| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
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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 | LLT |
| E.1.2 | Classification code | 10010952 |
| E.1.2 | Term | COPD |
| 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 assess the effect on change from baseline in average 24h HR at Visit 5 of combination of FOSTER® HFA pMDI (beclomethasone dipropionate (BDP) + formoterol fumarate (FF) 100/6 µg), 2 inhalations BID, + Glycopyrrolate HFA pMDI (GB) 12.5 µg 2 inhalations BID (therapeutic dose) and FOSTER® HFA pMDI, 2 inhalations BID, + Glycopyrrolate HFA pMDI 25µg 2 inhalations BID (supratherapeutic dose) compared to FOSTER® HFA pMDI, 2 inhalations BID in moderate to severe COPD patients |
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| E.2.2 | Secondary objectives of the trial |
•To assess the effect of study treatments in terms of other parameters of Cardiovascular Safety (change of ECG parameters and evidence and incidence of arrhythmias).
•Evaluation of Pulmonary function parameters (evening trough FEV1 and trough FVC measured at 12h post dose).
•Evaluation of PK profile of GB, BDP, B17MP and FF to correlate to cardiac safety parameters.
•Full PK evaluation to permit heart rate-concentration modeling, using mean hourly heart rate as the PD variables.
•Evaluation of Adverse Events
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1.Male and female adults ≥ 40years and ≤ 80years old.
2.Male subjects: they and/or their partner must be willing to use an approved method of contraception (see exclusion criteria n. 1) from the time of dose administration and until 30 days after the last dose of study. Subjects must not donate sperm for 30 days after the last dose of study drug.
3.Written informed consent obtained by the patient prior to any study-related procedures.
4.Outpatient with diagnosis of COPD (defined in GOLD guidelines, up to date 2010) at least in the 6 months before the screening visit, including:
a)Smoking history of at least 10 pack years defined as [(number of cigarettes smoked per day) x (number of years of smoking)]/20; both current and ex smokers are eligible. For patients who are in smoking cessation therapy this must be completed at least 1 week before study enrolment;
b)Regular use of bronchodilators (e.g. β2-agonist or/and anticholinergics) in the previous 2 months at Visit 0;
c)Post-bronchodilator FEV1 ≥ 30% and ≤ 60% of the predicted normal value;
d)Post-bronchodilator FEV1/FVC ≤ 0.70.
5.Body Mass Index (BMI) ≥ 18kg/m2 and ≤ 35 kg/m2 and a total body weight ≥ 50 kg (110Ibs).
6.Ability to be trained to the proper use of pMDI inhalers.
7.A cooperative attitude to be compliant with study procedures.
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| E.4 | Principal exclusion criteria |
1.Pregnant or lactating women or all women physiologically capable of becoming pregnant UNLESS they meet the required definition of postmenopausal or are using one of the required acceptable methods of contraception.
2.Current diagnosis of asthma or other respiratory disorders (other than COPD) which may interfere with data interpretation according to the investigator’s opinion.
3.Hospitalization due to COPD exacerbation in the 3months prior to screening and during run-in period or COPD exacerbation requiring systemic steroids and or antibiotics in the 6 weeks prior to screening and during run-in period.
4.Patient with COPD who requires regular long term use of oxygen therapy, chronic mechanical ventilation,regular treatment with oral or parenteral corticosteroids
5.Unstable CV diseases (e.g. unstable angina, unstable hypertension) outside the common guidelines as reported in the protocol and known abnormality of any cardiac valve that is greater than moderate in severity
6.Abnormal resting ECG resulting from ECG machine out of the ranges specfied in the protocol.
7.Patients not in a normal sinus rhythm at screening based the 24-hours digital ECG Holter recordings specified in the protocol
8.Patient with narrow angle glaucoma.
9.Clinical or functional unstable concurrent diseases and patient with major surgery in the last 3 months or during the study
10.Any clinically significant laboratory result which may impact the evaluation of the results of the study and the safety of the patient according to the investigator’s judgment
11.Patients with known allergy, sensitivity or intolerance to sympathomimetic drugs or inhaled corticosteroids or M3 antagonists or to any of excipients contained in the study treatments.
12Heavy caffeine drinker , patient with evidence of liquorice use and patients who refuse to abstain form alcohol of caffeine or graperfriut as defined in the protocol
13Patients with unsuitable veins for repeated venipuncture.
14 Blood donation or blood loss in the 8 weeks before randomization.
15Intake of another investigational drug in the 2 months preceding the study entry. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| •Change from baseline in average 24-hour heart rate at Visit 5 |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| The ECG parameters like HR will be extracted as triplicate at pre-dose (-30, -15, -5 minutes) and post morning-dose (10 minutes, 30 minutes, 4h, 8h, 12h and 24h) timepoints from 12-lead digital ECG Holters performed during Visit 1, Visit 2, Visit 3 and Visit 5 |
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| E.5.2 | Secondary end point(s) |
•HR, ΔHR at Visit 3 and Visit 5 at pre-morning dose and at each timepoint post- dose;
•Hourly HR, Δ hourly HR at Visit 3 and Visit 5 and Δ hourly HR between Visit 5 and Visit 3 in 24 hours time monitoring;
•QRS interval, ΔQRS interval at Visit 3 and Visit 5 at pre-morning dose and at each timepoint post-dose;
•PR interval, ΔPR interval at Visit 3 and Visit 5 at pre-morning dose and at each timepoint post-dose;
•QT interval, ΔQT interval at Visit 3 and Visit 5 at pre-morning dose and at each timepoint post-dose;
•QTcF interval, ΔQTcF interval at Visit 3 and Visit 5 at pre-morning dose and at each timepoint post-dose;
•QTcP interval (population based), ΔQTcP interval at Visit 3 and Visit 5 at pre-morning dose and at each timepoint post-dose;
•Change from baseline in AUC for 24-hour HR at Visit 3 and Visit 5 and change from Visit 3 to Visit 5;
•New Myocardial Infarction statement onset at Visit 5 at 24h post- dose in comparison to baseline;
•Number and percentage of patients with abnormal values of QTcF intervals at each timepoint post morning dose at Visit 3 and Visit 5;
•Number and percentage of patients with significant changes of QTcF intervals from baseline at each timepoint post morning dose at Visit 3 and Visit 5;
•PVC burden, ΔPVC burden, over 24h on Visit 3 and Visit 5;
•PAC burden, ΔPAC burden over 24h on Visit 3 and Visit 5;
•Adverse Events and Adverse Drug Reactions;
•Vital signs: pulse rate, systolic and diastolic blood pressure;
•Pre-dose chemistry and haematology parameters collected at Visit 3 and Visit 5;
•Serum potassium Cmin, tmin and AUC0-12h on Visit 3 and Visit 5;
•Serum glucose Cmax, tmax and AUC0-12h on Visit 3 and Visit 5
•Evening trough FEV1 and evening trough FVC measured 12 h post dose at Visit 3 and Visit 5.
•AUC0-30min (BDP excluded), AUC0-t, AUC0-12h, AUC0-∞, Cmax, tmax, t½, on Visit 3;
•AUC0-30min,ss (BDP excluded), AUC0-t,ss, AUC0-12h,ss, Cmax,ss, tmax,ss, Cmin,ss, tmin,ss, Cav,ss, Rac (accumulation ratio), t½,ss, on Visit 5 at steady state
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
•ECG parameters timepoints:pre-dose (-30, -15, -5 min) and post morning-dose (10 min, 30 min, 4h, 8h, 12h and 24h) at Visit 1, Visit 2, Visit 3 and Visit 5
•Lung Function Tests timepoints at Visit 3 and Visit 5: -45 and -15 min pre-morning dose; 1, 2, 4, 8, 12 and 12h 30min post morning dose
•Glucose and Potassium timepoints at Vist 3 and 5:within 30 min pre-morning dose; 5, 10, 15, 30 min, 1, 1.5, 2, 4, 6, 8, 12, 24 h post morning dose
•PK sample collection time points at Visit3 and Visit5:within 30 min pre-morning dose and at 5, 10, 15, 30 min, and 1, 1.5, 2, 4, 6, 8, 12 and 24 h after morning dose. A single PK sample collection 30 minutes pre-morning dose will be done at Visit 4
•vital signs:30 minutes pre and post-morning dose at all visits
•Adverse Events recording:all visits |
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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 | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | No |
| E.6.6 | Pharmacokinetic | Yes |
| 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 | 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) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
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| 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 | 11 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 37 |
| 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 | 10 |
| 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 | 10 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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