Trial Outcomes & Findings for Safety of Exercise and High-dose Salbutamol in Patients With Chronic Obstructive Pulmonary Disease (COPD) Receiving Therapeutic Doses of Indacaterol (QAB 149) and Salmeterol (NCT NCT00531050)

Last Updated: 2012-05-23

Results Overview

The percentage of patients with an increase of more than 10 beats per minute (bpm) in their heart rate following treatment with indacaterol and salmeterol compared to treatment with placebo was determined.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

27 participants

Primary outcome timeframe

24-hours post-dose on Day 1 (of each treatment)

Results posted on

2012-05-23

Participant Flow

The study was double blind with regard to the administration of indacaterol and placebo and open label with regard to salmeterol. The study had 2 parts. Each Part of the study consisted of 3 treatment periods separated by a minimum of 7 days. The two parts of the study were separated by a minimum of 7 days.

Participant milestones

Participant milestones
Measure	Part 1: Sequence A, Part 2: Sequence A Part 1: Sequence 'A' consisted of - Period 1, patient received a single inhaled dose of indacaterol 300μg capsule via the Concept1 inhaler device. Period 2, patient received single dose of salmeterol 50μg via Diskus dry powder inhaler (DPI). Period 3, patient received single dose of indacaterol matching placebo via the Concept1 inhaler device. Part 2: Sequence 'A' consisted of - Period 1, patients received a morning single inhalational dose of indacaterol 300μg and an evening single inhalation dose of indacaterol matching placebo via the Concept1 inhaler device. Period 2, patients received morning and evening single inhalational dose of salmeterol 50μg via Diskus DPI. Period 3, patients received single inhalation dose of indacaterol matching placebo in morning and evening via Concept1 device. In Part 2 of the study, at 20 minutes following each dose, patients received three doses of nebulized salbutamol 2.5 mg at 20 minute intervals.	Part 1 : Sequence B, Part 2: Sequence B Part 1: Sequence 'B' consisted of - Period 1, patient received a single inhaled dose of indacaterol 300μg capsule administered via the Concept1 inhaler device. Period 2, patient received single dose of indacaterol matching placebo via the Concept1 inhaler device. Period 3, patient received single dose of salmeterol 50μg via Diskus DPI. Part 2: Sequence 'B' consisted of - Period 1, patients received a morning single inhalational dose of indacaterol 300μg and an evening single inhalation dose of indacaterol matching placebo via the Concept1 inhaler device. Period 2, patients received single inhalation dose of indacaterol matching placebo in morning and evening via Concept1 device. Period 3, patients received morning and evening single inhalational dose of salmeterol 50μg via Diskus DPI. In Part 2 of the study, at 20 minutes following each dose, patients received three doses of nebulized salbutamol 2.5 mg at 20 minute intervals.	Part 1: Sequence C, Part 2: Sequence C Part 1: Sequence 'C' consisted of - Period 1, patient received single dose of indacaterol matching placebo via the Concept1 inhaler device. Period 2, patient received single dose of salmeterol 50μg via Diskus DPI. Period 3, patient received a single inhaled dose of indacaterol 300μg capsule administered via the Concept1 inhaler device. Part 2: Sequence 'C' consisted of - Period 1, patients received single inhalation dose of indacaterol matching placebo in morning and evening via Concept1 device. Period 2, patients received morning and evening single inhalational dose of salmeterol 50μg via Diskus DPI. Period 3, patients received a morning single inhalational dose of indacaterol 300μg and an evening single inhalation dose of indacaterol matching placebo via the Concept1 inhaler device . In Part 2 of the study, at 20 minutes following each dose, patients received three doses of nebulized salbutamol 2.5 mg at 20 minute intervals.	Part 1; Sequence D, Part 2: Sequence D Part 1: Sequence 'D' consisted of - Period 1, patient received single dose of indacaterol matching placebo via the Concept1 inhaler device. Period 2, patient received a single inhaled dose of indacaterol 300μg capsule administered via the Concept1 inhaler device. Period 3, patient received single dose of salmeterol 50μg via Diskus DPI. Part 2: Sequence 'D' consisted of - Period 1, patients received single inhalation dose of indacaterol matching placebo in morning and evening via Concept1 device. Period 2, patients received a morning single inhalational dose of indacaterol 300μg and an evening single inhalation dose of indacaterol matching placebo via the Concept1 inhaler device. Period 3, patients received morning and evening single inhalational dose of salmeterol 50μg via Diskus DPI. In Part 2 of the study, at 20 minutes following each dose, patients received three doses of nebulized salbutamol 2.5 mg at 20 minute intervals.	Part 1: Sequence E, Part 2: Sequence E Part 1: Sequence 'E' consisted of - Period 1, patient received single dose of salmeterol 50μg via Diskus DPI. Period 2, patient received a single inhaled dose of indacaterol 300μg capsule administered via the Concept1 inhaler device. Period 3, patient received single dose of indacaterol matching placebo via the Concept1 inhaler device. Part 2: Sequence 'E' consisted of - Period 1, patients received morning and evening single inhalational dose of salmeterol 50μg via Diskus DPI. Period 2, patients received a morning single inhalational dose of indacaterol 300μg and an evening single inhalation dose of indacaterol matching placebo via the Concept1 inhaler device. Period 3, patients received single inhalation dose of indacaterol matching placebo in morning and evening via Concept1 device. In Part 2 of the study, at 20 minutes following each dose, patients received three doses of nebulized salbutamol 2.5 mg at 20 minute intervals.	Part 1: Sequence F, Part 2: Sequence F Part 1: Sequence 'F' consisted of - Period 1, patient received single dose of salmeterol 50μg via Diskus DPI. Period 2, patient received single dose of indacaterol matching placebo via the Concept1 inhaler device. Period 3, patient received a single inhaled dose of indacaterol 300μg capsule administered via the Concept1 inhaler device. Part 2: Sequence 'F' consisted of - Period 1, patients received morning and evening single inhalational dose of salmeterol 50μg via Diskus DPI. Period 2, patients received single inhalation dose of indacaterol matching placebo in morning and evening via Concept1 device. Period 3, patients received a morning single inhalational dose of indacaterol 300μg and an evening single inhalation dose of indacaterol matching placebo via the Concept1 inhaler device. In Part 2 of the study, at 20 minutes following each dose, patients received three doses of nebulized salbutamol 2.5 mg at 20 minute intervals.
Part 1: Period 1 STARTED	4	5	4	5	4	5
Part 1: Period 1 COMPLETED	4	4	4	4	4	5
Part 1: Period 1 NOT COMPLETED	0	1	0	1	0	0
Part 1: Period 2 STARTED	4	4	4	4	4	5
Part 1: Period 2 COMPLETED	4	4	4	4	4	5
Part 1: Period 2 NOT COMPLETED	0	0	0	0	0	0
Part 1: Period 3 STARTED	4	4	4	4	4	5
Part 1: Period 3 COMPLETED	3	4	4	4	4	5
Part 1: Period 3 NOT COMPLETED	1	0	0	0	0	0
Part 2: Period 1 STARTED	3	4	4	4	4	5
Part 2: Period 1 COMPLETED	3	4	4	4	4	4
Part 2: Period 1 NOT COMPLETED	0	0	0	0	0	1
Part 2: Period 2 STARTED	3	4	4	4	4	4
Part 2: Period 2 COMPLETED	3	4	4	4	4	4
Part 2: Period 2 NOT COMPLETED	0	0	0	0	0	0
Part 2: Period 3 STARTED	3	4	4	4	4	4
Part 2: Period 3 COMPLETED	2	4	4	4	4	3
Part 2: Period 3 NOT COMPLETED	1	0	0	0	0	1

Reasons for withdrawal

Reasons for withdrawal
Measure	Part 1: Sequence A, Part 2: Sequence A Part 1: Sequence 'A' consisted of - Period 1, patient received a single inhaled dose of indacaterol 300μg capsule via the Concept1 inhaler device. Period 2, patient received single dose of salmeterol 50μg via Diskus dry powder inhaler (DPI). Period 3, patient received single dose of indacaterol matching placebo via the Concept1 inhaler device. Part 2: Sequence 'A' consisted of - Period 1, patients received a morning single inhalational dose of indacaterol 300μg and an evening single inhalation dose of indacaterol matching placebo via the Concept1 inhaler device. Period 2, patients received morning and evening single inhalational dose of salmeterol 50μg via Diskus DPI. Period 3, patients received single inhalation dose of indacaterol matching placebo in morning and evening via Concept1 device. In Part 2 of the study, at 20 minutes following each dose, patients received three doses of nebulized salbutamol 2.5 mg at 20 minute intervals.	Part 1 : Sequence B, Part 2: Sequence B Part 1: Sequence 'B' consisted of - Period 1, patient received a single inhaled dose of indacaterol 300μg capsule administered via the Concept1 inhaler device. Period 2, patient received single dose of indacaterol matching placebo via the Concept1 inhaler device. Period 3, patient received single dose of salmeterol 50μg via Diskus DPI. Part 2: Sequence 'B' consisted of - Period 1, patients received a morning single inhalational dose of indacaterol 300μg and an evening single inhalation dose of indacaterol matching placebo via the Concept1 inhaler device. Period 2, patients received single inhalation dose of indacaterol matching placebo in morning and evening via Concept1 device. Period 3, patients received morning and evening single inhalational dose of salmeterol 50μg via Diskus DPI. In Part 2 of the study, at 20 minutes following each dose, patients received three doses of nebulized salbutamol 2.5 mg at 20 minute intervals.	Part 1; Sequence D, Part 2: Sequence D Part 1: Sequence 'D' consisted of - Period 1, patient received single dose of indacaterol matching placebo via the Concept1 inhaler device. Period 2, patient received a single inhaled dose of indacaterol 300μg capsule administered via the Concept1 inhaler device. Period 3, patient received single dose of salmeterol 50μg via Diskus DPI. Part 2: Sequence 'D' consisted of - Period 1, patients received single inhalation dose of indacaterol matching placebo in morning and evening via Concept1 device. Period 2, patients received a morning single inhalational dose of indacaterol 300μg and an evening single inhalation dose of indacaterol matching placebo via the Concept1 inhaler device. Period 3, patients received morning and evening single inhalational dose of salmeterol 50μg via Diskus DPI. In Part 2 of the study, at 20 minutes following each dose, patients received three doses of nebulized salbutamol 2.5 mg at 20 minute intervals.	Part 1: Sequence F, Part 2: Sequence F Part 1: Sequence 'F' consisted of - Period 1, patient received single dose of salmeterol 50μg via Diskus DPI. Period 2, patient received single dose of indacaterol matching placebo via the Concept1 inhaler device. Period 3, patient received a single inhaled dose of indacaterol 300μg capsule administered via the Concept1 inhaler device. Part 2: Sequence 'F' consisted of - Period 1, patients received morning and evening single inhalational dose of salmeterol 50μg via Diskus DPI. Period 2, patients received single inhalation dose of indacaterol matching placebo in morning and evening via Concept1 device. Period 3, patients received a morning single inhalational dose of indacaterol 300μg and an evening single inhalation dose of indacaterol matching placebo via the Concept1 inhaler device. In Part 2 of the study, at 20 minutes following each dose, patients received three doses of nebulized salbutamol 2.5 mg at 20 minute intervals.
Part 1: Period 1 Adverse Event	0	1	0	0
Part 1: Period 1 Protocol Deviation	0	0	1	0
Part 1: Period 3 Adverse Event	1	0	0	0
Part 2: Period 1 Adverse Event	0	0	0	1
Part 2: Period 3 Abnormal test procedure	1	0	0	1

Baseline Characteristics

Safety of Exercise and High-dose Salbutamol in Patients With Chronic Obstructive Pulmonary Disease (COPD) Receiving Therapeutic Doses of Indacaterol (QAB 149) and Salmeterol

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Part 1: Sequence A, Part 2: Sequence A n=4 Participants Part 1: Sequence 'A' consisted of - Period 1, patient received a single inhaled dose of indacaterol 300μg capsule via the Concept1 inhaler device. Period 2, patient received single dose of salmeterol 50μg via Diskus dry powder inhaler (DPI). Period 3, patient received single dose of indacaterol matching placebo via the Concept1 inhaler device. Part 2: Sequence 'A' consisted of - Period 1, patients received a morning single inhalational dose of indacaterol 300μg and an evening single inhalation dose of indacaterol matching placebo via the Concept1 inhaler device. Period 2, patients received morning and evening single inhalational dose of salmeterol 50μg via Diskus DPI. Period 3, patients received single inhalation dose of indacaterol matching placebo in morning and evening via Concept1 device. In Part 2 of the study, at 20 minutes following each dose, patients received three doses of nebulized salbutamol 2.5 mg at 20 minute intervals.	Part 1 : Sequence B, Part 2: Sequence B n=5 Participants Part 1: Sequence 'B' consisted of - Period 1, patient received a single inhaled dose of indacaterol 300μg capsule administered via the Concept1 inhaler device. Period 2, patient received single dose of indacaterol matching placebo via the Concept1 inhaler device. Period 3, patient received single dose of salmeterol 50μg via Diskus DPI. Part 2: Sequence 'B' consisted of - Period 1, patients received a morning single inhalational dose of indacaterol 300μg and an evening single inhalation dose of indacaterol matching placebo via the Concept1 inhaler device. Period 2, patients received single inhalation dose of indacaterol matching placebo in morning and evening via Concept1 device. Period 3, patients received morning and evening single inhalational dose of salmeterol 50μg via Diskus DPI. In Part 2 of the study, at 20 minutes following each dose, patients received three doses of nebulized salbutamol 2.5 mg at 20 minute intervals.	Part 1: Sequence C, Part 2: Sequence C n=4 Participants Part 1: Sequence 'C' consisted of - Period 1, patient received single dose of indacaterol matching placebo via the Concept1 inhaler device. Period 2, patient received single dose of salmeterol 50μg via Diskus DPI. Period 3, patient received a single inhaled dose of indacaterol 300μg capsule administered via the Concept1 inhaler device. Part 2: Sequence 'C' consisted of - Period 1, patients received single inhalation dose of indacaterol matching placebo in morning and evening via Concept1 device. Period 2, patients received morning and evening single inhalational dose of salmeterol 50μg via Diskus DPI. Period 3, patients received a morning single inhalational dose of indacaterol 300μg and an evening single inhalation dose of indacaterol matching placebo via the Concept1 inhaler device . In Part 2 of the study, at 20 minutes following each dose, patients received three doses of nebulized salbutamol 2.5 mg at 20 minute intervals.	Part 1; Sequence D, Part 2: Sequence D n=5 Participants Part 1: Sequence 'D' consisted of - Period 1, patient received single dose of indacaterol matching placebo via the Concept1 inhaler device. Period 2, patient received a single inhaled dose of indacaterol 300μg capsule administered via the Concept1 inhaler device. Period 3, patient received single dose of salmeterol 50μg via Diskus DPI. Part 2: Sequence 'D' consisted of - Period 1, patients received single inhalation dose of indacaterol matching placebo in morning and evening via Concept1 device. Period 2, patients received a morning single inhalational dose of indacaterol 300μg and an evening single inhalation dose of indacaterol matching placebo via the Concept1 inhaler device. Period 3, patients received morning and evening single inhalational dose of salmeterol 50μg via Diskus DPI. In Part 2 of the study, at 20 minutes following each dose, patients received three doses of nebulized salbutamol 2.5 mg at 20 minute intervals.	Part 1: Sequence E, Part 2: Sequence E n=4 Participants Part 1: Sequence 'E' consisted of - Period 1, patient received single dose of salmeterol 50μg via Diskus DPI. Period 2, patient received a single inhaled dose of indacaterol 300μg capsule administered via the Concept1 inhaler device. Period 3, patient received single dose of indacaterol matching placebo via the Concept1 inhaler device. Part 2: Sequence 'E' consisted of - Period 1, patients received morning and evening single inhalational dose of salmeterol 50μg via Diskus DPI. Period 2, patients received a morning single inhalational dose of indacaterol 300μg and an evening single inhalation dose of indacaterol matching placebo via the Concept1 inhaler device. Period 3, patients received single inhalation dose of indacaterol matching placebo in morning and evening via Concept1 device. In Part 2 of the study, at 20 minutes following each dose, patients received three doses of nebulized salbutamol 2.5 mg at 20 minute intervals.	Part 1: Sequence F, Part 2: Sequence F n=5 Participants Part 1: Sequence 'F' consisted of - Period 1, patient received single dose of salmeterol 50μg via Diskus DPI. Period 2, patient received single dose of indacaterol matching placebo via the Concept1 inhaler device. Period 3, patient received a single inhaled dose of indacaterol 300μg capsule administered via the Concept1 inhaler device. Part 2: Sequence 'F' consisted of - Period 1, patients received morning and evening single inhalational dose of salmeterol 50μg via Diskus DPI. Period 2, patients received single inhalation dose of indacaterol matching placebo in morning and evening via Concept1 device. Period 3, patients received a morning single inhalational dose of indacaterol 300μg and an evening single inhalation dose of indacaterol matching placebo via the Concept1 inhaler device. In Part 2 of the study, at 20 minutes following each dose, patients received three doses of nebulized salbutamol 2.5 mg at 20 minute intervals.	Total n=27 Participants Total of all reporting groups
Age Continuous	59.0 years STANDARD_DEVIATION 9.20 • n=5 Participants	63.0 years STANDARD_DEVIATION 7.58 • n=7 Participants	58.5 years STANDARD_DEVIATION 5.07 • n=5 Participants	58.4 years STANDARD_DEVIATION 5.18 • n=4 Participants	60.5 years STANDARD_DEVIATION 5.80 • n=21 Participants	61.6 years STANDARD_DEVIATION 5.86 • n=8 Participants	60.3 years STANDARD_DEVIATION 6.17 • n=8 Participants
Sex: Female, Male Female	2 Participants n=5 Participants	2 Participants n=7 Participants	1 Participants n=5 Participants	1 Participants n=4 Participants	1 Participants n=21 Participants	0 Participants n=8 Participants	7 Participants n=8 Participants
Sex: Female, Male Male	2 Participants n=5 Participants	3 Participants n=7 Participants	3 Participants n=5 Participants	4 Participants n=4 Participants	3 Participants n=21 Participants	5 Participants n=8 Participants	20 Participants n=8 Participants

PRIMARY outcome

Timeframe: 24-hours post-dose on Day 1 (of each treatment)

Population: The safety population consisted of all subjects who received at least one dose of study medication after randomization.

Outcome measures

Outcome measures
Measure	Part 1: Indacaterol 300μg n=25 Participants Patient received a single inhaled dose of indacaterol 300μg capsule via the Concept1 inhaler device. For each treatment period and for each patient, the doses were to be administered at approximately the same time in the morning (i.e. between 8 and 9am).	Part 1 : Salmeterol 50μg n=25 Participants Patient received single dose of salmeterol 50μg via Diskus DPI. For each treatment period and for each patient, the doses were to be administered at approximately the same time in the morning (i.e. between 8 and 9am).	Part 1: Placebo Patient received single dose of indacaterol matching placebo via the Concept1 inhaler device. For each treatment period and for each patient, the doses were to be administered at approximately the same time in the morning (i.e. between 8 and 9am).	Part 2:Indacaterol 300μg Morning/Placebo Evening Patients received a morning single inhalational dose of indacaterol 300μg and an evening single inhalation dose of indacaterol matching placebo via the Concept1 inhaler device. For each treatment period and for each patient, the doses were to be administered at approximately the same time in the morning (i.e. between 8 and 9am) and the evening dose between 8 and 9pm. 20 minutes following each dose, patients received three doses of nebulized salbutamol 2.5 mg at 20 minute intervals.	Part 2:Salmeterol 50μg Morning/Salmeterol 50μg Evening Patients received morning and evening single inhalational dose of salmeterol 50μg via Diskus dry powder inhaler (DPI). For each treatment period and for each patient, the doses were to be administered at approximately the same time in the morning (i.e. between 8 and 9am) and the evening dose between 8 and 9pm. 20 minutes following each dose, patients received three doses of nebulized salbutamol 2.5 mg at 20 minute intervals.	Part 2:Placebo Morning/Placebo Evening Patients received single inhalation dose of indacaterol matching placebo in morning and evening via Concept1 device. For each treatment period and for each patient, the doses were to be administered at approximately the same time in the morning (i.e. between 8 and 9am) and the evening dose between 8 and 9pm. 20 minutes following each dose, patients received three doses of nebulized salbutamol 2.5 mg at 20 minute intervals.
Percentage of Participants With Maximum Heart Rate Increase During Exercise in Part 1 of the Study	20.00 Percentage of participants Interval 6.83 to 40.7	16.0 Percentage of participants Interval 4.54 to 36.0	—	—	—	—

PRIMARY outcome

Timeframe: 24 hours post dose on Day 1

Population: Safety population. ECG monitoring was not performed successfully for three subjects in Part 2 during the afternoon monitoring. These subjects were therefore excluded from the analysis of heart rate. In a patient where data for the second 12 hour period is missing, 0-24 is not reported; hence the discrepancy of 4 and 3 subjects.

The percentage of patients with an increase of \>= 10 beats per minute (bpm) in their heart rate (HR) following treatment with indacaterol and salmeterol compared to treatment with placebo over 24 hours in Part 2 was determined. * 0-12 hours: post first dose measurements up to second dose * 12-24 hours: post second dose measurement up to and including the 24 hour measurement * 0-24 hours: all post dose measurements up to and including the 24 hour measurement

Outcome measures

Outcome measures
Measure	Part 1: Indacaterol 300μg n=23 Participants Patient received a single inhaled dose of indacaterol 300μg capsule via the Concept1 inhaler device. For each treatment period and for each patient, the doses were to be administered at approximately the same time in the morning (i.e. between 8 and 9am).	Part 1 : Salmeterol 50μg n=23 Participants Patient received single dose of salmeterol 50μg via Diskus DPI. For each treatment period and for each patient, the doses were to be administered at approximately the same time in the morning (i.e. between 8 and 9am).	Part 1: Placebo Patient received single dose of indacaterol matching placebo via the Concept1 inhaler device. For each treatment period and for each patient, the doses were to be administered at approximately the same time in the morning (i.e. between 8 and 9am).	Part 2:Indacaterol 300μg Morning/Placebo Evening Patients received a morning single inhalational dose of indacaterol 300μg and an evening single inhalation dose of indacaterol matching placebo via the Concept1 inhaler device. For each treatment period and for each patient, the doses were to be administered at approximately the same time in the morning (i.e. between 8 and 9am) and the evening dose between 8 and 9pm. 20 minutes following each dose, patients received three doses of nebulized salbutamol 2.5 mg at 20 minute intervals.	Part 2:Salmeterol 50μg Morning/Salmeterol 50μg Evening Patients received morning and evening single inhalational dose of salmeterol 50μg via Diskus dry powder inhaler (DPI). For each treatment period and for each patient, the doses were to be administered at approximately the same time in the morning (i.e. between 8 and 9am) and the evening dose between 8 and 9pm. 20 minutes following each dose, patients received three doses of nebulized salbutamol 2.5 mg at 20 minute intervals.	Part 2:Placebo Morning/Placebo Evening Patients received single inhalation dose of indacaterol matching placebo in morning and evening via Concept1 device. For each treatment period and for each patient, the doses were to be administered at approximately the same time in the morning (i.e. between 8 and 9am) and the evening dose between 8 and 9pm. 20 minutes following each dose, patients received three doses of nebulized salbutamol 2.5 mg at 20 minute intervals.
Percentage of Participants With Maximum Heart Rate Increase During Salbutamol Administration in Part 2 of the Study 0 - 12 hours (N= 23,23)	17.39 Percentage of participants Interval 4.95 to 38.78	17.39 Percentage of participants Interval 4.95 to 38.78	—	—	—	—
Percentage of Participants With Maximum Heart Rate Increase During Salbutamol Administration in Part 2 of the Study 0 - 24 hours (N= 23, 23)	13.04 Percentage of participants Interval 2.78 to 33.59	17.39 Percentage of participants Interval 4.95 to 38.78	—	—	—	—
Percentage of Participants With Maximum Heart Rate Increase During Salbutamol Administration in Part 2 of the Study 12 - 24 hours (N= 20, 20)	10.00 Percentage of participants Interval 1.23 to 31.7	25.00 Percentage of participants Interval 8.66 to 49.1	—	—	—	—

PRIMARY outcome

Timeframe: 2 hour post-dose on Day 1

Population: The safety population consisted of all subjects who received at least one dose of study medication after randomization.

Maximum heart rate was generally taken from the continuous ECG monitoring. Analysis based on mixed effects analysis using model with treatment and period as fixed effects and subject as random effect.

Outcome measures

Outcome measures
Measure	Part 1: Indacaterol 300μg n=26 Participants Patient received a single inhaled dose of indacaterol 300μg capsule via the Concept1 inhaler device. For each treatment period and for each patient, the doses were to be administered at approximately the same time in the morning (i.e. between 8 and 9am).	Part 1 : Salmeterol 50μg n=25 Participants Patient received single dose of salmeterol 50μg via Diskus DPI. For each treatment period and for each patient, the doses were to be administered at approximately the same time in the morning (i.e. between 8 and 9am).	Part 1: Placebo n=26 Participants Patient received single dose of indacaterol matching placebo via the Concept1 inhaler device. For each treatment period and for each patient, the doses were to be administered at approximately the same time in the morning (i.e. between 8 and 9am).	Part 2:Indacaterol 300μg Morning/Placebo Evening Patients received a morning single inhalational dose of indacaterol 300μg and an evening single inhalation dose of indacaterol matching placebo via the Concept1 inhaler device. For each treatment period and for each patient, the doses were to be administered at approximately the same time in the morning (i.e. between 8 and 9am) and the evening dose between 8 and 9pm. 20 minutes following each dose, patients received three doses of nebulized salbutamol 2.5 mg at 20 minute intervals.	Part 2:Salmeterol 50μg Morning/Salmeterol 50μg Evening Patients received morning and evening single inhalational dose of salmeterol 50μg via Diskus dry powder inhaler (DPI). For each treatment period and for each patient, the doses were to be administered at approximately the same time in the morning (i.e. between 8 and 9am) and the evening dose between 8 and 9pm. 20 minutes following each dose, patients received three doses of nebulized salbutamol 2.5 mg at 20 minute intervals.	Part 2:Placebo Morning/Placebo Evening Patients received single inhalation dose of indacaterol matching placebo in morning and evening via Concept1 device. For each treatment period and for each patient, the doses were to be administered at approximately the same time in the morning (i.e. between 8 and 9am) and the evening dose between 8 and 9pm. 20 minutes following each dose, patients received three doses of nebulized salbutamol 2.5 mg at 20 minute intervals.
Maximum Heart Rate During Exercise in Part 1	133.13 Beats per minute (bpm) Interval 125.9 to 140.36	131.18 Beats per minute (bpm) Interval 123.86 to 138.49	129.96 Beats per minute (bpm) Interval 122.73 to 137.19	—	—	—

PRIMARY outcome

Timeframe: 24 hours post dose on Day 1

Population: The safety population consisted of all subjects who received at least one dose of study medication after randomization. ECG monitoring was not performed successfully for three subjects in Part 2 during the afternoon monitoring. These subjects were therefore excluded from the analysis of heart rate.

Maximum HR (0-12 hours): maximum (max) of post dose measurement up to second administration. Maximum HR (12-24 hours): max of the post second administration of salbutamol measurements. Maximum HR (0-24 hours): max of all post dose measurements up to and including the 24 hour measurement. Mixed effects analysis model used period baseline HR as the covariate. The maximum HR for 0-24 hours (h) is the maximum of the maximum HR for the two 12h periods and thus the average (LS means) of the maximum HRs for 0-24h will be equal to or greater than the average of the maximum for the two periods.

Outcome measures

Outcome measures
Measure	Part 1: Indacaterol 300μg n=23 Participants Patient received a single inhaled dose of indacaterol 300μg capsule via the Concept1 inhaler device. For each treatment period and for each patient, the doses were to be administered at approximately the same time in the morning (i.e. between 8 and 9am).	Part 1 : Salmeterol 50μg n=24 Participants Patient received single dose of salmeterol 50μg via Diskus DPI. For each treatment period and for each patient, the doses were to be administered at approximately the same time in the morning (i.e. between 8 and 9am).	Part 1: Placebo n=23 Participants Patient received single dose of indacaterol matching placebo via the Concept1 inhaler device. For each treatment period and for each patient, the doses were to be administered at approximately the same time in the morning (i.e. between 8 and 9am).	Part 2:Indacaterol 300μg Morning/Placebo Evening Patients received a morning single inhalational dose of indacaterol 300μg and an evening single inhalation dose of indacaterol matching placebo via the Concept1 inhaler device. For each treatment period and for each patient, the doses were to be administered at approximately the same time in the morning (i.e. between 8 and 9am) and the evening dose between 8 and 9pm. 20 minutes following each dose, patients received three doses of nebulized salbutamol 2.5 mg at 20 minute intervals.	Part 2:Salmeterol 50μg Morning/Salmeterol 50μg Evening Patients received morning and evening single inhalational dose of salmeterol 50μg via Diskus dry powder inhaler (DPI). For each treatment period and for each patient, the doses were to be administered at approximately the same time in the morning (i.e. between 8 and 9am) and the evening dose between 8 and 9pm. 20 minutes following each dose, patients received three doses of nebulized salbutamol 2.5 mg at 20 minute intervals.	Part 2:Placebo Morning/Placebo Evening Patients received single inhalation dose of indacaterol matching placebo in morning and evening via Concept1 device. For each treatment period and for each patient, the doses were to be administered at approximately the same time in the morning (i.e. between 8 and 9am) and the evening dose between 8 and 9pm. 20 minutes following each dose, patients received three doses of nebulized salbutamol 2.5 mg at 20 minute intervals.
Maximum Heart Rate (HR) During Salbutamol Administration in Part 2 12 - 24 hours (N= 20, 21, 20)	97.179 Beats per minute (bpm) Interval 91.195 to 103.164	99.954 Beats per minute (bpm) Interval 94.047 to 105.861	97.786 Beats per minute (bpm) Interval 91.779 to 103.794	—	—	—
Maximum Heart Rate (HR) During Salbutamol Administration in Part 2 0 - 24 hours (N= 23, 24, 23)	102.501 Beats per minute (bpm) Interval 95.504 to 109.498	102.303 Beats per minute (bpm) Interval 95.394 to 109.212	103.951 Beats per minute (bpm) Interval 96.931 to 110.971	—	—	—
Maximum Heart Rate (HR) During Salbutamol Administration in Part 2 0 - 12 hours (N= 23, 24, 23)	98.026 Beats per minute (bpm) Interval 90.407 to 105.645	98.087 Beats per minute (bpm) Interval 90.575 to 105.598	97.960 Beats per minute (bpm) Interval 90.317 to 105.603	—	—	—

SECONDARY outcome

Timeframe: 1.5 hour post dose to max heart rate during exercise

Population: The safety population consisted of all subjects who received at least one dose of study medication after randomization.

Change in heart rate is calculated from the 1.5 hour post dose to the maximum heart rate during exercise. Analysis of covariance included treatment and period as fixed effects, subject as random effect and 1.5 hour pre-exercise/post dose heart rate as a covariate.

Outcome measures

Outcome measures
Measure	Part 1: Indacaterol 300μg n=26 Participants Patient received a single inhaled dose of indacaterol 300μg capsule via the Concept1 inhaler device. For each treatment period and for each patient, the doses were to be administered at approximately the same time in the morning (i.e. between 8 and 9am).	Part 1 : Salmeterol 50μg n=25 Participants Patient received single dose of salmeterol 50μg via Diskus DPI. For each treatment period and for each patient, the doses were to be administered at approximately the same time in the morning (i.e. between 8 and 9am).	Part 1: Placebo n=26 Participants Patient received single dose of indacaterol matching placebo via the Concept1 inhaler device. For each treatment period and for each patient, the doses were to be administered at approximately the same time in the morning (i.e. between 8 and 9am).	Part 2:Indacaterol 300μg Morning/Placebo Evening Patients received a morning single inhalational dose of indacaterol 300μg and an evening single inhalation dose of indacaterol matching placebo via the Concept1 inhaler device. For each treatment period and for each patient, the doses were to be administered at approximately the same time in the morning (i.e. between 8 and 9am) and the evening dose between 8 and 9pm. 20 minutes following each dose, patients received three doses of nebulized salbutamol 2.5 mg at 20 minute intervals.	Part 2:Salmeterol 50μg Morning/Salmeterol 50μg Evening Patients received morning and evening single inhalational dose of salmeterol 50μg via Diskus dry powder inhaler (DPI). For each treatment period and for each patient, the doses were to be administered at approximately the same time in the morning (i.e. between 8 and 9am) and the evening dose between 8 and 9pm. 20 minutes following each dose, patients received three doses of nebulized salbutamol 2.5 mg at 20 minute intervals.	Part 2:Placebo Morning/Placebo Evening Patients received single inhalation dose of indacaterol matching placebo in morning and evening via Concept1 device. For each treatment period and for each patient, the doses were to be administered at approximately the same time in the morning (i.e. between 8 and 9am) and the evening dose between 8 and 9pm. 20 minutes following each dose, patients received three doses of nebulized salbutamol 2.5 mg at 20 minute intervals.
Change in Heart Rate During Exercise in Part 1	66.246 Beats per minute (bpm) Interval 58.941 to 73.551	64.265 Beats per minute (bpm) Interval 56.868 to 71.663	63.058 Beats per minute (bpm) Interval 55.761 to 70.355	—	—	—

SECONDARY outcome

Timeframe: 23 hours 30 minutes and 24 hours post-dose at Day 1

Population: The safety population consisted of all subjects who received at least one dose of study medication after randomization.

FEV1 was measured with spirometry conducted according to internationally accepted standards. Trough FEV1 was defined as the mean of the 23 hours 30 minutes and 24 hours post morning dose FEV1 measurements. Analysis of covariance included pre-dose FEV1 as covariate.

Outcome measures

Outcome measures
Measure	Part 1: Indacaterol 300μg n=26 Participants Patient received a single inhaled dose of indacaterol 300μg capsule via the Concept1 inhaler device. For each treatment period and for each patient, the doses were to be administered at approximately the same time in the morning (i.e. between 8 and 9am).	Part 1 : Salmeterol 50μg n=25 Participants Patient received single dose of salmeterol 50μg via Diskus DPI. For each treatment period and for each patient, the doses were to be administered at approximately the same time in the morning (i.e. between 8 and 9am).	Part 1: Placebo n=26 Participants Patient received single dose of indacaterol matching placebo via the Concept1 inhaler device. For each treatment period and for each patient, the doses were to be administered at approximately the same time in the morning (i.e. between 8 and 9am).	Part 2:Indacaterol 300μg Morning/Placebo Evening n=23 Participants Patients received a morning single inhalational dose of indacaterol 300μg and an evening single inhalation dose of indacaterol matching placebo via the Concept1 inhaler device. For each treatment period and for each patient, the doses were to be administered at approximately the same time in the morning (i.e. between 8 and 9am) and the evening dose between 8 and 9pm. 20 minutes following each dose, patients received three doses of nebulized salbutamol 2.5 mg at 20 minute intervals.	Part 2:Salmeterol 50μg Morning/Salmeterol 50μg Evening n=24 Participants Patients received morning and evening single inhalational dose of salmeterol 50μg via Diskus dry powder inhaler (DPI). For each treatment period and for each patient, the doses were to be administered at approximately the same time in the morning (i.e. between 8 and 9am) and the evening dose between 8 and 9pm. 20 minutes following each dose, patients received three doses of nebulized salbutamol 2.5 mg at 20 minute intervals.	Part 2:Placebo Morning/Placebo Evening n=23 Participants Patients received single inhalation dose of indacaterol matching placebo in morning and evening via Concept1 device. For each treatment period and for each patient, the doses were to be administered at approximately the same time in the morning (i.e. between 8 and 9am) and the evening dose between 8 and 9pm. 20 minutes following each dose, patients received three doses of nebulized salbutamol 2.5 mg at 20 minute intervals.
Trough Forced Expiratory Volume in 1 Second (FEV1) During Part 1 and Part 2	1.72 Liters Interval 1.65 to 1.79	1.59 Liters Interval 1.52 to 1.66	1.56 Liters Interval 1.49 to 1.63	1.75 Liters Interval 1.67 to 1.82	1.68 Liters Interval 1.6 to 1.75	1.54 Liters Interval 1.46 to 1.62

Adverse Events

Part 1:Indacaterol 300mcg

Serious events: 1 serious events

Other events: 9 other events

Deaths: 0 deaths

Part 1:Salmeterol 50mcg

Serious events: 0 serious events

Other events: 4 other events

Deaths: 0 deaths

Part 1:Placebo

Serious events: 1 serious events

Other events: 4 other events

Deaths: 0 deaths

Part 2:Indacaterol 300μg Morning/Placebo Evening

Serious events: 0 serious events

Other events: 8 other events

Deaths: 0 deaths

Part 2:Salmeterol AM 50mcg/Salmeterol PM 50mcg

Serious events: 0 serious events

Other events: 8 other events

Deaths: 0 deaths

Part 2:Placebo Morning/Placebo Evening

Serious events: 0 serious events

Other events: 6 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Part 1:Indacaterol 300mcg n=26 participants at risk Patient received a single inhaled dose of indacaterol 300μg capsule via the Concept1 inhaler device. For each treatment period and for each patient, the doses were to be administered at approximately the same time in the morning (i.e. between 8 and 9am).	Part 1:Salmeterol 50mcg n=25 participants at risk Patient received single dose of salmeterol 50μg via Diskus DPI. For each treatment period and for each patient, the doses were to be administered at approximately the same time in the morning (i.e. between 8 and 9am).	Part 1:Placebo n=26 participants at risk Patient received single dose of indacaterol matching placebo via the Concept1 inhaler device. For each treatment period and for each patient, the doses were to be administered at approximately the same time in the morning (i.e. between 8 and 9am).	Part 2:Indacaterol 300μg Morning/Placebo Evening n=23 participants at risk Patients received a morning single inhalational dose of indacaterol 300μg and an evening single inhalation dose of indacaterol matching placebo via the Concept1 inhaler device. For each treatment period and for each patient, the doses were to be administered at approximately the same time in the morning (i.e. between 8 and 9am) and the evening dose between 8 and 9pm. 20 minutes following each dose, patients received three doses of nebulized salbutamol 2.5 mg at 20 minute intervals.	Part 2:Salmeterol AM 50mcg/Salmeterol PM 50mcg n=24 participants at risk Patients received morning and evening single inhalational dose of salmeterol 50μg via Diskus dry powder inhaler (DPI). For each treatment period and for each patient, the doses were to be administered at approximately the same time in the morning (i.e. between 8 and 9am) and the evening dose between 8 and 9pm. 20 minutes following each dose, patients received three doses of nebulized salbutamol 2.5 mg at 20 minute intervals.	Part 2:Placebo Morning/Placebo Evening n=23 participants at risk Patients received single inhalation dose of indacaterol matching placebo in morning and evening via Concept1 device. For each treatment period and for each patient, the doses were to be administered at approximately the same time in the morning (i.e. between 8 and 9am) and the evening dose between 8 and 9pm. 20 minutes following each dose, patients received three doses of nebulized salbutamol 2.5 mg at 20 minute intervals.
Respiratory, thoracic and mediastinal disorders Chronic obstructive pulmonary disease	0.00% 0/26 All patients who received at least one dose of treatment were included in the safety and tolerability evaluation.	0.00% 0/25 All patients who received at least one dose of treatment were included in the safety and tolerability evaluation.	3.8% 1/26 All patients who received at least one dose of treatment were included in the safety and tolerability evaluation.	0.00% 0/23 All patients who received at least one dose of treatment were included in the safety and tolerability evaluation.	0.00% 0/24 All patients who received at least one dose of treatment were included in the safety and tolerability evaluation.	0.00% 0/23 All patients who received at least one dose of treatment were included in the safety and tolerability evaluation.
Surgical and medical procedures Tonsillectomy	3.8% 1/26 All patients who received at least one dose of treatment were included in the safety and tolerability evaluation.	0.00% 0/25 All patients who received at least one dose of treatment were included in the safety and tolerability evaluation.	0.00% 0/26 All patients who received at least one dose of treatment were included in the safety and tolerability evaluation.	0.00% 0/23 All patients who received at least one dose of treatment were included in the safety and tolerability evaluation.	0.00% 0/24 All patients who received at least one dose of treatment were included in the safety and tolerability evaluation.	0.00% 0/23 All patients who received at least one dose of treatment were included in the safety and tolerability evaluation.

Other adverse events

Other adverse events
Measure	Part 1:Indacaterol 300mcg n=26 participants at risk Patient received a single inhaled dose of indacaterol 300μg capsule via the Concept1 inhaler device. For each treatment period and for each patient, the doses were to be administered at approximately the same time in the morning (i.e. between 8 and 9am).	Part 1:Salmeterol 50mcg n=25 participants at risk Patient received single dose of salmeterol 50μg via Diskus DPI. For each treatment period and for each patient, the doses were to be administered at approximately the same time in the morning (i.e. between 8 and 9am).	Part 1:Placebo n=26 participants at risk Patient received single dose of indacaterol matching placebo via the Concept1 inhaler device. For each treatment period and for each patient, the doses were to be administered at approximately the same time in the morning (i.e. between 8 and 9am).	Part 2:Indacaterol 300μg Morning/Placebo Evening n=23 participants at risk Patients received a morning single inhalational dose of indacaterol 300μg and an evening single inhalation dose of indacaterol matching placebo via the Concept1 inhaler device. For each treatment period and for each patient, the doses were to be administered at approximately the same time in the morning (i.e. between 8 and 9am) and the evening dose between 8 and 9pm. 20 minutes following each dose, patients received three doses of nebulized salbutamol 2.5 mg at 20 minute intervals.	Part 2:Salmeterol AM 50mcg/Salmeterol PM 50mcg n=24 participants at risk Patients received morning and evening single inhalational dose of salmeterol 50μg via Diskus dry powder inhaler (DPI). For each treatment period and for each patient, the doses were to be administered at approximately the same time in the morning (i.e. between 8 and 9am) and the evening dose between 8 and 9pm. 20 minutes following each dose, patients received three doses of nebulized salbutamol 2.5 mg at 20 minute intervals.	Part 2:Placebo Morning/Placebo Evening n=23 participants at risk Patients received single inhalation dose of indacaterol matching placebo in morning and evening via Concept1 device. For each treatment period and for each patient, the doses were to be administered at approximately the same time in the morning (i.e. between 8 and 9am) and the evening dose between 8 and 9pm. 20 minutes following each dose, patients received three doses of nebulized salbutamol 2.5 mg at 20 minute intervals.
Cardiac disorders Atrial fibrillation	0.00% 0/26 All patients who received at least one dose of treatment were included in the safety and tolerability evaluation.	0.00% 0/25 All patients who received at least one dose of treatment were included in the safety and tolerability evaluation.	0.00% 0/26 All patients who received at least one dose of treatment were included in the safety and tolerability evaluation.	0.00% 0/23 All patients who received at least one dose of treatment were included in the safety and tolerability evaluation.	4.2% 1/24 All patients who received at least one dose of treatment were included in the safety and tolerability evaluation.	0.00% 0/23 All patients who received at least one dose of treatment were included in the safety and tolerability evaluation.
Cardiac disorders Palpitations	0.00% 0/26 All patients who received at least one dose of treatment were included in the safety and tolerability evaluation.	0.00% 0/25 All patients who received at least one dose of treatment were included in the safety and tolerability evaluation.	0.00% 0/26 All patients who received at least one dose of treatment were included in the safety and tolerability evaluation.	0.00% 0/23 All patients who received at least one dose of treatment were included in the safety and tolerability evaluation.	4.2% 1/24 All patients who received at least one dose of treatment were included in the safety and tolerability evaluation.	0.00% 0/23 All patients who received at least one dose of treatment were included in the safety and tolerability evaluation.
Gastrointestinal disorders Abdominal pain	0.00% 0/26 All patients who received at least one dose of treatment were included in the safety and tolerability evaluation.	0.00% 0/25 All patients who received at least one dose of treatment were included in the safety and tolerability evaluation.	0.00% 0/26 All patients who received at least one dose of treatment were included in the safety and tolerability evaluation.	4.3% 1/23 All patients who received at least one dose of treatment were included in the safety and tolerability evaluation.	0.00% 0/24 All patients who received at least one dose of treatment were included in the safety and tolerability evaluation.	0.00% 0/23 All patients who received at least one dose of treatment were included in the safety and tolerability evaluation.
Gastrointestinal disorders Diarrhoea	3.8% 1/26 All patients who received at least one dose of treatment were included in the safety and tolerability evaluation.	0.00% 0/25 All patients who received at least one dose of treatment were included in the safety and tolerability evaluation.	0.00% 0/26 All patients who received at least one dose of treatment were included in the safety and tolerability evaluation.	4.3% 1/23 All patients who received at least one dose of treatment were included in the safety and tolerability evaluation.	4.2% 1/24 All patients who received at least one dose of treatment were included in the safety and tolerability evaluation.	0.00% 0/23 All patients who received at least one dose of treatment were included in the safety and tolerability evaluation.
Gastrointestinal disorders Gingivitis	0.00% 0/26 All patients who received at least one dose of treatment were included in the safety and tolerability evaluation.	0.00% 0/25 All patients who received at least one dose of treatment were included in the safety and tolerability evaluation.	0.00% 0/26 All patients who received at least one dose of treatment were included in the safety and tolerability evaluation.	0.00% 0/23 All patients who received at least one dose of treatment were included in the safety and tolerability evaluation.	4.2% 1/24 All patients who received at least one dose of treatment were included in the safety and tolerability evaluation.	0.00% 0/23 All patients who received at least one dose of treatment were included in the safety and tolerability evaluation.
Gastrointestinal disorders Toothache	0.00% 0/26 All patients who received at least one dose of treatment were included in the safety and tolerability evaluation.	0.00% 0/25 All patients who received at least one dose of treatment were included in the safety and tolerability evaluation.	3.8% 1/26 All patients who received at least one dose of treatment were included in the safety and tolerability evaluation.	0.00% 0/23 All patients who received at least one dose of treatment were included in the safety and tolerability evaluation.	0.00% 0/24 All patients who received at least one dose of treatment were included in the safety and tolerability evaluation.	0.00% 0/23 All patients who received at least one dose of treatment were included in the safety and tolerability evaluation.
General disorders Catheter thrombosis	0.00% 0/26 All patients who received at least one dose of treatment were included in the safety and tolerability evaluation.	4.0% 1/25 All patients who received at least one dose of treatment were included in the safety and tolerability evaluation.	0.00% 0/26 All patients who received at least one dose of treatment were included in the safety and tolerability evaluation.	0.00% 0/23 All patients who received at least one dose of treatment were included in the safety and tolerability evaluation.	0.00% 0/24 All patients who received at least one dose of treatment were included in the safety and tolerability evaluation.	0.00% 0/23 All patients who received at least one dose of treatment were included in the safety and tolerability evaluation.
General disorders Chills	0.00% 0/26 All patients who received at least one dose of treatment were included in the safety and tolerability evaluation.	0.00% 0/25 All patients who received at least one dose of treatment were included in the safety and tolerability evaluation.	0.00% 0/26 All patients who received at least one dose of treatment were included in the safety and tolerability evaluation.	4.3% 1/23 All patients who received at least one dose of treatment were included in the safety and tolerability evaluation.	0.00% 0/24 All patients who received at least one dose of treatment were included in the safety and tolerability evaluation.	0.00% 0/23 All patients who received at least one dose of treatment were included in the safety and tolerability evaluation.
General disorders Fatigue	0.00% 0/26 All patients who received at least one dose of treatment were included in the safety and tolerability evaluation.	0.00% 0/25 All patients who received at least one dose of treatment were included in the safety and tolerability evaluation.	0.00% 0/26 All patients who received at least one dose of treatment were included in the safety and tolerability evaluation.	0.00% 0/23 All patients who received at least one dose of treatment were included in the safety and tolerability evaluation.	0.00% 0/24 All patients who received at least one dose of treatment were included in the safety and tolerability evaluation.	4.3% 1/23 All patients who received at least one dose of treatment were included in the safety and tolerability evaluation.
General disorders Feeling hot	0.00% 0/26 All patients who received at least one dose of treatment were included in the safety and tolerability evaluation.	0.00% 0/25 All patients who received at least one dose of treatment were included in the safety and tolerability evaluation.	3.8% 1/26 All patients who received at least one dose of treatment were included in the safety and tolerability evaluation.	0.00% 0/23 All patients who received at least one dose of treatment were included in the safety and tolerability evaluation.	0.00% 0/24 All patients who received at least one dose of treatment were included in the safety and tolerability evaluation.	0.00% 0/23 All patients who received at least one dose of treatment were included in the safety and tolerability evaluation.
General disorders Pyrexia	3.8% 1/26 All patients who received at least one dose of treatment were included in the safety and tolerability evaluation.	0.00% 0/25 All patients who received at least one dose of treatment were included in the safety and tolerability evaluation.	0.00% 0/26 All patients who received at least one dose of treatment were included in the safety and tolerability evaluation.	0.00% 0/23 All patients who received at least one dose of treatment were included in the safety and tolerability evaluation.	0.00% 0/24 All patients who received at least one dose of treatment were included in the safety and tolerability evaluation.	0.00% 0/23 All patients who received at least one dose of treatment were included in the safety and tolerability evaluation.
Infections and infestations Nasopharyngitis	3.8% 1/26 All patients who received at least one dose of treatment were included in the safety and tolerability evaluation.	0.00% 0/25 All patients who received at least one dose of treatment were included in the safety and tolerability evaluation.	0.00% 0/26 All patients who received at least one dose of treatment were included in the safety and tolerability evaluation.	4.3% 1/23 All patients who received at least one dose of treatment were included in the safety and tolerability evaluation.	0.00% 0/24 All patients who received at least one dose of treatment were included in the safety and tolerability evaluation.	4.3% 1/23 All patients who received at least one dose of treatment were included in the safety and tolerability evaluation.
Infections and infestations Tooth abscess	0.00% 0/26 All patients who received at least one dose of treatment were included in the safety and tolerability evaluation.	0.00% 0/25 All patients who received at least one dose of treatment were included in the safety and tolerability evaluation.	3.8% 1/26 All patients who received at least one dose of treatment were included in the safety and tolerability evaluation.	0.00% 0/23 All patients who received at least one dose of treatment were included in the safety and tolerability evaluation.	0.00% 0/24 All patients who received at least one dose of treatment were included in the safety and tolerability evaluation.	0.00% 0/23 All patients who received at least one dose of treatment were included in the safety and tolerability evaluation.
Injury, poisoning and procedural complications Procedural dizziness	0.00% 0/26 All patients who received at least one dose of treatment were included in the safety and tolerability evaluation.	0.00% 0/25 All patients who received at least one dose of treatment were included in the safety and tolerability evaluation.	3.8% 1/26 All patients who received at least one dose of treatment were included in the safety and tolerability evaluation.	0.00% 0/23 All patients who received at least one dose of treatment were included in the safety and tolerability evaluation.	0.00% 0/24 All patients who received at least one dose of treatment were included in the safety and tolerability evaluation.	0.00% 0/23 All patients who received at least one dose of treatment were included in the safety and tolerability evaluation.
Musculoskeletal and connective tissue disorders Musculoskeletal chest pain	3.8% 1/26 All patients who received at least one dose of treatment were included in the safety and tolerability evaluation.	0.00% 0/25 All patients who received at least one dose of treatment were included in the safety and tolerability evaluation.	0.00% 0/26 All patients who received at least one dose of treatment were included in the safety and tolerability evaluation.	0.00% 0/23 All patients who received at least one dose of treatment were included in the safety and tolerability evaluation.	0.00% 0/24 All patients who received at least one dose of treatment were included in the safety and tolerability evaluation.	0.00% 0/23 All patients who received at least one dose of treatment were included in the safety and tolerability evaluation.
Musculoskeletal and connective tissue disorders Neck pain	0.00% 0/26 All patients who received at least one dose of treatment were included in the safety and tolerability evaluation.	0.00% 0/25 All patients who received at least one dose of treatment were included in the safety and tolerability evaluation.	0.00% 0/26 All patients who received at least one dose of treatment were included in the safety and tolerability evaluation.	0.00% 0/23 All patients who received at least one dose of treatment were included in the safety and tolerability evaluation.	0.00% 0/24 All patients who received at least one dose of treatment were included in the safety and tolerability evaluation.	4.3% 1/23 All patients who received at least one dose of treatment were included in the safety and tolerability evaluation.
Nervous system disorders Dizziness	3.8% 1/26 All patients who received at least one dose of treatment were included in the safety and tolerability evaluation.	0.00% 0/25 All patients who received at least one dose of treatment were included in the safety and tolerability evaluation.	0.00% 0/26 All patients who received at least one dose of treatment were included in the safety and tolerability evaluation.	0.00% 0/23 All patients who received at least one dose of treatment were included in the safety and tolerability evaluation.	4.2% 1/24 All patients who received at least one dose of treatment were included in the safety and tolerability evaluation.	8.7% 2/23 All patients who received at least one dose of treatment were included in the safety and tolerability evaluation.
Nervous system disorders Headache	0.00% 0/26 All patients who received at least one dose of treatment were included in the safety and tolerability evaluation.	4.0% 1/25 All patients who received at least one dose of treatment were included in the safety and tolerability evaluation.	3.8% 1/26 All patients who received at least one dose of treatment were included in the safety and tolerability evaluation.	0.00% 0/23 All patients who received at least one dose of treatment were included in the safety and tolerability evaluation.	8.3% 2/24 All patients who received at least one dose of treatment were included in the safety and tolerability evaluation.	4.3% 1/23 All patients who received at least one dose of treatment were included in the safety and tolerability evaluation.
Nervous system disorders Neuropathy peripheral	3.8% 1/26 All patients who received at least one dose of treatment were included in the safety and tolerability evaluation.	0.00% 0/25 All patients who received at least one dose of treatment were included in the safety and tolerability evaluation.	0.00% 0/26 All patients who received at least one dose of treatment were included in the safety and tolerability evaluation.	0.00% 0/23 All patients who received at least one dose of treatment were included in the safety and tolerability evaluation.	0.00% 0/24 All patients who received at least one dose of treatment were included in the safety and tolerability evaluation.	0.00% 0/23 All patients who received at least one dose of treatment were included in the safety and tolerability evaluation.
Nervous system disorders Tremor	0.00% 0/26 All patients who received at least one dose of treatment were included in the safety and tolerability evaluation.	0.00% 0/25 All patients who received at least one dose of treatment were included in the safety and tolerability evaluation.	0.00% 0/26 All patients who received at least one dose of treatment were included in the safety and tolerability evaluation.	8.7% 2/23 All patients who received at least one dose of treatment were included in the safety and tolerability evaluation.	12.5% 3/24 All patients who received at least one dose of treatment were included in the safety and tolerability evaluation.	8.7% 2/23 All patients who received at least one dose of treatment were included in the safety and tolerability evaluation.
Respiratory, thoracic and mediastinal disorders Cough	7.7% 2/26 All patients who received at least one dose of treatment were included in the safety and tolerability evaluation.	0.00% 0/25 All patients who received at least one dose of treatment were included in the safety and tolerability evaluation.	3.8% 1/26 All patients who received at least one dose of treatment were included in the safety and tolerability evaluation.	4.3% 1/23 All patients who received at least one dose of treatment were included in the safety and tolerability evaluation.	0.00% 0/24 All patients who received at least one dose of treatment were included in the safety and tolerability evaluation.	0.00% 0/23 All patients who received at least one dose of treatment were included in the safety and tolerability evaluation.
Respiratory, thoracic and mediastinal disorders Dyspnoea	3.8% 1/26 All patients who received at least one dose of treatment were included in the safety and tolerability evaluation.	4.0% 1/25 All patients who received at least one dose of treatment were included in the safety and tolerability evaluation.	3.8% 1/26 All patients who received at least one dose of treatment were included in the safety and tolerability evaluation.	0.00% 0/23 All patients who received at least one dose of treatment were included in the safety and tolerability evaluation.	0.00% 0/24 All patients who received at least one dose of treatment were included in the safety and tolerability evaluation.	0.00% 0/23 All patients who received at least one dose of treatment were included in the safety and tolerability evaluation.
Respiratory, thoracic and mediastinal disorders Pharyngolaryngeal pain	3.8% 1/26 All patients who received at least one dose of treatment were included in the safety and tolerability evaluation.	0.00% 0/25 All patients who received at least one dose of treatment were included in the safety and tolerability evaluation.	0.00% 0/26 All patients who received at least one dose of treatment were included in the safety and tolerability evaluation.	0.00% 0/23 All patients who received at least one dose of treatment were included in the safety and tolerability evaluation.	0.00% 0/24 All patients who received at least one dose of treatment were included in the safety and tolerability evaluation.	0.00% 0/23 All patients who received at least one dose of treatment were included in the safety and tolerability evaluation.
Respiratory, thoracic and mediastinal disorders Productive cough	0.00% 0/26 All patients who received at least one dose of treatment were included in the safety and tolerability evaluation.	4.0% 1/25 All patients who received at least one dose of treatment were included in the safety and tolerability evaluation.	0.00% 0/26 All patients who received at least one dose of treatment were included in the safety and tolerability evaluation.	0.00% 0/23 All patients who received at least one dose of treatment were included in the safety and tolerability evaluation.	4.2% 1/24 All patients who received at least one dose of treatment were included in the safety and tolerability evaluation.	0.00% 0/23 All patients who received at least one dose of treatment were included in the safety and tolerability evaluation.
Skin and subcutaneous tissue disorders Erythema	3.8% 1/26 All patients who received at least one dose of treatment were included in the safety and tolerability evaluation.	0.00% 0/25 All patients who received at least one dose of treatment were included in the safety and tolerability evaluation.	0.00% 0/26 All patients who received at least one dose of treatment were included in the safety and tolerability evaluation.	0.00% 0/23 All patients who received at least one dose of treatment were included in the safety and tolerability evaluation.	0.00% 0/24 All patients who received at least one dose of treatment were included in the safety and tolerability evaluation.	0.00% 0/23 All patients who received at least one dose of treatment were included in the safety and tolerability evaluation.
Skin and subcutaneous tissue disorders Hyperhidrosis	0.00% 0/26 All patients who received at least one dose of treatment were included in the safety and tolerability evaluation.	0.00% 0/25 All patients who received at least one dose of treatment were included in the safety and tolerability evaluation.	3.8% 1/26 All patients who received at least one dose of treatment were included in the safety and tolerability evaluation.	0.00% 0/23 All patients who received at least one dose of treatment were included in the safety and tolerability evaluation.	0.00% 0/24 All patients who received at least one dose of treatment were included in the safety and tolerability evaluation.	0.00% 0/23 All patients who received at least one dose of treatment were included in the safety and tolerability evaluation.
Skin and subcutaneous tissue disorders Hypoaesthesia facial	0.00% 0/26 All patients who received at least one dose of treatment were included in the safety and tolerability evaluation.	0.00% 0/25 All patients who received at least one dose of treatment were included in the safety and tolerability evaluation.	0.00% 0/26 All patients who received at least one dose of treatment were included in the safety and tolerability evaluation.	4.3% 1/23 All patients who received at least one dose of treatment were included in the safety and tolerability evaluation.	4.2% 1/24 All patients who received at least one dose of treatment were included in the safety and tolerability evaluation.	4.3% 1/23 All patients who received at least one dose of treatment were included in the safety and tolerability evaluation.
Skin and subcutaneous tissue disorders Nail disorder	0.00% 0/26 All patients who received at least one dose of treatment were included in the safety and tolerability evaluation.	0.00% 0/25 All patients who received at least one dose of treatment were included in the safety and tolerability evaluation.	0.00% 0/26 All patients who received at least one dose of treatment were included in the safety and tolerability evaluation.	0.00% 0/23 All patients who received at least one dose of treatment were included in the safety and tolerability evaluation.	4.2% 1/24 All patients who received at least one dose of treatment were included in the safety and tolerability evaluation.	0.00% 0/23 All patients who received at least one dose of treatment were included in the safety and tolerability evaluation.
Skin and subcutaneous tissue disorders Pruritus generalised	0.00% 0/26 All patients who received at least one dose of treatment were included in the safety and tolerability evaluation.	0.00% 0/25 All patients who received at least one dose of treatment were included in the safety and tolerability evaluation.	0.00% 0/26 All patients who received at least one dose of treatment were included in the safety and tolerability evaluation.	4.3% 1/23 All patients who received at least one dose of treatment were included in the safety and tolerability evaluation.	0.00% 0/24 All patients who received at least one dose of treatment were included in the safety and tolerability evaluation.	0.00% 0/23 All patients who received at least one dose of treatment were included in the safety and tolerability evaluation.
Vascular disorders Diastolic hypertension	0.00% 0/26 All patients who received at least one dose of treatment were included in the safety and tolerability evaluation.	0.00% 0/25 All patients who received at least one dose of treatment were included in the safety and tolerability evaluation.	0.00% 0/26 All patients who received at least one dose of treatment were included in the safety and tolerability evaluation.	4.3% 1/23 All patients who received at least one dose of treatment were included in the safety and tolerability evaluation.	0.00% 0/24 All patients who received at least one dose of treatment were included in the safety and tolerability evaluation.	0.00% 0/23 All patients who received at least one dose of treatment were included in the safety and tolerability evaluation.

Additional Information

Study Director

Novartis Pharmaceuticals

Phone: 862-778-8300

Results disclosure agreements

Principal investigator is a sponsor employee The terms and conditions of Novartis' agreements with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of the pooled data (i.e., data from all sites) in the clinical trial.
Publication restrictions are in place

Restriction type: OTHER