<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/NCT04483947</url>
  </required_header>
  <id_info>
    <org_study_id>D7830C00002</org_study_id>
    <nct_id>NCT04483947</nct_id>
  </id_info>
  <brief_title>A Study to Assess Safety, Tolerability, PK and PD of AZD2693 in Non-alcoholic Steatohepatitis Patients</brief_title>
  <official_title>A Phase 1, Double Blind, Randomised, Placebo-Controlled, Multi-centre, Multiple Ascending Dose Study to Assess the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of AZD2693 in Patients With Non-alcoholic Steatohepatitis (NASH) With Fibrosis Stage 0-3 and Carriers of the PNPLA3 148M Risk Alleles</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>AstraZeneca</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Parexel</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>AstraZeneca</source>
  <oversight_info>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>Yes</is_fda_regulated_device>
    <is_unapproved_device>Yes</is_unapproved_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      This study is intended to investigate the safety and tolerability, pharmacokinetics (PK) and&#xD;
      pharmacodynamics (PD) of AZD2693, following subcutaneous (SC) administration of multiple&#xD;
      ascending doses in participants with Non-alcoholic Steatohepatitis (NASH) with fibrosis Stage&#xD;
      0 to 3 and who are carriers of the patatin-like phospholipase domain-containing 3 (PNPLA3)&#xD;
      148M risk alleles.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This study is a double blind, randomised, placebo-controlled, multi-centre study in&#xD;
      participants with NASH and fibrosis stage between F0 (no fibrosis) and F3 (bridging&#xD;
      fibrosis), and who are carriers of the PNPLA3 148M risk alleles.&#xD;
&#xD;
      The study will comprise of:&#xD;
&#xD;
        -  An optional Pre-Screening Visit may be completed to determine PNPLA3 genotype and&#xD;
           collect minimal baseline data and participants who are carriers of the PNPLA3 148M risk&#xD;
           allele(s) will continue the study and enter the Screening Period.&#xD;
&#xD;
        -  A Screening Period with a maximum of 60 days.&#xD;
&#xD;
        -  For participants in all Cohorts, the dosing period will be 8 weeks during which&#xD;
           participants will be resident of the study site for Dose 1 and Dose 3. Dose 1 will have&#xD;
           participants reside at the study site from the day prior to study intervention&#xD;
           administration (Day -1) until at least 2 days after study intervention administration&#xD;
           with discharge on Day 3. Dose 2 will be administered at the study site on Day 29 with no&#xD;
           overnight stay. Dose 3 will have participants reside at the study site from the day&#xD;
           prior to study intervention administration (Day 56) until at least 2 days after study&#xD;
           intervention administration with discharge on Day 59.&#xD;
&#xD;
        -  Each participant will be followed for approximately 15 weeks post last dose.&#xD;
&#xD;
      The study will be performed at up to 30 study sites in the United States (US) and up to 5&#xD;
      study sites in Mexico. Approximately 80 participants comprising of male and female&#xD;
      participants of non-childbearing potential may be enrolled into the first 4 cohorts of this&#xD;
      study in order to achieve a target of 56 to 64 evaluable participants.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">November 6, 2020</start_date>
  <completion_date type="Anticipated">December 18, 2023</completion_date>
  <primary_completion_date type="Anticipated">December 18, 2023</primary_completion_date>
  <phase>Phase 1</phase>
  <study_type>Interventional</study_type>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Sequential Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Double (Participant, Investigator)</masking>
    <masking_description>The study will be blinded for all study site personal including the principal investigator during the clinical conduct of a given cohort. Investigators will remain blinded to each participant's assigned study intervention throughout the course of the study.</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>Number of participants with adverse events</measure>
    <time_frame>Up to 32 weeks (From Screening to Final Visit)</time_frame>
  </primary_outcome>
  <secondary_outcome>
    <measure>Absolute change from baseline to Week 8 and Week 12 in liver fat content (LFC)</measure>
    <time_frame>Baseline (Day 1), Week 8, Week 12</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Percent change from baseline to Week 8 and Week 12 in liver fat content (LFC)</measure>
    <time_frame>Baseline (Day 1), Week 8, Week 12</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Absolute change from baseline in Alanine Aminotransferase</measure>
    <time_frame>Up to 32 weeks (From Pre-Screening to Final Visit)</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Percent change from baseline in Alanine Aminotransferase</measure>
    <time_frame>Up to 32 weeks (From Pre-Screening to Final Visit)</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Absolute change from baseline in Aspartate Aminotransferase</measure>
    <time_frame>Up to 32 weeks (From Pre-Screening to Final Visit)</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Percent change from baseline in Aspartate Aminotransferase</measure>
    <time_frame>Up to 32 weeks (From Pre-Screening to Final Visit)</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Absolute change from baseline in Gamma Glutamyl Transferase</measure>
    <time_frame>Up to 32 weeks (From Pre-Screening to Final Visit)</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Percent change from baseline in Gamma Glutamyl Transferase</measure>
    <time_frame>Up to 32 weeks (From Pre-Screening to Final Visit)</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Absolute change from baseline in Enhanced Liver Fibrosis (ELF) score</measure>
    <time_frame>Up to 32 weeks (From Pre-Screening to Final Visit)</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Percent change from baseline in ELF score</measure>
    <time_frame>Up to 32 weeks (From Pre-Screening to Final Visit)</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Absolute change from baseline in plasma pharmacodynamic biomarker</measure>
    <time_frame>Days 1, 8, 29, 36, 50, 64, and 78</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Percent change from baseline in plasma pharmacodynamic biomarker</measure>
    <time_frame>Days 1, 8, 29, 36, 50, 64, and 78</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Absolute change from baseline in disease-specific biomarkers</measure>
    <time_frame>Days 1, 8, 29, 36, 50, 64, and 78</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Percentage change from baseline in disease-specific biomarkers</measure>
    <time_frame>Days 1, 8, 29, 36, 50, 64, and 78</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Absolute change from baseline β-Hydroxybutyrate and lipid profile</measure>
    <time_frame>Days 1, 8, 29, 36, 50, 64, and 78</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Percent change from baseline β-Hydroxybutyrate and lipid profile</measure>
    <time_frame>Days 1, 8, 29, 36, 50, 64, and 78</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Maximum observed plasma drug concentration (Cmax)</measure>
    <time_frame>Day 1 to Day 162</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Time to reach maximum observed plasma concentration (tmax)</measure>
    <time_frame>Day 1 to Day 162</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Terminal elimination rate constant, estimated by log-linear least-squares regression of the terminal part of the concentration-time curve (λz)</measure>
    <time_frame>Day 1 to Day 162</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Apparent terminal elimination half-life associated with the terminal slope (λz) of the semi-logarithmic concentration-time curve, estimated as (ln2)/λz (t½λz)</measure>
    <time_frame>Day 1 to Day 162</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Area under the plasma concentration-time curve from time zero to 48 hours after dosing (AUC(0-48h))</measure>
    <time_frame>Day 1 to Day 162</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Area under the plasma concentration-curve from time zero to the time of last quantifiable analyte concentration (AUClast)</measure>
    <time_frame>Day 1 to Day 162</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Area under the concentration-time curve from time zero extrapolated to infinity. AUC is estimated by AUClast + Clast/λz where Clast is the last observed quantifiable concentration (AUC)</measure>
    <time_frame>Day 1 to Day 162</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Apparent total body clearance of drug from plasma after extravascular administration calculated as Dose/AUC (CL/F)</measure>
    <time_frame>Day 1 to Day 162</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Mean residence time (MRT)</measure>
    <time_frame>Day 1 to Day 162</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Time delay between drug administration and the first observed concentration in plasma (tlag)</measure>
    <time_frame>Day 1 to Day 162</time_frame>
  </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>Day 1 to Day 162</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Area under the plasma concentration-time curve from time zero to time of last quantifiable analyte concentration divided by the dose administered (AUClast/D)</measure>
    <time_frame>Day 1 to Day 162</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Area under the plasma concentration-time curve from time zero extrapolated to infinity divided by the dose administered (AUC/D)</measure>
    <time_frame>Day 1 to Day 162</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Observed maximum plasma concentration divided by the dose administered (Cmax/D)</measure>
    <time_frame>Day 1 to Day 162</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Time of the last quantifiable concentration (tlast)</measure>
    <time_frame>Day 1 to Day 162</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Maximum observed plasma drug concentration at steady state (Cssmax)</measure>
    <time_frame>Day 1 to Day 162</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Minimum observed drug concentration at steady state (Cssmin)</measure>
    <time_frame>Day 1 to Day 162</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Time to reach maximum observed plasma concentration at steady state (tssmax)</measure>
    <time_frame>Day 1 to Day 162</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Area under the concentration-time curve in the dose interval (AUCss)</measure>
    <time_frame>Day 1 to Day 162</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Apparent total body clearance of drug from plasma after extravascular administration calculated as Dose/AUCss (CLss/F)</measure>
    <time_frame>Day 1 to Day 162</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Area under the plasma concentration-time curve from time zero extrapolated to infinity divided by the dose administered (AUCss/D)</measure>
    <time_frame>Day 1 to Day 162</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Observed maximum plasma concentration divided by the dose administered (Cssmax/D)</measure>
    <time_frame>Day 1 to Day 162</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Accumulation ratio based on Cmax (RacCmax)</measure>
    <time_frame>Day 1 to Day 162</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Accumulation ratio based on AUC (RacAUC)</measure>
    <time_frame>Day 1 to Day 162</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Temporal change parameter in systemic exposure (TCP)</measure>
    <time_frame>Day 1 to Day 162</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Amount of analyte excreted into the urine from time t1 to t2 (Ae(t1-t2))</measure>
    <time_frame>Day 1 and Day 57: Pre-dose and between 0-6 hours, 6-12 hours, 12-24 hours, 24-36 hours and 36-48 hours post-dose</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cumulative amount of analyte excreted from time zero through the last sampling interval (Ae(0-last))</measure>
    <time_frame>Day 1 and Day 57: Pre-dose and between 0-6 hours, 6-12 hours, 12-24 hours, 24-36 hours and 36-48 hours post-dose</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Fraction of dose excreted unchanged into the urine from time t1 to t2 (fe(t1-t2))</measure>
    <time_frame>Day 1 and Day 57: Pre-dose and between 0-6 hours, 6-12 hours, 12-24 hours, 24-36 hours and 36-48 hours post-dose</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cumulative fraction (%) of dose excreted unchanged into the urine from time zero to the last measured time point (fe(0-last))</measure>
    <time_frame>Day 1 and Day 57: Pre-dose and between 0-6 hours, 6-12 hours, 12-24 hours, 24-36 hours and 36-48 hours post-dose</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Renal clearance of drug from plasma, estimated by dividing Ae(0-t) by AUC(0-t) where the 0-t interval is the same for both Ae and AUC (CLR)</measure>
    <time_frame>Day 1 and Day 57: Pre-dose and between 0-6 hours, 6-12 hours, 12-24 hours, 24-36 hours and 36-48 hours post-dose</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change from placebo to Week 10 in PNPLA3 messenger ribonucleic acid (mRNA) and protein expression (Cohort 4 only)</measure>
    <time_frame>Week 10</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change from baseline to Week 10 in PNPLA3 mRNA and protein expression (Cohort 4 only)</measure>
    <time_frame>Baseline, Week 10</time_frame>
  </secondary_outcome>
  <number_of_arms>4</number_of_arms>
  <enrollment type="Actual">74</enrollment>
  <condition>Non-alcoholic Steatohepatitis (NASH)</condition>
  <arm_group>
    <arm_group_label>Cohort 1</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>15 participants will receive AZD2693 dose 1 and 5 participants will receive placebo</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Cohort 2</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>15 participants will receive AZD2693 dose 2 and 5 participants will receive placebo</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Cohort 3</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>15 participants will receive AZD2693 dose 1 and 5 participants will receive placebo</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Cohort 4</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>15 participants will receive AZD2693 dose 3 and 5 participants will receive placebo</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>AZD2693</intervention_name>
    <description>Subcutaneous administration of AZD2693 multiple ascending doses in participants with NASH and who are carriers of the PNPLA3 148M risk allele(s).</description>
    <arm_group_label>Cohort 1</arm_group_label>
    <arm_group_label>Cohort 2</arm_group_label>
    <arm_group_label>Cohort 3</arm_group_label>
    <arm_group_label>Cohort 4</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>Participants randomised to placebo will receive the corresponding dose volume of solution as participants receiving AZD2693 within the same cohort</description>
    <arm_group_label>Cohort 1</arm_group_label>
    <arm_group_label>Cohort 2</arm_group_label>
    <arm_group_label>Cohort 3</arm_group_label>
    <arm_group_label>Cohort 4</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
        For Cohorts 1 to 3:&#xD;
&#xD;
          -  An MRI-PDFF ≥7% and one of the following:&#xD;
&#xD;
               -  Previous liver biopsy: Acceptable if taken in the previous 3 years for fibrosis&#xD;
                  stages F0 to F2, or within the previous 1 year for stage F3; or&#xD;
&#xD;
               -  Previous imaging results taken in the previous 2 years: An MRE between 2.55 kPa&#xD;
                  and 3.63 kPa, or a vibration-controlled transient elastography (VCTE) between 7.1&#xD;
                  kPa and 11.9 kPa;&#xD;
&#xD;
          -  Participants who are homozygous for rs738409 (PNPLA3 148M). Cohort 2 will enroll&#xD;
             participants who are heterozygous for PNPLA3 148M.&#xD;
&#xD;
        For Cohort 4:&#xD;
&#xD;
        • An MRI-PDFF ≥ 7% and participant's consent for a liver biopsy.&#xD;
&#xD;
          -  Participants with suspected or confirmed Non-alcoholic fatty liver disease (NAFLD) or&#xD;
             NASH are eligible for the Screening liver biopsy if they meet main protocol&#xD;
             inclusion/exclusion criteria AND have any of the following:&#xD;
&#xD;
        Alanine aminotransferase &gt; Upper Limit of Normal (ULN) but &lt; 3 × ULN, OR Imaging&#xD;
        demonstrating hepatic steatosis including attenuation parameter (CAP) &gt; 290dB/m, OR A&#xD;
        Magnetic resonance elastography (MRE) between 2.55 kPa and 3.63 kPa, or a&#xD;
        vibration-controlled transient elastography (VCTE) between 7.1 kPa and 11.9 kPa.&#xD;
&#xD;
          -  Histologic evidence of NAFLD or NASH with a NASH Activity Score (NAS) ≥ 3 (independent&#xD;
             of subcategory scoring) following Screening liver biopsy.&#xD;
&#xD;
          -  Participants who are homozygous for rs738409 (PNPLA3 148M).&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  History of liver transplant, or current placement on a liver transplant list (this may&#xD;
             be checked at the optional Pre-Screening Visit).&#xD;
&#xD;
          -  History or presence of hepatic disease (with the exception of hepatic steatosis, NASH)&#xD;
             or evidence of other known forms of known chronic liver disease such as alcoholic&#xD;
             liver disease, hepatitis B, primary biliary cirrhosis, primary sclerotic cirrhosis,&#xD;
             autoimmune hepatitis, Wilson disease, iron overload, alpha-1-antitrypsin deficiency,&#xD;
             drug-induced liver injury, known or suspected hepatocellular carcinoma (this may be&#xD;
             checked at the optional Pre-Screening Visit).&#xD;
&#xD;
          -  Histological or imaging (MRE or VCTE) evidence of cirrhosis.&#xD;
&#xD;
          -  Participants with history or pre-existing renal disease, as defined below:&#xD;
&#xD;
             - estimated glomerular filtration rate &lt; 60 mL/min/1.73 m^2 (calculated using the&#xD;
             Chronic Kidney Disease Epidemiology Collaboration formula)&#xD;
&#xD;
          -  Blood dyscrasias with increased risk of bleeding including idiopathic thrombocytopenic&#xD;
             purpura and thrombotic thrombocytopenic purpura or symptoms of increased risk of&#xD;
             bleeding (frequent bleeding gums or nose bleeds).&#xD;
&#xD;
          -  History of major bleed or high-risk of bleeding diathesis.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>75 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Rohit Loomba, MD, MHSc</last_name>
    <role>Principal Investigator</role>
    <affiliation>Director, NAFLD Research Center Director of Hepatology, Professor of Medicine Vice Chief, Division of Gastroenterology University of California at San Diego ACTRI Building, 1W202 9500 Gilman Drive La Jolla, CA, 92037-0887</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Chula Vista</city>
        <state>California</state>
        <zip>91911</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>La Mesa</city>
        <state>California</state>
        <zip>91942</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Montclair</city>
        <state>California</state>
        <zip>91763</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>San Diego</city>
        <state>California</state>
        <zip>92103</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Doral</city>
        <state>Florida</state>
        <zip>33166</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Hialeah</city>
        <state>Florida</state>
        <zip>33014</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Hialeah</city>
        <state>Florida</state>
        <zip>33016</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Miami Lakes</city>
        <state>Florida</state>
        <zip>33014</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Indianapolis</city>
        <state>Indiana</state>
        <zip>46202</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Morehead City</city>
        <state>North Carolina</state>
        <zip>28557</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Columbus</city>
        <state>Ohio</state>
        <zip>43213</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Hershey</city>
        <state>Pennsylvania</state>
        <zip>17033</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Arlington</city>
        <state>Texas</state>
        <zip>76012</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Dallas</city>
        <state>Texas</state>
        <zip>75203</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>San Antonio</city>
        <state>Texas</state>
        <zip>78215</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>San Antonio</city>
        <state>Texas</state>
        <zip>78229</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <removed_countries>
    <country>Mexico</country>
  </removed_countries>
  <verification_date>September 2023</verification_date>
  <study_first_submitted>July 6, 2020</study_first_submitted>
  <study_first_submitted_qc>July 21, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">July 23, 2020</study_first_posted>
  <last_update_submitted>September 6, 2023</last_update_submitted>
  <last_update_submitted_qc>September 6, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">September 7, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Pharmacokinetics</keyword>
  <keyword>Pharmacodynamics</keyword>
  <keyword>Obese</keyword>
  <keyword>PNPLA3 148M Risk Alleles</keyword>
  <keyword>Multiple Ascending Dose</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Fatty Liver</mesh_term>
    <mesh_term>Non-alcoholic Fatty Liver Disease</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 requests will be evaluated as per the AZ disclosure commitment:&#xD;
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_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 deidentified 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>
  <!-- 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/NCT04483947
org study id: D7830C00002
nct id: NCT04483947
lead sponsor: 
collaborator: 
is fda regulated drug: Yes
is fda regulated device: Yes
is unapproved device: Yes
This study is intended to investigate the safety and tolerability, pharmacokinetics (PK) and
      pharmacodynamics (PD) of AZD2693, following subcutaneous (SC) administration of multiple
      ascending doses in participants with Non-alcoholic Steatohepatitis (NASH) with fibrosis Stage
      0 to 3 and who are carriers of the patatin-like phospholipase domain-containing 3 (PNPLA3)
      148M risk alleles.
This study is a double blind, randomised, placebo-controlled, multi-centre study in
      participants with NASH and fibrosis stage between F0 (no fibrosis) and F3 (bridging
      fibrosis), and who are carriers of the PNPLA3 148M risk alleles.

      The study will comprise of:

        -  An optional Pre-Screening Visit may be completed to determine PNPLA3 genotype and
           collect minimal baseline data and participants who are carriers of the PNPLA3 148M risk
           allele(s) will continue the study and enter the Screening Period.

        -  A Screening Period with a maximum of 60 days.

        -  For participants in all Cohorts, the dosing period will be 8 weeks during which
           participants will be resident of the study site for Dose 1 and Dose 3. Dose 1 will have
           participants reside at the study site from the day prior to study intervention
           administration (Day -1) until at least 2 days after study intervention administration
           with discharge on Day 3. Dose 2 will be administered at the study site on Day 29 with no
           overnight stay. Dose 3 will have participants reside at the study site from the day
           prior to study intervention administration (Day 56) until at least 2 days after study
           intervention administration with discharge on Day 59.

        -  Each participant will be followed for approximately 15 weeks post last dose.

      The study will be performed at up to 30 study sites in the United States (US) and up to 5
      study sites in Mexico. Approximately 80 participants comprising of male and female
      participants of non-childbearing potential may be enrolled into the first 4 cohorts of this
      study in order to achieve a target of 56 to 64 evaluable participants.
allocation: Randomized
intervention model: Sequential Assignment
primary purpose: Treatment
masking: Double (Participant, Investigator)
masking description: The study will be blinded for all study site personal including the principal investigator during the clinical conduct of a given cohort. Investigators will remain blinded to each participant's assigned study intervention throughout the course of the study.
measure: Number of participants with adverse events
time frame: Up to 32 weeks (From Screening to Final Visit)
measure: Absolute change from baseline to Week 8 and Week 12 in liver fat content (LFC)
time frame: Baseline (Day 1), Week 8, Week 12
measure: Percent change from baseline to Week 8 and Week 12 in liver fat content (LFC)
time frame: Baseline (Day 1), Week 8, Week 12
measure: Absolute change from baseline in Alanine Aminotransferase
time frame: Up to 32 weeks (From Pre-Screening to Final Visit)
measure: Percent change from baseline in Alanine Aminotransferase
time frame: Up to 32 weeks (From Pre-Screening to Final Visit)
measure: Absolute change from baseline in Aspartate Aminotransferase
time frame: Up to 32 weeks (From Pre-Screening to Final Visit)
measure: Percent change from baseline in Aspartate Aminotransferase
time frame: Up to 32 weeks (From Pre-Screening to Final Visit)
measure: Absolute change from baseline in Gamma Glutamyl Transferase
time frame: Up to 32 weeks (From Pre-Screening to Final Visit)
measure: Percent change from baseline in Gamma Glutamyl Transferase
time frame: Up to 32 weeks (From Pre-Screening to Final Visit)
measure: Absolute change from baseline in Enhanced Liver Fibrosis (ELF) score
time frame: Up to 32 weeks (From Pre-Screening to Final Visit)
measure: Percent change from baseline in ELF score
time frame: Up to 32 weeks (From Pre-Screening to Final Visit)
measure: Absolute change from baseline in plasma pharmacodynamic biomarker
time frame: Days 1, 8, 29, 36, 50, 64, and 78
measure: Percent change from baseline in plasma pharmacodynamic biomarker
time frame: Days 1, 8, 29, 36, 50, 64, and 78
measure: Absolute change from baseline in disease-specific biomarkers
time frame: Days 1, 8, 29, 36, 50, 64, and 78
measure: Percentage change from baseline in disease-specific biomarkers
time frame: Days 1, 8, 29, 36, 50, 64, and 78
measure: Absolute change from baseline β-Hydroxybutyrate and lipid profile
time frame: Days 1, 8, 29, 36, 50, 64, and 78
measure: Percent change from baseline β-Hydroxybutyrate and lipid profile
time frame: Days 1, 8, 29, 36, 50, 64, and 78
measure: Maximum observed plasma drug concentration (Cmax)
time frame: Day 1 to Day 162
measure: Time to reach maximum observed plasma concentration (tmax)
time frame: Day 1 to Day 162
measure: Terminal elimination rate constant, estimated by log-linear least-squares regression of the terminal part of the concentration-time curve (λz)
time frame: Day 1 to Day 162
measure: Apparent terminal elimination half-life associated with the terminal slope (λz) of the semi-logarithmic concentration-time curve, estimated as (ln2)/λz (t½λz)
time frame: Day 1 to Day 162
measure: Area under the plasma concentration-time curve from time zero to 48 hours after dosing (AUC(0-48h))
time frame: Day 1 to Day 162
measure: Area under the plasma concentration-curve from time zero to the time of last quantifiable analyte concentration (AUClast)
time frame: Day 1 to Day 162
measure: Area under the concentration-time curve from time zero extrapolated to infinity. AUC is estimated by AUClast + Clast/λz where Clast is the last observed quantifiable concentration (AUC)
time frame: Day 1 to Day 162
measure: Apparent total body clearance of drug from plasma after extravascular administration calculated as Dose/AUC (CL/F)
time frame: Day 1 to Day 162
measure: Mean residence time (MRT)
time frame: Day 1 to Day 162
measure: Time delay between drug administration and the first observed concentration in plasma (tlag)
time frame: Day 1 to Day 162
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: Day 1 to Day 162
measure: Area under the plasma concentration-time curve from time zero to time of last quantifiable analyte concentration divided by the dose administered (AUClast/D)
time frame: Day 1 to Day 162
measure: Area under the plasma concentration-time curve from time zero extrapolated to infinity divided by the dose administered (AUC/D)
time frame: Day 1 to Day 162
measure: Observed maximum plasma concentration divided by the dose administered (Cmax/D)
time frame: Day 1 to Day 162
measure: Time of the last quantifiable concentration (tlast)
time frame: Day 1 to Day 162
measure: Maximum observed plasma drug concentration at steady state (Cssmax)
time frame: Day 1 to Day 162
measure: Minimum observed drug concentration at steady state (Cssmin)
time frame: Day 1 to Day 162
measure: Time to reach maximum observed plasma concentration at steady state (tssmax)
time frame: Day 1 to Day 162
measure: Area under the concentration-time curve in the dose interval (AUCss)
time frame: Day 1 to Day 162
measure: Apparent total body clearance of drug from plasma after extravascular administration calculated as Dose/AUCss (CLss/F)
time frame: Day 1 to Day 162
measure: Area under the plasma concentration-time curve from time zero extrapolated to infinity divided by the dose administered (AUCss/D)
time frame: Day 1 to Day 162
measure: Observed maximum plasma concentration divided by the dose administered (Cssmax/D)
time frame: Day 1 to Day 162
measure: Accumulation ratio based on Cmax (RacCmax)
time frame: Day 1 to Day 162
measure: Accumulation ratio based on AUC (RacAUC)
time frame: Day 1 to Day 162
measure: Temporal change parameter in systemic exposure (TCP)
time frame: Day 1 to Day 162
measure: Amount of analyte excreted into the urine from time t1 to t2 (Ae(t1-t2))
time frame: Day 1 and Day 57: Pre-dose and between 0-6 hours, 6-12 hours, 12-24 hours, 24-36 hours and 36-48 hours post-dose
measure: Cumulative amount of analyte excreted from time zero through the last sampling interval (Ae(0-last))
time frame: Day 1 and Day 57: Pre-dose and between 0-6 hours, 6-12 hours, 12-24 hours, 24-36 hours and 36-48 hours post-dose
measure: Fraction of dose excreted unchanged into the urine from time t1 to t2 (fe(t1-t2))
time frame: Day 1 and Day 57: Pre-dose and between 0-6 hours, 6-12 hours, 12-24 hours, 24-36 hours and 36-48 hours post-dose
measure: Cumulative fraction (%) of dose excreted unchanged into the urine from time zero to the last measured time point (fe(0-last))
time frame: Day 1 and Day 57: Pre-dose and between 0-6 hours, 6-12 hours, 12-24 hours, 24-36 hours and 36-48 hours post-dose
measure: Renal clearance of drug from plasma, estimated by dividing Ae(0-t) by AUC(0-t) where the 0-t interval is the same for both Ae and AUC (CLR)
time frame: Day 1 and Day 57: Pre-dose and between 0-6 hours, 6-12 hours, 12-24 hours, 24-36 hours and 36-48 hours post-dose
measure: Change from placebo to Week 10 in PNPLA3 messenger ribonucleic acid (mRNA) and protein expression (Cohort 4 only)
time frame: Week 10
measure: Change from baseline to Week 10 in PNPLA3 mRNA and protein expression (Cohort 4 only)
time frame: Baseline, Week 10
arm group label: Cohort 1
arm group type: Experimental
description: 15 participants will receive AZD2693 dose 1 and 5 participants will receive placebo
arm group label: Cohort 2
arm group type: Experimental
description: 15 participants will receive AZD2693 dose 2 and 5 participants will receive placebo
arm group label: Cohort 3
arm group type: Experimental
description: 15 participants will receive AZD2693 dose 1 and 5 participants will receive placebo
arm group label: Cohort 4
arm group type: Experimental
description: 15 participants will receive AZD2693 dose 3 and 5 participants will receive placebo
intervention type: Drug
intervention name: AZD2693
description: Subcutaneous administration of AZD2693 multiple ascending doses in participants with NASH and who are carriers of the PNPLA3 148M risk allele(s).
arm group label: Cohort 1
arm group label: Cohort 2
arm group label: Cohort 3
arm group label: Cohort 4
intervention type: Other
intervention name: Placebo
description: Participants randomised to placebo will receive the corresponding dose volume of solution as participants receiving AZD2693 within the same cohort
arm group label: Cohort 1
arm group label: Cohort 2
arm group label: Cohort 3
arm group label: Cohort 4
criteria: 
gender: All
minimum age: 18 Years
maximum age: 75 Years
healthy volunteers: No
last name: Rohit Loomba, MD, MHSc
role: Principal Investigator
affiliation: Director, NAFLD Research Center Director of Hepatology, Professor of Medicine Vice Chief, Division of Gastroenterology University of California at San Diego ACTRI Building, 1W202 9500 Gilman Drive La Jolla, CA, 92037-0887
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
country: United States
country: Mexico
responsible party type: Sponsor
mesh term: Fatty Liver
mesh term: Non-alcoholic Fatty Liver Disease
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 requests 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 deidentified 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