<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/NCT03762772</url>
  </required_header>
  <id_info>
    <org_study_id>A18-146</org_study_id>
    <nct_id>NCT03762772</nct_id>
  </id_info>
  <brief_title>Safety, PK, and PD Study of a Vaginal Insert Containing TAF and EVG</brief_title>
  <official_title>A Phase I Study to Assess Safety, Pharmacokinetics, and Pharmacodynamics of a Vaginal Insert Containing Tenofovir Alafenamide and Elvitegravir</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>CONRAD</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Eastern Virginia Medical School</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>United States Agency for International Development (USAID)</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>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      The purpose of this Phase I study is to assess the safety, pharmacokinetics, and&#xD;
      pharmacodynamics of a combination vaginal insert containing tenofovir alafenamide (TAF) and&#xD;
      elvitegravir (EVG).&#xD;
&#xD;
      This study will be the first-in-human study for a vaginally administered TAF/EVG insert and&#xD;
      will evaluate safety, PK and PD after a single dose. It is hypothesized that the combination&#xD;
      insert will be safe and well-tolerated by study participants and that the insert will offer&#xD;
      an expanded window of preventive activity and a regimen with flexibility and forgiveness.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This Phase I study aims to complete at least 16 healthy, non-pregnant, HIV-uninfected women&#xD;
      aged 18-50 years who are not at risk for pregnancy and are at low risk for sexually&#xD;
      transmitted infections (STIs) at one clinical site. The study will examine the safety, PK,&#xD;
      PD, disintegration, and acceptability of vaginal inserts containing the combination of&#xD;
      tenofovir alafenamide (TAF) and elvitegravir (EVG).&#xD;
&#xD;
      Participants will be randomized (1:1) into one of two sample collection time point groups:&#xD;
&#xD;
      [Timepoint group 1: 4 and 48 hours after using the single combination insert] or [Timepoint&#xD;
      group 2: 24 and 72 hours after using the single combination insert]&#xD;
&#xD;
      There will be 5 scheduled visits:&#xD;
&#xD;
      Visit 1 (Screening/Enrollment): Volunteers will be consented and undergo tests and procedures&#xD;
      to confirm they are eligible to continue in the study.&#xD;
&#xD;
      Visit 2 (Baseline): Once it has been confirmed that participants are eligible and willing to&#xD;
      continue, they will be asked to complete a short baseline questionnaire about the insert.&#xD;
      Participants will be randomized to Timepoint group 1 or Timepoint group 2 for sample&#xD;
      collection and will then undergo baseline sampling [cervicovaginal (CV) fluid and tissue].&#xD;
&#xD;
      Visit 3 (Insert use and sampling): Participants will use a single combination insert of&#xD;
      TAF/EVG in the clinic. Depending upon timepoint randomization, percentage disintegration of&#xD;
      the vaginal inserts will be assessed at either 4 hours or 24 hours, and PK and PD sample&#xD;
      collection (plasma, CV fluid, and CV tissue) will occur. Participants will also be asked to&#xD;
      complete a short acceptability questionnaire.&#xD;
&#xD;
      Visit 4 (Post-Dose Sampling): Participants will undergo sample collection of blood for safety&#xD;
      and PK evaluations; and CV fluid and CV tissue for PK at either 48 hours or 72 hours&#xD;
      depending upon timepoint randomization.&#xD;
&#xD;
      Visit 5 (Post-Dose Sampling): Participants will undergo a PK sample collection (CV fluid) 7&#xD;
      (±2) days post dose. Participants will be asked about adverse events and concomitant&#xD;
      medications taken. Participants will then be exited from the study, unless they have symptoms&#xD;
      that require follow-up.&#xD;
&#xD;
      There will be 5 scheduled visits over approximately 1-3 months.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">December 10, 2018</start_date>
  <completion_date type="Actual">March 20, 2019</completion_date>
  <primary_completion_date type="Actual">March 20, 2019</primary_completion_date>
  <phase>Phase 1</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>
    <intervention_model_description>All participants will use a single combination TAF/EVG vaginal insert.</intervention_model_description>
    <primary_purpose>Prevention</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Number of Participants with Grade 2 or higher treatment-emergent adverse events (TEAEs)</measure>
    <time_frame>Changes from baseline up to a maximum of 12 days post-dose</time_frame>
    <description>TEAEs are defined as adverse events starting or worsening after administration of the study product; Grade is determined by the DAIDS Grading Table</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Number of participants with adverse events</measure>
    <time_frame>Changes from baseline up to a maximum of 12 days post-dose</time_frame>
    <description>Adverse events for this outcome are those that are product-related urogenital in nature</description>
  </primary_outcome>
  <primary_outcome>
    <measure>systemic laboratory assessments</measure>
    <time_frame>Changes from baseline up to 72 hours post-dose</time_frame>
    <description>Number of participants with abnormal serum chemistry</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Systemic Laboratory Assessments</measure>
    <time_frame>Changes from baseline up to 72 hours post-dose</time_frame>
    <description>Number of participants with abnormal complete blood count</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Drug Concentrations of EVG, TFV, and TAF</measure>
    <time_frame>From dosing to 72 hours post-dose</time_frame>
    <description>Concentrations of EVG, TFV, and TAF in plasma</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Drug Concentrations of EVG, TFV, and TAF</measure>
    <time_frame>From dosing to a maximum of 12 days post-dose</time_frame>
    <description>Concentrations of EVG, TFV, and TAF in CV fluid</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Drug Concentrations of EVG, TFV, TFV-DP, and TAF</measure>
    <time_frame>From dosing to 72 hours post-dose</time_frame>
    <description>Concentrations of EVG, TFV, TFV-DP, TAF in CV tissue</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Percent (%) inhibition of HIV in vaginal cell assay (Anti-HIV activity)</measure>
    <time_frame>Changes from baseline to 24 hours post-dose</time_frame>
    <description>Anti-HIV activity in CV fluid</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Percent (%) inhibition of HSV in vaginal cell assay (Anti-HSV activity)</measure>
    <time_frame>Changes from baseline to 24 hours post-dose</time_frame>
    <description>Anti-HSV activity in CV fluid</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of participant tissue samples demonstrating HIV-1 infectivity</measure>
    <time_frame>Changes from baseline to 4 hours post-dose</time_frame>
    <description>p24 antigen production in CV tissue infected with HIV-1 ex vivo</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Disintegration of insert</measure>
    <time_frame>At 4 or 24 hours post-dose (per randomized time point)</time_frame>
    <description>Percent (%) disintegration at the first evaluation after dosing</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Acceptability of insert: questionnaire</measure>
    <time_frame>At baseline and at 48 or 72 hours post-dose (per randomized time point)</time_frame>
    <description>Responses to key questions on acceptability questionnaire (including prior experience with vaginal product use, initial and post-use impressions of insert, dissolution time, discharge amounts, and feelings about real-world use if insert was available for use</description>
  </secondary_outcome>
  <other_outcome>
    <measure>HSV infectivity</measure>
    <time_frame>Changes from baseline to 24 hours post-dose</time_frame>
    <description>HSV DNA fold change after ex vivo infection of CV tissue with HSV</description>
  </other_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">16</enrollment>
  <condition>Hiv</condition>
  <condition>HSV</condition>
  <arm_group>
    <arm_group_label>TAF/EVG vaginal insert</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Post-dose sampling at 4 and 48 hours or at 24 and 72 hours, per randomization</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>TAF/EVG Vaginal Insert</intervention_name>
    <description>1 combination vaginal insert (20mg TAF/16mg EVG)</description>
    <arm_group_label>TAF/EVG vaginal insert</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Age 18 to 50 years, inclusive&#xD;
&#xD;
          2. General good health (by volunteer history and per investigator judgment) without any&#xD;
             clinically significant systemic disease (including, but not limited to significant&#xD;
             liver disease/hepatitis, gastrointestinal disease, kidney disease, thyroid disease,&#xD;
             bone disease, and diabetes) and with an intact uterus and cervix.&#xD;
&#xD;
          3. History of regular menstrual cycles, by volunteer report (for cycling women)&#xD;
&#xD;
          4. 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;
          5. Able to communicate in spoken and written English&#xD;
&#xD;
          6. Willing to give voluntary consent and sign an informed consent form&#xD;
&#xD;
          7. Willing and able to comply with protocol requirements, including abstaining from&#xD;
             vaginal activity and product use at specified times&#xD;
&#xD;
          8. Must be protected from pregnancy by one of the following:&#xD;
&#xD;
               -  Hormonal methods, except vaginal rings and DMPA&#xD;
&#xD;
               -  Copper IUD&#xD;
&#xD;
               -  Sterilization of participant or partner&#xD;
&#xD;
               -  Consistent condom use&#xD;
&#xD;
               -  Abstinence from penile-vaginal intercourse&#xD;
&#xD;
               -  Same sex relationship&#xD;
&#xD;
          9. If in a relationship, must be in a mutually monogamous relationship with a partner who&#xD;
             is not known to be HIV positive and has no known risk of sexually transmitted&#xD;
             infections (STIs)&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Positive pregnancy test or plans to become pregnant during the course of the study&#xD;
&#xD;
          2. Currently breastfeeding or planning to breastfeed during the course of the study&#xD;
&#xD;
          3. History of sensitivity/allergy to any component of the study product, topical&#xD;
             anesthetic, or to both silver nitrate and Monsel's solution&#xD;
&#xD;
          4. In the last three months, diagnosed with or treated for any STI (For HSV, ideally no&#xD;
             outbreaks in the past year. More than two outbreaks in previous 12 month period is&#xD;
             exclusionary.)&#xD;
&#xD;
          5. Positive test for Trichomonas vaginalis (TV), Neisseria gonorrhea (GC), Chlamydia&#xD;
             trachomatis (CT), HIV, or Hepatitis B surface antigen (HBsAg)&#xD;
&#xD;
          6. Symptomatic bacterial vaginosis (BV)&#xD;
&#xD;
          7. Chronic or acute vulvar or vaginal symptoms (pain, irritation, spotting/bleeding,&#xD;
             discharge, etc.)&#xD;
&#xD;
          8. Known blood 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;
          9. NSAIDS, systemic corticosteroids (e.g. dexamethasone), Endothelin Receptor Antagonists&#xD;
             (e.g bosentan), antibiotics, Anticonvulsants (e.g. carbamazepine, oxcarbazepine,&#xD;
             phenobarbital, phenytoin), Antimycobacterials (Rifbutin, Rifampin, Rifapentine)&#xD;
             anticoagulants or other drugs known to prolong bleeding and/or clotting, antifungals&#xD;
             (i.e ketoconazole), or antivirals or antiretroviral (e.g. acyclovir, valacyclovir,&#xD;
             Viread®, Atripla®, Emtriva®, or Complera®), St. John's Wort or drugs that may interact&#xD;
             with TAF or EVG as specified in the Vitekta and Vemlidy Investigator Brochure, should&#xD;
             not be used during the study.&#xD;
&#xD;
         10. Current or anticipated chronic use of non-steroidal anti-inflammatory drugs (NSAIDs)&#xD;
             or acetominophen for the duration of the study.&#xD;
&#xD;
         11. 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;
         12. 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;
         13. 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>Medical Director</last_name>
    <role>Study Director</role>
    <affiliation>CONRAD</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Clinical Research Center at Eastern Virginia Medical School (NOT RECRUITING ADDITIONAL SITES)</name>
      <address>
        <city>Norfolk</city>
        <state>Virginia</state>
        <zip>23507</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>July 2019</verification_date>
  <study_first_submitted>November 16, 2018</study_first_submitted>
  <study_first_submitted_qc>December 3, 2018</study_first_submitted_qc>
  <study_first_posted type="Actual">December 4, 2018</study_first_posted>
  <last_update_submitted>July 15, 2019</last_update_submitted>
  <last_update_submitted_qc>July 15, 2019</last_update_submitted_qc>
  <last_update_posted type="Actual">July 16, 2019</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>HIV</keyword>
  <keyword>TAF</keyword>
  <keyword>EVG</keyword>
  <keyword>Prevention</keyword>
  <keyword>Vaginal Insert</keyword>
  <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/NCT03762772
org study id: A18-146
nct id: NCT03762772
lead sponsor: 
collaborator: 
collaborator: 
has dmc: No
is fda regulated drug: Yes
is fda regulated device: No
is us export: No
The purpose of this Phase I study is to assess the safety, pharmacokinetics, and
      pharmacodynamics of a combination vaginal insert containing tenofovir alafenamide (TAF) and
      elvitegravir (EVG).

      This study will be the first-in-human study for a vaginally administered TAF/EVG insert and
      will evaluate safety, PK and PD after a single dose. It is hypothesized that the combination
      insert will be safe and well-tolerated by study participants and that the insert will offer
      an expanded window of preventive activity and a regimen with flexibility and forgiveness.
This Phase I study aims to complete at least 16 healthy, non-pregnant, HIV-uninfected women
      aged 18-50 years who are not at risk for pregnancy and are at low risk for sexually
      transmitted infections (STIs) at one clinical site. The study will examine the safety, PK,
      PD, disintegration, and acceptability of vaginal inserts containing the combination of
      tenofovir alafenamide (TAF) and elvitegravir (EVG).

      Participants will be randomized (1:1) into one of two sample collection time point groups:

      [Timepoint group 1: 4 and 48 hours after using the single combination insert] or [Timepoint
      group 2: 24 and 72 hours after using the single combination insert]

      There will be 5 scheduled visits:

      Visit 1 (Screening/Enrollment): Volunteers will be consented and undergo tests and procedures
      to confirm they are eligible to continue in the study.

      Visit 2 (Baseline): Once it has been confirmed that participants are eligible and willing to
      continue, they will be asked to complete a short baseline questionnaire about the insert.
      Participants will be randomized to Timepoint group 1 or Timepoint group 2 for sample
      collection and will then undergo baseline sampling [cervicovaginal (CV) fluid and tissue].

      Visit 3 (Insert use and sampling): Participants will use a single combination insert of
      TAF/EVG in the clinic. Depending upon timepoint randomization, percentage disintegration of
      the vaginal inserts will be assessed at either 4 hours or 24 hours, and PK and PD sample
      collection (plasma, CV fluid, and CV tissue) will occur. Participants will also be asked to
      complete a short acceptability questionnaire.

      Visit 4 (Post-Dose Sampling): Participants will undergo sample collection of blood for safety
      and PK evaluations; and CV fluid and CV tissue for PK at either 48 hours or 72 hours
      depending upon timepoint randomization.

      Visit 5 (Post-Dose Sampling): Participants will undergo a PK sample collection (CV fluid) 7
      (±2) days post dose. Participants will be asked about adverse events and concomitant
      medications taken. Participants will then be exited from the study, unless they have symptoms
      that require follow-up.

      There will be 5 scheduled visits over approximately 1-3 months.
allocation: N/A
intervention model: Single Group Assignment
intervention model description: All participants will use a single combination TAF/EVG vaginal insert.
primary purpose: Prevention
masking: None (Open Label)
measure: Number of Participants with Grade 2 or higher treatment-emergent adverse events (TEAEs)
time frame: Changes from baseline up to a maximum of 12 days post-dose
description: TEAEs are defined as adverse events starting or worsening after administration of the study product; Grade is determined by the DAIDS Grading Table
measure: Number of participants with adverse events
time frame: Changes from baseline up to a maximum of 12 days post-dose
description: Adverse events for this outcome are those that are product-related urogenital in nature
measure: systemic laboratory assessments
time frame: Changes from baseline up to 72 hours post-dose
description: Number of participants with abnormal serum chemistry
measure: Systemic Laboratory Assessments
time frame: Changes from baseline up to 72 hours post-dose
description: Number of participants with abnormal complete blood count
measure: Drug Concentrations of EVG, TFV, and TAF
time frame: From dosing to 72 hours post-dose
description: Concentrations of EVG, TFV, and TAF in plasma
measure: Drug Concentrations of EVG, TFV, and TAF
time frame: From dosing to a maximum of 12 days post-dose
description: Concentrations of EVG, TFV, and TAF in CV fluid
measure: Drug Concentrations of EVG, TFV, TFV-DP, and TAF
time frame: From dosing to 72 hours post-dose
description: Concentrations of EVG, TFV, TFV-DP, TAF in CV tissue
measure: Percent (%) inhibition of HIV in vaginal cell assay (Anti-HIV activity)
time frame: Changes from baseline to 24 hours post-dose
description: Anti-HIV activity in CV fluid
measure: Percent (%) inhibition of HSV in vaginal cell assay (Anti-HSV activity)
time frame: Changes from baseline to 24 hours post-dose
description: Anti-HSV activity in CV fluid
measure: Number of participant tissue samples demonstrating HIV-1 infectivity
time frame: Changes from baseline to 4 hours post-dose
description: p24 antigen production in CV tissue infected with HIV-1 ex vivo
measure: Disintegration of insert
time frame: At 4 or 24 hours post-dose (per randomized time point)
description: Percent (%) disintegration at the first evaluation after dosing
measure: Acceptability of insert: questionnaire
time frame: At baseline and at 48 or 72 hours post-dose (per randomized time point)
description: Responses to key questions on acceptability questionnaire (including prior experience with vaginal product use, initial and post-use impressions of insert, dissolution time, discharge amounts, and feelings about real-world use if insert was available for use
measure: HSV infectivity
time frame: Changes from baseline to 24 hours post-dose
description: HSV DNA fold change after ex vivo infection of CV tissue with HSV
arm group label: TAF/EVG vaginal insert
arm group type: Experimental
description: Post-dose sampling at 4 and 48 hours or at 24 and 72 hours, per randomization
intervention type: Drug
intervention name: TAF/EVG Vaginal Insert
description: 1 combination vaginal insert (20mg TAF/16mg EVG)
arm group label: TAF/EVG vaginal insert
criteria: 
gender: Female
gender based: Yes
minimum age: 18 Years
maximum age: 50 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Medical Director
role: Study Director
affiliation: CONRAD
facility: 
country: United States
responsible party type: Sponsor
sharing ipd: No