Trial Outcomes & Findings for Evaluating the Control of COPD Symptoms in Patients Treated With Tiotropium Bromide 18mcg Once Daily Alone, ADOAIR 50/250mcg Twice Daily Alone or ADOAIR 50/250mcg Plus Tiotropium Bromide 18mcg (NCT NCT01762800)

Last Updated: 2016-11-10

Results Overview

The randomized treatment could be switched to TRIPLE therapy in the case that chronic obstructive pulmonary disease (COPD) is not controlled by the randomized treatment. Participants on TRIPLE therapy received SAL/FLU 50/250 µg BID plus TIO 18 µg QD together. The percentage of participants who were able to remain on the randomized treatment was calculated by the following formula: 100 minus percentage of participants who switched over to TRIPLE therapy.

Recruitment status

COMPLETED

Study phase

PHASE4

Target enrollment

407 participants

Primary outcome timeframe

24 weeks

Results posted on

2016-11-10

Participant Flow

A total of 570 participants were screened, 428 participants entered into the run-in period, 406 participants were randomized into the study (incorrectly 407 on protocol summary due to miss operation at study site that cannot be corrected), and 405 participant received study medication and comprised the modified Intent to Treat (mITT) Population.

Participant milestones

Participant milestones
Measure	TIO 18 µg QD Participants received 18 micrograms (µg) tiotropium bromide (TIO) once daily (QD) via HandiHaler inhaler and placebo twice daily (BID) via dry powder inhaler (DPI), during the 24-week study treatment period. Participants also received 400 µg salbutamol as relief medication and as a bronchodilator for pulmonary function testing as required throughout the study.	SAL/FLU 50/250 µg BID Participants received 50/250 µg salmeterol xinafoate (SAL)/fluticasone propionate (FLU) BID via DPI and placebo QD via HandiHaler inhaler, during the 24-week study treatment period. Participants also received 400 µg salbutamol as relief medication and as a bronchodilator for pulmonary function testing as required throughout the study.
Overall Study STARTED	202	204
Overall Study COMPLETED	183	183
Overall Study NOT COMPLETED	19	21

Reasons for withdrawal

Reasons for withdrawal
Measure	TIO 18 µg QD Participants received 18 micrograms (µg) tiotropium bromide (TIO) once daily (QD) via HandiHaler inhaler and placebo twice daily (BID) via dry powder inhaler (DPI), during the 24-week study treatment period. Participants also received 400 µg salbutamol as relief medication and as a bronchodilator for pulmonary function testing as required throughout the study.	SAL/FLU 50/250 µg BID Participants received 50/250 µg salmeterol xinafoate (SAL)/fluticasone propionate (FLU) BID via DPI and placebo QD via HandiHaler inhaler, during the 24-week study treatment period. Participants also received 400 µg salbutamol as relief medication and as a bronchodilator for pulmonary function testing as required throughout the study.
Overall Study Adverse Event	8	13
Overall Study Lack of Efficacy	3	2
Overall Study Study Closed/Terminated	0	1
Overall Study Physician Decision	1	1
Overall Study Withdrawal by Subject	7	4

Baseline Characteristics

Evaluating the Control of COPD Symptoms in Patients Treated With Tiotropium Bromide 18mcg Once Daily Alone, ADOAIR 50/250mcg Twice Daily Alone or ADOAIR 50/250mcg Plus Tiotropium Bromide 18mcg

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	TIO 18 µg QD n=201 Participants Participants received 18 µg TIO QD via HandiHaler inhaler and placebo BID via DPI, during the 24-week study treatment period. Participants also received 400 µg salbutamol as relief medication and as a bronchodilator for pulmonary function testing as required throughout the study.	SAL/FLU 50/250 µg BID n=204 Participants Participants received 50/250 µg SAL/FLU BID via DPI and placebo QD via HandiHaler inhaler, during the 24-week study treatment period. Participants also received 400 µg salbutamol as relief medication and as a bronchodilator for pulmonary function testing as required throughout the study.	Total n=405 Participants Total of all reporting groups
Age, Continuous	68.0 Years STANDARD_DEVIATION 7.12 • n=5 Participants	68.6 Years STANDARD_DEVIATION 6.93 • n=7 Participants	68.3 Years STANDARD_DEVIATION 7.02 • n=5 Participants
Sex: Female, Male Female	8 Participants n=5 Participants	12 Participants n=7 Participants	20 Participants n=5 Participants
Sex: Female, Male Male	193 Participants n=5 Participants	192 Participants n=7 Participants	385 Participants n=5 Participants
Race/Ethnicity, Customized African American/African Heritage	0 Participants n=5 Participants	1 Participants n=7 Participants	1 Participants n=5 Participants
Race/Ethnicity, Customized Asian - Japanese Heritage	201 Participants n=5 Participants	203 Participants n=7 Participants	404 Participants n=5 Participants

PRIMARY outcome

Timeframe: 24 weeks

Population: Modified Intent-to-Treat (mITT) population: randomized participants who received at least a single dose of the investigational product.

Outcome measures

Outcome measures
Measure	TIO 18 µg QD n=201 Participants Participants received 18 µg TIO QD via HandiHaler inhaler and placebo BID via DPI, during the 24-week study treatment period. Participants also received 400 µg salbutamol as relief medication and as a bronchodilator for pulmonary function testing as required throughout the study.	SAL/FLU 50/250 µg BID n=204 Participants Participants received 50/250 µg SAL/FLU BID via DPI and placebo QD via HandiHaler inhaler, during the 24-week study treatment period. Participants also received 400 µg salbutamol as relief medication and as a bronchodilator for pulmonary function testing as required throughout the study.	TIO 18 µg QD-Single Participants received 18 µg TIO QD via HandiHaler inhaler and placebo BID via DPI, during the 24-week study treatment period. Participants also received 400 µg salbutamol as relief medication and as a bronchodilator for pulmonary function testing as required throughout the study. Participants who remained on the single treatment of TIO 18 µg QD were included in this arm.	TIO 18 µg QD-TRIPLE Participants received 18 µg TIO QD via HandiHaler inhaler and placebo BID via DPI, during the 24-week study treatment period. Participants also received 400 µg salbutamol as relief medication and as a bronchodilator for pulmonary function testing as required throughout the study. Participants who switched from the single treatment of TIO 18 µg QD to TRIPLE therapy (SAL/FLU 50/250 µg BID+TIO 18 µg QD) were included in this arm.
Percentage of Participants Who Were Able to Remain on the Randomized Treatment	62.69 Percentage of participants Interval 55.6 to 69.39	66.67 Percentage of participants Interval 59.75 to 73.1	—	—

SECONDARY outcome

Timeframe: 24 weeks

Population: mITT population

Switched to TRIPLE therapy is defined as: 1. Date of switch: when SAL/FLU or TIO was administered additionally to randomised treatment. 2. Date of randomisation was a start point and timing of switching (first switch if there are more than once) to TRIPLE was event. For participants without switching, last day of study or follow up period was regarded as censored. Percentage of participants who switched to TRIPLE therapy was calculated as: number of participants who switched to TRIPLE therapy divided by number of evaluable population and then multiplied by 100.

Outcome measures

Outcome measures
Measure	TIO 18 µg QD n=201 Participants Participants received 18 µg TIO QD via HandiHaler inhaler and placebo BID via DPI, during the 24-week study treatment period. Participants also received 400 µg salbutamol as relief medication and as a bronchodilator for pulmonary function testing as required throughout the study.	SAL/FLU 50/250 µg BID n=204 Participants Participants received 50/250 µg SAL/FLU BID via DPI and placebo QD via HandiHaler inhaler, during the 24-week study treatment period. Participants also received 400 µg salbutamol as relief medication and as a bronchodilator for pulmonary function testing as required throughout the study.	TIO 18 µg QD-Single Participants received 18 µg TIO QD via HandiHaler inhaler and placebo BID via DPI, during the 24-week study treatment period. Participants also received 400 µg salbutamol as relief medication and as a bronchodilator for pulmonary function testing as required throughout the study. Participants who remained on the single treatment of TIO 18 µg QD were included in this arm.	TIO 18 µg QD-TRIPLE Participants received 18 µg TIO QD via HandiHaler inhaler and placebo BID via DPI, during the 24-week study treatment period. Participants also received 400 µg salbutamol as relief medication and as a bronchodilator for pulmonary function testing as required throughout the study. Participants who switched from the single treatment of TIO 18 µg QD to TRIPLE therapy (SAL/FLU 50/250 µg BID+TIO 18 µg QD) were included in this arm.
Percentage of Participants Who Switched to TRIPLE Therapy	37.31 Percentage of participants Interval 30.61 to 44.4	33.33 Percentage of participants Interval 26.9 to 40.25	—	—

SECONDARY outcome

Timeframe: 24 weeks

Population: mITT population

Percentage of participants managed by TRIPLE therapy was calculated as \[(number of participants who switched to TRIPLE therapy) - (number of participants who stepped down)/ number of evaluable population\]\*100

Outcome measures

Outcome measures
Measure	TIO 18 µg QD n=201 Participants Participants received 18 µg TIO QD via HandiHaler inhaler and placebo BID via DPI, during the 24-week study treatment period. Participants also received 400 µg salbutamol as relief medication and as a bronchodilator for pulmonary function testing as required throughout the study.	SAL/FLU 50/250 µg BID n=204 Participants Participants received 50/250 µg SAL/FLU BID via DPI and placebo QD via HandiHaler inhaler, during the 24-week study treatment period. Participants also received 400 µg salbutamol as relief medication and as a bronchodilator for pulmonary function testing as required throughout the study.	TIO 18 µg QD-Single Participants received 18 µg TIO QD via HandiHaler inhaler and placebo BID via DPI, during the 24-week study treatment period. Participants also received 400 µg salbutamol as relief medication and as a bronchodilator for pulmonary function testing as required throughout the study. Participants who remained on the single treatment of TIO 18 µg QD were included in this arm.	TIO 18 µg QD-TRIPLE Participants received 18 µg TIO QD via HandiHaler inhaler and placebo BID via DPI, during the 24-week study treatment period. Participants also received 400 µg salbutamol as relief medication and as a bronchodilator for pulmonary function testing as required throughout the study. Participants who switched from the single treatment of TIO 18 µg QD to TRIPLE therapy (SAL/FLU 50/250 µg BID+TIO 18 µg QD) were included in this arm.
Percentage of Participants Managed by TRIPLE Therapy	36.82 Percentage of participants Interval 30.14 to 43.89	32.35 Percentage of participants Interval 25.99 to 39.24	—	—

SECONDARY outcome

Timeframe: 24 weeks

Population: mITT population

The randomized treatment could be switched to TRIPLE therapy in the case that chronic obstructive pulmonary disease (COPD) was not controlled by the randomized treatment. Participants on TRIPLE therapy received SAL/FLU 50/250 µg BID plus TIO 18 µg QD together. Continuation TRIPLE proportion is defined as \[(number of subjects who switched to TRIPLE) - (number of subjects who stepped down)/ number of evaluable population\]\*100. Randomised treatment continuation proportion is calculated by a formula: (100 - switch proportion).

Outcome measures

Outcome measures
Measure	TIO 18 µg QD n=201 Participants Participants received 18 µg TIO QD via HandiHaler inhaler and placebo BID via DPI, during the 24-week study treatment period. Participants also received 400 µg salbutamol as relief medication and as a bronchodilator for pulmonary function testing as required throughout the study.	SAL/FLU 50/250 µg BID n=204 Participants Participants received 50/250 µg SAL/FLU BID via DPI and placebo QD via HandiHaler inhaler, during the 24-week study treatment period. Participants also received 400 µg salbutamol as relief medication and as a bronchodilator for pulmonary function testing as required throughout the study.	TIO 18 µg QD-Single Participants received 18 µg TIO QD via HandiHaler inhaler and placebo BID via DPI, during the 24-week study treatment period. Participants also received 400 µg salbutamol as relief medication and as a bronchodilator for pulmonary function testing as required throughout the study. Participants who remained on the single treatment of TIO 18 µg QD were included in this arm.	TIO 18 µg QD-TRIPLE Participants received 18 µg TIO QD via HandiHaler inhaler and placebo BID via DPI, during the 24-week study treatment period. Participants also received 400 µg salbutamol as relief medication and as a bronchodilator for pulmonary function testing as required throughout the study. Participants who switched from the single treatment of TIO 18 µg QD to TRIPLE therapy (SAL/FLU 50/250 µg BID+TIO 18 µg QD) were included in this arm.
Continuation Percentage of Participants Managed by Randomized Treatment Plus TRIPLE Therapy Randomised treatment	62.69 Percentage of participants Interval 55.6 to 69.39	66.67 Percentage of participants Interval 59.75 to 73.1	—	—
Continuation Percentage of Participants Managed by Randomized Treatment Plus TRIPLE Therapy TRIPLE therapy	36.82 Percentage of participants Interval 30.14 to 43.89	32.35 Percentage of participants Interval 25.99 to 39.24	—	—

SECONDARY outcome

Timeframe: 24 weeks

Population: mITT population

The day of first switch to TRIPLE therapy (SAL/FLU 50/250 µg BID+TIO 18 µg QD) for the first switching participant in each arm.

Outcome measures

Outcome measures
Measure	TIO 18 µg QD n=201 Participants Participants received 18 µg TIO QD via HandiHaler inhaler and placebo BID via DPI, during the 24-week study treatment period. Participants also received 400 µg salbutamol as relief medication and as a bronchodilator for pulmonary function testing as required throughout the study.	SAL/FLU 50/250 µg BID n=204 Participants Participants received 50/250 µg SAL/FLU BID via DPI and placebo QD via HandiHaler inhaler, during the 24-week study treatment period. Participants also received 400 µg salbutamol as relief medication and as a bronchodilator for pulmonary function testing as required throughout the study.	TIO 18 µg QD-Single Participants received 18 µg TIO QD via HandiHaler inhaler and placebo BID via DPI, during the 24-week study treatment period. Participants also received 400 µg salbutamol as relief medication and as a bronchodilator for pulmonary function testing as required throughout the study. Participants who remained on the single treatment of TIO 18 µg QD were included in this arm.	TIO 18 µg QD-TRIPLE Participants received 18 µg TIO QD via HandiHaler inhaler and placebo BID via DPI, during the 24-week study treatment period. Participants also received 400 µg salbutamol as relief medication and as a bronchodilator for pulmonary function testing as required throughout the study. Participants who switched from the single treatment of TIO 18 µg QD to TRIPLE therapy (SAL/FLU 50/250 µg BID+TIO 18 µg QD) were included in this arm.
Time to First Switching to TRIPLE Therapy	5 Days	5 Days	—	—

SECONDARY outcome

Timeframe: 24 weeks

Population: mITT population

The day of detection of first exacerbation in any participant in each arm as diagnosed by physician. Exacerbation is defined primarily by physician's judgment. Date of randomisation will be start point and timing of exacerbation (first exacerbation if there are more than one) will be event. For subjects without exacerbation, last day of study or follow up period is regarded as censor.

Outcome measures

Outcome measures
Measure	TIO 18 µg QD n=136 Participants Participants received 18 µg TIO QD via HandiHaler inhaler and placebo BID via DPI, during the 24-week study treatment period. Participants also received 400 µg salbutamol as relief medication and as a bronchodilator for pulmonary function testing as required throughout the study.	SAL/FLU 50/250 µg BID n=68 Participants Participants received 50/250 µg SAL/FLU BID via DPI and placebo QD via HandiHaler inhaler, during the 24-week study treatment period. Participants also received 400 µg salbutamol as relief medication and as a bronchodilator for pulmonary function testing as required throughout the study.	TIO 18 µg QD-Single n=126 Participants Participants received 18 µg TIO QD via HandiHaler inhaler and placebo BID via DPI, during the 24-week study treatment period. Participants also received 400 µg salbutamol as relief medication and as a bronchodilator for pulmonary function testing as required throughout the study. Participants who remained on the single treatment of TIO 18 µg QD were included in this arm.	TIO 18 µg QD-TRIPLE n=75 Participants Participants received 18 µg TIO QD via HandiHaler inhaler and placebo BID via DPI, during the 24-week study treatment period. Participants also received 400 µg salbutamol as relief medication and as a bronchodilator for pulmonary function testing as required throughout the study. Participants who switched from the single treatment of TIO 18 µg QD to TRIPLE therapy (SAL/FLU 50/250 µg BID+TIO 18 µg QD) were included in this arm.
Time to First Exacerbation by Physician's Diagnosis	3 Days	5 Days	10 Days	2 Days

SECONDARY outcome

Timeframe: 24 weeks

The EXAcerbations of Chronic pulmonary disease Tool (EXACT) is a 14-item patient-reported outcome (PRO) daily diary used to quantify and measure exacerbations of chronic obstructive pulmonary disease (COPD). Reported as units on a 0 \[best health status\] to 100 \[worst possible status\] scale). The day of detection of first exacerbation in any participant in each arm by EXACT.

Outcome measures

Outcome measures
Measure	TIO 18 µg QD n=136 Participants Participants received 18 µg TIO QD via HandiHaler inhaler and placebo BID via DPI, during the 24-week study treatment period. Participants also received 400 µg salbutamol as relief medication and as a bronchodilator for pulmonary function testing as required throughout the study.	SAL/FLU 50/250 µg BID n=68 Participants Participants received 50/250 µg SAL/FLU BID via DPI and placebo QD via HandiHaler inhaler, during the 24-week study treatment period. Participants also received 400 µg salbutamol as relief medication and as a bronchodilator for pulmonary function testing as required throughout the study.	TIO 18 µg QD-Single n=126 Participants Participants received 18 µg TIO QD via HandiHaler inhaler and placebo BID via DPI, during the 24-week study treatment period. Participants also received 400 µg salbutamol as relief medication and as a bronchodilator for pulmonary function testing as required throughout the study. Participants who remained on the single treatment of TIO 18 µg QD were included in this arm.	TIO 18 µg QD-TRIPLE n=75 Participants Participants received 18 µg TIO QD via HandiHaler inhaler and placebo BID via DPI, during the 24-week study treatment period. Participants also received 400 µg salbutamol as relief medication and as a bronchodilator for pulmonary function testing as required throughout the study. Participants who switched from the single treatment of TIO 18 µg QD to TRIPLE therapy (SAL/FLU 50/250 µg BID+TIO 18 µg QD) were included in this arm.
Time to First Exacerbation by EXAcerbations of Chronic Pulmonary Disease Tool (EXACT)	0 Days	0 Days	0 Days	1 Days

SECONDARY outcome

Timeframe: Baseline and up to 24 weeks

Population: mITT population. Only those participants available at the specified time points (represented by n=X, X, X, X in the category titles) were analyzed.

EXACT is a 14-item patient questionnaire used as a measure of respiratory symptoms (reported as units on a 0 \[best health status\] to 100 \[worst possible status\] scale). Scores were assessed at Baseline, Week 1-4, Week 5-8, Week 9-12, Week 13-16, Week 17-20 and Week 21-24. Daily EXACT total score is obtained as total score of 14 items from diary. Daily E-RS total score as 11 items and Daily E-RS subscale scores are subset of E-RS total score. Mean EXACT total score is mean value of daily EXACT total score within subject by every 4 weeks(Week1-4, Week5-8, Week9-12, Week13-16, Week17-20, Week21-24). Same calculation of mean values are applied to E-RS total and E-RS subscale scores.

Outcome measures

Outcome measures
Measure	TIO 18 µg QD n=136 Participants Participants received 18 µg TIO QD via HandiHaler inhaler and placebo BID via DPI, during the 24-week study treatment period. Participants also received 400 µg salbutamol as relief medication and as a bronchodilator for pulmonary function testing as required throughout the study.	SAL/FLU 50/250 µg BID n=68 Participants Participants received 50/250 µg SAL/FLU BID via DPI and placebo QD via HandiHaler inhaler, during the 24-week study treatment period. Participants also received 400 µg salbutamol as relief medication and as a bronchodilator for pulmonary function testing as required throughout the study.	TIO 18 µg QD-Single n=126 Participants Participants received 18 µg TIO QD via HandiHaler inhaler and placebo BID via DPI, during the 24-week study treatment period. Participants also received 400 µg salbutamol as relief medication and as a bronchodilator for pulmonary function testing as required throughout the study. Participants who remained on the single treatment of TIO 18 µg QD were included in this arm.	TIO 18 µg QD-TRIPLE n=75 Participants Participants received 18 µg TIO QD via HandiHaler inhaler and placebo BID via DPI, during the 24-week study treatment period. Participants also received 400 µg salbutamol as relief medication and as a bronchodilator for pulmonary function testing as required throughout the study. Participants who switched from the single treatment of TIO 18 µg QD to TRIPLE therapy (SAL/FLU 50/250 µg BID+TIO 18 µg QD) were included in this arm.
EXACT Total Score. Baseline; n=125, 66, 111, 71	28.99 Scores on a scale Standard Deviation 10.151	36.00 Scores on a scale Standard Deviation 10.499	29.77 Scores on a scale Standard Deviation 10.163	35.78 Scores on a scale Standard Deviation 9.222
EXACT Total Score. Week 1-4; n=120, 67, 109, 73	27.83 Scores on a scale Standard Deviation 10.225	36.92 Scores on a scale Standard Deviation 10.385	28.88 Scores on a scale Standard Deviation 10.182	38.26 Scores on a scale Standard Deviation 12.230
EXACT Total Score. Week 5-8; n=117, 63, 102, 69	27.35 Scores on a scale Standard Deviation 10.921	37.58 Scores on a scale Standard Deviation 9.831	28.80 Scores on a scale Standard Deviation 10.274	35.87 Scores on a scale Standard Deviation 11.117
EXACT Total Score. Week 9-12; n=109, 67, 101, 72	27.63 Scores on a scale Standard Deviation 11.847	36.16 Scores on a scale Standard Deviation 11.492	28.40 Scores on a scale Standard Deviation 9.619	35.57 Scores on a scale Standard Deviation 11.578
EXACT Total Score. Week 13-16; n=105, 65, 100, 71	27.33 Scores on a scale Standard Deviation 10.715	35.92 Scores on a scale Standard Deviation 11.550	28.93 Scores on a scale Standard Deviation 9.721	33.79 Scores on a scale Standard Deviation 12.334
EXACT Total Score. Week 17-20; n=107, 65, 97, 66	26.98 Scores on a scale Standard Deviation 10.971	34.92 Scores on a scale Standard Deviation 10.661	28.66 Scores on a scale Standard Deviation 10.970	34.03 Scores on a scale Standard Deviation 12.066
EXACT Total Score. Week 21-24; n=79, 51, 77, 46	26.50 Scores on a scale Standard Deviation 11.697	32.72 Scores on a scale Standard Deviation 11.992	28.80 Scores on a scale Standard Deviation 10.497	33.67 Scores on a scale Standard Deviation 12.722

SECONDARY outcome

Timeframe: Baseline and up to 24 weeks

Population: mITT population. Only those participants available at the specified time points (represented by n=X, X, X, X in the category titles) were analyzed.

The E-RS total score is an 11-item patient questionnaire, which provides information specific to respiratory symptoms-severity of respiratory symptoms overall and severity of breathlessness, cough and sputum, and chest symptoms. Scores were assessed at Baseline, Week 1-4, Week 5-8, Week 9-12, Week 13-16, Week 17-20 and at Week 21-24. Daily EXACT total score is obtained as total score of 14 items from diary. Daily E-RS total score as 11 items and Daily E-RS subscale scores are subset of E-RS total score. Mean EXACT total score is mean value of daily EXACT total score within subject by every 4 weeks(Week1-4, Week5-8, Week9-12, Week13-16, Week17-20, Week21-24). Same calculation of mean values are applied to E-RS total and E-RS subscale scores. Scores range from 0-100, high value in score indicate worse outcome.

Outcome measures

Outcome measures
Measure	TIO 18 µg QD n=136 Participants Participants received 18 µg TIO QD via HandiHaler inhaler and placebo BID via DPI, during the 24-week study treatment period. Participants also received 400 µg salbutamol as relief medication and as a bronchodilator for pulmonary function testing as required throughout the study.	SAL/FLU 50/250 µg BID n=68 Participants Participants received 50/250 µg SAL/FLU BID via DPI and placebo QD via HandiHaler inhaler, during the 24-week study treatment period. Participants also received 400 µg salbutamol as relief medication and as a bronchodilator for pulmonary function testing as required throughout the study.	TIO 18 µg QD-Single n=126 Participants Participants received 18 µg TIO QD via HandiHaler inhaler and placebo BID via DPI, during the 24-week study treatment period. Participants also received 400 µg salbutamol as relief medication and as a bronchodilator for pulmonary function testing as required throughout the study. Participants who remained on the single treatment of TIO 18 µg QD were included in this arm.	TIO 18 µg QD-TRIPLE n=75 Participants Participants received 18 µg TIO QD via HandiHaler inhaler and placebo BID via DPI, during the 24-week study treatment period. Participants also received 400 µg salbutamol as relief medication and as a bronchodilator for pulmonary function testing as required throughout the study. Participants who switched from the single treatment of TIO 18 µg QD to TRIPLE therapy (SAL/FLU 50/250 µg BID+TIO 18 µg QD) were included in this arm.
EXACT Respiratory Symptoms (E-RS) Total Score Baseline; n=135, 67, 124, 73	7.42 Scores on a scale Standard Deviation 5.541	11.43 Scores on a scale Standard Deviation 6.378	7.51 Scores on a scale Standard Deviation 5.583	11.36 Scores on a scale Standard Deviation 5.650
EXACT Respiratory Symptoms (E-RS) Total Score Week 5-8; n=126, 68, 115, 73	6.75 Scores on a scale Standard Deviation 5.618	11.86 Scores on a scale Standard Deviation 6.573	6.99 Scores on a scale Standard Deviation 5.720	11.11 Scores on a scale Standard Deviation 6.798
EXACT Respiratory Symptoms (E-RS) Total Score Week 9-12; n=122, 68, 116, 74	6.69 Scores on a scale Standard Deviation 6.489	11.79 Scores on a scale Standard Deviation 6.696	6.70 Scores on a scale Standard Deviation 5.244	11.30 Scores on a scale Standard Deviation 6.762
EXACT Respiratory Symptoms (E-RS) Total Score Week 13-16; n=121, 66, 116, 74	6.23 Scores on a scale Standard Deviation 5.667	11.66 Scores on a scale Standard Deviation 6.739	6.82 Scores on a scale Standard Deviation 5.392	10.26 Scores on a scale Standard Deviation 7.122
EXACT Respiratory Symptoms (E-RS) Total Score Week 17-20; n=118, 66, 114, 72	6.33 Scores on a scale Standard Deviation 5.786	10.80 Scores on a scale Standard Deviation 6.158	6.85 Scores on a scale Standard Deviation 6.035	9.89 Scores on a scale Standard Deviation 7.073
EXACT Respiratory Symptoms (E-RS) Total Score Week 1-4; n=131, 68, 121, 75	6.76 Scores on a scale Standard Deviation 5.405	12.39 Scores on a scale Standard Deviation 6.533	7.18 Scores on a scale Standard Deviation 5.745	13.23 Scores on a scale Standard Deviation 7.370
EXACT Respiratory Symptoms (E-RS) Total Score Week 21-24; n=93, 51, 94, 51	5.99 Scores on a scale Standard Deviation 6.044	9.82 Scores on a scale Standard Deviation 6.507	6.58 Scores on a scale Standard Deviation 5.702	9.59 Scores on a scale Standard Deviation 7.420

SECONDARY outcome

Timeframe: 24 weeks

Population: mITT population. Only those participants available at the specified time points (represented by n=X, X, X, X in the category titles) were analyzed.

The E-RS total score is an 11-item patient questionnaire, which provides information specific to respiratory symptoms-severity of respiratory symptoms overall and severity of breathlessness, cough and sputum, and chest symptoms. The E-RS subscale scores for respiratory symptoms (RS)-breathlessness (RS-BRL), RS-cough and sputum (RS-CSP), and RS-chest symptoms (RS-CSY) are presented. Scores were assessed at Baseline, Week 1-4, Week 5-8, Week 9-12, Week 13-16, Week 17-20 and at Week 21-24. Daily EXACT total score is obtained as total score of 14 items from diary. Daily E-RS total score as 11 items and Daily E-RS subscale scores are subset of E-RS total score. Mean EXACT total score is mean value of daily EXACT total score within subject by every 4 weeks(Week1-4, Week5-8, Week9-12, Week13-16, Week17-20, Week21-24). Same calculation of mean values are applied to E-RS total and E-RS subscale scores. RS total scores range from 0 to 40, high value in score indicate worse outcome.

Outcome measures

SECONDARY outcome

Timeframe: 24 weeks

Population: mITT population

The comparison of number of exacerbation between two detection methods EXACT and physician diagnosis: number of exacerbations detected by EXACT and number of exacerbations judged by physician.

Outcome measures

Outcome measures
Measure	TIO 18 µg QD n=201 Participants Participants received 18 µg TIO QD via HandiHaler inhaler and placebo BID via DPI, during the 24-week study treatment period. Participants also received 400 µg salbutamol as relief medication and as a bronchodilator for pulmonary function testing as required throughout the study.	SAL/FLU 50/250 µg BID n=204 Participants Participants received 50/250 µg SAL/FLU BID via DPI and placebo QD via HandiHaler inhaler, during the 24-week study treatment period. Participants also received 400 µg salbutamol as relief medication and as a bronchodilator for pulmonary function testing as required throughout the study.	TIO 18 µg QD-Single Participants received 18 µg TIO QD via HandiHaler inhaler and placebo BID via DPI, during the 24-week study treatment period. Participants also received 400 µg salbutamol as relief medication and as a bronchodilator for pulmonary function testing as required throughout the study. Participants who remained on the single treatment of TIO 18 µg QD were included in this arm.	TIO 18 µg QD-TRIPLE Participants received 18 µg TIO QD via HandiHaler inhaler and placebo BID via DPI, during the 24-week study treatment period. Participants also received 400 µg salbutamol as relief medication and as a bronchodilator for pulmonary function testing as required throughout the study. Participants who switched from the single treatment of TIO 18 µg QD to TRIPLE therapy (SAL/FLU 50/250 µg BID+TIO 18 µg QD) were included in this arm.
Comparison of Number of Exacerbations Between Two Detection Methods: EXACT and Physician Diagnosis EXACT	0.9 Number of exacerbations Standard Deviation 1.00	0.7 Number of exacerbations Standard Deviation 1.06	—	—
Comparison of Number of Exacerbations Between Two Detection Methods: EXACT and Physician Diagnosis Physician's diagnosis	0.2 Number of exacerbations Standard Deviation 0.44	0.1 Number of exacerbations Standard Deviation 0.36	—	—

SECONDARY outcome

Timeframe: 24 weeks

Population: mITT population. Only those participants available at the specified time points (represented by n=X, X, X, X in the category titles) were analyzed.

Participants were assessed for COPD symptoms by means of CAT at each Visit. This assessment was performed prior to the spirometry testing. A CAT total score of less than 10 represents best health status and greater than 15 represents worst health status. Scores were assessed at Visit 1 (Screening), Visit 2 (Baseline), Visit 3 (Week 4), Visit 4 (Week 8), Visit 5 (Week 8), Visit 6 (Week 12), Visit 7 (Week 16), and Visit 8 (Week 24). Scores range from 0 to 40, high value in score indicate worse outcome.

Outcome measures

Outcome measures
Measure	TIO 18 µg QD n=136 Participants Participants received 18 µg TIO QD via HandiHaler inhaler and placebo BID via DPI, during the 24-week study treatment period. Participants also received 400 µg salbutamol as relief medication and as a bronchodilator for pulmonary function testing as required throughout the study.	SAL/FLU 50/250 µg BID n=68 Participants Participants received 50/250 µg SAL/FLU BID via DPI and placebo QD via HandiHaler inhaler, during the 24-week study treatment period. Participants also received 400 µg salbutamol as relief medication and as a bronchodilator for pulmonary function testing as required throughout the study.	TIO 18 µg QD-Single n=126 Participants Participants received 18 µg TIO QD via HandiHaler inhaler and placebo BID via DPI, during the 24-week study treatment period. Participants also received 400 µg salbutamol as relief medication and as a bronchodilator for pulmonary function testing as required throughout the study. Participants who remained on the single treatment of TIO 18 µg QD were included in this arm.	TIO 18 µg QD-TRIPLE n=75 Participants Participants received 18 µg TIO QD via HandiHaler inhaler and placebo BID via DPI, during the 24-week study treatment period. Participants also received 400 µg salbutamol as relief medication and as a bronchodilator for pulmonary function testing as required throughout the study. Participants who switched from the single treatment of TIO 18 µg QD to TRIPLE therapy (SAL/FLU 50/250 µg BID+TIO 18 µg QD) were included in this arm.
Chronic Obstructive Pulmonary Disease (COPD) Assessment Test (CAT) Total Score Visit 1, n=136, 68, 126, 75	11.3 Scores on a scale Standard Deviation 5.83 • Interval 5.83 to	13.3 Scores on a scale Standard Deviation 6.35	11.2 Scores on a scale Standard Deviation 5.77	13.4 Scores on a scale Standard Deviation 6.49
Chronic Obstructive Pulmonary Disease (COPD) Assessment Test (CAT) Total Score Visit 2, n=136, 68, 126, 75	9.9 Scores on a scale Standard Deviation 6.35 • Interval 6.35 to	13.4 Scores on a scale Standard Deviation 7.52	9.6 Scores on a scale Standard Deviation 6.27	12.1 Scores on a scale Standard Deviation 6.08
Chronic Obstructive Pulmonary Disease (COPD) Assessment Test (CAT) Total Score Visit 3, n=132, 68, 121, 75	8.4 Scores on a scale Standard Deviation 6.09 • Interval 6.09 to	13.5 Scores on a scale Standard Deviation 8.12	9.2 Scores on a scale Standard Deviation 5.91	14.3 Scores on a scale Standard Deviation 7.28
Chronic Obstructive Pulmonary Disease (COPD) Assessment Test (CAT) Total Score Visit 4, n=127, 68, 116, 74	8.3 Scores on a scale Standard Deviation 5.99 • Interval 5.99 to	13.2 Scores on a scale Standard Deviation 7.59	8.8 Scores on a scale Standard Deviation 5.89	13.6 Scores on a scale Standard Deviation 6.65
Chronic Obstructive Pulmonary Disease (COPD) Assessment Test (CAT) Total Score Visit 5, n=123, 68, 116, 73	8.3 Scores on a scale Standard Deviation 7.12 • Interval 7.12 to	12.6 Scores on a scale Standard Deviation 7.56	8.4 Scores on a scale Standard Deviation 5.89	12.8 Scores on a scale Standard Deviation 7.02
Chronic Obstructive Pulmonary Disease (COPD) Assessment Test (CAT) Total Score Visit 6, n=120, 66, 115, 74	7.4 Scores on a scale Standard Deviation 6.11 • Interval 6.11 to	13.3 Scores on a scale Standard Deviation 8.26	8.5 Scores on a scale Standard Deviation 5.75	12.0 Scores on a scale Standard Deviation 7.52
Chronic Obstructive Pulmonary Disease (COPD) Assessment Test (CAT) Total Score Visit 7, n=120, 66, 113, 71	7.7 Scores on a scale Standard Deviation 6.51 • Interval 6.51 to	12.4 Scores on a scale Standard Deviation 7.69	8.3 Scores on a scale Standard Deviation 6.48	11.4 Scores on a scale Standard Deviation 7.09
Chronic Obstructive Pulmonary Disease (COPD) Assessment Test (CAT) Total Score Visit 8, n=117, 66, 113, 70	7.2 Scores on a scale Standard Deviation 6.42 • Interval 6.42 to	12.3 Scores on a scale Standard Deviation 7.56	7.8 Scores on a scale Standard Deviation 5.79	11.6 Scores on a scale Standard Deviation 7.70

SECONDARY outcome

Timeframe: Baseline and up to 24 weeks

Population: mITT population. Only those participants available at the specified time points (represented by n=X, X, X, X in the category titles) were analyzed.

Participants were assessed for COPD symptoms by means of CAT at each Visit. This assessment was performed prior to the spirometry testing. A CAT total score of less than 10 represents best health status and greater than 15 represents worst health status. Baseline was the value at Visit 2 (randomization). Change from Baseline was calculated as specific timepoint value minus Visit 2 value. Scores were assessed at Visit 2 (Baseline), Visit 3 (Week 4), Visit 4 (Week 8), Visit 5 (Week 8), Visit 6 (Week 12), Visit 7 (Week 16), and Visit 8 (Week 24). Scores range from 0 to 40, high value in score indicate worse outcome.

Outcome measures

Outcome measures
Measure	TIO 18 µg QD n=136 Participants Participants received 18 µg TIO QD via HandiHaler inhaler and placebo BID via DPI, during the 24-week study treatment period. Participants also received 400 µg salbutamol as relief medication and as a bronchodilator for pulmonary function testing as required throughout the study.	SAL/FLU 50/250 µg BID n=68 Participants Participants received 50/250 µg SAL/FLU BID via DPI and placebo QD via HandiHaler inhaler, during the 24-week study treatment period. Participants also received 400 µg salbutamol as relief medication and as a bronchodilator for pulmonary function testing as required throughout the study.	TIO 18 µg QD-Single n=126 Participants Participants received 18 µg TIO QD via HandiHaler inhaler and placebo BID via DPI, during the 24-week study treatment period. Participants also received 400 µg salbutamol as relief medication and as a bronchodilator for pulmonary function testing as required throughout the study. Participants who remained on the single treatment of TIO 18 µg QD were included in this arm.	TIO 18 µg QD-TRIPLE n=75 Participants Participants received 18 µg TIO QD via HandiHaler inhaler and placebo BID via DPI, during the 24-week study treatment period. Participants also received 400 µg salbutamol as relief medication and as a bronchodilator for pulmonary function testing as required throughout the study. Participants who switched from the single treatment of TIO 18 µg QD to TRIPLE therapy (SAL/FLU 50/250 µg BID+TIO 18 µg QD) were included in this arm.
Change From Baseline in CAT Total Score Visit 3, n=132, 68, 121, 75	-1.6 Scores on a scale Standard Deviation 4.74	0.1 Scores on a scale Standard Deviation 4.52	0.1 Scores on a scale Standard Deviation 3.97	2.1 Scores on a scale Standard Deviation 5.10
Change From Baseline in CAT Total Score Visit 4, n=127, 68, 116, 74	-1.7 Scores on a scale Standard Deviation 5.34	-0.2 Scores on a scale Standard Deviation 5.68	-0.3 Scores on a scale Standard Deviation 4.21	1.6 Scores on a scale Standard Deviation 5.53
Change From Baseline in CAT Total Score Visit 5, n=123, 68, 116, 73	-1.6 Scores on a scale Standard Deviation 6.04	-0.8 Scores on a scale Standard Deviation 5.68	-0.7 Scores on a scale Standard Deviation 5.14	0.8 Scores on a scale Standard Deviation 5.78
Change From Baseline in CAT Total Score Visit 6, n=120, 66, 115, 74	-2.3 Scores on a scale Standard Deviation 5.41	0.0 Scores on a scale Standard Deviation 6.28	-0.7 Scores on a scale Standard Deviation 4.55	0.0 Scores on a scale Standard Deviation 6.09
Change From Baseline in CAT Total Score Visit 7, n=120, 66, 113, 71	-2.0 Scores on a scale Standard Deviation 5.50	-0.8 Scores on a scale Standard Deviation 6.20	-0.8 Scores on a scale Standard Deviation 4.91	-0.6 Scores on a scale Standard Deviation 5.49
Change From Baseline in CAT Total Score Visit 8, n=117, 66, 113, 70	-2.4 Scores on a scale Standard Deviation 5.74	-1.0 Scores on a scale Standard Deviation 6.05	-1.4 Scores on a scale Standard Deviation 4.93	-0.5 Scores on a scale Standard Deviation 6.29

SECONDARY outcome

Timeframe: Up to 24 weeks

Population: mITT population. Only those participants available at the specified time points (represented by n=X, X, X, X in the category titles) were analyzed.

FEV1 is defined as the volume of air forcefully expelled from the lungs in one second. At Screening (Visit 1) spirometric assessments were conducted before (Visit 1A) and 30 to 60 minutes after a bronchodilator challenge (400 µg of salbutamol) (Visit 1B). FEV1 during each visit are presented. FEV1 was assessed at Visit 1A (Screening), Visit 1B (Screening), Visit 2 (Baseline), Visit 3 (Week 4), Visit 4 (Week 8), Visit 5 (Week 8), Visit 6 (Week 12), Visit 7 (Week 16), and Visit 8 (Week 24).

Outcome measures

Outcome measures
Measure	TIO 18 µg QD n=136 Participants Participants received 18 µg TIO QD via HandiHaler inhaler and placebo BID via DPI, during the 24-week study treatment period. Participants also received 400 µg salbutamol as relief medication and as a bronchodilator for pulmonary function testing as required throughout the study.	SAL/FLU 50/250 µg BID n=68 Participants Participants received 50/250 µg SAL/FLU BID via DPI and placebo QD via HandiHaler inhaler, during the 24-week study treatment period. Participants also received 400 µg salbutamol as relief medication and as a bronchodilator for pulmonary function testing as required throughout the study.	TIO 18 µg QD-Single n=126 Participants Participants received 18 µg TIO QD via HandiHaler inhaler and placebo BID via DPI, during the 24-week study treatment period. Participants also received 400 µg salbutamol as relief medication and as a bronchodilator for pulmonary function testing as required throughout the study. Participants who remained on the single treatment of TIO 18 µg QD were included in this arm.	TIO 18 µg QD-TRIPLE n=75 Participants Participants received 18 µg TIO QD via HandiHaler inhaler and placebo BID via DPI, during the 24-week study treatment period. Participants also received 400 µg salbutamol as relief medication and as a bronchodilator for pulmonary function testing as required throughout the study. Participants who switched from the single treatment of TIO 18 µg QD to TRIPLE therapy (SAL/FLU 50/250 µg BID+TIO 18 µg QD) were included in this arm.
Forced Expiratory Volume in One Second (FEV1) Visit 1A; n=136, 68, 126, 75	1.687 Liters Standard Deviation 0.4440	1.401 Liters Standard Deviation 0.4482	1.675 Liters Standard Deviation 0.4564	1.349 Liters Standard Deviation 0.4032
Forced Expiratory Volume in One Second (FEV1) Visit 1B; n=136, 68, 126, 75	1.764 Liters Standard Deviation 0.4363	1.471 Liters Standard Deviation 0.4394	1.754 Liters Standard Deviation 0.4691	1.429 Liters Standard Deviation 0.4346
Forced Expiratory Volume in One Second (FEV1) Visit 2; n=136, 68, 126, 75	1.695 Liters Standard Deviation 0.4650	1.385 Liters Standard Deviation 0.4336	1.681 Liters Standard Deviation 0.4929	1.362 Liters Standard Deviation 0.4267
Forced Expiratory Volume in One Second (FEV1) Visit 3; n=131, 68, 119, 75	1.731 Liters Standard Deviation 0.4904	1.342 Liters Standard Deviation 0.4563	1.710 Liters Standard Deviation 0.5458	1.285 Liters Standard Deviation 0.4570
Forced Expiratory Volume in One Second (FEV1) Visit 4; n=127, 68, 116, 74	1.713 Liters Standard Deviation 0.4943	1.355 Liters Standard Deviation 0.4555	1.703 Liters Standard Deviation 0.5215	1.336 Liters Standard Deviation 0.4638
Forced Expiratory Volume in One Second (FEV1) Visit 5; n=122, 68, 116, 72	1.718 Liters Standard Deviation 0.4859	1.384 Liters Standard Deviation 0.4497	1.708 Liters Standard Deviation 0.5408	1.376 Liters Standard Deviation 0.4536
Forced Expiratory Volume in One Second (FEV1) Visit 6; n=120, 66, 114, 74	1.716 Liters Standard Deviation 0.4817	1.413 Liters Standard Deviation 0.5104	1.712 Liters Standard Deviation 0.5353	1.405 Liters Standard Deviation 0.4938
Forced Expiratory Volume in One Second (FEV1) Visit 7; n=119, 66, 113, 71	1.710 Liters Standard Deviation 0.4850	1.404 Liters Standard Deviation 0.4913	1.694 Liters Standard Deviation 0.5402	1.423 Liters Standard Deviation 0.4916
Forced Expiratory Volume in One Second (FEV1) Visit 8; n=117, 66, 113, 70	1.694 Liters Standard Deviation 0.4808	1.435 Liters Standard Deviation 0.4871	1.688 Liters Standard Deviation 0.5426	1.390 Liters Standard Deviation 0.4695

SECONDARY outcome

Timeframe: Baseline (Visit 2) and up to 24 weeks

Population: mITT population. Only those participants available at the specified time points (represented by n=X, X, X, X in the category titles) were analyzed.

FEV1 is defined as the volume of air forcefully expelled from the lungs in one second. Baseline was a value at Visit 2 (randomization). Change from Baseline was calculated as specific timepoint value minus Visit 2 value. FEV1 was assessed at Visit 2 (Baseline), Visit 3 (Week 4), Visit 4 (Week 8), Visit 5 (Week 8), Visit 6 (Week 12), Visit 7 (Week 16), and Visit 8 (Week 24).

Outcome measures

Outcome measures
Measure	TIO 18 µg QD n=136 Participants Participants received 18 µg TIO QD via HandiHaler inhaler and placebo BID via DPI, during the 24-week study treatment period. Participants also received 400 µg salbutamol as relief medication and as a bronchodilator for pulmonary function testing as required throughout the study.	SAL/FLU 50/250 µg BID n=68 Participants Participants received 50/250 µg SAL/FLU BID via DPI and placebo QD via HandiHaler inhaler, during the 24-week study treatment period. Participants also received 400 µg salbutamol as relief medication and as a bronchodilator for pulmonary function testing as required throughout the study.	TIO 18 µg QD-Single n=126 Participants Participants received 18 µg TIO QD via HandiHaler inhaler and placebo BID via DPI, during the 24-week study treatment period. Participants also received 400 µg salbutamol as relief medication and as a bronchodilator for pulmonary function testing as required throughout the study. Participants who remained on the single treatment of TIO 18 µg QD were included in this arm.	TIO 18 µg QD-TRIPLE n=75 Participants Participants received 18 µg TIO QD via HandiHaler inhaler and placebo BID via DPI, during the 24-week study treatment period. Participants also received 400 µg salbutamol as relief medication and as a bronchodilator for pulmonary function testing as required throughout the study. Participants who switched from the single treatment of TIO 18 µg QD to TRIPLE therapy (SAL/FLU 50/250 µg BID+TIO 18 µg QD) were included in this arm.
Change From Baseline in FEV1 Visit 3; n=131, 68, 119, 75	0.024 Liters Standard Deviation 0.1917	-0.043 Liters Standard Deviation 0.1825	0.007 Liters Standard Deviation 0.1772	-0.077 Liters Standard Deviation 0.1843
Change From Baseline in FEV1 Visit 4; n=127, 68, 116, 74	0.008 Liters Standard Deviation 0.2092	-0.030 Liters Standard Deviation 0.1821	-0.011 Liters Standard Deviation 0.1977	-0.032 Liters Standard Deviation 0.2325
Change From Baseline in FEV1 Visit 5; n=122, 68, 116, 72	-0.010 Liters Standard Deviation 0.2066	-0.001 Liters Standard Deviation 0.1910	-0.006 Liters Standard Deviation 0.2002	0.005 Liters Standard Deviation 0.2171
Change From Baseline in FEV1 Visit 6; n=120, 66, 114, 74	-0.007 Liters Standard Deviation 0.2069	0.027 Liters Standard Deviation 0.2025	0.002 Liters Standard Deviation 0.1893	0.037 Liters Standard Deviation 0.2098
Change From Baseline in FEV1 Visit 7; n=119, 66, 113, 71	-0.012 Liters Standard Deviation 0.2252	0.018 Liters Standard Deviation 0.1874	-0.010 Liters Standard Deviation 0.2220	0.050 Liters Standard Deviation 0.2091
Change From Baseline in FEV1 Visit 8; n=117, 66, 113, 70	-0.019 Liters Standard Deviation 0.2293	0.049 Liters Standard Deviation 0.1892	-0.017 Liters Standard Deviation 0.2355	0.027 Liters Standard Deviation 0.1999

SECONDARY outcome

Timeframe: 24 weeks

Population: mITT population

Each evening participants recorded the number of occasions in the last 24 hours when they used their salbutamol for symptomatic relief of COPD symptoms. The percentage of participants who used relief medication in the study are presented.

Outcome measures

Outcome measures
Measure	TIO 18 µg QD n=136 Participants Participants received 18 µg TIO QD via HandiHaler inhaler and placebo BID via DPI, during the 24-week study treatment period. Participants also received 400 µg salbutamol as relief medication and as a bronchodilator for pulmonary function testing as required throughout the study.	SAL/FLU 50/250 µg BID n=68 Participants Participants received 50/250 µg SAL/FLU BID via DPI and placebo QD via HandiHaler inhaler, during the 24-week study treatment period. Participants also received 400 µg salbutamol as relief medication and as a bronchodilator for pulmonary function testing as required throughout the study.	TIO 18 µg QD-Single n=126 Participants Participants received 18 µg TIO QD via HandiHaler inhaler and placebo BID via DPI, during the 24-week study treatment period. Participants also received 400 µg salbutamol as relief medication and as a bronchodilator for pulmonary function testing as required throughout the study. Participants who remained on the single treatment of TIO 18 µg QD were included in this arm.	TIO 18 µg QD-TRIPLE n=75 Participants Participants received 18 µg TIO QD via HandiHaler inhaler and placebo BID via DPI, during the 24-week study treatment period. Participants also received 400 µg salbutamol as relief medication and as a bronchodilator for pulmonary function testing as required throughout the study. Participants who switched from the single treatment of TIO 18 µg QD to TRIPLE therapy (SAL/FLU 50/250 µg BID+TIO 18 µg QD) were included in this arm.
Percentage of Participants Who Used Relief Medication (Salbutamol)	40.4 Percentage of participants	61.8 Percentage of participants	43.7 Percentage of participants	70.7 Percentage of participants

SECONDARY outcome

Timeframe: 24 weeks

Population: mITT population

The percentage of participants who stepped down from TRIPLE therapy to initial randomized treatment was calculated as number of participants who step-down from TRIPLE therapy divided by number of participants who switch to TRIPLE therapy and then multiplied by 100.

Outcome measures

Outcome measures
Measure	TIO 18 µg QD n=201 Participants Participants received 18 µg TIO QD via HandiHaler inhaler and placebo BID via DPI, during the 24-week study treatment period. Participants also received 400 µg salbutamol as relief medication and as a bronchodilator for pulmonary function testing as required throughout the study.	SAL/FLU 50/250 µg BID n=204 Participants Participants received 50/250 µg SAL/FLU BID via DPI and placebo QD via HandiHaler inhaler, during the 24-week study treatment period. Participants also received 400 µg salbutamol as relief medication and as a bronchodilator for pulmonary function testing as required throughout the study.	TIO 18 µg QD-Single Participants received 18 µg TIO QD via HandiHaler inhaler and placebo BID via DPI, during the 24-week study treatment period. Participants also received 400 µg salbutamol as relief medication and as a bronchodilator for pulmonary function testing as required throughout the study. Participants who remained on the single treatment of TIO 18 µg QD were included in this arm.	TIO 18 µg QD-TRIPLE Participants received 18 µg TIO QD via HandiHaler inhaler and placebo BID via DPI, during the 24-week study treatment period. Participants also received 400 µg salbutamol as relief medication and as a bronchodilator for pulmonary function testing as required throughout the study. Participants who switched from the single treatment of TIO 18 µg QD to TRIPLE therapy (SAL/FLU 50/250 µg BID+TIO 18 µg QD) were included in this arm.
Percentage of Participants Who Stepped Down From TRIPLE Therapy to Initial Randomized Treatment	1.33 Percentage of participants Interval 0.03 to 7.21	2.94 Percentage of participants Interval 0.36 to 10.22	—	—

SECONDARY outcome

Timeframe: 24 weeks

Population: mITT population

The percentage of participants who required additional treatment to TRIPLE therapy is defined as number of participants who took additional medicine or therapy in TRIPLE therapy divided by number of participants who switch to TRIPLE therapy multiplied by 100.

Outcome measures

Outcome measures
Measure	TIO 18 µg QD n=201 Participants Participants received 18 µg TIO QD via HandiHaler inhaler and placebo BID via DPI, during the 24-week study treatment period. Participants also received 400 µg salbutamol as relief medication and as a bronchodilator for pulmonary function testing as required throughout the study.	SAL/FLU 50/250 µg BID n=204 Participants Participants received 50/250 µg SAL/FLU BID via DPI and placebo QD via HandiHaler inhaler, during the 24-week study treatment period. Participants also received 400 µg salbutamol as relief medication and as a bronchodilator for pulmonary function testing as required throughout the study.	TIO 18 µg QD-Single Participants received 18 µg TIO QD via HandiHaler inhaler and placebo BID via DPI, during the 24-week study treatment period. Participants also received 400 µg salbutamol as relief medication and as a bronchodilator for pulmonary function testing as required throughout the study. Participants who remained on the single treatment of TIO 18 µg QD were included in this arm.	TIO 18 µg QD-TRIPLE Participants received 18 µg TIO QD via HandiHaler inhaler and placebo BID via DPI, during the 24-week study treatment period. Participants also received 400 µg salbutamol as relief medication and as a bronchodilator for pulmonary function testing as required throughout the study. Participants who switched from the single treatment of TIO 18 µg QD to TRIPLE therapy (SAL/FLU 50/250 µg BID+TIO 18 µg QD) were included in this arm.
Percentage of Participants Who Required Additional Treatment to TRIPLE Therapy	77.33 Percentage of participants Interval 66.21 to 86.21	72.06 Percentage of participants Interval 59.85 to 82.27	—	—

SECONDARY outcome

Timeframe: 24 weeks

Population: All Subjects population: all participants who were enrolled into the study and whose data obtained at screening (visit1) was not missing and demography data was available.

The percentage of participants who were withdrawn from the study.

Outcome measures

Outcome measures
Measure	TIO 18 µg QD n=202 Participants Participants received 18 µg TIO QD via HandiHaler inhaler and placebo BID via DPI, during the 24-week study treatment period. Participants also received 400 µg salbutamol as relief medication and as a bronchodilator for pulmonary function testing as required throughout the study.	SAL/FLU 50/250 µg BID n=204 Participants Participants received 50/250 µg SAL/FLU BID via DPI and placebo QD via HandiHaler inhaler, during the 24-week study treatment period. Participants also received 400 µg salbutamol as relief medication and as a bronchodilator for pulmonary function testing as required throughout the study.	TIO 18 µg QD-Single Participants received 18 µg TIO QD via HandiHaler inhaler and placebo BID via DPI, during the 24-week study treatment period. Participants also received 400 µg salbutamol as relief medication and as a bronchodilator for pulmonary function testing as required throughout the study. Participants who remained on the single treatment of TIO 18 µg QD were included in this arm.	TIO 18 µg QD-TRIPLE Participants received 18 µg TIO QD via HandiHaler inhaler and placebo BID via DPI, during the 24-week study treatment period. Participants also received 400 µg salbutamol as relief medication and as a bronchodilator for pulmonary function testing as required throughout the study. Participants who switched from the single treatment of TIO 18 µg QD to TRIPLE therapy (SAL/FLU 50/250 µg BID+TIO 18 µg QD) were included in this arm.
Percentage of Participants Who Dropped Out	9 Percentage of participants	10 Percentage of participants	—	—

SECONDARY outcome

Timeframe: Up to 24 weeks

Population: mITT population

Participants evaluated treatment efficacy by using the following grades: significantly improved (SII), moderately improved (MOI), mildly improved (MII), no change (NC), mildly worse (MIW), moderately worse (MOW), and significantly worse (SIW). Treatment efficacy was assessed at Visit 3 (Week 4), Visit 4 (Week 8), Visit 5 (Week 8), Visit 6 (Week 12), Visit 7 (Week 16), and Visit 8 (Week 24).

Outcome measures

Outcome measures
Measure	TIO 18 µg QD n=136 Participants Participants received 18 µg TIO QD via HandiHaler inhaler and placebo BID via DPI, during the 24-week study treatment period. Participants also received 400 µg salbutamol as relief medication and as a bronchodilator for pulmonary function testing as required throughout the study.	SAL/FLU 50/250 µg BID n=68 Participants Participants received 50/250 µg SAL/FLU BID via DPI and placebo QD via HandiHaler inhaler, during the 24-week study treatment period. Participants also received 400 µg salbutamol as relief medication and as a bronchodilator for pulmonary function testing as required throughout the study.	TIO 18 µg QD-Single n=126 Participants Participants received 18 µg TIO QD via HandiHaler inhaler and placebo BID via DPI, during the 24-week study treatment period. Participants also received 400 µg salbutamol as relief medication and as a bronchodilator for pulmonary function testing as required throughout the study. Participants who remained on the single treatment of TIO 18 µg QD were included in this arm.	TIO 18 µg QD-TRIPLE n=75 Participants Participants received 18 µg TIO QD via HandiHaler inhaler and placebo BID via DPI, during the 24-week study treatment period. Participants also received 400 µg salbutamol as relief medication and as a bronchodilator for pulmonary function testing as required throughout the study. Participants who switched from the single treatment of TIO 18 µg QD to TRIPLE therapy (SAL/FLU 50/250 µg BID+TIO 18 µg QD) were included in this arm.
Number of Participants in Each Treatment Efficacy Grade Evaluated by Participants Visit 3; SIW	1 Participants	0 Participants	0 Participants	1 Participants
Number of Participants in Each Treatment Efficacy Grade Evaluated by Participants Visit 4; SII	3 Participants	1 Participants	2 Participants	1 Participants
Number of Participants in Each Treatment Efficacy Grade Evaluated by Participants Visit 3; SII	5 Participants	0 Participants	1 Participants	1 Participants
Number of Participants in Each Treatment Efficacy Grade Evaluated by Participants Visit 3; MOI	9 Participants	2 Participants	3 Participants	3 Participants
Number of Participants in Each Treatment Efficacy Grade Evaluated by Participants Visit 3; MII	35 Participants	10 Participants	20 Participants	7 Participants
Number of Participants in Each Treatment Efficacy Grade Evaluated by Participants Visit 3; NC	74 Participants	32 Participants	85 Participants	32 Participants
Number of Participants in Each Treatment Efficacy Grade Evaluated by Participants Visit 3; MIW	7 Participants	19 Participants	9 Participants	22 Participants
Number of Participants in Each Treatment Efficacy Grade Evaluated by Participants Visit 3; MOW	1 Participants	5 Participants	3 Participants	9 Participants
Number of Participants in Each Treatment Efficacy Grade Evaluated by Participants Visit 4; MOI	15 Participants	6 Participants	5 Participants	6 Participants
Number of Participants in Each Treatment Efficacy Grade Evaluated by Participants Visit 4; MII	31 Participants	12 Participants	25 Participants	21 Participants
Number of Participants in Each Treatment Efficacy Grade Evaluated by Participants Visit 4; NC	67 Participants	39 Participants	79 Participants	28 Participants
Number of Participants in Each Treatment Efficacy Grade Evaluated by Participants Visit 4; MIW	10 Participants	8 Participants	5 Participants	13 Participants
Number of Participants in Each Treatment Efficacy Grade Evaluated by Participants Visit 4; MOW	1 Participants	2 Participants	0 Participants	5 Participants
Number of Participants in Each Treatment Efficacy Grade Evaluated by Participants Visit 5; SII	2 Participants	1 Participants	2 Participants	4 Participants
Number of Participants in Each Treatment Efficacy Grade Evaluated by Participants Visit 5; MOI	13 Participants	7 Participants	3 Participants	6 Participants
Number of Participants in Each Treatment Efficacy Grade Evaluated by Participants Visit 5; MII	31 Participants	17 Participants	31 Participants	20 Participants
Number of Participants in Each Treatment Efficacy Grade Evaluated by Participants Visit 5; NC	66 Participants	34 Participants	78 Participants	31 Participants
Number of Participants in Each Treatment Efficacy Grade Evaluated by Participants Visit 5; MIW	10 Participants	7 Participants	2 Participants	9 Participants
Number of Participants in Each Treatment Efficacy Grade Evaluated by Participants Visit 5; MOW	0 Participants	2 Participants	0 Participants	3 Participants
Number of Participants in Each Treatment Efficacy Grade Evaluated by Participants Visit 5; SIW	1 Participants	0 Participants	0 Participants	0 Participants
Number of Participants in Each Treatment Efficacy Grade Evaluated by Participants Visit 6; SII	2 Participants	1 Participants	2 Participants	4 Participants
Number of Participants in Each Treatment Efficacy Grade Evaluated by Participants Visit 6; MOI	13 Participants	4 Participants	4 Participants	13 Participants
Number of Participants in Each Treatment Efficacy Grade Evaluated by Participants Visit 6; MII	35 Participants	16 Participants	30 Participants	14 Participants
Number of Participants in Each Treatment Efficacy Grade Evaluated by Participants Visit 6; NC	66 Participants	33 Participants	72 Participants	34 Participants
Number of Participants in Each Treatment Efficacy Grade Evaluated by Participants Visit 6; MIW	4 Participants	11 Participants	7 Participants	7 Participants
Number of Participants in Each Treatment Efficacy Grade Evaluated by Participants Visit 6; MOW	0 Participants	0 Participants	0 Participants	2 Participants
Number of Participants in Each Treatment Efficacy Grade Evaluated by Participants Visit 6; SIW	0 Participants	1 Participants	0 Participants	0 Participants
Number of Participants in Each Treatment Efficacy Grade Evaluated by Participants Visit 7; SII	1 Participants	2 Participants	2 Participants	4 Participants
Number of Participants in Each Treatment Efficacy Grade Evaluated by Participants Visit 7; MOI	13 Participants	4 Participants	5 Participants	11 Participants
Number of Participants in Each Treatment Efficacy Grade Evaluated by Participants Visit 7; MII	27 Participants	17 Participants	28 Participants	20 Participants
Number of Participants in Each Treatment Efficacy Grade Evaluated by Participants Visit 7; NC	75 Participants	37 Participants	71 Participants	26 Participants
Number of Participants in Each Treatment Efficacy Grade Evaluated by Participants Visit 7; MIW	4 Participants	5 Participants	7 Participants	9 Participants
Number of Participants in Each Treatment Efficacy Grade Evaluated by Participants Visit 7; MOW	0 Participants	1 Participants	0 Participants	1 Participants
Number of Participants in Each Treatment Efficacy Grade Evaluated by Participants Visit 8; SII	5 Participants	1 Participants	2 Participants	4 Participants
Number of Participants in Each Treatment Efficacy Grade Evaluated by Participants Visit 8; MOI	9 Participants	4 Participants	8 Participants	9 Participants
Number of Participants in Each Treatment Efficacy Grade Evaluated by Participants Visit 8; MII	39 Participants	19 Participants	30 Participants	19 Participants
Number of Participants in Each Treatment Efficacy Grade Evaluated by Participants Visit 8; NC	58 Participants	37 Participants	69 Participants	34 Participants
Number of Participants in Each Treatment Efficacy Grade Evaluated by Participants Visit 8; MIW	5 Participants	5 Participants	3 Participants	4 Participants
Number of Participants in Each Treatment Efficacy Grade Evaluated by Participants Visit 8; MOW	1 Participants	0 Participants	1 Participants	0 Participants

SECONDARY outcome

Timeframe: 24 weeks

Population: mITT population

Physician evaluated treatment efficacy by using the following grades: significantly improved (SII), moderately improved (MOI), mildly improved (MII), no change (NC), mildly worse (MIW), moderately worse (MOW), and significantly worse (SIW). Treatment efficacy was assessed at Visit 3 (Week 4), Visit 4 (Week 8), Visit 5 (Week 8), Visit 6 (Week 12), Visit 7 (Week 16), and Visit 8 (Week 24).

Outcome measures

Outcome measures
Measure	TIO 18 µg QD n=136 Participants Participants received 18 µg TIO QD via HandiHaler inhaler and placebo BID via DPI, during the 24-week study treatment period. Participants also received 400 µg salbutamol as relief medication and as a bronchodilator for pulmonary function testing as required throughout the study.	SAL/FLU 50/250 µg BID n=68 Participants Participants received 50/250 µg SAL/FLU BID via DPI and placebo QD via HandiHaler inhaler, during the 24-week study treatment period. Participants also received 400 µg salbutamol as relief medication and as a bronchodilator for pulmonary function testing as required throughout the study.	TIO 18 µg QD-Single n=126 Participants Participants received 18 µg TIO QD via HandiHaler inhaler and placebo BID via DPI, during the 24-week study treatment period. Participants also received 400 µg salbutamol as relief medication and as a bronchodilator for pulmonary function testing as required throughout the study. Participants who remained on the single treatment of TIO 18 µg QD were included in this arm.	TIO 18 µg QD-TRIPLE n=75 Participants Participants received 18 µg TIO QD via HandiHaler inhaler and placebo BID via DPI, during the 24-week study treatment period. Participants also received 400 µg salbutamol as relief medication and as a bronchodilator for pulmonary function testing as required throughout the study. Participants who switched from the single treatment of TIO 18 µg QD to TRIPLE therapy (SAL/FLU 50/250 µg BID+TIO 18 µg QD) were included in this arm.
Number of Participants in Each Treatment Efficacy Grade Evaluated by Physician Visit 5; NC	73 Participants	35 Participants	83 Participants	29 Participants
Number of Participants in Each Treatment Efficacy Grade Evaluated by Physician Visit 5; MIW	7 Participants	10 Participants	5 Participants	10 Participants
Number of Participants in Each Treatment Efficacy Grade Evaluated by Physician Visit 5; MOW	0 Participants	1 Participants	0 Participants	3 Participants
Number of Participants in Each Treatment Efficacy Grade Evaluated by Physician Visit 5; SIW	1 Participants	0 Participants	0 Participants	0 Participants
Number of Participants in Each Treatment Efficacy Grade Evaluated by Physician Visit 6; SII	2 Participants	1 Participants	2 Participants	2 Participants
Number of Participants in Each Treatment Efficacy Grade Evaluated by Physician Visit 6; MOI	10 Participants	1 Participants	3 Participants	11 Participants
Number of Participants in Each Treatment Efficacy Grade Evaluated by Physician Visit 6; MII	31 Participants	18 Participants	28 Participants	17 Participants
Number of Participants in Each Treatment Efficacy Grade Evaluated by Physician Visit 6; NC	74 Participants	33 Participants	72 Participants	32 Participants
Number of Participants in Each Treatment Efficacy Grade Evaluated by Physician Visit 6; MIW	3 Participants	11 Participants	10 Participants	9 Participants
Number of Participants in Each Treatment Efficacy Grade Evaluated by Physician Visit 6; MOW	0 Participants	1 Participants	0 Participants	3 Participants
Number of Participants in Each Treatment Efficacy Grade Evaluated by Physician Visit 6; SIW	0 Participants	1 Participants	0 Participants	0 Participants
Number of Participants in Each Treatment Efficacy Grade Evaluated by Physician Visit 7; SII	0 Participants	1 Participants	2 Participants	3 Participants
Number of Participants in Each Treatment Efficacy Grade Evaluated by Physician Visit 7; MOI	13 Participants	2 Participants	5 Participants	12 Participants
Number of Participants in Each Treatment Efficacy Grade Evaluated by Physician Visit 7; MII	25 Participants	18 Participants	23 Participants	12 Participants
Number of Participants in Each Treatment Efficacy Grade Evaluated by Physician Visit 7; NC	79 Participants	38 Participants	77 Participants	35 Participants
Number of Participants in Each Treatment Efficacy Grade Evaluated by Physician Visit 7; MIW	3 Participants	5 Participants	5 Participants	8 Participants
Number of Participants in Each Treatment Efficacy Grade Evaluated by Physician Visit 7; MOW	0 Participants	2 Participants	1 Participants	1 Participants
Number of Participants in Each Treatment Efficacy Grade Evaluated by Physician Visit 8; SII	2 Participants	1 Participants	3 Participants	3 Participants
Number of Participants in Each Treatment Efficacy Grade Evaluated by Physician Visit 8; MOI	7 Participants	4 Participants	7 Participants	9 Participants
Number of Participants in Each Treatment Efficacy Grade Evaluated by Physician Visit 8; MII	36 Participants	19 Participants	27 Participants	13 Participants
Number of Participants in Each Treatment Efficacy Grade Evaluated by Physician Visit 8; NC	70 Participants	39 Participants	71 Participants	40 Participants
Number of Participants in Each Treatment Efficacy Grade Evaluated by Physician Visit 8; MIW	1 Participants	2 Participants	4 Participants	5 Participants
Number of Participants in Each Treatment Efficacy Grade Evaluated by Physician Visit 8; MOW	1 Participants	1 Participants	1 Participants	0 Participants
Number of Participants in Each Treatment Efficacy Grade Evaluated by Physician Visit 3; SII	6 Participants	0 Participants	1 Participants	1 Participants
Number of Participants in Each Treatment Efficacy Grade Evaluated by Physician Visit 3; MOI	11 Participants	1 Participants	5 Participants	4 Participants
Number of Participants in Each Treatment Efficacy Grade Evaluated by Physician Visit 3; MII	40 Participants	12 Participants	21 Participants	3 Participants
Number of Participants in Each Treatment Efficacy Grade Evaluated by Physician Visit 3; NC	67 Participants	31 Participants	83 Participants	32 Participants
Number of Participants in Each Treatment Efficacy Grade Evaluated by Physician Visit 3; MIW	7 Participants	16 Participants	7 Participants	23 Participants
Number of Participants in Each Treatment Efficacy Grade Evaluated by Physician Visit 3; MOW	0 Participants	8 Participants	3 Participants	12 Participants
Number of Participants in Each Treatment Efficacy Grade Evaluated by Physician Visit 3; SIW	1 Participants	0 Participants	1 Participants	0 Participants
Number of Participants in Each Treatment Efficacy Grade Evaluated by Physician Visit 4; SII	3 Participants	1 Participants	2 Participants	0 Participants
Number of Participants in Each Treatment Efficacy Grade Evaluated by Physician Visit 4; MOI	14 Participants	3 Participants	8 Participants	9 Participants
Number of Participants in Each Treatment Efficacy Grade Evaluated by Physician Visit 4; MII	28 Participants	13 Participants	23 Participants	18 Participants
Number of Participants in Each Treatment Efficacy Grade Evaluated by Physician Visit 4; NC	74 Participants	33 Participants	79 Participants	27 Participants
Number of Participants in Each Treatment Efficacy Grade Evaluated by Physician Visit 4; MIW	6 Participants	12 Participants	4 Participants	12 Participants
Number of Participants in Each Treatment Efficacy Grade Evaluated by Physician Visit 4; MOW	1 Participants	6 Participants	0 Participants	8 Participants
Number of Participants in Each Treatment Efficacy Grade Evaluated by Physician Visit 4; SIW	1 Participants	0 Participants	0 Participants	0 Participants
Number of Participants in Each Treatment Efficacy Grade Evaluated by Physician Visit 5; SII	1 Participants	2 Participants	2 Participants	4 Participants
Number of Participants in Each Treatment Efficacy Grade Evaluated by Physician Visit 5; MOI	12 Participants	6 Participants	4 Participants	8 Participants
Number of Participants in Each Treatment Efficacy Grade Evaluated by Physician Visit 5; MII	29 Participants	14 Participants	22 Participants	19 Participants

Adverse Events

TIO 18 µg QD-Single

Serious events: 8 serious events

Other events: 29 other events

Deaths: 0 deaths

TIO 18 µg QD-TRIPLE

Serious events: 8 serious events

Other events: 29 other events

Deaths: 0 deaths

SAL/FLU 50/250 µg BID-Single

Serious events: 8 serious events

Other events: 48 other events

Deaths: 0 deaths

SAL/FLU 50/250 µg BID-TRIPLE

Serious events: 6 serious events

Other events: 25 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Other adverse events
Measure	TIO 18 µg QD-Single n=126 participants at risk Participants received 18 µg TIO QD via HandiHaler inhaler and placebo BID via DPI, during the 24-week study treatment period. Participants also received 400 µg salbutamol as relief medication and as a bronchodilator for pulmonary function testing as required throughout the study. Participants who remained on the single treatment of TIO 18 µg QD were included in this arm.	TIO 18 µg QD-TRIPLE n=75 participants at risk Participants received 18 µg TIO QD via HandiHaler inhaler and placebo BID via DPI, during the 24-week study treatment period. Participants also received 400 µg salbutamol as relief medication and as a bronchodilator for pulmonary function testing as required throughout the study. Participants who switched from the single treatment of TIO 18 µg QD to TRIPLE therapy (SAL/FLU 50/250 µg BID+TIO 18 µg QD) were included in this arm.	SAL/FLU 50/250 µg BID-Single n=136 participants at risk Participants received 50/250 µg SAL/FLU BID via DPI and placebo QD via HandiHaler inhaler, during the 24-week study treatment period. Participants also received 400 µg salbutamol as relief medication and as a bronchodilator for pulmonary function testing as required throughout the study. Participants who remained on the single treatment of SAL/FLU 50/250 µg BID were included in this arm.	SAL/FLU 50/250 µg BID-TRIPLE n=68 participants at risk Participants received 50/250 µg SAL/FLU BID via DPI and placebo QD via HandiHaler inhaler, during the 24-week study treatment period. Participants also received 400 µg salbutamol as relief medication and as a bronchodilator for pulmonary function testing as required throughout the study. Participants who switched from the single treatment of SAL/FLU 50/250 µg BID to TRIPLE therapy (SAL/FLU 50/250 µg BID+TIO 18 µg QD) were included in this arm.
Infections and infestations Nasopharyngitis	15.1% 19/126 • Serious adverse events and non-serious adverse events were collected from the start of study treatment and until the follow up contact (up to Week 26). Serious adverse events and non-serious adverse events were reported for Safety population	26.7% 20/75 • Serious adverse events and non-serious adverse events were collected from the start of study treatment and until the follow up contact (up to Week 26). Serious adverse events and non-serious adverse events were reported for Safety population	18.4% 25/136 • Serious adverse events and non-serious adverse events were collected from the start of study treatment and until the follow up contact (up to Week 26). Serious adverse events and non-serious adverse events were reported for Safety population	20.6% 14/68 • Serious adverse events and non-serious adverse events were collected from the start of study treatment and until the follow up contact (up to Week 26). Serious adverse events and non-serious adverse events were reported for Safety population
Infections and infestations Bronchitis	4.8% 6/126 • Serious adverse events and non-serious adverse events were collected from the start of study treatment and until the follow up contact (up to Week 26). Serious adverse events and non-serious adverse events were reported for Safety population	6.7% 5/75 • Serious adverse events and non-serious adverse events were collected from the start of study treatment and until the follow up contact (up to Week 26). Serious adverse events and non-serious adverse events were reported for Safety population	5.1% 7/136 • Serious adverse events and non-serious adverse events were collected from the start of study treatment and until the follow up contact (up to Week 26). Serious adverse events and non-serious adverse events were reported for Safety population	10.3% 7/68 • Serious adverse events and non-serious adverse events were collected from the start of study treatment and until the follow up contact (up to Week 26). Serious adverse events and non-serious adverse events were reported for Safety population
Infections and infestations Pneumonia	0.00% 0/126 • Serious adverse events and non-serious adverse events were collected from the start of study treatment and until the follow up contact (up to Week 26). Serious adverse events and non-serious adverse events were reported for Safety population	5.3% 4/75 • Serious adverse events and non-serious adverse events were collected from the start of study treatment and until the follow up contact (up to Week 26). Serious adverse events and non-serious adverse events were reported for Safety population	1.5% 2/136 • Serious adverse events and non-serious adverse events were collected from the start of study treatment and until the follow up contact (up to Week 26). Serious adverse events and non-serious adverse events were reported for Safety population	1.5% 1/68 • Serious adverse events and non-serious adverse events were collected from the start of study treatment and until the follow up contact (up to Week 26). Serious adverse events and non-serious adverse events were reported for Safety population
Respiratory, thoracic and mediastinal disorders Dysphonia	4.0% 5/126 • Serious adverse events and non-serious adverse events were collected from the start of study treatment and until the follow up contact (up to Week 26). Serious adverse events and non-serious adverse events were reported for Safety population	8.0% 6/75 • Serious adverse events and non-serious adverse events were collected from the start of study treatment and until the follow up contact (up to Week 26). Serious adverse events and non-serious adverse events were reported for Safety population	13.2% 18/136 • Serious adverse events and non-serious adverse events were collected from the start of study treatment and until the follow up contact (up to Week 26). Serious adverse events and non-serious adverse events were reported for Safety population	8.8% 6/68 • Serious adverse events and non-serious adverse events were collected from the start of study treatment and until the follow up contact (up to Week 26). Serious adverse events and non-serious adverse events were reported for Safety population

Additional Information

GSK Response Center

GlaxoSmithKline

Phone: 866-435-7343

Results disclosure agreements

Principal investigator is a sponsor employee GSK agreements may vary with individual investigators, but will not prohibit any investigator from publishing. GSK supports the publication of results from all centers of a multi-center trial but requests that reports based on single-site data not precede the primary publication of the entire clinical trial.
Publication restrictions are in place

Restriction type: OTHER

Measure	TIO 18 µg QD n=136 Participants Participants received 18 µg TIO QD via HandiHaler inhaler and placebo BID via DPI, during the 24-week study treatment period. Participants also received 400 µg salbutamol as relief medication and as a bronchodilator for pulmonary function testing as required throughout the study.	SAL/FLU 50/250 µg BID n=68 Participants Participants received 50/250 µg SAL/FLU BID via DPI and placebo QD via HandiHaler inhaler, during the 24-week study treatment period. Participants also received 400 µg salbutamol as relief medication and as a bronchodilator for pulmonary function testing as required throughout the study.	TIO 18 µg QD-Single n=126 Participants Participants received 18 µg TIO QD via HandiHaler inhaler and placebo BID via DPI, during the 24-week study treatment period. Participants also received 400 µg salbutamol as relief medication and as a bronchodilator for pulmonary function testing as required throughout the study. Participants who remained on the single treatment of TIO 18 µg QD were included in this arm.	TIO 18 µg QD-TRIPLE n=75 Participants Participants received 18 µg TIO QD via HandiHaler inhaler and placebo BID via DPI, during the 24-week study treatment period. Participants also received 400 µg salbutamol as relief medication and as a bronchodilator for pulmonary function testing as required throughout the study. Participants who switched from the single treatment of TIO 18 µg QD to TRIPLE therapy (SAL/FLU 50/250 µg BID+TIO 18 µg QD) were included in this arm.
E-RS Subscale Score RS-BRL; Baseline; n=135, 68, 125, 73	3.36 Scores on a scale Standard Deviation 3.113	5.81 Scores on a scale Standard Deviation 3.542	3.41 Scores on a scale Standard Deviation 3.122	5.62 Scores on a scale Standard Deviation 3.393
E-RS Subscale Score RS-BRL; Week 1-4; n=131, 68, 121, 75	3.06 Scores on a scale Standard Deviation 3.245	6.28 Scores on a scale Standard Deviation 3.498	3.36 Scores on a scale Standard Deviation 3.288	6.59 Scores on a scale Standard Deviation 4.191
E-RS Subscale Score RS-BRL; Week 5-8; n=126, 68, 115, 73	3.08 Scores on a scale Standard Deviation 3.281	5.96 Scores on a scale Standard Deviation 3.517	3.18 Scores on a scale Standard Deviation 3.110	5.38 Scores on a scale Standard Deviation 3.857
E-RS Subscale Score RS-BRL; Week 9-12; n=122, 68, 116, 74	3.08 Scores on a scale Standard Deviation 3.402	5.87 Scores on a scale Standard Deviation 3.612	2.98 Scores on a scale Standard Deviation 2.970	5.52 Scores on a scale Standard Deviation 3.793
E-RS Subscale Score RS-BRL; Week 13-16; n=121, 66, 116, 74	2.80 Scores on a scale Standard Deviation 3.151	5.81 Scores on a scale Standard Deviation 3.683	3.04 Scores on a scale Standard Deviation 3.084	5.11 Scores on a scale Standard Deviation 4.029
E-RS Subscale Score RS-BRL; Week 17-20; n=118, 66, 114, 72	2.82 Scores on a scale Standard Deviation 3.349	5.56 Scores on a scale Standard Deviation 3.678	3.04 Scores on a scale Standard Deviation 3.254	4.94 Scores on a scale Standard Deviation 3.908
E-RS Subscale Score RS-BRL; Week 21-24; n=93, 51, 94, 51	2.79 Scores on a scale Standard Deviation 3.316	4.94 Scores on a scale Standard Deviation 3.661	2.95 Scores on a scale Standard Deviation 3.160	4.71 Scores on a scale Standard Deviation 4.159
E-RS Subscale Score RS-CSP; Baseline; n=135, 68, 124, 73	2.29 Scores on a scale Standard Deviation 1.536	2.73 Scores on a scale Standard Deviation 1.778	2.23 Scores on a scale Standard Deviation 1.643	2.81 Scores on a scale Standard Deviation 1.601
E-RS Subscale Score RS-CSP; Week 1-4; n=131, 68, 121, 75	2.12 Scores on a scale Standard Deviation 1.453	2.90 Scores on a scale Standard Deviation 1.687	2.13 Scores on a scale Standard Deviation 1.517	3.05 Scores on a scale Standard Deviation 1.925
E-RS Subscale Score RS-CSP; Week 5-8; n=126, 68, 116, 73	2.03 Scores on a scale Standard Deviation 1.448	2.83 Scores on a scale Standard Deviation 1.814	2.13 Scores on a scale Standard Deviation 1.633	2.74 Scores on a scale Standard Deviation 1.763
E-RS Subscale Score RS-CSP; Week 9-12; n=122, 68, 116, 74	2.06 Scores on a scale Standard Deviation 1.850	2.81 Scores on a scale Standard Deviation 1.766	2.11 Scores on a scale Standard Deviation 1.635	2.77 Scores on a scale Standard Deviation 1.803
E-RS Subscale Score RS-CSP; Week 13-16; n=121, 66, 116, 74	1.98 Scores on a scale Standard Deviation 1.563	2.74 Scores on a scale Standard Deviation 1.769	2.09 Scores on a scale Standard Deviation 1.579	2.49 Scores on a scale Standard Deviation 1.797
E-RS Subscale Score RS-CSP; Week 17-20; n=119, 66, 114, 72	2.06 Scores on a scale Standard Deviation 1.612	2.43 Scores on a scale Standard Deviation 1.608	2.09 Scores on a scale Standard Deviation 1.702	2.40 Scores on a scale Standard Deviation 1.768
E-RS Subscale Score RS-CSP; Week 21-24; n=93, 51, 94, 51	1.82 Scores on a scale Standard Deviation 1.711	2.27 Scores on a scale Standard Deviation 1.604	1.99 Scores on a scale Standard Deviation 1.680	2.34 Scores on a scale Standard Deviation 1.783
E-RS Subscale Score RS-CSY; Baseline; n=135, 67, 125, 73	1.77 Scores on a scale Standard Deviation 1.768	2.93 Scores on a scale Standard Deviation 1.903	1.84 Scores on a scale Standard Deviation 1.729	2.92 Scores on a scale Standard Deviation 1.794
E-RS Subscale Score RS-CSY; Week 1-4; n=131, 68, 121, 75	1.58 Scores on a scale Standard Deviation 1.652	3.21 Scores on a scale Standard Deviation 2.071	1.69 Scores on a scale Standard Deviation 1.681	3.59 Scores on a scale Standard Deviation 2.306
E-RS Subscale Score RS-CSY; Week 5-8; n=126, 68, 116, 73	1.65 Scores on a scale Standard Deviation 1.760	3.05 Scores on a scale Standard Deviation 1.977	1.70 Scores on a scale Standard Deviation 1.695	2.99 Scores on a scale Standard Deviation 2.149
E-RS Subscale Score RS-CSY; Week 9-12; n=122, 68, 116, 74	1.54 Scores on a scale Standard Deviation 2.032	3.12 Scores on a scale Standard Deviation 2.069	1.60 Scores on a scale Standard Deviation 1.584	3.01 Scores on a scale Standard Deviation 2.204
E-RS Subscale Score RS-CSY; Week 13-16; n=121, 66, 116, 74	1.46 Scores on a scale Standard Deviation 1.752	3.11 Scores on a scale Standard Deviation 2.102	1.70 Scores on a scale Standard Deviation 1.623	2.66 Scores on a scale Standard Deviation 2.184
E-RS Subscale Score RS-CSY; Week 17-20; n=119, 66, 114, 72	1.48 Scores on a scale Standard Deviation 1.802	2.81 Scores on a scale Standard Deviation 1.873	1.72 Scores on a scale Standard Deviation 1.908	2.55 Scores on a scale Standard Deviation 2.171
E-RS Subscale Score RS-CSY; Week 21-24; n=93, 51, 94, 51	1.38 Scores on a scale Standard Deviation 1.944	2.61 Scores on a scale Standard Deviation 1.988	1.64 Scores on a scale Standard Deviation 1.741	2.53 Scores on a scale Standard Deviation 2.167