An Adaptive Phase 2/3, Randomized, Double-Blind, Placebo-Controlled Study Assessing Efficacy and Safety of Sarilumab for Hospitalized Patients With COVID-19
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 1,912
- 试验地点
- 3
- 主要终点
- Percentage of Participants With at Least a 1-point Improvement in Clinical Status From Baseline to Day 22 Using the 7-point Ordinal Scale in Participants With Critical COVID-19 Receiving Mechanical Ventilation at Baseline (Phase 3 Cohort 1)
研究概览
简要总结
Phase 2:
The primary objective of the study is to evaluate the clinical efficacy of sarilumab relative to the control arm in adult patients hospitalized with COVID-19 regardless of disease severity strata.
Phase 3 Cohort 1:
The primary objective of the study is to evaluate the clinical efficacy of sarilumab relative to the control arm in adult patients hospitalized with critical COVID-19 receiving mechanical ventilation at baseline.
Phase 3 Cohort 2:
The primary objective of the study is to evaluate the clinical efficacy of sarilumab relative to the control arm in adult patients hospitalized with COVID-19 receiving mechanical ventilation at baseline.
详细描述
Phase 2 and Phase 3 Cohort 1 completed. Cohorts 2 and 3 terminated early based on Phase 3 Cohort 1 results.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Laboratory-confirmed SARS-CoV-2 infection as determined by polymerase chain reaction (PCR), result from any specimen (or other commercial or public health assay) within 2 weeks prior to randomization and no alternative explanation for current clinical condition
- •Hospitalized with illness of any duration with evidence of pneumonia, requires supplemental oxygen and/or assisted ventilation and meets one of the following:
- •Phase 2 and Phase 3 Cohort 1:
- •Meets 1 of the following criteria at baseline:
- •Severe disease OR
- •Critical disease OR
- •Multi-system organ dysfunction OR
- •Immunocompromised
- •Phase 3 Cohort 2:
- •Patients must be receiving mechanical ventilation to treat respiratory failure due to COVID-19
- •Phase 3 Cohort 3:
- •Patients must be receiving supplemental oxygen to treat hypoxemia delivered by one of the following devices:
- •Non-rebreather mask, OR
- •High-flow device with at least 50% FiO2, OR
- •Non-invasive positive pressure ventilator
- •Ability to provide informed consent signed by study patient or legally acceptable representative
- •Willingness and ability to comply with study-related procedures/assessments
排除标准
- •In the opinion of the investigator, not expected to survive for more than 48 hours from screening
- •Presence of any of the following abnormal laboratory values at screening: absolute neutrophil count (ANC) less than 2000 mm3, aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 5 x upper limit of normal (ULN), platelets <50,000 per mm3
- •Treatment with anti-IL 6, anti-IL-6R antagonists, or with Janus kinase inhibitors (JAKi) in the past 30 days or plans to receive during the study period
- •Current treatment with the simultaneous combination of leflunomide and methotrexate
- •Known active tuberculosis (TB), history of incompletely treated TB, suspected or known extrapulmonary TB, suspected or known systemic bacterial or fungal infections
- •Participation in a double-blind clinical research study evaluating an investigational product (IP) or therapy within 3 months and less than 5 half-lives of IP prior to the screening visit (The use of remdesivir, hydroxychloroquine, or other treatments being used for COVID-19 treatments in the context of an open-label study, Emergency Use Authorization (EUA), compassionate use protocol or open-label use is permitted)
- •Any physical examination findings, and/or history of any illness, concomitant medications or recent live vaccines that, in the opinion of the study investigator, might confound the results of the study or pose an additional risk to the patient by their participation in the study
- •Known systemic hypersensitivity to sarilumab or the excipients of the drug product
- •Phase 3 Cohort 2 and Cohort 3 only:
- •Known or suspected history of immunosuppression or immunodeficiency disorder
- •Patients who require renal replacement therapy for acute kidney injury at randomization or who required renal replacement therapy within 72 hours prior to randomization
- •Patients who have circulatory shock requiring vasopressors at randomization or within 24 hours prior to randomization
- •Use of extracorporeal life support (eg, ECMO) or, in the opinion of the investigator, there is a high likelihood that extracorporeal life support will be initiated within 48 hours after randomization
- •NOTE: Other protocol defined inclusion / exclusion criteria may apply
研究组 & 干预措施
Sarilumab 400mg IV (P3:C1)
Phase 3: Cohort 1
干预措施: Placebo (Drug)
Sarilumab 200mg IV (P2)
Phase 2
干预措施: Sarilumab (Drug)
Sarilumab 200mg IV (P2)
Phase 2
干预措施: Placebo (Drug)
Sarilumab 200mg IV (P3:C1)
Phase 3: Cohort 1
干预措施: Sarilumab (Drug)
Sarilumab 200mg IV (P3:C1)
Phase 3: Cohort 1
干预措施: Placebo (Drug)
Sarilumab 400mg IV (P2)
Phase 2
干预措施: Sarilumab (Drug)
Sarilumab 400mg IV (P2)
Phase 2
干预措施: Placebo (Drug)
Sarilumab 400mg IV (P3:C1)
Phase 3: Cohort 1
干预措施: Sarilumab (Drug)
Sarilumab 800mg IV (P3:C2)
Phase 3: Cohort 2
干预措施: Sarilumab (Drug)
Sarilumab 800mg IV (P3:C2)
Phase 3: Cohort 2
干预措施: Placebo (Drug)
Sarilumab 800mg IV (P3: C3)
Phase 3: Cohort 3
干预措施: Sarilumab (Drug)
Sarilumab 800mg IV (P3: C3)
Phase 3: Cohort 3
干预措施: Placebo (Drug)
结局指标
主要结局
Percentage of Participants With at Least a 1-point Improvement in Clinical Status From Baseline to Day 22 Using the 7-point Ordinal Scale in Participants With Critical COVID-19 Receiving Mechanical Ventilation at Baseline (Phase 3 Cohort 1)
时间窗: Day 22
The ordinal scale is an assessment of the clinical status of a participant. The 7-point ordinal scale is as follows: 1. Death; 2. Hospitalized, requiring invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO); 3. Hospitalized, requiring non-invasive ventilation 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; higher score = less severity
Percentage of Participants With at Least 1-point Improvement in Clinical Status Using the 7-point Ordinal Scale in Participants With COVID-19 Receiving Mechanical Ventilation at Baseline (Phase 3 Cohort 2)
时间窗: Day 22
The ordinal scale is an assessment of the clinical status of a participant The 7-point ordinal scale is as follows: 1. Death; 2. Hospitalized, requiring invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO); 3. Hospitalized, requiring non-invasive ventilation 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; higher score = less severity
Percent Change From Baseline in CRP Levels at Day 4 in Participants With Serum IL-6 Level Greater Than the ULN (Phase 2)
时间窗: Baseline and Day 4
Percent Change from Baseline in C-Reactive Protein (CRP) Levels at Day 4 in Participants with Serum Interleukin 6 (IL-6) Level Greater than the Upper Limit of Normal (ULN) Least Squares (LS) means estimate of percent change from baseline at Day 4 (raw scale) for each treatment group is based on the Analysis of Covariance (ANCOVA) model. It is defined as anti-log of the estimate of dependent variable minus 1, i.e., (exp\[ln(CRP at day 4/Baseline CRP)\]-1. Negative numbers imply improvement in CRP.
次要结局
- Time to Resolution of Fever and Improvement in Oxygenation for at Least 48 Hours (Phase 2)(Up to day 29)
- Percentage of Participants Alive, Off Oxygen (Phase 2)(At Day 29)
- Time to Improvement (2 Points) in Clinical Status Assessment in Severe or Critical Patients With All Serum IL-6 Levels (Phase 2)(Up to Day 29)
- Time to Improvement (2 Points) in Clinical Status Assessment in Severe or Critical Patients With Serum IL-6 Levels Greater Than the Upper Limit of Normal (Phase 2)(Up to Day 29)
- Time to Resolution of Fever for at Least 48 Hours Without Antipyretics or Until Discharge, Whichever is Sooner, by Baseline IL-6 Levels (Phase 2)(Up to Day 29)
- Time to Improvement in Oxygenation for at Least 48 Hours by Baseline IL-6 Levels (Phase 2)(Up to day 29)
- Change From Baseline in NEWS2 Scoring System (Phase 2)(Days 3, 5, 8, 11, 15 and 29)
- Percentage of Participants Who Recover (Phase 3 Cohort 1: Critical on Mechanical Ventilation at Baseline)(Day 22)
- Percentage of Participants Who Die (Phase 3 Cohort 1: Critical on Mechanical Ventilation at Baseline)(Up to Day 29 and Day 60)
- Time to Discharge or to a National Early Warning Score 2 (NEWS2) of ≤2 and Maintained for 24 Hours (Phase 2)(Up to day 29)
- Number of Participants Who Initiated Mechanical Ventilation After Baseline (Phase 2)(Up to Day 29)
- Number of Days of Hospitalization Among Survivors (Phase 2)(Up to day 29)
- Time to Resolution of Fever for at Least 48 Hours Without Antipyretics or Until Discharge, Whichever is Sooner, in Patients With Documented Fever at Baseline (Phase 2)(Up to Day 29)
- Time to Resolution of Fever for at Least 48 Hours Without Antipyretics by Clinical Severity (Phase 2)(Up to day 29)
- Time to Improvement in Oxygenation for at Least 48 Hours (Phase 2)(Up to day 29)
- Percentage of Participants in Each Clinical Status Category Using the 7-point Ordinal Scale up to Day 29 (Phase 2)(Days 1, 3, 5, 8, 11, 15 and 29)
- Number of Days With Fever (Phase 2)(Up to Day 29)
- Number of Days of Resting Respiratory Rate >24 Breaths/Min (Phase 2)(Up to day 29)
- Number of Days With Hypoxemia (Phase 2)(Up to day 29)
- Number of Days of Supplemental Oxygen Use (Phase 2)(Up to day 29)
- Time to Saturation ≥94% on Room Air (Phase 2)(Up to day 29)
- Number of Ventilator Free Days (Phase 2)(Up to Day 22)
- Number of Days in an Intensive Care Unit (ICU) in Participants Who Were Not in ICU at Baseline (Phase 2)(Up to Day 29)
- Number of Deaths Due to Any Cause(Up to day 60)
- Percentage of Participants With at Least 1-point Improvement in Clinical Status Using the 7-point Ordinal Scale in Participants With Critical COVID-19 (Phase 3 Cohort 1: Critical ITT)(Day 22)
- Percentage of Participants Who Die (Phase 3 Cohort 1: Critical ITT)(Up to Day 29 and Day 60)
- Percentage of Participants Alive Not Receiving Mechanical Ventilation or ECMO at Day 22 (Phase 3 Cohort 1: Critical on Mechanical Ventilation at Baseline)(At Day 22)
- Time to at Least 1-point Improvement in Clinical Status Assessment on the 7-point Ordinal Scale (Phase 3 Cohort 1: Critical ITT)(Up to day 29)
- Time to at Least 2-point Improvement in Clinical Status Assessment on the 7-point Ordinal Scale (Phase 3 Cohort 1)(Up to day 29)
- Time to Recovery (Phase 3 Cohort 2)(Up to day 29)
- Time to Death (Phase 3 Cohort 1: Critical on Mechanical Ventilation at Baseline)(Up to day 60)
- Number of Ventilator-Free Days (Phase 3 Cohort 1: Critical ITT)(Days 8, 15, 22 and 29)
- Number of Participants With Grade 4 Neutropenia (ANC <500/mm3)(Up to day 60)
- Mean Observed Leukocyte Values Across Study Days (Phase 2)(Days 1, 4, 15 and 29)
- Mean Observed Hemoglobin Values Across Study Days (Phase 3)(Days 1, 4, 15 and 29)
- Mean Observed Total Bilirubin Across Study Days (Phase 3)(Days 1, 4, 15 and 29)
- Percentage of Participants Who Recover (Phase 3 Cohort 1: Critical ITT)(Day 22)
- Percentage of Participants With at Least a 2-point Improvement in Clinical Status From Baseline to Day 22 Using the 7-point Ordinal Scale (Phase 3 Cohort 1: Critical on Mechanical Ventilation at Baseline)(At Day 22)
- Percentage of Participants Alive Not Receiving Mechanical Ventilation or ECMO at Day 22 (Phase 3 Cohort 1: Critical ITT)(At Day 22)
- Percentage of Participants With at Least a 2-point Improvement in Clinical Status From Baseline to Day 22 Using the 7-point Ordinal Scale (Phase 3 Cohort 1: Critical ITT)(At Day 22)
- Time to at Least 1-point Improvement in Clinical Status Assessment on the 7-point Ordinal Scale (Phase 3 Cohort 1: Critical on Mechanical Ventilation at Baseline)(Up to day 29)
- Time to at Least 1-point Improvement in Clinical Status Assessment on the 7-point Ordinal Scale (Phase 3 Cohort 2)(Up to day 29)
- Time to at Least 2-point Improvement in Clinical Status Assessment on the 7-point Ordinal Scale (Phase 3 Cohort 1: Critical ITT)(Up to day 29)
- Percentage of Participants Receiving Mechanical Ventilation or ECMO at Day 22 (Phase 3 Cohort 1: Critical on Mechanical Ventilation at Baseline)(Day 22)
- Percentage of Patients Discharged and Alive (Phase 3 Cohort 1)(At Day 22)
- Percentage of Participants Discharged and Alive at Day 22 (Phase 3 Cohort 1: Critical ITT)(At Day 22)
- Time to Recovery (Phase 3 Cohort 1: Critical on Mechanical Ventilation at Baseline)(Up to day 29)
- Time to Recovery (Phase 3 Cohort 1: Critical ITT)(Up to day 29)
- Number of Ventilator-Free Days (Phase 3 Cohort 1: Critical on Mechanical Ventilation at Baseline)(Days 8, 15, 22 and 29)
- Number of Participants With Grade 4 Neutropenia and Concurrent Invasive Infection(Up to day 60)
- Mean Observed Platelet Count Across Study Days (Phase 2)(Days 1, 4, 15 and 29)
- Mean Observed Platelet Count Across Study Days (Phase 3)(Days 1, 4, 15 and 29)
- Percentage of Participants Receiving Mechanical Ventilation or ECMO at Day 22 (Phase 3 Cohort 1: Critical ITT)(Day 22)
- Time to Death (Phase 3 Cohort 1: Critical ITT)(Up to day 60)
- Time to Death (Phase 3 Cohort 2)(Up to day 60)
- Number of Days of Hospitalization Among Survivors (Phase 3 Cohort 1)(Days 8, 15, 22 and 29)
- Number of Days of Hospitalization Among Survivors (Phase 3 Cohort 1: Critical ITT)(Days 8, 15, 22 and 29)
- Number of Participants With Any Serious Adverse Event(Up to day 60)
- Number of Participants With Severe or Life-threatening Bacterial, Invasive Fungal, or Opportunistic Infection(Up to day 60)
- Number of Participants With Grade >=2 Infusion Related Reactions(Up to day 60)
- Number of Participants With Gastrointestinal Perforation(Up to day 60)
- Mean Observed Aspartate Aminotransferase Values Across Study Days (Phase 3)(Days 1, 4, 15 and 29)
- Mean Observed Alanine Aminotransferase Values Across Study Days (Phase 2)(Days 1, 4, 15 and 29)
- Number of Participants With Grade >=2 Hypersensitivity Reactions(Up to day 60)
- Mean Observed Leukocyte Values Across Study Days (Phase 3)(Days 1, 4, 15 and 29)
- Mean Observed Hemoglobin Values Across Study Days (Phase 2)(Days 1, 4, 15 and 29)
- Mean Observed Total Bilirubin Values Across Study Days (Phase 2)(Days 1, 4, 15 and 29)
- Mean Observed Aspartate Aminotransferase Values Across Study Days (Phase 2)(Days 1, 4, 15 and 29)
- Mean Observed Alanine Aminotransferase Values Across Study Days (Phase 3)(Days 1, 4, 15 and 29)
- Mean Observed Creatinine Values Across Study Days (Phase 2)(Days 1, 4, 15 and 29)
- Mean Observed Creatinine Values Across Study Days (Phase 3)(Days 1, 4, 15 and 29)