| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Chronic obstructive pulmonary disease |
|
| E.1.1.1 | Medical condition in easily understood language |
| Chronic obstructive pulmonary disease |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Respiratory Tract Diseases [C08] |
| MedDRA Classification |
| 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 |
| To explore the effect of of aclidinium/formoterol 340/12 mcg DPI twice daily compared to tiotropium respimat 5 mcg PMDI once daily on 24 hour static hyperinflation. |
|
| E.2.2 | Secondary objectives of the trial |
| To explore the effect of of aclidinium/formoterol 340/12 mcg DPI twice daily compared to tiotropium respimat 5 mcg PMDI once daily on 24 hour spirometry, dynamic hyperinflation, respiratory symptoms and sleep quality and nighttime activity as an inverse for sleep quality.</ |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Male and female adults (with an equal sex ratio not exceeding 35-65%) aged >40 years with written informed consent obtained prior to any study-related procedure.
2. Patients entering pulmonary rehabilitation at CIRO.
3. Patients with a diagnosis of moderate to very severe COPD at least 12 months before the screening visit (A post-bronchodilator FEV1 <80% of the predicted normal value and a post-bronchodilator FEV1/FVC <0.7 at least 10-15 min after 4 puffs (4 x 100 mcg) of salbutamol)
4. Patients with severe static hyperinflation defined as residual volume (body box) >150 % predicted.
5. Current smokers or ex-smokers with a smoking history of at least 10 pack years [pack-years = (number of cigarettes per day x number of years)/20].
6. MMRC score >2.
7. A cooperative attitude and ability to use correctly the inhalers. |
|
| E.4 | Principal exclusion criteria |
1. Pregnant or lactating women
2. Patients requiring use of the following medications:
a. A course of systemic steroids longer than 3 days for COPD exacerbation in the 4 weeks prior to screening.
b. A course of antibiotics for COPD exacerbation longer than 7 days in the 4 weeks prior to screening. NB; maintenance treatment of macrolides is allowed, without any changes in the regimen in the 4 weeks prior to the study.
c. PDE4 inhibitors in the 4 weeks prior to screening.
d. Xanthines in the 4 weeks prior to screening.
e. Use of antibiotics for a lower respiratory tract infection (e.g pneumonia) in the 4 weeks prior to screening.
3. COPD exacerbation requiring prescriptions of systemic corticosteroids and/or antibiotics or hospitalization during the run-in period.
4. Patients treated with non-cardio selective B-blockers in the month preceding the screening visit or during the run-in period.
5. Patients treated with long-acting antihistamines unless taken at stable regimen at least 2 months prior to screening and to be maintained constant during the study, or if taken as PRN.
6. Patients requiring long term oxygen therapy for chronic hypoxemia.
7. Known respiratory disorders other than COPD which may impact the efficacy of the study drug according the investigator's judgment.
8. Previous lung surgery or endoscopic lung volume reduction interventions.
9. Patients who have clinically significant cardiovascular condition
10. Patients with atrial fibrillation (AF):
11. An abnormal and clinically significant 12-lead ECG which may impact the safety of the patient according to investigator's judgement. Patients whose electrocardiogram (ECG12 lead) shows QTcF>450 ms for males or QTcF>470 ms for females at screening visit are not eligible (not applicable for patient with pacemaker).
12. Medical diagnosis of narrow-angle glaucoma, prostatic hypertrophy or bladder neck obstruction that in the opinion of the investigator would prevent use of anticholinergic agents.
13. History of hypersensitivity to anticholinergics, B2-agonist or any of the excipients contained in any of the formulations used in the trial which may raise contra-indications or impact the efficacy of the study drug according to the investigator's judgement.
14. Clinically significant laboratory abnormalities indicating a significant or unstable concomitant disease which may impact the efficacy or the safety of the study drug according to investigator's judgement.
15. Patients with hypokalaemia (serum potassium levels >3.5 mEq/L (or 3.5 mmol/L)) or uncontrolled hyperkalaemia according to investigator's judgment.
16. Unstable concurrent disease: e.g. uncontrolled hyperthyroidism, uncontrolled diabetes mellitus or other endocrine disease; significant hepatic impairment; significant renal impairment; uncontrolled gastrointestinal disease (e.g. active peptic ulcer); uncontrolled neurological disease; uncontrolled haematological disease; uncontrolled autoimmune disorders, or other which may impact the efficacy or the safety of the study drug according to investigator's judgment.
17. Patients with any history of malignancy likely to result in significant disability or likely to require significant medical or surgical intervention within the next six months (after V1) or with malignancy for which they are currently undergoing radiation therapy or chemotherapy.
18. History of alcohol abuse and/or substance/drug abuse within 12 months prior to screening visit.
19. Participation in another clinical trial where investigation drug was received less than 8 weeks prior to screening visit.
20. Patients with hypercapnia (>6.5 kPa) in the arterial blood gas. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The static hyperinflation will be used as the primary efficacy variable. A 3 level random-coefficient analysis will be performed. A regression analysis without random intercept and random slope will be performed at start. Random intercept and or random slope will be added to the model when the difference in -2LogLikelihood with the previous model is significant. A second random intercept will be added before at the first level a random slope is added. The assumptions of normal distribution of the random intercept and if applicable random slope and normal distribution of the residuals will be tested. If the assumptions are violated an examination of the data will be done which statistical analysis is allowed. Because of the exploratory nature of the study no confounding variables will be added to the model. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| End of study (the last visit of the last subject undergoing the study) |
|
| E.5.2 | Secondary end point(s) |
Dynamic hyperinflation measured by metronome paced breathing: A minimal decrease of 11.2% in IC will be considered as hyperinflation. Because of the exploratory nature of this part of the study, there are no clinically relevant changes defined. To analyse the outcomes, mainly descriptive statistics will be used.
Dyspnea symptoms measured by the BDI/TDI: The instrument consists of three components: functional impairment, magnitude of task and magnitude of effort. For the BDI, each of these three compoments are rated in five grades from 0 (severe) to 4 (unimpaired), and are summed to form a baseline total score from 0 to 12. For the TDI, changes in dyspnea are rated for each component by seven grades from -3 (major deterioration) to +3 (major improvement), and are added to form a total TDI score from -9 to +9.
Because of the exploratory nature of this study endpoint, there are no clinically relevant changes defined.
Sleep quality: Night-time awakenings due to COPD symptoms (wheezing, shortness of breath and coughing) will be scored daily by the subjects. For each night, the subject is asked to score the COPD-related awakenings using the following scale; 0 for no awakenings; 1 for one awakening; 2 for two or three awakenings; and 3 for being awake for most of the night. To evaluate the scores, a mean awakening score will be calculated for each subject per study period. The study will be divided in three periods; the period between visit 1 and the day the study medication will be started (3 days), the period between the start of the study medication and visit 2 (3 days), the periods between visit 2 and visit 3, visit 3 and visit 4 and visit 4 and visit 5 (each period consisting of 3 days). Over each period, a mean awakening score will be calculated, by counting up the scores of the subjects divided by the number of days.
Because of the exploratory nature of this study, there are no clinically relevant changes defined.
Nighttime physical activity as an inverse for sleep quality measured by an accelerometer: The accelerometer measures heart rate, blood oxygenation, skin temperature, skin blood perfusion and the number of steps.
Because of the exploratory nature of this study, there are no clinically relevant changes defined.
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| End of study (the last visit of the last subject undergoing the study) |
|
| 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 | No |
| 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 | No |
| 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) | No |
| E.7.4 | Therapeutic use (Phase IV) | Yes |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | Yes |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| 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 | 2 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
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