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    Summary
    EudraCT Number:2015-005444-33
    Sponsor's Protocol Code Number:D6571C00001
    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:2016-05-17
    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 number2015-005444-33
    A.3Full title of the trial
    A 24 week treatment, multicenter, randomized, double blinded, double dummy, parallel-group, clinical trial evaluating the efficacy and safety of aclidinium bromide 400 mcg/formoterol fumarate 12 mcg fixed-dose combination BID compared with each monotherapy (aclidinium bromide 400 mcg BID and formoterol fumarate 12 mcg BID) and tiotropium 18 mcg QD when administered to patients with stable chronic obstructive pulmonary disease.
    Ensayo clínico multicéntrico, aleatorizado, en doble ciego y con doble simulación, de grupos paralelos y 24 semanas de duración, para evaluar la eficacia y la seguridad de la combinación a dosis fijas de bromuro de aclidinio 400 mcg/formoterol fumarato 12 mcg dos veces al día en comparación con cada principio activo en monoterapia (bromuro de aclidinio 400 mcg dos veces al día y formoterol fumarato 12 mcg dos veces al día) y con tiotropio 18 mcg una vez al día en su administración a pacientes con enfermedad pulmonar obstructiva crónica estable.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A clinical trial to assess the efficacy and safety of aclidinium bromide 400 mcg/formoterol fumarate 12 mcg combination taken twice daily compared with each individual component (aclidinium bromide 400 mcg twice daily and formoterol fumarate 12 mcg twice daily) and tiotropium 18 mcg once daily when administered to patients with stable chronic obstructive pulmonary disease.
    Ensayo Ccínico para evaluar la eficacia y seguridad de una combinación de bromuro de aclidinio 400 mcg/formoterol fumarato 12 mcg tomadas dos veces/día comparada con cada componente individual (bromuro de aclidinio 400 mcg dos veces/día y formoterol fumarato 12 mcg dos veces/día) y tiotropio 18 mcg una vez al día cuando se administra a pacientes con enfermedad pulmonar obstructiva crónica estable.
    A.3.2Name or abbreviated title of the trial where available
    AMPLIFY
    A.4.1Sponsor's protocol code numberD6571C00001
    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 SponsorAstraZeneca AB
    B.1.3.4CountrySweden
    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 supportAstraZeneca AB
    B.4.2CountrySweden
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationAstraZeneca
    B.5.2Functional name of contact pointInformation Center
    B.5.3 Address:
    B.5.3.1Street Address-
    B.5.3.2Town/ city-
    B.5.3.3Post code-
    B.5.3.4CountryUnited States
    B.5.4Telephone number+34900162001
    B.5.6E-mailinformation.centre@astrazeneca.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Duaklir Genuair
    D.2.1.1.2Name of the Marketing Authorisation holderAstraZeneca AB
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    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 nameAclidinium bromide/Formoterol Fumarate 400/12 µg fixed-dose combination
    D.3.2Product code LAS40464
    D.3.4Pharmaceutical form Inhalation powder
    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 INNACLIDINIUM BROMIDE
    D.3.9.1CAS number 320345-99-1
    D.3.9.2Current sponsor codeLAS34273
    D.3.9.4EV Substance CodeSUB71687
    D.3.10 Strength
    D.3.10.1Concentration unit µg microgram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number400
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNFormoterol
    D.3.9.1CAS number 183814-30-4
    D.3.9.3Other descriptive nameFORMOTEROL FUMARATE DIHYDRATE
    D.3.9.4EV Substance CodeSUB25660
    D.3.10 Strength
    D.3.10.1Concentration unit µg microgram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number12
    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 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.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 Yes
    D.2.1.1.1Trade name Eklira Genuair
    D.2.1.1.2Name of the Marketing Authorisation holderAstraZeneca AB
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    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 nameAclidinium bromide 400 µg
    D.3.2Product code LAS34273
    D.3.4Pharmaceutical form Inhalation powder
    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 INNACLIDINIUM BROMIDE
    D.3.9.1CAS number 320345-99-1
    D.3.9.2Current sponsor codeLAS34273
    D.3.9.4EV Substance CodeSUB71687
    D.3.10 Strength
    D.3.10.1Concentration unit µg microgram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number400
    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 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.IMP: 3
    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 nameFormoterol Fumarate 12 µg
    D.3.4Pharmaceutical form Inhalation powder
    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 INNFormoterol
    D.3.9.1CAS number 183814-30-4
    D.3.9.3Other descriptive nameFORMOTEROL FUMARATE DIHYDRATE
    D.3.9.4EV Substance CodeSUB25660
    D.3.10 Strength
    D.3.10.1Concentration unit µg microgram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number12
    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 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.IMP: 4
    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 Spiriva Handihaler
    D.2.1.1.2Name of the Marketing Authorisation holderBoehringer Ingelheim Limited
    D.2.1.2Country which granted the Marketing AuthorisationUnited Kingdom
    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 nameTiotropium bromide 18 µg
    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.3.8INN - Proposed INNTIOTROPIUM BROMIDE
    D.3.9.1CAS number 136310-93-5
    D.3.9.4EV Substance CodeSUB11095MIG
    D.3.10 Strength
    D.3.10.1Concentration unit µg microgram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number18
    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 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
    D.8.4Route of administration of the placeboInhalation use
    D.8 Placebo: 2
    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
    Chronic obstructive pulmonary disease (COPD)
    Enfermedad pulmonar obstructiva crónica (EPOC)
    E.1.1.1Medical condition in easily understood language
    COPD is a chronic lung disease that causes shortness of breath and coughing.
    A bronchodilator helps to open your airways and makes it easier to get air in and out of the lungs.
    EPOC: enfermedad crónica de los pulmones que causa dificultad para respirar y tos. Un broncodilatador ayuda a abrir sus vías respiratorias y hace más fácil la entrada/salida de aire de los pulmones.
    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 19.0
    E.1.2Level LLT
    E.1.2Classification code 10010952
    E.1.2Term COPD
    E.1.2System Organ Class 100000004855
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Primary Objective for EU:
    To assess the non-inferior bronchodilation of AB 400 ?g BID as compared to TIO 18 ?g QD in COPD patients.

    Primary Objectives for USA:
    To assess the bronchodilatory effect of AB/FF 400/12 ?g compared to each individual component when administered twice daily via inhalation to COPD patients.
    Objetivo principal en la UE:
    Evaluar la ausencia de inferioridad de la broncodilatación con AB 400 mcg dos veces al día en comparación con TIO 18 mcg una vez al día en pacientes con EPOC.
    Objetivo principal en EEUU:
    Evaluar el efecto broncodilatador de AB/FF 400/12 mcg comparado con cada componente individual cuando se administra dos veces al día vía inhalación a pacientes con EPOC.
    E.2.2Secondary objectives of the trial
    To further characterize the effect of AB/FF 400/12 mcg on bronchodilation and health related quality of life compared to individual components when administered twice daily via inhalation to COPD patients.
    Caracterizar mejor el efecto de AB/FF 400/12 mcg sobre la broncodilatación y la calidad de vida relacionada con la salud en comparación con cada componente individual en su administración dos veces al día por vía inhalatoria a pacientes con EPOC.
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    Title: SERIAL SPIROMETRY SUBSTUDY

    Date and version: please be referred to section A.4.

    Patients participating in the sub-study will be requested to sign an additional informed consent form. Patients will be required to stay overnight at the study site at Visits 2 and Visit 7 to perform 24h-spirometry assessments.

    Additional Pulmonary Function Tests (PFTs) at Visit 2 and 7 only for 35% of patients who will participate in the 24-hour serial spirometry sub-study: +4h, +6h, +9h, +12h (pre-evening dose), +12.5h, +13h, +14h, +22, +23.5h and +24h after the morning dose.
    Titulo: SUBESTUDIO DE ESPIROMETRÍAS SERIADAS
    Fecha y versión: Por favor, consulten la sección A.4.
    Se requerirá a los pacientes que participen en el subestudio firmar un consentimiento informado adicional. Se requerirá a los pacientes permanecer durante la noche en el centro del estudio durante las Visitas 2 y Visita 7 para llevar a cabo evaluaciones de espirometría de 24 horas.
    Tests de Función Pulmonar adicionales (TFPs) a las Visitas 2 y 7 sólo para el 35% de pacientes que participarán en el sub-estudio de 24 horas de espirometria serial: +4h, +6h, +9h, +12h (dosis pre-noche), +12.5h, +13h, +14h, +22, +23.5h y +24h después de la dosis de la mañana.
    E.3Principal inclusion criteria
    1. Adult male or non-pregnant, non-lactating female patients aged >=40.
    Explanatory note: A female is considered to be of childbearing potential unless is at least one year post-menopausal or permanently sterilised (e.g. tubal occlusion, hysterectomy, bilateral salpingectomy). Women of childbearing potential are allowed to enter the trial if they show to have a negative pregnancy test at the Screening Visit and are using, during the last two months before the Screening Visit and during the whole duration of the trial, at least one medically approved and highly effective method of birth control defined as those, alone or in combination, which result in a low failure rate (i.e less than 1% per year) when used consistently and correctly. Male participants are not requested to use contraception methods during their participation on the trial.

    2. Patients with diagnosis of moderate to very severe stable COPD: post-bronchodilator FEV1 < 80% of the predicted normal and post-bronchodilator FEV1/FVC < 70% at Screening Visit.
    Explanatory note: Moderate to very severe COPD (Stage II or Stage IV, according to the GOLD guidelines classification 2015). Post-bronchodilation means FEV1 and FVC between 10 to 15 minutes after inhalation of 4 puffs of albuterol/salbutamol from acceptable and repeatable pulmonary function testing according to the American Thoracic Society (ATS)/European Respiratory Society (ERS) 2005 criteria. Predicted normal values to be used are based on the Global Lung Function Initiative predicted values (Quanjer et al. 2012).

    3. Symptomatic patients with a CAT score >=10 at Screening and Randomization visit (Visits 1 and 2).

    4. Current or former-smokers, with a smoking history of >=10 pack-years.
    Explanatory notes:
    a. Former smoker condition defined as having quit smoking >= 6 months before Visit 1 (Screening).
    b. Pack-years is calculated by dividing the number of cigarettes smoked per day by 20 (the number of cigarettes in a pack) and multiplying this figure by the number of years a person has smoked. For example, a person who smokes 40 cigarettes a day and has smoked for 10 years would have a 20 pack-year smoking history (40 cigarettes per day, 20 cigarettes per pack = 2; 2 x 10 years of smoking = 20 packyear history). In case of intermittent smoking/non-smoking periods, pack-years is calculated by summing all periods pack-years.
    c. Patients smoking other tobacco types will not be allowed, unless they meet the cigarette criterion as well.
    5. Patients able to perform acceptable and repeatable pulmonary function testing for FEV1 according to the American Thoracic Society (ATS)/European Respiratory Society (ERS) 2005 criteria at Visit 1.

    6. Patients eligible and able to participate in the study and who had signed an Informed Consent Form prior to initiation of any study-related procedures.
    1. El paciente debe ser un adulto, varón o mujer que no esté embarazada ni amamantando, de >=40 años.
    Nota explicativa: Una mujer se considera potencialmente fértil a menos que lleve como mínimo 1 año en amenorrea o haya sido esterilizada de forma permanente (p. ej., oclusión tubárica, histerectomía, salpingectomía bilateral). Se permite incluir en el ensayo a mujeres potencialmente fértiles si presentan una prueba de embarazo negativa en la visita de selección y están utilizando, desde al menos dos meses antes de la visita de selección y durante todo el ensayo, al menos un método anticonceptivo de gran eficacia médicamente aprobado, lo que se define como aquél que usado de forma continua y correcta, solo o en combinación, tiene una tasa de fallos baja (o sea, menos de un 1% al año). Los varones participantes no es necesario que utilicen métodos anticonceptivos durante su participación en el ensayo.

    2. Pacientes con un diagnóstico de enfermedad pulmonar obstructiva crónica (EPOC) estable, de moderada a muy severa: FEV1 posbroncodilatador < 80% del valor normal predicho y FEV1/FVC posbroncodilatador < 70% en la visita de selección.
    Nota explicativa: EPOC de moderada a muy severa (Estadio II o Estadio IV, según el sistema de clasificación GOLD de 2015). Posbroncodilatación significa el valor de FEV1 y FVC entre 10 y 15 minutos después de la inhalación de 4 disparos de salbutamol en una prueba de función pulmonar aceptable y reproducible según los criterios de la American Thoracic Society (ATS)/European Respiratory Society (ERS) 2005. Los valores normales predichos que se utilizarán se basan en los valores predichos de la Global Lung Function Initiative (Quanjer et al. 2012).

    3. Pacientes sintomáticos con una puntuación en el CAT >=10 en la visita de selección y en la visita de aleatorización (visitas 1 y 2).

    4. Fumadores o exfumadores con antecedentes de tabaquismo de >=10 paquetes-años.
    Notas explicativas:
    a. La condición de exfumador se define como haber dejado de fumar >=6 meses antes de la visita 1 (Selección).
    b. Paquetes-año se calcula dividiendo el número de cigarrillos fumados al día por 20 (el número de cigarrillos de un paquete) y multiplicando esa cifra por el número de años que una persona ha fumado. Por ejemplo, una persona que fuma 40 cigarrillos al día y ha fumado durante 10 años tiene una historia de 20 paquetes-año (40 cigarrillos al día dividido entre los 20 cigarrillos de un paquete = 2, y 2 x 10 años de exposición = historia de 20 paquetes-año. En caso de períodos intermitentes fumando y sin fumar, el número de paquetes-año se calcula sumando todos los paquetes-años de los períodos.
    c. No se permiten pacientes que fumen otros tipos de tabaco, salvo que cumplan también el criterio de cigarrillos.

    5. Pacientes capaces de realizar unas pruebas de función pulmonar aceptables y reproducibles del FEV1 según los criterios de la American Thoracic Society (ATS)/European Respiratory Society (ERS) de 2005 en la visita 1.

    6. Pacientes elegibles y capaces de participar en el estudio y que hayan firmado el documento de consentimiento informado antes de comenzar cualquier procedimiento relacionado con el estudio.
    E.4Principal exclusion criteria
    1. Involvement in the planning and/or conduct of the study (applies to AstraZeneca staff and/or site staff), or patients employed by or relatives of the employees of the site or
    sponsor.

    3. Patients with predominant asthma.
    Explanatory note: If the investigator in his or her medical judgement determines the prior asthma diagnosis is unrelated to subject current condition (e.g. misdiagnosis, premature diagnosis, or resolution of early onset disease), then the patient is eligible for the study.

    4. Any respiratory tract infection (including the upper respiratory tract) or COPD exacerbation (including the mild COPD exacerbation) within 6 weeks prior to screening or during the run-in period.

    5. Patients hospitalized for a COPD exacerbation (an emergency room visit for longer than 24 hours is considered a hospitalization) within 3 months prior to Screening Visit.

    6. Clinically significant respiratory conditions other than COPD.
    Explanatory note: Clinically significant respiratory conditions defined as:
    a. Known active tuberculosis.
    b. History of interstitial lung disease or massive pulmonary thromboembolic disease.
    c. Pulmonary resection or lung volume reduction surgery.
    d. History of lung transplantation.
    e. Patients who in the Investigator?s opinion might need thoracotomy or other lung surgery during the study.
    f. Bronchiectasis secondary to respiratory diseases other than COPD (e.g. cystic fibrosis, Kartagener?s syndrome, etc.)
    g. Known ?1-antitrypsin deficiency.

    7. Patients who in the Investigator?s opinion may need to start a pulmonary rehabilitation program during the study and/or patients who started/finished it within 3 months prior to Screening.

    8. Use of long-term oxygen therapy (>=15 hours/day).

    9. Patients who do not maintain regular day/night, waking/sleeping cycles including night shift workers.
    Explanatory note: the use of continuous positive airway pressure (CPAP) is not an exclusion criteria.

    10. Clinically significant cardiovascular conditions.
    Explanatory note: Clinically significant cardiovascular conditions, some examples are:
    a. Myocardial infarction within the 6 months prior to screening.
    b. Thoracic surgery within 6 months prior to screening.
    c. Unstable angina or unstable arrhythmia which had required changes in the pharmacological therapy or other intervention within 6 months prior to screening, or newly diagnosed arrhythmia within the 3 months prior to screening which required the pharmacological therapy or other intervention.
    d. Hospitalization within 6 months prior to screening for heart failure functional classes III (marked limitation of activity and only comfortable at rest) and IV (need of complete rest, confinement to bed or chair, discomfort at any physical activity and presence of symptoms at rest) as per the New York Heart Association.
    e. Presence of an implantable cardioverter-defibrillato (ICD) within the last year prior to Screening visit.

    11. Patients with uncontrolled Type I or Type II diabetes, uncontrolled hypo-or hyperthyroidism, hypokalaemia, or hyperadrenergic state, uncontrolled hypertension.

    12. Patients with history of long QT syndrome or whose QTc (calculated according to Fridericia?s Formula QTc=QT/RR1/3) > 470 ms as indicated in the centralised reading report assessed at Screening.

    13. Patients with clinically significant abnormalities in the laboratory tests, ECG parameters (other than QTc) or in the physical examination at Screening Visit that might comprise patient safety.
    14. Patient with known non-controlled history of infection with human immunodeficiency virus and/or active hepatitis.
    Explanatory note:
    a. Active hepatitis is defined as clinical symptoms associated with chronic portal inflammation with regional necrosis and fibrosis, which may progress to nodular postnecrotic cirrhosis or patients with antibody to hepatitis B core antigen (HBcAg) and hepatitis B surface antigen (HBsAg) test with positive results or antihepatitis C virus (HCV) antibody and HCV recombinant immunoblot assay HCV positive tests or genetic material (ribonucleic acid) testing positive results.
    b. Active infection with human immunodeficiency virus is defined as a confirmed viral load >200 copies/mL and or CD4 Count < 500 cells/mm3.

    15. Patient with a history of hypersensitivity reaction to inhaled medication or any component thereof, including paradoxical bronchospasm.

    16. Patients with known narrow-angle glaucoma, symptomatic bladder neck obstruction, acute urinary retention or symptomatic non-stable prostate hypertrophy.
    Explanatory note: Patients with well-controlled, stable, benign prostatic hypertrophy are not excluded.

    17. History of malignancy of any organ system (including lung cancer), treated or untreated, within the past 5 years other than basal or squamous cell skin cancer.
    Explanatory note: Patients are excluded whether or not there is evidence of local recurrence or metastases.
    1. Implicación en el diseño y/o la realización del estudio (se refiere al personal de AstraZeneca y al personal del centro), o pacientes empleados por el promotor o por el centro y sus familiares.
    3. Pacientes con asma predominante.
    4. Cualquier infección de las vías respiratorias (incluidas las vías respiratorias altas) o exacerbación de la EPOC (incluida la exacerbación de la EPOC leve) en las 6 semanas anteriores a la selección o durante la preinclusión.
    5. Pacientes hospitalizados por una exacerbación de la EPOC (una visita a urgencias que dura más de 24 horas se considera hospitalización) en los 3 meses anteriores a la visita de selección.
    6. Enfermedades respiratorias de importancia clínica distintas de la EPOC. Nota explicativa: Enfermedades respiratorias de importancia clínica se definen como:
    a. Tuberculosis activa conocida.
    b. Antecedentes de neumopatía intersticial o tromboembolia pulmonar masiva.
    c. Resección pulmonar o reducción quirúrgica del volumen pulmonar.
    d. Antecedente de trasplante de pulmón.
    e. Pacientes que, en opinión del investigador, podrían necesitar una toracotomía u otra intervención quirúrgica pulmonar durante el estudio.
    f. Bronquiectasias secundarias a enfermedades respiratorias distintas de la EPOC (p. ej., fibrosis quística, síndrome de Kartagener, etc.).
    g. Deficiencia de ?1-antitripsina conocida.
    7. Pacientes que, en opinión del investigador, podrían tener que comenzar un programa de rehabilitación pulmonar durante el estudio y/o pacientes que lo comenzaron/terminaron en el plazo de los 3 meses anteriores a la selección.
    8. Uso prolongado (>=15 horas/día) de oxigenoterapia.
    9. Pacientes que no mantienen ciclos día/noche, vigilia/sueño regulares, incluidos los trabajadores de turnos de noche.
    Nota explicativa: El uso de un aparato de presión positiva continua en las vías respiratorias (CPAP) no es un criterio de exclusión.
    10. Enfermedades cardiovasculares de importancia clínica.
    Nota explicativa: Algunos ejemplos de enfermedades cardiovasculares de importancia clínica son:
    a. Infarto de miocardio en los 6 meses anteriores a la selección.
    b. Cirugía torácica en los 6 meses anteriores a la selección.
    c. Angina inestable o arritmia inestable que haya precisado cambios en el tratamiento farmacológico u otra intervención en los 6 meses anteriores a la selección, o arritmia recién diagnosticada en los 3 meses anteriores a la selección que precisó tratamiento farmacológico u otra intervención.
    d. Hospitalización en los 6 meses anteriores a la selección por insuficiencia cardiaca de case funcional III y IV de la New York Heart Association.
    e. Portador de un desfibrilador-cardioversor implantable en el año anterior a la visita de selección.
    11. Pacientes con diabetes tipo I o tipo II no controlada, hipo o hipertiroidismo, hipopotasemia, o estado hiperadrenérgico o, hipertensión no controladosa.
    12. Pacientes con antecedentes del síndrome del QT largo o cuyo QTc (calculado mediante la fórmula de Fridericia, QTc=QT/RR1/3) sea > 470 ms según el informe de la lectura centralizada en la selección.
    13. Pacientes con valores anormales de importancia clínica en los análisis de laboratorio, los parámetros electrocardiográficos (aparte del QTc) o la exploración física en la visita de selección que pudieran comprometer la seguridad del paciente.
    14. Paciente con historia conocida y no controlada de infección por el virus de la inmunodeficiencia humana o hepatitis activa. Nota explicativa:
    a. La hepatitis activa se define como la presencia de síntomas clínicos asociados a inflamación portal crónica con necrosis y fibrosis regionales, que puede evolucionar a cirrosis posnecrótica, o pacientes con resultados positivos en el análisis de anticuerpos contra el antígeno central de la hepatitis B, contra el antígeno de superficieal de la hepatitis B, contra el virus de la hepatitis C y resultados positivos en el análisis de inmunotransferencia recombinante del VHC o del material genético (ácido ribonucleico) del VHC.
    b. Infección activa por el virus de la inmunodeficiencia humana se define como la confirmación de una carga viral >200 copias/ml y/o un recuento de CD4 de <500/mm3.
    15. Paciente con antecedentes de reacción de hipersensibilidad a los medicamentos inhalados o a cualquier de sus componentes; incluye el broncospasmo paradójico.
    16. Pacientes con glaucoma de ángulo estrecho conocido, obstrucción sintomática del cuello de la vejiga, retención urinaria aguda o hipertrofia de próstata inestable sintomática, conocidos. Nota explicativa: Podrán participar los pacientes con hipertrofia prostática benigna bien controlada y estable.
    17. Antecedentes de neoplasia maligna de cualquier órgano tratada o sin tratar, en los últimos 5 años, con excepción del cáncer de piel basocelular o espinocelular. Nota explicativa: Dichos pacientes no podrán participar, haya o no indicios de recidiva local o metástasis.
    E.5 End points
    E.5.1Primary end point(s)
    For EU: Outcome measure and primary comparison
    - Change from baseline in morning predose (trough) FEV1 at week 24 comparing AB 400 mcg versus TIO 18 mcg.

    For USA: Outcome measure and comparison
    - Change from baseline in 1-hour morning post-dose dose FEV1 of AB/FF 400/12 mcg compared to AB 400 mcg at week 24.
    - Change from baseline in morning predose (trough) FEV1 of AB/FF 400/12 mcg compared to FF 12 mcg at week 24.
    Para UE: Criterio de valoración y comparación principal
    -Variación respecto a la situación basal del valor matutino del FEV1 antes de la administración (valle) en la semana 24, con comparación entre AB 400 mcg y TIO 18 mcg.

    Para EEUU: Criterio de valoración y comparación
    -Variación respecto a la situación basal del valor matutino del FEV1 1 hora después de la administración de AB/FF 400/12 mcg en comparación con AB 400 mcg en la semana 24.
    -Variación respecto a la situación basal del valor matutino del FEV1 antes de la administración (valle) de AB/FF 400/12 mcg en comparación con FF 12 mcg en la semana 24.
    E.5.1.1Timepoint(s) of evaluation of this end point
    After 24 weeks of treatment.
    Después de 24 semanas de tratamiento.
    E.5.2Secondary end point(s)
    Outcome measure and primary comparison:

    - Change from baseline in normalized AUC0-3/3h FEV1 of AB/FF 400/12 ?g at week 24 compared to AB 400 ?g and FF
    12 ?g.
    - Number (%) of patients achieving a clinically meaningful improvement (a decrease of at least 4 units from baseline)
    with AB/FF 400/12 ?g in SGRQ total score at week 24 compared to AB 400 ?g and FF 12 ?g.
    Criterio de valoración y comparación principal:

    -Variación respecto a la situación basal del AUC0-3/3h normalizada del FEV1 con AB/FF 400/12 mcg en la semana 24 en comparación con AB 400 mcg y FF 12 mcg.
    -Número (%) de pacientes que alcancen una mejoría de importancia clínica (disminución mínima de 4 unidades respecto a la situación basal) en la puntuación total del SGRQ en la semana 24 con AB/FF 400/12 mcg en comparación con AB 400 mcg y FF 12 mcg.
    E.5.2.1Timepoint(s) of evaluation of this end point
    After 24 weeks on treatment.
    Después de 24 semanas de tratamiento.
    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) 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 Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial4
    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 concerned5
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA79
    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
    Bulgaria
    Czech Republic
    Germany
    Hungary
    Israel
    Poland
    Romania
    Russian Federation
    South Africa
    Spain
    Ukraine
    United Kingdom
    United States
    E.8.7Trial has a data monitoring committee No
    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
    The ?end of trial? is defined as the date when last subject randomized in the trial perform the last contact (either Visit 7 or Follow-up contact).
    El final del estudio se define como la fecha en la que el último sujeto aleatorizado en el ensayo lleve a cabo el último contacto (cualesquiera que sea Visita 7 o contacto de seguimiento).
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years1
    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 years1
    E.8.9.2In all countries concerned by the trial months2
    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: 1320
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 880
    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 state60
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 905
    F.4.2.2In the whole clinical trial 2200
    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)
    After last study procedure is performed at Visit 7, subjects should continue to take their usual medication, also allowed during the trial, and may resume other medications discontinued prior to trial enrolment (with investigator?s agreement).
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2016-06-16
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2016-05-19
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2017-06-08
    EU Clinical Trials Register Service Desk: https://servicedesk.ema.europa.eu
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