A Study to Evaluate the Efficacy and Safety of Sirukumab in Confirmed Severe or Critical Confirmed Coronavirus Disease (COVID)-19

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the clinical response of sirukumab (administered as a single intravenous dose) plus standard of care (SOC) compared to placebo plus SOC in COVID-19.

Detailed Description
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Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19), is an enveloped, positive-sense, single-stranded ribonucleic acid (RNA) betacoronavirus. Symptoms of COVID-19 infection may appear from 2 to 14 days following exposure, with the spectrum of illnesses ranging from mild symptoms to severe illness or death. The identification of SARS-CoV-2 follows the emergence of 2 other novel betacoronaviruses: SARS-CoV and Middle East respiratory syndrome coronavirus (MERS-CoV). Current management of COVID-19 is supportive, and respiratory failure from acute respiratory distress syndrome (ARDS) is the leading cause of mortality. While an understanding of the epidemiology and clinical spectrum of COVID-19 is still evolving during the ongoing pandemic, the current knowledge of the disease burden highlights the urgent medical need to develop a treatment. Sirukumab (also known as CNTO136) is a human anti-interleukin (IL)-6 immunoglobulin G1 kappa (IgG1k) monoclonal antibody (mAb). Sirukumab binds with high affinity and specificity to human IL-6 and as a result inhibits IL-6-mediated signaling and the biological effects of IL-6. The study will include a Screening Phase (up to 1 Day), a Treatment Phase (Day 1 to Day 28) and a Follow-up Phase (post Day 28, follow-up phone calls on Week 8, Week 12 and Week 16). Safety evaluations will include monitoring of adverse events and serious adverse events, physical examinations, vital sign measurements, electrocardiograms, clinical laboratory tests, pregnancy testing, and checking of vital status. The entire study duration for each participant will be 16 weeks.

Official Title
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Phase 2, Randomized, Double-blind, Placebo-controlled Study to Evaluate the Efficacy and Safety of Sirukumab in Confirmed Severe or Critical COVID-19 Disease

Conditions
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Critical Confirmed Coronavirus Disease (COVID)-19

Intervention / Treatment
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* Drug: Sirukumab
* Drug: Placebo
* Other: Standard of Care (SOC)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Hospitalized Has laboratory-confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection as determined by real time-polymerase chain reaction (PCR) at any time before randomization Evidence of infiltrates by chest X-ray, chest computed tomography (CT), lung ultrasound, or chest auscultation (rales, crackles) Informed consent must be obtained from the participant indicating that he or she understands the purpose of, and procedures required for, the study and is willing to participate in the study Critical COVID-19 disease, defined as: Requires supplemental oxygen delivered by nonrebreather mask or high-flow nasal cannula or use of non-invasive or invasive ventilation or requiring treatment in an intensive care unit AND corresponding to category 4 on the 6-point ordinal recovery scale, that is: requires one of the above modalities to sustain a peripheral capillary oxygen saturation (SpO2) greater than (>) 93 percent (%) with a fraction of inspired oxygen (FiO2) of 50% or higher. Note, the use of other devices may fit with category 4 if the FiO2 is 50% or higher. OR, corresponding to category 5 on the 6-point ordinal recovery scale, that is partial pressure of oxygen in arterial per percentage of inspired oxygen (PaO2/FiO2) ratio < 300 millimeter of mercury (mmHg) while on invasive mechanical ventilation or veno-venous extracorporeal membrane oxygenation (ECMO) for less than 48 hours prior to screening Exclusion Criteria: On invasive mechanical ventilation or on veno-venous ECMO for >48 hours at time of screening Received an investigational intervention (including investigational vaccines) or used an invasive investigational medical device within 30 days before the planned dose of study intervention. Note: the investigator must ensure that the participant is not enrolled in another COVID-19 study with an investigational intervention (apart from the exception specified below) prior to completion of Day 28 of the current study. Exception: participation in a single arm study, a non-blinded controlled study, expanded access, compassionate use program or any other program that is not a blinded study is allowed if it is conducted with one of the following: agents with demonstrated in vitro-effect against SARSCoV- 2, as mentioned in the center of disease control and prevention (CDC) guidelines and convalescent plasma Current confirmed or high suspicion for pulmonary embolus, hemodynamic significant pericardial effusion, myocarditis, or Class 3 or 4 congestive heart failure as defined by the New York Heart Association Functional Classification AND/OR Current evidence of active cardiac ischemia Has a history of respiratory condition (that is, asthma, chronic obstructive pulmonary disease (COPD), cystic fibrosis, fibrotic lung disease) that requires home oxygen supplementation, supportive non-invasive ventilation or, is status/post lung volume reduction surgery (LVRS). Exception: Participants with sleep apnea using supportive non-invasive ventilation (continuous positive airway pressure [CPAP]) at screening may be included On renal replacement therapy (defined as peritoneal dialysis or hemodialysis) Screening laboratory test result as follows: absolute neutrophil count (ANC) <1.0*10^3 cells/microliter; Platelet count <50*10^3 cells/microliter; estimated glomerular filtration rate (eGFR) <=30 milliliter per minute per 1.73 square meter (mL/min/1.73 m^2); Bilirubin >2* upper limit of normal (ULN) unless bilirubin rise is due to Gilbert's syndrome or of non-hepatic origin; alanine aminotransferase/ aspartate aminotransferase (ALT) >5*ULN; Prothrombin time (PT)/international normalized ratio (INR) >1.5*ULN or activated partial thromboplastin time (aPTT) >1.5*ULN related to known coagulopathy or bleeding disorder (the participant can receive anticoagulant therapies for underlying conditions, or as systematic thromboprophylaxis due to COVID-19, or as part of the treatment of complications of COVID-19, but cannot participate in a clinical study with anticoagulants for COVID-19) Pregnant or breastfeeding, unless in the opinion of the investigator, the benefit outweighs the risks Has active hepatitis B or C infection or has human immunodeficiency virus infection or acquired immune deficiency syndrome (HIV/AIDS) based on medical history and/or concomitant medication Known active or latent tuberculosis (TB), history of incompletely treated TB, suspected or known extrapulmonary TB based on medical history and/or concomitant medication Evidence of active bacterial (including but not limited to bacterial pneumonia), fungal, viral or opportunistic infection (other than SARS-CoV-2) Currently active clinically significant (example, causing hemodynamic instability and/or causing hypoxemia) and uncontrolled arrhythmia

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 84 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: Sirukumab<br>Participants will receive single intravenously (IV) dose infusion of sirukumab on Day 1 along with standard of care treatment. | Drug: Sirukumab<br>* Participants will receive single dose infusion of sirukumab on Day 1.<br>* Other names: CNTO136;Other: Standard of Care (SOC)<br>* SOC treatment will be determined by the investigator based on local practice and consists of supportive care.<br>|
| Placebo Comparator: Placebo<br>Participants will receive IV single dose infusion of placebo on Day 1 along with standard of care treatment. | Drug: Placebo<br>* Participants will receive placebo IV single dose infusion on Day 1.<br>Other: Standard of Care (SOC)<br>* SOC treatment will be determined by the investigator based on local practice and consists of supportive care.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Sustained Improvement of at Least 2 Categories on 6-point Ordinal Clinical Recovery Scale (CRS): Primary Analysis Set | Time to sustained improvement is defined as an improvement of at least 2 categories relative to baseline on the 6-point ordinal clinical recovery scale sustained until Day 28. The 6-point ordinal CRS provides 6 mutually exclusive conditions ordered from best (score 1) to worst (score 6) corresponding to below categories, reflects the participant's worst situation on the day assessed. The ordinal clinical recovery scale categories are: not hospitalized, including participants on low level of oxygen (category 1); Hospitalization, not requiring supplemental oxygen (category 2); hospitalized, requiring low flow supplemental oxygen (category 3); hospitalized, on non-invasive pressure ventilation or high flow oxygen devices (category 4); hospitalized, on invasive mechanical ventilation (IMV) or extracorporeal membrane oxygenation (ECMO) (category 5); death (category 6). Higher scores indicated greater worsening. | Up to Day 28 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With an Improvement of At Least 2 Categories Compared to Baseline on 6-point Ordinal CRS | Percentage of participants with an improvement of at least 2 Categories compared to baseline on 6-point ordinal CRS were reported. The 6-point ordinal CRS provides 6 mutually exclusive conditions ordered from best (score 1) to worst (score 6) corresponding to below categories, reflects the participant's worst situation on the day assessed. The ordinal clinical recovery scale categories are: not hospitalized, including participants on low level of oxygen (category 1); Hospitalization, not requiring supplemental oxygen (category 2); hospitalized, requiring low flow supplemental oxygen (category 3); hospitalized, on non-invasive pressure ventilation or high flow oxygen devices (category 4); hospitalized, on invasive mechanical ventilation (IMV) or extracorporeal membrane oxygenation (ECMO) (category 5); death (category 6). Higher scores indicated greater worsening. | Day 28 | 
| Percentage of Participants With All-cause Mortality Up to 28 Days | Percentage of participants with all-cause mortality up to 28 days were reported. All-cause mortality included all deaths of participants due to any cause. | Up to 28 days | 
| Time to Sustained Improvement of at Least 2 Categories on 6-point Ordinal CRS: Intent-to-Treat (ITT) Set | Time to sustained improvement is defined as an improvement of at least 2 categories relative to baseline on the 6-point ordinal clinical recovery scale, sustained until Day 28. The 6-point ordinal CRS provides 6 mutually exclusive conditions ordered from best (score 1) to worst (score 6) corresponding to below categories, reflects the participant's worst situation on the day assessed. The ordinal clinical recovery scale categories are: not hospitalized, including participants on low level of oxygen (category 1); Hospitalization, not requiring supplemental oxygen (category 2); hospitalized, requiring low flow supplemental oxygen (category 3); hospitalized, on non-invasive pressure ventilation or high flow oxygen devices (category 4); hospitalized, on invasive mechanical ventilation (IMV) or extracorporeal membrane oxygenation (ECMO) (category 5); death (category 6). Higher scores indicated greater worsening. | Up to Day 28 | 
| Percentage of Participants With an Improvement of at Least 2 Categories Compared to Baseline on 6-point Ordinal CRS: ITT Set | Percentage of participants with an improvement of at least 2 categories compared to baseline on 6-point ordinal CRS were reported. The 6-point ordinal CRS provides 6 mutually exclusive conditions ordered from best (score 1) to worst (score 6) corresponding to below categories, reflects the participant's worst situation on the day assessed. The ordinal clinical recovery scale categories are: not hospitalized, including participants on low level of oxygen (category 1); Hospitalization, not requiring supplemental oxygen (category 2); hospitalized, requiring low flow supplemental oxygen (category 3); hospitalized, on non-invasive pressure ventilation or high flow oxygen devices (category 4); hospitalized, on invasive mechanical ventilation (IMV) or extracorporeal membrane oxygenation (ECMO) (category 5); death (category 6). Higher scores indicated greater worsening. | Day 28 | 
| Percentage of Participants With All-cause Mortality: ITT Set | Percentage of participants with all-cause mortality were reported. All-cause mortality included all deaths of participants due to any cause. | Day 28 | 
| Percentage of Participants With Serious Adverse Events (SAEs) (Treatment Phase) | Percentage of participants with SAEs were reported. SAE is any AE that results in: death, persistent or significant disability/incapacity, requires inpatient hospitalization or prolongation of existing hospitalization, is life-threatening experience, is a congenital anomaly/birth defect and may jeopardize participant and/or may require medical or surgical intervention to prevent one of the outcomes listed above. | Up to Day 28 | 
| Percentage of Participants With Related Adverse Events (AEs) | Percentage of participants with related AEs were reported. An AE is any untoward medical occurrence in a participant participating in a clinical study that does not necessarily have a causal relationship with the pharmaceutical/biological agent under study. | Up to Day 28 | 
| Percentage of Participants With Severe or Life-threatening, Bacterial, Invasive Fungal, Viral or Opportunistic Infections | Percentage of participants with severe or Life-threatening, bacterial, invasive fungal, viral or opportunistic infections were reported. | Up to Day 28 | 
| Percentage of Participants With Grade 3 and 4 Neutropenia and Lymphocytopenia | Percentage of participants with Grade 3 and 4 neutropenia and lymphocytopenia were reported. The laboratory abnormalities were determined as per division of microbiology and infectious diseases (DMID) adult toxicity as Grade 1: mild (transient or mild discomfort [less than {<} 48 hours]; no medical intervention/therapy required); Grade 2: moderate (mild to moderate limitation in activity - some assistance may be needed; no or minimal medical intervention/therapy required); Grade 3: severe (severe marked limitation in activity, some assistance usually required; medical intervention/therapy required, hospitalizations possible); Grade 4: life-threatening (extreme limitation in activity, significant assistance required; significant medical intervention/therapy required, hospitalization or hospice care probable). | Up to Day 28 | 
| Percentage of Participants With Increased Alanine Transaminase (ALT) Greater Than or Equal to (>=)3*Upper Limit Normal (ULN) Combined With Increased Bilirubin Greater Than (>)2*ULN | Percentage of participants with increased ALT >=3*ULN combined with increased bilirubin >2*ULN were reported. | Up to Day 28 | 
| Time to Sustained Improvement of at Least 1 Category on 6-point Ordinal CRS: Primary Analysis Set | Time to sustained improvement is defined as an improvement of at least 1 category relative to baseline on the 6-point ordinal clinical recovery scale, sustained until Day 28. The 6-point ordinal CRS provides 6 mutually exclusive conditions ordered from best (score 1) to worst (score 6) corresponding to below categories, reflects the participant's worst situation on the day assessed. The ordinal clinical recovery scale categories are: not hospitalized, including participants on low level of oxygen (category 1); Hospitalization, not requiring supplemental oxygen (category 2); hospitalized, requiring low flow supplemental oxygen (category 3); hospitalized, on non-invasive pressure ventilation or high flow oxygen devices (category 4); hospitalized, on invasive mechanical ventilation (IMV) or extracorporeal membrane oxygenation (ECMO) (category 5); death (category 6). Higher scores indicated greater worsening. | Up to Day 28 | 
| Time to Sustained Improvement of at Least 1 Category on 6-point Ordinal CRS: ITT Set | Time to sustained improvement is defined as an improvement of at least 1 category relative to baseline on the 6-point ordinal clinical recovery scale, sustained until Day 28. The 6-point ordinal CRS provides 6 mutually exclusive conditions ordered from best (score 1) to worst (score 6) corresponding to below categories, reflects the participant's worst situation on the day assessed. The ordinal clinical recovery scale categories are: not hospitalized, including participants on low level of oxygen (category 1); Hospitalization, not requiring supplemental oxygen (category 2); hospitalized, requiring low flow supplemental oxygen (category 3); hospitalized, on non-invasive pressure ventilation or high flow oxygen devices (category 4); hospitalized, on invasive mechanical ventilation (IMV) or extracorporeal membrane oxygenation (ECMO) (category 5); death (category 6). Higher scores indicated greater worsening. | Up to Day 28 | 
| Percentage of Participants With an Improvement of at Least 1 Category Compared to Baseline on 6-point Ordinal CRS: Primary Analysis Set | The 6-point ordinal CRS provides 6 mutually exclusive conditions ordered from best (score 1) to worst (score 6), reflects the participant's worst situation on the day assessed. The ordinal clinical recovery scale categories are: (category 1) not hospitalized, including participants on low level of oxygen; Hospitalization, not requiring supplemental oxygen (category 2); hospitalized, requiring low flow supplemental oxygen (category 3); hospitalized, on non-invasive pressure ventilation or high flow oxygen devices (category 4); hospitalized, on invasive mechanical ventilation (IMV) or extracorporeal membrane oxygenation (ECMO) (category 5); death (category 6). Higher scores indicated greater worsening. | Day 28 | 
| Percentage of Participants With an Improvement of at Least 1 Category on 6-point Ordinal CRS: ITT Set | The 6-point ordinal CRS provides 6 mutually exclusive conditions ordered from best (score 1) to worst (score 6) corresponding to below categories, reflects the participant's worst situation on the day assessed. The ordinal clinical recovery scale categories are: not hospitalized, including participants on low level of oxygen (category 1); Hospitalization, not requiring supplemental oxygen (category 2); hospitalized, requiring low flow supplemental oxygen (category 3); hospitalized, on non-invasive pressure ventilation or high flow oxygen devices (category 4); hospitalized, on invasive mechanical ventilation (IMV) or extracorporeal membrane oxygenation (ECMO) (category 5); death (category 6). Higher scores indicated greater worsening | Day 28 | 
| Time From Study Intervention Administration to End of Oxygen Supplementation | Time from study intervention administration to end of oxygen supplementation was reported. | Up to Day 28 | 
| Time From Study Intervention Administration to Hospital Discharge Among the Surviving Participants | Time from study intervention administration to hospital discharge among the surviving participants was reported. | Up to Day 28 | 
| Total Length of Hospitalization Among the Surviving Participants | Total length of hospitalization, defined as total duration of hospital stay, among the surviving participants was reported. | Up to Day 28 | 
| Number of Ventilation Free Days | Number of ventilation free days in participants on invasive mechanical ventilation (IVM)/extracorporeal membrane oxygenation (ECMO) at baseline was reported. | Up to Day 28 | 
| Percentage of Participants With Clinical Status as Assessed by 6-point Ordinal CRS: Primary Analysis Set | Percentage of participants with clinical status as assessed by 6-point Ordinal CRS were reported. The 6-point ordinal CRS provides 6 mutually exclusive conditions ordered from best (score 1) to worst (score 6) corresponding to below categories, reflects the participant's worst situation on the day assessed. The ordinal clinical recovery scale categories are: Not hospitalized, not requiring supplemental oxygen (category 1.1); Not hospitalized, requiring supplemental oxygen (category 1.2); Hospitalization, not requiring supplemental oxygen (category 2); hospitalized, requiring low flow supplemental oxygen (category 3); hospitalized, on non-invasive pressure ventilation or high flow oxygen devices (category 4); hospitalized, on invasive mechanical ventilation (IMV) or extracorporeal membrane oxygenation (ECMO) (category 5); death (category 6). Higher scores indicated greater worsening. | On Day 7, 14, 21, 28 | 
| Percentage of Participants With Clinical Status as Assessed by 6-point Ordinal CRS: ITT Set | Percentage of participants with clinical status as assessed by 6-point Ordinal CRS (ITT Set) were reported. The 6-point ordinal CRS provides 6 mutually exclusive conditions ordered from best (score 1) to worst (score 6) corresponding to below categories, reflects the participant's worst situation on the day assessed. The ordinal clinical recovery scale categories are: Not hospitalized, not requiring supplemental oxygen (category 1.1); Not hospitalized, requiring supplemental oxygen (category 1.2); Hospitalization, not requiring supplemental oxygen (category 2); hospitalized, requiring low flow supplemental oxygen (category 3); hospitalized, on non-invasive pressure ventilation or high flow oxygen devices (category 4); hospitalized, on invasive mechanical ventilation (IMV) or extracorporeal membrane oxygenation (ECMO) (category 5); death (category 6). Higher scores indicated greater worsening. | On Days 7, 14, 21, 28 | 
| Total Time on Invasive Mechanical Ventilation | Total time on invasive mechanical ventilation in participants who were on invasive mechanical ventilation at baseline was reported. | Up to Day 28 | 
| Percentage of Participants With a Worse Category Relative to Baseline on the 6-point Ordinal CRS | Percentage of participants with a worse category relative to baseline on the 6-point ordinal CRS for at least one of the daily assessment during the reporting period Day 5 and Day 28 were reported. he 6-point ordinal CRS provides 6 mutually exclusive conditions ordered from best (score 1) to worst (score 6) corresponding to below categories, reflects the participant's worst situation on the day assessed. The ordinal clinical recovery scale categories are: not hospitalized, including participants on low level of oxygen (category 1); Hospitalization, not requiring supplemental oxygen (category 2); hospitalized, requiring low flow supplemental oxygen (category 3); hospitalized, on non-invasive pressure ventilation or high flow oxygen devices (category 4); hospitalized, on invasive mechanical ventilation (IMV) or extracorporeal membrane oxygenation (ECMO) (category 5); death (category 6). Higher scores indicated greater worsening. | From Day 5 up to Day 28 | 
| Percentage of Participants With Extracorporeal Membrane Oxygenation (ECMO) Over Time | Percentage of participants with ECMO over time were reported. | From Day 1 up to Day 28 | 
| Total Time on ECMO | Total time for participants on ECMO was reported. | Up to Day 28 | 
| Percentage of Alive Participants at Day 28, Week 8, and Week 16 | Percentage of alive participants at Day 28, Week 8, and Week 16 were reported. For this outcome measure, at Week 8, data was not collected for participants due to pandemic situation. | On Day 28, Week 8 and Week 16 | 
| Percentage of Alive Participants That Required Readmission at Week 8, and Week 16 | Percentage of alive participants that required readmission at Week 8, and Week 16 were reported. For this outcome measure, at Week 8 and Week 16, data was not collected for participants due to pandemic situation. | Week 8 and Week 16 | 
| Percentage of Participants With SAEs (Follow-up Phase) | Percentage of participants with SAEs were reported. SAE is any AE that results in: death, persistent or significant disability/incapacity, requires inpatient hospitalization or prolongation of existing hospitalization, is life-threatening experience, is a congenital anomaly/birth defect and may jeopardize participant and/or may require medical or surgical intervention to prevent one of the outcomes listed above. | From Week 4 up to Week 16 |