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

NCT01694407 | Completed Phase 1

• 1 other identifier: A11-117
• Study Type: interventional
• Target: 48
• Locations: 1 country
• Sites: 2

Brief Summary

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. The clinic will call the participant on day 3 of the multiple use phase to ask about any symptoms the participant may be experiencing. Each insertion in the clinic will be followed by sample collection and, at Visits 4 and 6, colposcopy at the participant's assigned time point.

Conditions

HIV

Keywords

Prevention

Outcome Measures

Primary Outcomes (13)

• Changes in Genitourinary AEs

  Genitourinary AEs, moderate to severe

  5 hours after first tablet insertion and after 7th and 14th daily tablet

• Changes on physical examination and colposcopy

  Changes on physical examination and colposcopy

  5 hours after first tablet insertion and after 7th and 14th daily tablet

• Changes Soluble markers of mucosal immunity, immune cell numbers, & characteristics in CVL

  Changes Soluble markers of mucosal immunity, immune cell numbers, \& characteristics in CVL

  5 hours after first tablet insertion and after 7th and 14th daily tablet

• Changes in Number, phenotype and activation status of immune cells in cervicovaginal mucosa

  Changes in Number, phenotype and activation status of immune cells in cervicovaginal mucosa

  5 hours after first tablet insertion and after 7th and 14th daily tablet

• Changes in Mucosal histology in cervicovaginal tissue

  Changes in Mucosal histology in cervicovaginal tissue

  5 hours after first tablet insertion and after 7th and 14th daily tablet

• Changes in Changes in microflora

  Changes in Changes in microflora (semiquantitative cultures and unculturable species)

  5 hours after first tablet insertion and after 7th and 14th daily tablet

• Changes in Systemic laboratory tests

  Changes in Systemic laboratory tests

  5 hours after first tablet insertion and after 7th and 14th daily tablet

• TFV & FTC concentrations in plasma, vaginal aspirate, & genital tissue

  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

  5 hours after first tablet insertion

• TFV-DP and FTC-TP concentrations in PBMCs, endocervical cells, & genital tissue

  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

  5 hours after first tablet insertion

• TFV & FTC concentrations in plasma, vaginal aspirate, & genital tissue

  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

  after 7th daily tablet

• TFV & FTC concentrations in plasma, vaginal aspirate, & genital tissue

  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

  after 14 daily tablet insertion

• TFV-DP and FTC-TP concentrations in PBMCs, endocervical cells, & genital tissue

  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

  after 7th daily tablet

• TFV-DP and FTC-TP concentrations in PBMCs, endocervical cells, & genital tissue

  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

  after 14th daily tablet

Secondary Outcomes (3)

• Pharmacodynamics

  5 hours after first tablet insertion and after 7th and 14th daily tablet

• Disintegration

  5 hours after first tablet insertion and after 7th and 14th daily tablet

• Acceptability

  5 hours after first tablet insertion and after 7th and 14th daily tablet

Study Arms (4)

TFV Alone Vaginal Tablet

ACTIVE COMPARATOR

Drug: Tenofovir (TFV) Alone Vaginal Tablet

Emtricitabine (FTC) Alone Vaginal Tablet

ACTIVE COMPARATOR

Drug: Emtricitabine (FTC) Alone Vaginal Tablet

TFV Combined with FTC Vaginal Tablet

ACTIVE COMPARATOR

Drug: TFV and FTC Combined Vaginal Tablet

Placebo Vaginal Tablet

PLACEBO COMPARATOR

Drug: Placebo Vaginal Tablet

Interventions

Tenofovir (TFV) Alone Vaginal Tablet DRUG

vaginal tablet containing 40 mg of TFV

TFV Alone Vaginal Tablet

Emtricitabine (FTC) Alone Vaginal Tablet DRUG

Vaginal Tablet containing 40 mg of TFV

Emtricitabine (FTC) Alone Vaginal Tablet

TFV and FTC Combined Vaginal Tablet DRUG

vaginal tablet with 40 mg TFV and 40 mg FTC

TFV Combined with FTC Vaginal Tablet

Placebo Vaginal Tablet DRUG

Vaginal Tablet containing no drug

Placebo Vaginal Tablet

Eligibility Criteria

• Age: 18 Years - 50 Years
• Sex: female
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• CONRAD: lead

Study Sites (2)

Albert Einstein College of Medicine

The Bronx, New York, 10451, United States

Location

Clinical Research Center, Eastern Virginia Medical School

Norfolk, Virginia, 23507, United States

Location

MeSH Terms

Interventions

Tenofovir; Emtricitabine; Racivir

Intervention Hierarchy (Ancestors)

Organophosphonates; Organophosphorus Compounds; Organic Chemicals; Adenine; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Deoxycytidine; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Deoxyribonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides

Study Officials

• Jill Schwartz, MD

  CONRAD

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, OUTCOMES ASSESSOR
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 17, 2012
• First Posted: September 27, 2012
• Study Start: February 1, 2013
• Primary Completion: December 1, 2013
• Study Completion: December 1, 2013
• Last Updated: April 3, 2015

Record last verified: 2015-03

Locations

US (2)