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

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.

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
• Female subjects:

• WOCBP fulfilling one of the following criteria: i. WOCBP with fertile male partners: they and/or their partner must be willing to use a highly effective birth control method from the signing of the informed consent form and until the follow-up contact or ii. WOCBP with non-fertile male partners (contraception is not required in this case).
• Female subjects of non-childbearing potential defined as physiologically incapable of becoming pregnant (i.e. post-menopausal or permanently sterile as per definitions given in Appendix 5). Tubal ligation or partial surgical interventions are not acceptable. If indicated, as per investigator's request, post-menopausal status may be confirmed by follicle-stimulating hormone levels (according to local laboratory ranges)
• 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 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