A randomized, comparative safety study of a prefilled plastic and user-filled paper applicator with candidate microbicide tenofovir 1% gel.

BACKGROUND: A bridging study was performed to compare the safety, dose delivery, and acceptability of a prefilled plastic and user-filled paper applicator to assess whether a low-cost, user-filled, paper applicator could serve as a delivery option for tenofovir (TFV) 1% vaginal microbicide gel. METHODS: The study used a randomized crossover design with 25 healthy women randomized to begin with the prefilled or user-filled applicator. Within each study arm, participants delivered two 4.0-mL doses of TFV 1% gel vaginally for 7 days, with one dose delivered at the clinic each morning and a second dose delivered at home each evening. To assess the primary objective, applicator safety, colposcopy examinations were performed at 2 time points in each study arm. RESULTS: There were no colposcopic findings or adverse events attributable to either applicator. One case of vulvovaginal candidiasis was considered possibly related to gel use. On average, the user-filled applicator delivered 96% of the target dose, with 85% of doses falling within ± 10% of the average dose volume. Participants found both applicators comparable for ease of use, insertion, and dispensing gel, with 60% of participants preferring the user-filled applicator. CONCLUSIONS: This study suggests that both applicators are safe, and most women delivered TFV with the user-filled applicator as directed. Participants found both applicators acceptable, with a slight majority preferring the user-filled applicator. Incorporating a low-cost, user-filled, paper applicator to deliver TFV could help reduce costs and improve access to TFV 1% gel, especially in resource-limited settings heavily impacted by HIV.

Baseline variation and associations between subject characteristics and five cytokine biomarkers of vaginal safety among healthy non-pregnant women in microbicide trials.

Interleukins (IL)-8, IL-1α, IL-1ß, and IL-1 receptor antagonist (IL-1RA) have emerged as indicators of vaginal inflammation and HIV-1 transmission risk. We provide values and factors of normal variation of these immune mediators in premenopausal women to allow their wider clinical application as biomarkers of vaginal health. Cross-sectional analyzes (Kruskal-Wallis and Wilcoxon exact tests) of cytokine concentrations in relation to sociodemographic variables and Nugent score were performed on baseline (prior to product) cervicovaginal lavage from two Phase I randomized microbicide trials. All women in the analysis had regular menstrual cycles, 72 h abstinence, normal blood and Pap tests, and absence of genitourinary infections, study-relevant allergies, antibiotics use and history of substance abuse. Cytokine norms were defined as the values among those with Nugent score <4. Among women with normal Nugent score (n=92), IL-8 and IL-1ß were lowest in those using abstinence as compared to hormonal contraceptives or male/female sterilization as their primary method for birth control. No difference was found by age, prior pregnancy, or education, and also by race after controlling for contraceptive method. Women with abnormal (>7) and borderline (4-6) Nugent scores had elevated IL-1α and/or IL-1ß although their IL-1RA-to-IL(α+ß) ratio remained within the normal range due to higher IL-1RA. Women with borderline Nugent scores had IL-8 levels above the normal range. IL-8 and the IL-1RA-to-IL-1 ratio can be used as independent biomarkers of vaginal immune balance. More studies must determine the role of sexual activity, contraceptive method, and borderline Nugent scores, which normally are not exclusion criteria for enrollment in microbicide trials but may affect product tolerability and HIV-1 risk due to the aberrant cytokine levels.

Noncomparative contraceptive efficacy of cellulose sulfate gel.

OBJECTIVE: To estimate the 6-month cumulative probability of pregnancy, short-term adverse effects, and acceptability of cellulose sulfate vaginal contraceptive gel. METHODS: Two hundred fertile heterosexual couples were enrolled in this single-center, phase II, 6-month noncomparative study conducted at the California Family Health Council in Los Angeles, California. Couples did not desire pregnancy, were at low risk for sexually transmitted diseases, and agreed to use 3.5 mL of cellulose sulfate gel intravaginally before each coital act as their primary means of contraception. Scheduled follow-up visits took place after one menstrual cycle and at study completion, which occurred after 6 months and six menstrual cycles had elapsed. In addition, participants were instructed to call the site at the onset of each menses to review their diary cards. RESULTS: The cumulative probabilities of pregnancy during 6 months and six cycles of typical use were 13.4% (95% confidence interval [CI] 7.5-19.4%) and 13.9% (95% CI 7.7-20.2%), respectively, and during 6 cycles of correct and consistent ("perfect") use: 3.9% (95% CI 0.0-9.2%). Slightly over one fourth of the women and one man reported experiencing gel-related adverse events, two thirds of which were mild and only possibly related to the gel. Three quarters of women and men reported that they would buy cellulose sulfate gel for contraception. CONCLUSION: Cellulose sulfate vaginal gel yields pregnancy rates comparable to nonoxynol-9 and few adverse events among couples at low risk for sexually transmitted diseases.

A Phase I study of the functional performance, safety and acceptability of the BufferGel Duet.

BACKGROUND: The purpose of this study was to assess the functional performance of the BufferGel Duet, a buffering microbicide and spermicide gel applied to the cervix and vagina by a novel applicator that also serves as a mechanical barrier. STUDY DESIGN: This was a noncomparative Phase I safety trial in 30 healthy couples, aged 20-50 years, at low risk for sexually transmitted infections, who agreed to use the gel-device combination twice in 1 week and respond to detailed questionnaires about their experience. The female participants were examined with colposcopy before and 6-18 h after using the second device. RESULTS: Based on written instructions alone, 25 women successfully placed and 28 women successfully removed the device. Three women reported feeling the device dislodge around the time of intercourse. The product was equally acceptable to both men and women. Most users concluded that intercourse was the same or better with the device than with no product. About 73% would choose Duet over male condoms, and no one preferred the standard diaphragm. Colposcopic findings were noted in 79% of women with external genital findings (9) or cervicovaginal peeling (18) predominating. Only one finding breached the epithelium. Most product-related adverse events were mild (10/11) and confined to the genitourinary tract. CONCLUSIONS: The successful placements and acceptability suggest that further product development is warranted and could target over-the-counter use. During increased duration of use or more frequent dosing, cervicovaginal monitoring is advised based on the extent of peeling and external colposcopic findings in this short-term study.

SILCS diaphragm: postcoital testing of a new single-size contraceptive device.

BACKGROUND: This study was conducted to compare the effectiveness of a new, single-size silicone contraceptive diaphragm used with either spermicide [2% nonoxynol-9 (N-9)] or lubricant in preventing sperm from penetrating midcycle cervical mucus. STUDY DESIGN: A crossover postcoital test (PCT) in healthy, sexually active women not at risk for pregnancy due to tubal occlusion was conducted. Couples had a baseline PCT without a device to verify normal fertility parameters. Qualified couples underwent up to two test cycles using the SILCS diaphragm with a metal spring. A subgroup of couples underwent a third test cycle with the SILCS polymer spring diaphragm used with N-9 gel. RESULTS: Fifteen couples completed a baseline cycle and were randomized to order of study gel. Of these, 14 couples completed a baseline cycle and at least one test cycle, 12 couples completed a baseline cycle and two test cycles and 8 couples completed a third test cycle with the polymer spring prototype. Sperm was detected in the vaginal pool in all completed test cycles. The SILCS metal spring diaphragms used with N-9 gel reduced the average number of progressively motile sperm per high power field in the cervical mucus from a baseline of 12.5 to 0, while use of this device with lubricant reduced the number to 0.5. The SILCS polymer spring diaphragm used with N-9 performed the same as the metal spring used with N-9. CONCLUSION: The SILCS diaphragm used with N-9 gel performed well. It is likely that the SILCS diaphragm will give acceptable results in a contraceptive effectiveness study but that adjunctive use of a chemical barrier such as N-9 gel will be necessary for it to be most effective.

Colposcopically observed vascular changes in the cervix in relation to the hormonal levels and menstrual cycle.

OBJECTIVE: We assessed colposcopically observed vascular changes occurring in the cervix in relation to cyclical hormonal variation in healthy women. MATERIALS AND METHODS: Thirty women with regular menstrual cycles and willing to remain sexually abstinent during a menstrual cycle were enrolled. Colposcopy was performed during the peak of the estrogen and progesterone levels. RESULTS: The mean (+/-SD) diameter of the largest visible blood vessel differed significantly between the estrogenic phase (0.38 +/- 0.14 mm) as compared with the progestogenic phase (0.47 +/- 0.12 mm; p <.01). The blood vessels were more prominent and dense and had a well-defined outline during the progestogenic phase than the estrogenic phase; however, these differences were not statistically significant. There was borderline increase in the interleukin 8 level during the estrogenic phase. CONCLUSIONS: Physiological changes of increased vascularity of the cervix observed colposcopically during the progestogenic phase are normal. If such changes do not correspond to the menstrual cycle phase in women using vaginal microbicides in early-phase clinical trials, presence of inflammatory markers should be evaluated. Elevated interleukin 8 during the estrogenic phase needs further evaluation.

Standardized definitions of failure modes for female condoms.

Definitions of male condom failure modes are now well documented, and failure events are usually reported as the proportion of the total number of condoms used and the proportion of men/couples who experience an event. The lack of standardized definitions for female condom (FC) failure has led to variability in reporting and hence difficulties in making comparisons across studies. As a result, the World Health Organization convened a technical review committee meeting in January 2006 through which the members compiled and agreed to a standard list of terms and definitions for each of the failure modes. These failure modes apply to FCs currently marketed or in advanced stages of clinical testing. They were designed to assist in the review and comparative assessment of different FCs.

Fourteen-day safety and acceptability study of the universal placebo gel.

OBJECTIVE: This study evaluated the effect of the so-called universal placebo compared to the polystyrene sulfonate (PSS) placebo on genital irritation. DESIGN: A single-center, Phase I, randomized, closed-label study was performed to evaluate the genital irritation of microbicide placebo gels. Thirty healthy, sexually abstinent women were randomly assigned to apply 3.5 mL of either the universal placebo or the PSS placebo gel intravaginally twice daily for 14 days. METHODS: Genital irritation was assessed by signs as seen on pelvic examination and colposcopy and reports of symptoms. Vaginal health was assessed by wet mounts, Gram stains for Nugent score and polymorphonuclear leukocytes, and semiquantitative vaginal cultures. Acceptability was assessed as reported on the follow-up questionnaire. RESULTS: The universal placebo was less irritating than the PSS placebo with a lower proportion of women experiencing signs and/or symptoms of genital irritation throughout follow-up (36% compared to 80%, p=.0253). The universal placebo was associated with few and mild genital symptoms, few and minor colposcopic findings and good vaginal health with no clinically significant changes in genital flora. Most participants found the feel of the universal placebo gel neutral or pleasant, and all participants found it odorless. CONCLUSIONS: The universal placebo appeared safe and acceptable when used twice daily for 14 days. The strategy of creating a de novo inert universal placebo is a successful approach. The universal placebo is appropriate for use as a placebo gel in HIV prevention trials with microbicide candidates.

Fourteen-day safety and acceptability study of 6% cellulose sulfate gel: a randomized double-blind Phase I safety study.

BACKGROUND: Topical microbicides against the human immunodeficiency virus (HIV) 1 that are nonirritating to the female genital epithelium are urgently needed to slow the heterosexual spread of HIV infection. Products that are also effective contraceptives provide additional benefits. Cellulose sulfate (CS) is a noncytotoxic antifertility agent that exhibits in vitro antimicrobial activity against sexually transmitted pathogens, including HIV. METHODS: We performed a multicenter, Phase I, placebo-controlled, randomized study to evaluate the genital toxicity of CS. Two cohorts of healthy women used 3.5 ml of 6% CS gel or 3.5 ml of K-Y Jelly, vaginally, bid, for 14 days. The first cohort was sexually abstinent, and the second cohort was sexually active. RESULTS: CS was associated with only a slightly higher odds ratio (OR) of symptoms of minor urogenital irritation compared to the inactive lubricant K-Y Jelly (OR=2.02, 95% confidence interval=0.90-4.53). In addition, there were minor shifts in some genital flora, but there was no evidence of greater inflammation as evidenced by few colposcopic findings, decreased influx of polymorphonuclear cells and minimal changes in proinflammatory cytokines. Moreover, both products appeared acceptable to most women. Product leakage was identified as more of a problem in sexually abstinent women, but less so in women using the product for sexual intercourse, as would be the case in actual practice. CONCLUSION: CS was safe for twice-daily use for 14 days. CS is appropriate for future studies in effectiveness trials.

FemCap with removal strap: ease of removal, safety and acceptability.

OBJECTIVES: FemCap is a silicone-rubber barrier contraceptive approved for marketing in the United States. To address reported problems with removal and dislodgment, the device's developer added a strap to the device and increased the height of the brim. This trial assessed whether the new design reduced removal difficulties and had any effects on dislodgment, genital pain/discomfort, safety, and acceptability. METHODS: Women used the strapped device for 8 weeks with follow-up visits at 2 and 8 weeks. Outcome measures were obtained through diary cards, questionnaires, and naked eye examination. Data from these 120 women were compared with data from 419 women who used the unstrapped FemCap in a previous contraceptive effectiveness study. RESULTS: The strapped device was not significantly easier for users to remove than the unstrapped device. Similar odds of dislodgment and cervical/vaginal irritation were seen with the two devices. Both female and male participants were significantly more likely to report pain/discomfort with use of the strapped device. Female users of the strapped device were significantly more likely to say they disliked their device. In six weeks, two pregnancies were observed, but pregnancy was not an endpoint in the study and no conclusions should be drawn regarding pregnancy rates. CONCLUSIONS: The modifications to the FemCap did not significantly improve the ease of device removal and appears to have resulted in significantly more female and male partner pain/discomfort and decreased acceptability, compared with the unstrapped device.

Efficacy and Safety of an Injectable Combination Hormonal Contraceptive for Men.

CONTEXT: The development of a safe and effective reversible method of male contraception is still an unmet need. OBJECTIVE: Evaluation of suppression of spermatogenesis and contraceptive protection by coadministered im injections of progestogen and testosterone. DESIGN: Prospective multicentre study. SETTING: Ten study centers. PARTICIPANTS: Healthy men, aged 18-45 years, and their 18- to 38-year-old female partners, both without known fertility problems. INTERVENTION: Intramuscular injections of 200-mg norethisterone enanthate combined with 1000-mg testosterone undecanoate, administered every 8 weeks. MAIN OUTCOMES MEASURES: Suppression of spermatogenesis by ejaculate analysis, contraceptive protection by pregnancy rate. RESULTS: Of the 320 participants, 95.9 of 100 continuing users (95% confidence interval [CI], 92.8-97.9) suppressed to a sperm concentration less than or equal to 1 million/mL within 24 weeks (Kaplan-Meier method). During the efficacy phase of up to 56 weeks, 4 pregnancies occurred among the partners of the 266 male participants, with the rate of 1.57 per 100 continuing users (95% CI, 0.59-4.14). The cumulative reversibility of suppression of spermatogenesis after 52 weeks of recovery was 94.8 per 100 continuing users (95% CI, 91.5-97.1). The most common adverse events were acne, injection site pain, increased libido, and mood disorders. Following the recommendation of an external safety review committee the recruitment and hormone injections were terminated early. CONCLUSIONS: The study regimen led to near-complete and reversible suppression of spermatogenesis. The contraceptive efficacy was relatively good compared with other reversible methods available for men. The frequencies of mild to moderate mood disorders were relatively high.

Expanded Phase I safety and acceptability study of 6% cellulose sulfate vaginal gel.

BACKGROUND: An expanded Phase I trial was performed to assess the safety and acceptability of 6% cellulose sulfate gel (CS) in comparison with K-Y Jelly. METHODS: Sexually abstinent (cohort I) and sexually active (cohort II) women in India, Nigeria and Uganda applied 3.5 ml of either 6% CS gel or K-Y Jelly for seven consecutive days. Safety was assessed by symptoms and signs (including colposcopy) of genital irritation, review of adverse events, and by changes in vaginal health as assessed by microscopy. RESULTS: One hundred and eighty women (90 on CS and 90 on K-Y Jelly) were enrolled. Baseline characteristics of women in both gel groups were similar. In cohort I, six (14%) women on CS and 12 (27%) on K-Y Jelly reported genital symptoms, two (in K-Y Jelly group) of whom withdrew from the study. New colposcopy findings or findings showing deterioration were detected in four (9%) women on CS and nine (21%) women on K-Y Jelly in cohort I. Two women on CS and three on K-Y Jelly in cohort II reported genital symptoms. Five women (11%) in each gel group in cohort II had new colposcopy findings or findings showing deterioration. The differences between the gel groups were not statistically significant. The majority of women had no problem with their assigned product. CONCLUSION: A vaginal application of 6% cellulose sulfate twice daily for seven consecutive days is as safe and well tolerated as a similar regimen of K-Y Jelly. Further development of 6% CS for prevention of HIV and pregnancy is recommended.

Male tolerance of ACIDFORM gel.

BACKGROUND: ACIDFORM gel is being studied as a vaginal contraceptive and microbicide. This study was conducted to make certain that males will not be subjected to an unacceptable risk of penile irritation as a result of exposure to the product in future studies. METHODS: This was a randomized, double-masked, single-center Phase I study in circumcised and uncircumcised men to assess penile irritation, safety and acceptability of seven consecutive doses of ACIDFORM gel compared with K-Y Jelly Personal Lubricant. Each participant was instructed to apply 2 mL of the study product to his penis at bedtime, to wash it off 6-10 h later and to record any symptoms on a diary card. At the follow-up visit, a genital examination was performed and participants were asked about adverse events (AEs) and completed an acceptability questionnaire. RESULTS: Of the 36 men enrolled, 2 out of 24 (8.3%) ACIDFORM gel users and 5 out of 12 (41.7%) K-Y Jelly users reported genital symptoms. Genital examination findings were observed in 2 out of 24 (8.3%) ACIDFORM gel users and in 1 out of 12 (8.3%) K-Y Jelly users. All product-related AEs were considered mild except for two in the K-Y Jelly group. Both products were acceptable. CONCLUSION: ACIDFORM gel applied to the penis for seven consecutive days appears to be at least as safe and well-tolerated as the marketed lubricant K-Y Jelly among healthy low-risk men.

Lea's Shield: colposcopic and microbiological testing during 8 weeks of use.

OBJECTIVES: The aims of this study were to assess the effects of Lea's Shield(R) plus nonoxynol-9 spermicide on signs and symptoms of female genital irritation and cervical and vaginal microflora during 8 weeks of use with intercourse and to analyze problems associated with the use of the device. METHODS: In this open-label, single-arm study, participants were evaluated by pelvic examination, colposcopy and vaginal and cervical cultures. RESULTS: About 13% of women (4/30) reported symptoms of irritation, and minor product-related colposcopic findings were seen in about one third (11/30). Although average colony counts for enterococcus, Escherichia coli and anaerobic gram-negative rods increased during product use, no clinical diagnoses of infection were made. Most users reported at least one problem using Lea's Shield. CONCLUSION: Lea's Shield, when used for 8 weeks during intercourse, is associated with evidence of genital irritation in a minority of users and with changes in vaginal microflora that do not appear to correlate with clinical infections.

Comparative acceptability study of the Reality female condom and the version 4 of modified Reddy female condom in India.

OBJECTIVE: Affordable, acceptable and effective female controlled options are required worldwide for prevention of human immunodeficiency virus (HIV) infection and other sexually transmitted diseases. We carried out a comparative acceptability study of Reality and Reddy (version 4) female condoms. METHODS: Sixty eligible couples were enrolled and randomly assigned to use either Reality or Reddy condom first. They used three Reality condoms and three Reddy condoms each with at least one condom use per week. RESULTS: Reddy female condom had a significantly better acceptability than Reality condom among women who were less educated and who had not used male condom before. In spite of higher acceptability score, participants were less confident about the Reddy condom for protecting them from HIV disease or pregnancy as compared to a male condom. CONCLUSIONS: Female condoms are being introduced in India. This study has generated data that is suggestive of optimism for this female controlled option.

Contraceptive efficacy, safety, fit, and acceptability of a single-size diaphragm developed with end-user input.

OBJECTIVE: To estimate contraceptive efficacy, safety, acceptability, and fit of a single-size diaphragm used with contraceptive gel. METHODS: We conducted a multicenter trial in which 450 couples used the single-size diaphragm, 300 randomized to acid-buffering gel and 150 to nonoxynol-9, for at least 190 days and six menstrual cycles. Visits were at enrollment and after menstrual cycles 1, 3, and 6. Study outcomes included pregnancy probability, safety, acceptability, and fit. Pregnancy and safety were compared with an historical control group who used a standard diaphragm with these gels. RESULTS: Most (439/450 [98%]) women could be fitted with the single-size diaphragm. A total of 421 of 450 (94%) provided follow-up. The 35 study pregnancies yielded 6-month Kaplan-Meier cumulative typical use pregnancy probabilities per 100 women with 95% confidence intervals (CIs) of 10.4 (6.9-14.0) for all users and 9.6 (5.5-13.6) and 12.5 (5.4-19.5) with acid-buffering gel and nonoxynol-9, respectively. Historical control analysis yielded a propensity score-adjusted estimate of this pregnancy probability for the single-size diaphragm of 11.3 compared with 10.7 per 100 women for the standard diaphragm ([rounded] difference 0.7, 95% CI -3.6 to 4.9). Approximately half (51%) reported at least one urogenital event but compared favorably to the standard diaphragm in historical control analysis. Most (282/342 [82%]) liked the diaphragm. Results suggest that if provided by a clinician, 94% (95% CI 92-96%) could insert, correctly position, and remove the diaphragm. CONCLUSION: The single-size diaphragm was safe, as effective as a standard diaphragm, and acceptable when used with contraceptive gel. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT00578877.

Male tolerance study of 1% C31G.

BACKGROUND: C31G is being studied as a vaginal contraceptive and microbicide. This study was conducted to ensure that male partners of the women in future trials of C31G will not be subjected to an undue risk of penile irritation. METHODS: This was a randomized, double-blinded, single-center Phase I study in circumcised and uncircumcised men to assess penile irritation, safety and acceptability of seven consecutive daily doses of 1.0% C31G compared with a marketed spermicide, Extra Strength Gynol II(R) (3% nonoxynol-9) (ES Gynol II). Each participant was instructed to apply the study product to his penis at bedtime, to wash it off 6-10 h later, and to record any symptoms on a diary card. At the follow-up visit, a genital examination was performed and participants were again asked about adverse events and to complete an acceptability questionnaire. RESULTS: Of the 36 men enrolled, 12.5% of C31G users and 16.7% of Extra Strength Gynol II users reported product-related adverse events (AEs). All product-related AEs were considered mild by the investigator, except for one in the ES Gynol II group. Both products were acceptable. CONCLUSION: The manner in which the products were used in this study is not the route by which men will be exposed to such products in actual use, and results should be considered in this light. Based on the observations in this study, C31G appears to be at least as safe and acceptable for male penile exposure as the marketed product ES Gynol II.

A phase I comparative postcoital testing study of three concentrations of C31G.

BACKGROUND: C31G is a broad-spectrum antibacterial agent that shows contraceptive properties in vitro. This postcoital testing study evaluated the ability of three C31G concentrations, 0.5%, 1.0% and 1.7%, administered as a 3.5-mL dose of a vaginal gel to prevent sperm from entering mid-cycle cervical mucus. Irritation of the genitalia and acceptability were also assessed. METHOD: At baseline, a mid-cycle cervical mucus test and a postcoital test were performed within 24 h of each other without use of any study products to establish normal mid-cycle cervical mucus and sperm penetration. Subjects then completed up to three test cycles using one of the three concentrations of study product during intercourse. RESULTS: Twenty-two of the 61 women enrolled completed a baseline cycle and at least one test cycle. An average of 14.6 progressively motile sperm per high power field was seen at baseline. This was reduced to 0.3 after use of 0.5% C31G, 0.5 after use of 1.0% C31G, and 0.4 after use of 1.7% C31G. There was no significant difference between test products (p >/= 1.000) but each test product was significantly different from baseline (p < 0.002). Very little genital irritation was observed. There were more reports of leakage and messiness with increasing C31G concentration. CONCLUSION: This study suggests that all three concentrations of C31G are likely to give reasonable results in a contraceptive effectiveness trial. Based on the results of this and other trials, the 1.0% concentration has been selected for further development, including Phase III trials of contraceptive effectiveness.

A randomized Phase I vaginal safety study of three concentrations of C31G vs. Extra Strength Gynol II.

BACKGROUND: C31G is an antimicrobial and spermicidal agent that contains two surface-active compounds, cetyl betaine and myristamine oxide. It is being developed as a vaginal microbicide and contraceptive. METHOD: Three C31G concentrations (0.5%, 1.0% and 1.7%) were tested and compared with Extra Strength Gynol II(R), a marketed spermicide containing 3% nonoxynol-9 (N-9), in a randomized, double-blinded, Phase I, dose-escalation study to assess genital irritation (by subject report, visual examination at pelvic examination and colposcopy), plasma and vaginal lavage levels of C31G, product leakage, systemic safety and acceptability. Women were randomized to use 3.5 mL of one of the three C31G products or the N-9 gel at night for 7 days then twice daily for another 7 days. Pelvic and colposcopic evaluations were performed after 7 and 14 days of product use. RESULTS: The percent of women experiencing irritation in the 0.5% and 1.0% C31G groups in the study were similar to each other and were lower than the percent experiencing irritation in the 1.7% and N-9 groups, which were also similar to each other. Differences were statistically significant between 1.0% C31G vs. N-9 at 7 days and between 0.5% C31G and 1.0% C31G vs. N-9 at 14 days. There was no significant difference between groups in leakage or acceptability. No C31G was detected in the plasma of any volunteer. CONCLUSIONS: These results suggest that 0.5% and 1.0% C31G are less irritating to the female genital tract than 1.7% C31G or Extra Strength Gynol II.

A comparison of techniques to assess cervicovaginal irritation and evaluation of the variability between two observers.

BACKGROUND: Colposcopy is used to evaluate effects of new vaginal products on cervicovaginal epithelium as part of the US Food and Drug Administration-mandated product approval process, yet few aspects of its use have been investigated. OBJECTIVES: To determine the effect of the colposcopic examination itself on the number and type of findings seen, to compare colposcopy with the AviScope hand-held device and the naked eye and to compare the findings reported by two examiners during a single visit. STUDY DESIGN: Fourteen healthy women volunteered for five paired examinations in random order: (1) naked eye inspection plus colposcopy done twice by a single examiner; (2) naked eye inspection plus AviScope examination, then naked eye inspection plus colposcopy by a single examiner; (3) Examination 2 repeated with the order of device reversed; (4) naked eye inspection plus colposcopy done by two examiners; (5) Examination 4 repeated with the order of examiner reversed. The colposcopic examinations were done per published standards but were limited to the areas visible without manipulation of the speculum. RESULTS: Length of colposcopic examination averaged 7 min. The number of colposcopic findings found when the examination was done twice by the same clinician was not statistically different (p = 0.12), suggesting that the examination itself did not induce findings. More findings were seen using magnification than naked eye. A similar number of findings were seen by AviScope compared to the colposcope (p = 0.99), but clinically significant findings were "undercalled" or "overcalled" by the AviScope. A weighted kappa score of the "worst" colposcopic finding was 0.32 (SE 0.10, p = 0.00), indicating moderate agreement between examiners. CONCLUSIONS: The colposcopic examination is not burdensome nor does it induce findings. If naked eye observation were used alone in practice, these data suggest that half the colposcopically detected findings would be missed. Using the naked eye observation for screening would minimally reduce the number of magnified observations carried out. For detecting epithelial changes, the colposcope seems to be the most sensitive technique, followed by the AviScope.