<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/NCT02238119</url>
  </required_header>
  <id_info>
    <org_study_id>1184.3</org_study_id>
    <nct_id>NCT02238119</nct_id>
  </id_info>
  <brief_title>Efficacy and Safety of Free Combination of Tiotropium + Formoterol Compared to Formoterol and Tiotropium in Patients With Chronic Obstructive Pulmonary Disease (COPD)</brief_title>
  <official_title>A Randomised, Double-blind, Double-dummy, Crossover Efficacy and Safety Comparison of 6-week Treatment Periods of the Free Combination of Tiotropium Inhalation Powder Capsule (18 μg) + Formoterol Inhalation Powder Capsule (12 μg) QD, Tiotropium Inhalation Powder Capsule (18 μg) QD and Formoterol Inhalation Powder Capsule (12 μg) BID in Patients With COPD</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Boehringer Ingelheim</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Boehringer Ingelheim</source>
  <brief_summary>
    <textblock>
      Study to evaluate the lung function response to the free once-daily combination of tiotropium&#xD;
      + formoterol compared to formoterol BID and tiotropium QD&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Completed</overall_status>
  <start_date>February 2002</start_date>
  <primary_completion_date type="Actual">August 2002</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Crossover Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Double</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Change in area under the curve from pre-dose to 12 hours of the forced expiratory volume in one second (FEV1 AUC0-12h)</measure>
    <time_frame>after 6 weeks of each treatment</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>Change in FEV1 AUC0-24h</measure>
    <time_frame>after 6 weeks of each treatment</time_frame>
  </primary_outcome>
  <secondary_outcome>
    <measure>Change in FEV1 AUC12-24h</measure>
    <time_frame>after 6 weeks of each treatment</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in AUC of the forced vital capacity (FVC AUC0-12h)</measure>
    <time_frame>after 6 weeks of each treatment</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in FVC AUC0-24h</measure>
    <time_frame>after 6 weeks of each treatment</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in FVC AUC12-24h</measure>
    <time_frame>after 6 weeks of each treatment</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in peak FEV1 response</measure>
    <time_frame>after 6 weeks of each treatment</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in trough FEV1 response</measure>
    <time_frame>after 6 weeks of each treatment</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in peak FVC response</measure>
    <time_frame>after 6 weeks of each treatment</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in trough FVC response</measure>
    <time_frame>after 6 weeks of each treatment</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Individual FEV1measurements at each time point</measure>
    <time_frame>up to 6 weeks</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Individual FVCmeasurements at each time point</measure>
    <time_frame>up to 6 weeks</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Peak expiratory flow rate (PEFR)</measure>
    <time_frame>weeks 4 to 6 of each treatment period</time_frame>
    <description>measured twice daily</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of inhalations of rescue salbutamol therapy used per day</measure>
    <time_frame>weeks 4 to 6 of each treatment period</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Assessment of daytime COPD symptom score rated on a 6-point rating scale</measure>
    <time_frame>weeks 4 to 6 of each treatment period</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Assessment of nighttime COPD symptom score rated on a 5-point rating scale</measure>
    <time_frame>weeks 4 to 6 of each treatment period</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of patients with adverse events</measure>
    <time_frame>up to 23 weeks</time_frame>
  </secondary_outcome>
  <number_of_arms>3</number_of_arms>
  <enrollment type="Actual">74</enrollment>
  <condition>Pulmonary Disease, Chronic Obstructive</condition>
  <arm_group>
    <arm_group_label>tiotropium + formoterol</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
  </arm_group>
  <arm_group>
    <arm_group_label>tiotropium</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
  </arm_group>
  <arm_group>
    <arm_group_label>formoterol</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Tiotropium + formoterol combination</intervention_name>
    <arm_group_label>tiotropium + formoterol</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Tiotropium</intervention_name>
    <arm_group_label>tiotropium</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Formoterol</intervention_name>
    <arm_group_label>formoterol</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. All patients had to sign an informed consent consistent with International Conference&#xD;
             on Harmonization Good Clinical Practice (ICH-GCP) guidelines prior to participation in&#xD;
             the trial, which included medication washout and restrictions&#xD;
&#xD;
          2. All patients had to have a diagnosis of chronic obstructive pulmonary disease and had&#xD;
             to meet the following spirometric criteria:&#xD;
&#xD;
               -  Patients had to have relatively stable moderate to severe airway obstruction with&#xD;
                  an FEV1 ≤ 60% of predicted normal and FEV1 ≤ 70% of FVC (Visits 1 and 2)&#xD;
&#xD;
          3. Male or female patients 40 years of age or older&#xD;
&#xD;
          4. Patients had to be current or ex-smokers with a smoking history of more than 10&#xD;
             pack-years (Patients who had never smoked cigarettes had to be excluded)&#xD;
&#xD;
          5. Patients had to be able to perform technically acceptable pulmonary function tests and&#xD;
             had to be able to maintain records (Patient Daily Diary Record) during the study&#xD;
             period as required in the protocol&#xD;
&#xD;
          6. Patients had to be able to inhale medication in a competent manner from the&#xD;
             HandiHaler® device, the Blue Inhaler device and from a metered dose inhaler (MDI)&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Patients with significant diseases other than COPD had to be excluded. A significant&#xD;
             disease was defined as a disease which in the opinion of the investigator may either&#xD;
             put the patient at risk because of participation in the study or a disease which may&#xD;
             influence the results of the study or the patient's ability to participate in the&#xD;
             study&#xD;
&#xD;
          2. Patients with clinically relevant abnormal baseline haematology, blood chemistry, or&#xD;
             urinalysis if the abnormality defined a disease listed as an exclusion criterion&#xD;
&#xD;
          3. All patients with an serum glutamate oxaloacetate transaminase (SGOT) &gt; 80 IU/L, serum&#xD;
             glutamate pyruvate transaminase (SGPT) &gt; 80 IU/L, bilirubin &gt; 17 μmol/L or creatinine&#xD;
             &gt; 110 μmol/L (males) / 95 μmol/L (females) had to be excluded regardless of clinical&#xD;
             condition&#xD;
&#xD;
          4. Patients with a recent history (i.e., six months or less) of myocardial infarction&#xD;
&#xD;
          5. Patients with any cardiac arrhythmia requiring drug therapy or who had been&#xD;
             hospitalised for heart failure within the past three years&#xD;
&#xD;
          6. Patients with a history of cancer within the last five years. Patients with treated&#xD;
             basal cell carcinoma were allowed&#xD;
&#xD;
          7. Patients with known symptomatic prostatic hypertrophy or bladder neck obstruction.&#xD;
&#xD;
             Patients with prostatic hypertrophy controlled by medication were allowed&#xD;
&#xD;
          8. Patients with known narrow-angle glaucoma&#xD;
&#xD;
          9. Patients with a history of asthma, allergic rhinitis or who had a total blood&#xD;
             eosinophil count ≥600 mm3&#xD;
&#xD;
         10. Patients with a history of life-threatening pulmonary obstruction, or a history of&#xD;
             cystic fibrosis or clinically evident bronchiectasis&#xD;
&#xD;
         11. Patients with known active tuberculosis&#xD;
&#xD;
         12. Patients with a history of and/or active significant alcohol or drug abuse. See&#xD;
             exclusion criterion No. 1.&#xD;
&#xD;
         13. Patients who had undergone thoracotomy with pulmonary resection. Patients with a&#xD;
             history of thoracotomy for other reasons had to be evaluated as per exclusion&#xD;
             criterion No. 1&#xD;
&#xD;
         14. Patients who completed a pulmonary rehabilitation program in the six weeks prior to&#xD;
             the Screening Visit (Visit 1)&#xD;
&#xD;
         15. Patients who regularly used daytime oxygen therapy&#xD;
&#xD;
         16. Patients who had taken an investigational drug within one month or six half lives&#xD;
             (whichever is greater) prior to Screening Visit (Visit 1)&#xD;
&#xD;
         17. Patients who were treated with beta-blocker medications. Note: cardioselective beta&#xD;
             blocker eye medications (e.g. Betoptic®) for treatment of non-narrow angle glaucoma&#xD;
             were allowed&#xD;
&#xD;
         18. Patients who were treated with oral beta-adrenergics&#xD;
&#xD;
         19. Patients who were treated with cromolyn sodium or nedocromil sodium&#xD;
&#xD;
         20. Patients who were treated with antihistamines (H1 receptor antagonists),&#xD;
             antileukotrienes or leukotriene receptor antagonists for asthma or excluded allergic&#xD;
             conditions. See exclusion criterion No. 9&#xD;
&#xD;
         21. Patients using oral corticosteroid medication at unstable doses (i.e., less than six&#xD;
             weeks on a stable dose) or at doses in excess of the equivalent of 10 mg of prednisone&#xD;
             per day or 20 mg every other day&#xD;
&#xD;
         22. Patients with known hypersensitivity to anticholinergic drugs, beta-adrenergics,&#xD;
             lactose or any other components of the inhalation capsule delivery systems&#xD;
&#xD;
         23. Pregnant or nursing women or women of childbearing potential not using a medically&#xD;
             approved means of contraception for the previous 3 months (i.e. oral contraceptives,&#xD;
             intrauterine devices, diaphragm or subdermal implants e.g., Norplant®)&#xD;
&#xD;
         24. Patients with previous participation (receipt of randomised treatment) in this study&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>40 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <link>
    <url>http://trials.boehringer-ingelheim.com</url>
    <description>Related Info</description>
  </link>
  <verification_date>September 2014</verification_date>
  <study_first_submitted>September 11, 2014</study_first_submitted>
  <study_first_submitted_qc>September 11, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">September 12, 2014</study_first_posted>
  <last_update_submitted>September 11, 2014</last_update_submitted>
  <last_update_submitted_qc>September 11, 2014</last_update_submitted_qc>
  <last_update_posted type="Estimate">September 12, 2014</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Lung Diseases</mesh_term>
    <mesh_term>Pulmonary Disease, Chronic Obstructive</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Formoterol Fumarate</mesh_term>
    <mesh_term>Tiotropium Bromide</mesh_term>
  </intervention_browse>
  <!-- Results have not yet been posted for this study                                          -->
</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/NCT02238119
org study id: 1184.3
nct id: NCT02238119
lead sponsor: 
Study to evaluate the lung function response to the free once-daily combination of tiotropium
      + formoterol compared to formoterol BID and tiotropium QD
allocation: Randomized
intervention model: Crossover Assignment
primary purpose: Treatment
masking: Double
measure: Change in area under the curve from pre-dose to 12 hours of the forced expiratory volume in one second (FEV1 AUC0-12h)
time frame: after 6 weeks of each treatment
measure: Change in FEV1 AUC0-24h
time frame: after 6 weeks of each treatment
measure: Change in FEV1 AUC12-24h
time frame: after 6 weeks of each treatment
measure: Change in AUC of the forced vital capacity (FVC AUC0-12h)
time frame: after 6 weeks of each treatment
measure: Change in FVC AUC0-24h
time frame: after 6 weeks of each treatment
measure: Change in FVC AUC12-24h
time frame: after 6 weeks of each treatment
measure: Change in peak FEV1 response
time frame: after 6 weeks of each treatment
measure: Change in trough FEV1 response
time frame: after 6 weeks of each treatment
measure: Change in peak FVC response
time frame: after 6 weeks of each treatment
measure: Change in trough FVC response
time frame: after 6 weeks of each treatment
measure: Individual FEV1measurements at each time point
time frame: up to 6 weeks
measure: Individual FVCmeasurements at each time point
time frame: up to 6 weeks
measure: Peak expiratory flow rate (PEFR)
time frame: weeks 4 to 6 of each treatment period
description: measured twice daily
measure: Number of inhalations of rescue salbutamol therapy used per day
time frame: weeks 4 to 6 of each treatment period
measure: Assessment of daytime COPD symptom score rated on a 6-point rating scale
time frame: weeks 4 to 6 of each treatment period
measure: Assessment of nighttime COPD symptom score rated on a 5-point rating scale
time frame: weeks 4 to 6 of each treatment period
measure: Number of patients with adverse events
time frame: up to 23 weeks
arm group label: tiotropium + formoterol
arm group type: Experimental
arm group label: tiotropium
arm group type: Active Comparator
arm group label: formoterol
arm group type: Active Comparator
intervention type: Drug
intervention name: Tiotropium + formoterol combination
arm group label: tiotropium + formoterol
intervention type: Drug
intervention name: Tiotropium
arm group label: tiotropium
intervention type: Drug
intervention name: Formoterol
arm group label: formoterol
criteria: 
gender: All
minimum age: 40 Years
maximum age: N/A
healthy volunteers: No
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: Formoterol Fumarate
mesh term: Tiotropium Bromide