A 6-week Dose Ranging Study of CHF 5259 pMDI in Subjects With Chronic Obstructive Pulmonary Disease

Chronic Obstructive Pulmonary Disease Clinical Trial

— GLIMMER  

Official title:

A 6-week, Multicenter, Randomized, Double-blind, Placebo and Active-controlled, Parallel Group, Dose-ranging Study to Evaluate the Efficacy and Safety of 4 Doses of CHF 5259 pMDI (HFA Glycopyrronium Bromide Via Pressurized Metered Dose Inhaler) in Subjects With Chronic Obstructive Pulmonary Disease (COPD)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03084796
• Other study ID #: CCD-05993AA3-02
• Status: Completed
• Phase: Phase 2
• Start date: July 28, 2017
• Est. completion date: June 6, 2018

Study information

• Verified date: May 2021
• Source: Chiesi Farmaceutici S.p.A.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The purpose of this study is to evaluate the dose-response of different doses of CHF 5259 pMDI on lung function and other clinical outcomes, to identify the optimal dose(s) in terms of benefit/ risk ratio for further development in the target subject population.

Description:

This is a phase II, multicenter, randomized, double-blind, placebo and active controlled dose-ranging 6-arm parallel group study to identify the optimal dose of CHF 5259 pMDI (pressurized metered dose inhaler) with respect to lung function as well as other clinical efficacy and safety outcomes. After a 2 week run-in period under rescue albuterol and background inhaled corticosteroid (ICS) as needed, patients were randomized to one of the 6 study treatment groups. Following randomization, subjects were assessed after 3 weeks and 6 weeks of study treatment at the study center. A follow-up phone was performed a week after the last visit. During the study, daily symptoms, rescue and background medication use and compliance with the study drug were recorded in a subject diary. Treatment-Emergent Adverse Events (TEAEs) were assessed and recorded throughout the study. At screening and subsequent visits, subjects underwent physical and vital signs examinations, spirometry measurements, and 12-lead electrocardiogram (ECG). Symptoms and chronic obstructive pulmonary disease (COPD) health status were assessed through validated questionnaires. Routine hematology, blood chemistry, and pregnancy testing were performed before enrollment and at end of study. 24-hour (24-H) digital recording of ECGs (Holter) was performed before and after the first dose and just before the last dose of study treatment.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 733
• Est. completion date: June 6, 2018
• Est. primary completion date: May 23, 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 40 Years and older

Eligibility

Inclusion Criteria:

• Male or female subjects aged = 40 who have signed an Informed Consent Form prior to initiation of any study-related procedure.
• Subjects with a diagnosis of COPD (according to GOLD 2017 Global Strategy for the Diagnosis, Management and Prevention of COPD Report) at least 12 months before the screening visit.
• 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
• A post-bronchodilator forced expiratory volume in the 1st second (FEV1) =50% and <80% of the predicted normal value and,
• a post-bronchodilator FEV1/ Forced Vital Capacity (FVC) < 0.7 at screening and
• a demonstrated reversibility to ipratropium defined as ?FEV1 = 5% over baseline 30-45 minutes after inhaling 4 puffs of ipratropium
• Subjects under regular COPD therapy for at least 2 months prior to screening with either inhaled long-acting muscarinic antagonist (LAMA), inhaled ICS/ long-acting ß2-agonist (LABA), inhaled ICS + LAMA
• Symptomatic subjects at screening with a CAT score =10. This criterion must be confirmed at randomization
• Symptomatic subjects with a BDI focal score = 10. This criterion must be confirmed at randomization
• A cooperative attitude and ability to demonstrate correct use of the inhalers and e-diary.

Exclusion Criteria:

• Pregnant or lactating women and all women physiologically capable of becoming pregnant UNLESS they are willing to use highly effective birth control methods
• Diagnosis of asthma or Asthma-COPD Overlap Syndrome (ACOS) as described in global initiative for asthma (GINA) Report 2016, history of allergic rhinitis or atopy (atopy which may raise contra-indications or impact the efficacy of the study treatment according to Investigator's judgment)
• COPD Exacerbations: a moderate or severe COPD exacerbation that has not resolved =14 days prior to screening and =30 days following the last dose of any oral/systemic corticosteroid or antibiotic (whichever comes last). A Moderate or Severe COPD exacerbation during the run-in period
• Use of antibiotics for a lower respiratory tract infection in the 4 weeks prior to screening or during run-in
• Subjects treated with non-cardio-selective ß-blockers in the month preceding screening or during the run-in period
• Subjects treated with long-acting anti-histamines unless taken at stable regimen at least 2 months prior to screening and to be maintained constant during the study, or if taken as needed
• Subjects requiring long term (at least 12 hours daily) oxygen therapy for chronic hypoxemia
• Known respiratory disorders other than COPD which may impact the efficacy of the study treatment according the Investigator's judgment.
• Subjects who have clinically significant cardiovascular condition
• Subjects who have a clinically significant abnormal 12-lead ECG that results in active medical problem which may impact the safety of the subject according to Investigator's judgement
• Subjects whose 12-lead ECG shows Fridericia corrected QT interval (QTcF) >450 ms for males or QTcF >470 ms for females at screening visit
• Medical diagnosis of narrow-angle glaucoma, clinically relevant prostatic hypertrophy or bladder neck obstruction that in the opinion of the Investigator would prevent use of anticholinergic agents
• History of hypersensitivity to M3 receptor antagonists, ß2-adrenergic receptor agonist, corticosteroids or any of the excipients contained in any of the formulations used in the study which may raise contra-indications or impact the efficacy of the study treatment according to the Investigator's judgement
• Clinically significant laboratory abnormalities indicating a significant or unstable concomitant disease which may impact the efficacy or the safety of the study treatment according to Investigator's judgement
• Subjects with serum potassium levels <3.5 mEq/L (or 3.5 mmol/L) at screening
• Use of potent cytochrome P450 2D6 and 3A4 inhibitors within 4 weeks prior to screening
• Unstable or uncontrolled concurrent disease; fever, endocrine disease, gastrointestinal disease; neurological disease; hematological disease; autoimmune disorders, or other which may impact the feasibility of the results of the study according to Investigator's judgment
• History of alcohol abuse and/or substance/drug abuse within 12 months prior to screening
• Subjects who have received an investigational drug within 1 month or 5 half-lives (whichever is greater) prior to screening visit, or have been previously randomized in this trial, or are currently participating in another clinical trial.
• Subjects who are mentally or legally incapacitated, or subjects accommodated in an establishment as a result of an official or judicial order.
• Subjects who have undergone major surgery in the 3 months prior to screening visit or have a planned surgery during the trial.

Related Conditions & MeSH terms

• Chronic Obstructive Pulmonary Disease
• COPD
• Lung Diseases
• Lung Diseases, Obstructive
• Pulmonary Disease, Chronic Obstructive

Intervention

Drug:
• CHF 5259
Dose Response: Test one of four different doses of CHF 5259
• Placebo
Placebo Control
• Tiotropium Bromide 18 µg Inhalation Capsule
Active Control

Locations

Country	Name	City	State
United States	Chiesi Investigational Site	Albuquerque	New Mexico
United States	Chiesi Investigational Site	Anaheim	California
United States	Chiesi Investigational Site	Anderson	South Carolina
United States	Chiesi Investigational Site	Ann Arbor	Michigan
United States	Chiesi Investigational Site	Birmingham	Alabama
United States	Chiesi Investigational Site	Blue Ridge	Georgia
United States	Chiesi Investigational Site	Boerne	Texas
United States	Chiesi Investigational Site	Boulder	Colorado
United States	Chiesi Investigational Site	Brandon	Florida
United States	Chiesi Investigational Site	Bronx	New York
United States	Chiesi Investigational Site	Centennial	Colorado
United States	Chiesi Investigational Site	Charleston	South Carolina
United States	Chiesi Investigational Site	Charlotte	North Carolina
United States	Chiesi Investigational Site	Chicago	Illinois
United States	Chiesi Investigational Site	Cincinnati	Ohio
United States	Chiesi Investigational Site	Clearwater	Florida
United States	Chiesi Investigational Site	Columbus	Ohio
United States	Chiesi Investigational Site	Columbus	Ohio
United States	Chiesi Investigational Site	Crowley	Louisiana
United States	Chiesi Investigational Site	Cypress	Texas
United States	Chiesi Investigational Site	Dacula	Georgia
United States	Clinical Research Solutions	Dayton	Ohio
United States	Chiesi Investigational Site	Daytona Beach	Florida
United States	Chiesi Investigational Site	Denver	Colorado
United States	Chiesi Investigational Site	Dothan	Alabama
United States	Chiesi Investigational Site	Duluth	Georgia
United States	Chiesi Investigational Site	Easley	South Carolina
United States	Chiesi Investigational Site	East Providence	Rhode Island
United States	Chiesi Investigational Site	Edgewater	Florida
United States	Chiesi Investigational Site	Edmond	Oklahoma
United States	Chiesi Investigational Site	Escondido	California
United States	Chiesi Investigational Site	Evansville	Indiana
United States	Chiesi Investigational Site	Everett	Washington
United States	Chiesi Investigational Site	Fall River	Massachusetts
United States	Chiesi Investigational Site	Fall River	Massachusetts
United States	Chiesi Investigational Site	Farmington Hills	Michigan
United States	Chiesi Investigational Site	Flagstaff	Arizona
United States	Chiesi Investigational Site	Fort Mill	South Carolina
United States	Chiesi Investigational Site	Franklin	Tennessee
United States	Chiesi Investigational Site	Fullerton	California
United States	Chiesi Investigational Site	Gaffney	South Carolina
United States	Chiesi Investigational Site	Gastonia	North Carolina
United States	Chiesi Investigational Site	Glendale	Arizona
United States	Chiesi Investigational Site	Greenville	South Carolina
United States	Chiesi Investigational Site	Grove City	Ohio
United States	Chiesi Investigational Site	Hendersonville	North Carolina
United States	Chiesi Investigational Site	Hialeah	Florida
United States	Chiesi Investigational Site	Jackson	Tennessee
United States	Chiesi Investigational Site	Kissimmee	Florida
United States	Chiesi Investigational Site	Knoxville	Tennessee
United States	Chiesi Investigational Site	Lafayette	Colorado
United States	Chiesi Investigational Site	Lake Charles	Louisiana
United States	Chiesi Investigational Site	Las Vegas	Nevada
United States	Chiesi Investigational Site	Lawrenceville	Georgia
United States	Clinical Trials Research	Lincoln	California
United States	Chiesi Investigational Site	Long Beach	California
United States	Chiesi Investigational Site	Los Angeles	California
United States	Chiesi Investigational Site	Los Angeles	California
United States	Chiesi Investigational Site	Los Angeles	California
United States	Chiesi Investigational Site	Louisville	Kentucky
United States	Chiesi Investigational Site	Louisville	Kentucky
United States	Chiesi Investigational Site	Lutherville	Maryland
United States	Chiesi Investigational Site	Marietta	Georgia
United States	Chiesi Investigational Site	Medford	Oregon
United States	Chiesi Investigational Site	Miami	Florida
United States	Chiesi Investigational Site	Miami	Florida
United States	Chiesi Investigational Site	Miami	Florida
United States	Chiesi Investigational Site	Miami	Florida
United States	Chiesi Investigational Site	Minneapolis	Minnesota
United States	Chiesi Investigational Site	Missoula	Montana
United States	Chiesi Investigational Site	Montgomery	Alabama
United States	Chiesi Investigational Site	Mooresville	North Carolina
United States	Chiesi Investigational Site	Mount Pleasant	South Carolina
United States	Chiesi Investigational Site	New Braunfels	Texas
United States	Chiesi Investigational Site	Newport Beach	California
United States	Chiesi Investigational Site	Oklahoma City	Oklahoma
United States	Chiesi Investigational Site	Omaha	Nebraska
United States	Chiesi Investigational Site	Orangeburg	South Carolina
United States	Chiesi Investigational Site	Orlando	Florida
United States	Chiesi Investigational Site	Panama City	Florida
United States	Chiesi Investigational Site	Philadelphia	Pennsylvania
United States	Chiesi Investigational Site	Phoenix	Arizona
United States	Chiesi Investigational Site	Phoenix	Arizona
United States	Chiesi Investigational Site	Phoenix	Arizona
United States	Chiesi Investigational Site	Portland	Oregon
United States	Chiesi Investigational Site	Raleigh	North Carolina
United States	Chiesi Investigational Site	Rapid City	South Dakota
United States	Chiesi Investigational Site	Richland	Washington
United States	Chiesi Investigational Site	Richmond	Virginia
United States	Chiesi Investigational Site	Rock Hill	South Carolina
United States	Chiesi Investigational Site	Saint Charles	Missouri
United States	Chiesi Investigational Site	Saint Louis	Missouri
United States	Chiesi Investigational Site	San Diego	California
United States	Chiesi Investigational Site	Savannah	Georgia
United States	Chiesi Investigational Site	Seneca	South Carolina
United States	Chiesi Investigational Site	Shelby	North Carolina
United States	Chiesi Investigational Site	Sherman	Texas
United States	Chiesi Investigational Site	South Burlington	Vermont
United States	Chiesi Investigational Site	Spartanburg	South Carolina
United States	Chiesi Investigational Site	Summit	New Jersey
United States	Chiesi Investigational Site	Surprise	Arizona
United States	Chiesi Investigational Site	Tacoma	Washington
United States	Chiesi Investigational Site	Tempe	Arizona
United States	Chiesi Investigational Site	Tomball	Texas
United States	Chiesi Investigational Site	Tucson	Arizona
United States	Chiesi Investigational Site	Tullahoma	Tennessee
United States	Chiesi Investigational Site	Tustin	California
United States	Chiesi Investigational Site	Union	South Carolina
United States	Chiesi Investigational Site	Valparaiso	Indiana
United States	Chiesi Investigational Site	Westminster	California
United States	Chiesi Investigational Site	Wilmington	North Carolina
United States	Chiesi Investigational Site	Winston-Salem	North Carolina

Sponsors (1)

Lead Sponsor	Collaborator
Chiesi Farmaceutici S.p.A.

Country where clinical trial is conducted

United States, 

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* Note: There are 80 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change From Baseline in FEV1 AUC(0-12h) Normalized by Time at Week 6	Change from baseline in FEV1 AUC(0-12h), normalized by time, at the end of treatment (Week 6).; Spirometry, used to measure FEV1, was performed according to internationally accepted standards. The AUC for FEV1 at Week 6 of treatment was calculated by using the linear trapezoidal rule, based on the changes in FEV1 from the baseline values, and divided by the observation time (12 hours).; Definitions: AUC=Area under the curve; Baseline=Baseline value was the average of the pre-dose measurements (at 45 mins and 15 mins pre-dose), at Visit 2 (Week 0); FEV1=Forced expiratory volume in the 1st second; FEV1 AUC(0-12h)=Mean FEV1 after inhalation, measured at prespecified times for up to 12-h observation period (0-12 h), normalized by time;	Baseline, Week 6
Secondary	Change From Baseline in FEV1 AUC(0-12h) Normalized by Time on Day 1	Change from baseline in FEV1 AUC(0-12h), normalized by time, on Day 1.; Spirometry, used to measure FEV1, was performed according to internationally accepted standards. The AUC for FEV1 on Day 1 of treatment was calculated by using the linear trapezoidal rule, based on the changes in FEV1 from the baseline values, and divided by the observation time (12 hours).; Definitions: AUC=Area under the curve; Baseline=Baseline value was the average of the pre-dose measurements (at 45 mins and 15 mins pre-dose), at Visit 2 (Week 0); Day 1=Day of the first dose of randomized study drug at Visit 2 (Week 0); FEV1=Forced expiratory volume in the 1st second; FEV1 AUC(0-12h)=Mean FEV1 after inhalation, measured at prespecified times for up to 12-h observation period (0-12 h), normalized by time;	Baseline, Day 1
Secondary	Change From Baseline in FEV1 AUC(0-4h) Normalized by Time on Day 1 and at Week 6	Change from baseline in FEV1 AUC(0-4h), normalized by time on Day 1 of treatment (Week 0).; Spirometry, used to measure FEV1, was performed according to internationally accepted standards. The AUC for FEV1 on Day 1 and at Week 6 of treatment was calculated by using the linear trapezoidal rule, based on the changes in FEV1 from the baseline values, and divided by the observation time (4 hours).; Definitions: AUC=Area under the curve; Baseline=Baseline value was the average of the pre-dose measurements (at 45 mins and 15 mins pre-dose), at Visit 2 (Week 0); Day 1=Day of the first dose of randomized study drug at Visit 2 (Week 0); FEV1=Forced expiratory volume in the 1st second; FEV1 AUC(0-4h)=Mean FEV1 after inhalation, measured at prespecified times for up to 4-h observation period (0-4h), normalized by time;	Baseline, Day 1, Week 6
Secondary	Change From Baseline in FEV1 Peak(0-4h) at Day 1 and Week 6	Change from baseline in FEV1 peak(0-4h) (L) on Day 1 and at Week 6.; Peak FEV1 is defined as the maximum FEV1 observed in the first 4 hours after dose of study medication.; Definitions: Baseline=Baseline value was the average of the pre-dose measurements (at 45 mins and 15 mins pre-dose), at Visit 2 (Week 0); Day 1=Day of the first dose of randomized study drug at Visit 2 (Week 0); FEV1=Forced expiratory volume in the 1st second; Peak(0-4h)=Maximum FEV1 between 0 and 4 h.	Baseline, Day 1, Week 6
Secondary	Change From Baseline in FVC AUC(0-12h), Normalized by Time on Day 1 and at Week 6	Change from baseline in FVC AUC(0-12h), normalized by time, on Day 1 and at the end of treatment (Week 6).; Spirometry, used to measure FVC, was performed according to internationally accepted standards. The AUC for FVC was calculated by using the linear trapezoidal rule, based on the changes in FVC from the baseline values, and divided by the observation time (4 hours).; Definitions: AUC=Area under the curve; Baseline=Baseline value was the average of the pre-dose measurements (at 45 mins and 15 mins pre-dose), at Visit 2 (Week 0); Day 1=Day of the first dose of randomized study drug at Visit 2 (Week 0); FVC=Forced Vital Capacity; FVC AUC(0-12h)=Mean FVC after inhalation, measured at prespecified times for up to 12-h observation period (0-12 h), normalized by time;	Baseline, Day 1, Week 6
Secondary	Change From Baseline in FVC AUC(0-4h) Normalized by Time on Day 1 and at Week 6	Change from baseline in FVC AUC(0-4h), normalized by time, on Day 1 and at the end of treatment (Week 6).; Spirometry, used to measure FVC, was performed according to internationally accepted standards. The AUC for FVC was calculated by using the linear trapezoidal rule, based on the changes in FVC from the baseline values, and divided by the observation time (4 hours).; Definitions: AUC=Area under the curve; Baseline=Baseline value was the average of the pre-dose measurements (at 45 mins and 15 mins pre-dose), at Visit 2 (Week 0); Day 1=Day of the first dose of randomized study drug at Visit 2 (Week 0); FVC=Forced Vital Capacity; FVC AUC(0-4)=Mean FVC after inhalation, measured at prespecified times for up to 4-h observation period (0-4 h), normalized by time;	Baseline, Day 1, Week 6
Secondary	Change From Baseline in FVC Peak(0-4h) on Day 1 and at Week 6	Change from baseline in FVC peak(0-4h) (L) on Day 1 and at the end of treatment at Week 6. Peak FEV1 is defined as the maximum FEV1 observed in the first 4 hours after dose of study medication.; Definitions: Baseline=Baseline value was the average of the pre-dose measurements (at 45 mins and 15 mins pre-dose), at Visit 2 (Week 0); Day 1=Day of the first dose of randomized study drug at Visit 2 (Week 0); FVC=Forced Vital Capacity; Peak(0-4h)=Maximum FEV1 between 0 and 4 h.	Baseline, Day 1, Week 6
Secondary	Time to Onset of Action (Change From Baseline in Post-dose FEV1 = 100 mL) on Day 1	Time to onset of action is defined as the time (in minutes) from receiving the study drug on Day 1, until the FEV1 change from baseline is =100 mL.	Day 1
Secondary	Number of Patients Achieving Onset of Action - Change From Baseline in Post-dose FEV1 =100 mL on Day 1	Number of patients achieving onset of action was defined as a change from baseline in post-dose FEV1 =100 mL on Day 1. These are the patients who contributed to the results, reported as median and 95% CI for 'time to onset of action' presented in Outcome Measure 8, above.	Day 1
Secondary	Change From Baseline in Pre-dose Morning FEV1 at Week 3 and Week 6	Change from baseline in FEV1 at treatment visit 3 (Week 3) and treatment visit 4 (Week 6) of treatment. Spirometry, used to measure FEV1, was performed according to internationally accepted standards.; Definitions: Baseline=Baseline value was the average of the pre-dose measurements (at 45 mins and 15 mins pre-dose), at Visit 2 (Week 0); FEV1=Forced expiratory volume in the 1st second;	Baseline, Week 3, Week 6
Secondary	Change From Baseline in Pre-Dose Morning Inspiratory Capacity (IC) at Week 3 and Week 6	Change from baseline in IC at treatment Visit 3 (Week 3) and treatment Visit 4 (Week 6). Spirometry was used to measure IC and was performed according to internationally accepted standards.; Definitions: Baseline: value of the measurement recorded at 45 mins pre-dose at Visit 2 (Week 0); IC=Inspiratory capacity;	Baseline, Week 3, Week 6
Secondary	Transition Dyspnea Index (TDI) Response (Focal Score =1) at Week 3 and Week 6	Number of subjects achieving TDI focal score =1, at treatment visit 3 (Week 3) and at treatment visit 4 (Week 6).; TDI is a validated, interviewer-administered questionnaire that measures changes in dyspnea severity from the baseline established by the BDI questionnaire. TDI consists of the same 24 items and 3 domains as the BDI, with the same 2-week recall period. Each category is rated by 7 grades ranging from -3 (major deterioration) to +3 (major improvement); total score ranging from -9 to +9, with higher scores indicating better outcomes. The minimal clinically important differences (MCID) is considered a change of =1 unit. The same investigator or designee interviewed the subject for the BDI and TDI during the study period. A TDI focal score of =1 is considered as clinically important.; Definitions: Baseline=The BDI focal score value at Visit 2 (Week 0); BDI=Baseline Dyspnea Index; MCID=Minimal Clinically Important Differences; TDI=Transition Dyspnea Index;	Baseline, Week 3, Week 6
Secondary	Transition Dyspnea Index (TDI) Focal Score at Week 3 and Week 6	Transitional Dyspnea Index (TDI) focal score at treatment visit 3 (Week 3) and treatment visit 4 (Week 6).; TDI is a validated, interviewer-administered questionnaire that measures changes in dyspnea severity from the baseline established by the BDI questionnaire. TDI consists of the same 24 items and 3 domains as the BDI, with the same 2-week recall period. Each category is rated by 7 grades ranging from -3 (major deterioration) to +3 (major improvement), with a total score ranging from -9 to +9, with higher scores indicating better outcomes. The minimal clinically important differences (MCID) is considered a change of =1 unit. The same investigator or designee interviewed the subject for the BDI and TDI during the study period. A TDI focal score of =1 is considered as clinically important.; Definitions: Baseline=The BDI focal score value at Visit 2 (Week 0); BDI=Baseline Dyspnea Index; MCID=Minimal Clinically Important Differences; TDI=Transition Dyspnea Index;	Baseline, Week 3, Week 6
Secondary	Change From Baseline in Percentage of Rescue Medication-Free Days During Inter-Visit Periods and the Entire Treatment Period	Evaluate the number of rescue medication-free days compared with baseline. Results are shown as percentage (%) of rescue medication-free days; an increased value indicates improvement from baseline.; Definitions: Baseline=Data recorded during the run-in period (a 2-week period prior to randomization to study treatment and study drug intake); Inter-visit period 1=Starts at randomization to treatment (Visit 2, Week 0) and runs to the day before the subject returns to the clinic (Visit 3, Week 3); Inter-visit period 2=Starts when the subject returns to the clinic (Visit 3, Week 3) and runs to the end of the randomized treatment period (Visit 4, Week 6); Entire Treatment period=From day of randomization to drug intake to the end of the randomized treatment period (Visit 4, Week 6); Randomization=Randomization to study drug treatment (Visit 2, Week 0).	Baseline, Inter-visit period 1, Inter-visit period 2, Entire treatment period
Secondary	Change From Baseline in Average Use of Rescue Medication During Inter-Visit Periods and the Entire Treatment Period	Evaluate the change from baseline in average use of rescue medication (number of puffs/day) during the inter-visit periods and the entire treatment period.; Results are shown as number of puffs/day; a decrease (implies improvement) from baseline in average use of rescue medication.; Definitions: Baseline=Data recorded during the run-in period (a 2-week period prior to randomization to study treatment and study drug intake); Inter-visit period 1=Starts at randomization to treatment (Visit 2, Week 0) and runs to the day before the subject returns to the clinic (Visit 3 (Week 3); Inter-visit period 2=Starts when the subject returns to the clinic (Visit 3, Week 3) and runs to the end of the randomized treatment period (Visit 4, Week 6); Entire Treatment period=From day of randomization to drug intake to the end of the randomized treatment period (Visit 4, Week 6); Randomization=Randomization to study drug treatment (Visit 2, Week 0);	Baseline, Inter-visit period 1, Inter-visit period 2, Entire treatment period
Secondary	Change From Baseline in Average EXACT-Respiratory Symptom (E-RS) Total Score During Inter-Visit Periods and the Entire Treatment Period	Change from baseline in average EXACT-Respiratory Symptom (E-RS) total score during inter-visit periods and the entire treatment period; E-RS in COPD uses 11 respiratory symptom items from the 14-item EXAcerbations of COPD tool (EXACT). E-RS total score quantifies respiratory symptom severity on a scale ranging from 0 to 40. Higher E-RS total scores indicate more severe symptoms and a declining total score indicates health improvement. E-RS questionnaire was completed by the patient each evening (e-diary).; Definitions: For details on baseline, inter-visit periods, and the entire treatment period, please refer to outcome measure #15.	Baseline, Inter-visit period 1, Inter-visit period 2, Entire treatment period
Secondary	Vital Signs -- Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP)	Vital signs -- Systolic blood pressure (SBP), Diastolic blood pressure (DBP) were measured at prespecified times, using a 12-Lead single ECGs were recorded at all study visits (pre-dose at V1 (Week -2) and V3 (Week 3), as well as at pre-dose and 1.5 hours post-dose at Visit 2 (Week 0) and Visit 4 (Week 6).; Results are shown by treatment group, as change from baseline (in mmHg) for representative timepoints.; Definitions: Baseline=Values recorded pre-dose (Visit 2, Week 0); Day 1=Day of the first dose of randomized study drug (Visit 2, Week 0);	Baseline, Day 1, Week 6
Secondary	Change From Baseline in 24-Hour Holter Electrocardiogram (ECG) Parameters - Heart Rate (HR)	Change from baseline in 24-Hour Holter electrocardiogram (ECG) parameters - Heart rate (HR); Subjects had a 24-h Holter recording before and 24 h after the 1st dose of study drug (Visit 2) and for 24 h before the last dose of study drug (Visit 4). The time-matched values recorded during the 24 h before the 1st dose of study drug on Visit 2 and served as the baseline for the Holter-extracted ECG parameters. The time-averaged baseline score is the average of the Day -1 scores at +5m, +55m, and at +2.5 h.	Baseline, Day 1, Week 6
Secondary	Change From Baseline in 24-Hour Holter Electrocardiogram (ECG) Parameters - PR Interval	Change from baseline in 24-Hour Holter electrocardiogram (ECG) parameters - PR Interval; Subjects had a 24-h Holter recording before and 24 h after the 1st dose of study drug (Visit 2) and for 24 h before the last dose of study drug (Visit 4). The time-matched values were recorded during the 24 h before the 1st dose of study drug on Visit 2 and served as the baseline for the Holter-extracted ECG parameters. The time-averaged baseline score is the average of the Day -1 scores at +5 min, +55 min, and at +2.5 h.	Baseline, Day 1, Week 6
Secondary	Change From Baseline in 24-Hour Holter Electrocardiogram (ECG) Parameters - QRS Interval	Change from baseline in 24-Hour Holter electrocardiogram (ECG) parameters - QRS Interval; Subjects had a 24-h Holter recording before and 24 h after the 1st dose of study drug (Visit 2) and for 24 h before the last dose of study drug (Visit 4). The time-matched values were recorded during the 24 h before the 1st dose of study drug on Visit 2 and served as the baseline for the Holter-extracted ECG parameters. The time-averaged baseline score is the average of the Day -1 scores at +5 min, +55 min, and at +2.5 h.	Baseline, Day 1, Week 6
Secondary	Change From Baseline in 24-Hour Holter Electrocardiogram (ECG) Parameters - Fridericia-corrected QT Interval (QTcF)	Change from baseline in 24-Hour Holter electrocardiogram (ECG) parameters - Fridericia-corrected QT interval (QTcF).; Subjects had a 24-h Holter recording before and 24 h after the 1st dose of study drug (Visit 2) and for 24 h before the last dose of study drug (Visit 4). The time-matched values recorded during the 24 h before the 1st dose of study drug on Visit 2 and served as the baseline for the Holter-extracted ECG parameters. The time-averaged baseline score is the average of the Day -1 scores at +5 min, +55 min, and at +2.5 h.	Baseline, Day 1, Week 6
Secondary	24-hour Holter ECG - Prolonged QTcF - Male Subjects	24-hour Holter ECG - Prolonged QTcF - Male subjects.; Subjects had a 24-h Holter recording before and 24 h after the 1st dose of study drug (Visit 2) and for 24 h before the last dose of study drug (Visit 4). The time-matched values recorded during the 24 h before the 1st dose of study drug on Visit 2 and served as the baseline for the Holter-extracted ECG parameters. The time-averaged baseline score is the average of the Day -1 scores at +5 min, +55 min, and at +2.5 h.	Baseline, Day 1, Week 6
Secondary	24-hour Holter ECG - Prolonged QTcF - Female Subjects	24-hour Holter ECG - Prolonged QTcF - Female subjects.; Subjects had a 24-h Holter recording before and 24 h after the 1st dose of study drug (Visit 2) and for 24 h before the last dose of study drug (Visit 4). The time-matched values recorded during the 24 h before the 1st dose of study drug on Visit 2 and served as the baseline for the Holter-extracted ECG parameters. The time-averaged baseline score is the average of the Day -1 scores at +5 min, +55 min, and at +2.5 h.	Baseline, Day 1, Week 6
Secondary	24-hour Holter ECG - Prolonged QTcF - Change From Baseline	24-hour Holter ECG - Prolonged QTcF - Change from baseline.; Subjects had a 24-h Holter recording before and 24 h after the 1st dose of study drug (Visit 2) and for 24 h before the last dose of study drug (Visit 4). The time-matched values recorded during the 24 h before the 1st dose of study drug on Visit 2 and served as the baseline for the Holter-extracted ECG parameters. The time-averaged baseline score is the average of the Day -1 scores at +5 min, +55 min, and at +2.5 h.; Results are presented as the number of subjects who had a change from baseline in QTcF of: > 30 msec, > 60 msec, and no prolongation (by > 30 msec or > 60 msec).	Baseline, Day 1, Week 6

External Links

•   American Thoracic Society: Baseline Dyspnea Index (BDI) & Transition Dyspnea Index (TDI).
•   American Thoracic Society: COPD Assessment Test (CAT).
•   Chiesi Farmaceutici is the first company to submit a marketing authorisation application to the European Medicine Agency for a Triple Combination for the treatment of COPD
•   Chiesi Respiratory
•   From the Global Strategy for the Diagnosis, Management and Prevention of COPD, Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2017.
•   Glycopyrronium bromide