Trial Outcomes & Findings for 26 Week Efficacy, Safety and Tolerability Study of Indacaterol in Patients With Chronic Obstructive Pulmonary Disease (COPD) (NCT NCT00463567)

NCT ID: NCT00463567

Last Updated: 2011-08-18

Results Overview

FEV1 was measured with spirometry conducted according to internationally accepted standards. Trough FEV1 was defined as the average of the 23 h 10 min and the 23 h 45 min post dose values. Mixed model used baseline FEV1, FEV1 prior to and 30 minutes post inhalation of salbutamol/albuterol, and FEV1 prior to and 1 hour post inhalation of ipratropium as covariates.

• Recruitment status: COMPLETED
• Study phase: PHASE2/PHASE3
• Target enrollment: 2059 participants
• Primary outcome timeframe: after 12 weeks of treatment
• Results posted on: 2011-08-18

Participant Flow

This study consisted of two stages: a dose selection stage (Stage 1, 2 weeks) from which 2 out of 4 Indacaterol doses were selected following interim analysis to continue into Stage 2 for comparisons of efficacy, safety, and tolerability for total treatment of up to 26 weeks.

Participant milestones

Measure	Indacaterol 150 µg (Continued Into Stage 2) In the morning, Indacaterol 150 µg once daily orally inhaled via a single dose dry powder inhaler (SDDPI) + Placebo to Indacaterol delivered via SDDPI + Placebo to Formoterol delivered via Aerolizer. In the evening, Placebo to Formoterol delivered via Aerolizer. Participated in the 2 week Stage 1 and continued treatment up to 26 weeks in Stage 2. Placebo to Formoterol inhalation in the morning and in the evening was discontinued after Stage 1. Daily Inhaled Corticosteroid (ICS) monotherapy (if applicable) was to remain stable and Salbutamol/albuterol was available for rescue use throughout study.	Indacaterol 300 µg (Continued Into Stage 2) In the morning, Indacaterol 300 µg once daily orally inhaled via a SDDPI + Placebo to Indacaterol delivered via SDDPI + Placebo to Formoterol delivered via Aerolizer. In evening, Placebo to Formoterol delivered via Aerolizer. Participated in the 2 week Stage 1 and continued treatment up to 26 weeks in Stage 2. Placebo to Formoterol inhalation in the morning and in the evening was discontinued after Stage 1. Daily ICS monotherapy (if applicable) was to remain stable and Salbutamol/albuterol was available for rescue use throughout study.	Tiotropium (Continued Into Stage 2) Tiotropium 18 µg dry powder capsules delivered (open label) via manufacturer's proprietary SDDPI, (Handihaler®). Participated in the 2 week Stage 1 and continued treatment up to 26 weeks in Stage 2. Daily ICS monotherapy (if applicable) was to remain stable and Salbutamol/albuterol was available for rescue use throughout study.	Placebo (Continued Into Stage 2) In the morning, Placebo to Indacaterol delivered via two SDDPI devices + Placebo to Formoterol delivered via Aerolizer. In the evening, Placebo to Formoterol delivered via Aerolizer. Participated in the 2 week Stage 1 and continued treatment up to 26 weeks in Stage 2. Placebo to Formoterol inhalation in the morning and in the evening was discontinued after Stage 1. Daily ICS monotherapy (if applicable) was to remain stable and Salbutamol/albuterol was available for rescue use throughout study.	Indacaterol 75 µg (Not Continued Into Stage 2) In the morning, Indacaterol 75 µg once daily orally inhaled via a SDDPI + Placebo to Indacaterol delivered via SDDPI + Placebo to Formoterol delivered via Aerolizer. In the evening, Placebo to Formoterol delivered via Aerolizer. Participated in the 2 week Stage 1 but did not continue to Stage 2. Daily ICS monotherapy (if applicable) was to remain stable and Salbutamol/albuterol was available for rescue use throughout study.	Indacaterol 600 µg (Not Continued Into Stage 2) In the morning, 2 capsules of Indacaterol 300 µg once daily orally inhaled via two SDDPI devices + Placebo to Formoterol delivered via Aerolizer. In the evening, Placebo to Formoterol delivered via Aerolizer. Participated in the 2 week Stage 1 but did not continue to Stage 2. Daily ICS monotherapy (if applicable) was to remain stable and Salbutamol/albuterol was available for rescue use throughout study.	Formoterol 12 µg (Not Continued Into Stage 2) In the morning, Placebo to Indacaterol delivered via two SDDPI devices + Formoterol 12 µg delivered via Aerolizer. In evening, Formoterol 12 µg delivered via Aerolizer. Participated in the 2 week Stage 1 but did not continue to Stage 2. Daily ICS monotherapy (if applicable) was to remain stable and Salbutamol/albuterol was available for rescue use throughout study.
Overall Study STARTED	420	418	420	425	130	123	123
Overall Study Safety Population: Received Study Drug	416	416	415	418	127	122	122
Overall Study COMPLETED	325	341	331	294	107	102	112
Overall Study NOT COMPLETED	95	77	89	131	23	21	11

Reasons for withdrawal

Measure	Indacaterol 150 µg (Continued Into Stage 2) In the morning, Indacaterol 150 µg once daily orally inhaled via a single dose dry powder inhaler (SDDPI) + Placebo to Indacaterol delivered via SDDPI + Placebo to Formoterol delivered via Aerolizer. In the evening, Placebo to Formoterol delivered via Aerolizer. Participated in the 2 week Stage 1 and continued treatment up to 26 weeks in Stage 2. Placebo to Formoterol inhalation in the morning and in the evening was discontinued after Stage 1. Daily Inhaled Corticosteroid (ICS) monotherapy (if applicable) was to remain stable and Salbutamol/albuterol was available for rescue use throughout study.	Indacaterol 300 µg (Continued Into Stage 2) In the morning, Indacaterol 300 µg once daily orally inhaled via a SDDPI + Placebo to Indacaterol delivered via SDDPI + Placebo to Formoterol delivered via Aerolizer. In evening, Placebo to Formoterol delivered via Aerolizer. Participated in the 2 week Stage 1 and continued treatment up to 26 weeks in Stage 2. Placebo to Formoterol inhalation in the morning and in the evening was discontinued after Stage 1. Daily ICS monotherapy (if applicable) was to remain stable and Salbutamol/albuterol was available for rescue use throughout study.	Tiotropium (Continued Into Stage 2) Tiotropium 18 µg dry powder capsules delivered (open label) via manufacturer's proprietary SDDPI, (Handihaler®). Participated in the 2 week Stage 1 and continued treatment up to 26 weeks in Stage 2. Daily ICS monotherapy (if applicable) was to remain stable and Salbutamol/albuterol was available for rescue use throughout study.	Placebo (Continued Into Stage 2) In the morning, Placebo to Indacaterol delivered via two SDDPI devices + Placebo to Formoterol delivered via Aerolizer. In the evening, Placebo to Formoterol delivered via Aerolizer. Participated in the 2 week Stage 1 and continued treatment up to 26 weeks in Stage 2. Placebo to Formoterol inhalation in the morning and in the evening was discontinued after Stage 1. Daily ICS monotherapy (if applicable) was to remain stable and Salbutamol/albuterol was available for rescue use throughout study.	Indacaterol 75 µg (Not Continued Into Stage 2) In the morning, Indacaterol 75 µg once daily orally inhaled via a SDDPI + Placebo to Indacaterol delivered via SDDPI + Placebo to Formoterol delivered via Aerolizer. In the evening, Placebo to Formoterol delivered via Aerolizer. Participated in the 2 week Stage 1 but did not continue to Stage 2. Daily ICS monotherapy (if applicable) was to remain stable and Salbutamol/albuterol was available for rescue use throughout study.	Indacaterol 600 µg (Not Continued Into Stage 2) In the morning, 2 capsules of Indacaterol 300 µg once daily orally inhaled via two SDDPI devices + Placebo to Formoterol delivered via Aerolizer. In the evening, Placebo to Formoterol delivered via Aerolizer. Participated in the 2 week Stage 1 but did not continue to Stage 2. Daily ICS monotherapy (if applicable) was to remain stable and Salbutamol/albuterol was available for rescue use throughout study.	Formoterol 12 µg (Not Continued Into Stage 2) In the morning, Placebo to Indacaterol delivered via two SDDPI devices + Formoterol 12 µg delivered via Aerolizer. In evening, Formoterol 12 µg delivered via Aerolizer. Participated in the 2 week Stage 1 but did not continue to Stage 2. Daily ICS monotherapy (if applicable) was to remain stable and Salbutamol/albuterol was available for rescue use throughout study.
Overall Study Adverse Event	29	26	17	46	10	10	4
Overall Study Withdrawal by Subject	29	22	20	37	6	5	1
Overall Study Protocol Deviation	13	9	14	11	1	1	2
Overall Study Lost to Follow-up	12	6	13	8	1	1	1
Overall Study Administrative problems	5	3	6	9	3	2	2
Overall Study Lack of Efficacy	4	9	9	17	1	0	1
Overall Study Abnormal lab value(s)	1	1	2	1	1	0	0
Overall Study Abnormal test procedure result(s)	1	1	6	2	0	2	0
Overall Study Death	1	0	2	0	0	0	0

Baseline Characteristics

26 Week Efficacy, Safety and Tolerability Study of Indacaterol in Patients With Chronic Obstructive Pulmonary Disease (COPD)

Baseline characteristics by cohort

Measure	Indacaterol 150 µg (Continued Into Stage 2) n=416 Participants In the morning, Indacaterol 150 µg once daily orally inhaled via a single dose dry powder inhaler (SDDPI) + Placebo to Indacaterol delivered via SDDPI + Placebo to Formoterol delivered via Aerolizer. In the evening, Placebo to Formoterol delivered via Aerolizer. Participated in the 2 week Stage 1 and continued treatment up to 26 weeks in Stage 2. Placebo to Formoterol inhalation in the morning and in the evening was discontinued after Stage 1. Daily Inhaled Corticosteroid (ICS) monotherapy (if applicable) was to remain stable and Salbutamol/albuterol was available for rescue use throughout study.	Indacaterol 300 µg (Continued Into Stage 2) n=416 Participants In the morning, Indacaterol 300 µg once daily orally inhaled via a SDDPI + Placebo to Indacaterol delivered via SDDPI + Placebo to Formoterol delivered via Aerolizer. In evening, Placebo to Formoterol delivered via Aerolizer. Participated in the 2 week Stage 1 and continued treatment up to 26 weeks in Stage 2. Placebo to Formoterol inhalation in the morning and in the evening was discontinued after Stage 1. Daily ICS monotherapy (if applicable) was to remain stable and Salbutamol/albuterol was available for rescue use throughout study.	Tiotropium 18 µg (Continued Into Stage 2) n=415 Participants Tiotropium 18 µg dry powder capsules delivered (open label) via manufacturer's proprietary SDDPI, (Handihaler®). Participated in the 2 week Stage 1 and continued treatment up to 26 weeks in Stage 2. Daily ICS monotherapy (if applicable) was to remain stable and Salbutamol/albuterol was available for rescue use throughout study.	Placebo (Continued Into Stage 2) n=418 Participants In the morning, Placebo to Indacaterol delivered via two SDDPI devices + Placebo to Formoterol delivered via Aerolizer. In the evening, Placebo to Formoterol delivered via Aerolizer. Participated in the 2 week Stage 1 and continued treatment up to 26 weeks in Stage 2. Placebo to Formoterol inhalation in the morning and in the evening was discontinued after Stage 1. Daily ICS monotherapy (if applicable) was to remain stable and Salbutamol/albuterol was available for rescue use throughout study.	Indacaterol 75 µg (Not Continued Into Stage 2) n=127 Participants In the morning, Indacaterol 75 µg once daily orally inhaled via a SDDPI + Placebo to Indacaterol delivered via SDDPI + Placebo to Formoterol delivered via Aerolizer. In the evening, Placebo to Formoterol delivered via Aerolizer. Participated in the 2 week Stage 1 but did not continue to Stage 2. Daily ICS monotherapy (if applicable) was to remain stable and Salbutamol/albuterol was available for rescue use throughout study.	Indacaterol 600 µg (Not Continued Into Stage 2) n=122 Participants In the morning, 2 capsules of Indacaterol 300 µg once daily orally inhaled via two SDDPI devices + Placebo to Formoterol delivered via Aerolizer. In the evening, Placebo to Formoterol delivered via Aerolizer. Participated in the 2 week Stage 1 but did not continue to Stage 2. Daily ICS monotherapy (if applicable) was to remain stable and Salbutamol/albuterol was available for rescue use throughout study.	Formoterol 12 µg (Not Continued Into Stage 2) n=122 Participants In the morning, Placebo to Indacaterol delivered via two SDDPI devices + Formoterol 12 µg delivered via Aerolizer. In evening, Formoterol 12 µg delivered via Aerolizer. Participated in the 2 week Stage 1 but did not continue to Stage 2. Daily ICS monotherapy (if applicable) was to remain stable and Salbutamol/albuterol was available for rescue use throughout study.	Total n=2036 Participants Total of all reporting groups
Age, Customized Between 40 and 64 years	214 participants n=5 Participants	230 participants n=7 Participants	215 participants n=5 Participants	215 participants n=4 Participants	58 participants n=21 Participants	60 participants n=8 Participants	56 participants n=8 Participants	1048 participants n=24 Participants
Age, Customized ≥65 years	202 participants n=5 Participants	186 participants n=7 Participants	200 participants n=5 Participants	203 participants n=4 Participants	69 participants n=21 Participants	62 participants n=8 Participants	66 participants n=8 Participants	988 participants n=24 Participants
Sex: Female, Male Female	157 Participants n=5 Participants	153 Participants n=7 Participants	146 Participants n=5 Participants	163 Participants n=4 Participants	51 Participants n=21 Participants	48 Participants n=8 Participants	52 Participants n=8 Participants	770 Participants n=24 Participants
Sex: Female, Male Male	259 Participants n=5 Participants	263 Participants n=7 Participants	269 Participants n=5 Participants	255 Participants n=4 Participants	76 Participants n=21 Participants	74 Participants n=8 Participants	70 Participants n=8 Participants	1266 Participants n=24 Participants

PRIMARY outcome

Timeframe: after 12 weeks of treatment

Population: Participants from the Intent to Treat Population of Stage 2 of the study who received at least one dose of study drug and for whom data was available for FEV1 at 12 weeks. Imputed with last observation carried forward.

FEV1 was measured with spirometry conducted according to internationally accepted standards. Trough FEV1 was defined as the average of the 23 h 10 min and the 23 h 45 min post dose values. Mixed model used baseline FEV1, FEV1 prior to and 30 minutes post inhalation of salbutamol/albuterol, and FEV1 prior to and 1 hour post inhalation of ipratropium as covariates.

Outcome measures

Measure	Indacaterol 300 µg n=389 Participants In the morning, Indacaterol 300 µg once daily orally inhaled via a SDDPI + Placebo to Indacaterol delivered via SDDPI + Placebo to Formoterol delivered via Aerolizer. In evening, Placebo to Formoterol delivered via Aerolizer. Daily ICS monotherapy (if applicable) was to remain stable and Salbutamol/albuterol was available for rescue use throughout study.	Tiotropium 18 µg n=393 Participants Tiotropium 18 µg dry powder capsules delivered (open label) via manufacturer's proprietary SDDPI, (Handihaler®). Daily ICS monotherapy (if applicable) was to remain stable and Salbutamol/albuterol was available for rescue use throughout study.	Placebo n=376 Participants In the morning, Placebo to Indacaterol delivered via two SDDPI devices + Placebo to Formoterol delivered via Aerolizer. In evening, Placebo to Formoterol delivered via Aerolizer. Daily ICS monotherapy (if applicable) was to remain stable and Salbutamol/albuterol was available for rescue use throughout study.	Indacaterol 75 µg In the morning, Indacaterol 75 µg once daily orally inhaled via a SDDPI + Placebo to Indacaterol delivered via SDDPI + Placebo to Formoterol delivered via Aerolizer. In the evening, Placebo to Formoterol delivered via Aerolizer. Daily ICS monotherapy (if applicable) was to remain stable and Salbutamol/albuterol was available for rescue use throughout study.	Indacaterol 600 µg In the morning, 2 capsules of Indacaterol 300 µg once daily orally inhaled via two SDDPI devices + Placebo to Formoterol delivered via Aerolizer. In the evening, Placebo to Formoterol delivered via Aerolizer. Daily ICS monotherapy (if applicable) was to remain stable and Salbutamol/albuterol was available for rescue use throughout study.	Formoterol 12 µg In the morning, Placebo to Indacaterol delivered via SDDPI devices + Formoterol 12 µg delivered via Aerolizer. In evening, Formoterol 12 µg delivered via Aerolizer. Daily ICS monotherapy (if applicable) was to remain stable and Salbutamol/albuterol was available for rescue use throughout study.	Indacaterol 150 µg (Continued Into Stage 2) n=389 Participants In the morning, Indacaterol 150 µg once daily orally inhaled via a single dose dry powder inhaler (SDDPI) + Placebo to Indacaterol delivered via SDDPI + Placebo to Formoterol delivered via Aerolizer. In the evening, Placebo to Formoterol delivered via Aerolizer. Participated in the 2 week Stage 1 and continued treatment up to 26 weeks in Stage 2. Placebo to Formoterol inhalation in the morning and in the evening was discontinued after Stage 1. Daily Inhaled Corticosteroid (ICS) monotherapy (if applicable) was to remain stable and Salbutamol/albuterol was available for rescue use throughout study.
Trough Forced Expiratory Volume in 1 Second (FEV1) Assessed by Spirometry 24 Hour Post Dose After 12 Weeks of Treatment	1.46 Liters Standard Error 0.015	1.42 Liters Standard Error 0.015	1.28 Liters Standard Error 0.015	—	—	—	1.46 Liters Standard Error 0.015

SECONDARY outcome

Timeframe: up to 26 weeks

Population: Intent to Treat population consisting of all participants in Stage 2 of the study who received at least one dose of study drug. Eligible participants for the analysis were those with ≥7 evaluable diary days in the baseline period and ≥30% evaluable diary days (at least 20 days) in total.

A Chronic Obstructive Pulmonary Disease (COPD) "day of poor control" was defined as any day in the participant's diary with a score ≥2 (moderate or severe) for at least 2 of 5 symptoms (cough, wheeze, production of sputum, color of sputum, breathlessness). Score for each symptom ranges from 0-3; a higher number indicates a more severe symptom. The model contained baseline percentage of "days of poor control" as well as FEV1 reversibility components as covariates.

Outcome measures

Measure	Indacaterol 300 µg n=384 Participants In the morning, Indacaterol 300 µg once daily orally inhaled via a SDDPI + Placebo to Indacaterol delivered via SDDPI + Placebo to Formoterol delivered via Aerolizer. In evening, Placebo to Formoterol delivered via Aerolizer. Daily ICS monotherapy (if applicable) was to remain stable and Salbutamol/albuterol was available for rescue use throughout study.	Tiotropium 18 µg n=391 Participants Tiotropium 18 µg dry powder capsules delivered (open label) via manufacturer's proprietary SDDPI, (Handihaler®). Daily ICS monotherapy (if applicable) was to remain stable and Salbutamol/albuterol was available for rescue use throughout study.	Placebo n=362 Participants In the morning, Placebo to Indacaterol delivered via two SDDPI devices + Placebo to Formoterol delivered via Aerolizer. In evening, Placebo to Formoterol delivered via Aerolizer. Daily ICS monotherapy (if applicable) was to remain stable and Salbutamol/albuterol was available for rescue use throughout study.	Indacaterol 75 µg In the morning, Indacaterol 75 µg once daily orally inhaled via a SDDPI + Placebo to Indacaterol delivered via SDDPI + Placebo to Formoterol delivered via Aerolizer. In the evening, Placebo to Formoterol delivered via Aerolizer. Daily ICS monotherapy (if applicable) was to remain stable and Salbutamol/albuterol was available for rescue use throughout study.	Indacaterol 600 µg In the morning, 2 capsules of Indacaterol 300 µg once daily orally inhaled via two SDDPI devices + Placebo to Formoterol delivered via Aerolizer. In the evening, Placebo to Formoterol delivered via Aerolizer. Daily ICS monotherapy (if applicable) was to remain stable and Salbutamol/albuterol was available for rescue use throughout study.	Formoterol 12 µg In the morning, Placebo to Indacaterol delivered via SDDPI devices + Formoterol 12 µg delivered via Aerolizer. In evening, Formoterol 12 µg delivered via Aerolizer. Daily ICS monotherapy (if applicable) was to remain stable and Salbutamol/albuterol was available for rescue use throughout study.	Indacaterol 150 µg (Continued Into Stage 2) n=385 Participants In the morning, Indacaterol 150 µg once daily orally inhaled via a single dose dry powder inhaler (SDDPI) + Placebo to Indacaterol delivered via SDDPI + Placebo to Formoterol delivered via Aerolizer. In the evening, Placebo to Formoterol delivered via Aerolizer. Participated in the 2 week Stage 1 and continued treatment up to 26 weeks in Stage 2. Placebo to Formoterol inhalation in the morning and in the evening was discontinued after Stage 1. Daily Inhaled Corticosteroid (ICS) monotherapy (if applicable) was to remain stable and Salbutamol/albuterol was available for rescue use throughout study.
The Percentage of "Days of Poor Control" Reported Over the 26 Week Treatment Period	30.8 Percentage of days Standard Error 1.51	31.0 Percentage of days Standard Error 1.50	34.0 Percentage of days Standard Error 1.53	—	—	—	31.5 Percentage of days Standard Error 1.51

OTHER_PRE_SPECIFIED outcome

Timeframe: Day 15, After 2 Weeks of treatment in Stage 1

Population: Interim Intent-to-treat (ITT) population included participants in Stage 1 of the study who received at least one dose of study drug and for whom data were available for Trough FEV1 at Day 15. Missing data were imputed using last observation carried forward (LOCF).

Interim Analysis: Stage 1.

Spirometry was conducted according to internationally accepted standards. Trough FEV1 was defined as the average of the 23 h 10 min and the 23 h 45 min post dose values. Mixed model used baseline FEV1, FEV1 prior to and 30 minutes post inhalation of salbutamol/albuterol, and FEV1 prior to and 1 hour post inhalation of ipratropium as covariates.

Outcome measures

Measure	Indacaterol 300 µg n=110 Participants In the morning, Indacaterol 300 µg once daily orally inhaled via a SDDPI + Placebo to Indacaterol delivered via SDDPI + Placebo to Formoterol delivered via Aerolizer. In evening, Placebo to Formoterol delivered via Aerolizer. Daily ICS monotherapy (if applicable) was to remain stable and Salbutamol/albuterol was available for rescue use throughout study.	Tiotropium 18 µg n=112 Participants Tiotropium 18 µg dry powder capsules delivered (open label) via manufacturer's proprietary SDDPI, (Handihaler®). Daily ICS monotherapy (if applicable) was to remain stable and Salbutamol/albuterol was available for rescue use throughout study.	Placebo n=104 Participants In the morning, Placebo to Indacaterol delivered via two SDDPI devices + Placebo to Formoterol delivered via Aerolizer. In evening, Placebo to Formoterol delivered via Aerolizer. Daily ICS monotherapy (if applicable) was to remain stable and Salbutamol/albuterol was available for rescue use throughout study.	Indacaterol 75 µg n=104 Participants In the morning, Indacaterol 75 µg once daily orally inhaled via a SDDPI + Placebo to Indacaterol delivered via SDDPI + Placebo to Formoterol delivered via Aerolizer. In the evening, Placebo to Formoterol delivered via Aerolizer. Daily ICS monotherapy (if applicable) was to remain stable and Salbutamol/albuterol was available for rescue use throughout study.	Indacaterol 600 µg n=108 Participants In the morning, 2 capsules of Indacaterol 300 µg once daily orally inhaled via two SDDPI devices + Placebo to Formoterol delivered via Aerolizer. In the evening, Placebo to Formoterol delivered via Aerolizer. Daily ICS monotherapy (if applicable) was to remain stable and Salbutamol/albuterol was available for rescue use throughout study.	Formoterol 12 µg n=105 Participants In the morning, Placebo to Indacaterol delivered via SDDPI devices + Formoterol 12 µg delivered via Aerolizer. In evening, Formoterol 12 µg delivered via Aerolizer. Daily ICS monotherapy (if applicable) was to remain stable and Salbutamol/albuterol was available for rescue use throughout study.	Indacaterol 150 µg (Continued Into Stage 2) n=105 Participants In the morning, Indacaterol 150 µg once daily orally inhaled via a single dose dry powder inhaler (SDDPI) + Placebo to Indacaterol delivered via SDDPI + Placebo to Formoterol delivered via Aerolizer. In the evening, Placebo to Formoterol delivered via Aerolizer. Participated in the 2 week Stage 1 and continued treatment up to 26 weeks in Stage 2. Placebo to Formoterol inhalation in the morning and in the evening was discontinued after Stage 1. Daily Inhaled Corticosteroid (ICS) monotherapy (if applicable) was to remain stable and Salbutamol/albuterol was available for rescue use throughout study.
Trough Forced Expiratory Volume in 1 Second (FEV1) Assessed by Spirometry 24 Hour Post Dose After 2 Weeks of Treatment	1.52 Liters Standard Error 0.024	1.45 Liters Standard Error 0.023	1.31 Liters Standard Error 0.024	1.46 Liters Standard Error 0.024	1.51 Liters Standard Error 0.024	1.42 Liters Standard Error 0.024	1.49 Liters Standard Error 0.024

OTHER_PRE_SPECIFIED outcome

Timeframe: Day 14, After 2 Weeks of treatment in Stage 1

Population: Interim Intent-to-treat (ITT) population included participants in Stage 1 of the study who received at least one dose of study drug and for whom data were available for AUC 1h-4h FEV1 at Day 14. Missing data were imputed using last observation carried forward (LOCF).

Interim Analysis: Stage 1.

Spirometry was conducted according to internationally accepted standards. Standardized with respect to time (AUC 1h-4h) for FEV1 measurements taken from 1 hour to 4 hour post morning dose on Day 14. Standardized FEV1 AUC was calculated by the trapezoidal rule. Mixed model used baseline FEV1, FEV1 prior to and 30 minutes post inhalation of salbutamol/albuterol, and FEV1 prior to and 1 hour post inhalation of ipratropium as covariates.

Outcome measures

Measure	Indacaterol 300 µg n=99 Participants In the morning, Indacaterol 300 µg once daily orally inhaled via a SDDPI + Placebo to Indacaterol delivered via SDDPI + Placebo to Formoterol delivered via Aerolizer. In evening, Placebo to Formoterol delivered via Aerolizer. Daily ICS monotherapy (if applicable) was to remain stable and Salbutamol/albuterol was available for rescue use throughout study.	Tiotropium 18 µg n=99 Participants Tiotropium 18 µg dry powder capsules delivered (open label) via manufacturer's proprietary SDDPI, (Handihaler®). Daily ICS monotherapy (if applicable) was to remain stable and Salbutamol/albuterol was available for rescue use throughout study.	Placebo n=90 Participants In the morning, Placebo to Indacaterol delivered via two SDDPI devices + Placebo to Formoterol delivered via Aerolizer. In evening, Placebo to Formoterol delivered via Aerolizer. Daily ICS monotherapy (if applicable) was to remain stable and Salbutamol/albuterol was available for rescue use throughout study.	Indacaterol 75 µg n=95 Participants In the morning, Indacaterol 75 µg once daily orally inhaled via a SDDPI + Placebo to Indacaterol delivered via SDDPI + Placebo to Formoterol delivered via Aerolizer. In the evening, Placebo to Formoterol delivered via Aerolizer. Daily ICS monotherapy (if applicable) was to remain stable and Salbutamol/albuterol was available for rescue use throughout study.	Indacaterol 600 µg n=97 Participants In the morning, 2 capsules of Indacaterol 300 µg once daily orally inhaled via two SDDPI devices + Placebo to Formoterol delivered via Aerolizer. In the evening, Placebo to Formoterol delivered via Aerolizer. Daily ICS monotherapy (if applicable) was to remain stable and Salbutamol/albuterol was available for rescue use throughout study.	Formoterol 12 µg n=93 Participants In the morning, Placebo to Indacaterol delivered via SDDPI devices + Formoterol 12 µg delivered via Aerolizer. In evening, Formoterol 12 µg delivered via Aerolizer. Daily ICS monotherapy (if applicable) was to remain stable and Salbutamol/albuterol was available for rescue use throughout study.	Indacaterol 150 µg (Continued Into Stage 2) n=96 Participants In the morning, Indacaterol 150 µg once daily orally inhaled via a single dose dry powder inhaler (SDDPI) + Placebo to Indacaterol delivered via SDDPI + Placebo to Formoterol delivered via Aerolizer. In the evening, Placebo to Formoterol delivered via Aerolizer. Participated in the 2 week Stage 1 and continued treatment up to 26 weeks in Stage 2. Placebo to Formoterol inhalation in the morning and in the evening was discontinued after Stage 1. Daily Inhaled Corticosteroid (ICS) monotherapy (if applicable) was to remain stable and Salbutamol/albuterol was available for rescue use throughout study.
Forced Expiratory Volume in 1 Second (FEV1) Standardized (With Respect to Time) Area Under the Curve (AUC) From 1 Hour to 4 Hour Post Morning Dose After 2 Weeks of Treatment	1.58 Liters Standard Error 0.034	1.49 Liters Standard Error 0.034	1.30 Liters Standard Error 0.033	1.50 Liters Standard Error 0.034	1.53 Liters Standard Error 0.034	1.52 Liters Standard Error 0.035	1.53 Liters Standard Error 0.034

Adverse Events

Indacaterol 150 µg (Continued Into Stage 2)

Serious events: 35 serious events

Other events: 159 other events

Deaths: 0 deaths

Indacaterol 300 µg (Continued Into Stage 2)

Serious events: 32 serious events

Other events: 159 other events

Deaths: 0 deaths

Tiotropium 18 µg (Continued Into Stage 2)

Serious events: 34 serious events

Other events: 156 other events

Deaths: 0 deaths

Placebo (Continued Into Stage 2)

Serious events: 35 serious events

Other events: 155 other events

Deaths: 0 deaths

Indacaterol 75 µg (Not Continued Into Stage 2)

Serious events: 9 serious events

Other events: 39 other events

Deaths: 0 deaths

Indacaterol 600 µg (Not Continued Into Stage 2)

Serious events: 5 serious events

Other events: 44 other events

Deaths: 0 deaths

Formoterol 12 µg (Not Continued Into Stage 2)

Serious events: 4 serious events

Other events: 31 other events

Deaths: 0 deaths

Serious adverse events

Measure	Indacaterol 150 µg (Continued Into Stage 2) n=416 participants at risk In the morning, Indacaterol 150 µg once daily orally inhaled via a single dose dry powder inhaler (SDDPI) + Placebo to Indacaterol delivered via SDDPI + Placebo to Formoterol delivered via Aerolizer. In the evening, Placebo to Formoterol delivered via Aerolizer. Participated in the 2 week Stage 1 and continued treatment up to 26 weeks in Stage 2. Placebo to Formoterol inhalation in the morning and in the evening was discontinued after Stage 1. Daily Inhaled Corticosteroid (ICS) monotherapy (if applicable) was to remain stable and Salbutamol/albuterol was available for rescue use throughout study.	Indacaterol 300 µg (Continued Into Stage 2) n=416 participants at risk In the morning, Indacaterol 300 µg once daily orally inhaled via a SDDPI + Placebo to Indacaterol delivered via SDDPI + Placebo to Formoterol delivered via Aerolizer. In evening, Placebo to Formoterol delivered via Aerolizer. Participated in the 2 week Stage 1 and continued treatment up to 26 weeks in Stage 2. Placebo to Formoterol inhalation in the morning and in the evening was discontinued after Stage 1. Daily ICS monotherapy (if applicable) was to remain stable and Salbutamol/albuterol was available for rescue use throughout study.	Tiotropium 18 µg (Continued Into Stage 2) n=415 participants at risk Tiotropium 18 µg dry powder capsules delivered (open label) via manufacturer's proprietary SDDPI, (Handihaler®). Participated in the 2 week Stage 1 and continued treatment up to 26 weeks in Stage 2. Daily ICS monotherapy (if applicable) was to remain stable and Salbutamol/albuterol was available for rescue use throughout study.	Placebo (Continued Into Stage 2) n=418 participants at risk In the morning, Placebo to Indacaterol delivered via two SDDPI devices + Placebo to Formoterol delivered via Aerolizer. In the evening, Placebo to Formoterol delivered via Aerolizer. Participated in the 2 week Stage 1 and continued treatment up to 26 weeks in Stage 2. Placebo to Formoterol inhalation in the morning and in the evening was discontinued after Stage 1. Daily ICS monotherapy (if applicable) was to remain stable and Salbutamol/albuterol was available for rescue use throughout study.	Indacaterol 75 µg (Not Continued Into Stage 2) n=127 participants at risk In the morning, Indacaterol 75 µg once daily orally inhaled via a SDDPI + Placebo to Indacaterol delivered via SDDPI + Placebo to Formoterol delivered via Aerolizer. In the evening, Placebo to Formoterol delivered via Aerolizer. Participated in the 2 week Stage 1 but did not continue to Stage 2. Daily ICS monotherapy (if applicable) was to remain stable and Salbutamol/albuterol was available for rescue use throughout study.	Indacaterol 600 µg (Not Continued Into Stage 2) n=122 participants at risk In the morning, 2 capsules of Indacaterol 300 µg once daily orally inhaled via two SDDPI devices + Placebo to Formoterol delivered via Aerolizer. In the evening, Placebo to Formoterol delivered via Aerolizer. Participated in the 2 week Stage 1 but did not continue to Stage 2. Daily ICS monotherapy (if applicable) was to remain stable and Salbutamol/albuterol was available for rescue use throughout study.	Formoterol 12 µg (Not Continued Into Stage 2) n=122 participants at risk In the morning, Placebo to Indacaterol delivered via two SDDPI devices + Formoterol 12 µg delivered via Aerolizer. In evening, Formoterol 12 µg delivered via Aerolizer. Participated in the 2 week Stage 1 but did not continue to Stage 2. Daily ICS monotherapy (if applicable) was to remain stable and Salbutamol/albuterol was available for rescue use throughout study.
Blood and lymphatic system disorders Idiopathic thrombocytopenic purpura	0.24% 1/416 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/415 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/418 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/127 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.
Blood and lymphatic system disorders Microcytic anaemia	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/415 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/418 Safety Population including all participants who received at least one dose of study drug.	0.79% 1/127 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.
Cardiac disorders Acute coronary syndrome	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.48% 2/415 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/418 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/127 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.
Cardiac disorders Acute myocardial infarction	0.24% 1/416 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/415 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/418 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/127 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.
Cardiac disorders Angina pectoris	0.48% 2/416 Safety Population including all participants who received at least one dose of study drug.	0.24% 1/416 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/415 Safety Population including all participants who received at least one dose of study drug.	0.24% 1/418 Safety Population including all participants who received at least one dose of study drug.	0.79% 1/127 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.
Cardiac disorders Angina unstable	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.48% 2/416 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/415 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/418 Safety Population including all participants who received at least one dose of study drug.	0.79% 1/127 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.
Cardiac disorders Arrhythmia supraventricular	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.24% 1/415 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/418 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/127 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.
Cardiac disorders Atrial fibrillation	0.72% 3/416 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.72% 3/415 Safety Population including all participants who received at least one dose of study drug.	0.48% 2/418 Safety Population including all participants who received at least one dose of study drug.	0.79% 1/127 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.
Cardiac disorders Atrial flutter	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.24% 1/415 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/418 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/127 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.
Cardiac disorders Cardiac failure congestive	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.24% 1/416 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/415 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/418 Safety Population including all participants who received at least one dose of study drug.	0.79% 1/127 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.
Cardiac disorders Coronary artery disease	0.24% 1/416 Safety Population including all participants who received at least one dose of study drug.	0.48% 2/416 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/415 Safety Population including all participants who received at least one dose of study drug.	0.24% 1/418 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/127 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.
Cardiac disorders Coronary artery occlusion	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.48% 2/415 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/418 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/127 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.
Cardiac disorders Ischaemic cardiomyopathy	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.24% 1/415 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/418 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/127 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.
Cardiac disorders Myocardial infarction	0.24% 1/416 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/415 Safety Population including all participants who received at least one dose of study drug.	0.24% 1/418 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/127 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.
Cardiac disorders Sick sinus syndrome	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.24% 1/416 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/415 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/418 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/127 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.
Cardiac disorders Ventricular tachycardia	0.24% 1/416 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/415 Safety Population including all participants who received at least one dose of study drug.	0.24% 1/418 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/127 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.
Congenital, familial and genetic disorders Endocardial fibroelastosis	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/415 Safety Population including all participants who received at least one dose of study drug.	0.24% 1/418 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/127 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.
Ear and labyrinth disorders Deafness neurosensory	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.24% 1/415 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/418 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/127 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.
Eye disorders Cataract	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.24% 1/416 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/415 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/418 Safety Population including all participants who received at least one dose of study drug.	0.79% 1/127 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.
Eye disorders Retinal artery occlusion	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.24% 1/415 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/418 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/127 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.
Gastrointestinal disorders Abdominal pain lower	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/415 Safety Population including all participants who received at least one dose of study drug.	0.24% 1/418 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/127 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.
Gastrointestinal disorders Diarrhoea	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.24% 1/415 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/418 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/127 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.
Gastrointestinal disorders Dysphagia	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.24% 1/415 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/418 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/127 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.
Gastrointestinal disorders Faecaloma	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/415 Safety Population including all participants who received at least one dose of study drug.	0.24% 1/418 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/127 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.
Gastrointestinal disorders Ileus paralytic	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/415 Safety Population including all participants who received at least one dose of study drug.	0.24% 1/418 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/127 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.
Gastrointestinal disorders Inguinal hernia	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/415 Safety Population including all participants who received at least one dose of study drug.	0.24% 1/418 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/127 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.
Gastrointestinal disorders Intestinal obstruction	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/415 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/418 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/127 Safety Population including all participants who received at least one dose of study drug.	0.82% 1/122 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.
Gastrointestinal disorders Nausea	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/415 Safety Population including all participants who received at least one dose of study drug.	0.24% 1/418 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/127 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.
Gastrointestinal disorders Pancreatitis acute	0.24% 1/416 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.24% 1/415 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/418 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/127 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.
Gastrointestinal disorders Small intestinal obstruction	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/415 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/418 Safety Population including all participants who received at least one dose of study drug.	0.79% 1/127 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.
Gastrointestinal disorders Volvulus	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/415 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/418 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/127 Safety Population including all participants who received at least one dose of study drug.	1.6% 2/122 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.
Gastrointestinal disorders Vomiting	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.24% 1/415 Safety Population including all participants who received at least one dose of study drug.	0.24% 1/418 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/127 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.
General disorders Chest discomfort	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/415 Safety Population including all participants who received at least one dose of study drug.	0.24% 1/418 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/127 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.
General disorders Chills	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/415 Safety Population including all participants who received at least one dose of study drug.	0.24% 1/418 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/127 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.
General disorders Fatigue	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.24% 1/415 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/418 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/127 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.
General disorders Non-cardiac chest pain	0.24% 1/416 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/415 Safety Population including all participants who received at least one dose of study drug.	0.24% 1/418 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/127 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.
General disorders Pain	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.24% 1/415 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/418 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/127 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.
General disorders Sudden death	0.24% 1/416 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/415 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/418 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/127 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.
Hepatobiliary disorders Bile duct stone	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/415 Safety Population including all participants who received at least one dose of study drug.	0.24% 1/418 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/127 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.
Hepatobiliary disorders Cholelithiasis	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.24% 1/416 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/415 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/418 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/127 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.
Immune system disorders Drug hypersensitivity	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/415 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/418 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/127 Safety Population including all participants who received at least one dose of study drug.	0.82% 1/122 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.
Infections and infestations Bronchitis	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.48% 2/416 Safety Population including all participants who received at least one dose of study drug.	0.24% 1/415 Safety Population including all participants who received at least one dose of study drug.	0.72% 3/418 Safety Population including all participants who received at least one dose of study drug.	0.79% 1/127 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.
Infections and infestations Bronchopneumonia	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.24% 1/415 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/418 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/127 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.
Infections and infestations Cellulitis	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/415 Safety Population including all participants who received at least one dose of study drug.	0.24% 1/418 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/127 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.
Infections and infestations Clostridium difficile colitis	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/415 Safety Population including all participants who received at least one dose of study drug.	0.24% 1/418 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/127 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.
Infections and infestations Diverticulitis	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/415 Safety Population including all participants who received at least one dose of study drug.	0.24% 1/418 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/127 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.
Infections and infestations Herpes zoster oticus	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/415 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/418 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/127 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.	0.82% 1/122 Safety Population including all participants who received at least one dose of study drug.
Infections and infestations Infection	0.24% 1/416 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/415 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/418 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/127 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.
Infections and infestations Lobar pneumonia	0.24% 1/416 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/415 Safety Population including all participants who received at least one dose of study drug.	0.24% 1/418 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/127 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.
Infections and infestations Localised infection	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/415 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/418 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/127 Safety Population including all participants who received at least one dose of study drug.	0.82% 1/122 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.
Infections and infestations Lower respiratory tract infection	0.48% 2/416 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/415 Safety Population including all participants who received at least one dose of study drug.	0.24% 1/418 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/127 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.
Infections and infestations Mycobacterial infection	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/415 Safety Population including all participants who received at least one dose of study drug.	0.24% 1/418 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/127 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.
Infections and infestations Osteomyelitis	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.24% 1/415 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/418 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/127 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.
Infections and infestations Pneumonia	0.48% 2/416 Safety Population including all participants who received at least one dose of study drug.	0.72% 3/416 Safety Population including all participants who received at least one dose of study drug.	0.96% 4/415 Safety Population including all participants who received at least one dose of study drug.	0.96% 4/418 Safety Population including all participants who received at least one dose of study drug.	0.79% 1/127 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.
Infections and infestations Pneumonia bacterial	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.24% 1/415 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/418 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/127 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.
Infections and infestations Pneumonia streptococcal	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.24% 1/416 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/415 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/418 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/127 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.
Infections and infestations Sinusitis	0.24% 1/416 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/415 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/418 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/127 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.
Infections and infestations Staphylococcal infection	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.24% 1/415 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/418 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/127 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.
Infections and infestations Upper respiratory tract infection	0.24% 1/416 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/415 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/418 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/127 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.
Infections and infestations Upper respiratory tract infection bacterial	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/415 Safety Population including all participants who received at least one dose of study drug.	0.48% 2/418 Safety Population including all participants who received at least one dose of study drug.	0.79% 1/127 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.
Injury, poisoning and procedural complications Accidental overdose	0.24% 1/416 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/415 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/418 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/127 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.
Injury, poisoning and procedural complications Chest injury	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.24% 1/416 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/415 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/418 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/127 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.
Injury, poisoning and procedural complications Contusion	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.24% 1/415 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/418 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/127 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.
Injury, poisoning and procedural complications Device failure	0.24% 1/416 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/415 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/418 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/127 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.
Injury, poisoning and procedural complications Ear injury	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.24% 1/415 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/418 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/127 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.
Injury, poisoning and procedural complications Excoriation	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.24% 1/415 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/418 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/127 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.
Injury, poisoning and procedural complications Fall	0.24% 1/416 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/415 Safety Population including all participants who received at least one dose of study drug.	0.24% 1/418 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/127 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.
Injury, poisoning and procedural complications Foot fracture	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.24% 1/416 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/415 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/418 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/127 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.
Injury, poisoning and procedural complications Hand fracture	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/415 Safety Population including all participants who received at least one dose of study drug.	0.24% 1/418 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/127 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.
Injury, poisoning and procedural complications Hip fracture	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.24% 1/416 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/415 Safety Population including all participants who received at least one dose of study drug.	0.24% 1/418 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/127 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.
Injury, poisoning and procedural complications Rib fracture	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.24% 1/416 Safety Population including all participants who received at least one dose of study drug.	0.24% 1/415 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/418 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/127 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.
Injury, poisoning and procedural complications Road traffic accident	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.24% 1/416 Safety Population including all participants who received at least one dose of study drug.	0.48% 2/415 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/418 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/127 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.
Injury, poisoning and procedural complications Skull fractured base	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.24% 1/415 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/418 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/127 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.
Injury, poisoning and procedural complications Spinal fracture	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.24% 1/415 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/418 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/127 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.
Investigations Blood potassium increased	0.24% 1/416 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/415 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/418 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/127 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.
Investigations Blood urine present	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.24% 1/415 Safety Population including all participants who received at least one dose of study drug.	0.24% 1/418 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/127 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.
Investigations Glasgow coma scale abnormal	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.24% 1/415 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/418 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/127 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.
Metabolism and nutrition disorders Dehydration	0.24% 1/416 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/415 Safety Population including all participants who received at least one dose of study drug.	0.24% 1/418 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/127 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.
Musculoskeletal and connective tissue disorders Arthritis	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/415 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/418 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/127 Safety Population including all participants who received at least one dose of study drug.	0.82% 1/122 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.
Musculoskeletal and connective tissue disorders Intervertebral disc protrusion	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/415 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/418 Safety Population including all participants who received at least one dose of study drug.	0.79% 1/127 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.
Musculoskeletal and connective tissue disorders Joint swelling	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.24% 1/415 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/418 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/127 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.
Musculoskeletal and connective tissue disorders Muscle spasms	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.24% 1/415 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/418 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/127 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.	0.82% 1/122 Safety Population including all participants who received at least one dose of study drug.
Musculoskeletal and connective tissue disorders Osteoarthritis	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.24% 1/415 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/418 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/127 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.
Musculoskeletal and connective tissue disorders Osteonecrosis	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.24% 1/416 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/415 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/418 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/127 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.
Musculoskeletal and connective tissue disorders Pain in extremity	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/415 Safety Population including all participants who received at least one dose of study drug.	0.24% 1/418 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/127 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.
Musculoskeletal and connective tissue disorders Rotator cuff syndrome	0.24% 1/416 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/415 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/418 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/127 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Acute leukaemia	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/415 Safety Population including all participants who received at least one dose of study drug.	0.24% 1/418 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/127 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Anaplastic large cell lymphoma T- and null-cell types	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.24% 1/416 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/415 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/418 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/127 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Benign lung neoplasm	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.24% 1/415 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/418 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/127 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Breast cancer	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/415 Safety Population including all participants who received at least one dose of study drug.	0.24% 1/418 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/127 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Laryngeal cancer	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.24% 1/416 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/415 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/418 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/127 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Lipoma	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.24% 1/416 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/415 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/418 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/127 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Lung adenocarcinoma	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.24% 1/415 Safety Population including all participants who received at least one dose of study drug.	0.48% 2/418 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/127 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Lung neoplasm malignant	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.24% 1/416 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/415 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/418 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/127 Safety Population including all participants who received at least one dose of study drug.	0.82% 1/122 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Oesophageal carcinoma	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/415 Safety Population including all participants who received at least one dose of study drug.	0.24% 1/418 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/127 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Prostate cancer	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.24% 1/416 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/415 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/418 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/127 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Renal cancer	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.24% 1/415 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/418 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/127 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Squamous cell carcinoma	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.24% 1/416 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/415 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/418 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/127 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Thyroid neoplasm	0.24% 1/416 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/415 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/418 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/127 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.
Nervous system disorders Carotid artery occlusion	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.24% 1/416 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/415 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/418 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/127 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.
Nervous system disorders Cerebellar infarction	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/415 Safety Population including all participants who received at least one dose of study drug.	0.24% 1/418 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/127 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.
Nervous system disorders Cerebral haematoma	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.24% 1/415 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/418 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/127 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.
Nervous system disorders Cerebral haemorrhage	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.24% 1/416 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/415 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/418 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/127 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.
Nervous system disorders Dizziness	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/415 Safety Population including all participants who received at least one dose of study drug.	0.24% 1/418 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/127 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.
Nervous system disorders Loss of consciousness	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.24% 1/415 Safety Population including all participants who received at least one dose of study drug.	0.24% 1/418 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/127 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.
Nervous system disorders Presyncope	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.24% 1/416 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/415 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/418 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/127 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.
Nervous system disorders Sciatica	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/415 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/418 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/127 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.	0.82% 1/122 Safety Population including all participants who received at least one dose of study drug.
Nervous system disorders Syncope	0.24% 1/416 Safety Population including all participants who received at least one dose of study drug.	0.48% 2/416 Safety Population including all participants who received at least one dose of study drug.	0.24% 1/415 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/418 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/127 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.
Nervous system disorders Syncope vasovagal	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.24% 1/415 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/418 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/127 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.
Nervous system disorders Transient ischaemic attack	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/415 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/418 Safety Population including all participants who received at least one dose of study drug.	0.79% 1/127 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.
Nervous system disorders Visual midline shift syndrome	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.24% 1/415 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/418 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/127 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.
Psychiatric disorders Disorientation	0.24% 1/416 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/415 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/418 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/127 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.
Psychiatric disorders Psychiatric decompensation	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/415 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/418 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/127 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.	0.82% 1/122 Safety Population including all participants who received at least one dose of study drug.
Psychiatric disorders Suicide attempt	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/415 Safety Population including all participants who received at least one dose of study drug.	0.24% 1/418 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/127 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.
Renal and urinary disorders Calculus ureteric	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.24% 1/416 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/415 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/418 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/127 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.
Renal and urinary disorders Haematuria	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.24% 1/416 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/415 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/418 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/127 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.
Reproductive system and breast disorders Benign prostatic hyperplasia	0.24% 1/416 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/415 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/418 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/127 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.
Reproductive system and breast disorders Pelvic peritoneal adhesions	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/415 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/418 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/127 Safety Population including all participants who received at least one dose of study drug.	0.82% 1/122 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.
Respiratory, thoracic and mediastinal disorders Chronic obstructive pulmonary disease	2.6% 11/416 Safety Population including all participants who received at least one dose of study drug.	1.7% 7/416 Safety Population including all participants who received at least one dose of study drug.	1.7% 7/415 Safety Population including all participants who received at least one dose of study drug.	2.4% 10/418 Safety Population including all participants who received at least one dose of study drug.	2.4% 3/127 Safety Population including all participants who received at least one dose of study drug.	0.82% 1/122 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.
Respiratory, thoracic and mediastinal disorders Cough	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.24% 1/416 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/415 Safety Population including all participants who received at least one dose of study drug.	0.24% 1/418 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/127 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.
Respiratory, thoracic and mediastinal disorders Dyspnoea	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.48% 2/416 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/415 Safety Population including all participants who received at least one dose of study drug.	0.72% 3/418 Safety Population including all participants who received at least one dose of study drug.	0.79% 1/127 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.
Respiratory, thoracic and mediastinal disorders Increased upper airway secretion	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.24% 1/416 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/415 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/418 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/127 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.
Respiratory, thoracic and mediastinal disorders Pleural effusion	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/415 Safety Population including all participants who received at least one dose of study drug.	0.24% 1/418 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/127 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.
Respiratory, thoracic and mediastinal disorders Pneumothorax	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.24% 1/415 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/418 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/127 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.
Respiratory, thoracic and mediastinal disorders Respiratory failure	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.24% 1/415 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/418 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/127 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.
Respiratory, thoracic and mediastinal disorders Wheezing	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/415 Safety Population including all participants who received at least one dose of study drug.	0.24% 1/418 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/127 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.
Skin and subcutaneous tissue disorders Hyperhidrosis	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/415 Safety Population including all participants who received at least one dose of study drug.	0.24% 1/418 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/127 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.
Surgical and medical procedures Cardioversion	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.24% 1/415 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/418 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/127 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.
Vascular disorders Aortic aneurysm	0.24% 1/416 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.24% 1/415 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/418 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/127 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.
Vascular disorders Arteriosclerosis	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.24% 1/415 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/418 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/127 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.
Vascular disorders Deep vein thrombosis	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.24% 1/415 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/418 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/127 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.
Vascular disorders Haematoma	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.24% 1/415 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/418 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/127 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.
Vascular disorders Intermittent claudication	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.24% 1/416 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/415 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/418 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/127 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.
Vascular disorders Orthostatic hypotension	0.24% 1/416 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/415 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/418 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/127 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.
Vascular disorders Peripheral arterial occlusive disease	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.24% 1/415 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/418 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/127 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.
Vascular disorders Peripheral vascular disorder	0.24% 1/416 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/416 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/415 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/418 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/127 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.	0.00% 0/122 Safety Population including all participants who received at least one dose of study drug.

Other adverse events

Measure	Indacaterol 150 µg (Continued Into Stage 2) n=416 participants at risk In the morning, Indacaterol 150 µg once daily orally inhaled via a single dose dry powder inhaler (SDDPI) + Placebo to Indacaterol delivered via SDDPI + Placebo to Formoterol delivered via Aerolizer. In the evening, Placebo to Formoterol delivered via Aerolizer. Participated in the 2 week Stage 1 and continued treatment up to 26 weeks in Stage 2. Placebo to Formoterol inhalation in the morning and in the evening was discontinued after Stage 1. Daily Inhaled Corticosteroid (ICS) monotherapy (if applicable) was to remain stable and Salbutamol/albuterol was available for rescue use throughout study.	Indacaterol 300 µg (Continued Into Stage 2) n=416 participants at risk In the morning, Indacaterol 300 µg once daily orally inhaled via a SDDPI + Placebo to Indacaterol delivered via SDDPI + Placebo to Formoterol delivered via Aerolizer. In evening, Placebo to Formoterol delivered via Aerolizer. Participated in the 2 week Stage 1 and continued treatment up to 26 weeks in Stage 2. Placebo to Formoterol inhalation in the morning and in the evening was discontinued after Stage 1. Daily ICS monotherapy (if applicable) was to remain stable and Salbutamol/albuterol was available for rescue use throughout study.	Tiotropium 18 µg (Continued Into Stage 2) n=415 participants at risk Tiotropium 18 µg dry powder capsules delivered (open label) via manufacturer's proprietary SDDPI, (Handihaler®). Participated in the 2 week Stage 1 and continued treatment up to 26 weeks in Stage 2. Daily ICS monotherapy (if applicable) was to remain stable and Salbutamol/albuterol was available for rescue use throughout study.	Placebo (Continued Into Stage 2) n=418 participants at risk In the morning, Placebo to Indacaterol delivered via two SDDPI devices + Placebo to Formoterol delivered via Aerolizer. In the evening, Placebo to Formoterol delivered via Aerolizer. Participated in the 2 week Stage 1 and continued treatment up to 26 weeks in Stage 2. Placebo to Formoterol inhalation in the morning and in the evening was discontinued after Stage 1. Daily ICS monotherapy (if applicable) was to remain stable and Salbutamol/albuterol was available for rescue use throughout study.	Indacaterol 75 µg (Not Continued Into Stage 2) n=127 participants at risk In the morning, Indacaterol 75 µg once daily orally inhaled via a SDDPI + Placebo to Indacaterol delivered via SDDPI + Placebo to Formoterol delivered via Aerolizer. In the evening, Placebo to Formoterol delivered via Aerolizer. Participated in the 2 week Stage 1 but did not continue to Stage 2. Daily ICS monotherapy (if applicable) was to remain stable and Salbutamol/albuterol was available for rescue use throughout study.	Indacaterol 600 µg (Not Continued Into Stage 2) n=122 participants at risk In the morning, 2 capsules of Indacaterol 300 µg once daily orally inhaled via two SDDPI devices + Placebo to Formoterol delivered via Aerolizer. In the evening, Placebo to Formoterol delivered via Aerolizer. Participated in the 2 week Stage 1 but did not continue to Stage 2. Daily ICS monotherapy (if applicable) was to remain stable and Salbutamol/albuterol was available for rescue use throughout study.	Formoterol 12 µg (Not Continued Into Stage 2) n=122 participants at risk In the morning, Placebo to Indacaterol delivered via two SDDPI devices + Formoterol 12 µg delivered via Aerolizer. In evening, Formoterol 12 µg delivered via Aerolizer. Participated in the 2 week Stage 1 but did not continue to Stage 2. Daily ICS monotherapy (if applicable) was to remain stable and Salbutamol/albuterol was available for rescue use throughout study.
Infections and infestations Bronchitis	1.7% 7/416 Safety Population including all participants who received at least one dose of study drug.	4.1% 17/416 Safety Population including all participants who received at least one dose of study drug.	3.1% 13/415 Safety Population including all participants who received at least one dose of study drug.	5.7% 24/418 Safety Population including all participants who received at least one dose of study drug.	1.6% 2/127 Safety Population including all participants who received at least one dose of study drug.	2.5% 3/122 Safety Population including all participants who received at least one dose of study drug.	2.5% 3/122 Safety Population including all participants who received at least one dose of study drug.
Infections and infestations Nasopharyngitis	7.9% 33/416 Safety Population including all participants who received at least one dose of study drug.	9.4% 39/416 Safety Population including all participants who received at least one dose of study drug.	8.7% 36/415 Safety Population including all participants who received at least one dose of study drug.	8.6% 36/418 Safety Population including all participants who received at least one dose of study drug.	5.5% 7/127 Safety Population including all participants who received at least one dose of study drug.	6.6% 8/122 Safety Population including all participants who received at least one dose of study drug.	3.3% 4/122 Safety Population including all participants who received at least one dose of study drug.
Infections and infestations Upper respiratory tract infection	8.2% 34/416 Safety Population including all participants who received at least one dose of study drug.	6.5% 27/416 Safety Population including all participants who received at least one dose of study drug.	7.5% 31/415 Safety Population including all participants who received at least one dose of study drug.	7.4% 31/418 Safety Population including all participants who received at least one dose of study drug.	7.9% 10/127 Safety Population including all participants who received at least one dose of study drug.	9.0% 11/122 Safety Population including all participants who received at least one dose of study drug.	2.5% 3/122 Safety Population including all participants who received at least one dose of study drug.
Musculoskeletal and connective tissue disorders Muscle spasms	3.1% 13/416 Safety Population including all participants who received at least one dose of study drug.	3.1% 13/416 Safety Population including all participants who received at least one dose of study drug.	1.4% 6/415 Safety Population including all participants who received at least one dose of study drug.	0.96% 4/418 Safety Population including all participants who received at least one dose of study drug.	0.79% 1/127 Safety Population including all participants who received at least one dose of study drug.	7.4% 9/122 Safety Population including all participants who received at least one dose of study drug.	3.3% 4/122 Safety Population including all participants who received at least one dose of study drug.
Nervous system disorders Headache	6.7% 28/416 Safety Population including all participants who received at least one dose of study drug.	4.3% 18/416 Safety Population including all participants who received at least one dose of study drug.	4.6% 19/415 Safety Population including all participants who received at least one dose of study drug.	3.3% 14/418 Safety Population including all participants who received at least one dose of study drug.	7.9% 10/127 Safety Population including all participants who received at least one dose of study drug.	2.5% 3/122 Safety Population including all participants who received at least one dose of study drug.	4.9% 6/122 Safety Population including all participants who received at least one dose of study drug.
Respiratory, thoracic and mediastinal disorders Chronic obstructive pulmonary disease	16.1% 67/416 Safety Population including all participants who received at least one dose of study drug.	17.3% 72/416 Safety Population including all participants who received at least one dose of study drug.	18.1% 75/415 Safety Population including all participants who received at least one dose of study drug.	20.6% 86/418 Safety Population including all participants who received at least one dose of study drug.	8.7% 11/127 Safety Population including all participants who received at least one dose of study drug.	15.6% 19/122 Safety Population including all participants who received at least one dose of study drug.	13.1% 16/122 Safety Population including all participants who received at least one dose of study drug.
Respiratory, thoracic and mediastinal disorders Cough	7.2% 30/416 Safety Population including all participants who received at least one dose of study drug.	7.2% 30/416 Safety Population including all participants who received at least one dose of study drug.	6.3% 26/415 Safety Population including all participants who received at least one dose of study drug.	6.5% 27/418 Safety Population including all participants who received at least one dose of study drug.	5.5% 7/127 Safety Population including all participants who received at least one dose of study drug.	4.9% 6/122 Safety Population including all participants who received at least one dose of study drug.	3.3% 4/122 Safety Population including all participants who received at least one dose of study drug.

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