Acute Respiratory FailurePhase 3EFRAIM IINCT04680884
Empirical Steroids and/or Antifungals in Immunocompromised Patients With Acute Respiratory Failure From Undetermined Etiology: a Multicenter Double-blind Randomized Controlled Trial
A Phase 3 study testing Experimental for steroid, Experimental for antifungals and Experimental for steroids and antifungals in people with Acute Respiratory Failure and Immunocompromised Patients, run by Assistance Publique - Hôpitaux de Paris.
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. Read more about this study
- Who is it for?
- Ages 18 to 90 years
- Conditions the study is for
- Acute Respiratory Failure, Immunocompromised Patients
- What is being tested?
- Experimental for steroid, Experimental for antifungals and Experimental for steroids and antifungals
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 420 participants
- Where
- No sites listed yet
- Study dates
- 21 Dec 2020to 21 Dec 2023
- Phase
- Phase 3
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 90 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Age >18 years and < 90 years
- Known immunosuppression:
- immunosuppressive drug
- solid organ transplant
- solid tumor
- hematological malignancies
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- 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
Who cannot join
- 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
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- 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
Trial locations and contacts
No sites are listed yet.
About this study
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.
- Being tested
- Experimental for steroid, Experimental for antifungals, Experimental for steroids and antifungals, Standard of care
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Experimental for steroidDrug
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 antifungalsDrug
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 antifungalsDrug
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)
Standard of careOther
IV placebo of methylprednisolone + IV placebo of isavuconazole. This group receives the treatment that is currently recommended.
| Study group | Role | What they receive |
|---|---|---|
| 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 Receives: 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) Receives: 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) Receives: 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. Receives: Other: Standard of care |
What is being measured
The primary outcome is the main question the study is designed to answer.
Mortality
Overall death
Measured: at day 90
Secondary outcomes (16)
ICU mortality
Mortality at ICU discharge
Measured: at ICU discharge within 6 months
Hospital mortality
Mortality at hospital discharge
Measured: at hospital discharge within 6 months
Mortality
Overall death
Measured: at day 28
Proportion of patients with ICU acquired microbiologically documented bacterial infections
Measured: at day 28
Proportion of patients with invasive fungal infection
Measured: at day 28
Proportion of patients with herpes simplex virus (HSV) reactivation
Measured: at day 28
Proportion of patients with varicella-zoster virus (VZV) reactivation
Measured: at day 28
Proportion of patients with cytomegalovirus (CMV) reactivation
Measured: at day 28
Occurrence of severe hypokalemia
Severe hypokalemia will be defined as kalemia <2,5 meq/l
Measured: at day 28
Occurence of decompensated diabetes
Measured: at day 28
Occurence of severe or newly acquired hypertension
Measured: at day 28
Emergence of aspergillus species
Measured: at day 28
Incidence of candida infection
Measured: at day 28
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.
Measured: at 6 months
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).
Measured: at 6 months
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
Measured: at 6 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted23 Dec 2020
- Study start21 Dec 2020 (estimated)
- Primary completion21 Sep 2023 (estimated)
- Study completion21 Dec 2023 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Acute Respiratory FailureStudies of the same condition, open and under way.
- More trials run by Assistance Publique - Hôpitaux de ParisThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Factorial
- Masking
- Double blind
- Who is masked
- Participant, Investigator
- Enrolment
- 420 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Assistance Publique - Hôpitaux de Paris
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04680884
- Sponsor's protocol ID
- APHP180584
- Acronym
- EFRAIM II
- Status last verified
- Dec 2020
- First submitted
- 18 Dec 2020
- Last updated
- 23 Dec 2020
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Undecided
Study at a glance
From the registry record, last updated by the sponsor on 23 Dec 2020. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Empirical Steroids and/or Antifungals in Immunocompromised Patients With Acute Respiratory Failure From Undetermined Etiology: a Multicenter Double-blind Randomized Controlled Trial
- ClinicalTrials.gov ID
- NCT04680884
- Acronym / sponsor ID
- EFRAIM II / APHP180584
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 420 participants (estimated)
- Lead sponsor
- Assistance Publique - Hôpitaux de ParisUniversity, hospital or other
- Study start
- 21 Dec 2020 (estimated)
- Primary completion
- 21 Sep 2023 (estimated)
- Study completion
- 21 Dec 2023 (estimated)
- First posted
- 23 Dec 2020 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Factorial
- Masking
- Double blind (participant, investigator)
- Number of arms
- 4
| Arm | Type | Receives |
|---|---|---|
| Experimental for steroid | Experimental | Drug: Experimental for steroid2 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 | Experimental | Drug: Experimental for antifungalsIV 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 | Experimental | Drug: Experimental for steroids and antifungalsIV 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 | Other | Other: Standard of careIV placebo of methylprednisolone + IV placebo of isavuconazole. This group receives the treatment that is currently recommended. |
Who may qualify
- Ages
- 18 to 90 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (18 listed)
- Age >18 years and < 90 years
- Known immunosuppression:
- ICU admission for acute respiratory failure as defined by
- No established ARF etiology at day 3
- Informed consent signed:
Key exclusion criteria (13 listed)
- 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)
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Experimental for steroid2 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 antifungalsIV 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 antifungalsIV 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 |
| Standard of careIV placebo of methylprednisolone + IV placebo of isavuconazole. This group receives the treatment that is currently recommended. | Other | Best standard of care |
Primary outcome
Mortality
Time frame: at day 90
Overall death
16 secondary outcomes
ICU mortality
Time frame: at ICU discharge within 6 months
Hospital mortality
Time frame: at hospital discharge within 6 months
Mortality
Time frame: at day 28
Proportion of patients with ICU acquired microbiologically documented bacterial infections
Time frame: at day 28
Proportion of patients with invasive fungal infection
Time frame: at day 28
Proportion of patients with herpes simplex virus (HSV) reactivation
Time frame: at day 28
Proportion of patients with varicella-zoster virus (VZV) reactivation
Time frame: at day 28
Proportion of patients with cytomegalovirus (CMV) reactivation
Time frame: at day 28
Occurrence of severe hypokalemia
Time frame: at day 28
Occurence of decompensated diabetes
Time frame: at day 28
Occurence of severe or newly acquired hypertension
Time frame: at day 28
Emergence of aspergillus species
Time frame: at day 28
Incidence of candida infection
Time frame: at day 28
Incidence of post-traumatic Stress Disorder
Time frame: at 6 months
Incidence of anxiety and depression
Time frame: at 6 months
Quality of life
Time frame: at 6 months
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 23 Dec 2020.
- Individual participant dataSharing planned: Undecided
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing Experimental for steroid, Experimental for antifungals and Experimental for steroids and antifungals in people with Acute Respiratory Failure and Immunocompromised Patients, run by Assistance Publique - Hôpitaux de Paris.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 18 inclusion and 13 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: status not confirmed, as of the sponsor's last update on 23 Dec 2020. Status can change between updates, so confirm with the study contact before making plans.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
Contact Elie Azoulay, Pr (+331 42 49 34 21, elie.azoulay@aphp.fr), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Mortality (time frame: at day 90). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 23 Dec 2020.