<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/NCT04463680</url>
  </required_header>
  <id_info>
    <org_study_id>19-2829</org_study_id>
    <nct_id>NCT04463680</nct_id>
  </id_info>
  <brief_title>Rifampin and the Contraceptive Implant</brief_title>
  <official_title>The Effect of Rifampin on Etonogestrel Concentrations in Contraceptive Implant Users</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Colorado, Denver</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Merck Sharp &amp; Dohme LLC</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>University of Colorado, Denver</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>
      It is important for women taking rifampin to be aware if they are at greater risk of an&#xD;
      unintended pregnancy while on the implant. An unintended pregnancy has many social,&#xD;
      emotional, and financial impacts on women and society. Rifampin is also a Class C medication&#xD;
      for pregnancy and could have potential negative effects on a developing fetus. Additionally,&#xD;
      women considering rifampin for treatment of LTBI face additional risks with an unintended&#xD;
      pregnancy, making the reliability of contraception even more important for these women. The&#xD;
      results of this study can directly inform counseling on a national and international basis&#xD;
      for women who use the contraceptive implant and are considering their treatment options for&#xD;
      LTBI.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Rifampin is an antibiotic historically prescribed as part of a treatment regimen for active&#xD;
      tuberculosis (TB) infection. Though active TB infections have become rarer over time in the&#xD;
      US, it is estimated that up to 13 million people in the US may have latent TB infections&#xD;
      (LTBIs), with even greater numbers of LTBIs worldwide1. In efforts to combat the persistent&#xD;
      rate of LTBI, the US Centers for Disease Control and Prevention (CDC) released updated&#xD;
      treatment guidelines for LTBI in 20181. This recommended treatment guideline consists of four&#xD;
      treatment regimens, varying in duration from 3 to 9 months. The CDC recommends utilization of&#xD;
      the shorter regimens when possible to achieve higher patient compliance and infection clear&#xD;
      rates. The second shortest duration treatment regimen (4 months) consists of daily rifampin&#xD;
      only1.&#xD;
&#xD;
      In addition to its antitubercular properties, rifampin is a known strong cytochrome P-450&#xD;
      (CYP) 3A4 enzyme inducer2. Similar to other strong CYP3A4 enzyme inducers (e.g.&#xD;
      carbamazepine), rifampin can affect the serum concentrations of exogenous steroid hormones&#xD;
      found in hormonal contraception2. The only published literature on the interaction between&#xD;
      rifampin and hormonal contraception has focused on combined oral contraceptives3. Five&#xD;
      studies that investigated the pharmacokinetics of combined oral contraceptives all found&#xD;
      significant reductions in serum ethinyl estradiol and progestin concentrations with rifampin&#xD;
      co-administration3. This pharmacokinetic effect is significant enough to warrant a category 3&#xD;
      recommendation (theoretical or proven risks usually outweigh the advantages) from the CDC&#xD;
      Medical Eligibility Criteria (MEC) for Contraceptive Use for concomitant rifampin and&#xD;
      combined hormonal contraceptive methods4. This pharmacokinetic effect is large enough to&#xD;
      raise concerns for combined hormonal contraceptive method efficacy and recommendation of&#xD;
      alternative methods. One of those alternative methods is the etonogestrel (ENG) implant&#xD;
      (Nexplanon®), which has a category 2 recommendation in the CDC MEC for concomitant rifampin&#xD;
      use4. However, in the clarifications for this recommendation, the CDC MEC warns that rifampin&#xD;
      is &quot;likely to reduce the effectiveness&quot; of the ENG implant, with no supporting evidence&#xD;
      provided4.&#xD;
&#xD;
      Prior work found that a strong CYP3A4 inducer (carbamazepine) caused clinically significant&#xD;
      reductions in serum etonogestrel concentrations among contraceptive implant users5. The&#xD;
      investigators found a median decrease in serum ENG of 61% (range 25-87) with 8/10&#xD;
      participants having serum ENG concentrations &lt;90pg/mL after concomitant carbamazepine5.&#xD;
      Though there is currently no published data on the pharmacokinetic interaction between&#xD;
      rifampin and the ENG implant, given its similar enzyme induction properties, there is concern&#xD;
      that the CDC MEC recommendation for rifampin and the ENG implant may underestimate the&#xD;
      potential risk for contraceptive failure.&#xD;
&#xD;
      Given the social, financial, and healthcare costs of unintended pregnancies, it is imperative&#xD;
      that the investigators better understand the drug-drug interaction between rifampin and the&#xD;
      ENG implant. Especially in light of the contradictory category 2 recommendation and&#xD;
      clarification in the CDC MEC4, more data are needed to determine if rifampin has a&#xD;
      significant enough pharmacokinetic effect on the ENG implant to potentially cause&#xD;
      contraceptive failure. This information would allow healthcare providers around the world the&#xD;
      ability to provide improved counseling to patients needing treatment for LTBI in regards to&#xD;
      both their TB treatment regimen and their concurrent contraceptive options.&#xD;
&#xD;
      Specific Aim:&#xD;
&#xD;
        -  To evaluate the pharmacokinetic effect of rifampin on serum etonogestrel concentrations&#xD;
           in contraceptive implant users at the dose of rifampin used for latent tuberculosis&#xD;
           infection (LTBI) treatment (600mg per day)&#xD;
&#xD;
        -  Exploratory Aim - to evaluate the effect of rifampin on serologic measures of ovulatory&#xD;
           suppression (estradiol and progesterone) in contraceptive implant users&#xD;
&#xD;
      Hypothesis:&#xD;
&#xD;
      · The investigators hypothesize that rifampin will have a significant pharmacokinetic effect&#xD;
      on participants' etonogestrel levels resulting in etonogestrel concentrations at least 35%&#xD;
      decreased from baseline measurements.&#xD;
&#xD;
      Methods:&#xD;
&#xD;
      The investigators propose a prospective, pre and post study to evaluate the pharmacokinetic&#xD;
      effect of rifampin on serum ENG levels in contraceptive implant users. The investigators will&#xD;
      enroll healthy women using an ENG implant for at least 12 months and no greater than 36&#xD;
      months.&#xD;
&#xD;
      Participants will then begin a 2 week regimen of rifampin at 600mg per day. This dose is the&#xD;
      recommended dose for treatment of LTBI and duration of 2 weeks will achieve steady state&#xD;
      rifampin levels with adequate time for liver enzyme induction. All participants will then&#xD;
      return at the end of the second week for a repeat blood draw. The investigators will again&#xD;
      obtain serum as described above for planned measurement of serum ENG concentrations. The&#xD;
      investigators will also obtain blood samples for repeat measurements of serum estradiol and&#xD;
      progesterone. The investigators will also measure a serum rifampin level at the time of the&#xD;
      second ENG blood draw to confirm compliance. Serum estradiol, serum progesterone, and serum&#xD;
      rifampin levels will all be measured at the UCH Clinical Laboratory. At the conclusion of&#xD;
      enrollment, all stored serum samples will be de-identified and shipped to a Merck® laboratory&#xD;
      for serum ENG concentration measurement. Batch analysis will be performed using a liquid&#xD;
      chromatography mass-spectrometry method that has been previously validated. Participants will&#xD;
      serve as their own controls for this study.&#xD;
&#xD;
      All participants will be required to use either a back-up non-hormonal method of birth&#xD;
      control or abstain from intercourse during the study and for 2 weeks after the last dose of&#xD;
      rifampin. Rifampin has a half-life of 3-4 hours, and thus, will be eliminated within 1-2 days&#xD;
      of the last dose, but the investigators will allow a full 2 weeks of buffer to ensure that&#xD;
      the contraceptive effect of the implant has reinitiated before recommending resuming&#xD;
      unprotected intercourse.&#xD;
&#xD;
      All study visits will occur at the Comprehensive Women's Health Clinic in Lowry.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">September 23, 2020</start_date>
  <completion_date type="Actual">February 22, 2022</completion_date>
  <primary_completion_date type="Actual">February 22, 2022</primary_completion_date>
  <phase>Phase 4</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>Basic Science</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Serum Etonogestrel Concentrations</measure>
    <time_frame>2 weeks</time_frame>
    <description>Blood drawn before and after rifampin administration (2 weeks) for serum extraction and etonogestrel analysis</description>
  </primary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">24</enrollment>
  <condition>Contraception</condition>
  <condition>Tuberculosis</condition>
  <arm_group>
    <arm_group_label>Intervention</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Will receive 2 week regimen of rifampin 600mg per day</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Rifampin 600 MG</intervention_name>
    <description>Administered daily for 2 weeks</description>
    <arm_group_label>Intervention</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Healthy women, who have had an ENG implant for 12-36 months at the time of enrollment&#xD;
             and will maintain their implant during the study without modifications.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  o Women who are taking any known cytochrome P-450 3A4 enzyme inducers or inhibitors.&#xD;
&#xD;
               -  Women with a known allergy or insensitivity to rifampin.&#xD;
&#xD;
               -  Women with a body mass index (BMI) &lt;18.5, as underweight women may have altered&#xD;
                  metabolism. The investigators will not have an upper BMI cut-off as studies have&#xD;
                  shown that overweight and obese women have equivalent metabolism and efficacy&#xD;
                  with the ENG contraceptive implant6,7.&#xD;
&#xD;
                  • Exclusions Criteria (screening laboratory testing)&#xD;
&#xD;
               -  Women with any hepatic or renal dysfunction as determined by a comprehensive&#xD;
                  metabolic panel. For purposes of this study, liver function tests will be&#xD;
                  evaluated and evidence of hepatic dysfunction will be defined as an ALT &gt;52 or&#xD;
                  AST &gt;39, which are beyond the reference range of normal values used by the&#xD;
                  University of Colorado clinical laboratory. Renal function will be assessed by a&#xD;
                  serum creatinine and a value &gt;1.2 will be evidence of renal dysfunction as this&#xD;
                  is greater than the reference range used by the University of Colorado clinical&#xD;
                  laboratory.&#xD;
&#xD;
               -  Women with any abnormal hematology as determined by a complete blood count. For&#xD;
                  purposes of this study, abnormal hematology will be defined as a WBC, RBC, or PLT&#xD;
                  value beyond the reference range of normal values used by the University of&#xD;
                  Colorado clinical laboratory.&#xD;
&#xD;
               -  Women with abnormal coagulation factors as determined by coagulation factor tests&#xD;
                  (PT/INR, PTT). For purposes of this study, abnormal coagulation factors will be&#xD;
                  defined as any test value beyond the reference range of normal values used by the&#xD;
                  University of Colorado clinical laboratory.&#xD;
      </textblock>
    </criteria>
    <gender>Female</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>45 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <location>
    <facility>
      <name>University of Colorado Denver</name>
      <address>
        <city>Aurora</city>
        <state>Colorado</state>
        <zip>80045</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>May 2023</verification_date>
  <study_first_submitted>July 6, 2020</study_first_submitted>
  <study_first_submitted_qc>July 6, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">July 9, 2020</study_first_posted>
  <results_first_submitted>April 18, 2023</results_first_submitted>
  <results_first_submitted_qc>April 18, 2023</results_first_submitted_qc>
  <results_first_posted type="Actual">May 9, 2023</results_first_posted>
  <last_update_submitted>May 11, 2023</last_update_submitted>
  <last_update_submitted_qc>May 11, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">May 16, 2023</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>Tuberculosis</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Rifampin</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <provided_document_section>
    <provided_document>
      <document_type>Study Protocol and Statistical Analysis Plan</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>May 8, 2020</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/80/NCT04463680/Prot_SAP_000.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <group_list>
        <group group_id="P1">
          <title>Rifampin 600 mg</title>
          <description>Will receive 2 week regimen of rifampin 600mg per day&#xD;
Rifampin 600 MG: Administered daily for 2 weeks</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="24"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="15"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="9"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Not eligible due to laboratory criteria</title>
              <participants_list>
                <participants group_id="P1" count="5"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Not eligible due to implant duration of use</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Withdrawal by Subject</title>
              <participants_list>
                <participants group_id="P1" count="3"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>Rifampin 600 mg</title>
          <description>Will receive 2 week regimen of rifampin 600mg per day&#xD;
Rifampin 600 MG: Administered daily for 2 weeks</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="15"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>years</units>
          <param>Median</param>
          <dispersion>Full Range</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="28.2" lower_limit="21.8" upper_limit="34.1"/>
                  </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="15"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>American Indian or Alaska Native</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Asian</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Native Hawaiian or Other Pacific Islander</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Black or African American</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="14"/>
                  </measurement_list>
                </category>
                <category>
                  <title>More than one race</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Region of Enrollment</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <title>United States</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="15"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Body mass index</title>
          <units>kg/m^2</units>
          <param>Median</param>
          <dispersion>Full Range</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="25.2" lower_limit="18.9" upper_limit="37.3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Duration of implant use</title>
          <units>months</units>
          <param>Median</param>
          <dispersion>Full Range</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="22" lower_limit="12" upper_limit="32"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Serum Etonogestrel Concentrations</title>
        <description>Blood drawn before and after rifampin administration (2 weeks) for serum extraction and etonogestrel analysis</description>
        <time_frame>2 weeks</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Rifampin 600 mg</title>
            <description>Will receive 2 week regimen of rifampin 600mg per day&#xD;
Rifampin 600 MG: Administered daily for 2 weeks</description>
          </group>
        </group_list>
        <measure>
          <title>Serum Etonogestrel Concentrations</title>
          <description>Blood drawn before and after rifampin administration (2 weeks) for serum extraction and etonogestrel analysis</description>
          <units>pg/mL</units>
          <param>Median</param>
          <dispersion>Full Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="15"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Baseline</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="164.0" lower_limit="94.4" upper_limit="265.0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Post-rifampin</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="47.8" lower_limit="24.7" upper_limit="82.8"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>2 weeks</time_frame>
      <group_list>
        <group group_id="E1">
          <title>Rifampin 600 mg</title>
          <description>Will receive 2 week regimen of rifampin 600mg per day&#xD;
Rifampin 600 MG: Administered daily for 2 weeks</description>
        </group>
      </group_list>
      <serious_events>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, all-cause mortality</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="15"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>0</frequency_threshold>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="15"/>
              </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>Aaron Lazorwitz</name_or_title>
      <organization>University of Colorado Anschutz Medical Campus</organization>
      <phone>3037242019</phone>
      <email>aaron.lazorwitz@cuanschutz.edu</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/NCT04463680
org study id: 19-2829
nct id: NCT04463680
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
is us export: No
It is important for women taking rifampin to be aware if they are at greater risk of an
      unintended pregnancy while on the implant. An unintended pregnancy has many social,
      emotional, and financial impacts on women and society. Rifampin is also a Class C medication
      for pregnancy and could have potential negative effects on a developing fetus. Additionally,
      women considering rifampin for treatment of LTBI face additional risks with an unintended
      pregnancy, making the reliability of contraception even more important for these women. The
      results of this study can directly inform counseling on a national and international basis
      for women who use the contraceptive implant and are considering their treatment options for
      LTBI.
Rifampin is an antibiotic historically prescribed as part of a treatment regimen for active
      tuberculosis (TB) infection. Though active TB infections have become rarer over time in the
      US, it is estimated that up to 13 million people in the US may have latent TB infections
      (LTBIs), with even greater numbers of LTBIs worldwide1. In efforts to combat the persistent
      rate of LTBI, the US Centers for Disease Control and Prevention (CDC) released updated
      treatment guidelines for LTBI in 20181. This recommended treatment guideline consists of four
      treatment regimens, varying in duration from 3 to 9 months. The CDC recommends utilization of
      the shorter regimens when possible to achieve higher patient compliance and infection clear
      rates. The second shortest duration treatment regimen (4 months) consists of daily rifampin
      only1.

      In addition to its antitubercular properties, rifampin is a known strong cytochrome P-450
      (CYP) 3A4 enzyme inducer2. Similar to other strong CYP3A4 enzyme inducers (e.g.
      carbamazepine), rifampin can affect the serum concentrations of exogenous steroid hormones
      found in hormonal contraception2. The only published literature on the interaction between
      rifampin and hormonal contraception has focused on combined oral contraceptives3. Five
      studies that investigated the pharmacokinetics of combined oral contraceptives all found
      significant reductions in serum ethinyl estradiol and progestin concentrations with rifampin
      co-administration3. This pharmacokinetic effect is significant enough to warrant a category 3
      recommendation (theoretical or proven risks usually outweigh the advantages) from the CDC
      Medical Eligibility Criteria (MEC) for Contraceptive Use for concomitant rifampin and
      combined hormonal contraceptive methods4. This pharmacokinetic effect is large enough to
      raise concerns for combined hormonal contraceptive method efficacy and recommendation of
      alternative methods. One of those alternative methods is the etonogestrel (ENG) implant
      (Nexplanon®), which has a category 2 recommendation in the CDC MEC for concomitant rifampin
      use4. However, in the clarifications for this recommendation, the CDC MEC warns that rifampin
      is "likely to reduce the effectiveness" of the ENG implant, with no supporting evidence
      provided4.

      Prior work found that a strong CYP3A4 inducer (carbamazepine) caused clinically significant
      reductions in serum etonogestrel concentrations among contraceptive implant users5. The
      investigators found a median decrease in serum ENG of 61% (range 25-87) with 8/10
      participants having serum ENG concentrations <90pg/mL after concomitant carbamazepine5.
      Though there is currently no published data on the pharmacokinetic interaction between
      rifampin and the ENG implant, given its similar enzyme induction properties, there is concern
      that the CDC MEC recommendation for rifampin and the ENG implant may underestimate the
      potential risk for contraceptive failure.

      Given the social, financial, and healthcare costs of unintended pregnancies, it is imperative
      that the investigators better understand the drug-drug interaction between rifampin and the
      ENG implant. Especially in light of the contradictory category 2 recommendation and
      clarification in the CDC MEC4, more data are needed to determine if rifampin has a
      significant enough pharmacokinetic effect on the ENG implant to potentially cause
      contraceptive failure. This information would allow healthcare providers around the world the
      ability to provide improved counseling to patients needing treatment for LTBI in regards to
      both their TB treatment regimen and their concurrent contraceptive options.

      Specific Aim:

        -  To evaluate the pharmacokinetic effect of rifampin on serum etonogestrel concentrations
           in contraceptive implant users at the dose of rifampin used for latent tuberculosis
           infection (LTBI) treatment (600mg per day)

        -  Exploratory Aim - to evaluate the effect of rifampin on serologic measures of ovulatory
           suppression (estradiol and progesterone) in contraceptive implant users

      Hypothesis:

      · The investigators hypothesize that rifampin will have a significant pharmacokinetic effect
      on participants' etonogestrel levels resulting in etonogestrel concentrations at least 35%
      decreased from baseline measurements.

      Methods:

      The investigators propose a prospective, pre and post study to evaluate the pharmacokinetic
      effect of rifampin on serum ENG levels in contraceptive implant users. The investigators will
      enroll healthy women using an ENG implant for at least 12 months and no greater than 36
      months.

      Participants will then begin a 2 week regimen of rifampin at 600mg per day. This dose is the
      recommended dose for treatment of LTBI and duration of 2 weeks will achieve steady state
      rifampin levels with adequate time for liver enzyme induction. All participants will then
      return at the end of the second week for a repeat blood draw. The investigators will again
      obtain serum as described above for planned measurement of serum ENG concentrations. The
      investigators will also obtain blood samples for repeat measurements of serum estradiol and
      progesterone. The investigators will also measure a serum rifampin level at the time of the
      second ENG blood draw to confirm compliance. Serum estradiol, serum progesterone, and serum
      rifampin levels will all be measured at the UCH Clinical Laboratory. At the conclusion of
      enrollment, all stored serum samples will be de-identified and shipped to a Merck® laboratory
      for serum ENG concentration measurement. Batch analysis will be performed using a liquid
      chromatography mass-spectrometry method that has been previously validated. Participants will
      serve as their own controls for this study.

      All participants will be required to use either a back-up non-hormonal method of birth
      control or abstain from intercourse during the study and for 2 weeks after the last dose of
      rifampin. Rifampin has a half-life of 3-4 hours, and thus, will be eliminated within 1-2 days
      of the last dose, but the investigators will allow a full 2 weeks of buffer to ensure that
      the contraceptive effect of the implant has reinitiated before recommending resuming
      unprotected intercourse.

      All study visits will occur at the Comprehensive Women's Health Clinic in Lowry.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Basic Science
masking: None (Open Label)
measure: Serum Etonogestrel Concentrations
time frame: 2 weeks
description: Blood drawn before and after rifampin administration (2 weeks) for serum extraction and etonogestrel analysis
arm group label: Intervention
arm group type: Experimental
description: Will receive 2 week regimen of rifampin 600mg per day
intervention type: Drug
intervention name: Rifampin 600 MG
description: Administered daily for 2 weeks
arm group label: Intervention
criteria: 
gender: Female
minimum age: 18 Years
maximum age: 45 Years
healthy volunteers: Accepts Healthy Volunteers
facility: 
country: United States
responsible party type: Sponsor
mesh term: Tuberculosis
mesh term: Rifampin
sharing ipd: No
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 