Any concomitant usage of anti-COVID-19 drugs during the trial: no. 
8.2.7.5 
Subgroup: Country 
• USA; 
• Brazil. 
8.3 
Study Periods Relative to Treatment 
Screening Period starts with the date (and time) of the signed informed consent and ends 
before the date (and time) of randomization. 
Treatment Period starts with the date (and time) of randomization and ends on the Day 28 
visit. 
EOS is at Day 28, the last day of the Treatment Period. 
 Study Population 
Unless otherwise stated, tables in this section will be based on the ITT Analysis Set. Listings 
will be based on the ITT Analysis unless otherwise stated. 
9.1 
Subject Disposition 
Number and percentage of subjects will be presented in a summary table for the Screened 
Analysis Set (where meaningful by treatment and total) including the following information: 
• Subjects who underwent Screening – only total; 
• Screening failures with reason for failure – only total; 
• Subjects randomized – by treatment and total; 
• Subjects randomized but not treated – by treatment and total; 
• Subjects treated – by treatment and total; 
• Subjects treated who completed the study – by treatment and total; 
• Subjects treated who discontinued from the study with reason – by treatment and total. 


 
C S L Be hri n g  
St u d y N u m ber:  C S L 3 1 2 _ C O VI D -1 9  
 
St u d y Pr o d uct:  C S L 3 1 2  
 
S A P versi o n: 1. 0 
 
Pa ge 2 2  of 4 9  
Date: 2 8 A u g  2 0 2 0  
C o nfi de ntial  
C S -S O P -0 1 -F 0 1 Versi o n 2. 0  
Effecti ve Date: Wee k c o m me nci n g 2 5 -J u ne-2 0 1 8  
Reas o ns f or st u d y disc o nti n uati o n will be prese nte d i n t he or der t he y are dis pla ye d i n t he 
C R F.  
N u m ber a n d p erce nta ge of ra n d o mize d s u bjects p er site a n d c o u ntr y will be prese nt e d.  
T he f oll o wi n g b y- s u bject listi n gs will be pr o vi de d i ncl u di n g all a vaila ble data: 
•  Ra n d o mizati o n s c he me b ase d o n t he I T T A n al ysis Set ; 
•  S u bject dis p ositi o n wit h date of Scree ni n g (i n cas e of re-scree ni n g, all scree ni n g rec or ds 
will be list e d), date (a n d ti me) of t he ra n d o mizati o n, date  (a n d ti me) of I P  a d mi nistrati o n, 
Da y  2 8 date/ dat e of wit h dra wal ; 
•  Scree ni n g f ail ures wit h r eas o n;  
•  S u bjects w h o disc o nti n ue d fr o m t he st u d y wit h reas o n f or disc o nti n uati o n. 
9. 2  
Pr ot oc ol D e vi ati o ns / Re as o ns f or E xcl usi o n Fr o m A n al ysis Sets 
A pr ot oc ol de viati o n occ urs w he n a n i n vesti gat or, site, or st u d y s u bject, d oes n ot a d here t o 
pr ot oc ol-sti p ulate d re q uir e me nts. De viati o ns will be assesse d b y C S L as t he y are re p orte d 
a n d t he n e val u ate d peri o dicall y d uri n g st u d y c o n d uct. 
I n t his st u d y, pr ot oc ol de viati o ns will n ot lea d t o e xcl usi o n of a s u bject fr o m a n a nal ysis set.  
Ot her reas o ns t ha n pr ot o c ol de viati o ns ma y e xist t o e xcl u de a s u bject fr o m a n a nal ysis set. 
T he fi nal decisi o n a b o ut t he assi g n me nt of s u bjects t o a nal ysis sets will be ma de d uri n g t he 
Bli n d Data Re vie w Meeti n g pri or t o data base l oc k.  
T he lis t of reas o ns pr ese nte d i n  Ta ble 2  ma y lea d t o e xcl usi o n of a s u bject fr o m a n a nal ysis 
set a n d will be disc usse d d uri n g t he Bli n d Data Re vie w Meeti n g. T he list ma y be m o difie d, 
a n d ot her r eas o ns ma y be a d de d. T he fi nal decisi o n a b o ut t he e xcl usi o n of s u bjects fr o m 
a nal ysis sets will be ma de d uri n g t he meeti n g a n d will be d oc u me nte d i n t he meeti n g 
mi n utes.  
Ta ble 2 
P ote nti al Re as o ns f or E xcl usi o n Fr o m a n A n al ysis Set 
Re as o n f or E xcl usi o n  
(P ote nti all y ) Le a di n g t o E xcl usi o n Fr o m  
I nf or me d c o ns e nt date missi n g 
Scree ne d, I T T, mI T T , Safet y, P K, 
 
N o eli gi bilit y assess me nt  
Scree ne d, I T T, mI T T , Safet y, P K, 
 
C CI
C CI


 
C S L Be hri n g  
St u d y N u m ber:  C S L 3 1 2 _ C O VI D -1 9  
 
St u d y Pr o d uct:  C S L 3 1 2  
 
S A P versi o n: 1. 0 
 
Pa ge 2 3  of 4 9  
Date: 2 8 A u g  2 0 2 0  
C o nfi de ntial  
C S -S O P -0 1 -F 0 1 Versi o n 2. 0  
Effecti ve Date: Wee k c o m me nci n g 2 5 -J u ne-2 0 1 8  
Re as o n f or E xcl usi o n  
(P ote nti all y ) Le a di n g t o E xcl usi o n Fr o m  
N ot ra n d o mize d  
I T T, mI T T , Safet y, P K, 
 
N ot treate d  wit h I P  
mI T T , Safet y, P K, 
 
N o bl o o d sa m ple a vaila ble f or C S L 3 1 2 
c o nce ntr ati o n  meas ure m e nt  after C S L 3 1 2 
a d mi nistrati o n  
P K  
N o bl o o d sa m ple a vaila ble f or t he a n al ysis of 
 
 
 
T he f oll o wi n g s u m maries f or n u m ber a n d p erce nt a ge of s u bjects will b e pr o vi de d b y 
treat me nt a n d t otal usi n g t he Scree n e d A n al ysis S et: 
•  N u m ber a n d p erce nta ge of s u bjects i n eac h of t he a nal ysis sets descri be d i n Secti o n 6 ; 
•  I ncl usi o n a n d e xcl usi o n criteria vi olati o ns; 
•  Reas o n s f or e x cl usi o n fr o m a n a nal ysis set. 
T he f oll o wi n g b y- s u bject listi n gs will be pr o vi de d base d o n t he Scree ne d A nal ysis Set : 
•  I ncl usi o n a n d e xcl usi o n criteria vi olati o ns ; 
•  All ot her pr ot oc ol de viati o ns; 
•  S u bject assi g n me nt t o a nal ysis sets a n d reas o ns f or e xcl usi o n. 
9. 3  
De m o gr a p hic a n d B aseli ne C h ar acteristics  
Descri pti ve statistics as s pecifie d i n Secti o n  7  will be pr o vi de d f or c o nti n u o us varia bles, 
n u m ber a n d perce nt a ge of s u bjects f or cate g ori cal varia bles.  
B MI  ( k g/ m2) will be calc ulate d as b o d y wei g ht ( k g) / hei g ht ( m)2. 
N u m ber of pac k- y ears   = ( pac ks s m o k e d per d a y) * ( years as a s m o ker) 
 
= n u m ber of ci garettes p er da y/ 2 0 * d urati o n of s m o ki n g ( years). 
D urati o n of s m o ki n g will be deri ve d fr o m start year of s m o ki n g a n d year of ra n d o mizati o n 
f or c urre nt s m o kers a n d usi n g t he st o p year of s m o ki n g f or f or mer s m o kers. 
C o m or bi dit y will be defi ne d as i n dicati o n f or t he prese nce of: 
C CI
C CI
C C
I
C C
I


 
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• hypertension; 
• diabetes or; 
• obesity, defined as BMI ≥ 30. 
For each subject, the presence and type of the above comorbidities will be identified. BMI 
will be used to assess obesity. The preferred terms entered for diabetes and hypertension in 
the medical history CRF page will be used to assess the comorbidity factors. CSL will 
provide a list of preferred terms indicative for diabetes or hypertension. 
The following summaries will be provided by treatment and total for the ITT and the mITT 
Analysis Set. 
• Demographic characteristics (age, race, ethnicity, sex, height, body weight, and BMI at 
Screening). In addition to summarization as a continuous variable, age will also be 
categorized and summarized by the categories given in Section 8.2.7.2; 
• Disease history (Positive SARS-CoV-2 test, time since onset of symptoms relative to 
randomization, time since admission to hospital relative to randomization, time since 
admission to ICU relative to randomization, chest-CT or chest-X-ray [yes, no], signs of 
interstitial pneumonia [yes, no]); 
• Smoking status and pack years of cigarettes for current and former smokers; 
• Comorbidity factors (yes, no) and type of comorbidity (hypertension, diabetes, obesity); 
• Medical history (coded using the Medical Dictionary for Regulatory Activities 
[MedDRA] – MedDRA version will be provided in the output) will be presented by 
System Organ Class and Preferred Term –medical history terms with end date / evidence 
for end date before informed consent date will be included; 
• Concomitant diseases –medical history terms with end date / evidence for end date on or 
after informed consent date will be included. 
The following by-subject listings will be provided based on the ITT Analysis Set: 
• Demographics and baseline characteristics; 
• Disease history (SARS-CoV-2 CRF page, chest-CT and chest-X-ray CRF page); 
• Smoking status, pack-years of cigarettes, and comorbidity factors; 
• Medical history and concomitant diseases; 
• Reproductive system findings, pregnancy tests, and contraception in man. 


 
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9.4 
Prior/Concomitant Medications and Procedures 
Prior/concomitant medications will be coded using the World Health Organization Drug 
Dictionary. The version will be provided in the output tables and listings. 
The reported medication will be classified as ‘Prior’, ‘Prior and Concomitant’ or 
‘Concomitant Only’: 
• ‘Prior’: if the subject has not taken any IP; or if the medication end date is before IP start 
date. If the medication end date is partially missing, the medication will only be assigned 
to ‘Prior’ if the partial date gives clear evidence that the medication stopped before IP 
start; 
• ‘Prior and Concomitant’: if the medication is not classified as ‘Prior’ or as ‘Concomitant 
Only’; 
• ‘Concomitant Only’: if the medication started on or after IP start date. If the medication 
start or end date are partially missing, the medication will only be assigned to 
‘Concomitant Only’ if the partial dates give clear evidence that the medication started on 
or after IP start. 
Concomitant medications, i.e., medications classified as ‘Concomitant Only’ or ‘Prior and 
Concomitant’, will be summarized for the ITT Analysis Set by treatment and total showing 
the number and percentage of subjects taking concomitant medications by Anatomical 
Therapeutic Chemical (ATC) classification level 4 and preferred term. If the ATC level 4 
coding is not available for a preferred term, the next available lower level ATC code will be 
used. 
Concomitant medications flagged as anti-COVID-19-drugs will be summarized by treatment 
and total with their ATC classification showing the number and percentages of subjects 
stratified by prior use, prior and concomitant use, and concomitant only use. The duration of 
anti-COVID-19 drug use will be summarized descriptively for the categories prior, prior and 
concomitant, and concomitant only. 
The following by-subject listings will be provided based on the ITT Analysis Set: 
• Prior/concomitant medication; 
• Use of anti-COVID-19 drugs. 
 Efficacy 
The randomized treatment will be used for the efficacy analyses described in this section. 


 
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10.1 Progression to Tracheal Intubation or Death Prior to Tracheal Intubation 
Progression to tracheal intubation will be defined as presence of a record for this procedure 
(“Endotracheal Intubation” ticked on the Respiratory Support CRF) with a start date from 
randomization to Day 28. All deaths will be reported as SAEs. An SAE with outcome “Death 
Related to Adverse Event” and SAE end date from randomization to Day 28 will be 
considered as death for the primary endpoint. 
 
Primary Estimand 
Clinical question of interest: Is there a treatment benefit of CSL312 after IV infusion in 
patients with COVID-19, i.e. does treatment with CSL312 + SOC reduce the risk to progress 
to tracheal intubation or to die prior to tracheal intubation in subjects with severe COVID-19 
disease while subjects are treated with SOC? 
The primary estimand in line with the primary interest of the study follows the treatment 
policy strategy and is described as follows: 
A. Subject population: the target subject population defined by eligibility criteria. 
B. Treatment condition of interest: One dose (700 mg) of IP (CSL312 + SOC or 
Placebo + SOC) via IV infusion on peripheral vein. 
C. Variable: subject’s progression to tracheal intubation or death prior to tracheal intubation 
at any time from randomization to Day 28. 
D. Intercurrent events: 
1. Concomitant use of anti-COVID-19 drugs. 
2. Early discontinuation of the study for any reason. 
3. Randomized without treatment. 
E. Population level summary: risk difference of progression to tracheal intubation or death 
prior to tracheal intubation (CSL312 + SOC minus placebo + SOC). 
In this study, the treatment policy strategy will be used for all intercurrent events. It is 
reasonable to assume for subjects who are losses to follow-up after hospital discharge likely 
not to have experienced the event under randomized treatment. If subjects are still in hospital 
after withdrawal from the study (but not withdrawal of consent), missing data is unlikely to 
occur. 


 
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Primary Efficacy Analysis 
The primary endpoint for this study is the risk of tracheal intubation or death prior to tracheal 
intubation from randomization to Day 28. The ITT Analysis Set will be used for the primary 
efficacy analysis. 
Subjects with less than 28 days of the Treatment Period (i.e., who discontinued from the 
study prematurely) and without documented intubation or death will be considered to not 
have progressed to tracheal intubation or died prior to tracheal intubation (see Section 
10.1.3). 
Firth logistic regression model including age as continuous covariate, treatment group, 
gender (male or female), country (USA or Brazil), and baseline comorbidities (yes or no) as 
categorical covariates in the model will be used to compare the risks of progression between 
the 2 treatment groups. Comorbidities will include hypertension, diabetes, and obesity 
(defined as BMI ≥ 30 kg/m2). A 1-sided p-value will be estimated from the model and the 
null hypothesis (see Section 4.1.2) will be rejected if that p-value is < 0.025. The risk 
difference and associated 2-sided 95% confidence interval (CI) will be estimated using the 
method described by Ge et al [2011]. 
 
Sensitivity Analyses for Progression to Tracheal Intubation or Death Prior 
to Tracheal Intubation 
The mITT Analysis Set will be used as sensitivity analysis for the primary analysis with the 
same endpoint and model as specified in Section 10.1.2. 
The ITT Analysis Set will be used as sensitivity analysis for the primary analysis assuming 
that subjects with less than 28 days of the Treatment Period (i.e., who discontinued from the 
study prematurely) and without documented intubation or death progressed to tracheal 
intubation or died prior to tracheal intubation using the same model as specified in Section 
10.1.2. 
Another sensitivity analysis will be conducted where the subjects who started use of 
anti-COVID-19 drugs after randomization will be considered as having experienced 
progression to tracheal intubation or died prior to tracheal intubation using the same model as 
specified in Section 10.1.2. 
For reference purpose, a complete-case analysis (i.e., including only subjects who completed 
Day 28 or who died) will also be done. 


 
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10.1.3.1 
Tipping Point Analysis 
Missing primary efficacy outcome is defined as subjects with less than 28 days of the 
Treatment Period and without documented tracheal intubation or death. Missing primary 
efficacy outcome will be imputed in a systematic way as having or not having experienced 
the event, where the event is progression to tracheal intubation or death prior to tracheal 
intubation. 
The purpose of the tipping point analysis is to show which combination of imputed values for 
the missing primary efficacy outcome may alter the result of the primary efficacy 
comparison. Thus, the tipping point analysis will only be performed if the primary efficacy 
analysis indicates a significant treatment effect. 
Analyses will be run for each possible combination of missing outcomes considering the 
subjects as not interchangeable: for each subject with missing outcome the two possible 
outcomes (1 = having experienced the event, 0 = not having experienced the event) will be 
imputed in combination with every other subject with missing outcome with the two possible 
outcomes of these subjects. This will result in 2m possible combinations, with m being the 
number of subjects with missing outcome in both treatment group combined. All 
combinations of imputed data will be analyzed with the primary model as specified in 
Section 10.1.2. 
The possible combinations will be derived as illustrated below for up to 4 subjects: 
Number of Subjects 
With Missing Outcome 
Possible Combinations* 
(Number of Analyses) 
Proportion of Subjects 
Experiencing the Event 
1 
2 (0, 1) 
0, 1 
2 
4 (00, 01, 10, 11) 
0, 0.5 (twice), 1 
3 
8 (000, 001, 010, 011, 100, 
101, 110, 111) 
0, 0.33 (three times), 0.67 (3 
times), 1 
4 
16 (0000, 0001, 0010, 0011, 
0100, 0101, 0110, 0111, 
1000, 1001, 1010, 1011, 
1100, 1101, 1110, 1111) 
0, 0.25 (4 times), 0.5 (6 times), 
0.75 (4 times), 1 


 
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0 = subject did not experience the event, 1 = subject experienced the event 
The treatment comparisons obtained from each combination will be classified into favorable 
(1-sided p-value < 0.025 symbolized by black color) and unfavorable (1-sided p-
value ≥ 0.025 symbolized by red color) and depicted in a graph where the x-axis and y-axis 
will present the proportion of subjects with missing endpoint imputed as having experienced 
the event for CSL312 + SOC and placebo + SOC, respectively. 
If each subject with missing outcome is combined with every other subject with missing 
outcome, there will be more than one combination with the same proportion of subjects 
having experienced the event if m > 1 as illustrated in the last column of the above table. The 
median p-value of the combinations with the same proportion of subjects having experienced 
the event will be used in the graph. 
An example for such a graphical display could look like this (the axes represent the number 
of missing subjects in this graph, but maybe translated to the proportion of subjects having or 
not having experienced the event): 
 
Red: 1-sided p-value ≥ 0.025, black: 1-sided p-value < 0.025 
The number of subjects with missing outcome in this study is expected to be small. However, 
if the number of subjects with missing outcome is large and all possible 2m combinations 
become too cumbersome for above described method to be implemented, an alternative 
method will be used (e.g., if appropriate, treating subjects as interchangeable, i.e., no 
covariates besides treatment will be included in the logistic regression model and there will 


 
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be (a+1)*(b+1) combinations for possible outcomes where a and b are the number of subjects 
with missing outcome in each treatment group, respectively).  
 
Subgroup Analyses for Progression to Tracheal Intubation or Death Prior to 
Tracheal Intubation 
Subgroup analyses by the variables defined in Sections 8.2.7.1, 8.2.7.2, 8.2.7.3, 8.2.7.4, and 
8.2.7.5 will be performed using the ITT Analysis Set as described above in Section 10.1.2. 
The logistic regressions will not include the factor for the respective subgroup analysis as 
independent variable (if applicable), but they will include the other covariates as specified for 
the primary analysis. 
A forest-plot will be provided for the estimated risk difference and 95% CIs for each 
subgroup level. 
10.2 Analysis of Secondary Endpoints 
Secondary Efficacy Endpoints are: 
• All-cause mortality: calculated as number of deaths of any cause from randomization to 
Day 28 divided by the number of subjects in the treatment group. All deaths will be 
entered as SAEs in the AE CRF. Thus, the information will be obtained from the AE CRF 
as SAEs with outcome “Death Related to Adverse Event” and SAE end date (death date) 
occurring within the 28 days of the Treatment Period. 
• Incidence of tracheal intubation from randomization to Day 28: calculated as number of 
subjects experiencing intubation from randomization to Day 28 divided by the number 
subjects in the treatment group. Tracheal intubation is defined as presence of a record for 
this procedure (“Endotracheal Intubation” ticked on the Respiratory Support CRF) with a 
start date during the 28 days of the Treatment Period. 
• Proportions of subjects using CPAP or BiPAP: calculated as number of subjects using 
CPAP or BiPAP within 28 days of randomization divided by the number subjects in the 
treatment group. Use of CPAP or BiPAP is defined as presence of a record for this 
procedure (“CPAP” or “BiPAP” ticked on the Respiratory Support CRF) with a start date 
during the 28 days of the Treatment Period. 
• Proportion of subjects using HFNC: calculated as number of subjects using HFNC within 
28 days of randomization divided by the number subjects in the treatment group. Use of 
HFNC is defined as presence of a record for this procedure (“HFNC” ticked on the 
Respiratory Support CRF) with a start date during the 28 days of the Treatment Period. 


 
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• Proportion of subjects using ECMO: calculated as number of subjects using ECMO 
within 28 days of randomization divided by the number subjects in the treatment group. 
Use of ECMO is defined as presence of a record for this procedure (“ECMO” ticked on 
the Respiratory Support CRF) with a start date during the 28 days of the Treatment 
Period. 
• Clinical status assessed on an 8-point NIAID ordinal scale as entered in the CRF. 
• Length of hospital stay defined as time interval from randomization to hospital discharge 
alive. The information will be derived from the SARS-CoV-2 CRF along with the AE 
CRF for the survival status (no SAE with outcome “Death Related to Adverse Event” 
reported). 
• Subject’s maximum SOFA score, subject’s maximum change from baseline in SOFA 
score, and subject’s mean SOFA score during the study will be calculated. 
 
Secondary Efficacy Analysis 
The ITT and mITT Analysis Set will be used for the secondary efficacy analyses. Number 
and percentage of subjects will be presented by treatment for the following secondary 
efficacy endpoints: 
• All-cause mortality; 
• Incidence of tracheal intubation; 
• Proportion of subjects using CPAP or BiPAP; 
• Proportion of subjects using HFNC; 
• Proportion of subjects using ECMO. 
The same statistical model and testing methodology as used for the primary efficacy variable 
will be used to compare the above secondary efficacy endpoints between the 2 treatments. 
The risk differences, associated 95% CIs, and 1-sided p-values will be reported. 
Subjects with less than 28 days of the Treatment Period and without documented secondary 
endpoints as defined above will be assumed as not having experienced the secondary 
endpoint. 
Clinical Status Assessed on an 8-Point NIAID Ordinal Scale 
Number and percentages of subjects within each category of the 8-point NIAID ordinal scale 
will be summarized by visit for each treatment group. Number and percentages of subjects 
with an improvement from baseline of ≥ 2 points will be analyzed by visit using descriptive 
statistics as specified in Section 7. 


 
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A bar chart showing the frequencies in each category of the scale in the segments of each bar 
for the two treatment groups by visit will be provided. 
Hospital Length of Stay 
Hospital LOS will be defined as the time interval from randomization to hospital discharge 
alive. Survival status will be obtained from the AE CRF as absence of an SAE with outcome 
“Death Related to Adverse Event”. In this analysis, for subjects who did not have a recorded 
date of hospital discharge and did not die, the time to hospital discharge will be censored at 
the last known in-hospital date if the subject did not complete the 28-day Treatment Period 
(i.e., the date of premature study discontinuation). For subjects who do not have a hospital 
discharge event or censoring time within the 28 days after randomization or for subjects who 
have died, an administrative censoring will be applied at 28 days. 
Hospital LOS will be analyzed using Cox proportional hazard model including age as a 
continuous covariate, treatment group, gender (male or female), country (USA or Brazil), and 
baseline comorbidities (yes or no) as categorical covariates in the model. The hazard ratio, its 
95% CI and 1-sided Wald p-value will be estimated from the model. Cumulative event rates 
will be calculated using the Kaplan-Meier (KM) method. The effect over time will be 
illustrated with a plot of the complement (1 – KM) of the KM estimates. Event counts and 
percentages will be summarized. If ties occur, Efron’s method will be used to adjust for ties. 
Sequential Organ Failure Assessment 
The SOFA score assesses organ failure. A subject who does not fall into grade 1 to 4 in any of 
the components will be assigned a grade 0, representing no organ failure. The SOFA score is 
calculated as the summation of the six components grades. For the component ‘Respiration’, 
the grade for partial pressure oxygen (PaO2)/ fraction of inspired oxygen (FiO2) ratio 
(mmHg) will be used, if it is missing, the grade for peripheral arterial oxygen saturation 
(SaO2)/FiO2 ratio (mmHg) will be used. 
Maximum SOFA score, maximum change from baseline in SOFA score, and mean SOFA 
score during the study will be calculated for each subject and summarized descriptively as 
specified in Section 7 by treatment group. Median differences in maximum SOFA score, 
maximum change from baseline in SOFA score, and mean SOFA score during the study 
between treatment groups and 95% CIs using Hodges-Lehmann’s method will be reported. 
Non-parametric Wilcoxon rank-sum test will be used to compare the 2 treatment groups. 


 
C S L Be hri n g  
St u d y N u m ber:  C S L 3 1 2 _ C O VI D -1 9  
 
St u d y Pr o d uct:  C S L 3 1 2  
 
S A P versi o n: 1. 0 
 
Pa ge 3 3  of 4 9  
Date: 2 8 A u g  2 0 2 0  
C o nfi de ntial  
C S -S O P -0 1 -F 0 1 Versi o n 2. 0  
Effecti ve Date: Wee k c o m me nci n g 2 5 -J u ne-2 0 1 8  
T he S O F A sc ore a n d its c o m p o ne nts will be s u m marize d b y treat me nt a n d visit usi n g 
descri pti ve statistics as s pecifie d i n Secti o n 7  f or t he gra des a n d c h a n ge fr o m baseli ne i n t he 
gra des : 
•  Res pirati o n; 
•  C oa g ulati o n; 
•  Li ver;  
•  Car di o vasc ular;  
•  Ce ntral Ner v o us S yste m; 
•  Re nal.  
T he o bser ve d val ues of t he la b orat or y t ests, vital si g ns, res pirat or y, car di o vasc ular, or ce ntral 
ner v o us s yste m assess me nts al o n g wit h c ha n ges fr o m baseli ne of t he i n di vi d ual c o m p o ne nts 
w hic h fee d i nt o t he S O F A sc ore will be s u m marize d b y treat me nt a n d visit usi n g descri pti ve 
statistics as s pecifie d i n Secti o n 7  i n t he c orres p o n di n g secti o ns of t he Safet y a nal ysis. 
 S u b gr o u p A n al yses f or Sec o n d ar y Effic ac y E n d p oi nts  
S u b gr o u p a nal yses b y t h e varia bles d efi ne d i n Secti o ns 8. 2. 7. 1 , 8. 2. 7. 2 , 8. 2. 7. 3 , 8. 2. 7. 4 , a n d 
8. 2. 7. 5  will be perf or me d usi n g t he I T T A n al ysis Set as descri b e d i n Secti o n 1 0. 2. 1  f or t he 
f oll o wi n g sec o n dar y e n d p oi nts: 
•  All -ca use m ortalit y;  
•  I nci de nce of trac heal i nt u bati o n fr o m ra n d o mizati o n t o Da y 2 8; 
•  Cli nical stat us assesse d o n a n 8 - p oi nt NI AI D or di nal scale. 
T he l o gistic re gressi o ns will n ot i ncl u de t he fact or f or t he res pecti ve s u b gr o u p a nal ysis as 
i n de pe n de nt vari a ble  (if a p plica ble), b ut t he y will i ncl u de t he ot her c o v ariates as s pecifie d f or 
t he pri mar y a n al ysis. 
F orest - pl ots will be pr o vi de d f or t he treat me nt c o m paris o n a n d 9 5 % CIs f or eac h s u b gr o u p 
le vel. 
 
 
C CI
C CI


 
C S L Be hri n g  
St u d y N u m ber:  C S L 3 1 2 _ C O VI D -1 9  
 
St u d y Pr o d uct:  C S L 3 1 2  
S A P versi o n: 1. 0 
 
Pa ge 3 4  of 4 9  
Date: 2 8 A u g  2 0 2 0  
C o nfi de ntial  
C S -S O P -0 1 -F 0 1 Versi o n 2. 0  
Effecti ve Date: Wee k c o m me nci n g 2 5 -J u ne-2 0 1 8  
C CI


 
C S L Be hri n g  
St u d y N u m ber:  C S L 3 1 2 _ C O VI D -1 9  
 
St u d y Pr o d uct:  C S L 3 1 2  
S A P versi o n: 1. 0 
 
Pa ge 3 5  of 4 9  
Date: 2 8 A u g  2 0 2 0  
C o nfi de ntial  
C S -S O P -0 1 -F 0 1 Versi o n 2. 0  
Effecti ve Date: Wee k c o m me nci n g 2 5 -J u ne-2 0 1 8  
1 0. 3  M ult i ple C o m p aris o ns a n d M ulti plicit y 
T here will be  1 c o nfir mat or y test. All ot her statistical tests  are m ea nt t o be descr i pti ve. T he 
sa m ple size re-esti mati o n at t he i nteri m a nal ysis s h o ul d n ot ha ve a n i m pact o n t he Ty pe I 
err or rate acc or di n g t o C he n  et al [ 2 0 0 4] a n d Me ht a  a n d P oc oc k [2 0 1 1 ]. 
1 0. 4  Missi n g D at a a n d I m p ut ati o n 
F or t he pri mar y efficac y a nal ysis usi n g t he I T T A nal ysis Set, s u bjects  wit h less t ha n 2 8 da ys 
of t he Treat me nt Peri o d  a n d wit h o ut d oc u me nte d i nt u bati o n or deat h will be c o nsi dere d as 
n ot ha vi n g pr o gress e d t o trac heal i nt u bati o n or deat h  pri or t o trac heal i nt u bati o n i n t he 
pri mar y a nal ysis. 
S e nsiti vit y a nal ys es as descri be d i n Secti o n 1 0. 1. 3. 1  will be perf or me d t o assess t he i m pact of 
missi n g data o n t he pri mar y efficac y res ults. 
1 0. 5  Tre at m e nt C o m pli a nce  
Ra n d o mize d s u bjects will recei ve 1 d os e of I P a d mi nistere d b y st u d y pers o n ne l at t he 
h os pital. It is n ot e x pecte d t hat t here will be a n y c o m plia nce iss ues. 
 S afet y A n al yses 
T he  safet y a nal yses will be base d o n t he Safet y A nal ysis Set as defi ne d i n Secti o n 6  a n d o n 
t he treat me nt w hic h t he s u bject recei ve d. 
1 1. 1  E xte nt of E x p os ure 
S u bjects will recei ve 1 d ose of I P. D urati o n of e x p os ure is n ot rele va nt i n t his st u d y. D urati o n 
of f oll o w- u p is of i nterest as t his has a n i m pact o n t he re p orti n g of efficac y e ve nts a n d A Es. 
D urati o n of f oll o w- u p will be descri pti vel y s u m marize d b y treat me nt a n d t otal. T he d urati o n 
of f oll o w- u p is defi ne d as: 
S u bject’s d urati o n of f oll o w- u p ( da ys) = E O S date – date of ra n d o mizati o n + 1,  
w here E O S date is eit her Da y  2 8 or wit h dra wal dat e f or s u bjects w h o dis c o nti n ue d. 
C CI


 
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A summary table will be provided with descriptive statistics as specified in Section 7 for: 
• Duration of follow-up [days] per subject; 
• Volume [mL] received per subject. 
A by-subject listing will be provided based on the Safety Analysis Set including: 
• Infusion date, start and end time, and duration (if start and end time is available); 
• Volume administered [mL], location of infusion; 
• Dose modified with reason. 
11.2 Adverse Events 
AEs will be coded using MedDRA. The version will be presented in the tables and listings. 
Treatment-emergent AEs (TEAEs), defined as AEs starting on or after the date (and time) of 
the administration of IP will be summarized. All AEs will be listed regardless of their start 
date. 
Where AE start dates and/or times are missing or partially missing, AEs will be assumed to 
be treatment-emergent, except the partial dates and/or times or the AE end date and/or time 
indicate that the AE started before the first administration of IP: 
Missing Elements 
of AE Start 
Rule 
Assignment 
any 
AE end date and time < IP start date and time 
non-TEAE 
any 
AE end date and time ≥ IP start date and time 
TEAE 
otherwise 
 
 
all 
 
TEAE 
day and month 
AE start year ≥ IP start year 
TEAE 
AE start year < IP start year 
non-TEAE 
day 
AE start month / year ≥ IP start month / year 
TEAE 
AE start month / year < IP start month / year 
non-TEAE 
time 
AE start date ≥ IP start date 
TEAE 
AE start date < IP start date 
non-TEAE 
 
If AE start dates or end dates are missing or partially missing for an AE, duration will not be 
calculated. If for a TEAE the relationship to study treatment is missing the relationship to 
study treatment will be assumed to be “Yes” following a worst-case approach. No imputation 


 
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will be done in case of missing study treatment relationship for non-treatment emergent AEs. 
No other imputations for missing AE information will be done. 
TEAEs occurring within 24 hours of IP administration will be defined as TEAEs with start 
date and time during IP administration or until 24 hours after the end of IP administration. 
AEs with missing start time will be assigned following the worst-case principle, i.e. when the 
start date of the TEAE is less or equal than the end date of the infusion + 1, the TEAE will be 
considered to having occurred within 24 hours after IP administration. 
AEs fulfilling the definition of an AESI for this study will be ticked in the AE CRF. It will be 
ensured during data cleaning that the AESI recording on the AE CRF matches the AESI 
definition obtained by Standardized MedDRA Queries (SMQ): 
• Hypersensitivity events corresponding to Hypersensitivity (SMQ) (broad); 
• Anaphylactic reactions corresponding to Anaphylactic reaction (SMQ) (broad); 
• Thromboembolic events (TEE) corresponding to Embolic and thrombotic events (SMQ); 
• Bleeding events corresponding to Haemorrhages (SMQ). 
All summary tables will be presented by actual treatment and total.  
An overview summary table of TEAEs, including the number and percentage of subjects and 
the number of events will be provided for the following entries: 
• Any TEAE; 
• TEAEs related to study treatment; 
• TEAEs occurring within 24 hours of IP administration; 
• TEAEs leading to study discontinuation; 
• TEAEs leading to dose modifications; 
• Treatment-emergent AESIs; 
• Treatment-emergent AESIs related to study treatment; 
• Any serious TEAEs; 
• Serious TEAEs related to study treatment; 
• Serious TEAEs occurring within 24 hours of IP administration; 
• Fatal TEAEs; 
• Fatal TEAEs related to study treatment; 
• TEAEs by intensity. 


 
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The following tables will be generated for TEAEs, including the number and percentages of 
subjects and the number of events. The tables will always be sorted by System Organ Class 
(for tables including System Organ Class) and Preferred Term within System Organ Class or 
Preferred Term alone (for the table not including System Organ Class). The order of the 
System Organ Class blocks or the order of the Preferred Terms alone or within System Organ 
Class block (if applicable) will be by descending frequency of number of subjects using the 
total column (in case of equal number of subjects sorting will be by descending frequency of 
number of events, in case of equal number of events sorting will be alphabetically). 
• TEAEs by System Organ Class and Preferred Term; 
• TEAEs by Preferred Term; 
• TEAEs by System Organ Class, Preferred Term, and intensity; 
• Related TEAEs by System Organ Class and Preferred Term; 
• TEAEs occurring within 24 hours of IP administration by System Organ Class and 
Preferred Term; 
• Fatal TEAEs by System Organ Class and Preferred Term; 
• Treatment-emergent AESIs by System Organ Class and Preferred Term; 
• Serious TEAEs by System Organ Class and Preferred Term. 
The following by-subject listings based on the ITT Analysis Set will be provided including 
the information from the CRF: 
• Deaths; 
• Non-TEAEs; 
• TEAEs; 
• SAEs; 
• AEs leading to study discontinuation; 
• AESIs: hypersensitivity including anaphylactic reactions; 
• AESIs: TEEs; 
• AESIs bleeding events. 
11.3 Clinical Laboratory Evaluations 
The laboratory tests for hematology, biochemistry, and coagulation listed in the Schedule of 
Assessments of the protocol will be summarized (in the same sequence as in the protocol). 
Separate summary tables for hematology, biochemistry, and coagulation will be provided. 
Descriptive statistics as specified in Section 7 will be presented by treatment and total at 
scheduled visits for observed values and change from baseline. Number and percentage of 


 
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subjects will be presented for categorical tests by treatment and total at scheduled visits. The 
names and units of the laboratory tests will be used as provided in the data. 
The following laboratory tests feeding into the SOFA score (see Section 10.2.1) will be 
indicated in the laboratory summary tables as SOFA score components: platelet count, 
bilirubin, creatinine. These tests will also be flagged in the listings as components of the 
SOFA score. 
Laboratory values outside the normal range will be graded following Common Terminology 
Criteria for Adverse Events (CTCAE) 5.0 by clinical review. For laboratory tests with values 
outside normal range, the number and percentage of subjects in each grade will be presented. 
For the definition of the baseline assessment see Section 8.2.3. 
The denominator in percentage calculation at each scheduled visit will be based on the 
number of subjects with a non-missing value at each visit. 
By-subject listings will be provided based on the ITT Analysis Set (date [and time] of 
sampling, test result, normal range, comments if applicable will be presented in a separate 
listing): 
• Laboratory data for subjects with values outside the normal range; 
• Hematology tests including flags for values outside the normal range and change from 
baseline; 
• Biochemistry tests including flags for values outside the normal range and change from 
baseline; 
• Coagulation tests including flags for values outside the normal range and change from 
baseline; 
• Urinalysis tests. 
11.4 Other Safety Measures 
 
Vital Signs 
Vital signs (blood pressure [systolic, diastolic], heart rate, respiratory rate) will be 
summarized by treatment and total at scheduled visits and time points. Descriptive statistics 
as specified in Section 7 will be presented for observed values and change from baseline. 
For the definition of the baseline assessment see Section 8.2.3. 


 
C S L Be hri n g  
St u d y N u m ber:  C S L 3 1 2 _ C O VI D -1 9  
 
St u d y Pr o d uct:  C S L 3 1 2  
 
S A P versi o n: 1. 0 
 
Pa ge 4 0  of 4 9  
Date: 2 8 A u g  2 0 2 0  
C o nfi de ntial  
C S -S O P -0 1 -F 0 1 Versi o n 2. 0  
Effecti ve Date: Wee k c o m me nci n g 2 5 -J u ne-2 0 1 8  
A b y-s u bject listi n g will be pr o vi de d bas e d o n t he I T T A n al ysis Set ( date [a n d ti me] of 
assess me nt , s u bject’s p ositi o n, l ocati o n of b o d y te m perat ure m eas ure me nt, test [ bl o o d 
press ure : s yst olic a n d diast olic; heart  rate, res pirat or y rate, te m p erat ure, hei g ht a n d b o d y 
wei g ht at Scree ni n g ], test res ult, c ha n ge fr o m baseli ne). A n ot her b y-s u bject listi n g will be 
pr o vi de d f or t he h y p ote nsi o n assess me nt fee di n g i nt o t he S O F A s c ore.  
 Res pir at or y Tests  
Res pirat or y tests as e nter e d i n t he Res pirat or y Para meter C R F (res pirat or y rate, peri p heral 
o x y ge n sat urati o n [ S p O 2], Fi O 2, Pa O 2) will be s u m marize d b y treat me nt a n d t otal at 
sc he d ule d visits a n d ti me p oi nts. Descri pti ve statistics  as s pecifie d i n Secti o n 7  b y treat me nt 
gr o u p will be prese nte d f or o bser ve d v al ues a n d c ha n ge fr o m b aseli ne. T h e res pirat or y 
c o m p o ne nt of t he S O F A sc ore, Pa O 2/ Fi O2, will be a nal yze d i n t he sa me w a y as t he ot her 
res pirat or y tests. 
F or t he defi niti o n of t he baseli ne assess me nt see Secti o n 8. 2. 3 . 
A b y -s u bject listi n g will be pr o vi de d bas e d o n t he I T T A n al ysis Set ( date [a n d ti me] of 
assess me nt, test [res pir at or y rate, S p O 2, Fi O2, Pa O2, Pa O 2/ Fi O2], test res ult, c ha n ge fr o m 
baseli ne).  Pa O 2/ Fi O2will be fla g ge d i n t he listi n g as a c o m p o ne nt of t he S O F A sc ore. 
 Gl as g o w C o m a Sc ale ( S O F A Sc ore C o m p o ne nt)  
N u m ber a n d p erce nta ges of s u bjects i n t he res p o ns e cate g ories of t he 3 feat ures (e y e o pe ni n g, 
best ver bal r es p o nse, a n d best m ot or res p o nse) a n d descri pti ve statistics as s pecifie d i n 
Secti o n 7  f or t he t otal sc ore will be pres e nte d b y treat me nt gr o u p at sc he d ule d visits. 
A b y -s u bject listi n g will be pr o vi de d bas e d o n t he I T T A n al ysis Set ( date a n d ti me of t he 
assess me nt, feat ure, scale res p o nse, sc ore).  
 P h ysic al E x a mi n ati o n 
Date a n d assess me nt perf or me d f or p h ysical e xa mi nati o n will be liste d  base d o n t he I T T 
A nal ysis Set . 
 P h ar m ac o ki netic A n al yses  
T he P K a nal ysis will be perf or me d usi n g t he P K A nal ysis Set . 
 will c o n d uct t he d eri vati o n of t he P K para meters  u n der t he s u p er visi o n of t he C S L 
Be hri n g Cli nical P har mac ol o g y de part me nt . All n o nc o m part me ntal a n al yses will  be 
P P D


C S L Be hri n g 
St u d y N u m ber:  C S L 3 1 2 _ C O VI D -1 9  
St u d y Pr o d uct:  C S L 3 1 2  
S A P versi o n: 1. 0 
Pa ge 4 1  of 4 9  
Date: 2 8 A u g  2 0 2 0  
C o nfi de ntial  
C S -S O P -0 1 -F 0 1 Versi o n 2. 0  
Effecti ve Date: Wee k c o m me nci n g 2 5 -J u ne-2 0 1 8  
perf or me d acc or di n g t o P K -G D L - 0 1. PK  para met ers will be  deri ve d bas e d o n t he C S L 3 1 2 
c o nce ntr ati o n after th e ad mi nistrati o n of C S L 3 1 2 o n Da y 1. 
Aft er dat a base l oc k, C S L  will pr o d uce all SD T M d o m ai ns ne e ded f or the P K anal ysis . T he 
P C d o m ai n c o ntai ni n g t he C S L 3 1 2 c o nce ntrati o ns, n o mi nal bl o o d sa m pli n g ti mes, act ual 
sa m pli n g ti me relati ve to t he start of the d os e inf usi o n, act ual d os i n g a n d i nf usi o n d urati o ns 
a n d t he P P d o m ai n c o ntai ni n g t he P K pa ra meters w ill be pr o vi de d. A n y C S L 3 1 2 plas ma 
c o nce nt r ati o ns w hic h will ha ve be en e xcl u ded fr o m the de ri vati o n of the P K pa ra met ers w ill 
be fla g ge d  in  the d ata.  
 w ill pr o d uce the T F Ls for the C S L 3 1 2 plas ma co nce ntrati o ns an d t he P K pa ra met ers 
as specifie d  bel o w. 
1 2. 1  D r u g Co n ce ntr ati o n  Me as ures 
T he ha n dli n g a n d i m p utati o n of bel o w li mit of q ua ntificati o n ( B L Q) val ues f or P K para meter 
deri vati o n is descri be d i n P K - GD L - 0 1. T he i m p utati o n r ules bel o w will be use d f or 
s u m mar y statistics of C S L 3 1 2 plas ma c o nce ntrati o ns. T he s u m maries will be gi ve n b y 
pla n ne d t i me p oi nt. 
•
T he sa m pl i n g ti me of pre- d ose sa m ples relati ve t o start of t he d ose i nf usi o n will be
treate d as zer o;
•
C o nce ntrati o n val ues bel o w B L Q i n pre- d ose s a m ples a n d i n sa m ples ta ke n bef ore t h e
ti me of t he first q ua ntifia ble c o nce ntrati o n will be treate d as zer o;
•
P ost- d ose B L Q c o nce ntr ati o ns fla n ke d b y q ua ntifia ble c o nce ntrati o ns will be set t o
missi n g;
•
P ost- d ose B L Q c o nce n tr ati o ns after t he last q u a ntifia ble p oi nt will be set t o missi n g f or
s u m mar y statistics of plas ma c o nce ntrati o ns;
•
T he mea n/ me dia n v al ue at a ti me p oi nt w here o n e or m ore sa m ples ha v e B L Q val ues will
be re p ort e d (i n ta b ular or gra p hical fas hi o n) e v e n if t h e mea n/ me dia n v al ue is B L Q of t he
assa y;
•
Zer o mea n or me dia n val ues will be i ncl u de d i n s u m mar y ta bles.
It s h o ul d be n ote d t hat a hi g h pr o p orti o n of B L Q val ues ma y affect t he s u m mar y statistics; if 
m ore t ha n 5 0 % of t he v al ues are i m p ute d (i. e., B L Q), t he n t he s u m mar y statistics ( mea n, S D, 
me dia n, q uartiles) will n ot be dis pla ye d. 
P P D


CSL Behring 
Study Number: 
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Study Product: 
CSL312 
SAP version: 1.0 
Page 42 of 49 
Date: 28 Aug 2020 
Confidential 
CS-SOP-01-F01 Version 2.0 
Effective Date: Week commencing 25-June-2018 
Summary statistics for concentration-time data will include the percentage of BLQ values 
relative to the total N 
%BLQ = 100 * (number of subjects who have BLQ values / total number of subjects) 
at each time point. 
Descriptive statistics will be provided as outlined in Section 7, and in addition the CV% and 
geometric mean. 
Individual CSL312 plasma concentration plots (on log-linear scale) will be plotted versus 
actual sampling time. Multiple subject plots will be presented on 1 page. 
Plots for mean (± SD) CSL312 plasma concentrations (on linear and on log-linear scales) 
versus nominal (planned) time will be provided. If more than 50% of the individual values 
are BLQ, the mean and SD will be set to missing in the plots. 
Plasma concentrations excluded from the derivation of the PK parameters will also be 
excluded from the summary statistics and the mean plots. A footnote will indicate if plasma 
concentrations have been excluded from the analysis. 
A by-subject listing of CSL312 plasma concentrations with the concentrations flagged that 
have been excluded from the derivation of the PK parameters based on the PK Analysis Set 
will support the summaries. 
12.2 Deriving and Summarizing Pharmacokinetic Parameters 
For subjects belonging to the PK Analysis Set, the PK parameters provided in Appendix 15.1 
will be determined from the CSL312 plasma concentration-time data.  
The PK parameter derivation including imputation of the values BLQ and missing data will 
be conducted in accordance to PK-GDL-01 which gives guidance on how to derive PK 
parameters in the presence of missing data. 
PK parameters of CSL312 will be summarized with the following statistics being provided. 
Variable 
Statistical Parameters: 
Cmax, AUC0-last, T1/2 
n, arithmetic mean, SD, CV%, minimum, median, 
maximum, geometric mean and geometric CV% 
Tmax 
n, minimum, median, and maximum 


 
C S L Be hri n g  
St u d y N u m ber:  C S L 3 1 2 _ C O VI D -1 9  
 
St u d y Pr o d uct:  C S L 3 1 2  
 
S A P versi o n: 1. 0 
 
Pa ge 4 3  of 4 9  
Date: 2 8 A u g  2 0 2 0  
C o nfi de ntial  
C S -S O P -0 1 -F 0 1 Versi o n 2. 0  
Effecti ve Date: Wee k c o m me nci n g 2 5 -J u ne-2 0 1 8  
T he ge o metric C V % will be calc ul ate d as 1 0 0 *s qrt(e x p(l n( S D 2))-1).  
A b y -s u bject listi n g of C S L 3 1 2 P K para meters  b ase d o n t he P K A nal ysis Set will be 
pr o vi de d. 
 
 
 
1 3. 1  
 
C CI
C CI
C CI
C CI


 
C S L Be hri n g  
St u d y N u m ber:  C S L 3 1 2 _ C O VI D -1 9  
 
St u d y Pr o d uct:  C S L 3 1 2  
S A P versi o n: 1. 0 
 
Pa ge 4 4  of 4 9  
Date: 2 8 A u g  2 0 2 0  
C o nfi de ntial  
C S -S O P -0 1 -F 0 1 Versi o n 2. 0  
Effecti ve Date: Wee k c o m me nci n g 2 5 -J u ne-2 0 1 8  
C CI


 
CSL Behring  
Study Number: 
CSL312_COVID-19 
 
Study Product: 
CSL312 
 
SAP version: 1.0 
 
Page 45 of 49 
Date: 28 Aug 2020 
Confidential 
CS-SOP-01-F01 Version 2.0 
Effective Date: Week commencing 25-June-2018 
 References 
Chen YH, DeMets DL, Lan KK. Increasing the sample size when the unblinded interim result 
is promising. Statistics in Medicine. 2004;23(7):1023-1038. 
Ge M, Durham LK, Meyer RD, Xie W, Thomas N. Covariate-adjusted difference in 
proportions from clinical trials using logistic regression and weighted risk differences. Drug 
Information Journal. 2011;45:481-493. 
Jones AE, Trzeciak S, Kline JA. The Sequential Organ Failure Assessments score for 
predicting outcome in patients with severe sepsis and evidence of hypoperfusion at the time 
of emergent department presentation. Crit Care Med. 2009;37(5):1649-1654. 
Mehta, C and Pocock, S. Adaptive increase in sample size when interim results are 
promising: A practical guide with examples. Statistics in Medicine. 2011;30(28):3267-3284. 
National Institute of Allergy and Infectious Diseases (NIAID). ClinicalTrials.gov. Adaptive 
COVID-19 Treatment Trial (ACTT). Available at: 
https://clinicaltrials.gov/ct2/show/NCT04280705. Accessed: May 05, 2020. 
Newcombe RG. Confidence intervals for an effect size measure based on the Mann-Whitney 
statistic. Part 2: asymptomatic methods and evaluation. Statist. Med. 2006;25(4):559-573. 
Novack V, Beitler JR, Yitshak-Sade M, Thompson BT, Schoenfeld DA, Rubenfeld G, et al. 
Alive and ventilator free: a hierarchical, composite outcome for clinical trials in the acute 
respiratory distress syndrome. Crit Care Med. 2020;48(2):158-166. 
PK-GDL-01, Guideline on the Conduct of Non-compartmental Pharmacokinetic Analyses, 
CSL Behring. 
Teasdale G, Maas A, Lecky F, Manley G, Stocchetti N, Murray G. The Glasgow Coma Scale 
at 40 years: standing the test of time. Lancet Neurol. 2014;13(8):844-854. 
 
 


 
CSL Behring  
Study Number: 
CSL312_COVID-19 
 
Study Product: 
CSL312 
 
SAP version: 1.0 
 
Page 46 of 49 
Date: 28 Aug 2020 
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CS-SOP-01-F01 Version 2.0 
Effective Date: Week commencing 25-June-2018 
 Appendices 
15.1 PK Parameters 
Term 
Definition [unit] 
Calculation method 
AUC0-last 
Partial AUC from time point 0 to time 
point of the last measurable concentration 
[mass * time * volume-1]. 
AUC from the time of dosing to a 
specified timepoint (t), using the linear 
up/log down trapezoidal rule. 
Cmax 
The maximum (peak) observed plasma 
drug concentration [mass * volume-1] 
 
T1/2 
The terminal half-life [time] 
t1/2 = ln(2) /λz 
Tmax 
The time to reach maximum (peak) drug 
concentration in measured biological fluid 
[time] 
 
 


CSL Behring 
Study Number: 
CSL312_COVID-19 
Study Product: 
CSL312 
SAP version: 1.0 
Page 47 of 49 
Date: 28 Aug 2020 
Confidential 
CS-SOP-01-F01 Version 2.0 
Effective Date: Week commencing 25-June-2018 
15.2 Sequential Organ Failure Assessment (SOFA) Scale 
SOFA Score 
0 
1 
2 
3 
4 
Respirationa 
PaO2/FIO2 
(mmHg) 
≥ 400 
< 400 
< 300 
< 220 
< 100 
SaO2/FIO2 
(mmHg) 
> 301
221-30
1 
142-220
67-141
< 67 
Coagulation 
Platelets 
× 103/mm3 
≥ 150 
< 150 
< 100 
< 50 
< 20 
Liver 
Bilirubin (mg/dL) 
< 1.2 
1.2-1.9 
2.0-5.9 
6.0-11.9 
> 12.0
Cardiovascularb 
Hypotension 
≥ 70 
MAP 
< 70 
Dopamine 
≤ 5 or 
dobutamine 
(any) 
Dopamine > 5 
or norepi-
nephrine ≤ 0.1 
Dopamine 
> 15 or norepi-
nephrine > 0.1
Central Nervous System 
Glasgow Coma 
Score 
15 
13-14
10-12
6-9
< 6 
Renal 
Creatinine (mg/dL) 
or urine output 
(mL/d) 
< 1.2 
1.2-1.9 
2.0-3.4 
3.5-4.9 
or < 500 
> 5.0
or < 200 
MAP = mean arterial pressure; SaO2 = peripheral arterial oxygen saturation. 
a.
PaO2/FIO2 ratio is preferable. If not available, the SaO2/FIO2 ratio may be used.
b.
Vasoactive medications administered for ≥ 1 hour (dopamine and norepinephrine µg/kg/min).
Source: Ge M, Durham LK, Meyer RD, Xie W, Thomas N. Covariate-adjusted difference in proportions from
clinical trials using logistic regression and weighted risk differences. Drug Information Journal. 
2011;45:481-493. 
Jones et al, 2009. 


 
CSL Behring  
Study Number: 
CSL312_COVID-19 
 
Study Product: 
CSL312 
 
SAP version: 1.0 
 
Page 48 of 49 
Date: 28 Aug 2020 
Confidential 
CS-SOP-01-F01 Version 2.0 
Effective Date: Week commencing 25-June-2018 
15.3 National Institute of Allergy and Infectious Diseases (NIAID) 8-point Ordinal 
Scale 
The ordinal scale is an assessment of the clinical status at the first assessment of a given 
study day. 
NIAID 
Score 
Description 
1 
Death 
2 
Hospitalized, on invasive mechanical ventilation or ECMO 
3 
Hospitalized, on NIV or high-flow oxygen devices 
4 
Hospitalized, requiring supplemental oxygen 
5 
Hospitalized, not requiring supplemental oxygen – requiring ongoing medical 
care (COVID-19 related or otherwise) 
6 
Hospitalized, not requiring supplemental oxygen – no longer requires ongoing 
medical care 
7 
Not hospitalized, limitation on activities and/or requiring home oxygen 
8 
Not hospitalized, no limitations on activities 
COVID-19 = Coronavirus Disease 2019; ECMO = extracorporeal membrane oxygenation; NIAID = National 
Institute of Allergy and Infectious Diseases; NIV = non-invasive ventilation. 
Source: NIAID, 2020. 
 
 
 


 
CSL Behring  
Study Number: 
CSL312_COVID-19 
 
Study Product: 
CSL312 
 
SAP version: 1.0 
 
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Date: 28 Aug 2020 
Confidential 
CS-SOP-01-F01 Version 2.0 
Effective Date: Week commencing 25-June-2018 
15.4 Glasgow Coma Scale 
Feature 
Scale Responses 
Score 
Eye opening (E) 
Spontaneous 
4 
To speech 
3 
To pain 
2 
None 
1 
Best verbal response (V) 
Oriented 
5 
Sounds 
4 
Words 
3 
Confused 
2 
None 
1 
Best motor response (M) 
Obeying commands 
6 
Localizing 
5 
Normal flexion (withdrawal) 
4 
Abnormal flexion 
3 
Extension 
2 
None 
1 
Total comma score 
3-15 
Source: Teasdale et al, 2014. 
 


V er si o n: 1. 0
Si g n at ur e P a g e 1  of 1
--- D o N ot D et a c h T hi s Si g n at ur e P a g e ---
gl b d ct m p
Pri nt D at e: 1 8- A u g- 2 0 2 1 0 9: 4 8: 3 0 G M T- 0 4: 0 0
Si g n at ur e P a g e
C S L 3 1 2 _ C O VI D- 1 9 - St ati sti c al A n al y si s Pl a n - V 1. 0 - 2 8 A u g 2 0 2 0
Si g n e d B y
D at e ( G M T)
A p pr o v e d-
 A p pr o v al
0 1- S e p- 2 0 2 0 0 5: 5 9: 0 5
A p pr o v e d-
 A p pr o v al
3 1- A u g- 2 0 2 0 1 8: 0 7: 5 6
P P D
P P D
P P D
P P D