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

NCT04680884 | Unknown Phase 3 DMC

• 1 other identifier: APHP180584
• Study Type: interventional
• Target: 420
• Locations: 0 countries
• Sites: N/A

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.

Conditions

Acute Respiratory Failure; Immunocompromised Patients

Outcome Measures

Primary Outcomes (1)

• Mortality

  Overall death

  at day 90

Secondary Outcomes (16)

• ICU mortality

  at ICU discharge within 6 months

• Hospital mortality

  at hospital discharge within 6 months

• Mortality

  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

Study Arms (4)

Experimental for steroid

EXPERIMENTAL

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

Experimental for antifungals

EXPERIMENTAL

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

Experimental for steroids and antifungals

EXPERIMENTAL

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

Best standard of care

OTHER

IV placebo of methylprednisolone + IV placebo of isavuconazole. This group receives the treatment that is currently recommended.

Other: Standard of care

Interventions

Experimental for steroid DRUG

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 steroid

Experimental for antifungals DRUG

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 for antifungals

Experimental for steroids and antifungals DRUG

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 steroids and antifungals

Standard of care OTHER

IV placebo of methylprednisolone + IV placebo of isavuconazole. This group receives the treatment that is currently recommended.

Best standard of care

Eligibility Criteria

• Age: 18 Years - 90 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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)
• cyanosis
• 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,

You may not qualify if:

• 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

Sponsors & Collaborators

• Assistance Publique - Hôpitaux de Paris: lead

MeSH Terms

Interventions

Steroids; Antifungal Agents; Standard of Care

Intervention Hierarchy (Ancestors)

Fused-Ring Compounds; Polycyclic Compounds; Anti-Infective Agents; Therapeutic Uses; Pharmacologic Actions; Chemical Actions and Uses; Quality Indicators, Health Care; Quality of Health Care; Health Services Administration; Health Care Quality, Access, and Evaluation

Central Study Contacts

Elie Azoulay, Pr

CONTACT

+331 42 49 34 21; elie.azoulay@aphp.fr

Matthieu Resche-Rigon, Pr

CONTACT

+33142499742; matthieu.resche-rigon@univ-paris-diderot.fr

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: FACTORIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 18, 2020
• First Posted: December 23, 2020
• Study Start: December 21, 2020
• Primary Completion: September 21, 2023
• Study Completion: December 21, 2023
• Last Updated: December 23, 2020

Record last verified: 2020-12