Trial Outcomes & Findings for Investigate the Impact of Early Treatment Initiation With Tiotropium in Patients Recovering From Hospitalization for an Acute COPD Exacerbation 2 (NCT NCT01662986)

Last Updated: 2018-10-17

Results Overview

Percentage (number) of patients with next adverse clinical outcome event occured during the study, defined as the combined endpoint of Chronic obstructive pulmonary disease (COPD) exacerbations per Boehringer Ingelheim (BI) definition, all-cause re-hospitalization, or all-cause mortality. Time to the next adverse clinical outcome event from the Two Twin Trials, present 205.478 (NCT01662986) and 205.477 (NCT01663987) was not analysed, only Kaplan Meier curve was plotted. So this endpoint has not been disclosed. This endpoint was analysed using combined data, as specified in the analysis plan

Recruitment status

COMPLETED

Study phase

PHASE4

Target enrollment

79 participants

Primary outcome timeframe

from first drug administration to the last timepoint with information of clinical adverse outcome available, Up to 2 years

Results posted on

2018-10-17

Participant Flow

Randomized, placebo-controlled, double blind, parallel group design involving an event-driven treatment period up to the close of the study and a minimum 30-day follow-up period up to the close of the study

Participant milestones

Participant milestones
Measure	Placebo Patient to receive oral inhalation of one placebo powder capsule once daily in the morning via HandiHaler.	Tiotropium Bromide (18 μg) Patient to receive oral inhalation of one tiotropium bromide powder capsule once daily in the morning via HandiHaler
Overall Study STARTED	40	39
Overall Study COMPLETED	22	26
Overall Study NOT COMPLETED	18	13

Reasons for withdrawal

Reasons for withdrawal
Measure	Placebo Patient to receive oral inhalation of one placebo powder capsule once daily in the morning via HandiHaler.	Tiotropium Bromide (18 μg) Patient to receive oral inhalation of one tiotropium bromide powder capsule once daily in the morning via HandiHaler
Overall Study Adverse Event	5	4
Overall Study Protocol Violation	2	3
Overall Study Lost to Follow-up	5	4
Overall Study Withdrawal by Subject	2	2
Overall Study Not Treated	1	0
Overall Study Other than stated above	3	0

Baseline Characteristics

Investigate the Impact of Early Treatment Initiation With Tiotropium in Patients Recovering From Hospitalization for an Acute COPD Exacerbation 2

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Placebo n=39 Participants Patient to receive oral inhalation of one placebo powder capsule once daily in the morning via HandiHaler.	Tiotropium Bromide (18 μg) n=39 Participants Patient to receive oral inhalation of one tiotropium bromide powder capsule once daily in the morning via HandiHaler	Total n=78 Participants Total of all reporting groups
Age, Continuous	60.0 Years STANDARD_DEVIATION 8.6 • n=5 Participants	58.4 Years STANDARD_DEVIATION 7.0 • n=7 Participants	59.2 Years STANDARD_DEVIATION 7.8 • n=5 Participants
Sex: Female, Male Female	19 Participants n=5 Participants	21 Participants n=7 Participants	40 Participants n=5 Participants
Sex: Female, Male Male	20 Participants n=5 Participants	18 Participants n=7 Participants	38 Participants n=5 Participants

PRIMARY outcome

Timeframe: Baseline and 12 weeks

Population: Treated Set (TS): The treated set included all patients randomized and who took at least one dose of the study drug. The number of patients analyzed at week 12 from the treated set were 29 for Placebo and 30 for Tiotropium.

Change from baseline of trough forced expiratory volume in 1 second (FEV1) at 12 weeks on study drug. Trough FEV1 is defined as the FEV1 measurement prior to the next dosing of study drug and approximately 24 hours after last inhalation of drug.

Outcome measures

Outcome measures
Measure	Placebo n=29 Participants Patient to receive oral inhalation of one placebo powder capsule once daily in the morning via HandiHaler.	Tiotropium Bromide (18 μg) n=30 Participants Patient to receive oral inhalation of one tiotropium bromide powder capsule once daily in the morning via HandiHaler
Change From Baseline of Trough FEV1 at 12 Weeks on Study Drug.	0.124 Litres Standard Deviation 0.271	0.186 Litres Standard Deviation 0.475

PRIMARY outcome

Timeframe: from first drug administration to the last timepoint with information of clinical adverse outcome available, Up to 2 years

Population: Treated Set of the pooled twin studies 205.478 and 205.477 : This set includes all patients who were randomized and took at least one dose of the study drug, 157 patients (79 tiotropium and 78 placebo) were included in this set.

Outcome measures

Outcome measures
Measure	Placebo n=78 Participants Patient to receive oral inhalation of one placebo powder capsule once daily in the morning via HandiHaler.	Tiotropium Bromide (18 μg) n=79 Participants Patient to receive oral inhalation of one tiotropium bromide powder capsule once daily in the morning via HandiHaler
Percentage of Patients With Next Adverse Clinical Outcome Event From the Two Twin Trials, Present 205.478 (NCT01662986) and 205.477 (NCT01663987).	47.4 Percentage of participants	53.2 Percentage of participants

SECONDARY outcome

Timeframe: baseline and 12 weeks

Population: Treated Set (TS). The number of patients analyzed at week 12 from the treated set were 29 for Placebo and 30 for Tiotropium.

Change from baseline of trough Forced Vital Capacity (FVC) at 12 weeks on study drug.

Outcome measures

Outcome measures
Measure	Placebo n=29 Participants Patient to receive oral inhalation of one placebo powder capsule once daily in the morning via HandiHaler.	Tiotropium Bromide (18 μg) n=30 Participants Patient to receive oral inhalation of one tiotropium bromide powder capsule once daily in the morning via HandiHaler
Change From Baseline of Trough FVC at 12 Weeks on Study Drug.	0.090 Litres Standard Deviation 0.399	0.282 Litres Standard Deviation 0.558

SECONDARY outcome

Timeframe: from first drug administration to the last timepoint with information of clinical adverse outcome available, Up to 2 years

Population: Treated Set (TS)

Percentage (number) of patients with adverse clinical event on study, which is defined as the combined endpoint of Chronic obstructive pulmonary disease (COPD) exacerbations per Boehringer Ingelheim (BI) definition, all-cause re-hospitalization, or all-cause mortality.

Outcome measures

Outcome measures
Measure	Placebo n=39 Participants Patient to receive oral inhalation of one placebo powder capsule once daily in the morning via HandiHaler.	Tiotropium Bromide (18 μg) n=39 Participants Patient to receive oral inhalation of one tiotropium bromide powder capsule once daily in the morning via HandiHaler
Percentage of Patients With Adverse Clinical Event During on Study.	35.9 percentage of participants	46.2 percentage of participants

SECONDARY outcome

Timeframe: Baseline and week 12

Population: Treated Set of the pooled twin studies 205.478 and 205.477. The number of patients analyzed at week 12 from the treated set were 59 for Placebo and 60 for Tiotropium.

Change from baseline of trough FEV1 (forced expiratory volume in 1 second) at 12 weeks on study drug. Trough FEV1 is defined as the FEV1 measurement prior to the next dosing of study drug and approximately 24 hours after last inhalation of drug.

Outcome measures

Outcome measures
Measure	Placebo n=59 Participants Patient to receive oral inhalation of one placebo powder capsule once daily in the morning via HandiHaler.	Tiotropium Bromide (18 μg) n=60 Participants Patient to receive oral inhalation of one tiotropium bromide powder capsule once daily in the morning via HandiHaler
Change From Baseline of Trough FEV1 at 12 Weeks on Study Drug From the Two Twin Trials, Present 205.478 (NCT01662986) and 205.477 (NCT01663987)	0.035 Litres Standard Deviation 0.262	0.185 Litres Standard Deviation 0.384

SECONDARY outcome

Timeframe: Baseline and week 12

Population: Treated Set of the pooled twin studies 205.478 and 205.477. The number of patients analyzed at week 12 from the treated set were 59 for Placebo and 60 for Tiotropium.

Change from baseline of trough Forced Vital Capacity (FVC) at 12 weeks on study drug.

Outcome measures

Outcome measures
Measure	Placebo n=59 Participants Patient to receive oral inhalation of one placebo powder capsule once daily in the morning via HandiHaler.	Tiotropium Bromide (18 μg) n=60 Participants Patient to receive oral inhalation of one tiotropium bromide powder capsule once daily in the morning via HandiHaler
Change From Baseline of Trough FVC at 12 Weeks From the Two Twin Trials, Present 205.478 (NCT01662986) and 205.477 (NCT01663987)	-0.015 Litres Standard Deviation 0.396	0.278 Litres Standard Deviation 0.447

SECONDARY outcome

Timeframe: from first drug administration to the last timepoint with information of clinical adverse outcome available, Up to 2 years

Population: Treated Set of the pooled twin studies 205.478 and 205.477

Percentage (number) of patients with COPD exacerbation on study was analysed for the combined study. A COPD exacerbation was defined as a complex of lower respiratory events/symptoms (increase or new onset) related to the underlying COPD with duration of three days or more, requiring a change in treatment where a complex of lower respiratory events/symptoms was defined as at least two of the following: 1\) Shortness of breath; 2) Sputum production (volume) ; 3) Occurrence of purulent sputum; 4) Cough; 5) Wheezing; 6) Chest tightness. Onset of exacerbation was defined by the onset of first recorded symptom.The end of exacerbation was decided by the investigator based on clinical judgment. A required change in treatment included either prescription of antibiotics and/or systemic steroids; and/or a newly prescribed maintenance respiratory medication (i.e., bronchodilators including theophyllines and PDE4-inhibitors).

Outcome measures

Outcome measures
Measure	Placebo n=78 Participants Patient to receive oral inhalation of one placebo powder capsule once daily in the morning via HandiHaler.	Tiotropium Bromide (18 μg) n=79 Participants Patient to receive oral inhalation of one tiotropium bromide powder capsule once daily in the morning via HandiHaler
Percentage of Patients With COPD Exacerbation From the Two Twin Trials, Present 205.478 (NCT01662986) and 205.477 (NCT01663987)	44.9 percentage of participants	40.5 percentage of participants

SECONDARY outcome

Timeframe: from first drug administration to the last timepoint with information of clinical adverse outcome available, Up to 2 years

Population: Treated Set of the pooled twin studies 205.478 and 205.477

Percentage (number) of patients with all-cause hospitalization outcome event occured during the study was analysed for the combined study. All-cause hospitalization included all hospitalizations, except planned hospitalizations for elective procedures. Hospitalizations occurring on the same day as discharge were not considered a separate admission.

Outcome measures

Outcome measures
Measure	Placebo n=78 Participants Patient to receive oral inhalation of one placebo powder capsule once daily in the morning via HandiHaler.	Tiotropium Bromide (18 μg) n=79 Participants Patient to receive oral inhalation of one tiotropium bromide powder capsule once daily in the morning via HandiHaler
Percentage of Patients With All-cause Hospitalization From the Two Twin Trials, Present 205.478 (NCT01662986) and 205.477 (NCT01663987).	26.9 percentage of participants	26.6 percentage of participants

SECONDARY outcome

Timeframe: from date of hospital discharge prior to randomization upto readmission days >1 and <31 days

Population: Treated Set of the pooled twin studies 205.478 and 205.477

Percentage (number) of patients with 30-day hospital readmission rates outcome events was analysed. Days to hospital readmission were calculated as:Hospital readmission days = Readmission date - Date of hospital discharge + 1. The 30-day hospital readmission analysis summarized the frequency of patients with hospital readmission and readmission days \>1 and \<31 days using the TS.

Outcome measures

Outcome measures
Measure	Placebo n=78 Participants Patient to receive oral inhalation of one placebo powder capsule once daily in the morning via HandiHaler.	Tiotropium Bromide (18 μg) n=79 Participants Patient to receive oral inhalation of one tiotropium bromide powder capsule once daily in the morning via HandiHaler
Percentage of Patients With 30-day Hospital Readmission Rates Outcome Event From the Two Twin Trials, Present 205.478 (NCT01662986) and 205.477 (NCT01663987)	5.1 percentage of participants	5.1 percentage of participants

SECONDARY outcome

Timeframe: start of treatment to the last timepoint with information of clinical adverse outcome available,Up to 2 years

Population: Treated Set of the pooled twin studies 205.478 and 205.477. The number of patients analyzed for this endpoint from the treated set were 73 for Placebo and 54 for Tiotropium.

Number of COPD exacerbation per patient year outcome event occured during the study was analysed descriptively by calculating average occurrence (number of events per patient year drug exposure) by treatment group for on study period using the TS.

Outcome measures

Outcome measures
Measure	Placebo n=73 Participants Patient to receive oral inhalation of one placebo powder capsule once daily in the morning via HandiHaler.	Tiotropium Bromide (18 μg) n=54 Participants Patient to receive oral inhalation of one tiotropium bromide powder capsule once daily in the morning via HandiHaler
Number of COPD Exacerbation Events From the Two Twin Trials, Present 205.478 (NCT01662986) and 205.477 (NCT01663987)	1.3 exacerbations per patient year	0.9 exacerbations per patient year

SECONDARY outcome

Timeframe: start of treatment to the last timepoint with information of clinical adverse outcome available,Up to 2 years

Population: Treated Set of the pooled twin studies 205.478 and 205.477. The number of patients analyzed for this endpoint from the treated set were 73 for Placebo and 54 for Tiotropium.

Total patient year exposure of COPD was calculated by aggregating the time to min(treatment stop +30, last contact) for on-treatment analysis, or time to last contact for on-study analysis.

Outcome measures

Outcome measures
Measure	Placebo n=73 Participants Patient to receive oral inhalation of one placebo powder capsule once daily in the morning via HandiHaler.	Tiotropium Bromide (18 μg) n=54 Participants Patient to receive oral inhalation of one tiotropium bromide powder capsule once daily in the morning via HandiHaler
Exposure of COPD Exacerbation Events From the Two Twin Trials, Present 205.478 (NCT01662986) and 205.477 (NCT01663987)	58.0 Patient years	60.2 Patient years

SECONDARY outcome

Timeframe: from first drug administration to the last timepoint with information of clinical adverse outcome available, Up to 2 years

Population: Treated Set of the pooled twin studies 205.478 and 205.477. The number of patients analyzed for this endpoint from the treated set were 47 for Placebo and 38 for Tiotropium.

Number of all-cause hospitalization per patient year outcome event occured during the study was analysed descriptively by calculating average occurrence (number of events per patient year drug exposure) by treatment group for on study period using the TS.

Outcome measures

Outcome measures
Measure	Placebo n=47 Participants Patient to receive oral inhalation of one placebo powder capsule once daily in the morning via HandiHaler.	Tiotropium Bromide (18 μg) n=38 Participants Patient to receive oral inhalation of one tiotropium bromide powder capsule once daily in the morning via HandiHaler
Number of All-cause Hospitalization Event From the Two Twin Trials, Present 205.478 (NCT01662986) and 205.477 (NCT01663987)	0.8 hospitalizations per patient year	0.6 hospitalizations per patient year

SECONDARY outcome

Timeframe: from first drug administration to the last timepoint with information of clinical adverse outcome available, Up to 2 years

Population: Treated Set of the pooled twin studies 205.478 and 205.477. The number of patients analyzed for this endpoint from the treated set were 47 for Placebo and 38 for Tiotropium.

Total patient year exposure of all-cause hospitalization was calculated by aggregating the time to min(treatment stop +30, last contact) for on-treatment analysis, or time to last contact for on-study analysis.

Outcome measures

Outcome measures
Measure	Placebo n=47 Participants Patient to receive oral inhalation of one placebo powder capsule once daily in the morning via HandiHaler.	Tiotropium Bromide (18 μg) n=38 Participants Patient to receive oral inhalation of one tiotropium bromide powder capsule once daily in the morning via HandiHaler
Exposure of All-cause Hospitalization Event From the Two Twin Trials, Present 205.478 (NCT01662986) and 205.477 (NCT01663987)	58.0 patient years	60.2 patient years

SECONDARY outcome

Timeframe: from first drug administration to the last timepoint with information of EXACT-PRO, Up to 2 years

Population: Patients who had baseline and post-baseline measurements of EXACT-PRO.

Time to event: Time to recovery based on EXACT-PRO total score. The percentage of observed patients recovered by end of study was reported. Time to recovery was assessed with the EXACT-PRO questionnaire. EXACT-PRO total scores were transformed to smooth scores for determining time to recovery and all other endpoints related to the EXACT questionnaire. The day-2 score was transformed to the mean of the total scores recorded on Day 1, 2, and 3. Similarly, each subsequent day's score was transformed to the mean score using a rolling 3-day average. Analysis based on Kaplan Meier estimate

Outcome measures

Outcome measures
Measure	Placebo n=76 Participants Patient to receive oral inhalation of one placebo powder capsule once daily in the morning via HandiHaler.	Tiotropium Bromide (18 μg) n=76 Participants Patient to receive oral inhalation of one tiotropium bromide powder capsule once daily in the morning via HandiHaler
Time to Event: Time to Recovery (EXACT-PRO) From the Two Twin Trials, Present 205.478 (NCT01662986) and 205.477 (NCT01663987)	94.0 Percentage of patients recovered	88.0 Percentage of patients recovered

Adverse Events

Placebo

Serious events: 9 serious events

Other events: 11 other events

Deaths: 0 deaths

Tiotropium Bromide (18 μg)

Serious events: 10 serious events

Other events: 23 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Boehringer Ingelheim Call Center

Boehringer Ingelheim

Phone: 1-800-243-0127

Email: [email protected]

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.
Publication restrictions are in place

Restriction type: OTHER

Measure	Placebo n=39 participants at risk Patient to receive one placebo inhalation powder capsule once daily in the morning via HandiHaler	Tiotropium Bromide (18 μg) n=39 participants at risk Patient to receive oral inhalation of one tiotropium bromide powder capsule once daily in the morning via HandiHaler
Blood and lymphatic system disorders Leukocytosis	2.6% 1/39 • From first drug administration until 30 days after the last drug administration, up to 405 days	0.00% 0/39 • From first drug administration until 30 days after the last drug administration, up to 405 days
Endocrine disorders Hypothyroidism	2.6% 1/39 • From first drug administration until 30 days after the last drug administration, up to 405 days	0.00% 0/39 • From first drug administration until 30 days after the last drug administration, up to 405 days
Gastrointestinal disorders Abdominal pain	0.00% 0/39 • From first drug administration until 30 days after the last drug administration, up to 405 days	2.6% 1/39 • From first drug administration until 30 days after the last drug administration, up to 405 days
Gastrointestinal disorders Melaena	0.00% 0/39 • From first drug administration until 30 days after the last drug administration, up to 405 days	2.6% 1/39 • From first drug administration until 30 days after the last drug administration, up to 405 days
Gastrointestinal disorders Upper gastrointestinal haemorrhage	0.00% 0/39 • From first drug administration until 30 days after the last drug administration, up to 405 days	2.6% 1/39 • From first drug administration until 30 days after the last drug administration, up to 405 days
General disorders Oedema peripheral	2.6% 1/39 • From first drug administration until 30 days after the last drug administration, up to 405 days	0.00% 0/39 • From first drug administration until 30 days after the last drug administration, up to 405 days
Hepatobiliary disorders Bile duct stone	0.00% 0/39 • From first drug administration until 30 days after the last drug administration, up to 405 days	2.6% 1/39 • From first drug administration until 30 days after the last drug administration, up to 405 days
Hepatobiliary disorders Cholangitis	0.00% 0/39 • From first drug administration until 30 days after the last drug administration, up to 405 days	2.6% 1/39 • From first drug administration until 30 days after the last drug administration, up to 405 days
Hepatobiliary disorders Cholecystitis	0.00% 0/39 • From first drug administration until 30 days after the last drug administration, up to 405 days	2.6% 1/39 • From first drug administration until 30 days after the last drug administration, up to 405 days
Infections and infestations Bronchitis	0.00% 0/39 • From first drug administration until 30 days after the last drug administration, up to 405 days	2.6% 1/39 • From first drug administration until 30 days after the last drug administration, up to 405 days
Infections and infestations Cellulitis	2.6% 1/39 • From first drug administration until 30 days after the last drug administration, up to 405 days	0.00% 0/39 • From first drug administration until 30 days after the last drug administration, up to 405 days
Infections and infestations Pneumonia	0.00% 0/39 • From first drug administration until 30 days after the last drug administration, up to 405 days	2.6% 1/39 • From first drug administration until 30 days after the last drug administration, up to 405 days
Infections and infestations Respiratory tract infection viral	2.6% 1/39 • From first drug administration until 30 days after the last drug administration, up to 405 days	0.00% 0/39 • From first drug administration until 30 days after the last drug administration, up to 405 days
Infections and infestations Urinary tract infection	0.00% 0/39 • From first drug administration until 30 days after the last drug administration, up to 405 days	2.6% 1/39 • From first drug administration until 30 days after the last drug administration, up to 405 days
Injury, poisoning and procedural complications Femur fracture	0.00% 0/39 • From first drug administration until 30 days after the last drug administration, up to 405 days	2.6% 1/39 • From first drug administration until 30 days after the last drug administration, up to 405 days
Metabolism and nutrition disorders Hypoglycaemia	0.00% 0/39 • From first drug administration until 30 days after the last drug administration, up to 405 days	2.6% 1/39 • From first drug administration until 30 days after the last drug administration, up to 405 days
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Adenocarcinoma	0.00% 0/39 • From first drug administration until 30 days after the last drug administration, up to 405 days	2.6% 1/39 • From first drug administration until 30 days after the last drug administration, up to 405 days
Psychiatric disorders Confusional state	2.6% 1/39 • From first drug administration until 30 days after the last drug administration, up to 405 days	0.00% 0/39 • From first drug administration until 30 days after the last drug administration, up to 405 days
Psychiatric disorders Mental status changes	0.00% 0/39 • From first drug administration until 30 days after the last drug administration, up to 405 days	2.6% 1/39 • From first drug administration until 30 days after the last drug administration, up to 405 days
Psychiatric disorders Substance abuse	2.6% 1/39 • From first drug administration until 30 days after the last drug administration, up to 405 days	0.00% 0/39 • From first drug administration until 30 days after the last drug administration, up to 405 days
Renal and urinary disorders Hydronephrosis	0.00% 0/39 • From first drug administration until 30 days after the last drug administration, up to 405 days	2.6% 1/39 • From first drug administration until 30 days after the last drug administration, up to 405 days
Renal and urinary disorders Nephrolithiasis	0.00% 0/39 • From first drug administration until 30 days after the last drug administration, up to 405 days	2.6% 1/39 • From first drug administration until 30 days after the last drug administration, up to 405 days
Renal and urinary disorders Renal colic	0.00% 0/39 • From first drug administration until 30 days after the last drug administration, up to 405 days	2.6% 1/39 • From first drug administration until 30 days after the last drug administration, up to 405 days
Renal and urinary disorders Renal failure acute	0.00% 0/39 • From first drug administration until 30 days after the last drug administration, up to 405 days	2.6% 1/39 • From first drug administration until 30 days after the last drug administration, up to 405 days
Respiratory, thoracic and mediastinal disorders Acute respiratory failure	2.6% 1/39 • From first drug administration until 30 days after the last drug administration, up to 405 days	2.6% 1/39 • From first drug administration until 30 days after the last drug administration, up to 405 days
Respiratory, thoracic and mediastinal disorders Chronic obstructive pulmonary disease	17.9% 7/39 • From first drug administration until 30 days after the last drug administration, up to 405 days	7.7% 3/39 • From first drug administration until 30 days after the last drug administration, up to 405 days
Respiratory, thoracic and mediastinal disorders Dyspnoea	2.6% 1/39 • From first drug administration until 30 days after the last drug administration, up to 405 days	0.00% 0/39 • From first drug administration until 30 days after the last drug administration, up to 405 days
Respiratory, thoracic and mediastinal disorders Pneumonia aspiration	0.00% 0/39 • From first drug administration until 30 days after the last drug administration, up to 405 days	2.6% 1/39 • From first drug administration until 30 days after the last drug administration, up to 405 days
Respiratory, thoracic and mediastinal disorders Pneumothorax	0.00% 0/39 • From first drug administration until 30 days after the last drug administration, up to 405 days	2.6% 1/39 • From first drug administration until 30 days after the last drug administration, up to 405 days
Respiratory, thoracic and mediastinal disorders Respiratory failure	2.6% 1/39 • From first drug administration until 30 days after the last drug administration, up to 405 days	2.6% 1/39 • From first drug administration until 30 days after the last drug administration, up to 405 days

Measure	Placebo n=39 participants at risk Patient to receive one placebo inhalation powder capsule once daily in the morning via HandiHaler	Tiotropium Bromide (18 μg) n=39 participants at risk Patient to receive oral inhalation of one tiotropium bromide powder capsule once daily in the morning via HandiHaler
Gastrointestinal disorders Constipation	0.00% 0/39 • From first drug administration until 30 days after the last drug administration, up to 405 days	5.1% 2/39 • From first drug administration until 30 days after the last drug administration, up to 405 days
Gastrointestinal disorders Diarrhoea	0.00% 0/39 • From first drug administration until 30 days after the last drug administration, up to 405 days	5.1% 2/39 • From first drug administration until 30 days after the last drug administration, up to 405 days
General disorders Chest discomfort	0.00% 0/39 • From first drug administration until 30 days after the last drug administration, up to 405 days	5.1% 2/39 • From first drug administration until 30 days after the last drug administration, up to 405 days
General disorders Chest pain	0.00% 0/39 • From first drug administration until 30 days after the last drug administration, up to 405 days	5.1% 2/39 • From first drug administration until 30 days after the last drug administration, up to 405 days
General disorders Oedema peripheral	0.00% 0/39 • From first drug administration until 30 days after the last drug administration, up to 405 days	7.7% 3/39 • From first drug administration until 30 days after the last drug administration, up to 405 days
Infections and infestations Bronchitis	2.6% 1/39 • From first drug administration until 30 days after the last drug administration, up to 405 days	5.1% 2/39 • From first drug administration until 30 days after the last drug administration, up to 405 days
Infections and infestations Candida infection	0.00% 0/39 • From first drug administration until 30 days after the last drug administration, up to 405 days	5.1% 2/39 • From first drug administration until 30 days after the last drug administration, up to 405 days
Infections and infestations Oral candidiasis	0.00% 0/39 • From first drug administration until 30 days after the last drug administration, up to 405 days	7.7% 3/39 • From first drug administration until 30 days after the last drug administration, up to 405 days
Infections and infestations Upper respiratory tract infection	2.6% 1/39 • From first drug administration until 30 days after the last drug administration, up to 405 days	5.1% 2/39 • From first drug administration until 30 days after the last drug administration, up to 405 days
Infections and infestations Urinary tract infection	0.00% 0/39 • From first drug administration until 30 days after the last drug administration, up to 405 days	7.7% 3/39 • From first drug administration until 30 days after the last drug administration, up to 405 days
Injury, poisoning and procedural complications Contusion	0.00% 0/39 • From first drug administration until 30 days after the last drug administration, up to 405 days	7.7% 3/39 • From first drug administration until 30 days after the last drug administration, up to 405 days
Musculoskeletal and connective tissue disorders Muscle spasms	0.00% 0/39 • From first drug administration until 30 days after the last drug administration, up to 405 days	5.1% 2/39 • From first drug administration until 30 days after the last drug administration, up to 405 days
Psychiatric disorders Insomnia	5.1% 2/39 • From first drug administration until 30 days after the last drug administration, up to 405 days	2.6% 1/39 • From first drug administration until 30 days after the last drug administration, up to 405 days
Respiratory, thoracic and mediastinal disorders Chronic obstructive pulmonary disease	15.4% 6/39 • From first drug administration until 30 days after the last drug administration, up to 405 days	25.6% 10/39 • From first drug administration until 30 days after the last drug administration, up to 405 days
Respiratory, thoracic and mediastinal disorders Cough	0.00% 0/39 • From first drug administration until 30 days after the last drug administration, up to 405 days	5.1% 2/39 • From first drug administration until 30 days after the last drug administration, up to 405 days
Respiratory, thoracic and mediastinal disorders Dyspnoea	2.6% 1/39 • From first drug administration until 30 days after the last drug administration, up to 405 days	5.1% 2/39 • From first drug administration until 30 days after the last drug administration, up to 405 days