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Clinical Trial Results:
A randomised, double-blind, placebo-controlled, parallel-group trial to evaluate efficacy and safety of tiotropium inhalation solution (2.5 μg and 5 μg) delivered via Respimat® inhaler once daily in the evening over 48 weeks in children (6 to 11 years old) with moderate persistent asthma

Summary
EudraCT number	2011-001758-26
Trial protocol	LV LT PT DE BG SE HU GB
Global end of trial date	08 Dec 2015

Results information
Results version number	v1(current)
This version publication date	19 Jun 2016
First version publication date	19 Jun 2016
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

205.445

ISRCTN number

US NCT number

NCT01634139

WHO universal trial number (UTN)

Sponsor organisation name

Boehringer Ingelheim

Sponsor organisation address

173 Binger Strasse, Ingelheim am Rhein , Germany, 55216

Public contact

QRPE Processes and Systems Coordination Clinical Trial Information Disclosure, Boehringer Ingelheim, +1 8002430127, clintriage.rdg@boehringer-ingelheim.com

Scientific contact

QRPE Processes and Systems Coordination Clinical Trial Information Disclosure, Boehringer Ingelheim, +1 8002430127, clintriage.rdg@boehringer-ingelheim.com

Is trial part of an agreed paediatric investigation plan (PIP)

Yes

EMA paediatric investigation plan number(s)

EMEA-000035-PIP02-09

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Yes

Analysis stage

Final

Date of interim/final analysis

05 Jan 2016

Is this the analysis of the primary completion data?

Yes

Primary completion date

02 Jun 2015

Global end of trial reached?

Yes

Global end of trial date

08 Dec 2015

Was the trial ended prematurely?

Main objective of the trial

The overall purpose of the trial was to evaluate efficacy and safety of tiotropium inhalation solution delivered via Respimat® inhaler (2.5 μg and 5 μg once daily in the evening) over 48 weeks, compared to placebo, in children (6 to 11 years old) with moderate persistent asthma. The primary objective of the trial was to demonstrate superiority of tiotropium (5 μg and possibly 2.5 μg once daily in the evening) over placebo with regard to the primary pulmonary function endpoint after 24 weeks of treatment. Secondary objectives were to evaluate efficacy of tiotropium with regard to other efficacy endpoints after 24 and 48 week of treatment, and to evaluate the long-term safety of tiotropium of a 48 week treatment, compared to placebo, as add-on controller therapy on top of usual care in this patient population.

Protection of trial subjects

Only subjects that met all the study inclusion and none of the exclusion criteria were to be entered in the study. All subjects were free to withdraw from the clinical trial at any time for any reason given. Close monitoring of all subjects was adhered to throughout the trial conduct. Salbutamol (albuterol) was provided as rescue medication for use as necessary during the trial.

Background therapy

Evidence for comparator

Actual start date of recruitment

03 Aug 2012

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Bulgaria: 31

Country: Number of subjects enrolled

Canada: 5

Country: Number of subjects enrolled

Germany: 16

Country: Number of subjects enrolled

Guatemala: 81

Country: Number of subjects enrolled

Hungary: 52

Country: Number of subjects enrolled

Korea, Republic of: 27

Country: Number of subjects enrolled

Latvia: 94

Country: Number of subjects enrolled

Lithuania: 13

Country: Number of subjects enrolled

Norway: 5

Country: Number of subjects enrolled

Portugal: 24

Country: Number of subjects enrolled

Romania: 12

Country: Number of subjects enrolled

Russian Federation: 74

Country: Number of subjects enrolled

Sweden: 5

Country: Number of subjects enrolled

Ukraine: 123

Country: Number of subjects enrolled

United Kingdom: 6

Country: Number of subjects enrolled

United States: 47

Worldwide total number of subjects

615

EEA total number of subjects

258

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

614

Adolescents (12-17 years)

Adults (18-64 years)

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Screening details

All subjects were screened for eligibility to participate in the trial. Subjects attended specialist sites which would then ensure that they (the subjects) met all strictly implemented inclusion/exclusion criteria. Subjects were not to be randomised to trial treatment if any one of the specific entry criteria were violated.

Period 1 title

Treatment period (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Carer

Are arms mutually exclusive

Yes

Placebo Respimat

Arm description

Inhalation of placebo solution (2 puffs) once daily for 48 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care. One patient was randomised to the Placebo arm, however this patient was not treated. Consequently, number of subject that started is 132 but only 131 reported to ensure consistent reporting with baseline characteristics that includes only treated patients.

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Inhalation solution

Routes of administration

Inhalation use

Dosage and administration details

2 actuations once daily in the evening. Dose not applicable.

Tio R2.5

Arm description

Inhalation of 2.5mcg tiotropium (Tio R2.5) solution (2 puffs of 1.25mcg) once daily for 48 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care. One patient was randomised to the Tio R2.5 arm, however this patient was not treated. Consequently, number of subject that started is 136 but only 135 reported to ensure consistent reporting with baseline characteristics that includes only treated patients.

Arm type

Experimental

Investigational medicinal product name

Tiotropium

Investigational medicinal product code

Other name

Pharmaceutical forms

Inhalation solution

Routes of administration

Inhalation use

Dosage and administration details

2 actuations once daily in the evening, for a total dose of 2.5 mcg.

Tio R5

Arm description

Inhalation of 5mcg tiotropium (Tio R5) solution (2 puffs of 2.5mcg) once daily for 48 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.

Arm type

Experimental

Investigational medicinal product name

Tiotropium

Investigational medicinal product code

Other name

Pharmaceutical forms

Inhalation solution

Routes of administration

Inhalation use

Dosage and administration details

2 actuations once daily in the evening, for a total dose of 5 mcg.

Number of subjects in period 1 ^[1]	Placebo Respimat	Tio R2.5	Tio R5
Started	131	135	135
Completed	122	130	130
Not completed	9	5	5
Other reason not defined above	4	-	3
Non compliant with protocol	1	-	-
Lost to follow-up	-	2	-
Consent withdrawn not due to AE	4	3	2

Notes
[1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
Justification: Baseline characteristics are based on patients who were randomised after successfully completing the screening period and received at least one dose of the trial medication.

Baseline characteristics

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Reporting group title

Placebo Respimat

Reporting group description

Reporting group title

Tio R2.5

Reporting group description

Reporting group title

Tio R5

Reporting group description

Inhalation of 5mcg tiotropium (Tio R5) solution (2 puffs of 2.5mcg) once daily for 48 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.

Reporting group values	Placebo Respimat	Tio R2.5	Tio R5	Total
Number of subjects	131	135	135	401
Age categorical
Units: Subjects
Age Continuous
Treated set (TS) which included all randomised patients who were dispensed study medication and were documented to have taken at least 1 dose of investigational treatment.
Units: Years
arithmetic mean (standard deviation)	9 ( 1.6 )	9 ( 1.6 )	8.9 ( 1.7 )	-
Gender, Male/Female
Units: Participants
Female	46	38	53	137
Male	85	97	82	264

End points

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Reporting group title

Placebo Respimat

Reporting group description

Reporting group title

Tio R2.5

Reporting group description

Reporting group title

Tio R5

Reporting group description

Inhalation of 5mcg tiotropium (Tio R5) solution (2 puffs of 2.5mcg) once daily for 48 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.

Primary: FEV1 Peak (0-3h) Change From Baseline

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End point title

FEV1 Peak (0-3h) Change From Baseline

End point description

Change from baseline in peak forced expiratory volume (FEV) in 1 second within the first 3 hours (h) post dosing (FEV1 peak(0-3h)) measured at week 24. Measured values presented are actually adjusted means. The number of participants analysed displays the number of participants with available data at the timepoint of interest. Full Analysis Set (FAS) was equal to treated set which included all randomised patients who received at least 1 documented dose of study medication. Missing data at a visit was imputed by available data from the patient at that visit. Completely missing data were handled by the statistical model.

End point type

Primary

End point timeframe

Baseline and 24 Weeks

End point values	Placebo Respimat	Tio R2.5	Tio R5
Number of subjects analysed	126 ^[1]	131 ^[2]	134 ^[3]
Units: Litres (L)
arithmetic mean (standard error)	0.225 ( 0.027 )	0.395 ( 0.026 )	0.389 ( 0.026 )

Notes
[1] - FAS including patients with available endpoint data at week 24
[2] - FAS including patients with available endpoint data at week 24
[3] - FAS including patients with available endpoint data at week 24

Statistical Analysis 1

Statistical analysis description

Repeated measures restricted maximum likelihood model was used. The model included the fixed, categorical effects of treatment, country, visit and treatment-by-visit interaction, as well the continuous fixed covariates of baseline and baseline-by-visit interaction. Patient was included as random effect. Difference calculated as Tio R2.5 minus placebo.

Comparison groups

Placebo Respimat v Tio R2.5

Number of subjects included in analysis

257

Analysis specification

Pre-specified

Analysis type

superiority ^[4]

P-value

< 0.0001 ^[5]

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

0.17

Confidence interval

level

95%

sides

2-sided

lower limit

0.108

upper limit

0.231

Variability estimate

Standard error of the mean

Dispersion value

0.031

Notes
[4] - Stepwise testing of the null hypothesis was used to test the efficacy of Tio R5 and then Tio R2.5, each over placebo. The analysis was performed in a stepwise manner, firstly for this endpoint, then Trough FEV1. Each step was only considered confirmatory if all previous steps were successful.
[5] - The actual number of subjects analyzed is 266, the automatically calculated number that is provided in the statistical analysis (257) reflects only patients with value at week 24, rather than all patients that were included in the analysis.

Statistical Analysis 2

Statistical analysis description

Comparison groups

Placebo Respimat v Tio R5

Number of subjects included in analysis

260

Analysis specification

Pre-specified

Analysis type

superiority ^[6]

P-value

< 0.0001 ^[7]

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

0.164

Confidence interval

level

95%

sides

2-sided

lower limit

0.103

upper limit

0.255

Variability estimate

Standard error of the mean

Dispersion value

0.031

Notes
[6] - Stepwise testing of the null hypothesis was used to test the efficacy of Tio R5 and then Tio R2.5, each over placebo. The analysis was performed in a stepwise manner, firstly for this endpoint, then Trough FEV1. Each step was only considered confirmatory if all previous steps were successful.
[7] - The actual number of subjects analyzed is 266, the automatically calculated number that is provided in the statistical analysis (260) reflects only patients with value at week 24, rather than all patients that were included in the analysis.

Secondary: Trough FEV1 Change From Baseline

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End point title

Trough FEV1 Change From Baseline

End point description

Change from Baseline in Trough (pre-dose) Forced Expiratory Volume (FEV) in 1 second (FEV1) measured at week 24 and 48. Measured values presented are actually adjusted means. The number of participants analysed displays the number of participants included in the statistical model whereas the N’s for each timepoint display the number of participants with available data at that timepoint. Missing data at a visit was imputed by the available data from the patient at that visit. Completely missing data were handled by the statistical model.

End point type

Secondary

End point timeframe

Baseline and Week 24, Baseline and Week 48

End point values	Placebo Respimat	Tio R2.5	Tio R5
Number of subjects analysed	131 ^[8]	135 ^[9]	135 ^[10]
Units: Litres (L)
arithmetic mean (standard error)
Week 24 (N=126, 131, 134)	0.156 ( 0.031 )	0.272 ( 0.03 )	0.274 ( 0.03 )
Week 48 (N=124, 130, 130)	0.266 ( 0.032 )	0.337 ( 0.03 )	0.365 ( 0.031 )

Notes
[8] - FAS
[9] - FAS
[10] - FAS

Statistical Analysis 1

Statistical analysis description

Comparison groups

Placebo Respimat v Tio R2.5

Number of subjects included in analysis

266

Analysis specification

Pre-specified

Analysis type

superiority ^[11]

P-value

= 0.0012

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

0.116

Confidence interval

level

95%

sides

2-sided

lower limit

0.046

upper limit

0.186

Variability estimate

Standard error of the mean

Dispersion value

0.036

Notes
[11] - Stepwise testing of the null hypothesis was used to test the efficacy of Tio R5 and then Tio R2.5, each over placebo. The analysis for this endpoint was performed in a stepwise manner after the analysis of the primary endpoint was performed. Each step was only considered confirmatory if all previous steps were successful.

Statistical Analysis 2

Statistical analysis description

Comparison groups

Placebo Respimat v Tio R5

Number of subjects included in analysis

266

Analysis specification

Pre-specified

Analysis type

superiority ^[12]

P-value

= 0.001

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

0.118

Confidence interval

level

95%

sides

2-sided

lower limit

0.048

upper limit

0.188

Variability estimate

Standard error of the mean

Dispersion value

0.036

Notes
[12] - Stepwise testing of the null hypothesis was used to test the efficacy of Tio R5 and then Tio R2.5, each over placebo. The analysis for this endpoint was performed in a stepwise manner after the analysis of the primary endpoint was performed. Each step was only considered confirmatory if all previous steps were successful.

Statistical Analysis 3

Statistical analysis description

Comparison groups

Placebo Respimat v Tio R2.5

Number of subjects included in analysis

266

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0477

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

0.071

Confidence interval

level

95%

sides

2-sided

lower limit

0.001

upper limit

0.142

Variability estimate

Standard error of the mean

Dispersion value

0.036

Statistical Analysis 4

Statistical analysis description

Comparison groups

Placebo Respimat v Tio R5

Number of subjects included in analysis

266

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0059

Method

Mixed models analysis

Parameter type

Median difference (net)

Point estimate

0.099

Confidence interval

level

95%

sides

2-sided

lower limit

0.029

upper limit

0.17

Variability estimate

Standard error of the mean

Dispersion value

0.036

Secondary: FEV1 Peak (0-3h) at Week 48 Change From Baseline

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End point title

FEV1 Peak (0-3h) at Week 48 Change From Baseline

End point description

Change from baseline in peak forced expiratory volume (FEV) in 1 second within the first 3 hours (h) post dosing (FEV1 peak(0-3h)) measured at week 48. Measured values presented are actually adjusted means. Missing data at a visit was imputed by the available data from the patient at that visit. Completely missing data were handled by the statistical model.

End point type

Secondary

End point timeframe

Baseline and 48 Weeks

End point values	Placebo Respimat	Tio R2.5	Tio R5
Number of subjects analysed	124 ^[13]	130 ^[14]	130 ^[15]
Units: Litres (L)
arithmetic mean (standard error)	0.351 ( 0.027 )	0.474 ( 0.026 )	0.477 ( 0.026 )

Notes
[13] - FAS including patients with available endpoint data at week 48
[14] - FAS including patients with available endpoint data at week 48
[15] - FAS including patients with available endpoint data at week 48

Statistical Analysis 1

Statistical analysis description

Comparison groups

Placebo Respimat v Tio R2.5

Number of subjects included in analysis

254

Analysis specification

Pre-specified

Analysis type

other ^[16]

P-value

< 0.0001 ^[17]

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

0.124

Confidence interval

level

95%

sides

2-sided

lower limit

0.062

upper limit

0.185

Variability estimate

Standard error of the mean

Dispersion value

0.031

Notes
[16] - All treatment comparisons were exploratory, no formal hypothesis testing was performed.
[17] - The actual number of subjects analyzed is 266, the automatically calculated number that is provided in the statistical analysis (254) reflects only patients with value at week 48, rather than all patients that were included in the analysis.

Statistical Analysis 2

Statistical analysis description

Comparison groups

Placebo Respimat v Tio R5

Number of subjects included in analysis

254

Analysis specification

Pre-specified

Analysis type

other ^[18]

P-value

< 0.0001 ^[19]

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

0.127

Confidence interval

level

95%

sides

2-sided

lower limit

0.065

upper limit

0.188

Variability estimate

Standard error of the mean

Dispersion value

0.031

Notes
[18] - All treatment comparisons were exploratory, no formal hypothesis testing was performed.
[19] - The actual number of subjects analyzed is 266, the automatically calculated number that is provided in the statistical analysis (254) reflects only patients with value at week 48, rather than all patients that were included in the analysis.

Secondary: FEV1 AUC (0-3h) Change From Baseline

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End point title

FEV1 AUC (0-3h) Change From Baseline

End point description

Change from baseline of area under the curve (AUC) from 0 to 3 hours for FEV1 (FEV1 AUC (0-3h)) after 24 weeks of treatment. The AUC was calculated by using the trapezoidal rule divided by the observation time (3h). Measured values presented are actually adjusted means. Missing data at a visit was imputed by the available data from the patient at that visit. Completely missing data were handled by the statistical model.

End point type

Secondary

End point timeframe

Baseline and 10 mins before drug administration and 30 mins, 1 hour (h), 2h, 3h after drug administration at week 24.

End point values	Placebo Respimat	Tio R2.5	Tio R5
Number of subjects analysed	126 ^[20]	131 ^[21]	134 ^[22]
Units: Litres (L)
arithmetic mean (standard error)	0.152 ( 0.026 )	0.306 ( 0.025 )	0.309 ( 0.025 )

Notes
[20] - FAS including patients with available endpoint data at week 24
[21] - FAS including patients with available endpoint data at week 24
[22] - FAS including patients with available endpoint data at week 24

Statistical Analysis 1

Statistical analysis description

Comparison groups

Placebo Respimat v Tio R2.5

Number of subjects included in analysis

257

Analysis specification

Pre-specified

Analysis type

other ^[23]

P-value

< 0.0001 ^[24]

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

0.154

Confidence interval

level

95%

sides

2-sided

lower limit

0.095

upper limit

0.212

Variability estimate

Standard error of the mean

Dispersion value

0.03

Notes
[23] - All treatment comparisons were exploratory, no formal hypothesis testing was performed.
[24] - The actual number of subjects analyzed is 266, the automatically calculated number that is provided in the statistical analysis (257) reflects only patients with value at week 24, rather than all patients that were included in the analysis.

Statistical Analysis 2

Statistical analysis description

Comparison groups

Placebo Respimat v Tio R5

Number of subjects included in analysis

260

Analysis specification

Pre-specified

Analysis type

other ^[25]

P-value

< 0.0001 ^[26]

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

0.157

Confidence interval

level

95%

sides

2-sided

lower limit

0.098

upper limit

0.215

Variability estimate

Standard error of the mean

Dispersion value

0.03

Notes
[25] - All treatment comparisons were exploratory, no formal hypothesis testing was performed.
[26] - The actual number of subjects analyzed is 266, the automatically calculated number that is provided in the statistical analysis (260) reflects only patients with value at week 24, rather than all patients that were included in the analysis.

Secondary: FVC AUC (0-3h) Change From Baseline

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End point title

FVC AUC (0-3h) Change From Baseline

End point description

Change from baseline of area under the curve (AUC) from 0 to 3 hours for FVC (Forced vital capacity) (FVC AUC (0-3h)) after 24 weeks of treatment. The AUC was calculated by using the trapezoidal rule divided by the observation time (3h). Measured values presented are actually adjusted means. Missing data at a visit was imputed by the available data from the patient at that visit. Completely missing data were handled by the statistical model.

End point type

Secondary

End point timeframe

Baseline and 10 mins before drug administration and 30 mins, 1 hour (h), 2h, 3h after drug administration at 24 weeks

End point values	Placebo Respimat	Tio R2.5	Tio R5
Number of subjects analysed	126 ^[27]	131 ^[28]	134 ^[29]
Units: Litres (L)
arithmetic mean (standard error)	0.13 ( 0.03 )	0.235 ( 0.029 )	0.207 ( 0.029 )

Notes
[27] - FAS including patients with available endpoint data at week 24
[28] - FAS including patients with available endpoint data at week 24
[29] - FAS including patients with available endpoint data at week 24

Statistical Analysis 1

Statistical analysis description

Comparison groups

Placebo Respimat v Tio R2.5

Number of subjects included in analysis

257

Analysis specification

Pre-specified

Analysis type

other ^[30]

P-value

= 0.0023 ^[31]

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

0.105

Confidence interval

level

95%

sides

2-sided

lower limit

0.037

upper limit

0.172

Variability estimate

Standard error of the mean

Dispersion value

0.034

Notes
[30] - All treatment comparisons were exploratory, no formal hypothesis testing was performed.
[31] - The actual number of subjects analyzed is 266, the automatically calculated number that is provided in the statistical analysis (257) reflects only patients with value at week 24, rather than all patients that were included in the analysis.

Statistical Analysis 2

Statistical analysis description

Comparison groups

Placebo Respimat v Tio R5

Number of subjects included in analysis

260

Analysis specification

Pre-specified

Analysis type

other ^[32]

P-value

= 0.0255 ^[33]

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

0.076

Confidence interval

level

95%

sides

2-sided

lower limit

0.009

upper limit

0.143

Variability estimate

Standard error of the mean

Dispersion value

0.034

Notes
[32] - All treatment comparisons were exploratory, no formal hypothesis testing was performed.
[33] - The actual number of subjects analyzed is 266, the automatically calculated number that is provided in the statistical analysis (260) reflects only patients with value at week 24, rather than all patients that were included in the analysis.

Secondary: Trough FVC Change From Baseline

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End point title

Trough FVC Change From Baseline

End point description

Change from baseline in Trough (pre-dose) FVC measured at week 24 and 48. Measured values presented are actually adjusted means. The number of participants analysed displays the number of participants included in the statistical model whereas the N’s for each timepoint display the number of participants with available data at that timepoint. Missing data at a visit was imputed by the available data from the patient at that visit. Completely missing data were handled by the statistical model.

End point type

Secondary

End point timeframe

Baseline and Week 24, Baseline and Week 48

End point values	Placebo Respimat	Tio R2.5	Tio R5
Number of subjects analysed	131 ^[34]	135 ^[35]	135 ^[36]
Units: Litres (L)
arithmetic mean (standard error)
Week 24 (N=126, 131, 134)	0.154 ( 0.035 )	0.246 ( 0.034 )	0.206 ( 0.034 )
Week 48 (N=124, 130, 130)	0.28 ( 0.035 )	0.341 ( 0.034 )	0.333 ( 0.034 )

Notes
[34] - FAS
[35] - FAS
[36] - FAS

Statistical Analysis 1

Statistical analysis description

Comparison groups

Placebo Respimat v Tio R2.5

Number of subjects included in analysis

266

Analysis specification

Pre-specified

Analysis type

other ^[37]

P-value

= 0.0228

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

0.092

Confidence interval

level

95%

sides

2-sided

lower limit

0.013

upper limit

0.171

Variability estimate

Standard error of the mean

Dispersion value

0.04

Notes
[37] - All treatment comparisons were exploratory, no formal hypothesis testing was performed.

Statistical Analysis 2

Statistical analysis description

Comparison groups

Placebo Respimat v Tio R5

Number of subjects included in analysis

266

Analysis specification

Pre-specified

Analysis type

other ^[38]

P-value

= 0.198

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

0.052

Confidence interval

level

95%

sides

2-sided

lower limit

-0.027

upper limit

0.131

Variability estimate

Standard error of the mean

Dispersion value

0.04

Notes
[38] - All treatment comparisons were exploratory, no formal hypothesis testing was performed.

Statistical Analysis 3

Statistical analysis description

Comparison groups

Placebo Respimat v Tio R2.5

Number of subjects included in analysis

266

Analysis specification

Pre-specified

Analysis type

other ^[39]

P-value

= 0.1256

Method

Mixed models analysis

Parameter type

Median difference (net)

Point estimate

0.062

Confidence interval

level

95%

sides

2-sided

lower limit

-0.017

upper limit

0.141

Variability estimate

Standard error of the mean

Dispersion value

0.04

Notes
[39] - All treatment comparisons were exploratory, no formal hypothesis testing was performed.

Statistical Analysis 4

Statistical analysis description

Comparison groups

Placebo Respimat v Tio R5

Number of subjects included in analysis

266

Analysis specification

Pre-specified

Analysis type

other ^[40]

P-value

= 0.188

Method

Mixed models analysis

Parameter type

Median difference (net)

Point estimate

0.053

Confidence interval

level

95%

sides

2-sided

lower limit

-0.026

upper limit

0.133

Variability estimate

Standard error of the mean

Dispersion value

0.04

Notes
[40] - All treatment comparisons were exploratory, no formal hypothesis testing was performed.

Secondary: FVC peak(0-3h) Change From Baseline

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End point title

FVC peak(0-3h) Change From Baseline

End point description

Change from baseline in Maximum forced vital capacity (FVC) measured within the first 3 hours after administration of trial medication (FVC peak(0-3h)) after 24 and 48 Weeks of treatment. Measured values presented are actually adjusted means. The number of participants analysed displays the number of participants included in the statistical model whereas the N’s for each timepoint display the number of participants with available data at that timepoint. Missing data at a visit was imputed by the available data from the patient at that visit. Completely missing data were handled by the statistical model.

End point type

Secondary

End point timeframe

Baseline and Week 24, Baseline and Week 48

End point values	Placebo Respimat	Tio R2.5	Tio R5
Number of subjects analysed	131 ^[41]	135 ^[42]	135 ^[43]
Units: Litres (L)
arithmetic mean (standard error)
Week 24 (N=124, 130, 134)	0.215 ( 0.033 )	0.325 ( 0.032 )	0.307 ( 0.032 )
Week 48 (N=124, 130, 130)	0.361 ( 0.033 )	0.43 ( 0.032 )	0.413 ( 0.032 )

Notes
[41] - FAS
[42] - FAS
[43] - FAS

Statistical Analysis 1

Statistical analysis description

Comparison groups

Placebo Respimat v Tio R2.5

Number of subjects included in analysis

266

Analysis specification

Pre-specified

Analysis type

other ^[44]

P-value

= 0.0036

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

0.11

Confidence interval

level

95%

sides

2-sided

lower limit

0.036

upper limit

0.184

Variability estimate

Standard error of the mean

Dispersion value

0.038

Notes
[44] - All treatment comparisons were exploratory, no formal hypothesis testing was performed.

Statistical Analysis 2

Statistical analysis description

Comparison groups

Placebo Respimat v Tio R5

Number of subjects included in analysis

266

Analysis specification

Pre-specified

Analysis type

other ^[45]

P-value

= 0.0152

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

0.091

Confidence interval

level

95%

sides

2-sided

lower limit

0.018

upper limit

0.165

Variability estimate

Standard error of the mean

Dispersion value

0.037

Notes
[45] - All treatment comparisons were exploratory, no formal hypothesis testing was performed.

Statistical Analysis 3

Statistical analysis description

Comparison groups

Placebo Respimat v Tio R2.5

Number of subjects included in analysis

266

Analysis specification

Pre-specified

Analysis type

other ^[46]

P-value

= 0.0687

Method

Mixed models analysis

Parameter type

Median difference (net)

Point estimate

0.069

Confidence interval

level

95%

sides

2-sided

lower limit

-0.005

upper limit

0.143

Variability estimate

Standard error of the mean

Dispersion value

0.038

Notes
[46] - All treatment comparisons were exploratory, no formal hypothesis testing was performed.

Statistical Analysis 4

Statistical analysis description

Comparison groups

Placebo Respimat v Tio R5

Number of subjects included in analysis

266

Analysis specification

Pre-specified

Analysis type

other ^[47]

P-value

= 0.1666

Method

Mixed models analysis

Parameter type

Median difference (net)

Point estimate

0.052

Confidence interval

level

95%

sides

2-sided

lower limit

-0.022

upper limit

0.126

Variability estimate

Standard error of the mean

Dispersion value

0.038

Notes
[47] - All treatment comparisons were exploratory, no formal hypothesis testing was performed.

Secondary: FEV1 change from baseline at each individual timepoint

Top of page

End point title

FEV1 change from baseline at each individual timepoint

End point description

FEV1 change from baseline to week 24 at each individual timepoint. The measured values presented are actually adjusted means. The number of participants analysed displays the number of participants included in the statistical model whereas the N’s for each timepoint display the number of participants with available data at that timepoint. Missing data at a visit was imputed by the available data from the patient at that visit. Completely missing data were handled by the statistical model.

End point type

Secondary

End point timeframe

Baseline and 10 mins before drug administration and 30 mins, 1 hour (h), 2h, 3h after drug administration at 24 weeks

End point values	Placebo Respimat	Tio R2.5	Tio R5
Number of subjects analysed	131 ^[48]	135 ^[49]	135 ^[50]
Units: Litres (L)
arithmetic mean (standard error)
10 minutes pre-dose (Week 24) (N=126, 131, 134)	0.156 ( 0.031 )	0.272 ( 0.03 )	0.274 ( 0.03 )
30 minutes post-dose (Week 24) (N=126, 131, 134)	0.156 ( 0.027 )	0.295 ( 0.026 )	0.307 ( 0.027 )
1 hour post-dose (Week 24) (N=126, 131, 134)	0.165 ( 0.028 )	0.313 ( 0.027 )	0.312 ( 0.027 )
2 hours post-dose (Week 24) (N=126, 131, 134)	0.144 ( 0.028 )	0.307 ( 0.027 )	0.312 ( 0.027 )
3 hours post-dose (Week 24) (N=126, 131, 134)	0.147 ( 0.027 )	0.325 ( 0.026 )	0.322 ( 0.026 )

Notes
[48] - FAS
[49] - FAS
[50] - FAS

Statistical Analysis 1

Statistical analysis description

Comparison groups

Placebo Respimat v Tio R2.5

Number of subjects included in analysis

266

Analysis specification

Pre-specified

Analysis type

other ^[51]

P-value

= 0.0012

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

0.116

Confidence interval

level

95%

sides

2-sided

lower limit

0.046

upper limit

0.186

Variability estimate

Standard error of the mean

Dispersion value

0.036

Notes
[51] - All treatment comparisons were exploratory, no formal hypothesis testing was performed.

Statistical Analysis 2

Statistical analysis description

Comparison groups

Placebo Respimat v Tio R5

Number of subjects included in analysis

266

Analysis specification

Pre-specified

Analysis type

other ^[52]

P-value

= 0.001

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

0.118

Confidence interval

level

95%

sides

2-sided

lower limit

0.048

upper limit

0.188

Variability estimate

Standard error of the mean

Dispersion value

0.036

Notes
[52] - All treatment comparisons were exploratory, no formal hypothesis testing was performed.

Statistical Analysis 3

Statistical analysis description

Comparison groups

Placebo Respimat v Tio R2.5

Number of subjects included in analysis

266

Analysis specification

Pre-specified

Analysis type

other ^[53]

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

Median difference (net)

Point estimate

0.139

Confidence interval

level

95%

sides

2-sided

lower limit

0.076

upper limit

0.201

Variability estimate

Standard error of the mean

Dispersion value

0.032

Notes
[53] - All treatment comparisons were exploratory, no formal hypothesis testing was performed.

Statistical Analysis 4

Statistical analysis description

Comparison groups

Placebo Respimat v Tio R5

Number of subjects included in analysis

266

Analysis specification

Pre-specified

Analysis type

other ^[54]

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

Median difference (net)

Point estimate

0.151

Confidence interval

level

95%

sides

2-sided

lower limit

0.088

upper limit

0.213

Variability estimate

Standard error of the mean

Dispersion value

0.032

Notes
[54] - All treatment comparisons were exploratory, no formal hypothesis testing was performed.

Statistical Analysis 5

Statistical analysis description

Comparison groups

Placebo Respimat v Tio R2.5

Number of subjects included in analysis

266

Analysis specification

Pre-specified

Analysis type

other ^[55]

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

0.148

Confidence interval

level

95%

sides

2-sided

lower limit

0.084

upper limit

0.211

Variability estimate

Standard error of the mean

Dispersion value

0.032

Notes
[55] - All treatment comparisons were exploratory, no formal hypothesis testing was performed.

Statistical Analysis 6

Statistical analysis description

Comparison groups

Placebo Respimat v Tio R5

Number of subjects included in analysis

266

Analysis specification

Pre-specified

Analysis type

other ^[56]

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

0.147

Confidence interval

level

95%

sides

2-sided

lower limit

0.084

upper limit

0.21

Variability estimate

Standard error of the mean

Dispersion value

0.032

Notes
[56] - All treatment comparisons were exploratory, no formal hypothesis testing was performed.

Statistical Analysis 7

Statistical analysis description

Comparison groups

Placebo Respimat v Tio R2.5

Number of subjects included in analysis

266

Analysis specification

Pre-specified

Analysis type

other ^[57]

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

Median difference (net)

Point estimate

0.163

Confidence interval

level

95%

sides

2-sided

lower limit

0.101

upper limit

0.226

Variability estimate

Standard error of the mean

Dispersion value

0.032

Notes
[57] - All treatment comparisons were exploratory, no formal hypothesis testing was performed.

Statistical Analysis 8

Statistical analysis description

Comparison groups

Placebo Respimat v Tio R5

Number of subjects included in analysis

266

Analysis specification

Pre-specified

Analysis type

other ^[58]

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

0.168

Confidence interval

level

95%

sides

2-sided

lower limit

0.106

upper limit

0.231

Variability estimate

Standard error of the mean

Dispersion value

0.032

Notes
[58] - All treatment comparisons were exploratory, no formal hypothesis testing was performed.

Statistical Analysis 9

Statistical analysis description

Comparison groups

Placebo Respimat v Tio R2.5

Number of subjects included in analysis

266

Analysis specification

Pre-specified

Analysis type

other ^[59]

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

0.178

Confidence interval

level

95%

sides

2-sided

lower limit

0.116

upper limit

0.24

Variability estimate

Standard error of the mean

Dispersion value

0.032

Notes
[59] - All treatment comparisons were exploratory, no formal hypothesis testing was performed.

Statistical Analysis 10

Statistical analysis description

Comparison groups

Placebo Respimat v Tio R5

Number of subjects included in analysis

266

Analysis specification

Pre-specified

Analysis type

other ^[60]

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

0.176

Confidence interval

level

95%

sides

2-sided

lower limit

0.114

upper limit

0.238

Variability estimate

Standard error of the mean

Dispersion value

0.032

Notes
[60] - All treatment comparisons were exploratory, no formal hypothesis testing was performed.

Secondary: FVC change from baseline to week 24 at each individual timepoint

Top of page

End point title

FVC change from baseline to week 24 at each individual timepoint

End point description

FVC change from baseline to week 24 at each individual timepoint. The measured values presented are actually adjusted means The number of participants analysed displays the number of participants included in the statistical model whereas the N’s for each timepoint display the number of participants with available data at that timepoint. Missing data at a visit was imputed by the available data from the patient at that visit. Completely missing data were handled by the statistical model.

End point type

Secondary

End point timeframe

Baseline and 10 mins before drug administration and 30 mins, 1 hour (h), 2h, 3h after drug administration at Week 24

End point values	Placebo Respimat	Tio R2.5	Tio R5
Number of subjects analysed	131 ^[61]	135 ^[62]	135 ^[63]
Units: Litres (L)
arithmetic mean (standard error)
10 minues pre-dose (Week 24) (N=124, 131, 134)	0.154 ( 0.035 )	0.246 ( 0.034 )	0.206 ( 0.034 )
30 minutes post-dose (Week 24) (N=124, 131, 13	0.144 ( 0.032 )	0.222 ( 0.031 )	0.211 ( 0.031 )
1 hour post-dose (Week 24) (N=124, 131, 134)	0.142 ( 0.032 )	0.252 ( 0.031 )	0.202 ( 0.031 )
2 hours post-dose (Week 24) (N=124, 131, 134)	0.117 ( 0.033 )	0.23 ( 0.031 )	0.21 ( 0.032 )
3 hours post-dose (Week 24) (N=124, 131, 134)	0.118 ( 0.033 )	0.233 ( 0.032 )	0.21 ( 0.032 )

Notes
[61] - FAS
[62] - FAS
[63] - FAS

Statistical Analysis 1

Statistical analysis description

Comparison groups

Placebo Respimat v Tio R2.5

Number of subjects included in analysis

266

Analysis specification

Pre-specified

Analysis type

other ^[64]

P-value

= 0.0228

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

0.092

Confidence interval

level

95%

sides

2-sided

lower limit

0.013

upper limit

0.171

Variability estimate

Standard error of the mean

Dispersion value

0.04

Notes
[64] - All treatment comparisons were exploratory, no formal hypothesis testing was performed.

Statistical Analysis 2

Statistical analysis description

Comparison groups

Placebo Respimat v Tio R5

Number of subjects included in analysis

266

Analysis specification

Pre-specified

Analysis type

other ^[65]

P-value

= 0.198

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

0.052

Confidence interval

level

95%

sides

2-sided

lower limit

-0.027

upper limit

0.131

Variability estimate

Standard error of the mean

Dispersion value

0.04

Notes
[65] - All treatment comparisons were exploratory, no formal hypothesis testing was performed.

Statistical Analysis 3

Statistical analysis description

Comparison groups

Placebo Respimat v Tio R2.5

Number of subjects included in analysis

266

Analysis specification

Pre-specified

Analysis type

other ^[66]

P-value

= 0.0344

Method

Mixed models analysis

Parameter type

Median difference (net)

Point estimate

0.078

Confidence interval

level

95%

sides

2-sided

lower limit

0.006

upper limit

0.15

Variability estimate

Standard error of the mean

Dispersion value

0.037

Notes
[66] - All treatment comparisons were exploratory, no formal hypothesis testing was performed.

Statistical Analysis 4

Statistical analysis description

Comparison groups

Placebo Respimat v Tio R5

Number of subjects included in analysis

266

Analysis specification

Pre-specified

Analysis type

other ^[67]

P-value

= 0.0696

Method

Mixed models analysis

Parameter type

Median difference (net)

Point estimate

0.067

Confidence interval

level

95%

sides

2-sided

lower limit

-0.005

upper limit

0.139

Variability estimate

Standard error of the mean

Dispersion value

0.037

Notes
[67] - All treatment comparisons were exploratory, no formal hypothesis testing was performed.

Statistical Analysis 5

Statistical analysis description

Comparison groups

Placebo Respimat v Tio R2.5

Number of subjects included in analysis

266

Analysis specification

Pre-specified

Analysis type

other ^[68]

P-value

= 0.0032

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

0.109

Confidence interval

level

95%

sides

2-sided

lower limit

0.037

upper limit

0.182

Variability estimate

Standard error of the mean

Dispersion value

0.037

Notes
[68] - All treatment comparisons were exploratory, no formal hypothesis testing was performed.

Statistical Analysis 6

Statistical analysis description

Comparison groups

Placebo Respimat v Tio R5

Number of subjects included in analysis

266

Analysis specification

Pre-specified

Analysis type

other ^[69]

P-value

= 0.1044

Method

Mixed models analysis

Parameter type

Median difference (net)

Point estimate

0.06

Confidence interval

level

95%

sides

2-sided

lower limit

-0.012

upper limit

0.132

Variability estimate

Standard error of the mean

Dispersion value

0.037

Notes
[69] - All treatment comparisons were exploratory, no formal hypothesis testing was performed.

Statistical Analysis 7

Statistical analysis description

Comparison groups

Placebo Respimat v Tio R2.5

Number of subjects included in analysis

266

Analysis specification

Pre-specified

Analysis type

other ^[70]

P-value

= 0.0027

Method

Mixed models analysis

Parameter type

Median difference (net)

Point estimate

0.113

Confidence interval

level

95%

sides

2-sided

lower limit

0.039

upper limit

0.186

Variability estimate

Standard error of the mean

Dispersion value

0.037

Notes
[70] - All treatment comparisons were exploratory, no formal hypothesis testing was performed.

Statistical Analysis 8

Statistical analysis description

Comparison groups

Placebo Respimat v Tio R5

Number of subjects included in analysis

266

Analysis specification

Pre-specified

Analysis type

other ^[71]

P-value

= 0.013

Method

Mixed models analysis

Parameter type

Median difference (net)

Point estimate

0.093

Confidence interval

level

95%

sides

2-sided

lower limit

0.02

upper limit

0.166

Variability estimate

Standard error of the mean

Dispersion value

0.037

Notes
[71] - All treatment comparisons were exploratory, no formal hypothesis testing was performed.

Statistical Analysis 9

Statistical analysis description

Comparison groups

Placebo Respimat v Tio R2.5

Number of subjects included in analysis

266

Analysis specification

Pre-specified

Analysis type

other ^[72]

P-value

= 0.0025

Method

Mixed models analysis

Parameter type

Median difference (net)

Point estimate

0.115

Confidence interval

level

95%

sides

2-sided

lower limit

0.041

upper limit

0.19

Variability estimate

Standard error of the mean

Dispersion value

0.038

Notes
[72] - All treatment comparisons were exploratory, no formal hypothesis testing was performed.

Statistical Analysis 10

Statistical analysis description

Comparison groups

Placebo Respimat v Tio R5

Number of subjects included in analysis

266

Analysis specification

Pre-specified

Analysis type

other ^[73]

P-value

= 0.0156

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

0.092

Confidence interval

level

95%

sides

2-sided

lower limit

0.017

upper limit

0.166

Variability estimate

Standard error of the mean

Dispersion value

0.038

Notes
[73] - All treatment comparisons were exploratory, no formal hypothesis testing was performed.

Secondary: Use of PRN Rescue Medication per Day

Top of page

End point title

Use of PRN Rescue Medication per Day

End point description

Change from baseline in the number of puffs rescue medication (salbutamol/albuterol) used per day (24 hour period) based on the weekly mean at weeks 24 and 48. The measured values presented are actually adjusted means. The number of participants analysed displays the number of participants included in the statistical model whereas the N’s for each timepoint display the number of participants with available data at that timepoint. Missing data at a visit was imputed by the available data from the patient at that visit. Completely missing data were handled by the statistical model.

End point type

Secondary

End point timeframe

Baseline and Week 24, Baseline and Week 48

End point values	Placebo Respimat	Tio R2.5	Tio R5
Number of subjects analysed	131 ^[74]	135 ^[75]	135 ^[76]
Units: Number of puffs of rescue medication
arithmetic mean (standard error)
Week 24 (N=122, 130, 133)	-0.437 ( 0.079 )	-0.603 ( 0.077 )	0.646 ( 0.077 )
Week 48 (N=120, 123, 127)	-0.484 ( 0.079 )	0.638 ( 0.078 )	0.685 ( 0.078 )

Notes
[74] - FAS
[75] - FAS
[76] - FAS

Statistical Analysis 1

Statistical analysis description

Comparison groups

Placebo Respimat v Tio R2.5

Number of subjects included in analysis

266

Analysis specification

Pre-specified

Analysis type

other ^[77]

P-value

= 0.1349

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

-0.165

Confidence interval

level

95%

sides

2-sided

lower limit

-0.382

upper limit

0.051

Variability estimate

Standard error of the mean

Dispersion value

0.11

Notes
[77] - All treatment comparisons were exploratory, no formal hypothesis testing was performed.

Statistical Analysis 2

Statistical analysis description

Comparison groups

Placebo Respimat v Tio R5

Number of subjects included in analysis

266

Analysis specification

Pre-specified

Analysis type

other ^[78]

P-value

= 0.0588

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

-0.209

Confidence interval

level

95%

sides

2-sided

lower limit

-0.425

upper limit

0.008

Variability estimate

Standard error of the mean

Dispersion value

0.11

Notes
[78] - All treatment comparisons were exploratory, no formal hypothesis testing was performed.

Statistical Analysis 3

Statistical analysis description

Comparison groups

Placebo Respimat v Tio R2.5

Number of subjects included in analysis

266

Analysis specification

Pre-specified

Analysis type

other ^[79]

P-value

= 0.1675

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

-0.154

Confidence interval

level

95%

sides

2-sided

lower limit

-0.372

upper limit

0.065

Variability estimate

Standard error of the mean

Dispersion value

0.111

Notes
[79] - All treatment comparisons were exploratory, no formal hypothesis testing was performed.

Statistical Analysis 4

Statistical analysis description

Comparison groups

Placebo Respimat v Tio R5

Number of subjects included in analysis

266

Analysis specification

Pre-specified

Analysis type

other ^[80]

P-value

= 0.0709

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

-0.201

Confidence interval

level

95%

sides

2-sided

lower limit

-0.419

upper limit

0.017

Variability estimate

Standard error of the mean

Dispersion value

0.111

Notes
[80] - All treatment comparisons were exploratory, no formal hypothesis testing was performed.

Secondary: Use of PRN Rescue Medication during daytime

Top of page

End point title

Use of PRN Rescue Medication during daytime

End point description

Change from baseline in the number of puffs of rescue medication (salbutamol/albuterol) used during daytime based on the weekly mean at weeks 24 and 48. Measured values presented are actually adjusted means The number of participants analysed displays the number of participants included in the statistical model whereas the N’s for each timepoint display the number of participants with available data at that timepoint. Missing data at a visit was imputed by the available data from the patient at that visit. Completely missing data were handled by the statistical model.

End point type

Secondary

End point timeframe

Baseline and Week 24, Baseline and Week 48

End point values	Placebo Respimat	Tio R2.5	Tio R5
Number of subjects analysed	131 ^[81]	135 ^[82]	135 ^[83]
Units: Number of puffs of rescue medication
arithmetic mean (standard error)
Week 24 (N=121, 130, 133)	-0.234 ( 0.055 )	-0.35 ( 0.053 )	-0.375 ( 0.053 )
Week 48 (N=119, 123, 125)	-0.247 ( 0.055 )	-0.372 ( 0.053 )	-0.378 ( 0.053 )

Notes
[81] - FAS
[82] - FAS
[83] - FAS

Statistical Analysis 1

Statistical analysis description

Comparison groups

Placebo Respimat v Tio R2.5

Number of subjects included in analysis

266

Analysis specification

Pre-specified

Analysis type

other ^[84]

P-value

= 0.0749

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

-0.116

Confidence interval

level

95%

sides

2-sided

lower limit

-0.245

upper limit

0.012

Variability estimate

Standard error of the mean

Dispersion value

0.065

Notes
[84] - All treatment comparisons were exploratory, no formal hypothesis testing was performed.

Statistical Analysis 2

Statistical analysis description

Comparison groups

Placebo Respimat v Tio R5

Number of subjects included in analysis

266

Analysis specification

Pre-specified

Analysis type

other ^[85]

P-value

= 0.0305

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

-0.141

Confidence interval

level

95%

sides

2-sided

lower limit

-0.269

upper limit

-0.013

Variability estimate

Standard error of the mean

Dispersion value

0.065

Notes
[85] - All treatment comparisons were exploratory, no formal hypothesis testing was performed.

Statistical Analysis 3

Statistical analysis description

Comparison groups

Placebo Respimat v Tio R2.5

Number of subjects included in analysis

266

Analysis specification

Pre-specified

Analysis type

other ^[86]

P-value

= 0.0581

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

-0.125

Confidence interval

level

95%

sides

2-sided

lower limit

-0.255

upper limit

0.004

Variability estimate

Standard error of the mean

Dispersion value

0.066

Notes
[86] - All treatment comparisons were exploratory, no formal hypothesis testing was performed.

Statistical Analysis 4

Statistical analysis description

Comparison groups

Placebo Respimat v Tio R5

Number of subjects included in analysis

266

Analysis specification

Pre-specified

Analysis type

other ^[87]

P-value

= 0.0464

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

-0.131

Confidence interval

level

95%

sides

2-sided

lower limit

-0.26

upper limit

-0.002

Variability estimate

Standard error of the mean

Dispersion value

0.066

Notes
[87] - All treatment comparisons were exploratory, no formal hypothesis testing was performed.

Secondary: Use of PRN Rescue Medication during nighttime

Top of page

End point title

Use of PRN Rescue Medication during nighttime

End point description

Change from baseline in the number of puffs of rescue medication (salbutamol/albuterol) used during nighttime based on the weekly mean at weeks 24 and 48. Measured values presented are actually adjusted means. The number of participants analysed displays the number of participants included in the statistical model whereas the N’s for each timepoint display the number of participants with available data at that timepoint. Missing data at a visit was imputed by the available data from the patient at that visit. Completely missing data were handled by the statistical model.

End point type

Secondary

End point timeframe

Baseline and Week 24, Baseline and Week 48

End point values	Placebo Respimat	Tio R2.5	Tio R5
Number of subjects analysed	131 ^[88]	135 ^[89]	135 ^[90]
Units: Number of puffs of rescue medication
arithmetic mean (standard error)
Week 24 (N=122, 130, 130)	-0.178 ( 0.051 )	-0.274 ( 0.05 )	-0.304 ( 0.05 )
Week 48 (N=119, 122, 125)	-0.198 ( 0.052 )	-0.298 ( 0.05 )	-0.301 ( 0.05 )

Notes
[88] - FAS
[89] - FAS
[90] - FAS

Statistical Analysis 1

Statistical analysis description

Comparison groups

Placebo Respimat v Tio R2.5

Number of subjects included in analysis

266

Analysis specification

Pre-specified

Analysis type

other ^[91]

P-value

= 0.1182

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

-0.096

Confidence interval

level

95%

sides

2-sided

lower limit

-0.217

upper limit

0.025

Variability estimate

Standard error of the mean

Dispersion value

0.062

Notes
[91] - All treatment comparisons were exploratory, no formal hypothesis testing was performed.

Statistical Analysis 2

Statistical analysis description

Comparison groups

Placebo Respimat v Tio R5

Number of subjects included in analysis

266

Analysis specification

Pre-specified

Analysis type

other ^[92]

P-value

= 0.0404

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

-0.126

Confidence interval

level

95%

sides

2-sided

lower limit

-0.246

upper limit

-0.006

Variability estimate

Standard error of the mean

Dispersion value

0.061

Notes
[92] - All treatment comparisons were exploratory, no formal hypothesis testing was performed.

Statistical Analysis 3

Statistical analysis description

Comparison groups

Placebo Respimat v Tio R2.5

Number of subjects included in analysis

266

Analysis specification

Pre-specified

Analysis type

other ^[93]

P-value

= 0.1105

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

-0.099

Confidence interval

level

95%

sides

2-sided

lower limit

-0.221

upper limit

0.023

Variability estimate

Standard error of the mean

Dispersion value

0.062

Notes
[93] - All treatment comparisons were exploratory, no formal hypothesis testing was performed.

Statistical Analysis 4

Statistical analysis description

Comparison groups

Placebo Respimat v Tio R5

Number of subjects included in analysis

266

Analysis specification

Pre-specified

Analysis type

other ^[94]

P-value

= 0.0983

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

-0.103

Confidence interval

level

95%

sides

2-sided

lower limit

-0.224

upper limit

0.019

Variability estimate

Standard error of the mean

Dispersion value

0.062

Notes
[94] - All treatment comparisons were exploratory, no formal hypothesis testing was performed.

Secondary: Peak expiratory flow (PEF) a.m. change from baseline

Top of page

End point title

Peak expiratory flow (PEF) a.m. change from baseline

End point description

Change from baseline in the morning (a.m.) peak expiratory flow based on the weekly mean at weeks 24 and 48. Measured values presented are actually adjusted means. The number of participants analysed displays the number of participants included in the statistical model whereas the N’s for each timepoint display the number of participants with available data at that timepoint. Missing data at a visit was imputed by the available data from the patient at that visit. Completely missing data were handled by the statistical model.

End point type

Secondary

End point timeframe

Baseline and Week 24, Baseline and Week 48

End point values	Placebo Respimat	Tio R2.5	Tio R5
Number of subjects analysed	131 ^[95]	135 ^[96]	135 ^[97]
Units: Litres per min (L/min)
arithmetic mean (standard error)
Week 24 (N=122, 130, 130)	14.153 ( 4.556 )	22.66 ( 4.406 )	21.646 ( 4.434 )
Week 48 (N=119, 122, 125)	20.824 ( 4.581 )	26.362 ( 4.44 )	29.598 ( 4.466 )

Notes
[95] - FAS
[96] - FAS
[97] - FAS

Statistical Analysis 1

Statistical analysis description

Comparison groups

Placebo Respimat v Tio R2.5

Number of subjects included in analysis

266

Analysis specification

Pre-specified

Analysis type

other ^[98]

P-value

= 0.1146

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

8.507

Confidence interval

level

95%

sides

2-sided

lower limit

-2.063

upper limit

19.077

Variability estimate

Standard error of the mean

Dispersion value

5.387

Notes
[98] - All treatment comparisons were exploratory, no formal hypothesis testing was performed.

Statistical Analysis 2

Statistical analysis description

Comparison groups

Placebo Respimat v Tio R5

Number of subjects included in analysis

266

Analysis specification

Pre-specified

Analysis type

other ^[99]

P-value

= 0.1628

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

7.493

Confidence interval

level

95%

sides

2-sided

lower limit

-3.034

upper limit

18.02

Variability estimate

Standard error of the mean

Dispersion value

5.365

Notes
[99] - All treatment comparisons were exploratory, no formal hypothesis testing was performed.

Statistical Analysis 3

Statistical analysis description

Comparison groups

Placebo Respimat v Tio R2.5

Number of subjects included in analysis

266

Analysis specification

Pre-specified

Analysis type

other ^[100]

P-value

= 0.3085

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

5.538

Confidence interval

level

95%

sides

2-sided

lower limit

-5.127

upper limit

16.203

Variability estimate

Standard error of the mean

Dispersion value

5.435

Notes
[100] - All treatment comparisons were exploratory, no formal hypothesis testing was performed.

Statistical Analysis 4

Statistical analysis description

Comparison groups

Placebo Respimat v Tio R5

Number of subjects included in analysis

266

Analysis specification

Pre-specified

Analysis type

other ^[101]

P-value

= 0.1053

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

8.774

Confidence interval

level

95%

sides

2-sided

lower limit

-1.847

upper limit

19.394

Variability estimate

Standard error of the mean

Dispersion value

5.413

Notes
[101] - All treatment comparisons were exploratory, no formal hypothesis testing was performed.

Secondary: Peak expiratory flow (PEF) p.m. change from baseline

Top of page

End point title

Peak expiratory flow (PEF) p.m. change from baseline

End point description

Change from baseline in the evening (p.m.) peak expiratory flow based on the weekly mean at weeks 24 and 48. Measured values presented are actually adjusted means. The number of participants analysed displays the number of participants included in the statistical model whereas the N’s for each timepoint display the number of participants with available data at that timepoint. Missing data at a visit was imputed by the available data from the patient at that visit. Completely missing data were handled by the statistical model.

End point type

Secondary

End point timeframe

Baseline and Week 24, Baseline and Week 48

End point values	Placebo Respimat	Tio R2.5	Tio R5
Number of subjects analysed	131 ^[102]	135 ^[103]	135 ^[104]
Units: Litres per min (L/min)
arithmetic mean (standard error)
Week 24 (N= 121, 130, 133)	3.179 ( 4.597 )	15.539 ( 4.444 )	17.325 ( 4.464 )
Week 48 (N=119, 123, 125)	17.1 ( 4.622 )	15.219 ( 4.475 )	21.276 ( 4.504 )

Notes
[102] - FAS
[103] - FAS
[104] - FAS

Statistical Analysis 1

Statistical analysis description

Comparison groups

Placebo Respimat v Tio R2.5

Number of subjects included in analysis

266

Analysis specification

Pre-specified

Analysis type

other ^[105]

P-value

= 0.0236

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

12.36

Confidence interval

level

95%

sides

2-sided

lower limit

1.663

upper limit

23.056

Variability estimate

Standard error of the mean

Dispersion value

5.451

Notes
[105] - All treatment comparisons were exploratory, no formal hypothesis testing was performed.

Statistical Analysis 2

Statistical analysis description

Comparison groups

Placebo Respimat v Tio R5

Number of subjects included in analysis

266

Analysis specification

Pre-specified

Analysis type

other ^[106]

P-value

= 0.0093

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

14.146

Confidence interval

level

95%

sides

2-sided

lower limit

3.497

upper limit

24.794

Variability estimate

Standard error of the mean

Dispersion value

5.427

Notes
[106] - All treatment comparisons were exploratory, no formal hypothesis testing was performed.

Statistical Analysis 3

Statistical analysis description

Comparison groups

Placebo Respimat v Tio R2.5

Number of subjects included in analysis

266

Analysis specification

Pre-specified

Analysis type

other ^[107]

P-value

= 0.7322

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

-1.882

Confidence interval

level

95%

sides

2-sided

lower limit

-12.667

upper limit

8.904

Variability estimate

Standard error of the mean

Dispersion value

5.497

Notes
[107] - All treatment comparisons were exploratory, no formal hypothesis testing was performed.

Statistical Analysis 4

Statistical analysis description

Comparison groups

Placebo Respimat v Tio R5

Number of subjects included in analysis

266

Analysis specification

Pre-specified

Analysis type

other ^[108]

P-value

= 0.4463

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

4.176

Confidence interval

level

95%

sides

2-sided

lower limit

-6.578

upper limit

14.929

Variability estimate

Standard error of the mean

Dispersion value

5.481

Notes
[108] - All treatment comparisons were exploratory, no formal hypothesis testing was performed.

Secondary: Peak expiratory flow (PEF) variability change from baseline

Top of page

End point title

Peak expiratory flow (PEF) variability change from baseline

End point description

Change from baseline in the peak expiratory flow variability based on the weekly mean at week 24 and 48. Measured values presented are actually adjusted means. The number of participants analysed displays the number of participants included in the statistical model whereas the N’s for each timepoint display the number of participants with available data at that timepoint. Missing data at a visit was imputed by the available data from the patient at that visit. Completely missing data were handled by the statistical model.

End point type

Secondary

End point timeframe

Baseline and Week 24, Baseline and Week 48

End point values	Placebo Respimat	Tio R2.5	Tio R5
Number of subjects analysed	131 ^[109]	135 ^[110]	135 ^[111]
Units: Percentage of PEF
arithmetic mean (standard error)
Week 24 (N=121, 129, 128)	-1.204 ( 0.826 )	-0.942 ( 0.798 )	-1.038 ( 0.803 )
Week 48 (N=117, 120, 121)	-0.32 ( 0.835 )	-0.048 ( 0.814 )	-0.899 ( 0.818 )

Notes
[109] - FAS
[110] - FAS
[111] - FAS

Statistical Analysis 1

Statistical analysis description

Comparison groups

Placebo Respimat v Tio R2.5

Number of subjects included in analysis

266

Analysis specification

Pre-specified

Analysis type

other ^[112]

P-value

= 0.8008

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

0.262

Confidence interval

level

95%

sides

2-sided

lower limit

-1.775

upper limit

2.299

Variability estimate

Standard error of the mean

Dispersion value

1.039

Notes
[112] - All treatment comparisons were exploratory, no formal hypothesis testing was performed.

Statistical Analysis 2

Statistical analysis description

Comparison groups

Placebo Respimat v Tio R5

Number of subjects included in analysis

266

Analysis specification

Pre-specified

Analysis type

other ^[113]

P-value

= 0.8731

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

0.166

Confidence interval

level

95%

sides

2-sided

lower limit

-1.875

upper limit

2.208

Variability estimate

Standard error of the mean

Dispersion value

1.041

Notes
[113] - All treatment comparisons were exploratory, no formal hypothesis testing was performed.

Statistical Analysis 3

Statistical analysis description

Comparison groups

Placebo Respimat v Tio R2.5

Number of subjects included in analysis

266

Analysis specification

Pre-specified

Analysis type

other ^[114]

P-value

= 0.7975

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

0.272

Confidence interval

level

95%

sides

2-sided

lower limit

-1.803

upper limit

2.346

Variability estimate

Standard error of the mean

Dispersion value

1.058

Notes
[114] - All treatment comparisons were exploratory, no formal hypothesis testing was performed.

Statistical Analysis 4

Statistical analysis description

Comparison groups

Placebo Respimat v Tio R5

Number of subjects included in analysis

266

Analysis specification

Pre-specified

Analysis type

other ^[115]

P-value

= 0.5845

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

-0.579

Confidence interval

level

95%

sides

2-sided

lower limit

-2.656

upper limit

1.498

Variability estimate

Standard error of the mean

Dispersion value

1.059

Notes
[115] - All treatment comparisons were exploratory, no formal hypothesis testing was performed.

Secondary: FEV1 p.m. change from baseline

Top of page

End point title

FEV1 p.m. change from baseline

End point description

Change from baseline in evening (p.m.) FEV1 based on the weekly mean at week 24 and 48. Measured values presented are actually adjusted means. The number of participants analysed displays the number of participants included in the statistical model whereas the N’s for each timepoint display the number of participants with available data at that timepoint. Missing data at a visit was imputed by the available data from the patient at that visit. Completely missing data were handled by the statistical model.

End point type

Secondary

End point timeframe

Baseline and Week 24, Baseline and Week 48

End point values	Placebo Respimat	Tio R2.5	Tio R5
Number of subjects analysed	131 ^[116]	135 ^[117]	135 ^[118]
Units: Litres (L)
arithmetic mean (standard error)
Week 24 (N=121, 129, 128)	0.167 ( 0.042 )	0.142 ( 0.041 )	0.092 ( 0.041 )
Week 48 (N=119, 123, 125)	0.202 ( 0.042 )	0.208 ( 0.041 )	0.159 ( 0.041 )

Notes
[116] - FAS
[117] - FAS
[118] - FAS

Statistical Analysis 1

Statistical analysis description

Comparison groups

Placebo Respimat v Tio R2.5

Number of subjects included in analysis

266

Analysis specification

Pre-specified

Analysis type

other ^[119]

P-value

= 0.6166

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

-0.025

Confidence interval

level

95%

sides

2-sided

lower limit

-0.122

upper limit

0.073

Variability estimate

Standard error of the mean

Dispersion value

0.05

Notes
[119] - All treatment comparisons were exploratory, no formal hypothesis testing was performed.

Statistical Analysis 2

Statistical analysis description

Comparison groups

Placebo Respimat v Tio R5

Number of subjects included in analysis

266

Analysis specification

Pre-specified

Analysis type

other ^[120]

P-value

= 0.1267

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

-0.076

Confidence interval

level

95%

sides

2-sided

lower limit

-0.173

upper limit

0.021

Variability estimate

Standard error of the mean

Dispersion value

0.049

Notes
[120] - All treatment comparisons were exploratory, no formal hypothesis testing was performed.

Statistical Analysis 3

Statistical analysis description

Comparison groups

Placebo Respimat v Tio R2.5

Number of subjects included in analysis

266

Analysis specification

Pre-specified

Analysis type

other ^[121]

P-value

= 0.9

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

0.006

Confidence interval

level

95%

sides

2-sided

lower limit

-0.092

upper limit

0.105

Variability estimate

Standard error of the mean

Dispersion value

0.05

Notes
[121] - All treatment comparisons were exploratory, no formal hypothesis testing was performed.

Statistical Analysis 4

Statistical analysis description

Comparison groups

Placebo Respimat v Tio R5

Number of subjects included in analysis

266

Analysis specification

Pre-specified

Analysis type

other ^[122]

P-value

= 0.3897

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

-0.043

Confidence interval

level

95%

sides

2-sided

lower limit

-0.141

upper limit

0.055

Variability estimate

Standard error of the mean

Dispersion value

0.05

Notes
[122] - All treatment comparisons were exploratory, no formal hypothesis testing was performed.

Secondary: ACQ−IA total score

Top of page

End point title

ACQ−IA total score

End point description

Interviewer Administered Asthma Control Questionnaire (ACQ-IA) total score change after 24 and 48 weeks of treatment. The ACQ-IA is a scale containing 7 questions. Each question has a 7 point scale which ranges from 0 to 6. A score of 0 corresponds to no impairment and a score of 6 corresponds to maximum impairment. ACQ-IA total score is calculated as the mean of the responses to all 7 questions. The measured values presented are actually adjusted means. Missing data at a visit was imputed by the available data from the patient at that visit. Completely missing data were handled by the statistical model. The number of participants analysed displays the number of participants included in the statistical model whereas the N’s for each timepoint display the number of participants with available data at that timepoint.

End point type

Secondary

End point timeframe

Week 24 and Week 48

End point values	Placebo Respimat	Tio R2.5	Tio R5
Number of subjects analysed	131 ^[123]	135 ^[124]	135 ^[125]
Units: Units on a Scale
arithmetic mean (standard error)
Week 24 (N=126, 131, 134)	1.017 ( 0.062 )	0.897 ( 0.06 )	0.835 ( 0.06 )
Week 48 (N=124, 130, 130)	0.817 ( 0.062 )	0.752 ( 0.06 )	0.723 ( 0.061 )

Notes
[123] - FAS
[124] - FAS
[125] - FAS

Statistical Analysis 1

Statistical analysis description

Comparison groups

Tio R2.5 v Placebo Respimat

Number of subjects included in analysis

266

Analysis specification

Pre-specified

Analysis type

other ^[126]

P-value

= 0.0975

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

-0.12

Confidence interval

level

95%

sides

2-sided

lower limit

-0.262

upper limit

0.022

Variability estimate

Standard error of the mean

Dispersion value

0.072

Notes
[126] - All treatment comparisons were exploratory, no formal hypothesis testing was performed.

Statistical Analysis 2

Statistical analysis description

Comparison groups

Placebo Respimat v Tio R5

Number of subjects included in analysis

266

Analysis specification

Pre-specified

Analysis type

other ^[127]

P-value

= 0.0116

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

-0.182

Confidence interval

level

95%

sides

2-sided

lower limit

-0.323

upper limit

-0.041

Variability estimate

Standard error of the mean

Dispersion value

0.072

Notes
[127] - All treatment comparisons were exploratory, no formal hypothesis testing was performed.

Statistical Analysis 3

Statistical analysis description

Comparison groups

Placebo Respimat v Tio R2.5

Number of subjects included in analysis

266

Analysis specification

Pre-specified

Analysis type

other ^[128]

P-value

= 0.3732

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

-0.065

Confidence interval

level

95%

sides

2-sided

lower limit

-0.208

upper limit

0.078

Variability estimate

Standard error of the mean

Dispersion value

0.073

Notes
[128] - All treatment comparisons were exploratory, no formal hypothesis testing was performed.

Statistical Analysis 4

Statistical analysis description

Comparison groups

Placebo Respimat v Tio R5

Number of subjects included in analysis

266

Analysis specification

Pre-specified

Analysis type

other ^[129]

P-value

= 0.1985

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

-0.093

Confidence interval

level

95%

sides

2-sided

lower limit

-0.236

upper limit

0.049

Variability estimate

Standard error of the mean

Dispersion value

0.073

Notes
[129] - All treatment comparisons were exploratory, no formal hypothesis testing was performed.

Secondary: ACQ−IA responder analysis

Top of page

End point title

ACQ−IA responder analysis

End point description

Responder categories based on the ACQ-IA total score after 24 and 48 weeks of treatment. Analysis was performed using the following categories and definitions: responder (change from trial baseline ≤-0.5), no change (-0.5 <change from trial baseline <0.5) and worsening (change from trial baseline ≥0.5). No statistical testing was performed for ACQ-IA total score responders. The ACQ-IA is a scale containing 7 questions, each question has a 7-point scale which ranges from 0 to 6; a score of 0 corresponds to no impairment and a score of 6 corresponds to maximum impairment. Missing data for patients not withdrawn from the study were either categorised as no change or based on available data, withdrawn patients were imputed based upon discontinuation reason.

End point type

Secondary

End point timeframe

Weeks 24 and 48

End point values	Placebo Respimat	Tio R2.5	Tio R5
Number of subjects analysed	131 ^[130]	135 ^[131]	135 ^[132]
Units: Patients
number (not applicable)
Responders at Week 24	97	108	118
No Change at Week 24	34	27	16
Worsening at Week 24	0	0	1
Responder at Week 48	114	118	117
No Change at Week 48	16	14	17
Worsening at Week 48	1	3	1

Notes
[130] - FAS
[131] - FAS
[132] - FAS

No statistical analyses for this end point

Secondary: PAQLQ(S) total score

Top of page

End point title

PAQLQ(S) total score

End point description

Standardised Paediatric Asthma Quality of Life Questionnaire (PAQLQ(S)) total score at weeks 24 and 48. The PAQLQ(S) is 23 questions on a 7-point scale, ranging from 1 (worst control) to 7 (best control). Total Score is calculated as mean of all 23 questions. The measured values presented are actually adjusted means. The number of participants analysed displays the number of participants included in the statistical model whereas the N’s for each timepoint display the number of participants with available data at that timepoint. Missing data at a visit was imputed by the available data from the patient at that visit. Completely missing data were handled by the statistical model.

End point type

Secondary

End point timeframe

Week 24 and Week 48

End point values	Placebo Respimat	Tio R2.5	Tio R5
Number of subjects analysed	131 ^[133]	135 ^[134]	135 ^[135]
Units: Units on a Scale
arithmetic mean (standard error)
Week 24 (N= 126, 131, 134)	5.966 ( 0.065 )	6.142 ( 0.063 )	6.093 ( 0.062 )
Week 48 (N=124, 130, 130)	6.309 ( 0.065 )	6.288 ( 0.063 )	6.327 ( 0.063 )

Notes
[133] - FAS
[134] - FAS
[135] - FAS

Statistical Analysis 1

Statistical analysis description

Comparison groups

Placebo Respimat v Tio R2.5

Number of subjects included in analysis

266

Analysis specification

Pre-specified

Analysis type

other ^[136]

P-value

= 0.0144

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

0.176

Confidence interval

level

95%

sides

2-sided

lower limit

0.035

upper limit

0.316

Variability estimate

Standard error of the mean

Dispersion value

0.072

Notes
[136] - All treatment comparisons were exploratory, no formal hypothesis testing was performed.

Statistical Analysis 2

Statistical analysis description

Comparison groups

Placebo Respimat v Tio R5

Number of subjects included in analysis

266

Analysis specification

Pre-specified

Analysis type

other ^[137]

P-value

= 0.0747

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

0.127

Confidence interval

level

95%

sides

2-sided

lower limit

-0.013

upper limit

0.267

Variability estimate

Standard error of the mean

Dispersion value

0.071

Notes
[137] - All treatment comparisons were exploratory, no formal hypothesis testing was performed.

Statistical Analysis 3

Statistical analysis description

Comparison groups

Placebo Respimat v Tio R2.5

Number of subjects included in analysis

266

Analysis specification

Pre-specified

Analysis type

other ^[138]

P-value

= 0.7654

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

-0.021

Confidence interval

level

95%

sides

2-sided

lower limit

-0.163

upper limit

0.12

Variability estimate

Standard error of the mean

Dispersion value

0.072

Notes
[138] - All treatment comparisons were exploratory, no formal hypothesis testing was performed.

Statistical Analysis 4

Statistical analysis description

Comparison groups

Placebo Respimat v Tio R5

Number of subjects included in analysis

266

Analysis specification

Pre-specified

Analysis type

other ^[139]

P-value

= 0.8082

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

0.017

Confidence interval

level

95%

sides

2-sided

lower limit

-0.124

upper limit

0.158

Variability estimate

Standard error of the mean

Dispersion value

0.072

Notes
[139] - All treatment comparisons were exploratory, no formal hypothesis testing was performed.

Secondary: PAQLQ(S) symptom domain score

Top of page

End point title

PAQLQ(S) symptom domain score

End point description

PAQLQ(S) symptom domain score at weeks 24 and 48. The PAQLQ(S) is 23 questions on a 7-point scale, ranging from 1 (worst control) to 7 (best control). The individual domain score was calculated as the mean of the items in the domain. The measured values presented are actually adjusted means. The number of participants analysed displays the number of participants included in the statistical model whereas the N’s for each timepoint display the number of participants with available data at that timepoint. Missing data at a visit was imputed by the available data from the patient at that visit. Completely missing data were handled by the statistical model.

End point type

Secondary

End point timeframe

Week 24 and Week 48

End point values	Placebo Respimat	Tio R2.5	Tio R5
Number of subjects analysed	131 ^[140]	135 ^[141]	135 ^[142]
Units: Units on a Scale
arithmetic mean (standard error)
Week 24 (N=126, 131, 134)	5.84 ( 0.076 )	6.015 ( 0.074 )	5.967 ( 0.073 )
Week 48 (N=124, 130, 130)	6.195 ( 0.076 )	6.177 ( 0.074 )	6.199 ( 0.074 )

Notes
[140] - FAS
[141] - FAS
[142] - FAS

Statistical Analysis 1

Statistical analysis description

Comparison groups

Placebo Respimat v Tio R2.5

Number of subjects included in analysis

266

Analysis specification

Pre-specified

Analysis type

other ^[143]

P-value

= 0.0392

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

0.175

Confidence interval

level

95%

sides

2-sided

lower limit

0.009

upper limit

0.341

Variability estimate

Standard error of the mean

Dispersion value

0.085

Notes
[143] - All treatment comparisons were exploratory, no formal hypothesis testing was performed.

Statistical Analysis 2

Statistical analysis description

Comparison groups

Placebo Respimat v Tio R5

Number of subjects included in analysis

266

Analysis specification

Pre-specified

Analysis type

other ^[144]

P-value

= 0.1351

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

0.126

Confidence interval

level

95%

sides

2-sided

lower limit

-0.039

upper limit

0.292

Variability estimate

Standard error of the mean

Dispersion value

0.084

Notes
[144] - All treatment comparisons were exploratory, no formal hypothesis testing was performed.

Statistical Analysis 3

Statistical analysis description

Comparison groups

Placebo Respimat v Tio R2.5

Number of subjects included in analysis

266

Analysis specification

Pre-specified

Analysis type

other ^[145]

P-value

= 0.8291

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

-0.018

Confidence interval

level

95%

sides

2-sided

lower limit

-0.185

upper limit

0.149

Variability estimate

Standard error of the mean

Dispersion value

0.085

Notes
[145] - All treatment comparisons were exploratory, no formal hypothesis testing was performed.

Statistical Analysis 4

Statistical analysis description

Comparison groups

Placebo Respimat v Tio R5

Number of subjects included in analysis

266

Analysis specification

Pre-specified

Analysis type

other ^[146]

P-value

= 0.9655

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

0.004

Confidence interval

level

95%

sides

2-sided

lower limit

-0.163

upper limit

0.171

Variability estimate

Standard error of the mean

Dispersion value

0.085

Notes
[146] - All treatment comparisons were exploratory, no formal hypothesis testing was performed.

Secondary: PAQLQ(S) activity limitation domain score

Top of page

End point title

PAQLQ(S) activity limitation domain score

End point description

PAQLQ(S) activity limitation domain score at weeks 24 and 48. The PAQLQ(S) is 23 questions on a 7-point scale, ranging from 1 (worst control) to 7 (best control). The individual domain score is calculated as the mean of the items in this domain. The measured values presented are actually adjusted means. The number of participants analysed displays the number of participants included in the statistical model whereas the N’s for each timepoint display the number of participants with available data at that timepoint. Missing data at a visit was imputed by the available data from the patient at that visit. Completely missing data were handled by the statistical model.

End point type

Secondary

End point timeframe

Week 24 and Week 48

End point values	Placebo Respimat	Tio R2.5	Tio R5
Number of subjects analysed	131 ^[147]	135 ^[148]	135 ^[149]
Units: Units on a Scale
arithmetic mean (standard error)
Week 24 (N= 126, 131, 134)	5.898 ( 0.069 )	6.089 ( 0.067 )	6.023 ( 0.067 )
Week 48 (N=124, 130, 130)	6.249 ( 0.07 )	6.284 ( 0.068 )	6.319 ( 0.067 )

Notes
[147] - FAS
[148] - FAS
[149] - FAS

Statistical Analysis 1

Statistical analysis description

Comparison groups

Placebo Respimat v Tio R2.5

Number of subjects included in analysis

266

Analysis specification

Pre-specified

Analysis type

other ^[150]

P-value

= 0.0139

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

0.191

Confidence interval

level

95%

sides

2-sided

lower limit

0.039

upper limit

0.343

Variability estimate

Standard error of the mean

Dispersion value

0.077

Notes
[150] - All treatment comparisons were exploratory, no formal hypothesis testing was performed.

Statistical Analysis 2

Statistical analysis description

Comparison groups

Placebo Respimat v Tio R5

Number of subjects included in analysis

266

Analysis specification

Pre-specified

Analysis type

other ^[151]

P-value

= 0.1043

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

0.125

Confidence interval

level

95%

sides

2-sided

lower limit

-0.026

upper limit

0.276

Variability estimate

Standard error of the mean

Dispersion value

0.077

Notes
[151] - All treatment comparisons were exploratory, no formal hypothesis testing was performed.

Statistical Analysis 3

Statistical analysis description

Comparison groups

Placebo Respimat v Tio R2.5

Number of subjects included in analysis

266

Analysis specification

Pre-specified

Analysis type

other ^[152]

P-value

= 0.6547

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

0.035

Confidence interval

level

95%

sides

2-sided

lower limit

-0.118

upper limit

0.187

Variability estimate

Standard error of the mean

Dispersion value

0.078

Notes
[152] - All treatment comparisons were exploratory, no formal hypothesis testing was performed.

Statistical Analysis 4

Statistical analysis description

Comparison groups

Placebo Respimat v Tio R5

Number of subjects included in analysis

266

Analysis specification

Pre-specified

Analysis type

other ^[153]

P-value

= 0.3648

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

0.07

Confidence interval

level

95%

sides

2-sided

lower limit

-0.082

upper limit

0.222

Variability estimate

Standard error of the mean

Dispersion value

0.077

Notes
[153] - All treatment comparisons were exploratory, no formal hypothesis testing was performed.

Secondary: PAQLQ(S) emotional function domain score

Top of page

End point title

PAQLQ(S) emotional function domain score

End point description

PAQLQ(S) emotional function domain score at weeks 24 and 48. The PAQLQ(S) is 23 questions on a 7-point scale, ranging from 1 (worst control) to 7 (best control). The individual domain score is calculated as the mean of the items in this domain. The measured values presented are actually adjusted means. The number of participants analysed displays the number of participants included in the statistical model whereas the N’s for each timepoint display the number of participants with available data at that timepoint. Missing data at a visit was imputed by the available data from the patient at that visit. Completely missing data were handled by the statistical model.

End point type

Secondary

End point timeframe

Week 24 Week 48

End point values	Placebo Respimat	Tio R2.5	Tio R5
Number of subjects analysed	131 ^[154]	135 ^[155]	135 ^[156]
Units: Units on a Scale
arithmetic mean (standard error)
Week 24 (N=126, 131, 134)	6.157 ( 0.067 )	6.323 ( 0.065 )	6.298 ( 0.064 )
Week 48 (N=124, 130, 130)	6.481 ( 0.067 )	6.42 ( 0.065 )	6.491 ( 0.065 )

Notes
[154] - FAS
[155] - FAS
[156] - FAS

Statistical Analysis 1

Statistical analysis description

Comparison groups

Placebo Respimat v Tio R2.5

Number of subjects included in analysis

266

Analysis specification

Pre-specified

Analysis type

other ^[157]

P-value

= 0.0256

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

0.166

Confidence interval

level

95%

sides

2-sided

lower limit

0.02

upper limit

0.312

Variability estimate

Standard error of the mean

Dispersion value

0.074

Notes
[157] - All treatment comparisons were exploratory, no formal hypothesis testing was performed.

Statistical Analysis 2

Statistical analysis description

Comparison groups

Placebo Respimat v Tio R5

Number of subjects included in analysis

266

Analysis specification

Pre-specified

Analysis type

other ^[158]

P-value

= 0.0561

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

0.141

Confidence interval

level

95%

sides

2-sided

lower limit

-0.004

upper limit

0.286

Variability estimate

Standard error of the mean

Dispersion value

0.074

Notes
[158] - All treatment comparisons were exploratory, no formal hypothesis testing was performed.

Statistical Analysis 3

Statistical analysis description

Comparison groups

Placebo Respimat v Tio R2.5

Number of subjects included in analysis

266

Analysis specification

Pre-specified

Analysis type

other ^[159]

P-value

= 0.4127

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

-0.061

Confidence interval

level

95%

sides

2-sided

lower limit

-0.208

upper limit

0.085

Variability estimate

Standard error of the mean

Dispersion value

0.075

Notes
[159] - All treatment comparisons were exploratory, no formal hypothesis testing was performed.

Statistical Analysis 4

Statistical analysis description

Comparison groups

Placebo Respimat v Tio R5

Number of subjects included in analysis

266

Analysis specification

Pre-specified

Analysis type

other ^[160]

P-value

= 0.8922

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

0.01

Confidence interval

level

95%

sides

2-sided

lower limit

-0.136

upper limit

0.156

Variability estimate

Standard error of the mean

Dispersion value

0.074

Notes
[160] - All treatment comparisons were exploratory, no formal hypothesis testing was performed.

Secondary: Responders in PAQLQ(S) at weeks 24 and 48

Top of page

End point title

Responders in PAQLQ(S) at weeks 24 and 48

End point description

Responders in PAQLQ(S) at weeks 24 and 48. Analysis was performed using the following categories and definitions: responder (change from trial baseline ≥0.5), no change (-0.5 <change from trial baseline <0.5) and worsening (change from trial baseline ≤-0.5). No statistical testing was performed for PAQLQ(S) total score responders. The PAQLQ(S) is 23 questions on a 7-point scale, ranging from 1 (worst control) to 7 (best control). Missing data for patients not withdrawn from the study were either categorised as no change or based on available data, withdrawn patients were imputed based upon discontinuation reason.

End point type

Secondary

End point timeframe

Weeks 24 and 48

End point values	Placebo Respimat	Tio R2.5	Tio R5
Number of subjects analysed	131 ^[161]	135 ^[162]	135 ^[163]
Units: Patients
number (not applicable)
Responders at Week 24	67	82	73
No Change at Week 24	58	47	56
Worsening at Week 24	6	6	6
Responders at Week 48	89	96	92
No Change at Week 48	39	33	42
Worsening at Week 48	3	6	1

Notes
[161] - FAS
[162] - FAS
[163] - FAS

No statistical analyses for this end point

Secondary: FEV1 a.m. change from baseline

Top of page

End point title

FEV1 a.m. change from baseline

End point description

Change from baseline in morning (a.m.) FEV1 based on the weekly mean at week 24 and 48. The measured values presented are actually adjusted means. The number of participants analysed displays the number of participants included in the statistical model whereas the N’s for each timepoint display the number of participants with available data at that timepoint. Missing data at a visit was imputed by the available data from the patient at that visit. Completely missing data were handled by the statistical model.

End point type

Secondary

End point timeframe

Baseline and Week 24, Baseline and Week 48

End point values	Placebo Respimat	Tio R2.5	Tio R5
Number of subjects analysed	131 ^[164]	135 ^[165]	135 ^[166]
Units: Litres
arithmetic mean (standard error)
Week 24 (N=122, 130, 130)	0.191 ( 0.041 )	0.209 ( 0.039 )	0.126 ( 0.039 )
Week 48 (N=119, 122, 125)	0.236 ( 0.041 )	0.259 ( 0.04 )	0.221 ( 0.04 )

Notes
[164] - FAS
[165] - FAS
[166] - FAS

Statistical Analysis 1

Statistical analysis description

Comparison groups

Placebo Respimat v Tio R2.5

Number of subjects included in analysis

266

Analysis specification

Pre-specified

Analysis type

other ^[167]

P-value

= 0.6932

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

0.019

Confidence interval

level

95%

sides

2-sided

lower limit

-0.075

upper limit

0.113

Variability estimate

Standard error of the mean

Dispersion value

0.048

Notes
[167] - All treatment comparisons were exploratory, no formal hypothesis testing was performed.

Statistical Analysis 2

Statistical analysis description

Comparison groups

Placebo Respimat v Tio R5

Number of subjects included in analysis

266

Analysis specification

Pre-specified

Analysis type

other ^[168]

P-value

= 0.1741

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

-0.065

Confidence interval

level

95%

sides

2-sided

lower limit

-0.158

upper limit

0.029

Variability estimate

Standard error of the mean

Dispersion value

0.048

Notes
[168] - All treatment comparisons were exploratory, no formal hypothesis testing was performed.

Statistical Analysis 3

Statistical analysis description

Comparison groups

Placebo Respimat v Tio R2.5

Number of subjects included in analysis

266

Analysis specification

Pre-specified

Analysis type

other ^[169]

P-value

= 0.625

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

0.024

Confidence interval

level

95%

sides

2-sided

lower limit

-0.071

upper limit

0.118

Variability estimate

Standard error of the mean

Dispersion value

0.048

Notes
[169] - All treatment comparisons were exploratory, no formal hypothesis testing was performed.

Statistical Analysis 4

Statistical analysis description

Comparison groups

Placebo Respimat v Tio R5

Number of subjects included in analysis

266

Analysis specification

Pre-specified

Analysis type

other ^[170]

P-value

= 0.7597

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

-0.015

Confidence interval

level

95%

sides

2-sided

lower limit

-0.109

upper limit

0.08

Variability estimate

Standard error of the mean

Dispersion value

0.048

Notes
[170] - All treatment comparisons were exploratory, no formal hypothesis testing was performed.

Secondary: Change from baseline in nighttime awakenings

Top of page

End point title

Change from baseline in nighttime awakenings

End point description

Change from baseline in nighttime awakenings based on the weekly mean at weeks 24 and 48. Nighttime awakenings was assessed by the question "Did you wake up during the night due to your asthma?" from the e-diary. Scores range from 1 (did not wake up) to 5 (was awake all night). Measured values presented are actually adjusted means. The number of participants analysed displays the number of participants included in the statistical model whereas the N’s for each timepoint display the number of participants with available data at that timepoint. Missing data at a visit was imputed by the available data from the patient at that visit. Completely missing data were handled by the statistical model.

End point type

Secondary

End point timeframe

Baseline and Week 24, Baseline and Week 48

End point values	Placebo Respimat	Tio R2.5	Tio R5
Number of subjects analysed	131 ^[171]	135 ^[172]	135 ^[173]
Units: Units on a scale
arithmetic mean (standard error)
Week 24 (N=122, 130, 130)	-0.07 ( 0.03 )	-0.079 ( 0.029 )	-0.144 ( 0.029 )
Week 48 (N=119, 122, 125)	-0.101 ( 0.03 )	-0.131 ( 0.029 )	-0.127 ( 0.029 )

Notes
[171] - FAS
[172] - FAS
[173] - FAS

Statistical Analysis 1

Statistical analysis description

Comparison groups

Placebo Respimat v Tio R2.5

Number of subjects included in analysis

266

Analysis specification

Pre-specified

Analysis type

other ^[174]

P-value

= 0.7931

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

-0.009

Confidence interval

level

95%

sides

2-sided

lower limit

-0.08

upper limit

0.061

Variability estimate

Standard error of the mean

Dispersion value

0.036

Notes
[174] - All treatment comparisons were exploratory, no formal hypothesis testing was performed.

Statistical Analysis 2

Statistical analysis description

Comparison groups

Placebo Respimat v Tio R5

Number of subjects included in analysis

266

Analysis specification

Pre-specified

Analysis type

other ^[175]

P-value

= 0.0369

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

-0.075

Confidence interval

level

95%

sides

2-sided

lower limit

-0.145

upper limit

-0.005

Variability estimate

Standard error of the mean

Dispersion value

0.036

Notes
[175] - All treatment comparisons were exploratory, no formal hypothesis testing was performed.

Statistical Analysis 3

Statistical analysis description

Comparison groups

Placebo Respimat v Tio R2.5

Number of subjects included in analysis

266

Analysis specification

Pre-specified

Analysis type

other ^[176]

P-value

= 0.4086

Method

Mixed models analysis

Parameter type

Median difference (net)

Point estimate

-0.03

Confidence interval

level

95%

sides

2-sided

lower limit

-0.101

upper limit

0.041

Variability estimate

Standard error of the mean

Dispersion value

0.036

Notes
[176] - All treatment comparisons were exploratory, no formal hypothesis testing was performed.

Statistical Analysis 4

Statistical analysis description

Comparison groups

Placebo Respimat v Tio R5

Number of subjects included in analysis

266

Analysis specification

Pre-specified

Analysis type

other ^[177]

P-value

= 0.4714

Method

Mixed models analysis

Parameter type

Median difference (net)

Point estimate

-0.026

Confidence interval

level

95%

sides

2-sided

lower limit

-0.097

upper limit

0.045

Variability estimate

Standard error of the mean

Dispersion value

0.036

Notes
[177] - All treatment comparisons were exploratory, no formal hypothesis testing was performed.

Secondary: Change from baseline in morning asthma symptoms

Top of page

End point title

Change from baseline in morning asthma symptoms

End point description

Change from baseline in morning asthma symptoms based on the weekly mean at weeks 24 and 48. Morning asthma symptoms was assessed by the question "how were your asthma symptoms this morning?" from the e-diary. Scores range from 1 (no asthma symptoms) to 5 (very severe asthma symptoms). Measured values presented are actually adjusted means. The number of participants analysed displays the number of participants included in the statistical model whereas the N’s for each timepoint display the number of participants with available data at that timepoint. Missing data at a visit was imputed by the available data from the patient at that visit. Completely missing data were handled by the statistical model.

End point type

Secondary

End point timeframe

Baseline and Week 24, Baseline and Week 48

End point values	Placebo Respimat	Tio R2.5	Tio R5
Number of subjects analysed	131 ^[178]	135 ^[179]	135 ^[180]
Units: Units on a scale
arithmetic mean (standard error)
Week 24 (N=122, 130, 130)	-0.138 ( 0.039 )	-0.138 ( 0.038 )	-0.22 ( 0.038 )
Week 48 (N=119, 122, 125)	-0.177 ( 0.039 )	-0.23 ( 0.038 )	-0.221 ( 0.038 )

Notes
[178] - FAS
[179] - FAS
[180] - FAS

Statistical Analysis 1

Statistical analysis description

Comparison groups

Placebo Respimat v Tio R2.5

Number of subjects included in analysis

266

Analysis specification

Pre-specified

Analysis type

other ^[181]

P-value

= 0.988

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

0.001

Confidence interval

level

95%

sides

2-sided

lower limit

-0.091

upper limit

0.092

Variability estimate

Standard error of the mean

Dispersion value

0.047

Notes
[181] - All treatment comparisons were exploratory, no formal hypothesis testing was performed.

Statistical Analysis 2

Statistical analysis description

Comparison groups

Placebo Respimat v Tio R5

Number of subjects included in analysis

266

Analysis specification

Pre-specified

Analysis type

other ^[182]

P-value

= 0.0794

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

-0.082

Confidence interval

level

95%

sides

2-sided

lower limit

-0.173

upper limit

0.01

Variability estimate

Standard error of the mean

Dispersion value

0.046

Notes
[182] - All treatment comparisons were exploratory, no formal hypothesis testing was performed.

Statistical Analysis 3

Statistical analysis description

Comparison groups

Placebo Respimat v Tio R2.5

Number of subjects included in analysis

266

Analysis specification

Pre-specified

Analysis type

other ^[183]

P-value

= 0.2623

Method

Mixed models analysis

Parameter type

Median difference (net)

Point estimate

-0.053

Confidence interval

level

95%

sides

2-sided

lower limit

-0.145

upper limit

0.04

Variability estimate

Standard error of the mean

Dispersion value

0.047

Notes
[183] - All treatment comparisons were exploratory, no formal hypothesis testing was performed.

Statistical Analysis 4

Statistical analysis description

Comparison groups

Placebo Respimat v Tio R5

Number of subjects included in analysis

266

Analysis specification

Pre-specified

Analysis type

other ^[184]

P-value

= 0.3552

Method

Mixed models analysis

Parameter type

Median difference (net)

Point estimate

-0.043

Confidence interval

level

95%

sides

2-sided

lower limit

-0.136

upper limit

0.04

Variability estimate

Standard error of the mean

Dispersion value

0.047

Notes
[184] - All treatment comparisons were exploratory, no formal hypothesis testing was performed.

Secondary: Change from baseline in daytime asthma symptoms

Top of page

End point title

Change from baseline in daytime asthma symptoms

End point description

Change from baseline in daytime asthma symptoms based on the weekly mean at weeks 24 and 48. Daytime asthma symptoms was assessed by the question "how were your asthma symptoms during the day?" from the e-diary. Scores range from 1 (no asthma symptoms) to 5 (very severe asthma symptoms). Measured values presented are actually adjusted means. The number of participants analysed displays the number of participants included in the statistical model whereas the N’s for each timepoint display the number of participants with available data at that timepoint. Missing data at a visit was imputed by the available data from the patient at that visit. Completely missing data were handled by the statistical model.

End point type

Secondary

End point timeframe

Baseline and Week 24, Baseline and Week 48

End point values	Placebo Respimat	Tio R2.5	Tio R5
Number of subjects analysed	131 ^[185]	135 ^[186]	135 ^[187]
Units: Units on a scale
arithmetic mean (standard error)
Week 24 (N=121, 130, 133)	-0.204 ( 0.041 )	-0.243 ( 0.04 )	-0.263 ( 0.04 )
Week 48 (N=119, 123, 125)	-0.261 ( 0.042 )	-0.272 ( 0.041 )	-0.312 ( 0.041 )

Notes
[185] - FAS
[186] - FAS
[187] - FAS

Statistical Analysis 1

Statistical analysis description

Comparison groups

Placebo Respimat v Tio R2.5

Number of subjects included in analysis

266

Analysis specification

Pre-specified

Analysis type

other ^[188]

P-value

= 0.4359

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

-0.039

Confidence interval

level

95%

sides

2-sided

lower limit

-0.135

upper limit

0.058

Variability estimate

Standard error of the mean

Dispersion value

0.049

Notes
[188] - All treatment comparisons were exploratory, no formal hypothesis testing was performed.

Statistical Analysis 2

Statistical analysis description

Comparison groups

Placebo Respimat v Tio R5

Number of subjects included in analysis

266

Analysis specification

Pre-specified

Analysis type

other ^[189]

P-value

= 0.2293

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

-0.059

Confidence interval

level

95%

sides

2-sided

lower limit

-0.155

upper limit

0.037

Variability estimate

Standard error of the mean

Dispersion value

0.049

Notes
[189] - All treatment comparisons were exploratory, no formal hypothesis testing was performed.

Statistical Analysis 3

Statistical analysis description

Comparison groups

Placebo Respimat v Tio R2.5

Number of subjects included in analysis

266

Analysis specification

Pre-specified

Analysis type

other ^[190]

P-value

= 0.8372

Method

Mixed models analysis

Parameter type

Median difference (net)

Point estimate

-0.01

Confidence interval

level

95%

sides

2-sided

lower limit

-0.108

upper limit

0.088

Variability estimate

Standard error of the mean

Dispersion value

0.05

Notes
[190] - All treatment comparisons were exploratory, no formal hypothesis testing was performed.

Statistical Analysis 4

Statistical analysis description

Comparison groups

Placebo Respimat v Tio R5

Number of subjects included in analysis

266

Analysis specification

Pre-specified

Analysis type

other ^[191]

P-value

= 0.3022

Method

Mixed models analysis

Parameter type

Median difference (net)

Point estimate

-0.051

Confidence interval

level

95%

sides

2-sided

lower limit

-0.148

upper limit

0.046

Variability estimate

Standard error of the mean

Dispersion value

0.049

Notes
[191] - All treatment comparisons were exploratory, no formal hypothesis testing was performed.

Secondary: Change from baseline in daytime activity limitations

Top of page

End point title

Change from baseline in daytime activity limitations

End point description

Change from baseline in daytime activity limitations based on the weekly mean at weeks 24 and 48. Daytime activity limitations was assessed by the question "how limited were you in your activities today because of your asthma?" from the e-diary. Scores range from 1 (not limited) to 5 (totally limited). Measured values presented are actually adjusted means. The number of participants analysed displays the number of participants included in the statistical model whereas the N’s for each timepoint display the number of participants with available data at that timepoint. Missing data at a visit was imputed by the available data from the patient at that visit. Completely missing data were handled by the statistical model.

End point type

Secondary

End point timeframe

Baseline and Week 24, Baseline and Week 48

End point values	Placebo Respimat	Tio R2.5	Tio R5
Number of subjects analysed	131 ^[192]	135 ^[193]	135 ^[194]
Units: Units on a scale
arithmetic mean (standard error)
Week 24 (N=121, 130, 133)	-0.181 ( 0.039 )	-0.212 ( 0.038 )	-0.24 ( 0.038 )
Week 48 (N=119, 123, 125)	-0.227 ( 0.039 )	-0.238 ( 0.038 )	-0.259 ( 0.038 )

Notes
[192] - FAS
[193] - FAS
[194] - FAS

Statistical Analysis 1

Statistical analysis description

Comparison groups

Placebo Respimat v Tio R2.5

Number of subjects included in analysis

266

Analysis specification

Pre-specified

Analysis type

other ^[195]

P-value

= 0.5004

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

-0.031

Confidence interval

level

95%

sides

2-sided

lower limit

-0.122

upper limit

0.06

Variability estimate

Standard error of the mean

Dispersion value

0.046

Notes
[195] - All treatment comparisons were exploratory, no formal hypothesis testing was performed.

Statistical Analysis 2

Statistical analysis description

Comparison groups

Placebo Respimat v Tio R5

Number of subjects included in analysis

266

Analysis specification

Pre-specified

Analysis type

other ^[196]

P-value

= 0.1982

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

-0.059

Confidence interval

level

95%

sides

2-sided

lower limit

-0.149

upper limit

0.031

Variability estimate

Standard error of the mean

Dispersion value

0.046

Notes
[196] - All treatment comparisons were exploratory, no formal hypothesis testing was performed.

Statistical Analysis 3

Statistical analysis description

Comparison groups

Placebo Respimat v Tio R2.5

Number of subjects included in analysis

266

Analysis specification

Pre-specified

Analysis type

other ^[197]

P-value

= 0.8019

Method

Mixed models analysis

Parameter type

Median difference (net)

Point estimate

-0.012

Confidence interval

level

95%

sides

2-sided

lower limit

-0.103

upper limit

0.08

Variability estimate

Standard error of the mean

Dispersion value

0.047

Notes
[197] - All treatment comparisons were exploratory, no formal hypothesis testing was performed.

Statistical Analysis 4

Statistical analysis description

Comparison groups

Placebo Respimat v Tio R5

Number of subjects included in analysis

266

Analysis specification

Pre-specified

Analysis type

other ^[198]

P-value

= 0.4872

Method

Mixed models analysis

Parameter type

Median difference (net)

Point estimate

-0.032

Confidence interval

level

95%

sides

2-sided

lower limit

-0.123

upper limit

0.059

Variability estimate

Standard error of the mean

Dispersion value

0.046

Notes
[198] - All treatment comparisons were exploratory, no formal hypothesis testing was performed.

Secondary: Change from baseline in daytime experiences of shortness of breath

Top of page

End point title

Change from baseline in daytime experiences of shortness of breath

End point description

Change from baseline in daytime experiences of shortness of breath based on the weekly mean at weeks 24 and 48. Daytime experiences of shortness of breath was assessed by the question "how much shortness of breath did you experience during the day" from the e-diary. Scores range from 1 (none) to 5 (a very great deal). Measured values presented are actually adjusted means. The number of participants analysed displays the number of participants included in the statistical model whereas the N’s for each timepoint display the number of participants with available data at that timepoint. Missing data at a visit was imputed by the available data from the patient at that visit. Completely missing data were handled by the statistical model.

End point type

Secondary

End point timeframe

Baseline and Week 24, Baseline and Week 48

End point values	Placebo Respimat	Tio R2.5	Tio R5
Number of subjects analysed	131 ^[199]	135 ^[200]	135 ^[201]
Units: Units on a scale
arithmetic mean (standard error)
Week 24 (N=121, 130, 133)	-0.134 ( 0.039 )	-0.178 ( 0.038 )	-0.24 ( 0.038 )
Week 48 (N=119, 123, 125)	-0.219 ( 0.039 )	-0.231 ( 0.038 )	-0.253 ( 0.038 )

Notes
[199] - FAS
[200] - FAS
[201] - FAS

Statistical Analysis 1

Statistical analysis description

Comparison groups

Placebo Respimat v Tio R2.5

Number of subjects included in analysis

266

Analysis specification

Pre-specified

Analysis type

other ^[202]

P-value

= 0.3498

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

-0.043

Confidence interval

level

95%

sides

2-sided

lower limit

-0.135

upper limit

0.048

Variability estimate

Standard error of the mean

Dispersion value

0.046

Notes
[202] - All treatment comparisons were exploratory, no formal hypothesis testing was performed.

Statistical Analysis 2

Statistical analysis description

Comparison groups

Placebo Respimat v Tio R5

Number of subjects included in analysis

266

Analysis specification

Pre-specified

Analysis type

other ^[203]

P-value

= 0.0222

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

-0.106

Confidence interval

level

95%

sides

2-sided

lower limit

-0.196

upper limit

-0.015

Variability estimate

Standard error of the mean

Dispersion value

0.046

Notes
[203] - All treatment comparisons were exploratory, no formal hypothesis testing was performed.

Statistical Analysis 3

Statistical analysis description

Comparison groups

Placebo Respimat v Tio R2.5

Number of subjects included in analysis

266

Analysis specification

Pre-specified

Analysis type

other ^[204]

P-value

= 0.799

Method

Mixed models analysis

Parameter type

Median difference (net)

Point estimate

-0.012

Confidence interval

level

95%

sides

2-sided

lower limit

-0.104

upper limit

0.08

Variability estimate

Standard error of the mean

Dispersion value

0.047

Notes
[204] - All treatment comparisons were exploratory, no formal hypothesis testing was performed.

Statistical Analysis 4

Statistical analysis description

Comparison groups

Placebo Respimat v Tio R5

Number of subjects included in analysis

266

Analysis specification

Pre-specified

Analysis type

other ^[205]

P-value

= 0.4586

Method

Mixed models analysis

Parameter type

Median difference (net)

Point estimate

-0.035

Confidence interval

level

95%

sides

2-sided

lower limit

-0.126

upper limit

0.057

Variability estimate

Standard error of the mean

Dispersion value

0.047

Notes
[205] - All treatment comparisons were exploratory, no formal hypothesis testing was performed.

Secondary: Change from baseline in daytime experiences of wheeze or cough

Top of page

End point title

Change from baseline in daytime experiences of wheeze or cough

End point description

Change from baseline in daytime experiences of wheeze or cough based on the weekly mean at weeks 24 and 48. Daytime experiences of wheeze or cough was assessed by the question "did you experience wheeze or cough during the day?" from the e-diary. Scores range from 1 (not at all) to 5 (all the time). Measured values presented are actually adjusted means. The number of participants analysed displays the number of participants included in the statistical model whereas the N’s for each timepoint display the number of participants with available data at that timepoint. Missing data at a visit was imputed by the available data from the patient at that visit. Completely missing data were handled by the statistical model.

End point type

Secondary

End point timeframe

Baseline and Week 24, Baseline and Week 48

End point values	Placebo Respimat	Tio R2.5	Tio R5
Number of subjects analysed	131 ^[206]	135 ^[207]	135 ^[208]
Units: Units on a scale
arithmetic mean (standard error)
Week 24 (N=121, 130, 133)	-0.261 ( 0.046 )	-0.307 ( 0.045 )	-0.355 ( 0.045 )
Week 48 (N=119, 123, 125)	-0.34 ( 0.047 )	-0.337 ( 0.045 )	-0.393 ( 0.046 )

Notes
[206] - FAS
[207] - FAS
[208] - FAS

Statistical Analysis 1

Statistical analysis description

Comparison groups

Placebo Respimat v Tio R2.5

Number of subjects included in analysis

266

Analysis specification

Pre-specified

Analysis type

other ^[209]

P-value

= 0.4221

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

-0.045

Confidence interval

level

95%

sides

2-sided

lower limit

-0.156

upper limit

0.065

Variability estimate

Standard error of the mean

Dispersion value

0.056

Notes
[209] - All treatment comparisons were exploratory, no formal hypothesis testing was performed.

Statistical Analysis 2

Statistical analysis description

Comparison groups

Placebo Respimat v Tio R5

Number of subjects included in analysis

266

Analysis specification

Pre-specified

Analysis type

other ^[210]

P-value

= 0.0959

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

-0.093

Confidence interval

level

95%

sides

2-sided

lower limit

-0.204

upper limit

0.017

Variability estimate

Standard error of the mean

Dispersion value

0.056

Notes
[210] - All treatment comparisons were exploratory, no formal hypothesis testing was performed.

Statistical Analysis 3

Statistical analysis description

Comparison groups

Placebo Respimat v Tio R2.5

Number of subjects included in analysis

266

Analysis specification

Pre-specified

Analysis type

other ^[211]

P-value

= 0.9627

Method

Mixed models analysis

Parameter type

Median difference (net)

Point estimate

0.003

Confidence interval

level

95%

sides

2-sided

lower limit

-0.109

upper limit

0.114

Variability estimate

Standard error of the mean

Dispersion value

0.057

Notes
[211] - All treatment comparisons were exploratory, no formal hypothesis testing was performed.

Statistical Analysis 4

Statistical analysis description

Comparison groups

Placebo Respimat v Tio R5

Number of subjects included in analysis

266

Analysis specification

Pre-specified

Analysis type

other ^[212]

P-value

= 0.3457

Method

Mixed models analysis

Parameter type

Median difference (net)

Point estimate

-0.054

Confidence interval

level

95%

sides

2-sided

lower limit

-0.165

upper limit

0.058

Variability estimate

Standard error of the mean

Dispersion value

0.057

Notes
[212] - All treatment comparisons were exploratory, no formal hypothesis testing was performed.

Secondary: Change from baseline in asthma symptom-free days

Top of page

End point title

Change from baseline in asthma symptom-free days

End point description

Change from baseline in asthma symptom-free days based on the weekly mean at weeks 24 and 48. A day was considered as an asthma symptom-free day if there were no symptoms reported via the e-Diary and no use of rescue medication reported via the eDiary during that day. Measured values presented are actually adjusted means. The number of participants analysed displays the number of participants included in the statistical model whereas the N’s for each timepoint display the number of participants with available data at that timepoint. Missing data at a visit was imputed by the available data from the patient at that visit. Completely missing data were handled by the statistical model.

End point type

Secondary

End point timeframe

Baseline and Week 24, Baseline and Week 48

End point values	Placebo Respimat	Tio R2.5	Tio R5
Number of subjects analysed	131 ^[213]	135 ^[214]	135 ^[215]
Units: Days
arithmetic mean (standard error)
Week 24 (N=122, 130, 133)	0.135 ( 0.036 )	0.176 ( 0.034 )	0.172 ( 0.035 )
Week 48 (N=120, 123, 127)	0.151 ( 0.036 )	0.17 ( 0.035 )	0.18 ( 0.035 )

Notes
[213] - FAS
[214] - FAS
[215] - FAS

Statistical Analysis 1

Statistical analysis description

Comparison groups

Placebo Respimat v Tio R2.5

Number of subjects included in analysis

266

Analysis specification

Pre-specified

Analysis type

other ^[216]

P-value

= 0.3375

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

0.041

Confidence interval

level

95%

sides

2-sided

lower limit

-0.043

upper limit

0.125

Variability estimate

Standard error of the mean

Dispersion value

0.043

Notes
[216] - All treatment comparisons were exploratory, no formal hypothesis testing was performed.

Statistical Analysis 2

Statistical analysis description

Comparison groups

Placebo Respimat v Tio R5

Number of subjects included in analysis

266

Analysis specification

Pre-specified

Analysis type

other ^[217]

P-value

= 0.388

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

0.037

Confidence interval

level

95%

sides

2-sided

lower limit

-0.047

upper limit

0.121

Variability estimate

Standard error of the mean

Dispersion value

0.043

Notes
[217] - All treatment comparisons were exploratory, no formal hypothesis testing was performed.

Statistical Analysis 3

Statistical analysis description

Comparison groups

Placebo Respimat v Tio R2.5

Number of subjects included in analysis

266

Analysis specification

Pre-specified

Analysis type

other ^[218]

P-value

= 0.6541

Method

Mixed models analysis

Parameter type

Median difference (net)

Point estimate

0.019

Confidence interval

level

95%

sides

2-sided

lower limit

-0.066

upper limit

0.104

Variability estimate

Standard error of the mean

Dispersion value

0.043

Notes
[218] - All treatment comparisons were exploratory, no formal hypothesis testing was performed.

Statistical Analysis 4

Statistical analysis description

Comparison groups

Placebo Respimat v Tio R5

Number of subjects included in analysis

266

Analysis specification

Pre-specified

Analysis type

other ^[219]

P-value

= 0.5089

Method

Mixed models analysis

Parameter type

Median difference (net)

Point estimate

0.028

Confidence interval

level

95%

sides

2-sided

lower limit

-0.056

upper limit

0.133

Variability estimate

Standard error of the mean

Dispersion value

0.043

Notes
[219] - All treatment comparisons were exploratory, no formal hypothesis testing was performed.

Adverse events

Top of page

Timeframe for reporting adverse events

From first drug intake until 30 days after last drug intake, up to day 407.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

18.1

Reporting group title

Placebo

Reporting group description

Inhalation of placebo solution (2 puffs) once daily for 48 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.

Reporting group title

Tio R2.5

Reporting group description

Inhalation of 2.5mcg tiotropium (Tio R2.5) solution (2 puffs of 1.25mcg) once daily for 48 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.

Reporting group title

Tio R5

Reporting group description

Inhalation of 5mcg tiotropium (Tio R5) solution (2 puffs of 2.5mcg) once daily for 48 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.

Serious adverse events	Placebo	Tio R2.5	Tio R5
Total subjects affected by serious adverse events
subjects affected / exposed	6 / 131 (4.58%)	3 / 135 (2.22%)	1 / 135 (0.74%)
number of deaths (all causes)	0	0	0
number of deaths resulting from adverse events	0	0	0
Injury, poisoning and procedural complications
Concussion
subjects affected / exposed	1 / 131 (0.76%)	0 / 135 (0.00%)	0 / 135 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Fall
subjects affected / exposed	1 / 131 (0.76%)	0 / 135 (0.00%)	0 / 135 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Skull fracture
subjects affected / exposed	1 / 131 (0.76%)	0 / 135 (0.00%)	0 / 135 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Immune system disorders
Anaphylactic reaction
subjects affected / exposed	1 / 131 (0.76%)	0 / 135 (0.00%)	0 / 135 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Ileus paralytic
subjects affected / exposed	0 / 131 (0.00%)	0 / 135 (0.00%)	1 / 135 (0.74%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Asthma
subjects affected / exposed	2 / 131 (1.53%)	2 / 135 (1.48%)	0 / 135 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Paranasal sinus haematoma
subjects affected / exposed	1 / 131 (0.76%)	0 / 135 (0.00%)	0 / 135 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Infections and infestations
Appendicitis
subjects affected / exposed	0 / 131 (0.00%)	1 / 135 (0.74%)	1 / 135 (0.74%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastroenteritis
subjects affected / exposed	1 / 131 (0.76%)	0 / 135 (0.00%)	0 / 135 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Renal abscess
subjects affected / exposed	1 / 131 (0.76%)	0 / 135 (0.00%)	0 / 135 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	Placebo	Tio R2.5	Tio R5
Total subjects affected by non serious adverse events
subjects affected / exposed	79 / 131 (60.31%)	76 / 135 (56.30%)	71 / 135 (52.59%)
Investigations
Peak expiratory flow rate decreased
subjects affected / exposed	27 / 131 (20.61%)	31 / 135 (22.96%)	29 / 135 (21.48%)
occurrences all number	63	73	89
Respiratory, thoracic and mediastinal disorders
Asthma
subjects affected / exposed	57 / 131 (43.51%)	49 / 135 (36.30%)	46 / 135 (34.07%)
occurrences all number	132	122	131
Rhinitis allergic
subjects affected / exposed	8 / 131 (6.11%)	4 / 135 (2.96%)	6 / 135 (4.44%)
occurrences all number	11	4	9
Infections and infestations
Nasopharyngitis
subjects affected / exposed	13 / 131 (9.92%)	15 / 135 (11.11%)	12 / 135 (8.89%)
occurrences all number	18	21	14
Respiratory tract infection
subjects affected / exposed	16 / 131 (12.21%)	11 / 135 (8.15%)	13 / 135 (9.63%)
occurrences all number	29	18	26
Respiratory tract infection viral
subjects affected / exposed	8 / 131 (6.11%)	8 / 135 (5.93%)	8 / 135 (5.93%)
occurrences all number	10	11	14
Rhinitis
subjects affected / exposed	7 / 131 (5.34%)	5 / 135 (3.70%)	2 / 135 (1.48%)
occurrences all number	7	5	2

More information

Top of page

Were there any global substantial amendments to the protocol? Yes

21 Mar 2013

This amendment introduced changes to clarify wording and trial procedures, to replace the name and contact information of the former CI with the name and contact information of the new CI, to correct minor typographical errors and inconsistencies, and to update the information and risk assessment for tiotropium based on newly available data. Some clarification in regard to inclusion and exclusion criteria was introduced. The amendment also clarified the process to administer information to the patient and collect assent from the patient in case the patient him/herself was not able to read or sign him/herself.

01 Apr 2015

With the second amendment, the CTP was updated with definitions and procedures used by the sponsor for AEs, SAEs, AESI, and reporting of such events. To be in line with other clinical trials of the same development program, the endpoint ‘FEF25-75 response determined at the end of the 48-week treatment period’ was amended to ‘individual FEF25-75 response at each time point and visit during the 48-week treatment period’. The following further endpoints were added for the same reason: FEV1 peak0-3h expressed as percentage of patient’s predicted FEV1 after 24 and 48 weeks of treatment, trough FEV1 expressed as percentage of patient’s predicted FEV1 after 24 and 48 weeks of treatment, time to first symptomatic asthma exacerbation during the 48-week treatment period, ACQ-IA6 and ACQ-IA6 responder. The description of the safety analyses was amended to remove frequency tables with the number and percentage of patients with marked changes in vital signs recorded in conjunction with spirometry at any time during the trial and at each time point separately by treatment. Furthermore, the amendment introduced changes to include updated information on tiotropium based on newly available data and to correct minor typographical errors and inconsistencies.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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Clinical trials

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: FEV1 Peak (0-3h) Change From Baseline

Primary: FEV1 Peak (0-3h) Change From Baseline

Secondary: Trough FEV1 Change From Baseline

Secondary: Trough FEV1 Change From Baseline

Secondary: FEV1 Peak (0-3h) at Week 48 Change From Baseline

Secondary: FEV1 Peak (0-3h) at Week 48 Change From Baseline

Secondary: FEV1 AUC (0-3h) Change From Baseline

Secondary: FEV1 AUC (0-3h) Change From Baseline

Secondary: FVC AUC (0-3h) Change From Baseline

Secondary: FVC AUC (0-3h) Change From Baseline

Secondary: Trough FVC Change From Baseline

Secondary: Trough FVC Change From Baseline

Secondary: FVC peak(0-3h) Change From Baseline

Secondary: FVC peak(0-3h) Change From Baseline

Secondary: FEV1 change from baseline at each individual timepoint

Secondary: FEV1 change from baseline at each individual timepoint

Secondary: FVC change from baseline to week 24 at each individual timepoint

Secondary: FVC change from baseline to week 24 at each individual timepoint

Secondary: Use of PRN Rescue Medication per Day

Secondary: Use of PRN Rescue Medication per Day

Secondary: Use of PRN Rescue Medication during daytime

Secondary: Use of PRN Rescue Medication during daytime

Secondary: Use of PRN Rescue Medication during nighttime

Secondary: Use of PRN Rescue Medication during nighttime

Secondary: Peak expiratory flow (PEF) a.m. change from baseline

Secondary: Peak expiratory flow (PEF) a.m. change from baseline

Secondary: Peak expiratory flow (PEF) p.m. change from baseline

Secondary: Peak expiratory flow (PEF) p.m. change from baseline

Secondary: Peak expiratory flow (PEF) variability change from baseline

Secondary: Peak expiratory flow (PEF) variability change from baseline

Secondary: FEV1 p.m. change from baseline

Secondary: FEV1 p.m. change from baseline

Secondary: ACQ−IA total score

Secondary: ACQ−IA total score

Secondary: ACQ−IA responder analysis

Secondary: ACQ−IA responder analysis

Secondary: PAQLQ(S) total score

Secondary: PAQLQ(S) total score

Secondary: PAQLQ(S) symptom domain score

Secondary: PAQLQ(S) symptom domain score

Secondary: PAQLQ(S) activity limitation domain score

Secondary: PAQLQ(S) activity limitation domain score

Secondary: PAQLQ(S) emotional function domain score

Secondary: PAQLQ(S) emotional function domain score

Secondary: Responders in PAQLQ(S) at weeks 24 and 48

Secondary: Responders in PAQLQ(S) at weeks 24 and 48

Secondary: FEV1 a.m. change from baseline

Secondary: FEV1 a.m. change from baseline

Secondary: Change from baseline in nighttime awakenings

Secondary: Change from baseline in nighttime awakenings

Secondary: Change from baseline in morning asthma symptoms

Secondary: Change from baseline in morning asthma symptoms

Secondary: Change from baseline in daytime asthma symptoms

Secondary: Change from baseline in daytime asthma symptoms

Secondary: Change from baseline in daytime activity limitations

Secondary: Change from baseline in daytime activity limitations

Secondary: Change from baseline in daytime experiences of shortness of breath

Secondary: Change from baseline in daytime experiences of shortness of breath

Secondary: Change from baseline in daytime experiences of wheeze or cough

Secondary: Change from baseline in daytime experiences of wheeze or cough

Secondary: Change from baseline in asthma symptom-free days

Secondary: Change from baseline in asthma symptom-free days

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information