study of uc-781 vaginal microbicide

Conditions: HIV Infections

Summary: 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

Eligibility criteria:
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

Keywords: hiv topical microbicides