<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/NCT01681680</url>
  </required_header>
  <id_info>
    <org_study_id>6112</org_study_id>
    <nct_id>NCT01681680</nct_id>
  </id_info>
  <brief_title>Effect of Genetic Variation in the Transporter OCT2, MATE1 and MATE2-K on the PKPD of Metformin</brief_title>
  <acronym>#6112</acronym>
  <official_title>Effect of Genetic Variation in the Transporter OCT2, MATE1 and MATE2-K on the Pharmacokinetics and Pharmacodynamics of Metformin</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of California, San Francisco</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>University of California, San Francisco</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      The current study is part of a large multi-investigator grant to look at the pharmacogenetics&#xD;
      of a number of membrane transporters. The investigators will study individuals with&#xD;
      particular genotypes of the human organic cation transporter, (hOCT2), and the multidrug and&#xD;
      toxin extrusion transporters, MATE1, MATE2-K to test the hypothesis that genetic variation in&#xD;
      hOCT2, hMATEE1 and hMATE2-K are associated with variation in the pharmacokinetics and/or&#xD;
      pharmacodynamics of the antidiabetic agent, metformin.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      In the proposed study, a genotype to phenotype strategy is employed to study the role of the&#xD;
      transporters, OCT2, MATE1, and MATE2-K and related variants in response and disposition to a&#xD;
      known substrate, metformin. Recently, one polymorphic variant in MATE1 (PMT4302, g.-66T&gt;C)&#xD;
      showed decreased promoter activity by 40-45% (p&lt;0.01), and one MATE2-K variant (PMT5597,&#xD;
      g.-130G&gt;A) showed increased promoter activity by 30% (p&lt;0.05), compared to the reference.&#xD;
      Both are the most common promoter variants in each gene (the frequencies of PMT4302: 32.1%&#xD;
      and 23.1% in Caucasian and Asian; PMT5597: 26.2% and 48.5% in Caucasian and Asian)&#xD;
      (unpublished data, Giacomini group). Specifically, the investigators will measure renal&#xD;
      clearance of metformin, and plasma glucose and insulin levels, in healthy Caucasian and Asian&#xD;
      subjects who carry either the reference or variant alleles in order to evaluate the effects&#xD;
      of these variants on metformin disposition and response.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>October 2010</start_date>
  <completion_date type="Actual">October 2013</completion_date>
  <primary_completion_date type="Actual">October 2013</primary_completion_date>
  <phase>Phase 1</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>
    <primary_purpose>Diagnostic</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Renal clearance of Metformin based on genotypes</measure>
    <time_frame>Study day procedures 48 hours</time_frame>
    <description>Renal clearance of Metformin of study participants using reference genotype for transporters of OCT2, MATE1, and MATE2-K. In addition, Cmax for plasma glucose will be analyzed for all study participants.</description>
  </primary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">41</enrollment>
  <condition>Healthy</condition>
  <arm_group>
    <arm_group_label>Metformin</arm_group_label>
    <arm_group_type>Other</arm_group_type>
    <description>Subjects will be given an oral dose of metformin once per day for two days.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Metformin</intervention_name>
    <description>Subjects will be given an oral dose of metformin once per day for two days.</description>
    <arm_group_label>Metformin</arm_group_label>
    <other_name>GLUCOPHAGE</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Subjects self-identify racial background, identify themselves, parents and four&#xD;
             grandparents as Caucasian and or Chinese.&#xD;
&#xD;
          -  Subject status is healthy volunteer from the SOPHIE cohort&#xD;
&#xD;
          -  Subjects over 18 years old&#xD;
&#xD;
          -  Subjects who are healthy on the basis of medical history, physical examinations and&#xD;
             laboratory tests if healthy volunteer from SOPHIE&#xD;
&#xD;
          -  Subjects who agree with the written informed consent to participate in the study.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Under 18 years old&#xD;
&#xD;
          -  Pregnant or lactating woman (female subjects will have a urine pregnancy test at the&#xD;
             Day 1 visit)&#xD;
&#xD;
          -  They report a prior history of any allergic reaction to metformin&#xD;
&#xD;
          -  Has a risk of congestive heart failure requiring pharmacologic treatment (medical&#xD;
             history)&#xD;
&#xD;
          -  Has a prior history of renal* or hepatic dysfunction (renal and hepatic function will&#xD;
             be evaluated based on screening blood tests conducted prior to study enrollment)&#xD;
&#xD;
          -  Anemic (screening lab values, hemoglobin &lt;10 g)&#xD;
&#xD;
          -  Taking a medication that could confound study results (such as known substrates or&#xD;
             inhibitors of OCT2, MATE1 and MATE2-K such as cimetidine)&#xD;
&#xD;
          -  Subjects are undergoing radiologic studies involving intravascular administration of&#xD;
             iodinated contrast materials, because use of such products may result in acute&#xD;
             alteration of renal function&#xD;
&#xD;
          -  They do not consent to participate in the study&#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>Kathleen M Giacomini, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of California, San Francisco</affiliation>
  </overall_official>
  <removed_countries>
    <country>United States</country>
  </removed_countries>
  <verification_date>June 2014</verification_date>
  <study_first_submitted>August 1, 2012</study_first_submitted>
  <study_first_submitted_qc>September 5, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">September 10, 2012</study_first_posted>
  <last_update_submitted>June 30, 2014</last_update_submitted>
  <last_update_submitted_qc>June 30, 2014</last_update_submitted_qc>
  <last_update_posted type="Estimate">July 2, 2014</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Metformin</mesh_term>
  </intervention_browse>
  <!-- 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/NCT01681680
org study id: 6112
nct id: NCT01681680
lead sponsor: 
has dmc: Yes
The current study is part of a large multi-investigator grant to look at the pharmacogenetics
      of a number of membrane transporters. The investigators will study individuals with
      particular genotypes of the human organic cation transporter, (hOCT2), and the multidrug and
      toxin extrusion transporters, MATE1, MATE2-K to test the hypothesis that genetic variation in
      hOCT2, hMATEE1 and hMATE2-K are associated with variation in the pharmacokinetics and/or
      pharmacodynamics of the antidiabetic agent, metformin.
In the proposed study, a genotype to phenotype strategy is employed to study the role of the
      transporters, OCT2, MATE1, and MATE2-K and related variants in response and disposition to a
      known substrate, metformin. Recently, one polymorphic variant in MATE1 (PMT4302, g.-66T>C)
      showed decreased promoter activity by 40-45% (p<0.01), and one MATE2-K variant (PMT5597,
      g.-130G>A) showed increased promoter activity by 30% (p<0.05), compared to the reference.
      Both are the most common promoter variants in each gene (the frequencies of PMT4302: 32.1%
      and 23.1% in Caucasian and Asian; PMT5597: 26.2% and 48.5% in Caucasian and Asian)
      (unpublished data, Giacomini group). Specifically, the investigators will measure renal
      clearance of metformin, and plasma glucose and insulin levels, in healthy Caucasian and Asian
      subjects who carry either the reference or variant alleles in order to evaluate the effects
      of these variants on metformin disposition and response.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Diagnostic
masking: None (Open Label)
measure: Renal clearance of Metformin based on genotypes
time frame: Study day procedures 48 hours
description: Renal clearance of Metformin of study participants using reference genotype for transporters of OCT2, MATE1, and MATE2-K. In addition, Cmax for plasma glucose will be analyzed for all study participants.
arm group label: Metformin
arm group type: Other
description: Subjects will be given an oral dose of metformin once per day for two days.
intervention type: Drug
intervention name: Metformin
description: Subjects will be given an oral dose of metformin once per day for two days.
arm group label: Metformin
other name: GLUCOPHAGE
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: Accepts Healthy Volunteers
last name: Kathleen M Giacomini, PhD
role: Principal Investigator
affiliation: University of California, San Francisco
country: United States
responsible party type: Sponsor
mesh term: Metformin