Empirical Steroids and/or Antifungals in Immunocompromised Patients With Acute Respiratory Failure From Undetermined Etiology: a Multicenter Double-blind Randomized Controlled Trial (EFRAIM II)

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.

Study Overview

• Status: Not yet recruiting
• Conditions: Acute Respiratory Failure; Immunocompromised Patients
• Intervention / Treatment: Drug: Experimental for steroid; Drug: Experimental for antifungals; Drug: Experimental for steroids and antifungals; Other: Standard of care

• Study Type: Interventional
• Enrollment (Anticipated): 420
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Matthieu Resche-Rigon, Pr; Phone Number: +33142499742; Email: matthieu.resche-rigon@univ-paris-diderot.fr
• Study Contact Backup: Name: Elie Azoulay, Pr; Phone Number: +331 42 49 34 21; Email: elie.azoulay@aphp.fr

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 90 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Factorial Assignment
• Masking: Double

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 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	Drug: 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
Experimental: 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)	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)
Experimental: 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)	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)
Other: Best standard of care; IV placebo of methylprednisolone + IV placebo of isavuconazole. This group receives the treatment that is currently recommended.	Other: Standard of care; IV placebo of methylprednisolone + IV placebo of isavuconazole. This group receives the treatment that is currently recommended.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mortality	Overall death	at day 90

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
ICU mortality	Mortality at ICU discharge	at ICU discharge within 6 months
Hospital mortality	Mortality at hospital discharge	at hospital discharge within 6 months
Mortality	Overall death	at day 28
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
Proportion of patients with varicella-zoster virus (VZV) reactivation		at day 28
Proportion of patients with cytomegalovirus (CMV) reactivation		at day 28
Occurrence of severe hypokalemia	Severe hypokalemia will be defined as kalemia <2,5 meq/l	at day 28
Occurence of decompensated diabetes		at day 28
Occurence of severe or newly acquired hypertension		at day 28
Emergence of aspergillus species		at day 28
Incidence of candida infection		at day 28
Incidence of post-traumatic Stress Disorder	Post-traumatic Stress Disorder will be evaluated using IES-R scale. Impact of Event Scale - Revised (IES-R) is a 22-item self-report measure that assesses subjective distress caused by traumatic events. The higher the score, the more severe the symptoms.	at 6 months
Incidence of anxiety and depression	Depression and anxiety will be assessed using Hospital Anxiety and Depression Scale (HADS) questionnaire. HADS is a self-administered scale of 14 items which assessed levels of depression and anxiety, divided into 2 subscales of 7 items (Anxiety or HADS-A, Depression or HADS-D). Each item is scored on a scale of 0 to 3. A score is generated for each of the two sub-scales (sum of the 7 items, ranging from 0 to 21). Limit scores : clearly or clinically symptomatic cases (score ≥ 11).	at 6 months
Quality of life	Quality of life will be evaluated using SF36. SF-36 is a set of generic, coherent, and easily administered quality-of-life measures. These measures rely upon patient self-reporting. Items are grouped into three categories: functional status, well-being, overall health assessment. In two dimensions, the answer is binary (yes / no) and in the other 6 in ordinal quality (3 to 6 possible answers). For each dimension, the scores for the different items are coded and then summed and transformed linearly on a scale ranging from 0 to 100. A physical composite score and a mental composite score can be calculated according to an established algorithm	at 6 months

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris

Study record dates

Study Major Dates

• Study Start (Anticipated): December 21, 2020
• Primary Completion (Anticipated): September 21, 2023
• Study Completion (Anticipated): December 21, 2023

Study Registration Dates

• First Submitted: December 18, 2020
• First Submitted That Met QC Criteria: December 18, 2020
• First Posted (Actual): December 23, 2020

Study Record Updates

• Last Update Posted (Actual): December 23, 2020
• Last Update Submitted That Met QC Criteria: December 18, 2020
• Last Verified: December 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Respiration Disorders; Lung Diseases; Respiratory Insufficiency; Respiratory Distress Syndrome; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents, Local; Anti-Infective Agents; Enzyme Inhibitors; Hormones, Hormone Substitutes, and Hormone Antagonists; Cytochrome P-450 CYP3A Inhibitors; Cytochrome P-450 Enzyme Inhibitors; Hormone Antagonists; Steroid Synthesis Inhibitors; 14-alpha Demethylase Inhibitors; Cytochrome P-450 CYP2C9 Inhibitors; Antifungal Agents; Clotrimazole; Miconazole
• Other Study ID Numbers: APHP180584

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No