<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/NCT03275116</url>
  </required_header>
  <id_info>
    <org_study_id>59452</org_study_id>
    <nct_id>NCT03275116</nct_id>
  </id_info>
  <brief_title>The Effect of Twice Daily vs. Once Daily Bronchodilation on Hyperinflation in COPD Patients During 24 Hours.</brief_title>
  <acronym>BOTH</acronym>
  <official_title>The Effect of Twice Daily Aclidinium Bromide/Formoterol Fumarate 340/12 mcg vs. Once Daily Tiotropium 'Respimat' 5mcg on Static and Dynamic Hyperinflation in Patients With COPD During 24 Hours</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Maastricht University Medical Center</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Center for Integrated Rehabilitation and Organ Failure Horn</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>AstraZeneca</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>Maastricht University Medical Center</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      To study the effect of twice daily dual bronchodilation versus once daily single&#xD;
      bronchodilation in patients with chronic obstructive pulmonary disease on 24-hour static and&#xD;
      dynamic hyperinflation.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      To study the effect of twice daily dual bronchodilation (Aclidinium Bromide/Formoterol&#xD;
      Fumarate 340/12 mcg) versus once daily single bronchodilation (Tiotropium 'respimat' 5 mcg)&#xD;
      in patients with COPD on 24-hour static and dynamic hyperinflation, spirometry respiratory&#xD;
      symptoms and sleep quality.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Recruiting</last_known_status>
  <start_date type="Actual">July 7, 2017</start_date>
  <completion_date type="Anticipated">December 2020</completion_date>
  <primary_completion_date type="Anticipated">April 2020</primary_completion_date>
  <phase>Phase 4</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Crossover Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Static hyperinflation</measure>
    <time_frame>24 hours</time_frame>
    <description>Residual volume (RV) measured by repeated body box measurements</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Dynamic hyperinflation</measure>
    <time_frame>24 hours</time_frame>
    <description>∆ICMPT (inspiratory capacity, measured by metronome paced tachypnea)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Airway obstruction</measure>
    <time_frame>24 hours</time_frame>
    <description>Measured by FEV1 (forced expiratory capacity in 1 second) by repeated spirometry</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Forced vital capacity</measure>
    <time_frame>24 hours</time_frame>
    <description>Measured by FVC (forced vital capacity) by repeated spirometry</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Inspiratory vital capacity</measure>
    <time_frame>24 hours</time_frame>
    <description>Measured by IVC (inspiratory vital capacity) by repeated spirometry</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Momentarily symptoms of dyspnea</measure>
    <time_frame>24 hours</time_frame>
    <description>Momentarily symptoms of dyspnea during 24 hours will be measured by the BORG scale on dyspnea.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Respiratory symptoms</measure>
    <time_frame>4 days</time_frame>
    <description>Dyspnea throughout the week will be measured by the Baseline Dyspnea Index and the Transition Dyspnea Index</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Night-time awakenings due to respiratory symptoms</measure>
    <time_frame>4 days</time_frame>
    <description>Quality of sleep will be measured using night-time awakening scores, counting the night-time awakenings due to COPD symptoms (wheezing, shortness of breath and coughing). Also a VAS score for sleep quality will be used. A visual score in which patients will assign a number from 0-10 on the question: &quot;How did you sleep the last few days?&quot;. In wich 0 is &quot;couldn't be worse&quot; and 10 is &quot;couldn't be better&quot;.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Sleep quality</measure>
    <time_frame>4 days</time_frame>
    <description>A visual score in which patients will assign a number from 0-10 on the question: &quot;How did you sleep the last few days?&quot;. In wich 0 is &quot;couldn't be worse&quot; and 10 is &quot;couldn't be better&quot;.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Nighttime physical activity</measure>
    <time_frame>4 days</time_frame>
    <description>Measured by an accelerometer, as inverse surrogate for sleep quality</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">49</enrollment>
  <condition>Chronic Obstructive Airway Disease</condition>
  <arm_group>
    <arm_group_label>Twice daily dual bronchodilation</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Twice daily Aclidinium Bromide/Formoterol Fumarate 340/12 mcg during 4 days</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Once daily single bronchodilation</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Once daily Tiotropium 'Respimat' 5 mcg during 4 days</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Tiotropium 'Respimat' 5 mcg</intervention_name>
    <description>Once daily single bronchodilation</description>
    <arm_group_label>Twice daily dual bronchodilation</arm_group_label>
    <other_name>Spiriva 'Respimat'</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Aclidinium Bromide/Formoterol Fumarate 340/12 mcg</intervention_name>
    <description>Twice daily dual bronchodilation</description>
    <arm_group_label>Once daily single bronchodilation</arm_group_label>
    <other_name>Duaklir Genuair</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Male and female adults (with an equal sex ratio not exceeding 35-65%) aged ≥ 40 years&#xD;
             with written informed consent obtained prior to any study-related procedure.&#xD;
&#xD;
          2. Patients entering pulmonary rehabilitation at CIRO.&#xD;
&#xD;
          3. Patients with a diagnosis of moderate to very severe COPD at least 12 months before&#xD;
             the screening visit (A post-bronchodilator FEV1 &lt; 80% of the predicted normal value&#xD;
             and a post-bronchodilator FEV1/FVC &lt; 0.7 at least 10-15 min after 4 puffs (4 x 100 μg)&#xD;
             of salbutamol)&#xD;
&#xD;
          4. Patients with severe static hyperinflation defined as residual volume (body box) &gt; 150&#xD;
             % predicted.&#xD;
&#xD;
          5. Current smokers or ex-smokers with a smoking history of at least 10 pack years&#xD;
             [pack-years = (number of cigarettes per day x number of years)/20].&#xD;
&#xD;
          6. MMRC (modified Medical Research Council Dyspnea scale) score ≥ 2.&#xD;
&#xD;
          7. A cooperative attitude and ability to use correctly the inhalers. ICS (inhalation&#xD;
             corticosteroids) use is not an exclusion criterion for participation in the study and&#xD;
             will be continued during the study. During the study, patients receive fluticasone in&#xD;
             an equivalent dose of their own regimen.&#xD;
&#xD;
        The use of neomacrolides and/or leukotriene antagonists is not an exclusion criterion for&#xD;
        participation in the study and will be continued in the study, as long as there are no&#xD;
        changes in the regiments in the 4 weeks prior to the study. Also, the use of corticosteroid&#xD;
        maintenance therapy is allowed, provided that no changes in the regiments took place in the&#xD;
        4 weeks prior to study.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Pregnant or lactating women and all women physiologically capable of becoming pregnant&#xD;
             (i.e. women of childbearing potential)&#xD;
&#xD;
          2. Patients requiring use of the following medications:&#xD;
&#xD;
               1. A course of systemic steroids longer than 3 days for COPD exacerbation in the 4&#xD;
                  weeks prior to screening.&#xD;
&#xD;
               2. A course of antibiotics for COPD exacerbation longer than 7 days in the 4 weeks&#xD;
                  prior to screening. NB; maintenance treatment of macrolides is allowed, without&#xD;
                  any changes in the regimen in the 4 weeks prior to the study.&#xD;
&#xD;
               3. PDE4 (phosphodiesterase-4) inhibitors in the 4 weeks prior to screening.&#xD;
&#xD;
               4. Xanthines in the 4 weeks prior to screening.&#xD;
&#xD;
               5. Use of antibiotics for a lower respiratory tract infection (e.g pneumonia) in the&#xD;
                  4 weeks prior to screening.&#xD;
&#xD;
          3. COPD exacerbation requiring prescriptions of systemic corticosteroids and/or&#xD;
             antibiotics or hospitalization during the run-in period.&#xD;
&#xD;
          4. Patients treated with non-cardio selective β-blockers in the month preceding the&#xD;
             screening visit or during the run-in period. Those patients may enter the study after&#xD;
             non-selective β-blockers withdrawal and/or cardio selective β-blockers intake for at&#xD;
             least 10 days before the first study day.&#xD;
&#xD;
          5. Patients treated with long-acting antihistamines unless taken at stable regimen at&#xD;
             least 2 months prior to screening and to be maintained constant during the study, or&#xD;
             if taken as PRN (Pro Re Nata).&#xD;
&#xD;
          6. Patients requiring long term (at least 12 hours daily) oxygen therapy for chronic&#xD;
             hypoxemia.&#xD;
&#xD;
          7. Known respiratory disorders other than COPD which may impact the efficacy of the study&#xD;
             drug according the investigator's judgment. This can include but is not limited to&#xD;
             alpha-1 antitrypsin deficiency, active tuberculosis, a history of asthma, lung cancer,&#xD;
             bronchiectasis, sarcoidosis, lung fibrosis, pulmonary hypertension and interstitial&#xD;
             lung disease.&#xD;
&#xD;
          8. Previous lung surgery or endoscopic lung volume reduction interventions.&#xD;
&#xD;
          9. Patients who have clinically significant cardiovascular condition such as, but not&#xD;
             limited to, unstable ischemic heart disease, NYHA Class III/IV left ventricular&#xD;
             failure, acute ischemic heart disease in the last year prior to study screening,&#xD;
             history of sustained cardiac arrhythmias or sustained and non-sustained cardiac&#xD;
             arrhythmias diagnosed in the last 6 months (sustained means lasting more than 30&#xD;
             seconds and or ending only with external action, and or leads to hemodynamic collapse;&#xD;
             non-sustained means &gt; 3 beats &lt; 30 seconds, and or ending spontaneously, and or&#xD;
             asymptomatic), impulse conduction high degree blocks, patients with Implantable&#xD;
             Cardioverter Defribrillator (ICD).&#xD;
&#xD;
         10. Patients with atrial fibrillation (AF):&#xD;
&#xD;
               1. Paroxysmal Atrial Fibrillation&#xD;
&#xD;
               2. Persistent: AF episode either lasts longer than 7 days or requires termination by&#xD;
                  cardioversion, either with drugs or by direct current cardioversion (DCC) within&#xD;
                  6 months from screening.&#xD;
&#xD;
               3. Long standing persistent as defined by continuous atrial fibrillation diagnosed&#xD;
                  for less than 6 months with or without a rhythm control strategy.&#xD;
&#xD;
               4. Permanent: for at least 6 months with a resting ventricular rate ≥ 100/min&#xD;
                  controlled with a rate control strategy (i.e., selective β-blocker, calcium&#xD;
                  channel blocker, pacemaker placement, digoxin or ablation therapy).&#xD;
&#xD;
         11. An abnormal and clinically significant 12-lead ECG which may impact the safety of the&#xD;
             patient according to investigator's judgement. Patients whose electrocardiogram (ECG12&#xD;
             lead) shows QTcF &gt;450 ms for males or QTcF &gt;470 ms for females at screening visit are&#xD;
             not eligible (not applicable for patient with pacemaker).&#xD;
&#xD;
         12. Medical diagnosis of narrow-angle glaucoma, prostatic hypertrophy or bladder neck&#xD;
             obstruction that in the opinion of the investigator would prevent use of&#xD;
             anticholinergic agents.&#xD;
&#xD;
         13. History of hypersensitivity to anticholinergics, β2-agonist or any of the excipients&#xD;
             contained in any of the formulations used in the trial which may raise&#xD;
             contra-indications or impact the efficacy of the study drug according to the&#xD;
             investigator's judgement.&#xD;
&#xD;
         14. Clinically significant laboratory abnormalities indicating a significant or unstable&#xD;
             concomitant disease which may impact the efficacy or the safety of the study drug&#xD;
             according to investigator's judgement.&#xD;
&#xD;
         15. Patients with hypokalaemia (serum potassium levels &lt;3.5 mEq/L (or 3.5 mmol/L)) or&#xD;
             uncontrolled hyperkalaemia according to investigator's judgment.&#xD;
&#xD;
         16. Unstable concurrent disease: e.g. uncontrolled hyperthyroidism, uncontrolled diabetes&#xD;
             mellitus or other endocrine disease; significant hepatic impairment; significant renal&#xD;
             impairment; uncontrolled gastrointestinal disease (e.g. active peptic ulcer);&#xD;
             uncontrolled neurological disease; uncontrolled haematological disease; uncontrolled&#xD;
             autoimmune disorders, or other which may impact the efficacy or the safety of the&#xD;
             study drug according to investigator's judgment.&#xD;
&#xD;
         17. Patients with any history of malignancy likely to result in significant disability or&#xD;
             likely to require significant medical or surgical intervention within the next six&#xD;
             months (after V1) or with malignancy for which they are currently undergoing radiation&#xD;
             therapy or chemotherapy.&#xD;
&#xD;
         18. History of alcohol abuse and/or substance/drug abuse within 12 months prior to&#xD;
             screening visit.&#xD;
&#xD;
         19. Participation in another clinical trial where investigation drug was received less&#xD;
             than 8 weeks prior to screening visit.&#xD;
&#xD;
         20. Patients with hypercapnia (≥6.5 kPa) in the arterial blood gas. At screening visit&#xD;
             (V1), all exclusion criteria will be checked.&#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>Lowie Vanfleteren, MD, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>CIRO, centre of expertise for chronic organ failure</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Lowie Vanfleteren, MD, PhD</last_name>
    <phone>+31475587644</phone>
    <email>lowievanfleteren@ciro-horn.nl</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Maud Koopman, MD</last_name>
    <phone>+31475587653</phone>
    <email>maudkoopman@ciro-horn.nl</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>Ciro, center of expertise in chronic organ failure</name>
      <address>
        <city>Horn</city>
        <zip>6085NM</zip>
        <country>Netherlands</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Maud Koopman, MD</last_name>
      <phone>+31475587653</phone>
      <email>maudkoopman@ciro-horn.nl</email>
    </contact>
  </location>
  <location_countries>
    <country>Netherlands</country>
  </location_countries>
  <verification_date>March 2020</verification_date>
  <study_first_submitted>November 8, 2016</study_first_submitted>
  <study_first_submitted_qc>September 5, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">September 7, 2017</study_first_posted>
  <last_update_submitted>March 9, 2020</last_update_submitted>
  <last_update_submitted_qc>March 9, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">March 10, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Bronchodilation</keyword>
  <keyword>Hyperinflation</keyword>
  <keyword>Physical activity</keyword>
  <keyword>Sleep quality</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Lung Diseases, Obstructive</mesh_term>
    <mesh_term>Pulmonary Disease, Chronic Obstructive</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Bromides</mesh_term>
    <mesh_term>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/NCT03275116
org study id: 59452
nct id: NCT03275116
lead sponsor: 
collaborator: 
collaborator: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
To study the effect of twice daily dual bronchodilation versus once daily single
      bronchodilation in patients with chronic obstructive pulmonary disease on 24-hour static and
      dynamic hyperinflation.
To study the effect of twice daily dual bronchodilation (Aclidinium Bromide/Formoterol
      Fumarate 340/12 mcg) versus once daily single bronchodilation (Tiotropium 'respimat' 5 mcg)
      in patients with COPD on 24-hour static and dynamic hyperinflation, spirometry respiratory
      symptoms and sleep quality.
allocation: Randomized
intervention model: Crossover Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Static hyperinflation
time frame: 24 hours
description: Residual volume (RV) measured by repeated body box measurements
measure: Dynamic hyperinflation
time frame: 24 hours
description: ∆ICMPT (inspiratory capacity, measured by metronome paced tachypnea)
measure: Airway obstruction
time frame: 24 hours
description: Measured by FEV1 (forced expiratory capacity in 1 second) by repeated spirometry
measure: Forced vital capacity
time frame: 24 hours
description: Measured by FVC (forced vital capacity) by repeated spirometry
measure: Inspiratory vital capacity
time frame: 24 hours
description: Measured by IVC (inspiratory vital capacity) by repeated spirometry
measure: Momentarily symptoms of dyspnea
time frame: 24 hours
description: Momentarily symptoms of dyspnea during 24 hours will be measured by the BORG scale on dyspnea.
measure: Respiratory symptoms
time frame: 4 days
description: Dyspnea throughout the week will be measured by the Baseline Dyspnea Index and the Transition Dyspnea Index
measure: Night-time awakenings due to respiratory symptoms
time frame: 4 days
description: Quality of sleep will be measured using night-time awakening scores, counting the night-time awakenings due to COPD symptoms (wheezing, shortness of breath and coughing). Also a VAS score for sleep quality will be used. A visual score in which patients will assign a number from 0-10 on the question: "How did you sleep the last few days?". In wich 0 is "couldn't be worse" and 10 is "couldn't be better".
measure: Sleep quality
time frame: 4 days
description: A visual score in which patients will assign a number from 0-10 on the question: "How did you sleep the last few days?". In wich 0 is "couldn't be worse" and 10 is "couldn't be better".
measure: Nighttime physical activity
time frame: 4 days
description: Measured by an accelerometer, as inverse surrogate for sleep quality
arm group label: Twice daily dual bronchodilation
arm group type: Active Comparator
description: Twice daily Aclidinium Bromide/Formoterol Fumarate 340/12 mcg during 4 days
arm group label: Once daily single bronchodilation
arm group type: Active Comparator
description: Once daily Tiotropium 'Respimat' 5 mcg during 4 days
intervention type: Drug
intervention name: Tiotropium 'Respimat' 5 mcg
description: Once daily single bronchodilation
arm group label: Twice daily dual bronchodilation
other name: Spiriva 'Respimat'
intervention type: Drug
intervention name: Aclidinium Bromide/Formoterol Fumarate 340/12 mcg
description: Twice daily dual bronchodilation
arm group label: Once daily single bronchodilation
other name: Duaklir Genuair
criteria: 
gender: All
minimum age: 40 Years
maximum age: N/A
healthy volunteers: No
last name: Lowie Vanfleteren, MD, PhD
role: Principal Investigator
affiliation: CIRO, centre of expertise for chronic organ failure
last name: Lowie Vanfleteren, MD, PhD
phone: +31475587644
email: lowievanfleteren@ciro-horn.nl
last name: Maud Koopman, MD
phone: +31475587653
email: maudkoopman@ciro-horn.nl
facility: 
status: Recruiting
contact: 
country: Netherlands
responsible party type: Sponsor
mesh term: Lung Diseases, Obstructive
mesh term: Pulmonary Disease, Chronic Obstructive
mesh term: Bromides
mesh term: Formoterol Fumarate
mesh term: Tiotropium Bromide