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    Summary
    EudraCT Number:2017-004420-30
    Sponsor's Protocol Code Number:CL3-95008-002
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2018-06-06
    Trial results View 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 ConcernedSpain - AEMPS
    A.2EudraCT number2017-004420-30
    A.3Full title of the trial
    Efficacy and safety of bumetanide oral liquid formulation in children aged from 2 to less than 7 years old with Autism Spectrum Disorder.
    A 6-month randomised, double-blind, placebo controlled multicentre parallel group study to evaluate efficacy and safety of bumetanide 0.5mg twice a day followed by an open label active 6-month treatment period with bumetanide (0.5mg twice a day) and a 6 weeks discontinuation period after treatment stop.
    Eficacia y seguridad de la formulación líquida oral de bumetanida en niños de 2 a menos de 7 años de edad con trastorno del espectro autista.
    Estudio multicéntrico, aleatorizado, doble ciego, controlado con placebo, con grupos paralelos de 6 meses de duración para evaluar la eficacia y seguridad de 0,5 mg de bumetanida dos veces al día seguido de un período abierto de tratamiento activo de 6 meses con bumetanida (0,5 mg dos veces al día) y un período de seguimiento de 6 semanas tras el fin del tratamiento.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Efficacy and safety of bumetanide oral liquid formulation in children aged from 2 to less than 7 years old with Autism Spectrum Disorder.
    Eficacia y seguridad de la formulación líquida oral de bumetanida en niños de 2 a menos de 7 años de edad con trastorno del espectro autista.
    A.4.1Sponsor's protocol code numberCL3-95008-002
    A.7Trial is part of a Paediatric Investigation Plan Yes
    A.8EMA Decision number of Paediatric Investigation PlanP/340/2017
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorInstitut de Recherches Internationales Servier
    B.1.3.4CountryFrance
    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 supportLaboratorios Servier SL
    B.4.2CountrySpain
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationLaboratorios Servier SL
    B.5.2Functional name of contact pointDpto. Investigación y Desarrollo
    B.5.3 Address:
    B.5.3.1Street AddressAvda. de Los Madroños 33
    B.5.3.2Town/ cityMadrid
    B.5.3.3Post code28043
    B.5.3.4CountrySpain
    B.5.4Telephone number+34917489662
    B.5.5Fax number+34913003249
    B.5.6E-mailitziar.martinezmelchor@servier.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 No
    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 nameS95008
    D.3.2Product code S95008
    D.3.4Pharmaceutical form Oral solution
    D.3.4.1Specific paediatric formulation Yes
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNBumetanide
    D.3.9.2Current sponsor codeS95008
    D.3.9.3Other descriptive nameBUMETANIDE
    D.3.9.4EV Substance CodeSUB05971MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number0.5
    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 placeboOral solution
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Autism Spectrum Disorder (ASD)
    Trastorno del Espectro Autista
    E.1.1.1Medical condition in easily understood language
    Autism Spectrum Disorder (ASD)
    Trastorno del Espectro Autista
    E.1.1.2Therapeutic area Psychiatry and Psychology [F] - Mental Disorders [F03]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10063844
    E.1.2Term Autism spectrum disorder
    E.1.2System Organ Class 10037175 - Psychiatric disorders
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To demonstrate the superiority of bumetanide (0.5mg BID) oral liquid formulation compared to placebo in the improvement of ASD core symptoms after 6 months of treatment in ASD children aged from 2 to less than 7 years old
    Demostrar la superioridad de la formulación líquida oral de bumetanida (0,5 mg 2 veces al día) en comparación con placebo en la mejoría de los síntomas principales de TEA después de 6 meses de tratamiento en niños de 2 a menos de 7 años de edad .
    E.2.2Secondary objectives of the trial
    - To assess the effect of bumetanide on the other efficacy endpoints
    - To assess the safety of bumetanide
    - To confirm the acceptability and palatability of the oral liquid formulation
    - To describe the bumetanide effects on patients quality of life
    - To improve existing pharmacokinetic model of bumetanide in this population
    -Evaluar el efecto de la bumetanida sobre los criterios secundarios de valoración de la eficacia
    -Evaluar la seguridad de la bumetanida
    -Confirmar la aceptabilidad y palatabilidad de la formulación líquida oral
    -Describir los efectos de la bumetanida sobre la calidad de vida de los pacientes
    -Mejorar el modelo farmacocinético existente de la bumetanida en esta población
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    - Male and female patients from 2 to less than 7 years
    - Out patients
    - Primary diagnosis of ASD as per DSM-5 criteria
    - Criteria met for ASD on Autism Diagnostic Observation Schedule (ADOS-2) and Autism Diagnosis Interview Revised (ADI-R)
    - CGI (Clinical Global Impression) – Severity rating Score ≥ 4
    - Childhood Autism Rating Scale second edition (CARS2-ST or HF) total
    raw score ≥ 34
    - Social Responsiveness Scale second edition total score (SRS-2 T-Score) ≥ 66
    - Absence of known monogenic syndrome (Fragile X, Rett syndrome ...)
    - Absence of any clinically significant abnormality likely to interfere with the conduct of the study according to the judgment of the investigator
    -Hombres y mujeres de 2 a menos de 7 años de edad
    -Pacientes ambulatorios
    -Diagnóstico principal de TEA según los criterios DSM-5
    -Cumplir los criterios de TEA según la Escala de Observación para el Diagnóstico del Autismo-2 (ADOS-2) y la Entrevista para el Diagnóstico del Autismo -Revisada (ADI-R)
    -Puntuación de la gravedad > 4 en la escala de Impresión Clínica Global (CGI)
    -Puntuación bruta total > 34 en la segunda edición de la Escala de Evaluación del Autismo Infantil (CARS2-ST o HF)
    -Puntuación total > 66T en la segunda edición de la Escala de Respuesta Social (SRS-2)
    -Ausencia de diagnóstico de síndrome del cromosoma X frágil o de Rett
    -Ausencia de cualquier anomalía de importancia clínica que pueda interferir en la realización del estudio a criterio del investigador.
    E.4Principal exclusion criteria
    - Patients not able to follow the study assessments defined by the protocol, with the exception of self-rating questionnaires which will be assessed by parent/legal representative/caregiver for those patients unable to complete them
    - Patients having a high suicidal risk according to the investigator judgement
    - Chronic renal dysfunction
    - Chronic cardiac dysfunction
    - Patient with unstable psychotherapy, behavioural, cognitive or cognitive-behavioural therapy
    - Absence of electrolyte imbalance that is likely to interfere with the study conduct or evaluation
    -Pacientes no capaces de cumplir con las evaluaciones de seguimiento previstas en el protocolo a excepción de los cuestionarios que pueden ser completados por los padres/representantes legales/cuidadores para los pacientes que no sean capaces de hacerlo por sí mismos
    -Pacientes con alto riesgo de suicidio a juicio del investigador
    -Disfunción renal crónica
    -Disfunción cardiaca crónica
    -Paciente con terapias cognitivas, de comportamiento, mixtas o psicoterapia inestables
    -Desequilibrio electrolítico severo que pueda interferir con el desarrollo o evaluación del estudio
    E.5 End points
    E.5.1Primary end point(s)
    CARS2 total raw score
    puntuación bruta total de CARS2
    E.5.1.1Timepoint(s) of evaluation of this end point
    Change from baseline to 6 month
    Cambio de basal a mes 6
    E.5.2Secondary end point(s)
    - Each individual CARS2 domain, SRS-2 total raw score, CGI-I score, VABS II subscores
    - Adverse events, Paediatric Adverse Event Rating Scale (PAERS), clinical laboratory evaluation, vital signs and clinical examination, electrocardiogram, renal ultrasound, Columbia Suicide Severity Rating Scale Children's version (C-SSRS-C)
    - Acceptability and palatability questionnaire
    - Paediatric Quality of Life Inventory (PedsQL), WHOQOL-Bref questionnaire
    - PK parameters of bumetanide
    -Variación en cada dominio individual de CARS2, puntuación bruta total de SRS-2, puntuación de CGI-I, VABS II
    -Acontecimientos adversos, Escala de Puntuación de
    Acontecimientos Adversos Pediátricos (PAERS), evaluación del laboratorio clínico, constantes vitales y exploración clínica, electrocardiograma, ecografía renal, escala Columbia para evaluar
    -Evaluaciones de la aceptabilidad y palatabilidad
    -Inventario de Calidad de Vida Pediátrico (PedsQL), cuestionario WHOQOL-Bref
    -Parámetros farmacocinéticos de bumetanida
    E.5.2.1Timepoint(s) of evaluation of this end point
    SRS-2 total raw score: W000/W004/W012/W026/W038/W052
    CGI-I score: W000+Day17/W004/W008/W012/W016/W020/W026/W038/W052/WEND
    VABS II subscores: W000/W026/W052
    Each individual CARS2 domain: W000/W004/W012/W026/W038/W052/WEND
    Adverse events/PAERS/Clinical laboratory evaluation/Electrolytes monitoring (sodium, potassium)/Clinical examination: all along the study
    Vital signs: ASSE/W000/W00+D17/W012/W026/W026+Day17/W038/W052
    Electrocardiogram: ASSE/W004/W008/W012, W026/W030/W034/W038/W052
    Renal ultrasound: ASSE/W026/W052
    C-SSRS-C: W000/W012/W026/W038/W052
    Acceptability and palatability questionnaire: W026
    PedsQL / WHOQOL-Bref questionnaire: W000/W004/W012/W026/W030/W038/W052 + W008/W034 for WHOQOL-Bref questionnaire
    PK parameters of bumetanide: W012/W026
    Puntuación bruta total SRS-2: W000/W004/W012/W026/W038/W052
    Puntuación CGI-I: W000+Day17/W004/W008/W012/W016/W020/W026/W038/W052/WEND
    Sub puntuaciones VABS II: W000/W026/W052
    Cada dominio individual CARS2 : W000/W004/W012/W026/W038/W052/WEND
    Acontecimientos adversos/PAERS/evaluación de laboratorio/monitorización electrolitos (sodio, potasio)/exploración clínica: durante todo el estudio Signos vitales: ASSE/W000/W000+Day17/W012/W026/W026+Day17/W038/W052
    Electrocardiograma: ASSE/W004/W008/W012/W026/W030/W034/W038/W052
    Ecografía renal :ASSE/W026/W052
    C-SSRS-C: W000/W012/W026/W038/W052
    Cuestionario de aceptabilidad y palatabilidad: W026
    Cuestionarios PedsQL / WHOQOL-Bref: W000/W004/W012/W026/W030/W038/W052 + W008/W034 fpara el cuestionario WHOQOL-Bref
    PK: W012/W026
    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 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.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 Yes
    E.8.1.7.1Other trial design description
    Double-blind treatment period of 6 months followed by an open-label treatment period of 6 months
    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 concerned7
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA50
    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
    Last Visit Last Participant as stated in the protocol
    última visita del último paciente como indicado en el protocolo
    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 months6
    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: 200
    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) Yes
    F.1.1.5.1Number of subjects for this age range: 200
    F.1.1.6Adolescents (12-17 years) No
    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 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 No
    F.3.3.6Subjects incapable of giving consent personally Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    The investigator is to collect written consent from each participant when of appropriate intellectual maturity and from his/her parent(s)/legal representative/caregiver before participation in the study.
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state19
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 200
    F.4.2.2In the whole clinical trial 200
    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)
    The participants' treatment is left to the physician's discretion.
    El tratamiento de los pacientes será a criterio del médcio
    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 Decision2018-07-04
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-06-25
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
    P.Date of the global end of the trial2021-08-18
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