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

NCT ID: NCT04680884

Last Updated: 2020-12-23

Basic Information

• Recruitment Status: UNKNOWN
• Clinical Phase: PHASE3
• Total Enrollment: 420 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2020-12-21
• Study Completion Date: 2023-12-21

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

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: FACTORIAL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: DOUBLE

Study Groups

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

Group Type: EXPERIMENTAL

Experimental for steroid

Intervention Type: 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 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)

Group Type: EXPERIMENTAL

Experimental for antifungals

Intervention Type: 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 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)

Group Type: EXPERIMENTAL

Experimental for steroids and antifungals

Intervention Type: 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)

Best standard of care

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

Group Type: OTHER

Standard of care

Intervention Type: OTHER

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

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 Type: 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)

Intervention Type: 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)

Intervention Type: DRUG

Standard of care

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

Intervention Type: OTHER

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

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 90 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Assistance Publique - Hôpitaux de Paris

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Central Contacts

Elie Azoulay, Pr

Role: CONTACT

Phone: +331 42 49 34 21

Email: elie.azoulay@aphp.fr

Matthieu Resche-Rigon, Pr

Role: CONTACT

Phone: +33142499742

Email: matthieu.resche-rigon@univ-paris-diderot.fr

Other Identifiers

APHP180584

Identifier Type: -

Identifier Source: org_study_id