COVIDOSE-2: A Multi-center, Randomized, Controlled Phase 2 Trial Comparing Early Administration of Low-dose Tocilizumab to Standard of Care in Hospitalized Patients With COVID-19 Pneumonitis Not Requiring Invasive Ventilation
试验速览
- 阶段
- 2 期
- 状态
- 终止
- 入组人数
- 85
- 试验地点
- 2
- 主要终点
- Time to Recovery
研究概览
简要总结
Tocilizumab is an effective treatment for severe coronavirus disease 2019 (Covid-19) pneumonia and related inflammation. Given limited global supplies, clarification of the optimal tocilizumab dose is critical. We conducted an open-label, randomized, controlled trial evaluating two different dose levels of tocilizumab in Covid-19 (40mg and 120mg). Randomization was stratified on remdesivir and corticosteroid at enrollment. The primary outcome was the time to recovery. The key secondary outcome was 28-day mortality.
详细描述
COVID-19's high mortality may be driven by hyperinflammation. Interleukin-6 (IL-6) axis therapies may reduce COVID-19 mortality. Retrospective analyses of tocilizumab in severe to critical COVID-19 patients have demonstrated survival advantage and lower likelihood of requiring invasive ventilation following tocilizumab administration. The majority of patients have rapid resolution (i.e., within 24-72 hours following administration) of both clinical and biochemical signs (fever and CRP, respectively) of hyperinflammation with only a single tocilizumab dose.
The investigators hypothesized that a dose of tocilizumab significantly lower than the EMA- and FDA-labeled dose (8mg/kg) as well as the emerging standard of care dose (400mg) may be effective in patients with COVID-19 pneumonitis and hyperinflammation. Advantages to the lower dose of tocilizumab may include lower likelihood of secondary bacterial infections as well as extension of this drug's limited supply. The investigators conducted an adaptive single-arm phase 2 trial (NCT04331795) evaluating clinical and biochemical response to low-dose tocilizumab in patients with COVID-19 pneumonitis and hyperinflammation.
This multi-center, prospective, randomized controlled phase 2 trial -- designed as two sub-studies to allow for the possible emergence of data demonstrating the clinical efficacy of tocilizumab 8mg/kg or 400mg -- formally tests the clinical efficacy of low-dose tocilizumab in COVID-19 pneumonia.
Sub-Study A Primary Objective A: To establish whether low-dose tocilizumab reduces the time to clinical recovery in patients with COVID-19 pneumonitis and hyperinflammation, when compared to a tocilizumab-free standard of care.
Hypothesis A: The investigators hypothesize that low-dose tocilizumab, when compared to a tocilizumab-free standard of care, decreases the time to recovery in hospitalized, non-invasively ventilated patients with COVID-19 pneumonitis and hyperinflammation by three days or more.
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
- 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
- •Adults ≥ 18 years of age
- •Approval from the patient's primary inpatient service
- •Hospitalized
- •Fever, documented in electronic medical record and defined as: T ≥ 38 degrees C by any conventional clinical method (forehead, tympanic, oral, axillary, rectal)
- •Positive test for active SARS-CoV-2 infection
- •Radiographic evidence of infiltrates on chest radiograph (CXR) or computed tomography (CT)
- •Ability to provide written informed consent on the part of the subject or, in the absence of decisional capacity of the subject, an appropriate surrogate (e.g. a legally authorized representative).
排除标准
- •Concurrent use of invasive mechanical ventilation
- •Concurrent use of vasopressor or inotropic medications
- •Previous receipt of tocilizumab or another anti-IL6R or IL-6 inhibitor in the year prior.
- •Known history of hypersensitivity to tocilizumab.
- •Diagnosis of end-stage liver disease or listed for liver transplant.
- •Elevation of AST or ALT in excess of 10 times the upper limit of normal.
- •Neutropenia (Absolute neutrophil count < 500/uL).
- •Thrombocytopenia (Platelets < 50,000/uL).
- •On active therapy with a Bruton's tyrosine kinase-targeted agent, which include the following:
- •Acalabrutinib
- •Ibrutinib
- •Zanubrutinib
- •On active therapy with a JAK2-targeted agent, which include the following:
- •Tofacitinib
- •Baricitinib
- •Upadacitinib
- •Ruxolitinib
- •Any of the following biologic immunosuppressive agent (and any biosimilar versions thereof) administered in the past 6 months or less::
- •Abatacept
- •Adalimumab
- •Alemtuzumab
- •Atezolizumab
- •Belimumab
- •Blinatumomab
- •Brentuximab
- •Certolizumab
- •Daratumumab
- •Durvalumab
- •Eculizumab
- •Elotuzumab
- •Etanercept
- •Gemtuzumab
- •Golimumab
- •Ibritumomab
- •Infliximab
- •Inotuzumab
- •Ipilimumab
- •Ixekizumab
- •Moxetumomab
- •Nivolumab
- •Obinutuzumab
- •Ocrelizumab
- •Ofatumumab
- •Pembrolizumab
- •Polatuzumab
- •Rituximab
- •Rituximab
- •Sarilumab
- •Secukinumab
- •Tocilizumab
- 另有 14 项未显示
研究组 & 干预措施
Sub-study B, Tocilizumab 400mg or 8mg/kg Standard of Care
Patient assigned to Sub-study B by primary treating physicians. Patient enrolled on trial sub-study B and randomized to receive standard of care tocilizumab dose (400mg or 8mgkg).
干预措施: Standard of Care (Other)
Sub-study A, Tocilizumab-Free Standard of Care
Patient assigned to Sub-study A by primary treating physicians. Patient enrolled on trial sub-study A and randomized to receive no tocilizumab.
干预措施: Standard of Care (Other)
Sub-study A, Tocilizumab 40mg
Patient assigned to Sub-study A by primary treating physicians. Patient enrolled on trial sub-study A and randomized to receive tocilizumab 40mg.
干预措施: Tocilizumab (Drug)
Sub-study B, Tocilizumab 40mg
Patient assigned to Sub-study B by primary treating physicians. Patient enrolled on trial sub-study B and randomized to receive standard of care tocilizumab 40mg.
干预措施: Tocilizumab (Drug)
Sub-study A, Tocilizumab 120mg
Patient assigned to Sub-study A by primary treating physicians. Patient enrolled on trial sub-study A and randomized to receive tocilizumab 120mg.
干预措施: Tocilizumab (Drug)
Sub-study B, Tocilizumab 120mg
Patient assigned to Sub-study B by primary treating physicians. Patient enrolled on trial sub-study B and randomized to receive standard of care tocilizumab 120mg.
干预措施: Tocilizumab (Drug)
结局指标
主要结局
Time to Recovery
时间窗: 28 days
Day of recovery is defined as the first day on which the patient achieves one of the following two categories from a seven-point ordinal scale: 6) Hospitalized, not requiring supplemental oxygen or ongoing medical care or 7) Not hospitalized. Time to recovery is the number of days from randomization to achievement of this status. Note that the ordinal scale is measured once daily, with the patient's worst clinical status during the 24-hour time period (0:00-23:59) being documented.
次要结局
- Clinical Response: Rate of Vasopressor/Inotrope Utilization(Up to 28 days)
- Achievement of Recovery(7 days)
- Clinical Response: Time to Non-Elective Invasive Mechanical Ventilation(Up to 28 days)
- Overall Survival(28 days)
- Hospital Length of Stay(Up to 1 year)
- Clinical Response: Maximum Temperature (Tmax) Response(24 hours)
- Clinical Response: Rate of Non-Elective Invasive Mechanical Ventilation(Up to 28 days)
- Clinical Response: Duration of Non-Elective Invasive Mechanical Ventilation(Up to 28 days)
- Clinical Response: Duration of Vasopressor/Inotrope Utilization(Up to 28 days)
- Clinical Response: Duration of Increased Supplemental Oxygen From Baseline(28 days)
- Biochemical Response: C-reactive Protein Response Rate(24 hours)
- Safety: Rate of Secondary Infection(28 days)
- Clinical Response: Time to Vasopressor/Inotrope Utilization(Up to 28 days)