A Study Comparing Efficacy, Safety and Tolerability of the Fixed Dose Triple Combination CHF 5993 With the Fixed Dose Dual Combination CHF 1535 in Subjects With COPD

Study Overview
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Brief Summary
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The purpose of this study is to compare CHF 5993 with CHF 1535 in improving lung function, reducing moderate and severe COPD exacerbations, and other clinical efficacy and safety outcomes in the target subject population.

Detailed Description
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This is a phase III, multinational, multicenter, randomized, double-blind active controlled 2-arm parallel group study to compare efficacy, safety, and tolerability of CHF 5993 pMDI with CHF 1535 pMDI with respect to lung function, incidence of moderate and severe COPD exacerbations, and other clinical efficacy and safety outcomes. After screening, eligible subjects will enter 2-week run-in period using their regular COPD maintenance therapies after which they will be randomized to one of 2 study treatment groups. Following randomization, subjects will be assessed after 4 weeks then at 6-week intervals thereafter for a period of 52 weeks. A follow-up safety phone call will be performed a week after the last clinic visit. A subset of subjects consenting to participate in the pharmacokinetic substudy will undergo additional assessments (totaling 3 visits) during the scheduled study visits. During the study, daily symptoms, rescue medication use and compliance with the study drug will be recorded via a subject electronic diary. Subject concomitant medications, adverse events, and healthcare resource utilization will be assessed and recorded throughout the study. At intermittent study visits, subjects will undergo vital signs examinations including weight, spirometry measurements, and 12-lead ECG. Symptoms and COPD health status will be assessed through disease specific questionnaires. Routine hematology, blood chemistry, and serum pregnancy testing will be performed before enrollment and at end of study.

Official Title
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A Phase III, 52-week, Multinational, Multicenter, Randomized, Double-blind, 2-arm Parallel Group Study Comparing Efficacy, Safety and Tolerability of the Fixed Dose Triple Combination of Beclomethasone Dipropionate Plus Formoterol Fumarate Plus Glycopyrronium Bromide (CHF 5993) With the Fixed Dose Dual Combination of Beclomethasone Dipropionate Plus Formoterol Fumarate (CHF 1535), Both Administered Via pMDI in Subjects With Chronic Obstructive Pulmonary Disease (COPD)

Conditions
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COPD, COPD Exacerbation

Intervention / Treatment
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* Drug: Beclomethasone Dipropionate
* Drug: Glycopyrronium Bromide
* Drug: Formoterol Fumarate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed and dated written informed consent must be obtained prior to initiating any study-related procedures Outpatient Male or female subjects aged ≥40 years A female is eligible to participate in the study if she is of non-childbearing potential defined as physiologically incapable of becoming pregnant OR childbearing potential with negative serum and urine pregnancy tests at screening, and is willing to use highly effective birth control methods for the full duration of the study COPD diagnosis for at least 12 months before the screening visit in accordance with the definition by the GOLD 2020 Report Current or ex-smokers who quit smoking at least 6 months prior to screening with a smoking history of at least 10 pack-years [pack-years = (number of cigarettes per day x number of years)/20] COPD Assessment Test (CAT) score ≥10 A pre- and post-bronchodilator FEV1/FVC ratio <0.70 at screening A post-bronchodilator FEV1 <50% predicted normal at screening and a documented history of ≥1 moderate or severe COPD exacerbation in the previous 12 months OR a post-bronchodilator FEV1 ≥50% and <80% of predicted normal at screening and a documented history of ≥2 moderate COPD exacerbations or ≥1 severe COPD exacerbation in the previous 12 months Subjects receiving daily inhaled maintenance therapy for their COPD, at a stable dose for at least 3 months prior to the screening and randomization visits Documentation (including imagery and report) of chest x-ray (CXR) or CT scan performed within 6 months prior to the screening visit, without evidence of significant abnormalities (other than those related to the presence of COPD). A cooperative attitude and ability to demonstrate correct use of the pMDI inhalers and eDiary. Exclusion Criteria: Female subjects who are pregnant (as evident by a positive urine hCG or serum β-hCG test) or lactating Subjects using the following medications prior to the screening visit and during the run-in period: Systemic/oral/parenteral corticosteroids in the prior 4 weeks Use of antibiotics for a lower respiratory tract infection (e.g. pneumonia) or COPD exacerbation in the prior 4 weeks Any long-term chronic maintenance use of antibiotic treatment in the prior 4 weeks Oral xanthine derivatives (e.g. theophylline) in the prior 7 days A moderate or severe COPD exacerbation or a respiratory tract infection (e.g., pneumonia) that has not resolved ≤14 days prior to the screening visit or during the run-in period Current treatment with non-cardioselective β-blockers Requirement of long term (> 15 hours daily) oxygen therapy Known respiratory disorders other than COPD which may impact the efficacy of the study drug according to investigator's judgement. Lung transplant surgery or lung volume reduction surgery (subjects with lung volume reduction surgery are excluded if the procedure was performed within 1 year before the Screening visit) 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 History of hypersensitivity to M3 receptor antagonists, β2 agonists, corticosteroids or any of the excipients contained in any of the study drugs used in the trial which may raise contra-indications or impact the efficacy of the study drug according to the investigator's judgement Subject has severe, acute or uncontrolled cardiovascular condition (such as but not limited to unstable ischemic heart disease, NYHA Class IV, left ventricular failure, acute myocardial infarction or unstable angina) in the last 6 months An abnormal and clinically significant 12-lead ECG at either the screening or randomization visit. This is characterized as but not limited to any of the following findings: Atrial fibrillation (AF) with rapid ventricular response > 120 bpm Ventricular tachycardias (sustained, non-sustained [>3 up to 30 sec]) Evidence of Mobitz Type II second degree or third-degree atrioventricular block Prolonged QTcF (>450ms for males, or >470ms for females). This criterion is not applicable for subjects with a pacemaker or permanent AF. 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 Unstable or uncontrolled concurrent disease which may impact the efficacy or safety of the study drug or the subject's participation in the study according to investigator's judgment Malignancy that has not been in complete remission for at least 1 year or any untreated localized carcinomas History of alcohol abuse and/or substance/drug abuse (including marijuana inhaled and oral) within 12 months prior to the screening visit Receipt of any other investigational drug within 1 month or 5 half-lives (whichever is greater) prior to the screening visit or have been previously randomized in this trial, or are currently participating in another clinical trial Currently in the acute phase of a pulmonary rehabilitation program within 4 weeks before the screening visit or planning to enroll in the acute phase of such a program during the study. Subjects who are in the maintenance phase of a pulmonary rehabilitation program are not excluded Mentally or legally incapacitated, or subjects incarcerated as a result of an official or judicial order Major surgery in the 3 months prior to the screening visit or have a planned surgery during the trial Non-satisfactory compliance with the eDiary (<65% or >135%) during the run-in period Subjects requiring the use of spacer device or nebulizer for administration of maintenance COPD therapies. Veins unsuitable for repeat venipuncture Blood donation or blood loss (≥450mL) in the 4 weeks before randomization

Ages Eligible for Study
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Minimum Age: 40 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: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: BDP/FF/GB - CHF 5993<br>Two inhalations twice daily of BDP/FF/GB (100/6/12.5μg) for a period of 52 weeks via pressurized metered dose inhaler | Drug: Beclomethasone Dipropionate<br>* Available in pressurized inhalation solution BDP/FF/GB 100/6/12.5μg and BDP/FF 100/6μg<br>* Other names: BDP;Drug: Glycopyrronium Bromide<br>* Available in pressurized inhalation solution BDP/FF/GB 100/6/12.5μg<br>* Other names: GB;Drug: Formoterol Fumarate<br>* Available in pressurized inhalation solution BDP/FF/GB 100/6/12.5μg and BDP/FF 100/6μg<br>* Other names: FF;|
| Active Comparator: BDP/FF - CHF 1535<br>Two inhalations twice daily of BDP/FF (100/6μg) for a period of 52 weeks via pressurized metered dose inhaler | Drug: Beclomethasone Dipropionate<br>* Available in pressurized inhalation solution BDP/FF/GB 100/6/12.5μg and BDP/FF 100/6μg<br>* Other names: BDP;Drug: Formoterol Fumarate<br>* Available in pressurized inhalation solution BDP/FF/GB 100/6/12.5μg and BDP/FF 100/6μg<br>* Other names: FF;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in pre-dose morning Forced Expiratory Volume in the 1st second (FEV1) at Week 28 |  | Week 28 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in 2-hour post-dose morning FEV1 at Week 28 |  | Week 28 | 
| Rate of moderate and severe COPD exacerbations over 52 weeks of treatment | Annualized rate of moderate and severe COPD exacerbations as observed during the 52-week study treatment period. | 52-week treatment period | 
| Change from baseline in pre-dose morning FEV1 at designated clinic visits |  | Week 4, Week 10, Week 40, & Week 52 | 
| Change from baseline in 2-hour post-dose morning FEV1 designated clinic visits |  | Day 1, Week 4, Week 10, Week 40, & Week 52 | 
| Change from pre-dose to 2-hour post-dose morning FEV1 at designated clinic visits |  | Day 1, Week 4, Week 10, Week 28, Week 40, & Week 52 | 
| FEV1 response (change from baseline in pre-dose morning FEV1 ≥100ml) at designated clinic visits |  | Day 1, Week 4, Week 10, Week 28, Week 40, & Week 52 | 
| Time to first moderate or severe COPD exacerbation |  | 52-week treatment period | 
| Rate of severe COPD exacerbations over 52 weeks of treatment | Annualized rate of severe COPD exacerbations as observed during 52-week treatment period | 52-week treatment period | 
| Time to first severe COPD exacerbation |  | 52-week treatment period | 
| Saint George's Respiratory Questionnaire (SGRQ) response (a decrease from baseline in total score ≥4) at designated clinic visits |  | Week 4, Week 10, Week 28, Week 40, & Week 52 | 
| Change from baseline in the SGRQ total score and domain scores at each designated clinic visit |  | Week 4, Week 10, Week 28, Week 40, & Week 52 | 
| Change from baseline to each inter-visit period in the percentage of days without intake of rescue medication | Change from baseline (defined as the 2-week run-in period prior to randomization) to each inter-visit period (defined as the period of time between designated clinic visits) in percentage of days without rescue medication | Day 1-Week 4, Week 4-Week 10, Week 10-Week 28, Week 28-Week 40, Week 40-Week 52 | 
| Change from baseline to each inter-visit period in the average use of rescue medication (number of puffs/day) | Change from baseline (defined as the 2-week run-in period prior to randomization) in the average number of puffs per day of rescue medication for each inter-visit period (defined as the period of time between designated clinic visits). | Day 1-Week 4, Week 4-Week 10, Week 10-Week 28, Week 28-Week 40, Week 40-Week 52 | 
| Change from baseline in pre-dose morning Forced Vital Capacity (FVC) at designated clinic visits |  | Week 4, Week 10, Week 28, Week 40, & Week 52 | 
| Change from baseline in 2-hour post-dose morning FVC at designated clinic visits | Change from baseline (defined as the pre-dose value on Day 1) in 2-hour post-dose morning FVC at designated clinic visits | Day 1, Week 4, Week 10, Week 28, Week 40, & Week 52 | 
| Change from pre-dose to 2-hour post-dose morning FVC at designated clinic visits |  | Day 1, Week 4, Week 10, Week 28, Week 40, & Week 52 | 
| Change from baseline to each inter-visit period in the average E-RS total score and domain scores | Change from baseline (defined as the 2-week run-in period prior to randomization) in the average E-RS total score and E-RS domain scores for the period of time between designated clinic visits. | Day 1-Week 4, Week 4-Week 10, Week 10-Week 28, Week 28-Week 40, Week 40-Week 52 | 
| Change from baseline in COPD Assessment Test (CAT) score at designated clinic visit | The CAT is composed of 8 questions to measure the impact of COPD on daily life, which are scored from 0 to 5 with higher scores reflecting greater impact. | Week 4, Week 10, Week 28, Week 40, & Week 52 | 
| CAT response (decrease from baseline ≥2 points) at designated clinic visits |  | Week 4, Week 10, Week 28, Week 40, & Week 52 | 
| Modified Medical Research Council (mMRC) dyspnea scale at designated clinic visits | Descriptive statistics of the mMRC dyspnea scale score at designated clinic visits. The mMRC dyspnea scale is graded from 0 to 4, with higher grades reflecting greater severity. | Day 1, Week 4, Week 10, Week 28, Week 40, & Week 52 | 
| Change from baseline in health-related quality of life (decrease from baseline in total SGRQ score ≥4) over 52 weeks of treatment. |  | 52-week treatment period | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Lung Function, Safety Profile, Beclomethasone Dipropionate, Glycopyrronium Bromide, Formoterol Fumarate