A Phase II, 5-way Cross-over Study to Evaluate the Pharmacodynamics of Nexthaler Dry Powder Inhaler in COPD Patients

Study Overview
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Brief Summary
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The study aim is to compare the pharmacodynamic effects (cardiovascular effects- primary variable: Heart rate over 4 hours post dosing- ) after administration of BDP and formoterol administered as CHF 1535 100/6 NEXThaler DPI or CHF1535 pMDI at two different dose levels.

Detailed Description
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The effects of both formulations on serum potassium and serum glucose and the general safety and tolerability of study treatments will be also evaluated

Official Title
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Phase II, Partial Blind, Randomized, Placebo Controlled, 5-way Cross-over Study to Evaluate the Pharmacodynamics of BDP(Beclomethasone Diproprionate)/B17MP (Beclomethasone-17-Monoproprionate) and FORMOTEROL FUMARATE (FF) Across Two Different Dose Levels of CHF 1535 NEXThaler DPI (Dry Powder Inhaler) and CHF 1535 pMDI (Pressurized Metered-dose Inhaler)in Adult COPD (Chronic Obstructive Pumonary Disease) Patients

Conditions
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COPD

Intervention / Treatment
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* Drug: CHF 1535 NEXThaler 800/48
* Drug: CHF 1535 NEXThaler 200/12
* Drug: CHF 1535 NEXThaler PLACEBO
* Drug: CHF 1535 pMDI 200/12
* Drug: CHF1535 pMDI 800/48


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male and female adults (≥ 40 and ≤ 75 years old). Outpatients with diagnosis of moderate/severe stable COPD, according to GOLD (Global Initiative for Chronic Obstructive Lung Disease) guidelines update 2013 at least in the 6 months before the screening visit. A post-bronchodilator FEV1(Forced Expiratory Volume in one second) ≥ 40 and < 80% of the predicted normal value and FEV1/FVC (Forced Vital Capacity) < 0.7, 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. Ability to use pMDI (pressured metered-dose inhaler)and DPI (dry powder Inhaler) devices Current or past smoker of at least 10 pack/years where one pack-year is equivalent to 20 cigarettes per day for 1 year Exclusion Criteria: Pregnant or lactating female subjects. Current diagnosis of Asthma (as defined by the current GINA (Global Initiative for Asthma guidelines 2012 (update), or history of allergic rhinitis. COPD exacerbations requiring systemic steroids and /or antibiotics and/or oral or nebulized beta 2-agonists in the 4 weeks prior to screening and until randomization. Lower Respiratory Tract Infection (LRTI) in the 4 weeks prior to screening and until randomization. Patients with serum potassium levels < 3.5 mEq/L (milliequivalent per liter). History of substance abuse or drug abuse within 12 months prior to screening visit. Known respiratory disorders other than COPD including but not limited to α1 antitrypsin deficiency, active tuberculosis, bronchiectasis, sarcoidosis, lung fibrosis, pulmonary hypertension, restrictive lung disease and interstitial lung disease. Intolerance or contra-indication to treatment with beta 2-agonists and/or inhaled corticosteroids or allergy to any component of the study treatments. Patients treated with non-cardioselective β-blockers in the month preceding the screening visit or during the study period. 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 Atrioventricular conduction block; Left Bundle Branch Block. An abnormal 12-lead ECG (QRS> 120 msec, PR> 220 msec, HR < 40 bpm, Heart Rate > 110 bpm) at screening or at randomization. Patients whose electrocardiogram (12-lead ECG) shows QTcF >450 ms for males or QTcF > 470 ms for females at screening or at randomisation. Patients whose DBP/SBP is higher than: DBP 90 mmHg or SBP 160 mmHg at screening or at randomization.

Ages Eligible for Study
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Minimum Age: 40 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: CHF 1535 NEXThaler 800/48 ug<br>single dose administration of CHF 1535 100/6 NEXThaler DPI, total dose: 800ug BDP, 48 ug Formoterol Fumarate | Drug: CHF 1535 NEXThaler 800/48<br> <br> |
| Placebo Comparator: CHF 1535 NEXThaler PLACEBO<br>single dose administration of placebo via NEXThaler DPI | Drug: CHF 1535 NEXThaler PLACEBO<br> <br> |
| Active Comparator: CHF 1535 pMDI 200/12<br>single dose administration of CHF 1535 100/6 pMDI , total dose: 200 ug BDP, 12 ug Formoterol Fumarate | Drug: CHF 1535 pMDI 200/12<br> <br> |
| Active Comparator: CHF 1535 100/6 pMDI 800/48<br>single dose administration of CHF 1535 100/6 pMDI total dose: 800ug BDP, 48 ug Formoterol Fumarate | Drug: CHF1535 pMDI 800/48<br> <br> |
| Active Comparator: CHF 1535 NEXThaler 200/12<br>single dose administration of CHF 1535 100/6 pMDI, total dose: 200 ug BDP, 12 ug Formoterol Fumarate | Drug: CHF 1535 NEXThaler 200/12<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Average 4-hour Heart Rate bpm (beats per minutes) |  | 4 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| QTcF (QT interval Fridericia's formula corrected) (milliseconds), QRS (milliseconds) and PR (milliseconds) intervals, PAC (Premature Atrial Contraction- percentage) burden, PVC (Premature Ventricular Contraction-percentage) burden, Blood Pressure (mmHg) |  | -45, -30, -15min pre-dose, 5, 10, 20, 30, 45min, 1, 1.5, 2, 3, 4, 5, 5, 7, 8, 10 12 hr post dose | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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pharmacodynamics COPD