<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/NCT01694771</url>
  </required_header>
  <id_info>
    <org_study_id>1222.51</org_study_id>
    <nct_id>NCT01694771</nct_id>
  </id_info>
  <brief_title>Co-administration of Olodaterol Respimat® and Tiotropium Handihaler®</brief_title>
  <official_title>A Randomised, Double Blind, Parallel Group Study to Assess the Efficacy and Safety of 12 Weeks of Once Daily, Orally Inhaled, Co-administration of Olodaterol 5µg (Delivered by the Respimat® Inhaler) and Tiotropium 18µg (Delivered by the HandiHaler®) Compared to Once Daily, Orally Inhaled, Co-administration of Placebo (Delivered by the Respimat® Inhaler) and Tiotropium 18µg (Delivered by the HandiHaler®) in Patients With Chronic Obstructive Pulmonary Disease (COPD)[ANHELTO TM 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>
      The overall objective of this study is to assess efficacy and safety of 12 weeks, once daily,&#xD;
      orally inhaled co-administration of olodaterol 5 µg (delivered by the Respimat® Inhaler) and&#xD;
      tiotropium (delivered by the Handihaler® as Spiriva Handihaler®), compared to tiotropium&#xD;
      (Spiriva Handihaler®) monotherapy on lung function in patients with COPD.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Completed</overall_status>
  <start_date>September 2012</start_date>
  <completion_date type="Actual">August 2013</completion_date>
  <primary_completion_date type="Actual">August 2013</primary_completion_date>
  <phase>Phase 3</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>FEV1 AUC0-3h Response at 12 Weeks; Defined as Change From Baseline to Week 12</measure>
    <time_frame>baseline and 12 weeks</time_frame>
    <description>FEV1 (Forced expiratory volume in 1 second) AUC0-3h (area under the curve) response at 12 weeks; defined as change from baseline to Week 12</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Trough FEV1 Response at 12 Weeks; Defined as Change From Baseline to Week 12</measure>
    <time_frame>baseline and 12 weeks</time_frame>
    <description>Trough FEV1 (Forced expiratory volume in 1 second) response at 12 weeks; defined as change from baseline to Week 12</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Peak FEV1 Response at 12 Weeks - Defined as Change From Baseline</measure>
    <time_frame>baseline and 12 weeks</time_frame>
    <description>Peak FEV1 (Forced Expiratory Volume in 1 second) response at 12 Weeks - defined as changes from baseline</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>FVC AUC0-3h Response at 12 Weeks - Defined as Change From Baseline</measure>
    <time_frame>baseline and 12 weeks</time_frame>
    <description>Forced Vital Capacity (FVC) AUC0-3h response at 12 weeks - defined as change from baseline.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Trough FVC Response at 12 Weeks- Defined as Change From Baseline</measure>
    <time_frame>baseline and 12 weeks</time_frame>
    <description>Trough Forced Vital Capacity (FVC) response at 12 weeks- defined as change from baseline.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Peak FVC Response at 12 Weeks - Defined as Change From Baseline</measure>
    <time_frame>baseline and 12 weeks</time_frame>
    <description>Peak FVC response at 12 weeks - defined as change from baseline.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Rescue Medication Usage - Percentage of Rescue Free Days</measure>
    <time_frame>over 12 weeks</time_frame>
    <description>Rescue medication usage - the percentage of rescue free days. The percentage of rescue free days is defined as: number of rescue free days divided by total exposure, multiplied by 100%. The baseline for the number of rescue-free days was defined as the number of rescue-free days observed during the last week of the baseline period (i.e., the 7 days prior to administration of the first dose of randomized treatment).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Rescue Medication Usage - Mean Weekly Rescue Usage (Total Daily)</measure>
    <time_frame>over 12 weeks</time_frame>
    <description>Rescue medication usage - mean weekly rescue usage (total daily). The baseline for the rescue use was the mean of the observations during the last week of the baseline period. Administration of rescue medication could occur at any point during the trial as deemed necessary by the patient or the investigator. Open label albuterol MDI (100 μg per puff) was provided as rescue medication . Daily, between clinic visits, patients recorded the number of puffs of albuterol in a paper diary.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Rescue Medication Usage - Mean Weekly Rescue Usage (Daytime)</measure>
    <time_frame>over 12 weeks</time_frame>
    <description>Rescue medication usage - Mean weekly rescue usage during daytime hours. Administration of rescue medication could occur at any point during the trial as deemed necessary by the patient or the investigator. Open label albuterol MDI (100 μg per puff) was provided as rescue medication by BI, and only the albuterol MDI provided by BI was allowed for rescue medication use. Daily, between clinic visits, patients recorded the number of puffs of albuterol in a paper diary.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Rescue Medication Usage - Mean Weekly Rescue Usage (Nighttime)</measure>
    <time_frame>over 12 weeks</time_frame>
    <description>Rescue medication usage - Mean weekly rescue usage during nighttime hours. Administration of rescue medication could occur at any point during the trial as deemed necessary by the patient or the investigator. Open label albuterol MDI (100 μg per puff) was provided as rescue medication by BI, and only the albuterol MDI provided by BI was allowed for rescue medication use. Daily, between clinic visits, patients recorded the number of puffs of albuterol in a paper diary.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">1134</enrollment>
  <condition>Pulmonary Disease, Chronic Obstructive</condition>
  <arm_group>
    <arm_group_label>Olodaterol and Tiotropium</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>2 puffs olodaterol from Respimat and one capsule tiotropium from Handihaler once daily in am, co-administered</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo and Tiotropium</arm_group_label>
    <arm_group_type>Other</arm_group_type>
    <description>2 puffs placebo inhalation solution from Respimat and one capsule tiotropium from Handihaler once daily in am, co-administered</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Tiotropium</intervention_name>
    <description>Marketed dose</description>
    <arm_group_label>Placebo and Tiotropium</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo matching Olodaterol</intervention_name>
    <description>One dose</description>
    <arm_group_label>Placebo and Tiotropium</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Olodaterol</intervention_name>
    <description>One dose</description>
    <arm_group_label>Olodaterol and Tiotropium</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Tiotropium</intervention_name>
    <description>Marketed dose</description>
    <arm_group_label>Olodaterol and Tiotropium</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion criteria:&#xD;
&#xD;
          1. All patients must sign an informed consent consistent with International Conference on&#xD;
             Harmonization-Good Clinical Practice (ICH-GCP) guidelines prior to participation in&#xD;
             the trial, which includes medication washout and restrictions.&#xD;
&#xD;
          2. All patients must have a diagnosis of chronic obstructive pulmonary disease and must&#xD;
             meet the following spirometric criteria: Patients must have a relatively stable airway&#xD;
             obstruction with a post-bronchodilator FEV1 = 30 % and &lt; 80% of predicted normal and a&#xD;
             post-bronchodilator FEV1/FVC &lt;70% at Visit 1.&#xD;
&#xD;
          3. Male or female patients, 40 years of age or older.&#xD;
&#xD;
          4. Patients must be current or ex-smokers with a smoking history of more than 10 pack&#xD;
             years&#xD;
&#xD;
          5. Patients must be able to: perform technically acceptable pulmonary function tests, and&#xD;
             maintain records(paper diary).&#xD;
&#xD;
          6. Patients must be able to inhale medication in a competent manner from the Respimat&#xD;
             Inhaler as well as the Handihaler.&#xD;
&#xD;
        Exclusion criteria:&#xD;
&#xD;
          1. Patients with a significant disease other than COPD; a significant disease is defined&#xD;
             as a disease which, in the opinion of the investigator, may (i) put the patient at&#xD;
             risk because of participation in the study, (ii) influence the results of the study,&#xD;
             or (iii) cause concern regarding the patients ability to participate in the study.&#xD;
&#xD;
          2. Patients with clinically relevant abnormal baseline haematology, blood chemistry, or&#xD;
             urinalysis; all patients with an AST &gt;x2 ULN, ALT &gt;x2 ULN, bilirubin &gt;x2 ULN or&#xD;
             creatinine &gt;x2 ULN will be excluded regardless of clinical condition (a repeat&#xD;
             laboratory evaluation will not be conducted in these patients).&#xD;
&#xD;
          3. Patients with a history of asthma. For patients with allergic rhinitis or atopy,&#xD;
             source documentation is required to verify that the patient does not have asthma. If a&#xD;
             patient has a total blood eosinophil count =600/mm3, source documentation is required&#xD;
             to verify that the increased eosinophil count is related to a non-asthmatic condition.&#xD;
&#xD;
          4. A diagnosis of thyrotoxicosis (due to the known class side effect profile of&#xD;
             ß2-agonists).&#xD;
&#xD;
          5. A diagnosis of paroxysmal tachycardia (&gt;100 beats per minute) (due to the known class&#xD;
             side effect profile of ß2-agonists).&#xD;
&#xD;
          6. A history of myocardial infarction within 1 year of screening visit (Visit 1).&#xD;
&#xD;
          7. Unstable or life-threatening cardiac arrhythmia.&#xD;
&#xD;
          8. Hospitalization for heart failure within the past year.&#xD;
&#xD;
          9. Known active tuberculosis.&#xD;
&#xD;
         10. A malignancy for which patient has undergone resection, radiation therapy or&#xD;
             chemotherapy within last five years (patients with treated basal cell carcinoma are&#xD;
             allowed).&#xD;
&#xD;
         11. A history of life-threatening pulmonary obstruction.&#xD;
&#xD;
         12. A history of cystic fibrosis.&#xD;
&#xD;
         13. Clinically evident bronchiectasis.&#xD;
&#xD;
         14. A history of significant alcohol or drug abuse.&#xD;
&#xD;
         15. Patients who have undergone thoracotomy with pulmonary resection (patients with a&#xD;
             history of thoracotomy for other reasons should be evaluated as per exclusion&#xD;
             criterion No. 1).&#xD;
&#xD;
         16. Patients being treated with oral or patch ß-adrenergics.&#xD;
&#xD;
         17. Patients being treated with oral corticosteroid medication at unstable doses (i.e.,&#xD;
             less than six weeks on a stable dose) or at doses in excess of the equivalent of 10 mg&#xD;
             of prednisone per day or 20 mg every other day.&#xD;
&#xD;
         18. Patients who regularly use daytime oxygen therapy for more than one hour per day and&#xD;
             in the investigators opinion will be unable to abstain from the use of oxygen therapy&#xD;
             during clinic visits.&#xD;
&#xD;
         19. Patients who have completed a pulmonary rehabilitation program in the six weeks prior&#xD;
             to the screening visit (Visit 1) or patients who are currently in a pulmonary&#xD;
             rehabilitation program.&#xD;
&#xD;
         20. Patients who have taken an investigational drug within one month or six half lives&#xD;
             (whichever is greater) prior to screening visit (Visit 1).&#xD;
&#xD;
         21. Patients with known hypersensitivity to ß-adrenergic drugs, BAC, EDTA, or any other&#xD;
             component of the Respimat® inhalation solution.&#xD;
&#xD;
         22. Patients with known hypersensitivity to anticholinergic drugs, lactose, or any other&#xD;
             components of the HandiHaler®.&#xD;
&#xD;
         23. Pregnant or nursing women.&#xD;
&#xD;
         24. Women of childbearing potential not using a highly effective method of birth control*.&#xD;
             Female patients will be considered to be of childbearing potential unless surgically&#xD;
             sterilised by hysterectomy or bilateral tubal ligation, or post-menopausal for at&#xD;
             least two years.&#xD;
&#xD;
             * as per ICH M3(R2) a highly effective method of birth control is defined as those&#xD;
             which result in a low failure rate (i.e. less than 1% per year).&#xD;
&#xD;
         25. Patients who have previously been randomised in this study or are currently&#xD;
             participating in another study.&#xD;
&#xD;
         26. Patients who are unable to comply with pulmonary medication restrictions prior to&#xD;
             randomisation.&#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>1222.51.01055 Boehringer Ingelheim Investigational Site</name>
      <address>
        <city>Florence</city>
        <state>Alabama</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>1222.51.01087 Boehringer Ingelheim Investigational Site</name>
      <address>
        <city>Jasper</city>
        <state>Alabama</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>1222.51.01066 Boehringer Ingelheim Investigational Site</name>
      <address>
        <city>Phoenix</city>
        <state>Arizona</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>1222.51.01069 Boehringer Ingelheim Investigational Site</name>
      <address>
        <city>Scottsdale</city>
        <state>Arizona</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>1222.51.01040 Boehringer Ingelheim Investigational Site</name>
      <address>
        <city>Anaheim</city>
        <state>California</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>1222.51.01064 Boehringer Ingelheim Investigational Site</name>
      <address>
        <city>Encinitas</city>
        <state>California</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>1222.51.01060 Boehringer Ingelheim Investigational Site</name>
      <address>
        <city>Fullerton</city>
        <state>California</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>1222.51.01084 Boehringer Ingelheim Investigational Site</name>
      <address>
        <city>Lincoln</city>
        <state>California</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>1222.51.01041 Boehringer Ingelheim Investigational Site</name>
      <address>
        <city>San Diego</city>
        <state>California</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>1222.51.01094 Boehringer Ingelheim Investigational Site</name>
      <address>
        <city>San Diego</city>
        <state>California</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>1222.51.01015 Boehringer Ingelheim Investigational Site</name>
      <address>
        <city>Torrance</city>
        <state>California</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>1222.51.01052 Boehringer Ingelheim Investigational Site</name>
      <address>
        <city>Boulder</city>
        <state>Colorado</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>1222.51.01010 Boehringer Ingelheim Investigational Site</name>
      <address>
        <city>Wheat Ridge</city>
        <state>Colorado</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>1222.51.01042 Boehringer Ingelheim Investigational Site</name>
      <address>
        <city>Wheat Ridge</city>
        <state>Colorado</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>1222.51.01070 Boehringer Ingelheim Investigational Site</name>
      <address>
        <city>Stamford</city>
        <state>Connecticut</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>1222.51.01006 Boehringer Ingelheim Investigational Site</name>
      <address>
        <city>Clearwater</city>
        <state>Florida</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>1222.51.01021 Boehringer Ingelheim Investigational Site</name>
      <address>
        <city>Clearwater</city>
        <state>Florida</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>1222.51.01082 Boehringer Ingelheim Investigational Site</name>
      <address>
        <city>Clearwater</city>
        <state>Florida</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>1222.51.01065 Boehringer Ingelheim Investigational Site</name>
      <address>
        <city>DeLand</city>
        <state>Florida</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>1222.51.01051 Boehringer Ingelheim Investigational Site</name>
      <address>
        <city>Jacksonville</city>
        <state>Florida</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>1222.51.01092 Boehringer Ingelheim Investigational Site</name>
      <address>
        <city>Jacksonville</city>
        <state>Florida</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>1222.51.01081 Boehringer Ingelheim Investigational Site</name>
      <address>
        <city>Ormond Beach</city>
        <state>Florida</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>1222.51.01054 Boehringer Ingelheim Investigational Site</name>
      <address>
        <city>Panama City</city>
        <state>Florida</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>1222.51.01062 Boehringer Ingelheim Investigational Site</name>
      <address>
        <city>Pensacola</city>
        <state>Florida</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>1222.51.01088 Boehringer Ingelheim Investigational Site</name>
      <address>
        <city>Port Orange</city>
        <state>Florida</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>1222.51.01079 Boehringer Ingelheim Investigational Site</name>
      <address>
        <city>Tamarac</city>
        <state>Florida</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>1222.51.01075 Boehringer Ingelheim Investigational Site</name>
      <address>
        <city>Atlanta</city>
        <state>Georgia</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>1222.51.01076 Boehringer Ingelheim Investigational Site</name>
      <address>
        <city>Austell</city>
        <state>Georgia</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>1222.51.01057 Boehringer Ingelheim Investigational Site</name>
      <address>
        <city>Duluth</city>
        <state>Georgia</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>1222.51.01086 Boehringer Ingelheim Investigational Site</name>
      <address>
        <city>Lawrenceville</city>
        <state>Georgia</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>1222.51.01019 Boehringer Ingelheim Investigational Site</name>
      <address>
        <city>Coeur d'Alene</city>
        <state>Idaho</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>1222.51.01027 Boehringer Ingelheim Investigational Site</name>
      <address>
        <city>Eagle</city>
        <state>Idaho</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>1222.51.01048 Boehringer Ingelheim Investigational Site</name>
      <address>
        <city>Arlingron Heights</city>
        <state>Illinois</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>1222.51.01044 Boehringer Ingelheim Investigational Site</name>
      <address>
        <city>River Forest</city>
        <state>Illinois</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>1222.51.01043 Boehringer Ingelheim Investigational Site</name>
      <address>
        <city>Skokie</city>
        <state>Illinois</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>1222.51.01090 Boehringer Ingelheim Investigational Site</name>
      <address>
        <city>Louisville</city>
        <state>Kentucky</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>1222.51.01023 Boehringer Ingelheim Investigational Site</name>
      <address>
        <city>Lafayette</city>
        <state>Louisiana</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>1222.51.01071 Boehringer Ingelheim Investigational Site</name>
      <address>
        <city>Opelousas</city>
        <state>Louisiana</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>1222.51.01050 Boehringer Ingelheim Investigational Site</name>
      <address>
        <city>North Dartmouth</city>
        <state>Massachusetts</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>1222.51.01049 Boehringer Ingelheim Investigational Site</name>
      <address>
        <city>Ann Arbor</city>
        <state>Michigan</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>1222.51.01025 Boehringer Ingelheim Investigational Site</name>
      <address>
        <city>Livonia</city>
        <state>Michigan</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>1222.51.01078 Boehringer Ingelheim Investigational Site</name>
      <address>
        <city>Edina</city>
        <state>Minnesota</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>1222.51.01033 Boehringer Ingelheim Investigational Site</name>
      <address>
        <city>Fridley</city>
        <state>Minnesota</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>1222.51.01074 Boehringer Ingelheim Investigational Site</name>
      <address>
        <city>St. Charles</city>
        <state>Missouri</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>1222.51.01037 Boehringer Ingelheim Investigational Site</name>
      <address>
        <city>St. Louis</city>
        <state>Missouri</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>1222.51.01039 Boehringer Ingelheim Investigational Site</name>
      <address>
        <city>Reno</city>
        <state>Nevada</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>1222.51.01045 Boehringer Ingelheim Investigational Site</name>
      <address>
        <city>Larchmont</city>
        <state>New York</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>1222.51.01018 Boehringer Ingelheim Investigational Site</name>
      <address>
        <city>Rochester</city>
        <state>New York</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>1222.51.01014 Boehringer Ingelheim Investigational Site</name>
      <address>
        <city>Asheville</city>
        <state>North Carolina</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>1222.51.01077 Boehringer Ingelheim Investigational Site</name>
      <address>
        <city>Charlotte</city>
        <state>North Carolina</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>1222.51.01056 Boehringer Ingelheim Investigational Site</name>
      <address>
        <city>Greensboro</city>
        <state>North Carolina</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>1222.51.01032 Boehringer Ingelheim Investigational Site</name>
      <address>
        <city>Canton</city>
        <state>Ohio</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>1222.51.01011 Boehringer Ingelheim Investigational Site</name>
      <address>
        <city>Cincinnati</city>
        <state>Ohio</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>1222.51.01005 Boehringer Ingelheim Investigational Site</name>
      <address>
        <city>Columbus</city>
        <state>Ohio</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>1222.51.01093 Boehringer Ingelheim Investigational Site</name>
      <address>
        <city>Dayton</city>
        <state>Ohio</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>1222.51.01089 Boehringer Ingelheim Investigational Site</name>
      <address>
        <city>Sylvania</city>
        <state>Ohio</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>1222.51.01080 Boehringer Ingelheim Investigational Site</name>
      <address>
        <city>Toledo</city>
        <state>Ohio</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>1222.51.01017 Boehringer Ingelheim Investigational Site</name>
      <address>
        <city>Oklahoma City</city>
        <state>Oklahoma</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>1222.51.01047 Boehringer Ingelheim Investigational Site</name>
      <address>
        <city>Tulsa</city>
        <state>Oklahoma</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>1222.51.01031 Boehringer Ingelheim Investigational Site</name>
      <address>
        <city>Corvallis</city>
        <state>Oregon</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>1222.51.01020 Boehringer Ingelheim Investigational Site</name>
      <address>
        <city>Medford</city>
        <state>Oregon</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>1222.51.01053 Boehringer Ingelheim Investigational Site</name>
      <address>
        <city>Portland</city>
        <state>Oregon</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>1222.51.01016 Boehringer Ingelheim Investigational Site</name>
      <address>
        <city>Erie</city>
        <state>Pennsylvania</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>1222.51.01004 Boehringer Ingelheim Investigational Site</name>
      <address>
        <city>Philadelphia</city>
        <state>Pennsylvania</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>1222.51.01030 Boehringer Ingelheim Investigational Site</name>
      <address>
        <city>East Providence</city>
        <state>Rhode Island</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>1222.51.01009 Boehringer Ingelheim Investigational Site</name>
      <address>
        <city>Johnston</city>
        <state>Rhode Island</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>1222.51.01036 Boehringer Ingelheim Investigational Site</name>
      <address>
        <city>Charleston</city>
        <state>South Carolina</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>1222.51.01061 Boehringer Ingelheim Investigational Site</name>
      <address>
        <city>Columbia</city>
        <state>South Carolina</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>1222.51.01038 Boehringer Ingelheim Investigational Site</name>
      <address>
        <city>Easley</city>
        <state>South Carolina</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>1222.51.01046 Boehringer Ingelheim Investigational Site</name>
      <address>
        <city>Easley</city>
        <state>South Carolina</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>1222.51.01022 Boehringer Ingelheim Investigational Site</name>
      <address>
        <city>Gaffney</city>
        <state>South Carolina</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>1222.51.01063 Boehringer Ingelheim Investigational Site</name>
      <address>
        <city>Greenville</city>
        <state>South Carolina</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>1222.51.01013 Boehringer Ingelheim Investigational Site</name>
      <address>
        <city>Greer</city>
        <state>South Carolina</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>1222.51.01024 Boehringer Ingelheim Investigational Site</name>
      <address>
        <city>Spartanburg</city>
        <state>South Carolina</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>1222.51.01012 Boehringer Ingelheim Investigational Site</name>
      <address>
        <city>Union</city>
        <state>South Carolina</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>1222.51.01008 Boehringer Ingelheim Investigational Site</name>
      <address>
        <city>Rapid City</city>
        <state>South Dakota</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>1222.51.01035 Boehringer Ingelheim Investigational Site</name>
      <address>
        <city>Johnson City</city>
        <state>Tennessee</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>1222.51.01028 Boehringer Ingelheim Investigational Site</name>
      <address>
        <city>Boerne</city>
        <state>Texas</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>1222.51.01083 Boehringer Ingelheim Investigational Site</name>
      <address>
        <city>Corsicana</city>
        <state>Texas</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>1222.51.01085 Boehringer Ingelheim Investigational Site</name>
      <address>
        <city>Killeen</city>
        <state>Texas</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>1222.51.01073 Boehringer Ingelheim Investigational Site</name>
      <address>
        <city>Longview</city>
        <state>Texas</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>1222.51.01003 Boehringer Ingelheim Investigational Site</name>
      <address>
        <city>San Antonio</city>
        <state>Texas</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>1222.51.01058 Boehringer Ingelheim Investigational Site</name>
      <address>
        <city>Murray</city>
        <state>Utah</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>1222.51.01068 Boehringer Ingelheim Investigational Site</name>
      <address>
        <city>Abingdon</city>
        <state>Virginia</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>1222.51.01029 Boehringer Ingelheim Investigational Site</name>
      <address>
        <city>Richmond</city>
        <state>Virginia</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>1222.51.01034 Boehringer Ingelheim Investigational Site</name>
      <address>
        <city>Richmond</city>
        <state>Virginia</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>1222.51.01072 Boehringer Ingelheim Investigational Site</name>
      <address>
        <city>Richmond</city>
        <state>Virginia</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>1222.51.01091 Boehringer Ingelheim Investigational Site</name>
      <address>
        <city>Spokane</city>
        <state>Washington</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>1222.51.01002 Boehringer Ingelheim Investigational Site</name>
      <address>
        <city>Vancouver</city>
        <state>Washington</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>1222.51.01001 Boehringer Ingelheim Investigational Site</name>
      <address>
        <city>Morgantown</city>
        <state>West Virginia</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>August 2014</verification_date>
  <study_first_submitted>September 25, 2012</study_first_submitted>
  <study_first_submitted_qc>September 25, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">September 27, 2012</study_first_posted>
  <results_first_submitted>July 23, 2014</results_first_submitted>
  <results_first_submitted_qc>August 25, 2014</results_first_submitted_qc>
  <results_first_posted type="Estimate">September 4, 2014</results_first_posted>
  <last_update_submitted>August 25, 2014</last_update_submitted>
  <last_update_submitted_qc>August 25, 2014</last_update_submitted_qc>
  <last_update_posted type="Estimate">September 4, 2014</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>Tiotropium Bromide</mesh_term>
    <mesh_term>Olodaterol</mesh_term>
  </intervention_browse>

  <clinical_results>

    <participant_flow>
      <pre_assignment_details>1134 patients were entered and randomized to treatment and 1132 patients were treated with study medication.</pre_assignment_details>
      <group_list>
        <group group_id="P1">
          <title>Olodaterol (5µg) and Tiotropium (18µg)</title>
          <description>2 puffs olodaterol from Respimat and one capsule tiotropium from Handihaler once daily in am, co-administered&#xD;
Olodaterol: One dose&#xD;
Tiotropium: Marketed dose</description>
        </group>
        <group group_id="P2">
          <title>Placebo and Tiotropium (18µg)</title>
          <description>2 puffs placebo inhalation solution from Respimat and one capsule tiotropium from Handihaler once daily in am, co-administered&#xD;
Tiotropium: Marketed dose, 2 inhalations from 1 capsule once daily in the morning&#xD;
Placebo matching Olodaterol: One dose, 2 inhalations once daily in the morning</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="567"/>
                <participants group_id="P2" count="565"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="527"/>
                <participants group_id="P2" count="525"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="40"/>
                <participants group_id="P2" count="40"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Adverse Event</title>
              <participants_list>
                <participants group_id="P1" count="18"/>
                <participants group_id="P2" count="16"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Lack of Efficacy</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Non compliance protocol</title>
              <participants_list>
                <participants group_id="P1" count="7"/>
                <participants group_id="P2" count="6"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Lost to Follow-up</title>
              <participants_list>
                <participants group_id="P1" count="2"/>
                <participants group_id="P2" count="3"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Consent withdrawn</title>
              <participants_list>
                <participants group_id="P1" count="7"/>
                <participants group_id="P2" count="9"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Other reasons</title>
              <participants_list>
                <participants group_id="P1" count="5"/>
                <participants group_id="P2" count="6"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <population>Treated set (TS), which includes all randomized patients who receive at least one dose of double-blind study treatment.</population>
      <group_list>
        <group group_id="B1">
          <title>Olodaterol (5µg) and Tiotropium (18µg)</title>
          <description>2 puffs olodaterol from Respimat and one capsule tiotropium from Handihaler once daily in am, co-administered&#xD;
Olodaterol: One dose&#xD;
Tiotropium: Marketed dose</description>
        </group>
        <group group_id="B2">
          <title>Placebo and Tiotropium (18µg)</title>
          <description>2 puffs placebo inhalation solution from Respimat and one capsule tiotropium from Handihaler once daily in am, co-administered&#xD;
Tiotropium: Marketed dose, 2 inhalations from 1 capsule once daily in the morning&#xD;
Placebo matching Olodaterol: One dose, 2 inhalations once daily in the morning</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="567"/>
            <count group_id="B2" value="565"/>
            <count group_id="B3" value="1132"/>
          </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="64.3" spread="9.1"/>
                    <measurement group_id="B2" value="64.8" spread="9.1"/>
                    <measurement group_id="B3" value="64.6" spread="9.1"/>
                  </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="288"/>
                    <measurement group_id="B2" value="280"/>
                    <measurement group_id="B3" value="568"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="279"/>
                    <measurement group_id="B2" value="285"/>
                    <measurement group_id="B3" value="564"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>FEV1 AUC0-3h Response at 12 Weeks; Defined as Change From Baseline to Week 12</title>
        <description>FEV1 (Forced expiratory volume in 1 second) AUC0-3h (area under the curve) response at 12 weeks; defined as change from baseline to Week 12</description>
        <time_frame>baseline and 12 weeks</time_frame>
        <population>Full analysis set (FAS) with last observation carried forward (LOCF) imputation at 12 weeks. FAS included all patients in the treated set who had both baseline and at least one post-baseline measurement at or before 12 weeks for any of the co-primary efficacy variables</population>
        <group_list>
          <group group_id="O1">
            <title>Olodaterol (5µg) and Tiotropium (18µg)</title>
            <description>2 puffs olodaterol from Respimat and one capsule tiotropium from Handihaler once daily in am, co-administered&#xD;
Olodaterol: One dose, 2 inhalations once daily in the morning&#xD;
Tiotropium: Marketed dose, 2 inhalations from 1 capsule once daily in the morning</description>
          </group>
          <group group_id="O2">
            <title>Placebo and Tiotropium (18µg)</title>
            <description>2 puffs placebo inhalation solution from Respimat and one capsule tiotropium from Handihaler once daily in am, co-administered&#xD;
Tiotropium: Marketed dose, 2 inhalations from 1 capsule once daily in the morning&#xD;
Placebo matching Olodaterol: One dose, 2 inhalations once daily in the morning</description>
          </group>
        </group_list>
        <measure>
          <title>FEV1 AUC0-3h Response at 12 Weeks; Defined as Change From Baseline to Week 12</title>
          <description>FEV1 (Forced expiratory volume in 1 second) AUC0-3h (area under the curve) response at 12 weeks; defined as change from baseline to Week 12</description>
          <population>Full analysis set (FAS) with last observation carried forward (LOCF) imputation at 12 weeks. FAS included all patients in the treated set who had both baseline and at least one post-baseline measurement at or before 12 weeks for any of the co-primary efficacy variables</population>
          <units>Area Under the Curve (L)</units>
          <param>Least Squares Mean</param>
          <dispersion>Standard Error</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="563"/>
                <count group_id="O2" value="564"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.313" spread="0.010"/>
                    <measurement group_id="O2" value="0.196" spread="0.010"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>Results are from an MMRM model. Fixed effects include treatment, visit, treatment by visit interaction, baseline and baseline by visit interaction. Patient is considered random and an unstructured covariance structure was used. Number of patients contributing to models: Tio+Placebo (564), Tio+Olo 5ug (563).</groups_desc>
            <non_inferiority_type>Superiority or Other</non_inferiority_type>
            <p_value>&lt;0.0001</p_value>
            <method>Mixed Model Repeated Measure</method>
            <param_type>Mean Difference (Final Values)</param_type>
            <param_value>0.117</param_value>
            <dispersion_type>Standard Error of the Mean</dispersion_type>
            <dispersion_value>0.014</dispersion_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>0.090</ci_lower_limit>
            <ci_upper_limit>0.144</ci_upper_limit>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Trough FEV1 Response at 12 Weeks; Defined as Change From Baseline to Week 12</title>
        <description>Trough FEV1 (Forced expiratory volume in 1 second) response at 12 weeks; defined as change from baseline to Week 12</description>
        <time_frame>baseline and 12 weeks</time_frame>
        <population>Full Analysis set (FAS) with last observation carried forward (LOCF) imputation at 12 weeks.</population>
        <group_list>
          <group group_id="O1">
            <title>Olodaterol (5µg) and Tiotropium (18µg)</title>
            <description>2 puffs olodaterol from Respimat and one capsule tiotropium from Handihaler once daily in am, co-administered&#xD;
Olodaterol: One dose, 2 inhalations once daily in the morning&#xD;
Tiotropium: Marketed dose, 2 inhalations from 1 capsule once daily in the morning</description>
          </group>
          <group group_id="O2">
            <title>Placebo and Tiotropium (18µg)</title>
            <description>2 puffs placebo inhalation solution from Respimat and one capsule tiotropium from Handihaler once daily in am, co-administered&#xD;
Tiotropium: Marketed dose, 2 inhalations from 1 capsule once daily in the morning&#xD;
Placebo matching Olodaterol: One dose, 2 inhalations once daily in the morning</description>
          </group>
        </group_list>
        <measure>
          <title>Trough FEV1 Response at 12 Weeks; Defined as Change From Baseline to Week 12</title>
          <description>Trough FEV1 (Forced expiratory volume in 1 second) response at 12 weeks; defined as change from baseline to Week 12</description>
          <population>Full Analysis set (FAS) with last observation carried forward (LOCF) imputation at 12 weeks.</population>
          <units>L</units>
          <param>Least Squares Mean</param>
          <dispersion>Standard Error</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="548"/>
                <count group_id="O2" value="551"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.195" spread="0.009"/>
                    <measurement group_id="O2" value="0.133" spread="0.009"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>Results are from an MMRM model. Fixed effects include treatment, visit, treatment by visit interaction, baseline and baseline by visit interaction. Patient is considered random and an unstructured covariance structure was used. Number of patients contributing to models: Tio+Placebo (551), Tio+Olo 5ug (548).</groups_desc>
            <non_inferiority_type>Superiority or Other</non_inferiority_type>
            <p_value>&lt;0.0001</p_value>
            <method>Mixed Model Repeated Measure</method>
            <param_type>Mean Difference (Final Values)</param_type>
            <param_value>0.062</param_value>
            <dispersion_type>Standard Error of the Mean</dispersion_type>
            <dispersion_value>0.013</dispersion_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>0.037</ci_lower_limit>
            <ci_upper_limit>0.088</ci_upper_limit>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Peak FEV1 Response at 12 Weeks - Defined as Change From Baseline</title>
        <description>Peak FEV1 (Forced Expiratory Volume in 1 second) response at 12 Weeks - defined as changes from baseline</description>
        <time_frame>baseline and 12 weeks</time_frame>
        <population>Full analysis set (FAS) with last observation carried forward (LOCF) imputation at 12 weeks.</population>
        <group_list>
          <group group_id="O1">
            <title>Olodaterol (5µg) and Tiotropium (18µg)</title>
            <description>2 puffs olodaterol from Respimat and one capsule tiotropium from Handihaler once daily in am, co-administered&#xD;
Olodaterol: One dose, 2 inhalations once daily in the morning&#xD;
Tiotropium: Marketed dose, 2 inhalations from 1 capsule once daily in the morning</description>
          </group>
          <group group_id="O2">
            <title>Placebo and Tiotropium (18µg)</title>
            <description>2 puffs placebo inhalation solution from Respimat and one capsule tiotropium from Handihaler once daily in am, co-administered&#xD;
Tiotropium: Marketed dose, 2 inhalations from 1 capsule once daily in the morning&#xD;
Placebo matching Olodaterol: One dose, 2 inhalations once daily in the morning</description>
          </group>
        </group_list>
        <measure>
          <title>Peak FEV1 Response at 12 Weeks - Defined as Change From Baseline</title>
          <description>Peak FEV1 (Forced Expiratory Volume in 1 second) response at 12 Weeks - defined as changes from baseline</description>
          <population>Full analysis set (FAS) with last observation carried forward (LOCF) imputation at 12 weeks.</population>
          <units>L</units>
          <param>Least Squares Mean</param>
          <dispersion>Standard Error</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="563"/>
                <count group_id="O2" value="564"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.389" spread="0.010"/>
                    <measurement group_id="O2" value="0.270" spread="0.010"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>Results are from an MMRM model. Fixed effects include treatment, visit, treatment by visit interaction, baseline and baseline by visit interaction. Patient is considered random and an unstructured covariance structure was used. Number of patients contributing to models: Tio+Placebo (564), Tio+Olo 5ug (563).</groups_desc>
            <non_inferiority_type>Superiority or Other</non_inferiority_type>
            <p_value>&lt;0.0001</p_value>
            <method>Mixed model repeated measure</method>
            <param_type>Mean change from baseline</param_type>
            <param_value>0.119</param_value>
            <dispersion_type>Standard Error of the Mean</dispersion_type>
            <dispersion_value>0.014</dispersion_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>0.090</ci_lower_limit>
            <ci_upper_limit>0.147</ci_upper_limit>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>FVC AUC0-3h Response at 12 Weeks - Defined as Change From Baseline</title>
        <description>Forced Vital Capacity (FVC) AUC0-3h response at 12 weeks - defined as change from baseline.</description>
        <time_frame>baseline and 12 weeks</time_frame>
        <population>Full analysis set (FAS) with last observation carried forward (LOCF) imputation at 12 weeks.</population>
        <group_list>
          <group group_id="O1">
            <title>Olodaterol (5µg) and Tiotropium (18µg)</title>
            <description>2 puffs olodaterol from Respimat and one capsule tiotropium from Handihaler once daily in am, co-administered&#xD;
Olodaterol: One dose, 2 inhalations once daily in the morning&#xD;
Tiotropium: Marketed dose, 2 inhalations from 1 capsule once daily in the morning</description>
          </group>
          <group group_id="O2">
            <title>Placebo and Tiotropium (18µg)</title>
            <description>2 puffs placebo inhalation solution from Respimat and one capsule tiotropium from Handihaler once daily in am, co-administered&#xD;
Tiotropium: Marketed dose, 2 inhalations from 1 capsule once daily in the morning&#xD;
Placebo matching Olodaterol: One dose, 2 inhalations once daily in the morning</description>
          </group>
        </group_list>
        <measure>
          <title>FVC AUC0-3h Response at 12 Weeks - Defined as Change From Baseline</title>
          <description>Forced Vital Capacity (FVC) AUC0-3h response at 12 weeks - defined as change from baseline.</description>
          <population>Full analysis set (FAS) with last observation carried forward (LOCF) imputation at 12 weeks.</population>
          <units>L</units>
          <param>Least Squares Mean</param>
          <dispersion>Standard Error</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="563"/>
                <count group_id="O2" value="564"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.438" spread="0.017"/>
                    <measurement group_id="O2" value="0.292" spread="0.017"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>Results are from an MMRM model. Fixed effects include treatment, visit, treatment by visit interaction, baseline and baseline by visit interaction. Patient is considered random and an unstructured covariance structure was used. Number of patients contributing to models: Tio+Placebo (564), Tio+Olo 5ug (563).</groups_desc>
            <non_inferiority_type>Superiority or Other</non_inferiority_type>
            <p_value>&lt;0.0001</p_value>
            <method>Mixed model repeated measure</method>
            <param_type>Mean difference from Tio + Placebo</param_type>
            <param_value>0.146</param_value>
            <dispersion_type>Standard Error of the Mean</dispersion_type>
            <dispersion_value>0.024</dispersion_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>0.100</ci_lower_limit>
            <ci_upper_limit>0.192</ci_upper_limit>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Trough FVC Response at 12 Weeks- Defined as Change From Baseline</title>
        <description>Trough Forced Vital Capacity (FVC) response at 12 weeks- defined as change from baseline.</description>
        <time_frame>baseline and 12 weeks</time_frame>
        <population>Full analysis set (FAS) with last observation carried forward (LOCF) imputation</population>
        <group_list>
          <group group_id="O1">
            <title>Olodaterol (5µg) and Tiotropium (18µg)</title>
            <description>2 puffs olodaterol from Respimat and one capsule tiotropium from Handihaler once daily in am, co-administered&#xD;
Olodaterol: One dose, 2 inhalations once daily in the morning&#xD;
Tiotropium: Marketed dose, 2 inhalations from 1 capsule once daily in the morning</description>
          </group>
          <group group_id="O2">
            <title>Placebo and Tiotropium (18µg)</title>
            <description>2 puffs placebo inhalation solution from Respimat and one capsule tiotropium from Handihaler once daily in am, co-administered&#xD;
Tiotropium: Marketed dose, 2 inhalations from 1 capsule once daily in the morning&#xD;
Placebo matching Olodaterol: One dose, 2 inhalations once daily in the morning</description>
          </group>
        </group_list>
        <measure>
          <title>Trough FVC Response at 12 Weeks- Defined as Change From Baseline</title>
          <description>Trough Forced Vital Capacity (FVC) response at 12 weeks- defined as change from baseline.</description>
          <population>Full analysis set (FAS) with last observation carried forward (LOCF) imputation</population>
          <units>L</units>
          <param>Least Squares Mean</param>
          <dispersion>Standard Error</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="548"/>
                <count group_id="O2" value="551"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.276" spread="0.016"/>
                    <measurement group_id="O2" value="0.213" spread="0.016"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>Results are from an MMRM model. Fixed effects include treatment, visit, treatment by visit interaction, baseline and baseline by visit interaction. Patient is considered random and an unstructured covariance structure was used. Number of patients contributing to models: Tio+Placebo (551), Tio+Olo 5ug (548).</groups_desc>
            <non_inferiority_type>Superiority or Other</non_inferiority_type>
            <p_value>0.0047</p_value>
            <method>Mixed model repeated measure</method>
            <param_type>Mean difference from Tio + Placebo</param_type>
            <param_value>0.063</param_value>
            <dispersion_type>Standard Error of the Mean</dispersion_type>
            <dispersion_value>0.022</dispersion_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>0.019</ci_lower_limit>
            <ci_upper_limit>0.106</ci_upper_limit>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Peak FVC Response at 12 Weeks - Defined as Change From Baseline</title>
        <description>Peak FVC response at 12 weeks - defined as change from baseline.</description>
        <time_frame>baseline and 12 weeks</time_frame>
        <population>Full analysis set (FAS) with last observation carried forward (LOCF) imputation at 12 weeks.</population>
        <group_list>
          <group group_id="O1">
            <title>Olodaterol (5µg) and Tiotropium (18µg)</title>
            <description>2 puffs olodaterol from Respimat and one capsule tiotropium from Handihaler once daily in am, co-administered&#xD;
Olodaterol: One dose, 2 inhalations once daily in the morning&#xD;
Tiotropium: Marketed dose, 2 inhalations from 1 capsule once daily in the morning</description>
          </group>
          <group group_id="O2">
            <title>Placebo and Tiotropium (18µg)</title>
            <description>2 puffs placebo inhalation solution from Respimat and one capsule tiotropium from Handihaler once daily in am, co-administered&#xD;
Tiotropium: Marketed dose, 2 inhalations from 1 capsule once daily in the morning&#xD;
Placebo matching Olodaterol: One dose, 2 inhalations once daily in the morning</description>
          </group>
        </group_list>
        <measure>
          <title>Peak FVC Response at 12 Weeks - Defined as Change From Baseline</title>
          <description>Peak FVC response at 12 weeks - defined as change from baseline.</description>
          <population>Full analysis set (FAS) with last observation carried forward (LOCF) imputation at 12 weeks.</population>
          <units>L</units>
          <param>Least Squares Mean</param>
          <dispersion>Standard Error</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="563"/>
                <count group_id="O2" value="564"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.586" spread="0.017"/>
                    <measurement group_id="O2" value="0.433" spread="0.017"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>Results are from an MMRM model. Fixed effects include treatment, visit, treatment by visit interaction, baseline and baseline by visit interaction. Patient is considered random and an unstructured covariance structure was used. Number of patients contributing to models: Tio+Placebo (564), Tio+Olo 5ug (563).</groups_desc>
            <non_inferiority_type>Superiority or Other</non_inferiority_type>
            <p_value>&lt;0.0001</p_value>
            <method>Mixed model repeated measure</method>
            <param_type>Mean difference from Tio + Placebo</param_type>
            <param_value>0.153</param_value>
            <dispersion_type>Standard Error of the Mean</dispersion_type>
            <dispersion_value>0.024</dispersion_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>0.106</ci_lower_limit>
            <ci_upper_limit>0.201</ci_upper_limit>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Rescue Medication Usage - Percentage of Rescue Free Days</title>
        <description>Rescue medication usage - the percentage of rescue free days. The percentage of rescue free days is defined as: number of rescue free days divided by total exposure, multiplied by 100%. The baseline for the number of rescue-free days was defined as the number of rescue-free days observed during the last week of the baseline period (i.e., the 7 days prior to administration of the first dose of randomized treatment).</description>
        <time_frame>over 12 weeks</time_frame>
        <population>Full analysis set (FAS) with last observation carried forward (LOCF) imputation</population>
        <group_list>
          <group group_id="O1">
            <title>Olodaterol (5µg) and Tiotropium (18µg)</title>
            <description>2 puffs olodaterol from Respimat and one capsule tiotropium from Handihaler once daily in am, co-administered&#xD;
Olodaterol: One dose, 2 inhalations once daily in the morning&#xD;
Tiotropium: Marketed dose, 2 inhalations from 1 capsule once daily in the morning</description>
          </group>
          <group group_id="O2">
            <title>Placebo and Tiotropium (18µg)</title>
            <description>2 puffs placebo inhalation solution from Respimat and one capsule tiotropium from Handihaler once daily in am, co-administered&#xD;
Tiotropium: Marketed dose, 2 inhalations from 1 capsule once daily in the morning&#xD;
Placebo matching Olodaterol: One dose, 2 inhalations once daily in the morning</description>
          </group>
        </group_list>
        <measure>
          <title>Rescue Medication Usage - Percentage of Rescue Free Days</title>
          <description>Rescue medication usage - the percentage of rescue free days. The percentage of rescue free days is defined as: number of rescue free days divided by total exposure, multiplied by 100%. The baseline for the number of rescue-free days was defined as the number of rescue-free days observed during the last week of the baseline period (i.e., the 7 days prior to administration of the first dose of randomized treatment).</description>
          <population>Full analysis set (FAS) with last observation carried forward (LOCF) imputation</population>
          <units>percentage of days</units>
          <param>Least Squares Mean</param>
          <dispersion>Standard Error</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="557"/>
                <count group_id="O2" value="561"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Week 1</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="52.633" spread="1.507"/>
                    <measurement group_id="O2" value="48.606" spread="1.502"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Week 2</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="54.915" spread="1.534"/>
                    <measurement group_id="O2" value="50.774" spread="1.528"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Week 3</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="56.562" spread="1.565"/>
                    <measurement group_id="O2" value="50.262" spread="1.562"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Week 4</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="60.580" spread="1.405"/>
                    <measurement group_id="O2" value="55.577" spread="1.399"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Week 5</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="60.405" spread="1.581"/>
                    <measurement group_id="O2" value="52.614" spread="1.572"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Week 6</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="57.782" spread="1.632"/>
                    <measurement group_id="O2" value="50.547" spread="1.625"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Week 7</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="58.642" spread="1.625"/>
                    <measurement group_id="O2" value="50.727" spread="1.614"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Week 8</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="58.931" spread="1.648"/>
                    <measurement group_id="O2" value="51.618" spread="1.636"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Week 9</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="59.350" spread="1.652"/>
                    <measurement group_id="O2" value="51.399" spread="1.637"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Week 10</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="59.991" spread="1.624"/>
                    <measurement group_id="O2" value="52.535" spread="1.615"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Week 11</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="59.543" spread="1.651"/>
                    <measurement group_id="O2" value="50.584" spread="1.643"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Week 12</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="63.353" spread="1.553"/>
                    <measurement group_id="O2" value="54.894" spread="1.546"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>Week 12: Results are from non-MMRM ANCOVA models by week with LOCF up to each week. Fixed effects include treatment and baseline.&#xD;
Number of patients contributing to models: Tio+Placebo (561), Tio+Olo 5ug (557).</groups_desc>
            <non_inferiority_type>Superiority or Other</non_inferiority_type>
            <p_value>0.0001</p_value>
            <method>ANCOVA</method>
            <param_type>Mean difference from Tio+Placebo Week 12</param_type>
            <param_value>8.459</param_value>
            <dispersion_type>Standard Error of the Mean</dispersion_type>
            <dispersion_value>2.192</dispersion_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>4.159</ci_lower_limit>
            <ci_upper_limit>12.759</ci_upper_limit>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Rescue Medication Usage - Mean Weekly Rescue Usage (Total Daily)</title>
        <description>Rescue medication usage - mean weekly rescue usage (total daily). The baseline for the rescue use was the mean of the observations during the last week of the baseline period. Administration of rescue medication could occur at any point during the trial as deemed necessary by the patient or the investigator. Open label albuterol MDI (100 μg per puff) was provided as rescue medication . Daily, between clinic visits, patients recorded the number of puffs of albuterol in a paper diary.</description>
        <time_frame>over 12 weeks</time_frame>
        <population>Full analysis set (FAS) with last observation carried forward (LOCF) imputation</population>
        <group_list>
          <group group_id="O1">
            <title>Olodaterol (5µg) and Tiotropium (18µg)</title>
            <description>2 puffs olodaterol from Respimat and one capsule tiotropium from Handihaler once daily in am, co-administered&#xD;
Olodaterol: One dose, 2 inhalations once daily in the morning&#xD;
Tiotropium: Marketed dose, 2 inhalations from 1 capsule once daily in the morning</description>
          </group>
          <group group_id="O2">
            <title>Placebo and Tiotropium (18µg)</title>
            <description>2 puffs placebo inhalation solution from Respimat and one capsule tiotropium from Handihaler once daily in am, co-administered&#xD;
Tiotropium: Marketed dose, 2 inhalations from 1 capsule once daily in the morning&#xD;
Placebo matching Olodaterol: One dose, 2 inhalations once daily in the morning</description>
          </group>
        </group_list>
        <measure>
          <title>Rescue Medication Usage - Mean Weekly Rescue Usage (Total Daily)</title>
          <description>Rescue medication usage - mean weekly rescue usage (total daily). The baseline for the rescue use was the mean of the observations during the last week of the baseline period. Administration of rescue medication could occur at any point during the trial as deemed necessary by the patient or the investigator. Open label albuterol MDI (100 μg per puff) was provided as rescue medication . Daily, between clinic visits, patients recorded the number of puffs of albuterol in a paper diary.</description>
          <population>Full analysis set (FAS) with last observation carried forward (LOCF) imputation</population>
          <units>usage (total daily) number of puffs</units>
          <param>Least Squares Mean</param>
          <dispersion>Standard Error</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="557"/>
                <count group_id="O2" value="561"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Week 1</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1.760" spread="0.074"/>
                    <measurement group_id="O2" value="2.028" spread="0.074"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Week 2</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1.747" spread="0.079"/>
                    <measurement group_id="O2" value="2.073" spread="0.079"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Week 3</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1.699" spread="0.079"/>
                    <measurement group_id="O2" value="2.094" spread="0.078"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Week 4</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1.730" spread="0.080"/>
                    <measurement group_id="O2" value="2.057" spread="0.080"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Week 5</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1.609" spread="0.080"/>
                    <measurement group_id="O2" value="2.037" spread="0.079"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Week 6</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1.682" spread="0.085"/>
                    <measurement group_id="O2" value="2.047" spread="0.084"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Week 7</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1.657" spread="0.087"/>
                    <measurement group_id="O2" value="2.053" spread="0.086"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Week 8</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1.613" spread="0.085"/>
                    <measurement group_id="O2" value="2.042" spread="0.084"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Week 9</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1.622" spread="0.084"/>
                    <measurement group_id="O2" value="2.056" spread="0.083"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Week 10</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1.571" spread="0.084"/>
                    <measurement group_id="O2" value="2.050" spread="0.083"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Week 11</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1.533" spread="0.080"/>
                    <measurement group_id="O2" value="2.020" spread="0.079"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Week 12</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1.520" spread="0.082"/>
                    <measurement group_id="O2" value="1.998" spread="0.082"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>Week 12: Results are from non-MMRM ANCOVA models by week with LOCF up to each week. Fixed effects include treatment and baseline.&#xD;
Number of patients contributing to models: Tio+Placebo (561), Tio+Olo 5ug (557).</groups_desc>
            <non_inferiority_type>Superiority or Other</non_inferiority_type>
            <p_value>&lt;.0001</p_value>
            <method>ANCOVA</method>
            <param_type>Mean difference from Tio+Placebo Week 12</param_type>
            <param_value>-0.478</param_value>
            <dispersion_type>Standard Error of the Mean</dispersion_type>
            <dispersion_value>0.116</dispersion_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-0.706</ci_lower_limit>
            <ci_upper_limit>-0.250</ci_upper_limit>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Rescue Medication Usage - Mean Weekly Rescue Usage (Daytime)</title>
        <description>Rescue medication usage - Mean weekly rescue usage during daytime hours. Administration of rescue medication could occur at any point during the trial as deemed necessary by the patient or the investigator. Open label albuterol MDI (100 μg per puff) was provided as rescue medication by BI, and only the albuterol MDI provided by BI was allowed for rescue medication use. Daily, between clinic visits, patients recorded the number of puffs of albuterol in a paper diary.</description>
        <time_frame>over 12 weeks</time_frame>
        <population>Full analysis set (FAS) with last observation carried forward (LOCF) imputation</population>
        <group_list>
          <group group_id="O1">
            <title>Olodaterol (5µg) and Tiotropium (18µg)</title>
            <description>2 puffs olodaterol from Respimat and one capsule tiotropium from Handihaler once daily in am, co-administered&#xD;
Olodaterol: One dose, 2 inhalations once daily in the morning&#xD;
Tiotropium: Marketed dose, 2 inhalations from 1 capsule once daily in the morning</description>
          </group>
          <group group_id="O2">
            <title>Placebo and Tiotropium (18µg)</title>
            <description>2 puffs placebo inhalation solution from Respimat and one capsule tiotropium from Handihaler once daily in am, co-administered&#xD;
Tiotropium: Marketed dose, 2 inhalations from 1 capsule once daily in the morning&#xD;
Placebo matching Olodaterol: One dose, 2 inhalations once daily in the morning</description>
          </group>
        </group_list>
        <measure>
          <title>Rescue Medication Usage - Mean Weekly Rescue Usage (Daytime)</title>
          <description>Rescue medication usage - Mean weekly rescue usage during daytime hours. Administration of rescue medication could occur at any point during the trial as deemed necessary by the patient or the investigator. Open label albuterol MDI (100 μg per puff) was provided as rescue medication by BI, and only the albuterol MDI provided by BI was allowed for rescue medication use. Daily, between clinic visits, patients recorded the number of puffs of albuterol in a paper diary.</description>
          <population>Full analysis set (FAS) with last observation carried forward (LOCF) imputation</population>
          <units>percentage of days</units>
          <param>Least Squares Mean</param>
          <dispersion>Standard Error</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="557"/>
                <count group_id="O2" value="561"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Week 1</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.392" spread="0.025"/>
                    <measurement group_id="O2" value="0.409" spread="0.025"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Week 2</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.415" spread="0.030"/>
                    <measurement group_id="O2" value="0.449" spread="0.029"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Week 3</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.394" spread="0.028"/>
                    <measurement group_id="O2" value="0.437" spread="0.028"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Week 4</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.393" spread="0.029"/>
                    <measurement group_id="O2" value="0.416" spread="0.029"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Week 5</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.383" spread="0.030"/>
                    <measurement group_id="O2" value="0.454" spread="0.030"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Week 6</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.404" spread="0.031"/>
                    <measurement group_id="O2" value="0.447" spread="0.030"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Week 7</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.402" spread="0.033"/>
                    <measurement group_id="O2" value="0.455" spread="0.032"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Week 8</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.385" spread="0.030"/>
                    <measurement group_id="O2" value="0.451" spread="0.030"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Week 9</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.404" spread="0.031"/>
                    <measurement group_id="O2" value="0.457" spread="0.031"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Week 10</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.390" spread="0.031"/>
                    <measurement group_id="O2" value="0.448" spread="0.031"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Week 11</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.360" spread="0.030"/>
                    <measurement group_id="O2" value="0.441" spread="0.029"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Week 12</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.346" spread="0.029"/>
                    <measurement group_id="O2" value="0.429" spread="0.029"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>Results are from non-MMRM ANCOVA models by week with LOCF up to each week. Fixed effects include treatment and baseline.&#xD;
Number of patients contributing to models: Tio+Placebo (561), Tio+Olo 5ug (557).</groups_desc>
            <non_inferiority_type>Superiority or Other</non_inferiority_type>
            <p_value>0.0442</p_value>
            <method>ANCOVA</method>
            <param_type>Mean difference from Tio+Placebo Week 12</param_type>
            <param_value>-0.083</param_value>
            <dispersion_type>Standard Error of the Mean</dispersion_type>
            <dispersion_value>0.041</dispersion_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-0.164</ci_lower_limit>
            <ci_upper_limit>-0.002</ci_upper_limit>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Rescue Medication Usage - Mean Weekly Rescue Usage (Nighttime)</title>
        <description>Rescue medication usage - Mean weekly rescue usage during nighttime hours. Administration of rescue medication could occur at any point during the trial as deemed necessary by the patient or the investigator. Open label albuterol MDI (100 μg per puff) was provided as rescue medication by BI, and only the albuterol MDI provided by BI was allowed for rescue medication use. Daily, between clinic visits, patients recorded the number of puffs of albuterol in a paper diary.</description>
        <time_frame>over 12 weeks</time_frame>
        <population>Full analysis set (FAS) with last observation carried forward (LOCF) imputation</population>
        <group_list>
          <group group_id="O1">
            <title>Olodaterol (5µg) and Tiotropium (18µg)</title>
            <description>2 puffs olodaterol from Respimat and one capsule tiotropium from Handihaler once daily in am, co-administered&#xD;
Olodaterol: One dose, 2 inhalations once daily in the morning&#xD;
Tiotropium: Marketed dose, 2 inhalations from 1 capsule once daily in the morning</description>
          </group>
          <group group_id="O2">
            <title>Placebo and Tiotropium (18µg)</title>
            <description>2 puffs placebo inhalation solution from Respimat and one capsule tiotropium from Handihaler once daily in am, co-administered&#xD;
Tiotropium: Marketed dose, 2 inhalations from 1 capsule once daily in the morning&#xD;
Placebo matching Olodaterol: One dose, 2 inhalations once daily in the morning</description>
          </group>
        </group_list>
        <measure>
          <title>Rescue Medication Usage - Mean Weekly Rescue Usage (Nighttime)</title>
          <description>Rescue medication usage - Mean weekly rescue usage during nighttime hours. Administration of rescue medication could occur at any point during the trial as deemed necessary by the patient or the investigator. Open label albuterol MDI (100 μg per puff) was provided as rescue medication by BI, and only the albuterol MDI provided by BI was allowed for rescue medication use. Daily, between clinic visits, patients recorded the number of puffs of albuterol in a paper diary.</description>
          <population>Full analysis set (FAS) with last observation carried forward (LOCF) imputation</population>
          <units>percentage of days</units>
          <param>Least Squares Mean</param>
          <dispersion>Standard Error</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="557"/>
                <count group_id="O2" value="561"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Week 1</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1.370" spread="0.062"/>
                    <measurement group_id="O2" value="1.617" spread="0.061"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Week 2</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1.336" spread="0.064"/>
                    <measurement group_id="O2" value="1.620" spread="0.064"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Week 3</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1.309" spread="0.065"/>
                    <measurement group_id="O2" value="1.654" spread="0.064"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Week 4</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1.340" spread="0.065"/>
                    <measurement group_id="O2" value="1.640" spread="0.065"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Week 5</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1.230" spread="0.066"/>
                    <measurement group_id="O2" value="1.581" spread="0.065"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Week 6</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1.285" spread="0.070"/>
                    <measurement group_id="O2" value="1.596" spread="0.069"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Week 7</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1.265" spread="0.070"/>
                    <measurement group_id="O2" value="1.600" spread="0.069"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Week 8</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1.237" spread="0.070"/>
                    <measurement group_id="O2" value="1.587" spread="0.069"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Week 9</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1.597" spread="0.069"/>
                    <measurement group_id="O2" value="1.225" spread="0.068"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Week 10</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1.186" spread="0.070"/>
                    <measurement group_id="O2" value="1.600" spread="0.069"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Week 11</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1.177" spread="0.067"/>
                    <measurement group_id="O2" value="1.581" spread="0.067"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Week 12</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1.178" spread="0.070"/>
                    <measurement group_id="O2" value="1.571" spread="0.069"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>Results are from non-MMRM ANCOVA models by week with LOCF up to each week. Fixed effects include treatment and baseline.&#xD;
Number of patients contributing to models: Tio+Placebo (561), Tio+Olo 5ug (557).</groups_desc>
            <non_inferiority_type>Superiority or Other</non_inferiority_type>
            <p_value>&lt;.0001</p_value>
            <method>ANCOVA</method>
            <param_type>Mean difference from Tio+Placebo Week 12</param_type>
            <param_value>-0.393</param_value>
            <dispersion_type>Standard Error of the Mean</dispersion_type>
            <dispersion_value>0.098</dispersion_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-0.586</ci_lower_limit>
            <ci_upper_limit>-0.200</ci_upper_limit>
          </analysis>
        </analysis_list>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>Adverse events were to be documented throughout the trial, i.e., starting with informed consent and ending 21 days after last administration of trial medication. the duration of treatment was up to 12 weeks.</time_frame>
      <group_list>
        <group group_id="E1">
          <title>Olodaterol (5µg) and Tiotropium (18µg)</title>
          <description>2 puffs olodaterol from Respimat and one capsule tiotropium from Handihaler once daily in am, co-administered&#xD;
Olodaterol: One dose, 2 inhalations once daily in the morning&#xD;
Tiotropium: Marketed dose, 2 inhalations from 1 capsule once daily in the morning</description>
        </group>
        <group group_id="E2">
          <title>Placebo and Tiotropium (18µg)</title>
          <description>2 puffs placebo inhalation solution from Respimat and one capsule tiotropium from Handihaler once daily in am, co-administered&#xD;
Tiotropium: Marketed dose, 2 inhalations from 1 capsule once daily in the morning&#xD;
Placebo matching Olodaterol: One dose, 2 inhalations once daily in the morning</description>
        </group>
      </group_list>
      <serious_events>
        <default_vocab>MEDDRA 16.0</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="40" subjects_at_risk="567"/>
                <counts group_id="E2" subjects_affected="26" subjects_at_risk="565"/>
              </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="1" subjects_at_risk="567"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="565"/>
              </event>
              <event>
                <sub_title>Atrial fibrillation</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="567"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="565"/>
              </event>
              <event>
                <sub_title>Atrial flutter</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="567"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="565"/>
              </event>
              <event>
                <sub_title>Cardiac failure congestive</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="567"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="565"/>
              </event>
              <event>
                <sub_title>Myocardial infarction</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="567"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="565"/>
              </event>
              <event>
                <sub_title>Myocardial ischaemia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="567"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="565"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Gastritis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="567"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="565"/>
              </event>
              <event>
                <sub_title>Ileus</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="567"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="565"/>
              </event>
              <event>
                <sub_title>Intestinal ischaemia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="567"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="565"/>
              </event>
              <event>
                <sub_title>Intestinal obstruction</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="567"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="565"/>
              </event>
              <event>
                <sub_title>Obstruction gastric</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="567"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="565"/>
              </event>
              <event>
                <sub_title>Oesophagitis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="567"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="565"/>
              </event>
              <event>
                <sub_title>Rectal haemorrhage</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="567"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="565"/>
              </event>
              <event>
                <sub_title>Volvulus</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="567"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="565"/>
              </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="567"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="565"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Hepatobiliary disorders</title>
            <event_list>
              <event>
                <sub_title>Cholelithiasis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="567"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="565"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Bronchitis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="567"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="565"/>
              </event>
              <event>
                <sub_title>Campylobacter gastroenteritis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="567"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="565"/>
              </event>
              <event>
                <sub_title>Cellulitis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="567"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="565"/>
              </event>
              <event>
                <sub_title>Gastroenteritis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="567"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="565"/>
              </event>
              <event>
                <sub_title>Groin infection</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="567"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="565"/>
              </event>
              <event>
                <sub_title>Haemophilus infection</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="567"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="565"/>
              </event>
              <event>
                <sub_title>Influenza</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="567"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="565"/>
              </event>
              <event>
                <sub_title>Pneumonia</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="567"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="565"/>
              </event>
              <event>
                <sub_title>Pneumonia necrotising</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="567"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="565"/>
              </event>
              <event>
                <sub_title>Post procedural infection</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="567"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="565"/>
              </event>
              <event>
                <sub_title>Urinary tract infection</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="567"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="565"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Injury, poisoning and procedural complications</title>
            <event_list>
              <event>
                <sub_title>Arthropod bite</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="567"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="565"/>
              </event>
              <event>
                <sub_title>Chest injury</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="567"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="565"/>
              </event>
              <event>
                <sub_title>Post procedural haematoma</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="567"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="565"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Metabolism and nutrition disorders</title>
            <event_list>
              <event>
                <sub_title>Dehydration</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="567"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="565"/>
              </event>
              <event>
                <sub_title>Hypokalaemia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="567"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="565"/>
              </event>
              <event>
                <sub_title>Hyponatraemia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="567"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="565"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Muscle spasms</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="567"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="565"/>
              </event>
              <event>
                <sub_title>Osteoarthritis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="567"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="565"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Neoplasms benign, malignant and unspecified (incl cysts and polyps)</title>
            <event_list>
              <event>
                <sub_title>Breast cancer</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="567"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="565"/>
              </event>
              <event>
                <sub_title>Intraductal proliferative breast lesion</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="567"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="565"/>
              </event>
              <event>
                <sub_title>Lung cancer metastatic</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="567"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="565"/>
              </event>
              <event>
                <sub_title>Oesophageal carcinoma</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="567"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="565"/>
              </event>
              <event>
                <sub_title>Squamous cell carcinoma of skin</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="567"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="565"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Haemorrhagic cerebral infarction</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="567"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="565"/>
              </event>
              <event>
                <sub_title>Loss of consciousness</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="567"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="565"/>
              </event>
              <event>
                <sub_title>Presyncope</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="567"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="565"/>
              </event>
              <event>
                <sub_title>Vascular encephalopathy</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="567"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="565"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Psychiatric disorders</title>
            <event_list>
              <event>
                <sub_title>Anxiety</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="567"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="565"/>
              </event>
              <event>
                <sub_title>Mental status changes</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="567"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="565"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Renal and urinary disorders</title>
            <event_list>
              <event>
                <sub_title>Nephrolithiasis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="567"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="565"/>
              </event>
              <event>
                <sub_title>Renal failure acute</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="567"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="565"/>
              </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="3" subjects_at_risk="567"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="565"/>
              </event>
              <event>
                <sub_title>Chronic obstructive pulmonary disease</sub_title>
                <counts group_id="E1" subjects_affected="14" subjects_at_risk="567"/>
                <counts group_id="E2" subjects_affected="9" subjects_at_risk="565"/>
              </event>
              <event>
                <sub_title>Dyspnoea</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="567"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="565"/>
              </event>
              <event>
                <sub_title>Pulmonary hypertension</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="567"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="565"/>
              </event>
              <event>
                <sub_title>Respiratory failure</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="567"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="565"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Vascular disorders</title>
            <event_list>
              <event>
                <sub_title>Aortic aneurysm</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="567"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="565"/>
              </event>
              <event>
                <sub_title>Arteriosclerosis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="567"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="565"/>
              </event>
              <event>
                <sub_title>Haemorrhage</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="567"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="565"/>
              </event>
              <event>
                <sub_title>Hypertensive crisis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="567"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="565"/>
              </event>
              <event>
                <sub_title>Peripheral arterial occlusive disease</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="567"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="565"/>
              </event>
              <event>
                <sub_title>Peripheral artery stenosis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="567"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="565"/>
              </event>
              <event>
                <sub_title>Peripheral vascular disorder</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="567"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="565"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>5</frequency_threshold>
        <default_vocab>MEDDRA 16.0</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="60" subjects_at_risk="567"/>
                <counts group_id="E2" subjects_affected="52" subjects_at_risk="565"/>
              </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="60" subjects_at_risk="567"/>
                <counts group_id="E2" subjects_affected="52" subjects_at_risk="565"/>
              </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>
    <point_of_contact>
      <name_or_title>Boehringer Ingelheim Call Center</name_or_title>
      <organization>Boehringer Ingelheim Pharmaceuticals</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/NCT01694771
org study id: 1222.51
nct id: NCT01694771
lead sponsor: 
The overall objective of this study is to assess efficacy and safety of 12 weeks, once daily,
      orally inhaled co-administration of olodaterol 5 µg (delivered by the Respimat® Inhaler) and
      tiotropium (delivered by the Handihaler® as Spiriva Handihaler®), compared to tiotropium
      (Spiriva Handihaler®) monotherapy on lung function in patients with COPD.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Double
measure: FEV1 AUC0-3h Response at 12 Weeks; Defined as Change From Baseline to Week 12
time frame: baseline and 12 weeks
description: FEV1 (Forced expiratory volume in 1 second) AUC0-3h (area under the curve) response at 12 weeks; defined as change from baseline to Week 12
measure: Trough FEV1 Response at 12 Weeks; Defined as Change From Baseline to Week 12
time frame: baseline and 12 weeks
description: Trough FEV1 (Forced expiratory volume in 1 second) response at 12 weeks; defined as change from baseline to Week 12
measure: Peak FEV1 Response at 12 Weeks - Defined as Change From Baseline
time frame: baseline and 12 weeks
description: Peak FEV1 (Forced Expiratory Volume in 1 second) response at 12 Weeks - defined as changes from baseline
measure: FVC AUC0-3h Response at 12 Weeks - Defined as Change From Baseline
time frame: baseline and 12 weeks
description: Forced Vital Capacity (FVC) AUC0-3h response at 12 weeks - defined as change from baseline.
measure: Trough FVC Response at 12 Weeks- Defined as Change From Baseline
time frame: baseline and 12 weeks
description: Trough Forced Vital Capacity (FVC) response at 12 weeks- defined as change from baseline.
measure: Peak FVC Response at 12 Weeks - Defined as Change From Baseline
time frame: baseline and 12 weeks
description: Peak FVC response at 12 weeks - defined as change from baseline.
measure: Rescue Medication Usage - Percentage of Rescue Free Days
time frame: over 12 weeks
description: Rescue medication usage - the percentage of rescue free days. The percentage of rescue free days is defined as: number of rescue free days divided by total exposure, multiplied by 100%. The baseline for the number of rescue-free days was defined as the number of rescue-free days observed during the last week of the baseline period (i.e., the 7 days prior to administration of the first dose of randomized treatment).
measure: Rescue Medication Usage - Mean Weekly Rescue Usage (Total Daily)
time frame: over 12 weeks
description: Rescue medication usage - mean weekly rescue usage (total daily). The baseline for the rescue use was the mean of the observations during the last week of the baseline period. Administration of rescue medication could occur at any point during the trial as deemed necessary by the patient or the investigator. Open label albuterol MDI (100 μg per puff) was provided as rescue medication . Daily, between clinic visits, patients recorded the number of puffs of albuterol in a paper diary.
measure: Rescue Medication Usage - Mean Weekly Rescue Usage (Daytime)
time frame: over 12 weeks
description: Rescue medication usage - Mean weekly rescue usage during daytime hours. Administration of rescue medication could occur at any point during the trial as deemed necessary by the patient or the investigator. Open label albuterol MDI (100 μg per puff) was provided as rescue medication by BI, and only the albuterol MDI provided by BI was allowed for rescue medication use. Daily, between clinic visits, patients recorded the number of puffs of albuterol in a paper diary.
measure: Rescue Medication Usage - Mean Weekly Rescue Usage (Nighttime)
time frame: over 12 weeks
description: Rescue medication usage - Mean weekly rescue usage during nighttime hours. Administration of rescue medication could occur at any point during the trial as deemed necessary by the patient or the investigator. Open label albuterol MDI (100 μg per puff) was provided as rescue medication by BI, and only the albuterol MDI provided by BI was allowed for rescue medication use. Daily, between clinic visits, patients recorded the number of puffs of albuterol in a paper diary.
arm group label: Olodaterol and Tiotropium
arm group type: Experimental
description: 2 puffs olodaterol from Respimat and one capsule tiotropium from Handihaler once daily in am, co-administered
arm group label: Placebo and Tiotropium
arm group type: Other
description: 2 puffs placebo inhalation solution from Respimat and one capsule tiotropium from Handihaler once daily in am, co-administered
intervention type: Drug
intervention name: Tiotropium
description: Marketed dose
arm group label: Placebo and Tiotropium
intervention type: Drug
intervention name: Placebo matching Olodaterol
description: One dose
arm group label: Placebo and Tiotropium
intervention type: Drug
intervention name: Olodaterol
description: One dose
arm group label: Olodaterol and Tiotropium
intervention type: Drug
intervention name: Tiotropium
description: Marketed dose
arm group label: Olodaterol and Tiotropium
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: United States
responsible party type: Sponsor
mesh term: Lung Diseases
mesh term: Pulmonary Disease, Chronic Obstructive
mesh term: Tiotropium Bromide
mesh term: Olodaterol
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