Efficacy and Safety of 2 Doses of Tiotropium Respimat® Co... | NCT01634139

ID	Type	Description	Link
2011-001758-26	EudraCT Number	EudraCT

Name	Class
Pfizer	INDUSTRY

Label	Type	Intervention Names
Tiotropium high dose QD	Experimental	Drug: Tiotropium high dose QD
Tiotropium low dose QD	Experimental	Drug: Tiotropium low dose QD
Placebo QD	Experimental	Drug: Placebo

Name	Type	Description	Arm Group Labels	Other Names
Tiotropium low dose QD	Drug	2 actuations once daily in the evening	Tiotropium low dose QD

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
FEV1 Peak (0-3h) Change From Baseline	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.	Baseline and 24 Weeks.

Secondary Outcomes

Measure	Description	Time Frame
Trough FEV1 Change From Baseline	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.

Eligibility Module

Eligibility Criteria

Inclusion criteria:

Inclusion criteria are:

All patients' parent(s) (or legal guardian) must sign and date an informed consent prior to participation in the trial. In addition, an informed assent suitable for this age group has to be obtained from patients. A separate informed consent/assent is required for pharmacogenomic sampling.
Male or female patients between 6 and 11 years of age.
All patients must have at least a 6-month history of asthma.
All patients must have been on maintenance treatment with an inhaled corticosteroid at a stable medium dose, either as mono treatment or in combination with another controller medication, for at least 4 weeks before Visit 1. While the LTRA is permitted throughout the trial, the LABA has to be stopped at least 24 hours prior to Visit 1, as no LABAs are permitted during screening and treatment period of this trial.
All patients must be symptomatic (partly controlled) at Visit 1 and prior to randomisation at Visit 2 as defined by an Asthma Control Questionnaire (ACQ-IA) mean score >= 1.5.
All patients must have a pre-bronchodilator forced expiratory volume in one second (FEV1) >= 60% and =< 90% of predicted normal at Visit 1.
Variation of absolute FEV1 values of Visit 1 (pre-bronchodilator, considered as 100%) as compared to Visit 2 (pre-dose) must be within ± 30%.
All patients must confirm the diagnosis of asthma by bronchodilator reversibility at Visit 1, resulting in an increase in FEV1 of >= 12%, 15 to 30 minutes after 200 mcg salbutamol/albuterol.
Patients must be able to use the Respimat inhaler correctly.
Patients must be able to perform all trial related procedures including technically acceptable pulmonary function tests and use of electronic diary/peak flow meter (diary compliance of at least 80% is required).

Exclusion criteria:

Exclusion criteria are:

Patients with a significant disease other than asthma.
Patients with a clinically relevant abnormal haematology or blood chemistry at screening.
Patients with a history of congenital or acquired heart disease, or patients who have been hospitalized for cardiac syncope or failure during the past year.
Patients with any unstable or life-threatening cardiac arrhythmia or cardiac arrhythmia requiring intervention or a change in drug therapy within the past year.
Patients with a malignancy for which the patient has undergone resection, radiation therapy or chemotherapy within the last five years.
Patients with known active tuberculosis.
Patients who have undergone thoracotomy with pulmonary resection.
Patients who are currently in a pulmonary rehabilitation program or have completed a pulmonary rehabilitation program in the six weeks prior to Visit 1.
Patients with known hypersensitivity to anticholinergic drugs, BAC, EDTA or any other components of the inhalation solution used with the Respimat inhaler.
Pregnant or nursing female patients, including postmenarchal girl with a positive urine pregnancy test at Visit 1.
Postmenarchal girl of child-bearing potential not using a highly effective method of birth control.
Patients who have been treated with anti-IgE treatment within the last six months prior to Visit 1 and/or during the screening period.
Patients who have been treated with systemic corticosteroids within four weeks prior to Visit 1.
Patients who have been treated with systemic beta-adrenergics within four weeks prior to Visit 1.
Patients who have been treated with oral beta-blocker medication within four weeks prior to Visit 1 and/or during the screening period.
Patients who have been treated with inhaled long-acting anticholinergics or systemic anticholinergic treatment within four weeks prior to Visit 1 and/or during the screening period or who have been treated with inhaled short-acting anticholinergics within two weeks prior to Visit 1.
Patients who have been treated with long-acting theophylline preparations within four weeks prior to Visit 1 and/or during the screening period or who have been treated with short-acting theophylline preparations within two weeks prior to Visit 1.
Patients who have been treated with non-approved and according to international guidelines not recommended experimental drugs for routine asthma therapy within four weeks prior to Visit 1 and/or during the screening period.
Patients who have taken an investigational drug within six half lives according to the investigator's information, or four weeks (whichever is greater) prior to Visit 1 and/or during the screening period.
Patients who have previously been randomised in this trial or are currently participating in another trial.
Patients with any acute asthma exacerbation or respiratory tract infection in the four weeks prior to Visit 1 and /or in four weeks prior to Visit 2. In case of an asthma deterioration occurring in the four weeks prior to Visit 1 and/or in the four weeks prior to Visit 2, the visit must be postponed.
Patients requiring six or more puffs of rescue medication per day on more than two consecutive days in the four weeks prior to Visit 1 and/or in the four weeks prior to Visit 2. In case of an asthma deterioration occurring in the four weeks prior to Visit 1 and/or in the four weeks prior to Visit 2, the visit must be postponed.
Patients who are unable to comply with medication restrictions prior to Visit 1 and or Visit 2.
Patients with a known narrow-angle glaucoma, or any other disease where anticholinergic treatment is contraindicated.
Patients with moderate to severe renal impairment, as defined by a creatinine clearance <50 mL/min/1.73 m2 BSA, as tiotropium is a predominantly renally excreted drug.

Name	Affiliation	Role
Boehringer Ingelheim	Boehringer Ingelheim	Study Chair

Facility	Status	City	State	ZIP	Country	Contacts
205.445.01002 Boehringer Ingelheim Investigational Site		Columbia	Missouri		United States
205.445.01001 Boehringer Ingelheim Investigational Site

ID	Title	Description
FG000	Placebo Respimat	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.
FG001	Tio R2.5

Type

Title

Description

Population Description

Reporting Status

Anticipated Posting Date

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Time Frame

Units Analyzed

Denominator Units Selected

Arm/Group Information

Denominators

Classes

Analyses

Primary

FEV1 Peak (0-3h) Change From Baseline

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.

Posted

Mean

Standard Error

Litres (L)

Baseline and 24 Weeks.

ID	Title	Description
OG000	Placebo Respimat	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.
OG001	Tio R2.5	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.
OG002	Tio R5	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.

Units	Counts
Participants	OG000126 OG001131 OG002134

Title

Denominators

Categories

Title	Measurements
	OG0000.225± 0.027 OG0010.395± 0.026 OG0020.389± 0.026

Group IDs	Group Description	Statistical Method	Statistical Comment	P-Value	P-Value Comment	Parameter Type	Parameter Value	Dispersion Type	Dispersion Value	Confidence Interval Sides	Confidence Interval %	CI Lower Limit	CI Upper Limit	CI Lower Limit Comment	CI Upper Limit Comment	Estimate Comment	Tested Non-Inferiority	Non-Inferiority Type	Non-Inferiority Comment	Other Analysis Description
OG000 OG001	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.	Mixed Models Analysis	Repeated measures restricted maximum likelihood model	<0.0001		Mean Difference (Net)	0.170	Standard Error of the Mean	0.031	2-Sided	95	0.108	0.231			Difference calculated as Tio R2.5 minus placebo	No

Secondary

Trough FEV1 Change From Baseline

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.

Posted

Mean

Standard Error

Litres (L)

Baseline and Week 24, Baseline and Week 48.

ID	Title	Description
OG000	Placebo Respimat	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.
OG001	Tio R2.5	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.
OG002	Tio R5

Secondary

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

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.

The number of participants analysed displays the number of participants with available data at the timepoint of interest.

FAS. 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.

Posted

Mean

Standard Error

Litres (L)

Baseline and Week 48.

ID	Title	Description
OG000	Placebo Respimat	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.
OG001	Tio R2.5	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.
OG002	Tio R5	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.

Secondary

FEV1 AUC (0-3h) Change From Baseline

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.

The number of participants analysed displays the number of participants with available data at the timepoint of interest.

FAS, 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.

Posted

Mean

Standard Error

Litres (L)

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

ID	Title	Description
OG000	Placebo Respimat	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.
OG001	Tio R2.5	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.
OG002	Tio R5	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.

Secondary

FEV1 Change From Baseline at Each Individual Timepoint

FEV1 change from baseline to week 24 at each individual timepoint.

The measured values presented are actually adjusted means.

FAS, 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.

Posted

Mean

Standard Error

Litres (L)

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

ID	Title	Description
OG000	Placebo Respimat	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.
OG001	Tio R2.5	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.
OG002	Tio R5	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.

Secondary

FVC Peak(0-3h) Change From Baseline

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.

FAS, 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.

Posted

Mean

Standard Error

Litres (L)

Baseline and Week 24, Baseline and Week 48.

ID	Title	Description
OG000	Placebo Respimat	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.
OG001	Tio R2.5	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.
OG002	Tio R5	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.

Secondary

Trough FVC Change From Baseline

Change from baseline in Trough (pre-dose) FVC measured at week 24 and 48.

Measured values presented are actually adjusted means.

FAS, 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.

Posted

Mean

Standard Error

Litres (L)

Baseline and Week 24, Baseline and Week 48

ID	Title	Description
OG000	Placebo Respimat	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.
OG001	Tio R2.5	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.
OG002	Tio R5	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.

Secondary

FVC AUC (0-3h) Change From Baseline

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.

The number of participants analysed displays the number of participants with available data at the timepoint of interest.

FAS, 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.

Posted

Mean

Standard Error

Litres (L)

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

ID	Title	Description
OG000	Placebo Respimat	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.
OG001	Tio R2.5	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.
OG002	Tio R5	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.

Secondary

FVC Change From Baseline at Each Individual Timepoint

FVC change from baseline to week 24 at each individual timepoint.

The measured values presented are actually adjusted means

FAS, 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.

Posted

Mean

Standard Error

Litres (L)

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

ID	Title	Description
OG000	Placebo Respimat	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.
OG001	Tio R2.5	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.
OG002	Tio R5	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.

Secondary

Use of PRN (Pro re Nata) Rescue Medication Per Day

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 weeks 24 and 48.

The measured values presented are actually adjusted means.

FAS, 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.

Posted

Mean

Standard Error

Number of puffs of rescue medication

Baseline and Week 24, Baseline and Week 48.

ID	Title	Description
OG000	Placebo Respimat	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.
OG001	Tio R2.5	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.
OG002	Tio R5	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.

Secondary

Use of PRN Rescue Medication During Daytime

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

FAS, 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.

Posted

Mean

Standard Error

Number of puffs of rescue medication

Baseline and Week 24, Baseline and Week 48.

ID	Title	Description
OG000	Placebo Respimat	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.
OG001	Tio R2.5	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.
OG002	Tio R5	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.

Secondary

Use of PRN Rescue Medication During Nighttime

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.

FAS, 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.

Posted

Mean

Standard Error

Number of puffs of rescue medication

Baseline and Week 24, Baseline and Week 48.

ID	Title	Description
OG000	Placebo Respimat	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.
OG001	Tio R2.5	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.
OG002	Tio R5	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.

Secondary

Peak Expiratory Flow (PEF) a.m. Change From Baseline

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.

FAS, 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.

Posted

Mean

Standard Error

Litres per min (L/min)

Baseline and Week 24, Baseline and Week 48.

ID	Title	Description
OG000	Placebo Respimat	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.
OG001	Tio R2.5	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.
OG002	Tio R5	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.

Secondary

PEF p.m. Change From Baseline

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.

FAS, 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.

Posted

Mean

Standard Error

Litres per min (L/min)

Baseline and Week 24, Baseline and Week 48.

ID	Title	Description
OG000	Placebo Respimat	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.
OG001	Tio R2.5	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.
OG002	Tio R5	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.

Secondary

PEF Variability Change From Baseline

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.

FAS, 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.

Posted

Mean

Standard Error

Percentage of PEF

Baseline and Week 24, Baseline and Week 48.

ID	Title	Description
OG000	Placebo Respimat	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.
OG001	Tio R2.5	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.
OG002	Tio R5	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.

Secondary

FEV1 a.m Change From Baseline

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.

FAS, 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.

Posted

Mean

Standard Error

Litres

Baseline and Week 24, Baseline and Week 48.

ID	Title	Description
OG000	Placebo Respimat	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.
OG001	Tio R2.5	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.
OG002	Tio R5	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.

Secondary

FEV1 p.m. Change From Baseline

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.

FAS, 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.

Posted

Mean

Standard Error

Litres (L)

Baseline and Week 24, Baseline and Week 48.

ID	Title	Description
OG000	Placebo Respimat	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.
OG001	Tio R2.5	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.
OG002	Tio R5	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.

Secondary

ACQ-IA Total Score

Interviewer Administered Asthma Control Questionnaire (ACQ-IA) total score 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.

FAS, 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.

Posted

Mean

Standard Error

Units on a Scale

Weeks 24 and 48.

ID	Title	Description
OG000	Placebo Respimat	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.
OG001	Tio R2.5	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.
OG002	Tio R5

Secondary

ACQ-IA Responder Analysis

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 \

FAS, 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

Posted

Number

Patients

Weeks 24 and 48

ID	Title	Description
OG000	Placebo Respimat	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.
OG001	Tio R2.5	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.
OG002	Tio R5

Secondary

PAQLQ(S) Total Score

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.

FAS, 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.

Posted

Mean

Standard Error

Units on a Scale

Weeks 24 and 48.

ID	Title	Description
OG000	Placebo Respimat	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.
OG001	Tio R2.5	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.
OG002	Tio R5	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.

Secondary

PAQLQ(S) Symptom Domain Score

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.

FAS, 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.

Posted

Mean

Standard Error

Units on a Scale

Weeks 24 and 48.

ID	Title	Description
OG000	Placebo Respimat	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.
OG001	Tio R2.5	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.
OG002	Tio R5	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.

Secondary

PAQLQ(S) Activity Limitation Domain Score

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.

FAS, 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.

Posted

Mean

Standard Error

Units on a Scale

Weeks 24 and 48.

ID	Title	Description
OG000	Placebo Respimat	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.
OG001	Tio R2.5	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.
OG002	Tio R5	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.

Secondary

PAQLQ(S) Emotional Function Domain Score

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.

FAS, 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.

Posted

Mean

Standard Error

Units on a Scale

Weeks 24 and 48.

ID	Title	Description
OG000	Placebo Respimat	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.
OG001	Tio R2.5	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.
OG002	Tio R5	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.

Secondary

Responders in PAQLQ(S) at Weeks 24 and 48

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 \

FAS, 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.

Posted

Number

Patients

Weeks 24 and 48.

ID	Title	Description
OG000	Placebo Respimat	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.
OG001	Tio R2.5	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.
OG002	Tio R5	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.

Secondary

Change From Baseline in Nighttime Awakenings

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.

FAS, 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.

Posted

Mean

Standard Error

Units on a scale

Baseline and Week 24, Baseline and Week 48.

ID	Title	Description
OG000	Placebo Respimat	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.
OG001	Tio R2.5	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.
OG002	Tio R5

Secondary

Change From Baseline in Morning Asthma Symptoms

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.

FAS, 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.

Posted

Mean

Standard Error

Units on a scale

Baseline and Week 24, Baseline and Week 48.

ID	Title	Description
OG000	Placebo Respimat	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.
OG001	Tio R2.5	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.
OG002	Tio R5

Secondary

Change From Baseline in Daytime Asthma Symptoms

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.

FAS, 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.

Posted

Mean

Standard Error

Units on a scale

Baseline and Week 24, Baseline and Week 48.

ID	Title	Description
OG000	Placebo Respimat	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.
OG001	Tio R2.5	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.
OG002	Tio R5

Secondary

Change From Baseline in Daytime Activity Limitations

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.

FAS, 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.

Posted

Mean

Standard Error

Units on a scale

Baseline and Week 24, Baseline and Week 48.

ID	Title	Description
OG000	Placebo Respimat	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.
OG001	Tio R2.5	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.
OG002	Tio R5

Secondary

Change From Baseline in Daytime Experiences of Shortness of Breath

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.

FAS, 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.

Posted

Mean

Standard Error

Units on a scale

Baseline and Week 24, Baseline and Week 48.

ID	Title	Description
OG000	Placebo Respimat	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.
OG001	Tio R2.5	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.
OG002	Tio R5

Secondary

Change From Baseline in Daytime Experiences of Wheeze or Cough

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.

FAS, 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.

Posted

Mean

Standard Error

Units on a scale

Baseline and Week 24, Baseline and Week 48.

ID	Title	Description
OG000	Placebo Respimat	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.
OG001	Tio R2.5	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.
OG002	Tio R5

Secondary

Change From Baseline in Asthma Symptom-free Days

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 (electronic diary) and no use of rescue medication reported via the eDiary during that day.

Measured values presented are actually adjusted means.

FAS, 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.

Posted

Mean

Standard Error

Days

Baseline and Week 24, Baseline and Week 48.

ID	Title	Description
OG000	Placebo Respimat	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.
OG001	Tio R2.5	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.
OG002	Tio R5

Serious Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Ileus paralytic	Gastrointestinal disorders	MedDRA 18.1	Systematic Assessment	EG0000 affected131 at risk EG0010 affected135 at risk EG0021 affected135 at risk
Anaphylactic reaction	Immune system disorders	MedDRA 18.1	Systematic Assessment	EG0001 affected131 at risk EG0010 affected135 at risk EG0020 affected135 at risk
Appendicitis	Infections and infestations	MedDRA 18.1	Systematic Assessment	EG0000 affected131 at risk EG0011 affected135 at risk EG0021 affected135 at risk
Gastroenteritis	Infections and infestations	MedDRA 18.1	Systematic Assessment	EG0001 affected131 at risk EG0010 affected135 at risk EG0020 affected135 at risk
Renal abscess	Infections and infestations	MedDRA 18.1	Systematic Assessment	EG0001 affected131 at risk EG0010 affected135 at risk EG0020 affected135 at risk
Concussion	Injury, poisoning and procedural complications	MedDRA 18.1	Systematic Assessment	EG0001 affected131 at risk EG0010 affected135 at risk EG0020 affected135 at risk
Fall	Injury, poisoning and procedural complications	MedDRA 18.1	Systematic Assessment	EG0001 affected131 at risk EG0010 affected135 at risk EG0020 affected135 at risk
Skull fracture	Injury, poisoning and procedural complications	MedDRA 18.1	Systematic Assessment	EG0001 affected131 at risk EG0010 affected135 at risk EG0020 affected135 at risk
Asthma	Respiratory, thoracic and mediastinal disorders	MedDRA 18.1	Systematic Assessment	EG0002 affected131 at risk EG0012 affected135 at risk EG0020 affected135 at risk
Paranasal sinus haematoma	Respiratory, thoracic and mediastinal disorders	MedDRA 18.1	Systematic Assessment	EG0001 affected131 at risk EG0010 affected135 at risk EG0020 affected135 at risk

Other Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Nasopharyngitis	Infections and infestations	MedDRA 18.1	Systematic Assessment	EG00013 affected131 at risk EG00115 affected135 at risk EG00212 affected135 at risk
Rhinitis	Infections and infestations	MedDRA 18.1	Systematic Assessment	EG0007 affected131 at risk EG0015 affected135 at risk EG0022 affected135 at risk
Peak expiratory flow rate decreased	Investigations	MedDRA 18.1	Systematic Assessment	EG00027 affected131 at risk EG00131 affected135 at risk EG00229 affected135 at risk
Asthma	Respiratory, thoracic and mediastinal disorders	MedDRA 18.1	Systematic Assessment	EG00057 affected131 at risk EG00149 affected135 at risk EG00246 affected135 at risk
Rhinitis allergic	Respiratory, thoracic and mediastinal disorders	MedDRA 18.1	Systematic Assessment	EG0008 affected131 at risk EG0014 affected135 at risk EG0026 affected135 at risk
Respiratory tract infection	Infections and infestations	MedDRA 18.1	Systematic Assessment	EG00016 affected131 at risk EG00111 affected135 at risk EG00213 affected135 at risk
Respiratory tract infection viral	Infections and infestations	MedDRA 18.1	Systematic Assessment	EG0008 affected131 at risk EG0018 affected135 at risk EG0028 affected135 at risk

ID	Term
D001982	Bronchial Diseases
D012140	Respiratory Tract Diseases
D008173	Lung Diseases, Obstructive
D008171	Lung Diseases
D012130	Respiratory Hypersensitivity
D006969	Hypersensitivity, Immediate
D006967	Hypersensitivity
D007154	Immune System Diseases

ID	Term
D012602	Scopolamine Derivatives
D014326	Tropanes
D053961	Azabicyclo Compounds
D001372	Aza Compounds
D009930	Organic Chemicals
D000470	Alkaloids
D006571	Heterocyclic Compounds
D019086	Bridged Bicyclo Compounds, Heterocyclic
D006572	Heterocyclic Compounds, Bridged-Ring

ID	Title	Description
BG000	Placebo Respimat	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.
BG001	Tio R2.5	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.
BG002	Tio R5	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.
BG003	Total	Total of all reporting groups

ID	Title	Description	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	Placebo	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.	6	131	79	131
EG001	Tio R2.5	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.	3	135	76	135
EG002	Tio R5	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.	1	135	71	135