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

• ClinicalTrials.gov Identifier: NCT04680884
• Recruitment Status: Not yet recruiting
• First Posted: December 23, 2020
• Last Update Posted: December 23, 2020
• Sponsor: Assistance Publique - Hôpitaux de Paris
• Information provided by (Responsible Party): Assistance Publique - Hôpitaux de Paris

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Acute Respiratory Failure; Immunocompromised Patients	Drug: Experimental for steroid; Drug: Experimental for antifungals; Drug: Experimental for steroids and antifungals; Other: Standard of care	Phase 3

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 420 participants
• Allocation: Randomized
• Intervention Model: Factorial Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: Empirical Steroids and/or Antifungals in Immunocompromised Patients With Acute Respiratory Failure From Undetermined Etiology: a Multicenter Double-blind Randomized Controlled Trial
• Estimated Study Start Date: December 21, 2020
• Estimated Primary Completion Date: September 21, 2023
• Estimated Study Completion Date: December 21, 2023

Arms and Interventions

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)
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.

Outcome Measures

Primary Outcome Measures :

1. Mortality [ Time Frame: at day 90 ]
   Overall death

Secondary Outcome Measures :

1. ICU mortality [ Time Frame: at ICU discharge within 6 months ]
   Mortality at ICU discharge
2. Hospital mortality [ Time Frame: at hospital discharge within 6 months ]
   Mortality at hospital discharge
3. Mortality [ Time Frame: at day 28 ]
   Overall death
4. Proportion of patients with ICU acquired microbiologically documented bacterial infections [ Time Frame: at day 28 ]
5. Proportion of patients with invasive fungal infection [ Time Frame: at day 28 ]
6. Proportion of patients with herpes simplex virus (HSV) reactivation [ Time Frame: at day 28 ]
7. Proportion of patients with varicella-zoster virus (VZV) reactivation [ Time Frame: at day 28 ]
8. Proportion of patients with cytomegalovirus (CMV) reactivation [ Time Frame: at day 28 ]
9. Occurrence of severe hypokalemia [ Time Frame: at day 28 ]
   Severe hypokalemia will be defined as kalemia <2,5 meq/l
10. Occurence of decompensated diabetes [ Time Frame: at day 28 ]
11. Occurence of severe or newly acquired hypertension [ Time Frame: at day 28 ]
12. Emergence of aspergillus species [ Time Frame: at day 28 ]
13. Incidence of candida infection [ Time Frame: at day 28 ]
14. Incidence of post-traumatic Stress Disorder [ Time Frame: 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.
15. Incidence of anxiety and depression [ Time Frame: 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).
16. Quality of life [ Time Frame: 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

Eligibility Criteria

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

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

Contacts and Locations

Contacts

Contact: Elie Azoulay, Pr; +331 42 49 34 21; elie.azoulay@aphp.fr

Contact: Matthieu Resche-Rigon, Pr; +33142499742; matthieu.resche-rigon@univ-paris-diderot.fr

Sponsors and Collaborators

Assistance Publique - Hôpitaux de Paris

More Information

• Responsible Party: Assistance Publique - Hôpitaux de Paris
• ClinicalTrials.gov Identifier: NCT04680884
• Other Study ID Numbers: APHP180584
• First Posted: December 23, 2020
• Last Update Posted: December 23, 2020
• Last Verified: December 2020

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Undecided

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

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