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    Summary
    EudraCT Number:2020-001754-21
    Sponsor's Protocol Code Number:2020-23
    National Competent Authority:France - ANSM
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2020-04-17
    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 number2020-001754-21
    A.3Full title of the trial
    An open prospective randomized therapeutic trial using ANAKINRA or TOCILIZUMAB alone or in combination with RUXOLITINIB in severe stage 2b and 3 COVID-19 disease
    Etude prospective randomisée évaluant l'efficacité thérapeutique de l'anakinra ou du tocilizumab seuls ou associés au ruxolitinib dans les formes graves 2b et 3 de la maladie liée au COVID-19
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    An open prospective randomized therapeutic trial using ANAKINRA or TOCILIZUMAB alone or in combination with RUXOLITINIB in severe stage 2b and 3 COVID-19 disease
    Etude prospective randomisée évaluant l'efficacité thérapeutique de l'anakinra ou du tocilizumab seuls ou associés au ruxolitinib dans les formes graves 2b et 3 de la maladie liée au COVID-19
    A.3.2Name or abbreviated title of the trial where available
    INFLAMMACOV
    INFLAMMACOV
    A.4.1Sponsor's protocol code number2020-23
    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 Marseille
    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 supportAssistance Publique Hôpitaux de Marseille
    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 Marseille
    B.5.2Functional name of contact pointDirection Recherche Santé
    B.5.3 Address:
    B.5.3.1Street Address80 rue Brochier
    B.5.3.2Town/ cityMarseille
    B.5.3.3Post code13005
    B.5.3.4CountryFrance
    B.5.4Telephone number00330491381705
    B.5.5Fax number00330491381479
    B.5.6E-mailpromotion.interne@ap-hm.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 Kineret
    D.2.1.1.2Name of the Marketing Authorisation holderSwedish Orphan Biovitrum SARL
    D.2.1.2Country which granted the Marketing AuthorisationFrance
    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.3.4Pharmaceutical form Injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    Subcutaneous use
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    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 Yes
    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.2.1.1.1Trade name ROACTEMRA
    D.2.1.1.2Name of the Marketing Authorisation holderRoche
    D.2.1.2Country which granted the Marketing AuthorisationFrance
    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.3.4Pharmaceutical form Solution 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 No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    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 Yes
    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: 3
    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 JAKAVI
    D.2.1.1.2Name of the Marketing Authorisation holderNovartis Pharma SAS
    D.2.1.2Country which granted the Marketing AuthorisationFrance
    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.3.4Pharmaceutical form Tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPNasogastric use (Noncurrent)
    Oral 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.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    COVID-19-associated disease
    maladie COVID-19
    E.1.1.1Medical condition in easily understood language
    COVID-19-associated disease
    maladie COVID-19
    E.1.1.2Therapeutic area Diseases [C] - Immune System Diseases [C20]
    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
    Evaluate the therapeutic efficacy of anakinra or tocilizumab alone or in combination with ruxolitinib in severe (2b and 3) forms of COVID-19.
    The primary outcome criteria is ventilation free days at D28 (VFD28).
    Evaluer l’efficacité thérapeutique de l’anakinra ou du tocilizumab seuls ou associés au ruxolitinib dans les formes graves (2b et 3) de la maladie liée au COVID-19 sur l'augmentation du nombre de jours sans ventilation mécanique, évaluée à J28.
    E.2.2Secondary objectives of the trial
    Evaluate the therapeutic efficacy of anakinra or tocilizumab alone or in combination with ruxolitinib in severe (2b and 3) forms of COVID-19 on:
    Number of patients admitted in ICU (for stage 2b)
    Number of days in ICU (for stage 3)
    Death at D28 for all patients
    Number of days in hospital
    Time to oxygenation weaning
    Visceral insufficiency improvement (SOFA score)
    Number of days without fever at D7 (without antipyretics for 48h)
    No increase in the number of bacteriamia or fungemia
    Time to improvement of biological inflammatory markers (C reactive protein, fibrinogen, ferritinemia)
    Time to improvement of biological markers (blood cells counts, creatininemia, transaminases, LDH, gGT, coagulation tests)
    Improvement of blood cytokine concentrations and NLRP3 constituents
    Blood concentrations of tocilizumab and search for acquired circulating anti-tocilizumab inhibitory antibodies
    Lung tomodensitometry and lung ventilation capacity evaluation at D90 after hospitalization exit
    Evaluer l’efficacité thérapeutique de l’anakinra ou du tocilizumab seuls ou associés au ruxolitinib dans les formes graves (2b et 3) de la maladie liée au COVID19 sur:
    Nombre d’admission en réanimation
    Nombre de jours en réanimation
    Mortalité à J28
    Nombre de jours d’hospitalisation
    Amélioration des défaillances d’organe (score SOFA)
    Délai de sevrage de l’oxygénothérapie
    Nombre de jour sans fièvre à J7
    Pas d'augmentation du nombre des bactériémies ou fongémies
    Temps de normalisation des marqueurs inflammatoires biologiques (protéine C réactive, fibrinogène, ferritinémie)
    Temps de normalisation des marqueurs biologiques (NFS, créatininémie, transaminases, LDH, gammagt, TP, TCA)
    Dosage des taux sérique de tocilizumab et recherche d’anticorps neutralisants anti-tocilizumab
    Normalisation des concentrations sériques de cytokines inflammatoires et des constituants sériques de NLRP-3
    Evaluation des images pulmonaires scanographiques et des explorations fonctionnelles respiratoires
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    -Patients older than 18 and younger than 75, potentially eligible for admission in ICU
    -with proven infection with COVID19, using at least one positive pharyngeal polymerase chain reaction (PCR) test
    -COVID19 infection at stage 2b or 3
    -Ability to provide informed consent signed by study patient or legally acceptable representative

    1/ Stage 2b: hypoxemia necessitating oxygen therapy>5l/min in order to maintain SpO2>94% (in conventional hospitalization unit or ICU) and CRP>150 mg/l
    2/ Stage 3: Moderate or severe ARDS necessitating invasive mechanical ventilation with a PaO2/FiO2<200 during more than 24hours
    3/Etremely severe stage 3:
    a) very severe ARDS defined by invasive mechanical ventilation and requirement for veno-venous extracorporeal membrane oxygenation (ECMO)
    b) or ARDS associated with at least on the following:
    -Shock with requirement for continuous IV adrenalin infusion>3mg/h
    -Myocarditis with cardiogenic shock
    -Oligo-anuric acute renal insufficiency or requirement for extrarenal epuration
    -Hemophagocytic syndrome associated with blood cytopenia or hyperferritinemia>5000 micrograms/l
    -Patients âgés de plus de 18 ans et moins de 75 ans, éligibles pour une hospitalisation en réanimation
    -infection à COVID19 documentée par au moins un test de PCR positif dans le prélèvement pharyngé
    -infection à COVID-19 en stade 2b ou 3 selon les définitions sous-citées
    -ayant signé eux-mêmes ou leur personne de confiance, un consentement pour participer à l’étude

    1) Stade 2b : Hypoxémie justifiant une oxygénothérapie conventionnelle ≥ 5L/min pour maintenir une SpO2 > 94% (patient en service conventionnel ou en réanimation) associé à un syndrome inflammatoire biologique marqué (CRP>150 mg/l).
    2) Stade 3 : SDRA modéré ou sévère défini par un patient justifiant une ventilation mécanique invasive avec un rapport PaO2/FiO2 < 200 pendant plus de 24h.
    3) stade 3 évolué
    a) SDRA sévère défini par une ventilation mécanique invasive et la nécessité d’un recours à l’ECMO veino-veineuse.
    b)Ou SDRA associé à au moins une autre défaillance d’organe parmi :
    - Un état de choc justifiant de la noradrénaline > 3 mg/h
    - Une myocardite compliquée d’un état de choc cardiogénique
    - Une insuffisance rénale aigue oligo-anurique ou justifiant le recours à l’épuration extra-rénale
    - Un syndrome hémophagocytaire associée à une cytopénie périphérique et/ou hyperferritinémie > 5000 microg/L
    E.4Principal exclusion criteria
    -Patients younger than 18 or older than 75
    -non-eligible for ICU
    -Patients without legal rights
    -No personal or familial consent
    -Ongoing pregnancy
    -Patient being treated for Anakinra, tocilizumab, or ruxolitinib for an underlying condition.
    - Patient already included in another therapeutic trial to modulate inflammation
    -Uncontrolled bacterial or fungal infection
    -Hypersensitivity to anakinra
    -Hypersensitivity to tocilizumab
    - hypersensitivity to ruxolitinib
    - Patients mineurs ou d’âge supérieur à 75 ans
    - non éligibles pour une admission en réanimation
    - Patients privés de droits ou de liberté
    - Patient ou personne de confiance refusant de signer le consentement
    - Femmes enceintes ou allaitantes
    - Infections bactériennes ou mycotiques non contrôlées
    - Patient déjà inclus dans un autre essai thérapeutique visant à moduler l’inflammation
    - Patient en cours de traitement pour Anakinra, tocilizumab, ou ruxolitinib dans le cadre d’une pathologie sous-jacente.
    -Hypersensibilité à l’anakinra
    -Hypersensibilité au tocilizumab
    - hypersensibilité au ruxolitinib
    E.5 End points
    E.5.1Primary end point(s)
    ventilation free days at D28 (VFD28) (an increase of 5 days VFD28 is expected)
    nombre de jours vivant sans ventilation mécanique à J28 (VFD28)
    E.5.1.1Timepoint(s) of evaluation of this end point
    28 days
    28 jours
    E.5.2Secondary end point(s)
    -Number of patients admitted in ICU (for stage 2b)
    -Number of days in ICU (for stage 3)
    -Death at D28 for all patients
    -Number of days in hospital
    -Visceral insufficiency improvement (SOFA score)
    -Number of days without fever at D7 (without antipyretics for 48h)
    -No increase in the number of bacterial or fungal sepsis
    -Biological parameters
    -Immunological parameters
    -Lung tomodensitometry and ventilation capacity
    -Nombre d’admission en réanimation (patients inclus au stade 2b)
    -Nombre de jours en réanimation (patients pris en charge en réanimation)
    -Mortalité à J28
    -Nombre de jours totaux d’hospitalisation
    -Amélioration des défaillances d’organe (score SOFA)
    -Délai de sevrage de l’oxygénothérapie
    -Nombre de jour sans fièvre à J7 (sans antipyrétiques pendant 48h)
    -Nombre de bactériémies, fongémies, pneumopathies nosocomiales et infections urinaires nosocomiales
    -Temps de normalisation des marqueurs inflammatoires biologiques (protéine C réactive, fibrinogène, ferritinémie) avec évaluation à J1 (1er jour du traitement par biothérapie), J2, J3, J5, J7, J10, J15, J20 et J28.
    -Temps de normalisation des marqueurs biologiques (NFS, créatininémie, transaminases, LDH, gamma GT, TP, TCA) évalués à J1, J2, J3, J5, J7, J10, J15, J20 et J28.
    -Dosage des taux sérique de tocilizumab et recherche d’anticorps neutralisants anti-tocilizumab à J2, J3 et J20.

    E.5.2.1Timepoint(s) of evaluation of this end point
    12 months
    12 mois
    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 Yes
    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 Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    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 No
    E.8.2.3Other Yes
    E.8.2.3.1Comparator description
    prise en charge habituelle
    standart of care
    E.8.2.4Number of treatment arms in the trial3
    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 concerned6
    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
    DVDS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years2
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days0
    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: 100
    F.1.3Elderly (>=65 years) No
    F.1.3.1Number of subjects for this age range: 50
    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 Yes
    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
    Subjects incapable of giving consent for physical reasons, linked to their medical condition (coma)
    Sujets incapables de donner leur consentement pour des raisons physiques, liées à leur état de santé (coma)
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state150
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 0
    F.4.2.2In the whole clinical trial 150
    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
    Aucun
    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 Decision2020-05-19
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2020-05-07
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
    P.Date of the global end of the trial2021-07-09
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