Trial Outcomes & Findings for Triple in Asthma Dose Finding (NCT NCT02127866)

This multinational study was conducted at 44 clinical sites (43 active) in 6 countries. The recruitment took place in: Bulgaria (10 sites) Germany (8 sites) Hungary (7 sites) Italy (5 sites: 4 active and 1 non-active) Poland (12 sites) UK (2 sites)

Screening details: A total of 322 patients were screened, of whom 211 were randomised to one of the following treatment sequence groups: * Sequence A-C-B: n = 53; * Sequence B-D-C: n = 53; * Sequence C-A-D: n = 53; * Sequence B-D-A: n = 52.

Triple in Asthma Dose Finding

FEV1 = Forced expiratory volume in the first second. AUC0-12h = area under the curve between the time 0 and 12 hours. Post-dose FEV1 on Day 42 of each treatment period was recorded at 15'; 30'; 45'; 1h; 2h; 3h, 4h,6h,8h, 11h30 and 12h post-study drug intake. The baseline FEV1 was the average FEV1 recorded on Day 1 at 45 and 10 minutes prior to study intake.

Change from Baseline in peak FEV1 on Day 42 is the study key secondary outcome. It represents the maximum value of all FEV1 assessments from 15 minutes to 12 hours post-dose of the respective day. Post-dose FEV1 on Day 42 of each treatment period was recorded at 15'; 30'; 45'; 1h; 2h; 3h, 4h, 6h, 8h, 11h30 and 12h post-study drug intake. Baseline is the average of the FEV1 pre-dose measurements on Day 1 of each period (recorded at 45 and 10 minuted prior to study drug intake).

AUC0-3h = area under the curve between time 0 and 3 hours. The pre-dose and post-dose lung function assessments were recorded under supervision at the following timing: * Pre-dose FEV1 on Day 1 at 45 and 10 minutes prior to study drug intake (baseline FEV1); * Post-dose FEV1 on Day 1 of each treatment period: at 15'; 30'; 45'; 1h; 2h; 3h post-study drug intake.

AUC0-3h = area under the curve between time 0 and 3 hours. The pre-dose and post-dose lung function assessments were recorded under supervision at the following timings: * Pre-dose FEV1 on Day 1 at 45 and 10 minutes prior to study drug intake (baseline FEV1); * Post-dose FEV1 on Day 42 of each treatment period: at 15'; 30'; 45'; 1h; 2h; 3h post-study drug intake.

The pre-dose morning FEV1 is defined as the mean of the two measurements at 45 and 10 minutes predose.

The pre-dose morning FEV1 is defined as the mean of the two measurements at 45 and 10 minutes predose.

Trough FEV1 at 12 hours is determined as the average of the 11.5 and 12 hours post-dose FEV1 assessments. Baseline value is the mean of the pre-dose measurement of FEV1 at Day 1 of each treatment period recorded at 45 and 10 minutes prior to study drug intake.

Trough FEV1 at 12 hours is determined as the average of the 11.5 and 12 hours post-dose FEV1 assessments. Baseline value is the mean of the pre-dose measurement of FEV1 at Day 1 of each treatment period recorded at 45 and 10 minutes prior to study drug intake.

Peak FEV1 represents the maximum value of all FEV1 assessments from 15 minutes to 12 hours post-dose of the respective day (in this case on Day 1). Post-dose FEV1 on Day 1 of each treatment period was recorded at 15'; 30'; 45'; 1h; 2h; 3h, 4h,6h, 8h, 11h30 and 12h post-study drug intake. Baseline is the average of the FEV1 pre-dose measurements on Day 1 of each period (recorded at 45 and 10 minuted prior to study drug intake).

AUC0-12h = area under the curve between time 0 and 12 hours. Post-dose FEV1 on Day 1 of each treatment period was recorded at 15'; 30'; 45'; 1h; 2h; 3h, 4h,6h, 8h, 11h30 and 12h post-study drug intake. The baseline FEV1 was the average FEV1 recorded on Day 1 at 45 and 10 minutes prior to study intake.

ACQ-7 allows identification of the adequacy of asthma control in individual patients. The first 6 items of the questionnaire refer to symptoms and rescue use in the previous 7 days (patients were asked to recall how their asthma was during the previous week and to respond to the symptom and bronchodilator use questions on a 7-point scale with 0 = no impairment and 6 = maximum impairment); the 7th item relates to FEV1 (completed by the clinical staff), used the value of FEV1 % of predicted when reversibility was met at screening (Week -2) and considering the pre-dose FEV1 % of predicted taken at -15 minutes at the visit. The 7th item ranges as well from 0 (best value) to 6 (worst value). The questions are equally weighted and the ACQ total score is the mean of the 7 questions and therefore between 0 (asthma totally controlled) and 6 (asthma severely uncontrolled).

FVC=Forced vital Capacity Pre-dose FVC was recorded on Day 14 at 45 minutes and 10 minutes prior to study drug intake.

FVC=Forced Vital Capacity. Pre-dose FVC was recorded on Day 42 at 45 minutes and 10 minutes prior to study drug intake.

The peak FVC is the maximum FVC value obtained between 15 minutes and 12 hours post-dose. Post-dose FVC on Day 1 of each treatment period was recorded at 15'; 30'; 45'; 1h; 2h; 3h, 4h,6h, 8h, 11h30 and 12h post-study drug intake. Baseline is the average of the FVC pre-dose measurements on Day 1 of each period (recorded at 45 and 10 minuted prior to study drug intake).

The peak FVC is the maximum FVC value obtained between 15 minutes and 12 hours post-dose. Post-dose FVC on Day 1 of each treatment period was recorded at 15'; 30'; 45'; 1h; 2h; 3h, 4h,6h, 8h, 11h30 and 12h post-study drug intake. Baseline is the average of the FVC pre-dose measurements on Day 1 of each period (recorded at 45 and 10 minuted prior to study drug intake).

The baseline FVC is the mean of the pre-dose measurements recorded on Day 1 of each treatment period. Post-dose FVC was recorded at 15'; 30'; 45'; 1h; 2h; 3h, 4h,6h, 8h, 11h30 and 12h post-study drug intake on Day 1. Only change from baseline at the last timepoint (12h post-dose) on Day 1 is reported in the system.

The baseline FVC is the mean of the pre-dose measurements recorded on Day 1 of each treatment period. Post-dose FVC was recorded at 2h on Day 14.

The baseline FVC is the mean of the pre-dose measurements recorded on Day 1 of each treatment period. Post-dose FVC was recorded at 15'; 30'; 45'; 1h; 2h; 3h, 4h,6h, 8h, 11h30 and 12h post-study drug intake on Day 42. Only change from baseline at the last timepoint (12h post-dose) on Day 42 is reported in the system.

Baseline is the average of the pre-dose measurements of FEV1 Percentage of Predicted Normal Value. Measurements were done: 15 min, 30 min, 45 min, 1h, 2h, 3h, 4h, 6h, 8h, 11h and 30 min, 12h post-dose on Day 1. Only data about the change from baseline at the last timepoint (12h post-dose) of the Day 1 are reported in the database.

Baseline is the average of the pre-dose measurements of FEV1 Percentage of Predicted Normal Value. Measurements were done 2h post-dose on Day 14. Only the change from baseline (not the actual value) is reported in the database.

Baseline is the average of the pre-dose measurements of FEV1 Percentage of Predicted Normal Value. Measurements were done: 15 min, 30 min, 45 min, 1h, 2h, 3h, 4h, 6h, 8h, 11h and 30 min, 12h postdose on Day 42. Only data about the change from baseline at the last timepoint (12h post-dose) of the Day 42 are reported in the database.

PEF (L/min) was monitored by patients at home, twice daily using a portable e-peak flow meter, before the intake of the run-in medication or study medication: in the morning (between 7:00 am and 9:00 am) and in the evening (7:00 pm and 9:00 pm). An alarm reminded the patients to perform measurements. During each measure, 3 blows were performed and data recorded in the device. Average Daily PEF morning is the mean value of all morning measurements of Peak Expiratory Flow (PEF) = Σ all morning measurements of PEF / number of days with available data

PEF (L/min) was monitored by patients at home, twice daily using a portable e-peak flow meter, before the intake of the run-in medication or study medication: in the morning (between 7:00 am and 9:00 am) and in the evening (7:00 pm and 9:00 pm). An alarm reminded the patients to perform measurements. During each measure, 3 blows were performed and data recorded in the device. Average Daily PEF evening is the mean of all evening measurements of Peak Expiratory Flow (PEF) = Σ all evening measurements of PEF / number of days with available data

Asthma symptoms (cough, wheeze, chest tightness and breathlessness) were recorded, always before PEF measurements, twice daily - morning and evening - through the \[ as follows: Morning (nighttime) asthma symptom score (ranging 0-3, where the lower the score the better the outcome): 0=No symptom 1. Mild: symptoms not causing awakening 2. Moderate: discomfort causing awakenings 3. Severe: causing awakenings for most of the night / don't allow to sleep at all. The average score of each symptom is the mean value of all measurements. Total average Daily Asthma Symptoms score nighttime = Σ \[Cough nighttime score + Wheeze nighttime score + Chest Tightness nighttime score + Breathlessness nighttime score\] / Number of days with available data. The average of nighttime asthma symptoms is the mean value of all nighttime measurements, ranging from 0 (no symptoms) to 12 (maximum severity). The lower the score, the better the symptom.

Asthma symptoms (cough, wheeze, chest tightness and breathlessness) were recorded, always before PEF measurements, twice daily - morning and evening - on the ediary as follows: Evening (daytime) asthma symptom score (ranging 0-3, where the lower the score the better the outcome): 0=No symptom 1. Mild: symptoms which can be easily tolerated 2. Moderate: discomfort causing interference with daily activity 3. Severe: incapacitating with inability to work/take part in usual activity. The average score of each symptom is the mean value of all measurements. Total average Daily Asthma Symptoms score daytime = Σ \[Cough daytime score + Wheeze daytime score + Chest Tightness daytime score + Breathlessness daytime score\] / Number of days with available data. The average of daytime asthma symptoms is the mean value of all daytime measurements, ranging from 0 (no symptoms) to 12 (maximum severity). The lower the score, the better the symptom.

The percentage is calculated as the number of asthma control days / number of days with available data. If there are less than 20 non-missing values, the percentage of control days was considered missing. "Asthma control day", derived from patient diary data, is defined as any day during the treatment period that fulfils criteria: 1. Days with a total asthma score of 0; 2. No rescue medication use. The adjusted mean percentage (of asthma control days) is reported.

The average use of rescue medication (number of puffs per day) is determined as the total number of puffs of rescue mediation taken / number of days with available data.

The average use of rescue medication (number of times per day) is determined as the total number of times of rescue medication taken/ number of days with available data.

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.