Treatment With CSL312 in Adults With Coronavirus Disease 2019 (COVID-19)

• Sponsor: CSL Behring (Industry)
• Overall Status: Completed
• CT.gov ID: NCT04409509
• Collaborator: (none)
• Enrollment: 124
• Locations: 14
• Arms: 2
• Actual Duration (Months): 6.4
• Patients Per Site: 8.9
• Patients Per Site Per Month: 1.4

Study Details

Study Description

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)

Condition or Disease	Intervention/Treatment	Phase
Coronavirus Disease 2019 (COVID-19)	Biological: Garadacimab, Factor XIIa Antagonist Monoclonal Antibody; Drug: Placebo	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 124 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Phase 2, Multicenter, Double Blind, Randomized, Placebo-Controlled Study to Evaluate CSL312 in Coronavirus Disease 2019 (COVID 19)
• Actual Study Start Date: Jul 1, 2020
• Actual Primary Completion Date: Jan 12, 2021
• Actual Study Completion Date: Jan 12, 2021

Arms and Interventions

Arm	Intervention/Treatment
Experimental: CSL312 Garadacimab, Factor XIIa Antagonist Monoclonal Antibody administered intravenously	Biological: Garadacimab, Factor XIIa Antagonist Monoclonal Antibody; Garadacimab, Factor XIIa Antagonist Monoclonal Antibody administered intravenously
Placebo Comparator: Placebo CSL312 diluent administered intravenously	Drug: Placebo; CSL312 diluent administered intravenously

Outcome Measures

Primary Outcome Measures

1. The Percent of Participants With Tracheal Intubation or Death Prior to Tracheal Intubation [From randomization to Day 28]

Secondary Outcome Measures

1. Percent of Participants With Death From All Causes [From randomization to Day 28]

2. Percent of Participants With Tracheal Intubation [From randomization to Day 28]

3. Number of Participants With ≥ 2-Point Improvement Compared to Baseline on National Institute of Allergy and Infectious Diseases (NIAID) Ordinal Scale [From randomization to Day 28]

   The ordinal scale is an assessment of the clinical status at the first assessment of a given study day. The scale is as follows: 8) Death; 7) Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO); 6) Hospitalized, on non-invasive ventilation or high flow oxygen devices; 5) Hospitalized, requiring supplemental oxygen; 4) Hospitalized, not requiring supplemental oxygen - requiring ongoing medical care (COVID-19 related or otherwise); 3) Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care; 2) Not hospitalized, limitation on activities and/or requiring home oxygen; 1) Not hospitalized, no limitations on activities.

4. Percent of Participants With ≥ 2-Point Improvement Compared to Baseline on NIAID [From randomization to Day 28]

   The ordinal scale is an assessment of the clinical status at the first assessment of a given study day. The scale is as follows: 8) Death; 7) Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO); 6) Hospitalized, on non-invasive ventilation or high flow oxygen devices; 5) Hospitalized, requiring supplemental oxygen; 4) Hospitalized, not requiring supplemental oxygen - requiring ongoing medical care (COVID-19 related or otherwise); 3) Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care; 2) Not hospitalized, limitation on activities and/or requiring home oxygen; 1) Not hospitalized, no limitations on activities.

5. Number of Participants Within Each of the Categories of the NIAID at End of Study [Day 28]

   The ordinal scale is an assessment of the clinical status at the first assessment of a given study day. The scale is as follows: 8) Death; 7) Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO); 6) Hospitalized, on non-invasive ventilation or high flow oxygen devices; 5) Hospitalized, requiring supplemental oxygen; 4) Hospitalized, not requiring supplemental oxygen - requiring ongoing medical care (COVID-19 related or otherwise); 3) Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care; 2) Not hospitalized, limitation on activities and/or requiring home oxygen; 1) Not hospitalized, no limitations on activities.

6. Percent of Participants Within Each of the Categories of the NIAID at End of Study [Day 28]

   The ordinal scale is an assessment of the clinical status at the first assessment of a given study day. The scale is as follows: 8) Death; 7) Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO); 6) Hospitalized, on non-invasive ventilation or high flow oxygen devices; 5) Hospitalized, requiring supplemental oxygen; 4) Hospitalized, not requiring supplemental oxygen - requiring ongoing medical care (COVID-19 related or otherwise); 3) Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care; 2) Not hospitalized, limitation on activities and/or requiring home oxygen; 1) Not hospitalized, no limitations on activities.

7. Percent of Participants Requiring Continuous Positive Airway Pressure (CPAP) or Bilevel Positive Airway Pressure (BiPAP) [From randomization to Day 28]

8. Percent of Participants Requiring Extracorporeal Membrane Oxygenation (ECMO) [From randomization to Day 28]

   None of the enrolled subjects required the use of ECMO during their participation in this study. Therefore, no data to report for this outcome measure.

9. Percent of Participants Requiring High-Flow Nasal Cannula (HFNC) [From randomization to Day 28]

10. Maximum Change From Baseline in Sequential Organ Failure Assessment (SOFA) Score [From randomization to Day 28]

    The score is based on six different scores, one each for the respiratory, cardiovascular, hepatic, coagulation, renal and neurological systems. Each system is scored from 0 (normal function) to 4 (most abnormal) with a total score ranging from 0 to 24. A high total SOFA score have been shown to be related to a worse outcome.

11. Change From Baseline in SOFA Total Score [From randomization to Day 28]

    The score is based on six different scores, one each for the respiratory, cardiovascular, hepatic, coagulation, renal and neurological systems. Each system is scored from 0 (normal function) to 4 (most abnormal) with a total score ranging from 0 to 24. A high total SOFA score have been shown to be related to a worse outcome.

12. Change From Baseline in the Individual Components of SOFA Score [From randomization to Day 28]

    The score is based on six different scores, one each for the respiratory, cardiovascular, hepatic, coagulation, renal and neurological systems. Each system is scored from 0 (normal function) to 4 (most abnormal) with a total score ranging from 0 to 24. A high total SOFA score have been shown to be related to a worse outcome.

13. Length of Hospital Stay [From randomization to Day 28 (+/- 2 days)]

14. Number of Participants Experiencing Adverse Events (AEs) [Up to 28 days after CSL312 or placebo administration]

15. Percent of Participants Experiencing AEs [Up to 28 days after CSL312 or placebo administration]

16. Number of Participants Experiencing Serious Adverse Events (SAEs) [Up to 28 days after CSL312 or placebo administration]

17. Percent of Participants Experiencing SAEs [Up to 28 days after CSL312 or placebo administration]

18. Number of Participants With Adverse Events of Special Interest (AESIs) [Up to 28 days after CSL312 or placebo administration]

19. Percent of Participants With AESIs [Up to 28 days after CSL312 or placebo administration]

20. Number of Participants With Anti-CSL312 Antibodies [Up to 28 days after CSL312 or placebo administration]

21. Maximum Plasma Concentration (Cmax) of CSL312 [Up to 28 days after CSL312 administration]

22. Time to Maximum Plasma Concentration (Tmax) of CSL312 [Up to 28 days after CSL312 administration]

23. Area Under the Plasma Concentration-Time Curve From Time Zero to the Time of the Last Measurable Concentration (AUC0-Last) of CSL312 [Up to 28 days after CSL312 administration]

24. Terminal Half-life (T1/2) of CSL312 [Up to 28 days after CSL312 administration]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Age ≥ 18 years

• 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.

• Chest CT scan or X ray results confirming interstitial pneumonia

• 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

• SpO2 ≤ 93% on room air

• Ratio of partial pressure of arterial oxygen to fraction of inspired oxygen (PaO2/FiO2) < 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%

Exclusion Criteria:

• 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.

• Pregnant or breastfeeding (female subjects)

• Intubated and require mechanical ventilation (including ECMO) at the time of randomization

• In the opinion of the investigator, the subject is expected to be intubated in the first 24 hours after IMP administration

• Has a Do-Not-Intubate (DNI) or Do-Not-Resuscitate (DNR) order

• In the opinion of the investigator, not expected to survive for > 48 hours after admission

• 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

• 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)

• 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)

• 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 IMP or any excipients of the IMP

• Currently receiving a therapy not permitted during the study.

• 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 IMP

• 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Nova Clinical Research, LLC	Bradenton	Florida	United States	34209
2	Theia Clinical Research, LLC	Saint Petersburg	Florida	United States	33707
3	MercyOne North Iowa Medical Center	Mason City	Iowa	United States	50401
4	Northeast Iowa Medical Education Foundation	Waterloo	Iowa	United States	50702
5	Lahey Hospital and Medical Center	Burlington	Massachusetts	United States	01805
6	University of Mississippi Medical Center	Jackson	Mississippi	United States	39216
7	Holy Name Hospital	Teaneck	New Jersey	United States	07666
8	Inspira Health Center Vineland	Vineland	New Jersey	United States	08360
9	Sisters of Charity Hospital/ St. Joseph's Campus	Buffalo	New York	United States	14225
10	Carolina Institute for Clinical Research	Fayetteville	North Carolina	United States	28304
11	Monument Health Clinical Research	Rapid City	South Dakota	United States	57701
12	PharmaTex Research	Amarillo	Texas	United States	79109
13	UT Health Science Center, McGovern Medical School	Houston	Texas	United States	77030
14	Inova Alexandria Hospital	Alexandria	Virginia	United States	22304

Sponsors and Collaborators

• CSL Behring

Investigators

• Study Director: Study Director, CSL Behring

Study Documents (Full-Text)

• Study Protocol - Sep 16, 2020
• Statistical Analysis Plan - Aug 28, 2020

More Information

Publications

None provided.

• Responsible Party: CSL Behring
• ClinicalTrials.gov Identifier: NCT04409509
• Other Study ID Numbers: CSL312_COVID-19
• First Posted: Jun 1, 2020
• Last Update Posted: Jan 24, 2022
• Last Verified: Jan 1, 2022

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by CSL Behring: Prevention of respiratory failure
• Additional relevant MeSH terms: COVID-19; Coronavirus Infections; Antibodies; Antibodies, Monoclonal

Study Results

Participant Flow

Arm/Group Title	Placebo	CSL312
Arm/Group Description	CSL312 diluent administered intravenously Placebo: CSL312 diluent administered intravenously	Garadacimab, Factor XIIa Antagonist Monoclonal Antibody administered intravenously Garadacimab, Factor XIIa Antagonist Monoclonal Antibody: Garadacimab, Factor XIIa Antagonist Monoclonal Antibody administered intravenously
Period Title: Overall Study
STARTED	61	63
COMPLETED	48	43
NOT COMPLETED	13	20

Baseline Characteristics

Arm/Group Title	Placebo	CSL312	Total
Arm/Group Description	CSL312 diluent administered intravenously Placebo: CSL312 diluent administered intravenously	Garadacimab, Factor XIIa Antagonist Monoclonal Antibody administered intravenously Garadacimab, Factor XIIa Antagonist Monoclonal Antibody: Garadacimab, Factor XIIa Antagonist Monoclonal Antibody administered intravenously	Total of all reporting groups
Overall Participants	61	63	124
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	33 54.1%	32 50.8%	65 52.4%
>=65 years	28 45.9%	31 49.2%	59 47.6%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	62.2 (12.74)	62.7 (14.61)	62.5 (13.67)
Sex: Female, Male (Count of Participants)
Female	20 32.8%	30 47.6%	50 40.3%
Male	41 67.2%	33 52.4%	74 59.7%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	10 16.4%	14 22.2%	24 19.4%
Not Hispanic or Latino	48 78.7%	48 76.2%	96 77.4%
Unknown or Not Reported	3 4.9%	1 1.6%	4 3.2%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	2 3.3%	2 3.2%	4 3.2%
Native Hawaiian or Other Pacific Islander	1 1.6%	0 0%	1 0.8%
Black or African American	6 9.8%	7 11.1%	13 10.5%
White	49 80.3%	44 69.8%	93 75%
More than one race	0 0%	1 1.6%	1 0.8%
Unknown or Not Reported	3 4.9%	9 14.3%	12 9.7%
Region of Enrollment (participants) [Number]
United States	61 100%	63 100%	124 100%

Outcome Measures

1. Primary Outcome

Title	The Percent of Participants With Tracheal Intubation or Death Prior to Tracheal Intubation
Time Frame	From randomization to Day 28

Outcome Measure Data

Analysis Population Description

Intent-to-treat Analysis Set (ITT) comprises all subjects who were randomly assigned to treatment and who were assigned randomization numbers.

Arm/Group Title	Placebo	CSL312
Arm/Group Description	CSL312 diluent administered intravenously Placebo: CSL312 diluent administered intravenously	Garadacimab, Factor XIIa Antagonist Monoclonal Antibody administered intravenously Garadacimab, Factor XIIa Antagonist Monoclonal Antibody: Garadacimab, Factor XIIa Antagonist Monoclonal Antibody administered intravenously
Measure Participants	61	63
Number [percentage of participants]	26.2 43%	22.2 35.2%

2. Secondary Outcome

Title	Percent of Participants With Death From All Causes
Time Frame	From randomization to Day 28

Outcome Measure Data

Analysis Population Description

ITT

Arm/Group Title	Placebo	CSL312
Arm/Group Description	CSL312 diluent administered intravenously Placebo: CSL312 diluent administered intravenously	Garadacimab, Factor XIIa Antagonist Monoclonal Antibody administered intravenously Garadacimab, Factor XIIa Antagonist Monoclonal Antibody: Garadacimab, Factor XIIa Antagonist Monoclonal Antibody administered intravenously
Measure Participants	61	63
Number [percentage of participants]	18.0 29.5%	17.5 27.8%

3. Secondary Outcome

Title	Percent of Participants With Tracheal Intubation
Time Frame	From randomization to Day 28

Outcome Measure Data

Analysis Population Description

ITT

Arm/Group Title	Placebo	CSL312
Arm/Group Description	CSL312 diluent administered intravenously Placebo: CSL312 diluent administered intravenously	Garadacimab, Factor XIIa Antagonist Monoclonal Antibody administered intravenously Garadacimab, Factor XIIa Antagonist Monoclonal Antibody: Garadacimab, Factor XIIa Antagonist Monoclonal Antibody administered intravenously
Measure Participants	61	63
Number [percentage of participants]	24.6 40.3%	17.5 27.8%

4. Secondary Outcome

Title	Number of Participants With ≥ 2-Point Improvement Compared to Baseline on National Institute of Allergy and Infectious Diseases (NIAID) Ordinal Scale
Description	The ordinal scale is an assessment of the clinical status at the first assessment of a given study day. The scale is as follows: 8) Death; 7) Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO); 6) Hospitalized, on non-invasive ventilation or high flow oxygen devices; 5) Hospitalized, requiring supplemental oxygen; 4) Hospitalized, not requiring supplemental oxygen - requiring ongoing medical care (COVID-19 related or otherwise); 3) Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care; 2) Not hospitalized, limitation on activities and/or requiring home oxygen; 1) Not hospitalized, no limitations on activities.
Time Frame	From randomization to Day 28

Outcome Measure Data

Analysis Population Description

ITT

Arm/Group Title	Placebo	CSL312
Arm/Group Description	CSL312 diluent administered intravenously Placebo: CSL312 diluent administered intravenously	Garadacimab, Factor XIIa Antagonist Monoclonal Antibody administered intravenously Garadacimab, Factor XIIa Antagonist Monoclonal Antibody: Garadacimab, Factor XIIa Antagonist Monoclonal Antibody administered intravenously
Measure Participants	61	63
Number [participants]	44 72.1%	42 66.7%

5. Secondary Outcome

Title	Percent of Participants With ≥ 2-Point Improvement Compared to Baseline on NIAID
Description	The ordinal scale is an assessment of the clinical status at the first assessment of a given study day. The scale is as follows: 8) Death; 7) Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO); 6) Hospitalized, on non-invasive ventilation or high flow oxygen devices; 5) Hospitalized, requiring supplemental oxygen; 4) Hospitalized, not requiring supplemental oxygen - requiring ongoing medical care (COVID-19 related or otherwise); 3) Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care; 2) Not hospitalized, limitation on activities and/or requiring home oxygen; 1) Not hospitalized, no limitations on activities.
Time Frame	From randomization to Day 28

Outcome Measure Data

Analysis Population Description

ITT

Arm/Group Title	Placebo	CSL312
Arm/Group Description	CSL312 diluent administered intravenously Placebo: CSL312 diluent administered intravenously	Garadacimab, Factor XIIa Antagonist Monoclonal Antibody administered intravenously Garadacimab, Factor XIIa Antagonist Monoclonal Antibody: Garadacimab, Factor XIIa Antagonist Monoclonal Antibody administered intravenously
Measure Participants	61	63
Number [percentage of participants]	72.1 118.2%	66.7 105.9%

6. Secondary Outcome

Title	Number of Participants Within Each of the Categories of the NIAID at End of Study
Description	The ordinal scale is an assessment of the clinical status at the first assessment of a given study day. The scale is as follows: 8) Death; 7) Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO); 6) Hospitalized, on non-invasive ventilation or high flow oxygen devices; 5) Hospitalized, requiring supplemental oxygen; 4) Hospitalized, not requiring supplemental oxygen - requiring ongoing medical care (COVID-19 related or otherwise); 3) Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care; 2) Not hospitalized, limitation on activities and/or requiring home oxygen; 1) Not hospitalized, no limitations on activities.
Time Frame	Day 28

Outcome Measure Data

Analysis Population Description

ITT

Arm/Group Title	Placebo	CSL312
Arm/Group Description	CSL312 diluent administered intravenously Placebo: CSL312 diluent administered intravenously	Garadacimab, Factor XIIa Antagonist Monoclonal Antibody administered intravenously Garadacimab, Factor XIIa Antagonist Monoclonal Antibody: Garadacimab, Factor XIIa Antagonist Monoclonal Antibody administered intravenously
Measure Participants	61	63
Death	11 18%	11 17.5%
Hospitalized, on Invasive Mechanical Ventilation or ECMO	2 3.3%	1 1.6%
Hospitalized, on Non-invasive Ventilation or High-flow Oxygen Devices	2 3.3%	0 0%
Hospitalized, Requiring Supplemental Oxygen	1 1.6%	2 3.2%
Hospitalized, Not Requiring Supplemental Oxygen - Requiring Ongoing Medical Care	0 0%	0 0%
Hospitalized, Not Requiring Supplemental Oxygen - no Longer Requiring Medical Care	0 0%	0 0%
Not Hospitalized, Limitation on Activities and/or Requiring Home Oxygen	14 23%	11 17.5%
Not Hospitalized, no Limitations on Activities	25 41%	26 41.3%
Not Done	5 8.2%	6 9.5%
Missing	1 1.6%	6 9.5%

7. Secondary Outcome

Title	Percent of Participants Within Each of the Categories of the NIAID at End of Study
Description	The ordinal scale is an assessment of the clinical status at the first assessment of a given study day. The scale is as follows: 8) Death; 7) Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO); 6) Hospitalized, on non-invasive ventilation or high flow oxygen devices; 5) Hospitalized, requiring supplemental oxygen; 4) Hospitalized, not requiring supplemental oxygen - requiring ongoing medical care (COVID-19 related or otherwise); 3) Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care; 2) Not hospitalized, limitation on activities and/or requiring home oxygen; 1) Not hospitalized, no limitations on activities.
Time Frame	Day 28

Outcome Measure Data

Analysis Population Description

ITT

Arm/Group Title	Placebo	CSL312
Arm/Group Description	CSL312 diluent administered intravenously Placebo: CSL312 diluent administered intravenously	Garadacimab, Factor XIIa Antagonist Monoclonal Antibody administered intravenously Garadacimab, Factor XIIa Antagonist Monoclonal Antibody: Garadacimab, Factor XIIa Antagonist Monoclonal Antibody administered intravenously
Measure Participants	61	63
Death	18.0 29.5%	17.5 27.8%
Hospitalized, on Invasive Mechanical Ventilation or ECMO	3.3 5.4%	1.6 2.5%
Hospitalized, on Non-invasive Ventilation or High-flow Oxygen Devices	3.3 5.4%	0 0%
Hospitalized, Requiring Supplemental Oxygen	1.6 2.6%	3.2 5.1%
Hospitalized, Not Requiring Supplemental Oxygen - Requiring Ongoing Medical Care	0 0%	0 0%
Hospitalized, Not Requiring Supplemental Oxygen - no Longer Requiring Medical Care	0 0%	0 0%
Not Hospitalized, Limitation on Activities and/or Requiring Home Oxygen	23.0 37.7%	17.5 27.8%
Not Hospitalized, no Limitations on Activities	41.0 67.2%	41.3 65.6%
Not Done	8.2 13.4%	9.5 15.1%
Missing	1.6 2.6%	9.5 15.1%

8. Secondary Outcome

Title	Percent of Participants Requiring Continuous Positive Airway Pressure (CPAP) or Bilevel Positive Airway Pressure (BiPAP)
Time Frame	From randomization to Day 28

Outcome Measure Data

Analysis Population Description

ITT

Arm/Group Title	Placebo	CSL312
Arm/Group Description	CSL312 diluent administered intravenously Placebo: CSL312 diluent administered intravenously	Garadacimab, Factor XIIa Antagonist Monoclonal Antibody administered intravenously Garadacimab, Factor XIIa Antagonist Monoclonal Antibody: Garadacimab, Factor XIIa Antagonist Monoclonal Antibody administered intravenously
Measure Participants	61	63
Number [percentage of participants]	16.4 26.9%	19.0 30.2%

9. Secondary Outcome

Title	Percent of Participants Requiring Extracorporeal Membrane Oxygenation (ECMO)
Description	None of the enrolled subjects required the use of ECMO during their participation in this study. Therefore, no data to report for this outcome measure.
Time Frame	From randomization to Day 28

Outcome Measure Data

Analysis Population Description

ITT. None of the enrolled subjects required the use of ECMO during their participation in this study. Therefore, no data to report for this outcome measure.

Arm/Group Title	Placebo	CSL312
Arm/Group Description	CSL312 diluent administered intravenously Placebo: CSL312 diluent administered intravenously	Garadacimab, Factor XIIa Antagonist Monoclonal Antibody administered intravenously Garadacimab, Factor XIIa Antagonist Monoclonal Antibody: Garadacimab, Factor XIIa Antagonist Monoclonal Antibody administered intravenously
Measure Participants	61	63
Number [percentage of participants]	0 0%	0 0%

10. Secondary Outcome

Title	Percent of Participants Requiring High-Flow Nasal Cannula (HFNC)
Time Frame	From randomization to Day 28

Outcome Measure Data

Analysis Population Description

ITT

Arm/Group Title	Placebo	CSL312
Arm/Group Description	CSL312 diluent administered intravenously Placebo: CSL312 diluent administered intravenously	Garadacimab, Factor XIIa Antagonist Monoclonal Antibody administered intravenously Garadacimab, Factor XIIa Antagonist Monoclonal Antibody: Garadacimab, Factor XIIa Antagonist Monoclonal Antibody administered intravenously
Measure Participants	61	63
Number [percentage of participants]	18.0 29.5%	14.3 22.7%

11. Secondary Outcome

Title	Maximum Change From Baseline in Sequential Organ Failure Assessment (SOFA) Score
Description	The score is based on six different scores, one each for the respiratory, cardiovascular, hepatic, coagulation, renal and neurological systems. Each system is scored from 0 (normal function) to 4 (most abnormal) with a total score ranging from 0 to 24. A high total SOFA score have been shown to be related to a worse outcome.
Time Frame	From randomization to Day 28

Outcome Measure Data

Analysis Population Description

ITT. Participants with missing values were not included in the analysis.

Arm/Group Title	Placebo	CSL312
Arm/Group Description	CSL312 diluent administered intravenously Placebo: CSL312 diluent administered intravenously	Garadacimab, Factor XIIa Antagonist Monoclonal Antibody administered intravenously Garadacimab, Factor XIIa Antagonist Monoclonal Antibody: Garadacimab, Factor XIIa Antagonist Monoclonal Antibody administered intravenously
Measure Participants	50	45
Mean (Standard Deviation) [score on a scale]	0.5 (1.54)	0.1 (0.79)

12. Secondary Outcome

Title	Change From Baseline in SOFA Total Score
Description	The score is based on six different scores, one each for the respiratory, cardiovascular, hepatic, coagulation, renal and neurological systems. Each system is scored from 0 (normal function) to 4 (most abnormal) with a total score ranging from 0 to 24. A high total SOFA score have been shown to be related to a worse outcome.
Time Frame	From randomization to Day 28

Outcome Measure Data

Analysis Population Description

ITT. Participants with missing values were not included in the analysis.

Arm/Group Title	Placebo	CSL312
Arm/Group Description	CSL312 diluent administered intravenously Placebo: CSL312 diluent administered intravenously	Garadacimab, Factor XIIa Antagonist Monoclonal Antibody administered intravenously Garadacimab, Factor XIIa Antagonist Monoclonal Antibody: Garadacimab, Factor XIIa Antagonist Monoclonal Antibody administered intravenously
Measure Participants	15	12
Mean (Standard Deviation) [score on a scale]	-1.0 (1.77)	-1.3 (0.89)

13. Secondary Outcome

Title	Change From Baseline in the Individual Components of SOFA Score
Description	The score is based on six different scores, one each for the respiratory, cardiovascular, hepatic, coagulation, renal and neurological systems. Each system is scored from 0 (normal function) to 4 (most abnormal) with a total score ranging from 0 to 24. A high total SOFA score have been shown to be related to a worse outcome.
Time Frame	From randomization to Day 28

Outcome Measure Data

Analysis Population Description

ITT. Participants with missing values were not included in the analysis.

Arm/Group Title	Placebo	CSL312
Arm/Group Description	CSL312 diluent administered intravenously Placebo: CSL312 diluent administered intravenously	Garadacimab, Factor XIIa Antagonist Monoclonal Antibody administered intravenously Garadacimab, Factor XIIa Antagonist Monoclonal Antibody: Garadacimab, Factor XIIa Antagonist Monoclonal Antibody administered intravenously
Measure Participants	61	63
Respiration Score	-0.6 (1.32)	-1.2 (1.16)
Coagulation Score	-0.1 (0.42)	0.4 (1.12)
Liver Score	0.0 (0.22)	0.0 (0.00)
Cardiovascular Score	0.4 (1.65)	0.5 (1.35)
Central Nervous System Score	0.0 (0.00)	0.0 (0.19)
Renal Score	0.3 (0.93)	0.5 (1.10)

14. Secondary Outcome

Title	Length of Hospital Stay
Time Frame	From randomization to Day 28 (+/- 2 days)

Outcome Measure Data

Analysis Population Description

ITT

Arm/Group Title	Placebo	CSL312
Arm/Group Description	CSL312 diluent administered intravenously Placebo: CSL312 diluent administered intravenously	Garadacimab, Factor XIIa Antagonist Monoclonal Antibody administered intravenously Garadacimab, Factor XIIa Antagonist Monoclonal Antibody: Garadacimab, Factor XIIa Antagonist Monoclonal Antibody administered intravenously
Measure Participants	61	63
Median (Full Range) [Days]	7.00	6.50

15. Secondary Outcome

Title	Number of Participants Experiencing Adverse Events (AEs)
Time Frame	Up to 28 days after CSL312 or placebo administration

Outcome Measure Data

Analysis Population Description

The Safety Analysis Set (SA) comprises all subjects in the ITT Analysis Set who receive any amount of CSL312 or placebo.

Arm/Group Title	Placebo	CSL312
Arm/Group Description	CSL312 diluent administered intravenously Placebo: CSL312 diluent administered intravenously	Garadacimab, Factor XIIa Antagonist Monoclonal Antibody administered intravenously Garadacimab, Factor XIIa Antagonist Monoclonal Antibody: Garadacimab, Factor XIIa Antagonist Monoclonal Antibody administered intravenously
Measure Participants	59	58
Number [participants]	40 65.6%	35 55.6%

16. Secondary Outcome

Title	Percent of Participants Experiencing AEs
Time Frame	Up to 28 days after CSL312 or placebo administration

Outcome Measure Data

Analysis Population Description

SA

Arm/Group Title	Placebo	CSL312
Arm/Group Description	CSL312 diluent administered intravenously Placebo: CSL312 diluent administered intravenously	Garadacimab, Factor XIIa Antagonist Monoclonal Antibody administered intravenously Garadacimab, Factor XIIa Antagonist Monoclonal Antibody: Garadacimab, Factor XIIa Antagonist Monoclonal Antibody administered intravenously
Measure Participants	59	58
Number [percentage of participants]	67.8 111.1%	60.3 95.7%

17. Secondary Outcome

Title	Number of Participants Experiencing Serious Adverse Events (SAEs)
Time Frame	Up to 28 days after CSL312 or placebo administration

Outcome Measure Data

Analysis Population Description

SA

Arm/Group Title	Placebo	CSL312
Arm/Group Description	CSL312 diluent administered intravenously Placebo: CSL312 diluent administered intravenously	Garadacimab, Factor XIIa Antagonist Monoclonal Antibody administered intravenously Garadacimab, Factor XIIa Antagonist Monoclonal Antibody: Garadacimab, Factor XIIa Antagonist Monoclonal Antibody administered intravenously
Measure Participants	59	58
Number [participants]	19 31.1%	20 31.7%

18. Secondary Outcome

Title	Percent of Participants Experiencing SAEs
Time Frame	Up to 28 days after CSL312 or placebo administration

Outcome Measure Data

Analysis Population Description

SA

Arm/Group Title	Placebo	CSL312
Arm/Group Description	CSL312 diluent administered intravenously Placebo: CSL312 diluent administered intravenously	Garadacimab, Factor XIIa Antagonist Monoclonal Antibody administered intravenously Garadacimab, Factor XIIa Antagonist Monoclonal Antibody: Garadacimab, Factor XIIa Antagonist Monoclonal Antibody administered intravenously
Measure Participants	59	58
Number [percentage of participants]	32.2 52.8%	34.5 54.8%

19. Secondary Outcome

Title	Number of Participants With Adverse Events of Special Interest (AESIs)
Time Frame	Up to 28 days after CSL312 or placebo administration

Outcome Measure Data

Analysis Population Description

SA

Arm/Group Title	Placebo	CSL312
Arm/Group Description	CSL312 diluent administered intravenously Placebo: CSL312 diluent administered intravenously	Garadacimab, Factor XIIa Antagonist Monoclonal Antibody administered intravenously Garadacimab, Factor XIIa Antagonist Monoclonal Antibody: Garadacimab, Factor XIIa Antagonist Monoclonal Antibody administered intravenously
Measure Participants	59	58
Number [participants]	6 9.8%	5 7.9%

20. Secondary Outcome

Title	Percent of Participants With AESIs
Time Frame	Up to 28 days after CSL312 or placebo administration

Outcome Measure Data

Analysis Population Description

SA

Arm/Group Title	Placebo	CSL312
Arm/Group Description	CSL312 diluent administered intravenously Placebo: CSL312 diluent administered intravenously	Garadacimab, Factor XIIa Antagonist Monoclonal Antibody administered intravenously Garadacimab, Factor XIIa Antagonist Monoclonal Antibody: Garadacimab, Factor XIIa Antagonist Monoclonal Antibody administered intravenously
Measure Participants	59	58
Number [percentage of participants]	10.2 16.7%	8.6 13.7%

21. Secondary Outcome

Title	Number of Participants With Anti-CSL312 Antibodies
Time Frame	Up to 28 days after CSL312 or placebo administration

Outcome Measure Data

Analysis Population Description

The pharmacodynamic (PD) Analysis Set will comprise all subjects in the Safety Analysis Set who received any amount of CSL312 or placebo and have ≥ 1 blood sample available for analysis of biomarkers.

Arm/Group Title	Placebo	CSL312
Arm/Group Description	CSL312 diluent administered intravenously Placebo: CSL312 diluent administered intravenously	Garadacimab, Factor XIIa Antagonist Monoclonal Antibody administered intravenously Garadacimab, Factor XIIa Antagonist Monoclonal Antibody: Garadacimab, Factor XIIa Antagonist Monoclonal Antibody administered intravenously
Measure Participants	59	58
Number [participants]	1 1.6%	0 0%

22. Secondary Outcome

Title	Maximum Plasma Concentration (Cmax) of CSL312
Time Frame	Up to 28 days after CSL312 administration

Outcome Measure Data

Analysis Population Description

The pharmacokinetic (PK) Analysis Set will comprise all subjects in the Safety Analysis Set who received any amount of CSL312 or placebo and have ≥ 1 blood sample available for CSL312 concentration measurement.

Arm/Group Title	CSL312
Arm/Group Description	Garadacimab, Factor XIIa Antagonist Monoclonal Antibody administered intravenously Garadacimab, Factor XIIa Antagonist Monoclonal Antibody: Garadacimab, Factor XIIa Antagonist Monoclonal Antibody administered intravenously
Measure Participants	57
Mean (Standard Deviation) [ug/mL]	147.335 (77.1286)

23. Secondary Outcome

Title	Time to Maximum Plasma Concentration (Tmax) of CSL312
Time Frame	Up to 28 days after CSL312 administration

Outcome Measure Data

Analysis Population Description

PK

Arm/Group Title	CSL312
Arm/Group Description	Garadacimab, Factor XIIa Antagonist Monoclonal Antibody administered intravenously Garadacimab, Factor XIIa Antagonist Monoclonal Antibody: Garadacimab, Factor XIIa Antagonist Monoclonal Antibody administered intravenously
Measure Participants	57
Median (Full Range) [hours]	0.667

24. Secondary Outcome

Title	Area Under the Plasma Concentration-Time Curve From Time Zero to the Time of the Last Measurable Concentration (AUC0-Last) of CSL312
Time Frame	Up to 28 days after CSL312 administration

Outcome Measure Data

Analysis Population Description

PK

Arm/Group Title	CSL312
Arm/Group Description	Garadacimab, Factor XIIa Antagonist Monoclonal Antibody administered intravenously Garadacimab, Factor XIIa Antagonist Monoclonal Antibody: Garadacimab, Factor XIIa Antagonist Monoclonal Antibody administered intravenously
Measure Participants	57
Mean (Standard Deviation) [h*ug/mL]	15806.644 (9393.6295)

25. Secondary Outcome

Title	Terminal Half-life (T1/2) of CSL312
Time Frame	Up to 28 days after CSL312 administration

Outcome Measure Data

Analysis Population Description

PK. Participants with missing values were not included in the analysis.

Arm/Group Title	CSL312
Arm/Group Description	Garadacimab, Factor XIIa Antagonist Monoclonal Antibody administered intravenously Garadacimab, Factor XIIa Antagonist Monoclonal Antibody: Garadacimab, Factor XIIa Antagonist Monoclonal Antibody administered intravenously
Measure Participants	9
Mean (Standard Deviation) [hours]	226.165 (102.6690)

Adverse Events

Time Frame	Up to 28 days per participant after CSL312 or placebo administration
Adverse Event Reporting Description	All-Cause mortality uses ITT set and treatment emergent adverse events uses the safety analysis set.
Arm/Group Title	Placebo		CSL312
Arm/Group Description	CSL312 diluent administered intravenously Placebo: CSL312 diluent administered intravenously		Garadacimab, Factor XIIa Antagonist Monoclonal Antibody administered intravenously Garadacimab, Factor XIIa Antagonist Monoclonal Antibody: Garadacimab, Factor XIIa Antagonist Monoclonal Antibody administered intravenously
All Cause Mortality
	Placebo		CSL312
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	11/61 (18%)		11/63 (17.5%)
Serious Adverse Events
	Placebo		CSL312
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	19/59 (32.2%)		20/58 (34.5%)
Blood and lymphatic system disorders
Anaemia	1/59 (1.7%)	1	0/58 (0%)	0
Disseminated intravascular coagulation	0/59 (0%)	0	1/58 (1.7%)	1
Thrombocytopenia	1/59 (1.7%)	1	0/58 (0%)	0
Cardiac disorders
Cardiac arrest	1/59 (1.7%)	1	3/58 (5.2%)	3
Sinus tachycardia	0/59 (0%)	0	1/58 (1.7%)	1
Tachycardia	0/59 (0%)	0	1/58 (1.7%)	1
General disorders
Asthenia	1/59 (1.7%)	1	0/58 (0%)	0
Infections and infestations
Septic shock	4/59 (6.8%)	4	1/58 (1.7%)	1
Pneumonia	1/59 (1.7%)	1	1/58 (1.7%)	2
Sepsis	2/59 (3.4%)	2	0/58 (0%)	0
Diverticulitis	0/59 (0%)	0	1/58 (1.7%)	1
Enterobacter bacteraemia	1/59 (1.7%)	1	0/58 (0%)	0
Enterobacter pneumonia	1/59 (1.7%)	1	0/58 (0%)	0
Pneumonia escherichia	1/59 (1.7%)	1	0/58 (0%)	0
Pneumonia streptococcal	1/59 (1.7%)	1	0/58 (0%)	0
Injury, poisoning and procedural complications
Subdural haematoma	1/59 (1.7%)	1	0/58 (0%)	0
Metabolism and nutrition disorders
Hypoglycaemia	1/59 (1.7%)	1	0/58 (0%)	0
Nervous system disorders
Brain hypoxia	0/59 (0%)	0	1/58 (1.7%)	1
Cerebellar infarction	1/59 (1.7%)	1	0/58 (0%)	0
Cerebral infarction	1/59 (1.7%)	1	0/58 (0%)	0
Haemorrhagic stroke	1/59 (1.7%)	1	0/58 (0%)	0
Subarachnoid haemorrhage	1/59 (1.7%)	1	0/58 (0%)	0
Psychiatric disorders
Mental status changes	0/59 (0%)	0	1/58 (1.7%)	1
Renal and urinary disorders
Acute kidney injury	2/59 (3.4%)	2	1/58 (1.7%)	1
Respiratory, thoracic and mediastinal disorders
Respiratory failure	7/59 (11.9%)	8	6/58 (10.3%)	6
Hypoxia	1/59 (1.7%)	1	4/58 (6.9%)	5
Acute respiratory failure	1/59 (1.7%)	1	4/58 (6.9%)	4
Pulmonary embolism	2/59 (3.4%)	2	2/58 (3.4%)	3
Pneumothorax	1/59 (1.7%)	1	1/58 (1.7%)	1
Acute respiratory distress syndrome	1/59 (1.7%)	1	0/58 (0%)	0
Dyspnoea	1/59 (1.7%)	1	0/58 (0%)	0
Epistaxis	0/59 (0%)	0	1/58 (1.7%)	1
Vascular disorders
Deep vein thrombosis	1/59 (1.7%)	1	3/58 (5.2%)	3
Hypotension	3/59 (5.1%)	3	1/58 (1.7%)	1
Arterial thrombosis	1/59 (1.7%)	1	0/58 (0%)	0
Peripheral artery thrombosis	1/59 (1.7%)	1	0/58 (0%)	0
Peripheral ischaemia	0/59 (0%)	0	1/58 (1.7%)	1
Venous thrombosis	1/59 (1.7%)	1	0/58 (0%)	0
Other (Not Including Serious) Adverse Events
	Placebo		CSL312
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	21/59 (35.6%)		18/58 (31%)
Cardiac disorders
Atrial fibrillation	5/59 (8.5%)	5	2/58 (3.4%)	2
Bradycardia	0/59 (0%)	0	3/58 (5.2%)	3
Gastrointestinal disorders
Constipation	3/59 (5.1%)	3	0/58 (0%)	0
Infections and infestations
Septic shock	2/59 (3.4%)	2	3/58 (5.2%)	3
Investigations
Transaminases increased	4/59 (6.8%)	4	1/58 (1.7%)	1
Fibrin D dimer increased	3/59 (5.1%)	3	1/58 (1.7%)	1
Metabolism and nutrition disorders
Hyperglycaemia	5/59 (8.5%)	5	5/58 (8.6%)	5
Hyperkalaemia	3/59 (5.1%)	3	2/58 (3.4%)	2
Hypokalaemia	3/59 (5.1%)	3	2/58 (3.4%)	2
Psychiatric disorders
Anxiety	2/59 (3.4%)	2	3/58 (5.2%)	3
Renal and urinary disorders
Acute kidney injury	6/59 (10.2%)	6	0/58 (0%)	0
Respiratory, thoracic and mediastinal disorders
Dyspnoea	3/59 (5.1%)	3	2/58 (3.4%)	2
Vascular disorders
Hypotension	6/59 (10.2%)	6	2/58 (3.4%)	2

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.