Safety, Pharmacokinetics, Pharmacodynamics, and Disintegration Time of Vaginal Tablets Containing Tenofovir and/or Emtricitabine

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
CONRAD
ClinicalTrials.gov Identifier:
NCT01694407
First received: July 17, 2012
Last updated: December 11, 2013
Last verified: December 2013
  Purpose

This prospective, double-blinded, randomized, parallel cohort study will examine the genital and systemic safety, pharmacokinetics (PK), pharmacodynamics (PD), disintegration and disappearance times, and acceptability of four vaginal tablets: 1) Tenofovir (TFV) alone; 2) Emtricitabine (FTC) alone; 3) TFV combined with FTC; and 4) placebo. Participants will be randomized to treatment group, to number of tablets to be inserted in the Single Use Phase (1 tablet or 1 tablet followed by a second tablet two hours later to mimic the BAT24 dosing regimen), and to one of four collection time points (2, 4, 6, or 24 hours after tablet insertion) for assessments only after the last dose of the Multiple Use Phase.

In the Single Use Phase of the study, the participant will insert one tablet in the clinic to estimate times to disintegration and disappearance. Those randomized to two tablets will insert a second tablet 2 hours later. In all women, sample collection will occur 5 hours after the initial tablet insertion.

In the Multiple Use Phase of the study, participants will insert a tablet once daily for 14 days. The 1st, 7th, and 14th tablets will be inserted in the clinic; the remaining tablets will be inserted at home. Each insertion in the clinic will be followed sample collection and, at Visits 4 and 6, colposcopy at the participant's assigned time point.


Condition Intervention Phase
HIV
Drug: Tenofovir (TFV) Alone Vaginal Tablet
Drug: Emtricitabine (FTC) Alone Vaginal Tablet
Drug: TFV and FTC Combined Vaginal Tablet
Drug: Placebo Vaginal Tablet
Phase 1

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Outcomes Assessor)
Primary Purpose: Prevention
Official Title: A Phase I Clinical Trial Assessing the Safety, Pharmacokinetics, Pharmacodynamics, and Disintegration Time of Vaginal Tablets Containing Tenofovir and/or Emtricitabine

Resource links provided by NLM:


Further study details as provided by CONRAD:

Primary Outcome Measures:
  • Changes in Genitourinary AEs [ Time Frame: 5 hours after first tablet insertion and after 7th and 14th daily tablet ] [ Designated as safety issue: Yes ]
    Genitourinary AEs, moderate to severe

  • Changes on physical examination and colposcopy [ Time Frame: 5 hours after first tablet insertion and after 7th and 14th daily tablet ] [ Designated as safety issue: Yes ]
    Changes on physical examination and colposcopy

  • Changes Soluble markers of mucosal immunity, immune cell numbers, & characteristics in CVL [ Time Frame: 5 hours after first tablet insertion and after 7th and 14th daily tablet ] [ Designated as safety issue: Yes ]
    Changes Soluble markers of mucosal immunity, immune cell numbers, & characteristics in CVL

  • Changes in Number, phenotype and activation status of immune cells in cervicovaginal mucosa [ Time Frame: 5 hours after first tablet insertion and after 7th and 14th daily tablet ] [ Designated as safety issue: Yes ]
    Changes in Number, phenotype and activation status of immune cells in cervicovaginal mucosa

  • Changes in Mucosal histology in cervicovaginal tissue [ Time Frame: 5 hours after first tablet insertion and after 7th and 14th daily tablet ] [ Designated as safety issue: Yes ]
    Changes in Mucosal histology in cervicovaginal tissue

  • Changes in Changes in microflora [ Time Frame: 5 hours after first tablet insertion and after 7th and 14th daily tablet ] [ Designated as safety issue: Yes ]
    Changes in Changes in microflora (semiquantitative cultures and unculturable species)

  • Changes in Systemic laboratory tests [ Time Frame: 5 hours after first tablet insertion and after 7th and 14th daily tablet ] [ Designated as safety issue: Yes ]
    Changes in Systemic laboratory tests

  • TFV & FTC concentrations in plasma, vaginal aspirate, & genital tissue [ Time Frame: 5 hours after first tablet insertion ] [ Designated as safety issue: No ]
    TFV & FTC concentrations in plasma, vaginal aspirate, & genital tissue Pharmacokinetics Mean (SD) and Median (Min, Max, C-Max, T-Max) of TFV and FTC in blood, vaginal aspirate,and genital tissue at Visit 2, 3, 4, 5, 6

  • TFV-DP and FTC-TP concentrations in PBMCs, endocervical cells, & genital tissue [ Time Frame: 5 hours after first tablet insertion ] [ Designated as safety issue: No ]
    TFV-DP and FTC-TP concentrations in PBMCs, endocervical cells, & genital tissue Pharmacokinetics C-Max and T-Max of Blood TFV and FTC levels at single dose phase, by site and overall, Evaluable Population

  • TFV & FTC concentrations in plasma, vaginal aspirate, & genital tissue [ Time Frame: after 7th daily tablet ] [ Designated as safety issue: No ]
    TFV & FTC concentrations in plasma, vaginal aspirate, & genital tissue Pharmacokinetics Mean (SD) and Median (Min, Max, C-Max, T-Max) of TFV and FTC in blood, vaginal aspirate,and genital tissue at Visit 2, 3, 4, 5, 6

  • TFV & FTC concentrations in plasma, vaginal aspirate, & genital tissue [ Time Frame: after 14 daily tablet insertion ] [ Designated as safety issue: No ]
    TFV & FTC concentrations in plasma, vaginal aspirate, & genital tissue Pharmacokinetics Mean (SD) and Median (Min, Max, C-Max, T-Max) of TFV and FTC in blood, vaginal aspirate,and genital tissue at Visit 2, 3, 4, 5, 6

  • TFV-DP and FTC-TP concentrations in PBMCs, endocervical cells, & genital tissue [ Time Frame: after 7th daily tablet ] [ Designated as safety issue: No ]
    TFV-DP and FTC-TP concentrations in PBMCs, endocervical cells, & genital tissue Pharmacokinetics C-Max and T-Max of Blood TFV and FTC levels at single dose phase, by site and overall, Evaluable Population

  • TFV-DP and FTC-TP concentrations in PBMCs, endocervical cells, & genital tissue [ Time Frame: after 14th daily tablet ] [ Designated as safety issue: No ]
    TFV-DP and FTC-TP concentrations in PBMCs, endocervical cells, & genital tissue Pharmacokinetics C-Max and T-Max of Blood TFV and FTC levels at single dose phase, by site and overall, Evaluable Population


Secondary Outcome Measures:
  • Pharmacodynamics [ Time Frame: 5 hours after first tablet insertion and after 7th and 14th daily tablet ] [ Designated as safety issue: No ]

    Anti-HIV and anti-HSV activity in CVL

    Anti-HIV and anti-HSV activity as a percent of anti-HIV and anti-HSV activity before exposure to test product


  • Disintegration [ Time Frame: 5 hours after first tablet insertion and after 7th and 14th daily tablet ] [ Designated as safety issue: No ]
    Medians and interquartile ranges of (a) time to disintegration (tablet no longer coherent but residual product is visible) and (b) time to complete disappearance

  • Acceptability [ Time Frame: 5 hours after first tablet insertion and after 7th and 14th daily tablet ] [ Designated as safety issue: No ]
    Responses on acceptability questionnaires


Estimated Enrollment: 48
Study Start Date: February 2013
Estimated Study Completion Date: January 2014
Estimated Primary Completion Date: January 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: TFV Alone Vaginal Tablet Drug: Tenofovir (TFV) Alone Vaginal Tablet
vaginal tablet containing 40 mg of TFV
Active Comparator: Emtricitabine (FTC) Alone Vaginal Tablet Drug: Emtricitabine (FTC) Alone Vaginal Tablet
Vaginal Tablet containing 40 mg of TFV
Active Comparator: TFV Combined with FTC Vaginal Tablet Drug: TFV and FTC Combined Vaginal Tablet
vaginal tablet with 40 mg TFV and 40 mg FTC
Placebo Comparator: Placebo Vaginal Tablet Drug: Placebo Vaginal Tablet
Vaginal Tablet containing no drug

Detailed Description:

Objectives:

Primary:

  • To assess genital safety after a single use (consisting of one tablet in half of participants and one tablet followed by a second tablet two hours later in the other half) and during and after two weeks of daily tablet use
  • To assess systemic safety after two weeks of daily tablet use
  • To assess the pharmacokinetics (PK) of TFV and FTC after a single use (as defined above) and during and after two weeks of daily tablet use

Secondary:

  • To estimate the time needed for tablet disintegration and the time needed for full tablet disappearance
  • To assess acceptability of the tablet
  • To assess indicators of the pharmacodynamics (PD) of TFV and FTC in vitro using biological samples (fluids) from study participants obtained before use, after a single (use as define above), and after two weeks of daily tablet use
  Eligibility

Ages Eligible for Study:   18 Years to 50 Years
Genders Eligible for Study:   Female
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • General good health (by volunteer history and per investigator discretion) without any clinically significant systemic disease (including, but not limited to significant liver disease/hepatitis, gastrointestinal disease, kidney disease, thyroid disease, osteoporosis or bone disease, and diabetes)
  • Currently having regular menstrual cycles of 25 - 35 days by participant report
  • History of Pap smears and follow-up consistent with American Congress of Obstetricians and Gynecologist (ACOG) practice guidelines #99 and #109 or willing to undergo a Pap smear at Visit 1
  • Protected from pregnancy
  • Willing to abstain from vaginal activity as follows:

Starting 48 hours before Visit 2 until the sixth day after Visit 2 Starting 48 hours before Visit 3 until the sixth day after Visit 3 Starting 48 hours before Visit 4 until the sixth day after Visit 6

  • Willing to abstain from the use of any vaginal product other than the study product including spermicides, lubricants, and douches starting 48 hours before Visit 2 until the sixth day after Visit 6 (tampons may be used, but for menses only)
  • Vaginal and cervical anatomy that, in the opinion of the investigator, lends itself to easy colposcopy and genital tract sample collection
  • Negative urine pregnancy test
  • Willing to give voluntary consent, sign an informed consent form and comply with study procedures as required by the protocol

Exclusion Criteria:

  • History of hysterectomy
  • Currently pregnant or within two calendar months from the last pregnancy outcome. Note: If recently pregnant must have had at least two spontaneous menses since pregnancy outcome
  • Use of any hormonal contraceptive method in the last 30 days (oral, transdermal, transvaginal, implant, or hormonal intrauterine contraceptive device)
  • Injection of Depo-Provera in the last 6 months
  • Current use of IUD
  • Currently breastfeeding or having breastfed an infant in the last two months, or planning to breastfeed during the course of the study
  • History of sensitivity/allergy to any component of the study products, topical anesthetic, or allergy to both silver nitrate and Monsel's solution
  • In the last six months, diagnosed with or treated for any STI or pelvic inflammatory disease. Note: Women with a history of genital herpes or condylomata who have been asymptomatic for at least six months may be considered for eligibility
  • Nugent score greater than or equal to 7 at Visit 1 or symptomatic bacterial vaginosis (BV) as defined by Amsel's criteria at Visit 1 or 2
  • Symptomatic vulvovaginal candidiasis or symptomatic urinary tract infection (UTI)
  • Positive test for Trichomonas vaginalis, Neisseria gonorrhea or Chlamydia trachomatis
  • Deep epithelial genital findings such as abrasions, ulcerations, and lacerations, or vesicles suspicious for an STI
  • Positive test for HIV
  • Positive test for Hepatitis B surface antigen (HBsAg)
  • Known bleeding disorder that could lead to prolonged or continuous bleeding with biopsy
  • Chronic or acute vulvar or vaginal symptoms (pain, irritation, spotting, etc.)
  • Known current drug or alcohol abuse which could impact study compliance
  • Grade 1 or higher laboratory abnormality, per the August 2009 update of the Division of AIDS, National Institute of Allergy and Infectious Disease (DAIDS) Table for Grading the Severity of Adverse Events (AEs)
  • Systemic use in the last two weeks or anticipated use during the study of any of the following: corticosteroids, antibiotics, antifungals, antivirals (e.g., acyclovir or valacyclovir) or antiretrovirals (e.g., Viread, Atripla, Emtriva, Complera). Note: Participants should avoid non-steroidal anti-inflammatory drugs (NSAIDs) except for treatment of dysmenorrhea during menses. Participants may use Tylenol® on an as-needed but not daily basis during the study.
  • Participation in any other investigational trial (device, drug, or vaginal trial) within the last 30 days or planned participation in any other investigational trial during the study
  • History of gynecological procedures (including genital piercing) on the external genitalia, vagina or cervix within the last 14 days
  • Abnormal finding on laboratory or physical examination or a social or medical condition which, in the opinion of the investigator, would make participation in the study unsafe or would complicate interpretation of data
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT01694407

Locations
United States, New York
Albert Einstein College of Medicine
Bronx, New York, United States, 10451
United States, Virginia
Clinical Research Center, Eastern Virginia Medical School
Norfolk, Virginia, United States, 23507
Sponsors and Collaborators
CONRAD
Investigators
Study Director: Jill Schwartz, MD CONRAD
  More Information

No publications provided

Responsible Party: CONRAD
ClinicalTrials.gov Identifier: NCT01694407     History of Changes
Other Study ID Numbers: A11-117
Study First Received: July 17, 2012
Last Updated: December 11, 2013
Health Authority: United States: Food and Drug Administration

Keywords provided by CONRAD:
Prevention

Additional relevant MeSH terms:
Tenofovir
Tenofovir disoproxil
Emtricitabine
Reverse Transcriptase Inhibitors
Nucleic Acid Synthesis Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Anti-Retroviral Agents
Antiviral Agents
Anti-Infective Agents
Therapeutic Uses
Anti-HIV Agents

ClinicalTrials.gov processed this record on April 16, 2014