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    EudraCT Number:2019-002408-42
    Sponsor's Protocol Code Number:ASPER-III-19-1
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2020-01-10
    Trial results
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    A. Protocol Information
    A.1Member State ConcernedSpain - AEMPS
    A.2EudraCT number2019-002408-42
    A.3Full title of the trial
    A Phase 3, Double Blind, Multicentric, Randomised, Placebo-Controlled Study to Assess the Efficacy, Safety and Tolerability of Itraconazole Dry Powder for Inhalation for the Prevention of Invasive Mould Disease in Patients with Acute Leukaemia and Neutropaenia
    Estudio en fase III, doble ciego, multicéntrico, aleatorizado, controlado con placebo para evaluar la eficacia, la seguridad y la tolerabilidad de itraconazol polvo seco para inhalación para la prevención de la enfermedad fúngica invasiva en pacientes con leucemia aguda y neutropenia
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Study aiming at proving the efficacy, safety and tolerability of inhaled Itraconazole in the prevention of Invasive Mould Disease (infections of the lungs by fungi) in patients with Acute Leukaemia and Neutropaenia (abnormally low concentration of neutrophils in the blood)
    Estudio destinado a demostrar la eficacia, seguridad y tolerabilidad del Itraconazol inhalado en la prevención de la enfermedad de moho invasivo (infecciones de los pulmones por hongos) en pacientes con leucemia aguda y neutropenia (concentración anormalmente baja de neutrófilos en la sangre)
    A.4.1Sponsor's protocol code numberASPER-III-19-1
    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 SponsorLABORATOIRES SMB S.A.
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportLABORATOIRES SMB S.A
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationLABORATOIRES SMB S.A
    B.5.2Functional name of contact pointCLINICAL DEPARTMENT
    B.5.3 Address:
    B.5.3.1Street Address26-28 Rue de la Pastorale
    B.5.3.2Town/ cityBrussels
    B.5.3.3Post code1080
    B.5.4Telephone number+322411 48 28
    B.5.5Fax number+322411 28 28
    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 No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community Yes
    D.2.5.1Orphan drug designation numberEU/3/18/2024
    D.3 Description of the IMP
    D.3.1Product nameITRACONAZOLE 4.8 mg
    D.3.4Pharmaceutical form Inhalation powder, hard capsule
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPInhalation use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.9.1CAS number 84625-61-6
    D.3.9.4EV Substance CodeSUB08353MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number4.8
    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. cell therapy medicinal product No
    D. therapy medical product No
    D. Engineered Product No
    D. ATIMP (i.e. one involving a medical device) No
    D. 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 Yes
    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 placeboInhalation powder, hard capsule
    D.8.4Route of administration of the placeboInhalation use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    prevention of invasive mould disease
    Prevención de infección fúngica invasiva
    E.1.1.1Medical condition in easily understood language
    Infection of the lungs by fungi
    Infección de los pulmones por hongos
    E.1.1.2Therapeutic area Diseases [C] - Respiratory Tract Diseases [C08]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10003488
    E.1.2Term Aspergillosis
    E.1.2System Organ Class 100000004862
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To investigate whether prophylaxis with ITZ DPI can reduce the incidence rate of IMD in patients with acute leukaemia undergoing remission induction chemotherapy
    Investigar si la profilaxis con ITZ IPS puede reducir la incidencia de ratio de EFI en pacientes con leucemia aguda que se someten a tratamiento de inducción de remisión con quimioterapia.
    E.2.2Secondary objectives of the trial
    -To investigate the safety and tolerability of ITZ DPI in patients with acute leukaemia undergoing remission-induction chemotherapy
    -To evaluate the PK of ITZ DPI in patients with acute leukaemia undergoing remission induction chemotherapy
    -Investigar la seguridad y tolerabilidad de ITZ IPS en pacientes con leucemia aguda que se someten a tratamiento de inducción de remisión con quimioterapia.
    -Evaluar la farmacocinética (FC) del ITZ IPS en pacientes con leucemia aguda que se someten a tratamiento de inducción de remisión con quimioterapia
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1.Male or female patients ≥12 years of age
    2.Patients with new or relapsed ALL or AML who cannot receive posaconazole for any reason and who are to undergo remission-induction chemotherapy
    3.Current neutropaenia resulting from the diagnosis of new or relapsed acute leukaemia or patients with expected neutropaenia for at least 10 days (an absolute neutrophil count <500 cell/mm3 or 0.5 x 109 cell/L) following remission-induction chemotherapy
    4.Able to have all Screening tests performed quickly to ensure results can be obtained and evaluated before randomisation, so that the first dose of study drug for the prevention of IMD can be administered as soon as possible within 5 days of the start of remission induction chemotherapy. In ALL patients, as soon as possible within 5 days of the start of remission-induction chemotherapy means as soon as possible within 5 days of the start of high dose steroid therapy.
    5.Able to comply with all study procedures, including the use of inhalers
    6.If patient is a female of childbearing potential (FOCP), patient must agree to use an effective means of birth control (oral contraceptives, intrauterine device [IUD], condoms and spermicides, vaginal ring, hormonal patch, implants), as determined by the Investigator from the first dose of study drug until 100 days following the last dose of study drug. Female patients of childbearing potential must also provide a negative blood pregnancy test at the Screening Visit. Male patients must be vasectomised, abstain from sexual intercourse, or agree to use barrier contraception (condom with spermicide), and also agree not to donate sperm from the first dose of study drug until 100 days following the last dose of study drug.
    7.Patients (and/or the patient’s parents or legally authorised representatives) must give written informed consent to participate in the study by signing and dating the Informed Consent Form (ICF)/Adolescent Assent Form (to be obtained prior to initiation of any study procedure)
    1.Pacientes varones o mujeres de ≥12 años de edad
    2.Pacientes con LLA o LMA nuevas o recidivantes que no puedan recibir posaconazol por ningún motivo y que vayan a someterse a tratamiento de inducción de remisión con quimioterapia
    3.Neutropenia actual resultante del diagnóstico de leucemia aguda nueva o recidivante o de pacientes con neutropenia esperada durante al menos 10 días (un recuento absoluto de neutrófilos <500 células/mm3 o 0,5 x 109 células/L) después del tratamiento de inducción de remisión con quimioterapia
    4.Capaz de tener realizadas todas las pruebas de selección con rapidez para garantizar que los resultados se puedan obtener y evaluar antes de la aleatorización, de modo que la primera dosis del fármaco del estudio para la prevención de la EFI se pueda administrar lo antes posible en los 5 días posteriores al inicio del tratamiento de inducción de remisión con quimioterapia. En el caso de los pacientes con LLA, tan pronto como sea posible en el plazo de 5 días desde el inicio del tratamiento de inducción con quimioterapia de remisión significa lo antes posible en un plazo de 5 días desde el inicio del tratamiento con esteroides en dosis altas.
    5.Capaz de cumplir todos los procedimientos del estudio, incluido el uso de inhaladores
    6.Si el paciente es una mujer en edad fértil (MEF), la paciente debe aceptar utilizar un método de anticonceptivo eficaz (anticonceptivos orales, dispositivo intrauterino [DIU], preservativos y espermicidas, anillo vaginal, parche hormonal, implantes), según lo determinado por el investigador desde la primera dosis del fármaco del estudio hasta 100 días después de la última dosis del fármaco del estudio. Las pacientes que sean mujeres en edad fértil también deben proporcionar una prueba de embarazo en sangre negativa en la visita de selección. Los pacientes varones deben estar vasectomizados, abstenerse de mantener relaciones sexuales o aceptar utilizar métodos anticonceptivos de barrera (preservativo con espermicida) así como aceptar no donar esperma a partir de la primera dosis del fármaco del estudio hasta los 100 días después de la última dosis del fármaco del estudio.
    7.Los pacientes (y/o los padres o representantes legales autorizados del paciente) deben dar su consentimiento informado por escrito para participar en el estudio firmando y fechando el formulario de consentimiento informado/formulario de asentimiento para adolescentes (que se obtendrá antes del inicio de cualquier procedimiento del estudio)
    E.4Principal exclusion criteria
    1.Proven, probable, or possible IMD (according to the most recent European Organisation for Research and Treatment of Cancer/National Institute of Allergy and Infectious Diseases Mycoses Study Group [EORTC/MSG] criteria) at Screening or in the patient’s medical history
    2.Pulmonary complications or infiltrates assessed by a chest CT
    3.Patients with ventricular dysfunction defined as ejection fraction <55% at Screening
    4.Concomitant or previous treatment with a mould-active antifungal drug within 30 days, unless the plasma level is below the limit of detection or ≥5 half-lives of the antifungal has elapsed since the treatment was given.
    5.Participating in another clinical trial with exposure to any investigational drug within 30 days prior to Screening, with the exception of the current anti-leukemic treatment
    6.Pregnant or nursing females
    7.Any severe co-morbidity other than underlying haematological disease that may interfere with study procedures or affect the patient’s safety
    8.Grade 3 liver function test results, including aspartate aminotransferase (ASAT), alanine aminotransferase (ALAT), or total bilirubin >5 times the upper limit of normal (ULN)
    9.Any contraindication or hypersensitivity to the use of fluconazole or ITZ or the excipient (mannitol) in the study drug and placebo formulations
    10.Co-administration of astemizole, atorvastatin, bepridil, cisapride, dihydroergotamine, dofetilide, eletriptan, ergometrine (erginovine), ergotamine, erythromycin, levacetylmethadol (levomethadyl), lovastatin, methylergometrine (methylergonovine), midazolam, mizolastine, nisoldipine, pimozide, quinidine, sertindole, simvastatin, terfenadine and triazolam.
    11.Abnormal QT interval corrected by Fridericia (QTcF): males >450 ms and females >470 ms
    1.EFI demostrada, probable o posible (de acuerdo con los criterios más recientes de la Organización Europea para la Investigación y el Tratamiento del Cáncer/Grupo de Estudio de Micosis del Instituto Nacional de Alergias y Enfermedades Infecciosas [EORTC/MSG]) en la selección o en el historial médico del paciente
    2.Complicaciones pulmonares o infiltrados evaluados mediante TAC torácica
    3.Pacientes con disfunción ventricular definida como una fracción de eyección <55 % en la selección
    4.Tratamiento concomitante o previo con un antifúngico activo contra los hongos durante los 30 días anteriores, a menos que el nivel plasmático esté por debajo del límite de detección o que hayan transcurrido ≥5 semividas del antifúngico desde que se administró el tratamiento.
    5.Participar en otro ensayo clínico con exposición a cualquier fármaco en investigación en los 30 días anteriores a la selección, con la excepción del tratamiento antileucémico actual
    6.Mujeres embarazadas o en periodo de lactancia
    7.Cualquier comorbilidad grave que no sea la enfermedad hematológica subyacente que pueda interferir con los procedimientos del estudio o afectar a la seguridad del paciente
    8.Resultados de la prueba de función hepática de grado 3, incluyendo aspartato aminotransferasa (ASAT), alanina aminotransferasa (ALAT) o bilirrubina total >5 veces el límite superior de la normalidad (LSN)
    9.Cualquier contraindicación o hipersensibilidad al uso de fluconazol o ITZ o del excipiente (manitol) en las formulaciones del fármaco del estudio y placebo
    10.Coadministración de astemizol, atorvastatina, bepridil, cisaprida, dihidroergotamina, dofetilida, eletriptán, ergometrina (ergonovina), ergotamina, eritromicina, levacetilmetadol (levometadil), lovastatina, metilergometrina (metilergonovina), midazolam, mizolastina, nisoldipino, pimozida, quinidina, sertindol, simvastatina, terfenadina y triazolam.
    11.Intervalo QT corregido por Fridericia QTcF anómalo (hombres >450 ms, mujeres >470 ms)
    E.5 End points
    E.5.1Primary end point(s)
    The primary efficacy endpoint is the:
    •Proportion of patients with proven or probable IMD at EOT. Diagnoses of proven or probable IMD will be evaluated according to the most recent EORTC/MSG criteria, as assessed by the Independent Data Review Board (IDRB) that will be blinded to treatment assignment.
    El criterio de valoración principal de la eficacia es:
    •Proporción de pacientes con EFI demostrada o probable al FdT. Los diagnósticos de EFI probada o probable se evaluarán de acuerdo con los criterios de la EORTC/MSG más recientes, según la evaluación del Comité Independiente de Revisión de Datos (CIRD) que será ciego al tratamiento asignado.
    E.5.1.1Timepoint(s) of evaluation of this end point
    End of treatment
    Fin de tratamiento
    E.5.2Secondary end point(s)
    The secondary efficacy endpoints are:
    •Treatment success at EOT (success defined as patients who completed treatment without developing a proven, probable, or possible IMD, without requiring systemic mould-active antifungal treatment, without discontinuation from the study due to an adverse event [AE], and who are alive).
    •The proportion of patients:
    owith proven, probable, or possible IMD at EOT and EOS
    o who had neutropaenia ≥10 days and with proven, probable, or possible IMD at EOT and EOS
    o with radiographic pulmonary infiltrates according to the central image reader at EOT and EOS
    o with bronchopulmonary aspergillosis at EOT and EOS
    o with fungal sinusitis at EOT and EOS
    o with proven or probable or possible IA at EOT and at EOS
    o with candidemia/candidiasis at EOT and EOS
    o requiring systemic mould-active antifungal treatment at EOT and EOS to treat a breakthrough fungal infection
    o alive at EOT and EOS
    o who died at EOT and EOS due to IMD or IA
    o in complete remission of their underlying malignancy at EOT and EOS
    •The proportion of pathogenic moulds causing proven and probable IMDs at EOT and EOS
    •Time to:
    o diagnosis of proven, probable, or possible IMD
    o diagnosis of IA
    o the onset of systemic mould-active antifungal treatment for a breakthrough fungal infection
    o death of any cause
    Los criterios de valoración de la eficacia secundarios son:
    •Éxito del tratamiento al FdT (éxito definido como pacientes que completaron el tratamiento sin desarrollar una EFI demostrada, probable o posible, que no necesiten tratamiento antifúngico activo contra los hongos sistémico, sin interrupción del estudio debida a un acontecimiento adverso [AA] y que estén vivos).
    •La proporción de pacientes:
    -con EFI demostrada, probable o posible al FdT y FdE
    -que tuvieron neutropenia ≥10 días con EFI demostrada, probable o posible al FdT y FdE
    -con infiltrados pulmonares radiográficos de acuerdo con el lector de imágenes central al FdT y FdE
    -con aspergilosis broncopulmonar al FdT y FdE
    -con sinusitis fúngica al FdT y FdE
    -con AI demostrada o probable al FdT y al FdE
    -con candidemia/candidiasis al FdT y FdE
    -que requieren tratamiento antifúngico activo contra los hongos sistémico al FdT y FdE para tratar una recaída de la infección fúngica
    -vivos al FdT y FdE
    -que murieron al FdT y FdE debido a EFI o AI
    -en remisión completa de su neoplasia maligna subyacente al FdT y FdE
    •La proporción de hongos patógenos que causan EFI demostrada y probable al FdT y FdE
    •El tiempo hasta:
    -el diagnóstico de EFI demostrada, probable o posible
    -el diagnóstico de AI
    -el inicio de un tratamiento antifúngico activo contra los hongos sistémico para una recaída de la infección fúngica
    -la muerte por cualquier causa
    E.5.2.1Timepoint(s) of evaluation of this end point
    End of treatment and end of study
    Fin de tratamiento y fin de estudio
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis Yes
    E.6.3Therapy No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    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. 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 trial2
    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 concerned10
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA44
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Russian Federation
    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
    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 months2
    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 months6
    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.1.1Number of subjects for this age range: 23
    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) Yes
    F. of subjects for this age range: 23
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 339
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 100
    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 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 state58
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 281
    F.4.2.2In the whole clinical trial 462
    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)
    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 Decision2020-05-04
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2020-02-04
    P. End of Trial
    P.End of Trial StatusOngoing
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