E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Chronic Obstructive Pulmonary Disease (COPD) |
Enfermedad Pulmonar Obstructiva Crónica (EPOC) |
|
E.1.1.1 | Medical condition in easily understood language |
Chronic obstructive pulmonary disease (COPD) |
Enfermedad Pulmonar Obstructiva Crónica (EPOC) |
|
E.1.1.2 | Therapeutic area | Diseases [C] - Respiratory Tract Diseases [C08] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 14.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10010952 |
E.1.2 | Term | COPD |
E.1.2 | System Organ Class | 10038738 - Respiratory, thoracic and mediastinal disorders |
|
E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The primary objective of this study is to compare the effects of orally inhaled tiotropium + olodaterol fixed dose combination (2.5/5 µg; 5/5 µg) with placebo on exercise tolerance after 12 weeks of treatment in patients with COPD. Exercise tolerance will be assessed by measurement of symptom-limited endurance time during constant work rate cycle ergometry. |
El objetivo principal de este estudio es comparar con placebo los efectos de la combinación a dosis fijas de tiotropio y olodaterol (2,5 / 5 ?g; 5 / 5 ?g) para inhalación sobre la tolerancia al ejercicio después de 12 semanas de tratamiento en pacientes con EPOC. La tolerancia al ejercicio se evaluará mediante la determinación de la duración del ejercicio limitado por los síntomas durante una cicloergometría a carga constante. |
|
E.2.2 | Secondary objectives of the trial |
- to compare the effects of orally inhaled tiotropium + olodaterol fixed dose combination with placebo on symptom-limited endurance time during endurance shuttle walk test after 12 weeks of treatment (subset of patients). - to compare the effects of orally inhaled tiotropium + olodaterol fixed dose with placebo on lung hyperinflation during constant work rate cycle ergometry and endurance shuttle walk test after 12 weeks of treatment. - to compare the effects of orally inhaled tiotropium + olodaterol fixed dose combination (2.5/5 µg; 5/5 µg) with placebo on the intensity of breathing discomfort experienced during constant work rate cycle ergometry and endurance shuttle walk test after 12 weeks of treatment. |
- Comparar los efectos sobre la duración del ejercicio limitado por los síntomas durante la prueba de resistencia de lanzadera (ESWT) después de 12 semanas de tratamiento con la combinación a dosis fijas de tiotropio y olodaterol para inhalación comparado con placebo (para un subgrupo de pacientes). - Comparar los efectos de la asociación a dosis fijas de tiotropio y olodaterol para inhalación respecto a placebo, sobre la hiperinsuflación pulmonar durante una cicloergometría a carga constante después de 12 semanas de tratamiento. - Comparar la combinación a dosis fijas de tiotropio y olodaterol (2,5 / 5 ?g; 5 / 5 ?g) para inhalación respecto a placebo en cuanto a los efectos sobre la intensidad de la disnea o dificultad respiratoria durante una cicloergometría, después de 12 semanas de tratamiento. |
|
E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
to compare the effects of orally inhaled tiotropium + olodaterol fixed dose combination (2.5/5 µg; 5/5 µg) with placebo on endurance time during endurance shuttle walk test after 12 weeks of treatment in patients with COPD |
Comparar los efectos sobre la duración del ejercicio limitado por los síntomas durante la prueba de resistencia de lanzadera (ESWT) después de 12 semanas de tratamiento con la combinación a dosis fijas de tiotropio y olodaterol (2,5 / 5 ?g; 5 / 5 ?g) para inhalación comparado con placebo en pacientes con EPOC |
|
E.3 | Principal inclusion criteria |
1. All patients must sign an informed consent consistent with ICH-GCP guidelines prior to participation in the trial, which includes medication washout and restrictions. 2. All patients must have a diagnosis of chronic obstructive pulmonary disease and must meet the following spirometric criteria: Patients must have relatively stable airway obstruction with, at visit 1: - a post-bronchodilator FEV1 <80% of predicted normal (ECSC) and - a post-bronchodilator FEV1/FVC <70% at Visit 1 3. Male or female patients, between 40 and 75 years (inclusive) of age on day of signing informed consent. 4. Patients must be current or ex-smokers with a smoking history of more than 10 pack years. Patients who have never smoked cigarettes must be excluded. 5. Patients must be able to perform technically acceptable pulmonary function tests (spirometry), must be able to complete multiple symptom-limited cycle ergometry tests (and for a subset also shuttle walk tests), as required in the protocol. 6. Patients must be able to inhale medication in a competent manner from the RESPIMAT inhaler and from a metered dose inhaler (MDI). |
1. Todos los pacientes firmarán un consentimiento informado en conformidad con las guías de la Buena Práctica Clínica de las normas ICH antes de iniciar su participación en el estudio, donde se incluye un periodo de lavado farmacológico, así como restricciones de medicación. 2. Los pacientes deben presentar un diagnóstico de enfermedad pulmonar obstructiva crónica y deben cumplir los siguientes criterios espirométricos: Los pacientes deben presentar una obstrucción de las vías respiratorias relativamente estable en la visita 1, con: - un valor del FEV1 posterior a la administración del broncodilatador < 80% del valor normal de referencia (ECSC) y - un valor del FEV1/FVC posterior a la administración del broncodilatador < 70% en la visita 1 3. Pacientes varones o mujeres, entre los 40 y los 75 años (inclusive) de edad el día de la firma del consentimiento informado. 4. Los pacientes deben ser actualmente fumadores o ser ex fumadores con antecedentes de tabaquismo superior a los 10 paquetes-año. Deben excluirse los pacientes que no hayan fumado cigarrillos nunca. 5. Los pacientes deberán ser capaces de realizar, de forma técnicamente aceptable, las pruebas funcionales respiratorias (espirometría), completar múltiples cicloergometrías hasta limitación por los síntomas (y para un subgrupo de pacientes, también la prueba de lanzadera o SWT), tal como requiere el protocolo. 6. Los pacientes deberán ser capaces de inhalar el fármaco mediante el dispositivo RESPIMAT de forma adecuada y de un inhalador presurizado de dosis medidas (MDI). |
|
E.4 | Principal exclusion criteria |
1. Patients with a significant disease other than COPD; a significant disease is defined as a disease which, in the opinion of the investigator, may (i) put the patient at risk because of participation in the study, (ii) influence the results of the study, or (iii) cause concern regarding the patient?s ability to participate in the study 2. Patients with clinically relevant abnormal baseline haematology, blood chemistry, or urinalysis 3. Patients with a history of asthma. Patients with any of the following conditions: 4. A diagnosis of thyrotoxicosis 5. A diagnosis of paroxysmal tachycardia (>100 beats per minute) 6. A history of myocardial infarction within 1 year of screening visit 7. Unstable or life-threatening cardiac arrhythmia 8. Hospitalized for heart failure within the past year 9. Known active tuberculosis 10. A malignancy for which patient has undergone resection, radiation therapy or chemotherapy within last five years (patients with treated basal cell carcinoma are allowed) 11. A history of life-threatening pulmonary obstruction 12. A history of cystic fibrosis 13. Clinically evident bronchiectasis 14. A history of significant alcohol or drug abuse 15. Any contraindications for exercise testing. 16. Patients who have undergone thoracotomy with pulmonary resection (patients with a history of thoracotomy for other reasons should be evaluated as per exclusion criterion No. 1) 17. Patients being treated with any oral ?-adrenergics 18. Patients being treated with oral corticosteroid medication at unstable doses (i.e., less than six weeks on a stable dose) or at doses in excess of the equivalent of 10 mg of prednisone per day or 20 mg every other day 19. Patients who regularly use daytime oxygen therapy for more than one hour per day and in the investigator?s opinion will be unable to abstain from the use of oxygen therapy during clinic visits 20. Patients who have completed a pulmonary rehabilitation program in the six weeks prior to the screening visit (Visit 1) or patients who are currently in a pulmonary rehabilitation program 21. Patients who have a limitation of exercise performance as a result of factors other than fatigue or exertional dyspnoea, such as arthritis in the leg, angina pectoris or claudication or morbid obesity 22. Patients with an endurance time more than 25 minutes during the training (Visit 2) or baseline (Visit 3) constant work rate cycle ergometry 23. Patients who have taken an investigational drug within one month or six half lives (whichever is greater) prior to screening visit (Visit 1) 24. Patients with known hypersensitivity to ?-adrenergic drugs, anticholinergic drugs, BAC, EDTA or any other component of the RESPIMAT inhalation solution delivery system 25. Pregnant or nursing women 26. Women of childbearing potential not using a highly effective method of birth control. 27. Patients who have previously been randomized in this study or are currently participating in another study 28. Patients who are unable to comply with pulmonary medication restrictions prior to randomization
At sites performing the shuttle walk tests, patients with the following criteria will be excluded from the shuttle walk tests:
29. Patients who reach level 12 at the incremental shuttle walk test at visit 1a. 30. Patients with an endurance time more than 15 minutes during the training (Visit 2a) or baseline (visit 3a) endurance shuttle walk test. |
|
E.5 End points |
E.5.1 | Primary end point(s) |
endurance time during constant work rate cycle ergometry at 75% Wcap (maximal work capacity). |
tiempo de duración del ejercicio a carga constante al 75% de la capacidad máxima de esfuerzo (Wcap) |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
E.5.2 | Secondary end point(s) |
1. Endurance time during the endurance shuttle walk test at walking speed corresponding to 85% of predicted maximum oxygen consumption (subset of patients) 2. Inspiratory capacity (IC) during constant work rate cycle ergometry 3. Intensity of breathing discomfort (Borg Category-Ratio Scale) during constant work rate cycle ergometry 4. Intensity of breathing discomfort (Borg Category-Ratio Scale) during endurance shuttle walk test (subset of patients) 5. Inspiratory capacity (IC) during endurance shuttle walk test (subset of patients) 6. Intensity of leg discomfort (Borg Category-Ratio Scale) during constant work rate cycle ergometry 7. Intensity of leg discomfort during the endurance shuttle walk test (subset of patients) 8. Locus of symptom limitation during constant work rate cycle ergometry 9. Locus of symptom limitation during the endurance shuttle walk test (subset of patients) 10. FEV1, FVC (trough, 1 hr post-dose) 11. endurance time during constant work rate cycle ergometry (day 1) |
1. Duración del ejercicio durante la prueba de resistencia de lanzadera (ESWT) a una velocidad de marcha correspondiente al 85% del consumo máximo de oxígeno previsto (para un subgrupo de pacientes). 2. La capacidad inspiratoria (CI) durante la cicloergometría a carga constante 3. Intensidad de la dificultad respiratoria o disnea (según la escala de Borg modificada) durante la cicloergometría a carga constante. 4. Intensidad de la dificultad respiratoria o disnea (Según la escala de Borg modificada) durante la prueba de resistencia de lanzadera (ESWT) (subset de pacientes) 5. La capacidad inspiratoria (CI) durante la prueba de resistencia de lanzadera (ESWT) (subset de pacientes) 6. Intensidad de las molestias en las piernas (según la escala de Borg modificada) durante una cicloergometría a carga constante 7. Intensidad de las molestias en las piernas durante la prueba de resistencia de lanzadera (ESWT) (subset de pacientes) 8. Locus de la limitación por síntomas durante la cicloergometría a carga constante. 9. Locus de la limitación por síntomas durante la prueba de resistencia de lanzadera (ESWT) (subset de pacientes) 10. FEV1, FVC: trough 1 hora después de la administración de la dosis. 11. duración del ejercicio durante la cicloergometría a carga constante (día 1) |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
endpoints 1 to 10: at 12 weeks endpoints 2,3,6 and 8 also on day 1 of treatment endpoint 11: on day one of treatment |
endpoints 1 a 10: 12 semanas endpoints 2,3,6 y 8 también en el día 1 de tratamiento endpoint 11: en el día 1 de tratamiento |
|
E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | Yes |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 3 |
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.8.4.1 | Number of sites anticipated in Member State concerned | 6 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 42 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Argentina |
Canada |
United States |
|
E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 8 |
E.8.9.2 | In all countries concerned by the trial days | 0 |