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

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

Exploratory:

•To assess exploratory indicators of the PD of TFV and FTC in vitro using biological samples (tissues) from study participants obtained before use, after a single use (as defined above), and after two weeks of daily tablet use

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, meaning one of the following:

• Sexually abstinent and planning to remain abstinent for the duration of the study;
• In a monogamous heterosexual relationship for at least four months with a partner who is not known to be HIV positive and has no known risks for sexually transmitted infections (STIs) and:
• Couple is using condoms and is willing to use non-spermicidally lubricated condoms throughout the study or
• One partner is sterilized; or

• In a monogamous same sex relationship for at least four months with a partner who is not known to be HIV positive and has no known risks for STIs.
• 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