A clinical trial, of 52 weeks in duration, to compare the effects of CHF 5993 (a fixed combination of beclometasone dipropionate with formoterol fumarate and glycopyrrolate bromide) with a known product (Foster), which is a fixed combination of beclometasone dipropionate with formoterol fumarate. Both products are to be adminsitered by inhaler.

Phase 1

Conditions: Chronic obstructive pulmonary disease (COPD)
MedDRA version: 18.0Level: PTClassification code 10009033Term: Chronic obstructive pulmonary diseaseSystem Organ Class: 10038738 - Respiratory, thoracic and mediastinal disorders
Therapeutic area: Diseases [C] - Respiratory Tract Diseases [C08]

Registration Number: EUCTR2013-001057-27-BG

Lead Sponsor: Chiesi Farmaceutici S.p.A.

Brief Summary: Not available

Detailed Description: Not available

Recruitment & Eligibility

Status: ot Recruiting

Sex: All

Target Recruitment: 1304

Inclusion Criteria

1.Male or female adults aged = 40 years with written informed consent obtained prior to any study-related procedure.
2.Patients with a diagnosis of COPD (according to GOLD guidelines, revised 2013) at least 12 months before the screening visit.
3.Current smokers or ex-smokers who quit smoking at least 6 months prior to screening visit, with a smoking history of at least 10 pack years [pack-years = (number of cigarettes per day x number of years)/20].
4.A post-bronchodilator FEV1 < 50% of the predicted normal value and a post-bronchodilator FEV1/FVC < 0.7, within 30 min after 4 puffs (4 x 100 µg) of salbutamol pMDI.
5.A documented history of at least one exacerbation in the 12 months preceding the screening visit.
6.Patients under double therapy for at least 2 months prior to screening with either:
-Inhaled corticosteroids/long-acting ß-agonist or
-Inhaled corticosteroids/long-acting muscarinic antagonist or
-Inhaled long-acting ß-agonist and inhaled long-acting muscarinic antagonist or
Patients under monotherapy with long-acting muscarinic antagonist for at least 2 months prior to screening.
7.Symptomatic patients at screening with a CAT score =10.
8.Symptomatic patients at screening with a BDI focal score = 10. This criterion must be confirmed at randomisation (Visit 2).
9.A cooperative attitude and ability to be trained to use correctly the pMDI inhalers.
10.A cooperative attitude and ability to be trained to use correctly the spacer Aerochamber PlusTM.
11.A cooperative attitude and ability to be trained to use correctly electronic devices with COPD questionnaire.

Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 880
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 424

Exclusion Criteria

1.Pregnant or lactating women and all women physiologically capable of becoming pregnant (i.e. women of childbearing potential) UNLESS are willing to use a reliable methods of contraception.
2.Diagnosis of asthma or history of allergic rhinitis or atopy
3.Patients requiring use of the following medications:
a.Systemic steroids 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
c.PDE 4 inhibitors in the 4 weeks prior to screening
d.Use of antibiotics for a lower respiratory tract infection (e.g pneumonia) in the 4 weeks prior to screening.
4.COPD exacerbation requiring prescriptions of systemic corticosteroids and/or antibiotics or hospitalization during the run-in period.
5.Patients treated with non-cardioselective ß-blockers in the month preceding the screening visit or during the run-in period.
6.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.
7.Patients requiring long term (at least 12 hours daily) oxygen therapy for chronic hypoxemia.
8.Known respiratory disorders other than COPD which may impact the efficacy of the study drug according to investigator’s judgement.
9.Patients who have clinically significant cardiovascular condition (such as but not limited to unstable ischemic heart disease, NYHA Class III/IV, left ventricular failure, acute myocardial infarction).
10.Patients with atrial fibrillation (AF)
11.An abnormal and clinically significant 12-lead ECG that results in active medical problem which may impact the safety of the patient according to investigator’s judgement.
Patients whose electrocardiogram (ECG) (12 lead) shows QTcF >450 ms for males or QTcF >470 ms for females at screening or at randomisation visits are not eligible.
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 M3 Antagonists, ß2-agonist, corticosteroids 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 investgator’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 serum potassium levels < 3.5 mEq/L (or 3.5 mmol/L).
16.Unstable concurrent disease.
17.History of alcohol abuse and/or substance/drug abuse within 12 months prior to screening visit.
18.Participation in another clinical trial where investigational drug was received less than 8 weeks prior to screening visit.

Study & Design

Study Type: Interventional clinical trial of medicinal product

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Main Objective: •To demonstrate the superiority of CHF 5993 pMDI over CHF 1535 pMDI in terms of lung function (change from baseline in pre-dose and 2-hour post-dose morning FEV1 at Week 26).<br>•To demonstrate the superiority of CHF 5993 pMDI over CHF 1535 pMDI in terms of dyspnea (Transition Dyspnea Index focal score at Week 26).<br>;Secondary Objective: To evaluate the effect of CHF 5993 pMDI on other lung function parameters, patient’s health status, clinical outcome measures and COPD exacerbations.<br>To collect data in order to assess the impact of study treatments on health economic outcomes.<br>To assess the safety and the tolerability of the study treatments.<br>;Primary end point(s): Primary efficacy variables<br>•Change from baseline in pre-dose morning FEV1 at Week 26.<br>•Change from baseline to the 2-hour post-dose value of FEV1 at Week 26<br>•TDI focal score at Week 26.<br><br>;Timepoint(s) of evaluation of this end point: Week 26

Secondary Outcome Measures

Name	Time	Method
Secondary end point(s): Secondary efficacy variables:<br>- Pre-dose morning FEV1 (change from baseline, change from baseline to the average over treatment period)<br>- FEV1 response (Change from baseline and from pre-dose to the 2-hour post-dose value of FEV1)<br>- TDI focal score and response<br>-SGRQ score and change from baseline<br>- Percentage of days without and use of rescue medication<br>- Moderate and severe COPD exacerbation (rate and time to first)<br><br>Safety variables<br>•Adverse events (AEs) and adverse drug reactions (ADRs).<br>•Vital signs (systolic and diastolic blood pressure).<br>•BMI.<br>•12-lead ECG parameters: heart rate (HR), QTcF, PR and QRS. <br>•24-hour ECG Holter (on a subset of 10% of the randomised patients).<br>•Standard haematology and blood chemistry.<br>;Timepoint(s) of evaluation of this end point: Each visit or week 26 and week 52<br>Safety variables: throughout the trial