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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 mcg and 5 mcg) delivered via Respimat inhaler once daily in the evening over 12 weeks as add-on controller therapy on top of usual care in children (6 to 11 years old) with severe persistent asthma.

Due to the EudraCT – Results system being out of service between 31 July 2015 and 12 January 2016, these results have been published in compliance with revised timelines.

Summary
EudraCT number	2011-001777-43
Trial protocol	LV LT DE BE CZ HU PL SK RO BG
Global end of trial date	18 May 2015

Results information
Results version number	v1(current)
This version publication date	06 Apr 2016
First version publication date	06 Apr 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

205.446

ISRCTN number

US NCT number

NCT01634152

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

10 Jun 2015

Is this the analysis of the primary completion data?

Yes

Primary completion date

18 May 2015

Global end of trial reached?

Yes

Global end of trial date

18 May 2015

Was the trial ended prematurely?

Main objective of the trial

The overall purpose of the trial is to evaluate efficacy and safety of tiotropium inhalation solution (2.5 mcg and 5 mcg) delivered via Respimat inhaler once daily in the evening over 12 weeks, compared to placebo, as add-on controller therapy on top of usual care in children (6 to 11 years old) with severe persistent asthma. The primary objective of the trial is to demonstrate superiority of tiotropium (5 mcg and possibly 2.5 mcg once daily in the evening) over placebo with regard to the primary pulmonary function endpoint after 12 weeks of treatment. Secondary objectives are to evaluate efficacy of tiotropium with regard to other efficacy endpoints, and to evaluate the safety of tiotropium, 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

13 Jul 2012

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Argentina: 60

Country: Number of subjects enrolled

Australia: 5

Country: Number of subjects enrolled

Belgium: 5

Country: Number of subjects enrolled

Brazil: 28

Country: Number of subjects enrolled

Canada: 2

Country: Number of subjects enrolled

Czech Republic: 25

Country: Number of subjects enrolled

Germany: 23

Country: Number of subjects enrolled

Guatemala: 60

Country: Number of subjects enrolled

Hungary: 65

Country: Number of subjects enrolled

Latvia: 62

Country: Number of subjects enrolled

Lithuania: 34

Country: Number of subjects enrolled

Poland: 36

Country: Number of subjects enrolled

Romania: 2

Country: Number of subjects enrolled

Russian Federation: 67

Country: Number of subjects enrolled

Slovakia: 10

Country: Number of subjects enrolled

Ukraine: 106

Country: Number of subjects enrolled

United States: 45

Worldwide total number of subjects

635

EEA total number of subjects

262

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)

635

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 12 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.

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 12 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 137 but only 136 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 12 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	134	136	130
Completed	130	136	126
Not completed	4	0	4
Other reason not defined above	1	-	1
Adverse event, non-fatal	2	-	2
Consent withdrawn not due to AE	1	-	1

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

Inhalation of placebo solution (2 puffs) once daily for 12 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.

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 12 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	134	136	130
Age categorical
Units: Subjects
Age Continuous \|
Treated set (TS) which included all randomised patients who received at least one dose of trial medication represents the baseline analysis population.
Units: years
arithmetic mean (standard deviation)	9.1 ± 1.6	8.8 ± 1.7	9.2 ± 1.6	-
Gender, Male/Female
Units: Participants
Female	41	40	40	121
Male	93	96	90	279

End points

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Reporting group title

Placebo Respimat

Reporting group description

Inhalation of placebo solution (2 puffs) once daily for 12 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.

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 12 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 in 1 second within the first 3 hours post dosing (FEV1 peak(0-3h)) measured at week 12. Measured values presented are actually adjusted means.Full analysis set (FAS) was the same as the treated set which included all randomised patients who were dispensed and received at least one documented dose of trial medication. 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

Primary

End point timeframe

Baseline and 12 weeks

End point values	Placebo Respimat	Tio R2.5	Tio R5
Number of subjects analysed	130 ^[1]	135 ^[2]	128 ^[3]
Units: Litres
arithmetic mean (standard error)	0.252 ± 0.025	0.287 ± 0.025	0.391 ± 0.026

Notes
[1] - FAS including patients with available endpoint data at week 12
[2] - FAS including patients with available endpoint data at week 12
[3] - FAS including patients with available endpoint data at week 12

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

Tio R2.5 v Placebo Respimat

Number of subjects included in analysis

265

Analysis specification

Pre-specified

Analysis type

superiority ^[4]

P-value

= 0.2724

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

0.035

Confidence interval

level

95%

sides

2-sided

lower limit

-0.028

upper limit

0.099

Variability estimate

Standard error of the mean

Dispersion value

0.032

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.

Statistical analysis 2

Statistical analysis description

Comparison groups

Placebo Respimat v Tio R5

Number of subjects included in analysis

258

Analysis specification

Pre-specified

Analysis type

superiority ^[5]

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

0.139

Confidence interval

level

95%

sides

2-sided

lower limit

0.075

upper limit

0.203

Variability estimate

Standard error of the mean

Dispersion value

0.033

Notes
[5] - 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.

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 in 1 second (FEV1) measured at week 12. 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 12 weeks

End point values	Placebo Respimat	Tio R2.5	Tio R5
Number of subjects analysed	130 ^[6]	135 ^[7]	128 ^[8]
Units: Litres
arithmetic mean (standard error)	0.136 ± 0.027	0.154 ± 0.026	0.223 ± 0.027

Notes
[6] - FAS including patients with available endpoint data at week 12
[7] - FAS including patients with available endpoint data at week 12
[8] - FAS including patients with available endpoint data at week 12

Statistical analysis 1

Statistical analysis description

Comparison groups

Placebo Respimat v Tio R2.5

Number of subjects included in analysis

265

Analysis specification

Pre-specified

Analysis type

superiority ^[9]

P-value

= 0.5898

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

0.018

Confidence interval

level

95%

sides

2-sided

lower limit

-0.048

upper limit

0.085

Variability estimate

Standard error of the mean

Dispersion value

0.034

Notes
[9] - 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

258

Analysis specification

Pre-specified

Analysis type

superiority ^[10]

P-value

= 0.0117

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

0.087

Confidence interval

level

95%

sides

2-sided

lower limit

0.019

upper limit

0.154

Variability estimate

Standard error of the mean

Dispersion value

0.034

Notes
[10] - 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.

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 12 weeks of treatment. 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.

End point type

Secondary

End point timeframe

Baseline and 12 weeks

End point values	Placebo Respimat	Tio R2.5	Tio R5
Number of subjects analysed	130 ^[11]	135 ^[12]	128 ^[13]
Units: Litres
arithmetic mean (standard error)	0.244 ± 0.028	0.201 ± 0.027	0.275 ± 0.028

Notes
[11] - FAS including patients with available endpoint data at week 12
[12] - FAS including patients with available endpoint data at week 12
[13] - FAS including patients with available endpoint data at week 12

Statistical analysis 1

Statistical analysis description

Comparison groups

Placebo Respimat v Tio R2.5

Number of subjects included in analysis

265

Analysis specification

Pre-specified

Analysis type

other ^[14]

P-value

= 0.2277

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

-0.043

Confidence interval

level

95%

sides

2-sided

lower limit

-0.113

upper limit

0.027

Variability estimate

Standard error of the mean

Dispersion value

0.036

Notes
[14] - 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

258

Analysis specification

Pre-specified

Analysis type

other ^[15]

P-value

= 0.3998

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

0.03

Confidence interval

level

95%

sides

2-sided

lower limit

-0.04

upper limit

0.101

Variability estimate

Standard error of the mean

Dispersion value

0.036

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

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 12. 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 12 weeks

End point values	Placebo Respimat	Tio R2.5	Tio R5
Number of subjects analysed	130 ^[16]	135 ^[17]	128 ^[18]
Units: Litres
arithmetic mean (standard error)	0.141 ± 0.029	0.094 ± 0.029	0.15 ± 0.03

Notes
[16] - FAS including patients with available endpoint data at week 12
[17] - FAS including patients with available endpoint data at week 12
[18] - FAS including patients with available endpoint data at week 12

Statistical analysis 1

Statistical analysis description

Comparison groups

Placebo Respimat v Tio R2.5

Number of subjects included in analysis

265

Analysis specification

Pre-specified

Analysis type

other ^[19]

P-value

= 0.203

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

-0.048

Confidence interval

level

95%

sides

2-sided

lower limit

-0.121

upper limit

0.026

Variability estimate

Standard error of the mean

Dispersion value

0.037

Notes
[19] - 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

258

Analysis specification

Pre-specified

Analysis type

other ^[20]

P-value

= 0.8194

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

0.009

Confidence interval

level

95%

sides

2-sided

lower limit

-0.066

upper limit

0.083

Variability estimate

Standard error of the mean

Dispersion value

0.038

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

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 12 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 12 weeks

End point values	Placebo Respimat	Tio R2.5	Tio R5
Number of subjects analysed	130 ^[21]	135 ^[22]	128 ^[23]
Units: Litres
arithmetic mean (standard error)	0.175 ± 0.023	0.206 ± 0.022	0.301 ± 0.023

Notes
[21] - FAS including patients with available endpoint data at week 12
[22] - FAS including patients with available endpoint data at week 12
[23] - FAS including patients with available endpoint data at week 12

Statistical analysis 1

Statistical analysis description

Comparison groups

Placebo Respimat v Tio R2.5

Number of subjects included in analysis

265

Analysis specification

Pre-specified

Analysis type

other ^[24]

P-value

= 0.2907

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

0.031

Confidence interval

level

95%

sides

2-sided

lower limit

-0.026

upper limit

0.088

Variability estimate

Standard error of the mean

Dispersion value

0.029

Notes
[24] - 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

258

Analysis specification

Pre-specified

Analysis type

other ^[25]

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

0.126

Confidence interval

level

95%

sides

2-sided

lower limit

0.068

upper limit

0.184

Variability estimate

Standard error of the mean

Dispersion value

0.03

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

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 12 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 12 weeks

End point values	Placebo Respimat	Tio R2.5	Tio R5
Number of subjects analysed	130 ^[26]	135 ^[27]	128 ^[28]
Units: Litres
arithmetic mean (standard error)	0.145 ± 0.025	0.105 ± 0.024	0.182 ± 0.025

Notes
[26] - FAS including patients with available endpoint data at week 12
[27] - FAS including patients with available endpoint data at week 12
[28] - FAS including patients with available endpoint data at week 12

Statistical analysis 1

Statistical analysis description

Comparison groups

Placebo Respimat v Tio R2.5

Number of subjects included in analysis

265

Analysis specification

Pre-specified

Analysis type

other ^[29]

P-value

= 0.2008

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

-0.041

Confidence interval

level

95%

sides

2-sided

lower limit

-0.103

upper limit

0.022

Variability estimate

Standard error of the mean

Dispersion value

0.032

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

Statistical Analysis 2

Statistical analysis description

Comparison groups

Tio R5 v Placebo Respimat

Number of subjects included in analysis

258

Analysis specification

Pre-specified

Analysis type

other ^[30]

P-value

= 0.2545

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

0.037

Confidence interval

level

95%

sides

2-sided

lower limit

-0.026

upper limit

0.1

Variability estimate

Standard error of the mean

Dispersion value

0.032

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

Secondary: FEV1 change from baseline at each individual timepoint

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End point title

FEV1 change from baseline at each individual timepoint

End point description

Forced expiratory volume in one second (FEV1) change from baseline at each individual timepoint. 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.

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 12 weeks

End point values	Placebo Respimat	Tio R2.5	Tio R5
Number of subjects analysed	130 ^[31]	135 ^[32]	128 ^[33]
Units: Litres
arithmetic mean (standard error)
10 minutes pre-dose	0.136 ± 0.027	0.154 ± 0.026	0.223 ± 0.027
30 minutes post-dose	0.166 ± 0.024	0.202 ± 0.023	0.285 ± 0.024
1 hour post-dose	0.177 ± 0.025	0.203 ± 0.024	0.3 ± 0.025
2 hours post-dose	0.191 ± 0.025	0.216 ± 0.025	0.324 ± 0.026
3 hours post-dose	0.168 ± 0.026	0.215 ± 0.026	0.308 ± 0.026

Notes
[31] - FAS including patients with available endpoint data at week 12
[32] - FAS including patients with available endpoint data at week 12
[33] - FAS including patients with available endpoint data at week 12

No statistical analyses for this end point

Secondary: FVC change from baseline at each individual timepoint

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End point title

FVC change from baseline at each individual timepoint

End point description

FVC change from baseline at each individual timepoint. 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.

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 12 weeks

End point values	Placebo Respimat	Tio R2.5	Tio R5
Number of subjects analysed	130 ^[34]	135 ^[35]	128 ^[36]
Units: Litres
arithmetic mean (standard error)
10 minutes pre-dose	0.141 ± 0.029	0.094 ± 0.029	0.15 ± 0.03
30 minutes post-dose	0.13 ± 0.026	0.096 ± 0.026	0.164 ± 0.027
1 hour post-dose	0.146 ± 0.027	0.097 ± 0.026	0.181 ± 0.027
2 hours post-dose	0.159 ± 0.028	0.113 ± 0.027	0.199 ± 0.028
3 hours post-dose	0.132 ± 0.028	0.11 ± 0.028	0.176 ± 0.029

Notes
[34] - FAS including patients with available endpoint data at week 12
[35] - FAS including patients with available endpoint data at week 12
[36] - FAS including patients with available endpoint data at week 12

No statistical analyses for this end point

Secondary: Control of Asthma as Assessed by ACQ-IA Total Score

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End point title

Control of Asthma as Assessed by ACQ-IA Total Score

End point description

Change from baseline in Interviewer-Administered Asthma Control Questionnaire (ACQ-IA) total score measured at week 12. 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.

End point type

Secondary

End point timeframe

Baseline and 12 weeks

End point values	Placebo Respimat	Tio R2.5	Tio R5
Number of subjects analysed	130 ^[37]	136 ^[38]	126 ^[39]
Units: Units on a scale
arithmetic mean (standard error)	1.026 ± 0.06	1.046 ± 0.059	0.948 ± 0.061

Notes
[37] - FAS including patients with available endpoint data at week 12
[38] - FAS including patients with available endpoint data at week 12
[39] - FAS including patients with available endpoint data at week 12

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 ^[40]

P-value

= 0.798

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

0.02

Confidence interval

level

95%

sides

2-sided

lower limit

-0.133

upper limit

0.173

Variability estimate

Standard error of the mean

Dispersion value

0.078

Notes
[40] - 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

256

Analysis specification

Pre-specified

Analysis type

other ^[41]

P-value

= 0.3166

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

-0.079

Confidence interval

level

95%

sides

2-sided

lower limit

-0.233

upper limit

0.076

Variability estimate

Standard error of the mean

Dispersion value

0.079

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

Secondary: ACQ-IA Total Score Responders

Top of page

End point title

ACQ-IA Total Score Responders

End point description

Responder categories based on the ACQ-IA total score after 12 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

12 weeks

End point values	Placebo Respimat	Tio R2.5	Tio R5
Number of subjects analysed	134 ^[42]	136 ^[43]	130 ^[44]
Units: Percentage of participants
number (not applicable)
Responder	76.9	79.4	80.8
No change	20.9	18.4	16.2
Worsening	2.2	2.2	3.1

Notes
[42] - FAS
[43] - FAS
[44] - FAS

No statistical analyses for this end point

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 of rescue medication (salbutamol/albuterol) used per day (24 hour period) based on the weekly mean at week 12. 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.

End point type

Secondary

End point timeframe

Baseline and 12 weeks

End point values	Placebo Respimat	Tio R2.5	Tio R5
Number of subjects analysed	128 ^[45]	136 ^[46]	127 ^[47]
Units: Number of puffs of rescue medication
arithmetic mean (standard error)	-0.57 ± 0.096	-0.553 ± 0.094	-0.66 ± 0.097

Notes
[45] - FAS including patients with available endpoint data at week 12
[46] - FAS including patients with available endpoint data at week 12
[47] - FAS including patients with available endpoint data at week 12

Statistical analysis 1

Statistical analysis description

Comparison groups

Placebo Respimat v Tio R2.5

Number of subjects included in analysis

264

Analysis specification

Pre-specified

Analysis type

other ^[48]

P-value

= 0.8916

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

0.017

Confidence interval

level

95%

sides

2-sided

lower limit

-0.227

upper limit

0.261

Variability estimate

Standard error of the mean

Dispersion value

0.124

Notes
[48] - 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

255

Analysis specification

Pre-specified

Analysis type

other ^[49]

P-value

= 0.4789

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

-0.089

Confidence interval

level

95%

sides

2-sided

lower limit

-0.336

upper limit

0.158

Variability estimate

Standard error of the mean

Dispersion value

0.126

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

Secondary: Use of PRN Rescue Medication During the Daytime

Top of page

End point title

Use of PRN Rescue Medication During the Daytime

End point description

Change from baseline in the number of puffs of rescue medication (salbutamol/albuterol) used during the daytime based on the weekly mean at week 12. 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 12 weeks

End point values	Placebo Respimat	Tio R2.5	Tio R5
Number of subjects analysed	127 ^[50]	136 ^[51]	126 ^[52]
Units: Number of puffs of rescue medication
arithmetic mean (standard error)	-0.279 ± 0.057	-0.294 ± 0.055	-0.365 ± 0.057

Notes
[50] - FAS including patients with available endpoint data at week 12
[51] - FAS including patients with available endpoint data at week 12
[52] - FAS including patients with available endpoint data at week 12

Statistical analysis 1

Statistical analysis description

Comparison groups

Placebo Respimat v Tio R2.5

Number of subjects included in analysis

263

Analysis specification

Pre-specified

Analysis type

other ^[53]

P-value

= 0.8361

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

-0.015

Confidence interval

level

95%

sides

2-sided

lower limit

-0.16

upper limit

0.129

Variability estimate

Standard error of the mean

Dispersion value

0.074

Notes
[53] - 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

253

Analysis specification

Pre-specified

Analysis type

other ^[54]

P-value

= 0.2461

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

-0.087

Confidence interval

level

95%

sides

2-sided

lower limit

-0.233

upper limit

0.06

Variability estimate

Standard error of the mean

Dispersion value

0.075

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

Secondary: Use of PRN Rescue Medication During the Night-time

Top of page

End point title

Use of PRN Rescue Medication During the Night-time

End point description

Change from baseline in the number of puffs of rescue medication (salbutamol/albuterol) used during the night-time based on the weekly mean at week 12. 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 12 weeks

End point values	Placebo Respimat	Tio R2.5	Tio R5
Number of subjects analysed	128 ^[55]	136 ^[56]	126 ^[57]
Units: Number of puffs of rescue medication
arithmetic mean (standard error)	-0.285 ± 0.051	-0.25 ± 0.05	-0.31 ± 0.052

Notes
[55] - FAS including patients with available endpoint data at week 12
[56] - FAS including patients with available endpoint data at week 12
[57] - FAS including patients with available endpoint data at week 12

Statistical analysis 1

Statistical analysis description

Comparison groups

Placebo Respimat v Tio R2.5

Number of subjects included in analysis

264

Analysis specification

Pre-specified

Analysis type

other ^[58]

P-value

= 0.6029

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

0.035

Confidence interval

level

95%

sides

2-sided

lower limit

-0.096

upper limit

0.165

Variability estimate

Standard error of the mean

Dispersion value

0.067

Notes
[58] - 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

254

Analysis specification

Pre-specified

Analysis type

other ^[59]

P-value

= 0.7034

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

-0.026

Confidence interval

level

95%

sides

2-sided

lower limit

-0.158

upper limit

0.107

Variability estimate

Standard error of the mean

Dispersion value

0.067

Notes
[59] - 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 week 12. 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 12 weeks

End point values	Placebo Respimat	Tio R2.5	Tio R5
Number of subjects analysed	128 ^[60]	136 ^[61]	126 ^[62]
Units: L/min
arithmetic mean (standard error)	8.343 ± 3.613	13.119 ± 3.5	13.086 ± 3.63

Notes
[60] - FAS including patients with available endpoint data at week 12
[61] - FAS including patients with available endpoint data at week 12
[62] - FAS including patients with available endpoint data at week 12

Statistical analysis 1

Statistical analysis description

Comparison groups

Placebo Respimat v Tio R2.5

Number of subjects included in analysis

264

Analysis specification

Pre-specified

Analysis type

other ^[63]

P-value

= 0.3083

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

4.776

Confidence interval

level

95%

sides

2-sided

lower limit

-4.419

upper limit

13.97

Variability estimate

Standard error of the mean

Dispersion value

4.686

Notes
[63] - 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

254

Analysis specification

Pre-specified

Analysis type

other ^[64]

P-value

= 0.3179

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

4.743

Confidence interval

level

95%

sides

2-sided

lower limit

-4.571

upper limit

14.057

Variability estimate

Standard error of the mean

Dispersion value

4.747

Notes
[64] - 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 week 12. 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 12 weeks

End point values	Placebo Respimat	Tio R2.5	Tio R5
Number of subjects analysed	127 ^[65]	136 ^[66]	126 ^[67]
Units: L/min
arithmetic mean (standard error)	7.892 ± 3.717	8.459 ± 3.599	3.785 ± 3.731

Notes
[65] - FAS including patients with available endpoint data at week 12
[66] - FAS including patients with available endpoint data at week 12
[67] - FAS including patients with available endpoint data at week 12

Statistical analysis 1

Statistical analysis description

Comparison groups

Placebo Respimat v Tio R2.5

Number of subjects included in analysis

263

Analysis specification

Pre-specified

Analysis type

other ^[68]

P-value

= 0.9061

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

0.567

Confidence interval

level

95%

sides

2-sided

lower limit

-8.866

upper limit

10.001

Variability estimate

Standard error of the mean

Dispersion value

4.807

Notes
[68] - 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

253

Analysis specification

Pre-specified

Analysis type

other ^[69]

P-value

= 0.399

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

-4.107

Confidence interval

level

95%

sides

2-sided

lower limit

-13.658

upper limit

5.444

Variability estimate

Standard error of the mean

Dispersion value

4.867

Notes
[69] - 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 12. 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 12 weeks

End point values	Placebo Respimat	Tio R2.5	Tio R5
Number of subjects analysed	127 ^[70]	136 ^[71]	125 ^[72]
Units: Percentage of PEF
arithmetic mean (standard error)	0.15 ± 0.777	-0.8 ± 0.749	-0.352 ± 0.78

Notes
[70] - FAS including patients with available endpoint data at week 12
[71] - FAS including patients with available endpoint data at week 12
[72] - FAS including patients with available endpoint data at week 12

Statistical analysis 1

Statistical analysis description

Comparison groups

Placebo Respimat v Tio R2.5

Number of subjects included in analysis

263

Analysis specification

Pre-specified

Analysis type

other ^[73]

P-value

= 0.3542

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

-0.95

Confidence interval

level

95%

sides

2-sided

lower limit

-2.959

upper limit

1.06

Variability estimate

Standard error of the mean

Dispersion value

1.025

Notes
[73] - 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

252

Analysis specification

Pre-specified

Analysis type

other ^[74]

P-value

= 0.6298

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

-0.502

Confidence interval

level

95%

sides

2-sided

lower limit

-2.545

upper limit

1.541

Variability estimate

Standard error of the mean

Dispersion value

1.042

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

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 12. 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 12 weeks

End point values	Placebo Respimat	Tio R2.5	Tio R5
Number of subjects analysed	128 ^[75]	136 ^[76]	126 ^[77]
Units: Litres
arithmetic mean (standard error)	0.174 ± 0.03	0.142 ± 0.029	0.125 ± 0.03

Notes
[75] - FAS including patients with available endpoint data at week 12
[76] - FAS including patients with available endpoint data at week 12
[77] - FAS including patients with available endpoint data at week 12

Statistical analysis 1

Statistical analysis description

Comparison groups

Placebo Respimat v Tio R2.5

Number of subjects included in analysis

264

Analysis specification

Pre-specified

Analysis type

other ^[78]

P-value

= 0.4066

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

-0.032

Confidence interval

level

95%

sides

2-sided

lower limit

-0.107

upper limit

0.043

Variability estimate

Standard error of the mean

Dispersion value

0.038

Notes
[78] - 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

254

Analysis specification

Pre-specified

Analysis type

other ^[79]

P-value

= 0.2032

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

-0.049

Confidence interval

level

95%

sides

2-sided

lower limit

-0.125

upper limit

0.027

Variability estimate

Standard error of the mean

Dispersion value

0.039

Notes
[79] - 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 12. 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 12 weeks

End point values	Placebo Respimat	Tio R2.5	Tio R5
Number of subjects analysed	127 ^[80]	136 ^[81]	126 ^[82]
Units: Litres
arithmetic mean (standard error)	0.155 ± 0.031	0.104 ± 0.03	0.094 ± 0.032

Notes
[80] - FAS including patients with available endpoint data at week 12
[81] - FAS including patients with available endpoint data at week 12
[82] - FAS including patients with available endpoint data at week 12

Statistical analysis 1

Statistical analysis description

Comparison groups

Placebo Respimat v Tio R2.5

Number of subjects included in analysis

263

Analysis specification

Pre-specified

Analysis type

other ^[83]

P-value

= 0.2064

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

-0.051

Confidence interval

level

95%

sides

2-sided

lower limit

-0.131

upper limit

0.028

Variability estimate

Standard error of the mean

Dispersion value

0.041

Notes
[83] - 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

253

Analysis specification

Pre-specified

Analysis type

other ^[84]

P-value

= 0.141

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

-0.061

Confidence interval

level

95%

sides

2-sided

lower limit

-0.142

upper limit

0.02

Variability estimate

Standard error of the mean

Dispersion value

0.041

Notes
[84] - 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 week 12. 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. 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 12 weeks

End point values	Placebo Respimat	Tio R2.5	Tio R5
Number of subjects analysed	128 ^[85]	136 ^[86]	126 ^[87]
Units: Units on a scale
arithmetic mean (standard error)	-0.165 ± 0.032	-0.166 ± 0.031	-0.159 ± 0.033

Notes
[85] - FAS including patients with available endpoint data at week 12
[86] - FAS including patients with available endpoint data at week 12
[87] - FAS including patients with available endpoint data at week 12

Statistical analysis 1

Statistical analysis description

Comparison groups

Placebo Respimat v Tio R2.5

Number of subjects included in analysis

264

Analysis specification

Pre-specified

Analysis type

other ^[88]

P-value

= 0.9869

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

-0.001

Confidence interval

level

95%

sides

2-sided

lower limit

-0.083

upper limit

0.082

Variability estimate

Standard error of the mean

Dispersion value

0.042

Notes
[88] - 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

254

Analysis specification

Pre-specified

Analysis type

other ^[89]

P-value

= 0.873

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

0.007

Confidence interval

level

95%

sides

2-sided

lower limit

-0.077

upper limit

0.09

Variability estimate

Standard error of the mean

Dispersion value

0.043

Notes
[89] - 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 week 12. 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. 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 12 weeks

End point values	Placebo Respimat	Tio R2.5	Tio R5
Number of subjects analysed	128 ^[90]	136 ^[91]	126 ^[92]
Units: Units on a scale
arithmetic mean (standard error)	-0.207 ± 0.038	-0.213 ± 0.037	-0.221 ± 0.038

Notes
[90] - FAS including patients with available endpoint data at week 12
[91] - FAS including patients with available endpoint data at week 12
[92] - FAS including patients with available endpoint data at week 12

Statistical analysis 1

Statistical analysis description

Comparison groups

Placebo Respimat v Tio R2.5

Number of subjects included in analysis

264

Analysis specification

Pre-specified

Analysis type

other ^[93]

P-value

= 0.9043

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

-0.006

Confidence interval

level

95%

sides

2-sided

lower limit

-0.103

upper limit

0.091

Variability estimate

Standard error of the mean

Dispersion value

0.049

Notes
[93] - 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

254

Analysis specification

Pre-specified

Analysis type

other ^[94]

P-value

= 0.7708

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

-0.015

Confidence interval

level

95%

sides

2-sided

lower limit

-0.112

upper limit

0.083

Variability estimate

Standard error of the mean

Dispersion value

0.05

Notes
[94] - 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 week 12. 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. 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 12 weeks

End point values	Placebo Respimat	Tio R2.5	Tio R5
Number of subjects analysed	127 ^[95]	136 ^[96]	126 ^[97]
Units: Units on a scale
arithmetic mean (standard error)	-0.226 ± 0.04	-0.262 ± 0.039	-0.239 ± 0.041

Notes
[95] - FAS including patients with available endpoint data at week 12
[96] - FAS including patients with available endpoint data at week 12
[97] - FAS including patients with available endpoint data at week 12

Statistical analysis 1

Statistical analysis description

Comparison groups

Placebo Respimat v Tio R2.5

Number of subjects included in analysis

263

Analysis specification

Pre-specified

Analysis type

other ^[98]

P-value

= 0.4864

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

-0.036

Confidence interval

level

95%

sides

2-sided

lower limit

-0.139

upper limit

0.066

Variability estimate

Standard error of the mean

Dispersion value

0.052

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

253

Analysis specification

Pre-specified

Analysis type

other ^[99]

P-value

= 0.7991

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

-0.013

Confidence interval

level

95%

sides

2-sided

lower limit

-0.117

upper limit

0.09

Variability estimate

Standard error of the mean

Dispersion value

0.053

Notes
[99] - 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 week 12. 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. 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 12 weeks

End point values	Placebo Respimat	Tio R2.5	Tio R5
Number of subjects analysed	127 ^[100]	136 ^[101]	126 ^[102]
Units: Units on a scale
arithmetic mean (standard error)	-0.21 ± 0.039	-0.203 ± 0.038	-0.222 ± 0.039

Notes
[100] - FAS including patients with available endpoint data at week 12
[101] - FAS including patients with available endpoint data at week 12
[102] - FAS including patients with available endpoint data at week 12

Statistical analysis 1

Statistical analysis description

Comparison groups

Placebo Respimat v Tio R2.5

Number of subjects included in analysis

263

Analysis specification

Pre-specified

Analysis type

other ^[103]

P-value

= 0.8884

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

0.007

Confidence interval

level

95%

sides

2-sided

lower limit

-0.092

upper limit

0.106

Variability estimate

Standard error of the mean

Dispersion value

0.05

Notes
[103] - 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

253

Analysis specification

Pre-specified

Analysis type

other ^[104]

P-value

= 0.8115

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

-0.012

Confidence interval

level

95%

sides

2-sided

lower limit

-0.112

upper limit

0.088

Variability estimate

Standard error of the mean

Dispersion value

0.051

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

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

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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 week 12. 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. 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 12 weeks

End point values	Placebo Respimat	Tio R2.5	Tio R5
Number of subjects analysed	127 ^[105]	136 ^[106]	126 ^[107]
Units: Units on a scale
arithmetic mean (standard error)	-0.204 ± 0.039	-0.187 ± 0.038	-0.287 ± 0.04

Notes
[105] - FAS including patients with available endpoint data at week 12
[106] - FAS including patients with available endpoint data at week 12
[107] - FAS including patients with available endpoint data at week 12

Statistical analysis 1

Statistical analysis description

Comparison groups

Placebo Respimat v Tio R2.5

Number of subjects included in analysis

263

Analysis specification

Pre-specified

Analysis type

other ^[108]

P-value

= 0.7498

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

0.016

Confidence interval

level

95%

sides

2-sided

lower limit

-0.084

upper limit

0.117

Variability estimate

Standard error of the mean

Dispersion value

0.051

Notes
[108] - 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

253

Analysis specification

Pre-specified

Analysis type

other ^[109]

P-value

= 0.1108

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

-0.083

Confidence interval

level

95%

sides

2-sided

lower limit

-0.185

upper limit

0.019

Variability estimate

Standard error of the mean

Dispersion value

0.052

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

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

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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 week 12. 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. 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 12 weeks

End point values	Placebo Respimat	Tio R2.5	Tio R5
Number of subjects analysed	127 ^[110]	136 ^[111]	126 ^[112]
Units: Units on a scale
arithmetic mean (standard error)	-0.249 ± 0.045	-0.263 ± 0.044	-0.32 ± 0.046

Notes
[110] - FAS including patients with available endpoint data at week 12
[111] - FAS including patients with available endpoint data at week 12
[112] - FAS including patients with available endpoint data at week 12

Statistical analysis 1

Statistical analysis description

Comparison groups

Placebo Respimat v Tio R2.5

Number of subjects included in analysis

263

Analysis specification

Pre-specified

Analysis type

other ^[113]

P-value

= 0.8055

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

-0.015

Confidence interval

level

95%

sides

2-sided

lower limit

-0.131

upper limit

0.102

Variability estimate

Standard error of the mean

Dispersion value

0.059

Notes
[113] - 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

253

Analysis specification

Pre-specified

Analysis type

other ^[114]

P-value

= 0.236

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

-0.071

Confidence interval

level

95%

sides

2-sided

lower limit

-0.189

upper limit

0.047

Variability estimate

Standard error of the mean

Dispersion value

0.06

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

Secondary: Change from baseline in asthma symptom-free days

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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 week 12. 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. 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 12 weeks

End point values	Placebo Respimat	Tio R2.5	Tio R5
Number of subjects analysed	128 ^[115]	136 ^[116]	127 ^[117]
Units: Days
arithmetic mean (standard error)	0.147 ± 0.031	0.13 ± 0.03	0.172 ± 0.031

Notes
[115] - FAS including patients with available endpoint data at week 12
[116] - FAS including patients with available endpoint data at week 12
[117] - FAS including patients with available endpoint data at week 12

Statistical analysis 1

Statistical analysis description

Comparison groups

Placebo Respimat v Tio R2.5

Number of subjects included in analysis

264

Analysis specification

Pre-specified

Analysis type

other ^[118]

P-value

= 0.6748

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

-0.017

Confidence interval

level

95%

sides

2-sided

lower limit

-0.097

upper limit

0.063

Variability estimate

Standard error of the mean

Dispersion value

0.041

Notes
[118] - 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

255

Analysis specification

Pre-specified

Analysis type

other ^[119]

P-value

= 0.5497

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

0.025

Confidence interval

level

95%

sides

2-sided

lower limit

-0.056

upper limit

0.105

Variability estimate

Standard error of the mean

Dispersion value

0.041

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

Adverse events

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Timeframe for reporting adverse events

From first drug intake until 30 days after last drug intake, up to 164 days

Adverse event reporting additional description

The final study visit was postponed if the status of the patient could affect the primary endpoint, for example, in cases of asthma exacerbations, therefore patients could remain on treatment for longer than the planned 12 weeks.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

18.0

Reporting group title

Placebo Respimat

Reporting group description

Inhalation of placebo solution (2 puffs) once daily for 12 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 solution (2 puffs of 1.25mcg) once daily for 12 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 solution (2 puffs of 2.5mcg) once daily for 12 weeks delivered by the Respimat inhaler, as add on therapy on top of usual care.

Serious adverse events	Placebo Respimat	Tio R2.5	Tio R5
Total subjects affected by serious adverse events
subjects affected / exposed	2 / 134 (1.49%)	2 / 136 (1.47%)	4 / 130 (3.08%)
number of deaths (all causes)	0	0	0
number of deaths resulting from adverse events	0	0	0
Nervous system disorders
Epilepsy
subjects affected / exposed	0 / 134 (0.00%)	1 / 136 (0.74%)	0 / 130 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Asthma
subjects affected / exposed	1 / 134 (0.75%)	1 / 136 (0.74%)	3 / 130 (2.31%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Asthmatic crisis
subjects affected / exposed	1 / 134 (0.75%)	0 / 136 (0.00%)	0 / 130 (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 / 134 (0.00%)	0 / 136 (0.00%)	1 / 130 (0.77%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
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 Respimat	Tio R2.5	Tio R5
Total subjects affected by non serious adverse events
subjects affected / exposed	49 / 134 (36.57%)	36 / 136 (26.47%)	35 / 130 (26.92%)
Investigations
Peak expiratory flow rate decreased
subjects affected / exposed	20 / 134 (14.93%)	15 / 136 (11.03%)	15 / 130 (11.54%)
occurrences all number	32	23	29
Respiratory, thoracic and mediastinal disorders
Asthma
subjects affected / exposed	29 / 134 (21.64%)	20 / 136 (14.71%)	22 / 130 (16.92%)
occurrences all number	47	29	29
Infections and infestations
Nasopharyngitis
subjects affected / exposed	11 / 134 (8.21%)	6 / 136 (4.41%)	6 / 130 (4.62%)
occurrences all number	12	6	6

More information

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Were there any global substantial amendments to the protocol? Yes

25 Feb 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, and to correct minor typographical errors and inconsistencies and 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.

12 Feb 2015

The second protocol amendment introduced changes to update the affiliation and contact information of the CI, to correct minor typographical errors and inconsistencies, and to include updated information on tiotropium based on newly available data. The CTP was also 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 12-week treatment period’ was amended to ‘individual FEF25-75 response at each time point and visit during the 12-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 12 weeks of treatment, trough FEV1 expressed as percentage of patient’s predicted FEV1 after 12 weeks of treatment, time to first symptomatic asthma exacerbation during the 12-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.

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

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

Secondary: Trough FVC Change From Baseline

Secondary: Trough FVC 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: FEV1 change from baseline at each individual timepoint

Secondary: FEV1 change from baseline at each individual timepoint

Secondary: FVC change from baseline at each individual timepoint

Secondary: FVC change from baseline at each individual timepoint

Secondary: Control of Asthma as Assessed by ACQ-IA Total Score

Secondary: Control of Asthma as Assessed by ACQ-IA Total Score

Secondary: ACQ-IA Total Score Responders

Secondary: ACQ-IA Total Score Responders

Secondary: Use of PRN Rescue Medication per Day

Secondary: Use of PRN Rescue Medication per Day

Secondary: Use of PRN Rescue Medication During the Daytime

Secondary: Use of PRN Rescue Medication During the Daytime

Secondary: Use of PRN Rescue Medication During the Night-time

Secondary: Use of PRN Rescue Medication During the Night-time

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 a.m. change from baseline

Secondary: FEV1 a.m. change from baseline

Secondary: FEV1 p.m. change from baseline

Secondary: FEV1 p.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