Trial Outcomes & Findings for Effect of Tiotropium Plus Salmeterol vs. Fluticasone/Salmeterol on Static Lung Volumes and Exercise Endurance in COPD (NCT NCT00530842)

NCT ID: NCT00530842

Last Updated: 2013-12-24

Results Overview

Post-dose TGV(FRC) (Thoracic Gas Volume; co-primary endpoint) after 8 weeks

• Recruitment status: COMPLETED
• Study phase: PHASE4
• Target enrollment: 344 participants
• Primary outcome timeframe: 8 weeks
• Results posted on: 2013-12-24

Participant Flow

All participant flow data are presented by treatment sequence

Participant milestones

Measure	Tiotropium + Salmeterol / Fluticasone + Salmeterol Tio 18mcg o.d. + Sal 50mcg b.i.d. / Flu+Sal 500+50mcg b.i.d.	Fluticasone + Salmeterol / Tiotropium + Salmeterol Flu+Sal 500+50mcg b.i.d. / Tio 18mcg o.d. + Sal 50mcg b.i.d.
Overall Study STARTED	172	172
Overall Study COMPLETED	149	151
Overall Study NOT COMPLETED	23	21
Period 1 STARTED	172	172
Period 1 COMPLETED	158	161
Period 1 NOT COMPLETED	14	11
Period 2 STARTED	157	160
Period 2 COMPLETED	149	151
Period 2 NOT COMPLETED	8	9

Reasons for withdrawal

Measure	Tiotropium + Salmeterol / Fluticasone + Salmeterol Tio 18mcg o.d. + Sal 50mcg b.i.d. / Flu+Sal 500+50mcg b.i.d.	Fluticasone + Salmeterol / Tiotropium + Salmeterol Flu+Sal 500+50mcg b.i.d. / Tio 18mcg o.d. + Sal 50mcg b.i.d.
Overall Study Adverse Event	10	6
Overall Study Lack of Efficacy	2	1
Overall Study Lost to Follow-up	0	4
Overall Study Protocol Violation	3	2
Overall Study Withdrawal by Subject	4	5
Overall Study Individual different reasons	4	3
Period 1 Adverse Event	7	3
Period 1 Lack of Efficacy	1	1
Period 1 Protocol Violation	2	1
Period 1 Withdrawal by Subject	2	3
Period 1 Individual different reasons	2	3
Period 2 Adverse Event	3	3
Period 2 Lack of Efficacy	1	0
Period 2 Lost to Follow-up	0	4
Period 2 Protocol Violation	1	0
Period 2 Withdrawal by Subject	1	2
Period 2 Individual different reasons	2	0

Baseline Characteristics

Effect of Tiotropium Plus Salmeterol vs. Fluticasone/Salmeterol on Static Lung Volumes and Exercise Endurance in COPD

Baseline characteristics by cohort

Measure	Tiotropium + Salmeterol / Fluticasone + Salmeterol n=172 Participants Tio 18mcg o.d. + Sal 50mcg b.i.d. / Flu+Sal 500+50mcg b.i.d.	Fluticasone + Salmeterol / Tiotropium + Salmeterol n=172 Participants Flu+Sal 500+50mcg b.i.d. / Tio 18mcg o.d. + Sal 50mcg b.i.d.	Total n=344 Participants Total of all reporting groups
Age, Continuous	61.5 Years STANDARD_DEVIATION 7.5 • n=5 Participants	60.6 Years STANDARD_DEVIATION 7.6 • n=7 Participants	61.0 Years STANDARD_DEVIATION 7.6 • n=5 Participants
Sex: Female, Male Female	48 Participants n=5 Participants	49 Participants n=7 Participants	97 Participants n=5 Participants
Sex: Female, Male Male	124 Participants n=5 Participants	123 Participants n=7 Participants	247 Participants n=5 Participants

PRIMARY outcome

Timeframe: 8 weeks

Population: FAS using imputed values. The full analysis set (FAS) was defined to include all treated patients with any post-dosing efficacy data after at least 4 weeks for both investigational treatments in TGV(FRC) or endurance time.

Post-dose TGV(FRC) (Thoracic Gas Volume; co-primary endpoint) after 8 weeks

Outcome measures

Measure	Tiotropium + Salmeterol n=309 Participants Tio 18mcg o.d. + Sal 50mcg b.i.d. in Period 1 or 2	Fluticasone + Salmeterol n=309 Participants Flu+Sal 500+50mcg b.i.d. in Period 1 or 2
Post-dose TGV(FRC) (After 8 Weeks)	4.99 Litres Standard Error 0.07	5.07 Litres Standard Error 0.07

PRIMARY outcome

Timeframe: 8 weeks

Population: FAS using imputed values

Endurance time to the point of symptom limitation after 8 weeks during a constant work rate exercise test at 75% Wcap (co-primary endpoint)

Outcome measures

Measure	Tiotropium + Salmeterol n=309 Participants Tio 18mcg o.d. + Sal 50mcg b.i.d. in Period 1 or 2	Fluticasone + Salmeterol n=309 Participants Flu+Sal 500+50mcg b.i.d. in Period 1 or 2
Endurance Time (After 8 Weeks)	463 Seconds Inter-Quartile Range 375 • Interval 316.0 to 691.0	453 Seconds Inter-Quartile Range 413 • Interval 307.0 to 720.0

SECONDARY outcome

Timeframe: 4 weeks

Population: FAS using imputed values

Post-dose TGV(FRC) (Thoracic Gas Volume) after 4 weeks

Outcome measures

Measure	Tiotropium + Salmeterol n=309 Participants Tio 18mcg o.d. + Sal 50mcg b.i.d. in Period 1 or 2	Fluticasone + Salmeterol n=307 Participants Flu+Sal 500+50mcg b.i.d. in Period 1 or 2
Post-dose TGV(FRC) (After 4 Weeks)	5.00 Litres Standard Error 0.07	5.19 Litres Standard Error 0.07

SECONDARY outcome

Timeframe: 4 weeks

Population: FAS using imputed values

Endurance time to the point of symptom limitation after 4 weeks during a constant work rate exercise test at 75% Wcap (co-primary endpoint)

Outcome measures

Measure	Tiotropium + Salmeterol n=309 Participants Tio 18mcg o.d. + Sal 50mcg b.i.d. in Period 1 or 2	Fluticasone + Salmeterol n=309 Participants Flu+Sal 500+50mcg b.i.d. in Period 1 or 2
Endurance Time (After 4 Weeks)	458 Seconds Inter-Quartile Range 331 • Interval 343.0 to 674.0	450 Seconds Inter-Quartile Range 375 • Interval 301.0 to 676.0

SECONDARY outcome

Timeframe: 8 weeks

Population: FAS using imputed values

Trough TGV(FRC) (Thoracic Gas Volume) after 8 weeks (measured by bodyphlethysmography)

Outcome measures

Measure	Tiotropium + Salmeterol n=309 Participants Tio 18mcg o.d. + Sal 50mcg b.i.d. in Period 1 or 2	Fluticasone + Salmeterol n=309 Participants Flu+Sal 500+50mcg b.i.d. in Period 1 or 2
Static Lung Volumes	5.24 Litres Standard Error 0.08	5.25 Litres Standard Error 0.08

SECONDARY outcome

Timeframe: 4 weeks

Population: FAS using imputed values

Trough TGV(FRC) (Thoracic Gas Volume) after 4 weeks (measured by bodyphlethysmography)

Outcome measures

Measure	Tiotropium + Salmeterol n=309 Participants Tio 18mcg o.d. + Sal 50mcg b.i.d. in Period 1 or 2	Fluticasone + Salmeterol n=309 Participants Flu+Sal 500+50mcg b.i.d. in Period 1 or 2
Static Lung Volumes	5.32 Litres Standard Error 0.08	5.34 Litres Standard Error 0.08

SECONDARY outcome

Timeframe: 8 weeks

Population: FAS using imputed values

Trough RV (Residual Volume) after 8 weeks (measured by bodyphlethysmography)

Outcome measures

Measure	Tiotropium + Salmeterol n=309 Participants Tio 18mcg o.d. + Sal 50mcg b.i.d. in Period 1 or 2	Fluticasone + Salmeterol n=309 Participants Flu+Sal 500+50mcg b.i.d. in Period 1 or 2
Static Lung Volumes	4.23 Litres Standard Error 0.08	4.25 Litres Standard Error 0.08

SECONDARY outcome

Timeframe: 4 weeks

Population: FAS using imputed values

Trough RV (Residual Volume) after 4 weeks (measured by bodyphlethysmography)

Outcome measures

Measure	Tiotropium + Salmeterol n=309 Participants Tio 18mcg o.d. + Sal 50mcg b.i.d. in Period 1 or 2	Fluticasone + Salmeterol n=307 Participants Flu+Sal 500+50mcg b.i.d. in Period 1 or 2
Static Lung Volumes	4.28 Litres Standard Error 0.08	4.35 Litres Standard Error 0.08

SECONDARY outcome

Timeframe: 8 weeks

Population: FAS using imputed values

Post-dose RV (Residual Volume) after 8 weeks (measured by bodyphlethysmography)

Outcome measures

Measure	Tiotropium + Salmeterol n=309 Participants Tio 18mcg o.d. + Sal 50mcg b.i.d. in Period 1 or 2	Fluticasone + Salmeterol n=309 Participants Flu+Sal 500+50mcg b.i.d. in Period 1 or 2
Static Lung Volumes	3.92 Litres Standard Error 0.07	4.07 Litres Standard Error 0.07

SECONDARY outcome

Timeframe: 4 weeks

Population: FAS using imputed values

Post-dose RV (Residual Volume) after 4 weeks (measured by bodyphlethysmography)

Outcome measures

Measure	Tiotropium + Salmeterol n=309 Participants Tio 18mcg o.d. + Sal 50mcg b.i.d. in Period 1 or 2	Fluticasone + Salmeterol n=307 Participants Flu+Sal 500+50mcg b.i.d. in Period 1 or 2
Static Lung Volumes	3.91 Litres Standard Error 0.07	4.14 Litres Standard Error 0.07

SECONDARY outcome

Timeframe: 8 weeks

Population: FAS using imputed values

Trough IC (Inspiratory Capacity) after 8 weeks (measured by bodyphlethysmography)

Outcome measures

Measure	Tiotropium + Salmeterol n=309 Participants Tio 18mcg o.d. + Sal 50mcg b.i.d. in Period 1 or 2	Fluticasone + Salmeterol n=309 Participants Flu+Sal 500+50mcg b.i.d. in Period 1 or 2
Static Lung Volumes	2.33 Litres Standard Error 0.04	2.23 Litres Standard Error 0.04

SECONDARY outcome

Timeframe: 4 weeks

Population: FAS using imputed values

Trough IC (Inspiratory Capacity) after 4 weeks (measured by bodyphlethysmography)

Outcome measures

Measure	Tiotropium + Salmeterol n=309 Participants Tio 18mcg o.d. + Sal 50mcg b.i.d. in Period 1 or 2	Fluticasone + Salmeterol n=308 Participants Flu+Sal 500+50mcg b.i.d. in Period 1 or 2
Static Lung Volumes	2.28 Litres Standard Error 0.04	2.23 Litres Standard Error 0.04

SECONDARY outcome

Timeframe: 8 weeks

Population: FAS using imputed values

Post-dose IC (Inspiratory Capacity) after 8 weeks (measured by bodyphlethysmography)

Outcome measures

Measure	Tiotropium + Salmeterol n=309 Participants Tio 18mcg o.d. + Sal 50mcg b.i.d. in Period 1 or 2	Fluticasone + Salmeterol n=309 Participants Flu+Sal 500+50mcg b.i.d. in Period 1 or 2
Static Lung Volumes	2.47 Litres Standard Error 0.04	2.35 Litres Standard Error 0.04

SECONDARY outcome

Timeframe: 4 weeks

Population: FAS using imputed values

Post-dose IC (Inspiratory Capacity) after 4 weeks (measured by bodyphlethysmography)

Outcome measures

Measure	Tiotropium + Salmeterol n=309 Participants Tio 18mcg o.d. + Sal 50mcg b.i.d. in Period 1 or 2	Fluticasone + Salmeterol n=308 Participants Flu+Sal 500+50mcg b.i.d. in Period 1 or 2
Static Lung Volumes	2.46 Litres Standard Error 0.05	2.37 Litres Standard Error 0.05

SECONDARY outcome

Timeframe: 8 weeks

Population: FAS using imputed values

Trough IRV (Inspiratory Reserve Volume) after 8 weeks (measured by bodyphlethysmography)

Outcome measures

Measure	Tiotropium + Salmeterol n=280 Participants Tio 18mcg o.d. + Sal 50mcg b.i.d. in Period 1 or 2	Fluticasone + Salmeterol n=281 Participants Flu+Sal 500+50mcg b.i.d. in Period 1 or 2
Static Lung Volumes	1.48 Litres Standard Error 0.04	1.41 Litres Standard Error 0.04

SECONDARY outcome

Timeframe: 4 weeks

Population: FAS using imputed values

Trough IRV (Inspiratory Reserve Volume) after 4 weeks (measured by bodyphlethysmography)

Outcome measures

Measure	Tiotropium + Salmeterol n=280 Participants Tio 18mcg o.d. + Sal 50mcg b.i.d. in Period 1 or 2	Fluticasone + Salmeterol n=280 Participants Flu+Sal 500+50mcg b.i.d. in Period 1 or 2
Static Lung Volumes	1.47 Litres Standard Error 0.04	1.42 Litres Standard Error 0.04

SECONDARY outcome

Timeframe: 8 weeks

Population: FAS using imputed values

Post-dose IRV (Inspiratory Reserve Volume) after 8 weeks (measured by bodyphlethysmography)

Outcome measures

Measure	Tiotropium + Salmeterol n=280 Participants Tio 18mcg o.d. + Sal 50mcg b.i.d. in Period 1 or 2	Fluticasone + Salmeterol n=281 Participants Flu+Sal 500+50mcg b.i.d. in Period 1 or 2
Static Lung Volumes	1.62 Litres Standard Error 0.04	1.55 Litres Standard Error 0.04

SECONDARY outcome

Timeframe: 4 weeks

Population: FAS using imputed values

Post-dose IRV (Inspiratory Reserve Volume) after 4 weeks (measured by bodyphlethysmography)

Outcome measures

Measure	Tiotropium + Salmeterol n=280 Participants Tio 18mcg o.d. + Sal 50mcg b.i.d. in Period 1 or 2	Fluticasone + Salmeterol n=280 Participants Flu+Sal 500+50mcg b.i.d. in Period 1 or 2
Static Lung Volumes	1.62 Litres Standard Error 0.04	1.55 Litres Standard Error 0.04

SECONDARY outcome

Timeframe: 8 weeks

Population: FAS using imputed values

Trough TLC (Total Lung Capacity) after 8 weeks (measured by bodyphlethysmography)

Outcome measures

Measure	Tiotropium + Salmeterol n=309 Participants Tio 18mcg o.d. + Sal 50mcg b.i.d. in Period 1 or 2	Fluticasone + Salmeterol n=309 Participants Flu+Sal 500+50mcg b.i.d. in Period 1 or 2
Static Lung Volumes	7.47 Litres Standard Error 0.09	7.39 Litres Standard Error 0.09

SECONDARY outcome

Timeframe: 4 weeks

Population: FAS using imputed values

Trough TLC (Total Lung Capacity) after 4 weeks (measured by bodyphlethysmography)

Outcome measures

Measure	Tiotropium + Salmeterol n=309 Participants Tio 18mcg o.d. + Sal 50mcg b.i.d. in Period 1 or 2	Fluticasone + Salmeterol n=307 Participants Flu+Sal 500+50mcg b.i.d. in Period 1 or 2
Static Lung Volumes	7.52 Litres Standard Error 0.09	7.51 Litres Standard Error 0.09

SECONDARY outcome

Timeframe: 8 weeks

Population: FAS using imputed values

Post-dose TLC (Total Lung Capacity) after 8 weeks (measured by bodyphlethysmography)

Outcome measures

Measure	Tiotropium + Salmeterol n=309 Participants Tio 18mcg o.d. + Sal 50mcg b.i.d. in Period 1 or 2	Fluticasone + Salmeterol n=309 Participants Flu+Sal 500+50mcg b.i.d. in Period 1 or 2
Static Lung Volumes	7.36 Litres Standard Error 0.09	7.36 Litres Standard Error 0.09

SECONDARY outcome

Timeframe: 4 weeks

Population: FAS using imputed values

Post-dose TLC (Total Lung Capacity) after 4 weeks (measured by bodyphlethysmography)

Outcome measures

Measure	Tiotropium + Salmeterol n=309 Participants Tio 18mcg o.d. + Sal 50mcg b.i.d. in Period 1 or 2	Fluticasone + Salmeterol n=307 Participants Flu+Sal 500+50mcg b.i.d. in Period 1 or 2
Static Lung Volumes	7.33 Litres Standard Error 0.09	7.47 Litres Standard Error 0.09

SECONDARY outcome

Timeframe: 8 weeks

Population: FAS using imputed values

Trough RV/TLC (Residual Volume over Total Lung Capacity) after 8 weeks (measured by bodyphlethysmography)

Outcome measures

Measure	Tiotropium + Salmeterol n=309 Participants Tio 18mcg o.d. + Sal 50mcg b.i.d. in Period 1 or 2	Fluticasone + Salmeterol n=309 Participants Flu+Sal 500+50mcg b.i.d. in Period 1 or 2
Static Lung Volumes (Percent)	56.10 Percent of RV over TLC Standard Error 0.54	57.18 Percent of RV over TLC Standard Error 0.54

SECONDARY outcome

Timeframe: 4 weeks

Population: FAS using imputed values

Trough RV/TLC (Residual Volume over Total Lung Capacity) after 4 weeks (measured by bodyphlethysmography)

Outcome measures

Measure	Tiotropium + Salmeterol n=309 Participants Tio 18mcg o.d. + Sal 50mcg b.i.d. in Period 1 or 2	Fluticasone + Salmeterol n=307 Participants Flu+Sal 500+50mcg b.i.d. in Period 1 or 2
Static Lung Volumes (Percent)	56.57 Percent of RV over TLC Standard Error 0.56	57.47 Percent of RV over TLC Standard Error 0.56

SECONDARY outcome

Timeframe: 8 weeks

Population: FAS using imputed values

Post-dose RV/TLC (Residual Volume over Total Lung Capacity) after 8 weeks (measured by bodyphlethysmography)

Outcome measures

Measure	Tiotropium + Salmeterol n=309 Participants Tio 18mcg o.d. + Sal 50mcg b.i.d. in Period 1 or 2	Fluticasone + Salmeterol n=309 Participants Flu+Sal 500+50mcg b.i.d. in Period 1 or 2
Static Lung Volumes (Percent)	52.79 Percent of RV over TLC Standard Error 0.54	55.02 Percent of RV over TLC Standard Error 0.54

SECONDARY outcome

Timeframe: 4 weeks

Population: FAS using imputed values

Post-dose RV/TLC (Residual Volume over Total Lung Capacity) after 4 weeks (measured by bodyphlethysmography)

Outcome measures

Measure	Tiotropium + Salmeterol n=309 Participants Tio 18mcg o.d. + Sal 50mcg b.i.d. in Period 1 or 2	Fluticasone + Salmeterol n=307 Participants Flu+Sal 500+50mcg b.i.d. in Period 1 or 2
Static Lung Volumes (Percent)	53.09 Percent of RV over TLC Standard Error 0.57	55.07 Percent of RV over TLC Standard Error 0.57

SECONDARY outcome

Timeframe: 8 weeks

Population: FAS using imputed values

Trough TGV/TLC (Thoracic Gas Volume over Total Lung Capacity) after 8 weeks (measured by bodyphlethysmography)

Outcome measures

Measure	Tiotropium + Salmeterol n=309 Participants Tio 18mcg o.d. + Sal 50mcg b.i.d. in Period 1 or 2	Fluticasone + Salmeterol n=309 Participants Flu+Sal 500+50mcg b.i.d. in Period 1 or 2
Static Lung Volumes (Percent)	69.87 Percent of TGV over TLC Standard Error 0.47	70.94 Percent of TGV over TLC Standard Error 0.47

SECONDARY outcome

Timeframe: 4 weeks

Population: FAS using imputed values

Trough TGV/TLC (Thoracic Gas Volume over Total Lung Capacity) after 4 weeks (measured by bodyphlethysmography)

Outcome measures

Measure	Tiotropium + Salmeterol n=309 Participants Tio 18mcg o.d. + Sal 50mcg b.i.d. in Period 1 or 2	Fluticasone + Salmeterol n=307 Participants Flu+Sal 500+50mcg b.i.d. in Period 1 or 2
Static Lung Volumes (Percent)	70.59 Percent of TGV over TLC Standard Error 0.47	70.99 Percent of TGV over TLC Standard Error 0.47

SECONDARY outcome

Timeframe: 8 weeks

Population: FAS using imputed values

Post-dose TGV/TLC (Thoracic Gas Volume over Total Lung Capacity) after 8 weeks (measured by bodyphlethysmography)

Outcome measures

Measure	Tiotropium + Salmeterol n=309 Participants Tio 18mcg o.d. + Sal 50mcg b.i.d. in Period 1 or 2	Fluticasone + Salmeterol n=309 Participants Flu+Sal 500+50mcg b.i.d. in Period 1 or 2
Static Lung Volumes (Percent)	67.65 Percent of TGV over TLC Standard Error 0.49	68.85 Percent of TGV over TLC Standard Error 0.49

SECONDARY outcome

Timeframe: 4 weeks

Population: FAS using imputed values

Post-dose TGV/TLC (Thoracic Gas Volume over Total Lung Capacity) after 4 weeks (measured by bodyphlethysmography)

Outcome measures

Measure	Tiotropium + Salmeterol n=309 Participants Tio 18mcg o.d. + Sal 50mcg b.i.d. in Period 1 or 2	Fluticasone + Salmeterol n=307 Participants Flu+Sal 500+50mcg b.i.d. in Period 1 or 2
Static Lung Volumes (Percent)	68.43 Percent of TGV over TLC Standard Error 0.49	69.22 Percent of TGV over TLC Standard Error 0.49

SECONDARY outcome

Timeframe: 8 weeks

Population: FAS using imputed values

Trough SVC (Slow Vital Capacity) after 8 weeks (measured by spirometry)

Outcome measures

Measure	Tiotropium + Salmeterol n=306 Participants Tio 18mcg o.d. + Sal 50mcg b.i.d. in Period 1 or 2	Fluticasone + Salmeterol n=304 Participants Flu+Sal 500+50mcg b.i.d. in Period 1 or 2
Slow Vital Capacity (SVC)	3.22 Litres Standard Error 0.05	3.12 Litres Standard Error 0.05

SECONDARY outcome

Timeframe: 4 weeks

Population: FAS using imputed values

Trough SVC (Slow Vital Capacity) after 4 weeks (measured by spirometry)

Outcome measures

Measure	Tiotropium + Salmeterol n=305 Participants Tio 18mcg o.d. + Sal 50mcg b.i.d. in Period 1 or 2	Fluticasone + Salmeterol n=301 Participants Flu+Sal 500+50mcg b.i.d. in Period 1 or 2
Slow Vital Capacity (SVC)	3.19 Litres Standard Error 0.05	3.12 Litres Standard Error 0.05

SECONDARY outcome

Timeframe: 8 weeks

Population: FAS using imputed values

Post-dose SVC (Slow Vital Capacity) after 8 weeks (measured by spirometry)

Outcome measures

Measure	Tiotropium + Salmeterol n=306 Participants Tio 18mcg o.d. + Sal 50mcg b.i.d. in Period 1 or 2	Fluticasone + Salmeterol n=304 Participants Flu+Sal 500+50mcg b.i.d. in Period 1 or 2
Slow Vital Capacity (SVC)	3.42 Litres Standard Error 0.05	3.28 Litres Standard Error 0.05

SECONDARY outcome

Timeframe: 4 weeks

Population: FAS using imputed values

Post-dose SVC (Slow Vital Capacity) after 4 weeks (measured by spirometry)

Outcome measures

Measure	Tiotropium + Salmeterol n=305 Participants Tio 18mcg o.d. + Sal 50mcg b.i.d. in Period 1 or 2	Fluticasone + Salmeterol n=301 Participants Flu+Sal 500+50mcg b.i.d. in Period 1 or 2
Slow Vital Capacity (SVC)	3.39 Litres Standard Error 0.05	3.27 Litres Standard Error 0.05

SECONDARY outcome

Timeframe: 8 weeks

Population: FAS using imputed values

Trough FEV1 (Forced Expiratory Volume in 1 second) after 8 weeks (measured by spirometry)

Outcome measures

Measure	Tiotropium + Salmeterol n=309 Participants Tio 18mcg o.d. + Sal 50mcg b.i.d. in Period 1 or 2	Fluticasone + Salmeterol n=309 Participants Flu+Sal 500+50mcg b.i.d. in Period 1 or 2
Forced Expiratory Volume in 1 Second (FEV1)	1.48 Litres Standard Error 0.03	1.44 Litres Standard Error 0.03

SECONDARY outcome

Timeframe: 4 weeks

Population: FAS using imputed values

Trough FEV1 (Forced Expiratory Volume in 1 second) after 4 weeks (measured by spirometry)

Outcome measures

Measure	Tiotropium + Salmeterol n=309 Participants Tio 18mcg o.d. + Sal 50mcg b.i.d. in Period 1 or 2	Fluticasone + Salmeterol n=308 Participants Flu+Sal 500+50mcg b.i.d. in Period 1 or 2
Forced Expiratory Volume in 1 Second (FEV1)	1.48 Litres Standard Error 0.03	1.45 Litres Standard Error 0.03

SECONDARY outcome

Timeframe: 8 weeks

Population: FAS using imputed values

Post-dose FEV1 (Forced Expiratory Volume in 1 second) after 8 weeks (measured by spirometry)

Outcome measures

Measure	Tiotropium + Salmeterol n=309 Participants Tio 18mcg o.d. + Sal 50mcg b.i.d. in Period 1 or 2	Fluticasone + Salmeterol n=309 Participants Flu+Sal 500+50mcg b.i.d. in Period 1 or 2
Forced Expiratory Volume in 1 Second (FEV1)	1.62 Litres Standard Error 0.03	1.55 Litres Standard Error 0.03

SECONDARY outcome

Timeframe: 4 weeks

Population: FAS using imputed values

Post-dose FEV1 (Forced Expiratory Volume in 1 second) after 4 weeks (measured by spirometry)

Outcome measures

Measure	Tiotropium + Salmeterol n=309 Participants Tio 18mcg o.d. + Sal 50mcg b.i.d. in Period 1 or 2	Fluticasone + Salmeterol n=308 Participants Flu+Sal 500+50mcg b.i.d. in Period 1 or 2
Forced Expiratory Volume in 1 Second (FEV1)	1.62 Litres Standard Error 0.03	1.55 Litres Standard Error 0.03

SECONDARY outcome

Timeframe: 8 weeks

Population: FAS using imputed values

Trough percent predicted FEV1 (Forced Expiratory Volume in 1 second) according to ECCS after 8 weeks (measured by spirometry)

Outcome measures

Measure	Tiotropium + Salmeterol n=309 Participants Tio 18mcg o.d. + Sal 50mcg b.i.d. in Period 1 or 2	Fluticasone + Salmeterol n=309 Participants Flu+Sal 500+50mcg b.i.d. in Period 1 or 2
Forced Expiratory Volume in 1 Second (FEV1)	50.27 Percent of predicted FEV1 Standard Error 0.78	49.12 Percent of predicted FEV1 Standard Error 0.78

SECONDARY outcome

Timeframe: 4 weeks

Population: FAS using imputed values

Trough percent predicted FEV1 (Forced Expiratory Volume in 1 second) according to ECCS after 4 weeks (measured by spirometry)

Outcome measures

Measure	Tiotropium + Salmeterol n=309 Participants Tio 18mcg o.d. + Sal 50mcg b.i.d. in Period 1 or 2	Fluticasone + Salmeterol n=308 Participants Flu+Sal 500+50mcg b.i.d. in Period 1 or 2
Forced Expiratory Volume in 1 Second (FEV1)	50.40 Percent of predicted FEV1 Standard Error 0.79	49.26 Percent of predicted FEV1 Standard Error 0.79

SECONDARY outcome

Timeframe: 8 weeks

Population: FAS using imputed values

Post-dose percent predicted FEV1 (Forced Expiratory Volume in 1 second) according to ECCS after 8 weeks (measured by spirometry)

Outcome measures

Measure	Tiotropium + Salmeterol n=309 Participants Tio 18mcg o.d. + Sal 50mcg b.i.d. in Period 1 or 2	Fluticasone + Salmeterol n=309 Participants Flu+Sal 500+50mcg b.i.d. in Period 1 or 2
Forced Expiratory Volume in 1 Second (FEV1)	54.99 Percent of predicted FEV1 Standard Error 0.82	52.59 Percent of predicted FEV1 Standard Error 0.82

SECONDARY outcome

Timeframe: 4 weeks

Population: FAS using imputed values

Post-dose percent predicted FEV1 (Forced Expiratory Volume in 1 second) according to ECCS after 4 weeks (measured by spirometry)

Outcome measures

Measure	Tiotropium + Salmeterol n=309 Participants Tio 18mcg o.d. + Sal 50mcg b.i.d. in Period 1 or 2	Fluticasone + Salmeterol n=308 Participants Flu+Sal 500+50mcg b.i.d. in Period 1 or 2
Forced Expiratory Volume in 1 Second (FEV1)	54.96 Percent of predicted FEV1 Standard Error 0.82	52.64 Percent of predicted FEV1 Standard Error 0.82

SECONDARY outcome

Timeframe: 8 weeks

Population: FAS using imputed values

Trough FVC (Forced Vital Capacity) after 8 weeks (measured by spirometry)

Outcome measures

Measure	Tiotropium + Salmeterol n=309 Participants Tio 18mcg o.d. + Sal 50mcg b.i.d. in Period 1 or 2	Fluticasone + Salmeterol n=309 Participants Flu+Sal 500+50mcg b.i.d. in Period 1 or 2
Forced Vital Capacity (FVC)	3.06 Litres Standard Error 0.05	2.94 Litres Standard Error 0.05

SECONDARY outcome

Timeframe: 4 weeks

Population: FAS using imputed values

Trough FVC (Forced Vital Capacity) after 4 weeks (measured by spirometry)

Outcome measures

Measure	Tiotropium + Salmeterol n=309 Participants Tio 18mcg o.d. + Sal 50mcg b.i.d. in Period 1 or 2	Fluticasone + Salmeterol n=308 Participants Flu+Sal 500+50mcg b.i.d. in Period 1 or 2
Forced Vital Capacity (FVC)	3.04 Litres Standard Error 0.05	2.93 Litres Standard Error 0.05

SECONDARY outcome

Timeframe: 8 weeks

Population: FAS using imputed values

Post-dose FVC (Forced Vital Capacity) after 8 weeks (measured by spirometry)

Outcome measures

Measure	Tiotropium + Salmeterol n=309 Participants Tio 18mcg o.d. + Sal 50mcg b.i.d. in Period 1 or 2	Fluticasone + Salmeterol n=309 Participants Flu+Sal 500+50mcg b.i.d. in Period 1 or 2
Forced Vital Capacity (FVC)	3.26 Litres Standard Error 0.05	3.11 Litres Standard Error 0.05

SECONDARY outcome

Timeframe: 4 weeks

Population: FAS using imputed values

Post-dose FVC (Forced Vital Capacity) after 4 weeks (measured by spirometry)

Outcome measures

Measure	Tiotropium + Salmeterol n=309 Participants Tio 18mcg o.d. + Sal 50mcg b.i.d. in Period 1 or 2	Fluticasone + Salmeterol n=308 Participants Flu+Sal 500+50mcg b.i.d. in Period 1 or 2
Forced Vital Capacity (FVC)	3.25 Litres Standard Error 0.05	3.11 Litres Standard Error 0.05

SECONDARY outcome

Timeframe: 8 weeks

Population: FAS using imputed values

Trough FEV1 (Forced Expiratory Volume in 1 second) over FVC (Forced Vital Capacity) after 8 weeks (measured by spirometry)

Outcome measures

Measure	Tiotropium + Salmeterol n=309 Participants Tio 18mcg o.d. + Sal 50mcg b.i.d. in Period 1 or 2	Fluticasone + Salmeterol n=309 Participants Flu+Sal 500+50mcg b.i.d. in Period 1 or 2
FEV1 Over FVC (Percent)	49.16 Percent of FEV1 over FVC Standard Error 0.68	49.67 Percent of FEV1 over FVC Standard Error 0.68

SECONDARY outcome

Timeframe: 4 weeks

Population: FAS using imputed values

Trough FEV1 (Forced Expiratory Volume in 1 second) over FVC (Forced Vital Capacity) after 4 weeks (measured by spirometry)

Outcome measures

Measure	Tiotropium + Salmeterol n=309 Participants Tio 18mcg o.d. + Sal 50mcg b.i.d. in Period 1 or 2	Fluticasone + Salmeterol n=308 Participants Flu+Sal 500+50mcg b.i.d. in Period 1 or 2
FEV1 Over FVC (Percent)	49.74 Percent of FEV1 over FVC Standard Error 0.82	50.62 Percent of FEV1 over FVC Standard Error 0.82

SECONDARY outcome

Timeframe: 8 weeks

Population: FAS using imputed values

Post-dose FEV1 (Forced Expiratory Volume in 1 second) over FVC (Forced Vital Capacity) after 8 weeks (measured by spirometry)

Outcome measures

Measure	Tiotropium + Salmeterol n=309 Participants Tio 18mcg o.d. + Sal 50mcg b.i.d. in Period 1 or 2	Fluticasone + Salmeterol n=309 Participants Flu+Sal 500+50mcg b.i.d. in Period 1 or 2
FEV1 Over FVC (Percent)	50.77 Percent of FEV1 over FVC Standard Error 0.72	50.66 Percent of FEV1 over FVC Standard Error 0.72

SECONDARY outcome

Timeframe: 4 weeks

Population: FAS using imputed values

Post-dose FEV1 (Forced Expiratory Volume in 1 second) over FVC (Forced Vital Capacity) after 4 weeks (measured by spirometry)

Outcome measures

Measure	Tiotropium + Salmeterol n=309 Participants Tio 18mcg o.d. + Sal 50mcg b.i.d. in Period 1 or 2	Fluticasone + Salmeterol n=308 Participants Flu+Sal 500+50mcg b.i.d. in Period 1 or 2
FEV1 Over FVC (Percent)	50.90 Percent of FEV1 over FVC Standard Error 0.73	50.91 Percent of FEV1 over FVC Standard Error 0.73

SECONDARY outcome

Timeframe: 8 weeks

Population: FAS using imputed values

Isotime Borg dyspnea scale after 8 weeks, Unit on a Scale (min. 0, max 10), 0 = no dyspnea, 10 = worst imaginable dyspnea

Outcome measures

Measure	Tiotropium + Salmeterol n=309 Participants Tio 18mcg o.d. + Sal 50mcg b.i.d. in Period 1 or 2	Fluticasone + Salmeterol n=309 Participants Flu+Sal 500+50mcg b.i.d. in Period 1 or 2
Symptom Intensity During Exercise	4.77 Unit on a Scale Standard Error 0.13	4.98 Unit on a Scale Standard Error 0.13

SECONDARY outcome

Timeframe: 4 weeks

Population: FAS using imputed values

Isotime Borg dyspnea scale after 4 weeks, Unit on a Scale (min. 0, max. 10), 0 = no dyspnea, 10 = worst imaginable dyspnea

Outcome measures

Measure	Tiotropium + Salmeterol n=309 Participants Tio 18mcg o.d. + Sal 50mcg b.i.d. in Period 1 or 2	Fluticasone + Salmeterol n=309 Participants Flu+Sal 500+50mcg b.i.d. in Period 1 or 2
Symptom Intensity During Exercise	4.80 Unit on a Scale Standard Error 0.13	5.02 Unit on a Scale Standard Error 0.13

SECONDARY outcome

Timeframe: 8 weeks

Population: FAS using imputed values

Isotime Borg leg discomfort scale after 8 weeks, Unit on a Scale (min. 0, max. 10), 0 = no leg dyscomfort, 10 = worst imaginable leg dyscomfort

Outcome measures

Measure	Tiotropium + Salmeterol n=309 Participants Tio 18mcg o.d. + Sal 50mcg b.i.d. in Period 1 or 2	Fluticasone + Salmeterol n=309 Participants Flu+Sal 500+50mcg b.i.d. in Period 1 or 2
Symptom Intensity During Exercise	4.64 Unit on a Scale Standard Error 0.15	4.53 Unit on a Scale Standard Error 0.15

SECONDARY outcome

Timeframe: 4 weeks

Population: FAS using imputed values

Isotime Borg leg discomfort scale after 4 weeks, Unit on a Scale (min. 0, max. 10), 0 = no leg dyscomfort, 10 = worst imaginable leg dyscomfort

Outcome measures

Measure	Tiotropium + Salmeterol n=309 Participants Tio 18mcg o.d. + Sal 50mcg b.i.d. in Period 1 or 2	Fluticasone + Salmeterol n=309 Participants Flu+Sal 500+50mcg b.i.d. in Period 1 or 2
Symptom Intensity During Exercise	4.63 Unit on a Scale Standard Error 0.15	4.63 Unit on a Scale Standard Error 0.15

SECONDARY outcome

Timeframe: 8 weeks

Population: FAS using imputed values

Peak Borg dyspnea scale after 8 weeks, Unit on a Scale (min. 0, max 10)

Outcome measures

Measure	Tiotropium + Salmeterol n=309 Participants Tio 18mcg o.d. + Sal 50mcg b.i.d. in Period 1 or 2	Fluticasone + Salmeterol n=309 Participants Flu+Sal 500+50mcg b.i.d. in Period 1 or 2
Dyspnea and Leg Discomfort	6.52 Unit on a Scale Standard Deviation 2.36	6.61 Unit on a Scale Standard Deviation 2.31

SECONDARY outcome

Timeframe: 8 weeks

Population: FAS using imputed values

Peak Borg leg discomfort scale after 8 weeks, Unit on a Scale (min. 0, max 10)

Outcome measures

Measure	Tiotropium + Salmeterol n=309 Participants Tio 18mcg o.d. + Sal 50mcg b.i.d. in Period 1 or 2	Fluticasone + Salmeterol n=309 Participants Flu+Sal 500+50mcg b.i.d. in Period 1 or 2
Dyspnea and Leg Discomfort	6.10 Unit on a Scale Standard Deviation 3.03	5.86 Unit on a Scale Standard Deviation 3.01

SECONDARY outcome

Timeframe: baseline

Population: FAS using imputed values

Reason for stopping exercise at baseline (leg discomfort, breathing discomfort, both or none)

Outcome measures

Measure	Tiotropium + Salmeterol n=309 Participants Tio 18mcg o.d. + Sal 50mcg b.i.d. in Period 1 or 2	Fluticasone + Salmeterol n=309 Participants Flu+Sal 500+50mcg b.i.d. in Period 1 or 2
Locus of Symptom Limitation at Peak Exercise During Exercise Leg discomfort	53 Participants	53 Participants
Locus of Symptom Limitation at Peak Exercise During Exercise Breathing discomfort	132 Participants	132 Participants
Locus of Symptom Limitation at Peak Exercise During Exercise Both (leg and breathing discomfort)	92 Participants	92 Participants
Locus of Symptom Limitation at Peak Exercise During Exercise None	32 Participants	32 Participants

SECONDARY outcome

Timeframe: 4 weeks

Population: FAS using imputed values

Reason for stopping exercise after 4 weeks (leg discomfort, breathing discomfort, both or none)

Outcome measures

Measure	Tiotropium + Salmeterol n=309 Participants Tio 18mcg o.d. + Sal 50mcg b.i.d. in Period 1 or 2	Fluticasone + Salmeterol n=309 Participants Flu+Sal 500+50mcg b.i.d. in Period 1 or 2
Locus of Symptom Limitation at Peak Exercise During Exercise None	38 Participants	40 Participants
Locus of Symptom Limitation at Peak Exercise During Exercise Leg discomfort	89 Participants	72 Participants
Locus of Symptom Limitation at Peak Exercise During Exercise Breathing discomfort	104 Participants	119 Participants
Locus of Symptom Limitation at Peak Exercise During Exercise Both (leg and breathing discomfort)	78 Participants	78 Participants

SECONDARY outcome

Timeframe: 8 weeks

Population: FAS using imputed values

Reason for stopping exercise after 8 weeks (leg discomfort, breathing discomfort, both or none)

Outcome measures

Measure	Tiotropium + Salmeterol n=309 Participants Tio 18mcg o.d. + Sal 50mcg b.i.d. in Period 1 or 2	Fluticasone + Salmeterol n=309 Participants Flu+Sal 500+50mcg b.i.d. in Period 1 or 2
Locus of Symptom Limitation at Peak Exercise During Exercise Breathing discomfort	112 Participants	131 Participants
Locus of Symptom Limitation at Peak Exercise During Exercise Both (leg and breathing discomfort)	82 Participants	78 Participants
Locus of Symptom Limitation at Peak Exercise During Exercise None	27 Participants	28 Participants
Locus of Symptom Limitation at Peak Exercise During Exercise Leg discomfort	88 Participants	72 Participants

Adverse Events

Tiotropium + Salmeterol (Period 1)

Serious events: 7 serious events

Other events: 18 other events

Deaths: 0 deaths

Tiotropium + Salmeterol (Period 2)

Serious events: 5 serious events

Other events: 18 other events

Deaths: 0 deaths

Fluticasone + Salmeterol (Period 1)

Serious events: 4 serious events

Other events: 21 other events

Deaths: 0 deaths

Fluticasone + Salmeterol (Period 2)

Serious events: 4 serious events

Other events: 12 other events

Deaths: 0 deaths

Serious adverse events

Measure	Tiotropium + Salmeterol (Period 1) n=172 participants at risk Tio 18mcg o.d. + Sal 50mcg b.i.d. in Period 1	Tiotropium + Salmeterol (Period 2) n=160 participants at risk Tio 18mcg o.d. + Sal 50mcg b.i.d. in Period 2	Fluticasone + Salmeterol (Period 1) n=172 participants at risk Flu+Sal 500+50mcg b.i.d. in Period 1	Fluticasone + Salmeterol (Period 2) n=157 participants at risk Flu+Sal 500+50mcg b.i.d. in Period 2
Cardiac disorders Arrhythmia	0.00% 0/172 • From drug administration until end of second treatment period plus 30 days.	0.00% 0/160 • From drug administration until end of second treatment period plus 30 days.	0.58% 1/172 • From drug administration until end of second treatment period plus 30 days.	0.00% 0/157 • From drug administration until end of second treatment period plus 30 days.
Vascular disorders Arterial occlusive disease	0.58% 1/172 • From drug administration until end of second treatment period plus 30 days.	0.00% 0/160 • From drug administration until end of second treatment period plus 30 days.	0.00% 0/172 • From drug administration until end of second treatment period plus 30 days.	0.00% 0/157 • From drug administration until end of second treatment period plus 30 days.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Basal cell carcinoma	0.00% 0/172 • From drug administration until end of second treatment period plus 30 days.	0.00% 0/160 • From drug administration until end of second treatment period plus 30 days.	0.58% 1/172 • From drug administration until end of second treatment period plus 30 days.	0.00% 0/157 • From drug administration until end of second treatment period plus 30 days.
Cardiac disorders Bundle branch block right	0.00% 0/172 • From drug administration until end of second treatment period plus 30 days.	0.00% 0/160 • From drug administration until end of second treatment period plus 30 days.	0.58% 1/172 • From drug administration until end of second treatment period plus 30 days.	0.00% 0/157 • From drug administration until end of second treatment period plus 30 days.
Respiratory, thoracic and mediastinal disorders Chronic obstructive pulmonary disease	1.7% 3/172 • From drug administration until end of second treatment period plus 30 days.	1.9% 3/160 • From drug administration until end of second treatment period plus 30 days.	0.00% 0/172 • From drug administration until end of second treatment period plus 30 days.	1.3% 2/157 • From drug administration until end of second treatment period plus 30 days.
Cardiac disorders Extrasystoles	0.58% 1/172 • From drug administration until end of second treatment period plus 30 days.	0.00% 0/160 • From drug administration until end of second treatment period plus 30 days.	0.00% 0/172 • From drug administration until end of second treatment period plus 30 days.	0.00% 0/157 • From drug administration until end of second treatment period plus 30 days.
Injury, poisoning and procedural complications Fall	0.00% 0/172 • From drug administration until end of second treatment period plus 30 days.	0.00% 0/160 • From drug administration until end of second treatment period plus 30 days.	0.00% 0/172 • From drug administration until end of second treatment period plus 30 days.	0.64% 1/157 • From drug administration until end of second treatment period plus 30 days.
Injury, poisoning and procedural complications Femur fracture	0.00% 0/172 • From drug administration until end of second treatment period plus 30 days.	0.00% 0/160 • From drug administration until end of second treatment period plus 30 days.	0.00% 0/172 • From drug administration until end of second treatment period plus 30 days.	0.64% 1/157 • From drug administration until end of second treatment period plus 30 days.
Musculoskeletal and connective tissue disorders Foot deformity	0.00% 0/172 • From drug administration until end of second treatment period plus 30 days.	0.62% 1/160 • From drug administration until end of second treatment period plus 30 days.	0.00% 0/172 • From drug administration until end of second treatment period plus 30 days.	0.00% 0/157 • From drug administration until end of second treatment period plus 30 days.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Lung adenocarcinoma	0.00% 0/172 • From drug administration until end of second treatment period plus 30 days.	0.00% 0/160 • From drug administration until end of second treatment period plus 30 days.	0.58% 1/172 • From drug administration until end of second treatment period plus 30 days.	0.00% 0/157 • From drug administration until end of second treatment period plus 30 days.
Musculoskeletal and connective tissue disorders Musculeskeletal pain	0.58% 1/172 • From drug administration until end of second treatment period plus 30 days.	0.00% 0/160 • From drug administration until end of second treatment period plus 30 days.	0.00% 0/172 • From drug administration until end of second treatment period plus 30 days.	0.00% 0/157 • From drug administration until end of second treatment period plus 30 days.
Respiratory, thoracic and mediastinal disorders Sleep apnoea syndrome	0.00% 0/172 • From drug administration until end of second treatment period plus 30 days.	0.62% 1/160 • From drug administration until end of second treatment period plus 30 days.	0.00% 0/172 • From drug administration until end of second treatment period plus 30 days.	0.00% 0/157 • From drug administration until end of second treatment period plus 30 days.
Injury, poisoning and procedural complications Subdural haematoma	0.58% 1/172 • From drug administration until end of second treatment period plus 30 days.	0.00% 0/160 • From drug administration until end of second treatment period plus 30 days.	0.00% 0/172 • From drug administration until end of second treatment period plus 30 days.	0.00% 0/157 • From drug administration until end of second treatment period plus 30 days.
Cardiac disorders Tachycardia	0.00% 0/172 • From drug administration until end of second treatment period plus 30 days.	0.00% 0/160 • From drug administration until end of second treatment period plus 30 days.	0.58% 1/172 • From drug administration until end of second treatment period plus 30 days.	0.00% 0/157 • From drug administration until end of second treatment period plus 30 days.
Injury, poisoning and procedural complications Upper limb fracture	0.00% 0/172 • From drug administration until end of second treatment period plus 30 days.	0.00% 0/160 • From drug administration until end of second treatment period plus 30 days.	0.00% 0/172 • From drug administration until end of second treatment period plus 30 days.	0.64% 1/157 • From drug administration until end of second treatment period plus 30 days.

Other adverse events

Measure	Tiotropium + Salmeterol (Period 1) n=172 participants at risk Tio 18mcg o.d. + Sal 50mcg b.i.d. in Period 1	Tiotropium + Salmeterol (Period 2) n=160 participants at risk Tio 18mcg o.d. + Sal 50mcg b.i.d. in Period 2	Fluticasone + Salmeterol (Period 1) n=172 participants at risk Flu+Sal 500+50mcg b.i.d. in Period 1	Fluticasone + Salmeterol (Period 2) n=157 participants at risk Flu+Sal 500+50mcg b.i.d. in Period 2
Respiratory, thoracic and mediastinal disorders Chronic obstructive pulmonary disease	9.3% 16/172 • From drug administration until end of second treatment period plus 30 days.	6.9% 11/160 • From drug administration until end of second treatment period plus 30 days.	7.0% 12/172 • From drug administration until end of second treatment period plus 30 days.	4.5% 7/157 • From drug administration until end of second treatment period plus 30 days.
Infections and infestations Nasopharyngitis	1.7% 3/172 • From drug administration until end of second treatment period plus 30 days.	5.6% 9/160 • From drug administration until end of second treatment period plus 30 days.	5.2% 9/172 • From drug administration until end of second treatment period plus 30 days.	3.8% 6/157 • From drug administration until end of second treatment period plus 30 days.

Additional Information

Boehringer Ingelheim Call Center

Boehringer Ingelheim Pharmaceuticals

Phone: 1-800-243-0127

Email: clintriage.rdg@boehringer-ingelheim.com

Results disclosure agreements

• Principal investigator is a sponsor employee Any publication of the result of this trial must be consistent with the Boehringer Ingelheim publication policy. The rights of the investigator and of the sponsor with regard to publication of the results of this trial are described in the investigator contract.
• Publication restrictions are in place

Restriction type: OTHER