<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/NCT03762382</url>
  </required_header>
  <id_info>
    <org_study_id>Protocol B17-144</org_study_id>
    <secondary_id>RFA-PS-17-005</secondary_id>
    <secondary_id>AID-OAA-A-14-000010</secondary_id>
    <nct_id>NCT03762382</nct_id>
  </id_info>
  <brief_title>Tenofovir/Levonorgestrel Intravaginal Ring and Tenofovir Intravaginal Ring</brief_title>
  <official_title>Phase IIa, 90-Day Safety, Adherence, and Acceptability Study of Intravaginal Rings Releasing Tenofovir With and Without Levonorgestrel Among Women in Western Kenya</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>CONRAD</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Kenya Medical Research Institute</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>University of Washington</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Centers for Disease Control and Prevention</agency>
      <agency_class>U.S. Fed</agency_class>
    </collaborator>
  </sponsors>
  <source>CONRAD</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      The purpose of the study is to evaluate the safety, pharmacokinetics and pharmacodynamics of,&#xD;
      and the tolerability and acceptance of an intravaginal ring (IVR) delivering both tenofovir&#xD;
      and levonorgestrel (TFV/LNG) and an IVR delivering TFV only, compared to a placebo IVR, in&#xD;
      women in Western Kenya.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This Phase 2a clinical trial will evaluate the safety, pharmacokinetics and pharmacodynamics&#xD;
      of, and the tolerability and adherence to two novel intravaginal rings (IVRs). The&#xD;
      tenofovir/levonorgestrel (TFV/LNG) IVR and TFV IVRs are designed to provide HIV (and HSV-2)&#xD;
      prevention with and without contraceptive for pregnancy prevention, respectively. Women will&#xD;
      be protected from pregnancy by abstinence from vaginal intercourse or agreeing to&#xD;
      consistently use condoms; concurrent use of a non-hormonal copper intrauterine device is&#xD;
      permitted.&#xD;
&#xD;
      The study will enroll healthy, HIV-negative, non-pregnant, menstruating women aged 18-34&#xD;
      years, inclusive, and not currently infected with hepatitis B virus, who are assessed to be&#xD;
      at lower risk for HIV. The goal is to enroll fifty (50) women in Western Kenya. The&#xD;
      participants will be randomized 2:2:1 to use one of the following continuous delivery IVRs:&#xD;
      twenty (20) women to use the TFV/LNG IVR; ten (10) women to use the TFV IVR; and ten (10)&#xD;
      women to use the placebo IVR. Participants will attend up to ten (10) routine study visits&#xD;
      that may include physical and pelvic exams, collection of venous blood, vaginal fluid and&#xD;
      cervical mucus, and behavioral questionnaires. A subset of twenty (20) women will participate&#xD;
      in in-depth interviews.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Active, not recruiting</last_known_status>
  <start_date type="Actual">December 12, 2018</start_date>
  <completion_date type="Anticipated">April 2020</completion_date>
  <primary_completion_date type="Actual">August 20, 2019</primary_completion_date>
  <phase>Phase 2</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, Care Provider, Investigator)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Treatment-emergent adverse events (TEAEs)</measure>
    <time_frame>Change from Baseline to up to 90 days of IVR use</time_frame>
    <description>Participants with Grade 2 or higher local female genital TEAEs as defined by DAIDS Table for Grading the Severity of Adult and Pediatric AEs (version 2.1) and DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events Addendum 1 Female Genital Grading Table for Use in Microbicide Studies</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Safety Laboratory Assessments- Serum chemistry</measure>
    <time_frame>Change from Baseline to up to 90 days of IVR use</time_frame>
    <description>Number of participants with abnormal serum chemistry</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Safety Laboratory Assessments- lipids</measure>
    <time_frame>Change from Baseline to up to 90 days of IVR use</time_frame>
    <description>Number of participants with abnormal lipids</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Safety Laboratory Assessments- complete blood counts</measure>
    <time_frame>Change from Baseline to up to 90 days of IVR use</time_frame>
    <description>Number of participants with abnormal complete blood counts</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Mucosal safety</measure>
    <time_frame>Change from Baseline to up to 90 days of IVR use</time_frame>
    <description>Changes in cervicovaginal mucosa by visual inspection</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Maximum blood concentrations (Cmax)</measure>
    <time_frame>Baseline; 6 and 24 hours post IVR insertion; Menstrual cycle 1, day 14; Menstrual cycle 1,day 21-25; Menstrual cycle 2, day 21-25; Menstrual cycle 3, day 14; Day 90 IVR use; 24 hours post-IVR use (anticipated cycle length is 28 days)</time_frame>
    <description>Maximum plasma concentration of TFV and maximum serum concentration of LNG</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Maximum CV fluid concentration</measure>
    <time_frame>6 and 24 hours post-IVR insertion; Menstrual cycle 1 day 14; Menstrual cycle 1 day 21-25; Menstrual cycle 2 day 21-25; Menstrual cycle 3, day 14; Day 90 of IVR use; and 24 hours post-IVR use (anticipated cycle length is 28 days)</time_frame>
    <description>Maximum CV fluid concentration of TFV</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Percent (%) inhibition of HIV resulting from product use (Anti-HIV activity)</measure>
    <time_frame>Baseline, Day 90 of IVR use</time_frame>
    <description>Anti-HIV and anti-HSV-2 activity in CV fluid (inhibition in cell assay)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Percent (%) inhibition of HSV resulting from product use (Anti-HSV activity)</measure>
    <time_frame>Baseline, Day 90 of IVR use</time_frame>
    <description>Anti-HSV-2 activity in CV fluid (inhibition in cell assay)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cervical mucus assessment and quality score</measure>
    <time_frame>Menstrual cycle 1, day 14; Menstrual cycle 3, day 14 (anticipated cycle length is 28 days)</time_frame>
    <description>Cervical mucus assessment and quality score (total summary score 0-15) as defined by WHO laboratory manual for the Examination and processing of human semen Fifth Edition, Appendix 5</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Confirmation of Ovulation</measure>
    <time_frame>Pre-IVR insertion; Menstrual cycle 1, day 20-25; Menstrual cycle 2, day 20-25; Day 90 of IVR use (anticipated cycle length is 28 days)</time_frame>
    <description>Serum progesterone (P4) level.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cervicovaginal (CV) fluid cytokines-IL-1α</measure>
    <time_frame>Change from Baseline to Day 90 of IVR use</time_frame>
    <description>Changes in IL-1α in CV fluid.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cervicovaginal (CV) fluid cytokines- IL-8</measure>
    <time_frame>Change from Baseline to Day 90 of IVR use</time_frame>
    <description>Changes in IL-8 in CV fluid.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in endogenous vaginal bacteria</measure>
    <time_frame>Change from Baseline to Day 90 of IVR use</time_frame>
    <description>Changes in endogenous vaginal bacteria in CV fluid</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in endogenous vaginal bacteria- Nugent score</measure>
    <time_frame>Change from Baseline to Day 90 of IVR use</time_frame>
    <description>Changes in Nugent score (score 0-10)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>qPCR of Ring Microbiota</measure>
    <time_frame>Day 90 of IVR use</time_frame>
    <description>Microbial growth on returned IVRs.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Tolerability - Somatic and non-specific non-treatment emergent adverse events</measure>
    <time_frame>Baseline; 6 and 24 hours post-IVR insertion; Menstrual cycle 1, day 14; Menstrual cycle 1, day 21-25; Menstrual cycle 2, day 21-25; Menstrual cycle 3, day 14; 90 days of IVR use; 24 hours post IVR use (anticipated cycle length is 28 days)</time_frame>
    <description>Subjective and objective assessment of new complaints (e.g., headache, nausea, weight change, breast tenderness, etc.)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Tolerability - Self-reported complaints of changes in menstrual cycle</measure>
    <time_frame>Screening; Menstrual cycle 1, day 14; Menstrual cycle 1, day 21-25; Menstrual cycle 2, day 21-25; Menstrual cycle 3, day 14; Day 90 of IVR use; 24 hours post-IVR use (anticipated cycle length is 28 days)</time_frame>
    <description>Percentage of women with changes in regularity of menstrual cycle</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Adherence - Drug concentrations</measure>
    <time_frame>Baseline; 6 and 24 hours post-IVR insertion; Menstrual cycle 1, day 14; Menstrual cycle 1, day 21-25; Menstrual cycle 2, day 21-25; Menstrual cycle 3, day 14; 90 days of IVR use; 24 hours post-IVR use (anticipated cycle length is 28 days)</time_frame>
    <description>Plasma, serum, and vaginal fluid drug concentrations.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Adherence - Residual drug concentrations</measure>
    <time_frame>Day 90 of IVR use</time_frame>
    <description>Residual drug (TFV and LNG) concentrations in returned TFV/LNG and TFV IVRs and residual excipients in returned placebo IVRs.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Adherence - Percentage of discontinuations</measure>
    <time_frame>Up to Day 90 of IVR use</time_frame>
    <description>Percentage of IVR discontinuations</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Acceptability - Quantitative assessment of acceptability based on Questionnaires administered pre- and post-IVR use</measure>
    <time_frame>Screening; 90 days of IVR use</time_frame>
    <description>Changes in responses to questionnaires pre- and post-IVR use on attitudes toward and perspectives of IVR use.</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Qualitative assessment of acceptability and adherence influences through In-depth interviews</measure>
    <time_frame>Between Menstrual cycle 2, day 21-25 and Menstrual cycle 3, day 14 (anticipated cycle length is 28 days)</time_frame>
    <description>In-depth interviews</description>
  </other_outcome>
  <number_of_arms>3</number_of_arms>
  <enrollment type="Anticipated">50</enrollment>
  <condition>HIV</condition>
  <condition>Contraception</condition>
  <condition>Prevention</condition>
  <condition>Anti-Retroviral Agent</condition>
  <arm_group>
    <arm_group_label>TFV/LNG IVR (10mg/20μg) (Continuous)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Tenofovir/Levonorgestrel Intravaginal Ring</description>
  </arm_group>
  <arm_group>
    <arm_group_label>TFV IVR (10mg) (Continuous)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Tenofovir Intravaginal Ring</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo IVR (Non-eluting)</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Placebo Intravaginal Ring</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>TFV/LNG IVR</intervention_name>
    <description>TFV/LNG IVR is an intravaginal ring that releases approximately 8-10 mg/day of TFV and approximately 20ug/day of LNG to be used for 90 continuous days.</description>
    <arm_group_label>TFV/LNG IVR (10mg/20μg) (Continuous)</arm_group_label>
    <other_name>Tenofovir/Levonorgestrel Intravaginal Ring</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>TFV IVR</intervention_name>
    <description>TFV IVR is an intravaginal ring that releases approximately 8-10mg/day of TFV to be used for 90 continuous days.</description>
    <arm_group_label>TFV IVR (10mg) (Continuous)</arm_group_label>
    <other_name>Tenofovir Intravaginal Ring</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo IVR</intervention_name>
    <description>Placebo IVR is an intravaginal ring containing no active experimental ingredients to be used for 90 continuous days.</description>
    <arm_group_label>Placebo IVR (Non-eluting)</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Female, aged 18-34 years, inclusive&#xD;
&#xD;
          -  General good health (by history and per clinician discretion) without any clinically&#xD;
             significant systemic disease (including, but not limited to significant liver&#xD;
             disease/hepatitis, gastrointestinal disease, kidney disease, thyroid disease,&#xD;
             osteoporosis or bone disease, and diabetes), uterus, and cervix&#xD;
&#xD;
          -  Not pregnant or planning to become pregnant&#xD;
&#xD;
          -  Pre-screening HIV risk score ≤4&#xD;
&#xD;
          -  Currently having regular menstrual cycles (approximately 24-35 days) OR with a history&#xD;
             of having regular menstrual cycles before contraceptive use, by report, and resumed&#xD;
             some menstruation or spotting (with biochemical confirmation of ovulation)&#xD;
&#xD;
          -  Willing to undergo Visual Inspection with Lugol's Iodine (VILI) for cervical&#xD;
             abnormalities during pelvic exam&#xD;
&#xD;
          -  Willing to abstain from use of vaginal products other than the study product,&#xD;
             including tampons (except for during menses) , menstrual cups, vaginally inserted&#xD;
             cloths or other materials, spermicides, lubricants, and douches for the whole study&#xD;
&#xD;
          -  Willing to abstain from any vaginal intercourse starting 48 hours before certain study&#xD;
             visits&#xD;
&#xD;
          -  Vaginal and cervical anatomy that, in the opinion of the clinician, lends itself to&#xD;
             easy genital tract sample collection and is absent of vesicles and ulcers&#xD;
&#xD;
          -  No use of hormonal contraceptives within the following periods specified for each type&#xD;
             of contraception method:&#xD;
&#xD;
               -  Oral contraceptives (combined or progestin-only), contraceptive patch or&#xD;
                  contraceptive vaginal ring in at least two (2) months&#xD;
&#xD;
               -  Last DMPA injection received at least four (4) months ago and has resumed regular&#xD;
                  menstruation&#xD;
&#xD;
               -  Hormonal IUD/IUS removed at least four (4) months ago and has resumed regular&#xD;
                  menstruation&#xD;
&#xD;
               -  Hormonal implant removed at least six (6) months ago and has resumed regular&#xD;
                  menstruation&#xD;
&#xD;
          -  Willing to refrain from using any hormonal contraceptives for the entire study and to&#xD;
             use only study-provided non-spermicidal male condoms with or without a study-provided&#xD;
             Cu-IUD&#xD;
&#xD;
          -  P4 ≥3.0 ng/ml&#xD;
&#xD;
          -  Estimated glomerular filtration rate (eGFR) ≥90ml/min/1.73m2&#xD;
&#xD;
          -  Willing to give voluntary consent and sign/mark an informed consent form&#xD;
&#xD;
          -  Willing and able to comply with protocol requirements&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Body mass index (BMI) ≥30 kg/m&#xD;
&#xD;
          -  History of hysterectomy&#xD;
&#xD;
          -  Currently pregnant or within less than three (3) calendar months of the last pregnancy&#xD;
             outcome.&#xD;
&#xD;
          -  Currently breastfeeding or having breastfed an infant in the last two (2) months, or&#xD;
             planning to breastfeed during the course of the study&#xD;
&#xD;
          -  Contraindication to any study products-LNG, TFV, or excipient ingredients&#xD;
&#xD;
          -  Contraindication to LNG&#xD;
&#xD;
          -  In the last three (3) months, diagnosed with or treated for any STI or pelvic&#xD;
             inflammatory disease&#xD;
&#xD;
          -  Positive test for HIV-1, syphilis, Trichomonas vaginalis (TV), Neisseria gonorrhea&#xD;
             (GC), Chlamydia trachomatis (CT) or HBsAg&#xD;
&#xD;
          -  Nugent score greater than or equal to 7 or a symptomatic BV clinical diagnosis as&#xD;
             defined by Amsel's criteria&#xD;
&#xD;
          -  Suspected breast cancer or other progestin-sensitive cancer&#xD;
&#xD;
          -  Suspected hepatic disease, including cirrhosis or viral hepatitis&#xD;
&#xD;
          -  History of bleeding or coagulation problems&#xD;
&#xD;
          -  Known current drug or alcohol abuse which could impact study compliance&#xD;
&#xD;
          -  Grade 2 or higher laboratory abnormality, per the Division of AIDS, National Institute&#xD;
             of Allergy and Infectious Disease (DAIDS) Table for Grading the Severity of Adverse&#xD;
             Events, or clinically significant laboratory abnormality as determined by the&#xD;
             clinician&#xD;
&#xD;
          -  Use of any concomitant medications&#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;
          -  Labial elongation (due to pulling practices and use of botanicals or caustic agents)&#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 site co-PI(s), would make&#xD;
             participation in the study unsafe or would complicate interpretation of data&#xD;
&#xD;
          -  Currently using, or has used within the preceding one (1) month,&#xD;
             emtricitabine/tenofovir disoproxil fumarate (TDF/FTC or Truvada®) or any other&#xD;
             tenofovir product, and/or has plans to use a non-study tenofovir product in any form&#xD;
             during the study&#xD;
      </textblock>
    </criteria>
    <gender>Female</gender>
    <gender_based>Yes</gender_based>
    <gender_description>Healthy, non-pregnant females of reproductive potential, ovulating and not using non-study hormonal contraception during the study period.</gender_description>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>34 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Nelly R. Mugo, MBChB</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Washington</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Kenya Medical Research Institute, Center for Global Health Research</name>
      <address>
        <city>Kisumu</city>
        <state>Kisumu County</state>
        <zip>40100</zip>
        <country>Kenya</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Kenya</country>
  </location_countries>
  <reference>
    <citation>Thurman AR, Schwartz JL, Brache V, Clark MR, McCormick T, Chandra N, Marzinke MA, Stanczyk FZ, Dezzutti CS, Hillier SL, Herold BC, Fichorova R, Asin SN, Rollenhagen C, Weiner D, Kiser P, Doncel GF. Randomized, placebo controlled phase I trial of safety, pharmacokinetics, pharmacodynamics and acceptability of tenofovir and tenofovir plus levonorgestrel vaginal rings in women. PLoS One. 2018 Jun 28;13(6):e0199778. doi: 10.1371/journal.pone.0199778. eCollection 2018.</citation>
    <PMID>29953547</PMID>
  </reference>
  <verification_date>January 2020</verification_date>
  <study_first_submitted>November 16, 2018</study_first_submitted>
  <study_first_submitted_qc>November 30, 2018</study_first_submitted_qc>
  <study_first_posted type="Actual">December 3, 2018</study_first_posted>
  <last_update_submitted>January 13, 2020</last_update_submitted>
  <last_update_submitted_qc>January 13, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">January 14, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Intravaginal Ring</keyword>
  <keyword>HIV Prevention</keyword>
  <keyword>Tenofovir</keyword>
  <keyword>Levonorgestrel</keyword>
  <keyword>Pregnancy 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>
    <ipd_description>Data sharing will comply with CDC's current Policy on Public Health Research and Non-research Data Management and Access. Except for the analyses outlined in the study protocol, all future requests to perform new analyses on data or specimens from this study protocol will require (1) agreement of all Parties owning or jointly owning the data and (2) Ethics Committee approval.</ipd_description>
  </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/NCT03762382
org study id: Protocol B17-144
secondary id: RFA-PS-17-005
secondary id: AID-OAA-A-14-000010
nct id: NCT03762382
lead sponsor: 
collaborator: 
collaborator: 
collaborator: 
has dmc: No
is fda regulated drug: Yes
is fda regulated device: No
The purpose of the study is to evaluate the safety, pharmacokinetics and pharmacodynamics of,
      and the tolerability and acceptance of an intravaginal ring (IVR) delivering both tenofovir
      and levonorgestrel (TFV/LNG) and an IVR delivering TFV only, compared to a placebo IVR, in
      women in Western Kenya.
This Phase 2a clinical trial will evaluate the safety, pharmacokinetics and pharmacodynamics
      of, and the tolerability and adherence to two novel intravaginal rings (IVRs). The
      tenofovir/levonorgestrel (TFV/LNG) IVR and TFV IVRs are designed to provide HIV (and HSV-2)
      prevention with and without contraceptive for pregnancy prevention, respectively. Women will
      be protected from pregnancy by abstinence from vaginal intercourse or agreeing to
      consistently use condoms; concurrent use of a non-hormonal copper intrauterine device is
      permitted.

      The study will enroll healthy, HIV-negative, non-pregnant, menstruating women aged 18-34
      years, inclusive, and not currently infected with hepatitis B virus, who are assessed to be
      at lower risk for HIV. The goal is to enroll fifty (50) women in Western Kenya. The
      participants will be randomized 2:2:1 to use one of the following continuous delivery IVRs:
      twenty (20) women to use the TFV/LNG IVR; ten (10) women to use the TFV IVR; and ten (10)
      women to use the placebo IVR. Participants will attend up to ten (10) routine study visits
      that may include physical and pelvic exams, collection of venous blood, vaginal fluid and
      cervical mucus, and behavioral questionnaires. A subset of twenty (20) women will participate
      in in-depth interviews.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Prevention
masking: Triple (Participant, Care Provider, Investigator)
measure: Treatment-emergent adverse events (TEAEs)
time frame: Change from Baseline to up to 90 days of IVR use
description: Participants with Grade 2 or higher local female genital TEAEs as defined by DAIDS Table for Grading the Severity of Adult and Pediatric AEs (version 2.1) and DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events Addendum 1 Female Genital Grading Table for Use in Microbicide Studies
measure: Safety Laboratory Assessments- Serum chemistry
time frame: Change from Baseline to up to 90 days of IVR use
description: Number of participants with abnormal serum chemistry
measure: Safety Laboratory Assessments- lipids
time frame: Change from Baseline to up to 90 days of IVR use
description: Number of participants with abnormal lipids
measure: Safety Laboratory Assessments- complete blood counts
time frame: Change from Baseline to up to 90 days of IVR use
description: Number of participants with abnormal complete blood counts
measure: Mucosal safety
time frame: Change from Baseline to up to 90 days of IVR use
description: Changes in cervicovaginal mucosa by visual inspection
measure: Maximum blood concentrations (Cmax)
time frame: Baseline; 6 and 24 hours post IVR insertion; Menstrual cycle 1, day 14; Menstrual cycle 1,day 21-25; Menstrual cycle 2, day 21-25; Menstrual cycle 3, day 14; Day 90 IVR use; 24 hours post-IVR use (anticipated cycle length is 28 days)
description: Maximum plasma concentration of TFV and maximum serum concentration of LNG
measure: Maximum CV fluid concentration
time frame: 6 and 24 hours post-IVR insertion; Menstrual cycle 1 day 14; Menstrual cycle 1 day 21-25; Menstrual cycle 2 day 21-25; Menstrual cycle 3, day 14; Day 90 of IVR use; and 24 hours post-IVR use (anticipated cycle length is 28 days)
description: Maximum CV fluid concentration of TFV
measure: Percent (%) inhibition of HIV resulting from product use (Anti-HIV activity)
time frame: Baseline, Day 90 of IVR use
description: Anti-HIV and anti-HSV-2 activity in CV fluid (inhibition in cell assay)
measure: Percent (%) inhibition of HSV resulting from product use (Anti-HSV activity)
time frame: Baseline, Day 90 of IVR use
description: Anti-HSV-2 activity in CV fluid (inhibition in cell assay)
measure: Cervical mucus assessment and quality score
time frame: Menstrual cycle 1, day 14; Menstrual cycle 3, day 14 (anticipated cycle length is 28 days)
description: Cervical mucus assessment and quality score (total summary score 0-15) as defined by WHO laboratory manual for the Examination and processing of human semen Fifth Edition, Appendix 5
measure: Confirmation of Ovulation
time frame: Pre-IVR insertion; Menstrual cycle 1, day 20-25; Menstrual cycle 2, day 20-25; Day 90 of IVR use (anticipated cycle length is 28 days)
description: Serum progesterone (P4) level.
measure: Cervicovaginal (CV) fluid cytokines-IL-1α
time frame: Change from Baseline to Day 90 of IVR use
description: Changes in IL-1α in CV fluid.
measure: Cervicovaginal (CV) fluid cytokines- IL-8
time frame: Change from Baseline to Day 90 of IVR use
description: Changes in IL-8 in CV fluid.
measure: Changes in endogenous vaginal bacteria
time frame: Change from Baseline to Day 90 of IVR use
description: Changes in endogenous vaginal bacteria in CV fluid
measure: Changes in endogenous vaginal bacteria- Nugent score
time frame: Change from Baseline to Day 90 of IVR use
description: Changes in Nugent score (score 0-10)
measure: qPCR of Ring Microbiota
time frame: Day 90 of IVR use
description: Microbial growth on returned IVRs.
measure: Tolerability - Somatic and non-specific non-treatment emergent adverse events
time frame: Baseline; 6 and 24 hours post-IVR insertion; Menstrual cycle 1, day 14; Menstrual cycle 1, day 21-25; Menstrual cycle 2, day 21-25; Menstrual cycle 3, day 14; 90 days of IVR use; 24 hours post IVR use (anticipated cycle length is 28 days)
description: Subjective and objective assessment of new complaints (e.g., headache, nausea, weight change, breast tenderness, etc.)
measure: Tolerability - Self-reported complaints of changes in menstrual cycle
time frame: Screening; Menstrual cycle 1, day 14; Menstrual cycle 1, day 21-25; Menstrual cycle 2, day 21-25; Menstrual cycle 3, day 14; Day 90 of IVR use; 24 hours post-IVR use (anticipated cycle length is 28 days)
description: Percentage of women with changes in regularity of menstrual cycle
measure: Adherence - Drug concentrations
time frame: Baseline; 6 and 24 hours post-IVR insertion; Menstrual cycle 1, day 14; Menstrual cycle 1, day 21-25; Menstrual cycle 2, day 21-25; Menstrual cycle 3, day 14; 90 days of IVR use; 24 hours post-IVR use (anticipated cycle length is 28 days)
description: Plasma, serum, and vaginal fluid drug concentrations.
measure: Adherence - Residual drug concentrations
time frame: Day 90 of IVR use
description: Residual drug (TFV and LNG) concentrations in returned TFV/LNG and TFV IVRs and residual excipients in returned placebo IVRs.
measure: Adherence - Percentage of discontinuations
time frame: Up to Day 90 of IVR use
description: Percentage of IVR discontinuations
measure: Acceptability - Quantitative assessment of acceptability based on Questionnaires administered pre- and post-IVR use
time frame: Screening; 90 days of IVR use
description: Changes in responses to questionnaires pre- and post-IVR use on attitudes toward and perspectives of IVR use.
measure: Qualitative assessment of acceptability and adherence influences through In-depth interviews
time frame: Between Menstrual cycle 2, day 21-25 and Menstrual cycle 3, day 14 (anticipated cycle length is 28 days)
description: In-depth interviews
arm group label: TFV/LNG IVR (10mg/20μg) (Continuous)
arm group type: Experimental
description: Tenofovir/Levonorgestrel Intravaginal Ring
arm group label: TFV IVR (10mg) (Continuous)
arm group type: Experimental
description: Tenofovir Intravaginal Ring
arm group label: Placebo IVR (Non-eluting)
arm group type: Placebo Comparator
description: Placebo Intravaginal Ring
intervention type: Drug
intervention name: TFV/LNG IVR
description: TFV/LNG IVR is an intravaginal ring that releases approximately 8-10 mg/day of TFV and approximately 20ug/day of LNG to be used for 90 continuous days.
arm group label: TFV/LNG IVR (10mg/20μg) (Continuous)
other name: Tenofovir/Levonorgestrel Intravaginal Ring
intervention type: Drug
intervention name: TFV IVR
description: TFV IVR is an intravaginal ring that releases approximately 8-10mg/day of TFV to be used for 90 continuous days.
arm group label: TFV IVR (10mg) (Continuous)
other name: Tenofovir Intravaginal Ring
intervention type: Drug
intervention name: Placebo IVR
description: Placebo IVR is an intravaginal ring containing no active experimental ingredients to be used for 90 continuous days.
arm group label: Placebo IVR (Non-eluting)
criteria: 
gender: Female
gender based: Yes
gender description: Healthy, non-pregnant females of reproductive potential, ovulating and not using non-study hormonal contraception during the study period.
minimum age: 18 Years
maximum age: 34 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Nelly R. Mugo, MBChB
role: Principal Investigator
affiliation: University of Washington
facility: 
country: Kenya
citation: Thurman AR, Schwartz JL, Brache V, Clark MR, McCormick T, Chandra N, Marzinke MA, Stanczyk FZ, Dezzutti CS, Hillier SL, Herold BC, Fichorova R, Asin SN, Rollenhagen C, Weiner D, Kiser P, Doncel GF. Randomized, placebo controlled phase I trial of safety, pharmacokinetics, pharmacodynamics and acceptability of tenofovir and tenofovir plus levonorgestrel vaginal rings in women. PLoS One. 2018 Jun 28;13(6):e0199778. doi: 10.1371/journal.pone.0199778. eCollection 2018.
PMID: 29953547
responsible party type: Sponsor
mesh term: Tenofovir
mesh term: Levonorgestrel
sharing ipd: No
ipd description: Data sharing will comply with CDC's current Policy on Public Health Research and Non-research Data Management and Access. Except for the analyses outlined in the study protocol, all future requests to perform new analyses on data or specimens from this study protocol will require (1) agreement of all Parties owning or jointly owning the data and (2) Ethics Committee approval.