Study of UC-781 Vaginal Microbicide

• Macroscopic and/or microscopic evidence of cervical, vulvar and/or vaginal epithelial damage, including ulceration, abrasion, severe erythema, and or severe edema. [ Time Frame: with two weeks of administration ] [ Designated as safety issue: Yes ]
• Symptoms of genital irritation, including burning, itching or soreness [ Time Frame: With 2 weeks of administration ] [ Designated as safety issue: Yes ]
• Laboratory evidence of grade 3 or higher toxicity for hematology, liver or renal function which cannot be attributed to another cause [ Time Frame: with 2 weeks of administration ] [ Designated as safety issue: Yes ]

• ·Macroscopic and/or microscopic evidence of cervical mucosal damage including ulceration, abrasion, severe erythema, and/or severe edema
• ·Symptoms of genital irritation, including burning, itching or soreness
• ·Laboratory evidence of grade 3 or higher toxicity for hematology, liver or renal function which cannot be attributed to another cause
• The safety and toxicity of 0.1% UC-781 Gel and 0.25% UC-781 Gel administered intravaginally twice-daily for 14 days in sexually-active HIV-uninfected women and 0.25% UC-781 Gel administered in sexually-abstinent HIV-infected women will be assessed by:
• Primary Endpoints:
• ·Macroscopic and/or microscopic evidence of vulvar and/or vaginal epithelium damage, including ulceration, abrasion, severe erythema, and/or severe edema

• Secondary Endpoints:
• Acceptability of 0.1% and 0.25% UC-781 Gel use by HIV-uninfected and 0.25% UC-781 Gel use by HIV-infected women will be assessed by:
• ·Proportion of participants who at Day 14 visit indicate they would be ‘somewhat unlikely’ or ‘very unlikely’ to use 0.1% and 0.25% UC-781 Gel during sexual intercourse in the future compared to Control Gel users
• ·Reported positive aspects of using 0.1% and 0.25% UC-781 Gel compared to Control Gel users
• ·Reported negative aspects of using 0.1% and 0.25% UC-781 gel compared to Control Gel users

This study will help determine whether the agent UC-781, formulated as a gel, is safe when applied to the vagina twice daily for 14 days. It will also assess whether women find the gel acceptable to use.

Purpose: To assess the safety and acceptability of vaginal use of 0.1% and 0.25% UC-781 gel in sexually active HIV-uninfected women, and their male partners, and sexually abstinent HIV-infected women

Design: Single-center, phase I randomized, double-blind, controlled trial with 14 days of twice-daily product or control gel exposure

Study population: Sexually active, HIV-uninfected women at low-risk for HIV and their male partners; sexually-abstinent HIV-infected women; all age 18-45

Size: 36 sexually active HIV-uninfected women and up to 36 of their male partners; 18 sexually abstinent HIV-infected women

Treatment regimen:

Stage 1: HIV-uninfected, sexually active women and 1 male partner per woman:

12 women assigned to 0.1% UC-781 twice daily x 14 days; 12 women assigned to 0.25% UC-781 twice daily x 14 days; 12 women assigned to control gel twice daily X 14 days.

Stage 2: HIV-infected, abstinent women: 12 assigned to 0.25% UC-781 twice daily x 14 days; 6 assigned to control gel twice daily x 14 days

Study duration: Participant accrual will take 6 months. Each participant will be followed for 14 days in Stage 1 and 21 days in Stage 2. Total study duration will be 9 months.

Study Site: The Hope Clinic of Emory University, Decatur, GA

Primary Objectives:

• To assess the safety and toxicity of 0.1% UC-781 gel and 0.25% UC-781 gel administered intravaginally twice-daily for 14 days on the vulvar and cervicovaginal mucosa of sexually active HIV-uninfected women
• To assess the safety and toxicity of 0.25% UC-781 gel administered intravaginally twice-daily for 14 days on the vulvar and cervicovaginal mucosa of sexually abstinent HIV-infected women

Secondary Objectives:

• To assess the acceptability of 0.1% and 0.25% UC-781 gel administered intravaginally twice-daily for 14 days among HIV-uninfected, and the acceptability of 0.25% gel similarly administered to HIV-infected women
• To assess the effect of study product on vaginal microflora of HIV-uninfected and HIV-infected women
• To assess the systemic absorption of 0.1% and 0.25% UC-781 gel when administered intravaginally
• To assess HIV viral load in genital secretions in HIV-infected women during 0.25% UC-781 gel use
• To assess the genotypic resistance patterns of HIV in genital secretions and peripheral blood in HIV-infected women during 0.25% UC-781 gel use
• To assess the acceptability of 0.1% and 0.25% UC-781 gel in male sexual partners of HIV-uninfected women

Primary Endpoints:

The safety and toxicity of 0.1% UC-781 gel and 0.25% UC-781 gel administered intravaginally twice-daily for 14 days in sexually-active HIV-uninfected women and 0.25% UC-781 gel administered in sexually-abstinent HIV-infected women will be assessed by:

• Macroscopic and/or microscopic evidence of vulvar and/or vaginal epithelium damage, including ulceration, abrasion, severe erythema, and/or severe edema
• Macroscopic and/or microscopic evidence of cervical mucosal damage including ulceration, abrasion, severe erythema, and/or severe edema
• Symptoms of genital irritation, including burning, itching or soreness
• Laboratory evidence of grade 3 or higher toxicity for hematology, liver or renal function which cannot be attributed to another cause

Secondary Endpoints:

Acceptability of 0.1% and 0.25% UC-781 gel use by HIV-uninfected and 0.25% UC-781 gel use by HIV-infected women will be assessed by:

• Proportion of participants who at Day 14 visit indicate they would be 'somewhat unlikely' or 'very unlikely' to use 0.1% and 0.25% UC-781 gel during sexual intercourse in the future compared to control gel users
• Reported positive aspects of using 0.1% and 0.25% UC-781 gel compared to control gel users
• Reported negative aspects of using 0.1% and 0.25% UC-781 gel compared to control gel users

• Active Comparator: 1
  0.25% gel
  Intervention: Drug: topical vaginal application of UC-781 gel
• Active Comparator: 2
  0.1% gel
  Intervention: Drug: topical vaginal application of UC-781 gel
• Placebo Comparator: 3
  Intervention: Drug: topical vaginal application of UC-781 gel

Inclusion Criteria:

For All Females:

• Ages 18-45 years of age
• Able to provide written informed consent
• Normal Pap smear at screening or documentation of such within six months prior
• Regular monthly menses or amenorrhea due to hormonal contraceptive use
• Agree to pelvic exam, colposcopy and biopsy (if indicated) per protocol
• Able/willing to complete Study Diary
• Agree to abstain from sexual intercourse for 48 hours prior to the enrollment visit
• Agree to apply assigned study gel as required per protocol

• Agree to abstain from the following activities from at least 48 hours prior to enrollment through the Day 14 visit:

  • Insertion of fingers/objects into the vagina
  • Receiving oral sex
  • Receiving anal sex
  • Using a diaphragm, cervical cap, female condom, or vaginal contraceptive ring
  • Using vaginal products other than the study gels
  • Participating in other vaginal microbicide or contraceptive studies

Additional Inclusion Criteria for Stage 1:

• HIV-uninfected
• In a monogamous sexually active relationship with one male partner throughout the study
• Report having vaginal intercourse only with that partner at least two times per week
• Agree to use study-provided male condoms for each act of vaginal intercourse while taking part in the study
• Agree to inform male partner about participation

Additional Inclusion Criteria for Stage 2:

• HIV-infected
• Sexually abstinent or agree to abstain from sexual intercourse while taking part in the study
• Under regular medical care for HIV management
• CD4+ lymphocyte count > 200/mm3 for the last 6 months
• HIV viral load > 4.0 log10 copies/ml at screening
• Documentation of prior HIV genotype with one or more mutations conferring resistance to a non-nucleoside reverse transcriptase inhibitor (NNRTI)
• Not currently on antiretrovirals
• Willing to provide study staff with access to medical records related to their HIV infection

Inclusion Criteria for Male Partners:

• Ages 18 years or older
• Able to give written informed consent
• Male sexual partners of HIV-uninfected women taking part in Stage 1 of the study

Exclusion Criteria:

Exclusion Criteria for All Females:

• Are post-menopausal
• Have had a hysterectomy
• Clinically significant chronic medical condition (other than HIV) that is considered progressive.
• History of malignancy, with the exception of basal cell or squamous cell skin cancer
• Pregnant or planning to become pregnant in the next three months
• Currently breastfeeding
• History of sensitivity or allergy to latex or any compound used in this study
• Have received antibiotics in the 14 days prior to enrollment
• Have used a spermicide or spermicidally lubricated condom within 7 days prior to enrollment
• Have been using a hormonal contraceptive method for less than 3 months prior to enrollment
• Have participated in other microbicide or contraceptive studies in the past three months
• Grade 3 or higher liver, renal or hematology abnormality, as defined by the Table for Grading the Severity of Adult Adverse Events at screening
• Have a positive bacterial urine culture
• Currently have a clinically detectable genital abnormality (i.e. vulvar, vaginal, cervical and/or perineal ulcer or lesions or abnormal Pap smear)

• In the three months prior to enrollment have had any of the following:

  • An abnormal Pap smear
  • A pregnancy
  • An abortion
  • An intrauterine device (IUD)
  • Breakthrough menstrual bleeding
  • Vaginal bleeding during or following vaginal intercourse
  • Gynecologic surgery
  • Signs consistent with a sexually transmitted disease (STD)
  • Signs of genital trauma
  • Signs of genital tract infection other than asymptomatic bacterial vaginosis (BV)

• In the six months prior to enrollment have had any of the following:

  • History of treatment for or a diagnosis with a new STD
  • Exchanged sex for money, drugs or gifts
  • Protected (with condoms) penile-vaginal or penile-anal sexual contact with more than 4 partners
  • Unprotected (without condoms) penile-vaginal or penile-anal sexual contact with more than 1 partner
  • A male sexual partner who was diagnosed or treated for an STD (other than HIV)
  • A male sexual partner who has injected drugs
• Are currently using, or in the last year have used intravenous drugs (except for therapeutic use), crack or other recreational drugs
• Are currently abusing, or in the last year have abused alcohol.
• Any other condition that, in the opinion of the investigator, might interfere with the evaluation of the study objectives

Additional Exclusion Criteria for Stage 1:

• Unprotected (without condoms) or protected (with condoms) penile-vaginal or penile-anal sexual contact with an HIV-infected partner in the past 6 months
• Unwilling to use study-provided male condoms while on study

Additional Exclusion Criteria for Stage 2:

• NNRTI mutations in plasma and/or genital secretions at screening

• Emory University
• Centers for Disease Control and Prevention