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

Phase 3

• Conditions: Immunocompromised Patients; Acute Respiratory Failure
• Interventions: Drug: Experimental for steroids and antifungals; Drug: Experimental for steroid; Drug: Experimental for antifungals; Other: Standard of care

• Registration Number: NCT04680884
• Lead Sponsor: Assistance Publique - Hôpitaux de Paris

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.

Detailed Description

Not available

Study Timeline

• Status Verified: 2020-12
• Study First Submitted: 2020-12-18
• Study First Submitted QC: 2020-12-18
• Last Update Submitted: 2020-12-18
• Study Start: 2020-12-21
• Study First Posted: 2020-12-23
• Last Update Posted: 2020-12-23
• Primary Completion: 2023-09-21
• Study Completion: 2023-12-21

Recruitment & Eligibility

• Status: UNKNOWN
• Sex: All
• Target Recruitment: 420

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 & Design

• Study Type: INTERVENTIONAL
• Study Design: FACTORIAL

Arm && Interventions

Group	Intervention	Description
Experimental for steroids and 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)
Experimental for steroid	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 for antifungals	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)
Best standard of care	Standard of care	IV placebo of methylprednisolone + IV placebo of isavuconazole. This group receives the treatment that is currently recommended.

Primary Outcome Measures

Name	Time	Method
Mortality	at day 90	Overall death

Secondary Outcome Measures

Name	Time	Method
Mortality	at day 28	Overall death
ICU mortality	at ICU discharge within 6 months	Mortality at ICU discharge
Hospital mortality	at hospital discharge within 6 months	Mortality at hospital discharge
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	Severe hypokalemia will be defined as kalemia \<2,5 meq/l
Incidence of candida infection	at day 28
Incidence of anxiety and depression	at 6 months	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).
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	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.
Quality of life	at 6 months	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
Occurence of severe or newly acquired hypertension	at day 28
Emergence of aspergillus species	at day 28