Evaluation of Tiotropium 2.5 and 5 mcg Once Daily Deliver... | NCT01172808

NCT01172808

ID	Type	Description	Link
2009-018004-18	EudraCT Number	EudraCT

Status Module

Name	Class
Pfizer	INDUSTRY

Label	Type	Description	Intervention Names
tiotropium low dose	Experimental	Once daily, delivered with Respimat® inhaler (+ inhalation of placebo HFA MDI twice daily)	Drug: Placebo Drug: tiotropium Respimat® low dose
tiotropium high dose	Experimental	Once daily, delivered with Respimat® inhaler (+ inhalation of placebo HFA MDI twice daily)	Drug: Placebo Drug: tiotropium Respimat® high dose
50 mcg salmeterol	Active Comparator	Twice daily, delivered with HFA MDI (+ inhalation of placebo Respimat® inhaler once daily)	Drug: 50 mcg salmeterol HFA MDI Drug: Placebo
placebo	Placebo Comparator	Once daily, delivered with Respimat® inhaler + twice daily delivered with HFA MDI	Drug: Placebo

Name	Type	Description	Arm Group Labels	Other Names
Placebo	Drug	Placebo that represents comparator	tiotropium low dose

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
Peak FEV1 Within 3 Hours Post-dose Response	Peak forced expiratory volume in one second (FEV1) response within 3 hours post-dose determined at the end of the 24-week treatment. Response was defined as change from baseline (10 minutes before the first dose of trial medication at visit 2). Means are adjusted for treatment, centre, week, baseline, treatment by week, and baseline by week.	24 weeks
Trough FEV1 Response	Trough FEV1 response determined at the end of the 24-week treatment. Response was defined as change from baseline (10 minutes before the first dose of trial medication at visit 2). Means are adjusted for treatment, centre, week, baseline, treatment by week, and baseline by week.	24 weeks
The Responder Rate as Assessed by the ACQ From the Two Twin Trials 205.419 (NCT01172821) and the Present 205.418 (NCT01172808)	The responder rate as assessed by the Asthma Control Questionnaire (ACQ) determined at the end of the 24-week treatment period (on combined data from the two twin trials 205.418 (NCT01172808) and 205.419 (NCT01172821)). A patient was considered to be a responder if he or she was reported with an improvement (decrease) in the ACQ total score of at least 0.5 points. The ACQ total score was calculated as the mean of the responses to 7 questions and was analysed as an absolute value. The score ranges from 0 (no impairment) to 6 (maximum impairment).	24 weeks

Secondary Outcomes

Measure	Description	Time Frame
Peak FVC Within 3 Hours Post-dose Response	Peak forced vital capacity (FVC) response within 3 hours post-dose determined at the end of the 24-week treatment. Response was defined as change from baseline (10 minutes before the first dose of trial medication at visit 2). Means are adjusted for treatment, centre, week, baseline, treatment by week, and baseline by week.	24 weeks

Eligibility Module

Eligibility Criteria

Inclusion criteria:

All patients must sign and date an Informed Consent Form consistent with International Conference on Harmonisation - Good Clinical Practice (ICH-GCP) guidelines and local legislation prior to participation in the trial (i.e. prior to any trial procedures, including any pre-trial washout of medications and medication restrictions for pulmonary function test at Visit 1).
Male or female patients aged at least 18 years but not more than 75 years.
All patients must have at least a 3 month history of asthma at the time of enrolment into the trial. The diagnosis should be confirmed at Visit 1 by fulfilling inclusion criterion 5.
The initial diagnosis of asthma must have been made before the patient's age of 40.
The diagnosis of asthma has to be confirmed at Visit 1 with a bronchodilator reversibility (15 minutes after 400 mcg salbutamol (albuterol)) resulting in a Forced Expiratory Volume in one second (FEV1) increase of at least 12% and at least 200mL.
All patients must have been on maintenance treatment with a medium, stable dose of inhaled corticosteroids for at least for 4 weeks prior to Visit 1.
All patients must be symptomatic at Visit 1 (screening) and prior to randomisation at Visit 2 as defined by an Asthma Control Questionnaire (ACQ) mean score of at least 1.5.
All patients must have a pre-bronchodilator FEV1 at least 60% and less than or equal to 90% of predicted normal at Visit 1.
Variation of absolute FEV1 values of Visit 1 (pre-bronchodilator) as compared to Visit 2 (pre-dose) must be within ± 30%.
Patients must be never-smokers or ex-smokers who stopped smoking at least one year prior to enrolment (Visit 0) and who have a smoking history of less than 10 pack years.
Patients must be able to use the Respimat® inhaler and metered dose 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.

Exclusion criteria:

Patients with a significant disease other than asthma. A significant disease is defined as a disease which, in the opinion of the investigator, may (i) put the patient at risk because of participation in the trial, or (ii) influence the results of the trial, or (iii) cause concern regarding the patient's ability to participate in the trial.
Patients with a clinically relevant abnormal screening (Visit 1) haematology or blood chemistry if the abnormality defines a significant disease as defined in exclusion criterion 1.
Patients with a recent history (i.e. six months or less) of myocardial infarction.
Patients who have been hospitalised for cardiac 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 lung diseases other than asthma (e.g. Chronic Obstructive Pulmonary Disease (COPD)).
Patients with known active tuberculosis.
Patients with malignancy for which the patient has undergone resection, radiation therapy or chemotherapy within the last five years. Patients with treated basal cell carcinoma are allowed.
Patients who have undergone thoracotomy with pulmonary resection. Patients with a history of thoracotomy for other reasons should be evaluated as per exclusion criterion no. 1.
Patients with significant alcohol or drug abuse within the past two years.
Patients who are currently in a pulmonary rehabilitation program or have completed a pulmonary rehabilitation program in the 6 weeks prior to Visit 1 (screening).
Patients with known hypersensitivity to anticholinergic drugs, benzalkonium chloride (BAC), ethylenediamineteraacetic acid (EDTA), salmeterol xinafoate or any other components of the study medication delivery systems.
Pregnant or nursing woman.
Women of childbearing potential not using a highly effective method of birth control.
Patients who have taken an investigational drug within four weeks prior to Visit 1.
Patients who have been treated with beta-blocker medication within four weeks prior to Visit 1 and/or during the screening period. Topical cardio-selective beta-blocker eye medications for non-narrow angle glaucoma are allowed.
Patients who have been treated with the long-acting anticholinergic tiotropium (Spiriva®) within four weeks prior to Visit 1 and/or during the screening period.
Patients who have been treated with oral or patch beta-adrenergics within four weeks prior to Visit 1 and/or during the Screening period.
Patients who have been treated with oral corticosteroids within four weeks prior to Visit 1 and/or during the screening period.
Patients who have been treated with anti-IgE antibodies, e.g. omalizumab (Xolair®), within 6 months prior to Visit 1 and/or during the screening period.
Patients who have been treated with cromone within two weeks prior to Visit 1 and/or during the screening period.
Patients who have been treated with methylxanthines or phosphodiesterase 4 inhibitors within two weeks prior to Visit 1 and/or during the screening period.
Patients who have been treated with other 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 with any asthma exacerbation or any respiratory tract infection iin the four weeks prior to Visit 1 and/or during the screening period.
Patients who have previously been randomised in this trial or in the respective twin trial (205.419) or are currently participating in another trial.

Name	Affiliation	Role
Boehringer Ingelheim	Boehringer Ingelheim	Study Chair

Facility	Status	City	State	ZIP	Country	Contacts
205.418.01020 Boehringer Ingelheim Investigational Site		Huntington Beach	California		United States

PubMed Identifier	Type	Citation	Retractions
32180164	Derived	Halpin DMG, Hamelmann EH, Frith PA, Moroni-Zentgraf PM, van Hecke B, Unseld A, Kerstjens HAM, Szefler SJ. Comparative Responses in Lung Function Measurements with Tiotropium in Adolescents and Adults, and Across Asthma Severities: A Post Hoc Analysis. Pulm Ther. 2020 Jun;6(1):131-140. doi: 10.1007/s41030-020-00113-w. Epub 2020 Mar 16.
31654891

ID	Title	Description
FG000	Placebo	Matching Placebo delivered by the Respimat Inhaler resp. MDI (hydrofluoroalkane (HFA 134a) metered inhaler).
FG001	Tio R2.5	Tiotropium 2.5 microgram (mcg) qd (evening) delivered by the Respimat Inhaler.

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

Peak FEV1 Within 3 Hours Post-dose Response

Peak forced expiratory volume in one second (FEV1) response within 3 hours post-dose determined at the end of the 24-week treatment. Response was defined as change from baseline (10 minutes before the first dose of trial medication at visit 2). Means are adjusted for treatment, centre, week, baseline, treatment by week, and baseline by week.

Full Analysis Set (FAS) - all treated patients who had baseline data and at least 1 on-treatment efficacy measurement excluding patients from one centre due to non-compliance with good clinical practice.

Posted

Mean

Standard Error

Litre

24 weeks

ID	Title	Description
OG000	Placebo	Matching Placebo delivered by the Respimat Inhaler resp. MDI (hydrofluoroalkane (HFA 134a) metered inhaler).
OG001	Tio R2.5	Tiotropium 2.5 microgram (mcg) qd (evening) delivered by the Respimat Inhaler.
OG002	Tio R5	Tiotropium 5 mcg qd (evening) delivered by the Respimat Inhaler.
OG003	Salmeterol	Salmeterol 50 mcg bid (morning and evening) delivered by the MDI (hydrofluoroalkane (HFA 134a) metered inhaler).

Units	Counts
Participants	OG000250 OG001247 OG002241 OG003

Title

Denominators

Categories

Title	Measurements
	OG0000.053± 0.021 OG0010.289± 0.021 OG0020.250± 0.021 OG003

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	Analyses included the fixed, categorical effects of treatment, centre, week, and treatment-by-week interaction, as well as the covariates of baseline value and baseline value-by-week interaction. Patient was included as a random effect in the model.	Mixed Models Analysis	Adjusted using a restricted maximum likelihood (REML)-based mixed effects model with repeated measures (MMRM).	<0.0001		Mean Difference (Final Values)	0.236	Standard Error of the Mean	0.028	2-Sided	95	0.181	0.291			Tio R2.5 - Placebo	No

Primary

Trough FEV1 Response

Trough FEV1 response determined at the end of the 24-week treatment. Response was defined as change from baseline (10 minutes before the first dose of trial medication at visit 2). Means are adjusted for treatment, centre, week, baseline, treatment by week, and baseline by week.

FAS

Posted

Mean

Standard Error

Litre

24 weeks

ID	Title	Description
OG000	Placebo	Matching Placebo delivered by the Respimat Inhaler resp. MDI (hydrofluoroalkane (HFA 134a) metered inhaler).
OG001	Tio R2.5	Tiotropium 2.5 microgram (mcg) qd (evening) delivered by the Respimat Inhaler.
OG002	Tio R5	Tiotropium 5 mcg qd (evening) delivered by the Respimat Inhaler.
OG003	Salmeterol	Salmeterol 50 mcg bid (morning and evening) delivered by the MDI (hydrofluoroalkane (HFA 134a) metered inhaler).

Secondary

Peak FVC Within 3 Hours Post-dose Response

Peak forced vital capacity (FVC) response within 3 hours post-dose determined at the end of the 24-week treatment. Response was defined as change from baseline (10 minutes before the first dose of trial medication at visit 2). Means are adjusted for treatment, centre, week, baseline, treatment by week, and baseline by week.

FAS

Posted

Mean

Standard Error

Litre

24 weeks

ID	Title	Description
OG000	Placebo	Matching Placebo delivered by the Respimat Inhaler resp. MDI (hydrofluoroalkane (HFA 134a) metered inhaler).
OG001	Tio R2.5	Tiotropium 2.5 microgram (mcg) qd (evening) delivered by the Respimat Inhaler.
OG002	Tio R5	Tiotropium 5 mcg qd (evening) delivered by the Respimat Inhaler.
OG003	Salmeterol	Salmeterol 50 mcg bid (morning and evening) delivered by the MDI (hydrofluoroalkane (HFA 134a) metered inhaler).

Secondary

Trough FVC Response

Trough FVC response determined at the end of the 24-week treatment. Response was defined as change from baseline (10 minutes before the first dose of trial medication at visit 2). Means are adjusted for treatment, country, week, baseline, treatment by week, and baseline by week.

FAS

Posted

Mean

Standard Error

Litre

24 weeks

ID	Title	Description
OG000	Placebo	Matching Placebo delivered by the Respimat Inhaler resp. MDI (hydrofluoroalkane (HFA 134a) metered inhaler).
OG001	Tio R2.5	Tiotropium 2.5 microgram (mcg) qd (evening) delivered by the Respimat Inhaler.
OG002	Tio R5	Tiotropium 5 mcg qd (evening) delivered by the Respimat Inhaler.
OG003	Salmeterol	Salmeterol 50 mcg bid (morning and evening) delivered by the MDI (hydrofluoroalkane (HFA 134a) metered inhaler).

Secondary

FEV1 Area Under Curve 0-3 Hours (AUC0-3h) Response

Response was defined as change from baseline (10 minutes before the first dose of trial medication at visit 2) determined at the end of the 24-week treatment. Means are adjusted for treatment, centre, week, baseline, treatment by week, and baseline by week. FEV1 AUC 0-3h was calculated from 0-3 hours post-dose using the trapezoidal rule, divided by the observation time (3h) to report in litres.

FAS

Posted

Mean

Standard Error

Litre

24 weeks

ID	Title	Description
OG000	Placebo	Matching Placebo delivered by the Respimat Inhaler resp. MDI (hydrofluoroalkane (HFA 134a) metered inhaler).
OG001	Tio R2.5	Tiotropium 2.5 microgram (mcg) qd (evening) delivered by the Respimat Inhaler.
OG002	Tio R5	Tiotropium 5 mcg qd (evening) delivered by the Respimat Inhaler.
OG003	Salmeterol	Salmeterol 50 mcg bid (morning and evening) delivered by the MDI (hydrofluoroalkane (HFA 134a) metered inhaler).

Secondary

FVC Area Under Curve 0-3 Hours (AUC0-3h) Response

Response was defined as change from baseline (10 minutes before the first dose of trial medication at visit 2) determined at the end of the 24-week treatment. Means are adjusted for treatment, country, week, baseline, treatment by week, and baseline by week. FVC AUC 0-3h was calculated from 0-3 hours post-dose using the trapezoidal rule, divided by the observation time (3h) to report in litres.

FAS

Posted

Mean

Standard Error

Litre

24 weeks

ID	Title	Description
OG000	Placebo	Matching Placebo delivered by the Respimat Inhaler resp. MDI (hydrofluoroalkane (HFA 134a) metered inhaler).
OG001	Tio R2.5	Tiotropium 2.5 microgram (mcg) qd (evening) delivered by the Respimat Inhaler.
OG002	Tio R5	Tiotropium 5 mcg qd (evening) delivered by the Respimat Inhaler.
OG003	Salmeterol	Salmeterol 50 mcg bid (morning and evening) delivered by the MDI (hydrofluoroalkane (HFA 134a) metered inhaler).

Secondary

Trough PEF Response

Trough peak expiratory flow (PEF) response determined at the end of the 24-week treatment. Response was defined as change from baseline (10 minutes before the first dose of trial medication at visit 2). Means are adjusted for treatment, centre, week, baseline, treatment by week, and baseline by week.

FAS

Posted

Mean

Standard Error

Litre/min

24 weeks

ID	Title	Description
OG000	Placebo	Matching Placebo delivered by the Respimat Inhaler resp. MDI (hydrofluoroalkane (HFA 134a) metered inhaler).
OG001	Tio R2.5	Tiotropium 2.5 microgram (mcg) qd (evening) delivered by the Respimat Inhaler.
OG002	Tio R5	Tiotropium 5 mcg qd (evening) delivered by the Respimat Inhaler.
OG003	Salmeterol	Salmeterol 50 mcg bid (morning and evening) delivered by the MDI (hydrofluoroalkane (HFA 134a) metered inhaler).

Secondary

Total Asthma Quality of Life Questionnaire (AQLQs)) Score

Total score from the Standardised Asthma Quality of Life Questionnaire (AQLQ(s)) determined at the end of 24-week treatment. The AQLQ(s) contains 32 questions, each question has a 7 point scale from 1 (highest intensity) till 7 (no symptoms). Total score was defined as the sum of all items divided by the number of items. Means are adjusted for treatment, centre, week, baseline, treatment by week, and baseline by week.

FAS

Posted

Mean

Standard Error

units on a scale

24 weeks

ID	Title	Description
OG000	Placebo	Matching Placebo delivered by the Respimat Inhaler resp. MDI (hydrofluoroalkane (HFA 134a) metered inhaler).
OG001	Tio R2.5	Tiotropium 2.5 microgram (mcg) qd (evening) delivered by the Respimat Inhaler.
OG002	Tio R5	Tiotropium 5 mcg qd (evening) delivered by the Respimat Inhaler.
OG003	Salmeterol	Salmeterol 50 mcg bid (morning and evening) delivered by the MDI (hydrofluoroalkane (HFA 134a) metered inhaler).

Secondary

Total Asthma Control Questionnaire (ACQ) Score at the End of the 24-week Treatment Period

Control of asthma as assessed by the ACQ determined at the end of 24-week treatment. The ACQ contains 7 questions, each question has a 7 point scale from 0 (no symptoms) till 6 (highest intensity). Total score was defined as the sum of all items divided by the number of items. Means are adjusted for treatment, centre, week, baseline, treatment by week, and baseline by week.

FAS

Posted

Mean

Standard Error

units on a scale

24 weeks

ID	Title	Description
OG000	Placebo	Matching Placebo delivered by the Respimat Inhaler resp. MDI (hydrofluoroalkane (HFA 134a) metered inhaler).
OG001	Tio R2.5	Tiotropium 2.5 microgram (mcg) qd (evening) delivered by the Respimat Inhaler.
OG002	Tio R5	Tiotropium 5 mcg qd (evening) delivered by the Respimat Inhaler.
OG003	Salmeterol	Salmeterol 50 mcg bid (morning and evening) delivered by the MDI (hydrofluoroalkane (HFA 134a) metered inhaler).

Secondary

The Responder Rate as Assessed by the ACQ

The responder rate as assessed by the Asthma Control Questionnaire (ACQ) determined at the end of the 24-week treatment period. A patient was considered to be a responder if he or she was reported with an improvement (decrease) in ACQ total score of at least 0.5 points. The ACQ total score was calculated as the mean of the responses to 7 questions and was analysed as an absolute value. The score ranges from 0 (no impairment) to 6 (maximum impairment).

FAS

Posted

Number

Percentage of Participants

24 weeks

ID	Title	Description
OG000	Placebo	Matching Placebo delivered by the Respimat Inhaler resp. MDI (hydrofluoroalkane (HFA 134a) metered inhaler).
OG001	Tio R2.5	Tiotropium 2.5 microgram (mcg) qd (evening) delivered by the Respimat Inhaler.
OG002	Tio R5	Tiotropium 5 mcg qd (evening) delivered by the Respimat Inhaler.
OG003	Salmeterol	Salmeterol 50 mcg bid (morning and evening) delivered by the MDI (hydrofluoroalkane (HFA 134a) metered inhaler).

Secondary

Mean Pre-dose Morning PEF (PEF a.m.) Based on the Weekly Mean Response at Week 24

Weekly means obtained during the last 7 days before week 24 measured by patients at home using the AM3 device. Response was defined as change from baseline. Means are adjusted for treatment, country, week, baseline, treatment by week, and baseline by week.

FAS

Posted

Mean

Standard Error

Litre/min

Baseline and last 7 days before week 24 visit

ID	Title	Description
OG000	Placebo	Matching Placebo delivered by the Respimat Inhaler resp. MDI (hydrofluoroalkane (HFA 134a) metered inhaler).
OG001	Tio R2.5	Tiotropium 2.5 microgram (mcg) qd (evening) delivered by the Respimat Inhaler.
OG002	Tio R5	Tiotropium 5 mcg qd (evening) delivered by the Respimat Inhaler.
OG003	Salmeterol	Salmeterol 50 mcg bid (morning and evening) delivered by the MDI (hydrofluoroalkane (HFA 134a) metered inhaler).

Secondary

Mean Pre-dose Evening PEF (PEF p.m.) Based on the Weekly Mean Response at Week 24

FAS

Posted

Mean

Standard Error

Litre/min

Baseline and last 7 days before week 24 visit

ID	Title	Description
OG000	Placebo	Matching Placebo delivered by the Respimat Inhaler resp. MDI (hydrofluoroalkane (HFA 134a) metered inhaler).
OG001	Tio R2.5	Tiotropium 2.5 microgram (mcg) qd (evening) delivered by the Respimat Inhaler.
OG002	Tio R5	Tiotropium 5 mcg qd (evening) delivered by the Respimat Inhaler.
OG003	Salmeterol	Salmeterol 50 mcg bid (morning and evening) delivered by the MDI (hydrofluoroalkane (HFA 134a) metered inhaler).

Secondary

PEF Variability

PEF daily variability was assesed by patients at home using the AM3 device. PEF variability is the absolute difference between morning and evening PEF value divided by their mean, based on the weekly mean response at week 24. Means are adjusted for treatment, centre, week, baseline, treatment by week, and baseline by week.

FAS

Posted

Mean

Standard Error

Percentage of mean PEF

Last 7 days before week 24 visit

ID	Title	Description
OG000	Placebo	Matching Placebo delivered by the Respimat Inhaler resp. MDI (hydrofluoroalkane (HFA 134a) metered inhaler).
OG001	Tio R2.5	Tiotropium 2.5 microgram (mcg) qd (evening) delivered by the Respimat Inhaler.
OG002	Tio R5	Tiotropium 5 mcg qd (evening) delivered by the Respimat Inhaler.
OG003	Salmeterol	Salmeterol 50 mcg bid (morning and evening) delivered by the MDI (hydrofluoroalkane (HFA 134a) metered inhaler).

Secondary

Mean Pre-dose Morning FEV1 (FEV1 a.m.) Based on the Weekly Mean Response at Week 24

FAS

Posted

Mean

Standard Error

Litre

Baseline and last 7 days before week 24 visit

ID	Title	Description
OG000	Placebo	Matching Placebo delivered by the Respimat Inhaler resp. MDI (hydrofluoroalkane (HFA 134a) metered inhaler).
OG001	Tio R2.5	Tiotropium 2.5 microgram (mcg) qd (evening) delivered by the Respimat Inhaler.
OG002	Tio R5	Tiotropium 5 mcg qd (evening) delivered by the Respimat Inhaler.
OG003	Salmeterol	Salmeterol 50 mcg bid (morning and evening) delivered by the MDI (hydrofluoroalkane (HFA 134a) metered inhaler).

Secondary

Mean Pre-dose Evening FEV1 (FEV1 p.m.) Based on the Weekly Mean Response at Week 24

FAS

Posted

Mean

Standard Error

Litre

Baseline and last 7 days before week 24 visit

ID	Title	Description
OG000	Placebo	Matching Placebo delivered by the Respimat Inhaler resp. MDI (hydrofluoroalkane (HFA 134a) metered inhaler).
OG001	Tio R2.5	Tiotropium 2.5 microgram (mcg) qd (evening) delivered by the Respimat Inhaler.
OG002	Tio R5	Tiotropium 5 mcg qd (evening) delivered by the Respimat Inhaler.
OG003	Salmeterol	Salmeterol 50 mcg bid (morning and evening) delivered by the MDI (hydrofluoroalkane (HFA 134a) metered inhaler).

Secondary

Mean Number of Puffs of Rescue Medication During the Entire 24-h Day Based on the Weekly Mean Response at Week 24

Daily use of salbutamol (albuterol) rescue medication as needed during the entire study period. Weekly means obtained during the last 7 days before week 24 measured by patients at home using the AM3 device. Response was defined as change from baseline. Means are adjusted for treatment, country, week, baseline, treatment by week, and baseline by week.

FAS

Posted

Mean

Standard Error

Number of Puffs

Baseline and last 7 days before week 24 visit

ID	Title	Description
OG000	Placebo	Matching Placebo delivered by the Respimat Inhaler resp. MDI (hydrofluoroalkane (HFA 134a) metered inhaler).
OG001	Tio R2.5	Tiotropium 2.5 microgram (mcg) qd (evening) delivered by the Respimat Inhaler.
OG002	Tio R5	Tiotropium 5 mcg qd (evening) delivered by the Respimat Inhaler.
OG003	Salmeterol	Salmeterol 50 mcg bid (morning and evening) delivered by the MDI (hydrofluoroalkane (HFA 134a) metered inhaler).

Secondary

Asthma Symptom-free Days Based on the Weekly Mean Response at Week 24

FAS

Posted

Mean

Standard Error

Days

Baseline and last 7 days before week 24 visit

ID	Title	Description
OG000	Placebo	Matching Placebo delivered by the Respimat Inhaler resp. MDI (hydrofluoroalkane (HFA 134a) metered inhaler).
OG001	Tio R2.5	Tiotropium 2.5 microgram (mcg) qd (evening) delivered by the Respimat Inhaler.
OG002	Tio R5	Tiotropium 5 mcg qd (evening) delivered by the Respimat Inhaler.
OG003	Salmeterol	Salmeterol 50 mcg bid (morning and evening) delivered by the MDI (hydrofluoroalkane (HFA 134a) metered inhaler).

Primary

The Responder Rate as Assessed by the ACQ From the Two Twin Trials 205.419 (NCT01172821) and the Present 205.418 (NCT01172808)

The responder rate as assessed by the Asthma Control Questionnaire (ACQ) determined at the end of the 24-week treatment period (on combined data from the two twin trials 205.418 (NCT01172808) and 205.419 (NCT01172821)). A patient was considered to be a responder if he or she was reported with an improvement (decrease) in the ACQ total score of at least 0.5 points.

The ACQ total score was calculated as the mean of the responses to 7 questions and was analysed as an absolute value. The score ranges from 0 (no impairment) to 6 (maximum impairment).

FAS of combined data from the two twin trials 205.419 (NCT01172821) and 205.418 (NCT01172808)

Posted

Number

Percentage of participants

24 weeks

ID	Title	Description
OG000	Placebo	Matching Placebo delivered by the Respimat Inhaler resp. MDI (hydrofluoroalkane (HFA 134a) metered inhaler).
OG001	Tio R2.5	Tiotropium 2.5 microgram (mcg) qd (evening) delivered by the Respimat Inhaler.
OG002	Tio R5	Tiotropium 5 mcg qd (evening) delivered by the Respimat Inhaler.

Secondary

Time to First Severe Asthma Exacerbation From the Two Twin Trials 205.419 (NCT01172821) and the Present 205.418 (NCT01172808)

Time to first severe asthma exacerbation during the 24-week treatment period on combined data from the two twin trials 205.418 (NCT01172808) and 205.419 (NCT01172821).

FAS of combined data from the two twin trials 205.419 (NCT01172821) and 205.418 (NCT01172808)

Posted

Median

95% Confidence Interval

weeks

24 weeks

ID	Title	Description
OG000	Placebo	Matching Placebo delivered by the Respimat Inhaler resp. MDI (hydrofluoroalkane (HFA 134a) metered inhaler).
OG001	Tio R2.5	Tiotropium 2.5 microgram (mcg) qd (evening) delivered by the Respimat Inhaler.
OG002	Tio R5	Tiotropium 5 mcg qd (evening) delivered by the Respimat Inhaler.
OG003	Salmeterol	Salmeterol 50 mcg bid (morning and evening) delivered by the MDI (hydrofluoroalkane (HFA 134a) metered inhaler).

Secondary

Time to First Asthma Exacerbation From the Two Twin Trials 205.419 (NCT01172821) and the Present 205.418 (NCT01172808)

Time to first asthma exacerbation (including severe, non-severe; symptomatic, asymptomatic; i.e. any exacerbation) during the 24-week treatment period on combined data from the two twin trials 205.418 (NCT01172808) and 205.419 (NCT01172821)

FAS of combined data from the two twin trials 205.419 (NCT01172821) and 205.418 (NCT01172808)

Posted

Median

95% Confidence Interval

weeks

24 weeks

ID	Title	Description
OG000	Placebo	Matching Placebo delivered by the Respimat Inhaler resp. MDI (hydrofluoroalkane (HFA 134a) metered inhaler).
OG001	Tio R2.5	Tiotropium 2.5 microgram (mcg) qd (evening) delivered by the Respimat Inhaler.
OG002	Tio R5	Tiotropium 5 mcg qd (evening) delivered by the Respimat Inhaler.
OG003	Salmeterol	Salmeterol 50 mcg bid (morning and evening) delivered by the MDI (hydrofluoroalkane (HFA 134a) metered inhaler).

Serious Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Acute myocardial infarction	Cardiac disorders	MEDDRA 15.1	Systematic Assessment	EG0001 affected269 at risk EG0010 affected262 at risk EG0020 affected264 at risk EG0030 affected275 at risk
Atrial fibrillation	Cardiac disorders	MEDDRA 15.1	Systematic Assessment	EG0000 affected269 at risk EG0011 affected262 at risk EG0020 affected264 at risk EG003
Coronary artery disease	Cardiac disorders	MEDDRA 15.1	Systematic Assessment	EG0001 affected269 at risk EG0010 affected262 at risk EG0020 affected264 at risk EG003
Myocardial infarction	Cardiac disorders	MEDDRA 15.1	Systematic Assessment	EG0000 affected269 at risk EG0011 affected262 at risk EG0020 affected264 at risk EG003
Vitreous haemorrhage	Eye disorders	MEDDRA 15.1	Systematic Assessment	EG0001 affected269 at risk EG0010 affected262 at risk EG0020 affected264 at risk EG003
Duodenal obstruction	Gastrointestinal disorders	MEDDRA 15.1	Systematic Assessment	EG0001 affected269 at risk EG0010 affected262 at risk EG0020 affected264 at risk EG003
Cholelithiasis	Hepatobiliary disorders	MEDDRA 15.1	Systematic Assessment	EG0000 affected269 at risk EG0010 affected262 at risk EG0021 affected264 at risk EG003
Appendicitis	Infections and infestations	MEDDRA 15.1	Systematic Assessment	EG0001 affected269 at risk EG0010 affected262 at risk EG0020 affected264 at risk EG003
Chikungunya virus infection	Infections and infestations	MEDDRA 15.1	Systematic Assessment	EG0001 affected269 at risk EG0010 affected262 at risk EG0020 affected264 at risk EG003
Gastroenteritis	Infections and infestations	MEDDRA 15.1	Systematic Assessment	EG0000 affected269 at risk EG0011 affected262 at risk EG0020 affected264 at risk EG003
Peritonsillar abscess	Infections and infestations	MEDDRA 15.1	Systematic Assessment	EG0001 affected269 at risk EG0010 affected262 at risk EG0020 affected264 at risk EG003
Pneumonia	Infections and infestations	MEDDRA 15.1	Systematic Assessment	EG0000 affected269 at risk EG0011 affected262 at risk EG0020 affected264 at risk EG003
Pyelonephritis	Infections and infestations	MEDDRA 15.1	Systematic Assessment	EG0000 affected269 at risk EG0010 affected262 at risk EG0020 affected264 at risk EG003
Urinary tract infection	Infections and infestations	MEDDRA 15.1	Systematic Assessment	EG0000 affected269 at risk EG0010 affected262 at risk EG0020 affected264 at risk EG003
Post procedural bile leak	Injury, poisoning and procedural complications	MEDDRA 15.1	Systematic Assessment	EG0001 affected269 at risk EG0010 affected262 at risk EG0020 affected264 at risk EG003
Dehydration	Metabolism and nutrition disorders	MEDDRA 15.1	Systematic Assessment	EG0001 affected269 at risk EG0010 affected262 at risk EG0020 affected264 at risk EG003
Osteoarthritis	Musculoskeletal and connective tissue disorders	MEDDRA 15.1	Systematic Assessment	EG0001 affected269 at risk EG0010 affected262 at risk EG0020 affected264 at risk EG003
Benign salivary gland neoplasm	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MEDDRA 15.1	Systematic Assessment	EG0000 affected269 at risk EG0010 affected262 at risk EG0021 affected264 at risk EG003
Gastrointestinal tract adenoma	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MEDDRA 15.1	Systematic Assessment	EG0001 affected269 at risk EG0010 affected262 at risk EG0020 affected264 at risk EG003
Cerebrovascular accident	Nervous system disorders	MEDDRA 15.1	Systematic Assessment	EG0002 affected269 at risk EG0010 affected262 at risk EG0020 affected264 at risk EG003
Intracranial haematoma	Nervous system disorders	MEDDRA 15.1	Systematic Assessment	EG0000 affected269 at risk EG0010 affected262 at risk EG0020 affected264 at risk EG003
Abortion spontaneous	Pregnancy, puerperium and perinatal conditions	MEDDRA 15.1	Systematic Assessment	EG0001 affected269 at risk EG0010 affected262 at risk EG0020 affected264 at risk EG003
Abortion spontaneous complete	Pregnancy, puerperium and perinatal conditions	MEDDRA 15.1	Systematic Assessment	EG0000 affected269 at risk EG0010 affected262 at risk EG0020 affected264 at risk EG003
Cervical dysplasia	Reproductive system and breast disorders	MEDDRA 15.1	Systematic Assessment	EG0000 affected269 at risk EG0010 affected262 at risk EG0021 affected264 at risk EG003
Asthma	Respiratory, thoracic and mediastinal disorders	MEDDRA 15.1	Systematic Assessment	EG0001 affected269 at risk EG0010 affected262 at risk EG0020 affected264 at risk EG003
Haemoptysis	Respiratory, thoracic and mediastinal disorders	MEDDRA 15.1	Systematic Assessment	EG0000 affected269 at risk EG0011 affected262 at risk EG0020 affected264 at risk EG003
Pulmonary embolism	Respiratory, thoracic and mediastinal disorders	MEDDRA 15.1	Systematic Assessment	EG0000 affected269 at risk EG0010 affected262 at risk EG0020 affected264 at risk EG003
Abortion induced	Surgical and medical procedures	MEDDRA 15.1	Systematic Assessment	EG0000 affected269 at risk EG0010 affected262 at risk EG0021 affected264 at risk EG003
Deep vein thrombosis	Vascular disorders	MEDDRA 15.1	Systematic Assessment	EG0000 affected269 at risk EG0010 affected262 at risk EG0020 affected264 at risk EG003
Hypertension	Vascular disorders	MEDDRA 15.1	Systematic Assessment	EG0000 affected269 at risk EG0011 affected262 at risk EG0020 affected264 at risk EG003

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	Title	Description
BG000	Placebo	Matching Placebo delivered by the Respimat Inhaler resp. MDI (hydrofluoroalkane (HFA 134a) metered inhaler).
BG001	Tio R2.5	Tiotropium 2.5 microgram (mcg) qd (evening) delivered by the Respimat Inhaler.
BG002	Tio R5	Tiotropium 5 mcg qd (evening) delivered by the Respimat Inhaler.
BG003	Salmeterol	Salmeterol 50 mcg bid (morning and evening) delivered by the MDI (hydrofluoroalkane (HFA 134a) metered inhaler).
BG004	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	Matching Placebo delivered by the Respimat Inhaler resp. MDI (hydrofluoroalkane (HFA 134a) metered inhaler).	10	269	115	269
EG001	Tio R2.5	Tiotropium 2.5 microgram (mcg) qd (evening) delivered by the Respimat Inhaler.	5	262	79	262
EG002	Tio R5	Tiotropium 5 mcg qd (evening) delivered by the Respimat Inhaler.	4	264	96	264
EG003	Salmeterol	Salmeterol 50 mcg bid (morning and evening) delivered by the MDI (hydrofluoroalkane (HFA 134a) metered inhaler).	7	275	95	275

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Nasopharyngitis	Infections and infestations	MEDDRA 15.1	Systematic Assessment	EG00022 affected269 at risk EG00118 affected262 at risk EG00222 affected264 at risk EG00316 affected275 at risk
Upper respiratory tract infection	Infections and infestations	MEDDRA 15.1	Systematic Assessment	EG00019 affected269 at risk EG00116 affected262 at risk EG0027 affected264 at risk EG003
Peak expiratory flow rate decreased	Investigations	MEDDRA 15.1	Systematic Assessment	EG00051 affected269 at risk EG00128 affected262 at risk EG00234 affected264 at risk EG003
Asthma	Respiratory, thoracic and mediastinal disorders	MEDDRA 15.1	Systematic Assessment	EG00058 affected269 at risk EG00136 affected262 at risk EG00260 affected264 at risk EG003