<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/NCT01663922</url>
  </required_header>
  <id_info>
    <org_study_id>SSAT 045</org_study_id>
    <nct_id>NCT01663922</nct_id>
  </id_info>
  <brief_title>Boceprevir and Ucalm (St John&amp;Apos;s Wort)</brief_title>
  <official_title>Phase I Evaluation of the Pharmacokinetics and Safety of Boceprevir and Ucalm (St John&amp;Apos;s Wort) When Co-administered to Male and Female Healthy Volunteers.</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>St Stephens Aids Trust</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>University of Liverpool</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>University of Turin, Italy</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>St Stephens Aids Trust</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      The purpose of the study is to look at whether taking a new medication for hepatitis C&#xD;
      (boceprevir) together with a herbal remedy commonly used for the treatment of depression&#xD;
      (SJW) has any effect on the levels of boceprevir in the blood, compared to when boceprevir is&#xD;
      taken on its own.&#xD;
&#xD;
      Treatment of hepatitis C genotype-1, has recently been significantly improved with the&#xD;
      addition of a new class of drugs called protease inhibitors (PIs). Boceprevir belongs to this&#xD;
      class of antiviral drugs and it is administered in combinations with other drugs to treat&#xD;
      hepatitis C. One of the common side effects of treatment for hepatitis C is low mood&#xD;
      (depression) for which treated patients may self-medicate with preparations containing St.&#xD;
      Johns Wort (SJW).&#xD;
&#xD;
      SJW is known to cause drug interactions, so taking SJW at the same time as boceprevir may&#xD;
      result in a change in how both of these drugs usually work. It is therefore important to find&#xD;
      out if the levels of boceprevir in the blood are significantly affected by taking SJW.&#xD;
&#xD;
      The study aims to help us understand whether it will be safe to take SJW whilst being&#xD;
      simultaneously treated for hepatitis C with boceprevir.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Boceprevir is a strong inhibitor of CYP3A4/5. Medicines metabolized primarily by CYP3A4/5 may&#xD;
      have increased exposure when administered with boceprevir, which could increase or prolong&#xD;
      their therapeutic and adverse reactions. Boceprevir does not inhibit or induce the other&#xD;
      enzymes of the CYP450 family.&#xD;
&#xD;
      Boceprevir has been shown to be a P-glycoprotein and breast cancer resistant protein (BCRP)&#xD;
      substrate in vitro. There is potential for inhibitors or inducers of these transporters to&#xD;
      alter the concentrations of boceprevir; the clinical implications of these interactions are&#xD;
      not known.Boceprevir is partly metabolized by CYP3A4/5. Co-administration of boceprevir with&#xD;
      medicines that induce or inhibit CYP3A4/5 could increase or decrease exposure to boceprevir&#xD;
      and affect its efficacy.Boceprevir, in combination with peginterferon and ribavirin, is&#xD;
      contraindicated when coadministered with medicines that are highly dependent on CYP3A4/5 for&#xD;
      clearance, and for which elevated plasma concentrations are associated with serious and/or&#xD;
      life-threatening events. Examples may include; orally administered midazolam and triazolam,&#xD;
      bepridil, pimozide, lumefantrine, halofantrine, and tyrosine kinase inhibitors, and ergot&#xD;
      derivatives (dihydroergotamine, ergonovine, ergotamine, methylergonovine).&#xD;
&#xD;
      Boceprevir is primarily metabolized by aldoketo reductase (AKR). In medicine interaction&#xD;
      trials conducted with AKR inhibitors diflunisal and ibuprofen, boceprevir exposure did not&#xD;
      increase to a clinically significant extent. Boceprevir may be co-administered with AKR&#xD;
      inhibitors. The concomitant use of boceprevir with stong CYP3A4 inducers such as rifampicin&#xD;
      or anticonvulsants (such as phenytoin, phenobarbital or carbamazepine) may significantly&#xD;
      reduce the plasma exposure of boceprevir. As no data is available, the combination of&#xD;
      boceprevir with these medicines is not recommended.&#xD;
&#xD;
      The metabolism of St John's Wort is not currently known. Treatment with St John's wort for 14&#xD;
      days resulted in significant increases in the urinary 6-beta-hydroxycortisol/ cortisol ratio,&#xD;
      suggesting that St John's wort is an inducer of CYP3A4. For this reason, it is not&#xD;
      recommended to administer SJW with CYP3A4 metabolized drugs. Furthermore,interactions may&#xD;
      occur with P-glycoprotein substrates, as St. John's wort can induce the activity of&#xD;
      transmembrane transporters. This might decrease the effectiveness of some medications.&#xD;
&#xD;
      For the reasons illustrated above, the potential for a drug interaction between SJW and&#xD;
      boceprevir is high and the co-administration must be studied in order to gain information on&#xD;
      whether: i) SJW leads to a decrease in boceprevir concentrations and therefore efficacy; ii)&#xD;
      boceprevir leads to an increase in SJW (hypericin) exposure with risk of toxicity.&#xD;
&#xD;
      The safety and PK of the combination should be known especially in view of the common side&#xD;
      effects caused by interferon, which is co-administered with boceprevir for the treatment of&#xD;
      hepatitis C: as interferon causes depression, patients may chose to take SJW rather than&#xD;
      prescribed anti-depressants to manage their mood changes during antihepatitis treatment.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>August 2012</start_date>
  <completion_date type="Actual">December 2012</completion_date>
  <primary_completion_date type="Actual">December 2012</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>Prevention</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Pharmacokinetic of Boceprevir in the Presence of Ucalm (St John's Wort)</measure>
    <time_frame>6 months</time_frame>
    <description>Pharmacokinetic parameters (maximum and trough concentrations, and area under concentratof boceprevir and SJW will be evaluated when given in combination at steady-state to evaluate possible differences in concentrations during co-administration versus drug given alone.&#xD;
The pharmacokinetic parameters calculated for boceprevir and SJW will be Ctrough,the maximum observed plasma concentration (Cmax), time point at Cmax (Tmax), and total drug exposure, expressed as the area under the plasma concentration-time curve.&#xD;
All pharmacokinetic parameters will be calculated using non-compartmental modelling techniques (WinNonlin®) and all statistical calculations performed within-participant changes in the assessed pharmacokinetic parameters (drug alone vs drug combination) will be evaluated by calculating geometric mean ratios.</description>
  </primary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">17</enrollment>
  <condition>Hepatitis C</condition>
  <arm_group>
    <arm_group_label>St John's Wort, then Boceprevir</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>D 1-14 St. John's Wort 2 x 300mg (Ucalm(r)) QD D 22-35 St. John's Wort 2 x 300mg (Ucalm(r)) QD D 31-35 Boceprevir 800mg tds D 52-56 Boceprevir 800mg tds</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Boceprevir, then St John's Wort</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>D 10-14 Boceprevir 800mg tds D 22-35 St. John's Wort 2 x 300mg (Ucalm(r)) QD D 31-35 Boceprevir 800mg tds D 43-56 St. John's Wort 2 x 300mg (Ucalm(r)) QD</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Boceprevir</intervention_name>
    <description>Boceprevir as Victrelis(r) 200mg capsules</description>
    <arm_group_label>Boceprevir, then St John's Wort</arm_group_label>
    <arm_group_label>St John's Wort, then Boceprevir</arm_group_label>
    <other_name>Boceprevir 800 mg three times daily</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>St John's Wort</intervention_name>
    <description>Each Ucalm(r) tablet contains 300mg of St Johns Wort extract</description>
    <arm_group_label>Boceprevir, then St John's Wort</arm_group_label>
    <arm_group_label>St John's Wort, then Boceprevir</arm_group_label>
    <other_name>Ucalm (R) tablets, two tablets given once daily</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
        Subjects must meet all of the following inclusion criteria within 28 days prior to day 0:&#xD;
&#xD;
          1. The ability to understand and sign a written informed consent form, prior to&#xD;
             participation in any screening procedures and must be willing to comply with all study&#xD;
             requirements&#xD;
&#xD;
          2. Male or non-pregnant, non-lactating females&#xD;
&#xD;
          3. Between 18 to 65 years, inclusive&#xD;
&#xD;
          4. Body Mass Index (BMI) of 18 to 35 kg/m2, inclusive.&#xD;
&#xD;
          5. Women of childbearing potential (WOCBP), who are sexually active, must be using an&#xD;
             adequate method of contraception to avoid pregnancy throughout the study and for a&#xD;
             period of at least one month after the study in addition to the consistent and correct&#xD;
             use of a condom. Examples of adequate methods of contraception for females in this&#xD;
             trial are diaphragm with spermicide, substance and intra-uterine device. Hormonal&#xD;
             contraceptives should not be considered a method of contraception and should be&#xD;
             avoided if containing drospirenone.&#xD;
&#xD;
          6. Willing to consent to their personal details being entered onto The Over volunteering&#xD;
             Prevention Scheme (TOPS) database.&#xD;
&#xD;
          7. Registered with a GP in the UK&#xD;
&#xD;
          8. Willing to bring photo ID to each visit&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
        Subjects who meet any of the following exclusion criteria are not to be enrolled in this&#xD;
        study.&#xD;
&#xD;
          1. Any significant acute or chronic medical illness&#xD;
&#xD;
          2. Evidence of organ dysfunction or any clinically significant deviation from normal in&#xD;
             physical examination, vital signs, ECG or clinical laboratory determinations&#xD;
&#xD;
          3. Positive blood screen for hepatitis B and/or C antibodies&#xD;
&#xD;
          4. Positive blood screen for HIV-1 and 2 antibodies&#xD;
&#xD;
          5. Current or recent (within three months) gastrointestinal disease&#xD;
&#xD;
          6. Clinically relevant alcohol or drug use (positive urine drug screen) or history of&#xD;
             alcohol or drug use considered by the Investigator to be sufficient to hinder&#xD;
             compliance with treatment, follow-up procedures or evaluation of adverse events.&#xD;
             Smoking is permitted, but tobacco intake should remain consistent throughout the study&#xD;
&#xD;
          7. Exposure to any investigational drug or placebo within three months of first dose of&#xD;
             study drug (additional check to be made on TOPS www.tops.org.uk).&#xD;
&#xD;
          8. Consumption of grapefruit or Seville oranges, or any grapefruit or Seville orange&#xD;
             containing product within one week of first dose of study drug and for the duration of&#xD;
             the study&#xD;
&#xD;
          9. Use of any other drugs, including over-the-counter medications and herbal&#xD;
             preparations, within two weeks prior to first dose of study drug, unless&#xD;
             approved/prescribed by the Principal Investigator as known not to interact with study&#xD;
             drugs (note OCPs containing drosperinone should be excluded)&#xD;
&#xD;
         10. Females of childbearing potential without the use of effective non-hormonal birth&#xD;
             control methods, or not willing to continue practising these birth control methods for&#xD;
             at least 30 days after the end of the treatment period&#xD;
&#xD;
         11. Previous allergy to any of the constituents of the pharmaceuticals administered in&#xD;
             this trial&#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>Marta Boffito</last_name>
    <role>Principal Investigator</role>
    <affiliation>HIV Consultant</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>St Stephen's AIDS Trust</name>
      <address>
        <city>London</city>
        <zip>SW10 9NH</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United Kingdom</country>
  </location_countries>
  <results_reference>
    <citation>Jackson A, D'Avolio A, Moyle G, Bonora S, Di Perri G, Else L, Simiele M, Singh GJ, Back D, Boffito M. Pharmacokinetics of the co-administration of boceprevir and St John's wort to male and female healthy volunteers. J Antimicrob Chemother. 2014 Jul;69(7):1911-5. doi: 10.1093/jac/dku060. Epub 2014 Mar 6.</citation>
    <PMID>24610312</PMID>
  </results_reference>
  <verification_date>September 2014</verification_date>
  <study_first_submitted>August 3, 2012</study_first_submitted>
  <study_first_submitted_qc>August 9, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">August 13, 2012</study_first_posted>
  <results_first_submitted>July 14, 2014</results_first_submitted>
  <results_first_submitted_qc>September 23, 2014</results_first_submitted_qc>
  <results_first_posted type="Estimate">September 29, 2014</results_first_posted>
  <last_update_submitted>September 23, 2014</last_update_submitted>
  <last_update_submitted_qc>September 23, 2014</last_update_submitted_qc>
  <last_update_posted type="Estimate">September 29, 2014</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>Hepatitis C</mesh_term>
  </condition_browse>

  <clinical_results>

    <participant_flow>
      <recruitment_details>All volunteers were recruited at a single centre, SSAT Research Unit, Chelsea &amp; Westminster Hospital, London, UK.</recruitment_details>
      <pre_assignment_details>Eligible participants took:&#xD;
SJW for 14 days Group A D1-D14 or boceprevir(BCP) for 5 D10-D14 days Group B (D 10-14); PK profile on D14 then 7 day washout period to D21 D22-D35, all took SJW (+ BCP on D31-D35); PK on D35 then washout to D42 Group A took BCP on D52-D56; Group B SJW on D43-D56; PK profile on D56.</pre_assignment_details>
      <group_list>
        <group group_id="P1">
          <title>Group A (St John's Wort Then Boceprevir)</title>
          <description>St John's Wort, (SJW) for 14 days (1-14)&#xD;
[wash out for 7 days (15-21)]&#xD;
SJW for 14 days (22-35) plus boceprevir from day 31 to day 35 (5 days in total)&#xD;
[wash out for 7 days (36-42)]&#xD;
boceprevir from day 52 to day 56</description>
        </group>
        <group group_id="P2">
          <title>Group B (Boceprevir Then St John's Wort)</title>
          <description>Boceprevir for 5 days (10-14)&#xD;
[wash out for 7 days (15-21)]&#xD;
SJW for 14 days (22-35) plus boceprevir from day 31 to day 35 (5 days in total)&#xD;
[wash out for 7 days (36-42)&#xD;
SJW from day 43 to day 56</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>First Intervention (14 Days or 5 Days)</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="8"/>
                <participants group_id="P2" count="9"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="8"/>
                <participants group_id="P2" count="9"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
        <period>
          <title>Washout (7 Days)</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="8"/>
                <participants group_id="P2" count="9"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="8"/>
                <participants group_id="P2" count="9"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
        <period>
          <title>Second Intervention (14 Days)</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="8"/>
                <participants group_id="P2" count="9"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="8"/>
                <participants group_id="P2" count="9"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
        <period>
          <title>Washout (7 Days)</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="8"/>
                <participants group_id="P2" count="9"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="8"/>
                <participants group_id="P2" count="9"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
        <period>
          <title>Third Intervention (14 Days or 5 Days)</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="8"/>
                <participants group_id="P2" count="9"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="8"/>
                <participants group_id="P2" count="9"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <population>All enrolled participants.</population>
      <group_list>
        <group group_id="B1">
          <title>All Participants</title>
          <description>Descriptive analysis of combined groups</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="17"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>&lt;=18 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Between 18 and 65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="17"/>
                  </measurement_list>
                </category>
                <category>
                  <title>&gt;=65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Sex: Female, Male</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Female</title>
                  <measurement_list>
                    <measurement group_id="B1" value="11"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="6"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Region of Enrollment</title>
          <units>participants</units>
          <param>Number</param>
          <class_list>
            <class>
              <title>United Kingdom</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="17"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Pharmacokinetic of Boceprevir in the Presence of Ucalm (St John's Wort)</title>
        <description>Pharmacokinetic parameters (maximum and trough concentrations, and area under concentratof boceprevir and SJW will be evaluated when given in combination at steady-state to evaluate possible differences in concentrations during co-administration versus drug given alone.&#xD;
The pharmacokinetic parameters calculated for boceprevir and SJW will be Ctrough,the maximum observed plasma concentration (Cmax), time point at Cmax (Tmax), and total drug exposure, expressed as the area under the plasma concentration-time curve.&#xD;
All pharmacokinetic parameters will be calculated using non-compartmental modelling techniques (WinNonlin®) and all statistical calculations performed within-participant changes in the assessed pharmacokinetic parameters (drug alone vs drug combination) will be evaluated by calculating geometric mean ratios.</description>
        <time_frame>6 months</time_frame>
        <population>All participants who completed the three PK assessments were included in the analysis. BCP metabolites (SCH534128 &amp; SCH523129) PK parameters were determined in the presence and absence of SJW, and hypericin PK parameters in the presence and absence of BCP; for the total study population.</population>
        <group_list>
          <group group_id="O1">
            <title>All Participants</title>
            <description>Combined analysis of both group sequences</description>
          </group>
        </group_list>
        <measure>
          <title>Pharmacokinetic of Boceprevir in the Presence of Ucalm (St John's Wort)</title>
          <description>Pharmacokinetic parameters (maximum and trough concentrations, and area under concentratof boceprevir and SJW will be evaluated when given in combination at steady-state to evaluate possible differences in concentrations during co-administration versus drug given alone.&#xD;
The pharmacokinetic parameters calculated for boceprevir and SJW will be Ctrough,the maximum observed plasma concentration (Cmax), time point at Cmax (Tmax), and total drug exposure, expressed as the area under the plasma concentration-time curve.&#xD;
All pharmacokinetic parameters will be calculated using non-compartmental modelling techniques (WinNonlin®) and all statistical calculations performed within-participant changes in the assessed pharmacokinetic parameters (drug alone vs drug combination) will be evaluated by calculating geometric mean ratios.</description>
          <population>All participants who completed the three PK assessments were included in the analysis. BCP metabolites (SCH534128 &amp; SCH523129) PK parameters were determined in the presence and absence of SJW, and hypericin PK parameters in the presence and absence of BCP; for the total study population.</population>
          <units>ng*h/mL</units>
          <param>Geometric Mean</param>
          <dispersion>90% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="17"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Total Boceprevir alone</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="4588" lower_limit="4160" upper_limit="5317"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Boceprevir in presence of St Johns Wort)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="4204" lower_limit="3785" upper_limit="4886"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Hypericin alone</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="11.6" lower_limit="9.3" upper_limit="17.0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Hypericin in presence of boceprevir</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="14.3" lower_limit="11.2" upper_limit="20.8"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>SCH534128 alone</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="3222" lower_limit="2929" upper_limit="3687"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>SCH534128 in presence of St. Johns Wort</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2935" lower_limit="2653" upper_limit="3687"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <group_list>
        <group group_id="E1">
          <title>Group A</title>
          <description>St John's Wort first</description>
        </group>
        <group group_id="E2">
          <title>Group B</title>
          <description>Boceprevir first</description>
        </group>
      </group_list>
      <serious_events>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="9"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>5</frequency_threshold>
        <default_assessment>Non-systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="6" subjects_at_risk="8"/>
                <counts group_id="E2" subjects_affected="9" subjects_at_risk="9"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Cardiac disorders</title>
            <event_list>
              <event>
                <sub_title>pre-syncope</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="9"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Eye disorders</title>
            <event_list>
              <event>
                <sub_title>conjunctival infection</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="9"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>vomiting</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="9"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>arthralgia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="9"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Headache</sub_title>
                <counts group_id="E1" events="5" subjects_affected="4" subjects_at_risk="8"/>
                <counts group_id="E2" events="9" subjects_affected="3" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>nausea</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="8"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="9"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Psychiatric disorders</title>
            <event_list>
              <event>
                <sub_title>Anxiety</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="8"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="9"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Reproductive system and breast disorders</title>
            <event_list>
              <event>
                <sub_title>dysmenorrhoea</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="9"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>coryzal symptoms</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="8"/>
                <counts group_id="E2" events="7" subjects_affected="4" subjects_at_risk="9"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>All Principal Investigators ARE employed by the organization sponsoring the study.</pi_employee>
      <restrictive_agreement>There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed. </restrictive_agreement>
    </certain_agreements>
    <point_of_contact>
      <name_or_title>Dr Akil Jackson</name_or_title>
      <organization>St Stephens AIDS Trust</organization>
      <phone>0203 315 6503</phone>
      <email>akil.jackson@chelwest.nhs.uk</email>
    </point_of_contact>
  </clinical_results>
</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/NCT01663922
org study id: SSAT 045
nct id: NCT01663922
lead sponsor: 
collaborator: 
collaborator: 
has dmc: No
The purpose of the study is to look at whether taking a new medication for hepatitis C
      (boceprevir) together with a herbal remedy commonly used for the treatment of depression
      (SJW) has any effect on the levels of boceprevir in the blood, compared to when boceprevir is
      taken on its own.

      Treatment of hepatitis C genotype-1, has recently been significantly improved with the
      addition of a new class of drugs called protease inhibitors (PIs). Boceprevir belongs to this
      class of antiviral drugs and it is administered in combinations with other drugs to treat
      hepatitis C. One of the common side effects of treatment for hepatitis C is low mood
      (depression) for which treated patients may self-medicate with preparations containing St.
      Johns Wort (SJW).

      SJW is known to cause drug interactions, so taking SJW at the same time as boceprevir may
      result in a change in how both of these drugs usually work. It is therefore important to find
      out if the levels of boceprevir in the blood are significantly affected by taking SJW.

      The study aims to help us understand whether it will be safe to take SJW whilst being
      simultaneously treated for hepatitis C with boceprevir.
Boceprevir is a strong inhibitor of CYP3A4/5. Medicines metabolized primarily by CYP3A4/5 may
      have increased exposure when administered with boceprevir, which could increase or prolong
      their therapeutic and adverse reactions. Boceprevir does not inhibit or induce the other
      enzymes of the CYP450 family.

      Boceprevir has been shown to be a P-glycoprotein and breast cancer resistant protein (BCRP)
      substrate in vitro. There is potential for inhibitors or inducers of these transporters to
      alter the concentrations of boceprevir; the clinical implications of these interactions are
      not known.Boceprevir is partly metabolized by CYP3A4/5. Co-administration of boceprevir with
      medicines that induce or inhibit CYP3A4/5 could increase or decrease exposure to boceprevir
      and affect its efficacy.Boceprevir, in combination with peginterferon and ribavirin, is
      contraindicated when coadministered with medicines that are highly dependent on CYP3A4/5 for
      clearance, and for which elevated plasma concentrations are associated with serious and/or
      life-threatening events. Examples may include; orally administered midazolam and triazolam,
      bepridil, pimozide, lumefantrine, halofantrine, and tyrosine kinase inhibitors, and ergot
      derivatives (dihydroergotamine, ergonovine, ergotamine, methylergonovine).

      Boceprevir is primarily metabolized by aldoketo reductase (AKR). In medicine interaction
      trials conducted with AKR inhibitors diflunisal and ibuprofen, boceprevir exposure did not
      increase to a clinically significant extent. Boceprevir may be co-administered with AKR
      inhibitors. The concomitant use of boceprevir with stong CYP3A4 inducers such as rifampicin
      or anticonvulsants (such as phenytoin, phenobarbital or carbamazepine) may significantly
      reduce the plasma exposure of boceprevir. As no data is available, the combination of
      boceprevir with these medicines is not recommended.

      The metabolism of St John's Wort is not currently known. Treatment with St John's wort for 14
      days resulted in significant increases in the urinary 6-beta-hydroxycortisol/ cortisol ratio,
      suggesting that St John's wort is an inducer of CYP3A4. For this reason, it is not
      recommended to administer SJW with CYP3A4 metabolized drugs. Furthermore,interactions may
      occur with P-glycoprotein substrates, as St. John's wort can induce the activity of
      transmembrane transporters. This might decrease the effectiveness of some medications.

      For the reasons illustrated above, the potential for a drug interaction between SJW and
      boceprevir is high and the co-administration must be studied in order to gain information on
      whether: i) SJW leads to a decrease in boceprevir concentrations and therefore efficacy; ii)
      boceprevir leads to an increase in SJW (hypericin) exposure with risk of toxicity.

      The safety and PK of the combination should be known especially in view of the common side
      effects caused by interferon, which is co-administered with boceprevir for the treatment of
      hepatitis C: as interferon causes depression, patients may chose to take SJW rather than
      prescribed anti-depressants to manage their mood changes during antihepatitis treatment.
allocation: Randomized
intervention model: Crossover Assignment
primary purpose: Prevention
masking: None (Open Label)
measure: Pharmacokinetic of Boceprevir in the Presence of Ucalm (St John's Wort)
time frame: 6 months
description: Pharmacokinetic parameters (maximum and trough concentrations, and area under concentratof boceprevir and SJW will be evaluated when given in combination at steady-state to evaluate possible differences in concentrations during co-administration versus drug given alone.
The pharmacokinetic parameters calculated for boceprevir and SJW will be Ctrough,the maximum observed plasma concentration (Cmax), time point at Cmax (Tmax), and total drug exposure, expressed as the area under the plasma concentration-time curve.
All pharmacokinetic parameters will be calculated using non-compartmental modelling techniques (WinNonlin®) and all statistical calculations performed within-participant changes in the assessed pharmacokinetic parameters (drug alone vs drug combination) will be evaluated by calculating geometric mean ratios.
arm group label: St John's Wort, then Boceprevir
arm group type: Experimental
description: D 1-14 St. John's Wort 2 x 300mg (Ucalm(r)) QD D 22-35 St. John's Wort 2 x 300mg (Ucalm(r)) QD D 31-35 Boceprevir 800mg tds D 52-56 Boceprevir 800mg tds
arm group label: Boceprevir, then St John's Wort
arm group type: Experimental
description: D 10-14 Boceprevir 800mg tds D 22-35 St. John's Wort 2 x 300mg (Ucalm(r)) QD D 31-35 Boceprevir 800mg tds D 43-56 St. John's Wort 2 x 300mg (Ucalm(r)) QD
intervention type: Drug
intervention name: Boceprevir
description: Boceprevir as Victrelis(r) 200mg capsules
arm group label: Boceprevir, then St John's Wort
arm group label: St John's Wort, then Boceprevir
other name: Boceprevir 800 mg three times daily
intervention type: Drug
intervention name: St John's Wort
description: Each Ucalm(r) tablet contains 300mg of St Johns Wort extract
arm group label: Boceprevir, then St John's Wort
arm group label: St John's Wort, then Boceprevir
other name: Ucalm (R) tablets, two tablets given once daily
criteria: 
gender: All
minimum age: 18 Years
maximum age: 65 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Marta Boffito
role: Principal Investigator
affiliation: HIV Consultant
facility: 
country: United Kingdom
citation: Jackson A, D'Avolio A, Moyle G, Bonora S, Di Perri G, Else L, Simiele M, Singh GJ, Back D, Boffito M. Pharmacokinetics of the co-administration of boceprevir and St John's wort to male and female healthy volunteers. J Antimicrob Chemother. 2014 Jul;69(7):1911-5. doi: 10.1093/jac/dku060. Epub 2014 Mar 6.
PMID: 24610312
responsible party type: Sponsor
mesh term: Hepatitis C
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 