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

Study Overview
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Brief Summary
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A randomized, placebo-controlled, double-blind, parallel group, multi-center study to assess the safety and efficacy of tiotropium bromide (18 µg) delivered via the HandiHaler® in Chronic Obstructive Pulmonary Disease (COPD) subjects recovering from hospitalization for an acute exacerbation (Hospital Discharge Study 2)

Official Title
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A Randomized, Placebo-controlled, Double-blind, Parallel Group, Multi Center Study to Assess the Safety and Efficacy of Tiotropium Bromide (18 µg) Delivered Via the HandiHaler® in Chronic Obstructive Pulmonary Disease (COPD) Subjects Recovering From Hospitalization for an Acute Exacerbation (Hospital Discharge Study 2)

Conditions
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Pulmonary Disease, Chronic Obstructive

Intervention / Treatment
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* Drug: tiotropium bromide
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: The following inclusion criteria apply at Visit 0: All subjects must sign an informed consent consistent with the International Conference on Harmonization - Good Clinical Practice (ICH-GCP) guidelines prior to participation in the trial and conducting any study procedures Male or female subjects 40 years of age or older. Hospitalization for a primary diagnosis of acute COPD exacerbation for =14 days. Determination of accuracy of admission diagnosis will be at the discretion of the investigator. Patient reported hospital length of stay and discharge date (confirmed with hospital discharge summary/hospital records; however, medical record confirmation may occur following randomization). The following inclusion criteria apply at Visit 1: Discharged from the hospital =10 days from date of randomization. All subjects must have a diagnosis of COPD (P12-01205), and have documented airway obstruction with a post-bronchodilator Force Expiratory Volume in 1 second (FEV1)\ Force vital capacity (FVC) <0.7(See Section 5.1.2, Pulmonary Function Testing). The diagnosis of COPD can be made at Visit 1 if no Pulmonary Function Testing (PFT) data available within the past 12 months. Subjects must be current or ex-smoker with a smoking history of =10 pack-years: Pack-years = Number of cigarettes/day x years of smoking 20 cigarettes/ pack 8. Subjects must be able to inhale medication in a competent manner from the HandiHaler® device (Appendix 10.1) and from a metered dose inhaler (MDI). Exclusion criteria: The following exclusion criterion applies at Visit 0: No more than 30 days of therapy with any long-acting inhaled anticholinergic over preceding 3 months prior to discharge from the hospital, and no therapy with any long acting anticholinergic post discharge (no use between hospital discharge and randomization) or any other restricted concomitant medications The following exclusion criteria apply at Visit 1: Presence of a significant disease (in the opinion of the investigator) which may put the subject at risk because of participation in the study or may influence the subject's ability to participate in the study for up to 2 years. A documented history of myocardial infarction during the hospitalization preceding randomization. Subjects being stable with a history of cardiac stents are permitted. Any unstable or life-threatening cardiac arrhythmia requiring intervention or change in drug therapy during the last year. Subjects with asthma (subject treated for asthma in the last 2 years, history of childhood asthma is permitted), cystic fibrosis, clinical diagnosis of bronchiectasis, interstitial lung disease, pulmonary thromboembolic disease or known active tuberculosis. 7. Malignancy for which the subject has undergone resection, radiation, chemotherapy or biological treatments within the last two years or is currently on active radiation therapy, chemotherapy or biological treatment. Subjects with treated basal cell carcinoma and non-invasive squamous cell skin carcinoma are allowed. 8. Hospitalization for cardiac failure (New York Heart Association (NYHA) class III or IV) during the hospitalization preceding randomization. 9. Known hypersensitivity to anticholinergic drugs, lactose, or any other components of the HandiHaler® or MDI inhalation solution delivery system. 10. Known moderate to severe renal impairment as judged by the investigator. 11. Known narrow angle glaucoma as judged by the investigator. 12. Significant symptomatic prostatic hyperplasia or bladder-neck obstruction. Subjects whose symptoms are controlled on treatment may be included. 13. Pregnant or nursing women or women of childbearing potential not using a medically approved means of contraception (i.e., oral contraceptives, intrauterine devices, diaphragm or sub dermal implants e.g., Norplant®) for at least three months prior to and for the duration of the trial. 14. Significant alcohol or drug abuse within the past 12 months. 15. Previously randomized in this study or currently participating in another interventional study. 16. Visual impairment that as judged by the investigator does not allow the subject to independently read and complete the questionnaires and eDiary. 17. Any significant or new ECG findings at Visit 1 as judged by the investigator, including, but not limited to signs of acute ischemia, arrhythmia. 18. Treatment with any restricted pulmonary medication. 19. Residing in an assisted living facility.

Ages Eligible for Study
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Minimum Age: 40 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: 18 mcg tiotropium bromide<br>Patient to receive one tiotropium bromide inhalation powder capsule daily (in the morning) via HandiHaler | Drug: tiotropium bromide<br>* 18 mcg once a day (QD)<br>|
| Placebo Comparator: placebo<br>Patient to receive one placebo inhalation powder capsule daily (in the morning) via HandiHaler | Drug: Placebo<br>* Once a day (QD)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline of Trough FEV1 at 12 Weeks on Study Drug. | 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. | Baseline and 12 weeks | 
| Percentage of Patients With Next Adverse Clinical Outcome Event From the Two Twin Trials, Present 205.478 (NCT01662986) and 205.477 (NCT01663987). | 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 | from first drug administration to the last timepoint with information of clinical adverse outcome available, Up to 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline of Trough FVC at 12 Weeks on Study Drug. | Change from baseline of trough Forced Vital Capacity (FVC) at 12 weeks on study drug. | baseline and 12 weeks | 
| Percentage of Patients With Adverse Clinical Event During on Study. | 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. | from first drug administration to the last timepoint with information of clinical adverse outcome available, Up to 2 years | 
| 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) | 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. | Baseline and week 12 | 
| Change From Baseline of Trough FVC at 12 Weeks From the Two Twin Trials, Present 205.478 (NCT01662986) and 205.477 (NCT01663987) | Change from baseline of trough Forced Vital Capacity (FVC) at 12 weeks on study drug. | Baseline and week 12 | 
| Percentage of Patients With COPD Exacerbation From the Two Twin Trials, Present 205.478 (NCT01662986) and 205.477 (NCT01663987) | 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). | from first drug administration to the last timepoint with information of clinical adverse outcome available, Up to 2 years | 
| Percentage of Patients With All-cause Hospitalization From the Two Twin Trials, Present 205.478 (NCT01662986) and 205.477 (NCT01663987). | 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. | from first drug administration to the last timepoint with information of clinical adverse outcome available, Up to 2 years | 
| Percentage of Patients With 30-day Hospital Readmission Rates Outcome Event From the Two Twin Trials, Present 205.478 (NCT01662986) and 205.477 (NCT01663987) | 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. | from date of hospital discharge prior to randomization upto readmission days >1 and <31 days | 
| Number of COPD Exacerbation Events From the Two Twin Trials, Present 205.478 (NCT01662986) and 205.477 (NCT01663987) | 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. | start of treatment to the last timepoint with information of clinical adverse outcome available,Up to 2 years | 
| Exposure of COPD Exacerbation Events From the Two Twin Trials, Present 205.478 (NCT01662986) and 205.477 (NCT01663987) | 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. | start of treatment to the last timepoint with information of clinical adverse outcome available,Up to 2 years | 
| Number of All-cause Hospitalization Event From the Two Twin Trials, Present 205.478 (NCT01662986) and 205.477 (NCT01663987) | 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. | from first drug administration to the last timepoint with information of clinical adverse outcome available, Up to 2 years | 
| Exposure of All-cause Hospitalization Event From the Two Twin Trials, Present 205.478 (NCT01662986) and 205.477 (NCT01663987) | 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. | from first drug administration to the last timepoint with information of clinical adverse outcome available, Up to 2 years | 
| Time to Event: Time to Recovery (EXACT-PRO) From the Two Twin Trials, Present 205.478 (NCT01662986) and 205.477 (NCT01663987) | 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 | from first drug administration to the last timepoint with information of EXACT-PRO, Up to 2 years |