<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/NCT03028142</url>
  </required_header>
  <id_info>
    <org_study_id>RPL554-CO-202</org_study_id>
    <nct_id>NCT03028142</nct_id>
  </id_info>
  <brief_title>The Effects of RPL554 in Addition to Tiotropium in COPD Patients</brief_title>
  <sponsors>
    <lead_sponsor>
      <agency>Verona Pharma plc</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Verona Pharma plc</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      This is a phase II, randomised, double blind, placebo controlled, complete block, three way&#xD;
      crossover study to investigate treatment with nebulised RPL554 and tiotropium together in&#xD;
      patients with moderate to severe chronic obstructive pulmonary disease (COPD). The purpose of&#xD;
      this study is to assess the bronchodilator effect (opening of the airways) of RPL554 when&#xD;
      used in combination with a long acting anti-muscarinic receptor antagonist (tiotropium)&#xD;
      whilst dosing the RPL554 to steady state blood levels. It is planned to randomise up to 30&#xD;
      patients to have 24 evaluable patients at one study centre. In each treatment period,&#xD;
      patients will receive an open label dose of tiotropium from a dry power inhaler (DPI)&#xD;
      followed immediately by a double blind dose of either RPL554 6mg, 1.5mg or placebo (depending&#xD;
      on treatment sequence) from a nebuliser in the morning on Day 1, Day 2 and Day 3. The dose of&#xD;
      RPL554 or placebo will be repeated in the evening on Day 1 and Day 2; there will not be an&#xD;
      evening dose on Day 3.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Completed</overall_status>
  <start_date>January 2017</start_date>
  <completion_date type="Actual">August 2017</completion_date>
  <primary_completion_date type="Actual">August 2017</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>Triple (Participant, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Peak Forced Expired Volume in 1 Second (FEV1) on the Third Day of Dosing</measure>
    <time_frame>Day 3</time_frame>
    <description>Peak forced expired volume in 1 second (FEV1) over 4 hours on the third day of dosing</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Average FEV1 Over 12 Hours on the Third Day of Dosing</measure>
    <time_frame>Day 3</time_frame>
    <description>Average FEV1 area under the curve (AUC) over 12 hours on the third day of dosing</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Peak FEV1 on Day 1</measure>
    <time_frame>Day 1</time_frame>
    <description>Peak FEV1 over 4 hours on Day 1</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Average FEV1 Over 12 Hours on Day 1</measure>
    <time_frame>Day 1</time_frame>
    <description>Average FEV1 AUC over 12 hours on Day 1</description>
  </secondary_outcome>
  <number_of_arms>3</number_of_arms>
  <enrollment type="Actual">30</enrollment>
  <condition>Chronic Obstructive Pulmonary Disease Moderate</condition>
  <arm_group>
    <arm_group_label>Lower Dose Nebulised Treatment</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>1.5 mg nebulised RPL554 twice daily plus 10 mcg tiotropium DPI once daily for 3 days</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Higher Dose Nebulised Treatment</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>6 mg nebulised RPL554 twice daily plus 10 mcg tiotropium DPI once daily for 3 days</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Nebulised RPL554 matched placebo twice daily plus 10 mcg tiotropium DPI once daily for 3 days</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>1.5 mg RPL554 plus tiotropium</intervention_name>
    <arm_group_label>Lower Dose Nebulised Treatment</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>6 mg RPL554 plus tiotropium</intervention_name>
    <arm_group_label>Higher Dose Nebulised Treatment</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo plus tiotropium</intervention_name>
    <arm_group_label>Placebo</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Sign an informed consent document indicating they understand the purpose of and&#xD;
             procedures required for the study and are willing to participate in the study.&#xD;
&#xD;
          2. Male or female aged between 40 and 75 years inclusive, at the time of informed&#xD;
             consent.&#xD;
&#xD;
          3. If male: must agree to meet the following from the first dose up to 1 month after the&#xD;
             last dose of study treatment:&#xD;
&#xD;
               -  Not donate sperm&#xD;
&#xD;
               -  Either: be sexually abstinent in accordance with a patient's usual and preferred&#xD;
                  lifestyle (but agree to abide by the contraception requirements below should&#xD;
                  their circumstances change) Or: use a condom with all sexual partners. If the&#xD;
                  partner is of childbearing potential the condom must be used with spermicide and&#xD;
                  a second highly effective form of contraception must also be used&#xD;
&#xD;
          4. If female: either be:&#xD;
&#xD;
               1. Of non-childbearing potential defined as being:&#xD;
&#xD;
                    -  Either: post-menopausal (being spontaneously amenorrhoeic for at least 1&#xD;
                       year with an appropriate clinical profile [e.g. age appropriate, history of&#xD;
                       vasomotor symptoms]&#xD;
&#xD;
                    -  Or: permanently sterilised e.g. tubal occlusion, hysterectomy, bilateral&#xD;
                       oophorectomy, bilateral salpingectomy&#xD;
&#xD;
               2. Of childbearing potential and agreeing to use a highly effective method of&#xD;
                  contraception until completion of the end of study visit.&#xD;
&#xD;
          5. Have a 12-lead ECG recording at screening and randomisation (pre-dose in Treatment&#xD;
             Period 1) showing the following:&#xD;
&#xD;
               -  Heart rate between 45 and 90 beats per minute (bpm)&#xD;
&#xD;
               -  QT interval corrected for heart rate using Fridericia's formula (QTcF) ≤450 msec&#xD;
                  for males and ≤470 ms for females&#xD;
&#xD;
               -  QRS interval ≤120 msec&#xD;
&#xD;
               -  No clinically significant abnormalities (as judged by the Investigator) including&#xD;
                  morphology (e.g. left bundle branch block, atrio-ventricular nodal dysfunction,&#xD;
                  ST segment abnormalities)&#xD;
&#xD;
          6. Have a screening Holter report with a minimum of 18 hours recording that is able to be&#xD;
             evaluated for rhythm analysis which shows no abnormality which indicates a significant&#xD;
             impairment of patient safety or which may significantly impairs interpretation in the&#xD;
             opinion of the Investigator including:&#xD;
&#xD;
               -  Significant arrhythmias including atrial flutter, atrial fibrillation,&#xD;
                  ventricular tachycardia&#xD;
&#xD;
               -  Any symptomatic arrhythmia (except isolated extra systoles)&#xD;
&#xD;
               -  Any sustained second or third degree heart block&#xD;
&#xD;
          7. Capable of complying with all study restrictions and procedures including ability to&#xD;
             use the study nebuliser and HandiHaler® DPI correctly.&#xD;
&#xD;
          8. Body mass index (BMI) between 18 and 33 kg/m2 (inclusive) with a minimum weight of 45&#xD;
             kg.&#xD;
&#xD;
          9. COPD diagnosis: Patients with a diagnosis of COPD as defined by the American Thoracic&#xD;
             Society (ATS)/European Respiratory Society (ERS) guidelines (Celli and MacNee, 2004)&#xD;
             with symptoms compatible with COPD for at least 1 year prior to screening.&#xD;
&#xD;
         10. Post-bronchodilator (four puffs of salbutamol) spirometry at screening:&#xD;
&#xD;
               -  Post-bronchodilator forced expiratory volume in 1 second (FEV1)/forced vital&#xD;
                  capacity (FVC) ratio of ≤0.70&#xD;
&#xD;
               -  Post-bronchodilator FEV1 ≥40 % and ≤80% of predicted normal&#xD;
&#xD;
               -  Demonstrates ≥150 mL increase from pre-bronchodilator FEV1&#xD;
&#xD;
         11. Clinically stable COPD in the 4 weeks prior to screening and randomisation (pre-dose&#xD;
             in Treatment Period 1).&#xD;
&#xD;
         12. A chest X-ray (post-anterior) at screening, or in the 12 months prior to screening&#xD;
             showing no abnormalities, which are both clinically significant and unrelated to COPD.&#xD;
&#xD;
         13. Meet the concomitant medication restrictions and be expected to do so for the rest of&#xD;
             the study.&#xD;
&#xD;
         14. Smoking history of ≥10 pack years.&#xD;
&#xD;
         15. Capable of withdrawing from long acting bronchodilators for the duration of the study,&#xD;
             and short acting bronchodilators for 8 hours prior to spirometry.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. A history of life-threatening COPD exacerbation including Intensive Care Unit&#xD;
             admission and/or requiring intubation.&#xD;
&#xD;
          2. COPD exacerbation requiring oral steroids, or lower respiratory tract infection&#xD;
             requiring antibiotics, in the 3 months prior to screening or randomisation (pre-dose&#xD;
             in Treatment Period 1).&#xD;
&#xD;
          3. A history of one or more hospitalisations for COPD in the 12 months prior to screening&#xD;
             or randomisation (pre-dose in Treatment Period 1).&#xD;
&#xD;
          4. Lactation (female patients only).&#xD;
&#xD;
          5. Positive urine or serum pregnancy test at screening, or a positive urine pregnancy&#xD;
             test prior to randomisation (female patients of childbearing potential only).&#xD;
&#xD;
          6. Prior exposure to RPL554 or known hypersensitivity to RPL554 or its components.&#xD;
&#xD;
          7. Intolerance or hypersensitivity to tiotropium.&#xD;
&#xD;
          8. Evidence of cor pulmonale.&#xD;
&#xD;
          9. Other respiratory disorders: Patients with a current diagnosis of asthma, active&#xD;
             tuberculosis, lung cancer, bronchiectasis, sarcoidosis, lung fibrosis, interstitial&#xD;
             lung diseases, sleep apnoea, known alpha-1 antitrypsin deficiency or other active&#xD;
             pulmonary diseases.&#xD;
&#xD;
         10. Previous lung resection or lung reduction surgery.&#xD;
&#xD;
         11. Use of oral COPD medications (e.g. oral steroids, theophylline and romifulast) in the&#xD;
             3 months prior to screening or randomisation (pre-dose in Treatment Period 1).&#xD;
&#xD;
         12. History of, or reason to believe, a patient has drug or alcohol abuse within the past&#xD;
             3 years.&#xD;
&#xD;
         13. Inability to perform technically acceptable spirometry or whole body plethysmography&#xD;
             (at screening or randomisation [pre dose in Treatment Period 1])&#xD;
&#xD;
         14. Received an experimental drug within 30 days or five half lives, whichever is longer.&#xD;
&#xD;
         15. Patients with a history of chronic uncontrolled disease including, but not limited to,&#xD;
             endocrine, active hyperthyroidism, neurological, hepatic, gastrointestinal, renal,&#xD;
             haematological, urological, immunological, or ophthalmic diseases that the&#xD;
             Investigator believes are clinically significant.&#xD;
&#xD;
         16. Documented cardiovascular disease: arrhythmias, angina, recent or suspected myocardial&#xD;
             infarction, congestive heart failure, a history of unstable, or uncontrolled&#xD;
             hypertension, or has been diagnosed with hypertension in the 3 months prior to&#xD;
             screening or randomisation.&#xD;
&#xD;
         17. Concurrent use of non-cardioselective oral beta-blockers.&#xD;
&#xD;
         18. Has had major surgery, (requiring general anaesthesia) in the 6 weeks prior to&#xD;
             screening or randomisation (pre-dose in Treatment Period 1), or will not have fully&#xD;
             recovered from surgery, or planned surgery through the end of the study.&#xD;
&#xD;
         19. A disclosed history or one known to the Investigator, of significant non compliance in&#xD;
             previous investigational studies or with prescribed medications.&#xD;
&#xD;
         20. Requires oxygen therapy, even on an occasional basis.&#xD;
&#xD;
         21. Clinically significant prostatic hyperplasia (judged by the Investigator) or&#xD;
             bladder-neck obstruction or with narrow-angle glaucoma.&#xD;
&#xD;
         22. Any other reason that the Investigator considers makes the patient unsuitable to&#xD;
             participate.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>40 Years</minimum_age>
    <maximum_age>75 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <verification_date>January 2019</verification_date>
  <study_first_submitted>January 3, 2017</study_first_submitted>
  <study_first_submitted_qc>January 18, 2017</study_first_submitted_qc>
  <study_first_posted type="Estimate">January 23, 2017</study_first_posted>
  <results_first_submitted>January 1, 2019</results_first_submitted>
  <results_first_submitted_qc>January 1, 2019</results_first_submitted_qc>
  <results_first_posted type="Actual">January 23, 2019</results_first_posted>
  <last_update_submitted>February 5, 2019</last_update_submitted>
  <last_update_submitted_qc>February 5, 2019</last_update_submitted_qc>
  <last_update_posted type="Actual">February 27, 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, 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>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <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>April 26, 2017</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/42/NCT03028142/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>September 19, 2017</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/42/NCT03028142/SAP_001.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <pre_assignment_details>74 were screened.Main reasons for screen failure were reversibility criteria not met (21), withdrew consent (5) and unsuitable chronic obstructive pulmonary disorder (COPD) history (4). Patients had to discontinue long acting bronchodilators on the day before screening and short acting bronchodilators for 8 hours before all spirometry assessments</pre_assignment_details>
      <group_list>
        <group group_id="P1">
          <title>Placebo Then Low Dose RPL554 Then High Dose RPL554</title>
          <description>Placebo twice daily plus 10 mcg tiotropium once daily for 3 days then 1.5 mg RPL554 twice daily plus 10 mcg tiotropium once daily for 3 days then 6 mg RPL554 twice daily plus 10 mcg tiotropium for 3 days, with a 7-21 day washout period between treatments</description>
        </group>
        <group group_id="P2">
          <title>Low Dose Dose RPL554 Then High Dose RPL554 Then Placebo</title>
          <description>1.5 mg RPL554 twice daily plus 10 mcg tiotropium once daily for 3 days then 6 mg RPL554 twice daily plus 10 mcg tiotropium once daily for 3 days then placebo twice daily plus 10 mcg tiotropium for 3 days, with a 7-21 day washout period between treatments</description>
        </group>
        <group group_id="P3">
          <title>High Dose RPL554 Then Placebo Then Low Dose RPL554</title>
          <description>High dose RPL554 twice daily plus 10 mcg tiotropium once daily for 3 days then placebo twice daily plus 10 mcg tiotropium once daily for 3 days then 1.5 mg RPL554 twice daily plus 10 mcg tiotropium for 3 days, with a 7-21 day washout period between treatments</description>
        </group>
        <group group_id="P4">
          <title>High Dose RPL554 Then Low Dose RPL554 Then Placebo</title>
          <description>High dose RPL554 twice daily plus 10 mcg tiotropium once daily for 3 days then 1.5 mg RPL554 twice daily plus 10 mcg tiotropium once daily for 3 days then placebo twice daily plus 10 mcg tiotropium for 3 days, with a 7-21 day washout period between treatments</description>
        </group>
        <group group_id="P5">
          <title>Low Dose RPL554 Then Placebo Then High Dose RPL554</title>
          <description>Low dose RPL554 twice daily plus 10 mcg tiotropium once daily for 3 days then placebo twice daily plus 10 mcg tiotropium once daily for 3 days then 6 mg RPL554 twice daily plus 10 mcg tiotropium for 3 days, with a 7-21 day washout period between treatments</description>
        </group>
        <group group_id="P6">
          <title>Placebo Then High Dose RPL554 Then Low Dose RPL554</title>
          <description>Placebo twice daily plus 10 mcg tiotropium once daily for 3 days then 6 mg RPL554 twice daily plus 10 mcg tiotropium once daily for 3 days then 1.5 mg RPL554 twice daily plus 10 mcg tiotropium for 3 days, with a 7-21 day washout period between treatments</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="5"/>
                <participants group_id="P2" count="5"/>
                <participants group_id="P3" count="6"/>
                <participants group_id="P4" count="4"/>
                <participants group_id="P5" count="6"/>
                <participants group_id="P6" count="4"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="4"/>
                <participants group_id="P2" count="4"/>
                <participants group_id="P3" count="6"/>
                <participants group_id="P4" count="4"/>
                <participants group_id="P5" count="5"/>
                <participants group_id="P6" count="3"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="1"/>
                <participants group_id="P3" count="0"/>
                <participants group_id="P4" count="0"/>
                <participants group_id="P5" count="1"/>
                <participants group_id="P6" count="1"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Adverse Event</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="1"/>
                <participants group_id="P3" count="0"/>
                <participants group_id="P4" count="0"/>
                <participants group_id="P5" count="0"/>
                <participants group_id="P6" count="1"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Withdrawal by Subject</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="0"/>
                <participants group_id="P4" count="0"/>
                <participants group_id="P5" count="1"/>
                <participants group_id="P6" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <population>All patients who received at least one dose of study treatment</population>
      <group_list>
        <group group_id="B1">
          <title>Overall</title>
          <description>All patients before the start of the study treatment sequence</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="30"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>years</units>
          <param>Median</param>
          <dispersion>Full Range</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="64.5" lower_limit="47" upper_limit="73"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Sex: Female, Male</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Female</title>
                  <measurement_list>
                    <measurement group_id="B1" value="13"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="17"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <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="0"/>
                  </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="30"/>
                  </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>
          <title>Percentage of predicted FEV1 post-bronchodilator</title>
          <units>%</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="60.1" spread="9.73"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Peak Forced Expired Volume in 1 Second (FEV1) on the Third Day of Dosing</title>
        <description>Peak forced expired volume in 1 second (FEV1) over 4 hours on the third day of dosing</description>
        <time_frame>Day 3</time_frame>
        <population>All randomized patients with sufficient data collected after intake of study treatment to compute the pharmacodynamics parameters on at least two treatment periods.</population>
        <group_list>
          <group group_id="O1">
            <title>Lower Dose Nebulised Treatment</title>
            <description>1.5 mg nebulised RPL554 twice daily plus 10 mcg tiotropium dry powder inhaler (DPI) once daily for 3 days&#xD;
1.5 mg RPL554 plus tiotropium</description>
          </group>
          <group group_id="O2">
            <title>Higher Dose Nebulised Treatment</title>
            <description>6 mg nebulised RPL554 twice daily plus 10 mcg tiotropium DPI once daily for 3 days&#xD;
6 mg RPL554 plus tiotropium</description>
          </group>
          <group group_id="O3">
            <title>Placebo</title>
            <description>Nebulised RPL554 matched placebo twice daily plus 10 mcg tiotropium DPI once daily for 3 days&#xD;
Placebo plus tiotropium</description>
          </group>
        </group_list>
        <measure>
          <title>Peak Forced Expired Volume in 1 Second (FEV1) on the Third Day of Dosing</title>
          <description>Peak forced expired volume in 1 second (FEV1) over 4 hours on the third day of dosing</description>
          <population>All randomized patients with sufficient data collected after intake of study treatment to compute the pharmacodynamics parameters on at least two treatment periods.</population>
          <units>Liters</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="28"/>
                <count group_id="O2" value="27"/>
                <count group_id="O3" value="27"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.477" spread="0.1673"/>
                    <measurement group_id="O2" value="0.500" spread="0.2157"/>
                    <measurement group_id="O3" value="0.373" spread="0.1970"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O3</group_id>
            </group_id_list>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>0.0022</p_value>
            <method>ANCOVA</method>
            <param_type>LS Means ratio</param_type>
            <param_value>1.05</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>1.02</ci_lower_limit>
            <ci_upper_limit>1.09</ci_upper_limit>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O2</group_id>
              <group_id>O3</group_id>
            </group_id_list>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>&lt;0.0001</p_value>
            <method>ANCOVA</method>
            <param_type>LS Means ratio</param_type>
            <param_value>1.09</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>1.05</ci_lower_limit>
            <ci_upper_limit>1.12</ci_upper_limit>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Average FEV1 Over 12 Hours on the Third Day of Dosing</title>
        <description>Average FEV1 area under the curve (AUC) over 12 hours on the third day of dosing</description>
        <time_frame>Day 3</time_frame>
        <population>All randomized patients with sufficient data collected after intake of study treatment to compute the pharmacodynamics parameters on at least two treatment periods.</population>
        <group_list>
          <group group_id="O1">
            <title>Lower Dose Nebulised Treatment</title>
            <description>1.5 mg nebulised RPL554 twice daily plus 10 mcg tiotropium DPI once daily for 3 days&#xD;
1.5 mg RPL554 plus tiotropium</description>
          </group>
          <group group_id="O2">
            <title>Higher Dose Nebulised Treatment</title>
            <description>6 mg nebulised RPL554 twice daily plus 10 mcg tiotropium DPI once daily for 3 days&#xD;
6 mg RPL554 plus tiotropium</description>
          </group>
          <group group_id="O3">
            <title>Placebo</title>
            <description>Nebulised RPL554 matched placebo twice daily plus 10 mcg tiotropium DPI once daily for 3 days&#xD;
Placebo plus tiotropium</description>
          </group>
        </group_list>
        <measure>
          <title>Average FEV1 Over 12 Hours on the Third Day of Dosing</title>
          <description>Average FEV1 area under the curve (AUC) over 12 hours on the third day of dosing</description>
          <population>All randomized patients with sufficient data collected after intake of study treatment to compute the pharmacodynamics parameters on at least two treatment periods.</population>
          <units>Liters*hour</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="28"/>
                <count group_id="O2" value="27"/>
                <count group_id="O3" value="27"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="3.804" spread="1.8512"/>
                    <measurement group_id="O2" value="3.967" spread="2.2134"/>
                    <measurement group_id="O3" value="3.197" spread="2.2826"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O3</group_id>
            </group_id_list>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>0.0988</p_value>
            <method>ANCOVA</method>
            <param_type>LS Means ratio</param_type>
            <param_value>1.03</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>0.99</ci_lower_limit>
            <ci_upper_limit>1.06</ci_upper_limit>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O2</group_id>
              <group_id>O3</group_id>
            </group_id_list>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>0.0009</p_value>
            <method>ANCOVA</method>
            <param_type>LS Means ratio</param_type>
            <param_value>1.06</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>1.02</ci_lower_limit>
            <ci_upper_limit>1.09</ci_upper_limit>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Peak FEV1 on Day 1</title>
        <description>Peak FEV1 over 4 hours on Day 1</description>
        <time_frame>Day 1</time_frame>
        <population>All randomized patients with sufficient data collected after intake of study treatment to compute the pharmacodynamics parameters on at least two treatment periods.</population>
        <group_list>
          <group group_id="O1">
            <title>Lower Dose Nebulised Treatment</title>
            <description>1.5 mg nebulised RPL554 twice daily plus 10 mcg tiotropium DPI once daily for 3 days&#xD;
1.5 mg RPL554 plus tiotropium</description>
          </group>
          <group group_id="O2">
            <title>Higher Dose Nebulised Treatment</title>
            <description>6 mg nebulised RPL554 twice daily plus 10 mcg tiotropium DPI once daily for 3 days&#xD;
6 mg RPL554 plus tiotropium</description>
          </group>
          <group group_id="O3">
            <title>Placebo</title>
            <description>Nebulised RPL554 matched placebo twice daily plus 10 mcg tiotropium DPI once daily for 3 days&#xD;
Placebo plus tiotropium</description>
          </group>
        </group_list>
        <measure>
          <title>Peak FEV1 on Day 1</title>
          <description>Peak FEV1 over 4 hours on Day 1</description>
          <population>All randomized patients with sufficient data collected after intake of study treatment to compute the pharmacodynamics parameters on at least two treatment periods.</population>
          <units>Liters</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="28"/>
                <count group_id="O2" value="27"/>
                <count group_id="O3" value="27"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.383" spread="0.1448"/>
                    <measurement group_id="O2" value="0.432" spread="0.1720"/>
                    <measurement group_id="O3" value="0.337" spread="0.1854"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O3</group_id>
            </group_id_list>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>0.2496</p_value>
            <method>ANCOVA</method>
            <param_type>LS Means ratio</param_type>
            <param_value>1.02</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>0.98</ci_lower_limit>
            <ci_upper_limit>1.06</ci_upper_limit>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O2</group_id>
              <group_id>O3</group_id>
            </group_id_list>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>0.0039</p_value>
            <method>ANCOVA</method>
            <param_type>LS Means ratio</param_type>
            <param_value>1.06</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>1.02</ci_lower_limit>
            <ci_upper_limit>1.1</ci_upper_limit>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Average FEV1 Over 12 Hours on Day 1</title>
        <description>Average FEV1 AUC over 12 hours on Day 1</description>
        <time_frame>Day 1</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Lower Dose Nebulised Treatment</title>
            <description>1.5 mg nebulised RPL554 twice daily plus 10 mcg tiotropium DPI once daily for 3 days&#xD;
1.5 mg RPL554 plus tiotropium</description>
          </group>
          <group group_id="O2">
            <title>Higher Dose Nebulised Treatment</title>
            <description>6 mg nebulised RPL554 twice daily plus 10 mcg tiotropium DPI once daily for 3 days&#xD;
6 mg RPL554 plus tiotropium</description>
          </group>
          <group group_id="O3">
            <title>Placebo</title>
            <description>Nebulised RPL554 matched placebo twice daily plus 10 mcg tiotropium DPI once daily for 3 days&#xD;
Placebo plus tiotropium</description>
          </group>
        </group_list>
        <measure>
          <title>Average FEV1 Over 12 Hours on Day 1</title>
          <description>Average FEV1 AUC over 12 hours on Day 1</description>
          <units>Liters*hour</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="28"/>
                <count group_id="O2" value="27"/>
                <count group_id="O3" value="27"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="3.058" spread="1.4851"/>
                    <measurement group_id="O2" value="3.094" spread="1.9624"/>
                    <measurement group_id="O3" value="2.510" spread="1.9381"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O3</group_id>
            </group_id_list>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>0.1404</p_value>
            <method>ANCOVA</method>
            <param_type>LS Means ratio</param_type>
            <param_value>1.03</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>0.99</ci_lower_limit>
            <ci_upper_limit>1.06</ci_upper_limit>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O2</group_id>
              <group_id>O3</group_id>
            </group_id_list>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>0.0228</p_value>
            <method>ANCOVA</method>
            <param_type>LS Means ratio</param_type>
            <param_value>1.04</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>1.01</ci_lower_limit>
            <ci_upper_limit>1.08</ci_upper_limit>
          </analysis>
        </analysis_list>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>From informed consent until the end of the study.</time_frame>
      <group_list>
        <group group_id="E1">
          <title>Lower Dose Nebulised Treatment</title>
          <description>1.5 mg nebulised RPL554 twice daily plus 10 mcg tiotropium DPI once daily for 3 days&#xD;
1.5 mg RPL554 plus tiotropium</description>
        </group>
        <group group_id="E2">
          <title>Higher Dose Nebulised Treatment</title>
          <description>6 mg nebulised RPL554 twice daily plus 10 mcg tiotropium DPI once daily for 3 days&#xD;
6 mg RPL554 plus tiotropium</description>
        </group>
        <group group_id="E3">
          <title>Placebo</title>
          <description>Nebulised RPL554 matched placebo twice daily plus 10 mcg tiotropium DPI once daily for 3 days&#xD;
Placebo plus tiotropium</description>
        </group>
      </group_list>
      <serious_events>
        <default_vocab>MedDRA 19.1</default_vocab>
        <default_assessment>Non-systematic Assessment</default_assessment>
        <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="29"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="27"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="28"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="29"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="27"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="28"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Pneumonia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="29"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="27"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="28"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>0</frequency_threshold>
        <default_vocab>MeddRA 19.1</default_vocab>
        <default_assessment>Non-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="12" subjects_at_risk="29"/>
                <counts group_id="E2" subjects_affected="12" subjects_at_risk="27"/>
                <counts group_id="E3" subjects_affected="12" subjects_at_risk="28"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Frequent bowel movements</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="29"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="27"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="28"/>
              </event>
              <event>
                <sub_title>Nausea</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="29"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="27"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="28"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Medical device site reaction</sub_title>
                <counts group_id="E1" events="4" subjects_affected="4" subjects_at_risk="29"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="27"/>
                <counts group_id="E3" events="4" subjects_affected="4" subjects_at_risk="28"/>
              </event>
              <event>
                <sub_title>Chest discomfort</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="29"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="27"/>
                <counts group_id="E3" events="3" subjects_affected="2" subjects_at_risk="28"/>
              </event>
              <event>
                <sub_title>Catheter site bruise</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="29"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="27"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="28"/>
              </event>
              <event>
                <sub_title>Chills</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="29"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="27"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="28"/>
              </event>
              <event>
                <sub_title>Fatigue</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="29"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="27"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="28"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Herpes simplex</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="29"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="27"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="28"/>
              </event>
              <event>
                <sub_title>Lower respiratory tract infection</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="29"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="27"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="28"/>
              </event>
              <event>
                <sub_title>Pneumonia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="29"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="27"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="28"/>
              </event>
              <event>
                <sub_title>Rhinitis</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="29"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="27"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="28"/>
              </event>
              <event>
                <sub_title>Skin infection</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="29"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="27"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="28"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Injury, poisoning and procedural complications</title>
            <event_list>
              <event>
                <sub_title>Arthropod bite</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="29"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="27"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="28"/>
              </event>
              <event>
                <sub_title>Contusion</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="29"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="27"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="28"/>
              </event>
              <event>
                <sub_title>Skin wound</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="29"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="27"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="28"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Arthralgia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="29"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="27"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="28"/>
              </event>
              <event>
                <sub_title>Muscle spasms</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="29"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="27"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="28"/>
              </event>
              <event>
                <sub_title>Musculoskeletal chest pain</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="29"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="27"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="28"/>
              </event>
              <event>
                <sub_title>Myalgia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="29"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="27"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="28"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Headache</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="29"/>
                <counts group_id="E2" events="8" subjects_affected="5" subjects_at_risk="27"/>
                <counts group_id="E3" events="3" subjects_affected="3" subjects_at_risk="28"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Dyspnoea</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="29"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="27"/>
                <counts group_id="E3" events="3" subjects_affected="2" subjects_at_risk="28"/>
              </event>
              <event>
                <sub_title>Chronic obstructive pulmonary disease</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="29"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="27"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="28"/>
              </event>
              <event>
                <sub_title>Cough</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="29"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="27"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="28"/>
              </event>
              <event>
                <sub_title>Larngeal discomfort</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="29"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="27"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="28"/>
              </event>
              <event>
                <sub_title>Sputum increased</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="29"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="27"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="28"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Skin and subcutaneous tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Rash</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="29"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="27"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="28"/>
              </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>The employees of the Medicines Evaluation shall not be permitted to present at symposia, national or regional professional meetings, and to publish in journals, theses or dissertations, or otherwise of their own choosing, methods and results of the Clinical Trial subject to the publication policy described in the Protocol without prior written approval of the Sponsor.</restrictive_agreement>
    </certain_agreements>
    <point_of_contact>
      <name_or_title>Brian Maurer</name_or_title>
      <organization>Verona Pharma plc</organization>
      <phone>+19147675037 ext 9147675037</phone>
      <email>brian.maurer@veronapharma.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/NCT03028142
org study id: RPL554-CO-202
nct id: NCT03028142
lead sponsor: 
has dmc: No
This is a phase II, randomised, double blind, placebo controlled, complete block, three way
      crossover study to investigate treatment with nebulised RPL554 and tiotropium together in
      patients with moderate to severe chronic obstructive pulmonary disease (COPD). The purpose of
      this study is to assess the bronchodilator effect (opening of the airways) of RPL554 when
      used in combination with a long acting anti-muscarinic receptor antagonist (tiotropium)
      whilst dosing the RPL554 to steady state blood levels. It is planned to randomise up to 30
      patients to have 24 evaluable patients at one study centre. In each treatment period,
      patients will receive an open label dose of tiotropium from a dry power inhaler (DPI)
      followed immediately by a double blind dose of either RPL554 6mg, 1.5mg or placebo (depending
      on treatment sequence) from a nebuliser in the morning on Day 1, Day 2 and Day 3. The dose of
      RPL554 or placebo will be repeated in the evening on Day 1 and Day 2; there will not be an
      evening dose on Day 3.
allocation: Randomized
intervention model: Crossover Assignment
primary purpose: Treatment
masking: Triple (Participant, Investigator, Outcomes Assessor)
measure: Peak Forced Expired Volume in 1 Second (FEV1) on the Third Day of Dosing
time frame: Day 3
description: Peak forced expired volume in 1 second (FEV1) over 4 hours on the third day of dosing
measure: Average FEV1 Over 12 Hours on the Third Day of Dosing
time frame: Day 3
description: Average FEV1 area under the curve (AUC) over 12 hours on the third day of dosing
measure: Peak FEV1 on Day 1
time frame: Day 1
description: Peak FEV1 over 4 hours on Day 1
measure: Average FEV1 Over 12 Hours on Day 1
time frame: Day 1
description: Average FEV1 AUC over 12 hours on Day 1
arm group label: Lower Dose Nebulised Treatment
arm group type: Experimental
description: 1.5 mg nebulised RPL554 twice daily plus 10 mcg tiotropium DPI once daily for 3 days
arm group label: Higher Dose Nebulised Treatment
arm group type: Experimental
description: 6 mg nebulised RPL554 twice daily plus 10 mcg tiotropium DPI once daily for 3 days
arm group label: Placebo
arm group type: Placebo Comparator
description: Nebulised RPL554 matched placebo twice daily plus 10 mcg tiotropium DPI once daily for 3 days
intervention type: Drug
intervention name: 1.5 mg RPL554 plus tiotropium
arm group label: Lower Dose Nebulised Treatment
intervention type: Drug
intervention name: 6 mg RPL554 plus tiotropium
arm group label: Higher Dose Nebulised Treatment
intervention type: Drug
intervention name: Placebo plus tiotropium
arm group label: Placebo
criteria: 
gender: All
minimum age: 40 Years
maximum age: 75 Years
healthy volunteers: No
responsible party type: Sponsor
mesh term: Lung Diseases, Obstructive
mesh term: Pulmonary Disease, Chronic Obstructive
mesh term: Tiotropium Bromide
sharing ipd: No
provided document: 
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 