A Randomised, Double- Blind, Placebo Controlled, Cross-ov... | NCT01152450

ID	Type	Description	Link
2009-018006-21	EudraCT Number	EudraCT

Name	Class
Pfizer	INDUSTRY

Label	Type	Description	Intervention Names
Tiotropium daily dose q.d.	Experimental	two actuations delivered via Respimat® inhaler	Drug: Tiotropium 5 µg q.d.
Tiotropium half daily dose b.i.d.	Experimental	two actuations delivered via Respimat® inhaler	Drug: Tiotropium 2.5 µg b.i.d
Placebo	Placebo Comparator	N/A (two actuations of placebo) delivered via Respimat® inhaler	Drug: Placebo

Name	Type	Description	Arm Group Labels	Other Names
Tiotropium 2.5 µg b.i.d	Drug	2.5 µg (two actuations of 1.25 µg) delivered via Respimat® inhaler	Tiotropium half daily dose b.i.d.

Measure	Description	Time Frame
Forced Expiratory Volume in One Second (FEV1) Area Under the Curve 0-24 Hours (AUC0-24h) Response	Mixed Model Repeated Measure (MMRM) results. Response was defined as change from baseline. Means are adjusted for treatment, period, patient and study baseline. Measurements performed in relation to evening dosing. AUC0-24h calculated using the trapezoidal rule divided by the observation time (24 hours) to report in litres.	10 minutes (min) prior to first dose (baseline) and -10 min, 30 min, 60 min, 2 hours (h) , 3 h, 4 h , 11 h 50 min, 12 h 30 min, 13 h, 14 h, 15 h, 16 h, 18 h, 20 h, 22 h, 23 h, and 23 h 50 min related to evening dose at week 4

Measure	Description	Time Frame
Mean Pre-dose Morning Peak Expiratory Flow (PEF a.m.) Response During the Last Week on Treatment	MMRM results. Response was defined as change from baseline. Means are adjusted for treatment, period, patient and study baseline. Measured by patients at home using the AM2+ device.	Baseline and during week 4 of each treatment period

Eligibility Module

Eligibility Criteria

Inclusion criteria:

All patients must sign and date an Informed Consent Form consistent with International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use 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 months history of asthma at the time of enrolment into the trial. The diagnosis of asthma has to be confirmed at Visit 1 with a bronchodilator reversibility resulting in a Forced Expiratory Volume in 1 Second (FEV1) increase of equal above 12% and equal above 200mL.
The initial diagnosis of asthma must have been made before the patient's age of 40.
All patients must have a diagnosis of moderate persistent asthma and must be symptomatic despite their current maintenance treatment with medium doses of inhaled corticosteroids.
All patients must have been on maintenance treatment with a medium, stable dose of inhaled corticosteroids (alone or in a fixed combination with a Long Acting Betaadrenergic (LABA) or Short Acting Betaadrenergic (SABA)) for at least 4 weeks prior to Visit 1.
All patients must be symptomatic at Visit 1 (screening) and Visit 2 as defined by an Asthma Control Questionnaire (ACQ) Score
All patients must have a pre-bronchodilator FEV1 above equal 60% predicted and below equal 90% of predicted normal at Visit 1. Predicted normal values will be calculated according to the European Coal and Steel Community Guidelines (ECSC).
All patients must have an increase in FEV1 of equal above 12% and equal above 200 mL 15 minutes after 400 µg salbutamol 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 and who have a smoking history of less than 10 pack years.
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 the e-Diary/peak flow meter.
Patients taking a chronic pulmonary medication allowed by the study protocol must be willing to continue this therapy for the entire duration of the study (exception: times of acute disease deterioration).

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 hematology or blood chemistry if the abnormality defines a significant disease as defined in exclusion criterion no. 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 Lung 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 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 V 1.
Patients with known hypersensitivity to anticholinergic drugs, Benzalconiumchloride (BAC), Ethylenediaminetetraacetate (EDTA) or any other components of the study medication delivery systems.
Pregnant or nursing women.
Women of childbearing potential not using a highly effective method of birth control.
Patients who have been treated with beta-blocker medication within four weeks prior to Visit 1 or during the screening period. Topical cardio-selective beta-blocker eye medications for non-arrow angle glaucoma are allowed.
Patients who have been treated with the long-acting anticholinergic tiotropium (Spiriva®) within four weeks prior to Visit 1 or during the screening period.
Patients who have been treated with oral beta-adrenergics within four weeks prior to Visit 1 or during the screening period.
Patients who have been treated with oral corticosteroids within four weeks prior to Visit 1 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 or during the screening period.20. Patients who have been treated with cromolyn sodium or nedocromil sodium within two weeks prior to Visit 1 or during the screening period.

21. Patients who have been treated with methylxanthines within two weeks prior to Visit 1 or during the screening period.

22. Patients who have taken an investigational drug within four weeks prior to Visit 1.

23. Patients who have been treated with other non-approved and according to international guidelines not recommended "experimental" drugs for routine asthma therapy (e.g. TNFalpha blockers, methotrexate, cyclosporin) within four weeks prior to Visit 1 or during the screening period.

24. Patients with any asthma exacerbation or any respiratory tract infection in the four weeks prior to Visit 1 or during the screening period. Visit 1 and/or Visit 2 should be postponed in case of an asthma exacerbation or respiratory tract infection.

25. Patients who have previously been randomised in this trial or are currently participating in another trial.

26.Patients who have been treated with depot corticosteroids within six months prior to Visit 1 or during the screening period.

27.Patients who have been treated with leukotriene modifiers within two weeks prior to Visit 1 or during the screening period.

Name	Affiliation	Role
Boehringer Ingelheim	Boehringer Ingelheim	Study Chair

Facility	Status	City	State	ZIP	Country	Contacts
205.420.43002 Boehringer Ingelheim Investigational Site		Linz			Austria
205.420.43004 Boehringer Ingelheim Investigational Site

PubMed Identifier	Type	Citation	Retractions
25661281	Derived	Timmer W, Moroni-Zentgraf P, Cornelissen P, Unseld A, Pizzichini E, Buhl R. Once-daily tiotropium Respimat((R)) 5 mug is an efficacious 24-h bronchodilator in adults with symptomatic asthma. Respir Med. 2015 Mar;109(3):329-38. doi: 10.1016/j.rmed.2014.12.005. Epub 2014 Dec 27.

ID	Title	Description
FG000	Tio R2.5 Twice Daily (Bid) /Tio R5 Once Daily (qd) /Placebo	Patients treated with Tiotropium 2.5 mcg in period 1 (morning and evening), with a matching placebo in the morning and Tiotropium 5 mcg in the evening in period 2 and with a matching Placebo in period 3 (morning and evening). All products were delivered by the Respimat inhaler, on top on maintenance therapy with inhaled corticosteroid (iCS). No washouts (off-treatment periods) between treatments. Duration of each treatment period was 4 weeks.

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

Forced Expiratory Volume in One Second (FEV1) Area Under the Curve 0-24 Hours (AUC0-24h) Response

Mixed Model Repeated Measure (MMRM) results. Response was defined as change from baseline. Means are adjusted for treatment, period, patient and study baseline. Measurements performed in relation to evening dosing. AUC0-24h calculated using the trapezoidal rule divided by the observation time (24 hours) to report in litres.

Full Analysis Set (FAS) defined as all treated patients who had baseline data and at least 1 on-treatment efficacy measurement after 4 weeks on treatment within a period.

Posted

Mean

Standard Error

10 minutes (min) prior to first dose (baseline) and -10 min, 30 min, 60 min, 2 hours (h) , 3 h, 4 h , 11 h 50 min, 12 h 30 min, 13 h, 14 h, 15 h, 16 h, 18 h, 20 h, 22 h, 23 h, and 23 h 50 min related to evening dose at week 4

ID	Title	Description
OG000	Placebo	Matching Placebo bid morning and evening delivered by the Respimat inhaler, on top on maintenance therapy with iCS.
OG001	Tio R2.5 Bid	Tiotropium 2.5 mcg bid morning and evening delivered by the Respimat inhaler, on top on maintenance therapy with iCS.
OG002	Tio R5 qd	Tiotropium 5 mcg qd in the evening and matching placebo qd in the morning delivered by the Respimat inhaler, on top on maintenance therapy with iCS.

Units	Counts
Participants	OG00090 OG00189 OG00290

Title

Denominators

Categories

Title	Measurements
	OG0000.091± 0.043 OG0010.241± 0.044 OG0020.250± 0.044

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		Mixed Models Analysis	MMRM, adjusted for treatment, period, patient and study baseline.	<0.0001		Mean Difference (Final Values)	0.149	Standard Error of the Mean	0.024		95	0.102	0.196			Tio R2.5 bid - Placebo		Superiority or Other (legacy)
OG000 OG002

Secondary

Mean Pre-dose Morning Peak Expiratory Flow (PEF a.m.) Response During the Last Week on Treatment

MMRM results. Response was defined as change from baseline. Means are adjusted for treatment, period, patient and study baseline. Measured by patients at home using the AM2+ device.

FAS

Posted

Mean

Standard Error

L/min

Baseline and during week 4 of each treatment period

ID	Title	Description
OG000	Placebo	Matching Placebo bid morning and evening delivered by the Respimat inhaler, on top on maintenance therapy with iCS.
OG001	Tio R2.5 Bid	Tiotropium 2.5 mcg bid morning and evening delivered by the Respimat inhaler, on top on maintenance therapy with iCS.
OG002	Tio R5 qd	Tiotropium 5 mcg qd in the evening and matching placebo qd in the morning delivered by the Respimat inhaler, on top on maintenance therapy with iCS.

Units	Counts
Participants

Secondary

Mean Pre-dose Evening Peak Expiratory Flow (PEF p.m.) Response During the Last Week on Treatment

MMRM results. Response was defined as change from baseline. Means are adjusted for treatment, period, patient and study baseline. Measured by patients at home using the AM2+ device.

FAS

Posted

Mean

Standard Error

L/min

Baseline and during week 4 of each treatment period

ID	Title	Description
OG000	Placebo	Matching Placebo bid morning and evening delivered by the Respimat inhaler, on top on maintenance therapy with iCS.
OG001	Tio R2.5 Bid	Tiotropium 2.5 mcg bid morning and evening delivered by the Respimat inhaler, on top on maintenance therapy with iCS.
OG002	Tio R5 qd	Tiotropium 5 mcg qd in the evening and matching placebo qd in the morning delivered by the Respimat inhaler, on top on maintenance therapy with iCS.

Units	Counts
Participants

Secondary

FEV1 Area Under the Curve 0-12 Hours (AUC0-12h) Response

MMRM results. Response was defined as change from baseline. Means are adjusted for treatment, period, patient and study baseline. Measured following the respective dosing determined at the end of each 4 week period of randomised treatment. AUC0-12h calculated using the trapezoidal rule divided by the observation time (12 hours) to report in litres.

FAS

Posted

Mean

Standard Error

10 min prior to first dose (baseline) and -10 min, 30 min, 60 min, 2 h, 3 h, 4 h and 11 h 50 min related to evening dose at week 4

ID	Title	Description
OG000	Placebo	Matching Placebo bid morning and evening delivered by the Respimat inhaler, on top on maintenance therapy with iCS.
OG001	Tio R2.5 Bid	Tiotropium 2.5 mcg bid morning and evening delivered by the Respimat inhaler, on top on maintenance therapy with iCS.
OG002	Tio R5 qd	Tiotropium 5 mcg qd in the evening and matching placebo qd in the morning delivered by the Respimat inhaler, on top on maintenance therapy with iCS.

Secondary

FEV1 Area Under the Curve 12-24 Hours (AUC12-24h) Response

MMRM results. Response was defined as change from baseline. Means are adjusted for treatment, period, patient and study baseline. Measured following the respective dosing determined at the end of each 4 week period of randomised treatment. AUC12-24h calculated using the trapezoidal rule divided by the observation time (12 hours) to report in litres.

FAS

Posted

Mean

Standard Error

10 min prior to first dose (baseline) and 11 h 50 min, 12 h 30 min, 13 h, 14 h, 15 h, 16 h, 18 h, 20 h, 22 h, 23 h, and 23 h 50 min related to evening dose at week 4

ID	Title	Description
OG000	Placebo	Matching Placebo bid morning and evening delivered by the Respimat inhaler, on top on maintenance therapy with iCS.
OG001	Tio R2.5 Bid	Tiotropium 2.5 mcg bid morning and evening delivered by the Respimat inhaler, on top on maintenance therapy with iCS.
OG002	Tio R5 qd	Tiotropium 5 mcg qd in the evening and matching placebo qd in the morning delivered by the Respimat inhaler, on top on maintenance therapy with iCS.

Secondary

Peak FEV1 Within 24 Hours Post-dose Response

MMRM results. Response was defined as change from baseline. Means are adjusted for treatment, period, patient and study baseline. Measured following the evening trial-drug inhalation at the end of each 4 week period of randomised treatment.

FAS

Posted

Mean

Standard Error

Baseline and 4 weeks

ID	Title	Description
OG000	Placebo	Matching Placebo bid morning and evening delivered by the Respimat inhaler, on top on maintenance therapy with iCS.
OG001	Tio R2.5 Bid	Tiotropium 2.5 mcg bid morning and evening delivered by the Respimat inhaler, on top on maintenance therapy with iCS.
OG002	Tio R5 qd	Tiotropium 5 mcg qd in the evening and matching placebo qd in the morning delivered by the Respimat inhaler, on top on maintenance therapy with iCS.

Units	Counts
Participants

Secondary

Trough FEV1 Response

MMRM results. Response was defined as change from baseline. Means are adjusted for treatment, period, patient and study baseline. Trough FEV1 is defined as FEV1 value (performed at 10 minutes prior to the evening trial-drug inhalation) at the end of each 4 week period of randomised treatment.

FAS

Posted

Mean

Standard Error

Baseline and 4 weeks

ID	Title	Description
OG000	Placebo	Matching Placebo bid morning and evening delivered by the Respimat inhaler, on top on maintenance therapy with iCS.
OG001	Tio R2.5 Bid	Tiotropium 2.5 mcg bid morning and evening delivered by the Respimat inhaler, on top on maintenance therapy with iCS.
OG002	Tio R5 qd	Tiotropium 5 mcg qd in the evening and matching placebo qd in the morning delivered by the Respimat inhaler, on top on maintenance therapy with iCS.

Units	Counts
Participants

Secondary

Trough Forced Vital Capacity (FVC) Response

MMRM results. Response was defined as change from baseline. Means are adjusted for treatment, period, patient and study baseline. Trough FVC is defined as FVC value (performed at 10 minutes prior to the evening trial-drug inhalation) at the end of each 4 week period of randomised treatment.

FAS

Posted

Mean

Standard Error

Baseline and 4 weeks

ID	Title	Description
OG000	Placebo	Matching Placebo bid morning and evening delivered by the Respimat inhaler, on top on maintenance therapy with iCS.
OG001	Tio R2.5 Bid	Tiotropium 2.5 mcg bid morning and evening delivered by the Respimat inhaler, on top on maintenance therapy with iCS.
OG002	Tio R5 qd	Tiotropium 5 mcg qd in the evening and matching placebo qd in the morning delivered by the Respimat inhaler, on top on maintenance therapy with iCS.

Units	Counts

Secondary

FVC Area Under the Curve 0-12 Hours (AUC0-12h) Response

MMRM results. Response was defined as change from baseline. Means are adjusted for treatment, period, patient and study baseline. Measured following each dosing determined at the end of each 4 week treatment period. AUC0-12h calculated using the trapezoidal rule divided by the observation time (12 hours) to report in litres.

FAS

Posted

Mean

Standard Error

10 min prior to first dose (baseline) and -10 min, 30 min, 60 min, 2 h, 3 h, 4 h and 11 h 50 min related to evening dose at week 4

ID	Title	Description
OG000	Placebo	Matching Placebo bid morning and evening delivered by the Respimat inhaler, on top on maintenance therapy with iCS.
OG001	Tio R2.5 Bid	Tiotropium 2.5 mcg bid morning and evening delivered by the Respimat inhaler, on top on maintenance therapy with iCS.
OG002	Tio R5 qd	Tiotropium 5 mcg qd in the evening and matching placebo qd in the morning delivered by the Respimat inhaler, on top on maintenance therapy with iCS.

Secondary

FVC Area Under the Curve 12-24 Hours (AUC12-24h) Response

MMRM results. Response was defined as change from baseline. Means are adjusted for treatment, period, patient and study baseline. Measured following each dosing determined at the end of each 4 week treatment period. AUC12-24h calculated using the trapezoidal rule divided by the observation time (12 hours) to report in litres.

FAS

Posted

Mean

Standard Error

10 min prior to first dose (baseline) and 11 h 50 min, 12 h 30 min, 13 h, 14 h, 15 h, 16 h, 18 h, 20 h, 22 h, 23 h, and 23 h 50 min related to evening dose at week 4

ID	Title	Description
OG000	Placebo	Matching Placebo bid morning and evening delivered by the Respimat inhaler, on top on maintenance therapy with iCS.
OG001	Tio R2.5 Bid	Tiotropium 2.5 mcg bid morning and evening delivered by the Respimat inhaler, on top on maintenance therapy with iCS.
OG002	Tio R5 qd	Tiotropium 5 mcg qd in the evening and matching placebo qd in the morning delivered by the Respimat inhaler, on top on maintenance therapy with iCS.

Secondary

Peak FVC Within 24 Hours Post-dose Response

FAS

Posted

Mean

Standard Error

Baseline and 4 weeks

ID	Title	Description
OG000	Placebo	Matching Placebo bid morning and evening delivered by the Respimat inhaler, on top on maintenance therapy with iCS.
OG001	Tio R2.5 Bid	Tiotropium 2.5 mcg bid morning and evening delivered by the Respimat inhaler, on top on maintenance therapy with iCS.
OG002	Tio R5 qd	Tiotropium 5 mcg qd in the evening and matching placebo qd in the morning delivered by the Respimat inhaler, on top on maintenance therapy with iCS.

Units	Counts
Participants

Secondary

Individual FEV1 Over Time (at Each Timepoint at Visits) Response

MMRM results. Response was defined as change from baseline. Means are adjusted for treatment, period, patient and study baseline.

FAS

Posted

Mean

Standard Error

Baseline and 4 weeks

ID	Title	Description
OG000	Placebo	Matching Placebo bid morning and evening delivered by the Respimat inhaler, on top on maintenance therapy with iCS.
OG001	Tio R2.5 Bid	Tiotropium 2.5 mcg bid morning and evening delivered by the Respimat inhaler, on top on maintenance therapy with iCS.
OG002	Tio R5 qd	Tiotropium 5 mcg qd in the evening and matching placebo qd in the morning delivered by the Respimat inhaler, on top on maintenance therapy with iCS.

Units	Counts
Participants

Secondary

Individual FVC Over Time (at Each Timepoint at Visits) Response

MMRM results. Response was defined as change from baseline. Means are adjusted for treatment, period, patient and study baseline.

FAS

Posted

Mean

Standard Error

Baseline and 4 weeks

ID	Title	Description
OG000	Placebo	Matching Placebo bid morning and evening delivered by the Respimat inhaler, on top on maintenance therapy with iCS.
OG001	Tio R2.5 Bid	Tiotropium 2.5 mcg bid morning and evening delivered by the Respimat inhaler, on top on maintenance therapy with iCS.
OG002	Tio R5 qd	Tiotropium 5 mcg qd in the evening and matching placebo qd in the morning delivered by the Respimat inhaler, on top on maintenance therapy with iCS.

Units	Counts
Participants

Secondary

Individual Peak Expiratory Flow (PEF) Over Time (at Each Timepoint at Visits) Response

MMRM results. Response was defined as change from baseline. Means are adjusted for treatment, period, patient and study baseline.

FAS

Posted

Mean

Standard Error

L/min

Baseline and 4 weeks

ID	Title	Description
OG000	Placebo	Matching Placebo bid morning and evening delivered by the Respimat inhaler, on top on maintenance therapy with iCS.
OG001	Tio R2.5 Bid	Tiotropium 2.5 mcg bid morning and evening delivered by the Respimat inhaler, on top on maintenance therapy with iCS.
OG002	Tio R5 qd	Tiotropium 5 mcg qd in the evening and matching placebo qd in the morning delivered by the Respimat inhaler, on top on maintenance therapy with iCS.

Units	Counts
Participants

Secondary

FVC Area Under the Curve 0-24 Hours (AUC0-24h) Response

MMRM results. Response was defined as change from baseline. Means are adjusted for treatment, period, patient and study baseline. AUC0-24h calculated using the trapezoidal rule divided by the observation time (24 hours) to report in litres.

FAS

Posted

Mean

Standard Error

10 min prior to first dose (baseline) and -10 min, 30 min, 60 min, 2 h, 3 h, 4 h , 11 h 50 min, 12 h 30 min, 13 h, 14 h, 15 h, 16 h, 18 h, 20 h, 22 h, 23 h, and 23 h 50 min related to evening dose at week 4

ID	Title	Description
OG000	Placebo	Matching Placebo bid morning and evening delivered by the Respimat inhaler, on top on maintenance therapy with iCS.
OG001	Tio R2.5 Bid	Tiotropium 2.5 mcg bid morning and evening delivered by the Respimat inhaler, on top on maintenance therapy with iCS.
OG002	Tio R5 qd	Tiotropium 5 mcg qd in the evening and matching placebo qd in the morning delivered by the Respimat inhaler, on top on maintenance therapy with iCS.

Secondary

PEF Area Under the Curve 0-24 Hours (AUC0-24h) Response

FAS

Posted

Mean

Standard Error

L/min

ID	Title	Description
OG000	Placebo	Matching Placebo bid morning and evening delivered by the Respimat inhaler, on top on maintenance therapy with iCS.
OG001	Tio R2.5 Bid	Tiotropium 2.5 mcg bid morning and evening delivered by the Respimat inhaler, on top on maintenance therapy with iCS.
OG002	Tio R5 qd	Tiotropium 5 mcg qd in the evening and matching placebo qd in the morning delivered by the Respimat inhaler, on top on maintenance therapy with iCS.

Secondary

PEF Variability Response (Last Week on Treatment)

MMRM results. Response was defined as change from baseline. Means are adjusted for treatment, period, patient and study baseline. PEF variability is the absolute difference between morning and evening PEF value divided by the mean of these two values, expressed as a percent (weekly means obtained during the last week of each period of randomised treatment will be compared).

FAS

Posted

Mean

Standard Error

Percent

Baseline and during week 4

ID	Title	Description
OG000	Placebo	Matching Placebo bid morning and evening delivered by the Respimat inhaler, on top on maintenance therapy with iCS.
OG001	Tio R2.5 Bid	Tiotropium 2.5 mcg bid morning and evening delivered by the Respimat inhaler, on top on maintenance therapy with iCS.
OG002	Tio R5 qd	Tiotropium 5 mcg qd in the evening and matching placebo qd in the morning delivered by the Respimat inhaler, on top on maintenance therapy with iCS.

Secondary

Mean Number of Puffs of Rescue Medication During the Whole Day (Last Week on Treatment, Response Values)

MMRM results. Response was defined as change from baseline. Means are adjusted for treatment, period, patient and study baseline. Weekly means obtained during the last week of each period of randomised treatment will be compared.

FAS

Posted

Mean

Standard Error

Puffs

Baseline and during week 4

ID	Title	Description
OG000	Placebo	Matching Placebo bid morning and evening delivered by the Respimat inhaler, on top on maintenance therapy with iCS.
OG001	Tio R2.5 Bid	Tiotropium 2.5 mcg bid morning and evening delivered by the Respimat inhaler, on top on maintenance therapy with iCS.
OG002	Tio R5 qd	Tiotropium 5 mcg qd in the evening and matching placebo qd in the morning delivered by the Respimat inhaler, on top on maintenance therapy with iCS.

Units	Counts

Secondary

Mean Number of Puffs of Rescue Medication During Daytime (Last Week on Treatment, Response Values)

FAS

Posted

Mean

Standard Error

Puffs

Baseline and during week 4

ID	Title	Description
OG000	Placebo	Matching Placebo bid morning and evening delivered by the Respimat inhaler, on top on maintenance therapy with iCS.
OG001	Tio R2.5 Bid	Tiotropium 2.5 mcg bid morning and evening delivered by the Respimat inhaler, on top on maintenance therapy with iCS.
OG002	Tio R5 qd	Tiotropium 5 mcg qd in the evening and matching placebo qd in the morning delivered by the Respimat inhaler, on top on maintenance therapy with iCS.

Units	Counts

Secondary

Mean Number of Puffs of Rescue Medication During Nighttime (Last Week on Treatment, Response Values)

FAS

Posted

Mean

Standard Error

Puffs

Baseline and during week 4

ID	Title	Description
OG000	Placebo	Matching Placebo bid morning and evening delivered by the Respimat inhaler, on top on maintenance therapy with iCS.
OG001	Tio R2.5 Bid	Tiotropium 2.5 mcg bid morning and evening delivered by the Respimat inhaler, on top on maintenance therapy with iCS.
OG002	Tio R5 qd	Tiotropium 5 mcg qd in the evening and matching placebo qd in the morning delivered by the Respimat inhaler, on top on maintenance therapy with iCS.

Units	Counts

Secondary

Mean Number of Night Awakenings During the Last Week on Treatment (Score, Response Values)

MMRM results. Response was defined as change from baseline. Means are adjusted for treatment, period, patient and study baseline. Assessed by the patient's electronic diary (eDiary incorporated in the AM2+ device), obtained during the last week of each period of randomised treatment.

FAS

Posted

Mean

Standard Error

Night awakenings

Baseline and during week 4

ID	Title	Description
OG000	Placebo	Matching Placebo bid morning and evening delivered by the Respimat inhaler, on top on maintenance therapy with iCS.
OG001	Tio R2.5 Bid	Tiotropium 2.5 mcg bid morning and evening delivered by the Respimat inhaler, on top on maintenance therapy with iCS.
OG002	Tio R5 qd	Tiotropium 5 mcg qd in the evening and matching placebo qd in the morning delivered by the Respimat inhaler, on top on maintenance therapy with iCS.

Units	Counts

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Haemorrhage	Vascular disorders	MedDRA 14.0	Systematic Assessment	EG0000 affected92 at risk EG0010 affected90 at risk EG0021 affected90 at risk
Hypertensive crisis	Vascular disorders	MedDRA 14.0	Systematic Assessment	EG0001 affected92 at risk EG0010 affected90 at risk EG0020 affected90 at risk
Venous thrombosis limb	Vascular disorders	MedDRA 14.0	Systematic Assessment	EG0000 affected92 at risk EG0010 affected90 at risk EG0021 affected90 at risk
Rib fracture	Injury, poisoning and procedural complications	MedDRA 14.0	Systematic Assessment	EG0000 affected92 at risk EG0010 affected90 at risk EG0021 affected90 at risk
Road traffic accident	Injury, poisoning and procedural complications	MedDRA 14.0	Systematic Assessment	EG0000 affected92 at risk EG0010 affected90 at risk EG0021 affected90 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	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	Placebo	Matching Placebo bid morning and evening delivered by the Respimat inhaler, on top on maintenance therapy with iCS.	1	92	4	92
EG001	Tio R2.5	Tiotropium 2.5 mcg bid morning and evening delivered by the Respimat inhaler, on top on maintenance therapy with iCS.	0	90	7	90
EG002	Tio R5 qd	Tiotropium 5 mcg qd in the evening and matching placebo qd in the morning delivered by the Respimat inhaler, on top on maintenance therapy with iCS.	2	90	5	90