TRIple in Asthma hiGh strenGth vErsus Ics/Laba hs and tiotRopium (TRIGGER)

3_Change From Baseline in Peak(0-3h) FEV1 at Week 26

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

Time frame: Week 0 (pre-treatment, baseline) and Week 26.

4_Change From Baseline in Morning Peak Expiratory Flow (PEF) Over the 26-Week Treatment

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.

Time frame: Week 0 (pre-treatment, baseline) to Week 26.

5_Severe Asthma Exacerbation Rate Over the 52-Week Treatment Period - Pooled Analysis

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.

Time frame: The entire treatment period; up to Week 52.

6_Change From Baseline in Peak FEV1 (0-3h) at All Clinical Visits

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

Time frame: Week 0 (pre-treatment, baseline) to Week 52.

7_Change From Baseline in Pre-Dose FEV1 at All Clinical Visits

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

Time frame: Week 0 (pre-treatment, baseline) to Week 52.

8_FEV1 Response (FEV1 ≥ 100 mL) at Week 26 and Week 52

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

Time frame: Week 0 (pre-treatment, baseline) to Week 26 and Week 52.

9_Change From Baseline in FEV1 Area Under the Curve (AUC) (0-3h) Normalised by Time at All Clinical Visits

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

Time frame: Week 0 (pre-treatment, baseline) to Week 52.

10_Change From Baseline in the Asthma Control Questionnaire-7 (ACQ-7) Score at All Clinical Visits

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.

Time frame: Week 0 (pre-treatment, baseline) to Week 52.

11_Asthma Control Questionnaire©-7 Response at Week 26 and Week 52

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.

Time frame: Week 0 (pre-treatment, baseline) to Week 26 and Week 52.

12_Change From Baseline in Average Morning PEF (L/Min) Over 52 Weeks of Treatment

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.

Time frame: Week 0 (pre-treatment, baseline) to Week 52.

12a_Change From Baseline in Average Evening PEF (L/Min) Over 26 and 52 Weeks of Treatment

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.

Time frame: Week 0 (pre-treatment, baseline) to Week 26 and Week 52.

13_Number of Patients at Risk of Moderate or Severe Asthma Exacerbation Over 52 Weeks

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.

Time frame: Week 0 (pre-treatment, baseline) to Week 52.

14_Number of Patients at Risk of Severe Asthma Exacerbation in the Pooled Analysis of the Two Pivotal Studies CCD-05993AB1-03 and CCD-05993AB2-02

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.

Time frame: Week 0 (Baseline) to 52 weeks for both studies in the pooled analysis.

15_Moderate Asthma Exacerbation Rate Over the 52-Week Treatment Period in the Pooled Analysis of the 2 Pivotal Studies CCD-05993AB1-03 and CCD-055993AB2-02.

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.

Time frame: Week 0 (Baseline) to 52 weeks for both studies in the pooled analysis.

16_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

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.

Time frame: Week 0 (Baseline) to 52 weeks for both studies in the pooled analysis.

17_Moderate and Severe Asthma Exacerbation Rate Over the 52-Week Treatment Period in the Pooled Analysis of the 2 Pivotal Studies CCD-05993AB1-03 and CCD-055993AB2-02

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 frame: Week 0 (Baseline) to 52 weeks for both studies in the pooled analysis.

18_Number of Patients at Risk of Moderate OR Severe Asthma Exacerbation in the Pooled Analysis of the Two Pivotal Studies CCD-05993AB1-03 and CCD-05993AB2-02

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.

Time frame: Week 0 (Baseline) to 52 weeks for both studies in the pooled analysis.

19_Moderate Asthma Exacerbation Rate Over the 52-Week Treatment Period

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;

Time frame: Week 0 (pre-treatment, baseline) to Week 52.

20_Number of Patients at Risk of a MODERATE Asthma Exacerbation

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

Time frame: Week 0 (pre-treatment, baseline) to Week 52.

21_Change From Baseline in the Average Use of Rescue Medication Over the 26- and 52-Week Treatment Periods

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.

Time frame: Week 0 (pre-treatment, baseline) to Week 26 and Week 52.

21a_Change From Baseline in the Average Use of Rescue Medication in Each Inter-Visit Period

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.

Time frame: Week 0 (pre-treatment, baseline) to Week 52.

22_Change From Baseline in the Percentage of Rescue Medication-Free Days Over the 26- and 52-Week Treatment Periods

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.

Time frame: Week 0 (pre-treatment, baseline) to Week 26 and Week 52.

22a_Change From Baseline in the Percentage of Rescue Medication-Free Days in Each Inter-Visit Period Over the Treatment

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.

Time frame: Week 0 (pre-treatment, baseline) to Week 52.

23_Change From Baseline in the Average Total Daily Asthma Symptom Scores Over the 26- and 52-Week Treatment Periods

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

Time frame: Week 0 (pre-treatment, baseline) to Week 26 and Week 52.

23a_Change From Baseline in the Average Daily Asthma Symptom Scores in Each Inter-Visit Period

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

Time frame: Week 0 (pre-treatment, baseline) to Week 52.

24_Change From Baseline in the Percentage of Asthma Symptom-Free Days Over the 26- and 52-Week Treatment Periods

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.

Time frame: Week 0 (pre-treatment, baseline) to Week 26 and Week 52.

24a_Change From Baseline in the Percentage of Asthma Symptom-Free Days in Each Inter-Visit Periods

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.

Time frame: Week 0 (pre-treatment, baseline) to Week 52.

25_Change From Baseline in the Percentage of Asthma Control Days Over the 26- and 52-Week Treatment Periods

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).

Time frame: Week 0 (pre-treatment, baseline) to Week 26 and Week 52.

25a_Change From Baseline in the Percentage of Asthma Control Days in Each Inter-Visit Period

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).

Time frame: Week 0 (pre-treatment, baseline) to Week 52.