<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/NCT02235233</url>
  </required_header>
  <id_info>
    <org_study_id>13-3362</org_study_id>
    <secondary_id>2R01GM041935</secondary_id>
    <nct_id>NCT02235233</nct_id>
  </id_info>
  <brief_title>Effect of Non-Alcoholic Steatohepatitis (NASH) on the Pharmacokinetics of 99mTechnetium-Mebrofenin</brief_title>
  <official_title>Clinical Study to Investigate the Effect of NASH (Non-alcoholic Steatohepatitis) on the Disposition of 99mTechnetium(Tc)-Mebrofenin in Healthy Subjects Compared to Patients With NASH.</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of North Carolina, Chapel Hill</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>National Institute of General Medical Sciences (NIGMS)</agency>
      <agency_class>NIH</agency_class>
    </collaborator>
  </sponsors>
  <source>University of North Carolina, Chapel Hill</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      This study is designed to investigate the effect of NASH (non-alcoholic steatohepatitis) on&#xD;
      the disposition of 99mTechnetium(Tc)-mebrofenin and to relate changes in 99mTc-mebrofenin&#xD;
      disposition to differences in the bile acid profile and Fibroscan Fibrosis Score of healthy&#xD;
      subjects compared to patients with NASH.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This will be an open-label, clinical study in male and female patients with NASH (n=10) and&#xD;
      healthy volunteers (n=10) of any race and ethnicity investigating the effect of liver disease&#xD;
      on the pharmacokinetics of 99mTechnetium-mebrofenin. The use of the gamma emitter 99m Tc-&#xD;
      labeled mebrofenin will allow real-time assessment of hepatic exposure. To determine the&#xD;
      differences between healthy subjects and patients with NASH, blood and hepatic concentrations&#xD;
      will be analyzed by non-compartmental analysis. Additionally, serum bile acid samples and&#xD;
      fibroscan data will be collected to determine whether the bile acid profile and/or fibroscan&#xD;
      readings are different between healthy subjects and patients with NASH. Changes in&#xD;
      99mTc-mebrofenin will be correlated with the patient specific bile acid profile and fibroscan&#xD;
      data. This study will increase our understating of the effect of liver disease on the&#xD;
      disposition of medications that undergo transporter-mediated hepatic clearance.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">April 2015</start_date>
  <completion_date type="Actual">July 2016</completion_date>
  <primary_completion_date type="Actual">July 2016</primary_completion_date>
  <phase>Phase 1</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Non-Randomized</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Basic Science</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Hepatic exposure (AUC0→∞)</measure>
    <time_frame>0-180 minutes</time_frame>
    <description>Area under the hepatic concentration-time curve</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Systemic exposure (AUC0 →∞)</measure>
    <time_frame>0-300 minutes</time_frame>
    <description>Area under the systemic concentration-time curve</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cmax (hepatic)</measure>
    <time_frame>0-180 minutes</time_frame>
    <description>Peak mebrofenin concentration in the liver</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Tmax (hepatic)</measure>
    <time_frame>0-180 minutes</time_frame>
    <description>Time to peak concentration of mebrofenin in the liver</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Xurine</measure>
    <time_frame>0-180 minutes</time_frame>
    <description>Mass excreted in urine</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>CLuptake</measure>
    <time_frame>0-180 minutes</time_frame>
    <description>Hepatic uptake clearance</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>CLrenal</measure>
    <time_frame>0-180 minutes</time_frame>
    <description>Renal clearance</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">21</enrollment>
  <condition>Non-alcoholic Steatohepatitis</condition>
  <arm_group>
    <arm_group_label>Patients with NASH</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Each subject will be injected with ~2.5 mCi of Technetium Tc 99M Mebrofenin</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Healthy Normal Volunteers</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Each subject will be injected with ~2.5 mCi of Technetium Tc 99M Mebrofenin</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Technetium Tc 99M Mebrofenin</intervention_name>
    <description>Each subject will be injected with ~2.5 mCi of Technetium Tc 99M Mebrofenin</description>
    <arm_group_label>Healthy Normal Volunteers</arm_group_label>
    <arm_group_label>Patients with NASH</arm_group_label>
    <other_name>Choletec</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Healthy subjects: defined as being free from significant cardiac, pulmonary,&#xD;
             gastrointestinal, hepatic, biliary, renal, hematological, neurological and psychiatric&#xD;
             disease as determined by history, physical examination and clinical laboratory test&#xD;
             results.&#xD;
&#xD;
          2. NASH subjects only: defined as those who have had a recent liver biopsy consistent&#xD;
             with NASH without cirrhosis; NAS score &gt;3.&#xD;
&#xD;
          3. Fluent and literate in English.&#xD;
&#xD;
          4. Willing and able to give informed consent prior to entering the study.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Donation of blood within last 30 days.&#xD;
&#xD;
          2. History of significant alcohol abuse (&gt;20g/day) and/or illicit drug use, whether&#xD;
             successfully treated or not.&#xD;
&#xD;
          3. Inability to abstain from alcohol for 48 hours prior to study visits.&#xD;
&#xD;
          4. Inability to fast for 8 hours prior to study sample collection.&#xD;
&#xD;
          5. Women who are pregnant, trying to become pregnant, or breast feeding.&#xD;
&#xD;
          6. Use of drugs associated with a clinical or histological picture consistent with fatty&#xD;
             liver disease or NASH for more than 12 consecutive weeks in the year prior to&#xD;
             screening; these include amiodarone, tamoxifen, methotrexate, glucocorticoids,&#xD;
             anabolic steroids, tetracyclines, estrogens at doses greater than those used for&#xD;
             hormone replacement or valproate/valproic acid&#xD;
&#xD;
          7. Type 2 diabetes treated with oral agents other than metformin; these include&#xD;
             secretagogues, thiazolidinediones, alpha-glucosidase inhibitors, exenatide and&#xD;
             pramlintide.&#xD;
&#xD;
          8. Current or recent use of bile acid sequestrants, bile acid derivatives (i.e. ursodiol)&#xD;
             or fibric acid derivatives.&#xD;
&#xD;
          9. Serum blood glucose reading at study enrollment of &gt;200 mg/dL.&#xD;
&#xD;
         10. Current use of antioxidants such as silymarin, vitamin C, glutathione, or&#xD;
             non-prescribed complementary alternative medications (including dietary supplements,&#xD;
             megadose vitamins, herbal preparations, and special teas) within 30 days prior to&#xD;
             screening. A multivitamin and vitamin E at standard doses will be allowed.&#xD;
&#xD;
         11. Previous liver biopsy that demonstrated presence of cirrhosis.&#xD;
&#xD;
         12. Radiologic imaging consistent with cirrhosis or portal hypertension.&#xD;
&#xD;
         13. Evidence of decompensated liver disease defined as any of the following: serum albumin&#xD;
             &lt;3.2 g/dL, total bilirubin &gt; 1.5 mg/dL, or PT/INR &gt; 1.3 times normal at screening, or&#xD;
             history or presence of ascites, encephalopathy, or bleeding from esophageal varices.&#xD;
&#xD;
         14. Serum creatinine of 2.0 mg/dL or greater, or on dialysis, at screening.&#xD;
&#xD;
         15. History of immunologically mediated disease (e.g., inflammatory bowel disease,&#xD;
             idiopathic thrombocytopenic purpura, lupus erythematosus, autoimmune hemolytic anemia,&#xD;
             severe psoriasis, rheumatoid arthritis) that could affect the assessment of biomarkers&#xD;
             (bile acids or inflammation).&#xD;
&#xD;
         16. Primary, secondary or extrahepatic malignancy.&#xD;
&#xD;
         17. History of bariatric surgery.&#xD;
&#xD;
         18. Participation in a research drug trial, exclusive of the SyNCH Phase I or II trials,&#xD;
             within 30 days of screening.&#xD;
&#xD;
         19. BMI &gt; 45 kg/m2 at screening (body weight is not within 20% of ideal body weight).&#xD;
&#xD;
         20. Inability or unwillingness to give informed consent or abide by the study protocol.&#xD;
&#xD;
         21. Estimated weekly strenuous exercise greater than 4 hours per week.&#xD;
&#xD;
         22. History or other evidence of illness or any other conditions or drug therapies that&#xD;
             would make the patient, in the opinion of the investigator, unsuitable for the study&#xD;
             (such as poorly controlled psychiatric disease, coronary artery disease, active&#xD;
             gastrointestinal conditions or taking drugs known to interfere with bile acid&#xD;
             synthesis or metabolism or the metabolism/transport of other drugs).&#xD;
&#xD;
         23. Undergone a radiographic procedure (other than dental X-rays), received radioactive&#xD;
             substances, or handled radioactive materials in conjunction with employment within the&#xD;
             last twelve months.&#xD;
&#xD;
         24. A history of hypersensitivity to 99mTc-mebrofenin, ultrasound gel, dairy products, or&#xD;
             their excipients.&#xD;
&#xD;
         25. Consumed caffeine (coffee, tea, colas, and chocolate) within 24 hours of the study.&#xD;
&#xD;
         26. A history of tobacco use within 12 months of the study.&#xD;
&#xD;
         27. Serology positive for Hepatitis B, Hepatitis C or HIV at screening.&#xD;
&#xD;
         28. A history of any gastrointestinal or hepatobiliary surgery or disorder.&#xD;
&#xD;
        Healthy Subjects:&#xD;
&#xD;
          1. Taking concomitant medications, either prescription and non-prescription (including&#xD;
             herbal products and over-the-counter medications), other than oral contraceptives and&#xD;
             multivitamins (women stabilized on hormonal methods of birth control will be allowed&#xD;
             to participate)&#xD;
&#xD;
          2. History or other evidence of liver disease in the opinion of the study investigators.&#xD;
&#xD;
          3. BMI &gt; 30 kg/m2 at screening&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>65 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Sidney Barritt, M.D., MSCR</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of North Carolina, Chapel Hill</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Jason R. Slizgi, B.S.</last_name>
    <role>Study Director</role>
    <affiliation>UNC School of Pharmacy</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Kim Brouwer, PharmD, PhD</last_name>
    <role>Study Director</role>
    <affiliation>UNC School of Pharmacy</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Josh Kaullen, Pharm.D.</last_name>
    <role>Study Director</role>
    <affiliation>UNC School of Pharmacy</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Marijia Ivanovic, Ph.D.</last_name>
    <role>Study Director</role>
    <affiliation>UNC Department of Radiology</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Paul Stewart, Ph.D.</last_name>
    <role>Study Director</role>
    <affiliation>UNC School of Public Health</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>UNC Hospitals</name>
      <address>
        <city>Chapel Hill</city>
        <state>North Carolina</state>
        <zip>27514</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <results_reference>
    <citation>Pfeifer ND, Goss SL, Swift B, Ghibellini G, Ivanovic M, Heizer WD, Gangarosa LM, Brouwer KL. Effect of Ritonavir on (99m)Technetium-Mebrofenin Disposition in Humans: A Semi-PBPK Modeling and In Vitro Approach to Predict Transporter-Mediated DDIs. CPT Pharmacometrics Syst Pharmacol. 2013 Jan 2;2(1):e20. doi: 10.1038/psp.2012.21.</citation>
    <PMID>23887590</PMID>
  </results_reference>
  <verification_date>May 2017</verification_date>
  <study_first_submitted>September 5, 2014</study_first_submitted>
  <study_first_submitted_qc>September 8, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">September 9, 2014</study_first_posted>
  <last_update_submitted>May 2, 2017</last_update_submitted>
  <last_update_submitted_qc>May 2, 2017</last_update_submitted_qc>
  <last_update_posted type="Actual">May 5, 2017</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <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>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Technetium Tc 99m mebrofenin</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/NCT02235233
org study id: 13-3362
secondary id: 2R01GM041935
nct id: NCT02235233
lead sponsor: 
collaborator: 
has dmc: No
This study is designed to investigate the effect of NASH (non-alcoholic steatohepatitis) on
      the disposition of 99mTechnetium(Tc)-mebrofenin and to relate changes in 99mTc-mebrofenin
      disposition to differences in the bile acid profile and Fibroscan Fibrosis Score of healthy
      subjects compared to patients with NASH.
This will be an open-label, clinical study in male and female patients with NASH (n=10) and
      healthy volunteers (n=10) of any race and ethnicity investigating the effect of liver disease
      on the pharmacokinetics of 99mTechnetium-mebrofenin. The use of the gamma emitter 99m Tc-
      labeled mebrofenin will allow real-time assessment of hepatic exposure. To determine the
      differences between healthy subjects and patients with NASH, blood and hepatic concentrations
      will be analyzed by non-compartmental analysis. Additionally, serum bile acid samples and
      fibroscan data will be collected to determine whether the bile acid profile and/or fibroscan
      readings are different between healthy subjects and patients with NASH. Changes in
      99mTc-mebrofenin will be correlated with the patient specific bile acid profile and fibroscan
      data. This study will increase our understating of the effect of liver disease on the
      disposition of medications that undergo transporter-mediated hepatic clearance.
allocation: Non-Randomized
intervention model: Single Group Assignment
primary purpose: Basic Science
masking: None (Open Label)
measure: Hepatic exposure (AUC0→∞)
time frame: 0-180 minutes
description: Area under the hepatic concentration-time curve
measure: Systemic exposure (AUC0 →∞)
time frame: 0-300 minutes
description: Area under the systemic concentration-time curve
measure: Cmax (hepatic)
time frame: 0-180 minutes
description: Peak mebrofenin concentration in the liver
measure: Tmax (hepatic)
time frame: 0-180 minutes
description: Time to peak concentration of mebrofenin in the liver
measure: Xurine
time frame: 0-180 minutes
description: Mass excreted in urine
measure: CLuptake
time frame: 0-180 minutes
description: Hepatic uptake clearance
measure: CLrenal
time frame: 0-180 minutes
description: Renal clearance
arm group label: Patients with NASH
arm group type: Experimental
description: Each subject will be injected with ~2.5 mCi of Technetium Tc 99M Mebrofenin
arm group label: Healthy Normal Volunteers
arm group type: Active Comparator
description: Each subject will be injected with ~2.5 mCi of Technetium Tc 99M Mebrofenin
intervention type: Drug
intervention name: Technetium Tc 99M Mebrofenin
description: Each subject will be injected with ~2.5 mCi of Technetium Tc 99M Mebrofenin
arm group label: Healthy Normal Volunteers
arm group label: Patients with NASH
other name: Choletec
criteria: 
gender: All
minimum age: 18 Years
maximum age: 65 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Sidney Barritt, M.D., MSCR
role: Principal Investigator
affiliation: University of North Carolina, Chapel Hill
last name: Jason R. Slizgi, B.S.
role: Study Director
affiliation: UNC School of Pharmacy
last name: Kim Brouwer, PharmD, PhD
role: Study Director
affiliation: UNC School of Pharmacy
last name: Josh Kaullen, Pharm.D.
role: Study Director
affiliation: UNC School of Pharmacy
last name: Marijia Ivanovic, Ph.D.
role: Study Director
affiliation: UNC Department of Radiology
last name: Paul Stewart, Ph.D.
role: Study Director
affiliation: UNC School of Public Health
facility: 
country: United States
citation: Pfeifer ND, Goss SL, Swift B, Ghibellini G, Ivanovic M, Heizer WD, Gangarosa LM, Brouwer KL. Effect of Ritonavir on (99m)Technetium-Mebrofenin Disposition in Humans: A Semi-PBPK Modeling and In Vitro Approach to Predict Transporter-Mediated DDIs. CPT Pharmacometrics Syst Pharmacol. 2013 Jan 2;2(1):e20. doi: 10.1038/psp.2012.21.
PMID: 23887590
responsible party type: Sponsor
mesh term: Fatty Liver
mesh term: Non-alcoholic Fatty Liver Disease
mesh term: Technetium Tc 99m mebrofenin