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

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.

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.

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.

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.

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.

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).

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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).

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).

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

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

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

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.