<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/NCT03836599</url>
  </required_header>
  <id_info>
    <org_study_id>D5495C00006</org_study_id>
    <nct_id>NCT03836599</nct_id>
  </id_info>
  <brief_title>A Study to Assess the Safety and Pharmacokinetics of Verinurad and Allopurinol in Asian and Chinese Subjects</brief_title>
  <official_title>A Phase I Randomized Double-blind Placebo-controlled Study With 2 Separate Cohorts to Assess the Safety, Tolerability and Pharmacokinetics of Verinurad and Allopurinol in Healthy Asian and Chinese Subjects</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>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      This is a randomized, placebo controlled, double-blind study with two separate cohorts to&#xD;
      assess safety, tolerability and pharmacokinetics of verinurad and allopurinol in healthy&#xD;
      subjects.&#xD;
&#xD;
      In cohort 1, twelve Asian subjects will be treated with allopurinol 300mg for 7 days followed&#xD;
      by either allopurinol 300mg and verinurad 24mg or matching placebo for 7 days.&#xD;
&#xD;
      In Cohort 2, nine Chinese subjects will be treated with allopurinol 300mg for 7 days followed&#xD;
      by allopurinol 300mg and verinurad 12mg administered on 7 out of 8 days.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This is a Phase I study with 2 parallel cohorts which will be performed at a single study&#xD;
      center.&#xD;
&#xD;
      Cohort-1 will comprise of 12 healthy Asian participants, and will follow a randomized,&#xD;
      double-blind, placebo-controlled design. The number of Chinese participants included in&#xD;
      Cohort 1 must be less than 50% of the total number of participants enrolled into the cohort.&#xD;
      Nine participants will be randomized to receive 24 mg verinurad and 300 mg allopurinol once&#xD;
      daily for 7 days and 3 participants will be randomized to receive matching placebos once&#xD;
      daily for 7 days. Cohort 1 participants will undergo a Screening Period of a maximum of 28&#xD;
      days followed by a 7-day Run-in Period during which participants will receive 300 mg&#xD;
      allopurinol or matching placebo once daily. Participants will then be randomized before the&#xD;
      start of the Run-in Period. The Run-in Period is intended to decrease the risk of skin&#xD;
      toxicity of allopurinol. Participants will be admitted to the clinical unit 2-days before the&#xD;
      treatment period, during which they will receive once daily doses of 24 mg verinurad and 300&#xD;
      mg allopurinol or matching placebos. Participants will be discharged from the clinical unit&#xD;
      on Day 8, but will return for a Follow-up Visit within 7 to 14 days.&#xD;
&#xD;
      Cohort-2 will comprise of 9 healthy Chinese participants and will follow an open-label&#xD;
      design. All 9 Chinese participants will receive 12 mg verinurad and 300 mg allopurinol on Day&#xD;
      1 and Day 3 to Day 9. For Cohort-2, participants will undergo a Screening Period of a maximum&#xD;
      of 28 days followed by a 7-day Run-in Period during which participants will receive 300 mg&#xD;
      allopurinol once daily. Participants will be admitted to the Clinical Unit on Day -2, and&#xD;
      will receive a single dose of 12 mg verinurad and 300 mg allopurinol on Day 1. No dosing will&#xD;
      be done on Day 2. Participants will continue dosing on Day 3 and will be dosed once daily&#xD;
      until Day 9. Participants will be discharged from the Clinical Unit on Day 10, but will&#xD;
      return for a Follow-up Visit within 7 to 14 days.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">January 16, 2019</start_date>
  <completion_date type="Actual">April 26, 2019</completion_date>
  <primary_completion_date type="Actual">April 26, 2019</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>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Double (Participant, Investigator)</masking>
    <masking_description>Cohort 1 is double blind Cohort 2 is open-label</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>Number of participants with adverse events</measure>
    <time_frame>From screening up to Follow-up visit/Early discontinuation visit (EDV) (7-14 Days Post-last PK Sample)</time_frame>
    <description>To assess the safety and tolerability of verinurad and allopurinol in healthy Asian and Chinese participants.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Number of participants with abnormal findings in electrocardiography (ECG)</measure>
    <time_frame>From screening up to Follow-up visit/EDV (7-14 Days Post-last PK Sample)</time_frame>
    <description>To assess abnormal resting digital 12-lead electrocardiograms as a variable of safety and tolerability of verinurad and allopurinol in healthy Asian and Chinese participants.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Number of participants with abnormal pulse rate</measure>
    <time_frame>From screening up to Follow-up visit/EDV (7-14 Days Post-last PK Sample)</time_frame>
    <description>To assess abnormal pulse rate as a variable of safety and tolerability of verinurad and allopurinol in healthy Asian and Chinese participants.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Number of participants with abnormal hematology</measure>
    <time_frame>From screening up to Follow-up visit/EDV (7-14 Days Post-last PK Sample)</time_frame>
    <description>To assess white blood cell count (WBC), red blood cell count (RBC), neutrophils absolute count, lymphocytes absolute count, monocytes absolute count, eosinophils absolute count, basophils absolute count, platelets, and reticulocytes absolute count as a variable of safety and tolerability of verinurad and allopurinol in healthy Asian and Chinese participants.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Number of participants with abnormal blood pressure (systolic and diastolic)</measure>
    <time_frame>From screening up to Follow-up visit/EDV (7-14 Days Post-last PK Sample)]</time_frame>
    <description>To assess abnormal blood pressure (systolic and diastolic) as a variable of safety and tolerability of verinurad and allopurinol in healthy Asian and Chinese participants.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Number of participants with abnormal physical examination</measure>
    <time_frame>From screening up to Follow-up visit/EDV (7-14 Days Post-last PK sample)]</time_frame>
    <description>To assess safety and tolerability by assessment of the general appearance, respiratory, cardiovascular, abdomen, skin, head, and neck (including ears, eyes, nose, and throat), lymph nodes, thyroid, musculoskeletal and neurological systems.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Number of participants with abnormal electrolytes</measure>
    <time_frame>From screening up to Follow-up visit/EDV (7-14 Days Post-last PK smaple)]</time_frame>
    <description>To assess serum level of sodium, potassium, calcium (total), and phosphate as a variable of safety and tolerability of verinurad and allopurinol in healthy Asian and Chinese participants.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Number of participants with abnormal hemoglobin (Hb)</measure>
    <time_frame>From screening up to Followup visit/EDV (7-14 Days Postlast PK Sample)</time_frame>
    <description>To assess Hb as a variable of safety and tolerability of verinurad and allopurinol in healthy Asian and Chinese participants.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Number of participants with abnormal hematocrit</measure>
    <time_frame>From screening up to Followup visit/EDV (7-14 Days Postlast PK Sample)</time_frame>
    <description>To assess hematocrit as a variable of safety and tolerability of verinurad and allopurinol in healthy Asian and Chinese participants.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Number of participants with abnormal Mean corpuscular volume (MCV)</measure>
    <time_frame>From screening up to Followup visit/EDV (7-14 Days Postlast PK Sample)</time_frame>
    <description>To assess MCV as a variable of safety and tolerability of verinurad and allopurinol in healthy Asian and Chinese participants.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Number of participants with abnormal mean corpuscular hemoglobin (MCH)</measure>
    <time_frame>From screening up to Followup visit/EDV (7-14 Days Postlast PK Sample)</time_frame>
    <description>To assess MCH as a variable of safety and tolerability of verinurad and allopurinol in healthy Asian and Chinese participants.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Number of participants with abnormal mean corpuscular hemoglobin concentration (MCHC)</measure>
    <time_frame>From screening up to Followup visit/EDV (7-14 Days Postlast PK Sample)</time_frame>
    <description>To assess MCHC as a variable of safety and tolerability of verinurad and allopurinol in healthy Asian and Chinese participants.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Number of participants with abnormal clinical chemistry</measure>
    <time_frame>From screening up to Follow-up visit/EDV (7-14 Days Post-last PK Sample)</time_frame>
    <description>To assess the safety and tolerability profile of verinurad and allopurinol treatment in terms of the number of participants with abnormal clinical chemistry values. The laboratory variables to be measured are: bilirubin, creatinine, albumin, alkaline phosphatase (ALP), alanine aminotransferase (ALT), aspartate aminotransferase (AST), cystatin C, gamma glutamyl transpeptidase, urea and uric acid.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Number of participants with abnormal urinalysis.</measure>
    <time_frame>From screening up to Follow-up visit/EDV (7-14 Days Post-last PK Sample)</time_frame>
    <description>To assess the safety and tolerability profile of verinurad and allopurinol treatment in terms of the number of participants with abnormal urinalysis values. The laboratory variables to be measured are: protein, glucose, blood, uric acid, pH, sodium, creatinine, and cystatin C.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Area under plasma concentration-time curve from zero to infinity (AUC), AUC(0-t), AUC(0-24), and AUCτ</measure>
    <time_frame>On Day 1, Days 3 to 6, Day 7 (cohort 1). On Day 1, Day 2, Days 3 to 8, and Day 9 (Cohort 2).</time_frame>
    <description>To evaluate the pharmacokinetics of verinurad, allopurinol and oxypurinol in healthy Asian and Chinese participants.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Observed concentration and percentage change from baseline in serum uric acid</measure>
    <time_frame>On Day -1: -24, -21, -18, and -12 hours prior to dosing on Day 1. On Days 1, 7 and 9 (Pre-dose, 3, 6, 12, and 24 hours post-dose).</time_frame>
    <description>To evaluate serum uric acid of verinurad and allopurinol treatment in terms of the number of participants with observed concentration and percentage change from baseline in serum uric acid.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Observed concentration and percentage change from baseline in urine uric acid</measure>
    <time_frame>On Day -1: baseline collection of urine: -24 to -22 h, -22 h to -20 h, -18 h to -16 h, -16 h to - 12 h and -12 h to 0 h prior to dosing on Day 1, on Days 1, 7 and 9 (0-2 h, 2-4 h, 4-6 h, 6-8 h, 8-12 h, and 12-24 h post-dose).</time_frame>
    <description>To evaluate urine uric acid of verinurad and allopurinol treatment in terms of the number of participants with observed concentration and percentage change from baseline in urine uric acid.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Maximum observed plasma concentration (Cmax) and Minimum observed plasma concentration (Cmin)</measure>
    <time_frame>On Day 1, Days 3 to 6, Day 7(cohort 1). On Day 1, Day 2, Days 3 to 8, and Day 9 (Cohort 2)</time_frame>
    <description>To evaluate the pharmacokinetics of verinurad, allopurinol and oxypurinol in healthy Asian and Chinese participants.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Time to reach maximum observed plasma concentration (tmax) and Time of last measurable concentration (tlast)</measure>
    <time_frame>On Day 1, Days 3 to 6, Day 7 (cohort 1). On Day 1, Day 2, Days 3 to 8, and Day 9 (Cohort 2).</time_frame>
    <description>To evaluate the pharmacokinetics of verinurad, allopurinol and oxypurinol in healthy Asian and Chinese participants.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Apparent total body clearance of drug from plasma after extravascular administration across the dosing interval (CL/F)</measure>
    <time_frame>On Day 1, Days 3 to 6, Day 7(cohort 1). On Day 1, Day 2, Days 3 to 8, and Day 9 (Cohort 2)</time_frame>
    <description>To evaluate the pharmacokinetics of verinurad, allopurinol and oxypurinol in healthy Asian and Chinese participants.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Half-life associated with terminal slope (λz) of a semi-logarithmic concentration-time curve (t½λz)</measure>
    <time_frame>On Day 1, Days 3 to 6, Day 7(cohort 1). On Day 1, Day 2, Days 3 to 8, and Day 9 (Cohort 2)</time_frame>
    <description>To evaluate the pharmacokinetics of verinurad, allopurinol and oxypurinol in healthy Asian and Chinese participants.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Apparent volume of distribution based on the terminal phase (Vz/F) and Apparent volume of distribution during the terminal phase after extravascular administration (Vss/F)</measure>
    <time_frame>On Day 1, Days 3 to 6, Day 7 (cohort 1). On Day 1, Day 2, Days 3 to 8, and Day 9 (Cohort 2)</time_frame>
    <description>To evaluate the pharmacokinetics of verinurad, allopurinol and oxypurinol in healthy Asian and Chinese participants.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Mean residence time (MRT)</measure>
    <time_frame>On Day 1</time_frame>
    <description>To evaluate the pharmacokinetics of verinurad, allopurinol and oxypurinol in healthy Asian and Chinese participants.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Accumulation ratio for Cmax and AUCτ</measure>
    <time_frame>On Day 7 (Cohort 1) or Day 9 (Cohort 2)</time_frame>
    <description>To evaluate the pharmacokinetics of verinurad, allopurinol and oxypurinol in healthy Asian and Chinese participants.</description>
  </secondary_outcome>
  <number_of_arms>3</number_of_arms>
  <enrollment type="Actual">6</enrollment>
  <condition>Chronic Kidney Disease</condition>
  <arm_group>
    <arm_group_label>24 mg Verinurad+300 mg allopurinol</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>During Run-in Period, participants will be dosed with 300 mg of allopurinol from Day -7 to Day -1. During the Treatment Period, participants will be administered 24 mg verinurad with 300 mg allopurinol once daily on Days 1 to 7.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>12 mg Verinurad+300 mg allopurinol</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>During Run-in Period, participants will be dosed with 300 mg of allopurinol once daily from Day -7 to Day -1. During Treatment Period, participants will receive a single dose of 12 mg verinurad and 300 mg allopurinol on Day 1. No dosing will be done on Day 2. Participants will continue dosing on Day 3 and will be dosed once daily until Day 9.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>During Run-in Period, participants in cohort 1 will receive placebo matching allopurinol capsule once daily from Day -7 to Day -1. During treatment period, participants in cohort 1 will receive placebo matching allopurinol capsule and placebo matching verinurad capsule once daily from Day 1 to Day 7.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Verinurad</intervention_name>
    <description>Participants will receive verinurad 24 mg in cohort 1 and 12 mg in cohort 2 once daily.</description>
    <arm_group_label>12 mg Verinurad+300 mg allopurinol</arm_group_label>
    <arm_group_label>24 mg Verinurad+300 mg allopurinol</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Allopurinol</intervention_name>
    <description>Participants will receive allopurinol 300 mg once daily.</description>
    <arm_group_label>12 mg Verinurad+300 mg allopurinol</arm_group_label>
    <arm_group_label>24 mg Verinurad+300 mg allopurinol</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>During Run-in Period, participants in cohort 1 will receive placebo matching allopurinol capsule once daily from Day -7 to Day -1. During treatment period, participants in cohort 1 will receive placebo matching allopurinol capsule and placebo matching verinurad capsule once daily from Day 1 to Day 7.</description>
    <arm_group_label>Placebo</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Provision of signed and dated, written informed consent prior to any study specific&#xD;
             procedures.&#xD;
&#xD;
          -  Applicable only to Cohort 1: Healthy male and female Asian subjects aged 18 to 50&#xD;
             years (inclusive) at the Screening Visit with suitable veins for cannulation or&#xD;
             repeated venipuncture. A subject will be considered Asian if the subject and both of&#xD;
             the subject's parents are part of the original peoples of the Far East, Southeast&#xD;
             Asia, or the Indian subcontinent, including, for example, Cambodia, China, India,&#xD;
             Japan, Korea, Malaysia, Pakistan, the Philippine Islands, Thailand, and Vietnam).&#xD;
&#xD;
          -  Applicable only to Cohort 2: Healthy male and female Chinese subjects aged 18 to 50&#xD;
             years (inclusive) at the Screening Visit with suitable veins for cannulation or&#xD;
             repeated venipuncture. A subject will be considered Chinese if:&#xD;
&#xD;
               -  Both parents and all grandparents are Chinese, and&#xD;
&#xD;
               -  Subject was born in China, and&#xD;
&#xD;
               -  Subject has not lived outside China for more than 10 years.&#xD;
&#xD;
          -  Subject has a sUA acid level &gt; 4.0 mg/dL at the Screening Visit. The assessment may be&#xD;
             repeated once during the Screening Period.&#xD;
&#xD;
          -  Females must have a negative pregnancy test at the Screening Visit and Day -7, must&#xD;
             not be lactating and must be:&#xD;
&#xD;
               1. Of non-childbearing potential, confirmed at the Screening Visit by fulfilling one&#xD;
                  of the following criteria:&#xD;
&#xD;
                    -  Post-menopausal defined as amenorrhea for at least 12 months or more&#xD;
                       following cessation of all exogenous hormonal treatments and&#xD;
                       Follicle-stimulating hormone (FSH) levels in the post-menopausal range (FSH&#xD;
                       levels &gt; 40 IU/mL).&#xD;
&#xD;
                    -  Documentation of irreversible surgical sterilization by hysterectomy,&#xD;
                       bilateral oophorectomy or bilateral salpingectomy but not tubal ligation.&#xD;
&#xD;
               2. OR if of childbearing potential must be willing to use an acceptable method of&#xD;
                  contraception to avoid pregnancy for the entire study period.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Any clinically significant abnormalities in clinical chemistry, hematology, or&#xD;
             urinalysis results, at the Screening Visit as judged by the Investigator including:&#xD;
&#xD;
               1. Alanine aminotransferase (ALT) &gt;1.5 x upper limit of normal (ULN);&#xD;
&#xD;
               2. Aspartate aminotransferase (AST) &gt;1.5 x ULN;&#xD;
&#xD;
               3. Bilirubin (total) &gt; 1.5 x ULN; and&#xD;
&#xD;
               4. Gamma glutamyl transpeptidase (GGT) &gt;1.5 x ULN. If any these tests are&#xD;
                  out-of-range the test can be repeated once at the Screening Visit at the&#xD;
                  discretion of the Investigator.&#xD;
&#xD;
          -  Known carrier of the Human Leukocyte Antigen-B (HLA-B) *58:01 allele.&#xD;
&#xD;
          -  Any positive result on screening for serum hepatitis B surface antigen, hepatitis C&#xD;
             antibody, and human immunodeficiency virus (HIV) antibody.&#xD;
&#xD;
          -  Suspected or known Gilbert's syndrome.&#xD;
&#xD;
          -  Current smokers or those who have smoked or used nicotine products (including&#xD;
             e-cigarettes within the previous 3 months).&#xD;
&#xD;
          -  Positive screen for drugs of abuse, cotinine (nicotine) or alcohol at the Screening&#xD;
             Visit or on Day -7.&#xD;
&#xD;
          -  Use of any prescribed or non-prescribed medication including antacids, analgesics&#xD;
             (other than paracetamol/acetaminophen), herbal remedies, megadose vitamins (intake of&#xD;
             20 to 600 times the recommended daily dose) and minerals during the 2 weeks prior to&#xD;
             the first administration of investigational product or within 5 half-lives (whichever&#xD;
             is longer). The use of hormonal contraception therapy and hormonal replacement therapy&#xD;
             for females are permitted.&#xD;
&#xD;
          -  Has received another new chemical or biological entity (defined as a compound which&#xD;
             has not been approved for marketing in the US) within 30 days or within 5 half-lives&#xD;
             (whichever is longer) of the first administration of investigational drug in this&#xD;
             study.&#xD;
&#xD;
          -  Involvement of any AstraZeneca, PAREXEL or study site employee or their close&#xD;
             relatives.&#xD;
&#xD;
          -  Subjects who are vegans or have medical dietary restrictions.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>50 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>David Han, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Parexel</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Glendale</city>
        <state>California</state>
        <zip>91206</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>May 2019</verification_date>
  <study_first_submitted>December 21, 2018</study_first_submitted>
  <study_first_submitted_qc>February 8, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">February 11, 2019</study_first_posted>
  <last_update_submitted>May 10, 2019</last_update_submitted>
  <last_update_submitted_qc>May 10, 2019</last_update_submitted_qc>
  <last_update_posted type="Actual">May 13, 2019</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Uric acid transporter 1 (URAT1) Inhibitor</keyword>
  <keyword>Xantine oxidoreductase inhibitor</keyword>
  <keyword>Pharmacokinetics</keyword>
  <keyword>Verinurad</keyword>
  <keyword>Allopurinol</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Kidney Diseases</mesh_term>
    <mesh_term>Renal Insufficiency, Chronic</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Allopurinol</mesh_term>
    <mesh_term>Verinurad</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Undecided</sharing_ipd>
  </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/NCT03836599
org study id: D5495C00006
nct id: NCT03836599
lead sponsor: 
collaborator: 
has dmc: No
is fda regulated drug: Yes
is fda regulated device: No
is us export: No
This is a randomized, placebo controlled, double-blind study with two separate cohorts to
      assess safety, tolerability and pharmacokinetics of verinurad and allopurinol in healthy
      subjects.

      In cohort 1, twelve Asian subjects will be treated with allopurinol 300mg for 7 days followed
      by either allopurinol 300mg and verinurad 24mg or matching placebo for 7 days.

      In Cohort 2, nine Chinese subjects will be treated with allopurinol 300mg for 7 days followed
      by allopurinol 300mg and verinurad 12mg administered on 7 out of 8 days.
This is a Phase I study with 2 parallel cohorts which will be performed at a single study
      center.

      Cohort-1 will comprise of 12 healthy Asian participants, and will follow a randomized,
      double-blind, placebo-controlled design. The number of Chinese participants included in
      Cohort 1 must be less than 50% of the total number of participants enrolled into the cohort.
      Nine participants will be randomized to receive 24 mg verinurad and 300 mg allopurinol once
      daily for 7 days and 3 participants will be randomized to receive matching placebos once
      daily for 7 days. Cohort 1 participants will undergo a Screening Period of a maximum of 28
      days followed by a 7-day Run-in Period during which participants will receive 300 mg
      allopurinol or matching placebo once daily. Participants will then be randomized before the
      start of the Run-in Period. The Run-in Period is intended to decrease the risk of skin
      toxicity of allopurinol. Participants will be admitted to the clinical unit 2-days before the
      treatment period, during which they will receive once daily doses of 24 mg verinurad and 300
      mg allopurinol or matching placebos. Participants will be discharged from the clinical unit
      on Day 8, but will return for a Follow-up Visit within 7 to 14 days.

      Cohort-2 will comprise of 9 healthy Chinese participants and will follow an open-label
      design. All 9 Chinese participants will receive 12 mg verinurad and 300 mg allopurinol on Day
      1 and Day 3 to Day 9. For Cohort-2, participants will undergo a Screening Period of a maximum
      of 28 days followed by a 7-day Run-in Period during which participants will receive 300 mg
      allopurinol once daily. Participants will be admitted to the Clinical Unit on Day -2, and
      will receive a single dose of 12 mg verinurad and 300 mg allopurinol on Day 1. No dosing will
      be done on Day 2. Participants will continue dosing on Day 3 and will be dosed once daily
      until Day 9. Participants will be discharged from the Clinical Unit on Day 10, but will
      return for a Follow-up Visit within 7 to 14 days.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Double (Participant, Investigator)
masking description: Cohort 1 is double blind Cohort 2 is open-label
measure: Number of participants with adverse events
time frame: From screening up to Follow-up visit/Early discontinuation visit (EDV) (7-14 Days Post-last PK Sample)
description: To assess the safety and tolerability of verinurad and allopurinol in healthy Asian and Chinese participants.
measure: Number of participants with abnormal findings in electrocardiography (ECG)
time frame: From screening up to Follow-up visit/EDV (7-14 Days Post-last PK Sample)
description: To assess abnormal resting digital 12-lead electrocardiograms as a variable of safety and tolerability of verinurad and allopurinol in healthy Asian and Chinese participants.
measure: Number of participants with abnormal pulse rate
time frame: From screening up to Follow-up visit/EDV (7-14 Days Post-last PK Sample)
description: To assess abnormal pulse rate as a variable of safety and tolerability of verinurad and allopurinol in healthy Asian and Chinese participants.
measure: Number of participants with abnormal hematology
time frame: From screening up to Follow-up visit/EDV (7-14 Days Post-last PK Sample)
description: To assess white blood cell count (WBC), red blood cell count (RBC), neutrophils absolute count, lymphocytes absolute count, monocytes absolute count, eosinophils absolute count, basophils absolute count, platelets, and reticulocytes absolute count as a variable of safety and tolerability of verinurad and allopurinol in healthy Asian and Chinese participants.
measure: Number of participants with abnormal blood pressure (systolic and diastolic)
time frame: From screening up to Follow-up visit/EDV (7-14 Days Post-last PK Sample)]
description: To assess abnormal blood pressure (systolic and diastolic) as a variable of safety and tolerability of verinurad and allopurinol in healthy Asian and Chinese participants.
measure: Number of participants with abnormal physical examination
time frame: From screening up to Follow-up visit/EDV (7-14 Days Post-last PK sample)]
description: To assess safety and tolerability by assessment of the general appearance, respiratory, cardiovascular, abdomen, skin, head, and neck (including ears, eyes, nose, and throat), lymph nodes, thyroid, musculoskeletal and neurological systems.
measure: Number of participants with abnormal electrolytes
time frame: From screening up to Follow-up visit/EDV (7-14 Days Post-last PK smaple)]
description: To assess serum level of sodium, potassium, calcium (total), and phosphate as a variable of safety and tolerability of verinurad and allopurinol in healthy Asian and Chinese participants.
measure: Number of participants with abnormal hemoglobin (Hb)
time frame: From screening up to Followup visit/EDV (7-14 Days Postlast PK Sample)
description: To assess Hb as a variable of safety and tolerability of verinurad and allopurinol in healthy Asian and Chinese participants.
measure: Number of participants with abnormal hematocrit
time frame: From screening up to Followup visit/EDV (7-14 Days Postlast PK Sample)
description: To assess hematocrit as a variable of safety and tolerability of verinurad and allopurinol in healthy Asian and Chinese participants.
measure: Number of participants with abnormal Mean corpuscular volume (MCV)
time frame: From screening up to Followup visit/EDV (7-14 Days Postlast PK Sample)
description: To assess MCV as a variable of safety and tolerability of verinurad and allopurinol in healthy Asian and Chinese participants.
measure: Number of participants with abnormal mean corpuscular hemoglobin (MCH)
time frame: From screening up to Followup visit/EDV (7-14 Days Postlast PK Sample)
description: To assess MCH as a variable of safety and tolerability of verinurad and allopurinol in healthy Asian and Chinese participants.
measure: Number of participants with abnormal mean corpuscular hemoglobin concentration (MCHC)
time frame: From screening up to Followup visit/EDV (7-14 Days Postlast PK Sample)
description: To assess MCHC as a variable of safety and tolerability of verinurad and allopurinol in healthy Asian and Chinese participants.
measure: Number of participants with abnormal clinical chemistry
time frame: From screening up to Follow-up visit/EDV (7-14 Days Post-last PK Sample)
description: To assess the safety and tolerability profile of verinurad and allopurinol treatment in terms of the number of participants with abnormal clinical chemistry values. The laboratory variables to be measured are: bilirubin, creatinine, albumin, alkaline phosphatase (ALP), alanine aminotransferase (ALT), aspartate aminotransferase (AST), cystatin C, gamma glutamyl transpeptidase, urea and uric acid.
measure: Number of participants with abnormal urinalysis.
time frame: From screening up to Follow-up visit/EDV (7-14 Days Post-last PK Sample)
description: To assess the safety and tolerability profile of verinurad and allopurinol treatment in terms of the number of participants with abnormal urinalysis values. The laboratory variables to be measured are: protein, glucose, blood, uric acid, pH, sodium, creatinine, and cystatin C.
measure: Area under plasma concentration-time curve from zero to infinity (AUC), AUC(0-t), AUC(0-24), and AUCτ
time frame: On Day 1, Days 3 to 6, Day 7 (cohort 1). On Day 1, Day 2, Days 3 to 8, and Day 9 (Cohort 2).
description: To evaluate the pharmacokinetics of verinurad, allopurinol and oxypurinol in healthy Asian and Chinese participants.
measure: Observed concentration and percentage change from baseline in serum uric acid
time frame: On Day -1: -24, -21, -18, and -12 hours prior to dosing on Day 1. On Days 1, 7 and 9 (Pre-dose, 3, 6, 12, and 24 hours post-dose).
description: To evaluate serum uric acid of verinurad and allopurinol treatment in terms of the number of participants with observed concentration and percentage change from baseline in serum uric acid.
measure: Observed concentration and percentage change from baseline in urine uric acid
time frame: On Day -1: baseline collection of urine: -24 to -22 h, -22 h to -20 h, -18 h to -16 h, -16 h to - 12 h and -12 h to 0 h prior to dosing on Day 1, on Days 1, 7 and 9 (0-2 h, 2-4 h, 4-6 h, 6-8 h, 8-12 h, and 12-24 h post-dose).
description: To evaluate urine uric acid of verinurad and allopurinol treatment in terms of the number of participants with observed concentration and percentage change from baseline in urine uric acid.
measure: Maximum observed plasma concentration (Cmax) and Minimum observed plasma concentration (Cmin)
time frame: On Day 1, Days 3 to 6, Day 7(cohort 1). On Day 1, Day 2, Days 3 to 8, and Day 9 (Cohort 2)
description: To evaluate the pharmacokinetics of verinurad, allopurinol and oxypurinol in healthy Asian and Chinese participants.
measure: Time to reach maximum observed plasma concentration (tmax) and Time of last measurable concentration (tlast)
time frame: On Day 1, Days 3 to 6, Day 7 (cohort 1). On Day 1, Day 2, Days 3 to 8, and Day 9 (Cohort 2).
description: To evaluate the pharmacokinetics of verinurad, allopurinol and oxypurinol in healthy Asian and Chinese participants.
measure: Apparent total body clearance of drug from plasma after extravascular administration across the dosing interval (CL/F)
time frame: On Day 1, Days 3 to 6, Day 7(cohort 1). On Day 1, Day 2, Days 3 to 8, and Day 9 (Cohort 2)
description: To evaluate the pharmacokinetics of verinurad, allopurinol and oxypurinol in healthy Asian and Chinese participants.
measure: Half-life associated with terminal slope (λz) of a semi-logarithmic concentration-time curve (t½λz)
time frame: On Day 1, Days 3 to 6, Day 7(cohort 1). On Day 1, Day 2, Days 3 to 8, and Day 9 (Cohort 2)
description: To evaluate the pharmacokinetics of verinurad, allopurinol and oxypurinol in healthy Asian and Chinese participants.
measure: Apparent volume of distribution based on the terminal phase (Vz/F) and Apparent volume of distribution during the terminal phase after extravascular administration (Vss/F)
time frame: On Day 1, Days 3 to 6, Day 7 (cohort 1). On Day 1, Day 2, Days 3 to 8, and Day 9 (Cohort 2)
description: To evaluate the pharmacokinetics of verinurad, allopurinol and oxypurinol in healthy Asian and Chinese participants.
measure: Mean residence time (MRT)
time frame: On Day 1
description: To evaluate the pharmacokinetics of verinurad, allopurinol and oxypurinol in healthy Asian and Chinese participants.
measure: Accumulation ratio for Cmax and AUCτ
time frame: On Day 7 (Cohort 1) or Day 9 (Cohort 2)
description: To evaluate the pharmacokinetics of verinurad, allopurinol and oxypurinol in healthy Asian and Chinese participants.
arm group label: 24 mg Verinurad+300 mg allopurinol
arm group type: Experimental
description: During Run-in Period, participants will be dosed with 300 mg of allopurinol from Day -7 to Day -1. During the Treatment Period, participants will be administered 24 mg verinurad with 300 mg allopurinol once daily on Days 1 to 7.
arm group label: 12 mg Verinurad+300 mg allopurinol
arm group type: Experimental
description: During Run-in Period, participants will be dosed with 300 mg of allopurinol once daily from Day -7 to Day -1. During Treatment Period, participants will receive a single dose of 12 mg verinurad and 300 mg allopurinol on Day 1. No dosing will be done on Day 2. Participants will continue dosing on Day 3 and will be dosed once daily until Day 9.
arm group label: Placebo
arm group type: Placebo Comparator
description: During Run-in Period, participants in cohort 1 will receive placebo matching allopurinol capsule once daily from Day -7 to Day -1. During treatment period, participants in cohort 1 will receive placebo matching allopurinol capsule and placebo matching verinurad capsule once daily from Day 1 to Day 7.
intervention type: Drug
intervention name: Verinurad
description: Participants will receive verinurad 24 mg in cohort 1 and 12 mg in cohort 2 once daily.
arm group label: 12 mg Verinurad+300 mg allopurinol
arm group label: 24 mg Verinurad+300 mg allopurinol
intervention type: Drug
intervention name: Allopurinol
description: Participants will receive allopurinol 300 mg once daily.
arm group label: 12 mg Verinurad+300 mg allopurinol
arm group label: 24 mg Verinurad+300 mg allopurinol
intervention type: Drug
intervention name: Placebo
description: During Run-in Period, participants in cohort 1 will receive placebo matching allopurinol capsule once daily from Day -7 to Day -1. During treatment period, participants in cohort 1 will receive placebo matching allopurinol capsule and placebo matching verinurad capsule once daily from Day 1 to Day 7.
arm group label: Placebo
criteria: 
gender: All
minimum age: 18 Years
maximum age: 50 Years
healthy volunteers: Accepts Healthy Volunteers
last name: David Han, MD
role: Principal Investigator
affiliation: Parexel
facility: 
country: United States
responsible party type: Sponsor
mesh term: Kidney Diseases
mesh term: Renal Insufficiency, Chronic
mesh term: Allopurinol
mesh term: Verinurad
sharing ipd: Undecided