Trial Outcomes & Findings for Efficacy and Safety of 2 Doses of Tiotropium Via Respimat Compared to Placebo in Adolescents With Moderate Persistent Asthma (NCT NCT01257230)

NCT ID: NCT01257230

Last Updated: 2014-09-05

Results Overview

Change from baseline in peak Forced expiratory volume in 1 second within the first 3 hours post dosing (FEV1 peak0-3) measured at week 24. Note, the measured values presented are actually adjusted means.

• Recruitment status: COMPLETED
• Study phase: PHASE3
• Target enrollment: 398 participants
• Primary outcome timeframe: Baseline and 24 weeks
• Results posted on: 2014-09-05

Participant Flow

Participant milestones

Measure	Placebo Respimat Inhalation of placebo solution once daily for 48 weeks, delivered by the Respimat Inhaler	Tio R2.5 Inhalation of 2.5μg tiotropium bromide solution once daily for 48 weeks, delivered by the Respimat Inhaler	Tio R5 Inhalation of 5μg tiotropium bromide solution once daily for 48 weeks, delivered by the Respimat Inhaler.
Overall Study STARTED	138	125	135
Overall Study COMPLETED	132	115	129
Overall Study NOT COMPLETED	6	10	6

Reasons for withdrawal

Measure	Placebo Respimat Inhalation of placebo solution once daily for 48 weeks, delivered by the Respimat Inhaler	Tio R2.5 Inhalation of 2.5μg tiotropium bromide solution once daily for 48 weeks, delivered by the Respimat Inhaler	Tio R5 Inhalation of 5μg tiotropium bromide solution once daily for 48 weeks, delivered by the Respimat Inhaler.
Overall Study Not Treated	0	0	1
Overall Study Adverse Event	2	0	0
Overall Study Lack of Efficacy	0	1	0
Overall Study Protocol Violation	3	0	1
Overall Study Withdrawal by Subject	0	4	1
Overall Study Other reason not defined above	1	5	3

Baseline Characteristics

Efficacy and Safety of 2 Doses of Tiotropium Via Respimat Compared to Placebo in Adolescents With Moderate Persistent Asthma

Baseline characteristics by cohort

Measure	Placebo Respimat n=138 Participants Inhalation of placebo solution once daily for 48 weeks, delivered by the Respimat Inhaler	Tio R2.5 n=125 Participants Inhalation of 2.5μg tiotropium bromide solution once daily for 48 weeks, delivered by the Respimat Inhaler	Tio R5 n=134 Participants Inhalation of 5μg tiotropium bromide solution once daily for 48 weeks, delivered by the Respimat Inhaler	Total n=397 Participants Total of all reporting groups
Age, Continuous	14.2 years STANDARD_DEVIATION 1.7 • n=5 Participants	14.2 years STANDARD_DEVIATION 1.8 • n=7 Participants	14.5 years STANDARD_DEVIATION 1.6 • n=5 Participants	14.3 years STANDARD_DEVIATION 1.7 • n=4 Participants
Sex: Female, Male Female	50 Participants n=5 Participants	44 Participants n=7 Participants	45 Participants n=5 Participants	139 Participants n=4 Participants
Sex: Female, Male Male	88 Participants n=5 Participants	81 Participants n=7 Participants	89 Participants n=5 Participants	258 Participants n=4 Participants

PRIMARY outcome

Timeframe: Baseline and 24 weeks

Population: Full analysis set (FAS) was the same as the treated set which included all randomised patients who were dispensed trial medication and received at least one documents dose of trial medication. Missing data at a visit was imputed by the available data from the patient at that visit, completely missing visits were handled by the statistical model.

Change from baseline in peak Forced expiratory volume in 1 second within the first 3 hours post dosing (FEV1 peak0-3) measured at week 24.

Note, the measured values presented are actually adjusted means.

Outcome measures

Measure	Placebo Respimat n=137 Participants Inhalation of placebo solution once daily for 48 weeks, delivered by the Respimat Inhaler	Tio R2.5 n=120 Participants Inhalation of 2.5μg tiotropium bromide solution once daily for 48 weeks, delivered by the Respimat Inhaler	Tio R5 n=131 Participants Inhalation of 5μg tiotropium bromide solution once daily for 48 weeks, delivered by the Respimat Inhaler
FEV1 peak0-3 Change From Baseline	0.373 Litres Standard Error 0.037	0.507 Litres Standard Error 0.040	0.547 Litres Standard Error 0.038

SECONDARY outcome

Timeframe: Baseline and 24 weeks

Population: Full analysis set. Missing data at a visit was imputed by the available data from the patient at that visit, completely missing visits were handled by the statistical model.

Change from baseline in Trough (pre-dose) Forced expiratory volume in 1 second (FEV1) measured at week 24.

The measured values presented are actually adjusted means.

Outcome measures

Measure	Placebo Respimat n=137 Participants Inhalation of placebo solution once daily for 48 weeks, delivered by the Respimat Inhaler	Tio R2.5 n=119 Participants Inhalation of 2.5μg tiotropium bromide solution once daily for 48 weeks, delivered by the Respimat Inhaler	Tio R5 n=131 Participants Inhalation of 5μg tiotropium bromide solution once daily for 48 weeks, delivered by the Respimat Inhaler
Trough FEV1 Change From Baseline	0.283 Litres Standard Error 0.040	0.367 Litres Standard Error 0.044	0.400 Litres Standard Error 0.041

SECONDARY outcome

Timeframe: Baseline and 24 weeks

Population: Full analysis set. Missing data at a visit was imputed by the available data from the patient at that visit, completely missing visits were handled by the statistical model.

Change from baseline in Maximum forced vital capacity (FVC) measured within the first 3 h after administration of trial medication (FVC peak0-3h) after 24 weeks of treatment.

The measured values presented are actually adjusted means.

Outcome measures

Measure	Placebo Respimat n=137 Participants Inhalation of placebo solution once daily for 48 weeks, delivered by the Respimat Inhaler	Tio R2.5 n=120 Participants Inhalation of 2.5μg tiotropium bromide solution once daily for 48 weeks, delivered by the Respimat Inhaler	Tio R5 n=131 Participants Inhalation of 5μg tiotropium bromide solution once daily for 48 weeks, delivered by the Respimat Inhaler
FVC peak0-3 Change From Baseline	0.331 Litres Standard Error 0.041	0.419 Litres Standard Error 0.045	0.403 Litres Standard Error 0.043

SECONDARY outcome

Timeframe: Baseline and 24 weeks

Population: Full analysis set. Missing data at a visit was imputed by the available data from the patient at that visit, completely missing visits were handled by the statistical model.

Change from baseline of Trough (pre-dose) forced vital capacity (FVC) measured 10 min before the administration of trial medication after 24 weeks of treatment.

The measured values presented are actually adjusted means..

Outcome measures

Measure	Placebo Respimat n=137 Participants Inhalation of placebo solution once daily for 48 weeks, delivered by the Respimat Inhaler	Tio R2.5 n=119 Participants Inhalation of 2.5μg tiotropium bromide solution once daily for 48 weeks, delivered by the Respimat Inhaler	Tio R5 n=131 Participants Inhalation of 5μg tiotropium bromide solution once daily for 48 weeks, delivered by the Respimat Inhaler
Trough FVC Change From Baseline	0.281 Litres Standard Error 0.043	0.345 Litres Standard Error 0.047	0.316 Litres Standard Error 0.045

SECONDARY outcome

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

Population: Full analysis set. Missing data at a visit was imputed by the available data from the patient at that visit, completely missing visits were handled by the statistical model.

Change from baseline of area under the curve (AUC) from 0 to 3 h 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).

The measured values presented are actually adjusted means.

Outcome measures

Measure	Placebo Respimat n=137 Participants Inhalation of placebo solution once daily for 48 weeks, delivered by the Respimat Inhaler	Tio R2.5 n=119 Participants Inhalation of 2.5μg tiotropium bromide solution once daily for 48 weeks, delivered by the Respimat Inhaler	Tio R5 n=131 Participants Inhalation of 5μg tiotropium bromide solution once daily for 48 weeks, delivered by the Respimat Inhaler
FEV1 AUC (0-3h) Change From Baseline	0.281 Litres Standard Error 0.035	0.411 Litres Standard Error 0.038	0.463 Litres Standard Error 0.036

SECONDARY outcome

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

Population: Full analysis set. Missing data at a visit was imputed by the available data from the patient at that visit, completely missing visits were handled by the statistical model.

Change from baseline of area under the curve (AUC) from 0 to 3 h for FVC (FVC AUC0-3h) after 24 weeks of treatment. The AUC was calculated by using the trapezoidal rule divided by the observation time (3h).

The measured values presented are actually adjusted means.

Outcome measures

Measure	Placebo Respimat n=137 Participants Inhalation of placebo solution once daily for 48 weeks, delivered by the Respimat Inhaler	Tio R2.5 n=119 Participants Inhalation of 2.5μg tiotropium bromide solution once daily for 48 weeks, delivered by the Respimat Inhaler	Tio R5 n=131 Participants Inhalation of 5μg tiotropium bromide solution once daily for 48 weeks, delivered by the Respimat Inhaler
FVC AUC (0-3h) Change From Baseline	0.240 Litres Standard Error 0.039	0.330 Litres Standard Error 0.042	0.311 Litres Standard Error 0.040

SECONDARY outcome

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

Population: Full analysis set. Missing data at a visit was imputed by the available data from the patient at that visit, completely missing visits were handled by the statistical model.

Change from baseline in mean forced expiratory flow between 25% and 75% of the FVC (FEF25-75%), also known as maximum mid-expiratory flow, at individual time points after 24 weeks of treatment.

The measured values presented are actually adjusted means.

Outcome measures

Measure	Placebo Respimat n=137 Participants Inhalation of placebo solution once daily for 48 weeks, delivered by the Respimat Inhaler	Tio R2.5 n=120 Participants Inhalation of 2.5μg tiotropium bromide solution once daily for 48 weeks, delivered by the Respimat Inhaler	Tio R5 n=131 Participants Inhalation of 5μg tiotropium bromide solution once daily for 48 weeks, delivered by the Respimat Inhaler
FEF25-75 Change From Baseline 10 minutes pre-dose (n=137, 119, 131)	0.332 Litres per second Standard Error 0.072	0.461 Litres per second Standard Error 0.079	0.609 Litres per second Standard Error 0.074
FEF25-75 Change From Baseline 30 minutes post-dose	0.372 Litres per second Standard Error 0.066	0.536 Litres per second Standard Error 0.072	0.763 Litres per second Standard Error 0.068
FEF25-75 Change From Baseline 1 hour post-dose	0.359 Litres per second Standard Error 0.067	0.596 Litres per second Standard Error 0.072	0.835 Litres per second Standard Error 0.069
FEF25-75 Change From Baseline 2 hours post-dose	0.403 Litres per second Standard Error 0.069	0.615 Litres per second Standard Error 0.075	0.857 Litres per second Standard Error 0.071
FEF25-75 Change From Baseline 3 hours post-dose	0.347 Litres per second Standard Error 0.068	0.653 Litres per second Standard Error 0.074	0.850 Litres per second Standard Error 0.070

SECONDARY outcome

Timeframe: Baseline and Week 24

Population: FAS

Change from baseline in the number of puffs of rescue medication (salbutamol/albuterol) used during the daytime based on the weekly mean at week 24.

The measured values presented are actually adjusted means.

Outcome measures

Measure	Placebo Respimat n=132 Participants Inhalation of placebo solution once daily for 48 weeks, delivered by the Respimat Inhaler	Tio R2.5 n=114 Participants Inhalation of 2.5μg tiotropium bromide solution once daily for 48 weeks, delivered by the Respimat Inhaler	Tio R5 n=122 Participants Inhalation of 5μg tiotropium bromide solution once daily for 48 weeks, delivered by the Respimat Inhaler
Use of PRN Rescue Medication During the Daytime	-0.206 Number of puffs of rescue medication Standard Error 0.066	-0.209 Number of puffs of rescue medication Standard Error 0.071	-0.215 Number of puffs of rescue medication Standard Error 0.068

SECONDARY outcome

Timeframe: Baseline and week 24

Population: FAS

Change from baseline in the number of puffs of rescue medication (salbutamol/albuterol) used during the night-time based on the weekly mean at week 24.

The measured values presented are actually adjusted means.

Outcome measures

Measure	Placebo Respimat n=132 Participants Inhalation of placebo solution once daily for 48 weeks, delivered by the Respimat Inhaler	Tio R2.5 n=110 Participants Inhalation of 2.5μg tiotropium bromide solution once daily for 48 weeks, delivered by the Respimat Inhaler	Tio R5 n=124 Participants Inhalation of 5μg tiotropium bromide solution once daily for 48 weeks, delivered by the Respimat Inhaler
Use of PRN Rescue Medication During the Night-time	-0.144 Number of puffs of rescue medication Standard Error 0.059	-0.122 Number of puffs of rescue medication Standard Error 0.064	-0.032 Number of puffs of rescue medication Standard Error 0.061

SECONDARY outcome

Timeframe: Baseline and week 24

Population: FAS

Change from baseline in the number of puffs of rescue medication (salbutamol/albuterol) used during the day (24 hour period) based on the weekly mean at week 24.

The measured values presented are actually adjusted means.

Outcome measures

Measure	Placebo Respimat n=135 Participants Inhalation of placebo solution once daily for 48 weeks, delivered by the Respimat Inhaler	Tio R2.5 n=117 Participants Inhalation of 2.5μg tiotropium bromide solution once daily for 48 weeks, delivered by the Respimat Inhaler	Tio R5 n=125 Participants Inhalation of 5μg tiotropium bromide solution once daily for 48 weeks, delivered by the Respimat Inhaler
Use of PRN Rescue Medication During the Day	-0.524 Number of puffs of rescue medication Standard Error 0.098	-0.556 Number of puffs of rescue medication Standard Error 0.104	-0.480 Number of puffs of rescue medication Standard Error 0.100

SECONDARY outcome

Timeframe: Baseline and week 24

Population: FAS

Change from baseline in Asthma Control Questionnaire (ACQ) total score measured at week 24.

The ACQ 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 total score was calculated as the mean of the responses to all 7 questions.

The measured values presented are actually adjusted means.

Outcome measures

Measure	Placebo Respimat n=136 Participants Inhalation of placebo solution once daily for 48 weeks, delivered by the Respimat Inhaler	Tio R2.5 n=120 Participants Inhalation of 2.5μg tiotropium bromide solution once daily for 48 weeks, delivered by the Respimat Inhaler	Tio R5 n=132 Participants Inhalation of 5μg tiotropium bromide solution once daily for 48 weeks, delivered by the Respimat Inhaler
Control of Asthma as Assessed by ACQ Total Score	1.213 Units on a scale Standard Error 0.062	1.053 Units on a scale Standard Error 0.067	1.116 Units on a scale Standard Error 0.064

SECONDARY outcome

Timeframe: Week 24

Population: FAS

Responder rates based on the ACQ total score after 24 weeks of treatment. Analysis was performed using the following categories and definitions: responder (change from trial baseline ≤-0.5), no change (-0.5 <change from trial baseline <0.5) and worsening (change from trial baseline ≥0.5)

The ACQ 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.

Outcome measures

Measure	Placebo Respimat n=138 Participants Inhalation of placebo solution once daily for 48 weeks, delivered by the Respimat Inhaler	Tio R2.5 n=125 Participants Inhalation of 2.5μg tiotropium bromide solution once daily for 48 weeks, delivered by the Respimat Inhaler	Tio R5 n=134 Participants Inhalation of 5μg tiotropium bromide solution once daily for 48 weeks, delivered by the Respimat Inhaler
ACQ Total Score Responders Responder	66.7 percentage of participants	76.0 percentage of participants	74.6 percentage of participants
ACQ Total Score Responders No change	27.5 percentage of participants	21.6 percentage of participants	23.1 percentage of participants
ACQ Total Score Responders Worsening	5.8 percentage of participants	2.4 percentage of participants	2.2 percentage of participants

SECONDARY outcome

Timeframe: Baseline and week 24

Population: FAS

Change from baseline in AQC6 score at week 24.

The ACQ6 score is calculated as the mean of the responses to the first 6 questions of the ACQ. The ACQ 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.

The measured values presented are actually adjusted means.

Outcome measures

Measure	Placebo Respimat n=136 Participants Inhalation of placebo solution once daily for 48 weeks, delivered by the Respimat Inhaler	Tio R2.5 n=120 Participants Inhalation of 2.5μg tiotropium bromide solution once daily for 48 weeks, delivered by the Respimat Inhaler	Tio R5 n=132 Participants Inhalation of 5μg tiotropium bromide solution once daily for 48 weeks, delivered by the Respimat Inhaler
Control of Asthma as Assessed by ACQ6	1.173 units on a scale Standard Error 0.068	1.026 units on a scale Standard Error 0.073	1.119 units on a scale Standard Error 0.070

SECONDARY outcome

Timeframe: Week 24

Population: FAS

Responder rates based on the ACQ6 after 24 weeks of treatment. Analysis was performed using the following categories and definitions: responder (change from trial baseline ≤-0.5), no change (-0.5 <change from trial baseline <0.5) and worsening (change from trial baseline ≥0.5)

The ACQ6 score is calculated as the mean of the responses to the first 6 questions of the ACQ. The ACQ 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.

Outcome measures

Measure	Placebo Respimat n=138 Participants Inhalation of placebo solution once daily for 48 weeks, delivered by the Respimat Inhaler	Tio R2.5 n=125 Participants Inhalation of 2.5μg tiotropium bromide solution once daily for 48 weeks, delivered by the Respimat Inhaler	Tio R5 n=134 Participants Inhalation of 5μg tiotropium bromide solution once daily for 48 weeks, delivered by the Respimat Inhaler
ACQ6 Responders Responder	69.6 percentage of participants	76.8 percentage of participants	72.4 percentage of participants
ACQ6 Responders No change	22.5 percentage of participants	20.0 percentage of participants	23.1 percentage of participants
ACQ6 Responders Worsening	8.0 percentage of participants	3.2 percentage of participants	4.5 percentage of participants

SECONDARY outcome

Timeframe: 48 weeks

Population: FAS

The median time to first severe asthma exacerbation was not calculable, so the number of patients who experienced a severe asthma exacerbation are presented for the measured values. A severe asthma exacerbation was defined as a subgroup of all asthma exacerbations that required treatment with systemic corticosteroid for at least 3 days.

Outcome measures

Measure	Placebo Respimat n=138 Participants Inhalation of placebo solution once daily for 48 weeks, delivered by the Respimat Inhaler	Tio R2.5 n=125 Participants Inhalation of 2.5μg tiotropium bromide solution once daily for 48 weeks, delivered by the Respimat Inhaler	Tio R5 n=134 Participants Inhalation of 5μg tiotropium bromide solution once daily for 48 weeks, delivered by the Respimat Inhaler
Time to First Severe Asthma Exacerbation During the 48 Week Treatment Period	9 Participants	5 Participants	2 Participants

SECONDARY outcome

Timeframe: Week 48

Population: FAS

The median time to first asthma exacerbation was not calculable, so the number of patients who experienced an asthma exacerbation are presented for the measured values.

Outcome measures

Measure	Placebo Respimat n=138 Participants Inhalation of placebo solution once daily for 48 weeks, delivered by the Respimat Inhaler	Tio R2.5 n=125 Participants Inhalation of 2.5μg tiotropium bromide solution once daily for 48 weeks, delivered by the Respimat Inhaler	Tio R5 n=134 Participants Inhalation of 5μg tiotropium bromide solution once daily for 48 weeks, delivered by the Respimat Inhaler
Time to First Asthma Exacerbation During the 48 Week Treatment Period	37 Participants	34 Participants	30 Participants

Adverse Events

Placebo Respimat

Serious events: 2 serious events

Other events: 62 other events

Deaths: 0 deaths

Tio R2.5

Serious events: 2 serious events

Other events: 55 other events

Deaths: 0 deaths

Tio R5

Serious events: 3 serious events

Other events: 61 other events

Deaths: 0 deaths

Serious adverse events

Measure	Placebo Respimat n=138 participants at risk Inhalation of placebo solution once daily for 48 weeks, delivered by the Respimat Inhaler	Tio R2.5 n=125 participants at risk Inhalation of 2.5μg tiotropium bromide solution once daily for 48 weeks, delivered by the Respimat Inhaler	Tio R5 n=134 participants at risk Inhalation of 5μg tiotropium bromide solution once daily for 48 weeks, delivered by the Respimat Inhaler
Gastrointestinal disorders Abdominal pain upper	0.00% 0/138 • From first drug administration until 30 days after last drug intake, up to 416 days Treated set which included all randomised patients who were dispensed trial medication and received at least one documented dose of trial medication.	0.00% 0/125 • From first drug administration until 30 days after last drug intake, up to 416 days Treated set which included all randomised patients who were dispensed trial medication and received at least one documented dose of trial medication.	0.75% 1/134 • From first drug administration until 30 days after last drug intake, up to 416 days Treated set which included all randomised patients who were dispensed trial medication and received at least one documented dose of trial medication.
Gastrointestinal disorders Gastrointestinal disorder	0.00% 0/138 • From first drug administration until 30 days after last drug intake, up to 416 days Treated set which included all randomised patients who were dispensed trial medication and received at least one documented dose of trial medication.	0.80% 1/125 • From first drug administration until 30 days after last drug intake, up to 416 days Treated set which included all randomised patients who were dispensed trial medication and received at least one documented dose of trial medication.	0.00% 0/134 • From first drug administration until 30 days after last drug intake, up to 416 days Treated set which included all randomised patients who were dispensed trial medication and received at least one documented dose of trial medication.
Gastrointestinal disorders Peritoneal haemorrhage	0.00% 0/138 • From first drug administration until 30 days after last drug intake, up to 416 days Treated set which included all randomised patients who were dispensed trial medication and received at least one documented dose of trial medication.	0.80% 1/125 • From first drug administration until 30 days after last drug intake, up to 416 days Treated set which included all randomised patients who were dispensed trial medication and received at least one documented dose of trial medication.	0.00% 0/134 • From first drug administration until 30 days after last drug intake, up to 416 days Treated set which included all randomised patients who were dispensed trial medication and received at least one documented dose of trial medication.
Gastrointestinal disorders Retroperitoneal haematoma	0.00% 0/138 • From first drug administration until 30 days after last drug intake, up to 416 days Treated set which included all randomised patients who were dispensed trial medication and received at least one documented dose of trial medication.	0.80% 1/125 • From first drug administration until 30 days after last drug intake, up to 416 days Treated set which included all randomised patients who were dispensed trial medication and received at least one documented dose of trial medication.	0.00% 0/134 • From first drug administration until 30 days after last drug intake, up to 416 days Treated set which included all randomised patients who were dispensed trial medication and received at least one documented dose of trial medication.
Hepatobiliary disorders Liver injury	0.00% 0/138 • From first drug administration until 30 days after last drug intake, up to 416 days Treated set which included all randomised patients who were dispensed trial medication and received at least one documented dose of trial medication.	0.80% 1/125 • From first drug administration until 30 days after last drug intake, up to 416 days Treated set which included all randomised patients who were dispensed trial medication and received at least one documented dose of trial medication.	0.00% 0/134 • From first drug administration until 30 days after last drug intake, up to 416 days Treated set which included all randomised patients who were dispensed trial medication and received at least one documented dose of trial medication.
Immune system disorders Allergy to plants	0.00% 0/138 • From first drug administration until 30 days after last drug intake, up to 416 days Treated set which included all randomised patients who were dispensed trial medication and received at least one documented dose of trial medication.	0.00% 0/125 • From first drug administration until 30 days after last drug intake, up to 416 days Treated set which included all randomised patients who were dispensed trial medication and received at least one documented dose of trial medication.	0.75% 1/134 • From first drug administration until 30 days after last drug intake, up to 416 days Treated set which included all randomised patients who were dispensed trial medication and received at least one documented dose of trial medication.
Immune system disorders Anaphylactic reaction	0.00% 0/138 • From first drug administration until 30 days after last drug intake, up to 416 days Treated set which included all randomised patients who were dispensed trial medication and received at least one documented dose of trial medication.	0.00% 0/125 • From first drug administration until 30 days after last drug intake, up to 416 days Treated set which included all randomised patients who were dispensed trial medication and received at least one documented dose of trial medication.	0.75% 1/134 • From first drug administration until 30 days after last drug intake, up to 416 days Treated set which included all randomised patients who were dispensed trial medication and received at least one documented dose of trial medication.
Infections and infestations Appendicitis	0.00% 0/138 • From first drug administration until 30 days after last drug intake, up to 416 days Treated set which included all randomised patients who were dispensed trial medication and received at least one documented dose of trial medication.	0.80% 1/125 • From first drug administration until 30 days after last drug intake, up to 416 days Treated set which included all randomised patients who were dispensed trial medication and received at least one documented dose of trial medication.	0.00% 0/134 • From first drug administration until 30 days after last drug intake, up to 416 days Treated set which included all randomised patients who were dispensed trial medication and received at least one documented dose of trial medication.
Infections and infestations Gastroenteritis	0.72% 1/138 • From first drug administration until 30 days after last drug intake, up to 416 days Treated set which included all randomised patients who were dispensed trial medication and received at least one documented dose of trial medication.	0.00% 0/125 • From first drug administration until 30 days after last drug intake, up to 416 days Treated set which included all randomised patients who were dispensed trial medication and received at least one documented dose of trial medication.	0.00% 0/134 • From first drug administration until 30 days after last drug intake, up to 416 days Treated set which included all randomised patients who were dispensed trial medication and received at least one documented dose of trial medication.
Injury, poisoning and procedural complications Arterial injury	0.00% 0/138 • From first drug administration until 30 days after last drug intake, up to 416 days Treated set which included all randomised patients who were dispensed trial medication and received at least one documented dose of trial medication.	0.80% 1/125 • From first drug administration until 30 days after last drug intake, up to 416 days Treated set which included all randomised patients who were dispensed trial medication and received at least one documented dose of trial medication.	0.00% 0/134 • From first drug administration until 30 days after last drug intake, up to 416 days Treated set which included all randomised patients who were dispensed trial medication and received at least one documented dose of trial medication.
Injury, poisoning and procedural complications Hepatic rupture	0.00% 0/138 • From first drug administration until 30 days after last drug intake, up to 416 days Treated set which included all randomised patients who were dispensed trial medication and received at least one documented dose of trial medication.	0.80% 1/125 • From first drug administration until 30 days after last drug intake, up to 416 days Treated set which included all randomised patients who were dispensed trial medication and received at least one documented dose of trial medication.	0.00% 0/134 • From first drug administration until 30 days after last drug intake, up to 416 days Treated set which included all randomised patients who were dispensed trial medication and received at least one documented dose of trial medication.
Injury, poisoning and procedural complications Multiple injuries	0.00% 0/138 • From first drug administration until 30 days after last drug intake, up to 416 days Treated set which included all randomised patients who were dispensed trial medication and received at least one documented dose of trial medication.	0.80% 1/125 • From first drug administration until 30 days after last drug intake, up to 416 days Treated set which included all randomised patients who were dispensed trial medication and received at least one documented dose of trial medication.	0.00% 0/134 • From first drug administration until 30 days after last drug intake, up to 416 days Treated set which included all randomised patients who were dispensed trial medication and received at least one documented dose of trial medication.
Injury, poisoning and procedural complications Wound	0.00% 0/138 • From first drug administration until 30 days after last drug intake, up to 416 days Treated set which included all randomised patients who were dispensed trial medication and received at least one documented dose of trial medication.	0.80% 1/125 • From first drug administration until 30 days after last drug intake, up to 416 days Treated set which included all randomised patients who were dispensed trial medication and received at least one documented dose of trial medication.	0.00% 0/134 • From first drug administration until 30 days after last drug intake, up to 416 days Treated set which included all randomised patients who were dispensed trial medication and received at least one documented dose of trial medication.
Musculoskeletal and connective tissue disorders Compartment syndrome	0.00% 0/138 • From first drug administration until 30 days after last drug intake, up to 416 days Treated set which included all randomised patients who were dispensed trial medication and received at least one documented dose of trial medication.	0.80% 1/125 • From first drug administration until 30 days after last drug intake, up to 416 days Treated set which included all randomised patients who were dispensed trial medication and received at least one documented dose of trial medication.	0.00% 0/134 • From first drug administration until 30 days after last drug intake, up to 416 days Treated set which included all randomised patients who were dispensed trial medication and received at least one documented dose of trial medication.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Teratoma	0.72% 1/138 • From first drug administration until 30 days after last drug intake, up to 416 days Treated set which included all randomised patients who were dispensed trial medication and received at least one documented dose of trial medication.	0.00% 0/125 • From first drug administration until 30 days after last drug intake, up to 416 days Treated set which included all randomised patients who were dispensed trial medication and received at least one documented dose of trial medication.	0.00% 0/134 • From first drug administration until 30 days after last drug intake, up to 416 days Treated set which included all randomised patients who were dispensed trial medication and received at least one documented dose of trial medication.
Respiratory, thoracic and mediastinal disorders Asthma	0.00% 0/138 • From first drug administration until 30 days after last drug intake, up to 416 days Treated set which included all randomised patients who were dispensed trial medication and received at least one documented dose of trial medication.	0.00% 0/125 • From first drug administration until 30 days after last drug intake, up to 416 days Treated set which included all randomised patients who were dispensed trial medication and received at least one documented dose of trial medication.	0.75% 1/134 • From first drug administration until 30 days after last drug intake, up to 416 days Treated set which included all randomised patients who were dispensed trial medication and received at least one documented dose of trial medication.

Other adverse events

Measure	Placebo Respimat n=138 participants at risk Inhalation of placebo solution once daily for 48 weeks, delivered by the Respimat Inhaler	Tio R2.5 n=125 participants at risk Inhalation of 2.5μg tiotropium bromide solution once daily for 48 weeks, delivered by the Respimat Inhaler	Tio R5 n=134 participants at risk Inhalation of 5μg tiotropium bromide solution once daily for 48 weeks, delivered by the Respimat Inhaler
Infections and infestations Nasopharyngitis	12.3% 17/138 • From first drug administration until 30 days after last drug intake, up to 416 days Treated set which included all randomised patients who were dispensed trial medication and received at least one documented dose of trial medication.	10.4% 13/125 • From first drug administration until 30 days after last drug intake, up to 416 days Treated set which included all randomised patients who were dispensed trial medication and received at least one documented dose of trial medication.	14.9% 20/134 • From first drug administration until 30 days after last drug intake, up to 416 days Treated set which included all randomised patients who were dispensed trial medication and received at least one documented dose of trial medication.
Infections and infestations Respiratory tract infection viral	8.0% 11/138 • From first drug administration until 30 days after last drug intake, up to 416 days Treated set which included all randomised patients who were dispensed trial medication and received at least one documented dose of trial medication.	8.8% 11/125 • From first drug administration until 30 days after last drug intake, up to 416 days Treated set which included all randomised patients who were dispensed trial medication and received at least one documented dose of trial medication.	7.5% 10/134 • From first drug administration until 30 days after last drug intake, up to 416 days Treated set which included all randomised patients who were dispensed trial medication and received at least one documented dose of trial medication.
Infections and infestations Tonsillitis	5.1% 7/138 • From first drug administration until 30 days after last drug intake, up to 416 days Treated set which included all randomised patients who were dispensed trial medication and received at least one documented dose of trial medication.	1.6% 2/125 • From first drug administration until 30 days after last drug intake, up to 416 days Treated set which included all randomised patients who were dispensed trial medication and received at least one documented dose of trial medication.	0.75% 1/134 • From first drug administration until 30 days after last drug intake, up to 416 days Treated set which included all randomised patients who were dispensed trial medication and received at least one documented dose of trial medication.
Infections and infestations Upper respiratory tract infection	4.3% 6/138 • From first drug administration until 30 days after last drug intake, up to 416 days Treated set which included all randomised patients who were dispensed trial medication and received at least one documented dose of trial medication.	1.6% 2/125 • From first drug administration until 30 days after last drug intake, up to 416 days Treated set which included all randomised patients who were dispensed trial medication and received at least one documented dose of trial medication.	5.2% 7/134 • From first drug administration until 30 days after last drug intake, up to 416 days Treated set which included all randomised patients who were dispensed trial medication and received at least one documented dose of trial medication.
Infections and infestations Viral infection	4.3% 6/138 • From first drug administration until 30 days after last drug intake, up to 416 days Treated set which included all randomised patients who were dispensed trial medication and received at least one documented dose of trial medication.	4.0% 5/125 • From first drug administration until 30 days after last drug intake, up to 416 days Treated set which included all randomised patients who were dispensed trial medication and received at least one documented dose of trial medication.	5.2% 7/134 • From first drug administration until 30 days after last drug intake, up to 416 days Treated set which included all randomised patients who were dispensed trial medication and received at least one documented dose of trial medication.
Investigations Peak expiratory flow rate decreased	5.8% 8/138 • From first drug administration until 30 days after last drug intake, up to 416 days Treated set which included all randomised patients who were dispensed trial medication and received at least one documented dose of trial medication.	7.2% 9/125 • From first drug administration until 30 days after last drug intake, up to 416 days Treated set which included all randomised patients who were dispensed trial medication and received at least one documented dose of trial medication.	4.5% 6/134 • From first drug administration until 30 days after last drug intake, up to 416 days Treated set which included all randomised patients who were dispensed trial medication and received at least one documented dose of trial medication.
Nervous system disorders Headache	1.4% 2/138 • From first drug administration until 30 days after last drug intake, up to 416 days Treated set which included all randomised patients who were dispensed trial medication and received at least one documented dose of trial medication.	5.6% 7/125 • From first drug administration until 30 days after last drug intake, up to 416 days Treated set which included all randomised patients who were dispensed trial medication and received at least one documented dose of trial medication.	6.7% 9/134 • From first drug administration until 30 days after last drug intake, up to 416 days Treated set which included all randomised patients who were dispensed trial medication and received at least one documented dose of trial medication.
Respiratory, thoracic and mediastinal disorders Asthma	23.2% 32/138 • From first drug administration until 30 days after last drug intake, up to 416 days Treated set which included all randomised patients who were dispensed trial medication and received at least one documented dose of trial medication.	21.6% 27/125 • From first drug administration until 30 days after last drug intake, up to 416 days Treated set which included all randomised patients who were dispensed trial medication and received at least one documented dose of trial medication.	16.4% 22/134 • From first drug administration until 30 days after last drug intake, up to 416 days Treated set which included all randomised patients who were dispensed trial medication and received at least one documented dose of trial medication.

Additional Information

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Email: clintriage.rdg@boehringer-ingelheim.com

Results disclosure agreements

• Principal investigator is a sponsor employee Boehringer Ingelheim (BI) acknowledges that investigators have the right to publish the study results. Investigators shall provide BI with a copy of any publication or presentation for review prior to any submission. Such review will be done with regard to proprietary information, information related to patentable inventions, medical, scientific, and statistical accuracy within 60 days. BI may request a delay of the publication in order to protect BI's intellectual property rights.
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