Trial Outcomes & Findings for TRIple in Asthma hiGh strenGth vErsus Ics/Laba hs and tiotRopium (TRIGGER) (NCT NCT02676089)

Overall, 2100 patients were screened according to inclusion and exclusion criteria; of these,1437 patients were randomised. Overall, 6 patients were randomised in error and did not start treatment (N=2 in the CHF 5993 pMDI 200/6/12.5 μg group, N=3 in the CHF 1535 pMDI 200/6 μg group, and N=1 in CHF 1535 pMDI 200/6 μg + tiotropium 2.5 µg group ). The data set Safety population used for the evaluations represents 1431 patients.

Row population differs from the 'Overall' number of subjects because only smokers are considered for the baseline characteristic.

Change from baseline in pre-dose FEV1, analysed at Week 26 of treatment. FEV1=Forced expiratory volume in the first second

Asthma exacerbation intensity: Moderate AND Severe Asthma Exacerbation Severe: asthma worsening requiring initiation of treatment with systemic corticosteroids for at least 3 days (courses of corticosteroids separated by ≥1 week treated as separate severe exacerbations). Moderate: ≥1 of the following criteria fulfilled and leading to a change in treatment (sustained increase of ≥1 puff of short acting beta 2-agonist \[SABA\] for 2 consecutive days) as shown below: * Nocturnal awakening(s) due to asthma requiring SABA for 2 consecutive nights/increase of ≥ 0.75 from baseline in daily symptom score on 2 consecutive days; increase from baseline in occasions of SABA use on 2 consecutive days (minimum increase 4 puffs/day); * ≥20% decrease in peak expiratory flow from baseline on at least 2 consecutive mornings/evenings or ≥ 20% decrease in FEV1 from baseline; * Visit to the ER/trial site for asthma treatment not requiring systemic corticosteroid;

Peak peak of forced expiratory volume in the first second (FEV1) within 3 hours post-dose. FEV1=Forced expiratory volume in the first second

Change from baseline in the average morning PEF (Litre/min), measured by patients at home over the 26-week treatment period (i.e., up to Week 26). PEF=Peak Expiratory Flow; is the maximal airflow forcefully expelled from the lungs in one quick exhalation.

Severe asthma exacerbation rate over the 52-Week treatment period in a pre-specified pooled analysis of 2 pivotal studies CCD-05993AB1-03 (TRIMARAN) and CCD-05993AB2-02 (TRIGGER). The pooled analysis of pivotal studies TRIMARAN and TRIGGER was a pre-specified secondary outcome measure for this study. Both studies have identical design, duration, endpoints, data collection, and statistical methodology for analyses. TRIMARAN and TRIGGER enrolled patients under medium dose and high dose ICS/LABA, respectively. Both studies were designed to assess the effect of the LAMA on ICS/LABA and showed homogeneity in terms of baseline characteristics, thus confirming the appropriateness of the pooling.

The peak (0-3h) FEV1 at baseline and at all subsequent visits, and the respective changes from baseline are presented by treatment group for all clinical visits. Baseline for pre-dose FEV1 was calculated as average of the FEV1 measurements (L) from the visit 2 (V2) Pre45min \& V2 Pre15min. If one of the two pre-dose values was missing, the baseline was equal to the available pre-dose value. FEV1=Forced expiratory volume in the first second

Results show the change from baseline in pre-dose FEV1 at all clinical visits. FEV1=Forced expiratory volume in the first second

Results show the percentage of patients classified as FEV1 responders at Week 26 and at Week 52. The FEV1 response was defined as: Change from baseline in pre-dose morning FEV1 ≥ 100 mL. FEV1=Forced expiratory volume in the first second

Baseline definition: mean of two pre-dose FEV1 measurements at visit 2 (V2). Results show the change from baseline in FEV1 area under the curve \[AUC\] (0-3h) at all subsequent visits (i.e. change from baseline of the AUC of the serial post-dose spirometry assessments till 3h post-dose). FEV1=Forced expiratory volume in the first second

ACQ-7 Questionnaire. ACQ-7 allows assessment of asthma control in individual patients. The ACQ-7 measured asthma symptom control and consists of 7 items: 5 on symptom assessment, 1 on rescue medication use and 1 on lung function (FEV1 % predicted). All seven items are scored on a 7-point Likert scale, with 0 indicating total control (no impairment) and 6 indicating poor control (maximum impairment). The questions are equally weighted and the total score is the mean of the seven items. The first 6 questions of the ACQ-7 were completed by the participant while the last question was completed by the study investigator using data from the Master Scope spirometer. Baseline for ACQ-7 was the total score recorded at Visit 2 (Week 0) of the study. The change from Baseline was calculated by subtracting the Baseline values from the individual post-randomization values. A negative change from baseline indicates improvement in lung function.

Asthma Control Questionnaire (ACQ) and Asthma Control Questionnaire-7 (QAC-7) are defined in the description of Outcome measure 10 above. An ACQ-7 response was defined as change from baseline (Week 0, pre-dose) in ACQ-7 score ≤ -0.5; non-response was defined as change from baseline in ACQ-7 score \>-0.5 or missing data. Results represent responders (i.e. change from baseline in ACQ-7 Score ≤ -0.5) at Week 26 and at Week 52.

Change from baseline in average MORNING PEF (L/min) over 52 weeks of treatment. PEF=Peak Expiratory Flow; is the maximal airflow forcefully expelled from the lungs in one quick exhalation.

Change from baseline in average EVENING PEF (L/min) over 26 and 52 weeks of treatment. PEF=Peak Expiratory Flow; is the maximal airflow forcefully expelled from the lungs in one quick exhalation.

Number of patients at risk of a moderate or severe asthma exacerbation. Results show the number of patients who had moderate or severe asthma exacerbation over the 52 weeks treatment period.

Number of patients at risk of a SEVERE asthma exacerbation in the pooled analysis of the two pivotal studies CCD-05993AB1-03 (TRIMARAN) and CCD-05993AB2-02 (TRIGGER), over the 52 weeks treatment period. The pooled analysis of pivotal studies TRIMARAN and TRIGGER was a pre-specified secondary outcome measure for this study. Both studies have identical design, duration, endpoints, data collection, and statistical methodology for analyses. TRIMARAN and TRIGGER enrolled patients under medium dose and high dose ICS/LABA, respectively. Both studies were designed to assess the effect of the LAMA on ICS/LABA and showed homogeneity in terms of baseline characteristics, thus confirming the appropriateness of the pooling.

MODERATE asthma exacerbation rate over the 52-Week treatment period in the pooled analysis of the 2 pivotal studies CCD-05993AB1-03 (TRIMARAN) and CCD-055993AB2-02 (TRIGGER). The pooled analysis of pivotal studies TRIMARAN and TRIGGER was a pre-specified secondary outcome measure for this study. Both studies have identical design, duration, endpoints, data collection, and statistical methodology for analyses. TRIMARAN and TRIGGER enrolled patients under medium dose and high dose ICS/LABA, respectively. Both studies were designed to assess the effect of the LAMA on ICS/LABA and showed homogeneity in terms of baseline characteristics, thus confirming the appropriateness of the pooling.

Number of Patients at Risk of MODERATE Asthma Exacerbation in the Pooled Analysis of the Two Pivotal Studies CCD-05993AB1-03 and CCD-05993AB2-02. The pooled analysis of pivotal studies TRIMARAN and TRIGGER was a pre-specified secondary outcome measure for this study. Both studies have identical design, duration, endpoints, data collection, and statistical methodology for analyses. TRIMARAN and TRIGGER enrolled patients under medium dose and high dose ICS/LABA, respectively. Both studies were designed to assess the effect of the LAMA on ICS/LABA and showed homogeneity in terms of baseline characteristics, thus confirming the appropriateness of the pooling.

Moderate AND severe asthma exacerbation rate over the 52-Week treatment period in the pooled analysis of the 2 pivotal studies CCD-05993AB1-03 (TRIMARAN) and CCD-05993AB2-02 (TRIGGER). The pooled analysis of pivotal studies TRIMARAN and TRIGGER was a pre-specified secondary outcome measure for this study. Both studies have identical design, duration, endpoints, data collection, and statistical methodology for analyses. TRIMARAN and TRIGGER enrolled patients under medium dose and high dose ICS/LABA, respectively. Both studies were designed to assess the effect of the LAMA on ICS/LABA and showed homogeneity in terms of baseline characteristics, thus confirming the appropriateness of the pooling.

Time to first MODERATE OR SEVERE asthma exacerbation in the Pooled Analysis of the 2 Pivotal Studies CCD-05993AB1-03 (TRIMARAN) and CCD-05993AB2-02 (TRIGGER). The pooled analysis of pivotal studies TRIMARAN and TRIGGER was a pre-specified secondary outcome measure for this study. Both studies have identical design, duration, endpoints, data collection, and statistical methodology for analyses. TRIMARAN and TRIGGER enrolled patients under medium dose and high dose ICS/LABA, respectively. Both studies were designed to assess the effect of the LAMA on ICS/LABA and showed homogeneity in terms of baseline characteristics, thus confirming the appropriateness of the pooling.

MODERATE asthma exacerbation rate over the 52-Week treatment period. Asthma exacerbation intensity: Moderate: ≥1 of the following criteria fulfilled and leading to a change in treatment (sustained increase of ≥1 puff of short acting beta 2-agonist \[SABA\] for 2 consecutive days) as shown below: * Nocturnal awakening(s) due to asthma requiring SABA for 2 consecutive nights/increase of ≥ 0.75 from baseline in daily symptom score on 2 consecutive days; increase from baseline in occasions of SABA use on 2 consecutive days (minimum increase 4 puffs/day); * ≥20% decrease in peak expiratory flow from baseline on at least 2 consecutive mornings/evenings or ≥ 20% decrease in FEV1 from baseline; * Visit to the ER/trial site for asthma treatment not requiring systemic corticosteroid;

Data were analysed for the number of patients at risk of a MODERATE asthma exacerbation.

Change from baseline in the average use of rescue medication over the 26- and 52-Week treatment periods. Data was collected through an electronic daily diary from screening to the end of the study.

Results show the change from baseline in the average use (puffs/day) of rescue medication in each inter-visit period. Data was collected through an electronic daily diary from screening to the end of the study.

Change from baseline in the percentage of rescue medication-free days over the 26- and 52-Week treatment periods. Data was collected using an electronic daily diary, from screening to the end of the study.

Results show the change from baseline in the percentage of rescue medication-free days in each inter-visit period over the entire treatment. Data was collected through an electronic daily diary from screening to the end of the study.

Results show the change from baseline in the average total daily asthma symptom scores over the 26- and 52-Weeks of treatment. A day represents data recorded in the evening session of that day plus the data recorded in the morning session of the next day. Symptoms considered: cough, wheeze, chest tightness, breathlessness. Morning (night-time asthma symptom score): * 0 No symptoms; * 1 Mild = Symptoms not causing awakening; * 2 Moderate = Discomfort enough to cause awakenings; * 3 Severe = Causing awakenings for most of the night/did not sleep at all. Evening (daytime asthma symptom score): * 0 No symptoms; * 1 Mild = Aware of symptoms, which could be easily tolerated; * 2 Moderate = Discomfort enough to cause interference with daily activity; * 3 Severe = Incapacitating

Results show the change from baseline in the average total daily asthma symptom scores over the 26- and 52-Weeks of treatment. A day represents data recorded in the evening session of that day plus the data recorded in the morning session of the next day. Symptoms considered: cough, wheeze, chest tightness, breathlessness. Morning (night-time asthma symptom score): * 0 No symptoms; * 1 Mild = Symptoms not causing awakening; * 2 Moderate = Discomfort enough to cause awakenings; * 3 Severe = Causing awakenings for most of the night/did not sleep at all. Evening (daytime asthma symptom score): * 0 No symptoms; * 1 Mild = Aware of symptoms, which could be easily tolerated; * 2 Moderate = Discomfort enough to cause interference with daily activity; * 3 Severe = Incapacitating

Change from baseline in the percentage of asthma symptom-free days over the 26- and 52-Week treatment periods. Data was collected through an electronic daily diary from screening to the end of the study. Results show the change from baseline in the average daily asthma symptom scores over the 26- and 52-Week treatment periods. A day represents data recorded in the evening session of that day plus the data recorded in the morning session of the next day. Symptoms considered by the questionnaire: cough, wheeze, chest tightness, breathlessness. An asthma symptom-free day is a day with total daily asthma symptom score = 0. For a description of the score see outcome measure number 23.

Results show the change from baseline in the percentage of asthma symptom-free days in each inter-visit periods over the entire treatment. Data was collected through an electronic daily diary from screening to end of the study. A day represents data recorded in the evening session of that day plus the data recorded in the morning session of the next day. Symptoms considered by the questionnaire: cough, wheeze, chest tightness, breathlessness. An asthma symptom-free day is a day with total daily asthma symptom score = 0. For a description of the score see outcome measure number 23.

Results show the change from baseline in the percentage of asthma control days over the 26- and 52-Week treatment periods. Data was collected through an electronic daily diary from screening to the end of the study. Scoring of asthma symptoms (overall symptoms, cough, wheeze, chest tightness and breathlessness): Morning (night-time asthma symptoms): 0 (no symptoms), 1 (mild - symptoms not causing awakening), 2 (moderate - discomfort enough to cause awakenings) and 3 (severe - causing awakenings for most of the night/did not sleep at all). Evening (daytime asthma symptoms): 0 (no symptoms), 1 (mild: aware of symptoms that could 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).

A day represents data recorded in the evening session of that day plus the data recorded in the morning session of the next day. Data was collected through an electronic daily diary from screening to the end of the study. Scoring of asthma symptoms (overall symptoms, cough, wheeze, chest tightness and breathlessness): Morning (night-time asthma symptoms): 0 (no symptoms), 1 (mild - symptoms not causing awakening), 2 (moderate - discomfort enough to cause awakenings) and 3 (severe - causing awakenings for most of the night/did not sleep at all). Evening (daytime asthma symptoms): 0 (no symptoms), 1 (mild: aware of symptoms that could 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).