Study on Foster Efficacy Maintenance and Reliever vs Foster Maintenance + Salbutamol Reliever in Asthmatics (MART2)

A severe asthma exacerbation was defined as asthma worsening resulting in hospitalization or emergency room treatment due to asthma worsening, or the need for systemic steroids for ≥ 3 days because of asthma. First severe asthma exacerbation occurred after the first dose of randomised study drug and within end of study was considered for the analysis. Patients without a severe asthma exacerbation or withdrawn before having it, are considered as 'censored' at the last day in the study or at the time of the withdrawal.

Since the median time (50th percentile) and the other key percentiles (25th and 75th) were not reached, the median time of first exacerbation is not available (N.A.). So, to provide meaningful information, the cumulative number of patients who experienced a severe exacerbation at the end of each time period was reported separately.

A severe asthma exacerbation was defined as asthma worsening resulting in hospitalization or emergency room treatment due to asthma worsening, or the need for systemic steroids for ≥ 3 days because of asthma. First severe asthma exacerbation occurred after the first dose of randomised study drug and within end of study was considered for the analysis. Patients without a severe asthma exacerbation or withdrawn before having it, are considered as 'censored' at the last day in the study or at the time of the withdrawal.

As already anticipated in the primary endpoint, since the median time (50th percentile) and the other key percentiles (25th and 75th) were not reached, and the median time of first exacerbation is not available (N.A.), to provide meaningful information, the cumulative number of patients who experienced a severe exacerbation at the end of each time period is here reported.

A severe asthma exacerbation was defined as asthma worsening, resulting in hospitalization or emergency room treatment due to asthma worsening, or the need for systemic steroids for ≥ 3 days. As per the outcome measure title, the total number of severe exacerbations (this outcome), of hospitalisations/emergency room treatment, of systemic corticosteroids use (other outcomes) is expressed as rate (events per 100 patients per year) and compared between arms.

Please note that in case of two close severe asthma exacerbations (start date of a severe asthma exacerbation is less than 10 days from the stop date of the previous severe asthma exacerbation), only the first was counted for the analysis.

Systemic corticosteroids courses to treat asthma started at or after the first dose of randomised study drug and with at least one day from the stop date of a systemic corticosteroids course and the start date of the following one have been considered for analysis. As per the outcome measure title, the total number of severe exacerbations (other outcome), of hospitalisations/emergency room treatment (other outcome), of systemic corticosteroids use (this outcome) is expressed as rate (events per 100 patients per year) and compared between arms.

Hospitalization or emergency room treatment due to asthma started at or after the first dose of randomised study drug was be considered for the analysis.

As per the outcome measure title, the total number of severe exacerbations (another outcome), of hospitalisations/emergency room treatment (this outcome), of systemic corticosteroids use (other outcomes) is expressed as rate (events per 100 patients per year) and compared between arms.

The Asthma Control Questionnaire is a tool used to asses how well a participant asthma is controlled and consists of seven questions scored. On average/in general, during the past week 0 (no impairment), 6 (maximum impairment for symptoms).

• how often were you woken by your asthma during the night?
• how bad were your asthma symptoms when you woke up in the morning?
• how limited were you in your activities because of your asthma?
• how much shortness of breath did you experience because of your asthma?
• how much of the time did you wheeze?
• how many puffs/inhalations of short-acting bronchodilator have you used each day?
• FEV1 pre-bronchodilator, FEV1 predicted FEV1 % predicted (by clinical staff)

The ACQ total score has been calculated as the mean of the seven question scores ranging from 0 (totally controlled) and 6 (severely uncontrolled). Higher scores indicate the worse outcomes. Adjusted means were reported.

A mild asthma exacerbation was defined as two consecutive mild asthma exacerbation days satisfying the same criterion. In case periods satisfying different criteria overlapping, only one mild asthma exacerbation was considered. In case of two close mild asthma exacerbations (start date of a mild asthma exacerbation is less than 7 days from the stop date of the previous mild asthma exacerbation), only the first was counted for the analysis. Mild asthma exacerbations occurred at or after the first dose of randomised study drug and within end of study is considered for the analysis.

As per the outcome measure title, the total number of mild asthma exacerbations is expressed as rate (events per 100 patients per year) and compared between arms.

A mild asthma exacerbation was defined as two consecutive mild asthma exacerbation days satisfying the same criterion. In case periods satisfying different criteria overlapping, only one mild asthma exacerbation was considered. In case of two close mild asthma exacerbations (start date of a mild asthma exacerbation is less than 7 days from the stop date of the previous mild asthma exacerbation), only the first was counted for the analysis. Total number of mild asthma exacerbation events were reported. Mild asthma exacerbations occurred at or after the first dose of randomised study drug and within end of study is considered for the analysis.

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A "mild asthma exacerbation" was defined as two consecutive mild asthma exacerbation days satisfying the same criterion. In case periods satisfying different criteria overlapping, only 1 mild exacerbation was considered. In case of two close mild exacerbations (start date of a mild exacerbation is less than 7 days from the stop date of the previous mild exacerbation), only the first was counted for the analysis. First mild exacerbation occurred after the first dose of randomised study drug and within end of study is considered for the analysis.

In patient with at least one mild exacerbation, the time to first mild exacerbation was calculated as the time in days between the first dose of randomised study drug (derived) and the time at which the first mild exacerbation occurs (date of the first day of the first mild exacerbation).

Time to first mild asthma exacerbation (days) = (date of first day of first mild exacerbation - date of first dose of randomised study drug (derived)) +1

PEF is measured twice a day (morning and evening) with Spirotel, a portable electronic peak flow meter. PEF measurement recorded in the morning of the day of each clinic visit was considered as data of the period before clinic visit. During each measurement session (morning or evening before the intake of the study medication) the participant performed 3 blows and only the best PEF parameter was saved into the Spirotel memory.

PEF is measured twice a day (morning and evening) with Spirotel. PEF measurement recorded in the morning of the day of each clinic visit was considered as data of the period before clinic visit. During each measurement session (morning or evening before the intake of the study medication) the participant will perform 3 blows and only the best PEF parameter will be saved into the Spirotel memory.

The variability of PEF of a day will be calculated using the Best PEF morning and the Best PEF evening recorded in the same day. Variability of PEF is measured daily with Spirotel using the following formula:

Best PEF evening - Best PEF morning/Best PEF evening + Best PEF morning/2 X 100

FEV1 is a measure of lung function and is defined as the maximal amount of air that can be forcefully exhaled in one second. FEV1 was measured using spirometry, conducted at baseline and all clinical visits. An increase in FEV1 reflects improved airway patency, while a decrease suggests worsening obstruction. Higher FEV1 values indicate better lung function. Adjusted means were reported.

FEF is a lung function test and is measured using the spirometery. The FEF25%-75% is the forced expiratory flow from 25% to 75% of FVC. FEF25%-75% measurement is conducted at baseline and all clinical visits. An increase in FEF25%-75% reflects improved airway patency, while a decrease suggests worsening obstruction. Higher FEF25%-75% values indicate better lung function. Adjusted means were reported.

The asthma symptoms are: cough, wheeze, chest tightness and breathlessness. Each morning and evening asthma symptoms are to be scored, as respectively occurred during the night and during the day, as follows:

Night-time asthma symptom score: 0 = No symptom, 1 = Mild: symptoms not causing awakening, 2 = Moderate: discomfort enough to cause awakening, 3 = Severe: causing awakening for most of the night / do not allow to sleep at all

Day-time asthma symptom score: 0 = No symptom, 1 = Mild: aware of symptoms which can be easily tolerated, 2 = Moderate: discomfort enough to cause interference with daily activity, 3 = Severe: incapacitating with inability to work / take part in usual activity

Total asthma symptoms score was calculated as the sum of the day-time and the night-time asthma symptoms score recorded on the following day and score ranges from 0 to 6, higher score indicates worse symptoms.

The daily use of reliever medication was calculated as sum of the number of puffs taken during the day and the number of puffs taken during the night recorded on the following day. In case one session in a day is missing, only the available session (evening or morning) was considered for the daily use of reliever medication. A minimum of seven evaluable measurements are required in each two-week treatment period and during the two-weeks of the run-in period (baseline).

Asthma symptom-free days are days with the total asthma symptom score equal to zero. Percentage of asthma symptom-free days will be calculated in each two-week period using the following formula:

% of asthma symptoms- free days = Number o f asthma symptoms- free days in that two - week period/Number o f days with data recorded for asthma symptom scores in that two - week period X 100.

A day without reliever medication is a day in which the number of puffs of reliever medication taken in the 24 hours is zero. A day will be considered as missing if both measurements (evening and morning) are missing. A day will be considered as "not-free" if one session is recorded and the other is missing. Percentage of reliever medication-free days will be calculated in each two-week period using the following formula:

% of reliever medication-free days = Number of reliever medication-free days in that two -week period/Number of days with data recorded for reliever medication in that two -week period X 100

Asthma control day is a day with total asthma symptom score equal to zero and without use of reliever medication. A day will be considered as missing if both measurements (evening and morning) are missing. A day will be considered as "not control" if one session is recorded and the other is missing. Percentage of asthma control days will be calculated in each two-week period using the following formula:

% of asthma control days = Number of asthma control days in that two -week period/Number of days with data recorded for asthma symptom scores and reliever medication in that two-week period X100

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.

Use of reliever medication was derived from the data of SpirotelTM. The event "more than six reliever medications per day for two consecutive days" is defined as at least two consecutive days with more than six puffs of reliever medication in the day.