Empirical Steroids and/or Antifungals in Immunocompromised Patients With Acute Respiratory Failure From Undetermined Etiology: a Multicenter Double-blind Randomized Controlled Trial
试验速览
- 阶段
- 3 期
- 入组人数
- 420
- 主要终点
- Mortality
研究概览
简要总结
Acute respiratory failure (ARF) is the leading reason of ICU admission in immunocompromised patients. Failure to identify the ARF etiology is associated with increased mechanical ventilation and mortality rates. This was confirmed in the large Efraim 1 study published in 2017, where undetermined ARF etiology affected 609/1611 (38%) patients at day 3, 402 (25%) patients at day 7 and 199 (12.3%) patients overall, and was associated with a case fatality of 55% (vs. 40% in other patients). In lung biopsy/autopsy findings from these patients, invasive fungal infection, steroid-sensitive affections (organized pneumonia, non-infectious interstitial involvement, drug-related pulmonary toxicity...), and lung infiltration by the underlying disease (lymphoma, carcinomatous lymphangitis, systemic vasculitis, connective tissue diseases, etc.) were the leading etiologies. No study has evaluated survival benefits from empirical steroids and/or antifungals in immunocompromised patients with ARF from undetermined etiology.
The main objective of this study is to reduce the 90-day mortality in immunocompromised patients with ARF from undetermined etiology at day-3. The intervention would evaluate the impact of steroids ± isavuconazole for 14 days or until ICU discharge.
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
- Double (Participant, Investigator)
入排标准
- 年龄范围
- 18 Years 至 90 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Age >18 years and < 90 years
- •Known immunosuppression:
- •immunosuppressive drug
- •solid organ transplant
- •solid tumor
- •hematological malignancies
- •primary immune deficiency
- •ICU admission for acute respiratory failure as defined by
- •respiratory distress with tachypnea (respiratory rate>30/min)
- •laboured breathing
- •need for more than 6L of standard oxygen to maintain SpO2>95%, or for high flow oxygen, non-invasive or invasive mechanical ventilation
- •No established ARF etiology at day 3
- •Informed consent signed:
- •by the patient,
- •Or informed consent signed by a family members/trustworthy person if his condition does not allow him to express his consent in written as per L1111-6,
- •Or in an emergency situation and in the absence of family members/trustworthy person, the patient can be enrolled. The consent to participate to the research will be requested as soon as the condition of the patient will allow).
- •Note: Patient with Pneumocystis pneumonia can be included given that their treatment does not require the use of neither antifungal drugs nor corticosteroids
排除标准
- •Patient who improved enough to be discharged from the ICU at day 3
- •Documented invasive fungal infection that requires antifungal therapy.
- •Patient needing or receiving prophylactic or empirical antifungal treatment for clinical care
- •Patient needing or receiving corticoid therapy
- •Patient receiving palliative care with comfort measures only (Do Not Intubate (DNI) and Do Not Resuscitate (DNR) patients can be included)
- •Pregnant or breastfeeding patient
- •No social security coverage
- •Known hypersensitivity to isavuconazole or to any of excipients of CRESEMBA® specialty
- •Patient treated by ketoconazole, ritonavir, or any CYP3A4/5 inductor
- •Short QT syndrome and/or patient with a family history of short QT syndrome;
- •Liver insufficiency (any stage)
- •Moribund patients
- •Participation in another interventional research
研究组 & 干预措施
Experimental for steroid
2 mg/kg/day of IV methylprednisolone for three days. As of day 4, the daily dose will be tapered to 1 mg/kg/day until day 7, followed by 0,5 mg/kg/day from day 8 to day 14 + IV placebo of isavuconazole
干预措施: Experimental for steroid (Drug)
Experimental for antifungals
IV placebo of methylprednisolone + IV isavuconazole (200 mg every 8 hours for 2 days followed by 200 mg per day until ICU discharge or for a total duration of 14 days)
干预措施: Experimental for antifungals (Drug)
Experimental for steroids and antifungals
IV methylprednisolone 2 mg/kg/day for three days. As of day 4, the daily dose will be tapered to 1 mg/kg/day until day 7, followed by 0.5 mg/kg/day from day 8 to day 14 + IV isavuconazole 200 mg every 8 hours for 2 days followed by 200 mg per day until ICU discharge or for a total duration of 14 days)
干预措施: Experimental for steroids and antifungals (Drug)
Best standard of care
IV placebo of methylprednisolone + IV placebo of isavuconazole. This group receives the treatment that is currently recommended.
干预措施: Standard of care (Other)
结局指标
主要结局
Mortality
时间窗: at day 90
Overall death
次要结局
- Mortality(at day 28)
- ICU mortality(at ICU discharge within 6 months)
- Hospital mortality(at hospital discharge within 6 months)
- Proportion of patients with ICU acquired microbiologically documented bacterial infections(at day 28)
- Proportion of patients with invasive fungal infection(at day 28)
- Proportion of patients with herpes simplex virus (HSV) reactivation(at day 28)
- Occurrence of severe hypokalemia(at day 28)
- Incidence of candida infection(at day 28)
- Incidence of anxiety and depression(at 6 months)
- Proportion of patients with varicella-zoster virus (VZV) reactivation(at day 28)
- Proportion of patients with cytomegalovirus (CMV) reactivation(at day 28)
- Occurence of decompensated diabetes(at day 28)
- Incidence of post-traumatic Stress Disorder(at 6 months)
- Quality of life(at 6 months)
- Occurence of severe or newly acquired hypertension(at day 28)
- Emergence of aspergillus species(at day 28)