<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/NCT04449471</url>
  </required_header>
  <id_info>
    <org_study_id>SITE00000671</org_study_id>
    <secondary_id>5P01GM116691</secondary_id>
    <nct_id>NCT04449471</nct_id>
  </id_info>
  <brief_title>Naproxen Pharmacogenetic Study (Project 1, Aim 2)</brief_title>
  <official_title>Project 1: Program on Genetic and Dietary Predictors of Drug Response in Rural and AI/AN Populations (Naproxen Study)</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Washington</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Oregon Health and Science University</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>National Institute of General Medical Sciences (NIGMS)</agency>
      <agency_class>NIH</agency_class>
    </collaborator>
  </sponsors>
  <source>University of Washington</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 mechanism-based study in healthy adults to determine the effect of the CYP2C9 M1L&#xD;
      gene polymorphism on the functional activity of the encoded CYP2C9 enzyme towards the probe&#xD;
      substrate naproxen. CYP2C9 activity will be evaluated by measurement of O-desmethyl naproxen&#xD;
      and unchanged naproxen in 24-hour urine following administration of a single oral dose of&#xD;
      naproxen (Aleve) in Yup'ik Alaska Native adult men and women who were previously determined&#xD;
      in a separate observational study to be homozygous for the CYP2C9*1 allele or a carrier of&#xD;
      the CYP2C9 M1L allele.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This pharmacogenetics study will test the hypothesis that inheritance of a M1L variant in the&#xD;
      CYP2C9 gene, which was first discovered in Yup'ik Alaska Native people, causes complete loss&#xD;
      of function in CYP-2C9-dependent catalytic activity.&#xD;
&#xD;
      Study participants will be selected from a cross-sectional population of &gt;750 Yup'ik men and&#xD;
      women, ≥18 years, for whom CYP2C9 genotype has already been determined as part of a SNP&#xD;
      discovery study, and who consented to be contacted for future research. There will be 15&#xD;
      participants in each of two genotyped groups ((1) Met1/Met1 and (2) Met1/Leu1 or Leu1/Leu1),&#xD;
      for a total of 30 participants. The two groups will be matched for sex of the participants;&#xD;
      the proportion determined by the composition of the least frequent Leu1 carrier group. The&#xD;
      investigators will attempt to recruit a similar range of ages in each genotyped group and the&#xD;
      widest range possible. Recruitment will occur in one of 10 communities in the Yukon-Kuskokwim&#xD;
      delta that participated in our original SNP discovery study.&#xD;
&#xD;
      Participants will be asked to fast overnight prior to the study and will be allowed to eat ad&#xD;
      libitum 2 hours after naproxen is taken. A fasting 13 ml venous blood sample will be&#xD;
      collected from each participant for isolation of DNA and plasma. Spot urine will be collected&#xD;
      from each participant as an analytic control the morning of the blood draw. At approximately&#xD;
      9 am, each participant will be given a single 220-mg dose of Naproxen, by mouth, with a glass&#xD;
      of water. The total urine output over the next 24-hour will be collected by the participant&#xD;
      and returned to the clinic the next day. The urine volume will be measured and recorded and&#xD;
      two 5 mL aliquots will be frozen at -80°C and stored for unchanged drug and metabolite&#xD;
      analysis analyses.&#xD;
&#xD;
      Total (conjugated and unconjugated) 6-O-Desmethyl naproxen and unchanged naproxen&#xD;
      concentrations in urine will be measured by LC-MS/MS. A ratio of the total 6-O-desmethyl&#xD;
      naproxen/naproxen (M/P) excreted in urine over 24-hours will be computed. 6-O-desmethyl&#xD;
      naproxen is formed selectively by CYP2C9.&#xD;
&#xD;
      Pairwise comparison of the mean M/P ratios, assuming unequal variance, will be evaluated&#xD;
      using a t-test to determine if there are significant differences in activity for carriers of&#xD;
      the Leu 1 variant. The sample size provides 80% power to detect a difference, at a&#xD;
      significance level of 0.05.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Recruiting</last_known_status>
  <start_date type="Actual">January 12, 2016</start_date>
  <completion_date type="Anticipated">July 31, 2022</completion_date>
  <primary_completion_date type="Anticipated">July 31, 2021</primary_completion_date>
  <phase>Phase 4</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <intervention_model_description>Healthy adults with predetermined CYP2C9 genotype will receive the probe drug, naproxen.</intervention_model_description>
    <primary_purpose>Basic Science</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>6-O-desmethyl naproxen/naproxen ratio</measure>
    <time_frame>24-hours</time_frame>
    <description>A ratio of the total mount of 6-O-desmethyl naproxen/unchanged naproxen in 24-hour urine</description>
  </primary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Anticipated">30</enrollment>
  <condition>Pharmacogenetics</condition>
  <arm_group>
    <arm_group_label>Naproxen Tablet</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Subjects will received a single 220-mg dose of naproxen sodium (Aleve) by mouth.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Naproxen tablet</intervention_name>
    <description>For this single intervention arm, each subject will receive a single 220-mg dose of naproxen sodium (Aleve), followed by urine collection for 24-hours.</description>
    <arm_group_label>Naproxen Tablet</arm_group_label>
    <other_name>Aleve</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. No history of significant medical conditions including cardiac, pulmonary,&#xD;
             gastrointestinal, or renal disease, HIV, or history of asthma, urticaria, or&#xD;
             allergic-type reactions with aspirin (ASA) or other NSAID (nonsteroidal&#xD;
             anti-inflammatory drug).&#xD;
&#xD;
          2. Both males or females 18 years and older.&#xD;
&#xD;
          3. Self-identified as Yup'ik or Cup'ik&#xD;
&#xD;
          4. Able to read and understand English or Yup'ik.&#xD;
&#xD;
          5. Able to provide informed consent.&#xD;
&#xD;
          6. Women not currently pregnant or lactating.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Individuals with any significant chronic medical condition, including cardiac,&#xD;
             pulmonary, hepatic, gastrointestinal, or renal disease, HIV, or history of asthma,&#xD;
             urticaria, or allergic-type reactions with aspirin (ASA) or other NSAID&#xD;
&#xD;
          2. Individuals less than 18 years of age.&#xD;
&#xD;
          3. Individuals unable to read and understand English or Yup'ik.&#xD;
&#xD;
          4. Individuals unable to provide informed consent.&#xD;
&#xD;
          5. Individuals taking drugs or natural products known to affect the metabolic activity of&#xD;
             CYP2C9 (e.g., rifampin, carbamazepine, barbiturates, phenytoin, valproic acid,&#xD;
             fluconazole, ketoconazole, miconazole, amiodarone, fluvastatin and milk thistle.&#xD;
&#xD;
          6. Women who are pregnant or lactating.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Kenneth E. Thummel, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Washington</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Kenneth E. Thummel, PhD</last_name>
    <phone>205-543-0819</phone>
    <email>thummel@uw.edu</email>
  </overall_contact>
  <location>
    <facility>
      <name>Oregon Health &amp; Science University</name>
      <address>
        <city>Portland</city>
        <state>Oregon</state>
        <zip>97239-3098</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Bert B. Boyer, PhD</last_name>
      <phone>503-494-3368</phone>
      <email>boyerbe@ohsu.edu</email>
    </contact>
    <contact_backup>
      <last_name>Scarlett Hopkins, RN, MA</last_name>
      <phone>503-494-3369</phone>
      <email>hopkisca@ohsu.edu</email>
    </contact_backup>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>June 2020</verification_date>
  <study_first_submitted>June 23, 2020</study_first_submitted>
  <study_first_submitted_qc>June 23, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">June 26, 2020</study_first_posted>
  <last_update_submitted>June 25, 2020</last_update_submitted>
  <last_update_submitted_qc>June 25, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">June 29, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>University of Washington</investigator_affiliation>
    <investigator_full_name>Kenneth Thummel</investigator_full_name>
    <investigator_title>Professor: Pharmaceutics</investigator_title>
  </responsible_party>
  <keyword>CYP2C9</keyword>
  <keyword>naproxen</keyword>
  <keyword>polymorphism</keyword>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Naproxen</mesh_term>
  </intervention_browse>
  <pending_results>
    <submitted>May 27, 2022</submitted>
    <returned>June 24, 2022</returned>
  </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/NCT04449471
org study id: SITE00000671
secondary id: 5P01GM116691
nct id: NCT04449471
lead sponsor: 
collaborator: 
collaborator: 
has dmc: No
is fda regulated drug: Yes
is fda regulated device: No
is us export: No
This is a mechanism-based study in healthy adults to determine the effect of the CYP2C9 M1L
      gene polymorphism on the functional activity of the encoded CYP2C9 enzyme towards the probe
      substrate naproxen. CYP2C9 activity will be evaluated by measurement of O-desmethyl naproxen
      and unchanged naproxen in 24-hour urine following administration of a single oral dose of
      naproxen (Aleve) in Yup'ik Alaska Native adult men and women who were previously determined
      in a separate observational study to be homozygous for the CYP2C9*1 allele or a carrier of
      the CYP2C9 M1L allele.
This pharmacogenetics study will test the hypothesis that inheritance of a M1L variant in the
      CYP2C9 gene, which was first discovered in Yup'ik Alaska Native people, causes complete loss
      of function in CYP-2C9-dependent catalytic activity.

      Study participants will be selected from a cross-sectional population of >750 Yup'ik men and
      women, ≥18 years, for whom CYP2C9 genotype has already been determined as part of a SNP
      discovery study, and who consented to be contacted for future research. There will be 15
      participants in each of two genotyped groups ((1) Met1/Met1 and (2) Met1/Leu1 or Leu1/Leu1),
      for a total of 30 participants. The two groups will be matched for sex of the participants;
      the proportion determined by the composition of the least frequent Leu1 carrier group. The
      investigators will attempt to recruit a similar range of ages in each genotyped group and the
      widest range possible. Recruitment will occur in one of 10 communities in the Yukon-Kuskokwim
      delta that participated in our original SNP discovery study.

      Participants will be asked to fast overnight prior to the study and will be allowed to eat ad
      libitum 2 hours after naproxen is taken. A fasting 13 ml venous blood sample will be
      collected from each participant for isolation of DNA and plasma. Spot urine will be collected
      from each participant as an analytic control the morning of the blood draw. At approximately
      9 am, each participant will be given a single 220-mg dose of Naproxen, by mouth, with a glass
      of water. The total urine output over the next 24-hour will be collected by the participant
      and returned to the clinic the next day. The urine volume will be measured and recorded and
      two 5 mL aliquots will be frozen at -80°C and stored for unchanged drug and metabolite
      analysis analyses.

      Total (conjugated and unconjugated) 6-O-Desmethyl naproxen and unchanged naproxen
      concentrations in urine will be measured by LC-MS/MS. A ratio of the total 6-O-desmethyl
      naproxen/naproxen (M/P) excreted in urine over 24-hours will be computed. 6-O-desmethyl
      naproxen is formed selectively by CYP2C9.

      Pairwise comparison of the mean M/P ratios, assuming unequal variance, will be evaluated
      using a t-test to determine if there are significant differences in activity for carriers of
      the Leu 1 variant. The sample size provides 80% power to detect a difference, at a
      significance level of 0.05.
allocation: N/A
intervention model: Single Group Assignment
intervention model description: Healthy adults with predetermined CYP2C9 genotype will receive the probe drug, naproxen.
primary purpose: Basic Science
masking: None (Open Label)
measure: 6-O-desmethyl naproxen/naproxen ratio
time frame: 24-hours
description: A ratio of the total mount of 6-O-desmethyl naproxen/unchanged naproxen in 24-hour urine
arm group label: Naproxen Tablet
arm group type: Experimental
description: Subjects will received a single 220-mg dose of naproxen sodium (Aleve) by mouth.
intervention type: Drug
intervention name: Naproxen tablet
description: For this single intervention arm, each subject will receive a single 220-mg dose of naproxen sodium (Aleve), followed by urine collection for 24-hours.
arm group label: Naproxen Tablet
other name: Aleve
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: Accepts Healthy Volunteers
last name: Kenneth E. Thummel, PhD
role: Principal Investigator
affiliation: University of Washington
last name: Kenneth E. Thummel, PhD
phone: 205-543-0819
email: thummel@uw.edu
facility: 
status: Recruiting
contact: 
contact backup: 
country: United States
responsible party type: Principal Investigator
investigator affiliation: University of Washington
investigator full name: Kenneth Thummel
investigator title: Professor: Pharmaceutics
mesh term: Naproxen
submitted: May 27, 2022
returned: June 24, 2022