| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Chronic Obstructive Pulmonary Disease |
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| E.1.1.1 | Medical condition in easily understood language |
COPD, or chronic obstructive pulmonary disease, is a progressive disease that makes it hard to breathe. "Progressive" means the disease gets worse over time.
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| 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 | PT |
| E.1.2 | Classification code | 10009033 |
| E.1.2 | Term | Chronic obstructive pulmonary disease |
| E.1.2 | System Organ Class | 10038738 - Respiratory, thoracic and mediastinal disorders |
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| 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 evaluate the efficacy of a free combination of glycopyrrolate at 3 dose levels with fixed combination beclomethasone dipropionate plus formoterol (Foster®) in a metered dose inhaler by comparison with Foster in terms of FEV1 AUC0-12h normalized by time on Day 7. |
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| E.2.2 | Secondary objectives of the trial |
To evaluate the effect of the free combination glycopyrrolate + Foster on other lung function parameters and on clinical outcome measures. To assess the safety and the tolerability of the study treatments.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Male and female adults (40 ≤ age ≤ 80 years) with written informed consent obtained prior to any study-related procedure.
2. Outpatients with a diagnosis of COPD (according to GOLD guidelines) with:
A smoking history of at least 10 pack years (pack-years = ((number of cigarettes per day x number of years)/20). Current and ex-smokers are eligible.
(Smoking cessation therapy must be completed within 3 months prior to screening visit and smoking status shall not change after screening and during the study period)
- A Post-bronchodilator 30%≤FEV1<60% of the predicted normal value
- A Post-bronchodilator FEV1/FVC < 0.7
- An increase from baseline of FEV1 value 30 min after 80µg ipratropium of at least 60mL
3. Patients treated with double therapy with inhaled corticosteroids/long-acting β-agonist combination or with triple therapy with inhaled corticosteroids/long-acting β-agonist combination and long-acting anticholinergic (tiotropium) if taken for not more than one month at stable regimen before screening.
4. A cooperative attitude and ability to be trained to use correctly the pMDI inhalers.
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| E.4 | Principal exclusion criteria |
1.Pregnant or lactating women.
In case of childbearing potential, patients and/or their partner must be willing to use an approved method of contraception unless they meet the post-menopausal definition (amenorrhea>12 Mo or >6 Mo with FSH >40 mIU/ml). Methods of contraception may include one or more of the following ones: Surgical sterilization, hormonal contraception, double-barrier methods and periodic abstinence
Reliable contraception should be maintained throughout the study.
2.Diagnosis of asthma or history of allergic rhinitis or atopy.
3.Participation in another clinical trial where investigation drug was received less than 8 weeks prior to first intake of the study medication.
4.Hospitalisation for COPD or pneumonia within 3 month prior to screening
5.Patients experiencing a COPD exacerbation requiring use of systemic steroids and/or antibiotics in the 4 weeks prior to screening and during the run-in period.
6.Patients treated with oral/parenteral β2-agonists or nebulised bronchodilators or PDE inhibitors in the 4 weeks prior to screening and during the run-in period.
7.Use of antibiotics for a lower respiratory tract infection in the 4 weeks prior to screening and during the run-in period.
8.Patients requiring long term (at least 12 hours daily) oxygen therapy for chronic hypoxemia.
9.Known respiratory disorders other than COPD including but not limited to alpha-1 antitrypsin deficiency, active tuberculosis, lung cancer, bronchiectasis, sarcoidosis, lung fibrosis, pulmonary hypertension and interstitial lung disease.
10.Medical diagnosis of narrow-angle glaucoma, prostatic hypertrophy or bladder neck obstruction that in the opinion of the investigator would prevent use of anticholinergic.
11.History of hypersensitivity to M3 Antagonists, β2-agonist, corticosteroids or any of the excipients contained in any of the formulations used in the trial.
12.History of alcohol abuse and/or substance/drug abuse within 12 months prior to screening visit
13.An abnormal and clinically significant 12-lead ECG that results in active medical problem.
14.Electrocardiogram (ECG) (12 lead) with QTcF >450 ms for males or QTcF > 470 ms for females.
15.Clinically significant laboratory abnormalities indicating a significant or unstable concomitant disease which may impact the feasibility of the results of the study according to investigator’s judgement.
16.Patients with serum potassium levels < 3.5 mEq/L (or 3.5 mmol/L).
17.Unstable concurrent disease: e.g. uncontrolled hyperthyroidism, uncontrolled diabetes mellitus or other endocrine disease; significant hepatic impairment; significant renal impairment; cardiovascular disease (e.g. uncontrolled coronary artery disease, uncontrolled hypertension); uncontrolled gastrointestinal disease (e.g. active peptic ulcer); neurological disease; uncontrolled haematological disease; uncontrolled autoimmune disorders, or other which may impact the feasibility of the results of the study according to investigator’s judgment.
18.Evidence of heart failure (NYHA class IV).
19.Changes in dose, schedule, formulation or product of oral xanthine derivatives (eg theophylline) in the three months prior to screening visit.
20.Change in dose, schedule, formulation or product of β-blockers in the month prior to screening.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| FEV1 AUC0-12h normalized by time on Day 7 |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
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| E.5.2 | Secondary end point(s) |
Efficacy variables:
•Trough FEV1, FVC and IC at 12 h on Day 1 and Day 7 (mean of the two measurements at 12h and 12.5h post-dose)
•Trough FEV1, FVC and IC at 24h (mean of the two measurements at 23.5h and 24h post-dose) on Day 7 (i.e. on the morning of Day 8)
•FEV1 AUC0-12h normalised by time on Day 1
•FEV1 AUC0-24h and AUC12-24h normalised by time on Day 7
•Peak FEV1, FVC and IC on Day 1 and Day 7
•FEV1, FVC and IC at each time point on Day 1 and Day 7
•Transition Dyspnoea Index (TDI) score on Day 8
•Average use of rescue medication (number of puffs/day) during the treatment period
•Percentage of rescue use-free days during the treatment period
Safety variables:
•Adverse events and adverse drug reactions
•Vital signs (systolic and diastolic blood pressure, heart rate)
•Standard haematology and blood chemistry
•12-lead ECG
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
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| 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 | 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) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| 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 | 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 | 4 |
| 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 | 10 |
| 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 |
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| E.8.7 | Trial 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
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 0 |
| E.8.9.1 | In the Member State concerned months | 9 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 0 |
| E.8.9.2 | In all countries concerned by the trial months | 9 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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