Active Controlled Trial of CHF5993 Pressurized Metered-dose Inhaler ( pMDI) vs Symbicort®Turbuhaler® in Patients With Chronic Obstructive Pulmonary Disease ( COPD) (TRIVERSYTI)

This was a phase III, 24-week, randomised, double-blind, double-dummy, Multinational (China, South Korea, Taiwan), Multicentre, 2-arm parallel-group, active-controlled study in patients with COPD. The study was designed to demonstrate the superiority of CHF 5993 pMDI over budesonide/formoterol in terms of pulmonary function (change from baseline in pre-dose morning FEV1 and 2-hour post-dose morning FEV1 at Week 24), both in the overall study population and in the Chinese population. The study lasted approximately 27 weeks for each patient, and a total of 7 clinic visits (Visit \[V\] 0 to V6) were performed during the study, plus a follow-up phone call. A pre-screening visit (Visit \[V\] 0) was planned to occur no more than 7 days before a screening visit (V1, Week -2), followed by a 2-week open-label run-in period on Symbicort® Turbuhaler® (budesonide/formoterol fumarate \[FF\] 160/4.5 μg per inhalation), 2 inhalations twice daily (BID) (total daily dose: 640/18 μg budesonide/FF). The 2-week run-in period was deemed sufficient in order to 'standardise' the target population on the same treatment (Symbicort® Turbuhaler® \[budesonide/FF 160/4.5 μg per inhalation\]) prior to randomisation to study treatments, without leading to a deterioration in the disease. At the randomisation visit (V2, Week 0), patients were randomised in a 1:1 ratio to one of the following two treatments for 24 weeks: * CHF 5993 pMDI, 2 inhalations BID (total daily dose: 400/24/50 μg beclometasone dipropionate \[BDP\]/FF/glycopyrronium bromide \[GB\]); * Symbicort® Turbuhaler®, 2 inhalations BID (total daily dose: 640/18 μg budesonide/FF). The length of the treatment period (24 weeks) was considered as adequate to evaluate the long-term efficacy and safety of CHF 5993 pMDI 100/6/12.5 μg versus (vs) budesonide/formoterol in terms of lung function. Salbutamol was purchased locally by the vendor and used as rescue medication on an as-needed basis during both the run-in and treatment periods. Four subsequent visits were performed after 4 weeks (V3), 12 weeks (V4), 18 weeks (V5), and 24 weeks (V6) of treatment. A time window of ±3 days was allowed for the visit dates from V2 to V6. An early termination (ET) visit was to be performed in the event of premature study discontinuation, during which all efforts were made to perform the assessments that should have been done at Week 24 (V6). A safety follow-up phone call was scheduled with the patient 7-10 days after last study treatment intake or ET visit in order to check the status of any unresolved adverse events (AEs) at the last visit. Following the outbreak of the coronavirus disease-19 (COVID-19) pandemic the conduct of the study was adapted to ensure the safety of the patients and staff as well as the study continuity (see Section 9.8.1.2). Sites were instructed that patient retention was privileged with continuity of investigational drug supply. As emergency measures, it was authorised to postpone planned patients' visits or conduct remote visits and have the investigational product delivered to patients' home. Specific process for performing and reporting of Remote Visits was followed to cover all remote visits conducted during the period of the COVID-19 outbreak. Study assessments During the study, from screening (V1, Week -2) to end of treatment (V6, Week 24): * Concomitant medications, smoking status, AEs, and physical examination were recorded at all visits. Height and weight were measured at V1 (Week -2); * Pregnancy tests (serum tests at V1 \[Week -2\] and V6 \[Week 24\], and urinary tests from V1 \[Week -2\] to V5 \[Week 18\]) were performed. Blood samples for haematology and blood chemistry were performed at V1 (Week -2), V4 (Week 12), V5 (Week 18), and V6 (Week 24); * Vital signs (blood pressure) were recorded pre-bronchodilator at V1 (Week -2), and at pre-dose and 10 minutes (mins) post-dose at all visits from V2 (Week 0) to V6 (Week 24); * A single 12-lead electrocardiogram (ECG) was recorded pre-bronchodilator at V1 (Week -2), triplicate 12-lead ECG was recorded pre-dose at V2 (Week 0), and single 12-lead ECGs were recorded post-dose at V2 (Week 0), and pre-dose and 10 mins post-dose at V4 (Week 12) and V6 (Week 24); * COPD exacerbations were assessed by the Investigator at all visits; the COPD assessment test (CAT) was also completed at all visits; * Lung function tests were carried out to assess FEV1, forced vital capacity (FVC), forced expiratory flow measured between 25% and 75% of a forced vital capacity (FEF25-75%), and inspiratory capacity (IC) pre-bronchodilator at V1 (Week -2) and pre-dose from V2 (Week 0) to V6 (Week 24). FEV1 and FVC were assessed 10-15 mins post-bronchodilator at V1 (Week -2) and 2 hours post-dose from V2 (Week 0) to V6 (Week 24); * The patient diary was completed daily from V1 (Week -2) until the end of treatment (V6, Week 24) to record medication intake, including study treatment and rescue medication, and treatment compliance; * The European Quality of Life-5-Dimensional-3-Level questionnaire (EQ-5D-3L) and St. George's Respiratory Questionnaire (SGRQ) were completed at V2 (Week 0), V4 (Week 12), and V6 (Week 24). Additionally, the health economic assessment was completed from V2 (Week 0) to V6 (Week 24). The final analysis included a total of 1053 screened patients and 708 randomised patients (353 patients received CHF 5993 pMDI and 355 patients received budesonide/formoterol). This included 826 patients screened in China of whom 578 patients were randomised to one of two treatments: CHF 5993 pMDI (288 patients) and budesonide/formoterol (290 patients). Overall there were 612 evaluable patients, including 506 evaluable patients in China. Of the 708 randomised patients, 706 patients were included in the Intention-to-treat (ITT) population (CHF 5993 pMDI: n=351; budesonide/formoterol: n=355).