Clinical trial NCT04680884: Empirical Steroids and/or Antifungals in Immunocompromised Patients With Acute Respiratory Failure From Undetermined Etiology: a Multicenter Double-blind Randomized Controlled Trial
Official title: Empirical Steroids and/or Antifungals in Immunocompromised Patients With Acute Respiratory Failure From Undetermined Etiology: a Multicenter Double-blind Randomized Controlled Trial
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE3
Conditions: Acute Respiratory Failure
Immunocompromised Patients
Lead sponsor: Assistance Publique - Hôpitaux de Paris
Sponsor class: OTHER
First posted: 2020-12-23
Enrollment: 420
Sex: ALL
Minimum age (years): 18
Maximum age (years): 90
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: FACTORIAL
Primary purpose: TREATMENT

Brief summary: 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.


Eligibility criteria: Inclusion Criteria:

* Age \>18 years and \< 90 years
* Known immunosuppression:

  1. immunosuppressive drug
  2. solid organ transplant
  3. solid tumor
  4. hematological malignancies
  5. primary immune deficiency
* ICU admission for acute respiratory failure as defined by

  1. respiratory distress with tachypnea (respiratory rate\>30/min)
  2. cyanosis
  3. laboured breathing
  4. 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

Exclusion Criteria:

* 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

Primary outcomes:
measure: Mortality
timeFrame: at day 90
Secondary outcomes:
measure: ICU mortality
timeFrame: at ICU discharge within 6 months
measure: Hospital mortality
timeFrame: at hospital discharge within 6 months
measure: Mortality
timeFrame: at day 28
measure: Proportion of patients with ICU acquired microbiologically documented bacterial infections
timeFrame: at day 28
measure: Proportion of patients with invasive fungal infection
timeFrame: at day 28
measure: Proportion of patients with herpes simplex virus (HSV) reactivation
timeFrame: at day 28
measure: Proportion of patients with varicella-zoster virus (VZV) reactivation
timeFrame: at day 28
measure: Proportion of patients with cytomegalovirus (CMV) reactivation
timeFrame: at day 28
measure: Occurrence of severe hypokalemia
timeFrame: at day 28
measure: Occurence of decompensated diabetes
timeFrame: at day 28
measure: Occurence of severe or newly acquired hypertension
timeFrame: at day 28
measure: Emergence of aspergillus species
timeFrame: at day 28
measure: Incidence of candida infection
timeFrame: at day 28
measure: Incidence of post-traumatic Stress Disorder
timeFrame: at 6 months
measure: Incidence of anxiety and depression
timeFrame: at 6 months
measure: Quality of life
timeFrame: at 6 months
Other outcomes:
Locations:
Study officials:
References: