<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/NCT02969317</url>
  </required_header>
  <id_info>
    <org_study_id>1237.30</org_study_id>
    <nct_id>NCT02969317</nct_id>
  </id_info>
  <brief_title>Bioavailability of Tiotropium + Olodaterol Fixed-dose Combination (5 μg/ 5 μg) in Chinese COPD Patients</brief_title>
  <official_title>An Open-label Trial to Assess Pharmacokinetics and Safety of Tiotropium + Olodaterol Fixed-dose Combination (5 µg/ 5 µg) Delivered by the RESPIMAT Inhaler After Single and Multiple Dose Treatment in Chinese Patients With Chronic Obstructive Pulmonary Disease (COPD)</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Boehringer Ingelheim</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Boehringer Ingelheim</source>
  <oversight_info>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      The primary objective of this study is to assess the pharmacokinetics of tiotropium +&#xD;
      olodaterol fixed-dose combination (FDC) (5 μg/ 5 μg) delivered by the RESPIMAT inhaler after&#xD;
      single dose and at steady state in Chinese patients with COPD.&#xD;
&#xD;
      The secondary objective is to assess the safety of tiotropium + olodaterol FDC (5 μg/ 5 μg)&#xD;
      delivered by the RESPIMAT inhaler after 3 weeks once daily treatment in Chinese patients with&#xD;
      COPD.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">February 24, 2017</start_date>
  <completion_date type="Actual">June 15, 2017</completion_date>
  <primary_completion_date type="Actual">June 15, 2017</primary_completion_date>
  <phase>Phase 1</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Area Under the Concentration Time Curve of Olodaterol in Plasma Over the Time Interval From 0 to 6 Hours After Drug Administration (AUC0-6)</measure>
    <time_frame>0:05 (hours:minutes) before drug administration and 0:02, 0:05, 0:07, 0:10, 0:20, 0:30, 0:40, 1:00, 2:00, 3:00, 4:00, 6:00 (hours:minutes) after drug administration</time_frame>
    <description>The descriptive statistics of AUC0-6 could not be evaluated. Since the plasma concentrations of olodaterol and tiotropium was only quantifiable in less than two-thirds of the patients after 4 hours and 1 hour, respectively, and the descriptive statistics is calculated in case that 2/3 patients of total could be evaluated as defined in Clinical trial Protocol (CTP).</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Time From Dosing to the Maximum Concentration of Olodaterol in Plasma (Tmax)</measure>
    <time_frame>Day 1, 7, 14, 18, 19 and 20</time_frame>
    <description>Tmax, time from dosing to the maximum concentration of olodaterol in plasma after single inhaled administration of tiotropium+olodaterol FDC 5 mg/5 mg is presented as unadjusted geometric mean (gMean) and geometric coefficient of variation (gCV) (%).&#xD;
detailed sampling time points: 0:05 (hours:minutes) before drug administration and 0:02, 0:05, 0:07, 0:10, 0:20, 0:30, 0:40, 1:00, 2:00, 3:00, 4:00, 6:00, 143:45, 144:20, 311:45, 312:20, 407:45, 408:20, 431:45, 432:20, 455:45, 456:20(hours:minutes) after drug administration.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Maximum Measured Concentration of Olodaterol in Plasma (Cmax)</measure>
    <time_frame>Day 1, 7, 14, 18, 19 and 20</time_frame>
    <description>Cmax, maximum measured concentration of olodaterol in plasma after single inhaled administration of tiotropium+olodaterol FDC 5 mg/5 mg is presented as unadjusted geometric mean (gMean) and geometric coefficient of variation (gCV) (%).&#xD;
detailed sampling time points: 0:05 (hours:minutes) before drug administration and 0:02, 0:05, 0:07, 0:10, 0:20, 0:30, 0:40, 1:00, 2:00, 3:00, 4:00, 6:00, 143:45, 144:20, 311:45, 312:20, 407:45, 408:20, 431:45, 432:20, 455:45, 456:20(hours:minutes) after drug administration.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Maximum Measured Concentration of Olodaterol in Plasma at Steady State (Cmax,ss)</measure>
    <time_frame>Day 21: 0:15 (hours:minutes) before drug administration and 0:02, 0:05, 0:07, 0:10, 0:20, 0:30, 0:40, 1:00, 2:00, 3:00, 4:00, 6:00, 12:00, 24:00 (hours:minutes) after drug administration</time_frame>
    <description>Cmax,ss, maximum measured concentration of olodaterol in plasma at steady state of olodaterol after multiple dosing at Visit 4 (day 21) of tiotropium+olodaterol FDC 5 mg/5 mg is presented as unadjusted geometric mean (gMean) and geometric coefficient of variation (gCV) (%).</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Pre-dose Concentration of Olodaterol in Plasma at Steady State (Cpre,ss)</measure>
    <time_frame>Day 21: 0:15 (hours:minutes) before drug administration and 0:02, 0:05, 0:07, 0:10, 0:20, 0:30, 0:40, 1:00, 2:00, 3:00, 4:00, 6:00, 12:00, 24:00 (hours:minutes) after drug administration</time_frame>
    <description>Cpre,ss, pre-dose concentration of olodaterol in plasma at steady state after multiple dosing at Day 21 of tiotropium+olodaterol FDC 5 mg/5 mg is presented as unadjusted geometric mean (gMean) and geometric coefficient of variation (gCV) (%).</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Area Under the Concentration Time Curve of Olodaterol in Plasma Over the Time Interval From 0 to 6 Hours at Steady State (AUC0-6,ss)</measure>
    <time_frame>Day 21: 0:15 (hours:minutes) before drug administration and 0:02, 0:05, 0:07, 0:10, 0:20, 0:30, 0:40, 1:00, 2:00, 3:00, 4:00, 6:00 (hours:minutes) after drug administration</time_frame>
    <description>AUC0-6,ss, area under the concentration time curve of olodaterol in plasma over the time interval from 0 to 6 hours at steady state after multiple dosing at Day 21 of tiotropium+olodaterol FDC 5 mg/5 mg is presented as unadjusted geometric mean (gMean) and geometric coefficient of variation (gCV) (%).</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Area Under the Concentration-time Curve of Olodaterol in Plasma at Steady State Over a Uniform Dosing Interval τ at Steady State (AUCτ,ss)</measure>
    <time_frame>Day 21: 0:15 (hours:minutes) before drug administration and 0:02, 0:05, 0:07, 0:10, 0:20, 0:30, 0:40, 1:00, 2:00, 3:00, 4:00, 6:00, 12:00, 24:00 (hours:minutes) after drug administration</time_frame>
    <description>AUCτ,ss, area under the concentration-time curve of olodaterol in plasma at steady state over a uniform dosing interval τ at steady state after multiple dosing at Day 21 is presented as unadjusted geometric mean (gMean) and geometric coefficient of variation (gCV) (%).</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Time From Dosing to the Maximum Concentration of Olodaterol in Plasma at Steady State (Tmax,ss)</measure>
    <time_frame>Day 21: 0:15 (hours:minutes) before drug administration and 0:02, 0:05, 0:07, 0:10, 0:20, 0:30, 0:40, 1:00, 2:00, 3:00, 4:00, 6:00, 12:00, 24:00 (hours:minutes) after drug administration</time_frame>
    <description>Tmax,ss,time from dosing to the maximum concentration of olodaterol in plasma at steady state after multiple dosing at Day 21 of tiotropium+olodaterol FDC 5 mg/5 mg is presented as unadjusted geometric mean (gMean) and geometric coefficient of variation (gCV) (%).</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Accumulation Ratios in Plasma of Olodaterol (RA,Cmax =Cmax,ss/Cmax)</measure>
    <time_frame>Day 1 and Day 21</time_frame>
    <description>Accumulation ratios in plasma of olodaterol (RA,Cmax =Cmax,ss/Cmax) after multiple dosing at Day 21 is presented as unadjusted geometric mean (gMean) and geometric coefficient of variation (gCV) (%).</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Accumulation Ratios in Plasma of Olodaterol (RA,AUC =AUC0-6,ss/AUC0-6)</measure>
    <time_frame>Day 1 and Day 21</time_frame>
    <description>Regarding AUC0-6 and RA,AUC0-6, the descriptive statistics of AUC0-6 could not be evaluated. Since the plasma concentrations of olodaterol and tiotropium was only quantifiable in less than two-thirds of the patients after 4 hours and 1 hour, respectively, and the descriptive statistics is calculated in case that 2/3 patients of total could be evaluated as defined in Clinical trial Protocol (CTP). And RA,AUC0-6 is the ratio of AUC0-6,ss to AUC0-6. So, the descriptive RA,AUC0-6 was not calculated either.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Area Under the Concentration Time Curve of Tiotropium in Plasma Over the Time Interval From 0 to 6 Hours After Drug Administration (AUC0-6)</measure>
    <time_frame>Day 1</time_frame>
    <description>The descriptive statistics of AUC0-6 could not be evaluated. Since the plasma concentrations of olodaterol and tiotropium was only quantifiable in less than two-thirds of the patients after 4 hours and 1 hour, respectively, and the descriptive statistics is calculated in case that 2/3 patients of total could be evaluated as defined in Clinical trial Protocol (CTP).</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Time From Dosing to the Maximum Concentration of Tiotropium in Plasma (Tmax)</measure>
    <time_frame>Day 1, 7, 14, 18, 19, 20</time_frame>
    <description>Tmax, time from dosing to the maximum concentration of Tiotropium in plasma after single inhaled administration of tiotropium+olodaterol FDC 5 mg/5 mgis presented as unadjusted geometric mean (gMean) and geometric coefficient of variation (gCV) (%).&#xD;
Detailed sampling time points:0:05 (hours:minutes) before drug administration and 0:02, 0:05, 0:07, 0:10, 0:20, 0:30, 0:40, 1:00, 2:00, 3:00, 4:00, 6:00, 143:45, 144:20, 311:45, 312:20, 407:45, 408:20, 431:45, 432:20, 455:45, 456:20 (hours:minutes) after drug administration</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Maximum Measured Concentration of Tiotropium in Plasma (Cmax)</measure>
    <time_frame>Day 1, 7, 14, 18, 19, 20</time_frame>
    <description>Cmax, maximum measured concentration of Tiotropium in plasma after single inhaled administration of tiotropium+olodaterol FDC 5 mg/5 mg is presented as unadjusted geometric mean (gMean) and geometric coefficient of variation (gCV) (%).&#xD;
Detailed sampling time points:0:05 (hours:minutes) before drug administration and 0:02, 0:05, 0:07, 0:10, 0:20, 0:30, 0:40, 1:00, 2:00, 3:00, 4:00, 6:00, 143:45, 144:20, 311:45, 312:20, 407:45, 408:20, 431:45, 432:20, 455:45, 456:20 (hours:minutes) after drug administration</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Maximum Measured Concentration of Tiotropium in Plasma at Steady State (Cmax,ss)</measure>
    <time_frame>Day 21: 0:15 (hours:minutes) before drug administration and 0:02, 0:05, 0:07, 0:10, 0:20, 0:30, 0:40, 1:00, 2:00, 3:00, 4:00, 6:00, 12:00, 24:00 (hours:minutes) after drug administration</time_frame>
    <description>Cmax,ss, maximum measured concentration of olodaterol in plasma at steady state of Tiotropium after multiple dosing at Visit 4 of tiotropium+olodaterol FDC 5 mg/5 mg is presented as unadjusted geometric mean (gMean) and geometric coefficient of variation (gCV) (%).</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Pre-dose Concentration of Tiotropium in Plasma at Steady State (Cpre,ss)</measure>
    <time_frame>Day 21: 0:15 (hours:minutes) before drug administration and 0:02, 0:05, 0:07, 0:10, 0:20, 0:30, 0:40, 1:00, 2:00, 3:00, 4:00, 6:00, 12:00, 24:00 (hours:minutes) after drug administration</time_frame>
    <description>Cpre,ss, pre-dose concentration of Tiotropium in plasma at steady state after multiple dosing at Visit 4 of tiotropium+olodaterol FDC 5 mg/5 mg is presented as unadjusted geometric mean (gMean) and geometric coefficient of variation (gCV) (%).</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Area Under the Concentration Time Curve of Tiotropium in Plasma Over the Time Interval From 0 to 6 Hours at Steady State (AUC0-6,ss)</measure>
    <time_frame>Day 21:0:15 (hours:minutes) before drug administration and 0:02, 0:05, 0:07, 0:10, 0:20, 0:30, 0:40, 1:00, 2:00, 3:00, 4:00, 6:00 (hours:minutes) after drug administration</time_frame>
    <description>AUC0-6,ss, area under the concentration time curve of Tiotropium in plasma over the time interval from 0 to 6 hours at steady state after multiple dosing at Visit 4 of tiotropium+olodaterol FDC 5 mg/5 mg is presented as unadjusted geometric mean (gMean) and geometric coefficient of variation (gCV) (%).</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Area Under the Concentration-time Curve of Tiotropium in Plasma at Steady State Over a Uniform Dosing Interval τ at Steady State (AUCτ,ss)</measure>
    <time_frame>Day 21: 0:15 (hours:minutes) before drug administration and 0:02, 0:05, 0:07, 0:10, 0:20, 0:30, 0:40, 1:00, 2:00, 3:00, 4:00, 6:00, 12:00, 24:00 (hours:minutes) after drug administration</time_frame>
    <description>AUCτ,ss, area under the concentration-time curve of Tiotropium in plasma at steady state over a uniform dosing interval τ at steady state after multiple dosing at Visit 4 is presented as unadjusted geometric mean (gMean) and geometric coefficient of variation (gCV) (%).</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Time From Dosing to the Maximum Concentration of Tiotropium in Plasma at Steady State (Tmax,ss)</measure>
    <time_frame>Day 21: 0:15 (hours:minutes) before drug administration and 0:02, 0:05, 0:07, 0:10, 0:20, 0:30, 0:40, 1:00, 2:00, 3:00, 4:00, 6:00, 12:00, 24:00 (hours:minutes) after drug administration</time_frame>
    <description>Tmax,ss,time from dosing to the maximum concentration of Tiotropium in plasma at steady state after multiple dosing at Visit 4 of tiotropium+olodaterol FDC 5 mg/5 mg is presented as unadjusted geometric mean (gMean) and geometric coefficient of variation (gCV) (%).</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Accumulation Ratios in Plasma of Tiotropium (RA,Cmax =Cmax,ss/Cmax)</measure>
    <time_frame>Day 1, 7, 14, 18, 19, 20 and 21</time_frame>
    <description>Accumulation ratios in plasma of Tiotropium (RA,Cmax =Cmax,ss/Cmax) after multiple dosing at Visit 4 is presented as unadjusted geometric mean (gMean) and geometric coefficient of variation (gCV) (%).</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Accumulation Ratios in Plasma of Tiotropium (RA,AUC =AUC0-6,ss/AUC0-6)</measure>
    <time_frame>Day 1 and Day 21</time_frame>
    <description>Regarding AUC0-6 and RA,AUC0-6, the descriptive statistics of AUC0-6 could not be evaluated. Since the plasma concentrations of olodaterol and tiotropium was only quantifiable in less than two-thirds of the patients after 4 hours and 1 hour, respectively, and the descriptive statistics is calculated in case that 2/3 patients of total could be evaluated as defined in CTP. And RA,AUC0-6 is the ratio of AUC0-6,ss to AUC0-6. So, the descriptive RA,AUC0-6 was not calculated either.</description>
  </primary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">12</enrollment>
  <condition>Pulmonary Disease, Chronic Obstructive</condition>
  <arm_group>
    <arm_group_label>Tiotropium + olodaterol fixed-dose combination</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Fixed dose combination</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Tiotropium</intervention_name>
    <description>Fixed dose combination</description>
    <arm_group_label>Tiotropium + olodaterol fixed-dose combination</arm_group_label>
    <other_name>INSPIOLTO, SPIOLTO, STIOLTO, VAHELVA, YANIMO</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Olodaterol</intervention_name>
    <description>Fixed dose combination</description>
    <arm_group_label>Tiotropium + olodaterol fixed-dose combination</arm_group_label>
    <other_name>INSPIOLTO, SPIOLTO, STIOLTO, VAHELVA, YANIMO</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion criteria:&#xD;
&#xD;
          -  All patients must sign an informed consent consistent with International Conference on&#xD;
             Harmonisation-Good Clinical Practice (ICH-GCP) guidelines and local legislations prior&#xD;
             to any study-related procedures, which includes medication washout and restrictions.&#xD;
&#xD;
          -  All patients must have a diagnosis of Chronic Obstructive Pulmonary Disease (COPD) and&#xD;
             must meet the following spirometric criteria:&#xD;
&#xD;
        Patients must have relatively stable airway obstruction with a post-bronchodilator Forced&#xD;
        Expiratory Volume in one second (FEV1) &gt;=30% of predicted normal and &lt;80% of predicted&#xD;
        normal (ECSC,; and a postbronchodilator FEV1/ Forced Vital Capacity (FVC)&lt;70% at Visit 1&#xD;
&#xD;
          -  Male or female patients, 40 years of age or older.&#xD;
&#xD;
          -  Patients must be current or ex-smokers with a smoking history of more than 10 pack&#xD;
             years.&#xD;
&#xD;
        Patients who have never smoked cigarettes must be excluded.&#xD;
&#xD;
          -  Patients must be able to&#xD;
&#xD;
               -  perform technically acceptable pulmonary function tests,&#xD;
&#xD;
               -  maintain medication worksheet records during the study period,&#xD;
&#xD;
               -  perform all other assessments as required in the protocol.&#xD;
&#xD;
          -  Patients must be able to inhale medication in a competent manner from the RESPIMAT&#xD;
             inhaler and from a metered dose inhaler (MDI).&#xD;
&#xD;
          -  Male or female patients. Women of childbearing potential* must be ready and able to&#xD;
             use highly effective methods of birth control per ICH M3(R2) that result in a low&#xD;
             failure rate of less than 1% per year when used consistently and correctly. A list of&#xD;
             contraception methods meeting these criteria is provided in the patient information.&#xD;
&#xD;
               -  Women of childbearing potential are defined as:&#xD;
&#xD;
        Any female who has experienced menarche and does not meet the criteria for &quot;women not of&#xD;
        childbearing potential&quot; as described below.&#xD;
&#xD;
        Women not of childbearing potential are defined as:&#xD;
&#xD;
        Women who are postmenopausal (12 months with no menses without an alternative medical&#xD;
        cause) or who are permanently sterilized (e.g., tubal occlusion, hysterectomy, bilateral&#xD;
        oophorectomy or bilateral salpingectomy).&#xD;
&#xD;
        Exclusion criteria:&#xD;
&#xD;
          -  Patients with a significant disease other than Chronic Obstructive Pulmonary Disease&#xD;
             (COPD); a significant disease is defined as a disease which, in the opinion of the&#xD;
             investigator, may (i) put the patient at risk because of participation in the study,&#xD;
             (ii) influence the results of the study, or (iii) cause concern regarding the&#xD;
             patient's ability to participate in the study.&#xD;
&#xD;
          -  Patients with a, in the opinion of the investigator, clinically relevant abnormal&#xD;
             baseline haematology, blood chemistry, or urinalysis; all patients with an Serum&#xD;
             Glutamic Oxaloacetic Transaminase (SGOT) &gt;x 2 Upper Limit of Normal (ULN), Serum&#xD;
             Glutamic Pyruvic Transaminase(SGPT) &gt;x 2 ULN, bilirubin &gt;x 2 ULN or creatinine &gt;x 2&#xD;
             ULN will be excluded regardless of clinical condition (a repeat laboratory evaluation&#xD;
             will not be conducted in these patients).&#xD;
&#xD;
          -  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;
        Patients with any of the following conditions:&#xD;
&#xD;
          -  A diagnosis of thyrotoxicosis (due to the known class side effect profile of&#xD;
             ß2-agonists).&#xD;
&#xD;
          -  A diagnosis of paroxysmal tachycardia (&gt;100 beats per minute) (due to the known class&#xD;
             side effect profile of ß2-agonists)&#xD;
&#xD;
          -  A history of myocardial infarction within 1 year of screening visit (Visit 1).&#xD;
&#xD;
          -  Unstable or life-threatening cardiac arrhythmia.&#xD;
&#xD;
          -  Hospitalization for heart failure within the past year.&#xD;
&#xD;
          -  Known active tuberculosis.&#xD;
&#xD;
          -  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;
          -  A history of life-threatening pulmonary obstruction.&#xD;
&#xD;
          -  A history of cystic fibrosis.&#xD;
&#xD;
          -  Clinically evident bronchiectasis.&#xD;
&#xD;
          -  A history of significant alcohol or drug abuse.&#xD;
&#xD;
          -  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;
          -  Patients being treated with oral or patch β-adrenergics.&#xD;
&#xD;
          -  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;
          -  Patients who regularly use daytime oxygen therapy for more than one hour per day and&#xD;
             in the investigator's opinion will be unable to abstain from the use of oxygen therapy&#xD;
             during clinic visits.&#xD;
&#xD;
          -  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;
          -  Patients who have taken an investigational drug within one month or six half lives or&#xD;
             within the wash out period (whichever is greater) prior to screening visit (Visit 1).&#xD;
&#xD;
          -  Patients with known hypersensitivity to β-adrenergics and/or anticholinergic drugs,&#xD;
             benzalkonium chloride (BAC), disodium edentate (EDTA) or any other component of the&#xD;
             RESPIMAT inhalation solution.&#xD;
&#xD;
          -  Women who are pregnant, nursing, or who plan to become pregnant while in the trial&#xD;
&#xD;
          -  Women of childbearing potential not using two highly effective methods of birth&#xD;
             control*.&#xD;
&#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 least two&#xD;
        years.&#xD;
&#xD;
        * as per ICH M3: a highly effective method of birth control is defined as those which&#xD;
        result in a low failure rate (i.e., less than 1% per year) when used consistently and&#xD;
        correctly.&#xD;
&#xD;
          -  Patients who have previously been allocated in this study or are currently&#xD;
             participating in another study.&#xD;
&#xD;
          -  Patients who are unable to comply with pulmonary medication restrictions prior to&#xD;
             allocation.&#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>West China Hospital</name>
      <address>
        <city>Chengdu</city>
        <zip>610041</zip>
        <country>China</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>China</country>
  </location_countries>
  <link>
    <url>http://trials.boehringer-ingelheim.com/</url>
    <description>Related Info</description>
  </link>
  <verification_date>December 2018</verification_date>
  <study_first_submitted>November 10, 2016</study_first_submitted>
  <study_first_submitted_qc>November 17, 2016</study_first_submitted_qc>
  <study_first_posted type="Estimate">November 21, 2016</study_first_posted>
  <results_first_submitted>June 12, 2018</results_first_submitted>
  <results_first_submitted_qc>December 19, 2018</results_first_submitted_qc>
  <results_first_posted type="Actual">March 29, 2019</results_first_posted>
  <last_update_submitted>December 19, 2018</last_update_submitted>
  <last_update_submitted_qc>December 19, 2018</last_update_submitted_qc>
  <last_update_posted type="Actual">March 29, 2019</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>
  <provided_document_section>
    <provided_document>
      <document_type>Study Protocol</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>No</document_has_sap>
      <document_date>February 20, 2017</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/17/NCT02969317/Prot_000.pdf</document_url>
    </provided_document>
    <provided_document>
      <document_type>Statistical Analysis Plan</document_type>
      <document_has_protocol>No</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>June 30, 2017</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/17/NCT02969317/SAP_001.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <recruitment_details>12 patients were entered to receive treatment with tiotropium+olodaterol fixed-dose combination (FDC) 5 microgram / 5 microgram (5 μg / 5 μg). All of the 12 entered patients were treated with trial medication.</recruitment_details>
      <pre_assignment_details>All patients were screened for eligibility to participate in the trial. Patients attended specialist sites which would then ensure that all patients met all inclusion/exclusion criteria. Patients were not to be entered to trial treatment if any one of the specific entry criteria were not met.</pre_assignment_details>
      <group_list>
        <group group_id="P1">
          <title>Tiotropium+Olodaterol 5 Microgram/5 Microgram</title>
          <description>Patients were administered with 2 oral inhalations once daily (AM dosing) via RESPIMAT® inhaler of 2.5 μg per actuation of Tiotropium solution and 2.5 μg per actuation of Olodaterol solution</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="12"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="12"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <population>Treated Set (TS): This set included all patients who were dispensed study medication and were documented to have taken at least one dose of investigational treatment.</population>
      <group_list>
        <group group_id="B1">
          <title>Tiotropium+Olodaterol 5 Microgram/5 Microgram</title>
          <description>Patients were administered with 2 oral inhalations once daily (AM dosing) via RESPIMAT® inhaler of 2.5 μg per actuation of Tiotropium solution and 2.5 μg per actuation of Olodaterol solution</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="12"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>Years</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="12"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="59.8" spread="8.1"/>
                  </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>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="12"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <title>Female</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="12"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Ethnicity (NIH/OMB)</title>
          <population>Ethnicity data were not collected from any participant</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="0"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <title>Hispanic or Latino</title>
                </category>
                <category>
                  <title>Not Hispanic or Latino</title>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="12"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <title>American Indian or Alaska Native</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Asian</title>
                  <measurement_list>
                    <measurement group_id="B1" value="12"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Native Hawaiian or Other Pacific Islander</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Black or African American</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>More than one race</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Area Under the Concentration Time Curve of Olodaterol in Plasma Over the Time Interval From 0 to 6 Hours After Drug Administration (AUC0-6)</title>
        <description>The descriptive statistics of AUC0-6 could not be evaluated. Since the plasma concentrations of olodaterol and tiotropium was only quantifiable in less than two-thirds of the patients after 4 hours and 1 hour, respectively, and the descriptive statistics is calculated in case that 2/3 patients of total could be evaluated as defined in Clinical trial Protocol (CTP).</description>
        <time_frame>0:05 (hours:minutes) before drug administration and 0:02, 0:05, 0:07, 0:10, 0:20, 0:30, 0:40, 1:00, 2:00, 3:00, 4:00, 6:00 (hours:minutes) after drug administration</time_frame>
        <population>Pharmacokinetic analysis set (PKS): This set included all patients in the treated set with at least one evaluable PK parameter in the treatment period without important protocol violations related to PK</population>
        <group_list>
          <group group_id="O1">
            <title>Tiotropium+Olodaterol FDC 5 mg/5 mg</title>
            <description>Patients were administered with 2 oral inhalations once daily (AM dosing) via RESPIMAT® inhaler of 2.5 μg per actuation of Olodaterol solution</description>
          </group>
        </group_list>
        <measure>
          <title>Area Under the Concentration Time Curve of Olodaterol in Plasma Over the Time Interval From 0 to 6 Hours After Drug Administration (AUC0-6)</title>
          <description>The descriptive statistics of AUC0-6 could not be evaluated. Since the plasma concentrations of olodaterol and tiotropium was only quantifiable in less than two-thirds of the patients after 4 hours and 1 hour, respectively, and the descriptive statistics is calculated in case that 2/3 patients of total could be evaluated as defined in Clinical trial Protocol (CTP).</description>
          <population>Pharmacokinetic analysis set (PKS): This set included all patients in the treated set with at least one evaluable PK parameter in the treatment period without important protocol violations related to PK</population>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="0"/>
              </count_list>
            </analyzed>
          </analyzed_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Time From Dosing to the Maximum Concentration of Olodaterol in Plasma (Tmax)</title>
        <description>Tmax, time from dosing to the maximum concentration of olodaterol in plasma after single inhaled administration of tiotropium+olodaterol FDC 5 mg/5 mg is presented as unadjusted geometric mean (gMean) and geometric coefficient of variation (gCV) (%).&#xD;
detailed sampling time points: 0:05 (hours:minutes) before drug administration and 0:02, 0:05, 0:07, 0:10, 0:20, 0:30, 0:40, 1:00, 2:00, 3:00, 4:00, 6:00, 143:45, 144:20, 311:45, 312:20, 407:45, 408:20, 431:45, 432:20, 455:45, 456:20(hours:minutes) after drug administration.</description>
        <time_frame>Day 1, 7, 14, 18, 19 and 20</time_frame>
        <population>PKS (evaluable cases)</population>
        <group_list>
          <group group_id="O1">
            <title>Tiotropium+Olodaterol FDC 5 mg/5 mg</title>
            <description>Patients were administered with 2 oral inhalations once daily (AM dosing) via RESPIMAT® inhaler of 2.5 μg per actuation of Olodaterol solution</description>
          </group>
        </group_list>
        <measure>
          <title>Time From Dosing to the Maximum Concentration of Olodaterol in Plasma (Tmax)</title>
          <description>Tmax, time from dosing to the maximum concentration of olodaterol in plasma after single inhaled administration of tiotropium+olodaterol FDC 5 mg/5 mg is presented as unadjusted geometric mean (gMean) and geometric coefficient of variation (gCV) (%).&#xD;
detailed sampling time points: 0:05 (hours:minutes) before drug administration and 0:02, 0:05, 0:07, 0:10, 0:20, 0:30, 0:40, 1:00, 2:00, 3:00, 4:00, 6:00, 143:45, 144:20, 311:45, 312:20, 407:45, 408:20, 431:45, 432:20, 455:45, 456:20(hours:minutes) after drug administration.</description>
          <population>PKS (evaluable cases)</population>
          <units>Hour [h]</units>
          <param>Median</param>
          <dispersion>Full Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="12"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.167" lower_limit="0.117" upper_limit="3.00"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Maximum Measured Concentration of Olodaterol in Plasma (Cmax)</title>
        <description>Cmax, maximum measured concentration of olodaterol in plasma after single inhaled administration of tiotropium+olodaterol FDC 5 mg/5 mg is presented as unadjusted geometric mean (gMean) and geometric coefficient of variation (gCV) (%).&#xD;
detailed sampling time points: 0:05 (hours:minutes) before drug administration and 0:02, 0:05, 0:07, 0:10, 0:20, 0:30, 0:40, 1:00, 2:00, 3:00, 4:00, 6:00, 143:45, 144:20, 311:45, 312:20, 407:45, 408:20, 431:45, 432:20, 455:45, 456:20(hours:minutes) after drug administration.</description>
        <time_frame>Day 1, 7, 14, 18, 19 and 20</time_frame>
        <population>PKS (evaluable cases)</population>
        <group_list>
          <group group_id="O1">
            <title>Tiotropium+Olodaterol FDC 5 mg/5 mg</title>
            <description>Patients were administered with 2 oral inhalations once daily (AM dosing) via RESPIMAT® inhaler of 2.5 μg per actuation of Olodaterol solution</description>
          </group>
        </group_list>
        <measure>
          <title>Maximum Measured Concentration of Olodaterol in Plasma (Cmax)</title>
          <description>Cmax, maximum measured concentration of olodaterol in plasma after single inhaled administration of tiotropium+olodaterol FDC 5 mg/5 mg is presented as unadjusted geometric mean (gMean) and geometric coefficient of variation (gCV) (%).&#xD;
detailed sampling time points: 0:05 (hours:minutes) before drug administration and 0:02, 0:05, 0:07, 0:10, 0:20, 0:30, 0:40, 1:00, 2:00, 3:00, 4:00, 6:00, 143:45, 144:20, 311:45, 312:20, 407:45, 408:20, 431:45, 432:20, 455:45, 456:20(hours:minutes) after drug administration.</description>
          <population>PKS (evaluable cases)</population>
          <units>Picograms per millilitre [pg/mL]</units>
          <param>Geometric Mean</param>
          <dispersion>Geometric Coefficient of Variation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="12"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1.26" spread="104"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Maximum Measured Concentration of Olodaterol in Plasma at Steady State (Cmax,ss)</title>
        <description>Cmax,ss, maximum measured concentration of olodaterol in plasma at steady state of olodaterol after multiple dosing at Visit 4 (day 21) of tiotropium+olodaterol FDC 5 mg/5 mg is presented as unadjusted geometric mean (gMean) and geometric coefficient of variation (gCV) (%).</description>
        <time_frame>Day 21: 0:15 (hours:minutes) before drug administration and 0:02, 0:05, 0:07, 0:10, 0:20, 0:30, 0:40, 1:00, 2:00, 3:00, 4:00, 6:00, 12:00, 24:00 (hours:minutes) after drug administration</time_frame>
        <population>PKS (evaluable cases)</population>
        <group_list>
          <group group_id="O1">
            <title>Tiotropium+Olodaterol FDC 5 mg/5 mg</title>
            <description>Patients were administered with 2 oral inhalations once daily (AM dosing) via RESPIMAT® inhaler of 2.5 μg per actuation of Olodaterol solution</description>
          </group>
        </group_list>
        <measure>
          <title>Maximum Measured Concentration of Olodaterol in Plasma at Steady State (Cmax,ss)</title>
          <description>Cmax,ss, maximum measured concentration of olodaterol in plasma at steady state of olodaterol after multiple dosing at Visit 4 (day 21) of tiotropium+olodaterol FDC 5 mg/5 mg is presented as unadjusted geometric mean (gMean) and geometric coefficient of variation (gCV) (%).</description>
          <population>PKS (evaluable cases)</population>
          <units>Picograms per millilitre [pg/mL]</units>
          <param>Geometric Mean</param>
          <dispersion>Geometric Coefficient of Variation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="12"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2.00" spread="98.4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Pre-dose Concentration of Olodaterol in Plasma at Steady State (Cpre,ss)</title>
        <description>Cpre,ss, pre-dose concentration of olodaterol in plasma at steady state after multiple dosing at Day 21 of tiotropium+olodaterol FDC 5 mg/5 mg is presented as unadjusted geometric mean (gMean) and geometric coefficient of variation (gCV) (%).</description>
        <time_frame>Day 21: 0:15 (hours:minutes) before drug administration and 0:02, 0:05, 0:07, 0:10, 0:20, 0:30, 0:40, 1:00, 2:00, 3:00, 4:00, 6:00, 12:00, 24:00 (hours:minutes) after drug administration</time_frame>
        <population>PKS (evaluable cases)</population>
        <group_list>
          <group group_id="O1">
            <title>Tiotropium+Olodaterol FDC 5 mg/5 mg</title>
            <description>Patients were administered with 2 oral inhalations once daily (AM dosing) via RESPIMAT® inhaler of 2.5 μg per actuation of Olodaterol solution</description>
          </group>
        </group_list>
        <measure>
          <title>Pre-dose Concentration of Olodaterol in Plasma at Steady State (Cpre,ss)</title>
          <description>Cpre,ss, pre-dose concentration of olodaterol in plasma at steady state after multiple dosing at Day 21 of tiotropium+olodaterol FDC 5 mg/5 mg is presented as unadjusted geometric mean (gMean) and geometric coefficient of variation (gCV) (%).</description>
          <population>PKS (evaluable cases)</population>
          <units>Picograms per millilitre [pg/mL]</units>
          <param>Geometric Mean</param>
          <dispersion>Geometric Coefficient of Variation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="9"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.788" spread="70.7"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Area Under the Concentration Time Curve of Olodaterol in Plasma Over the Time Interval From 0 to 6 Hours at Steady State (AUC0-6,ss)</title>
        <description>AUC0-6,ss, area under the concentration time curve of olodaterol in plasma over the time interval from 0 to 6 hours at steady state after multiple dosing at Day 21 of tiotropium+olodaterol FDC 5 mg/5 mg is presented as unadjusted geometric mean (gMean) and geometric coefficient of variation (gCV) (%).</description>
        <time_frame>Day 21: 0:15 (hours:minutes) before drug administration and 0:02, 0:05, 0:07, 0:10, 0:20, 0:30, 0:40, 1:00, 2:00, 3:00, 4:00, 6:00 (hours:minutes) after drug administration</time_frame>
        <population>PKS (evaluable cases)</population>
        <group_list>
          <group group_id="O1">
            <title>Tiotropium+Olodaterol FDC 5 mg/5 mg</title>
            <description>Patients were administered with 2 oral inhalations once daily (AM dosing) via RESPIMAT® inhaler of 2.5 μg per actuation of Olodaterol solution</description>
          </group>
        </group_list>
        <measure>
          <title>Area Under the Concentration Time Curve of Olodaterol in Plasma Over the Time Interval From 0 to 6 Hours at Steady State (AUC0-6,ss)</title>
          <description>AUC0-6,ss, area under the concentration time curve of olodaterol in plasma over the time interval from 0 to 6 hours at steady state after multiple dosing at Day 21 of tiotropium+olodaterol FDC 5 mg/5 mg is presented as unadjusted geometric mean (gMean) and geometric coefficient of variation (gCV) (%).</description>
          <population>PKS (evaluable cases)</population>
          <units>Picograms*hour per millilitre [pg*h/mL]</units>
          <param>Geometric Mean</param>
          <dispersion>Geometric Coefficient of Variation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="12"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="7.54" spread="79.7"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Area Under the Concentration-time Curve of Olodaterol in Plasma at Steady State Over a Uniform Dosing Interval τ at Steady State (AUCτ,ss)</title>
        <description>AUCτ,ss, area under the concentration-time curve of olodaterol in plasma at steady state over a uniform dosing interval τ at steady state after multiple dosing at Day 21 is presented as unadjusted geometric mean (gMean) and geometric coefficient of variation (gCV) (%).</description>
        <time_frame>Day 21: 0:15 (hours:minutes) before drug administration and 0:02, 0:05, 0:07, 0:10, 0:20, 0:30, 0:40, 1:00, 2:00, 3:00, 4:00, 6:00, 12:00, 24:00 (hours:minutes) after drug administration</time_frame>
        <population>PKS (evaluable cases)</population>
        <group_list>
          <group group_id="O1">
            <title>Tiotropium+Olodaterol FDC 5 mg/5 mg</title>
            <description>Patients were administered with 2 oral inhalations once daily (AM dosing) via RESPIMAT® inhaler of 2.5 μg per actuation of Olodaterol solution</description>
          </group>
        </group_list>
        <measure>
          <title>Area Under the Concentration-time Curve of Olodaterol in Plasma at Steady State Over a Uniform Dosing Interval τ at Steady State (AUCτ,ss)</title>
          <description>AUCτ,ss, area under the concentration-time curve of olodaterol in plasma at steady state over a uniform dosing interval τ at steady state after multiple dosing at Day 21 is presented as unadjusted geometric mean (gMean) and geometric coefficient of variation (gCV) (%).</description>
          <population>PKS (evaluable cases)</population>
          <units>Picograms*hour per millilitre [pg*h/mL]</units>
          <param>Geometric Mean</param>
          <dispersion>Geometric Coefficient of Variation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="10"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="25.5" spread="64.7"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Time From Dosing to the Maximum Concentration of Olodaterol in Plasma at Steady State (Tmax,ss)</title>
        <description>Tmax,ss,time from dosing to the maximum concentration of olodaterol in plasma at steady state after multiple dosing at Day 21 of tiotropium+olodaterol FDC 5 mg/5 mg is presented as unadjusted geometric mean (gMean) and geometric coefficient of variation (gCV) (%).</description>
        <time_frame>Day 21: 0:15 (hours:minutes) before drug administration and 0:02, 0:05, 0:07, 0:10, 0:20, 0:30, 0:40, 1:00, 2:00, 3:00, 4:00, 6:00, 12:00, 24:00 (hours:minutes) after drug administration</time_frame>
        <population>PKS (evaluable cases)</population>
        <group_list>
          <group group_id="O1">
            <title>Tiotropium+Olodaterol FDC 5 mg/5 mg</title>
            <description>Patients were administered with 2 oral inhalations once daily (AM dosing) via RESPIMAT® inhaler of 2.5 μg per actuation of Olodaterol solution</description>
          </group>
        </group_list>
        <measure>
          <title>Time From Dosing to the Maximum Concentration of Olodaterol in Plasma at Steady State (Tmax,ss)</title>
          <description>Tmax,ss,time from dosing to the maximum concentration of olodaterol in plasma at steady state after multiple dosing at Day 21 of tiotropium+olodaterol FDC 5 mg/5 mg is presented as unadjusted geometric mean (gMean) and geometric coefficient of variation (gCV) (%).</description>
          <population>PKS (evaluable cases)</population>
          <units>Hour [h]</units>
          <param>Median</param>
          <dispersion>Full Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="12"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2.00" lower_limit="0.117" upper_limit="12.0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Accumulation Ratios in Plasma of Olodaterol (RA,Cmax =Cmax,ss/Cmax)</title>
        <description>Accumulation ratios in plasma of olodaterol (RA,Cmax =Cmax,ss/Cmax) after multiple dosing at Day 21 is presented as unadjusted geometric mean (gMean) and geometric coefficient of variation (gCV) (%).</description>
        <time_frame>Day 1 and Day 21</time_frame>
        <population>PKS (evaluable cases)</population>
        <group_list>
          <group group_id="O1">
            <title>Tiotropium+Olodaterol FDC 5 mg/5 mg</title>
            <description>Patients were administered with 2 oral inhalations once daily (AM dosing) via RESPIMAT® inhaler of 2.5 μg per actuation of Olodaterol solution</description>
          </group>
        </group_list>
        <measure>
          <title>Accumulation Ratios in Plasma of Olodaterol (RA,Cmax =Cmax,ss/Cmax)</title>
          <description>Accumulation ratios in plasma of olodaterol (RA,Cmax =Cmax,ss/Cmax) after multiple dosing at Day 21 is presented as unadjusted geometric mean (gMean) and geometric coefficient of variation (gCV) (%).</description>
          <population>PKS (evaluable cases)</population>
          <units>Ratio</units>
          <param>Geometric Mean</param>
          <dispersion>Geometric Coefficient of Variation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="12"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1.58" spread="97.4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Accumulation Ratios in Plasma of Olodaterol (RA,AUC =AUC0-6,ss/AUC0-6)</title>
        <description>Regarding AUC0-6 and RA,AUC0-6, the descriptive statistics of AUC0-6 could not be evaluated. Since the plasma concentrations of olodaterol and tiotropium was only quantifiable in less than two-thirds of the patients after 4 hours and 1 hour, respectively, and the descriptive statistics is calculated in case that 2/3 patients of total could be evaluated as defined in Clinical trial Protocol (CTP). And RA,AUC0-6 is the ratio of AUC0-6,ss to AUC0-6. So, the descriptive RA,AUC0-6 was not calculated either.</description>
        <time_frame>Day 1 and Day 21</time_frame>
        <population>PKS (evaluable cases)</population>
        <group_list>
          <group group_id="O1">
            <title>Tiotropium+Olodaterol FDC 5 mg/5 mg</title>
            <description>Patients were administered with 2 oral inhalations once daily (AM dosing) via RESPIMAT® inhaler of 2.5 μg per actuation of Olodaterol solution</description>
          </group>
        </group_list>
        <measure>
          <title>Accumulation Ratios in Plasma of Olodaterol (RA,AUC =AUC0-6,ss/AUC0-6)</title>
          <description>Regarding AUC0-6 and RA,AUC0-6, the descriptive statistics of AUC0-6 could not be evaluated. Since the plasma concentrations of olodaterol and tiotropium was only quantifiable in less than two-thirds of the patients after 4 hours and 1 hour, respectively, and the descriptive statistics is calculated in case that 2/3 patients of total could be evaluated as defined in Clinical trial Protocol (CTP). And RA,AUC0-6 is the ratio of AUC0-6,ss to AUC0-6. So, the descriptive RA,AUC0-6 was not calculated either.</description>
          <population>PKS (evaluable cases)</population>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="0"/>
              </count_list>
            </analyzed>
          </analyzed_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Area Under the Concentration Time Curve of Tiotropium in Plasma Over the Time Interval From 0 to 6 Hours After Drug Administration (AUC0-6)</title>
        <description>The descriptive statistics of AUC0-6 could not be evaluated. Since the plasma concentrations of olodaterol and tiotropium was only quantifiable in less than two-thirds of the patients after 4 hours and 1 hour, respectively, and the descriptive statistics is calculated in case that 2/3 patients of total could be evaluated as defined in Clinical trial Protocol (CTP).</description>
        <time_frame>Day 1</time_frame>
        <population>PKS (evaluable cases)</population>
        <group_list>
          <group group_id="O1">
            <title>Tiotropium+Olodaterol FDC 5 mg/5 mg</title>
            <description>Patients were administered with 2 oral inhalations once daily (AM dosing) via RESPIMAT® inhaler of 2.5 μg per actuation of Tiotropium solution</description>
          </group>
        </group_list>
        <measure>
          <title>Area Under the Concentration Time Curve of Tiotropium in Plasma Over the Time Interval From 0 to 6 Hours After Drug Administration (AUC0-6)</title>
          <description>The descriptive statistics of AUC0-6 could not be evaluated. Since the plasma concentrations of olodaterol and tiotropium was only quantifiable in less than two-thirds of the patients after 4 hours and 1 hour, respectively, and the descriptive statistics is calculated in case that 2/3 patients of total could be evaluated as defined in Clinical trial Protocol (CTP).</description>
          <population>PKS (evaluable cases)</population>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="0"/>
              </count_list>
            </analyzed>
          </analyzed_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Time From Dosing to the Maximum Concentration of Tiotropium in Plasma (Tmax)</title>
        <description>Tmax, time from dosing to the maximum concentration of Tiotropium in plasma after single inhaled administration of tiotropium+olodaterol FDC 5 mg/5 mgis presented as unadjusted geometric mean (gMean) and geometric coefficient of variation (gCV) (%).&#xD;
Detailed sampling time points:0:05 (hours:minutes) before drug administration and 0:02, 0:05, 0:07, 0:10, 0:20, 0:30, 0:40, 1:00, 2:00, 3:00, 4:00, 6:00, 143:45, 144:20, 311:45, 312:20, 407:45, 408:20, 431:45, 432:20, 455:45, 456:20 (hours:minutes) after drug administration</description>
        <time_frame>Day 1, 7, 14, 18, 19, 20</time_frame>
        <population>PKS (evaluable cases)</population>
        <group_list>
          <group group_id="O1">
            <title>Tiotropium+Olodaterol FDC 5 mg/5 mg</title>
            <description>Patients were administered with 2 oral inhalations once daily (AM dosing) via RESPIMAT® inhaler of 2.5 μg per actuation of Tiotropium solution</description>
          </group>
        </group_list>
        <measure>
          <title>Time From Dosing to the Maximum Concentration of Tiotropium in Plasma (Tmax)</title>
          <description>Tmax, time from dosing to the maximum concentration of Tiotropium in plasma after single inhaled administration of tiotropium+olodaterol FDC 5 mg/5 mgis presented as unadjusted geometric mean (gMean) and geometric coefficient of variation (gCV) (%).&#xD;
Detailed sampling time points:0:05 (hours:minutes) before drug administration and 0:02, 0:05, 0:07, 0:10, 0:20, 0:30, 0:40, 1:00, 2:00, 3:00, 4:00, 6:00, 143:45, 144:20, 311:45, 312:20, 407:45, 408:20, 431:45, 432:20, 455:45, 456:20 (hours:minutes) after drug administration</description>
          <population>PKS (evaluable cases)</population>
          <units>Hour [h]</units>
          <param>Median</param>
          <dispersion>Full Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="11"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.167" lower_limit="0.0330" upper_limit="2.00"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Maximum Measured Concentration of Tiotropium in Plasma (Cmax)</title>
        <description>Cmax, maximum measured concentration of Tiotropium in plasma after single inhaled administration of tiotropium+olodaterol FDC 5 mg/5 mg is presented as unadjusted geometric mean (gMean) and geometric coefficient of variation (gCV) (%).&#xD;
Detailed sampling time points:0:05 (hours:minutes) before drug administration and 0:02, 0:05, 0:07, 0:10, 0:20, 0:30, 0:40, 1:00, 2:00, 3:00, 4:00, 6:00, 143:45, 144:20, 311:45, 312:20, 407:45, 408:20, 431:45, 432:20, 455:45, 456:20 (hours:minutes) after drug administration</description>
        <time_frame>Day 1, 7, 14, 18, 19, 20</time_frame>
        <population>PKS (evaluable cases)</population>
        <group_list>
          <group group_id="O1">
            <title>Tiotropium+Olodaterol FDC 5 mg/5 mg</title>
            <description>Patients were administered with 2 oral inhalations once daily (AM dosing) via RESPIMAT® inhaler of 2.5 μg per actuation of Tiotropium solution</description>
          </group>
        </group_list>
        <measure>
          <title>Maximum Measured Concentration of Tiotropium in Plasma (Cmax)</title>
          <description>Cmax, maximum measured concentration of Tiotropium in plasma after single inhaled administration of tiotropium+olodaterol FDC 5 mg/5 mg is presented as unadjusted geometric mean (gMean) and geometric coefficient of variation (gCV) (%).&#xD;
Detailed sampling time points:0:05 (hours:minutes) before drug administration and 0:02, 0:05, 0:07, 0:10, 0:20, 0:30, 0:40, 1:00, 2:00, 3:00, 4:00, 6:00, 143:45, 144:20, 311:45, 312:20, 407:45, 408:20, 431:45, 432:20, 455:45, 456:20 (hours:minutes) after drug administration</description>
          <population>PKS (evaluable cases)</population>
          <units>Picograms per millilitre [pg/mL]</units>
          <param>Geometric Mean</param>
          <dispersion>Geometric Coefficient of Variation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="11"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="6.12" spread="83.5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Maximum Measured Concentration of Tiotropium in Plasma at Steady State (Cmax,ss)</title>
        <description>Cmax,ss, maximum measured concentration of olodaterol in plasma at steady state of Tiotropium after multiple dosing at Visit 4 of tiotropium+olodaterol FDC 5 mg/5 mg is presented as unadjusted geometric mean (gMean) and geometric coefficient of variation (gCV) (%).</description>
        <time_frame>Day 21: 0:15 (hours:minutes) before drug administration and 0:02, 0:05, 0:07, 0:10, 0:20, 0:30, 0:40, 1:00, 2:00, 3:00, 4:00, 6:00, 12:00, 24:00 (hours:minutes) after drug administration</time_frame>
        <population>PKS (evaluable cases)</population>
        <group_list>
          <group group_id="O1">
            <title>Tiotropium+Olodaterol FDC 5 mg/5 mg</title>
            <description>Patients were administered with 2 oral inhalations once daily (AM dosing) via RESPIMAT® inhaler of 2.5 μg per actuation of Tiotropium solution</description>
          </group>
        </group_list>
        <measure>
          <title>Maximum Measured Concentration of Tiotropium in Plasma at Steady State (Cmax,ss)</title>
          <description>Cmax,ss, maximum measured concentration of olodaterol in plasma at steady state of Tiotropium after multiple dosing at Visit 4 of tiotropium+olodaterol FDC 5 mg/5 mg is presented as unadjusted geometric mean (gMean) and geometric coefficient of variation (gCV) (%).</description>
          <population>PKS (evaluable cases)</population>
          <units>Picograms per millilitre [pg/mL]</units>
          <param>Geometric Mean</param>
          <dispersion>Geometric Coefficient of Variation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="12"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="7.65" spread="112"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Pre-dose Concentration of Tiotropium in Plasma at Steady State (Cpre,ss)</title>
        <description>Cpre,ss, pre-dose concentration of Tiotropium in plasma at steady state after multiple dosing at Visit 4 of tiotropium+olodaterol FDC 5 mg/5 mg is presented as unadjusted geometric mean (gMean) and geometric coefficient of variation (gCV) (%).</description>
        <time_frame>Day 21: 0:15 (hours:minutes) before drug administration and 0:02, 0:05, 0:07, 0:10, 0:20, 0:30, 0:40, 1:00, 2:00, 3:00, 4:00, 6:00, 12:00, 24:00 (hours:minutes) after drug administration</time_frame>
        <population>PKS (evaluable cases)</population>
        <group_list>
          <group group_id="O1">
            <title>Tiotropium+Olodaterol FDC 5 mg/5 mg</title>
            <description>Patients were administered with 2 oral inhalations once daily (AM dosing) via RESPIMAT® inhaler of 2.5 μg per actuation of Tiotropium solution</description>
          </group>
        </group_list>
        <measure>
          <title>Pre-dose Concentration of Tiotropium in Plasma at Steady State (Cpre,ss)</title>
          <description>Cpre,ss, pre-dose concentration of Tiotropium in plasma at steady state after multiple dosing at Visit 4 of tiotropium+olodaterol FDC 5 mg/5 mg is presented as unadjusted geometric mean (gMean) and geometric coefficient of variation (gCV) (%).</description>
          <population>PKS (evaluable cases)</population>
          <units>Picograms per millilitre [pg/mL]</units>
          <param>Geometric Mean</param>
          <dispersion>Geometric Coefficient of Variation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="8"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1.90" spread="30.6"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Area Under the Concentration Time Curve of Tiotropium in Plasma Over the Time Interval From 0 to 6 Hours at Steady State (AUC0-6,ss)</title>
        <description>AUC0-6,ss, area under the concentration time curve of Tiotropium in plasma over the time interval from 0 to 6 hours at steady state after multiple dosing at Visit 4 of tiotropium+olodaterol FDC 5 mg/5 mg is presented as unadjusted geometric mean (gMean) and geometric coefficient of variation (gCV) (%).</description>
        <time_frame>Day 21:0:15 (hours:minutes) before drug administration and 0:02, 0:05, 0:07, 0:10, 0:20, 0:30, 0:40, 1:00, 2:00, 3:00, 4:00, 6:00 (hours:minutes) after drug administration</time_frame>
        <population>PKS (evaluable cases)</population>
        <group_list>
          <group group_id="O1">
            <title>Tiotropium+Olodaterol FDC 5 mg/5 mg</title>
            <description>Patients were administered with 2 oral inhalations once daily (AM dosing) via RESPIMAT® inhaler of 2.5 μg per actuation of Tiotropium solution</description>
          </group>
        </group_list>
        <measure>
          <title>Area Under the Concentration Time Curve of Tiotropium in Plasma Over the Time Interval From 0 to 6 Hours at Steady State (AUC0-6,ss)</title>
          <description>AUC0-6,ss, area under the concentration time curve of Tiotropium in plasma over the time interval from 0 to 6 hours at steady state after multiple dosing at Visit 4 of tiotropium+olodaterol FDC 5 mg/5 mg is presented as unadjusted geometric mean (gMean) and geometric coefficient of variation (gCV) (%).</description>
          <population>PKS (evaluable cases)</population>
          <units>Picograms*hour per millilitre [pg*h/mL]</units>
          <param>Geometric Mean</param>
          <dispersion>Geometric Coefficient of Variation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="11"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="22.0" spread="75.2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Area Under the Concentration-time Curve of Tiotropium in Plasma at Steady State Over a Uniform Dosing Interval τ at Steady State (AUCτ,ss)</title>
        <description>AUCτ,ss, area under the concentration-time curve of Tiotropium in plasma at steady state over a uniform dosing interval τ at steady state after multiple dosing at Visit 4 is presented as unadjusted geometric mean (gMean) and geometric coefficient of variation (gCV) (%).</description>
        <time_frame>Day 21: 0:15 (hours:minutes) before drug administration and 0:02, 0:05, 0:07, 0:10, 0:20, 0:30, 0:40, 1:00, 2:00, 3:00, 4:00, 6:00, 12:00, 24:00 (hours:minutes) after drug administration</time_frame>
        <population>PKS (evaluable cases)</population>
        <group_list>
          <group group_id="O1">
            <title>Tiotropium+Olodaterol FDC 5 mg/5 mg</title>
            <description>Patients were administered with 2 oral inhalations once daily (AM dosing) via RESPIMAT® inhaler of 2.5 μg per actuation of Tiotropium solution</description>
          </group>
        </group_list>
        <measure>
          <title>Area Under the Concentration-time Curve of Tiotropium in Plasma at Steady State Over a Uniform Dosing Interval τ at Steady State (AUCτ,ss)</title>
          <description>AUCτ,ss, area under the concentration-time curve of Tiotropium in plasma at steady state over a uniform dosing interval τ at steady state after multiple dosing at Visit 4 is presented as unadjusted geometric mean (gMean) and geometric coefficient of variation (gCV) (%).</description>
          <population>PKS (evaluable cases)</population>
          <units>Picograms*hour per millilitre [pg*h/mL]</units>
          <param>Geometric Mean</param>
          <dispersion>Geometric Coefficient of Variation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="11"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="54.8" spread="71.8"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Time From Dosing to the Maximum Concentration of Tiotropium in Plasma at Steady State (Tmax,ss)</title>
        <description>Tmax,ss,time from dosing to the maximum concentration of Tiotropium in plasma at steady state after multiple dosing at Visit 4 of tiotropium+olodaterol FDC 5 mg/5 mg is presented as unadjusted geometric mean (gMean) and geometric coefficient of variation (gCV) (%).</description>
        <time_frame>Day 21: 0:15 (hours:minutes) before drug administration and 0:02, 0:05, 0:07, 0:10, 0:20, 0:30, 0:40, 1:00, 2:00, 3:00, 4:00, 6:00, 12:00, 24:00 (hours:minutes) after drug administration</time_frame>
        <population>PKS (evaluable cases)</population>
        <group_list>
          <group group_id="O1">
            <title>Tiotropium+Olodaterol FDC 5 mg/5 mg</title>
            <description>Patients were administered with 2 oral inhalations once daily (AM dosing) via RESPIMAT® inhaler of 2.5 μg per actuation of Tiotropium solution</description>
          </group>
        </group_list>
        <measure>
          <title>Time From Dosing to the Maximum Concentration of Tiotropium in Plasma at Steady State (Tmax,ss)</title>
          <description>Tmax,ss,time from dosing to the maximum concentration of Tiotropium in plasma at steady state after multiple dosing at Visit 4 of tiotropium+olodaterol FDC 5 mg/5 mg is presented as unadjusted geometric mean (gMean) and geometric coefficient of variation (gCV) (%).</description>
          <population>PKS (evaluable cases)</population>
          <units>Hour [h]</units>
          <param>Median</param>
          <dispersion>Full Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="12"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.0830" lower_limit="0.0330" upper_limit="2.0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Accumulation Ratios in Plasma of Tiotropium (RA,Cmax =Cmax,ss/Cmax)</title>
        <description>Accumulation ratios in plasma of Tiotropium (RA,Cmax =Cmax,ss/Cmax) after multiple dosing at Visit 4 is presented as unadjusted geometric mean (gMean) and geometric coefficient of variation (gCV) (%).</description>
        <time_frame>Day 1, 7, 14, 18, 19, 20 and 21</time_frame>
        <population>PKS (evaluable cases)</population>
        <group_list>
          <group group_id="O1">
            <title>Tiotropium+Olodaterol FDC 5 mg/5 mg</title>
            <description>Patients were administered with 2 oral inhalations once daily (AM dosing) via RESPIMAT® inhaler of 2.5 μg per actuation of Tiotropium solution</description>
          </group>
        </group_list>
        <measure>
          <title>Accumulation Ratios in Plasma of Tiotropium (RA,Cmax =Cmax,ss/Cmax)</title>
          <description>Accumulation ratios in plasma of Tiotropium (RA,Cmax =Cmax,ss/Cmax) after multiple dosing at Visit 4 is presented as unadjusted geometric mean (gMean) and geometric coefficient of variation (gCV) (%).</description>
          <population>PKS (evaluable cases)</population>
          <units>ratio</units>
          <param>Geometric Mean</param>
          <dispersion>Geometric Coefficient of Variation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="11"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1.29" spread="127"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Accumulation Ratios in Plasma of Tiotropium (RA,AUC =AUC0-6,ss/AUC0-6)</title>
        <description>Regarding AUC0-6 and RA,AUC0-6, the descriptive statistics of AUC0-6 could not be evaluated. Since the plasma concentrations of olodaterol and tiotropium was only quantifiable in less than two-thirds of the patients after 4 hours and 1 hour, respectively, and the descriptive statistics is calculated in case that 2/3 patients of total could be evaluated as defined in CTP. And RA,AUC0-6 is the ratio of AUC0-6,ss to AUC0-6. So, the descriptive RA,AUC0-6 was not calculated either.</description>
        <time_frame>Day 1 and Day 21</time_frame>
        <population>PKS (evaluable cases)</population>
        <group_list>
          <group group_id="O1">
            <title>Tiotropium+Olodaterol FDC 5 mg/5 mg</title>
            <description>Patients were administered with 2 oral inhalations once daily (AM dosing) via RESPIMAT® inhaler of 2.5 μg per actuation of Tiotropium solution</description>
          </group>
        </group_list>
        <measure>
          <title>Accumulation Ratios in Plasma of Tiotropium (RA,AUC =AUC0-6,ss/AUC0-6)</title>
          <description>Regarding AUC0-6 and RA,AUC0-6, the descriptive statistics of AUC0-6 could not be evaluated. Since the plasma concentrations of olodaterol and tiotropium was only quantifiable in less than two-thirds of the patients after 4 hours and 1 hour, respectively, and the descriptive statistics is calculated in case that 2/3 patients of total could be evaluated as defined in CTP. And RA,AUC0-6 is the ratio of AUC0-6,ss to AUC0-6. So, the descriptive RA,AUC0-6 was not calculated either.</description>
          <population>PKS (evaluable cases)</population>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="0"/>
              </count_list>
            </analyzed>
          </analyzed_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>From first drug administration through the residual effect period (REP) [[REP, defined as 21 days after last trial medication application], until individual patient's end of trial); up to 6 weeks.</time_frame>
      <desc>All treated subjects (that is, all subjects who received at least 1 dose of trial drug), were included in the safety analysis.</desc>
      <group_list>
        <group group_id="E1">
          <title>Tiotropium+Olodaterol FDC 5 mg/5 mg</title>
          <description>Patients were administered with 2 oral inhalations once daily (AM dosing) via RESPIMAT® inhaler of 2.5 μg per actuation of Olodaterol solution</description>
        </group>
      </group_list>
      <serious_events>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, all-cause mortality</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="12"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="12"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>5</frequency_threshold>
        <default_vocab>MedDRA 20.0</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="3" subjects_at_risk="12"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Abdominal pain upper</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="12"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Dizziness</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="12"/>
              </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="12"/>
              </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 Centre</name_or_title>
      <organization>Boehringer Ingelheim</organization>
      <phone>1-800-243-0127</phone>
      <email>clintriage.rdg@boehringer-ingelheim.com</email>
    </point_of_contact>
  </clinical_results>
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT02969317
org study id: 1237.30
nct id: NCT02969317
lead sponsor: 
is fda regulated drug: No
is fda regulated device: No
The primary objective of this study is to assess the pharmacokinetics of tiotropium +
      olodaterol fixed-dose combination (FDC) (5 μg/ 5 μg) delivered by the RESPIMAT inhaler after
      single dose and at steady state in Chinese patients with COPD.

      The secondary objective is to assess the safety of tiotropium + olodaterol FDC (5 μg/ 5 μg)
      delivered by the RESPIMAT inhaler after 3 weeks once daily treatment in Chinese patients with
      COPD.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Area Under the Concentration Time Curve of Olodaterol in Plasma Over the Time Interval From 0 to 6 Hours After Drug Administration (AUC0-6)
time frame: 0:05 (hours:minutes) before drug administration and 0:02, 0:05, 0:07, 0:10, 0:20, 0:30, 0:40, 1:00, 2:00, 3:00, 4:00, 6:00 (hours:minutes) after drug administration
description: The descriptive statistics of AUC0-6 could not be evaluated. Since the plasma concentrations of olodaterol and tiotropium was only quantifiable in less than two-thirds of the patients after 4 hours and 1 hour, respectively, and the descriptive statistics is calculated in case that 2/3 patients of total could be evaluated as defined in Clinical trial Protocol (CTP).
measure: Time From Dosing to the Maximum Concentration of Olodaterol in Plasma (Tmax)
time frame: Day 1, 7, 14, 18, 19 and 20
description: Tmax, time from dosing to the maximum concentration of olodaterol in plasma after single inhaled administration of tiotropium+olodaterol FDC 5 mg/5 mg is presented as unadjusted geometric mean (gMean) and geometric coefficient of variation (gCV) (%).
detailed sampling time points: 0:05 (hours:minutes) before drug administration and 0:02, 0:05, 0:07, 0:10, 0:20, 0:30, 0:40, 1:00, 2:00, 3:00, 4:00, 6:00, 143:45, 144:20, 311:45, 312:20, 407:45, 408:20, 431:45, 432:20, 455:45, 456:20(hours:minutes) after drug administration.
measure: Maximum Measured Concentration of Olodaterol in Plasma (Cmax)
time frame: Day 1, 7, 14, 18, 19 and 20
description: Cmax, maximum measured concentration of olodaterol in plasma after single inhaled administration of tiotropium+olodaterol FDC 5 mg/5 mg is presented as unadjusted geometric mean (gMean) and geometric coefficient of variation (gCV) (%).
detailed sampling time points: 0:05 (hours:minutes) before drug administration and 0:02, 0:05, 0:07, 0:10, 0:20, 0:30, 0:40, 1:00, 2:00, 3:00, 4:00, 6:00, 143:45, 144:20, 311:45, 312:20, 407:45, 408:20, 431:45, 432:20, 455:45, 456:20(hours:minutes) after drug administration.
measure: Maximum Measured Concentration of Olodaterol in Plasma at Steady State (Cmax,ss)
time frame: Day 21: 0:15 (hours:minutes) before drug administration and 0:02, 0:05, 0:07, 0:10, 0:20, 0:30, 0:40, 1:00, 2:00, 3:00, 4:00, 6:00, 12:00, 24:00 (hours:minutes) after drug administration
description: Cmax,ss, maximum measured concentration of olodaterol in plasma at steady state of olodaterol after multiple dosing at Visit 4 (day 21) of tiotropium+olodaterol FDC 5 mg/5 mg is presented as unadjusted geometric mean (gMean) and geometric coefficient of variation (gCV) (%).
measure: Pre-dose Concentration of Olodaterol in Plasma at Steady State (Cpre,ss)
time frame: Day 21: 0:15 (hours:minutes) before drug administration and 0:02, 0:05, 0:07, 0:10, 0:20, 0:30, 0:40, 1:00, 2:00, 3:00, 4:00, 6:00, 12:00, 24:00 (hours:minutes) after drug administration
description: Cpre,ss, pre-dose concentration of olodaterol in plasma at steady state after multiple dosing at Day 21 of tiotropium+olodaterol FDC 5 mg/5 mg is presented as unadjusted geometric mean (gMean) and geometric coefficient of variation (gCV) (%).
measure: Area Under the Concentration Time Curve of Olodaterol in Plasma Over the Time Interval From 0 to 6 Hours at Steady State (AUC0-6,ss)
time frame: Day 21: 0:15 (hours:minutes) before drug administration and 0:02, 0:05, 0:07, 0:10, 0:20, 0:30, 0:40, 1:00, 2:00, 3:00, 4:00, 6:00 (hours:minutes) after drug administration
description: AUC0-6,ss, area under the concentration time curve of olodaterol in plasma over the time interval from 0 to 6 hours at steady state after multiple dosing at Day 21 of tiotropium+olodaterol FDC 5 mg/5 mg is presented as unadjusted geometric mean (gMean) and geometric coefficient of variation (gCV) (%).
measure: Area Under the Concentration-time Curve of Olodaterol in Plasma at Steady State Over a Uniform Dosing Interval τ at Steady State (AUCτ,ss)
time frame: Day 21: 0:15 (hours:minutes) before drug administration and 0:02, 0:05, 0:07, 0:10, 0:20, 0:30, 0:40, 1:00, 2:00, 3:00, 4:00, 6:00, 12:00, 24:00 (hours:minutes) after drug administration
description: AUCτ,ss, area under the concentration-time curve of olodaterol in plasma at steady state over a uniform dosing interval τ at steady state after multiple dosing at Day 21 is presented as unadjusted geometric mean (gMean) and geometric coefficient of variation (gCV) (%).
measure: Time From Dosing to the Maximum Concentration of Olodaterol in Plasma at Steady State (Tmax,ss)
time frame: Day 21: 0:15 (hours:minutes) before drug administration and 0:02, 0:05, 0:07, 0:10, 0:20, 0:30, 0:40, 1:00, 2:00, 3:00, 4:00, 6:00, 12:00, 24:00 (hours:minutes) after drug administration
description: Tmax,ss,time from dosing to the maximum concentration of olodaterol in plasma at steady state after multiple dosing at Day 21 of tiotropium+olodaterol FDC 5 mg/5 mg is presented as unadjusted geometric mean (gMean) and geometric coefficient of variation (gCV) (%).
measure: Accumulation Ratios in Plasma of Olodaterol (RA,Cmax =Cmax,ss/Cmax)
time frame: Day 1 and Day 21
description: Accumulation ratios in plasma of olodaterol (RA,Cmax =Cmax,ss/Cmax) after multiple dosing at Day 21 is presented as unadjusted geometric mean (gMean) and geometric coefficient of variation (gCV) (%).
measure: Accumulation Ratios in Plasma of Olodaterol (RA,AUC =AUC0-6,ss/AUC0-6)
time frame: Day 1 and Day 21
description: Regarding AUC0-6 and RA,AUC0-6, the descriptive statistics of AUC0-6 could not be evaluated. Since the plasma concentrations of olodaterol and tiotropium was only quantifiable in less than two-thirds of the patients after 4 hours and 1 hour, respectively, and the descriptive statistics is calculated in case that 2/3 patients of total could be evaluated as defined in Clinical trial Protocol (CTP). And RA,AUC0-6 is the ratio of AUC0-6,ss to AUC0-6. So, the descriptive RA,AUC0-6 was not calculated either.
measure: Area Under the Concentration Time Curve of Tiotropium in Plasma Over the Time Interval From 0 to 6 Hours After Drug Administration (AUC0-6)
time frame: Day 1
description: The descriptive statistics of AUC0-6 could not be evaluated. Since the plasma concentrations of olodaterol and tiotropium was only quantifiable in less than two-thirds of the patients after 4 hours and 1 hour, respectively, and the descriptive statistics is calculated in case that 2/3 patients of total could be evaluated as defined in Clinical trial Protocol (CTP).
measure: Time From Dosing to the Maximum Concentration of Tiotropium in Plasma (Tmax)
time frame: Day 1, 7, 14, 18, 19, 20
description: Tmax, time from dosing to the maximum concentration of Tiotropium in plasma after single inhaled administration of tiotropium+olodaterol FDC 5 mg/5 mgis presented as unadjusted geometric mean (gMean) and geometric coefficient of variation (gCV) (%).
Detailed sampling time points:0:05 (hours:minutes) before drug administration and 0:02, 0:05, 0:07, 0:10, 0:20, 0:30, 0:40, 1:00, 2:00, 3:00, 4:00, 6:00, 143:45, 144:20, 311:45, 312:20, 407:45, 408:20, 431:45, 432:20, 455:45, 456:20 (hours:minutes) after drug administration
measure: Maximum Measured Concentration of Tiotropium in Plasma (Cmax)
time frame: Day 1, 7, 14, 18, 19, 20
description: Cmax, maximum measured concentration of Tiotropium in plasma after single inhaled administration of tiotropium+olodaterol FDC 5 mg/5 mg is presented as unadjusted geometric mean (gMean) and geometric coefficient of variation (gCV) (%).
Detailed sampling time points:0:05 (hours:minutes) before drug administration and 0:02, 0:05, 0:07, 0:10, 0:20, 0:30, 0:40, 1:00, 2:00, 3:00, 4:00, 6:00, 143:45, 144:20, 311:45, 312:20, 407:45, 408:20, 431:45, 432:20, 455:45, 456:20 (hours:minutes) after drug administration
measure: Maximum Measured Concentration of Tiotropium in Plasma at Steady State (Cmax,ss)
time frame: Day 21: 0:15 (hours:minutes) before drug administration and 0:02, 0:05, 0:07, 0:10, 0:20, 0:30, 0:40, 1:00, 2:00, 3:00, 4:00, 6:00, 12:00, 24:00 (hours:minutes) after drug administration
description: Cmax,ss, maximum measured concentration of olodaterol in plasma at steady state of Tiotropium after multiple dosing at Visit 4 of tiotropium+olodaterol FDC 5 mg/5 mg is presented as unadjusted geometric mean (gMean) and geometric coefficient of variation (gCV) (%).
measure: Pre-dose Concentration of Tiotropium in Plasma at Steady State (Cpre,ss)
time frame: Day 21: 0:15 (hours:minutes) before drug administration and 0:02, 0:05, 0:07, 0:10, 0:20, 0:30, 0:40, 1:00, 2:00, 3:00, 4:00, 6:00, 12:00, 24:00 (hours:minutes) after drug administration
description: Cpre,ss, pre-dose concentration of Tiotropium in plasma at steady state after multiple dosing at Visit 4 of tiotropium+olodaterol FDC 5 mg/5 mg is presented as unadjusted geometric mean (gMean) and geometric coefficient of variation (gCV) (%).
measure: Area Under the Concentration Time Curve of Tiotropium in Plasma Over the Time Interval From 0 to 6 Hours at Steady State (AUC0-6,ss)
time frame: Day 21:0:15 (hours:minutes) before drug administration and 0:02, 0:05, 0:07, 0:10, 0:20, 0:30, 0:40, 1:00, 2:00, 3:00, 4:00, 6:00 (hours:minutes) after drug administration
description: AUC0-6,ss, area under the concentration time curve of Tiotropium in plasma over the time interval from 0 to 6 hours at steady state after multiple dosing at Visit 4 of tiotropium+olodaterol FDC 5 mg/5 mg is presented as unadjusted geometric mean (gMean) and geometric coefficient of variation (gCV) (%).
measure: Area Under the Concentration-time Curve of Tiotropium in Plasma at Steady State Over a Uniform Dosing Interval τ at Steady State (AUCτ,ss)
time frame: Day 21: 0:15 (hours:minutes) before drug administration and 0:02, 0:05, 0:07, 0:10, 0:20, 0:30, 0:40, 1:00, 2:00, 3:00, 4:00, 6:00, 12:00, 24:00 (hours:minutes) after drug administration
description: AUCτ,ss, area under the concentration-time curve of Tiotropium in plasma at steady state over a uniform dosing interval τ at steady state after multiple dosing at Visit 4 is presented as unadjusted geometric mean (gMean) and geometric coefficient of variation (gCV) (%).
measure: Time From Dosing to the Maximum Concentration of Tiotropium in Plasma at Steady State (Tmax,ss)
time frame: Day 21: 0:15 (hours:minutes) before drug administration and 0:02, 0:05, 0:07, 0:10, 0:20, 0:30, 0:40, 1:00, 2:00, 3:00, 4:00, 6:00, 12:00, 24:00 (hours:minutes) after drug administration
description: Tmax,ss,time from dosing to the maximum concentration of Tiotropium in plasma at steady state after multiple dosing at Visit 4 of tiotropium+olodaterol FDC 5 mg/5 mg is presented as unadjusted geometric mean (gMean) and geometric coefficient of variation (gCV) (%).
measure: Accumulation Ratios in Plasma of Tiotropium (RA,Cmax =Cmax,ss/Cmax)
time frame: Day 1, 7, 14, 18, 19, 20 and 21
description: Accumulation ratios in plasma of Tiotropium (RA,Cmax =Cmax,ss/Cmax) after multiple dosing at Visit 4 is presented as unadjusted geometric mean (gMean) and geometric coefficient of variation (gCV) (%).
measure: Accumulation Ratios in Plasma of Tiotropium (RA,AUC =AUC0-6,ss/AUC0-6)
time frame: Day 1 and Day 21
description: Regarding AUC0-6 and RA,AUC0-6, the descriptive statistics of AUC0-6 could not be evaluated. Since the plasma concentrations of olodaterol and tiotropium was only quantifiable in less than two-thirds of the patients after 4 hours and 1 hour, respectively, and the descriptive statistics is calculated in case that 2/3 patients of total could be evaluated as defined in CTP. And RA,AUC0-6 is the ratio of AUC0-6,ss to AUC0-6. So, the descriptive RA,AUC0-6 was not calculated either.
arm group label: Tiotropium + olodaterol fixed-dose combination
arm group type: Experimental
description: Fixed dose combination
intervention type: Drug
intervention name: Tiotropium
description: Fixed dose combination
arm group label: Tiotropium + olodaterol fixed-dose combination
other name: INSPIOLTO, SPIOLTO, STIOLTO, VAHELVA, YANIMO
intervention type: Drug
intervention name: Olodaterol
description: Fixed dose combination
arm group label: Tiotropium + olodaterol fixed-dose combination
other name: INSPIOLTO, SPIOLTO, STIOLTO, VAHELVA, YANIMO
criteria: 
gender: All
minimum age: 40 Years
maximum age: N/A
healthy volunteers: No
last name: Boehringer Ingelheim
role: Study Chair
affiliation: Boehringer Ingelheim
facility: 
country: China
url: http://trials.boehringer-ingelheim.com/
description: Related Info
responsible party type: Sponsor
mesh term: Lung Diseases
mesh term: Pulmonary Disease, Chronic Obstructive
mesh term: Tiotropium Bromide
mesh term: Olodaterol
provided document: 
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 