<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/NCT03760848</url>
  </required_header>
  <id_info>
    <org_study_id>Aramchol 016</org_study_id>
    <nct_id>NCT03760848</nct_id>
  </id_info>
  <brief_title>Study of Potential for Drug Interactions Mediated by CYP3A4 Inhibition With Aramchol in Healthy Volunteers</brief_title>
  <official_title>Study of Potential for Drug Interactions Mediated by CYP3A4 Inhibition With Aramchol in Healthy Volunteers</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Galmed Pharmaceuticals Ltd</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Hammersmith Medicines Research</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Analyst Research Laboratories</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Alderley Analytical</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Diamond Pharma Services Regulatory Affairs Consultancy</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Galmed Pharmaceuticals Ltd</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>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      The trial is an open-label, 2-period, single-sequence assessment of CYP3A4 inhibition by&#xD;
      aramchol using the probe substrates midazolam and atorvastatin to assess CYP3A4 activity.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Enrolment of 16 subjects is planned. Each subject will take part in 2 study periods.&#xD;
&#xD;
      In Period 1, subjects will receive a single oral dose of 2 mg midazolam on Day 1 and a single&#xD;
      oral dose of 40 mg atorvastatin on Day 3.&#xD;
&#xD;
      In Period 2, subjects will receive twice-daily oral doses of 300 mg aramchol (the IMP) for 18&#xD;
      days. During aramchol dosing, subjects will take a single dose of 2 mg midazolam in the&#xD;
      morning on Day 10 and 40 mg atorvastatin in the morning on Day 12.&#xD;
&#xD;
      Subjects will be screened within 21 days before their first dose of study medicine. In Period&#xD;
      1, they will remain resident on the ward from Day -1 to Day 10. In Period 2, subjects will be&#xD;
      admitted on Day -1 and discharged on Day 19. Subjects will attend a follow-up visit&#xD;
      approximately 2 weeks later, on Day 33 (±2 days). There will be an interval of at least 1 day&#xD;
      between Periods 1 and 2.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">November 12, 2018</start_date>
  <completion_date type="Actual">February 2, 2019</completion_date>
  <primary_completion_date type="Actual">February 2, 2019</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>Other</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Midazolam - cmax</measure>
    <time_frame>Blood samples for assay of midazolam will be taken before, and frequently up to 48 hours after each dose.</time_frame>
    <description>Maximum plasma concentration</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Atorvastatin - cmax</measure>
    <time_frame>Blood samples for assay of atorvastatin will be taken before, and frequently up to 168 hours after each dose.</time_frame>
    <description>Maximum plasma concentration</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Midazolam - tmax</measure>
    <time_frame>Blood samples for assay of midazolam will be taken before, and frequently up to 48 hours after each dose.</time_frame>
    <description>Time of maximum plasma concentration</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Atorvastatin - tmax</measure>
    <time_frame>Blood samples for assay of atorvastatin will be taken before, and frequently up to 168 hours after each dose.</time_frame>
    <description>Time of maximum plasma concentration</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Midazolam - Area under the concentration-time curve to last measurable concentration (AUClast)</measure>
    <time_frame>Blood samples for assay of midazolam will be taken before, and frequently up to 48 hours after each dose.</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>Atorvastatin - Area under the concentration-time curve to last measurable concentration (AUClast)</measure>
    <time_frame>Blood samples for assay of atorvastatin will be taken before, and frequently up to 168 hours after each dose.</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>Midazolam - Area under the concentration-time curve extrapolated to infinite time (AUCinf)</measure>
    <time_frame>Blood samples for assay of midazolam will be taken before, and frequently up to 48 hours after each dose.</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>Atorvastatin - Area under the concentration-time curve extrapolated to infinite time (AUCinf)</measure>
    <time_frame>Blood samples for assay of atorvastatin will be taken before, and frequently up to 168 hours after each dose.</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>Midazolam - %AUCextrapinf</measure>
    <time_frame>Blood samples for assay of midazolam will be taken before, and frequently up to 48 hours after each dose.</time_frame>
    <description>Percentage of AUC that was extrapolated</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Atorvastatin - %AUCextrapinf</measure>
    <time_frame>Blood samples for assay of atorvastatin will be taken before, and frequently up to 168 hours after each dose.</time_frame>
    <description>Percentage of AUC that was extrapolated</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Midazolam - t½</measure>
    <time_frame>Blood samples for assay of midazolam will be taken before, and frequently up to 48 hours after each dose.</time_frame>
    <description>Terminal elimination half-life</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Atorvastatin - t½</measure>
    <time_frame>Blood samples for assay of atorvastatin will be taken before, and frequently up to 168 hours after each dose.</time_frame>
    <description>Terminal elimination half-life</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Midazolam - CL/F</measure>
    <time_frame>Blood samples for assay of midazolam will be taken before, and frequently up to 48 hours after each dose.</time_frame>
    <description>Clearance/fraction of dose absorbed</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Atorvastatin - CL/F</measure>
    <time_frame>Blood samples for assay of atorvastatin will be taken before, and frequently up to 168 hours after each dose.</time_frame>
    <description>Clearance/fraction of dose absorbed</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Midazolam - VZ/F</measure>
    <time_frame>Blood samples for assay of midazolam will be taken before, and frequently up to 48 hours after each dose.</time_frame>
    <description>Volume of distribution/fraction of dose absorbed</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Atorvastatin - VZ/F</measure>
    <time_frame>Blood samples for assay of atorvastatin will be taken before, and frequently up to 168 hours after each dose.</time_frame>
    <description>Volume of distribution/fraction of dose absorbed</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Midazolam - MRT</measure>
    <time_frame>Blood samples for assay of midazolam will be taken before, and frequently up to 48 hours after each dose.</time_frame>
    <description>Mean residence time</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Atorvastatin - MRT</measure>
    <time_frame>Blood samples for assay of atorvastatin will be taken before, and frequently up to 168 hours after each dose.</time_frame>
    <description>Mean residence time</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Midazolam - λz</measure>
    <time_frame>Blood samples for assay of midazolam will be taken before, and frequently up to 48 hours after each dose.</time_frame>
    <description>Terminal rate constant</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Atorvastatin - λz</measure>
    <time_frame>Blood samples for assay of atorvastatin will be taken before, and frequently up to 168 hours after each dose.</time_frame>
    <description>Terminal rate constant</description>
  </primary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">15</enrollment>
  <condition>Healthy</condition>
  <arm_group>
    <arm_group_label>Midazolam, Atorvastatin / Aramchol, Midazolam, Atorvastatin</arm_group_label>
    <arm_group_type>Other</arm_group_type>
    <description>Midazolam 2 mg -atorvastatin 40 mg /Aramchol 600mg -midazolam 2 mg-atorvastatin 40 mg (MA/MAA)</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Aramchol</intervention_name>
    <description>Aramchol 600 mg</description>
    <arm_group_label>Midazolam, Atorvastatin / Aramchol, Midazolam, Atorvastatin</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Midazolam</intervention_name>
    <description>Midazolam 2 mg</description>
    <arm_group_label>Midazolam, Atorvastatin / Aramchol, Midazolam, Atorvastatin</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Atorvastatin</intervention_name>
    <description>atorvastatin 40 mg</description>
    <arm_group_label>Midazolam, Atorvastatin / Aramchol, Midazolam, Atorvastatin</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Male healthy volunteers.&#xD;
&#xD;
          2. Aged 18-45 years at time of consent.&#xD;
&#xD;
          3. A body mass index (BMI; Quetelet index) in the range 18.0-30.9.&#xD;
&#xD;
          4. Ability to understand the nature of the trial and any hazards of participating in it.&#xD;
             Ability to communicate satisfactorily with the investigator and to participate in, and&#xD;
             comply with the requirements of the entire trial.&#xD;
&#xD;
          5. Willingness to give written consent to participate after reading and understanding the&#xD;
             information and consent form, and after having the opportunity to discuss the trial&#xD;
             with the investigator or his delegate.&#xD;
&#xD;
          6. Agree to use effective contraception as described in section 9.&#xD;
&#xD;
          7. Agree not to donate blood or blood products during the study and for up to 3 months&#xD;
             after the administration of the trial medication.&#xD;
&#xD;
          8. Willingness to give written consent to have data entered into The Overvolunteering&#xD;
             Prevention System (TOPS).&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Volunteers of East Asian descent including, but not limited to, Chinese, Japanese,&#xD;
             Korean, Mongolian, and/or Vietnamese&#xD;
&#xD;
          2. Be a smoker, or have smoked cigarettes or other tobacco or nicotine products in the&#xD;
             last 12 months.&#xD;
&#xD;
          3. Clinically relevant abnormal history, physical findings, ECG, or laboratory values at&#xD;
             the pre-trial screening assessment that could interfere with the objectives of the&#xD;
             trial or the safety of the volunteer.&#xD;
&#xD;
          4. Alanine aminotransferase (ALT), aspartate aminotransferase (AST) or alkaline&#xD;
             phosphatase (AP) &gt; Upper Limit of Normal (ULN) at the screening visit. A repeat is&#xD;
             allowed on one occasion for determination of eligibility.&#xD;
&#xD;
          5. Presence of acute or chronic illness or history of chronic illness sufficient to&#xD;
             invalidate the volunteer's participation in the trial or make it unnecessarily&#xD;
             hazardous,&#xD;
&#xD;
          6. Presence or history of obstructive sleep apnoea.&#xD;
&#xD;
          7. History or presence of any disease or condition known to interfere with the&#xD;
             absorption, distribution, metabolism or excretion of drugs including gastrointestinal&#xD;
             disorder or of oesophageal, gastric, biliary or intestinal surgery (excluding&#xD;
             herniotomy and appendectomy).&#xD;
&#xD;
          8. Use of anticholinergic or other drugs known to affect gastrointestinal motility during&#xD;
             the 7 days before the first dose of trial medication.&#xD;
&#xD;
          9. Impaired endocrine, thyroid, hepatic, respiratory or renal function, diabetes&#xD;
             mellitus, coronary heart disease, or history of any psychotic mental illness.&#xD;
&#xD;
         10. Surgery (eg stomach bypass) or medical condition that might affect absorption of&#xD;
             medicines.&#xD;
&#xD;
         11. Presence or history of severe adverse reaction to any drug or a history of sensitivity&#xD;
             to aramchol, midazolam or atorvastatin, or any excipients in the tablets.&#xD;
&#xD;
         12. Use of a prescription medicine or any other medicine or herbal remedy (such as St&#xD;
             John's wort) during the 28 days before the first dose of trial medication or use of&#xD;
             any other over-the-counter medicine, with the exception of acetaminophen&#xD;
             (paracetamol), during the 7 days before the first dose of trial medication.&#xD;
&#xD;
         13. Receipt of an investigational product (including prescription medicines) as part of&#xD;
             another clinical trial within the 3 months before first admission to this study; in&#xD;
             the follow-up period of another clinical trial at the time of screening for this&#xD;
             study.&#xD;
&#xD;
         14. Presence or history of drug or alcohol abuse, or intake of more than 14 units of&#xD;
             alcohol weekly.&#xD;
&#xD;
         15. Blood pressure and heart rate in supine position at the screening examination outside&#xD;
             the ranges: blood pressure 100-140 mm Hg systolic, 50-90 mm Hg diastolic; heart rate&#xD;
             45_90 beats/min, unless judged not clinically significant.&#xD;
&#xD;
         16. Possibility that the volunteer will not cooperate with the requirements of the&#xD;
             protocol.&#xD;
&#xD;
         17. Evidence of drug abuse on urine testing.&#xD;
&#xD;
         18. Positive test for hepatitis B, hepatitis C or HIV.&#xD;
&#xD;
         19. Loss of more than 400 mL blood during the 3 months before the trial, eg as a blood&#xD;
             donor.&#xD;
&#xD;
         20. Objection by General Practitioner (GP) to volunteer entering trial.&#xD;
      </textblock>
    </criteria>
    <gender>Male</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>45 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Adeep Puri, M.D.</last_name>
    <role>Principal Investigator</role>
    <affiliation>HMR</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Hammersmith Medicines Research (HMR)</name>
      <address>
        <city>London</city>
        <zip>NW10 7EW</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United Kingdom</country>
  </location_countries>
  <verification_date>February 2019</verification_date>
  <study_first_submitted>November 22, 2018</study_first_submitted>
  <study_first_submitted_qc>November 29, 2018</study_first_submitted_qc>
  <study_first_posted type="Actual">November 30, 2018</study_first_posted>
  <last_update_submitted>August 20, 2019</last_update_submitted>
  <last_update_submitted_qc>August 20, 2019</last_update_submitted_qc>
  <last_update_posted type="Actual">August 22, 2019</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>Midazolam</mesh_term>
    <mesh_term>Atorvastatin</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</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/NCT03760848
org study id: Aramchol 016
nct id: NCT03760848
lead sponsor: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
is us export: No
The trial is an open-label, 2-period, single-sequence assessment of CYP3A4 inhibition by
      aramchol using the probe substrates midazolam and atorvastatin to assess CYP3A4 activity.
Enrolment of 16 subjects is planned. Each subject will take part in 2 study periods.

      In Period 1, subjects will receive a single oral dose of 2 mg midazolam on Day 1 and a single
      oral dose of 40 mg atorvastatin on Day 3.

      In Period 2, subjects will receive twice-daily oral doses of 300 mg aramchol (the IMP) for 18
      days. During aramchol dosing, subjects will take a single dose of 2 mg midazolam in the
      morning on Day 10 and 40 mg atorvastatin in the morning on Day 12.

      Subjects will be screened within 21 days before their first dose of study medicine. In Period
      1, they will remain resident on the ward from Day -1 to Day 10. In Period 2, subjects will be
      admitted on Day -1 and discharged on Day 19. Subjects will attend a follow-up visit
      approximately 2 weeks later, on Day 33 (±2 days). There will be an interval of at least 1 day
      between Periods 1 and 2.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Other
masking: None (Open Label)
measure: Midazolam - cmax
time frame: Blood samples for assay of midazolam will be taken before, and frequently up to 48 hours after each dose.
description: Maximum plasma concentration
measure: Atorvastatin - cmax
time frame: Blood samples for assay of atorvastatin will be taken before, and frequently up to 168 hours after each dose.
description: Maximum plasma concentration
measure: Midazolam - tmax
time frame: Blood samples for assay of midazolam will be taken before, and frequently up to 48 hours after each dose.
description: Time of maximum plasma concentration
measure: Atorvastatin - tmax
time frame: Blood samples for assay of atorvastatin will be taken before, and frequently up to 168 hours after each dose.
description: Time of maximum plasma concentration
measure: Midazolam - Area under the concentration-time curve to last measurable concentration (AUClast)
time frame: Blood samples for assay of midazolam will be taken before, and frequently up to 48 hours after each dose.
measure: Atorvastatin - Area under the concentration-time curve to last measurable concentration (AUClast)
time frame: Blood samples for assay of atorvastatin will be taken before, and frequently up to 168 hours after each dose.
measure: Midazolam - Area under the concentration-time curve extrapolated to infinite time (AUCinf)
time frame: Blood samples for assay of midazolam will be taken before, and frequently up to 48 hours after each dose.
measure: Atorvastatin - Area under the concentration-time curve extrapolated to infinite time (AUCinf)
time frame: Blood samples for assay of atorvastatin will be taken before, and frequently up to 168 hours after each dose.
measure: Midazolam - %AUCextrapinf
time frame: Blood samples for assay of midazolam will be taken before, and frequently up to 48 hours after each dose.
description: Percentage of AUC that was extrapolated
measure: Atorvastatin - %AUCextrapinf
time frame: Blood samples for assay of atorvastatin will be taken before, and frequently up to 168 hours after each dose.
description: Percentage of AUC that was extrapolated
measure: Midazolam - t½
time frame: Blood samples for assay of midazolam will be taken before, and frequently up to 48 hours after each dose.
description: Terminal elimination half-life
measure: Atorvastatin - t½
time frame: Blood samples for assay of atorvastatin will be taken before, and frequently up to 168 hours after each dose.
description: Terminal elimination half-life
measure: Midazolam - CL/F
time frame: Blood samples for assay of midazolam will be taken before, and frequently up to 48 hours after each dose.
description: Clearance/fraction of dose absorbed
measure: Atorvastatin - CL/F
time frame: Blood samples for assay of atorvastatin will be taken before, and frequently up to 168 hours after each dose.
description: Clearance/fraction of dose absorbed
measure: Midazolam - VZ/F
time frame: Blood samples for assay of midazolam will be taken before, and frequently up to 48 hours after each dose.
description: Volume of distribution/fraction of dose absorbed
measure: Atorvastatin - VZ/F
time frame: Blood samples for assay of atorvastatin will be taken before, and frequently up to 168 hours after each dose.
description: Volume of distribution/fraction of dose absorbed
measure: Midazolam - MRT
time frame: Blood samples for assay of midazolam will be taken before, and frequently up to 48 hours after each dose.
description: Mean residence time
measure: Atorvastatin - MRT
time frame: Blood samples for assay of atorvastatin will be taken before, and frequently up to 168 hours after each dose.
description: Mean residence time
measure: Midazolam - λz
time frame: Blood samples for assay of midazolam will be taken before, and frequently up to 48 hours after each dose.
description: Terminal rate constant
measure: Atorvastatin - λz
time frame: Blood samples for assay of atorvastatin will be taken before, and frequently up to 168 hours after each dose.
description: Terminal rate constant
arm group label: Midazolam, Atorvastatin / Aramchol, Midazolam, Atorvastatin
arm group type: Other
description: Midazolam 2 mg -atorvastatin 40 mg /Aramchol 600mg -midazolam 2 mg-atorvastatin 40 mg (MA/MAA)
intervention type: Drug
intervention name: Aramchol
description: Aramchol 600 mg
arm group label: Midazolam, Atorvastatin / Aramchol, Midazolam, Atorvastatin
intervention type: Drug
intervention name: Midazolam
description: Midazolam 2 mg
arm group label: Midazolam, Atorvastatin / Aramchol, Midazolam, Atorvastatin
intervention type: Drug
intervention name: Atorvastatin
description: atorvastatin 40 mg
arm group label: Midazolam, Atorvastatin / Aramchol, Midazolam, Atorvastatin
criteria: 
gender: Male
minimum age: 18 Years
maximum age: 45 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Adeep Puri, M.D.
role: Principal Investigator
affiliation: HMR
facility: 
country: United Kingdom
responsible party type: Sponsor
mesh term: Midazolam
mesh term: Atorvastatin
sharing ipd: No