A Phase iv, Interventional, Non-blinded, Randomized Controlled Multicenter Study of Posaconazole Prophylaxis for the Prevention of Influenza-associated Aspergillosis (IAA) in Critically Ill Patients
试验速览
- 阶段
- 4 期
- 状态
- 已完成
- 入组人数
- 88
- 试验地点
- 12
- 主要终点
- Number of Participants With IAA-infection at ICU Discharge
研究概览
简要总结
The objective of this study is to deliver proof of concept that antifungal prophylaxis can reduce the incidence of Influenza Associated Aspergillosis (IAA) in ICU (intensive care unit) patients with severe influenza.
The investigators will perform an interventional non-blinded randomized controlled multicentric proof-of-concept study in patients with severe influenza admitted to the ICU. Patients will be randomized to the posaconazole prophylaxis group or to the SOC (standard of care) group. Oseltamivir will be started at the discretion of the investigator. Patients in the posaconazole group will receive posaconazole prophylaxis for 7 days.
addendum: pharmacokinetics of posaconazole as prophylaxis for invasive fungal disease on ICU
详细描述
Critically ill patients with PCR-confirmed influenza criteria) are eligible for inclusion in this study and will be randomized to or the posaconazole prophylaxis group or the SOC group.
If a patient is randomized to the posaconazole prophylaxis group, posaconazole (Noxafil, MSD) will be started intravenously from day 1 of randomization (2*300mg( milligram) /d on day 1, followed by 1*300mg/d from day 2 for 7 days) In both patient groups (prophylaxis and SOC) oseltamivir (non-IMP) will be started at the discretion of the treating physician from the first day of ICU admission as 2*150 mg/day for 10 days. If oseltamivir had already been started up before ICU admission, oseltamivir treatment will be continued up to a total of 10 days.
Within 48 hours after influenza diagnosis a bronchoscopy with BAL (bronchoalveolar lavage) and a serum galactomannan will be performed as part of routine ICU care in this type of patients. If an IAA-infection is suspected based on the result of this BAL ((A) Aspergillus cultured from BAL, or (B) a galactomannan (GM)the patient will be withdrawn from the study and antifungal treatment will be started.
addendum: Extensive PK sampling (UZ Leuven and Radboud): full PK curve on day 2 and day 5 (predose, 1.5; 2,3,4,6,8,10,12,18,24 h post infusion).
on non PK days, until day 7, predose sample. PK in BAL fluid only in patients with mechanical ventilation and when medically indicated.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Prevention
- 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
- •Written informed consent must be obtained from the patient or his/her legal representative prior to any study procedures
- •Adult patient (≥ 18 years)
- •PCR-confirmed influenza based on nasopharyngeal swab (NS), bronchial aspirate (BA) or broncho-alveolar lavage (BAL) within 7 days before ICU admission or within 48 hours after ICU admission. If PCR is not available a positive result of a rapid test is required (a negative rapid test does not imply absence of influenza and thus requires confirmation by PCR)
- •Influenza symptoms present for no more than 10 days before ICU admission
- •Respiratory distress as the main reason for ICU admission. Respiratory distress will be defined as tachypnea with an respiratory rate ≥ 25x/min and a paO2/fiO2-ratio (fraction of inspired oxygen) ≤ 300 with or without (bilateral) infiltrates.
排除标准
- •Patients with age < 18 years
- •Pregnant women (based on a positive serum sample)
- •Expected survival on ICU admission ≤ 48h
- •Patients having influenza symptoms for more than 10 days before ICU admission
- •Patients being transferred from another hospital ward or another hospital who already have mycological evidence for an IAA-infection (based on sputum, BA or BAL culture, BAL or serum GM)
- •Patients with known intolerance or hypersensitivity to posaconazole or other azole antifungal agents
- •Patients that are being treated actively with antifungal agents for invasive aspergillosis
- •Patients with a QTc (corrected QT interval) interval ≥500 msec
- •Patients with liver cirrhosis (Child C)
- •Participation in another interventional clinical trial -
研究组 & 干预措施
SOC + 'Posaconazole 18 MG/ML'
standard of care (SOC) treatment for influenza pneumonia +posaconazole 2*300mg/d IV on day 1, followed by 1*300mg/d IV from day 2 for 7 days; vials containing 18mg posaconazole /mL, 300mg posaconazole/vial in total)
干预措施: SOC +Posaconazole 18 MG/ML (milligram/milliliter) (Drug)
SOC + 'Posaconazole 18 MG/ML'
standard of care (SOC) treatment for influenza pneumonia +posaconazole 2*300mg/d IV on day 1, followed by 1*300mg/d IV from day 2 for 7 days; vials containing 18mg posaconazole /mL, 300mg posaconazole/vial in total)
干预措施: standard of care (SOC) (Other)
Standard of Care
standard of care treatment for influenza pneumonia (at the investigators discretion)
干预措施: standard of care (SOC) (Other)
结局指标
主要结局
Number of Participants With IAA-infection at ICU Discharge
时间窗: from date of admission in ICU assessed up to ICU discharge, approximately 21 days
A patient with IAA-infection is defined as a patient having mycological evidence of Aspergillus and at least one Aspergillus compatible sign or symptom and radiological abnormalities
次要结局
- Time to IAPA Diagnosis(from date of inclusion to date of first sign/symptom of IAA infection, assessed up to ICU discharge, approximately 10 days)
- Length of ICU Stay(from date of admission in ICU to date of discharge from ICU, approximately 20 days)
- Length of Hospital Stay(from date of admission in hospital to date of discharge from hospital, approximately 25 days)
- ICU Mortality - Number of Participant Deaths(At ICU discharge)
- Hospital Mortality - Number of Participant Deaths(At hospital discharge)
- 90-day Mortality - Number of Participant Deaths(At 90 days after ICU admission)
研究者
Joost Wauters, prof. dr.
Principal Investigator
Universitaire Ziekenhuizen KU Leuven