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    Summary
    EudraCT Number:2015-000716-18
    Sponsor's Protocol Code Number:CCD-05993AB1-03
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2015-12-10
    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 number2015-000716-18
    A.3Full title of the trial
    A 52 week, randomized, double blind, multinational, multicentre, active controlled, 2-arm parallel group trial comparing CHF 5993 100/6/12.5 µg pMDI (fixed combination of extrafine beclometasone dipropionate plus formoterol fumarate plus glycopyrronium bromide) to CHF 1535 100/6 µg pMDI (fixed combination of extrafine beclomethasone dipropionate plus formoterol fumarate) in patients with asthma uncontrolled on medium doses of inhaled corticosteroids in combination with long-acting ß2-agonists
    Ensayo de 52 semanas, aleatorizado, doble ciego, multinacional, multicéntrico, con control activo, de 2 grupos paralelos que compara CHF 5993 100/6/12,5 µg por pMDI (combinación fija de dipropionato de beclometasona extrafino más fumarato de formoterol más bromuro de glicopirronio) con CHF 1535 100/6 µg por pMDI (combinación fija de dipropionato de beclometasona extrafino más fumarato de formoterol) en pacientes con asma no controlado con dosis medias de corticosteroides inhalados en combinación con agonistas de la ß2 de acción prolongada
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A research study to evaluate the effect of a new fixed triple combination of beclometasone dipropionate + formoterol fumarate + glycopyrronium bromide at medium dose in patients with uncontrolled asthma.
    Un estudio de investigación para evaluar el efecto de una nueva combinación fija combinada de dipropionato de beclometasona + fumarato de formoterol + bromuro de glicopirronio con asma no controlado con dosis medias.
    A.3.2Name or abbreviated title of the trial where available
    Trimaran
    A.4.1Sponsor's protocol code numberCCD-05993AB1-03
    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 SponsorChiesi Farmaceutici S.p.A.
    B.1.3.4CountryItaly
    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 supportChiesi Farmaceutici S.p.A.
    B.4.2CountryItaly
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationChiltern International Spain SA
    B.5.2Functional name of contact pointRicardo Diaz - Manager Director
    B.5.3 Address:
    B.5.3.1Street AddressCentro Empresarial Euronova 3, Ronda de Poniente 10, 2ª Planta
    B.5.3.2Town/ cityTres Cantos (Madrid)
    B.5.3.3Post code28760
    B.5.3.4CountrySpain
    B.5.4Telephone number+34911872700
    B.5.5Fax number+34911872849
    B.5.6E-mailspain.regulatory@chiltern.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 nameCHF 5993 pMDI
    D.3.2Product code CHF 5993
    D.3.4Pharmaceutical form Pressurised inhalation, solution
    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.3.8INN - Proposed INNBECLOMETASONE DIPROPIONATE
    D.3.9.1CAS number 5534-09-8
    D.3.9.3Other descriptive nameBDP
    D.3.9.4EV Substance CodeSUB00681MIG
    D.3.10 Strength
    D.3.10.1Concentration unit µg microgram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number100
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNFORMOTEROL FUMARATE
    D.3.9.1CAS number 43229-80-7
    D.3.9.3Other descriptive nameFF
    D.3.9.4EV Substance CodeSUB02257MIG
    D.3.10 Strength
    D.3.10.1Concentration unit µg microgram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number6
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNGLYCOPYRRONIUM BROMIDE
    D.3.9.1CAS number 596-51-0
    D.3.9.3Other descriptive nameGB
    D.3.9.4EV Substance CodeSUB07951MIG
    D.3.10 Strength
    D.3.10.1Concentration unit µg microgram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number12.5
    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 RoleComparator
    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 Foster
    D.2.1.1.2Name of the Marketing Authorisation holderChiesi Farmaceutici S.p.A.
    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 nameFoster
    D.3.2Product code CHF 1535
    D.3.4Pharmaceutical form Pressurised inhalation, solution
    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.3.8INN - Proposed INNBECLOMETASONE DIPROPIONATE
    D.3.9.1CAS number 5534-09-8
    D.3.9.3Other descriptive nameBDP
    D.3.9.4EV Substance CodeSUB00681MIG
    D.3.10 Strength
    D.3.10.1Concentration unit µg microgram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number100
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNFORMOTEROL FUMARATE
    D.3.9.1CAS number 43229-80-7
    D.3.9.3Other descriptive nameFF
    D.3.9.4EV Substance CodeSUB02257MIG
    D.3.10 Strength
    D.3.10.1Concentration unit µg microgram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number6
    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
    Uncontrolled asthma
    Asma no controlado
    E.1.1.1Medical condition in easily understood language
    Uncontrolled asthma
    Asma no controlado
    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 18.1
    E.1.2Level PT
    E.1.2Classification code 10003553
    E.1.2Term Asthma
    E.1.2System Organ Class 10038738 - Respiratory, thoracic and mediastinal 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 CHF 5993 100/6/12.5 pMDI compared to CHF 1535 100/6 pMDI in terms of change from baseline in pre-dose FEV1 at Week 26.
    - To demonstrate the reduction of moderate and severe asthma exacerbations rate with CHF 5993 100/6/12.5 pMDI compared to CHF 1535 100/6 pMDI during the entire 52-week treatment period.
    - Demostrar la superioridad de CHF 5993 100/6/12,5 por pMDI en comparación con CHF 1535 100/6 por pMDI en términos de cambio desde el inicio en el volumen espiratorio forzado (FEV1) previo a la dosis en la semana 26.
    - Demostrar la reducción de la tasa de exacerbaciones del asma moderadas e intensas con CHF 5993 100/6/12,5 por pMDI en comparación con CHF 1535 100/6 por pMDI durante todo el período de tratamiento de 52 semanas.
    E.2.2Secondary objectives of the trial
    Key Secondary Objectives:
    - To demonstrate the superiority of CHF 5993 100/6/12.5 pMDI compared to CHF 1535 100/6 pMDI in terms of change from baseline in peak FEV1 within 3 hours post-dose at Week 26.
    - To demonstrate the superiority of CHF 5993 100/6/12.5 compared to CHF 1535 100/6 in terms of change from baseline in morning PEF averaged over 26-week treatment period.
    - To demonstrate the reduction of severe asthma exacerbations rate with CHF 5993 100/6/12.5 pMDI compared to CHF 1535 100/6 pMDI during the entire 52-week treatment period in the pooled analysis of CCD-05993AB1-03 and CCD-05993AB2-02 trials.

    Secondary Objectives
    - To perform a population PK analysis (in a subset of patients treated with CHF 5993 pMDI) investigating the inter-subject variability in the drug exposure and the effects of selected covariates on PK parameters of BDP, FF and GB.
    - To assess the safety and tolerability of the study treatments.
    Objetivos secundarios clave
    - Demostrar la superioridad de CHF 5993 100/6/12,5 por pMDI en comparación con CHF 1535 100/6 por pMDI en términos de cambio desde el inicio en el FEV1 máximo en las 3 h siguientes a la dosis en la semana 26.
    - Demostrar la superioridad de CHF 5993 100/6/12,5 en comparación con CHF 1535 100/6 en términos de cambio desde el inicio en el FEM matutino promediado a lo largo del período de tratamiento de 26 semanas.
    - Demostrar la reducción de la tasa de exacerbaciones intensas del asma con CHF 5993 100/6/12,5 por pMDI en comparación con CHF 1535 100/6 por pMDI durante todo el período de tratamiento de 52 semanas en el análisis combinado de los ensayos CCD 05993AB1-03 y CCD-05993AB2-02.
    Objetivos secundarios:
    - Evaluar la seguridad y la tolerabilidad de los tratamientos del estudio.
    - Realizar un análisis FC de la población en un subconjunto de pacientes tratados con CHF 5993 investigando la variabilidad interindividual en la exposición al (..)
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Patient' s written informed consent obtained prior to any study-related procedures.
    2. Male or female patients aged greater than or equal to 18 and ≤75 years.
    3. Patients must have a documented history of asthma for at least 1 year and asthma must have been diagnosed before the patient's age of 40.
    4. Patients with uncontrolled asthma with double therapy only on medium doses of ICS in combination with a β2 long-acting bronchodilator (>500-1000 daily dose BDP non-extrafine or estimated clinical comparable dose plus formoterol 24 µg or salmeterol 100 µg or vilanterol 25 µg) at a stable dose for at least 4 weeks prior to screening.
    5. Patients with a pre-bronchodilator FEV1 <80% of their predicted normal value, after appropriate washout from bronchodilators, at the screening and randomization visits.
    6. Patients with a positive response to a reversibility test at screening, defined as ΔFEV1>12% and >200mL over baseline 10-15 minutes after inhaling 400 µg of salbutamol pMDI.
    7. Patients with uncontrolled asthma evidenced by a score at the Asthma Control Questionnaire 7 © (ACQ-7) ≥1.5 (this criterion must be met at screening and at the end of the run-in period).
    8. A documented history of one or more asthma exacerbations requiring treatment with systemic corticosteroids or emergency department visit or in-patient hospitalization in the previous 12 months.
    9. A co-operative attitude and ability:
    - to be trained to correctly use the pMDI inhalers;
    - to perform all trial related procedures including technically acceptable pulmonary function tests;
    - to correctly use the electronic diary/peak flow meter.
    1. Consentimiento informado por escrito del paciente obtenido antes de cualquier procedimiento relacionado con el estudio.
    2. Pacientes de sexo masculino o femenino ≥ 18 y ≤ 75 años.
    3. Los pacientes deben tener antecedentes documentados de asma durante al menos 1 año y el asma debe haber sido diagnosticada antes de que el paciente cumpliese 40 años.
    4. Pacientes con asma no controlada con tratamiento doble solo de dosis medias de corticosteroides inhalados (ICS) en combinación con un broncodilatador β2 de acción prolongada (dosis diaria > 500-1000 μg de DPB no extrafino o dosis clínica comparable estimada más formoterol 24 μg o salmeterol 100 μg o vilanterol 25 µg) a una dosis estable durante, al menos, 4 semanas antes de la selección.
    5. Pacientes con un volumen espiratorio forzado (FEV1) antes del broncodilatador < 80 % de su valor normal previsto, después de un reposo farmacológico adecuado de los broncodilatadores, en las visitas de selección y aleatorización.
    6. Pacientes con una respuesta positiva a una prueba de reversibilidad en la selección, definida como ΔFEV1 > 12 % y > 200 ml a lo largo de los 10-15 minutos iniciales después de inhalar 400 μg de salbutamol por pMDI.
    Nota: En caso de que no se cumpla en umbral de reversibilidad en la selección, se puede repetir la prueba una vez antes de la aleatorización.
    7. Pacientes con asma no controlada evidenciado por una puntuación en el Asthma Control Questionnaire 7© (ACQ-7) ≥ 1,5 (este criterio debe cumplirse en la selección y al final del período de preinclusión).
    8. Antecedentes documentados de una o más exacerbaciones del asma que requiriesen tratamiento con corticosteroides sistémicos, una visita al servicio de urgencias o la hospitalización del sujeto en los 12 meses anteriores.
    9. Capacidad y actitud de cooperación:
    - para recibir formación sobre el uso correcto de los inhaladores pMDI;
    - para realizar todos los procedimientos relacionados con el ensayo, incluidas pruebas de la función pulmonar aceptables técnicamente;
    - para usar correctamente el diario electrónico/medidor de flujo máximo.
    E.4Principal exclusion criteria
    1. Inability to carry out pulmonary lung function testing, to comply with study procedures or with study treatment intake.
    2. Run-in compliance < 50% at randomisation.
    3. History of near fatal asthma or of a past hospitalisation for asthma in intensive care unit which, in the judgement of the investigator, may place the patient at undue risk.
    4. Hospitalisation, emergency room admission or use of systemic corticosteroids for an asthma exacerbation in the 4 weeks prior to screening visit or during the run-in period.
    5. Patients with any asthma exacerbation or respiratory tract infection in the 4 weeks prior to the screening visit or during run-in period.
    6. Any change in dose, schedule or formulation of the combination ICS plus LABA in the 4 weeks prior to screening visit.
    7. Patients using systemic corticosteroid medication in the 4 weeks prior to screening or slow release corticosteroids in the 12 weeks before screening.
    8. Patients who suffer from COPD as defined by the current GOLD guidelines.
    9. History of a diagnosis of cystic fibrosis, bronchiectasis or alpha-1 antitrypsin deficiency, or any other significant lung disease which may interfere with study evaluations.
    10. Current smokers or ex-smokers with total cumulative exposure equal or more than 10 pack-years or having stopped smoking one year or less prior to screening visit.
    11. Patients who have clinically significant cardiovascular condition according to investigator's judgement
    12. An abnormal and clinically significant 12-lead ECG that results in active medical problem which may impact the safety of the patient according to investigator's judgement.
    13. Patients whose electrocardiogram (12-lead ECG) shows QTcF >450 ms for males or QTcF >470 ms for females at screening or at randomisation visits (criterion not applicable for patient with pacemaker or permanent atrial fibrillation).
    14. Patients with a medical history or current diagnosis of narrow-angle glaucoma, symptomatic prostatic hypertrophy, urinary retention bladder neck obstruction that, in the opinion of the investigator, would prevent use of anticholinergic agents.
    15. Other severe acute or chronic medical or malignancy or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or study drug administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the subject inappropriate for entry into this study.
    16. Patients having received a vaccination within 2 weeks prior to screening or during the run-in.
    17. Patients mentally or legally incapacitated, or patients accommodated in an establishment as a result of an official or judicial order.
    18. Patients with a history of alcohol or drug abuse within two years prior to the start of the study.
    19. Patients with known intolerance/hypersensitivity or contra-indication to treatment with ß2-agonists, inhaled corticosteroids, anticholinergics or propellant gases/excipients.
    20. Patients with major surgery in the 3 months prior to screening visit or planned surgery during the trial.
    21. Patients treated with non-potassium sparing diuretics (unless administered as a fixed-dose combination with a potassium conserving drug or changed to potassium sparing before the screening), non-selective beta-blocking drugs, quinidine, quinidine-like anti arrhythmics, or any medication with a QTc prolongation potential or a history of QTc prolongation.
    22. Patients treated with monoamine oxidase inhibitors (MAOIs) and tricyclic antidepressants.
    23. Patients being treated with monoclonal antibodies (e.g. anti-IgE or anti-IgG antibodies) or biological drugs.
    24. Patients who are receiving any therapy that could interfere with the study drugs according to investigator's opinion.
    25. Pregnant or lactating women and all women physiologically capable of becoming pregnant (i.e. women of childbearing potential) unless are willing to use one or more highly effective contraceptive measures.
    26. Patients who have received an investigational drug within 2 months or six half-lives (whichever is greater) prior to screening visit, or have been previously randomized in this trial, or are currently participating in another clinical trial.
    1. Incapacidad de llevar a cabo pruebas de función pulmonar, cumplir con los procedimientos del estudio o con el consumo del tratamiento del estudio.
    2. Cumplimiento de la preinclusión < 50 % en la aleatorización.
    3. Antecedentes de asma casi mortal o de una hospitalización anterior por asma en una unidad de cuidados intensivos que, a criterio del investigador, pueden poner al paciente en una situación de riesgo indebido.
    4. Hospitalización, ingreso en urgencias o uso de corticosteroides sistémicos para una exacerbación del asma en las 4 semanas previas a la visita de selección o durante el período de preinclusión.
    5. Pacientes con cualquier exacerbación del asma o infección de las vías respiratorias en las 4 semanas previas a la visita de selección o durante el período de preinclusión.
    6. Cualquier cambio en la dosis, programación o formulación de la combinación de ICS más LABA en las 4 semanas previas a la visita de selección.
    7. Pacientes que utilicen corticosteroides sistémicos en las 4 semanas previas a la selección o corticosteroides de liberación lenta en las 12 semanas previas a la selección.
    8. Pacientes que sufran EPOC, tal como se define en las directrices GOLD vigentes.
    9. Antecedentes de diagnóstico de fibrosis quística, bronquiectasia, deficiencia de alfa-1 antitripsina o cualquier otra enfermedad pulmonar importante que pueda interferir con las evaluaciones del estudio.
    10. Fumadores actuales o exfumadores con una exposición acumulativa total igual o superior a 10 cajetillas-año o que han dejado de fumar un año o menos antes de la visita de selección.
    11. Pacientes que tienen una enfermedad cardiovascular clínicamente significativa de acuerdo con el criterio de investigador.
    12. Un ECG de 12 derivaciones anómalo y clínicamente significativo que tiene como consecuencia un problema médico activo que puede afectar a la seguridad del paciente de acuerdo con el criterio del investigador.
    13. Pacientes cuyo electrocardiograma (ECG de 12 derivaciones) muestre un intervalo QTcF [fridericia - QTc corregido] > 450 ms en el caso de los hombres o un intervalo QTcF > 470 ms en el caso de las mujeres en las visitas de selección o aleatorización (criterio no aplicable para pacientes con un marcapasos o una fibrilación auricular permanente).
    14. Pacientes con antecedentes médicos o diagnóstico actual de glaucoma de ángulo cerrado, hipertrofia prostática sintomática u obstrucción del cuello vesical que provoca retención urinaria que, en opinión del investigador, impedirían el uso de agentes anticolinérgicos.
    15. Otra anomalía de laboratorio o afección médica, neoplásica o psiquiátrica grave, aguda o crónica que pueda aumentar el riesgo asociado con la participación en el estudio o con la administración del medicamento del estudio o pueda interferir con la interpretación de los resultados del estudio y, a criterio del investigador, haría que el sujeto resultase inadecuado para incorporarse a este estudio.
    16. Pacientes que han recibido una vacuna en las 2 semanas previas a la selección o durante la preinclusión.
    17. Pacientes discapacitados metal o legalmente, o pacientes alojados en una institución como resultado de una orden judicial u oficial.
    18. Pacientes con antecedentes de abuso del alcohol o las drogas en los dos años previos al comienzo del estudio.
    19. Pacientes con intolerancia/hipersensibilidad conocida o contraindicación respecto al tratamiento con agonistas ß2, corticosteroides inhalados, anticolinérgicos o excipientes/gases propulsores.
    20. Pacientes que se realizaron una cirugía mayor en los 3 meses previos a la visita de selección o tienen una cirugía planificada durante el ensayo.
    21. Pacientes tratados con diuréticos no ahorradores del potasio (salvo que se administren como una combinación de dosis fija con un medicamento conservador del potasio o cambien a un ahorrador del potasio antes de la selección), medicamentos betabloqueantes no selectivos, quinidina, antiarrítmicos similares a la quinidina o cualquier medicamento con un potencial de prolongación del intervalo QTc o antecedentes de prolongación del intervalo QTc.
    22. Pacientes tratados con MAOI y antidepresivos tricíclicos.
    23. Pacientes tratados con anticuerpos monoclonales (p. ej., anticuerpos anti-IgE o anti-IgG) o medicamentos biológicos.
    24. Pacientes que reciben cualquier tratamiento que podría interferir con los medicamentos del estudio, de acuerdo con la opinión del investigador.
    25. Mujeres embarazadas o que estén amamantando y todas las mujeres fisiológicamente capaces de quedar embarazadas (es decir, mujeres con capacidad para tener hijos) SALVO que estén usando uno o más de los siguientes métodos anticonceptivos de elevada eficacia.
    26. Pacientes que han recibido un medicamento en fase de investigación en los 2 meses o seis semividas (lo que sea superior) previos a la visita de selección, o que han sido previamente aleatorizados en este ensayo, o están participando en otro(..)
    E.5 End points
    E.5.1Primary end point(s)
    - Change from baseline in pre-dose FEV1 at Week 26
    - Moderate and severe exacerbations rate over 52 weeks of treatment
    - Cambio desde el inicio en el volumen espiratorio forzado (FEV1) previo a la dosis en la semana 26.
    - Exacerbaciones del asma moderadas e intensas durante todo el período de tratamiento de 52 semanas.
    E.5.1.1Timepoint(s) of evaluation of this end point
    26 weeks and 52 weeks
    Semana 26 y semana 52.
    E.5.2Secondary end point(s)
    - Change from baseline in peak FEV1 (within 3 hours post dosing) at Week 26.
    - Change from baseline in morning PEF measured by patients at home over the 26-week treatment period.
    - Severe exacerbations rate over 52 weeks of treatment in a pre-specified pooled analysis of the two pivotal studies CCD-5993AB1-03 and CCD-05993AB2-02
    - PK analysis
    - Safety variables, AEs, ADRs
    - Cambio desde el inicio en el volumen espiratorio forzado máximo (FEV1 máximo) en las 3 horas siguientes a la dosis en la semana 26.
    - Exacerbaciones intensas del asma durante todo el período de tratamiento de 52 semanas en el análisis combinado de los ensayos CCD 05993AB1-03 y CCD-05993AB2-02.
    - Análisis farmacocinético
    - Variables de seguridad, AAs, ADRs
    E.5.2.1Timepoint(s) of evaluation of this end point
    26 weeks and 52 weeks
    Plasma levels measured in week 4 & 40
    Safety throughout the study
    Semana 26 y semana 52
    Medidas de niveles de plasma en la semana 4 y 40
    Seguridad a lo largo del estudio
    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 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 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) Yes
    E.8.2.2Placebo No
    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 concerned6
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA134
    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
    Argentina
    Belarus
    Bulgaria
    Czech Republic
    Germany
    Hungary
    Italy
    Korea, Republic of
    Lithuania
    Poland
    Portugal
    Romania
    Russian Federation
    Slovakia
    Spain
    Ukraine
    United Kingdom
    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 del último paciente
    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 months4
    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 months4
    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 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: 861
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 287
    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 state24
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 708
    F.4.2.2In the whole clinical trial 1148
    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)
    Before discharge, the investigator will prescribe the most appropriate treatment or restore the initial therapy or refer to the General Practitioner.
    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 Decision2016-02-10
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2016-01-08
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2018-05-17
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