<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/NCT02203474</url>
  </required_header>
  <id_info>
    <org_study_id>TBB-COPD-20009</org_study_id>
    <nct_id>NCT02203474</nct_id>
  </id_info>
  <brief_title>A Study of 3 Doses of Tiotropium Hydrofluoralkane (HFA) Breath Actuated Inhaler (BAI), in Patients With Chronic Obstructive Pulmonary Disease</brief_title>
  <official_title>A Randomized, Double-Blind, Double-Dummy, Parallel Group, Dose-Ranging Study of 3 Doses of Tiotropium Hydrofluoralkane (HFA) Breath Actuated Inhaler (BAI), Placebo HFA BAI, and Open-Label SPIRIVA® HandiHaler® (18 mcg) in Patients With Chronic Obstructive Pulmonary Disease</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Teva Branded Pharmaceutical Products R&amp;D, Inc.</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Teva Branded Pharmaceutical Products R&amp;D, Inc.</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      The primary objective of this study is to demonstrate the superiority of tiotropium&#xD;
      hydrofluoroalkane (HFA) breath actuated inhaler (BAI) to placebo HFA BAI following repeated,&#xD;
      once-daily dosing.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Withdrawn</overall_status>
  <start_date>August 2014</start_date>
  <completion_date type="Actual">August 2014</completion_date>
  <primary_completion_date type="Actual">August 2014</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>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Triple (Participant, Care Provider, Investigator)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>FEV1 AUC0-24</measure>
    <time_frame>Day 28</time_frame>
  </primary_outcome>
  <secondary_outcome>
    <measure>FEV1 (AUC0-24)</measure>
    <time_frame>Day 1</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Trough FEV1</measure>
    <time_frame>Day 2</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Percentage of patients with a COPD exacerbation</measure>
    <time_frame>28 Days</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Percentage of Patients with Adverse Events</measure>
    <time_frame>28 Days</time_frame>
  </secondary_outcome>
  <number_of_arms>5</number_of_arms>
  <enrollment type="Actual">0</enrollment>
  <condition>Chronic Obstructive Pulmonary Disease</condition>
  <condition>COPD</condition>
  <arm_group>
    <arm_group_label>Tiotropium HFA BAI 5 mcg</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>1 inhalation from each of 3 inhalers containing either Tiotropium HFA BAI 5 mcg or placebo daily</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Tiotropium HFA BAI 10 mcg</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>1 inhalation from each of 3 inhalers containing either Tiotropium HFA BAI 5 mcg or placebo daily</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Tiotropium HFA BAI 15 mcg</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>1 inhalation from each of 3 inhalers containing either Tiotropium HFA BAI 5 mcg or placebo daily</description>
  </arm_group>
  <arm_group>
    <arm_group_label>SPIRIVA HandiHaler</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>2 inhalations from one 18 mcg capsule daily</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>1 inhalation from each of 3 inhalers containing either Tiotropium HFA BAI 5 mcg or placebo daily</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Tiotropium HFA BAI 5 mcg</intervention_name>
    <arm_group_label>Tiotropium HFA BAI 10 mcg</arm_group_label>
    <arm_group_label>Tiotropium HFA BAI 15 mcg</arm_group_label>
    <arm_group_label>Tiotropium HFA BAI 5 mcg</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Tiotropium 18 mcg Capsule</intervention_name>
    <arm_group_label>SPIRIVA HandiHaler</arm_group_label>
    <other_name>SPIRIVA HandiHaler</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>Placebo</description>
    <arm_group_label>Placebo</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Male or female patients 40 to 80 years of age, as of the screening visit (SV), who&#xD;
             have signed an informed consent prior to initiation of any study related procedures.&#xD;
&#xD;
          2. Diagnosis of COPD as defined by the Global Initiative for Chronic Obstructive Lung&#xD;
             Disease (GOLD) guidelines.&#xD;
&#xD;
          3. A measured post-bronchodilator (albuterol 360 mcg) forced expiratory volume in 1&#xD;
             second (FEV1) ≥30% and &lt;80% of predicted normal at the SV. Predicted normal will be&#xD;
             determined using National Health and Nutrition Examination Survey (NHANES) III&#xD;
             standard values for Caucasians, African Americans and Mexican-Americans with&#xD;
             adjustments to predicted values made for Asian American patients.&#xD;
&#xD;
          4. A measured post-bronchodilator (albuterol 360 mcg) FEV1/forced vital capacity (FVC)&#xD;
             &lt;0.70 at the SV.&#xD;
&#xD;
          5. A minimum body weight of 40 kg. (Note: For patients participating in the&#xD;
             pharmacokinetic [PK] sub study a minimum body weight of 50 kg is required.)&#xD;
&#xD;
          6. If female, is currently not pregnant, breast feeding, or attempting to become pregnant&#xD;
             (for 4 weeks before the SV and throughout the duration of the study), and is of&#xD;
             non-childbearing potential, defined as:&#xD;
&#xD;
               -  ≥1 year post-menopausal (6 months of spontaneous amenorrhea is permitted,&#xD;
                  provided there is a local record of serum follicle stimulating hormone &gt;40 mIU/mL&#xD;
                  and this is source documented) or&#xD;
&#xD;
               -  Surgically sterile (bilateral tubal ligation, bilateral oophorectomy,&#xD;
                  salpingectomy, or hysterectomy)&#xD;
&#xD;
             Or is of childbearing potential, has a negative serum pregnancy test, and is willing&#xD;
             to commit to using a consistent and acceptable method of birth control, as defined&#xD;
             below, for the duration of the study:&#xD;
&#xD;
               -  Systemic contraception used for ≥1 month prior to screening, including birth&#xD;
                  control pills, transdermal patch, vaginal ring, implants, or injectables or&#xD;
&#xD;
               -  Double barrier methods (spermicide with any of the following: condoms, cervical&#xD;
                  cap, diaphragm, and vaginal contraceptive film) or&#xD;
&#xD;
               -  Intrauterine device (IUD) with a low failure rate defined as &lt;1% per year (use of&#xD;
                  copper IUDs is not acceptable) Or is of childbearing potential and is not&#xD;
                  sexually active, has a negative serum pregnancy test, and, in the event the&#xD;
                  patient becomes sexually active, is willing to commit to using a consistent and&#xD;
                  acceptable method of birth control, as defined above, for the duration of the&#xD;
                  study. At the discretion of the investigator, total abstinence is acceptable in&#xD;
                  cases where the age, career (eg, priest), lifestyle, and/or sexual orientation of&#xD;
                  the patient ensures compliance.&#xD;
&#xD;
          7. Current or ex-smoker with ≥10 pack-year smoking history (number of cigarette packs&#xD;
             smoked per day multiplied by the number of years smoked; eg, 2 packs/day for 3 years&#xD;
             equals a 6 pack-year history).&#xD;
&#xD;
          8. Patient is free of any other medical conditions or concomitant treatment that could&#xD;
             interfere with study conduct, influence the interpretation of study&#xD;
             observations/results, or put the patient at increased risk during the study.&#xD;
&#xD;
          9. Able to perform technically acceptable and reproducible spirometry per American&#xD;
             Thoracic Society/European Respiratory Society (ATS/ERS) 2005 guidelines and study&#xD;
             guidelines, as defined in the protocol and study reference manual; this includes able&#xD;
             to tolerate withdrawal of applicable medications during required spirometry&#xD;
             assessments.&#xD;
&#xD;
         10. Able to perform acceptable peak expiratory flow measurements.&#xD;
&#xD;
         11. Able to maintain records (patient daily diary) during the study period as required by&#xD;
             the protocol.&#xD;
&#xD;
         12. Able to demonstrate the proper inhalation techniques required for correct use of all&#xD;
             delivery devices (BAI and dry powder inhaler [DPI]) required in the study.&#xD;
&#xD;
         13. Capable of understanding the requirements, risks, and benefits of study participation,&#xD;
             and, as judged by the investigator, capable of giving informed consent and being&#xD;
             compliant with all study requirements.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
        Chronic Obstructive Pulmonary Disease&#xD;
&#xD;
          1. Pregnancy, nursing, or plans to become pregnant or donate gametes (ova or sperm) for&#xD;
             in vitro fertilization during the study period or for 30 days following the patient's&#xD;
             last study related visit (for eligible patients only, if applicable).&#xD;
&#xD;
          2. Current evidence of a clinically significant or uncontrolled disease including, but&#xD;
             not limited to: cardiovascular (eg, uncontrolled hypertension, congestive heart&#xD;
             failure, known aortic aneurysm, clinically significant cardiac arrhythmia or coronary&#xD;
             heart disease), hepatic, renal, hematological, neuropsychological, endocrine (eg,&#xD;
             uncontrolled diabetes mellitus, uncontrolled thyroid disorder, Addison's disease,&#xD;
             Cushing's syndrome), gastrointestinal (eg, poorly controlled peptic ulcer,&#xD;
             gastroesophageal reflux disease), or pulmonary (other than COPD such as asthma,&#xD;
             sarcoidosis, non cystic fibrosis bronchiectasis, cystic fibrosis, bronchopulmonary&#xD;
             dysplasia or a diagnosis of alpha 1 antitrypsin deficiency). Significant is defined as&#xD;
             any disease that, in the opinion of the investigator, would put the safety of the&#xD;
             patient at risk through participation, or which could affect the endpoint analysis if&#xD;
             the disease/condition worsened during the study.&#xD;
&#xD;
          3. History of and/or current diagnosis of asthma.&#xD;
&#xD;
          4. History of a life-threatening COPD exacerbation - defined for this protocol as a COPD&#xD;
             episode that required intubation or was associated with respiratory arrest.&#xD;
&#xD;
          5. Thoracotomy with pulmonary resection.&#xD;
&#xD;
          6. Current congestive heart failure, history or current evidence of myocardial infarction&#xD;
             (within 1 year of the SV), or current history of active ischemic heart disease&#xD;
             (exertional or intermittent angina).&#xD;
&#xD;
          7. History or current evidence of clinically significant cardiac arrhythmia or&#xD;
             abnormality, including a diagnosis on screening ECG. Findings that are always&#xD;
             considered clinically significant and will exclude the patient from study&#xD;
             participation include, but are not limited to, the following:&#xD;
&#xD;
               -  ventricular rate &lt;45 beats per minute (bpm) or &gt;100 bpm&#xD;
&#xD;
               -  PR interval &gt;240 msec&#xD;
&#xD;
               -  evidence of 2nd- or 3rd-degree atrioventricular block (excluding MobitzI)&#xD;
&#xD;
               -  evidence of supraventricular or ventricular ectopy or arrhythmias&#xD;
&#xD;
               -  corrected QT interval (QTc) (Bazett's or Fridericia's method) &gt;500 msec&#xD;
&#xD;
               -  nonspecific intraventricular conduction delay &gt;120 msec&#xD;
&#xD;
               -  ST-T wave abnormalities (excluding nonspecific ST-T wave abnormalities)&#xD;
                  indicative of acute ischemia/infarction&#xD;
&#xD;
               -  right or left complete bundle branch block&#xD;
&#xD;
               -  artificial pacemaker&#xD;
&#xD;
          8. The patient has a medical condition that may potentially be aggravated by an&#xD;
             anticholinergic drug such as tiotropium, eg:&#xD;
&#xD;
               -  The patient has a history or presence of glaucoma (particularly angle-closure&#xD;
                  glaucoma)&#xD;
&#xD;
               -  The patient has symptomatic prostatic hyperplasia.&#xD;
&#xD;
               -  The patient has a known history or any current evidence of renal impairment or&#xD;
                  urinary retention (eg, bladder outlet obstruction). This includes abnormal renal&#xD;
                  function test results at screening.&#xD;
&#xD;
          9. History of malignancy (excluding treated non-melanoma skin cancers) within the past 5&#xD;
             years, regardless of the clinical significance or current stability of the disease.&#xD;
&#xD;
         10. History of silent (or active) infections, including positive tests for human&#xD;
             immunodeficiency virus (HIV) 1, HIV2, hepatitis B, hepatitis C, or tuberculosis.&#xD;
&#xD;
         11. Occurrence of any upper or lower respiratory infection, including but not limited to&#xD;
             the common cold and flu, sinusitis, tonsillitis, pneumonia, bronchitis, or an ear&#xD;
             infection (including otitis media and externa) which is not resolved by 4 weeks or&#xD;
             more prior to the SV/informed consent.&#xD;
&#xD;
         12. Occurrence of a COPD exacerbation which is not resolved by 4 weeks or more prior to&#xD;
             the SV/informed consent.&#xD;
&#xD;
             • Note: An exacerbation of COPD is defined as any worsening of the patient's baseline&#xD;
             COPD symptoms requiring any treatment beyond study medication, rescue albuterol or the&#xD;
             patient's regular maintenance treatment. This includes requiring the use of systemic&#xD;
             corticosteroids, antibiotics and/or emergency room visit or hospitalization.&#xD;
&#xD;
         13. Patients who require regular use of daytime oxygen therapy.&#xD;
&#xD;
         14. Patients who have started or stopped an exercise rehabilitation program within 4 weeks&#xD;
             of the SV.&#xD;
&#xD;
         15. Known or suspected hypersensitivity or idiosyncratic reaction to tiotropium, or to any&#xD;
             ingredients used in the study medication formulations.&#xD;
&#xD;
         16. Severe allergy to milk protein.&#xD;
&#xD;
         17. Significant adverse drug reactions, including allergy or hypersensitivity reactions,&#xD;
             to atropine or any anticholinergic substance related pharmacologically to atropine&#xD;
             (eg, ipratropium or oxitropium).&#xD;
&#xD;
         18. Use of any prohibited concomitant medications within the required (per protocol)&#xD;
             washout periods prior to the SV.&#xD;
&#xD;
         19. Treatment with orally administered (excluding orally inhaled) β-adrenergic agonists&#xD;
             (ie, oral albuterol).&#xD;
&#xD;
         20. Recent initiation of treatment or dose titration with β-adrenergic receptor&#xD;
             antagonists (eg, non-selective β-receptor blocking agents such as β-blocking&#xD;
             anti-hypertensive products) administered by any route. Permitted exceptions are: (1)&#xD;
             Patients treated on a stable dose of non-selective β-receptor blocking agents for 3&#xD;
             months prior to SV or longer may be considered for enrollment if expected to maintain&#xD;
             the same dose throughout the study and (2) Patients on a stable dose of&#xD;
             cardioselective β1 adrenergic receptor antagonists (eg, atenolol, metaprolol,&#xD;
             bisoprolol) for at least 1 week prior to the SV are permitted if expected to maintain&#xD;
             the same dose throughout the study.&#xD;
&#xD;
         21. Treatment with drugs commonly recognized to prolong the QTc interval (eg, quinolones,&#xD;
             amiodarone, disopyramide, quinidine, sotalol, chlorpromazine, haloperidol,&#xD;
             ketoconazole, terfenadine, cisapride, and terodiline).&#xD;
&#xD;
         22. Treatment with strong cytochrome P450 (CYP) 2D6 or CYP3A4 inducers or inhibitors (eg,&#xD;
             quinidine, ketoconazole and gestodene) within 30 days prior to the SV.&#xD;
&#xD;
         23. For patients using an inhaled corticosteroid, initiation or change in the dose of&#xD;
             inhaled corticosteroids within the last 30 days prior to the SV, and/or the patient is&#xD;
             not expected to maintain a stable dose of inhaled corticosteroids during the course of&#xD;
             the study.&#xD;
&#xD;
         24. For patients using maintenance oral corticosteroids for COPD, the average daily dose&#xD;
             should not be greater than10 mg of prednisone equivalent per day and the dose should&#xD;
             have been stable over the 6 weeks prior to the SV. The patient's prior oral&#xD;
             corticosteroid (OCS) dose should be maintained without change during the study. (Note&#xD;
             that oral steroid bursts completed 6 weeks or more prior to screening are acceptable.)&#xD;
&#xD;
         25. Exposure to any investigational drug within 30 days or 6 half-lives (whichever is&#xD;
             longer) prior to the SV.&#xD;
&#xD;
         26. Has a history of alcohol and/or substance abuse within the past 5 years. aa.&#xD;
             Vulnerable patients (eg, persons kept in detention). bb. The patient is an employee of&#xD;
             the study site or has an immediate family member or household member involved with the&#xD;
             conduct of the study (including participation in the study).&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>40 Years</minimum_age>
    <maximum_age>80 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Teva Medical Expert, MD</last_name>
    <role>Study Director</role>
    <affiliation>Teva Branded Pharmaceutical Products R&amp;D, Inc.</affiliation>
  </overall_official>
  <verification_date>November 2021</verification_date>
  <study_first_submitted>July 28, 2014</study_first_submitted>
  <study_first_submitted_qc>July 28, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">July 30, 2014</study_first_posted>
  <last_update_submitted>November 5, 2021</last_update_submitted>
  <last_update_submitted_qc>November 5, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">November 9, 2021</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>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>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/NCT02203474
org study id: TBB-COPD-20009
nct id: NCT02203474
lead sponsor: 
has dmc: No
The primary objective of this study is to demonstrate the superiority of tiotropium
      hydrofluoroalkane (HFA) breath actuated inhaler (BAI) to placebo HFA BAI following repeated,
      once-daily dosing.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Triple (Participant, Care Provider, Investigator)
measure: FEV1 AUC0-24
time frame: Day 28
measure: FEV1 (AUC0-24)
time frame: Day 1
measure: Trough FEV1
time frame: Day 2
measure: Percentage of patients with a COPD exacerbation
time frame: 28 Days
measure: Percentage of Patients with Adverse Events
time frame: 28 Days
arm group label: Tiotropium HFA BAI 5 mcg
arm group type: Experimental
description: 1 inhalation from each of 3 inhalers containing either Tiotropium HFA BAI 5 mcg or placebo daily
arm group label: Tiotropium HFA BAI 10 mcg
arm group type: Experimental
description: 1 inhalation from each of 3 inhalers containing either Tiotropium HFA BAI 5 mcg or placebo daily
arm group label: Tiotropium HFA BAI 15 mcg
arm group type: Experimental
description: 1 inhalation from each of 3 inhalers containing either Tiotropium HFA BAI 5 mcg or placebo daily
arm group label: SPIRIVA HandiHaler
arm group type: Active Comparator
description: 2 inhalations from one 18 mcg capsule daily
arm group label: Placebo
arm group type: Placebo Comparator
description: 1 inhalation from each of 3 inhalers containing either Tiotropium HFA BAI 5 mcg or placebo daily
intervention type: Drug
intervention name: Tiotropium HFA BAI 5 mcg
arm group label: Tiotropium HFA BAI 10 mcg
arm group label: Tiotropium HFA BAI 15 mcg
arm group label: Tiotropium HFA BAI 5 mcg
intervention type: Drug
intervention name: Tiotropium 18 mcg Capsule
arm group label: SPIRIVA HandiHaler
other name: SPIRIVA HandiHaler
intervention type: Drug
intervention name: Placebo
description: Placebo
arm group label: Placebo
criteria: 
gender: All
minimum age: 40 Years
maximum age: 80 Years
healthy volunteers: No
last name: Teva Medical Expert, MD
role: Study Director
affiliation: Teva Branded Pharmaceutical Products R&D, Inc.
responsible party type: Sponsor
mesh term: Lung Diseases
mesh term: Lung Diseases, Obstructive
mesh term: Pulmonary Disease, Chronic Obstructive
mesh term: Tiotropium Bromide