<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/NCT03772262</url>
  </required_header>
  <id_info>
    <org_study_id>16620</org_study_id>
    <secondary_id>U54AT008909</secondary_id>
    <nct_id>NCT03772262</nct_id>
  </id_info>
  <brief_title>Assessing Goldenseal-drug Interactions Using a Probe Drug Cocktail Approach</brief_title>
  <official_title>Assessing Goldenseal-drug Interactions Using a Probe Drug Cocktail Approach</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Washington State University</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>National Center for Complementary and Integrative Health (NCCIH)</agency>
      <agency_class>NIH</agency_class>
    </collaborator>
  </sponsors>
  <source>Washington State University</source>
  <oversight_info>
    <has_dmc>Yes</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>
      Goldenseal is a botanical natural product commonly used to self-treat symptoms of the common&#xD;
      cold and many digestive disorders. Goldenseal products typically contain the isoquinoline&#xD;
      alkaloids berberine, hydrastine, and hydrastinine. These constituents contain a&#xD;
      methylenedioxyphenyl ring, a 'structural alert' that can lead to irreversible inhibition of&#xD;
      drug metabolizing enzymes, particularly the cytochromes P450 (CYPs). Clinical studies&#xD;
      involving healthy volunteers demonstrated that, compared to baseline (absence of goldenseal),&#xD;
      CYP2D6 and CYP3A activities were reduced by 40-60% following treatment with goldenseal.&#xD;
      Compared to the CYPs, the effects of goldenseal products on drug transporters are&#xD;
      understudied, particularly in human subjects. Using a 'cocktail' consisting of 'probe' drug&#xD;
      substrates for CYP3A and various transporters, the effects of goldenseal on the&#xD;
      pharmacokinetics of each probe drug will be examined in healthy volunteers. Results will&#xD;
      provide useful information about the risk of co-consuming goldenseal with additional drugs&#xD;
      that are substrates for transporters.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Many patient groups often supplement their pharmacotherapeutic regimens with herbal and other&#xD;
      natural products (NPs), raising concern for adverse interactions with conventional drugs.&#xD;
      Unlike for drug-drug interactions, rigorous guidelines for assessing the risk of NP-drug&#xD;
      interactions do not exist. The NIH-funded Center of Excellence for Natural Product-Drug&#xD;
      Interaction (NaPDI) Research (U54 AT008909) was created in September, 2015. The mission of&#xD;
      the NaPDI Center is to provide leadership in the identification, evaluation, and&#xD;
      dissemination of potential clinically significant pharmacokinetic NP-drug interactions. One&#xD;
      over-arching goal of the Center is to develop a set of Recommended Approaches to guide&#xD;
      researchers in the proper conduct of NP-drug interaction studies. These Recommended&#xD;
      Approaches will be based on results generated from a series of Interaction Projects that will&#xD;
      include mechanistic human in vitro and clinical studies focused on four carefully selected&#xD;
      high priority NPs.&#xD;
&#xD;
      Using a systematic approach, the NaPDI Center selected four high priority NPs as precipitants&#xD;
      of NP-drug interactions. One of these NPs is goldenseal, which is typically used to&#xD;
      self-treat symptoms of the common cold, as well as numerous digestive disorders, both as a&#xD;
      single extract and in combination with other NPs, particularly Echinacea spp. Major&#xD;
      constituents of goldenseal include the isoquinoline alkaloids berberine, hydrastine, and&#xD;
      hydrastinine. These constituents contain a methylenedioxyphenyl ring, a 'structural alert'&#xD;
      that can lead to irreversible inhibition of drug metabolizing enzymes, particularly the&#xD;
      cytochromes P450 (CYPs). Indeed, clinical studies involving healthy volunteers demonstrated&#xD;
      that, compared to baseline (absence of goldenseal), CYP2D6 and CYP3A activities were reduced&#xD;
      by 40-60% following administration of ~1 g of a goldenseal extract three times daily for 14&#xD;
      or 28 days .&#xD;
&#xD;
      Compared to the CYPs, the effects of goldenseal products on drug transporters are&#xD;
      understudied, particularly in human subjects. A 'cocktail' consisting of 'probe' drug&#xD;
      substrates for CYPs and transporters is an efficient, cost-effective means to examine the&#xD;
      effects of a precipitant drug or NP on the pharmacokinetics of multiple object drugs&#xD;
      simultaneously. Such cocktails are used frequently by both academia and the pharmaceutical&#xD;
      industry to test for the interaction potential of new chemical entities, results of which are&#xD;
      often included in drug labels. A number of cocktails exist for the CYPs and have been used&#xD;
      successfully over the past 20+ years. A transporter cocktail was described recently that&#xD;
      consists of the probe drugs furosemide [organic anion transporter (OAT)1 and OAT3 substrate],&#xD;
      metformin [(organic cation transporter 2, multidrug and toxin extrusion protein (MATE)1, and&#xD;
      MATE2-K substrate)], and rosuvastatin [organic anion transporting polypeptide (OATP)1B1,&#xD;
      OATP1B3, and breast cancer resistance protein substrate].&#xD;
&#xD;
      Based on the multiple scientific gaps with respect to a commonly used NP, the purpose of this&#xD;
      healthy volunteer study is to assess the inhibitory effects of a well-characterized&#xD;
      goldenseal product on the pharmacokinetics of the aforementioned transporter probe drugs; the&#xD;
      CYP3A probe midazolam will be included to serve as a positive control object drug. Results&#xD;
      will be used to develop (1) a Recommended Approach regarding clinical study design of NP-drug&#xD;
      interactions and (2) mathematical models that can be used to predict the risk of potential&#xD;
      goldenseal-precipitated interactions with drugs whose pharmacokinetics are influenced by&#xD;
      CYP3A and/or transporters.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">April 5, 2018</start_date>
  <completion_date type="Actual">March 31, 2019</completion_date>
  <primary_completion_date type="Actual">November 30, 2018</primary_completion_date>
  <phase>Early Phase 1</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Non-Randomized</allocation>
    <intervention_model>Crossover Assignment</intervention_model>
    <primary_purpose>Basic Science</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>midazolam AUC ratio (treatment/control)</measure>
    <time_frame>0-96 hours</time_frame>
    <description>ratio of the area under of the plasma concentration time curve (AUC) of midazolam in the presence to absence of goldenseal</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>midazolam Cmax ratio (treatment/control)</measure>
    <time_frame>0-96 hours</time_frame>
    <description>ratio of the maximum plasma concentration (Cmax) of midazolam in the presence to absence of goldenseal</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">16</enrollment>
  <condition>Interaction Drug Food</condition>
  <arm_group>
    <arm_group_label>Control</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Study subjects will be administered a single dose of midazolam syrup (2.5 mg), metformin solution (50 mg), furosemide solution (1 mg), and one rosuvastatin tablet (10 mg) by mouth. Plasma will be collected from 0-96 hours. Urine will be collected from 0-24 hours.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Treatment</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Study subjects will be administered goldenseal 2 capsules (500 mg each) three times daily for 5 days. On day 6, subjects will be administered goldenseal 2 capsules (500 mg each), a single dose of midazolam syrup (2.5 mg), metformin solution (50 mg), furosemide solution (1 mg), and one tablet (10 mg) rosuvastatin. Goldenseal 2 capsules (500 mg each) will be administered approximately 4 and 8 hours later. Plasma will be collected from 0-96 hours. Urine will be collected from 0-24 hours.</description>
  </arm_group>
  <intervention>
    <intervention_type>Dietary Supplement</intervention_type>
    <intervention_name>goldenseal</intervention_name>
    <description>Oral 500 mg capsules</description>
    <arm_group_label>Treatment</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Metformin</intervention_name>
    <description>Oral solution</description>
    <arm_group_label>Control</arm_group_label>
    <arm_group_label>Treatment</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Furosemide</intervention_name>
    <description>Oral solution</description>
    <arm_group_label>Control</arm_group_label>
    <arm_group_label>Treatment</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Midazolam oral solution</intervention_name>
    <description>Oral syrup</description>
    <arm_group_label>Control</arm_group_label>
    <arm_group_label>Treatment</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Rosuvastatin Oral Tablet</intervention_name>
    <description>Oral tablet</description>
    <arm_group_label>Control</arm_group_label>
    <arm_group_label>Treatment</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Ability to participate in the study (time, transportation, etc.)&#xD;
&#xD;
          -  Ability to understand the informed consent form&#xD;
&#xD;
          -  Men and women aged from 18 to 65 years&#xD;
&#xD;
          -  Willingness to abstain from alcohol and caffeinated beverages for the evening prior to&#xD;
             and during each in-patient study day&#xD;
&#xD;
          -  Willingness to abstain from citrus juices and other dietary supplements for the&#xD;
             duration of the study&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Any current major illness or chronic illness including but not limited to kidney&#xD;
             disease, hepatic disease, diabetes mellitus, hypertension, coronary artery disease,&#xD;
             chronic obstructive pulmonary disease, previous stroke or embolic disease history,&#xD;
             cancer, and HIV/AIDS&#xD;
&#xD;
          -  History of allergy to goldenseal, midazolam, furosemide, metformin, or rosuvastatin&#xD;
&#xD;
          -  History of anemia or any other significant hematologic disorder&#xD;
&#xD;
          -  History of renal failure or lactic acidosis (metformin)&#xD;
&#xD;
          -  History of apnea (midazolam)&#xD;
&#xD;
          -  History of heart failure, electrolyte imbalance (furosemide)&#xD;
&#xD;
          -  History of hypotension (goldenseal)&#xD;
&#xD;
          -  History of drug or alcohol addiction or major psychiatric illness&#xD;
&#xD;
          -  Women who are intending to become pregnant within the next three months, are currently&#xD;
             pregnant, or are currently breastfeeding&#xD;
&#xD;
          -  Out-of-range clinical laboratory value that the study physician considers&#xD;
             participation in the study a health risk&#xD;
&#xD;
          -  Taking concomitant medications, both prescription and non-prescription (including&#xD;
             herbal/natural products) known to alter the pharmacokinetics or pharmacodynamics of&#xD;
             midazolam, furosemide, metformin, or rosuvastatin.&#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>
  <location>
    <facility>
      <name>Washington State University</name>
      <address>
        <city>Spokane</city>
        <state>Washington</state>
        <zip>99202</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>April 2023</verification_date>
  <study_first_submitted>October 1, 2018</study_first_submitted>
  <study_first_submitted_qc>December 7, 2018</study_first_submitted_qc>
  <study_first_posted type="Actual">December 11, 2018</study_first_posted>
  <last_update_submitted>April 26, 2023</last_update_submitted>
  <last_update_submitted_qc>April 26, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">April 28, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Washington State University</investigator_affiliation>
    <investigator_full_name>Mary Paine</investigator_full_name>
    <investigator_title>Professor</investigator_title>
  </responsible_party>
  <keyword>Pharmacokinetics</keyword>
  <keyword>Goldenseal</keyword>
  <keyword>Metformin</keyword>
  <keyword>Furosemide</keyword>
  <keyword>Rosuvastatin</keyword>
  <keyword>Midazolam</keyword>
  <keyword>Natural product</keyword>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Metformin</mesh_term>
    <mesh_term>Furosemide</mesh_term>
    <mesh_term>Midazolam</mesh_term>
    <mesh_term>Rosuvastatin Calcium</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/NCT03772262
org study id: 16620
secondary id: U54AT008909
nct id: NCT03772262
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
is us export: No
Goldenseal is a botanical natural product commonly used to self-treat symptoms of the common
      cold and many digestive disorders. Goldenseal products typically contain the isoquinoline
      alkaloids berberine, hydrastine, and hydrastinine. These constituents contain a
      methylenedioxyphenyl ring, a 'structural alert' that can lead to irreversible inhibition of
      drug metabolizing enzymes, particularly the cytochromes P450 (CYPs). Clinical studies
      involving healthy volunteers demonstrated that, compared to baseline (absence of goldenseal),
      CYP2D6 and CYP3A activities were reduced by 40-60% following treatment with goldenseal.
      Compared to the CYPs, the effects of goldenseal products on drug transporters are
      understudied, particularly in human subjects. Using a 'cocktail' consisting of 'probe' drug
      substrates for CYP3A and various transporters, the effects of goldenseal on the
      pharmacokinetics of each probe drug will be examined in healthy volunteers. Results will
      provide useful information about the risk of co-consuming goldenseal with additional drugs
      that are substrates for transporters.
Many patient groups often supplement their pharmacotherapeutic regimens with herbal and other
      natural products (NPs), raising concern for adverse interactions with conventional drugs.
      Unlike for drug-drug interactions, rigorous guidelines for assessing the risk of NP-drug
      interactions do not exist. The NIH-funded Center of Excellence for Natural Product-Drug
      Interaction (NaPDI) Research (U54 AT008909) was created in September, 2015. The mission of
      the NaPDI Center is to provide leadership in the identification, evaluation, and
      dissemination of potential clinically significant pharmacokinetic NP-drug interactions. One
      over-arching goal of the Center is to develop a set of Recommended Approaches to guide
      researchers in the proper conduct of NP-drug interaction studies. These Recommended
      Approaches will be based on results generated from a series of Interaction Projects that will
      include mechanistic human in vitro and clinical studies focused on four carefully selected
      high priority NPs.

      Using a systematic approach, the NaPDI Center selected four high priority NPs as precipitants
      of NP-drug interactions. One of these NPs is goldenseal, which is typically used to
      self-treat symptoms of the common cold, as well as numerous digestive disorders, both as a
      single extract and in combination with other NPs, particularly Echinacea spp. Major
      constituents of goldenseal include the isoquinoline alkaloids berberine, hydrastine, and
      hydrastinine. These constituents contain a methylenedioxyphenyl ring, a 'structural alert'
      that can lead to irreversible inhibition of drug metabolizing enzymes, particularly the
      cytochromes P450 (CYPs). Indeed, clinical studies involving healthy volunteers demonstrated
      that, compared to baseline (absence of goldenseal), CYP2D6 and CYP3A activities were reduced
      by 40-60% following administration of ~1 g of a goldenseal extract three times daily for 14
      or 28 days .

      Compared to the CYPs, the effects of goldenseal products on drug transporters are
      understudied, particularly in human subjects. A 'cocktail' consisting of 'probe' drug
      substrates for CYPs and transporters is an efficient, cost-effective means to examine the
      effects of a precipitant drug or NP on the pharmacokinetics of multiple object drugs
      simultaneously. Such cocktails are used frequently by both academia and the pharmaceutical
      industry to test for the interaction potential of new chemical entities, results of which are
      often included in drug labels. A number of cocktails exist for the CYPs and have been used
      successfully over the past 20+ years. A transporter cocktail was described recently that
      consists of the probe drugs furosemide [organic anion transporter (OAT)1 and OAT3 substrate],
      metformin [(organic cation transporter 2, multidrug and toxin extrusion protein (MATE)1, and
      MATE2-K substrate)], and rosuvastatin [organic anion transporting polypeptide (OATP)1B1,
      OATP1B3, and breast cancer resistance protein substrate].

      Based on the multiple scientific gaps with respect to a commonly used NP, the purpose of this
      healthy volunteer study is to assess the inhibitory effects of a well-characterized
      goldenseal product on the pharmacokinetics of the aforementioned transporter probe drugs; the
      CYP3A probe midazolam will be included to serve as a positive control object drug. Results
      will be used to develop (1) a Recommended Approach regarding clinical study design of NP-drug
      interactions and (2) mathematical models that can be used to predict the risk of potential
      goldenseal-precipitated interactions with drugs whose pharmacokinetics are influenced by
      CYP3A and/or transporters.
allocation: Non-Randomized
intervention model: Crossover Assignment
primary purpose: Basic Science
masking: None (Open Label)
measure: midazolam AUC ratio (treatment/control)
time frame: 0-96 hours
description: ratio of the area under of the plasma concentration time curve (AUC) of midazolam in the presence to absence of goldenseal
measure: midazolam Cmax ratio (treatment/control)
time frame: 0-96 hours
description: ratio of the maximum plasma concentration (Cmax) of midazolam in the presence to absence of goldenseal
arm group label: Control
arm group type: Experimental
description: Study subjects will be administered a single dose of midazolam syrup (2.5 mg), metformin solution (50 mg), furosemide solution (1 mg), and one rosuvastatin tablet (10 mg) by mouth. Plasma will be collected from 0-96 hours. Urine will be collected from 0-24 hours.
arm group label: Treatment
arm group type: Experimental
description: Study subjects will be administered goldenseal 2 capsules (500 mg each) three times daily for 5 days. On day 6, subjects will be administered goldenseal 2 capsules (500 mg each), a single dose of midazolam syrup (2.5 mg), metformin solution (50 mg), furosemide solution (1 mg), and one tablet (10 mg) rosuvastatin. Goldenseal 2 capsules (500 mg each) will be administered approximately 4 and 8 hours later. Plasma will be collected from 0-96 hours. Urine will be collected from 0-24 hours.
intervention type: Dietary Supplement
intervention name: goldenseal
description: Oral 500 mg capsules
arm group label: Treatment
intervention type: Drug
intervention name: Metformin
description: Oral solution
arm group label: Control
arm group label: Treatment
intervention type: Drug
intervention name: Furosemide
description: Oral solution
arm group label: Control
arm group label: Treatment
intervention type: Drug
intervention name: Midazolam oral solution
description: Oral syrup
arm group label: Control
arm group label: Treatment
intervention type: Drug
intervention name: Rosuvastatin Oral Tablet
description: Oral tablet
arm group label: Control
arm group label: Treatment
criteria: 
gender: All
minimum age: 18 Years
maximum age: 65 Years
healthy volunteers: Accepts Healthy Volunteers
facility: 
country: United States
responsible party type: Principal Investigator
investigator affiliation: Washington State University
investigator full name: Mary Paine
investigator title: Professor
mesh term: Metformin
mesh term: Furosemide
mesh term: Midazolam
mesh term: Rosuvastatin Calcium
sharing ipd: No