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    Summary
    EudraCT Number:2014-002715-41
    Sponsor's Protocol Code Number:P130934
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2020-12-18
    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 ConcernedItaly - Italian Medicines Agency
    A.2EudraCT number2014-002715-41
    A.3Full title of the trial
    A phase IIa multicenter trial to assess the efficacy, and safety of Anakinra in patients with intravenous immunoglobulin-resistant Kawasaki disease
    Kawakinra
    Studio multicentrico di fase II per valutare l'efficacia e la sicurezza di Anakinra nei pazienti affetti da malattia di Kawasaki con resistenza alle immunoglobuline endovena.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A phase IIa multicenter trial to assess the efficacy, and safety of Anakinra in patients with intravenous immunoglobulin-resistant Kawasaki disease
    Kawakinra
    Studio multicentrico di fase II per valutare l'efficacia e la sicurezza di Anakinra nei pazienti affetti da malattia di Kawasaki con resistenza alle immunoglobuline endovena.
    Kawakinra
    A.3.2Name or abbreviated title of the trial where available
    Kawakinra
    Kawakinra
    A.4.1Sponsor's protocol code numberP130934
    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 SponsorASSITANCE PUBLIQUE DES HOPITAUX 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 supportPHRC (finanziamento stato francese)
    B.4.2CountryFrance
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationCLINACT
    B.5.2Functional name of contact pointceline KUYPERS
    B.5.3 Address:
    B.5.3.1Street Address6-10 rue Troyon
    B.5.3.2Town/ citySEVRES
    B.5.3.3Post code92310
    B.5.3.4CountryFrance
    B.5.4Telephone number0033 1 46902727
    B.5.5Fax number0033 1 45078436
    B.5.6E-mailceline.kuypers@clinact.com
    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 - 100 MG/0.67 ML (150 MG/ML) SOLUZIONE INIETTABILE 1 SIRINGA PRERIEMPITA 0.67 ML USO SOTTOCUTANEO
    D.2.1.1.2Name of the Marketing Authorisation holderSWEDISH ORPHAN BIOVITRUM AB (PUBL)
    D.2.1.2Country which granted the Marketing AuthorisationItaly
    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 namekineret
    D.3.2Product code ATC : L04AC03
    D.3.4Pharmaceutical form Solution for injection
    D.3.4.1Specific paediatric formulation Yes
    D.3.7Routes of administration for this IMPSubcutaneous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNANAKINRA
    D.3.9.1CAS number 143090-92-0
    D.3.9.2Current sponsor codeP130934
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number150
    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 Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    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.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
    Anakinra treatment is expected to reduce the early and long term mortality of patients with Kawasaki Disease (KD), by a rapid and sustained effect on vascular inflammation
    Trattamento Anakinra dovrebbe ridurre la mortalit¿ precoce e lungo termine dei pazienti con malattia di Kawasaki (MK), da un effetto rapido e sostenuto sull'infiammazione vascolare
    E.1.1.1Medical condition in easily understood language
    Anakinra treatment is expected to reduce the early and long term mortality of patients with Kawasaki Disease (KD), by a rapid and sustained effect on vascular inflammation
    Trattamento Anakinra dovrebbe ridurre la mortalit¿ precoce e lungo termine dei pazienti con malattia di Kawasaki (MK), da un effetto rapido e sostenuto sull'infiammazione vascolare
    E.1.1.2Therapeutic area Diseases [C] - Cardiovascular Diseases [C14]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10023320
    E.1.2Term Kawasaki's disease
    E.1.2System Organ Class 10047065 - Vascular disorders
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Assess the efficacy of anakinra (IL-1R1receptor antagonist) in patients on fever with KD who fail to respond to one infusion of IVIg (standard treatment).
    Valutazione dell'efficacia di anakinra (antagonista recettoriale dell'IL-1R1) nei pazienti con febbre affetti da KD che non rispondono ad una somministrazione di IVIg (trattamento standard).
    E.2.2Secondary objectives of the trial
    -To assess the efficacy of anakinra on disease activity
    -To assess the efficacy of anakinra on coronary lesions (eg: dilatation and aneurysm)
    -To assess the efficacy of anakinra on inflammation
    -To assess the safety and tolerability of anakinra
    -Valutazione dell'efficacia di anakinra sull'attivit¿ della malattia
    -Valutazione dell'efficacia di anakinra sulle lesioni coronariche (ad es.:
    dilatazione e aneurisma)
    -Valutazione dell'efficacia di anakinra sull'infiammazione
    -Valutazione della sicurezza e la tollerabilit¿ di anakinra
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Patient, male and female, = 8 months of life and ¿ 18 years old,
    2. Patient = 10 kg
    3. Patient with KD according to the American Heart Association definition for complete or incomplete KD. (Fever = 5 days (or at least 3 days if KD with AHA criteria since the third day of fever) and = 4 of 5
    main clinical signs: modification of the extremities, polymorphic exanthema, bilateral bulbar not exudative conjunctivitis, erythema of the lips or oral cavity, and cervical lymph nodes usually unilateral > 1.5 cm in diameter. In the presence of less than 4 clinical criteria and 5 days of fever, the diagnosis of disease KD is proposed in case of coronary abnormalities (at least one dilated coronary artery with internal diameter = 2,5 SD from the mean normalized for body surface area (Z score) as determined by echocardiography). For indicative purpose, in case of incomplete KD, other biological supportive criteria for incomplete KD can help to ensure the diagnosis: leucocytosis, elevated CRP, elevated ESR, anaemia, hyponatremia, elevated ASAT, ALAT and gGT, hyperlipidaemia.
    4. Patient who failed to respond to standard therapy of KD: e.g. Persistence or recrudescence of fever = 38°C, 48 hours after the infusion of 2g/kg of IV Ig, The interval may be reduced to 24h after the end of the infusion if the patient is still febrile 24h after the end of the infusion.
    5. Patient, parents or legal guardian's written informed consent is required
    6. Patient of childbearing potential agrees to have effective contraception for the duration of participation in the research (i.e., a method that results in a less than 1% per year failure rate when used consistently and correctly, such as implants, injectables, combined oral contraceptives and intrauterine devices (IUDs)). Periodic abstinence (e.g., calendar, ovulation, symptothermal, post ovulation methods) is not acceptable.
    1. Paziente (maschio o femmina) = 8 mesi di vita e < 18 anni di età.
    2. Paziente = 10 kg.
    3. Paziente affetto da KD secondo la definizione dell'American Heart
    Association di KD completa o incompleta. Febbre = 5 giorni (o almeno 3 giorni se KD con criterio AHA dal terzo giorno di febbre) e = 4 dei 5 segni clinici principali: alterazione delle estremità, esantema polimorfo, congiuntivite bulbare bilaterale non essudativa, eritema delle labbra o del cavo orale e linfonodi cervicali (solitamente unilaterale) > 1,5 cm di diametro. In presenza di meno di 4 criteri clinici e di 5 giorni di febbre, la diagnosi della malattia KD viene proposta in caso di anomalie coronariche (almeno un'arteria coronaria dilatata con diametro interno =
    2,5 SD dalla media normalizzata per superficie corporea (unità Z) come determinato da ecocardiografia). A scopo indicativo, in caso di KD
    incompleta, altri criteri biologici di supporto possono aiutare a garantire la diagnosi: leucocitosi, CRP alta, ESR alta, anemia, iponatriemia, AST, ALT e gGT alti, iperlipidemia.
    4. Paziente che non ha risposto alla terapia standard di KD: ad esempio, persistenza o recrudescenza di febbre = 38 °C, 48 ore dopo la
    somministrazione di 2 g/kg di IV Ig. L'intervallo potrebbe essere ridotto a 24 ore dal termine della somministrazione se il paziente presenta ancora febbre 24 ore dopo la fine della somministrazione.
    5. È obbligatorio il consenso scritto informato di paziente, genitori o tutore legale.
    6. Pazienti in età fertile accettano di adottare metodi contraccettivi efficaci per la durata di partecipazione alla ricerca. (ovvero, un metodo che ha un tasso di fallimento inferiore all'1 % l'anno quando impiegato costantemente e correttamente, come per esempio impianti, contraccettivi iniettabili, contraccettivi orali combinati e dispositivi intrauterini (DIU). L'astinenza periodica (ad esempio, calendario, ovulazione, sintotermico, post-ovulazione) non è un metodo contraccettivo accettabile.
    E.4Principal exclusion criteria
    1. Preterm and neonates, pregnancy (+ß-hCG if appropriate)
    2. Patients suspected with another diagnosis
    3. Patients with overt concomitant bacterial infection
    4. Patients previously treated with steroids or/and another biotherapy
    5. Patients with any type of immunodeficiency or cancer
    6. Patients with increased risk of Tuberculosis (TB) infection
    7. Recent tuberculosis infection or with active TB
    8. Close contact with a patient with TB
    9. Patients recently arrived less than 3 months from a country with high prevalence of TB
    10. A chest radiograph suggestive of TB
    11. Patients with end stage renal disease: NKF stages =4; eGFR= 29mL/min/1.73 m2 or diabetes mellitus or neutropenia <1500/mm3 or liver failure
    12. Hypersensitivity to the active substance or to any of the excipients (citric acid and anhydrous; sodium chloride disodium edetate dehydrate polysorbate 80; sodium hydroxide; water for injections) and to proteins derived from Escherichia Coli
    13. Patient already included in a biomedical research other than observational (e.g.; cohort, registry)
    1. Prematuri e neonati, gravidanza (+ß-hCG se appropriato).
    2. Pazienti che sospettano un'altra diagnosi.
    3. Pazienti con infezione batterica concomitante manifesta.
    4. Pazienti precedentemente trattati con steroidi e/o altra bioterapia.
    5. Pazienti affetti da qualsiasi forma di immunodeficienza o tumore.
    6. Pazienti con aumentato rischio di infezione tubercolare (TB).
    7. Recente infezione tubercolare o TB attiva.
    8. Contatto ravvicinato con pazienti affetti da TB.
    9. Pazienti tornati da meno di 3 mesi da un paese con elevata incidenza di TB.
    10. Radiografia toracica che rivela possibile TB.
    11. Pazienti in stadio finale di malattia renale: fasi NKF =4; eGFR=29 mL/min/1,73 m2 o diabete mellitus o neutropenia <1500/mm3 o insufficienza epatica.
    12. Ipersensibilità al principio attivo o a qualsiasi eccipiente (acido citrico e anidro; sodio cloruro disodio edetato diidrato polisorbato 80; idrossido di sodio; acqua per iniezioni) e alle proteine derivate di Escherichia Coli.
    13. Paziente già incluso in una ricerca biomedica non basata sull'osservazione (ad es., gruppo, registro).
    E.5 End points
    E.5.1Primary end point(s)
    The primary statistical analysis of the proportion of patients succeeding to reach a body temperature <38°C within 24 hours of treatment by anakinra (even after dose escalation if any) at d15 will be purely descriptive through proportion of patients and its Agresti-Coull confidence interval at 95%. Based on the Intent-To-Treat principle, all
    included patients will be taken into account.
    L'analisi statistica primaria della proporzione di pazienti riuscendo a raggiungere una temperatura corporea <38 ° C in 24 ore di trattamento con Anakinra (anche dopo l'aumento della dose, se del caso) a d15 sarà
    puramente descrittivo attraverso proporzione di pazienti e la sua fiducia Agresti-Coull intervallo 95%. Sulla base del principio di Intent-To-Treat, tutto incluso saranno presi in considerazione i pazienti.
    E.5.1.1Timepoint(s) of evaluation of this end point
    at the end of the study
    al termine dello studio
    E.5.2Secondary end point(s)
    Secondary analyses: proportion of patients achieving secondary endpoints and their confidence intervals at 95% in all included patients. Safety analyses: descriptive only on all treated patients
    Analisi secondarie: proporzione di pazienti che raggiungono gli esiti secondari e i loro intervalli di confidenza del 95%, in tutti i pazienti inclusi. Analisi di sicurezza: solo descrittiva per tutti i pazienti trattati.
    E.5.2.1Timepoint(s) of evaluation of this end point
    at the end of the study
    al termine dello studio
    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) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised No
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    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 No
    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 concerned3
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA12
    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 Information not present in EudraCT
    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
    LVLS
    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 months1
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months1
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 Yes
    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) Yes
    F.1.1.4.1Number of subjects for this age range: 5
    F.1.1.5Children (2-11years) Yes
    F.1.1.5.1Number of subjects for this age range: 5
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 15
    F.1.2Adults (18-64 years) No
    F.1.3Elderly (>=65 years) No
    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 Yes
    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 No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state9
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 25
    F.4.2.2In the whole clinical trial 25
    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
    nessuno
    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 Decision2016-01-05
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2015-12-15
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
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