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    Summary
    EudraCT Number:2013-003714-40
    Sponsor's Protocol Code Number:HCQinpediatricILD
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Temporarily Halted
    Date on which this record was first entered in the EudraCT database:2018-11-05
    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 ConcernedSpain - AEMPS
    A.2EudraCT number2013-003714-40
    A.3Full title of the trial
    Hydroxychloroquine in pediatric ILD START randomized controlled in parallel-group, then switch placebo to active drug, and STOP randomized controlled in parallel-group
    to evaluate the efficacy and safety of hydroxychloroquine (HCQ)
    Hidroxicloroquina en EPI pediátrica. START aleatorizado, controlado, de grupos paralelos, con cambio de placebo a fármaco activo, y STOP aleatorizado, controlado, de grupos paralelos, para evaluar la eficacia y seguridad de hidroxicloroquina (HCQ)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    HCQ in pediatric ILD
    HCQ en EPI pediátrica
    A.3.2Name or abbreviated title of the trial where available
    HCQ in pediatric ILD
    HCQ en EPI pediátrica
    A.4.1Sponsor's protocol code numberHCQinpediatricILD
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT02615938
    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 SponsorKlinikum der Universität München
    B.1.3.4CountryGermany
    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 supportEUROPEAN COMMISSION DIRECTORATE-GENERAL FOR RESEARCH & INNOVATION
    B.4.2CountryEuropean Union
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationFundación Hospital Universitari Vall d'Hebron - Institut de recerca
    B.5.2Functional name of contact pointARO -ACADEMIC RESEARCH ORGANIZATION
    B.5.3 Address:
    B.5.3.1Street AddressPasseig de la Vall d'Hebron, 119-129
    B.5.3.2Town/ cityBarcelona
    B.5.3.3Post code08035
    B.5.3.4CountrySpain
    B.5.4Telephone number349348930002702
    B.5.6E-mailaro@vhir.org
    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 namehydrochloroquine
    D.3.4Pharmaceutical form Capsule
    D.3.4.1Specific paediatric formulation No
    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 INNHYDROXYCHLOROQUINE
    D.3.9.1CAS number 118-42-3
    D.3.9.4EV Substance CodeSUB08077MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/kg milligram(s)/kilogram
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number6.5
    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.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 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 namehydrochloroquine
    D.3.4Pharmaceutical form Capsule
    D.3.4.1Specific paediatric formulation No
    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 INNHYDROXYCHLOROQUINE
    D.3.9.1CAS number 118-42-3
    D.3.9.4EV Substance CodeSUB08077MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/kg milligram(s)/kilogram
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number10
    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 placeboCapsule
    D.8.4Route of administration of the placeboOral use
    D.8 Placebo: 2
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboCapsule, hard
    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
    interstitial lung disease
    enfermedad pulmonar intersticial de la infancia (chILD, children´s interstitial lung disease)
    E.1.1.1Medical condition in easily understood language
    interstititial lung disease
    enfermedad pulmonar intersticial de la infancia (chILD, children´s interstitial lung disease)
    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 PT
    E.1.2Classification code 10022611
    E.1.2Term Interstitial lung disease
    E.1.2System Organ Class 10038738 - Respiratory, thoracic and mediastinal disorders
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    START HCQ block
    To evaluate the efficacy of HCQ after 28 days of treatment in chILD compared to placebo.

    STOP HCQ block
    To evaluate the efficacy of HCQ after 84 days of treatment in chILD compared to Placebo
    Bloque START:
    Evaluar la eficacia de HCQ en chILD a los 28 días de tratamiento en comparación con placebo.

    Bloque STOP:
    Evaluar la eficacia de HCQ en chILD a los 84 días de tratamiento en comparación con placebo.
    E.2.2Secondary objectives of the trial
    START HCQ block
    - To evaluate the efficacy of HCQ after 56 days of treatment in chILD compared to 28 days.
    - To evaluate the safety of HCQ after 28 and 56 days of treatment in chILD.
    - To evaluate blood levels of HCQ after 28 and 56 days of treatment in chILD.

    STOP HCQ block
    - To evaluate the efficacy of chronic (> 3 months) HCQ treatment in chILD compared to placebo.
    - To evaluate the safety of HCQ after > 3 months of treatment in chILD.
    - To evaluate blood levels of HCQ before and after treatment in chILD
    - Evaluar la eficacia de HCQ en chILD a los 56 días de tratamiento y compararla con los resultados a los 28 días de tratamiento.

    - Evaluar la seguridad de HCQ en chILD a los 28 y 56 días de tratamiento.

    - Evaluar los niveles sanguíneos de HCQ en chILD a los 28 y 56 días de tratamiento.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1)Patients should be clinically stable during baseline (between Visit 1 and 2) for inclusion into the study
    a) To determine this, attending physicians can use SpO2 in room air for patients on room air or on O2-supplement; the absolute difference on SpO2 is expected not to be ≥ 5% between Visit 1 and 2. For patients on respiratory support, the summary key parameters should not change ≥ 20% between Visit 1 and 2
    and
    b) No major changes in other medications between Visit 1 and 2
    2)Mature newborn ≥ 37 weeks of gestation, age ≥ 3 wks and < 2y
    or
    Infants and children (≥ 2 y and < 18 y)
    or
    Adults (≥18 and ≤30 y)
    or
    Previously preterm (≤ 37 weeks of gestation) babies or children and adults of all ages if chILD genetically diagnosed (see inclusion criterion 3.)
    3) Diagnosis of chronic (≥ 3 wks of duration) diffuse parenchymal lung disease (DPLD = chILD), defined in at least one of the following ways:
    a) chILD genetically diagnosed
    Surfactant dysfunction disorders including patients with mutations in SFTPC, SFTPB, ABCA3, TTF1 (Nkx2-1), further extremely rare entities with specific mutations, for example in TBX4, NPC2, NPC1, NPB, COPA, LRBA and other genes. In this case, also previously preterm (≤ 37 weeks of gestation) babies or children and adults of all ages can be included into the study.
    b) chILD histologically diagnosed
    • Chronic pneumonitis of infancy (CPI)
    • Desquamative interstitial pneumonia (DIP)
    • Lipoid pneumonitis / Cholesterol pneumonia
    • Nonspecific interstitial pneumonia (NSIP)
    • PAP after the exclusion of mutations in GMCSF-Ra/b and GMCSF autoantibodies*
    • Usual interstitial pneumonia (UIP)
    • Follicular bronchitis/ bronchiolitis/ Lymphogenic interstitial pneumonia (LIP)
    • Storage disease with primary pulmonary involvement (e.g. Nieman Pick)
    • Hermansky Pudlak Syndrome
    • Idiopathic pulmonary haemorrhage (haemosiderosis)*
    • Other histology diagnosing chILD, in particular combination of the above pattern, but not exclusively
    4) Start block: no HCQ treatment in the last 12 weeks
    Stop block: stable HCQ treatment for at least the last 12 weeks
    5) Ability of subject or/and legal representatives to understand character and individual consequences of clinical trial.
    6) Signed and dated informed consent of the subject (if the subject has the ability) and the representatives (of underaged children) must be available before start of any specific trial procedures.
    1) Los pacientes deberían encontrarse clinicamente estables durante el periodo inicial (entre la visita 1 -2) para la inclusión en el estudio.
    a) Para su determinación, los médicos pueden usar SpO2 en pacientes que se encuentren en habitaciones al aire libre o aquellos que necessiten suplementación de oxigeno. La diferencia absoluta para SpO2 no se prevee que sea ≥ 5% entre la visita 1 y 2. Para pacientes con asistencia respiratòria, los parametros claves resuminos no deben cambiar ≥ 20% entre la visita 1 y 2.
    Además,
    b) Que no existan cambios importante en otras medicaciones entre la visita 1 y 2.

    2) Recién nacidos maduros (≥ 37 semanas de gestación, edad ≥ 3 semanas y < de 2 años) o bebes y ninos (≥ 2 años y < 18 años) o adultos (≥18 y ≤30 años).
    También, para el caso de bebes pre-términos (≤ 37 semanas de gestación) o ninos y adultos de todas las edades, si han sido diagnosticados geneticamente para chILD (ver criterio de inclusión 3)

    3) Diagnostico de Enfermedad pulmonar parenquimatosa difusa (DPLD= chILD) crònica (≥ 3 semanas de duración), descrito en, al menos, una de las siguientes formas:
    a) Diagnosticado geneticamente para chILD, definiéndose ello como: mutaciones en SFTPC, SFTPB, ABCA3, TTF1 (Nkx2-1), mutacions específicas en pacientes con enfermedades extremadamente rares (por ejemplo: mutaciones en TBX4, NPC2, NPC1, NPB, COPA, LRBA y otros genes). En este caso, estos pacientes podran ser incuidos dentro del estudio.
    b) Historial diagnostico para chILD, a partir de las siguientes afecciones:
    • Neumonia crònica infantil (CPI)
    • Neumonía insterticial descamativa (DIP)
    • Neumonitis lipoidea / Neumonia por colesterol
    • Neumonia intersticial no especifica (NSIP)
    • PAP después de la exclusión de mutaciones en GMCSF-Ra/b y GMCSF auto-anticuerpos*
    • Neumonía intersticial común (UIP)
    • Follicular bronchitis/ bronchiolitis/ Lymphogenic interstitial pneumonia (LIP)
    • Enfermedad de almacenamiento con pariticipación primaria pulmonar (e.g. Nieman Pick)
    • Síndrome Hermansky Pudlak
    • Hemorragia pulmonar idiopática (haemosiderosis)*
    • otro tipo de historial diagnostico para chILD, a través de la combinación de las afecciones arriba comentada, però no solo exclusivamente por estas.
    4) Bloque START: los pacientes no pueden haber sido tratados con HCQ en las últimes 12 semanas.
    El bloque STOP: Los pacientes deben de haber tenido un tratamiento estable de HCQ por, al menos, las 12 últimas semanas.
    5) Capacidad del sujeto y/o representante legal para entender la naturaleza y las consecuencias del ensayo clínico.
    6) Firma y fecha del consentimiento informado por el paciente (si el paciente puede realizar ello) y el representante (en caso de menores de edad) debe ser estar disponible antes de començar cualquier actividad expecífica del procedimiento del ensayo.
    E.4Principal exclusion criteria
    Subjects presenting with any of the following criteria will not be included in the trial:
    - chILD primarily related to developmental disorders
    - chILD primarily related to growth abnormalities reflecting deficient alveolarisation
    - hILD related to chronic aspiration
    - chILD related to immunodeficiency
    - chILD related to abnormalities in lung vessel structure
    - chILD related to organ transplantation/organ rejection/GvHD
    - chILD related to recurrent infections
    - Acute severe infectious exacerbations
    - Known hypersensitivity to HCQ, or other ingredients of the tablets (lactose-monohydrate, povidone, maize starch, magnesium stearate, hypromellose, macrogol or titanium dioxide (E 171), silicon dioxide or mannitol), to sucrose-octaacetate or sodium saccharine.
    - Proven retinopathy or maculopathy
    - Glucose-6-phosphate-dehydrogenase deficiency resulting in favism or hemolytic anemia
    - Myasthenia gravis
    - Hematopoetic disorders
    - Pregnancy and lactation (Women with childbearing potential have to practice a medically accepted contraception during trial and till three months after the end of the treatment with HCQ, and a negative pregnancy test (serum or urine) should be existent on Visit 1, if girls of childbearing age and only if sexual relations are known or probable. It is at the discretion and responsibility of the attending physician to decide, whether a pregnancy test is necessary or not. Reliable contraception are systematic contraceptives (oral, implant, injection). Women that are sterile by surgery can participate in the trial. At the discretion of the investigator, sexual abstinence is also accepted as contraceptive method. Girls after menarche have to receive a counselling about birth control methods in presence of at least one parent, which has to be documented in the patient notes.
    - Participation in other clinical trials during the present clinical trial or not beyond the time of 4 half-lives of the medication used, at least one week.
    - Hereditary galactose intolerance, lactase deficiency or glucose-galactose-malabsorption
    - Renal insufficiency at screening, defined as glomerular filtration rate (GFR)
    o < 40 mL/min/1.73 m2 in patients age 3 to 8 weeks
    o < 60 mL/min/1.73 m2 in patients ≥ 8 weeks of Age (KDIGO guideline 2012, K/DOQI guideline 2002)
    - Liver disease, gastrointestinal disorder, haematological disorder, epilepsy or other neurological disorder, psoriasis, porphyria at the discretion of the treating physician
    - Simultaneous prescription of other potentially nephrotoxic or hepatotoxic medication at the discretion of the treating physician
    Los sujetos que presenten alguno de los sigueintes criterios no seran incluidos en el ensayo:
    1) chILD relacionado primordialmente con trastornos del desarrollo.
    2) chILD relacionado primordialmente con anormalidades en el crecimiento reflejado en una deficiència de la alveolarización.
    3) chILD relacionado primordialmente con aspiración crònica
    4) chILD relacionado primordialmente con inmunodeficiencia
    5) chILD relacionado primordialmente con anormalidades en la estructura de los vasos pulmonares
    6) chILD relacionado primordialmente con trasplante de órganos/ rechazo de órganos/ GvHD
    7) chILD relacionado primordialmente con infección concurrente
    8) Exacerbación de una infección aguda grave.
    9) Conocimiento de hipersensibilidad a HCQ u otro excipiente de la cápsula a utilizar en el ensayo como HCQ (lactosa-monohidrato, povidona, almidón de maíz, estearato magnésico, hipromelosa, macrogol o dióxido de titanio (E-171), dióxido de silicona o manitol), o también a octoacetato de sacarosa o sacarina sódica.
    10) Retinopatía o maculopatía probada.
    11) Deficiencia de glucosa-6-fosfato-dihidrogenasa (favism) o anemia hemolítica
    12) Miastenia grave
    13) Desordenes hematopoyético
    14) Embarazo y lactancia (mujeres en edad fértil o potencialmente fértil tienen que aceptar un método anticonceptivo durante el ensayo y hasta 3 meses después de la finalización del tratamiento con HCQ. Además, un resultado negativo en la prueba de embarazo (por serum u orina) debe de existir en la visita 1, en aquellas chicas en edad fértil y que se conozca o sea probable las relaciones sexuales. El uso del test de embarazo queda bajo consideración del médico, si debe usarse o no. Los anticonceptivos más viables son: anticonceptivos sistemáticos (orales, implantados, inyectados). En el caso de mujeres estériles quirúrgicamente pueden participar en el ensayo. El método anticonceptivo de la no práctica sexual de los participante queda bajo consideración del médico si quiere usarse o no. Las niñas después de adquirir la menstruación tienen que recibir asesoramiento sobre métodos de control del embarazo, en presencia de al menos, uno de los padres, quedando ello recogido en la historia clínica del paciente.
    15) Participación en otros ensayos clínicos durante el tiempo de este ensayo, o que no haya pasado un tiempo más allá de 4 vidas medias del medicamento que se utilizó en el anterior ensayo (al menos 1 semana).
    16) Intolerancia hereditaria a la galactosa, deficiencia de lactosa o mala absorción de glucosa-galactosa.
    17) Insuficiencia renal en el screening, definido ello a partir de una tasa de infiltración glomerular (GFR) de: o < 40 mL/min/1.73 m2 en pacientes con una edad de entre 3-8 semanas o < 60 mL/min/1.73 m2 en pacientes ≥ 8 semanas de edad (guía KDIGO 2012, guia K/DOQI 2002)
    18) Desorden gastrointestinal, enfemerdad hepàtica, desorden hematologico, epilèpsia u otra ptología neurològica, psoriasis, porfíria considerada por el medico que esté tratando.
    19) Prescripción simultanea de otros medicamentos neurotóxicos o hepatotóxicos, a criterio del medico.
    E.5 End points
    E.5.1Primary end point(s)
    START HCQ block
    Relative change trial day 1 (i.e. Visit 2) through day 28 (i.e. Visit 3) and relative change day 28 to day 56, (i.e. Visit 4): change active compound compared to change placebo

    STOP HCQ block
    Relative change trial day 1 (i.e. Visit 2) through day 84 (i.e. Visit 5): change active compound compared to change placebo
    Bloque START HCQ
    Cambio relativo desde el día 1 del estudio (Visita 2) hasta el día 28 (Visita 3) y cambio relativo del día 28 al día 56 (Visita 4): cambio observado con tratamiento activo en comparación con el cambio observado con placebo.
    Bloque STOP HCQ
    Cambio relativo en la oxigenación desde el día 1 (Visita 2) hasta el día 84 (Visita 5): cambio observado con tratamiento activo en comparación con el cambio observado con placebo.
    E.5.1.1Timepoint(s) of evaluation of this end point
    28/56 / 84 days
    28/56 / 84 días
    E.5.2Secondary end point(s)
    - For both, START and STOP HCQ blocks absolute and relative change under the active compound from trial day 1 (i.e. Visit 2), to START block: day 28 (i.e. Visit 3), STOP block: day 84 (i.e. Visit 5) each, will be compared to change under placebo. The following variables will be investigated:

    - Oxygen saturation (O2-sat, in room air) (only absolute, as relative already primary outcome)
    - Respiratory rate (RR, in room air) (relative and absolute)

    - Retractions (yes/no)
    - Coughing (yes/no)
    - Oxygen demand

    - pO2, pCO2 (capillary, in room air)
    - Chest x-ray
    - Quality-of-life
    - Health economics
    - Overall survival
    - Weight for height
    - Cumulative amounts of steroid equivalents. Clinical course of lung disease (since last visit): Healthy/ Sick-better/ Sick-same/ Sick-worse/ Patient died
    - Pulmonary exacerbation (since last visit)
    If > 5y old (If a child ≤ 5 years is already able to perform the listed investigations (spirometry or bodyplethysmography), these should also be performed and documented at the discretion of the investigator.)
    The following lung function parameters will be assessed:
    FEV1 % predicted (recorded in L), FEV 1 (L), FVC % predicted (recorded in L), FVC (L); MEF 75 (L/s); MEF 50 (L/s); MEF 25 (L/s); TLC (L); ITGV (L); RV (L); R eff (kPa*s/L); R eff predicted (%).
    reference values according to the GLI 2012 lung function regression equations

    - 6 minute walking distance (meter)
    - O2-saturation before and after 6MWT
    - Borg scale

    - If ventilated:
    Duration (h) of mechanical ventilation
    NO (%), ECMO yes/no, if yes VA/VV, double lumen vs. single lumen, Flow-rate.

    - Safety monitoring
    Adverse events, clinical laboratory values (GOT, Creatinine, gGT, blood count, differential, LDH, potassium, steady state drug level), ECG, ophthalmologic review
    Cambio absoluto y cambio relativo, desde el día 1 del estudio (Visita 2) al día 28 para el bloque HCQ START, y desde el día 1 del estudio al día 84 (Visita 5) para el bloque HCQ STOP: cambio observado con tratamiento activo en comparación con el cambio observado con placebo. Se investigará el cambio en los siguientes parámetros:
    • Saturación de oxígeno (sólo cambio absoluto, el cambio relativo es el criterio de valoración principal)
    • Frecuencia respiratoria
    • Retracciones, tos
    • Demanda de oxígeno
    • pO2, pCO2
    • Radiografía de tórax
    • Calidad de vida
    • Economía de la salud
    • Supervivencia global
    • Peso por altura
    • Cantidades acumulativas de equivalentes de esteroides
    • Exacerbaciones pulmonares
    Si el paciente tiene > 5 años:
    • Parámetros de la espirometría o pletismografía corporal
    • Test de la marcha de los 6 minutos (TM6M): distancia y saturación de O2 antes y después del test
    • Escala de Borg
    Parámetros de seguridad
    • Acontecimientos adversos
    • Parámetros de laboratorio
    • Anormalidades en el ECG
    • Anormalidades oftalmológicas
    E.5.2.1Timepoint(s) of evaluation of this end point
    56 / 84 days
    56 / 84 días
    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 Yes
    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) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    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 EEA90
    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
    Austria
    Italy
    Poland
    Portugal
    Spain
    Turkey
    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
    última visita, último paciente
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years0
    E.8.9.1In the Member State concerned months36
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years0
    E.8.9.2In all countries concerned by the trial months36
    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: 80
    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) Yes
    F.1.1.3.1Number of subjects for this age range: 5
    F.1.1.4Infants and toddlers (28 days-23 months) Yes
    F.1.1.4.1Number of subjects for this age range: 10
    F.1.1.5Children (2-11years) Yes
    F.1.1.5.1Number of subjects for this age range: 30
    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) Yes
    F.1.2.1Number of subjects for this age range: 20
    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 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 Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    Subjects in this trial are mostly children, consent of both legally authorized representatives must be sought, Children who are able to understand nature, scope, and possible consequences of the clinical trial must also give their informed consent.
    Los paciente son principalmente niños donde el consentimiento de ambos representantes legales debe de ser buscado. Aquellos que puedan entender la naturaleza, objetivo y posibles consecuencias del estudio deben de obtener un consentimiento informado.
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state80
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 80
    F.4.2.2In the whole clinical trial 80
    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)
    According to Standard- of-Care
    De acuerdo a la práctica clínica habitual
    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 Decision2019-01-17
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-12-21
    P. End of Trial
    P.End of Trial StatusTemporarily Halted
    As of 1.2.2020, the UK is no longer an EU Member State. However, EU law still applies to the UK during the transition period
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