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

Phase 3CompletedNCT03197818

Chiesi Farmaceutici S.p.A.708 enrolled

Overview

Primary Objective • To demonstrate the superiority of CHF 5993 pressurised metered dose inhaler (pMDI) over Symbicort® Turbuhaler® in terms of pulmonary function (change from baseline in pre-dose morning forced expiratory volume in the first second of a forced vital capacity manoeuvre \[FEV1\] and 2-hour post-dose morning FEV1 at Week 24). Secondary Objectives Key secondary objective: • To demonstrate the superiority of CHF 5993 pMDI over Symbicort® Turbuhaler® in terms of pulmonary function (change from baseline in pre-dose morning FEV1 and 2-hour post-dose morning FEV1 at Week 24) in the subgroup of Chinese population. Other secondary objectives: * To evaluate the effect of CHF 5993 pMDI on other lung function parameters, patient's health status and clinical outcome measures; * To collect data in order to assess the impact of study treatments on health economic outcomes; * To assess the safety and the tolerability of the study treatments.

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).

Eligibility

Sex: ALLMin age: 40 Years

Medical Language ↔ Plain English

Inclusion criteria Patients had to meet all of the following inclusion criteria to be eligible for enrolment into the study: 1. Male and 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 2015 strategic document, updated January 2015) at least 12 months before the screening visit; 3. A smoking history of at least 10 pack years \[pack years = (number of cigarettes per day x number of years)/20\]. Current and ex-smokers were eligible; Note: Smoking cessation therapy had to be completed 6 months prior to screening visit. 4. A post-bronchodilator FEV1 \< 50% of the predicted normal value and a post-bronchodilator FEV1/FVC ratio \< 0.7 at least 10-15 mins 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. COPD exacerbation was defined according to the following: "A sustained worsening of the patient's condition (dyspnoea, cough and/or sputum production/purulence), from the stable state and beyond normal day-to-day variations, that is acute in onset and necessitates a change in regular medication in a patient with underlying COPD that includes prescriptions of systemic corticosteroids and/or antibiotics or need for hospitalisation"; 6. Patients under therapy for at least 2 months prior to screening with either: * ICS/LABA or * ICS/LAMA or * Inhaled LABA and inhaled LAMA or * LAMA or * LABA. 7. A cooperative attitude and ability to be trained to use correctly the study treatment inhalers (pMDI and Turbuhaler®); 8. A cooperative attitude and ability to be trained to use correctly the COPD questionnaires. All inclusion criteria were checked at screening (V1, Week -2). If criterion #4 was not met at V1, the test could be repeated once before the randomisation visit (V2, Week 0). Inclusion criteria #7 and #8 were to be re-checked at the randomisation visit (V2, Week 0). Exclusion Criteria: If a patient met any of the following criteria, he/she was not enrolled into the study: 1. Pregnant or lactating women and all women physiologically capable of becoming pregnant (i.e. women of childbearing potential) UNLESS are willing to use one or more of the following reliable methods of contraception: * Placement of an intrauterine device or intrauterine system; * Hormonal contraception (implantable, patch, oral); * Barrier methods of contraception: condom or occlusive cap (diaphragm or cervical vaults/caps) with spermicidal foam/gel/film/cream/suppository; * Male sterilisation (with the appropriate post-vasectomy documentation of the absence of sperm in the ejaculate). Reliable contraception had to be maintained throughout the study until last study visit. "True abstinence" was acceptable only if it was in line with the preferred and usual lifestyle of the patient. Pregnancy testing was carried out during the course of the study in all women of childbearing potential: serum pregnancy test was performed at screening (V1) and end of treatment (V6); and urine pregnancy test was performed at all visits except V0 and V6. Any postmenopausal women (physiologic menopause defined as "12 consecutive months of amenorrhea") or women permanently sterilised (e.g. tubal occlusion, hysterectomy or bilateral salpingectomy) could have been enrolled in the study; 2. Diagnosis of asthma, history of allergic rhinitis or atopy (atopy which may raise contra-indications or impact the efficacy of the study according to Investigator's judgement); 3. Patients requiring use of the following medications: * Systemic steroids for COPD exacerbation in the 4 weeks prior to screening; * A course of antibiotics for COPD exacerbation longer than 7 days in the 4 weeks prior to screening; * Phosphodiesterase E (PDE) inhibitors in the 4 weeks prior to screening; * 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 hospitalisation during the run-in period; 5. Changes in dose, schedule, formulation or product of oral xanthine derivatives (e.g. theophylline) in the month prior to screening visit or during the run-in period. Stop of xanthines prior to screening visit was allowed; 6. Patients treated with non-cardioselective β-blockers in the week preceding the screening visit or during the run-in period; 7. Patients treated with long-acting antihistamines (e.g. astemizole, terfenadine) unless taken at stable regimen at least 2 months prior to screening and to be maintained constant during the study, or if taken as required (PRN); 8. Patients requiring long term (at least 12 hours daily) oxygen therapy for chronic hypoxaemia; 9. Known respiratory disorders other than COPD which may impact the efficacy of the study treatment according to the Investigator's judgement. This can include but is not limited to alfa-1 antitrypsin deficiency, active tuberculosis, lung cancer, bronchiectasis, sarcoidosis, lung fibrosis, pulmonary hypertension and interstitial lung disease; 10. Patients who had a clinically significant (CS) cardiovascular condition (such as but not limited to unstable ischaemic heart disease, New York Heart Association (NYHA) Class III/IV, left ventricular failure, acute myocardial infarction), advanced atrio-ventricular conduction blocks; 11. Patients with atrial fibrillation (AF): * Paroxysmal (i.e. intermittent); * Persistent as defined by continuous AF diagnosed for less than 6 months; * Persistent for at least 6 months with a resting ventricular rate ≥ 100/minute controlled with a rate control strategy (i.e. selective β-blocker, calcium channel blocker, pacemaker placement, digoxin or ablation therapy); 12. An abnormal and CS 12-lead ECG that results in an active medical problem which may impact the safety of the patient according to Investigator's judgement. Patients whose ECG (12 lead) showed Fridericia-corrected QT interval (QTcF) \> 450 ms for males or QTcF \> 470 ms for females at screening and at randomisation visits were not eligible. 13. 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; 14. History of hypersensitivity to M3 antagonists, β2-agonist, corticosteroids or any of the excipients contained in any of the formulations used in the trial; 15. 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; 16. Patients with serum potassium levels \< 3.5 mEq/L (or 3.5 mmol/L) at screening; 17. Unstable concurrent disease: e.g. uncontrolled hyperthyroidism, uncontrolled diabetes mellitus or other endocrine disease; uncontrolled gastrointestinal disease (e.g. active peptic ulcer); neurological disease; uncontrolled haematological disease; uncontrolled autoimmune disorders, or other which may impact the feasibility of the results of the study according to Investigator's judgement; 18. History of alcohol abuse and/or substance/drug abuse within 12 months prior to screening visit; 19. Participation in another clinical trial where investigation drug was received less than 8 weeks prior to screening visit; 20. Patients treated with Traditional Chinese Medicines used for respiratory diseases. All exclusion criteria except for criterion #4 were checked at screening (V1, Week -2). The following exclusion criteria were to be re-checked at the randomisation visit (V2, Week 0): #1, #4, #5, #6, #7, #10, #11, #12, #17, and #20. For patients in South Korea (only), the following were added to the South Korea-specific protocol (version 3.0): * For exclusion criterion #14, it was additionally specified that patients with a history of lactose intolerance were to be excluded; * For exclusion criterion #17, it was additionally specified that patients with a known history of hypersensitivity to sympathomimetic amine were to be excluded; * An additional exclusion criterion (#21) was specified for patients with a known history of hypertrophic cardiomyopathy.

Outcomes

Primary Outcomes

Change From Baseline in Pre-dose Forced Expiratory Volume Within the First Second (FEV1) at Week 24

FEV1 measures the amount, or volume, exhaled by a patient in the first second of the expiration after a full inspiration. The lower the values, more severe the airflow limitation. For FEV1, the highest value from 3 technically acceptable attempts was recorded irrespective of the curve they were derived from. The chosen highest value had not to exceed the second highest by more than 150 mL; if the difference was larger, up to 8 measurements were performed and the largest value reported. Please note that the adjusted mean is reported with its 95%IC.

Time frame: Week 24 (Visit 6)

Change From Baseline in 2-hour Post-dose FEV1 at Week 24

Time frame: Week 24 (Visit 6)

Secondary Outcomes

Change From Baseline in Pre-dose Morning FEV1 at All the Other Clinic Visits

Time frame: Pre-dose morning at week 4 (visit 3), week 12 (visit 4), week 18 (visit 5), week 24 (visit 6)

Change From Baseline at 2-hour Post-dose FEV1 at All the Clinic Visits

Time frame: 2-hour post-dose morning at week 0 (V2), week 4 (V3), week 12 (V4), week 18 (V5), week 24 (V6)

Change From Baseline in Pre-dose FEV1 ≥ 100 mL at Week 24

FEV1 response is defined as a change from baseline in pre-dose morning FEV1 ≥ 100 mL. If the change from baseline is \< 100 mL the patient is classified as a non-responder in terms of FEV1. Patients with missing pre-dose morning FEV1 value at the relevant time points were also be classified as non-responders. The number and percentage of FEV1 responders/non-responders (distinguishing also the two categories of non-responders: with a change from baseline actually \< 100 mL or with missing data) at Visit 6 are presented by treatment group.

Time frame: Week 24 (V6)

Changes From Pre-Dose to the 2-Hour Post-Dose Value of FEV1 at Each Visit From Visit 3 Onwards

The changes from pre-dose to the 2-hour post-dose morning FEV1 at each clinic visit from V3 onwards are presented by treatment in the ITT population. Please note that the adjusted mean is reported with its 95%IC.

Time frame: Week 4 (V3), week 12 (V4), week 18 (V5), week 24 (V6)

Adjusted Rate Per Patient Per Year of Moderate or Severe COPD Exacerbations Over 24 Weeks of Treatment

Moderate or Severe COPD exacerbations during the randomised treatment period derived from the COPD exacerbations (E) eCRF form were considered for the analysis. Only E with start date ≥ date of start of randomised treatment period and ≤ date of end of randomised treatment period were considered. Please note that in the analysis, two COPD E were considered as a single episode if the 2nd E started less than 10 days: * after the end of the systemic corticosteroids and/or antibiotics intake for the previous E; * after the onset of the previous E. In case of at least 1 E occurring before the randomisation and at least 1 E occurring after randomisation satisfied the rules above to be considered as single episode, then the resulting event was considered as occurring before the randomisation (i.e. it wasn't considered in the analyses of moderate or severe Es). Adjusted exacerbation rate per patient per year was reported (= number) with its 95% IC.

Time frame: Over the 24-week treatment period

Time to First Moderate or Severe COPD Exacerbation Over 24 Weeks of Treatment

In patients with at least one moderate/severe COPD exacerbation, time to first moderate/severe COPD exacerbation was calculated as the time in weeks between the start date of randomised treatment period and the date at which the first COPD exacerbation occurs. Time to first moderate/severe COPD exacerbation (weeks) = (date of start of first moderate/severe COPD exacerbation - date of start of randomised treatment period)/7. Please note that the Rows don't represent mutually exclusive and exhaustive categories of the overall number of participants analyzed (N=351 for CHF 5993 and N=355 for Symbicort Turbuhaler). The number of exacerbation-free patients at the beginning of each study period is reported for each row (not the number of participants analyzed), with the relative cumulative number of patients with first moderate/severe exacerbation at the end of each study period (unit of measure).

Time frame: From baseline to week 24 (EOT)

Change From Baseline in Pre-Dose Morning Forced Vital Capacity (FVC) at All Clinic Visits

FVC is defined as the total amount of air exhaled during the FEV test. Forced vital capacity, together with Forced Expiratory Volume, are lung function tests that are measured during spirometry. The lower the capacity, the worse the respiratory functionality. Change from Baseline in Pre-Dose Morning Forced Vital Capacity (FVC) at all clinic visits are presented by treatment in the ITT population. Please note that adjusted mean was reported with its 95%IC.

Time frame: Pre-dose morning, week 4 (V3), week 12 (V4), week 18 (V5), week 24 (V6)

Change From Baseline in 2-Hour Post-Dose Morning FVC at All Clinic Visits

FVC is defined as the total amount of air exhaled during the FEV test. Forced vital capacity, together with Forced Expiratory Volume, are lung function tests that are measured during spirometry. The lower the capacity, the worse the respiratory functionality. Change from Baseline in 2-hour post-dose Forced Vital Capacity (FVC) at all clinic visits are presented by treatment in the ITT population. Please note that adjusted mean is reported with its 95%IC.

Time frame: 2-hour post dose, week 4 (V3), week 12 (V4), week 18 (V5), week 24 (V6)

Change From Pre-Dose to the 2-Hour Post-Dose Value of FVC at Each Visit From Visit 3 Onwards

FVC is defined as the total amount of air exhaled during the FEV test. Forced vital capacity, together with Forced Expiratory Volume, are lung function tests that are measured during spirometry. The lower the capacity, the worse the respiratory functionality. Change from Pre-Dose to the 2-Hour Post-Dose Value of Forced Vital Capacity (FVC) at all clinic visits from V3 onwards are presented by treatment in the ITT population. Please note that adjusted mean is reported with its 95%IC.

Time frame: From Pre-Dose to the 2-Hour Post-Dose at week 4 (V3), week 12 (V4), week 18 (V5) and week 24 (V6)

Pre-Dose FEV1/FVC at All Clinic Visits

The FEV1/FVC ratio, also called modified Tiffeneau-Pinelli index, is a calculated ratio used in the diagnosis of obstructive and restrictive lung disease. The FEV1/FVC ratio is used to determine if the pattern is obstructive, restrictive, or normal. Chronic airflow limitation can be generally defined as fixed ratio of forced expiratory volume in 1 s (FEV1) / forced vital capacity (FVC) \< 0.70 after bronchodilation. So the lower the value, the worse the outcome and the pattern. Pre-dose FEV1/FVC at each visit was summarised by treatment group using descriptive statistics.

Time frame: Pre-dose at baseline (V1), week 0 (V2), week 4 (V3), week 12 (V4), week 18 (V5), week 24 (V6)

Change From Baseline in Pre-dose Morning Forced Expiratory Flow Measured Between 25% and 75% of a Forced Vital Capacity (FEF25-75%) at All Clinic Visits

FEF25-75% is defined as "forced expiratory flow over the middle one-half of the FVC; the average flow from the point at which 25% of the FVC has been exhaled to the point at which 75% of the FVC has been exhaled." A reduced FEF25-75% is thought to be a marker of small airway obstruction. Hence, the lower the parameter, the worse the status of airways. Among the various measurements collected during conventional spirometry, forced expiratory flow at 25% and 75% of the pulmonary volume (FEF25-75) measures the average flow rates of medium-to-small airways during the forced vital capacity (FVC) segment to testing and presents the status of those airways in patients. The changes from baseline in pre-dose morning FEF25-75% at baseline and at all subsequent clinic visits are presented by treatment in the ITT population. Please note: adjusted mean is reported with its 95%IC.

Time frame: Pre-dose morning at week 4 (V3), week 12 (V4), week 18 (V5) and week 24 (V6)

Change From Baseline in Pre-dose Morning Inspiratory Capacity (IC) at All Clinic Visits

IC is the maximum volume of air that can be inspired following a normal, quiet expiration and is equal to tidal volume + inspiratory reserve volume. In airflow obstruction, hyperinflation of the lung and chest wall during tidal breathing (and during exercise) increases the work of breathing and contributes to the sensation of dyspnoea. The lower the volume, the worse the outcome and, consequently, the impairment. Please note that adjusted mean is reported with its 95%IC.

Time frame: Pre-dose morning at week 4 (V3), week 12 (V4), week 18 (V5) and week 24 (V6)

Change From Baseline in the Saint George's Respiratory Questionnaire (SGRQ) Total Score at Week 12 and Week 24

The SGRQ measures health impairment in patients with COPD. It is in two parts: Part I produces the Symptoms score, Part 2 the Activity and Impacts scores. Scaling of items * Section I (Symptoms): 5-point Likert * Sections II (Activity) and III (Impacts): Dichotomous (yes/no) Total score=(Summed weights from positive items in the SGRQ / Sum of weights for all items in the SGRQ) x 100. Lower the scores, better the health. Each item is "weighted" empirically. Scores range from 0 to 100, higher scores mean poor health. Part 1(Q 1-8) covers the patients' recollection of their symptoms over a preceding period that may range 1 month to 1 year. Part 2 (Q 9-16) addresses patients' current state. Activity score just measures disturbances to patients daily physical activity. Impacts score covers a wide range of disturbances of psycho-social function. Please note: adjusted mean is reported with its 95%IC.

Time frame: At weeks 12 and 24

Change From Baseline in the Number of Patients With SGRQ Total Score ≤ -4 (Defined as "Responders") at Week 24

The percentage of patients classified as SGRQ total score responders (i.e. change from baseline in total score ≤ -4) at Week 24 was reported. SGRQ response = Change from baseline in total score ≤ -4; SGRQ non-response = Change from baseline in total score \> -4 or missing data.

Time frame: At week 24

Changes From Baseline in Chronic Obstructive Pulmonary Disease (COPD) Assessment Test (CAT) at All Clinical Visits

The COPD assessment test (CAT) is a self-administered questionnaire assessing globally the impact of COPD (cough, sputum, dysnea, chest tighteness) on health status. It's a simple, eight-item/question, health status instrument for patients with COPD to define the level of its impact on daily life. Each item can score from 0 (best outcome) to 5 (worst outcome). Hence, CAT total score, which is the sum of the single items' scores, ranges from 0 to 40. Higher scores denote a more severe impact of COPD on a patient's life. No target score represents the best achievable outcome. Please note that adjusted mean is reported with its 95%IC.

Time frame: At week 4 (V3), week 12 (V4), week 18 (V5) and week 24 (V6)

Change From Baseline to Each Inter-Visit Period and to the Entire Randomised Treatment Period in the Percentage of Days Without Intake of Rescue Medication

The percentage (%) of days without intake of rescue medications was evaluated on the basis of the infos recorded daily by each patient. The % of days in the run-in period was calculated as follows: % of days without rescue medication = (Number of days without rescue medication during the run-in period / Number of days with consistent data recorded during this period)\*100. The % of days in each inter-visit period during the randomised treatment period was calculated as follows: • % of days without rescue medication = (Number of days without rescue medication during the inter-visit period / Number of days with consistent data recorded during this period)\*100. The % of days in the entire randomised treatment period was calculated as follows: • % of days without rescue medication = (Number of days without rescue medication during the randomised treatment period / Number of days with consistent data recorded during this period)\*100.

Time frame: Weeks 1-4 (V2-V3); Weeks 5-12 (V3-V4); Weeks 13-18 (V4-V5); Weeks 19-24 (V5-V6); Weeks 1-24 (randomised treatment period)

Change From Baseline to Each Inter-Visit Period and to the Entire Treatment Period in the Average Use of Rescue Medication (Number of Puffs/Day)

The average use of rescue medication is expressed in "puffs/day". Data on each interval indicated in the timeframe and over the 24-week of the randomised treatment period is presented.

Time frame: Weeks 1-4 (V2-V3); Weeks 5-12 (V3-V4); Weeks 13-18 (V4-V5); Weeks 19-24 (V5-V6); Weeks 1-24 (randomised treatment period)

EQ-5D-3L Index at All Clinic Visits

The EQ-5D-3L (euro quality of life) consists of the EQ-5D descriptive system and the EQ VAS. The EQ-5D descriptive system comprises 5 dimensions: * mobility * self-care * usual activities * pain/discomfort * anxiety /depression. Each dimension has 3 levels: no problems, some problems, extreme problems. A unique health state is defined by combining 1 level from each of the 5 dimensions. There are 243 possible health states/sequences defined in this way. Each state is referred to in terms of a 5-digit code (for example 11223). The 243 theoretical possible sequences can then be mapped to an index value to provide a summary across all dimensions. For the calculation of the index value, the Time Trade-Off method was used. The index can range from 1 (full health) to 0 (worst health).

Time frame: At week 0 (V2), week 12 (V4) and week 24 (V6)

EQ-5D-3L VAS Scores at All Clinic Visits

The EQ-5D-3L (euro quality of life) consists of the EQ-5D descriptive system and the EQ VAS. The EQ VAS records the patient's self-rated health on a vertical, visual analogue scale where the endpoints are 'Worst imaginable health state' (0) and 'Best imaginable health state' (100).

Time frame: At week 0 (V2), week 12 (V4) and week 24 (V6)

Total Number of Hospital Admissions Due to COPD and to Other Causes

This health-economic outcome is expressed by the number of Hospital Admissions due to COPD and to Other Causes overall.

Time frame: From baseline to week 24 (V6)

Total Number of Oxygen Therapy Use Due to COPD

This health-economic outcome is expressed by the number of oxygen therapy use due to COPD.

Time frame: From baseline to week 24 (V6)

Total Number of Unplanned Diagnostic or Instrumental Tests Performed Due to COPD

This health-economic outcome is expressed by the number of Diagnostic or Instrumental tests performed due to COPD.

Time frame: From baseline to week 24 (V6)

Number of Adverse Events (AEs) and Adverse Drug Reactions (ADRs)

AE=An untoward medical occurrence after exposure to a medicine, which is not necessarily caused by that medicine. Serious AE= An adverse event that results in death, is life-threatening, requires hospitalisation or prolongation of existing hospitalisation, results in persistent or significant disability or incapacity, or is a birth defect. ADR=A response to a medicinal product which is harmful and unintended. Response in this context means that a causal relationship between the medicinal product and an adverse event is at least a reasonable possibility Serious ADR=An adverse reaction that results in death, is life-threatening, requires hospitalisation or prolongation of existing hospitalisation, results in persistent or significant disability or incapacity, or is a birth defect. Severe AE= "Severe" refers to the intensity of an AE; the event itself may be of relatively minor medical significance but intense.

Time frame: From baseline to week 24 (V6)

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

Overview

Conditions

Interventions

Eligibility

Locations (64)

Outcomes

Primary Outcomes

Secondary Outcomes