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    Summary
    EudraCT Number:2019-002569-37
    Sponsor's Protocol Code Number:APHP180584
    National Competent Authority:France - ANSM
    Clinical Trial Type:EEA CTA
    Trial Status:Trial now transitioned
    Date on which this record was first entered in the EudraCT database:2020-01-14
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedFrance - ANSM
    A.2EudraCT number2019-002569-37
    A.3Full title of the trial
    Empirical steroids and/or antifungals in immunocompromised patients with acute respiratory failure from undetermined etiology: a multicenter double-blind randomized controlled trial
    Impact d’un traitement empirique par stéroïdes et/ou antifongiques sur la mortalité des patients immunodéprimés avec insuffisance respiratoire aiguë d’étiologie indéterminée.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Empirical steroids and/or antifungals treatment in patient with immunodeficiency experiencing acute respiratory failure from undetermined origin a multicenter double-blind randomized controlled trial
    Impact d’un traitement empirique par stéroïdes et/ou antifongiques sur la mortalité des patients immunodéprimés avec insuffisance respiratoire aiguë d'origine indéterminée.
    A.3.2Name or abbreviated title of the trial where available
    EFRAIM II
    A.4.1Sponsor's protocol code numberAPHP180584
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorAssistance Publique Hôpitaux de Paris
    B.1.3.4CountryFrance
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportAP-HP
    B.4.2CountryFrance
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationAssistance Publique Hôpitaux de Paris
    B.5.2Functional name of contact pointProject manager
    B.5.3 Address:
    B.5.3.1Street Address1 Avenue Claude Vellefaux
    B.5.3.2Town/ cityParis
    B.5.3.3Post code75010
    B.5.3.4CountryFrance
    B.5.4Telephone number33144841744
    B.5.5Fax number33144841701
    B.5.6E-maildidier.bouton@aphp.fr
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name CRESEMBA
    D.2.1.1.2Name of the Marketing Authorisation holderBasilea Pharmaceutica Deutschland GmbH
    D.2.1.2Country which granted the Marketing AuthorisationGermany
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameISAVUCONAZOLE
    D.3.4Pharmaceutical form Powder for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 2
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameMETHYLPREDNISOLONE
    D.3.4Pharmaceutical form Powder for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNMETHYLPREDNISOLONE
    D.3.9.3Other descriptive nameMETHYLPREDNISOLONE HEMISUCCINATE
    D.3.9.4EV Substance CodeSUB03256MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboSolution for infusion
    D.8.4Route of administration of the placeboIntravenous use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    immunocompromised patients with acute respiratory failure
    patients immunodéprimés avec insuffisance respiratoire aiguë
    E.1.1.1Medical condition in easily understood language
    immunocompromised patients with acute respiratory failure
    patients immunodéprimés avec insuffisance respiratoire aiguë
    E.1.1.2Therapeutic area Analytical, Diagnostic and Therapeutic Techniques and Equipment [E] - Therapeutic techniques [E02]
    MedDRA Classification
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    to reduce 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.
    E.2.2Secondary objectives of the trial
    -Evaluate how early empirical therapy can affect ICU, hospital and day-28 mortality.
    -Evaluate whether steroids increase the proportion of patients with ICU acquired microbiologically documented bacterial infections within 3 months following randomization.
    -Evaluate the proportion of patients with invasive fungal infection within 3 months following randomization.
    -Evaluate the proportion of patients with HSV, VZV or CMV reactivation within 3 months following randomization.
    -Evaluate whether steroids are complicated by severe hypokaliemia (<2,5 meq/l), newly acquired or decompensated diabetes, or severe or newly acquired hypertension
    -Evaluate whether isavuconazole will favor the emergence of Aspergillus or mucorale infections with decreased sensitivity to isavuconazole
    -occurence of Candida infection
    -Evaluate how steroids affect psychiatric symptoms (Post traumatic Stress Disorder, anxiety and depression)
    -Evaluate how early intervention can improve quality of life
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    Pharmacokinetics and pharmacodynamics preplanned sub- studies from EFRAIM II
    E.3Principal inclusion criteria
    1) Age >18 years and <90 years;
    2) Known immunosuppression: a) immunosuppressive drug b) solid organ transplant; c) solid tumor; d) hematological malignancies; e) primary immune deficiency;
    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) No established ARF etiology at day 3;
    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 an 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.
    Obs: Patient with Pneumocistis pneumonia can be included given that their treatment does not require the use of neither antifungal drugs nor corticosteroids
    E.4Principal exclusion criteria
    1) Patient who improved enough to be discharged from the ICU at day 3;
    2) Documented invasive fungal infection requiring antifungal therapy;
    3) Patient needing or receiving prophylactic or empirical antifungal treatment for clinical care
    4) Patient receiving corticoid therapy;
    5) Palliative care with comfort measures only (Do Not Intubate (DNI) and Do Not Resuscitate (DNR) patients can be included);
    6) Pregnant or breastfeeding;
    7) No social security coverage;
    8) Known hypersensitivity to isavuconazole or to any of excipients of CRESEMBA® specialty;
    9) Treatment with ketoconazole, ritonavir, or any CYP3A4/5 inductor;
    10) Short QT syndrome and/or patient with a family history of short QT syndrome;
    11) Liver insufficiency (any stage);
    12) moribund patients;
    13) Participation in another interventional research.
    14) Person deprived of liberty.
    15) Person subject of psychiatric care.
    16) Patient under enforced hospitalization.
    17) Adults under legal protection or unable to give their consent
    E.5 End points
    E.5.1Primary end point(s)
    All-cause day-90 mortality
    E.5.1.1Timepoint(s) of evaluation of this end point
    LVLS
    E.5.2Secondary end point(s)
    - ICU mortality
    - hospital mortality
    - day 28 mortality
    - proportion of patients with ICU acquired microbiologically documented bacterial infections
    - proportion of patients with invasive fungal infection within 3 months following randomization
    - proportion of patients with HSV, VZV or CMV reactivation within 3 months following randomization
    -occurrence of severe hypokalemia (<2,5 meq/l), decompensated diabetes or severe or newly acquired hypertension
    -emergence of Aspergillus species with decreased sensitivity to isavuconazole
    -incidence of Candida infection
    -incidence of post-traumatic Stress Disorder (IES-R), anxiety and depression at 6 months (HADS)
    - quality of life at 6 months (SF36)
    E.5.2.1Timepoint(s) of evaluation of this end point
    LVLS
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety No
    E.6.5Efficacy No
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial4
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned23
    E.8.5The trial involves multiple Member States No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years
    E.8.9.1In the Member State concerned months36
    E.8.9.1In the Member State concerned days
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 300
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 120
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception No
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation Yes
    F.3.3.6Subjects incapable of giving consent personally Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    patients included in the study but unable to give consent due to their medical condition
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state420
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    None
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2019-12-20
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2020-05-13
    P. End of Trial
    P.End of Trial StatusTrial now transitioned
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