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

Study Overview
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Brief Summary
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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)

Official Title
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A Phase 2, Multicenter, Double Blind, Randomized, Placebo-Controlled Study to Evaluate CSL312 in Coronavirus Disease 2019 (COVID 19)

Conditions
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Coronavirus Disease 2019 (COVID-19)

Intervention / Treatment
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* Biological: Garadacimab, Factor XIIa Antagonist Monoclonal Antibody
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: CSL312<br>Garadacimab, Factor XIIa Antagonist Monoclonal Antibody administered intravenously | Biological: Garadacimab, Factor XIIa Antagonist Monoclonal Antibody<br>* Garadacimab, Factor XIIa Antagonist Monoclonal Antibody administered intravenously<br>|
| Placebo Comparator: Placebo<br>CSL312 diluent administered intravenously | Drug: Placebo<br>* CSL312 diluent administered intravenously<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Percent of Participants With Tracheal Intubation or Death Prior to Tracheal Intubation |  | From randomization to Day 28 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent of Participants With Death From All Causes |  | From randomization to Day 28 | 
| Percent of Participants With Tracheal Intubation |  | From randomization to Day 28 | 
| Number of Participants With ≥ 2-Point Improvement Compared to Baseline on National Institute of Allergy and Infectious Diseases (NIAID) Ordinal Scale | 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. | From randomization to Day 28 | 
| Percent of Participants With ≥ 2-Point Improvement Compared to Baseline on NIAID | 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. | From randomization to Day 28 | 
| Number of Participants Within Each of the Categories of the NIAID at End of Study | 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. | Day 28 | 
| Percent of Participants Within Each of the Categories of the NIAID at End of Study | 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. | Day 28 | 
| Percent of Participants Requiring Continuous Positive Airway Pressure (CPAP) or Bilevel Positive Airway Pressure (BiPAP) |  | From randomization to Day 28 | 
| Percent of Participants Requiring Extracorporeal Membrane Oxygenation (ECMO) | 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. | From randomization to Day 28 | 
| Percent of Participants Requiring High-Flow Nasal Cannula (HFNC) |  | From randomization to Day 28 | 
| Maximum Change From Baseline in Sequential Organ Failure Assessment (SOFA) Score | 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. | From randomization to Day 28 | 
| Change From Baseline in SOFA Total Score | 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. | From randomization to Day 28 | 
| Change From Baseline in the Individual Components of SOFA Score | 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. | From randomization to Day 28 | 
| Length of Hospital Stay |  | From randomization to Day 28 (+/- 2 days) | 
| Number of Participants Experiencing Adverse Events (AEs) |  | Up to 28 days after CSL312 or placebo administration | 
| Percent of Participants Experiencing AEs |  | Up to 28 days after CSL312 or placebo administration | 
| Number of Participants Experiencing Serious Adverse Events (SAEs) |  | Up to 28 days after CSL312 or placebo administration | 
| Percent of Participants Experiencing SAEs |  | Up to 28 days after CSL312 or placebo administration | 
| Number of Participants With Adverse Events of Special Interest (AESIs) |  | Up to 28 days after CSL312 or placebo administration | 
| Percent of Participants With AESIs |  | Up to 28 days after CSL312 or placebo administration | 
| Number of Participants With Anti-CSL312 Antibodies |  | Up to 28 days after CSL312 or placebo administration | 
| Maximum Plasma Concentration (Cmax) of CSL312 |  | Up to 28 days after CSL312 administration | 
| Time to Maximum Plasma Concentration (Tmax) of CSL312 |  | Up to 28 days after CSL312 administration | 
| 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 | 
| Terminal Half-life (T1/2) of CSL312 |  | Up to 28 days after CSL312 administration | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Prevention of respiratory failure