<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/NCT03766399</url>
  </required_header>
  <id_info>
    <org_study_id>D5371C00001</org_study_id>
    <nct_id>NCT03766399</nct_id>
  </id_info>
  <brief_title>A Study in Healthy Volunteers and Patients With Mild Asthma to Investigate the Safety, Anti-inflammatory Effect of Inhaled AZD0449</brief_title>
  <official_title>A Single-blind, Randomized, Placebo-Controlled 3-Part Study in Healthy Volunteers and Patients With Mild Asthma to Investigate the Safety, Tolerability and Pharmacokinetics of Inhaled AZD0449 Following Single and Multiple Ascending Doses and to Investigate the Anti-Inflammatory Effect of Inhaled AZD0449</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>AstraZeneca</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>AstraZeneca</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      This will be a Phase I, first in human (FIH) study consisting of the following parts: Part 1a&#xD;
      (SAD), Part 1b (IV Cohort), Part 2 (Multiple ascending dose (MAD), and Part 3 dry-powder&#xD;
      inhalation (DPI)/ Proof of mechanism (PoM). Part 1a of the study will be a randomized,&#xD;
      single-blind, placebo-controlled, SAD, sequential group design study performed at a single&#xD;
      study center. Part 1b, will be an open-label, single-dose, single-cohort study. It will&#xD;
      follow a 2-stage design in the way that participants from Part 1a will be selected for the IV&#xD;
      Cohort in Part 1b. Part 2 of the study will be a randomized, single-blind,&#xD;
      placebo-controlled, MAD, sequential group design and study performed at 3 study centers. Part&#xD;
      3a/b will be a randomized, single-blind, placebo-controlled, DPI/PoM study. The expected&#xD;
      duration of each subject in Part 1a of the study is up to 36 days and up to 53 days for&#xD;
      subjects participating in Part 1b. The expected duration of each participant in Part 2 is up&#xD;
      to 52 days and Part 3 is up to 55 days.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This will be a Phase I, consisting of the following parts: Part 1a, Part 1b, Part 2a/b, Part&#xD;
      3a/b. Part 1a of the study will be a randomized, single-blind, placebo-controlled, SAD,&#xD;
      sequential group design study performed at a single study center. Six inhaled dose levels of&#xD;
      AZD0449 nebulized suspension are planned to be investigated in 6 cohorts. Depending on&#xD;
      emerging safety and PK data, up to 3 additional inhaled dose levels (cohorts), within the&#xD;
      pre-specified dose range, may be added at the discretion of the Sponsor. Within each cohort,&#xD;
      6 volunteers will be randomized to receive an inhaled dose of AZD0449 nebulized suspension&#xD;
      and 2 volunteers will be randomized to receive inhaled placebo. Intravenous (IV) dosing in&#xD;
      Part 1b of the study will be initiated after the completion of cohort 6 in Part 1a or (if&#xD;
      Part 1a is completed with less than 6 cohorts) after completion of the last cohort in Part&#xD;
      1a. Part 1b, will be open-label and consist of 2 dose cohorts (IV 0.090 mg and 0.360 mg) and&#xD;
      be conducted in 12 healthy volunteers. Six (6) volunteers will be selected for the first IV&#xD;
      dose cohort in Part 1b following a 2-stage design. If Part 1b cannot be completed with 6&#xD;
      volunteers from Part 1a or if some of the data are considered not evaluable, up to 6&#xD;
      additional naïve volunteers may be enrolled. A second IV dose cohort in Part 1b will be&#xD;
      initiated after the evaluation of the PK and safety results from all cohorts in Part 1a and&#xD;
      completion of the first IV dose cohort in Part 1b. The second IV dose cohort will consist of&#xD;
      6 healthy volunteers who have not previously participated in the study (naïve volunteers).&#xD;
      Part 2a/b of the study will be a randomized, single-blind, placebo-controlled, MAD,&#xD;
      sequential group design study performed at approximately 3 study centers. Part 2a will&#xD;
      include cohorts 1 and 2, each comprising of 9 patients with mild asthma. Within each of these&#xD;
      cohorts 6 patients will be randomized to receive AZD0449 nebulized suspension and 3 patients&#xD;
      randomized to receive placebo. Additional cohorts with 9 patients could be added to study PK,&#xD;
      PD and safety for doses lower than 1.2 mg or up to 5 mg. Part 2b will consist of 1 cohort of&#xD;
      8 healthy volunteers; 6 volunteers will be randomized to receive AZD0449 nebulized suspension&#xD;
      and 2 volunteers will be randomized to receive placebo. Part 3a/b of the study will be&#xD;
      initiated after the completion of Part 2b. Part 3a/b will be a randomized, single-blind,&#xD;
      placebo-controlled, DPI/PoM study. Part 3 will be conducted in up to 36 patients with mild&#xD;
      asthma (Part 3a) and 8 healthy volunteers (Part 3b, optional). Part 3a will consist of 36&#xD;
      patients, where 18 patients will be randomized to AZD0449 DPI and 18 patients to placebo. An&#xD;
      Interim Analysis (IA) will be conducted when 9 patients on each arm have completed the study&#xD;
      (50% Part 3a). Should new data on the variability of the FeNO measurements emerge at the IA,&#xD;
      the sample size in Part 3a could be changed. If the optional Part 3b is conducted, it will&#xD;
      comprise 8 healthy volunteers; 6 volunteers will be randomized to AZD0449 DPI and 2&#xD;
      volunteers to placebo.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">November 30, 2018</start_date>
  <completion_date type="Actual">June 24, 2021</completion_date>
  <primary_completion_date type="Actual">June 24, 2021</primary_completion_date>
  <phase>Phase 1</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Sequential Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Single (Participant)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Number of participants with treatment-emergent adverse events</measure>
    <time_frame>From screening up to follow-up visit [part 1 a/b (6±1 Days post-dose)] [part 2a (Day 22±1 (10±1 days post-last dose)], Safety Monitoring Period 2b/3a [Day 17 to 27 (15 day post-last dose)].</time_frame>
    <description>Safety and tolerability of AZD0449 following inhaled administration of single ascending doses to healthy volunteers, intravenous administration of a single dose to healthy volunteers, inhaled nebulized administration of multiple ascending doses healthy volunteers and patients with mild asthma, and repeated inhaled administration to patients with mild asthma using a DPI will be assessed.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Number of participants with abnormal ECGs</measure>
    <time_frame>From screening up to follow-up visit [part 1 a/b (6±1 Days post-dose)] [part 2a (Day 22±1 (10±1 days post-last dose)], Safety Monitoring Period 2b/3a [Day 17 to 27 (15 day post-last dose)].</time_frame>
    <description>The following parameters will be assessed using a 12-lead ECG: heart rate, PR, QRS, QT, QTcF (Fridericia's formula).</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Number of participants with abnormal findings in 12-lead digital electrocardiogram (12-lead dECG)</measure>
    <time_frame>Part 1a and 1b (at Days 1 to 3), part 2a (from Day 1 to 15), part 2b, 3a and 3b (from Day 1 to 16).</time_frame>
    <description>Abnormal findings in 12-lead dECG will be assessed using Mortara Telemetry Surveyor equipment.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Number of participants with abnormal telemetry findings</measure>
    <time_frame>Part 1a (at Day -1 to Day 3) 1b (at Days -1 to Day 2) part 2 &amp; 3 (at Day -1, Day 1 &amp; 2, and Day 3 to Day 15.)</time_frame>
    <description>Abnormal telemetry will be assessed as a variable of safety and tolerability after administration of AZD0449 following inhaled administration of single ascending doses to healthy volunteers, intravenous administration of a single dose to healthy volunteers, inhaled nebulized administration of multiple ascending doses to healthy volunteers and patients with mild asthma, and repeated inhaled administration to patients with mild asthma using a DPI.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Number of participants with abnormal physical examinations</measure>
    <time_frame>From screening up to follow-up visit [part 1a/b (6±1 Days post-dose)] [part 2a (Day 22±1 (10±1 days post-last dose)], Safety Monitoring Period 2b/3a [Day 17 to 27 (15 day post-last dose)].</time_frame>
    <description>Complete physical examinations will include an assessment of the skin, lungs, cardiovascular system, and abdomen (liver and spleen)</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Number of participants with spirometry findings</measure>
    <time_frame>From screening up to follow-up visit [part 1a &amp; 1b (6±1 Days post-dose) Part 2 &amp; 3 (6 Days post-last dose)]</time_frame>
    <description>Spirometry will be assessed as a variable of safety and tolerability after administration of AZD0449 following inhaled administration of single ascending doses to healthy volunteers, intravenous administration of a single dose to healthy volunteers, inhaled nebulized administration of multiple ascending doses to healthy volunteers and patients with mild asthma, and repeated inhaled administration to patients with mild asthma using a DPI.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Number of participants with pulse oximetry (SpO2) findings</measure>
    <time_frame>From screening up to follow-up visit [Part 1a &amp; 1b (6±1 Days post-dose) Part 2 &amp; 3 (6 Days post-last dose)]</time_frame>
    <description>Pulse oximetry findings will be assessed as a variable of safety and tolerability after administration of AZD0449 following inhaled administration of single ascending doses to healthy volunteers, intravenous administration of a single dose to healthy volunteers, inhaled nebulized administration of multiple ascending doses to healthy volunteers and patients with mild asthma, and repeated inhaled administration to patients with mild asthma using a DPI.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Number of participants with abnormal laboratory tests results</measure>
    <time_frame>From screening up to follow-up visit [Part 1a/b (6±1 Days post-dose)] [part 2a (Day 22±1 (10±1 days post-last dose)], Safety Monitoring Period 2b/3a [Day 17 to 27 (15 day post-last dose)].</time_frame>
    <description>Evaluation of clinically significant changes from baseline in laboratory evaluation (hematology, chemistry, coagulation, urinalysis)</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Number of participants with abnormal vital signs</measure>
    <time_frame>From screening up to follow-up visit [Part 1a/b (6±1 Days post-dose)] [part 2a (Day 22±1 (10±1 days post-last dose)], Safety Monitoring Period 2b/3a [Day 17 to 27 (15 day post-last dose)].</time_frame>
    <description>Evaluation of clinically significant changes in vital signs will include body temperature, respiratory rate, heart rate and systolic and diastolic blood pressure</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Maximum observed plasma concentration (Cmax)</measure>
    <time_frame>Part 1a: Day 1 to 4. Part 1b: Day 1 to 3. Part 2 &amp; 3: Days 1 to 2, Day 3 to 15, and Day 16 to 20.</time_frame>
    <description>Cmax of AZD0449 following inhaled administration of single ascending doses of AZD0449, intravenous administration of a single dose to healthy volunteers, inhaled nebulized administration of multiple ascending doses to healthy volunteers and patients with mild asthma, and repeated inhaled administration to patients with mild asthma using a DPI.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Time to reach peak or maximum observed concentration following drug administration (tmax)</measure>
    <time_frame>Part 1a: Day 1 to 4. Part 1b: Day 1 to 3. Part 2 &amp; 3: Days 1 to 2, Day 3 to 15, and Day 16 to 20.</time_frame>
    <description>tmax of AZD0449 following inhaled administration of single ascending doses of AZD0449, intravenous administration of a single dose to healthy volunteers, inhaled nebulized administration of multiple ascending doses to healthy volunteers and patients with mild asthma, and repeated inhaled administration to patients with mild asthma using a DPI.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Terminal rate constant, estimated by loglinear leastsquares regression of the terminal part of the -concentrationtime- curve (λz)</measure>
    <time_frame>Part 1a: Day 1 to 4. Part 1b: Day 1 to 3. Part 2 &amp; 3: Days 1 to 2, Day 3 to 15, and Day 16 to 20.</time_frame>
    <description>λz of AZD0449 following inhaled administration of single ascending doses of AZD0449, intravenous administration of a single dose to healthy volunteers, inhaled nebulized administration of multiple ascending doses to healthy volunteers and patients with mild asthma, and repeated inhaled administration to patients with mild asthma using a DPI.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Terminal halflife, estimated as (ln2)/-λz (t½λz )</measure>
    <time_frame>Part 1a: Day 1 to 4. Part 1b: Day 1 to 3. Part 2 &amp; 3: Days 1 to 2, Day 3 to 15, and Day 16 to 20.</time_frame>
    <description>t½λz of AZD0449 following inhaled administration of single ascending doses of AZD0449, intravenous administration of a single dose to healthy volunteers, inhaled nebulized administration of multiple ascending doses to healthy volunteers and patients with mild asthma, and repeated inhaled administration to patients with mild asthma using a DPI.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Area under the plasma concentration time curve from time zero to 24 hours after dosing (AUC(0-24))</measure>
    <time_frame>Part 1a: Day 1 to 4. Part 1b: Day 1 to 3. Part 2 &amp; 3: Days 1 to 2, Day 3 to 15, and Day 16 to 20.</time_frame>
    <description>AUC (0-24) of AZD0449 following inhaled administration of single ascending doses of AZD0449, intravenous administration of a single dose to healthy volunteers, inhaled nebulized administration of multiple ascending doses to healthy volunteers and patients with mild asthma, and repeated inhaled administration to patients with mild asthma using a DPI.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Area under the plasma concentration curve from time zero to the time of last quantifiable concentration (AUC(0-t))</measure>
    <time_frame>Part 1a: Day 1 to 4, Part 1b: Day 1 to 3, Part 2 &amp; 3 (QD): Day 1 to 2, Day 3 to 12, Day 13 to 15, Day 18, Part 2 &amp; 3 (BID): Day 1 to 2, Day 3 to 13, Day 14 to 16, Day 19.</time_frame>
    <description>AUC(0-t) of AZD0449 following inhaled administration of single ascending doses of AZD0449, intravenous administration of a single dose to healthy volunteers, inhaled nebulized administration of multiple ascending doses to healthy volunteers and patients with mild asthma, and repeated inhaled administration to patients with mild asthma using a DPI.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Area under the plasma concentration time curve (AUC)</measure>
    <time_frame>Part 1a: Day 1 to 4, Part 1b: Day 1 to 3, Part 2 &amp; 3: Days 1 to 2, Day 3 to 15, and Day 16 to 20.</time_frame>
    <description>AUC of AZD0449 following inhaled administration of single ascending doses of AZD0449, intravenous administration of a single dose to healthy volunteers, inhaled nebulized administration of multiple ascending doses to healthy volunteers and patients with mild asthma, and repeated inhaled administration to patients with mild asthma using a DPI.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Apparent total body clearance of drug from plasma after extravascular administration (CL/F)</measure>
    <time_frame>Part 1a: Day 1 to 4, Part 2 &amp; 3: Days 1 to 2, Day 3 to 15, and Day 16 to 20.</time_frame>
    <description>CL/F of AZD0449 following inhaled administration of single ascending doses of AZD0449, inhaled nebulized administration of multiple ascending doses to healthy volunteers and patients with mild asthma, and repeated inhaled administration to patients with mild asthma using a DPI.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Area under the plasma concentration-time curve from time zero to 12 hours post-dose (AUC(0-12))</measure>
    <time_frame>Part 1a: Day 1 to 4, Part 1b: Day 1 to 3, Part 2 &amp; 3 (QD): Day1 to 2, Day 3 to 12, Day 13 to 15, Day 18, Part 2 &amp; 3 (BID): Day 1 to 2, Day 3 to 13, Day 14 to 16, Day 19.</time_frame>
    <description>AUC(0-12) of AZD0449 following inhaled administration of single ascending doses of AZD0449, intravenous administration of a single dose to healthy volunteers, inhaled nebulized administration of multiple ascending doses to healthy volunteers and patients with mild asthma, and repeated inhaled administration to patients with mild asthma using a DPI.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Apparent volume of distribution for parent drug at terminal phase (extravascular administration), estimated by dividing the apparent clearance (CL/F) by λz (Vz/F)</measure>
    <time_frame>Part 1a: Day 1 to 4, Part 2 &amp; 3: Days 1 to 2, Day 3 to 15, and Day 16 to 20.</time_frame>
    <description>Vz/F of AZD0449 following inhaled administration of single ascending doses of AZD0449, inhaled nebulized administration of multiple ascending doses to healthy volunteers and patients with mild asthma, and repeated inhaled administration to patients with mild asthma using a DPI.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Dose normalized AUC(0-t) (AUC(0-t)/D)</measure>
    <time_frame>Part 1a: Day 1 to 4, Part 1b: Day 1 to 3, Part 2 &amp; 3 (QD): Day1 to 2, Day 3 to 12, Day 13 to 15, Day 18, Part 2 &amp; 3 (BID): Day 1 to 2, Day 3 to 13, Day 14 to 16, Day 19.</time_frame>
    <description>AUC(0-t)/D of AZD0449 following inhaled administration of single ascending doses of AZD0449, intravenous administration of a single dose to healthy volunteers, inhaled nebulized administration of multiple ascending doses to healthy volunteers and patients with mild asthma, and repeated inhaled administration to patients with mild asthma using a DPI.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Dose normalized AUC (AUC/D)</measure>
    <time_frame>Part 1a: Day 1 to 4, Part 1b: Day 1 to 3, Part 2 &amp; 3: Days 1 to 2, Day 3 to 15, and Day 16 to 20.</time_frame>
    <description>AUC/D of AZD0449 following inhaled administration of single ascending doses of AZD0449, intravenous administration of a single dose to healthy volunteers, inhaled nebulized administration of multiple ascending doses to healthy volunteers and patients with mild asthma, and repeated inhaled administration to patients with mild asthma using a DPI.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Dose normalized Cmax (Cmax/D)</measure>
    <time_frame>Part 1a: Day 1 to 4, Part 1b: Day 1 to 3, Part 2 &amp; 3: Days 1 to 2, Day 3 to 15, and Day 16 to 20.</time_frame>
    <description>Cmax/D of AZD0449 following inhaled administration of single ascending doses of AZD0449, intravenous administration of a single dose to healthy volunteers, inhaled nebulized administration of multiple ascending doses to healthy volunteers and patients with mild asthma, and repeated inhaled administration to patients with mild asthma using a DPI.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Time of last quantifiable concentration (tlast)</measure>
    <time_frame>Part 1a: Day 1 to 4, Part 1b: Day 1 to 3, Part 2 &amp; 3: Days 1 to 2, Day 3 to 15, and Day 16 to 20.</time_frame>
    <description>tlast of AZD0449 following inhaled administration of single ascending doses of AZD0449, intravenous administration of a single dose to healthy volunteers, inhaled nebulized administration of multiple ascending doses to healthy volunteers and patients with mild asthma, and repeated inhaled administration to patients with mild asthma using a DPI.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Volume of distribution for parent drug at terminal phase (intravenous administration), estimated by dividing the systemic clearance (CL) by λz</measure>
    <time_frame>Part 1b: Day 1 to 3</time_frame>
    <description>Vz of AZD0449 following inhaled administration of intravenous administration of a single dose to healthy volunteers.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Total body clearance of drug from plasma after intravascular administration (CL)</measure>
    <time_frame>Part 1b: Day 1 to 3</time_frame>
    <description>CL of AZD0449 following inhaled administration of intravenous administration of a single dose to healthy volunteers.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Fractional excretion of nitric oxide (FeNO)</measure>
    <time_frame>Part 2 &amp; 3 (QD): At screening (Day -28 to -3), Day -1 to Day 12, follow-up visit Day 13 to 15, and Day 18. Part 2 &amp; 3 (BID): At screening (Day -28 to -3), Day -1 to Day 13, follow-up visit Day 14 to 16, and Day 19.</time_frame>
    <description>To evaluate anti-inflammatory effect in patients with mild asthma.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>FeNO AUC(0-12)</measure>
    <time_frame>Part 2 &amp; 3 (QD): At screening (Day -28 to -3), Day -1 to Day 12, follow-up visit Day 13 to 15, and Day 18. Part 2 &amp; 3 (BID): At screening (Day -28 to -3), Day -1 to Day 13, follow-up visit Day 14 to 16, and Day 19.</time_frame>
    <description>To evaluate anti-inflammatory effect in patients with mild asthma.</description>
  </secondary_outcome>
  <number_of_arms>13</number_of_arms>
  <enrollment type="Actual">131</enrollment>
  <condition>Asthma</condition>
  <arm_group>
    <arm_group_label>Part 1a (SAD) Cohort 1</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>6 participants will receive inhaled dose 1 of AZD0449 nebulized suspension and 2 participants will receive inhaled placebo.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Part 1a (SAD) Cohort 2</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>6 participants will receive inhaled dose 2 of AZD0449 nebulized suspension and 2 participants will receive inhaled placebo.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Part 1a (SAD) Cohort 3</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>6 participants will receive inhaled dose 3 of AZD0449 nebulized suspension and 2 participants will receive inhaled placebo.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Part 1a (SAD) Cohort 4</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>6 participants will receive inhaled dose 4 of AZD0449 nebulized suspension and 2 participants will receive inhaled placebo.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Part 1a (SAD) Cohort 5</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>6 participants will receive inhaled dose 5 of AZD0449 nebulized suspension and 2 participants will receive inhaled placebo.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Part 1a (SAD) Cohort 6</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>6 participants will receive inhaled dose 6 of AZD0449 nebulized suspension and 2 participants will receive inhaled placebo.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Part 1b (IV cohort 1)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>All 6 participants will receive single IV dose of AZD0449 solution.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Part 2a (MAD) Cohort 1</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>6 participants will receive inhaled dose 7 of AZD0449 nebulized suspension and 3 participants will receive inhaled placebo.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Part 2a (MAD) Cohort 2</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>6 participants will receive inhaled dose 8 of AZD0449 nebulized suspension and 3 participants will receive inhaled placebo.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Part 2b (MAD/healthy volunteers) Cohort 3</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>18 healthy volunteers will receive inhaled dose 9 of AZD0449 nebulized suspension and 12 healthy volunteers will receive inhaled placebo.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Part 3a (DPI/PoM)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>18 participants will receive inhaled dose 10 of AZD0449 DPI and 6 participants will receive inhaled placebo.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Part 1b (IV cohort 2)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>6 healthy volunteers will receive single IV dose of AZD0449 solution.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Part 3b (DPI/healthy volunteers)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Part 3b is optional. 8 healthy volunteers; 6 volunteers will receive AZD0449 DPI and 2 volunteers will recieve placebo.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>AZD0449</intervention_name>
    <description>Participants will receive single inhaled AZD0449 nebulizer suspension and single IV dose of AZD0449 solution.</description>
    <arm_group_label>Part 1a (SAD) Cohort 1</arm_group_label>
    <arm_group_label>Part 1a (SAD) Cohort 2</arm_group_label>
    <arm_group_label>Part 1a (SAD) Cohort 3</arm_group_label>
    <arm_group_label>Part 1a (SAD) Cohort 4</arm_group_label>
    <arm_group_label>Part 1a (SAD) Cohort 5</arm_group_label>
    <arm_group_label>Part 1a (SAD) Cohort 6</arm_group_label>
    <arm_group_label>Part 1b (IV cohort 1)</arm_group_label>
    <arm_group_label>Part 1b (IV cohort 2)</arm_group_label>
    <arm_group_label>Part 2a (MAD) Cohort 1</arm_group_label>
    <arm_group_label>Part 2a (MAD) Cohort 2</arm_group_label>
    <arm_group_label>Part 2b (MAD/healthy volunteers) Cohort 3</arm_group_label>
    <arm_group_label>Part 3a (DPI/PoM)</arm_group_label>
    <arm_group_label>Part 3b (DPI/healthy volunteers)</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>Participants will receive single dose of placebo for AZD0449 (nebulizer suspension).</description>
    <arm_group_label>Part 1a (SAD) Cohort 1</arm_group_label>
    <arm_group_label>Part 1a (SAD) Cohort 2</arm_group_label>
    <arm_group_label>Part 1a (SAD) Cohort 3</arm_group_label>
    <arm_group_label>Part 1a (SAD) Cohort 4</arm_group_label>
    <arm_group_label>Part 1a (SAD) Cohort 5</arm_group_label>
    <arm_group_label>Part 1a (SAD) Cohort 6</arm_group_label>
    <arm_group_label>Part 1b (IV cohort 1)</arm_group_label>
    <arm_group_label>Part 1b (IV cohort 2)</arm_group_label>
    <arm_group_label>Part 2a (MAD) Cohort 1</arm_group_label>
    <arm_group_label>Part 2a (MAD) Cohort 2</arm_group_label>
    <arm_group_label>Part 2b (MAD/healthy volunteers) Cohort 3</arm_group_label>
    <arm_group_label>Part 3a (DPI/PoM)</arm_group_label>
    <arm_group_label>Part 3b (DPI/healthy volunteers)</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion criteria:&#xD;
&#xD;
        Part 1a/b: 1. Provision of signed and dated, written informed consent before any study&#xD;
        specific procedures (applicable for all parts). 2. Healthy male volunteers and healthy&#xD;
        female volunteers (for Part 1a and Part 1b first IV cohort, female volunteers must be of&#xD;
        non-childbearing potential), aged 18 to 55 years with suitable veins for cannulation or&#xD;
        repeated venipuncture. 3. Female patients must not be lactating and must have a negative&#xD;
        pregnancy test at the Screening Visit and on admission to the Clinical Unit. Women of&#xD;
        non-childbearing potential must fulfill one of the following criteria (Applicable for all&#xD;
        parts): 3.1. Postmenopausal defined as amenorrhea for at least 12 months or more following&#xD;
        cessation of all exogenous hormonal treatments and follicle-stimulating hormone (FSH)&#xD;
        levels in the postmenopausal range. 3.2. Documentation of irreversible surgical&#xD;
        sterilization by hysterectomy, bilateral oophorectomy or bilateral salpingectomy but not&#xD;
        tubal ligation. 4. Have a body mass index (BMI) between 18 and 30 kg/m2 inclusive and weigh&#xD;
        at least 60 kg. 5. Healthy volunteer has a Forced Expiratory Volume in one second (FEV1)&#xD;
        ≥80% of the predicted value regarding age, height, gender and ethnicity at the Screening&#xD;
        Visit. 6. Male volunteers and their WOCBP partners should be willing to use highly&#xD;
        effective contraception measures and should refrain from donating sperm or fathering a&#xD;
        child from the first day of dosing until 3 months after the last dose of IMP. 7. Female&#xD;
        volunteers in Part 1b second IV cohort should be willing to use highly effective&#xD;
        contraception measures from the first day of dosing until 1 month after the last dose of&#xD;
        IMP. 8. Provision of signed, written and dated informed consent for optional genetic&#xD;
        research. If a volunteer declines to participate in the genetic component of the study,&#xD;
        there will be no penalty or loss of benefit to the volunteer. The volunteer will not be&#xD;
        excluded from other aspects of the study described in this protocol. Patients with mild&#xD;
        asthma (Part 2a and Part 3a): 1. Male and female (including WOCBP) patients with mild&#xD;
        asthma aged 18 to 55 years with suitable veins for cannulation or repeated venipuncture. 2.&#xD;
        Patients must be willing to remain in house at the study center for 16 consecutive days&#xD;
        (part 2a) or for 30 consecutive days, optional from Day 17 for Germany (part 3a). 3. Have a&#xD;
        BMI between 18 and 35 kg/m2 inclusive and weigh at least 50 kg. 4. Physician diagnosed&#xD;
        (mild) asthma for at least 6 months prior to screening. 5. Lung function ≥70% predicted for&#xD;
        Forced Expiratory Volume in 1 second (FEV1) at the Screening Visit AND at the 12 h&#xD;
        timepoint on Day -1, in accordance with the American Thoracic Society (ATS)/European&#xD;
        Respiratory Society (ERS) criteria. 6. Have a FeNO of ≥30 ppb at the Screening Visit and at&#xD;
        the 12 h timepoint on Day -1. 7. Male patients and their WOCBP partners should be willing&#xD;
        to use highly effective contraception measures and should refrain from donating sperm or&#xD;
        fathering a child from the first day of dosing until 3 months after the last dose of IMP&#xD;
        (applicable for part 2b and 3b). 8. Female patients should be willing to use highly&#xD;
        effective contraception measures from the first day of dosing until 1 month after the last&#xD;
        dose of IMP. 9. Provision of signed, written and dated informed consent for optional&#xD;
        genetic research. If a patient declines to participate in the genetic component of the&#xD;
        study, there will be no penalty or loss of benefit to the patient. The patient will not be&#xD;
        excluded from other aspects of the study described in this protocol.&#xD;
&#xD;
        Healthy volunteers (Part 2b and Part 3b): 1. Healthy male and female (including WOCBP)&#xD;
        volunteers aged 18 to 55 years with suitable veins for cannulation or repeated&#xD;
        venipuncture. 2. Have a BMI between 18 and 30 kg/m2 inclusive and weigh at least 60 kg. 3.&#xD;
        Healthy volunteer has a Forced Expiratory Volume in one second (FEV1) ≥80% of the predicted&#xD;
        value regarding age, height, gender and ethnicity at the Screening Visit and at the 12 h&#xD;
        timepoint on Day -1, in accordance with the ATS/ERS criteria. 4. Female volunteers should&#xD;
        be willing to use highly effective contraception measures from the first day of dosing&#xD;
        until 1 month after the last dose of IMP. 5. Provision of signed, written and dated&#xD;
        informed consent for optional genetic research. If a healthy volunteer declines to&#xD;
        participate in the genetic component of the study, there will be no penalty or loss of&#xD;
        benefit to the healthy volunteer. The healthy volunteer will not be excluded from other&#xD;
        aspects of the study described in this protocol.&#xD;
&#xD;
        Exclusion criteria:&#xD;
&#xD;
        Part 1a/b: 1. History of any clinically important disease or disorder which, in the opinion&#xD;
        of the Investigator, may either put the volunteer at risk because of participation in the&#xD;
        study, or influence the results or the volunteer's ability to participate in the study. 2.&#xD;
        History of any respiratory disorders such as asthma, chronic obstructive pulmonary disease&#xD;
        (COPD) or idiopathic pulmonary fibrosis (IPF) (applicable for all parts). 3. Healthy&#xD;
        volunteer has an increased risk of infection. 4. History or presence of gastrointestinal,&#xD;
        hepatic or renal disease or any other condition known to interfere with absorption,&#xD;
        distribution, metabolism or excretion of drugs (applicable to all parts). 5. Any clinically&#xD;
        important illness, medical/surgical procedure or trauma within 4 weeks of the first&#xD;
        administration of IMP (applicable to all parts). 6. Any laboratory values with the&#xD;
        following deviations at the Screening Visit and on admission to the Clinical Unit. Abnormal&#xD;
        values may be repeated once at the discretion of the Investigator (applicable to all&#xD;
        parts): 6.1. Alanine aminotransferase (ALT) &gt;upper limit of normal (ULN). 6.2. Aspartate&#xD;
        aminotransferase (AST) &gt;ULN. 6.3. Creatinine &gt;ULN. 6.4. White blood cell (WBC) count &lt;LLN&#xD;
        (Lower limit of normal). 6.5. Hemoglobin &lt;LLN. 7. Any clinically important abnormalities in&#xD;
        clinical chemistry, hematology or urinalysis results, other than those described under&#xD;
        exclusion criteria numbers 3 and 6, as judged by the Investigator (Applicable to all&#xD;
        parts). 8. Abnormal vital signs, after 10 minutes supine rest. Abnormal values may be&#xD;
        repeated once at the discretion of the Investigator (applicable to all parts). 9. Any&#xD;
        clinically important abnormalities in rhythm, conduction or morphology of the resting ECG&#xD;
        and any clinically important abnormalities in the 12-lead electrocardiogram (ECG) as&#xD;
        considered by the Investigator that may interfere with the interpretation of QTc interval&#xD;
        changes, including abnormal ST-T-wave morphology, particularly in the protocol defined&#xD;
        primary lead or left ventricular hypertrophy at the Screening Visit and Day -1 (Applicable&#xD;
        to all parts). 10. Known or suspected history of drug abuse [within the past 2 years for&#xD;
        Part 2a and Part 3a] as judged by the Investigator (Applicable to all parts). 11.Current&#xD;
        smokers or those who have smoked or used nicotine products (including e-cigarettes) within&#xD;
        the previous 6 months or has smoking history of &gt;5 pack-years (applicable to all parts).&#xD;
        12. History of alcohol abuse or excessive intake of alcohol as judged by the Investigator&#xD;
        (in Germany only: excessive intake of alcohol defined as the regular consumption of more&#xD;
        than 3 units [24 g] of alcohol per day for men or 2 units [16 g] of alcohol per day for&#xD;
        women) (Applicable to all parts). 13. Positive screen for drugs of abuse, cotinine&#xD;
        (nicotine) or alcohol at the Screening Visit or on admission to the Clinical Unit&#xD;
        (Applicable to all parts). 14. History of severe allergy/hypersensitivity or ongoing&#xD;
        clinically important allergy/hypersensitivity, as judged by the Investigator or history of&#xD;
        hypersensitivity to drugs with a similar chemical structure or class to AZD0449 (Applicable&#xD;
        to all parts). 15. Use of drugs with enzyme inducing properties such as St John's Wort&#xD;
        within 3 weeks before the first administration of IMP (Applicable to all parts). 16. Plasma&#xD;
        donation within 1 month of the Screening Visit or any blood donation/blood loss &gt;500 mL&#xD;
        during the 3 months before the Screening Visit (Applicable to all parts). 17. Healthy&#xD;
        volunteers/patients who have previously received (Applicable to all parts). 18. Involvement&#xD;
        of any AstraZeneca or Clinical Unit employee or their close relatives (Applicable to all&#xD;
        parts). Patients with mild asthma (Part 2a and Part 3a): 1. History of any clinically&#xD;
        important disease other than asthma, or disorder which, in the opinion of the Investigator,&#xD;
        may either put the patient at risk because of participation in the study, or influence the&#xD;
        results or the patient's ability to participate in the study. 2. Patient has an increased&#xD;
        risk of infection. 3. Suspicion of Gilbert's syndrome. 4. Exacerbation of asthma symptoms&#xD;
        within 6 months prior to Screening and Day -1 and requiring the use of oral or IV steroids,&#xD;
        antibiotics, Accident and Emergency visit, or hospital admission to the Clinical Unit. 5.&#xD;
        Female patients who are pregnant, breastfeeding, or are planning a pregnancy during the&#xD;
        study period or within 1 month after the last dose of IMP. Healthy volunteers (Part 2b and&#xD;
        Part 3b): 1.History of any clinically important disease or disorder which, in the opinion&#xD;
        of the Investigator, may either put the volunteer at risk because of participation in the&#xD;
        study, or influence the results or the volunteer's ability to participate in the study. 2.&#xD;
        Female healthy volunteers who are pregnant, breastfeeding, or are planning a pregnancy&#xD;
        during the study period or within 1 month after the last dose of IMP.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>65 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Dave Singh</last_name>
    <role>Principal Investigator</role>
    <affiliation>The Medicines Evaluation Unit</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Wellington</city>
        <zip>6021</zip>
        <country>New Zealand</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Harrow</city>
        <zip>HA1 3UJ</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Manchester</city>
        <zip>M23 9GP</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>New Zealand</country>
    <country>United Kingdom</country>
  </location_countries>
  <removed_countries>
    <country>Germany</country>
  </removed_countries>
  <verification_date>June 2021</verification_date>
  <study_first_submitted>November 8, 2018</study_first_submitted>
  <study_first_submitted_qc>December 4, 2018</study_first_submitted_qc>
  <study_first_posted type="Actual">December 6, 2018</study_first_posted>
  <last_update_submitted>June 29, 2021</last_update_submitted>
  <last_update_submitted_qc>June 29, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">June 30, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Inhaled JAK inhibitor</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Asthma</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>Yes</sharing_ipd>
    <ipd_description>Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal. All request will be evaluated as per the AZ disclosure commitment: https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.&#xD;
Yes, indicates that AZ are accepting requests for IPD, but this does not mean all requests will be shared.</ipd_description>
    <ipd_time_frame>AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA Pharma Data Sharing Principles. For details of our timelines, please rerefer to our disclosure commitment at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.</ipd_time_frame>
    <ipd_access_criteria>When a request has been approved AstraZeneca will provide access to the de-identified individual patient-level data in an approved sponsored tool. Signed Data Sharing Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information. Additionally, all users will need to accept the terms and conditions of the SAS MSE to gain access. For additional details, please review the Disclosure Statements at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.</ipd_access_criteria>
    <ipd_url>https://astrazenecagroup-dt.pharmacm.com/DT/Home</ipd_url>
  </patient_data>
  <pending_results>
    <submitted>May 23, 2022</submitted>
    <returned>February 23, 2023</returned>
    <submitted>July 27, 2023</submitted>
  </pending_results>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03766399
org study id: D5371C00001
nct id: NCT03766399
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
This will be a Phase I, first in human (FIH) study consisting of the following parts: Part 1a
      (SAD), Part 1b (IV Cohort), Part 2 (Multiple ascending dose (MAD), and Part 3 dry-powder
      inhalation (DPI)/ Proof of mechanism (PoM). Part 1a of the study will be a randomized,
      single-blind, placebo-controlled, SAD, sequential group design study performed at a single
      study center. Part 1b, will be an open-label, single-dose, single-cohort study. It will
      follow a 2-stage design in the way that participants from Part 1a will be selected for the IV
      Cohort in Part 1b. Part 2 of the study will be a randomized, single-blind,
      placebo-controlled, MAD, sequential group design and study performed at 3 study centers. Part
      3a/b will be a randomized, single-blind, placebo-controlled, DPI/PoM study. The expected
      duration of each subject in Part 1a of the study is up to 36 days and up to 53 days for
      subjects participating in Part 1b. The expected duration of each participant in Part 2 is up
      to 52 days and Part 3 is up to 55 days.
This will be a Phase I, consisting of the following parts: Part 1a, Part 1b, Part 2a/b, Part
      3a/b. Part 1a of the study will be a randomized, single-blind, placebo-controlled, SAD,
      sequential group design study performed at a single study center. Six inhaled dose levels of
      AZD0449 nebulized suspension are planned to be investigated in 6 cohorts. Depending on
      emerging safety and PK data, up to 3 additional inhaled dose levels (cohorts), within the
      pre-specified dose range, may be added at the discretion of the Sponsor. Within each cohort,
      6 volunteers will be randomized to receive an inhaled dose of AZD0449 nebulized suspension
      and 2 volunteers will be randomized to receive inhaled placebo. Intravenous (IV) dosing in
      Part 1b of the study will be initiated after the completion of cohort 6 in Part 1a or (if
      Part 1a is completed with less than 6 cohorts) after completion of the last cohort in Part
      1a. Part 1b, will be open-label and consist of 2 dose cohorts (IV 0.090 mg and 0.360 mg) and
      be conducted in 12 healthy volunteers. Six (6) volunteers will be selected for the first IV
      dose cohort in Part 1b following a 2-stage design. If Part 1b cannot be completed with 6
      volunteers from Part 1a or if some of the data are considered not evaluable, up to 6
      additional naïve volunteers may be enrolled. A second IV dose cohort in Part 1b will be
      initiated after the evaluation of the PK and safety results from all cohorts in Part 1a and
      completion of the first IV dose cohort in Part 1b. The second IV dose cohort will consist of
      6 healthy volunteers who have not previously participated in the study (naïve volunteers).
      Part 2a/b of the study will be a randomized, single-blind, placebo-controlled, MAD,
      sequential group design study performed at approximately 3 study centers. Part 2a will
      include cohorts 1 and 2, each comprising of 9 patients with mild asthma. Within each of these
      cohorts 6 patients will be randomized to receive AZD0449 nebulized suspension and 3 patients
      randomized to receive placebo. Additional cohorts with 9 patients could be added to study PK,
      PD and safety for doses lower than 1.2 mg or up to 5 mg. Part 2b will consist of 1 cohort of
      8 healthy volunteers; 6 volunteers will be randomized to receive AZD0449 nebulized suspension
      and 2 volunteers will be randomized to receive placebo. Part 3a/b of the study will be
      initiated after the completion of Part 2b. Part 3a/b will be a randomized, single-blind,
      placebo-controlled, DPI/PoM study. Part 3 will be conducted in up to 36 patients with mild
      asthma (Part 3a) and 8 healthy volunteers (Part 3b, optional). Part 3a will consist of 36
      patients, where 18 patients will be randomized to AZD0449 DPI and 18 patients to placebo. An
      Interim Analysis (IA) will be conducted when 9 patients on each arm have completed the study
      (50% Part 3a). Should new data on the variability of the FeNO measurements emerge at the IA,
      the sample size in Part 3a could be changed. If the optional Part 3b is conducted, it will
      comprise 8 healthy volunteers; 6 volunteers will be randomized to AZD0449 DPI and 2
      volunteers to placebo.
allocation: Randomized
intervention model: Sequential Assignment
primary purpose: Treatment
masking: Single (Participant)
measure: Number of participants with treatment-emergent adverse events
time frame: From screening up to follow-up visit [part 1 a/b (6±1 Days post-dose)] [part 2a (Day 22±1 (10±1 days post-last dose)], Safety Monitoring Period 2b/3a [Day 17 to 27 (15 day post-last dose)].
description: Safety and tolerability of AZD0449 following inhaled administration of single ascending doses to healthy volunteers, intravenous administration of a single dose to healthy volunteers, inhaled nebulized administration of multiple ascending doses healthy volunteers and patients with mild asthma, and repeated inhaled administration to patients with mild asthma using a DPI will be assessed.
measure: Number of participants with abnormal ECGs
time frame: From screening up to follow-up visit [part 1 a/b (6±1 Days post-dose)] [part 2a (Day 22±1 (10±1 days post-last dose)], Safety Monitoring Period 2b/3a [Day 17 to 27 (15 day post-last dose)].
description: The following parameters will be assessed using a 12-lead ECG: heart rate, PR, QRS, QT, QTcF (Fridericia's formula).
measure: Number of participants with abnormal findings in 12-lead digital electrocardiogram (12-lead dECG)
time frame: Part 1a and 1b (at Days 1 to 3), part 2a (from Day 1 to 15), part 2b, 3a and 3b (from Day 1 to 16).
description: Abnormal findings in 12-lead dECG will be assessed using Mortara Telemetry Surveyor equipment.
measure: Number of participants with abnormal telemetry findings
time frame: Part 1a (at Day -1 to Day 3) 1b (at Days -1 to Day 2) part 2 & 3 (at Day -1, Day 1 & 2, and Day 3 to Day 15.)
description: Abnormal telemetry will be assessed as a variable of safety and tolerability after administration of AZD0449 following inhaled administration of single ascending doses to healthy volunteers, intravenous administration of a single dose to healthy volunteers, inhaled nebulized administration of multiple ascending doses to healthy volunteers and patients with mild asthma, and repeated inhaled administration to patients with mild asthma using a DPI.
measure: Number of participants with abnormal physical examinations
time frame: From screening up to follow-up visit [part 1a/b (6±1 Days post-dose)] [part 2a (Day 22±1 (10±1 days post-last dose)], Safety Monitoring Period 2b/3a [Day 17 to 27 (15 day post-last dose)].
description: Complete physical examinations will include an assessment of the skin, lungs, cardiovascular system, and abdomen (liver and spleen)
measure: Number of participants with spirometry findings
time frame: From screening up to follow-up visit [part 1a & 1b (6±1 Days post-dose) Part 2 & 3 (6 Days post-last dose)]
description: Spirometry will be assessed as a variable of safety and tolerability after administration of AZD0449 following inhaled administration of single ascending doses to healthy volunteers, intravenous administration of a single dose to healthy volunteers, inhaled nebulized administration of multiple ascending doses to healthy volunteers and patients with mild asthma, and repeated inhaled administration to patients with mild asthma using a DPI.
measure: Number of participants with pulse oximetry (SpO2) findings
time frame: From screening up to follow-up visit [Part 1a & 1b (6±1 Days post-dose) Part 2 & 3 (6 Days post-last dose)]
description: Pulse oximetry findings will be assessed as a variable of safety and tolerability after administration of AZD0449 following inhaled administration of single ascending doses to healthy volunteers, intravenous administration of a single dose to healthy volunteers, inhaled nebulized administration of multiple ascending doses to healthy volunteers and patients with mild asthma, and repeated inhaled administration to patients with mild asthma using a DPI.
measure: Number of participants with abnormal laboratory tests results
time frame: From screening up to follow-up visit [Part 1a/b (6±1 Days post-dose)] [part 2a (Day 22±1 (10±1 days post-last dose)], Safety Monitoring Period 2b/3a [Day 17 to 27 (15 day post-last dose)].
description: Evaluation of clinically significant changes from baseline in laboratory evaluation (hematology, chemistry, coagulation, urinalysis)
measure: Number of participants with abnormal vital signs
time frame: From screening up to follow-up visit [Part 1a/b (6±1 Days post-dose)] [part 2a (Day 22±1 (10±1 days post-last dose)], Safety Monitoring Period 2b/3a [Day 17 to 27 (15 day post-last dose)].
description: Evaluation of clinically significant changes in vital signs will include body temperature, respiratory rate, heart rate and systolic and diastolic blood pressure
measure: Maximum observed plasma concentration (Cmax)
time frame: Part 1a: Day 1 to 4. Part 1b: Day 1 to 3. Part 2 & 3: Days 1 to 2, Day 3 to 15, and Day 16 to 20.
description: Cmax of AZD0449 following inhaled administration of single ascending doses of AZD0449, intravenous administration of a single dose to healthy volunteers, inhaled nebulized administration of multiple ascending doses to healthy volunteers and patients with mild asthma, and repeated inhaled administration to patients with mild asthma using a DPI.
measure: Time to reach peak or maximum observed concentration following drug administration (tmax)
time frame: Part 1a: Day 1 to 4. Part 1b: Day 1 to 3. Part 2 & 3: Days 1 to 2, Day 3 to 15, and Day 16 to 20.
description: tmax of AZD0449 following inhaled administration of single ascending doses of AZD0449, intravenous administration of a single dose to healthy volunteers, inhaled nebulized administration of multiple ascending doses to healthy volunteers and patients with mild asthma, and repeated inhaled administration to patients with mild asthma using a DPI.
measure: Terminal rate constant, estimated by loglinear leastsquares regression of the terminal part of the -concentrationtime- curve (λz)
time frame: Part 1a: Day 1 to 4. Part 1b: Day 1 to 3. Part 2 & 3: Days 1 to 2, Day 3 to 15, and Day 16 to 20.
description: λz of AZD0449 following inhaled administration of single ascending doses of AZD0449, intravenous administration of a single dose to healthy volunteers, inhaled nebulized administration of multiple ascending doses to healthy volunteers and patients with mild asthma, and repeated inhaled administration to patients with mild asthma using a DPI.
measure: Terminal halflife, estimated as (ln2)/-λz (t½λz )
time frame: Part 1a: Day 1 to 4. Part 1b: Day 1 to 3. Part 2 & 3: Days 1 to 2, Day 3 to 15, and Day 16 to 20.
description: t½λz of AZD0449 following inhaled administration of single ascending doses of AZD0449, intravenous administration of a single dose to healthy volunteers, inhaled nebulized administration of multiple ascending doses to healthy volunteers and patients with mild asthma, and repeated inhaled administration to patients with mild asthma using a DPI.
measure: Area under the plasma concentration time curve from time zero to 24 hours after dosing (AUC(0-24))
time frame: Part 1a: Day 1 to 4. Part 1b: Day 1 to 3. Part 2 & 3: Days 1 to 2, Day 3 to 15, and Day 16 to 20.
description: AUC (0-24) of AZD0449 following inhaled administration of single ascending doses of AZD0449, intravenous administration of a single dose to healthy volunteers, inhaled nebulized administration of multiple ascending doses to healthy volunteers and patients with mild asthma, and repeated inhaled administration to patients with mild asthma using a DPI.
measure: Area under the plasma concentration curve from time zero to the time of last quantifiable concentration (AUC(0-t))
time frame: Part 1a: Day 1 to 4, Part 1b: Day 1 to 3, Part 2 & 3 (QD): Day 1 to 2, Day 3 to 12, Day 13 to 15, Day 18, Part 2 & 3 (BID): Day 1 to 2, Day 3 to 13, Day 14 to 16, Day 19.
description: AUC(0-t) of AZD0449 following inhaled administration of single ascending doses of AZD0449, intravenous administration of a single dose to healthy volunteers, inhaled nebulized administration of multiple ascending doses to healthy volunteers and patients with mild asthma, and repeated inhaled administration to patients with mild asthma using a DPI.
measure: Area under the plasma concentration time curve (AUC)
time frame: Part 1a: Day 1 to 4, Part 1b: Day 1 to 3, Part 2 & 3: Days 1 to 2, Day 3 to 15, and Day 16 to 20.
description: AUC of AZD0449 following inhaled administration of single ascending doses of AZD0449, intravenous administration of a single dose to healthy volunteers, inhaled nebulized administration of multiple ascending doses to healthy volunteers and patients with mild asthma, and repeated inhaled administration to patients with mild asthma using a DPI.
measure: Apparent total body clearance of drug from plasma after extravascular administration (CL/F)
time frame: Part 1a: Day 1 to 4, Part 2 & 3: Days 1 to 2, Day 3 to 15, and Day 16 to 20.
description: CL/F of AZD0449 following inhaled administration of single ascending doses of AZD0449, inhaled nebulized administration of multiple ascending doses to healthy volunteers and patients with mild asthma, and repeated inhaled administration to patients with mild asthma using a DPI.
measure: Area under the plasma concentration-time curve from time zero to 12 hours post-dose (AUC(0-12))
time frame: Part 1a: Day 1 to 4, Part 1b: Day 1 to 3, Part 2 & 3 (QD): Day1 to 2, Day 3 to 12, Day 13 to 15, Day 18, Part 2 & 3 (BID): Day 1 to 2, Day 3 to 13, Day 14 to 16, Day 19.
description: AUC(0-12) of AZD0449 following inhaled administration of single ascending doses of AZD0449, intravenous administration of a single dose to healthy volunteers, inhaled nebulized administration of multiple ascending doses to healthy volunteers and patients with mild asthma, and repeated inhaled administration to patients with mild asthma using a DPI.
measure: Apparent volume of distribution for parent drug at terminal phase (extravascular administration), estimated by dividing the apparent clearance (CL/F) by λz (Vz/F)
time frame: Part 1a: Day 1 to 4, Part 2 & 3: Days 1 to 2, Day 3 to 15, and Day 16 to 20.
description: Vz/F of AZD0449 following inhaled administration of single ascending doses of AZD0449, inhaled nebulized administration of multiple ascending doses to healthy volunteers and patients with mild asthma, and repeated inhaled administration to patients with mild asthma using a DPI.
measure: Dose normalized AUC(0-t) (AUC(0-t)/D)
time frame: Part 1a: Day 1 to 4, Part 1b: Day 1 to 3, Part 2 & 3 (QD): Day1 to 2, Day 3 to 12, Day 13 to 15, Day 18, Part 2 & 3 (BID): Day 1 to 2, Day 3 to 13, Day 14 to 16, Day 19.
description: AUC(0-t)/D of AZD0449 following inhaled administration of single ascending doses of AZD0449, intravenous administration of a single dose to healthy volunteers, inhaled nebulized administration of multiple ascending doses to healthy volunteers and patients with mild asthma, and repeated inhaled administration to patients with mild asthma using a DPI.
measure: Dose normalized AUC (AUC/D)
time frame: Part 1a: Day 1 to 4, Part 1b: Day 1 to 3, Part 2 & 3: Days 1 to 2, Day 3 to 15, and Day 16 to 20.
description: AUC/D of AZD0449 following inhaled administration of single ascending doses of AZD0449, intravenous administration of a single dose to healthy volunteers, inhaled nebulized administration of multiple ascending doses to healthy volunteers and patients with mild asthma, and repeated inhaled administration to patients with mild asthma using a DPI.
measure: Dose normalized Cmax (Cmax/D)
time frame: Part 1a: Day 1 to 4, Part 1b: Day 1 to 3, Part 2 & 3: Days 1 to 2, Day 3 to 15, and Day 16 to 20.
description: Cmax/D of AZD0449 following inhaled administration of single ascending doses of AZD0449, intravenous administration of a single dose to healthy volunteers, inhaled nebulized administration of multiple ascending doses to healthy volunteers and patients with mild asthma, and repeated inhaled administration to patients with mild asthma using a DPI.
measure: Time of last quantifiable concentration (tlast)
time frame: Part 1a: Day 1 to 4, Part 1b: Day 1 to 3, Part 2 & 3: Days 1 to 2, Day 3 to 15, and Day 16 to 20.
description: tlast of AZD0449 following inhaled administration of single ascending doses of AZD0449, intravenous administration of a single dose to healthy volunteers, inhaled nebulized administration of multiple ascending doses to healthy volunteers and patients with mild asthma, and repeated inhaled administration to patients with mild asthma using a DPI.
measure: Volume of distribution for parent drug at terminal phase (intravenous administration), estimated by dividing the systemic clearance (CL) by λz
time frame: Part 1b: Day 1 to 3
description: Vz of AZD0449 following inhaled administration of intravenous administration of a single dose to healthy volunteers.
measure: Total body clearance of drug from plasma after intravascular administration (CL)
time frame: Part 1b: Day 1 to 3
description: CL of AZD0449 following inhaled administration of intravenous administration of a single dose to healthy volunteers.
measure: Fractional excretion of nitric oxide (FeNO)
time frame: Part 2 & 3 (QD): At screening (Day -28 to -3), Day -1 to Day 12, follow-up visit Day 13 to 15, and Day 18. Part 2 & 3 (BID): At screening (Day -28 to -3), Day -1 to Day 13, follow-up visit Day 14 to 16, and Day 19.
description: To evaluate anti-inflammatory effect in patients with mild asthma.
measure: FeNO AUC(0-12)
time frame: Part 2 & 3 (QD): At screening (Day -28 to -3), Day -1 to Day 12, follow-up visit Day 13 to 15, and Day 18. Part 2 & 3 (BID): At screening (Day -28 to -3), Day -1 to Day 13, follow-up visit Day 14 to 16, and Day 19.
description: To evaluate anti-inflammatory effect in patients with mild asthma.
arm group label: Part 1a (SAD) Cohort 1
arm group type: Experimental
description: 6 participants will receive inhaled dose 1 of AZD0449 nebulized suspension and 2 participants will receive inhaled placebo.
arm group label: Part 1a (SAD) Cohort 2
arm group type: Experimental
description: 6 participants will receive inhaled dose 2 of AZD0449 nebulized suspension and 2 participants will receive inhaled placebo.
arm group label: Part 1a (SAD) Cohort 3
arm group type: Experimental
description: 6 participants will receive inhaled dose 3 of AZD0449 nebulized suspension and 2 participants will receive inhaled placebo.
arm group label: Part 1a (SAD) Cohort 4
arm group type: Experimental
description: 6 participants will receive inhaled dose 4 of AZD0449 nebulized suspension and 2 participants will receive inhaled placebo.
arm group label: Part 1a (SAD) Cohort 5
arm group type: Placebo Comparator
description: 6 participants will receive inhaled dose 5 of AZD0449 nebulized suspension and 2 participants will receive inhaled placebo.
arm group label: Part 1a (SAD) Cohort 6
arm group type: Experimental
description: 6 participants will receive inhaled dose 6 of AZD0449 nebulized suspension and 2 participants will receive inhaled placebo.
arm group label: Part 1b (IV cohort 1)
arm group type: Experimental
description: All 6 participants will receive single IV dose of AZD0449 solution.
arm group label: Part 2a (MAD) Cohort 1
arm group type: Experimental
description: 6 participants will receive inhaled dose 7 of AZD0449 nebulized suspension and 3 participants will receive inhaled placebo.
arm group label: Part 2a (MAD) Cohort 2
arm group type: Experimental
description: 6 participants will receive inhaled dose 8 of AZD0449 nebulized suspension and 3 participants will receive inhaled placebo.
arm group label: Part 2b (MAD/healthy volunteers) Cohort 3
arm group type: Experimental
description: 18 healthy volunteers will receive inhaled dose 9 of AZD0449 nebulized suspension and 12 healthy volunteers will receive inhaled placebo.
arm group label: Part 3a (DPI/PoM)
arm group type: Experimental
description: 18 participants will receive inhaled dose 10 of AZD0449 DPI and 6 participants will receive inhaled placebo.
arm group label: Part 1b (IV cohort 2)
arm group type: Experimental
description: 6 healthy volunteers will receive single IV dose of AZD0449 solution.
arm group label: Part 3b (DPI/healthy volunteers)
arm group type: Experimental
description: Part 3b is optional. 8 healthy volunteers; 6 volunteers will receive AZD0449 DPI and 2 volunteers will recieve placebo.
intervention type: Drug
intervention name: AZD0449
description: Participants will receive single inhaled AZD0449 nebulizer suspension and single IV dose of AZD0449 solution.
arm group label: Part 1a (SAD) Cohort 1
arm group label: Part 1a (SAD) Cohort 2
arm group label: Part 1a (SAD) Cohort 3
arm group label: Part 1a (SAD) Cohort 4
arm group label: Part 1a (SAD) Cohort 5
arm group label: Part 1a (SAD) Cohort 6
arm group label: Part 1b (IV cohort 1)
arm group label: Part 1b (IV cohort 2)
arm group label: Part 2a (MAD) Cohort 1
arm group label: Part 2a (MAD) Cohort 2
arm group label: Part 2b (MAD/healthy volunteers) Cohort 3
arm group label: Part 3a (DPI/PoM)
arm group label: Part 3b (DPI/healthy volunteers)
intervention type: Drug
intervention name: Placebo
description: Participants will receive single dose of placebo for AZD0449 (nebulizer suspension).
arm group label: Part 1a (SAD) Cohort 1
arm group label: Part 1a (SAD) Cohort 2
arm group label: Part 1a (SAD) Cohort 3
arm group label: Part 1a (SAD) Cohort 4
arm group label: Part 1a (SAD) Cohort 5
arm group label: Part 1a (SAD) Cohort 6
arm group label: Part 1b (IV cohort 1)
arm group label: Part 1b (IV cohort 2)
arm group label: Part 2a (MAD) Cohort 1
arm group label: Part 2a (MAD) Cohort 2
arm group label: Part 2b (MAD/healthy volunteers) Cohort 3
arm group label: Part 3a (DPI/PoM)
arm group label: Part 3b (DPI/healthy volunteers)
criteria: 
gender: All
minimum age: 18 Years
maximum age: 65 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Dave Singh
role: Principal Investigator
affiliation: The Medicines Evaluation Unit
facility: 
facility: 
facility: 
country: New Zealand
country: United Kingdom
country: Germany
responsible party type: Sponsor
mesh term: Asthma
sharing ipd: Yes
ipd description: Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal. All request will be evaluated as per the AZ disclosure commitment: https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
Yes, indicates that AZ are accepting requests for IPD, but this does not mean all requests will be shared.
ipd time frame: AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA Pharma Data Sharing Principles. For details of our timelines, please rerefer to our disclosure commitment at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
ipd access criteria: When a request has been approved AstraZeneca will provide access to the de-identified individual patient-level data in an approved sponsored tool. Signed Data Sharing Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information. Additionally, all users will need to accept the terms and conditions of the SAS MSE to gain access. For additional details, please review the Disclosure Statements at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
ipd url: https://astrazenecagroup-dt.pharmacm.com/DT/Home
submitted: May 23, 2022
returned: February 23, 2023
submitted: July 27, 2023