Dataset Information

Phase I randomized safety study of twice daily dosing of acidform vaginal gel: candidate antimicrobial contraceptive.

ABSTRACT:

Background

Acidform gel, an acid-buffering product that inactivates spermatozoa, may be an effective topical non-hormonal contraceptive. This study was designed to evaluate the safety of vaginal dosing and effects of Acidform on mucosal immune mediators, antimicrobial properties of genital secretions, and vaginal microbiota.

Methods

Thirty-six sexually abstinent U.S. women were randomized to apply Acidform or hydroxyethylcellulose (HEC) placebo gel twice daily for 14 consecutive days. Safety was assessed by symptoms and pelvic examination. The impact of gel on mucosal immunity was assessed by quantifying cytokines, chemokines, antimicrobial proteins and antimicrobial activity of genital secretions collected by cervicovaginal lavage (CVL) at screening, 2 hours after gel application, and on days 7, 14 and 21. Vaginal microbiota was characterized at enrollment and day 14 using species-specific quantitative PCR assays.

Results

The median vaginal and cervical pH was significantly lower 2 hours after application of Acidform and was associated with an increase in the bactericidal activity of CVL against E. coli. However, 65% of women who received Acidform had at least one local adverse event compared with 11% who received placebo (p?=?0.002). While there was no increase in inflammatory cytokines or chemokines, CVL concentrations of lactoferrin and interleukin-1 receptor antagonist (IL-1ra), an anti-inflammatory protein, were significantly lower following Acidform compared to HEC placebo gel application. There were no significant changes in Lactobacillus crispatus or Lactobacillus jensenii in either group but there was a decrease in Gardnerella vaginalis in the Acidform group (p?=?0.08).

Conclusions

Acidform gel may augment mucosal defense as evidenced by an increase in bactericidal activity of genital secretions against E. coli and a decrease in Gardnerella vaginalis colonization. However, Acidform was associated with more irritation than placebo and lower levels of antimicrobial (lactoferrin) and anti-inflammatory (IL-1ra) proteins. These findings indicate the need for additional safety studies of this candidate non-hormonal contraceptive.

Trial registration

ClinicalTrials.gov NCT00850837.

SUBMITTER: Keller MJ

PROVIDER: S-EPMC3466198 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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Publications

Phase I randomized safety study of twice daily dosing of acidform vaginal gel: candidate antimicrobial contraceptive.

Keller Marla J MJ Carpenter Colleen A CA Lo Yungtai Y Einstein Mark H MH Liu Congzhou C Fredricks David N DN Herold Betsy C BC

PloS one 20121008 10

<h4>Background</h4>Acidform gel, an acid-buffering product that inactivates spermatozoa, may be an effective topical non-hormonal contraceptive. This study was designed to evaluate the safety of vaginal dosing and effects of Acidform on mucosal immune mediators, antimicrobial properties of genital secretions, and vaginal microbiota.<h4>Methods</h4>Thirty-six sexually abstinent U.S. women were randomized to apply Acidform or hydroxyethylcellulose (HEC) placebo gel twice daily for 14 consecutive d ...[more]

PMID: 23056520

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Project description:UNLABELLED:Vaginal HIV microbicides offer great promise in preventing HIV transmission, but failures of phase 3 clinical trials, in which microbicide-treated subjects had an increased risk of HIV transmission, raised concerns about endpoints used to evaluate microbicide safety. A possible explanation for the increased transmission risk is that the agents shifted the vaginal bacterial community, resulting in loss of natural protection and enhanced HIV transmission susceptibility. We characterized vaginal microbiota, using pyrosequencing of bar-coded 16S rRNA gene fragments, in samples from 35 healthy, sexually abstinent female volunteer subjects (ages 18 to 50 years) with regular menses in a repeat phase 1 study of twice-daily application over 13.5 days of 1 of 3 gel products: a hydroxyethylcellulose (HEC)-based "universal" placebo (10 subjects), 6% cellulose sulfate (CS; 13 subjects), and 4% nonoxynol-9 (N-9; 12 subjects). We used mixed effects models inferred using Bayesian Markov chain Monte Carlo methods, which showed that treatment with active agents shifted the microbiota toward a community type lacking significant numbers of Lactobacillus spp. and dominated by strict anaerobes. This state of the vaginal microbiota was associated with a low or intermediate Nugent score and was not identical to bacterial vaginosis, an HIV transmission risk factor. The placebo arm contained a higher proportion of communities dominated by Lactobacillus spp., particularly L. crispatus, throughout treatment. The data suggest that molecular evaluation of microbicide effects on vaginal microbiota may be a critical endpoint that should be incorporated in early clinical assessment of microbicide candidates. IMPORTANCE:Despite large prevention efforts, HIV transmission and acquisition rates remain unacceptably high. In developing countries, transmission mainly occurs through heterosexual intercourse, where women are significantly more vulnerable to infection than men. Vaginal microbicides are considered to be one of the most promising female-controlled products, in that women themselves insert the microbicides into the vagina to prevent HIV transmission during sexual intercourse. The failure of several microbicides in clinical trials has raised questions concerning the low in vivo efficacy of such anti-HIV molecules. This study was designed to gain insights into the failures of two microbicides by testing the hypothesis that the microbicides negatively affect a critical line of defense against HIV, the vaginal microbiota. The results suggest that in the early assessment of candidate microbicides, culture-independent evaluation of their effect on the vaginal microbiota should be considered and may constitute a critical endpoint.

Project description:OBJECTIVES:To evaluate safety outcomes from clinical studies of a 12-month contraceptive vaginal system (CVS) releasing an average of segesterone acetate (SA) 150 mcg and ethinyl estradiol (EE) 13 mcg daily. STUDY DESIGN:We integrated clinical safety data from nine studies in which women used the CVS for 21 consecutive days and removed it for 7?days of each 28-day?cycle. Four studies used the final manufactured CVS, including a 1-year pharmacokinetic study, two 1-year phase 3 trials and a second-year treatment extension study. We assessed safety by evaluating adverse events women reported in a daily diary. We also included data from focused safety studies evaluating endometrial biopsies, vaginal microbiology and liver proteins from one of the phase 3 studies. RESULTS:The combined studies included 3052 women; 2308 women [mean age 26.7±5.1?years; mean body mass index (BMI) 24.1±3.7?kg/m2] received the final manufactured CVS, of whom 999 (43.3%) completed 13?cycles of use. Women using the final CVS most commonly reported adverse events of headache (n=601, 26%), nausea (n=420, 18%), vaginal discharge/vulvovaginal mycotic infection (n=242, 10%) and abdominal pain (n=225, 10%). Few (<1.5%) women discontinued for these complaints. Four (0.2%) women experienced venous thromboembolism (VTE), three of whom had risk factors for thrombosis [Factor V Leiden mutation (n=1); BMI>29?kg/m2 (n=2)]. During 21,482 treatment cycles in the phase 3 studies evaluable for expulsion, women reported partial expulsions in 4259 (19.5%) cycles and complete expulsions in 1509 (7%) cycles, most frequently in the initial cycle [499/2050 (24.3%) and 190/2050 (9.3%), respectively]. Safety-focused studies revealed no safety concerns. CONCLUSION:The 1-year SA/EE CVS has an acceptable safety profile. Additional studies are warranted in obese women at higher risk of VTE. IMPLICATIONS:This 1-year contraceptive vaginal system represents a new long-term, user-controlled and procedure-free option with a safety profile similar to other combination hormonal contraceptives. The same precautions currently used for combination hormonal contraceptive prescriptions apply to this new contraceptive vaginal system.

Dataset Information

Phase I randomized safety study of twice daily dosing of acidform vaginal gel: candidate antimicrobial contraceptive.

Background

Methods

Results

Conclusions

Trial registration

Publications

Phase I randomized safety study of twice daily dosing of acidform vaginal gel: candidate antimicrobial contraceptive.

Similar Datasets

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