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 | 16.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10010952 |
E.1.2 | Term | COPD |
E.1.2 | System Organ Class | 100000004855 |
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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 compare the average heart rate over 4 hours after administration of BDP and Formoterol using CHF 1535 100/6 NEXThaler® DPI and CHF 1535 100/6 pMDI at two different dose levels |
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E.2.2 | Secondary objectives of the trial |
• To evaluate the effects of both formulations on serum potassium and serum glucose and cardiovascular parameters
• 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 and ≤ 75 years old).
2. Female subjects must either be of non-childbearing potential, using at least one acceptable method of contraception or sexually abstinent, from screening until the end of the study.
3. Written informed consent obtained by the patient prior to any study-related procedures.
4. Outpatients with diagnosis of moderate/severe stable COPD, according to GOLD guidelines update 2013 at least in the 6 months before the screening visit.
5. A post-bronchodilator FEV1 ≥ 40 and < 80% of the predicted normal value and FEV1/FVC < 0.7, within 30 min after 4 puffs (4 x 100 µg) of salbutamol pMDI. If this criterion is not met at screening, the test can be repeated once before commencing of the run-in period.
6. Current or past smoker of at least 10 pack/years where one pack-year is equivalent to 20 cigarettes per day for 1 year. (If the subjects underwent smoking cessation therapy, it must be completed 3 months prior to the screening visit and smoking status should not change between the subjects screening visit and subjects last study visit).
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E.4 | Principal exclusion criteria |
1. Pregnant or lactating female subjects.
2. Current diagnosis of Asthma.
3. Hospitalization for COPD or pneumonia within 3 months prior to screening and until randomization.
4. COPD exacerbations requiring systemic steroids and /or antibiotics and/or oral or nebulized β2-agonists in the 4 weeks prior to screening and until randomization.
5. LRTI in the 4 weeks prior to screening and until randomization.
6. Patients with serum potassium levels < 3.5 mEq/L.
7. Known respiratory disorders other than COPD including but not limited to α1 antitrypsine deficiency, active tuberculosis, bronchiectasis, sarcoidosis, lung fibrosis, pulmonary hypertension, restrictive lung disease and interstitial lung disease.
8. Intolerance or contra-indication to treatment with β2-agonists and/or inhaled corticosteroids or allergy to any component of the study treatments.
9. Having received an investigational drug within 2 months before the screening visit.
10. Patients treated with non-cardioselective β-blockers in the month preceding the screening visit or during the study period.
11. Patients who have clinically significant cardiovascular disease according to investigator’s judgement. Thus includes but is not limited to congestive heart failure (NYHA class > 3); acute ischemic heart disease within the past 12 months of screening; Sustained cardiac arrhythmias (supraventricular or ventricular, >30 seconds duration) at or within 6 months of screening; Non sustained cardiac arrhythmias (supraventricular or ventricular, > 3 beats < 30 seconds and or ending spontaneously and or asymptomatic); History of sustained and non-sustained cardiac arrhythmias (supraventricular or ventricular); 2nd or 3rd degree AV conduction block; Left Bundle Branch Block.
12. Known respiratory disorders other than COPD
13. Patients whose DBP/SBP is higher than: DBP 90 mmHg or SBP 160 mmHg at screening or at randomization.
14. Patients taking Cardiac Anti-Arrythmics drugs, chronically or in the 4 weeks preceding the Screening Visit, patients taking oral/IV/IM corticosteroids, oral or nebulized β2-agonists and/or antibiotics for LRTI and xanthine derivative (e.g. theophylline) formulations in the 4 weeks preceding the screening visit.
15. Unstable concurrent disease
16. Any patient with active cancer or a history of cancer with less than 5 years disease free survival time (whether or not there is evidence of local recurrence or metastases). Localized basal cell carcinoma
(without metastases) of the skin is acceptable
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E.5 End points |
E.5.1 | Primary end point(s) |
Average 4-hour Heart Rate |
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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) |
Cardiovascular:
• Average Hourly HR 0-1hr, 1-2hr, 2-3hr, 3-4hr
• Maximum 4-hour Heart Rate
• Average 0-12 hour Heart Rate
• Heart Rate at 5 minutes post-dose (expected time of Formoterol Cmax)
• QTcF, PR, QRS
• PAC burden
• PVC burden
• Blood Pressure: SBP AUC0-12h/12h, DBP AUC0-12h/12h
Metabolic response:
• Serum Potassium (AUC0-4h, Cmin, tmin)
• Serum Glucose (AUC0-4h, Cmax, tmax)
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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 | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | No |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | Yes |
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 | Yes |
E.6.13.1 | Other scope of the trial description |
tolerability, pharmacology |
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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 | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | Yes |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
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E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Yes |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 5 |
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 | 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 | |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |