Back to resultsEmpirical Steroids and/or Antifungals in Immunocompromised Patients With Acute Respiratory Failure From Undetermined Etiology: a Multicenter Double-blind Randomized Controlled Trial (EFRAIM II)
Primary Purpose
Acute Respiratory Failure, Immunocompromised Patients
Status
Not yet recruiting
Phase
Phase 3
Locations
Study Type
Interventional
Intervention
Experimental for steroid
Experimental for antifungals
Experimental for steroids and antifungals
Standard of care
Sponsored by
About this trial
This is an interventional treatment trial for Acute Respiratory Failure
Eligibility Criteria
Inclusion Criteria:
- 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,
- 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
Sites / Locations
Arms of the Study
Arm 1
Arm 2
Arm 3
Arm 4
Arm Type
Experimental
Experimental
Experimental
Other
Arm Label
Experimental for steroid
Experimental for antifungals
Experimental for steroids and antifungals
Best standard of care
Arm Description
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
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)
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)
IV placebo of methylprednisolone + IV placebo of isavuconazole. This group receives the treatment that is currently recommended.
Outcomes
Primary Outcome Measures
Mortality
Overall death
Secondary Outcome Measures
ICU mortality
Mortality at ICU discharge
Hospital mortality
Mortality at hospital discharge
Mortality
Overall death
Proportion of patients with ICU acquired microbiologically documented bacterial infections
Proportion of patients with invasive fungal infection
Proportion of patients with herpes simplex virus (HSV) reactivation
Proportion of patients with varicella-zoster virus (VZV) reactivation
Proportion of patients with cytomegalovirus (CMV) reactivation
Occurrence of severe hypokalemia
Severe hypokalemia will be defined as kalemia <2,5 meq/l
Occurence of decompensated diabetes
Occurence of severe or newly acquired hypertension
Emergence of aspergillus species
Incidence of candida infection
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.
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).
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
Full Information
NCT ID
NCT04680884
First Posted
December 18, 2020
Last Updated
December 18, 2020
Sponsor
Assistance Publique - Hôpitaux de Paris
1. Study Identification
Unique Protocol Identification Number
NCT04680884
Brief Title
Empirical Steroids and/or Antifungals in Immunocompromised Patients With Acute Respiratory Failure From Undetermined Etiology: a Multicenter Double-blind Randomized Controlled Trial
Acronym
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
Study Type
Interventional
2. Study Status
Record Verification Date
December 2020
Overall Recruitment Status
Not yet recruiting
Study Start Date
December 21, 2020 (Anticipated)
Primary Completion Date
September 21, 2023 (Anticipated)
Study Completion Date
December 21, 2023 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Assistance Publique - Hôpitaux de Paris
4. Oversight
Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes
5. 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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Acute Respiratory Failure, Immunocompromised Patients
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Factorial Assignment
Masking
ParticipantInvestigator
Allocation
Randomized
Enrollment
420 (Anticipated)
8. Arms, Groups, and Interventions
Arm Title
Experimental for steroid
Arm Type
Experimental
Arm Description
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
Arm Title
Experimental for antifungals
Arm Type
Experimental
Arm Description
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)
Arm Title
Experimental for steroids and antifungals
Arm Type
Experimental
Arm Description
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)
Arm Title
Best standard of care
Arm Type
Other
Arm Description
IV placebo of methylprednisolone + IV placebo of isavuconazole. This group receives the treatment that is currently recommended.
Intervention Type
Drug
Intervention Name(s)
Experimental for steroid
Intervention Description
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
Intervention Name(s)
Experimental for antifungals
Intervention Description
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
Intervention Name(s)
Experimental for steroids and antifungals
Intervention Description
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
Other
Intervention Name(s)
Standard of care
Intervention Description
IV placebo of methylprednisolone + IV placebo of isavuconazole. This group receives the treatment that is currently recommended.
Primary Outcome Measure Information:
Title
Mortality
Description
Overall death
Time Frame
at day 90
Secondary Outcome Measure Information:
Title
ICU mortality
Description
Mortality at ICU discharge
Time Frame
at ICU discharge within 6 months
Title
Hospital mortality
Description
Mortality at hospital discharge
Time Frame
at hospital discharge within 6 months
Title
Mortality
Description
Overall death
Time Frame
at day 28
Title
Proportion of patients with ICU acquired microbiologically documented bacterial infections
Time Frame
at day 28
Title
Proportion of patients with invasive fungal infection
Time Frame
at day 28
Title
Proportion of patients with herpes simplex virus (HSV) reactivation
Time Frame
at day 28
Title
Proportion of patients with varicella-zoster virus (VZV) reactivation
Time Frame
at day 28
Title
Proportion of patients with cytomegalovirus (CMV) reactivation
Time Frame
at day 28
Title
Occurrence of severe hypokalemia
Description
Severe hypokalemia will be defined as kalemia <2,5 meq/l
Time Frame
at day 28
Title
Occurence of decompensated diabetes
Time Frame
at day 28
Title
Occurence of severe or newly acquired hypertension
Time Frame
at day 28
Title
Emergence of aspergillus species
Time Frame
at day 28
Title
Incidence of candida infection
Time Frame
at day 28
Title
Incidence of post-traumatic Stress Disorder
Description
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.
Time Frame
at 6 months
Title
Incidence of anxiety and depression
Description
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).
Time Frame
at 6 months
Title
Quality of life
Description
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
Time Frame
at 6 months
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
90 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
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,
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
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Elie Azoulay, Pr
Phone
+331 42 49 34 21
Email
elie.azoulay@aphp.fr
First Name & Middle Initial & Last Name or Official Title & Degree
Matthieu Resche-Rigon, Pr
Phone
+33142499742
Email
matthieu.resche-rigon@univ-paris-diderot.fr
12. IPD Sharing Statement
Plan to Share IPD
Undecided
Learn more about this trial
Empirical Steroids and/or Antifungals in Immunocompromised Patients With Acute Respiratory Failure From Undetermined Etiology: a Multicenter Double-blind Randomized Controlled Trial
We'll reach out to this number within 24 hrs