EFRAIM II _ Empirical steroids and/or antifungals treatment of immunocompromised patients with acute respiratory failure of uknown origin: a multicenter double-blind randomized controlled trial

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Assistance Publique Hopitaux De Paris

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Respiratory Tract Diseases [C08]

Trial duration

18 Feb 2021 → 15 Oct 2025

Decision date (initial)

2024-07-19

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

French Ministry of Health

External identifiers

EU CT number

2024-514344-82-00

EudraCT number

2019-002569-37

ClinicalTrials.gov

NCT04680884

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacodynamic, Therapy, Pharmacokinetic

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.

Secondary objectives 9

1. how early empirical therapy can affect ICU, hospital and day-28 mortality
2. whether steroids increase the proportion of patients with ICU acquired microbiologically documented bacterial infections within 3 months following randomization
3. the proportion of patients with invasive fungal infection within 3 months following randomization.
4. the proportion of patients with HSV, VZV or CMV reactivation within 3 months following randomization
5. whether steroids are complicated by severe hypokalemia (<2,5 meq/l), newly acquired or decompensated diabetes, or severe or newly acquired hypertension
6. whether isavuconazole will favor the emergence of infections with Aspergillus or mucorale species with decreased sensitivity to isavuconazole
7. Occurrence of Candida infection
8. how steroids affect psychiatric symptoms such as Post-traumatic Stress Disorder, anxiety and depression at 6 months
9. how this early intervention can improve quality of life at 6 months

Conditions and MedDRA coding

patients with acute respiratory failure from undetermined etiology

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 6

1. 1) Age >18 years and <90 years
2. 2) a) immunosuppressive drug b)solid organ transplant; c) solid tumor; d) hematological malignancies; e) primary immune deficiency;
3. 3) ICU admission for acute respiratory failure as defined by a) respiratory distress with tachypnea (respiratory rate>30/min); b) cyanosis; c) laboured breathing; d) Need for more than 6l of standard oxygen to maintain SpO2>95%, or for high flow oxygen, non-invasive or invasive mechanical ventilation
4. 4) No established ARF etiology 24 hours after hospital admission
5. 5) Patient admitted for at least 24 hours at hospital
6. 6) 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 by written as per L. 1111-6, -Or in a situation urgently 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 him to consent.

Exclusion criteria 18

1. 1) Patient who improved enough to be discharged from the ICU before inclusion
2. 10) Short QT syndrome and/or patient with a family history of short QT syndrome
3. 11) Liver insufficiency (any stage)
4. 12) moribund patients
5. 13) Participation in another interventional research on acute respiratory failure.
6. 14) Person deprived of liberty.
7. 16) Patient under enforced hospitalization.
8. 17) Adults under legal protection or unable to give their consent
9. 18) Isolated HIV
10. 2) Documented invasive fungal infection requiring antifungal therapy;
11. 3) • Patient needing or receiving prophylactic or empirical antifungal treatment for clinical care
12. 4) Patient receiving corticoid therapy
13. 5) Palliative care with comfort measures only (Do Not Intubate (DNI) and Do Not Resuscitate (DNR) patients can be included
14. 6) Pregnant or breastfeeding;
15. 7) No social security coverage
16. ) Known hypersensitivity to isavuconazole or to any of excipients of CRESEMBA® specialty
17. 9) Treatment with ketoconazole, ritonavir, or any CYP3A4/5 inductor
18. 15) Person subject of psychiatric care.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Mortality at day 90

Secondary endpoints 11

1. ICU mortality
2. hospital mortality
3. day 28 mortality
4. proportion of patients with ICU acquired microbiologically documented bacterial infections
5. proportion of patients with invasive fungal infection within 3 months following randomization
6. roportion of patients with HSV, VZV or CMV reactivation within 3 months following randomization
7. occurrence of severe hypokalemia (<2,5 meq/l), decompensated diabetes or severe or newly acquired hypertension
8. emergence of Aspergillus species with decreased sensitivity to isavuconazole
9. Incidence of Candida infection
10. incidence of post-traumatic Stress Disorder (IES-R), anxiety and depression at 6 months (HADS)
11. quality of life at 6 months (SF36)

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Placebo 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Assistance Publique Hopitaux De Paris

Sponsor organisation

Assistance Publique Hopitaux De Paris

Address

Porte 23, 1 Avenue Claude Vellefaux 1 Avenue Claude Vellefaux

City

Paris Cedex 10

Postcode

75475

Country

France

Scientific contact point

Organisation

Assistance Publique Hopitaux De Paris

Contact name

Elie Azoulay

Public contact point

Organisation

Assistance Publique Hopitaux De Paris

Contact name

Elie Azoulay

Locations

1 EU/EEA country · 30 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Oversight and notifications

Regulatory notifications under CTR Articles 38, 52, 53, 54 and 77

Urgent safety measures 1 · Art. 54 CTR

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 15 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

2 submissions — initial application plus substantial / non-substantial modifications