A Prospective, Randomized, Factorial Design, Interventional Study to Compare the Safety and Efficacy of Combinations of Blockade of Interleukin-6 Pathway and Interleukin-1 Pathway to Best Standard of Care in Improving Oxygenation and Short- and Long-term Outcome of COVID-19 Patients With Acute Hypoxic Respiratory Failure and Systemic Cytokine Release Syndrome
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 入组人数
- 342
- 试验地点
- 15
- 主要终点
- Time to Clinical Improvement
研究概览
简要总结
The purpose of this study is to test the safety and effectiveness of individually or simultaneously blocking IL-6 and IL-1 versus standard of care on blood oxygenation and systemic cytokine release syndrome in patients with COVID-19 coronavirus infection and acute hypoxic respiratory failure and systemic cytokine release syndrome
详细描述
There are currently no treatments directed at halting the cytokine storm and acute lung injury to stop the progression from manageable hypoxia to frank respiratory failure and ARDS in patients with COVID-19 infection. Preventing progression from early acute hypoxia and cytokine release syndrome to frank hypoxic respiratory failure and ARDS could have a huge impact on the foreseeable overflow of the ICU units. In ventilated patients, preventing the onset of ARDS, or shortening ICU stay could also be crucial in this regard.
The clinical status after 15 days treatment is evaluated to measure the effectiveness of tocilizumab, tocilizumab and anakinra, siltuximab, siltuximab and anakinra and anakinra on restoring lung homeostasis,using single IV injection (siltuximab or tocilizumab) combined or not with daily subcutaneous injections of anakinra until 28 days or hospital discharge, whichever is first. During the treatment period, daily clinical assesments of severity, daily laboratory check-up, measurements of oxygen saturation (pulse oximetry) in relation to FiO2, regular arterial blood gas measurements, regular chest X-rays, chest CT scans on indication will be performed.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Factorial
- 主要目的
- Treatment
- 盲法
- None
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
- •Recent ( ≥ 6 days of flu-like symptoms or malaise yet ≤16 days of flu-like symptoms or malaise prior to randomization) infection with COVID-
- •Confident COVID-19 diagnosis confirmed by antigen detection test and/or PCR and/or positive serology, or any emerging and validated diagnostic laboratory test for COVID-19 within this period.
- •In some patients, it may be impossible to get a confident laboratory confirmation of COVID-19 diagnosis after 24h of hospital admission because viral load is low and/or problems with diagnostic sensitivity. In those cases, in absence of an alternative diagnosis, and with highly suspect bilateral ground glass opacities on recent (<24h) chest-CT scan (confirmed by a radiologist and pulmonary physician as probable COVID-19), and a typical clinical and chemical diagnosis with signs of cytokine release syndrome, a patient can be enrolled as probable COVID-19 infected. In all cases, this needs confirmation by later seroconversion.
- •Presence of hypoxia defined as PaO2/FiO2 below 350 while breathing room air in upright position or PaO2/FiO2 below 280 on supplemental oxygen and immediately requiring high flow oxygen device or mechanical ventilation
- •signs of cytokine release syndrome defined as ANY of the following:
- •serum ferritin concentration >1000 mcg/L and rising since last 24h
- •single ferritin above 2000 mcg/L in patients requiring immediate high flow oxygen device or mechanical ventilation
- •lymphopenia defined as <800 lymphocytes/microliter) and two of the following extra criteria
- •Ferritin > 700 mcg/L and rising since last 24h
- •increased LDH (above 300 IU/L) and rising last 24h
- •D-Dimers > 1000 ng/mL and rising since last 24h
- •CRP above 70mg/L and rising since last 24h and absence of bacterial infection
- •if three of the above are present at admission, no need to document 24h rise
- •Chest X-ray or CT scan showing bilateral infiltrates within last 2 days
- •Admitted to specialized COVID-19 ward or an ICU ward taking care of COVID-19 patients
- •Age ≥ 18yrs
- •Male or Female
- •Willing and able to provide informed consent or legal representative willing to provide informed consent
排除标准
- •Patients with known history of serious allergic reactions, including anaphylaxis, to any of the study medications, or any component of the product.
- •mechanical ventilation > 24 h at Randomization
- •Patient on ECMO at time of screening
- •clinical frailty scale above 3 (This frailty score is the patient status before first symptoms of COVID-19 episode.)
- •active bacterial or fungal infection
- •unlikely to survive beyond 48h
- •neutrophil count below 1500 cells/microliter
- •platelets below 50.000/microliter
- •Patients enrolled in another investigational drug study
- •patients on high dose systemic steroids (> 20 mg methylprednisolone or equivalent) for COVID-19 unrelated disorder
- •patients on immunosuppressant or immunomodulatory drugs
- •patients on current anti-IL1 or anti-IL6 treatment
- •signs of active tuberculosis
- •serum transaminase levels >5 times upper limit of normal
- •bowel perforation or diverticulitis
- •pregnant or breastfeeding females (all female subjects deemed of childbearing potential by the investigator must have negative pregnancy test at screening)
- •Women of childbearing potential must have a negative serum pregnancy test pre-dose on day
- •Woùmen of childbearing potential must consistently and correctly use (during the entire treatment period and 3 months after last reatment) 1 highly effective method for contraception.
研究组 & 干预措施
Usual Care
干预措施: Usual Care (Other)
Anakinra + Siltuximab
干预措施: Anakinra (Drug)
Anakinra
干预措施: Anakinra (Drug)
Siltuximab
干预措施: Siltuximab (Drug)
Anakinra + Siltuximab
干预措施: Siltuximab (Drug)
Tocilizumab
干预措施: Tocilizumab (Drug)
Anakinra + Tocilizumab
干预措施: Anakinra (Drug)
Anakinra + Tocilizumab
干预措施: Tocilizumab (Drug)
结局指标
主要结局
Time to Clinical Improvement
时间窗: at day 15
Time to Clinical Improvement is defined as the time from randomization to either an increase of at least two points on a six category ordinal scale from the status at randomization or live discharge from the hospital.The 6-point ordinal scale for clinical improvement is defined as 1 = Death; 2 = Hospitalized, on invasive mechanical ventilation or ECMO; 3 = Hospitalized, on non-invasive ventilation or high flow oxygen devices; 4 = Hospitalized, requiring supplemental oxygen; 5 = Hospitalized, not requiring supplemental oxygen; 6 = Not hospitalized. A higher score represent a better outcome
次要结局
- Time Untill Discharge(during hospital admission (up to 28 days))
- Number of Days in ICU in Patients Ventilated at Day of Randomization(during hospital admission (up to 28 days))
- Number of Days Without Supplemental Oxygen Use(during hospital admission (up to 28 days))
- Number of Invasive Ventilator Days(during hospital admission (up to 28 days))
- Time Until Independence From Supplemental Oxygen or Discharge(during hospital admission (up to 28 days))
- Time Until Independence From Invasive Ventilation(during hospital admission (up to 54 days))
- Number of Days in ICU(during hospital admission (up to 28 days))
- Number of Invasive Ventilator Days in Patients Ventilated at Day of Randomization(during hospital admission (up to 28 days))
- Number of Invasive Ventilator-free Days(during hospital admission (up to 28 days))
- Number of Invasive Ventilator-free Days in Patients Ventilated at Day of Randomization(during hospital admission (up to 28 days))
- Percentage of Days in ICU(first 28 days after randomization)
- Percentage of Invasive Ventilator Days(the first 28 days after randomization)
- Time Until First Use of High-flow Oxygen Device, Ventilation, or Death(during hospital admission (up to 28 days))
研究者
Bart N. Lambrecht
Professor in Pulmonology, Director VIB-Inflammational Research Center
University Hospital, Ghent