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

Acute Respiratory Failure Clinical Trial

— EFRAIM II  

Official title:

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

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT04680884
• Other study ID #: APHP180584
• Status: Not yet recruiting
• Phase: Phase 3
• Start date: December 21, 2020
• Est. completion date: December 21, 2023

Study information

• Verified date: December 2020
• Source: Assistance Publique - Hôpitaux de Paris
• Contact: Elie Azoulay, Pr
• Phone: +331 42 49 34 21
• Email: elie.azoulay[@]aphp.fr
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 420
• Est. completion date: December 21, 2023
• Est. primary completion date: September 21, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 90 Years

Eligibility

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

Related Conditions & MeSH terms

• Acute Respiratory Failure
• Immunocompromised Patients
• Respiratory Distress Syndrome, Adult
• Respiratory Insufficiency

Intervention

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

Locations

Country	Name	City	State
n/a

Sponsors (1)

Lead Sponsor	Collaborator
Assistance Publique - Hôpitaux de Paris

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Mortality	Overall death	at day 90
Secondary	ICU mortality	Mortality at ICU discharge	at ICU discharge within 6 months
Secondary	Hospital mortality	Mortality at hospital discharge	at hospital discharge within 6 months
Secondary	Mortality	Overall death	at day 28
Secondary	Proportion of patients with ICU acquired microbiologically documented bacterial infections		at day 28
Secondary	Proportion of patients with invasive fungal infection		at day 28
Secondary	Proportion of patients with herpes simplex virus (HSV) reactivation		at day 28
Secondary	Proportion of patients with varicella-zoster virus (VZV) reactivation		at day 28
Secondary	Proportion of patients with cytomegalovirus (CMV) reactivation		at day 28
Secondary	Occurrence of severe hypokalemia	Severe hypokalemia will be defined as kalemia <2,5 meq/l	at day 28
Secondary	Occurence of decompensated diabetes		at day 28
Secondary	Occurence of severe or newly acquired hypertension		at day 28
Secondary	Emergence of aspergillus species		at day 28
Secondary	Incidence of candida infection		at day 28
Secondary	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
Secondary	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
Secondary	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