Empirical Steroids and/or Antifungals in Immunocompromised Patients With Acute Respiratory Failure From Undetermined Etiology: a Multicenter Double-blind Randomized Controlled Trial
Overview
- Phase
- Phase 3
- Intervention
- Experimental for steroid
- Conditions
- Acute Respiratory Failure
- Sponsor
- Assistance Publique - Hôpitaux de Paris
- Enrollment
- 420
- Primary Endpoint
- Mortality
- Last Updated
- 5 years ago
Overview
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.
Investigators
Eligibility Criteria
Inclusion Criteria
- •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
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;
Arms & Interventions
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
Intervention: Experimental for steroid
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)
Intervention: Experimental for antifungals
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)
Intervention: Experimental for steroids and antifungals
Best standard of care
IV placebo of methylprednisolone + IV placebo of isavuconazole. This group receives the treatment that is currently recommended.
Intervention: Standard of care
Outcomes
Primary Outcomes
Mortality
Time Frame: at day 90
Overall death
Secondary Outcomes
- 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)