A Study Comparing the Efficacy and Safety of Standard of Care With or Without Siltuximab in Selected Hospitalized Patients With Viral Acute Respiratory Distress Syndrome (SILVAR)
试验速览
- 阶段
- 3 期
- 状态
- 终止
- 发起方
- 入组人数
- 555
- 试验地点
- 2
- 主要终点
- 28-day all-cause mortality
研究概览
简要总结
This study will evaluate the efficacy and safety of siltuximab compared with normal saline in combination with standard of care (SOC) in selected hospitalized patients with COVID-19 previously treated with corticosteroids or another respiratory virus infection associated with acute respiratory distress syndrome (ARDS) and elevated C-reactive protein (CRP) levels.
详细描述
This is a prospective, multicenter, randomized (2:1), double-blind, parallel-arm, placebo-controlled, Phase 3 clinical trial of 1-3 doses of siltuximab 11 mg/kg IV over 1 hour plus SOC vs. matched-volume normal saline (NS) IV over 1 hour plus SOC in 555 patients with SARS CoV-2 previously treated with corticosteroids or another respiratory virus infection with elevated CRP levels who have developed serious respiratory complications.
The randomization will be stratified by age (<65, ≥65 years), respiratory virus infection (confirmed SARS-CoV-2, other), and MIV status (yes, no). Crossover between treatment arms will not be allowed.
All patients will receive ARDS SOC following the official American Thoracic Society/European Society of Intensive Care Medicine/Society of Critical Care Medicine clinical practice guideline13 and/or the World Health Organization's (WHO's) clinical management of severe acute respiratory infection when COVID-19 disease is suspected (WHO Interim Guidance 202014 or other local guidance). Patients may continue receiving their corticosteroid (up to a cumulative maximum dexamethasone or equivalent dose of 60 mg [except to treat treatment-emergent reactions or comorbid conditions]) or antiviral therapy (except aminoquinoline compounds and convalescent plasma) at the same or lower doses if started at least 4 days (corticosteroid therapy) or at least 2 days (antiviral therapy) prior to randomization. Patients randomized to Arm A will additionally receive siltuximab 11 mg/kg IV administered over 1 hour, while patients randomized to Arm B will additionally receive IV NS administered over 1 hour, with opportunity to repeat their assigned study treatment once or twice at least 2 days apart on or after Day 3 as their clinical condition and/or laboratory testing dictate.
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)
盲法说明
At all times, randomized study treatment assignment information will be kept confidential and will not be released to the patient, investigator, the study staff (except the pharmacist), or the Sponsor's Study Team until following the conclusion of the study, except as described below.
At the initiation of the study, the study site will be instructed on procedures for breaking the blind. Blinding codes should be broken only in emergency situations for reasons of patient safety. If a patient has an AE that may be considered treatment-related, treatment for the AE should be administered as if the patient is receiving siltuximab. Whenever possible, the investigator should contact the Sponsor's Medical Monitor before breaking the blind. When the blind for a patient has been broken, the reason must be fully documented. The patient for whom the blind has been broken will not receive further doses of study treatment.
入排标准
- 年龄范围
- 12 Years 至 65 Years（Child, Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Positive microbiological evidence of SARS-CoV-2 or another respiratory virus infection (eg, other coronaviruses, respiratory syncytial virus, influenza virus) following institutional diagnostic standards
- •Clinical and radiological diagnosis of pulmonary infection requiring noninvasive or mechanical invasive ventilatory support plus administration of rising supplemental oxygen concentrations
- •Treatment of SARS-CoV-2-infected patients with dexamethasone (or equivalent) administered by mouth or intravenous (IV) injection
- •Diagnosis of ARDS (PaO2/FiO2 ≤200 with positive end-expiratory pressure ≥5 cmH2O) in accordance with Berlin 2012 criteria1 (measured on or after the fourth day after the start of corticosteroid therapy in those patients for whom it was prescribed)
- •Serum CRP level greater than upper limit of normal (measured on or after the third day after the start of corticosteroid therapy in those patients for whom it was prescribed) on 2 consecutive days
- •Age ≥12 years
排除标准
- •Active bacterial or fungal infection, human immunodeficiency virus (HIV), HHV, Epstein-Barr virus, or other non-respiratory virus infection, or tuberculosis requiring initiation of anti-infective therapy
- •Prior treatment with an agent targeting the IL-6 signaling pathway
- •Current treatment in another therapeutic clinical trial (other than expanded remdesivir access protocol)
- •Start of new immunosuppressive therapy (including but not limited to corticosteroids and cytokine signaling pathway inhibitors) within 4 days prior to study entry (randomization); start of new antiviral treatment (including but not limited to nucleoside analogues, aminoquinoline compounds, and convalescent plasma) within 2 days prior to randomization; or received a live vaccine at any time prior to randomization, or plan to receive a live vaccine during the study
研究组 & 干预措施
Arm A
Drug - Siltuximab
干预措施: Siltuximab (Drug)
Arm B
Comparator - Normal Saline
干预措施: Normal Saline (Other)
结局指标
主要结局
28-day all-cause mortality
时间窗: Day 28
28-day all-cause mortality
次要结局
- Anti-siltuximab antibodies (ASA)(Up to 60 days)
- Duration of supplemental oxygen (DSO)(Up to 60 days)
- Time to National Early Warning Score 2 improvement (TNEWS2I)(Up to 60 days)
- Organ failure-free days (OFFD)(Up to 60 days)
- Hospital length of stay (HLOS)(Up to 60 days)
- Time to 7-category ordinal scale of clinical status improvement (T7COSCSI)(Up to 60 days)
- In-hospital all-cause mortality (IHACM)(Up to 60 days)
- Chest radiographic improvement (CRI)(Up to 60 days)
- Ventilator-free days (VFDs) within 28 days(Up to 28 days)
- Intensive care unit length of stay (ICU LOS)(Up to 60 days)
- Time to oxygenation improvement (TOI)(Up to 60 days)
- Treatment-emergent adverse events (TEAEs)(Up to 60 days)
- Plasma siltuximab concentrations (PSCs)(Up to 60 days)
- 60-day all-cause mortality (60DACM)(Up to 60 days)