<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/NCT03279120</url>
  </required_header>
  <id_info>
    <org_study_id>A15-138</org_study_id>
    <nct_id>NCT03279120</nct_id>
  </id_info>
  <brief_title>Safety, PK, and PD Study of IVRs Releasing TFV and LNG</brief_title>
  <acronym>TFV/LNG IVR</acronym>
  <official_title>Phase I, 90-Day Safety, Pharmacokinetic, And Pharmacodynamic Study Of Intravaginal Rings Releasing Tenofovir And Levonorgestrel</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>CONRAD</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>United States Agency for International Development (USAID)</agency>
      <agency_class>U.S. Fed</agency_class>
    </collaborator>
    <collaborator>
      <agency>Agility Clinical, Inc.</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>CONRAD</source>
  <oversight_info>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      This multi-center Phase I study is designed to characterize the safety, PK, and PD of TFV/LNG&#xD;
      IVR to assess systemic and genital tract bioavailability in healthy women. The IVRs to be&#xD;
      used in the study are TFV/LNG IVR (8-10mg per day/20μg per day) or placebo IVR. Samples will&#xD;
      be obtained before, during and after 90 days of continuous or interrupted IVR use.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The purpose of this multi-center Phase I protocol, titled Phase I, 90-Day Safety,&#xD;
      Pharmacokinetic, and Pharmacodynamic Study of Intravaginal Rings Releasing Tenofovir and&#xD;
      Levonorgestrel is to assess the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of&#xD;
      the Tenofovir/Levonorgestrel Intravaginal Ring (TFV/LNG IVR).&#xD;
&#xD;
      The study will enroll healthy, non-pregnant, ovulatory, HIV-uninfected women aged 18 to 50&#xD;
      with a body mass index (BMI) less than 30 kg/m2, regular menstrual cycles (approximately&#xD;
      26-35 days) by participant report, and willing to use non-spermicidal condoms for sex and&#xD;
      follow other study restrictions. Women will be protected from pregnancy by abstinence from&#xD;
      vaginal intercourse or agreeing to consistently use condoms.&#xD;
&#xD;
      The enrollment goal is for approximately 60 participants to complete the study. A subset of&#xD;
      approximately 20 women will be selected for an in-depth interview to take place during the&#xD;
      first month of IVR use and again after 90 days of use.&#xD;
&#xD;
      Women will be randomized to one of four arms: TFV/LNG IVR (8-10mg per day/20μg per day) for&#xD;
      90 days (Continuous), TFV/LNG IVR (8-10mg per day/20μg per day) for 3x28 days (Interrupted),&#xD;
      placebo IVR for 90 days (Continuous), or placebo IVR for 3x28 days (Interrupted) and will&#xD;
      undergo blood, cervicovaginal and rectal fluid sample collections, and cervicovaginal tissue&#xD;
      collections for PK and PD assessments before, during and after 90 days of continuous or&#xD;
      interrupted IVR use.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">September 28, 2017</start_date>
  <completion_date type="Actual">December 26, 2018</completion_date>
  <primary_completion_date type="Actual">December 26, 2018</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>Parallel Assignment</intervention_model>
    <primary_purpose>Prevention</primary_purpose>
    <masking>Triple (Participant, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Percentage of women with Treatment-emergent adverse events</measure>
    <time_frame>Day 90</time_frame>
    <description>Treatment-emergent adverse events (TEAEs)</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Changes in systemic laboratory values</measure>
    <time_frame>Change from Baseline at Day 90</time_frame>
    <description>Systemic laboratory values</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Changes in cervicovaginal mucosa by visual inspection</measure>
    <time_frame>Change from Baseline at Day 90</time_frame>
    <description>Mucosal safety</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Changes in soluble markers</measure>
    <time_frame>Change from Baseline at Day 90</time_frame>
    <description>Soluble markers in cervicovaginal fluid</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Changes in inflammatory markers in cervicovaginal tissue</measure>
    <time_frame>Change from Baseline at Day 90</time_frame>
    <description>Inflammatory markers in cervicovaginal tissue</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Changes in endogenous vaginal bacteria</measure>
    <time_frame>Change from Baseline at Day 90</time_frame>
    <description>Endogenous vaginal bacteria in cervicovaginal fluid</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Microbial growth</measure>
    <time_frame>Day 90</time_frame>
    <description>Microbial growth on returned IVRs</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Maximum Plasma Concentrations [Cmax]</measure>
    <time_frame>Baseline, 8 hours post-IVR insertion, Day 2 or 3 or 4 (randomized time point), 10, 21, 28, 32, 42, 53, 59, 63, 73, 84, 90; and 48 or 72 hours or 5 days after IVR removal (randomized time point)</time_frame>
    <description>Maximum Plasma Concentrations [Cmax] of TFV and LNG</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Maximum CV Fluid Concentrations</measure>
    <time_frame>2 and 8 hours post-IVR insertion, Day 2 or 3 or 4 (randomized time point), 10, 21, 32, 42, 53, 63, 73, 84; and 48 or 72 hours or 5 days after IVR removal (randomized time point)</time_frame>
    <description>Maximum CV Fluid Concentrations of TFV</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Maximum Rectal Fluid Concentrations</measure>
    <time_frame>Day 2 or 3 or 4 (randomized time point), 21, 53, 84; and 48 or 72 hours or 5 days after IVR removal (randomized time point)</time_frame>
    <description>Maximum Rectal Fluid Concentrations of TFV</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Maximum CV Tissue Concentrations</measure>
    <time_frame>Changes from baseline at day 90; and 48 or 72 hours or 5 days after IVR removal (randomized time point)</time_frame>
    <description>Maximum CV Tissue Concentrations of TFV</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Maximum CV Tissue Metabolite Concentrations</measure>
    <time_frame>Changes from baseline at day 90; and 48 or 72 hours or 5 days after IVR removal (randomized time point)</time_frame>
    <description>Maximum CV Tissue Concentrations of TFV-DP</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Maximum Serum Concentrations of LNG</measure>
    <time_frame>Baseline, 1, 2, 4, and 8 hours post-IVR insertion, Day 2 or 3 or 4 (randomized time point), 10, 21, 28, 32, 42, 53, 59, 63, 73, 84, 90; and 48 or 72 hours or 5 days after IVR removal (randomized time point)</time_frame>
    <description>Maximum Serum Concentrations of LNG</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Residual Drug Concentrations</measure>
    <time_frame>Day 90</time_frame>
    <description>Residual drug (TFV and LNG) in returned IVRs</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Surrogates of contraceptive efficacy of Mucus</measure>
    <time_frame>Day 30</time_frame>
    <description>Surrogates of contraceptive efficacy: Cervical mucus assessment (Cervical mucus quality [score of &gt;10])</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Surrogates of contraceptive efficacy of Sperm</measure>
    <time_frame>Day 30</time_frame>
    <description>Surrogates of contraceptive efficacy: Cervical mucus assessment (Sperm migration on the Simplified Slide test)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Ovulation</measure>
    <time_frame>Changes from baseline at day 90</time_frame>
    <description>Ovulation by serum progesterone (P4)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Follicular Development</measure>
    <time_frame>Changes from baseline at day 90</time_frame>
    <description>Effect on follicular development by serum estradiol concentration</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Antiviral activity in CV Fluid--HIV</measure>
    <time_frame>Changes from baseline at day 90</time_frame>
    <description>Anti-HIV-1 activity in CV fluid</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Antiviral activity in CV Fluid--HSV-2</measure>
    <time_frame>Changes from baseline at day 90</time_frame>
    <description>Anti-HSV-2 activity in CV fluid</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in Antiviral Activity</measure>
    <time_frame>Changes from baseline at day 90</time_frame>
    <description>Comparison of HIV-1 ex vivo infection in CV tissue (EVMS only) at baseline and after 90 days of IVR use</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Bleeding Patterns</measure>
    <time_frame>Baseline through Day 90 of IVR use</time_frame>
    <description>Participant self-report of bleeding</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Forgiveness--LNG</measure>
    <time_frame>Day 32 and 63; and 48 or 72 hours or 5 days after IVR removal (randomized time point)</time_frame>
    <description>Decay of LNG during 3-day periods of non-use in interrupted regimen, and after 90 days of IVR use</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Forgiveness--TFV</measure>
    <time_frame>Day 32 and 63; and 48 or 72 hours or 5 days after IVR removal (randomized time point)</time_frame>
    <description>Decay of TFV during 3-day periods of non-use in interrupted regimen, and after 90 days of IVR use</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Acceptability--Qualitative</measure>
    <time_frame>Baseline, Day 28 and 90</time_frame>
    <description>Responses to key questions on acceptability and psychosocial questionnaire(s) (all participants), and feedback during in-depth interviews (subset of participants)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Acceptability--IDI</measure>
    <time_frame>During first month of IVR use and Day 90</time_frame>
    <description>Responses to key questions on acceptability and psychosocial questionnaire(s) (all participants), and feedback during in-depth interviews (subset of participants)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Adherence</measure>
    <time_frame>Baseline, Day 28 and 90</time_frame>
    <description>Percentage of participants with Discontinuations/Expulsions/Removals by self-report</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Antiviral activity in Rectal Fluid--HIV</measure>
    <time_frame>Changes from baseline at day 90</time_frame>
    <description>Anti-HIV-1 activity in rectal fluid</description>
  </other_outcome>
  <other_outcome>
    <measure>Antiviral activity in Rectal Fluid--HSV-2</measure>
    <time_frame>Changes from baseline at day 90</time_frame>
    <description>Anti-HSV-2 activity in rectal fluid</description>
  </other_outcome>
  <other_outcome>
    <measure>Changes in Antiviral Activity--HSV-2</measure>
    <time_frame>Changes from baseline at day 90</time_frame>
    <description>Comparison of HSV-2 ex vivo infection in CV tissue (EVMS-only) at baseline and after 90 days of IVR use, as possible</description>
  </other_outcome>
  <other_outcome>
    <measure>Qualitative TFV measurement</measure>
    <time_frame>Day 90</time_frame>
    <description>Qualitative measure of TFV in a vaginal swab</description>
  </other_outcome>
  <other_outcome>
    <measure>Adherence Marker in returned vaginal ring-analytic</measure>
    <time_frame>Day 90</time_frame>
    <description>Analytical measures of drug or placebo products</description>
  </other_outcome>
  <other_outcome>
    <measure>Adherence marker in returned ring--bioassay</measure>
    <time_frame>Day 90</time_frame>
    <description>Characterization of returned IVRs (active and placebo) via objective IVR biomarkers (e.g., residual glycerin content and bioassay) and residual drug (TFV and LNG), as feasible</description>
  </other_outcome>
  <other_outcome>
    <measure>Adherence marker in returned ring--correlation</measure>
    <time_frame>Day 90</time_frame>
    <description>Correlation of IVR removal scale factors and objective biomarkers of IVR use</description>
  </other_outcome>
  <other_outcome>
    <measure>Adherence marker in returned ring--correlation</measure>
    <time_frame>Day 90</time_frame>
    <description>Correlation of baseline user characteristics and objective biomarkers of IVR use</description>
  </other_outcome>
  <number_of_arms>4</number_of_arms>
  <enrollment type="Actual">66</enrollment>
  <condition>Anti-Infective Agents</condition>
  <condition>Anti-Retroviral Agents</condition>
  <condition>Contraceptive Usage</condition>
  <arm_group>
    <arm_group_label>TFV/LNG IVR (8-10mg/20μg) (Continuous)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>TFV/LNG IVR is an intravaginal ring 55.0 mm in diameter, consisting of two segments of polyurethane tubing with an outer cross-sectional diameter of 5.5 mm: a longer segment (135 mm) containing white to off-white TFV paste and a shorter one (34 mm) with a translucent LNG core. Used for 90 days (continuous).</description>
  </arm_group>
  <arm_group>
    <arm_group_label>TFV/LNG IVR (8-10mg/20μg) (Interrupted)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>TFV/LNG IVR is an intravaginal ring 55.0 mm in diameter, consisting of two segments of polyurethane tubing with an outer cross-sectional diameter of 5.5 mm: a longer segment (135 mm) containing white to off-white TFV paste and a shorter one (34 mm) with a translucent LNG core. Used for 90 days (3x28 days interrupted).</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo (Continuous)</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Intravaginal ring 55.0 mm in diameter, consisting of two segments of polyurethane tubing with an outer diameter of 5.5 mm containing no active experimental ingredients. Used for one month. Used for 90 days (continuous).</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo (Interrupted)</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Intravaginal ring 55.0 mm in diameter, consisting of two segments of polyurethane tubing with an outer diameter of 5.5 mm containing no active experimental ingredients. Used for one month. Used for 90 days (3x28 days interrupted).</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>TFV/LNG IVR</intervention_name>
    <description>Used for 90 days (Continuous or Interrupted)</description>
    <arm_group_label>TFV/LNG IVR (8-10mg/20μg) (Continuous)</arm_group_label>
    <arm_group_label>TFV/LNG IVR (8-10mg/20μg) (Interrupted)</arm_group_label>
    <other_name>Tenofovir/Levonorgestrel Intravaginal Ring</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>Used for 90 days (Continuous or Interrupted)</description>
    <arm_group_label>Placebo (Continuous)</arm_group_label>
    <arm_group_label>Placebo (Interrupted)</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Female, age 18-50 years, inclusive&#xD;
&#xD;
          -  General good health (by volunteer history and per investigator discretion) without any&#xD;
             clinically significant systemic disease (including, but not limited to significant&#xD;
             liver disease/hepatitis, gastrointestinal disease, kidney disease, thyroid disease,&#xD;
             osteoporosis or bone disease, and diabetes) and with an intact gastrointestinal tract,&#xD;
             uterus, and cervix.&#xD;
&#xD;
          -  Currently having regular menstrual cycles (approximately 26-35 days) by participant&#xD;
             report&#xD;
&#xD;
          -  History of Pap smears and follow-up consistent with standard clinical practice as&#xD;
             outlined in the Study Manual or willing to undergo a Pap smear at Visit 1&#xD;
&#xD;
          -  Protected from pregnancy by one of the following:&#xD;
&#xD;
          -  Sterilization of either partner&#xD;
&#xD;
          -  Abstinence from vaginal intercourse&#xD;
&#xD;
          -  Consistent use of non-spermicidal condoms&#xD;
&#xD;
          -  Willing to abstain from use of vaginal products (other than the study product and&#xD;
             condoms) including tampons (except for menses), spermicides, lubricants, and douches&#xD;
             for the whole study&#xD;
&#xD;
          -  Willing to abstain from any vaginal and anal intercourse/activity starting 48 hours&#xD;
             before cervical mucus collection, as possible, and 48 hours before Visits 4 and 29,&#xD;
             and for 5 days after tissue collection&#xD;
&#xD;
          -  Vaginal and cervical anatomy that, in the opinion of the investigator, lends itself to&#xD;
             easy genital tract sample collection&#xD;
&#xD;
          -  Negative urine pregnancy test&#xD;
&#xD;
          -  P4 ≥3 ng/ml&#xD;
&#xD;
          -  Willing to give voluntary consent and sign an informed consent form&#xD;
&#xD;
          -  Willing and able to comply with protocol requirements&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  BMI ≥ 30 kg/m2&#xD;
&#xD;
          -  History of hysterectomy&#xD;
&#xD;
          -  Currently pregnant or within two calendar months from the last pregnancy outcome.&#xD;
&#xD;
        Note: If recently pregnant, must have had at least two spontaneous menses since pregnancy&#xD;
        outcome&#xD;
&#xD;
          -  Use of any hormonal contraceptive method in the last 3 months (oral, transdermal,&#xD;
             transvaginal, implant, or hormonal intrauterine contraceptive device)&#xD;
&#xD;
          -  Injection of Depo-Provera in the last 10 months&#xD;
&#xD;
          -  Use of copper IUD&#xD;
&#xD;
          -  Currently breastfeeding or having breastfed an infant in the last two months, or&#xD;
             planning to breastfeed during the course of the study&#xD;
&#xD;
          -  History of sensitivity/allergy to any component of the study products, topical&#xD;
             anesthetic, or to both silver nitrate and Monsel's solution&#xD;
&#xD;
          -  Contraindication to LNG&#xD;
&#xD;
          -  In the last three months, diagnosed with or treated for any STI or pelvic inflammatory&#xD;
             disease. Note: Women with a history of genital herpes or condylomata who have been&#xD;
             asymptomatic for at least six months may be considered for eligibility.&#xD;
&#xD;
          -  Nugent score greater than or equal to 7 or symptomatic bacterial vaginosis (BV) as&#xD;
             defined by Amsel's criteria&#xD;
&#xD;
          -  Positive test for Trichomonas vaginalis (TV), Neisseria gonorrhea (GC), Chlamydia&#xD;
             trachomatis (CT), HIV-1, or Hepatitis B surface antigen (HBsAg)&#xD;
&#xD;
          -  Known bleeding disorder, including deep vein thrombosis (DVT) and pulmonary embolism&#xD;
             (PE), or those that could lead to prolonged or continuous bleeding with biopsy&#xD;
&#xD;
          -  Chronic or acute vulvar or vaginal symptoms (pain, irritation, spotting/bleeding,&#xD;
             discharge, etc.)&#xD;
&#xD;
          -  Known current drug or alcohol abuse which could impact study compliance&#xD;
&#xD;
          -  Grade 2 or higher laboratory abnormality, per the 2014 update of the Division of AIDS,&#xD;
             National Institute of Allergy and Infectious Disease (DAIDS) Table for Grading the&#xD;
             Severity of Adverse Events, or clinically significant laboratory abnormality as&#xD;
             determined by the clinician&#xD;
&#xD;
          -  Systemic use in the last two weeks or anticipated use during the study of any of the&#xD;
             following: corticosteroids, antibiotics, anticoagulants or other drugs known to&#xD;
             prolong bleeding and/or clotting, antifungals, or antivirals or antiretrovirals (e.g.&#xD;
             acyclovir, valacyclovir, Viread®, Atripla®, Emtriva®, or Complera®), or CYP3A4&#xD;
             inducers or inhibitors as detailed in the Study Manual (e.g., St. John's Wort or&#xD;
             erythromycin).&#xD;
&#xD;
        Note: Participants should avoid non-steroidal anti-inflammatory drugs (NSAIDs) except for&#xD;
        treatment of dysmenorrhea during menses. Participants may use acetaminophen on an as-needed&#xD;
        but not daily basis during the study.&#xD;
&#xD;
          -  Participation in any other investigational trial with use of a drug/device within the&#xD;
             last 30 days or planned participation in any other investigational trial with use of a&#xD;
             drug/device during the study&#xD;
&#xD;
          -  History of gynecological procedures (including genital piercing) on the external&#xD;
             genitalia, vagina, or cervix within the last 14 days&#xD;
&#xD;
          -  Abnormal finding on laboratory or physical examination or a social or medical&#xD;
             condition in the volunteer which, in the opinion of the investigator, would make&#xD;
             participation in the study unsafe or would complicate interpretation of data&#xD;
      </textblock>
    </criteria>
    <gender>Female</gender>
    <gender_based>Yes</gender_based>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>50 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>study director</last_name>
    <role>Study Director</role>
    <affiliation>CONRAD</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Eastern Virginia Medical School</name>
      <address>
        <city>Norfolk</city>
        <state>Virginia</state>
        <zip>23507-1627</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Profamilia</name>
      <address>
        <city>Santo Domingo</city>
        <country>Dominican Republic</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Dominican Republic</country>
    <country>United States</country>
  </location_countries>
  <verification_date>July 2019</verification_date>
  <study_first_submitted>August 23, 2017</study_first_submitted>
  <study_first_submitted_qc>September 8, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">September 12, 2017</study_first_posted>
  <last_update_submitted>July 22, 2019</last_update_submitted>
  <last_update_submitted_qc>July 22, 2019</last_update_submitted_qc>
  <last_update_posted type="Actual">July 23, 2019</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>HIV</keyword>
  <keyword>LNG</keyword>
  <keyword>TFV</keyword>
  <keyword>IVR</keyword>
  <keyword>Contraception</keyword>
  <keyword>Prevention</keyword>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Tenofovir</mesh_term>
    <mesh_term>Levonorgestrel</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/NCT03279120
org study id: A15-138
nct id: NCT03279120
lead sponsor: 
collaborator: 
collaborator: 
is fda regulated drug: Yes
is fda regulated device: No
This multi-center Phase I study is designed to characterize the safety, PK, and PD of TFV/LNG
      IVR to assess systemic and genital tract bioavailability in healthy women. The IVRs to be
      used in the study are TFV/LNG IVR (8-10mg per day/20μg per day) or placebo IVR. Samples will
      be obtained before, during and after 90 days of continuous or interrupted IVR use.
The purpose of this multi-center Phase I protocol, titled Phase I, 90-Day Safety,
      Pharmacokinetic, and Pharmacodynamic Study of Intravaginal Rings Releasing Tenofovir and
      Levonorgestrel is to assess the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of
      the Tenofovir/Levonorgestrel Intravaginal Ring (TFV/LNG IVR).

      The study will enroll healthy, non-pregnant, ovulatory, HIV-uninfected women aged 18 to 50
      with a body mass index (BMI) less than 30 kg/m2, regular menstrual cycles (approximately
      26-35 days) by participant report, and willing to use non-spermicidal condoms for sex and
      follow other study restrictions. Women will be protected from pregnancy by abstinence from
      vaginal intercourse or agreeing to consistently use condoms.

      The enrollment goal is for approximately 60 participants to complete the study. A subset of
      approximately 20 women will be selected for an in-depth interview to take place during the
      first month of IVR use and again after 90 days of use.

      Women will be randomized to one of four arms: TFV/LNG IVR (8-10mg per day/20μg per day) for
      90 days (Continuous), TFV/LNG IVR (8-10mg per day/20μg per day) for 3x28 days (Interrupted),
      placebo IVR for 90 days (Continuous), or placebo IVR for 3x28 days (Interrupted) and will
      undergo blood, cervicovaginal and rectal fluid sample collections, and cervicovaginal tissue
      collections for PK and PD assessments before, during and after 90 days of continuous or
      interrupted IVR use.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Prevention
masking: Triple (Participant, Investigator, Outcomes Assessor)
measure: Percentage of women with Treatment-emergent adverse events
time frame: Day 90
description: Treatment-emergent adverse events (TEAEs)
measure: Changes in systemic laboratory values
time frame: Change from Baseline at Day 90
description: Systemic laboratory values
measure: Changes in cervicovaginal mucosa by visual inspection
time frame: Change from Baseline at Day 90
description: Mucosal safety
measure: Changes in soluble markers
time frame: Change from Baseline at Day 90
description: Soluble markers in cervicovaginal fluid
measure: Changes in inflammatory markers in cervicovaginal tissue
time frame: Change from Baseline at Day 90
description: Inflammatory markers in cervicovaginal tissue
measure: Changes in endogenous vaginal bacteria
time frame: Change from Baseline at Day 90
description: Endogenous vaginal bacteria in cervicovaginal fluid
measure: Microbial growth
time frame: Day 90
description: Microbial growth on returned IVRs
measure: Maximum Plasma Concentrations [Cmax]
time frame: Baseline, 8 hours post-IVR insertion, Day 2 or 3 or 4 (randomized time point), 10, 21, 28, 32, 42, 53, 59, 63, 73, 84, 90; and 48 or 72 hours or 5 days after IVR removal (randomized time point)
description: Maximum Plasma Concentrations [Cmax] of TFV and LNG
measure: Maximum CV Fluid Concentrations
time frame: 2 and 8 hours post-IVR insertion, Day 2 or 3 or 4 (randomized time point), 10, 21, 32, 42, 53, 63, 73, 84; and 48 or 72 hours or 5 days after IVR removal (randomized time point)
description: Maximum CV Fluid Concentrations of TFV
measure: Maximum Rectal Fluid Concentrations
time frame: Day 2 or 3 or 4 (randomized time point), 21, 53, 84; and 48 or 72 hours or 5 days after IVR removal (randomized time point)
description: Maximum Rectal Fluid Concentrations of TFV
measure: Maximum CV Tissue Concentrations
time frame: Changes from baseline at day 90; and 48 or 72 hours or 5 days after IVR removal (randomized time point)
description: Maximum CV Tissue Concentrations of TFV
measure: Maximum CV Tissue Metabolite Concentrations
time frame: Changes from baseline at day 90; and 48 or 72 hours or 5 days after IVR removal (randomized time point)
description: Maximum CV Tissue Concentrations of TFV-DP
measure: Maximum Serum Concentrations of LNG
time frame: Baseline, 1, 2, 4, and 8 hours post-IVR insertion, Day 2 or 3 or 4 (randomized time point), 10, 21, 28, 32, 42, 53, 59, 63, 73, 84, 90; and 48 or 72 hours or 5 days after IVR removal (randomized time point)
description: Maximum Serum Concentrations of LNG
measure: Residual Drug Concentrations
time frame: Day 90
description: Residual drug (TFV and LNG) in returned IVRs
measure: Surrogates of contraceptive efficacy of Mucus
time frame: Day 30
description: Surrogates of contraceptive efficacy: Cervical mucus assessment (Cervical mucus quality [score of >10])
measure: Surrogates of contraceptive efficacy of Sperm
time frame: Day 30
description: Surrogates of contraceptive efficacy: Cervical mucus assessment (Sperm migration on the Simplified Slide test)
measure: Ovulation
time frame: Changes from baseline at day 90
description: Ovulation by serum progesterone (P4)
measure: Follicular Development
time frame: Changes from baseline at day 90
description: Effect on follicular development by serum estradiol concentration
measure: Antiviral activity in CV Fluid--HIV
time frame: Changes from baseline at day 90
description: Anti-HIV-1 activity in CV fluid
measure: Antiviral activity in CV Fluid--HSV-2
time frame: Changes from baseline at day 90
description: Anti-HSV-2 activity in CV fluid
measure: Changes in Antiviral Activity
time frame: Changes from baseline at day 90
description: Comparison of HIV-1 ex vivo infection in CV tissue (EVMS only) at baseline and after 90 days of IVR use
measure: Bleeding Patterns
time frame: Baseline through Day 90 of IVR use
description: Participant self-report of bleeding
measure: Forgiveness--LNG
time frame: Day 32 and 63; and 48 or 72 hours or 5 days after IVR removal (randomized time point)
description: Decay of LNG during 3-day periods of non-use in interrupted regimen, and after 90 days of IVR use
measure: Forgiveness--TFV
time frame: Day 32 and 63; and 48 or 72 hours or 5 days after IVR removal (randomized time point)
description: Decay of TFV during 3-day periods of non-use in interrupted regimen, and after 90 days of IVR use
measure: Acceptability--Qualitative
time frame: Baseline, Day 28 and 90
description: Responses to key questions on acceptability and psychosocial questionnaire(s) (all participants), and feedback during in-depth interviews (subset of participants)
measure: Acceptability--IDI
time frame: During first month of IVR use and Day 90
description: Responses to key questions on acceptability and psychosocial questionnaire(s) (all participants), and feedback during in-depth interviews (subset of participants)
measure: Adherence
time frame: Baseline, Day 28 and 90
description: Percentage of participants with Discontinuations/Expulsions/Removals by self-report
measure: Antiviral activity in Rectal Fluid--HIV
time frame: Changes from baseline at day 90
description: Anti-HIV-1 activity in rectal fluid
measure: Antiviral activity in Rectal Fluid--HSV-2
time frame: Changes from baseline at day 90
description: Anti-HSV-2 activity in rectal fluid
measure: Changes in Antiviral Activity--HSV-2
time frame: Changes from baseline at day 90
description: Comparison of HSV-2 ex vivo infection in CV tissue (EVMS-only) at baseline and after 90 days of IVR use, as possible
measure: Qualitative TFV measurement
time frame: Day 90
description: Qualitative measure of TFV in a vaginal swab
measure: Adherence Marker in returned vaginal ring-analytic
time frame: Day 90
description: Analytical measures of drug or placebo products
measure: Adherence marker in returned ring--bioassay
time frame: Day 90
description: Characterization of returned IVRs (active and placebo) via objective IVR biomarkers (e.g., residual glycerin content and bioassay) and residual drug (TFV and LNG), as feasible
measure: Adherence marker in returned ring--correlation
time frame: Day 90
description: Correlation of IVR removal scale factors and objective biomarkers of IVR use
measure: Adherence marker in returned ring--correlation
time frame: Day 90
description: Correlation of baseline user characteristics and objective biomarkers of IVR use
arm group label: TFV/LNG IVR (8-10mg/20μg) (Continuous)
arm group type: Experimental
description: TFV/LNG IVR is an intravaginal ring 55.0 mm in diameter, consisting of two segments of polyurethane tubing with an outer cross-sectional diameter of 5.5 mm: a longer segment (135 mm) containing white to off-white TFV paste and a shorter one (34 mm) with a translucent LNG core. Used for 90 days (continuous).
arm group label: TFV/LNG IVR (8-10mg/20μg) (Interrupted)
arm group type: Experimental
description: TFV/LNG IVR is an intravaginal ring 55.0 mm in diameter, consisting of two segments of polyurethane tubing with an outer cross-sectional diameter of 5.5 mm: a longer segment (135 mm) containing white to off-white TFV paste and a shorter one (34 mm) with a translucent LNG core. Used for 90 days (3x28 days interrupted).
arm group label: Placebo (Continuous)
arm group type: Placebo Comparator
description: Intravaginal ring 55.0 mm in diameter, consisting of two segments of polyurethane tubing with an outer diameter of 5.5 mm containing no active experimental ingredients. Used for one month. Used for 90 days (continuous).
arm group label: Placebo (Interrupted)
arm group type: Placebo Comparator
description: Intravaginal ring 55.0 mm in diameter, consisting of two segments of polyurethane tubing with an outer diameter of 5.5 mm containing no active experimental ingredients. Used for one month. Used for 90 days (3x28 days interrupted).
intervention type: Drug
intervention name: TFV/LNG IVR
description: Used for 90 days (Continuous or Interrupted)
arm group label: TFV/LNG IVR (8-10mg/20μg) (Continuous)
arm group label: TFV/LNG IVR (8-10mg/20μg) (Interrupted)
other name: Tenofovir/Levonorgestrel Intravaginal Ring
intervention type: Drug
intervention name: Placebo
description: Used for 90 days (Continuous or Interrupted)
arm group label: Placebo (Continuous)
arm group label: Placebo (Interrupted)
criteria: 
gender: Female
gender based: Yes
minimum age: 18 Years
maximum age: 50 Years
healthy volunteers: Accepts Healthy Volunteers
last name: study director
role: Study Director
affiliation: CONRAD
facility: 
facility: 
country: Dominican Republic
country: United States
responsible party type: Sponsor
mesh term: Tenofovir
mesh term: Levonorgestrel
sharing ipd: No