<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/NCT04448821</url>
  </required_header>
  <id_info>
    <org_study_id>NM-DDI</org_study_id>
    <nct_id>NCT04448821</nct_id>
  </id_info>
  <brief_title>A Clinical Trial to Evaluate the Effect of Nilotinib on the PK/PD of Meformin</brief_title>
  <official_title>A Clinical Trial to Evaluate the Effect of Nilotinib on the Pharmacokinetics and Pharmacodynamics of Metformin in Healthy Male Adults</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Hyewon Chung</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Korea University Guro Hospital</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      The aim of the study is to evaluate the effect of nilotinib on the pharmacokinetics and&#xD;
      pharmacodynamics of metformin in healthy male adults&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Pharmacokinetics and pharmacodynamics of metformin without coadministration of nilotinib will&#xD;
      be compared with those after administration of nilotinib.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">July 23, 2020</start_date>
  <completion_date type="Actual">September 7, 2020</completion_date>
  <primary_completion_date type="Actual">September 7, 2020</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>Crossover Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Cmax</measure>
    <time_frame>24 hours post-dose</time_frame>
    <description>maximum concentration</description>
  </primary_outcome>
  <primary_outcome>
    <measure>AUCinf</measure>
    <time_frame>24 hours post-dose</time_frame>
    <description>Area under the concentration-time curve from time of administration extrapolated to infinity</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Gmax</measure>
    <time_frame>3 hours from 2 hour post-dose</time_frame>
    <description>maximum glucose level during oral glucose tolerance test</description>
  </primary_outcome>
  <primary_outcome>
    <measure>AUGC</measure>
    <time_frame>3 hours from 2 hour post-dose</time_frame>
    <description>Area under the concentration-time curve during oral glucose tolerance test</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Taste test</measure>
    <time_frame>7 hour post-dose</time_frame>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">16</enrollment>
  <condition>Healthy</condition>
  <arm_group>
    <arm_group_label>Sequence A</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Period 1: metformin; Period 2: metformin + nilotinib</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Sequence B</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Period 1: metformin + nilotinib; Period 2: metformin</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Metformin</intervention_name>
    <description>Single administration of metformin</description>
    <arm_group_label>Sequence A</arm_group_label>
    <arm_group_label>Sequence B</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Metformin + Nilotinib</intervention_name>
    <description>Coadministration of metformin and nilotinib</description>
    <arm_group_label>Sequence A</arm_group_label>
    <arm_group_label>Sequence B</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Healthy male subjects between the ages of 19 and 50 years&#xD;
&#xD;
          -  Subjects with body mass index (BMI) between 18.5 and 29.9 kg/m2 and weight more than&#xD;
             50 kg&#xD;
&#xD;
          -  Subjects who agree with performing contraception during the study&#xD;
&#xD;
          -  Subjects who provides written informed consent&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Subjects who have a current or prior history of cardiovascular, respiratory, hepatic,&#xD;
             renal, hematological, gastrointestinal, endocrine, immunologic, skin, psychiatric, or&#xD;
             neurological diseases that is clinically significant&#xD;
&#xD;
          -  Subjects who have clinically significant allergic history or allergy to metformin,&#xD;
             nilotinib, or other components of drug&#xD;
&#xD;
          -  Subjects with history of galactose intolerance, lapp lactase deficiency, or&#xD;
             glucose-galactose malabsorption&#xD;
&#xD;
          -  Subjects with hypokalemia or hypomagnesemia at screening&#xD;
&#xD;
          -  Subjects with QTcF &gt; 450 or clinically significant findings on 12-lead ECG at&#xD;
             screening&#xD;
&#xD;
          -  Subjects with fasting plasma glucose lower than 70 mg/dL or upper than 126 mg/dL at&#xD;
             screening&#xD;
&#xD;
          -  Subjects who have history of gastrointestinal surgery&#xD;
&#xD;
          -  Subjects with creatinine clearance ≤ 60mL/min at screening&#xD;
&#xD;
          -  Subjects with AST or ALT ≥ 2-folds of upper normal limit&#xD;
&#xD;
          -  Subjects who reports less than 12 points on taste test at screening&#xD;
&#xD;
          -  Subjects who have administrated drugs that are known to cause significant drug-drug&#xD;
             interaction with investigational drugs within 2 weeks prior to dosing&#xD;
&#xD;
          -  Whole blood donation within 60 days prior to dosing, or apheresis donation within 20&#xD;
             days prior to dosing, or received blood donation within 30 days prior to dosing&#xD;
&#xD;
          -  Subjects who participated in a previous clinical trial within 6 months prior to dosing&#xD;
&#xD;
          -  Subjects with a history of alcohol abuse&#xD;
&#xD;
          -  Subjects who are determined as unsuitable for clinical trial participation by&#xD;
             investigator's decision&#xD;
      </textblock>
    </criteria>
    <gender>Male</gender>
    <gender_based>Yes</gender_based>
    <minimum_age>19 Years</minimum_age>
    <maximum_age>50 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Hyewon Chung, MD, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Clinical Assistant Professor</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Korea University Guro Hospital</name>
      <address>
        <city>Seoul</city>
        <state>Guro-gu</state>
        <zip>08308</zip>
        <country>Korea, Republic of</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Korea, Republic of</country>
  </location_countries>
  <reference>
    <citation>Graham GG, Punt J, Arora M, Day RO, Doogue MP, Duong JK, Furlong TJ, Greenfield JR, Greenup LC, Kirkpatrick CM, Ray JE, Timmins P, Williams KM. Clinical pharmacokinetics of metformin. Clin Pharmacokinet. 2011 Feb;50(2):81-98. doi: 10.2165/11534750-000000000-00000.</citation>
    <PMID>21241070</PMID>
  </reference>
  <reference>
    <citation>Chen EC, Liang X, Yee SW, Geier EG, Stocker SL, Chen L, Giacomini KM. Targeted disruption of organic cation transporter 3 attenuates the pharmacologic response to metformin. Mol Pharmacol. 2015 Jul;88(1):75-83. doi: 10.1124/mol.114.096776. Epub 2015 Apr 28.</citation>
    <PMID>25920679</PMID>
  </reference>
  <reference>
    <citation>Kwon EY, Chung JY, Park HJ, Kim BM, Kim M, Choi JH. OCT3 promoter haplotype is associated with metformin pharmacokinetics in Koreans. Sci Rep. 2018 Nov 16;8(1):16965. doi: 10.1038/s41598-018-35322-6.</citation>
    <PMID>30446679</PMID>
  </reference>
  <reference>
    <citation>Lapczuk-Romanska J, Busch D, Gieruszczak E, Drozdzik A, Piotrowska K, Kowalczyk R, Oswald S, Drozdzik M. Membrane Transporters in Human Parotid Gland-Targeted Proteomics Approach. Int J Mol Sci. 2019 Sep 28;20(19):4825. doi: 10.3390/ijms20194825.</citation>
    <PMID>31569384</PMID>
  </reference>
  <reference>
    <citation>Lee N, Duan H, Hebert MF, Liang CJ, Rice KM, Wang J. Taste of a pill: organic cation transporter-3 (OCT3) mediates metformin accumulation and secretion in salivary glands. J Biol Chem. 2014 Sep 26;289(39):27055-27064. doi: 10.1074/jbc.M114.570564. Epub 2014 Aug 8.</citation>
    <PMID>25107910</PMID>
  </reference>
  <reference>
    <citation>Minematsu T, Giacomini KM. Interactions of tyrosine kinase inhibitors with organic cation transporters and multidrug and toxic compound extrusion proteins. Mol Cancer Ther. 2011 Mar;10(3):531-9. doi: 10.1158/1535-7163.MCT-10-0731. Epub 2011 Jan 20.</citation>
    <PMID>21252289</PMID>
  </reference>
  <reference>
    <citation>Rhee SJ, Choi Y, Lee S, Oh J, Kim SJ, Yoon SH, Cho JY, Yu KS. Pharmacokinetic and pharmacodynamic interactions between metformin and a novel dipeptidyl peptidase-4 inhibitor, evogliptin, in healthy subjects. Drug Des Devel Ther. 2016 Aug 10;10:2525-34. doi: 10.2147/DDDT.S110712. eCollection 2016.</citation>
    <PMID>27570447</PMID>
  </reference>
  <reference>
    <citation>Jang K, Chung H, Yoon JS, Moon SJ, Yoon SH, Yu KS, Kim K, Chung JY. Pharmacokinetics, Safety, and Tolerability of Metformin in Healthy Elderly Subjects. J Clin Pharmacol. 2016 Sep;56(9):1104-10. doi: 10.1002/jcph.699. Epub 2016 Feb 22.</citation>
    <PMID>26710683</PMID>
  </reference>
  <reference>
    <citation>Hwang CS, Kim JW, Al Sharhan SS, Kim JW, Cho HJ, Yoon JH, Kim CH. Development of a Gustatory Function Test for Clinical Application in Korean Subjects. Yonsei Med J. 2018 Mar;59(2):325-330. doi: 10.3349/ymj.2018.59.2.325.</citation>
    <PMID>29436203</PMID>
  </reference>
  <verification_date>November 2020</verification_date>
  <study_first_submitted>June 24, 2020</study_first_submitted>
  <study_first_submitted_qc>June 24, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">June 26, 2020</study_first_posted>
  <last_update_submitted>November 3, 2020</last_update_submitted>
  <last_update_submitted_qc>November 3, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">November 4, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor-Investigator</responsible_party_type>
    <investigator_affiliation>Korea University Guro Hospital</investigator_affiliation>
    <investigator_full_name>Hyewon Chung</investigator_full_name>
    <investigator_title>Clinical Assistant Professor</investigator_title>
  </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/NCT04448821
org study id: NM-DDI
nct id: NCT04448821
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
The aim of the study is to evaluate the effect of nilotinib on the pharmacokinetics and
      pharmacodynamics of metformin in healthy male adults
Pharmacokinetics and pharmacodynamics of metformin without coadministration of nilotinib will
      be compared with those after administration of nilotinib.
allocation: Randomized
intervention model: Crossover Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Cmax
time frame: 24 hours post-dose
description: maximum concentration
measure: AUCinf
time frame: 24 hours post-dose
description: Area under the concentration-time curve from time of administration extrapolated to infinity
measure: Gmax
time frame: 3 hours from 2 hour post-dose
description: maximum glucose level during oral glucose tolerance test
measure: AUGC
time frame: 3 hours from 2 hour post-dose
description: Area under the concentration-time curve during oral glucose tolerance test
measure: Taste test
time frame: 7 hour post-dose
arm group label: Sequence A
arm group type: Experimental
description: Period 1: metformin; Period 2: metformin + nilotinib
arm group label: Sequence B
arm group type: Experimental
description: Period 1: metformin + nilotinib; Period 2: metformin
intervention type: Drug
intervention name: Metformin
description: Single administration of metformin
arm group label: Sequence A
arm group label: Sequence B
intervention type: Drug
intervention name: Metformin + Nilotinib
description: Coadministration of metformin and nilotinib
arm group label: Sequence A
arm group label: Sequence B
criteria: 
gender: Male
gender based: Yes
minimum age: 19 Years
maximum age: 50 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Hyewon Chung, MD, PhD
role: Principal Investigator
affiliation: Clinical Assistant Professor
facility: 
country: Korea, Republic of
citation: Graham GG, Punt J, Arora M, Day RO, Doogue MP, Duong JK, Furlong TJ, Greenfield JR, Greenup LC, Kirkpatrick CM, Ray JE, Timmins P, Williams KM. Clinical pharmacokinetics of metformin. Clin Pharmacokinet. 2011 Feb;50(2):81-98. doi: 10.2165/11534750-000000000-00000.
PMID: 21241070
citation: Chen EC, Liang X, Yee SW, Geier EG, Stocker SL, Chen L, Giacomini KM. Targeted disruption of organic cation transporter 3 attenuates the pharmacologic response to metformin. Mol Pharmacol. 2015 Jul;88(1):75-83. doi: 10.1124/mol.114.096776. Epub 2015 Apr 28.
PMID: 25920679
citation: Kwon EY, Chung JY, Park HJ, Kim BM, Kim M, Choi JH. OCT3 promoter haplotype is associated with metformin pharmacokinetics in Koreans. Sci Rep. 2018 Nov 16;8(1):16965. doi: 10.1038/s41598-018-35322-6.
PMID: 30446679
citation: Lapczuk-Romanska J, Busch D, Gieruszczak E, Drozdzik A, Piotrowska K, Kowalczyk R, Oswald S, Drozdzik M. Membrane Transporters in Human Parotid Gland-Targeted Proteomics Approach. Int J Mol Sci. 2019 Sep 28;20(19):4825. doi: 10.3390/ijms20194825.
PMID: 31569384
citation: Lee N, Duan H, Hebert MF, Liang CJ, Rice KM, Wang J. Taste of a pill: organic cation transporter-3 (OCT3) mediates metformin accumulation and secretion in salivary glands. J Biol Chem. 2014 Sep 26;289(39):27055-27064. doi: 10.1074/jbc.M114.570564. Epub 2014 Aug 8.
PMID: 25107910
citation: Minematsu T, Giacomini KM. Interactions of tyrosine kinase inhibitors with organic cation transporters and multidrug and toxic compound extrusion proteins. Mol Cancer Ther. 2011 Mar;10(3):531-9. doi: 10.1158/1535-7163.MCT-10-0731. Epub 2011 Jan 20.
PMID: 21252289
citation: Rhee SJ, Choi Y, Lee S, Oh J, Kim SJ, Yoon SH, Cho JY, Yu KS. Pharmacokinetic and pharmacodynamic interactions between metformin and a novel dipeptidyl peptidase-4 inhibitor, evogliptin, in healthy subjects. Drug Des Devel Ther. 2016 Aug 10;10:2525-34. doi: 10.2147/DDDT.S110712. eCollection 2016.
PMID: 27570447
citation: Jang K, Chung H, Yoon JS, Moon SJ, Yoon SH, Yu KS, Kim K, Chung JY. Pharmacokinetics, Safety, and Tolerability of Metformin in Healthy Elderly Subjects. J Clin Pharmacol. 2016 Sep;56(9):1104-10. doi: 10.1002/jcph.699. Epub 2016 Feb 22.
PMID: 26710683
citation: Hwang CS, Kim JW, Al Sharhan SS, Kim JW, Cho HJ, Yoon JH, Kim CH. Development of a Gustatory Function Test for Clinical Application in Korean Subjects. Yonsei Med J. 2018 Mar;59(2):325-330. doi: 10.3349/ymj.2018.59.2.325.
PMID: 29436203
responsible party type: Sponsor-Investigator
investigator affiliation: Korea University Guro Hospital
investigator full name: Hyewon Chung
investigator title: Clinical Assistant Professor
mesh term: Metformin