Early Corticosteroids in Severe Influenza Pneumonia, a Phase III Randomized Controlled Trial
试验速览
- 阶段
- 3 期
- 状态
- 尚未招募
- 发起方
- 入组人数
- 544
- 试验地点
- 1
- 主要终点
- Hierarchical composite endpoint of all-cause mortality, number of ventilator-free days and number of ICU-free days
研究概览
简要总结
This is a Phase III, multicentre, randomized, controlled, double-blind, superiority trial aiming to evaluate the efficacy of dexamethasone versus placebo in patients admitted to intensive care or intermediate care with influenza and hypoxemic acute respiratory failure. Patients will receive state-of-the-art standard therapy for severe influenza. They will be randomized in a 1:1 ratio to one of the two arms. Patients, investigators and care providers will be blinded to the patient arm. Patients will receive antiviral treatment and antibiotic therapy if bacterial co-infection is suspected. All clinical interventions such as use of ventilatory strategy, laboratory tests, and hemodynamic management will be left at the discretion of the team in both arms. Special attention will be given to the prompt diagnosis and management of aspergillosis, with investigators provided with decision support tools and algorithms based on the most recent definition (i.e., FUNDICU). Patients will be followed for up to 28 days after enrolment and national registries will be used for 90-day vital status assessment. Telephone calls will be made on day 90 to assess quality of life.
详细描述
Influenza virus infections cause excessive hospitalizations and deaths during seasonal peaks and pandemics. It remains a leading cause of admission to intensive care units (ICU) for acute respiratory failure. Apart from annual vaccination and other preventive measures, early administration of neuraminidase inhibitors is the only recommended treatment, but with a low level of evidence. Corticosteroids attenuate the immune response to infection and improve outcomes in patients with several types of severe pulmonary infections. Low-dose corticosteroids have been shown to reduce mortality in patients with severe COVID-19 and communityacquired pneumonia. It may also benefit critically ill patients with acute respiratory distress syndrome by reducing mortality, duration of mechanical ventilation and length of hospital stay. Observational studies with a high risk of bias have suggested an increase in mortality in patients with influenza who receive corticosteroid therapy. Others have shown a beneficial effect of corticosteroids or no link between their use and mortality. One concern for clinicians is the risk of Influenza-associated pulmonary aspergillosis (IAPA), which affects 10-20% of patients and is associated with a poor prognosis. However, there is insufficient evidence on the effects of corticosteroids administered during the ICU stay. Based on these findings and in the absence of a randomized trial, current guidelines do not recommend corticosteroid therapy in severe influenza. Therefore, a wellpowered trial is needed to test the hypothesis that corticosteroids could improve outcomes in critically-ill patients with severe influenza and acute respiratory failure.
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
- Triple (Participant, Care Provider, Investigator)
盲法说明
Pharmacist
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
- •Admission to ICU or intermediate care for less than 2 days
- •Admission to hospital for less than 5 days
- •Diagnosis of influenza pneumonia with
- •PCR positive for Influenza dated less than 5 days
- •AND focal shadowing/infiltrates on chest X-ray or CT-scan
- •AND at least one of the following: cough, purulent sputum, chest pain or dyspnoea
- •Requirement of supplemental oxygen at a flow rate of at least 3L/min OR non-invasive ventilation OR high flow oxygen therapy OR invasive mechanical ventilation
- •Written informed or emergency consent
- •Ongoing medical insurance
排除标准
- •Moribund state
- •Bone marrow transplant or chemotherapy-induced neutropenia
- •Known allergy to dexamethasone or to one of its excipients
- •Uncontrolled psychotic states
- •Pheochromocytoma
- •Co-infection with COVID-19
- •Cardiogenic shock secondary to influenza myocarditis
- •Known active tuberculosis or fungal infection
- •Active viral hepatitis or active herpes virus infection
- •Patient at risk of strongyloidiasis
- •Subject with shock on enrolment and on ongoing vasopressor therapy (≥ 0.25 microg/kg/min)
- •Indication for corticosteroid therapy in a dosage above 0.5mg/kg/day prednisone-equivalent
- •Subject deprived of liberty or under a legal protective measure (example: patients under guardianship or curatorship)
- •Pregnant or breastfeeding woman
- •Lack of clinical equipoise by the attending physician and/or the presence of a substantial risk associated with the patients' participation in the trial
研究组 & 干预措施
Dexamethasone
a daily dose of 6 mg dexamethasone (investigational medicinal product) suspended in sodium chloride 0.9% and administered as a masked intravenous injection (total volume of 5 ml) once daily for up to 10 days from randomization OR until discharge from the participating intensive care or intermediate care unit.
干预措施: Dexametasone (Drug)
Placebo
a daily dose of placebo (sodium chloride 0.9%, total volume of 5 ml) intravenously once daily for up to 10 days from randomization OR until discharge from the participating intensive care or intermediate care unit.
干预措施: Sodium chloride 0.9% (placebo) (Drug)
结局指标
主要结局
Hierarchical composite endpoint of all-cause mortality, number of ventilator-free days and number of ICU-free days
时间窗: At baseline and day 28
To compare the efficacy of dexamethasone versus placebo in patients with severe influenza on a hierarchical composite endpoint of all-cause mortality, number of ventilator-free days and number of Intensive Care Unit (ICU)-free days. Hierarchical composite endpoint, scored as follows: 1. In-hospital death (all-cause) at day 28 (yes/no), 2. If alive at day 28, number of ventilator-free days between (day) 3. If mechanical ventilation never required, number of ICU-free days (day) Each patient in the intervention group will be compared with each patient in the control group according to this score: a win, loss, or tie will be defined for each pair based on which scored better.
次要结局
- In-hospital death(At day 28)
- Duration of extracorporeal membrane oxygenation(At day 28)
- Duration of invasive mechanical ventilation(At day 28)
- Duration of renal replacement therapy(At day 28)
- Duration of vasopressor therapy(At day 28)
- Days alive without life support(At day 28)
- Duration of supplemental oxygen, non-invasive ventilation, high flow oxygen(At day 28)
- Length of stay in hospital and ICU(At day 28 and day 90)
- Viral clearance(At baseline, day 4 and day 8)
- Change in quality of life(At day 90)
- Mortality(At day 90)
- Safety endpoint: occurrence of adverse events(Daily, from baseline until day 28)