<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT01663987</url>
  </required_header>
  <id_info>
    <org_study_id>205.477</org_study_id>
    <nct_id>NCT01663987</nct_id>
  </id_info>
  <brief_title>Investigate the Impact of Early Treatment Initiation With Tiotropium in Patients Recovering From Hospitalization for an Acute COPD Exacerbation 1</brief_title>
  <official_title>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 1)</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Boehringer Ingelheim</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Boehringer Ingelheim</source>
  <brief_summary>
    <textblock>
      A randomized, placebo-controlled, double-blind, parallel group, multi center study to assess&#xD;
      the safety and efficacy of tiotropium bromide (18 µg) delivered via the HandiHaler® in&#xD;
      Chronic Obstructive Pulmonary Disease (COPD) subjects recovering from hospitalization for an&#xD;
      acute exacerbation (Hospital Discharge 1)&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">August 1, 2012</start_date>
  <completion_date type="Actual">May 1, 2014</completion_date>
  <primary_completion_date type="Actual">May 1, 2014</primary_completion_date>
  <phase>Phase 4</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Double</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Change From Baseline of Trough FEV1 at 12 Weeks on Study Drug</measure>
    <time_frame>Baseline and 12 weeks</time_frame>
    <description>Change from baseline in trough forced expiratory volume in 1 second (FEV1) at 12 weeks on study medication. Trough FEV1 is defined as FEV1 measurement prior to the next dosing of study drug and approximately 24 hours after the last inhalation of drug.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Percentage of Patients With Next Adverse Clinical Outcome Event From the Two Twin Trials, Present 205.477 (NCT01663987) and 205.478 (NCT01662986)</measure>
    <time_frame>From first drug administration to the last timepoint with information of clinical adverse outcome available, up to 2 years</time_frame>
    <description>Percentage 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.&#xD;
Time to the next adverse clinical outcome event from the two twin trials, was defined as a primary endpoint but was not analysed numerically, so this endpoint is presented instead.&#xD;
This endpoint was analysed using combined data, as specified in the analysis plan.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Change From Baseline of Trough FVC at 12 Weeks on Study Drug</measure>
    <time_frame>Baseline and 12 weeks</time_frame>
    <description>Change from baseline of trough Forced Vital Capacity (FVC) at 12 weeks on study drug.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Percentage of Patients With Adverse Clinical Event on Study</measure>
    <time_frame>From first drug administration to the last timepoint with information of clinical adverse outcome available, up to 2 years</time_frame>
    <description>Percentage of patients with adverse clinical event during on study, which is defined as the combined endpoint of chronic obstructive pulmonary disease (COPD) exacerbations per Boehringer Ingelheim (BI) definition, all-cause re-hospitalisation, or all cause mortality.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change From Baseline of Trough FEV1 at 12 Weeks on Study Drug From the Two Twin Trials, Present 205.477 (NCT01663987) and 205.478 (NCT01662986)</measure>
    <time_frame>Baseline and 12 weeks</time_frame>
    <description>Change from baseline of Trough FEV1 (forced expiratory volume in one second) at 12 weeks on study drug.&#xD;
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.&#xD;
This endpoint was analysed using combined data, as specified in the analysis plan.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change From Baseline of Trough FVC at 12 Weeks From the Two Twin Trials, Present 205.477 (NCT01663987) and 205.478 (NCT01662986)</measure>
    <time_frame>Baseline and 12 weeks</time_frame>
    <description>Change from baseline of trough Forced Vital Capacity (FVC) at 12 weeks on study drug.&#xD;
This endpoint was analysed using combined data, as specified in the analysis plan.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Percentage of Patients With COPD Exacerbation From the Two Twin Trials, Present 205.477 (NCT01663987) and 205.478 (NCT01662986)</measure>
    <time_frame>from first drug administration to the last timepoint with information of clinical adverse outcome available, up to 2 years</time_frame>
    <description>Percentage of patients with COPD exacerbation on study was analysed for the combined study.&#xD;
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.&#xD;
A required change in treatment included either prescription of antibiotics and/or systemic steroids; and a newly prescribed maintenance respiratory medication (i.e. bronchodilators including theophyllines and PDE4-inhibitors).&#xD;
This endpoint was analysed using combined data, as specified in the analysis plan.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Percentage of Patients With All-cause Hospitalization From the Two Twin Trials, Present 205.477 (NCT01663987) and 205.478 (NCT01662986)</measure>
    <time_frame>from first drug administration to the last timepoint with information of clinical adverse outcome available, Up to 2 years</time_frame>
    <description>Percentage of patients with all-cause hospitalization outcome event occured during the study was analysed for the combined study.&#xD;
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.&#xD;
This endpoint was analysed using combined data, as specified in the analysis plan.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Percentage of Patients With 30-day Readmission Rates Outcome Event From the Two Twin Trials, Present 205.477 (NCT01663987) and 205.478 (NCT01662986)</measure>
    <time_frame>from date of hospital discharge prior to randomization up to readmission days &gt;1 and &lt;31 days</time_frame>
    <description>Percentage of patients with 30-day hospital readmission rates outcome events was analysed.&#xD;
Days to hospital readmission were calculated as:Hospital readmission days = Readmission date - Date of hospital discharge + 1.&#xD;
The 30-day hospital readmission analysis summarized the frequency of patients with hospital readmission and readmission days &gt;1 and &lt;31 days using the TS.&#xD;
This endpoint was analysed using combined data, as specified in the analysis plan.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of COPD Exacerbation Events From the Two Twin Trials, Present 205.477 (NCT01663987) and 205.478 (NCT01662986)</measure>
    <time_frame>Start of treatment to the last timepoint with information of clinical adverse outcome available, up to 2 years</time_frame>
    <description>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.&#xD;
This endpoint was analysed using combined data, as specified in the analysis plan.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of All-cause Hospitalization Event From the Two Twin Trials, Present 205.477 (NCT01663987) and 205.478 (NCT01662986)</measure>
    <time_frame>From first drug administration to the last timepoint with information of clinical adverse outcome available, up to 2 years</time_frame>
    <description>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.&#xD;
This endpoint was analysed using combined data, as specified in the analysis plan.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Time to Event: Time to Recovery (EXACT-PRO) From the Two Twin Trials, Present 205.477 (NCT01663987) and 205.478 (NCT01662986)</measure>
    <time_frame>From first drug administration to the last timepoint with information of EXACT-PRO, up to 2 years</time_frame>
    <description>Time to event: Time to recovery based on EXACT-PRO total score. The percentage of observed patients recovered by end of study was reported.&#xD;
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.&#xD;
Analysis based on Kaplan Meier estimate.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">79</enrollment>
  <condition>Pulmonary Disease, Chronic Obstructive</condition>
  <arm_group>
    <arm_group_label>18 mcg tiotropium</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Patient to receive one tiotropium bromide inhalation powder capsule daily (in the morning) via HandiHaler</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Patient to receive one placebo capsule daily (in the morning) identical to those containing tiotropium bromide inhalation powder via HandiHaler</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>tiotropium bromide</intervention_name>
    <description>18 mcg once a day (QD)</description>
    <arm_group_label>18 mcg tiotropium</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>once a day (QD)</description>
    <arm_group_label>Placebo</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion criteria:&#xD;
&#xD;
        The following inclusion criteria apply at Visit 0:&#xD;
&#xD;
          1. All subjects must sign an informed consent consistent with the International&#xD;
             Conference on Harmonization - Good Clinical Practice (ICH-GCP) guidelines prior to&#xD;
             participation in the trial and conducting any study procedures.&#xD;
&#xD;
          2. Male or female subjects 40 years of age or older.&#xD;
&#xD;
          3. Hospitalization for a primary diagnosis of acute COPD exacerbation for =14 days.&#xD;
             Determination of accuracy of admission diagnosis will be at the discretion of the&#xD;
             investigator.&#xD;
&#xD;
          4. Patient reported hospital length of stay and discharge date (confirmed with hospital&#xD;
             discharge summary/hospital records; however, medical record confirmation may occur&#xD;
             following randomization).&#xD;
&#xD;
             The following inclusion criteria apply at Visit 1:&#xD;
&#xD;
          5. Discharged from the hospital =10 days from date of randomization.&#xD;
&#xD;
          6. All subjects must have a diagnosis of COPD (P12-01205), and have documented airway&#xD;
             obstruction with a post-bronchodilator Force expiratory volume in 1 second&#xD;
             (FEV1)/Force vital capacity (FVC )&lt;0.7(See Section 5.1.2, Pulmonary Function Testing).&#xD;
             The diagnosis of COPD can be made at Visit 1 if no Pulmonary Function Testing (PFT)&#xD;
             data available within the past 12 months.&#xD;
&#xD;
          7. Subjects must be current or ex-smoker with a smoking history of =10 pack-years:&#xD;
&#xD;
        Pack-years = Number of cigarettes/day x years of smoking 20 cigarettes/ pack 8. Subjects&#xD;
        must be able to inhale medication in a competent manner from the HandiHaler® device&#xD;
        (Appendix 10.1) and from a metered dose inhaler (MDI).&#xD;
&#xD;
        Exclusion criteria:&#xD;
&#xD;
        The following exclusion criterion applies at Visit 0:&#xD;
&#xD;
          1. No more than 30 days of therapy with any long-acting inhaled anticholinergic over&#xD;
             preceding 3 months prior to discharge from the hospital, and no therapy with any long&#xD;
             acting anticholinergic post discharge (no use between hospital discharge and&#xD;
             randomization) or any other restricted concomitant medications&#xD;
&#xD;
             The following exclusion criteria apply at Visit 1:&#xD;
&#xD;
          2. Presence of a significant disease (in the opinion of the investigator) which may put&#xD;
             the subject at risk because of participation in the study or may influence the&#xD;
             subject's ability to participate in the study for up to 2 years.&#xD;
&#xD;
          3. A documented history of myocardial infarction during the hospitalization preceding&#xD;
             randomization. Subjects being stable with a history of cardiac stents are permitted.&#xD;
&#xD;
          4. Any unstable or life-threatening cardiac arrhythmia requiring intervention or change&#xD;
             in drug therapy during the last year.&#xD;
&#xD;
          5. Subjects with asthma (subject treated for asthma in the last 2 years, history of&#xD;
             childhood asthma is permitted), cystic fibrosis, clinical diagnosis of bronchiectasis,&#xD;
             interstitial lung disease, pulmonary thromboembolic disease or known active&#xD;
             tuberculosis.&#xD;
&#xD;
        7. Malignancy for which the subject has undergone resection, radiation, chemotherapy or&#xD;
        biological treatments within the last two years or is currently on active radiation&#xD;
        therapy, chemotherapy or biological treatment. Subjects with treated basal cell carcinoma&#xD;
        and non-invasive squamous cell skin carcinoma are allowed.&#xD;
&#xD;
        8. Hospitalization for cardiac failure (New York Heart Association (NYHA) class III or IV)&#xD;
        during the hospitalization preceding randomization.&#xD;
&#xD;
        9. Known hypersensitivity to anticholinergic drugs, lactose, or any other components of the&#xD;
        HandiHaler® or MDI inhalation solution delivery system.&#xD;
&#xD;
        10. Known moderate to severe renal impairment as judged by the investigator. 11. Known&#xD;
        narrow angle glaucoma as judged by the investigator. 12. Significant symptomatic prostatic&#xD;
        hyperplasia or bladder-neck obstruction. Subjects whose symptoms are controlled on&#xD;
        treatment may be included. 13. Pregnant or nursing women or women of childbearing potential&#xD;
        not using a medically approved means of contraception (i.e., oral contraceptives,&#xD;
        intrauterine devices, diaphragm or sub dermal implants e.g., Norplant) for at least three&#xD;
        months prior to and for the duration of the trial.&#xD;
&#xD;
        14. Significant alcohol or drug abuse within the past 12 months. 15. Previously randomized&#xD;
        in this study or currently participating in another interventional study.&#xD;
&#xD;
        16. Visual impairment that as judged by the investigator does not allow the subject to&#xD;
        independently read and complete the questionnaires and eDiary.&#xD;
&#xD;
        17. Any significant or new ECG findings at Visit 1 as judged by the investigator,&#xD;
        including, but not limited to signs of acute ischemia, arrhythmia.&#xD;
&#xD;
        18. Treatment with any restricted pulmonary medication. 19. Residing in an assisted living&#xD;
        facility.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>40 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Boehringer Ingelheim</last_name>
    <role>Study Chair</role>
    <affiliation>Boehringer Ingelheim</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>205.477.001039 Boehringer Ingelheim Investigational Site</name>
      <address>
        <city>Birmingham</city>
        <state>Alabama</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>205.477.001050 Boehringer Ingelheim Investigational Site</name>
      <address>
        <city>Birmingham</city>
        <state>Alabama</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>205.477.001021 Boehringer Ingelheim Investigational Site</name>
      <address>
        <city>Florence</city>
        <state>Alabama</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>205.477.001046 Boehringer Ingelheim Investigational Site</name>
      <address>
        <city>Fountain Valley</city>
        <state>California</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>205.477.001052 Boehringer Ingelheim Investigational Site</name>
      <address>
        <city>Sacramento</city>
        <state>California</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>205.477.001059 Boehringer Ingelheim Investigational Site</name>
      <address>
        <city>San Diego</city>
        <state>California</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>205.477.001009 Boehringer Ingelheim Investigational Site</name>
      <address>
        <city>Stamford</city>
        <state>Connecticut</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>205.477.001040 Boehringer Ingelheim Investigational Site</name>
      <address>
        <city>Waterbury</city>
        <state>Connecticut</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>205.477.001051 Boehringer Ingelheim Investigational Site</name>
      <address>
        <city>Brandon</city>
        <state>Florida</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>205.477.001044 Boehringer Ingelheim Investigational Site</name>
      <address>
        <city>Clearwater</city>
        <state>Florida</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>205.477.001037 Boehringer Ingelheim Investigational Site</name>
      <address>
        <city>Eustis</city>
        <state>Florida</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>205.477.001017 Boehringer Ingelheim Investigational Site</name>
      <address>
        <city>Miami</city>
        <state>Florida</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>205.477.001063 Boehringer Ingelheim Investigational Site</name>
      <address>
        <city>Miami</city>
        <state>Florida</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>205.477.001001 Boehringer Ingelheim Investigational Site</name>
      <address>
        <city>Saint Petersburg</city>
        <state>Florida</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>205.477.001004 Boehringer Ingelheim Investigational Site</name>
      <address>
        <city>Decatur</city>
        <state>Georgia</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>205.477.001012 Boehringer Ingelheim Investigational Site</name>
      <address>
        <city>Duluth</city>
        <state>Georgia</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>205.477.001064 Boehringer Ingelheim Investigational Site</name>
      <address>
        <city>Belleville</city>
        <state>Illinois</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>205.477.001038 Boehringer Ingelheim Investigational Site</name>
      <address>
        <city>Muncie</city>
        <state>Indiana</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>205.477.001007 Boehringer Ingelheim Investigational Site</name>
      <address>
        <city>Baltimore</city>
        <state>Maryland</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>205.477.001014 Boehringer Ingelheim Investigational Site</name>
      <address>
        <city>Columbia</city>
        <state>Maryland</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>205.477.001018 Boehringer Ingelheim Investigational Site</name>
      <address>
        <city>Livonia</city>
        <state>Michigan</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>205.477.001068 Boehringer Ingelheim Investigational Site</name>
      <address>
        <city>Union</city>
        <state>New Jersey</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>205.477.001035 Boehringer Ingelheim Investigational Site</name>
      <address>
        <city>Cooperstown</city>
        <state>New York</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>205.477.001023 Boehringer Ingelheim Investigational Site</name>
      <address>
        <city>New York</city>
        <state>New York</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>205.477.001061 Boehringer Ingelheim Investigational Site</name>
      <address>
        <city>Staten Island</city>
        <state>New York</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>205.477.001027 Boehringer Ingelheim Investigational Site</name>
      <address>
        <city>Burlington</city>
        <state>North Carolina</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>205.477.001032 Boehringer Ingelheim Investigational Site</name>
      <address>
        <city>Huntersville</city>
        <state>North Carolina</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>205.477.001020 Boehringer Ingelheim Investigational Site</name>
      <address>
        <city>Seneca</city>
        <state>North Carolina</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>205.477.001034 Boehringer Ingelheim Investigational Site</name>
      <address>
        <city>Cincinnati</city>
        <state>Ohio</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>205.477.001053 Boehringer Ingelheim Investigational Site</name>
      <address>
        <city>Columbus</city>
        <state>Ohio</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>205.477.001011 Boehringer Ingelheim Investigational Site</name>
      <address>
        <city>Dayton</city>
        <state>Ohio</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>205.477.001057 Boehringer Ingelheim Investigational Site</name>
      <address>
        <city>Tulsa</city>
        <state>Oklahoma</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>205.477.001006 Boehringer Ingelheim Investigational Site</name>
      <address>
        <city>Portland</city>
        <state>Oregon</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>205.477.001083 Boehringer Ingelheim Investigational Site</name>
      <address>
        <city>Downingtown</city>
        <state>Pennsylvania</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>205.477.001031 Boehringer Ingelheim Investigational Site</name>
      <address>
        <city>Monroeville</city>
        <state>Pennsylvania</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>205.477.001028 Boehringer Ingelheim Investigational Site</name>
      <address>
        <city>Anderson</city>
        <state>South Carolina</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>205.477.001019 Boehringer Ingelheim Investigational Site</name>
      <address>
        <city>Charleston</city>
        <state>South Carolina</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>205.477.001010 Boehringer Ingelheim Investigational Site</name>
      <address>
        <city>Fort Mill</city>
        <state>South Carolina</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>205.477.001025 Boehringer Ingelheim Investigational Site</name>
      <address>
        <city>Gaffney</city>
        <state>South Carolina</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>205.477.001002 Boehringer Ingelheim Investigational Site</name>
      <address>
        <city>Rock Hill</city>
        <state>South Carolina</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>205.477.001026 Boehringer Ingelheim Investigational Site</name>
      <address>
        <city>Spartanburg</city>
        <state>South Carolina</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>205.477.001015 Boehringer Ingelheim Investigational Site</name>
      <address>
        <city>Union</city>
        <state>South Carolina</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>205.477.001013 Boehringer Ingelheim Investigational Site</name>
      <address>
        <city>Nashville</city>
        <state>Tennessee</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>205.477.001022 Boehringer Ingelheim Investigational Site</name>
      <address>
        <city>Corsicana</city>
        <state>Texas</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>205.477.001055 Boehringer Ingelheim Investigational Site</name>
      <address>
        <city>Fort Worth</city>
        <state>Texas</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>205.477.001054 Boehringer Ingelheim Investigational Site</name>
      <address>
        <city>Katy</city>
        <state>Texas</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>205.477.001062 Boehringer Ingelheim Investigational Site</name>
      <address>
        <city>Tyler</city>
        <state>Texas</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>205.477.001030 Boehringer Ingelheim Investigational Site</name>
      <address>
        <city>Abingdon</city>
        <state>Virginia</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>205.477.001008 Boehringer Ingelheim Investigational Site</name>
      <address>
        <city>Roanoke</city>
        <state>Virginia</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>205.477.001043 Boehringer Ingelheim Investigational Site</name>
      <address>
        <city>San Juan</city>
        <country>Puerto Rico</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Puerto Rico</country>
    <country>United States</country>
  </location_countries>
  <link>
    <url>http://trials.boehringer-ingelheim.com/</url>
    <description>Related Info</description>
  </link>
  <verification_date>September 2018</verification_date>
  <study_first_submitted>August 9, 2012</study_first_submitted>
  <study_first_submitted_qc>August 10, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">August 14, 2012</study_first_posted>
  <results_first_submitted>May 1, 2015</results_first_submitted>
  <results_first_submitted_qc>June 17, 2015</results_first_submitted_qc>
  <results_first_posted type="Estimate">July 9, 2015</results_first_posted>
  <last_update_submitted>September 21, 2018</last_update_submitted>
  <last_update_submitted_qc>September 21, 2018</last_update_submitted_qc>
  <last_update_posted type="Actual">October 17, 2018</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Lung Diseases</mesh_term>
    <mesh_term>Pulmonary Disease, Chronic Obstructive</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Bromides</mesh_term>
    <mesh_term>Tiotropium Bromide</mesh_term>
  </intervention_browse>

  <clinical_results>

    <participant_flow>
      <pre_assignment_details>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</pre_assignment_details>
      <group_list>
        <group group_id="P1">
          <title>Placebo</title>
          <description>Patient to receive oral inhalation of one placebo powder capsule once daily in the morning via HandiHaler.</description>
        </group>
        <group group_id="P2">
          <title>Tiotropium Bromide (18μg)</title>
          <description>Patient to receive oral inhalation of one tiotropium bromide powder capsule once daily in the morning via HandiHaler.</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="39"/>
                <participants group_id="P2" count="40"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="26"/>
                <participants group_id="P2" count="34"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="13"/>
                <participants group_id="P2" count="6"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Adverse Event</title>
              <participants_list>
                <participants group_id="P1" count="7"/>
                <participants group_id="P2" count="2"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Lost to Follow-up</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="1"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Withdrawal by Subject</title>
              <participants_list>
                <participants group_id="P1" count="2"/>
                <participants group_id="P2" count="3"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Other reason not defined above</title>
              <participants_list>
                <participants group_id="P1" count="3"/>
                <participants group_id="P2" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <population>Treated Set (TS): The treated set included all patients randomized and who took at least one dose of the study drug.</population>
      <group_list>
        <group group_id="B1">
          <title>Placebo</title>
          <description>Patient to receive oral inhalation of one placebo powder capsule once daily in the morning via HandiHaler.</description>
        </group>
        <group group_id="B2">
          <title>Tiotropium Bromide (18μg)</title>
          <description>Patient to receive oral inhalation of one tiotropium bromide powder capsule once daily in the morning via HandiHaler.</description>
        </group>
        <group group_id="B3">
          <title>Total</title>
          <description>Total of all reporting groups</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="39"/>
            <count group_id="B2" value="40"/>
            <count group_id="B3" value="79"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>years</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="58.4" spread="7.5"/>
                    <measurement group_id="B2" value="58.9" spread="11.5"/>
                    <measurement group_id="B3" value="58.7" spread="9.7"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Sex: Female, Male</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Female</title>
                  <measurement_list>
                    <measurement group_id="B1" value="22"/>
                    <measurement group_id="B2" value="24"/>
                    <measurement group_id="B3" value="46"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="17"/>
                    <measurement group_id="B2" value="16"/>
                    <measurement group_id="B3" value="33"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Change From Baseline of Trough FEV1 at 12 Weeks on Study Drug</title>
        <description>Change from baseline in trough forced expiratory volume in 1 second (FEV1) at 12 weeks on study medication. Trough FEV1 is defined as FEV1 measurement prior to the next dosing of study drug and approximately 24 hours after the last inhalation of drug.</description>
        <time_frame>Baseline and 12 weeks</time_frame>
        <population>Treated Set (TS) including patients who had trough FEV1 data at both baseline and week 12</population>
        <group_list>
          <group group_id="O1">
            <title>Placebo</title>
            <description>Patient to receive oral inhalation of one placebo powder capsule once daily in the morning via HandiHaler.</description>
          </group>
          <group group_id="O2">
            <title>Tiotropium Bromide (18μg)</title>
            <description>Patient to receive oral inhalation of one tiotropium bromide powder capsule once daily in the morning via HandiHaler.</description>
          </group>
        </group_list>
        <measure>
          <title>Change From Baseline of Trough FEV1 at 12 Weeks on Study Drug</title>
          <description>Change from baseline in trough forced expiratory volume in 1 second (FEV1) at 12 weeks on study medication. Trough FEV1 is defined as FEV1 measurement prior to the next dosing of study drug and approximately 24 hours after the last inhalation of drug.</description>
          <population>Treated Set (TS) including patients who had trough FEV1 data at both baseline and week 12</population>
          <units>Litres</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="30"/>
                <count group_id="O2" value="30"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-0.051" spread="0.224"/>
                    <measurement group_id="O2" value="0.183" spread="0.273"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Percentage of Patients With Next Adverse Clinical Outcome Event From the Two Twin Trials, Present 205.477 (NCT01663987) and 205.478 (NCT01662986)</title>
        <description>Percentage 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.&#xD;
Time to the next adverse clinical outcome event from the two twin trials, was defined as a primary endpoint but was not analysed numerically, so this endpoint is presented instead.&#xD;
This endpoint was analysed using combined data, as specified in the analysis plan.</description>
        <time_frame>From first drug administration to the last timepoint with information of clinical adverse outcome available, up to 2 years</time_frame>
        <population>Treated set of the pooled twin studies 205.478 and 205.477: This set includes all patients who were randomised and took at least one dose of study drug, 157 patients (79 Tiotropium and 78 placebo) were included in this set.</population>
        <group_list>
          <group group_id="O1">
            <title>Placebo</title>
            <description>Patient to receive oral inhalation of one placebo powder capsule once daily in the morning via HandiHaler.</description>
          </group>
          <group group_id="O2">
            <title>Tiotropium Bromide (18μg)</title>
            <description>Patient to receive oral inhalation of one tiotropium bromide powder capsule once daily in the morning via HandiHaler.</description>
          </group>
        </group_list>
        <measure>
          <title>Percentage of Patients With Next Adverse Clinical Outcome Event From the Two Twin Trials, Present 205.477 (NCT01663987) and 205.478 (NCT01662986)</title>
          <description>Percentage 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.&#xD;
Time to the next adverse clinical outcome event from the two twin trials, was defined as a primary endpoint but was not analysed numerically, so this endpoint is presented instead.&#xD;
This endpoint was analysed using combined data, as specified in the analysis plan.</description>
          <population>Treated set of the pooled twin studies 205.478 and 205.477: This set includes all patients who were randomised and took at least one dose of study drug, 157 patients (79 Tiotropium and 78 placebo) were included in this set.</population>
          <units>Percentage of perticipants</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="78"/>
                <count group_id="O2" value="79"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="47.4"/>
                    <measurement group_id="O2" value="53.2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change From Baseline of Trough FVC at 12 Weeks on Study Drug</title>
        <description>Change from baseline of trough Forced Vital Capacity (FVC) at 12 weeks on study drug.</description>
        <time_frame>Baseline and 12 weeks</time_frame>
        <population>Treated Set (TS) including patients who had trough FVC data at both baseline and week 12</population>
        <group_list>
          <group group_id="O1">
            <title>Placebo</title>
            <description>Patient to receive oral inhalation of one placebo powder capsule once daily in the morning via HandiHaler.</description>
          </group>
          <group group_id="O2">
            <title>Tiotropium Bromide (18μg)</title>
            <description>Patient to receive oral inhalation of one tiotropium bromide powder capsule once daily in the morning via HandiHaler.</description>
          </group>
        </group_list>
        <measure>
          <title>Change From Baseline of Trough FVC at 12 Weeks on Study Drug</title>
          <description>Change from baseline of trough Forced Vital Capacity (FVC) at 12 weeks on study drug.</description>
          <population>Treated Set (TS) including patients who had trough FVC data at both baseline and week 12</population>
          <units>Litres</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="30"/>
                <count group_id="O2" value="30"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-0.117" spread="0.371"/>
                    <measurement group_id="O2" value="0.274" spread="0.308"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Percentage of Patients With Adverse Clinical Event on Study</title>
        <description>Percentage of patients with adverse clinical event during on study, which is defined as the combined endpoint of chronic obstructive pulmonary disease (COPD) exacerbations per Boehringer Ingelheim (BI) definition, all-cause re-hospitalisation, or all cause mortality.</description>
        <time_frame>From first drug administration to the last timepoint with information of clinical adverse outcome available, up to 2 years</time_frame>
        <population>Treated set</population>
        <group_list>
          <group group_id="O1">
            <title>Placebo</title>
            <description>Patient to receive oral inhalation of one placebo powder capsule once daily in the morning via HandiHaler.</description>
          </group>
          <group group_id="O2">
            <title>Tiotropium Bromide (18μg)</title>
            <description>Patient to receive oral inhalation of one tiotropium bromide powder capsule once daily in the morning via HandiHaler.</description>
          </group>
        </group_list>
        <measure>
          <title>Percentage of Patients With Adverse Clinical Event on Study</title>
          <description>Percentage of patients with adverse clinical event during on study, which is defined as the combined endpoint of chronic obstructive pulmonary disease (COPD) exacerbations per Boehringer Ingelheim (BI) definition, all-cause re-hospitalisation, or all cause mortality.</description>
          <population>Treated set</population>
          <units>Percentage of participants</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="39"/>
                <count group_id="O2" value="40"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="59.0"/>
                    <measurement group_id="O2" value="60.0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change From Baseline of Trough FEV1 at 12 Weeks on Study Drug From the Two Twin Trials, Present 205.477 (NCT01663987) and 205.478 (NCT01662986)</title>
        <description>Change from baseline of Trough FEV1 (forced expiratory volume in one second) at 12 weeks on study drug.&#xD;
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.&#xD;
This endpoint was analysed using combined data, as specified in the analysis plan.</description>
        <time_frame>Baseline and 12 weeks</time_frame>
        <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.</population>
        <group_list>
          <group group_id="O1">
            <title>Placebo</title>
            <description>Patient to receive oral inhalation of one placebo powder capsule once daily in the morning via HandiHaler.</description>
          </group>
          <group group_id="O2">
            <title>Tiotropium Bromide (18μg)</title>
            <description>Patient to receive oral inhalation of one tiotropium bromide powder capsule once daily in the morning via HandiHaler.</description>
          </group>
        </group_list>
        <measure>
          <title>Change From Baseline of Trough FEV1 at 12 Weeks on Study Drug From the Two Twin Trials, Present 205.477 (NCT01663987) and 205.478 (NCT01662986)</title>
          <description>Change from baseline of Trough FEV1 (forced expiratory volume in one second) at 12 weeks on study drug.&#xD;
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.&#xD;
This endpoint was analysed using combined data, as specified in the analysis plan.</description>
          <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.</population>
          <units>Litres</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="59"/>
                <count group_id="O2" value="60"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.035" spread="0.262"/>
                    <measurement group_id="O2" value="0.185" spread="0.384"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change From Baseline of Trough FVC at 12 Weeks From the Two Twin Trials, Present 205.477 (NCT01663987) and 205.478 (NCT01662986)</title>
        <description>Change from baseline of trough Forced Vital Capacity (FVC) at 12 weeks on study drug.&#xD;
This endpoint was analysed using combined data, as specified in the analysis plan.</description>
        <time_frame>Baseline and 12 weeks</time_frame>
        <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.</population>
        <group_list>
          <group group_id="O1">
            <title>Placebo</title>
            <description>Patient to receive oral inhalation of one placebo powder capsule once daily in the morning via HandiHaler.</description>
          </group>
          <group group_id="O2">
            <title>Tiotropium Bromide (18μg)</title>
            <description>Patient to receive oral inhalation of one tiotropium bromide powder capsule once daily in the morning via HandiHaler.</description>
          </group>
        </group_list>
        <measure>
          <title>Change From Baseline of Trough FVC at 12 Weeks From the Two Twin Trials, Present 205.477 (NCT01663987) and 205.478 (NCT01662986)</title>
          <description>Change from baseline of trough Forced Vital Capacity (FVC) at 12 weeks on study drug.&#xD;
This endpoint was analysed using combined data, as specified in the analysis plan.</description>
          <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.</population>
          <units>Litres</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="59"/>
                <count group_id="O2" value="60"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-0.015" spread="0.396"/>
                    <measurement group_id="O2" value="0.278" spread="0.447"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Percentage of Patients With COPD Exacerbation From the Two Twin Trials, Present 205.477 (NCT01663987) and 205.478 (NCT01662986)</title>
        <description>Percentage of patients with COPD exacerbation on study was analysed for the combined study.&#xD;
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.&#xD;
A required change in treatment included either prescription of antibiotics and/or systemic steroids; and a newly prescribed maintenance respiratory medication (i.e. bronchodilators including theophyllines and PDE4-inhibitors).&#xD;
This endpoint was analysed using combined data, as specified in the analysis plan.</description>
        <time_frame>from first drug administration to the last timepoint with information of clinical adverse outcome available, up to 2 years</time_frame>
        <population>Treated set of the pooled twin studies 205.478 and 205.477</population>
        <group_list>
          <group group_id="O1">
            <title>Placebo</title>
            <description>Patient to receive oral inhalation of one placebo powder capsule once daily in the morning via HandiHaler.</description>
          </group>
          <group group_id="O2">
            <title>Tiotropium Bromide (18μg)</title>
            <description>Patient to receive oral inhalation of one tiotropium bromide powder capsule once daily in the morning via HandiHaler.</description>
          </group>
        </group_list>
        <measure>
          <title>Percentage of Patients With COPD Exacerbation From the Two Twin Trials, Present 205.477 (NCT01663987) and 205.478 (NCT01662986)</title>
          <description>Percentage of patients with COPD exacerbation on study was analysed for the combined study.&#xD;
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.&#xD;
A required change in treatment included either prescription of antibiotics and/or systemic steroids; and a newly prescribed maintenance respiratory medication (i.e. bronchodilators including theophyllines and PDE4-inhibitors).&#xD;
This endpoint was analysed using combined data, as specified in the analysis plan.</description>
          <population>Treated set of the pooled twin studies 205.478 and 205.477</population>
          <units>Percentage of participants</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="78"/>
                <count group_id="O2" value="79"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="44.9"/>
                    <measurement group_id="O2" value="40.5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Percentage of Patients With All-cause Hospitalization From the Two Twin Trials, Present 205.477 (NCT01663987) and 205.478 (NCT01662986)</title>
        <description>Percentage of patients with all-cause hospitalization outcome event occured during the study was analysed for the combined study.&#xD;
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.&#xD;
This endpoint was analysed using combined data, as specified in the analysis plan.</description>
        <time_frame>from first drug administration to the last timepoint with information of clinical adverse outcome available, Up to 2 years</time_frame>
        <population>Treated set of the pooled twin studies 205.478 and 205.477</population>
        <group_list>
          <group group_id="O1">
            <title>Placebo</title>
            <description>Patient to receive oral inhalation of one placebo powder capsule once daily in the morning via HandiHaler.</description>
          </group>
          <group group_id="O2">
            <title>Tiotropium Bromide (18μg)</title>
            <description>Patient to receive oral inhalation of one tiotropium bromide powder capsule once daily in the morning via HandiHaler.</description>
          </group>
        </group_list>
        <measure>
          <title>Percentage of Patients With All-cause Hospitalization From the Two Twin Trials, Present 205.477 (NCT01663987) and 205.478 (NCT01662986)</title>
          <description>Percentage of patients with all-cause hospitalization outcome event occured during the study was analysed for the combined study.&#xD;
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.&#xD;
This endpoint was analysed using combined data, as specified in the analysis plan.</description>
          <population>Treated set of the pooled twin studies 205.478 and 205.477</population>
          <units>Percentage of participants</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="78"/>
                <count group_id="O2" value="79"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="26.9"/>
                    <measurement group_id="O2" value="26.6"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Percentage of Patients With 30-day Readmission Rates Outcome Event From the Two Twin Trials, Present 205.477 (NCT01663987) and 205.478 (NCT01662986)</title>
        <description>Percentage of patients with 30-day hospital readmission rates outcome events was analysed.&#xD;
Days to hospital readmission were calculated as:Hospital readmission days = Readmission date - Date of hospital discharge + 1.&#xD;
The 30-day hospital readmission analysis summarized the frequency of patients with hospital readmission and readmission days &gt;1 and &lt;31 days using the TS.&#xD;
This endpoint was analysed using combined data, as specified in the analysis plan.</description>
        <time_frame>from date of hospital discharge prior to randomization up to readmission days &gt;1 and &lt;31 days</time_frame>
        <population>Treated set of the pooled twin studies 205.478 and 205.477</population>
        <group_list>
          <group group_id="O1">
            <title>Placebo</title>
            <description>Patient to receive oral inhalation of one placebo powder capsule once daily in the morning via HandiHaler.</description>
          </group>
          <group group_id="O2">
            <title>Tiotropium Bromide (18μg)</title>
            <description>Patient to receive oral inhalation of one tiotropium bromide powder capsule once daily in the morning via HandiHaler.</description>
          </group>
        </group_list>
        <measure>
          <title>Percentage of Patients With 30-day Readmission Rates Outcome Event From the Two Twin Trials, Present 205.477 (NCT01663987) and 205.478 (NCT01662986)</title>
          <description>Percentage of patients with 30-day hospital readmission rates outcome events was analysed.&#xD;
Days to hospital readmission were calculated as:Hospital readmission days = Readmission date - Date of hospital discharge + 1.&#xD;
The 30-day hospital readmission analysis summarized the frequency of patients with hospital readmission and readmission days &gt;1 and &lt;31 days using the TS.&#xD;
This endpoint was analysed using combined data, as specified in the analysis plan.</description>
          <population>Treated set of the pooled twin studies 205.478 and 205.477</population>
          <units>Percentage of participants</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="78"/>
                <count group_id="O2" value="79"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="5.1"/>
                    <measurement group_id="O2" value="5.1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Number of COPD Exacerbation Events From the Two Twin Trials, Present 205.477 (NCT01663987) and 205.478 (NCT01662986)</title>
        <description>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.&#xD;
This endpoint was analysed using combined data, as specified in the analysis plan.</description>
        <time_frame>Start of treatment to the last timepoint with information of clinical adverse outcome available, up to 2 years</time_frame>
        <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.</population>
        <group_list>
          <group group_id="O1">
            <title>Placebo</title>
            <description>Patient to receive oral inhalation of one placebo powder capsule once daily in the morning via HandiHaler.</description>
          </group>
          <group group_id="O2">
            <title>Tiotropium Bromide (18μg)</title>
            <description>Patient to receive oral inhalation of one tiotropium bromide powder capsule once daily in the morning via HandiHaler.</description>
          </group>
        </group_list>
        <measure>
          <title>Number of COPD Exacerbation Events From the Two Twin Trials, Present 205.477 (NCT01663987) and 205.478 (NCT01662986)</title>
          <description>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.&#xD;
This endpoint was analysed using combined data, as specified in the analysis plan.</description>
          <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.</population>
          <units>exacerbations per patient year</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="73"/>
                <count group_id="O2" value="54"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1.3"/>
                    <measurement group_id="O2" value="0.9"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Number of All-cause Hospitalization Event From the Two Twin Trials, Present 205.477 (NCT01663987) and 205.478 (NCT01662986)</title>
        <description>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.&#xD;
This endpoint was analysed using combined data, as specified in the analysis plan.</description>
        <time_frame>From first drug administration to the last timepoint with information of clinical adverse outcome available, up to 2 years</time_frame>
        <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.</population>
        <group_list>
          <group group_id="O1">
            <title>Placebo</title>
            <description>Patient to receive oral inhalation of one placebo powder capsule once daily in the morning via HandiHaler.</description>
          </group>
          <group group_id="O2">
            <title>Tiotropium Bromide (18μg)</title>
            <description>Patient to receive oral inhalation of one tiotropium bromide powder capsule once daily in the morning via HandiHaler.</description>
          </group>
        </group_list>
        <measure>
          <title>Number of All-cause Hospitalization Event From the Two Twin Trials, Present 205.477 (NCT01663987) and 205.478 (NCT01662986)</title>
          <description>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.&#xD;
This endpoint was analysed using combined data, as specified in the analysis plan.</description>
          <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.</population>
          <units>Hospitalisation per patient year</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="47"/>
                <count group_id="O2" value="38"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.8"/>
                    <measurement group_id="O2" value="0.6"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Time to Event: Time to Recovery (EXACT-PRO) From the Two Twin Trials, Present 205.477 (NCT01663987) and 205.478 (NCT01662986)</title>
        <description>Time to event: Time to recovery based on EXACT-PRO total score. The percentage of observed patients recovered by end of study was reported.&#xD;
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.&#xD;
Analysis based on Kaplan Meier estimate.</description>
        <time_frame>From first drug administration to the last timepoint with information of EXACT-PRO, up to 2 years</time_frame>
        <population>This endpoint was not analysed due to the trials being terminated prematurely due to low patient enrollment and the limited amount of data.</population>
        <group_list>
          <group group_id="O1">
            <title>Placebo</title>
            <description>Patient to receive oral inhalation of one placebo powder capsule once daily in the morning via HandiHaler.</description>
          </group>
          <group group_id="O2">
            <title>Tiotropium Bromide (18μg)</title>
            <description>Patient to receive oral inhalation of one tiotropium bromide powder capsule once daily in the morning via HandiHaler.</description>
          </group>
        </group_list>
        <measure>
          <title>Time to Event: Time to Recovery (EXACT-PRO) From the Two Twin Trials, Present 205.477 (NCT01663987) and 205.478 (NCT01662986)</title>
          <description>Time to event: Time to recovery based on EXACT-PRO total score. The percentage of observed patients recovered by end of study was reported.&#xD;
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.&#xD;
Analysis based on Kaplan Meier estimate.</description>
          <population>This endpoint was not analysed due to the trials being terminated prematurely due to low patient enrollment and the limited amount of data.</population>
          <units>Percentage of patients recovered</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="76"/>
                <count group_id="O2" value="76"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="94.0"/>
                    <measurement group_id="O2" value="88.0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>From first dose of study drug up to 30 days after the last dose of study drug, up to 524 days</time_frame>
      <group_list>
        <group group_id="E1">
          <title>Placebo</title>
          <description>Patient to receive oral inhalation of one placebo powder capsule once daily in the morning via HandiHaler.</description>
        </group>
        <group group_id="E2">
          <title>Tiotropium Bromide (18μg)</title>
          <description>Patient to receive oral inhalation of one tiotropium bromide powder capsule once daily in the morning via HandiHaler.</description>
        </group>
      </group_list>
      <serious_events>
        <default_vocab>MEDDRA 17.0</default_vocab>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="15" subjects_at_risk="39"/>
                <counts group_id="E2" subjects_affected="15" subjects_at_risk="40"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Cardiac disorders</title>
            <event_list>
              <event>
                <sub_title>Acute myocardial infarction</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="39"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="40"/>
              </event>
              <event>
                <sub_title>Angina pectoris</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="39"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="40"/>
              </event>
              <event>
                <sub_title>Cardiac failure congestive</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="39"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="40"/>
              </event>
              <event>
                <sub_title>Coronary artery disease</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="39"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="40"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Diabetic gastroparesis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="39"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="40"/>
              </event>
              <event>
                <sub_title>Gastrointestinal haemorrhage</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="39"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="40"/>
              </event>
              <event>
                <sub_title>Large intestine perforation</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="39"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="40"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Chest pain</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="39"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="40"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Diverticulitis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="39"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="40"/>
              </event>
              <event>
                <sub_title>Incision site infection</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="39"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="40"/>
              </event>
              <event>
                <sub_title>Pneumonia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="39"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="40"/>
              </event>
              <event>
                <sub_title>Respiratory tract infection viral</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="39"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="40"/>
              </event>
              <event>
                <sub_title>Sepsis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="39"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="40"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Injury, poisoning and procedural complications</title>
            <event_list>
              <event>
                <sub_title>Cervical vertebral fracture</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="39"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="40"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Neoplasms benign, malignant and unspecified (incl cysts and polyps)</title>
            <event_list>
              <event>
                <sub_title>Rectal cancer</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="39"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="40"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Cerebrovascular accident</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="39"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="40"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Acute respiratory failure</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="39"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="40"/>
              </event>
              <event>
                <sub_title>Chronic obstructive pulmonary disease</sub_title>
                <counts group_id="E1" subjects_affected="11" subjects_at_risk="39"/>
                <counts group_id="E2" subjects_affected="12" subjects_at_risk="40"/>
              </event>
              <event>
                <sub_title>Hypoxia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="39"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="40"/>
              </event>
              <event>
                <sub_title>Pneumonia aspiration</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="39"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="40"/>
              </event>
              <event>
                <sub_title>Pulmonary embolism</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="39"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="40"/>
              </event>
              <event>
                <sub_title>Pulmonary hypertension</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="39"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="40"/>
              </event>
              <event>
                <sub_title>Respiratory failure</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="39"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="40"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>5</frequency_threshold>
        <default_vocab>MEDDRA 17.0</default_vocab>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="21" subjects_at_risk="39"/>
                <counts group_id="E2" subjects_affected="19" subjects_at_risk="40"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Blood and lymphatic system disorders</title>
            <event_list>
              <event>
                <sub_title>Anaemia</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="39"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="40"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Diarrhoea</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="39"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="40"/>
              </event>
              <event>
                <sub_title>Vomiting</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="39"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="40"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Bronchitis</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="39"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="40"/>
              </event>
              <event>
                <sub_title>Candida infection</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="39"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="40"/>
              </event>
              <event>
                <sub_title>Oral candidiasis</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="39"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="40"/>
              </event>
              <event>
                <sub_title>Sinusitis</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="39"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="40"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Metabolism and nutrition disorders</title>
            <event_list>
              <event>
                <sub_title>Hyperglycaemia</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="39"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="40"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Musculoskeletal chest pain</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="39"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="40"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Psychiatric disorders</title>
            <event_list>
              <event>
                <sub_title>Anxiety</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="39"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="40"/>
              </event>
              <event>
                <sub_title>Insomnia</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="39"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="40"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Chronic obstructive pulmonary disease</sub_title>
                <counts group_id="E1" subjects_affected="17" subjects_at_risk="39"/>
                <counts group_id="E2" subjects_affected="15" subjects_at_risk="40"/>
              </event>
              <event>
                <sub_title>Dyspnoea</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="39"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="40"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Skin and subcutaneous tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Rash</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="39"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="40"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>Principal Investigators are NOT employed by the organization sponsoring the study.</pi_employee>
      <restrictive_agreement>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.</restrictive_agreement>
    </certain_agreements>
    <limitations_and_caveats>The original protocol planned to randomize 604 subjects, however this was not reached due to low patient enrollment. All results are descriptive only.</limitations_and_caveats>
    <point_of_contact>
      <name_or_title>Boehringer Ingelheim Call Center</name_or_title>
      <organization>Boehringer Ingelheim</organization>
      <phone>1-800-243-0127</phone>
      <email>clintriage.rdg@boehringer-ingelheim.com</email>
    </point_of_contact>
  </clinical_results>
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT01663987
org study id: 205.477
nct id: NCT01663987
lead sponsor: 
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 1)
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Double
measure: Change From Baseline of Trough FEV1 at 12 Weeks on Study Drug
time frame: Baseline and 12 weeks
description: Change from baseline in trough forced expiratory volume in 1 second (FEV1) at 12 weeks on study medication. Trough FEV1 is defined as FEV1 measurement prior to the next dosing of study drug and approximately 24 hours after the last inhalation of drug.
measure: Percentage of Patients With Next Adverse Clinical Outcome Event From the Two Twin Trials, Present 205.477 (NCT01663987) and 205.478 (NCT01662986)
time frame: From first drug administration to the last timepoint with information of clinical adverse outcome available, up to 2 years
description: Percentage 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, was defined as a primary endpoint but was not analysed numerically, so this endpoint is presented instead.
This endpoint was analysed using combined data, as specified in the analysis plan.
measure: Change From Baseline of Trough FVC at 12 Weeks on Study Drug
time frame: Baseline and 12 weeks
description: Change from baseline of trough Forced Vital Capacity (FVC) at 12 weeks on study drug.
measure: Percentage of Patients With Adverse Clinical Event on Study
time frame: From first drug administration to the last timepoint with information of clinical adverse outcome available, up to 2 years
description: Percentage of patients with adverse clinical event during on study, which is defined as the combined endpoint of chronic obstructive pulmonary disease (COPD) exacerbations per Boehringer Ingelheim (BI) definition, all-cause re-hospitalisation, or all cause mortality.
measure: Change From Baseline of Trough FEV1 at 12 Weeks on Study Drug From the Two Twin Trials, Present 205.477 (NCT01663987) and 205.478 (NCT01662986)
time frame: Baseline and 12 weeks
description: Change from baseline of Trough FEV1 (forced expiratory volume in one 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.
This endpoint was analysed using combined data, as specified in the analysis plan.
measure: Change From Baseline of Trough FVC at 12 Weeks From the Two Twin Trials, Present 205.477 (NCT01663987) and 205.478 (NCT01662986)
time frame: Baseline and 12 weeks
description: Change from baseline of trough Forced Vital Capacity (FVC) at 12 weeks on study drug.
This endpoint was analysed using combined data, as specified in the analysis plan.
measure: Percentage of Patients With COPD Exacerbation From the Two Twin Trials, Present 205.477 (NCT01663987) and 205.478 (NCT01662986)
time frame: from first drug administration to the last timepoint with information of clinical adverse outcome available, up to 2 years
description: Percentage 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 a newly prescribed maintenance respiratory medication (i.e. bronchodilators including theophyllines and PDE4-inhibitors).
This endpoint was analysed using combined data, as specified in the analysis plan.
measure: Percentage of Patients With All-cause Hospitalization From the Two Twin Trials, Present 205.477 (NCT01663987) and 205.478 (NCT01662986)
time frame: from first drug administration to the last timepoint with information of clinical adverse outcome available, Up to 2 years
description: Percentage 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.
This endpoint was analysed using combined data, as specified in the analysis plan.
measure: Percentage of Patients With 30-day Readmission Rates Outcome Event From the Two Twin Trials, Present 205.477 (NCT01663987) and 205.478 (NCT01662986)
time frame: from date of hospital discharge prior to randomization up to readmission days >1 and <31 days
description: Percentage 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.
This endpoint was analysed using combined data, as specified in the analysis plan.
measure: Number of COPD Exacerbation Events From the Two Twin Trials, Present 205.477 (NCT01663987) and 205.478 (NCT01662986)
time frame: Start of treatment to the last timepoint with information of clinical adverse outcome available, up to 2 years
description: 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.
This endpoint was analysed using combined data, as specified in the analysis plan.
measure: Number of All-cause Hospitalization Event From the Two Twin Trials, Present 205.477 (NCT01663987) and 205.478 (NCT01662986)
time frame: From first drug administration to the last timepoint with information of clinical adverse outcome available, up to 2 years
description: 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.
This endpoint was analysed using combined data, as specified in the analysis plan.
measure: Time to Event: Time to Recovery (EXACT-PRO) From the Two Twin Trials, Present 205.477 (NCT01663987) and 205.478 (NCT01662986)
time frame: From first drug administration to the last timepoint with information of EXACT-PRO, up to 2 years
description: 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.
arm group label: 18 mcg tiotropium
arm group type: Active Comparator
description: Patient to receive one tiotropium bromide inhalation powder capsule daily (in the morning) via HandiHaler
arm group label: Placebo
arm group type: Placebo Comparator
description: Patient to receive one placebo capsule daily (in the morning) identical to those containing tiotropium bromide inhalation powder via HandiHaler
intervention type: Drug
intervention name: tiotropium bromide
description: 18 mcg once a day (QD)
arm group label: 18 mcg tiotropium
intervention type: Drug
intervention name: Placebo
description: once a day (QD)
arm group label: Placebo
criteria: 
gender: All
minimum age: 40 Years
maximum age: N/A
healthy volunteers: No
last name: Boehringer Ingelheim
role: Study Chair
affiliation: Boehringer Ingelheim
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country: Puerto Rico
country: United States
url: http://trials.boehringer-ingelheim.com/
description: Related Info
responsible party type: Sponsor
mesh term: Lung Diseases
mesh term: Pulmonary Disease, Chronic Obstructive
mesh term: Bromides
mesh term: Tiotropium Bromide
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
limitations and caveats: The original protocol planned to randomize 604 subjects, however this was not reached due to low patient enrollment. All results are descriptive only.
point of contact: 