<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/NCT04441788</url>
  </required_header>
  <id_info>
    <org_study_id>ION-827359-CS2</org_study_id>
    <secondary_id>2020-000210-15</secondary_id>
    <nct_id>NCT04441788</nct_id>
  </id_info>
  <brief_title>A Study to Assess the Safety, Tolerability, and Efficacy of ION-827359 in Participants With Mild to Moderate Chronic Obstructive Pulmonary Disease (COPD) With Chronic Bronchitis (CB)</brief_title>
  <official_title>A Double-Blind, Placebo-Controlled, Phase 2a Study to Assess the Safety, Tolerability, and Efficacy of ION-827359 in Patients With Mild to Moderate COPD With Chronic Bronchitis</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Ionis Pharmaceuticals, Inc.</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Ionis Pharmaceuticals, Inc.</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>Yes</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      The purpose of this study was to evaluate the effect of ION-827359 on forced expiratory&#xD;
      volume in 1 second (FEV1) in participants with mild to moderate COPD with CB.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This was a multi-center, double-blind, placebo-controlled, randomized, Phase 2a study of&#xD;
      ION-827359 in up to 180 participants. The participants were randomized to receive oral&#xD;
      inhalation of either ION-827359 or placebo for up to 13 weeks. At the end of 13 weeks,&#xD;
      participants entered a 10-week post-treatment evaluation period.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Terminated</overall_status>
  <why_stopped>
    Business Decision to Terminate Study&#xD;
  </why_stopped>
  <start_date type="Actual">December 22, 2020</start_date>
  <completion_date type="Actual">August 9, 2021</completion_date>
  <primary_completion_date type="Actual">April 27, 2021</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>Double (Participant, Investigator)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Change From Baseline to the Primary Time Point in Forced Expiratory Volume in 1 Second (FEV1) Compared to Placebo</measure>
    <time_frame>From Baseline up to average of Weeks 13 and 14</time_frame>
    <description>FEV1 is the amount of air which can be forcibly exhaled from the lungs in the first second of a forced exhalation. Baseline was defined as the last non-missing measurement prior to the first study drug administration. The primary time point was defined as the average of weeks 13 and 14. FAS=Full analysis set.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Change From Baseline in the Exacerbations of Chronic Pulmonary Disease Tool (EXACT) Respiratory Symptoms (E-RS) Daily Symptom Diary Total Score to the Primary Time Point</measure>
    <time_frame>From Baseline up to average of weeks 13 and 14</time_frame>
    <description>The E-RS scale is a participant-reported outcome (PRO) designed to measure the symptoms of participants with chronic obstructive pulmonary disease (COPD). The E-RS utilizes 11 respiratory symptom items from the existing and validated 14-item EXACT, which measures symptoms of exacerbation. The E-RS total score quantifies respiratory symptom severity, and 3 domains assess breathlessness (comprised of 5 items, score range [0-17]), cough and sputum (comprised of 3 items, score range [0-11]), and chest symptoms (comprised of 3 items, score range [0-12]). The E-RS was collected on the daily e-diary. The total score was derived by summing the 11-item scores and ranged between 0 to 40 with higher values indicating severe respiratory symptoms. The primary time point was defined as the average of weeks 13 and 14.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change From Baseline in the Chronic Obstructive Pulmonary Disease (COPD) Assessment Test (CAT) to the Week 14 Time Point</measure>
    <time_frame>From Baseline to Week 14</time_frame>
    <description>The CAT is an eight-item questionnaire that was completed by the participant and is designed to quantify the impact of COPD symptoms on the health status of participants. Each item is rated on a 6-point scale ranging from 0 (no impairment) to 5 (maximum impairment). The total CAT score is calculated by summing the scores of all items and ranges from 0 to 40. Higher scores indicate a severe condition (more severe impact of COPD on a participant's life).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change From Baseline in St. George's Respiratory Questionnaire - COPD Specific (SGRQ-C) Total Score to the Week 14 Time Point</measure>
    <time_frame>From Baseline to Week 14</time_frame>
    <description>The SGRQ is a participant completed, a disease-specific instrument designed to measure impact on overall health, daily life, and perceived well-being in participants with obstructive airway disease. The shorter 40-item version (SGRQ-C) which does not specify a Recall Period and has been validated specifically for COPD participants was used in this study. It consists of 40 items each weighted from 0 to a possible maximum of 100. Items 1-7 produced the symptoms score, 9-12 the activity score, and items 8, 10, 11, 13 and 14 the impacts score. Each component sub-score was calculated as a percentage of the summed weights of each item out of the sum of the maximum possible weight for that component (range 0-100). The total score was calculated by summing the weights to all positive responses in each component, where a positive item indicated the presence of symptoms, expressed as a percentage (range 0-100). Higher scores indicated a worse outcome (more limitations)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change From Baseline in Post-Bronchodilator FEV1</measure>
    <time_frame>From Baseline to end of treatment (EOT) [Up to Week 14]</time_frame>
    <description>Post-bronchodilator FEV1 is the amount of air which can be forcibly exhaled from the lungs in the first second of a forced exhalation after administration of bronchodilator. Baseline was defined as the last non-missing measurement prior to the first study drug administration.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cmax: Maximum Observed Plasma Concentration for ION-827359</measure>
    <time_frame>Days 1 and 85</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Tmax: Time to Reach the Maximum Plasma Concentration for ION-827359</measure>
    <time_frame>Days 1 and 85</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>AUC[0-24h]: Area Under the Plasma Concentration-Time Curve From Time Zero to 24 Hours for ION-827359</measure>
    <time_frame>Days 1 and 85</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Percentage of Participants With at Least One Treatment-Emergent Adverse Event (TEAE) Based on Severity</measure>
    <time_frame>Up to Week 24</time_frame>
    <description>An AE can be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of medicinal (investigational) product, whether or not the AE is considered related to the medicinal (investigational) product. A TEAE is defined as any AE starting or getting worse on or after the first dose of the study drug. The severity of a TEAE was assessed by the investigator and classified into one of the following: mild, moderate, and severe.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Percentage of Participants With Clinically Significant Change in Laboratory Values</measure>
    <time_frame>Up to Week 24</time_frame>
    <description>Laboratory parameters for serum chemistry, hematology, urinalysis, coagulation, complement, and lipids were assessed.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Percentage of Participants With Clinically Significant Change in Vital Sign Parameters</measure>
    <time_frame>Up to Week 24</time_frame>
    <description>Vital signs included assessment of heart rate, blood pressure, respiratory rate, and temperature.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Percentage of Participants With Clinically Significant Change in Electrocardiogram (ECG) Findings</measure>
    <time_frame>Up to Week 24</time_frame>
    <description>ECG parameters of ventricular rate, PR interval, QRS duration, QT, or QTc were assessed.</description>
  </secondary_outcome>
  <number_of_arms>3</number_of_arms>
  <enrollment type="Actual">60</enrollment>
  <condition>Chronic Bronchitis</condition>
  <condition>Chronic Obstructive Pulmonary Disease</condition>
  <arm_group>
    <arm_group_label>Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Single-dose of placebo was administered by oral inhalation via nebulizer, once every week for up to 13 weeks.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>ION-827359 37.5 milligrams (mg)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Single-dose of ION-827359 37.5 mg was administered by oral inhalation via nebulizer, once every week for up to 13 weeks.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>ION-827359 75 mg</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Single-dose of ION-827359 75 mg was administered by oral inhalation via nebulizer, once every week for up to 13 weeks.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>ION-827359</intervention_name>
    <description>ION-827359 administered by oral inhalation</description>
    <arm_group_label>ION-827359 37.5 milligrams (mg)</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>Placebo administered by oral inhalation</description>
    <arm_group_label>Placebo</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>ION-827359</intervention_name>
    <description>ION-827359 administered by oral inhalation</description>
    <arm_group_label>ION-827359 75 mg</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria&#xD;
&#xD;
          1. Must have given written informed consent (signed and dated) and any authorizations&#xD;
             required by local law and be able to comply with all study requirements&#xD;
&#xD;
          2. Males or females. Aged 40-70 inclusive at the time of informed consent&#xD;
&#xD;
          3. Females must be non-pregnant and non-lactating, and either surgically sterile (e.g.,&#xD;
             tubal occlusion, hysterectomy, bilateral salpingectomy, bilateral oophorectomy) or&#xD;
             postmenopausal&#xD;
&#xD;
          4. BMI &lt; 35.0 kg/m^2&#xD;
&#xD;
          5. Participants with a diagnosis of COPD as defined by the American Thoracic Society&#xD;
             (ATS)/European Respiratory Society (ERS)&#xD;
&#xD;
               1. Ability to perform acceptable and reproducible spirometry&#xD;
&#xD;
               2. Post-bronchodilator (4 puffs of albuterol) spirometry at Screening demonstrating&#xD;
                  the following:&#xD;
&#xD;
             i. FEV1/ forced vital capacity (FVC) ratio of &lt; 0.70 ii. FEV1 ≥ 50% and ≤ 90% of&#xD;
             predicted normal&#xD;
&#xD;
          6. Clinically stable COPD in the 4 weeks prior to Screening (Visit 1)&#xD;
&#xD;
          7. Current and former smokers with smoking history of ≥ 20 pack years&#xD;
&#xD;
          8. Meet SGRQ definition of CB&#xD;
&#xD;
          9. CAT score ≥ 10&#xD;
&#xD;
        Exclusion Criteria&#xD;
&#xD;
          1. Clinically significant abnormalities in medical history (e.g., previous acute coronary&#xD;
             syndrome within 6 months of screening, congestive heart failure, major surgery within&#xD;
             3 months of Screening) or physical examination&#xD;
&#xD;
          2. Screening laboratory results as follows, or any other clinically significant&#xD;
             abnormalities in screening laboratory values that would render a subject unsuitable&#xD;
             for inclusion&#xD;
&#xD;
               1. Urine protein/creatinine (P/C) ratio ≥ 0.3 mg/mg. In the event of P/C ratio above&#xD;
                  this threshold eligibility may be confirmed by a quantitative total urine protein&#xD;
                  measurement of &lt; 300 mg/24 hr&#xD;
&#xD;
               2. Positive test (including trace) for blood on urinalysis. In the event of a&#xD;
                  positive test eligibility may be confirmed with urine microscopy showing ≤ 5 red&#xD;
                  blood cells per high power field&#xD;
&#xD;
               3. alanine aminotransferase (ALT), aspartate aminotransferase (AST), bilirubin,&#xD;
                  alkaline phosphatase (ALP), serum creatinine, blood urea nitrogen (BUN) &gt; 1.5 ×&#xD;
                  upper limit of normal (ULN)&#xD;
&#xD;
               4. Platelet count &lt; LLN&#xD;
&#xD;
               5. Serum potassium &gt; 5.2 mmol/L&#xD;
&#xD;
               6. Estimated GFR &lt; 60 mL/min (as determined by the Cockcroft-Gault Equation for&#xD;
                  creatinine clearance)&#xD;
&#xD;
               7. A positive PCR test for SARS-CoV-2 at any time prior to randomization&#xD;
&#xD;
          3. Any active infection requiring systemic antiviral or antimicrobial therapy that will&#xD;
             not be completed prior to first day Study Drug product is administered to the&#xD;
             participant (Study Day 1)&#xD;
&#xD;
          4. Unwillingness to comply with study procedures, including follow-up, as specified by&#xD;
             this protocol, or unwillingness to cooperate fully with the Investigator&#xD;
&#xD;
          5. Clinically important pulmonary disease other than COPD&#xD;
&#xD;
          6. Asthma as a primary or main diagnosis according to the Global Initiative for Asthma&#xD;
             (GINA) guidelines (GINA 2011) or other accepted guidelines. Participants with a past&#xD;
             medical history of asthma (e.g. childhood or adolescence) may be included&#xD;
&#xD;
          7. Treatment with systemic corticosteroids and/or antibiotics, and/or hospitalization for&#xD;
             a COPD exacerbation within 4 weeks prior to enrolment (Visit 1)&#xD;
&#xD;
          8. Acute upper or lower respiratory infection requiring antibiotics or antiviral&#xD;
             medication within 4 weeks prior to enrolment (Visit 1)&#xD;
&#xD;
          9. Long term oxygen therapy (LTOT)&#xD;
&#xD;
         10. Participants participating in, or scheduled for, an intensive (active) COPD&#xD;
             rehabilitation program (participants who are in the maintenance phase of a&#xD;
             rehabilitation program are eligible to take part)&#xD;
&#xD;
         11. Concomitant medication restrictions: Oral anticoagulants, oral steroids (e.g.&#xD;
             prednisone or Medrol), theophylline, chronic azithromycin, or roflumilast&#xD;
&#xD;
         12. Have any other conditions, which, in the opinion of the Investigator would make the&#xD;
             subject unsuitable for inclusion, or could interfere with the subject participating in&#xD;
             or completing the Study&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>40 Years</minimum_age>
    <maximum_age>70 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <location>
    <facility>
      <name>MediTrial s.r.o.</name>
      <address>
        <city>Jindrichuv Hradec</city>
        <zip>37701</zip>
        <country>Czechia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Plicni ambulance Kralupy</name>
      <address>
        <city>Kralupy Nad Vltavou</city>
        <zip>27801</zip>
        <country>Czechia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>CEFISPIRO s.r.o.</name>
      <address>
        <city>Lovosice</city>
        <zip>410 02</zip>
        <country>Czechia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Plicni Ambulance Rokycany, s.r.o.</name>
      <address>
        <city>Rokycany</city>
        <zip>33701</zip>
        <country>Czechia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>PNEUMOLOGIE VARNSDORF s.r.o.</name>
      <address>
        <city>Varnsdorf</city>
        <zip>40747</zip>
        <country>Czechia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Pneumologisches Studienzentrum Markgrafenstrasse</name>
      <address>
        <city>Berlin</city>
        <zip>10969</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>MECS Research GmbH</name>
      <address>
        <city>Berlin</city>
        <zip>12203</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Pneumologisches Forschungsinstitut an der LungenClinic Grosshansdorf GmbH</name>
      <address>
        <city>Grosshansdorf</city>
        <zip>22927</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hamburger Institut far Therapieforschung GmbH</name>
      <address>
        <city>Hamburg</city>
        <zip>20354</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>KLB Gesundheitsforschung Lubeck GmbH</name>
      <address>
        <city>Lübeck</city>
        <zip>23552</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>IKF Pneumologie Mainz Helix Medical Excellence Center Mainz</name>
      <address>
        <city>Mainz</city>
        <zip>55128</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>ZMS-Zentrum fur medizinische Studien GmbH</name>
      <address>
        <city>Warendorf</city>
        <zip>48231</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Csongrad Megyei Mellkasi Betegsegek Szakkorhaza</name>
      <address>
        <city>Deszk</city>
        <zip>6772</zip>
        <country>Hungary</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Selye Janos Korhaz, Rendelointezet</name>
      <address>
        <city>Komarom</city>
        <zip>2900</zip>
        <country>Hungary</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Queen Anne Street Medical Centre, Heart Lung Center</name>
      <address>
        <city>London</city>
        <zip>Nw1 8HU</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Czechia</country>
    <country>Germany</country>
    <country>Hungary</country>
    <country>United Kingdom</country>
  </location_countries>
  <verification_date>November 2022</verification_date>
  <study_first_submitted>June 18, 2020</study_first_submitted>
  <study_first_submitted_qc>June 18, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">June 22, 2020</study_first_posted>
  <results_first_submitted>November 24, 2022</results_first_submitted>
  <results_first_submitted_qc>November 24, 2022</results_first_submitted_qc>
  <results_first_posted type="Actual">December 20, 2022</results_first_posted>
  <last_update_submitted>November 24, 2022</last_update_submitted>
  <last_update_submitted_qc>November 24, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">December 20, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Chronic Bronchitis</keyword>
  <keyword>IONIS-ENaCRx</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Bronchitis</mesh_term>
    <mesh_term>Bronchitis, Chronic</mesh_term>
    <mesh_term>Lung Diseases</mesh_term>
    <mesh_term>Lung Diseases, Obstructive</mesh_term>
    <mesh_term>Pulmonary Disease, Chronic Obstructive</mesh_term>
    <mesh_term>Acute Disease</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <provided_document_section>
    <provided_document>
      <document_type>Study Protocol and Statistical Analysis Plan</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>August 26, 2021</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/88/NCT04441788/Prot_SAP_000.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <recruitment_details>60 participants were randomized at 11 study centers in Czech Republic, Germany, Hungary and the United Kingdom.</recruitment_details>
      <pre_assignment_details>Of the 60 randomized participants, one was randomized but did not receive study treatment as the participant was ineligible. The study included a 2-week screening period (including a diet-stabilization period), a 12-week treatment period, and a 10-week post-treatment evaluation period.</pre_assignment_details>
      <group_list>
        <group group_id="P1">
          <title>Placebo</title>
          <description>Single-dose of placebo was administered by oral inhalation via nebulizer, once every week for up to 13 weeks.</description>
        </group>
        <group group_id="P2">
          <title>ION-827359 37.5 Milligrams (mg)</title>
          <description>Single-dose of ION-827359 37.5 mg was administered by oral inhalation via nebulizer, once every week for up to 13 weeks.</description>
        </group>
        <group group_id="P3">
          <title>ION-827359 75 mg</title>
          <description>Single-dose of ION-827359 75 mg was administered by oral inhalation via nebulizer, once every week for up to 13 weeks.</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="20"/>
                <participants group_id="P2" count="21"/>
                <participants group_id="P3" count="19"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="3"/>
                <participants group_id="P2" count="4"/>
                <participants group_id="P3" count="3"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="17"/>
                <participants group_id="P2" count="17"/>
                <participants group_id="P3" count="16"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Voluntary Withdrawl</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="1"/>
                <participants group_id="P3" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Ineligibility</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Adverse Event</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="4"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Study Terminated by Sponsor</title>
              <participants_list>
                <participants group_id="P1" count="16"/>
                <participants group_id="P2" count="16"/>
                <participants group_id="P3" count="12"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <population>Safety population included all the participants who were randomized and received at least 1 dose of study drug.</population>
      <group_list>
        <group group_id="B1">
          <title>Placebo</title>
          <description>Single-dose of placebo was administered by oral inhalation via nebulizer, once every week for up to 13 weeks.</description>
        </group>
        <group group_id="B2">
          <title>ION-827359 37.5 mg</title>
          <description>Single-dose of ION-827359 37.5 mg was administered by oral inhalation via nebulizer, once every week for up to 13 weeks.</description>
        </group>
        <group group_id="B3">
          <title>ION-827359 75 mg</title>
          <description>Single-dose of ION-827359 75 mg was administered by oral inhalation via nebulizer, once every week for up to 13 weeks.</description>
        </group>
        <group group_id="B4">
          <title>Total</title>
          <description>Total of all reporting groups</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="19"/>
            <count group_id="B2" value="21"/>
            <count group_id="B3" value="19"/>
            <count group_id="B4" value="59"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>years</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="61.3" spread="4.54"/>
                    <measurement group_id="B2" value="61.8" spread="5.86"/>
                    <measurement group_id="B3" value="61.8" spread="5.39"/>
                    <measurement group_id="B4" value="61.6" spread="5.23"/>
                  </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="9"/>
                    <measurement group_id="B2" value="7"/>
                    <measurement group_id="B3" value="5"/>
                    <measurement group_id="B4" value="21"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="10"/>
                    <measurement group_id="B2" value="14"/>
                    <measurement group_id="B3" value="14"/>
                    <measurement group_id="B4" value="38"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Ethnicity (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Not Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="19"/>
                    <measurement group_id="B2" value="21"/>
                    <measurement group_id="B3" value="19"/>
                    <measurement group_id="B4" value="59"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="0"/>
                  </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 group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Asian</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Native Hawaiian or Other Pacific Islander</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Black or African American</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="19"/>
                    <measurement group_id="B2" value="21"/>
                    <measurement group_id="B3" value="18"/>
                    <measurement group_id="B4" value="58"/>
                  </measurement_list>
                </category>
                <category>
                  <title>More than one race</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="1"/>
                    <measurement group_id="B4" value="1"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Forced Expiratory Volume in 1 Second (FEV1)</title>
          <description>FEV1 is the amount of air which can be forcibly exhaled from the lungs in the first second of a forced exhalation.</description>
          <units>liters</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="1.8317" spread="0.4670"/>
                    <measurement group_id="B2" value="1.9311" spread="0.6608"/>
                    <measurement group_id="B3" value="1.6536" spread="0.3498"/>
                    <measurement group_id="B4" value="1.8097" spread="0.5193"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Change From Baseline to the Primary Time Point in Forced Expiratory Volume in 1 Second (FEV1) Compared to Placebo</title>
        <description>FEV1 is the amount of air which can be forcibly exhaled from the lungs in the first second of a forced exhalation. Baseline was defined as the last non-missing measurement prior to the first study drug administration. The primary time point was defined as the average of weeks 13 and 14. FAS=Full analysis set.</description>
        <time_frame>From Baseline up to average of Weeks 13 and 14</time_frame>
        <population>FAS=all randomized participants who had ≥1 dose of study drug(ION 827359/placebo),≥1 post-Baseline efficacy assessment(i.e.,post-Baseline FEV1,Exacerbations of Chronic pulmonary Disease Tool[EXACT]Respiratory Symptoms[E-RS]score,Chronic Obstructive Pulmonary Disease[COPD]Assessment Test[CAT]score,or St.George's Respiratory Questionnaire-COPD Specific[SGRQ-C score],post-bronchodilator FEV1).Overall number analyzed:number of participants with data available for analyses in this outcome measure.</population>
        <group_list>
          <group group_id="O1">
            <title>Placebo</title>
            <description>Single-dose of placebo was administered by oral inhalation via nebulizer, once every week for up to 13 weeks.</description>
          </group>
          <group group_id="O2">
            <title>ION-827359 37.5 mg</title>
            <description>Single-dose of ION-827359 37.5 mg was administered by oral inhalation via nebulizer, once every week for up to 13 weeks.</description>
          </group>
          <group group_id="O3">
            <title>ION-827359 75 mg</title>
            <description>Single-dose of ION-827359 75 mg was administered by oral inhalation via nebulizer, once every week for up to 13 weeks.</description>
          </group>
        </group_list>
        <measure>
          <title>Change From Baseline to the Primary Time Point in Forced Expiratory Volume in 1 Second (FEV1) Compared to Placebo</title>
          <description>FEV1 is the amount of air which can be forcibly exhaled from the lungs in the first second of a forced exhalation. Baseline was defined as the last non-missing measurement prior to the first study drug administration. The primary time point was defined as the average of weeks 13 and 14. FAS=Full analysis set.</description>
          <population>FAS=all randomized participants who had ≥1 dose of study drug(ION 827359/placebo),≥1 post-Baseline efficacy assessment(i.e.,post-Baseline FEV1,Exacerbations of Chronic pulmonary Disease Tool[EXACT]Respiratory Symptoms[E-RS]score,Chronic Obstructive Pulmonary Disease[COPD]Assessment Test[CAT]score,or St.George's Respiratory Questionnaire-COPD Specific[SGRQ-C score],post-bronchodilator FEV1).Overall number analyzed:number of participants with data available for analyses in this outcome measure.</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="5"/>
                <count group_id="O2" value="5"/>
                <count group_id="O3" value="4"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.0642" spread="0.2506"/>
                    <measurement group_id="O2" value="-0.0240" spread="0.3581"/>
                    <measurement group_id="O3" value="0.1336" spread="0.1087"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change From Baseline in the Exacerbations of Chronic Pulmonary Disease Tool (EXACT) Respiratory Symptoms (E-RS) Daily Symptom Diary Total Score to the Primary Time Point</title>
        <description>The E-RS scale is a participant-reported outcome (PRO) designed to measure the symptoms of participants with chronic obstructive pulmonary disease (COPD). The E-RS utilizes 11 respiratory symptom items from the existing and validated 14-item EXACT, which measures symptoms of exacerbation. The E-RS total score quantifies respiratory symptom severity, and 3 domains assess breathlessness (comprised of 5 items, score range [0-17]), cough and sputum (comprised of 3 items, score range [0-11]), and chest symptoms (comprised of 3 items, score range [0-12]). The E-RS was collected on the daily e-diary. The total score was derived by summing the 11-item scores and ranged between 0 to 40 with higher values indicating severe respiratory symptoms. The primary time point was defined as the average of weeks 13 and 14.</description>
        <time_frame>From Baseline up to average of weeks 13 and 14</time_frame>
        <population>FAS included all randomized participants who received at least 1 dose of study drug (ION-827359 or placebo) and who had at least 1 post-Baseline efficacy assessment (i.e., post-Baseline FEV1 assessment, E-RS score, CAT score, or SGRQ-C score). Overall number of participants analyzed is the number of participants with data available for analyses in this outcome measure.</population>
        <group_list>
          <group group_id="O1">
            <title>Placebo</title>
            <description>Single-dose of placebo was administered by oral inhalation via nebulizer, once every week for up to 13 weeks.</description>
          </group>
          <group group_id="O2">
            <title>ION-827359 37.5 mg</title>
            <description>Single-dose of ION-827359 37.5 mg was administered by oral inhalation via nebulizer, once every week for up to 13 weeks</description>
          </group>
          <group group_id="O3">
            <title>ION-827359 75 mg</title>
            <description>Single-dose of ION-827359 75 mg was administered by oral inhalation via nebulizer, once every week for up to 13 weeks.</description>
          </group>
        </group_list>
        <measure>
          <title>Change From Baseline in the Exacerbations of Chronic Pulmonary Disease Tool (EXACT) Respiratory Symptoms (E-RS) Daily Symptom Diary Total Score to the Primary Time Point</title>
          <description>The E-RS scale is a participant-reported outcome (PRO) designed to measure the symptoms of participants with chronic obstructive pulmonary disease (COPD). The E-RS utilizes 11 respiratory symptom items from the existing and validated 14-item EXACT, which measures symptoms of exacerbation. The E-RS total score quantifies respiratory symptom severity, and 3 domains assess breathlessness (comprised of 5 items, score range [0-17]), cough and sputum (comprised of 3 items, score range [0-11]), and chest symptoms (comprised of 3 items, score range [0-12]). The E-RS was collected on the daily e-diary. The total score was derived by summing the 11-item scores and ranged between 0 to 40 with higher values indicating severe respiratory symptoms. The primary time point was defined as the average of weeks 13 and 14.</description>
          <population>FAS included all randomized participants who received at least 1 dose of study drug (ION-827359 or placebo) and who had at least 1 post-Baseline efficacy assessment (i.e., post-Baseline FEV1 assessment, E-RS score, CAT score, or SGRQ-C score). Overall number of participants analyzed is the number of participants with data available for analyses in this outcome measure.</population>
          <units>score on a scale</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="4"/>
                <count group_id="O2" value="5"/>
                <count group_id="O3" value="4"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-1.08" spread="1.171"/>
                    <measurement group_id="O2" value="-1.41" spread="2.486"/>
                    <measurement group_id="O3" value="-1.99" spread="4.217"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change From Baseline in the Chronic Obstructive Pulmonary Disease (COPD) Assessment Test (CAT) to the Week 14 Time Point</title>
        <description>The CAT is an eight-item questionnaire that was completed by the participant and is designed to quantify the impact of COPD symptoms on the health status of participants. Each item is rated on a 6-point scale ranging from 0 (no impairment) to 5 (maximum impairment). The total CAT score is calculated by summing the scores of all items and ranges from 0 to 40. Higher scores indicate a severe condition (more severe impact of COPD on a participant's life).</description>
        <time_frame>From Baseline to Week 14</time_frame>
        <population>FAS included all randomized participants who received at least 1 dose of study drug (ION-827359 or placebo) and who had at least 1 post-Baseline efficacy assessment (i.e., post-Baseline FEV1 assessment, E-RS score, CAT score, or SGRQ-C score). Overall number of participants analyzed is the number of participants with data available for analyses in this outcome measure.</population>
        <group_list>
          <group group_id="O1">
            <title>Placebo</title>
            <description>Single-dose of placebo was administered by oral inhalation via nebulizer, once every week for up to 13 weeks.</description>
          </group>
          <group group_id="O2">
            <title>ION-827359 37.5 mg</title>
            <description>Single-dose of ION-827359 37.5 mg was administered by oral inhalation via nebulizer, once every week for up to 13 weeks.</description>
          </group>
          <group group_id="O3">
            <title>ION-827359 75 mg</title>
            <description>Single-dose of ION-827359 75 mg was administered by oral inhalation via nebulizer, once every week for up to 13 weeks.</description>
          </group>
        </group_list>
        <measure>
          <title>Change From Baseline in the Chronic Obstructive Pulmonary Disease (COPD) Assessment Test (CAT) to the Week 14 Time Point</title>
          <description>The CAT is an eight-item questionnaire that was completed by the participant and is designed to quantify the impact of COPD symptoms on the health status of participants. Each item is rated on a 6-point scale ranging from 0 (no impairment) to 5 (maximum impairment). The total CAT score is calculated by summing the scores of all items and ranges from 0 to 40. Higher scores indicate a severe condition (more severe impact of COPD on a participant's life).</description>
          <population>FAS included all randomized participants who received at least 1 dose of study drug (ION-827359 or placebo) and who had at least 1 post-Baseline efficacy assessment (i.e., post-Baseline FEV1 assessment, E-RS score, CAT score, or SGRQ-C score). Overall number of participants analyzed is the number of participants with data available for analyses in this outcome measure.</population>
          <units>score on a scale</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="5"/>
                <count group_id="O2" value="5"/>
                <count group_id="O3" value="3"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-2.6" spread="2.51"/>
                    <measurement group_id="O2" value="-0.6" spread="3.78"/>
                    <measurement group_id="O3" value="0.0" spread="1.73"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change From Baseline in St. George's Respiratory Questionnaire - COPD Specific (SGRQ-C) Total Score to the Week 14 Time Point</title>
        <description>The SGRQ is a participant completed, a disease-specific instrument designed to measure impact on overall health, daily life, and perceived well-being in participants with obstructive airway disease. The shorter 40-item version (SGRQ-C) which does not specify a Recall Period and has been validated specifically for COPD participants was used in this study. It consists of 40 items each weighted from 0 to a possible maximum of 100. Items 1-7 produced the symptoms score, 9-12 the activity score, and items 8, 10, 11, 13 and 14 the impacts score. Each component sub-score was calculated as a percentage of the summed weights of each item out of the sum of the maximum possible weight for that component (range 0-100). The total score was calculated by summing the weights to all positive responses in each component, where a positive item indicated the presence of symptoms, expressed as a percentage (range 0-100). Higher scores indicated a worse outcome (more limitations)</description>
        <time_frame>From Baseline to Week 14</time_frame>
        <population>FAS included all randomized participants who received at least 1 dose of study drug (ION-827359 or placebo) and who had at least 1 post-Baseline efficacy assessment (i.e., post-Baseline FEV1 assessment, E-RS score, CAT score, or SGRQ-C score). Overall number of participants analyzed is the number of participants with data available for analyses in this outcome measure.</population>
        <group_list>
          <group group_id="O1">
            <title>Placebo</title>
            <description>Single-dose of placebo was administered by oral inhalation via nebulizer, once every week for up to 13 weeks.</description>
          </group>
          <group group_id="O2">
            <title>ION-827359 37.5 mg</title>
            <description>Single-dose of ION-827359 37.5 mg was administered by oral inhalation via nebulizer, once every week for up to 13 weeks.</description>
          </group>
          <group group_id="O3">
            <title>ION-827359 75 mg</title>
            <description>Single-dose of ION-827359 75 mg was administered by oral inhalation via nebulizer, once every week for up to 13 weeks.</description>
          </group>
        </group_list>
        <measure>
          <title>Change From Baseline in St. George's Respiratory Questionnaire - COPD Specific (SGRQ-C) Total Score to the Week 14 Time Point</title>
          <description>The SGRQ is a participant completed, a disease-specific instrument designed to measure impact on overall health, daily life, and perceived well-being in participants with obstructive airway disease. The shorter 40-item version (SGRQ-C) which does not specify a Recall Period and has been validated specifically for COPD participants was used in this study. It consists of 40 items each weighted from 0 to a possible maximum of 100. Items 1-7 produced the symptoms score, 9-12 the activity score, and items 8, 10, 11, 13 and 14 the impacts score. Each component sub-score was calculated as a percentage of the summed weights of each item out of the sum of the maximum possible weight for that component (range 0-100). The total score was calculated by summing the weights to all positive responses in each component, where a positive item indicated the presence of symptoms, expressed as a percentage (range 0-100). Higher scores indicated a worse outcome (more limitations)</description>
          <population>FAS included all randomized participants who received at least 1 dose of study drug (ION-827359 or placebo) and who had at least 1 post-Baseline efficacy assessment (i.e., post-Baseline FEV1 assessment, E-RS score, CAT score, or SGRQ-C score). Overall number of participants analyzed is the number of participants with data available for analyses in this outcome measure.</population>
          <units>score on a scale</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="5"/>
                <count group_id="O2" value="5"/>
                <count group_id="O3" value="3"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-15.93" spread="19.515"/>
                    <measurement group_id="O2" value="-1.74" spread="3.839"/>
                    <measurement group_id="O3" value="-0.76" spread="2.350"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change From Baseline in Post-Bronchodilator FEV1</title>
        <description>Post-bronchodilator FEV1 is the amount of air which can be forcibly exhaled from the lungs in the first second of a forced exhalation after administration of bronchodilator. Baseline was defined as the last non-missing measurement prior to the first study drug administration.</description>
        <time_frame>From Baseline to end of treatment (EOT) [Up to Week 14]</time_frame>
        <population>FAS included all randomized participants who received at least 1 dose of study drug (ION-827359 or placebo) and who had at least 1 post-Baseline efficacy assessment (i.e., post-Baseline FEV1 assessment, E-RS score, CAT score, or SGRQ-C score). Overall number of participants analyzed is the number of participants with data available for analyses in this outcome measure.</population>
        <group_list>
          <group group_id="O1">
            <title>Placebo</title>
            <description>Single-dose of placebo was administered by oral inhalation via nebulizer, once every week for up to 13 weeks.</description>
          </group>
          <group group_id="O2">
            <title>ION-827359 37.5 mg</title>
            <description>Single-dose of ION-827359 37.5 mg was administered by oral inhalation via nebulizer, once every week for up to 13 weeks.</description>
          </group>
          <group group_id="O3">
            <title>ION-827359 75 mg</title>
            <description>Single-dose of ION-827359 75 mg was administered by oral inhalation via nebulizer, once every week for up to 13 weeks.</description>
          </group>
        </group_list>
        <measure>
          <title>Change From Baseline in Post-Bronchodilator FEV1</title>
          <description>Post-bronchodilator FEV1 is the amount of air which can be forcibly exhaled from the lungs in the first second of a forced exhalation after administration of bronchodilator. Baseline was defined as the last non-missing measurement prior to the first study drug administration.</description>
          <population>FAS included all randomized participants who received at least 1 dose of study drug (ION-827359 or placebo) and who had at least 1 post-Baseline efficacy assessment (i.e., post-Baseline FEV1 assessment, E-RS score, CAT score, or SGRQ-C score). Overall number of participants analyzed is the number of participants with data available for analyses in this outcome measure.</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="3"/>
                <count group_id="O2" value="5"/>
                <count group_id="O3" value="3"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.0663" spread="0.0685"/>
                    <measurement group_id="O2" value="0.0320" spread="0.2379"/>
                    <measurement group_id="O3" value="0.1180" spread="0.1006"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Cmax: Maximum Observed Plasma Concentration for ION-827359</title>
        <time_frame>Days 1 and 85</time_frame>
        <population>Pharmacokinetic (PK) population included all participants who were randomized and received at least 1 dose of active study drug (ION-827359) and had at least 1 evaluable PK sample collected and analyzed with reportable result. Number analyzed is the number of participants with data available for analysis at the specified time point.</population>
        <group_list>
          <group group_id="O1">
            <title>ION-827359 37.5 mg</title>
            <description>Single-dose of ION-827359 37.5 mg was administered by oral inhalation via nebulizer, once every week for up to 13 weeks.</description>
          </group>
          <group group_id="O2">
            <title>ION-827359 75 mg</title>
            <description>Single-dose of ION-827359 75 mg was administered by oral inhalation via nebulizer, once every week for up to 13 weeks.</description>
          </group>
        </group_list>
        <measure>
          <title>Cmax: Maximum Observed Plasma Concentration for ION-827359</title>
          <population>Pharmacokinetic (PK) population included all participants who were randomized and received at least 1 dose of active study drug (ION-827359) and had at least 1 evaluable PK sample collected and analyzed with reportable result. Number analyzed is the number of participants with data available for analysis at the specified time point.</population>
          <units>nanogram per milliliter (ng/mL)</units>
          <param>Geometric Mean</param>
          <dispersion>Geometric Coefficient of Variation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="6"/>
                <count group_id="O2" value="6"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Day 1</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="6"/>
                    <count group_id="O2" value="6"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="85.6" spread="198"/>
                    <measurement group_id="O2" value="203" spread="52.6"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Day 85</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="1"/>
                    <count group_id="O2" value="2"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="53.5" spread="NA">The geometric coefficient of variation was not estimable due to lower number of participants.</measurement>
                    <measurement group_id="O2" value="195" spread="124"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Tmax: Time to Reach the Maximum Plasma Concentration for ION-827359</title>
        <time_frame>Days 1 and 85</time_frame>
        <population>PK population included all participants who were randomized and received at least 1 dose of active study drug (ION-827359) and had at least 1 evaluable PK sample collected and analyzed with reportable result. Number analyzed is the number of participants with data available for analysis at the specified time point.</population>
        <group_list>
          <group group_id="O1">
            <title>ION-827359 37.5 mg</title>
            <description>Single-dose of ION-827359 37.5 mg was administered by oral inhalation via nebulizer, once every week for up to 13 weeks.</description>
          </group>
          <group group_id="O2">
            <title>ION-827359 75 mg</title>
            <description>Single-dose of ION-827359 75 mg was administered by oral inhalation via nebulizer, once every week for up to 13 weeks.</description>
          </group>
        </group_list>
        <measure>
          <title>Tmax: Time to Reach the Maximum Plasma Concentration for ION-827359</title>
          <population>PK population included all participants who were randomized and received at least 1 dose of active study drug (ION-827359) and had at least 1 evaluable PK sample collected and analyzed with reportable result. Number analyzed is the number of participants with data available for analysis at the specified time point.</population>
          <units>hours</units>
          <param>Median</param>
          <dispersion>Full Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="6"/>
                <count group_id="O2" value="6"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Day 1</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="6"/>
                    <count group_id="O2" value="6"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1.54" lower_limit="0.567" upper_limit="2.05"/>
                    <measurement group_id="O2" value="1.64" lower_limit="0.667" upper_limit="2.12"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Day 85</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="1"/>
                    <count group_id="O2" value="2"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1.98" lower_limit="1.98" upper_limit="1.98"/>
                    <measurement group_id="O2" value="3.11" lower_limit="1.73" upper_limit="4.48"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>AUC[0-24h]: Area Under the Plasma Concentration-Time Curve From Time Zero to 24 Hours for ION-827359</title>
        <time_frame>Days 1 and 85</time_frame>
        <population>PK population consisted of all the participants who were randomized and received at least 1 dose of active study drug (ION-827359) and had at least 1 evaluable PK sample collected and analyzed with reportable result. Number analyzed is the number of participants with data available for analysis at the specified time point.</population>
        <group_list>
          <group group_id="O1">
            <title>ION-827359 37.5 mg</title>
            <description>Single-dose of ION-827359 37.5 mg was administered by oral inhalation via nebulizer, once every week for up to 13 weeks.</description>
          </group>
          <group group_id="O2">
            <title>ION-827359 75 mg</title>
            <description>Single-dose of ION-827359 75 mg was administered by oral inhalation via nebulizer, once every week for up to 13 weeks.</description>
          </group>
        </group_list>
        <measure>
          <title>AUC[0-24h]: Area Under the Plasma Concentration-Time Curve From Time Zero to 24 Hours for ION-827359</title>
          <population>PK population consisted of all the participants who were randomized and received at least 1 dose of active study drug (ION-827359) and had at least 1 evaluable PK sample collected and analyzed with reportable result. Number analyzed is the number of participants with data available for analysis at the specified time point.</population>
          <units>hours*nanogram per milliliter (h*ng/mL)</units>
          <param>Geometric Mean</param>
          <dispersion>Geometric Coefficient of Variation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="6"/>
                <count group_id="O2" value="6"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Day 1</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="6"/>
                    <count group_id="O2" value="6"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="528" spread="190"/>
                    <measurement group_id="O2" value="1323" spread="66.0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Day 85</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="1"/>
                    <count group_id="O2" value="2"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="312" spread="NA">The geometric coefficient of variation was not estimable due to lower number of participants.</measurement>
                    <measurement group_id="O2" value="2416" spread="252"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Percentage of Participants With at Least One Treatment-Emergent Adverse Event (TEAE) Based on Severity</title>
        <description>An AE can be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of medicinal (investigational) product, whether or not the AE is considered related to the medicinal (investigational) product. A TEAE is defined as any AE starting or getting worse on or after the first dose of the study drug. The severity of a TEAE was assessed by the investigator and classified into one of the following: mild, moderate, and severe.</description>
        <time_frame>Up to Week 24</time_frame>
        <population>Safety population included all participants who were randomized and received at least 1 dose of study drug.</population>
        <group_list>
          <group group_id="O1">
            <title>Placebo</title>
            <description>Single-dose of placebo was administered by oral inhalation via nebulizer, once every week for up to 13 weeks.</description>
          </group>
          <group group_id="O2">
            <title>ION-827359 37.5 mg</title>
            <description>Single-dose of ION-827359 37.5 mg was administered by oral inhalation via nebulizer, once every week for up to 13 weeks.</description>
          </group>
          <group group_id="O3">
            <title>ION-827359 75 mg</title>
            <description>Single-dose of ION-827359 75 mg was administered by oral inhalation via nebulizer, once every week for up to 13 weeks.</description>
          </group>
        </group_list>
        <measure>
          <title>Percentage of Participants With at Least One Treatment-Emergent Adverse Event (TEAE) Based on Severity</title>
          <description>An AE can be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of medicinal (investigational) product, whether or not the AE is considered related to the medicinal (investigational) product. A TEAE is defined as any AE starting or getting worse on or after the first dose of the study drug. The severity of a TEAE was assessed by the investigator and classified into one of the following: mild, moderate, and severe.</description>
          <population>Safety population included all participants who were randomized and received at least 1 dose of study drug.</population>
          <units>percentage of participants</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="19"/>
                <count group_id="O2" value="21"/>
                <count group_id="O3" value="19"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Mild</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="10.5"/>
                    <measurement group_id="O2" value="14.3"/>
                    <measurement group_id="O3" value="15.8"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Moderate</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="52.6"/>
                    <measurement group_id="O2" value="38.1"/>
                    <measurement group_id="O3" value="63.2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Severe</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="10.5"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="5.3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Percentage of Participants With Clinically Significant Change in Laboratory Values</title>
        <description>Laboratory parameters for serum chemistry, hematology, urinalysis, coagulation, complement, and lipids were assessed.</description>
        <time_frame>Up to Week 24</time_frame>
        <population>Safety population included all participants who are were randomized and received at least 1 dose of study drug.</population>
        <group_list>
          <group group_id="O1">
            <title>Placebo</title>
            <description>Single-dose of placebo was administered by oral inhalation via nebulizer, once every week for up to 13 weeks</description>
          </group>
          <group group_id="O2">
            <title>ION-827359 37.5 mg</title>
            <description>Single-dose of ION-827359 37.5 mg was administered by oral inhalation via nebulizer, once every week for up to 13 weeks.</description>
          </group>
          <group group_id="O3">
            <title>ION-827359 75 mg</title>
            <description>Single-dose of ION-827359 75 mg was administered by oral inhalation via nebulizer, once every week for up to 13 weeks.</description>
          </group>
        </group_list>
        <measure>
          <title>Percentage of Participants With Clinically Significant Change in Laboratory Values</title>
          <description>Laboratory parameters for serum chemistry, hematology, urinalysis, coagulation, complement, and lipids were assessed.</description>
          <population>Safety population included all participants who are were randomized and received at least 1 dose of study drug.</population>
          <units>percentage of participants</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="19"/>
                <count group_id="O2" value="21"/>
                <count group_id="O3" value="19"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Percentage of Participants With Clinically Significant Change in Vital Sign Parameters</title>
        <description>Vital signs included assessment of heart rate, blood pressure, respiratory rate, and temperature.</description>
        <time_frame>Up to Week 24</time_frame>
        <population>Safety population included all participants who are were randomized and received at least 1 dose of study drug.</population>
        <group_list>
          <group group_id="O1">
            <title>Placebo</title>
            <description>Single-dose of placebo was administered by oral inhalation via nebulizer, once every week for up to 13 weeks</description>
          </group>
          <group group_id="O2">
            <title>ION-827359 37.5 mg</title>
            <description>Single-dose of ION-827359 37.5 mg was administered by oral inhalation via nebulizer, once every week for up to 13 weeks.</description>
          </group>
          <group group_id="O3">
            <title>ION-827359 75 mg</title>
            <description>Single-dose of ION-827359 75 mg was administered by oral inhalation via nebulizer, once every week for up to 13 weeks.</description>
          </group>
        </group_list>
        <measure>
          <title>Percentage of Participants With Clinically Significant Change in Vital Sign Parameters</title>
          <description>Vital signs included assessment of heart rate, blood pressure, respiratory rate, and temperature.</description>
          <population>Safety population included all participants who are were randomized and received at least 1 dose of study drug.</population>
          <units>percentage of participants</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="19"/>
                <count group_id="O2" value="21"/>
                <count group_id="O3" value="19"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Percentage of Participants With Clinically Significant Change in Electrocardiogram (ECG) Findings</title>
        <description>ECG parameters of ventricular rate, PR interval, QRS duration, QT, or QTc were assessed.</description>
        <time_frame>Up to Week 24</time_frame>
        <population>Safety population included all participants who were randomized and received at least 1 dose of study drug.</population>
        <group_list>
          <group group_id="O1">
            <title>Placebo</title>
            <description>Single-dose of placebo was administered by oral inhalation via nebulizer, once every week for up to 13 weeks.</description>
          </group>
          <group group_id="O2">
            <title>ION-827359 37.5 mg</title>
            <description>Single-dose of ION-827359 37.5 mg was administered by oral inhalation via nebulizer, once every week for up to 13 weeks.</description>
          </group>
          <group group_id="O3">
            <title>ION-827359 75 mg</title>
            <description>Single-dose of ION-827359 75 mg was administered by oral inhalation via nebulizer, once every week for up to 13 weeks.</description>
          </group>
        </group_list>
        <measure>
          <title>Percentage of Participants With Clinically Significant Change in Electrocardiogram (ECG) Findings</title>
          <description>ECG parameters of ventricular rate, PR interval, QRS duration, QT, or QTc were assessed.</description>
          <population>Safety population included all participants who were randomized and received at least 1 dose of study drug.</population>
          <units>percentage of participants</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="19"/>
                <count group_id="O2" value="21"/>
                <count group_id="O3" value="19"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>Up to Week 24</time_frame>
      <desc>Safety population included all participants who were randomized and received at least 1 dose of study drug.</desc>
      <group_list>
        <group group_id="E1">
          <title>Placebo</title>
          <description>Single-dose of placebo was administered by oral inhalation via nebulizer, once every week for up to 13 weeks.</description>
        </group>
        <group group_id="E2">
          <title>ION-827359 37.5 mg</title>
          <description>Single-dose of ION-827359 37.5 mg was administered by oral inhalation via nebulizer, once every week for up to 13 weeks.</description>
        </group>
        <group group_id="E3">
          <title>ION-827359 75 mg</title>
          <description>Single-dose of ION-827359 75 mg was administered by oral inhalation via nebulizer, once every week for up to 13 weeks.</description>
        </group>
      </group_list>
      <serious_events>
        <default_vocab>MedDRA 23.0</default_vocab>
        <default_assessment>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="19"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="19"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="19"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Cardiac disorders</title>
            <event_list>
              <event>
                <sub_title>Atrial flutter</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="19"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="19"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Diarrhoea</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="19"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Bronchospasm</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Dyspnoea</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="19"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>5</frequency_threshold>
        <default_vocab>MedDRA 23.0</default_vocab>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="14" subjects_at_risk="19"/>
                <counts group_id="E2" subjects_affected="8" subjects_at_risk="21"/>
                <counts group_id="E3" subjects_affected="16" subjects_at_risk="19"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Cardiac disorders</title>
            <event_list>
              <event>
                <sub_title>Cyanosis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="19"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Eye disorders</title>
            <event_list>
              <event>
                <sub_title>Eye irritation</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="19"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Diarrhoea</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="19"/>
                <counts group_id="E2" subjects_affected="4" subjects_at_risk="21"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Abdominal pain</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="19"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Dyspepsia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Gastritis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Tongue dry</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="19"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Burning sensation</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="21"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Chest discomfort</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Cyst</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="19"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Pyrexia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="19"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="19"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Hepatobiliary disorders</title>
            <event_list>
              <event>
                <sub_title>Cholecystitis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="19"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="19"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Immune system disorders</title>
            <event_list>
              <event>
                <sub_title>Vaccination complication</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="19"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="19"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Nasopharyngitis</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="19"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Urinary tract infection</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="19"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Bronchitis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Oral candidiasis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="19"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Injury, poisoning and procedural complications</title>
            <event_list>
              <event>
                <sub_title>Skin laceration</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="19"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>Blood creatine phosphokinase increased</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Blood glucose decreased</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>FEV1/FVC ratio decreased</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>SARS-CoV-2 test positive</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="19"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Muscle spasms</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Neck pain</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="19"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Headache</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="19"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Product Issues</title>
            <event_list>
              <event>
                <sub_title>Product taste abnormal</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="19"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Psychiatric disorders</title>
            <event_list>
              <event>
                <sub_title>Sleep disorder</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="19"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="19"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Cough</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="19"/>
                <counts group_id="E2" subjects_affected="5" subjects_at_risk="21"/>
                <counts group_id="E3" subjects_affected="7" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Chronic obstructive pulmonary disease</sub_title>
                <counts group_id="E1" subjects_affected="5" subjects_at_risk="19"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E3" subjects_affected="4" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Dyspnoea</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="21"/>
                <counts group_id="E3" subjects_affected="5" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Chest pain</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="19"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Sputum increased</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Throat irritation</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="19"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Bronchial irritation</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Bronchospasm</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Dysphonia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="19"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Nasal congestion</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Oropharyngeal pain</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Rhinitis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Rhinorrhoea</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Sputum discoloured</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="19"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Vascular disorders</title>
            <event_list>
              <event>
                <sub_title>Arteriosclerosis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Peripheral vascular disorder</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="19"/>
              </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>
    </certain_agreements>
    <limitations_and_caveats>The study was terminated based on the toxicology findings from a 9-month study and participants who had not completed the treatment period were instructed to terminate dosing and return for an end of study visit, followed by the 10-week follow-up period.</limitations_and_caveats>
    <point_of_contact>
      <name_or_title>Ionis Pharmaceuticals, Inc</name_or_title>
      <organization>Ionis Pharmaceuticals, Inc</organization>
      <phone>800-679-4747</phone>
      <email>patients@ionisph.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/NCT04441788
org study id: ION-827359-CS2
secondary id: 2020-000210-15
nct id: NCT04441788
lead sponsor: 
has dmc: No
is fda regulated drug: Yes
is fda regulated device: No
is us export: Yes
The purpose of this study was to evaluate the effect of ION-827359 on forced expiratory
      volume in 1 second (FEV1) in participants with mild to moderate COPD with CB.
This was a multi-center, double-blind, placebo-controlled, randomized, Phase 2a study of
      ION-827359 in up to 180 participants. The participants were randomized to receive oral
      inhalation of either ION-827359 or placebo for up to 13 weeks. At the end of 13 weeks,
      participants entered a 10-week post-treatment evaluation period.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Double (Participant, Investigator)
measure: Change From Baseline to the Primary Time Point in Forced Expiratory Volume in 1 Second (FEV1) Compared to Placebo
time frame: From Baseline up to average of Weeks 13 and 14
description: FEV1 is the amount of air which can be forcibly exhaled from the lungs in the first second of a forced exhalation. Baseline was defined as the last non-missing measurement prior to the first study drug administration. The primary time point was defined as the average of weeks 13 and 14. FAS=Full analysis set.
measure: Change From Baseline in the Exacerbations of Chronic Pulmonary Disease Tool (EXACT) Respiratory Symptoms (E-RS) Daily Symptom Diary Total Score to the Primary Time Point
time frame: From Baseline up to average of weeks 13 and 14
description: The E-RS scale is a participant-reported outcome (PRO) designed to measure the symptoms of participants with chronic obstructive pulmonary disease (COPD). The E-RS utilizes 11 respiratory symptom items from the existing and validated 14-item EXACT, which measures symptoms of exacerbation. The E-RS total score quantifies respiratory symptom severity, and 3 domains assess breathlessness (comprised of 5 items, score range [0-17]), cough and sputum (comprised of 3 items, score range [0-11]), and chest symptoms (comprised of 3 items, score range [0-12]). The E-RS was collected on the daily e-diary. The total score was derived by summing the 11-item scores and ranged between 0 to 40 with higher values indicating severe respiratory symptoms. The primary time point was defined as the average of weeks 13 and 14.
measure: Change From Baseline in the Chronic Obstructive Pulmonary Disease (COPD) Assessment Test (CAT) to the Week 14 Time Point
time frame: From Baseline to Week 14
description: The CAT is an eight-item questionnaire that was completed by the participant and is designed to quantify the impact of COPD symptoms on the health status of participants. Each item is rated on a 6-point scale ranging from 0 (no impairment) to 5 (maximum impairment). The total CAT score is calculated by summing the scores of all items and ranges from 0 to 40. Higher scores indicate a severe condition (more severe impact of COPD on a participant's life).
measure: Change From Baseline in St. George's Respiratory Questionnaire - COPD Specific (SGRQ-C) Total Score to the Week 14 Time Point
time frame: From Baseline to Week 14
description: The SGRQ is a participant completed, a disease-specific instrument designed to measure impact on overall health, daily life, and perceived well-being in participants with obstructive airway disease. The shorter 40-item version (SGRQ-C) which does not specify a Recall Period and has been validated specifically for COPD participants was used in this study. It consists of 40 items each weighted from 0 to a possible maximum of 100. Items 1-7 produced the symptoms score, 9-12 the activity score, and items 8, 10, 11, 13 and 14 the impacts score. Each component sub-score was calculated as a percentage of the summed weights of each item out of the sum of the maximum possible weight for that component (range 0-100). The total score was calculated by summing the weights to all positive responses in each component, where a positive item indicated the presence of symptoms, expressed as a percentage (range 0-100). Higher scores indicated a worse outcome (more limitations)
measure: Change From Baseline in Post-Bronchodilator FEV1
time frame: From Baseline to end of treatment (EOT) [Up to Week 14]
description: Post-bronchodilator FEV1 is the amount of air which can be forcibly exhaled from the lungs in the first second of a forced exhalation after administration of bronchodilator. Baseline was defined as the last non-missing measurement prior to the first study drug administration.
measure: Cmax: Maximum Observed Plasma Concentration for ION-827359
time frame: Days 1 and 85
measure: Tmax: Time to Reach the Maximum Plasma Concentration for ION-827359
time frame: Days 1 and 85
measure: AUC[0-24h]: Area Under the Plasma Concentration-Time Curve From Time Zero to 24 Hours for ION-827359
time frame: Days 1 and 85
measure: Percentage of Participants With at Least One Treatment-Emergent Adverse Event (TEAE) Based on Severity
time frame: Up to Week 24
description: An AE can be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of medicinal (investigational) product, whether or not the AE is considered related to the medicinal (investigational) product. A TEAE is defined as any AE starting or getting worse on or after the first dose of the study drug. The severity of a TEAE was assessed by the investigator and classified into one of the following: mild, moderate, and severe.
measure: Percentage of Participants With Clinically Significant Change in Laboratory Values
time frame: Up to Week 24
description: Laboratory parameters for serum chemistry, hematology, urinalysis, coagulation, complement, and lipids were assessed.
measure: Percentage of Participants With Clinically Significant Change in Vital Sign Parameters
time frame: Up to Week 24
description: Vital signs included assessment of heart rate, blood pressure, respiratory rate, and temperature.
measure: Percentage of Participants With Clinically Significant Change in Electrocardiogram (ECG) Findings
time frame: Up to Week 24
description: ECG parameters of ventricular rate, PR interval, QRS duration, QT, or QTc were assessed.
arm group label: Placebo
arm group type: Placebo Comparator
description: Single-dose of placebo was administered by oral inhalation via nebulizer, once every week for up to 13 weeks.
arm group label: ION-827359 37.5 milligrams (mg)
arm group type: Experimental
description: Single-dose of ION-827359 37.5 mg was administered by oral inhalation via nebulizer, once every week for up to 13 weeks.
arm group label: ION-827359 75 mg
arm group type: Experimental
description: Single-dose of ION-827359 75 mg was administered by oral inhalation via nebulizer, once every week for up to 13 weeks.
intervention type: Drug
intervention name: ION-827359
description: ION-827359 administered by oral inhalation
arm group label: ION-827359 37.5 milligrams (mg)
intervention type: Drug
intervention name: Placebo
description: Placebo administered by oral inhalation
arm group label: Placebo
intervention type: Drug
intervention name: ION-827359
description: ION-827359 administered by oral inhalation
arm group label: ION-827359 75 mg
criteria: 
gender: All
minimum age: 40 Years
maximum age: 70 Years
healthy volunteers: No
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
country: Czechia
country: Germany
country: Hungary
country: United Kingdom
responsible party type: Sponsor
mesh term: Bronchitis
mesh term: Bronchitis, Chronic
mesh term: Lung Diseases
mesh term: Lung Diseases, Obstructive
mesh term: Pulmonary Disease, Chronic Obstructive
mesh term: Acute Disease
sharing ipd: No
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
limitations and caveats: The study was terminated based on the toxicology findings from a 9-month study and participants who had not completed the treatment period were instructed to terminate dosing and return for an end of study visit, followed by the 10-week follow-up period.
point of contact: 