Objectives: To assess the safety and acceptability of 2 vaginal microbicide gels (Acidform and BufferGel) used with a diaphragm compared to KY Jelly used with a diaphragm among low-risk, sexually abstinent women.
Study Design: Eighty-one women enrolled in a randomized, masked, phase I safety study using a diaphragm with Acidform, BufferGel, or KY Jelly for 6 to 10 hours nightly for 14 nights. Physical examination, colposcopy, and lab studies were performed after 1 and 2 weeks of use. Diaries and questionnaires were used to assess user acceptability.
Results: Sixty-nine participants (85%) completed the study. Safety and acceptability appeared similar among the 3 study groups and no serious adverse events related to the study products were reported. Adverse events were mild and anticipated.
Conclusions: Acidform and BufferGel compared to KY Jelly, when used with diaphragm daily for 14 days, appeared to be safe and acceptable in a small study of low-risk abstinent women.
A Phase I study of low-risk, sexually abstinent women found that Acidform and BufferGel, compared to KY Jelly when used with a diaphragm, appeared to be safe and acceptable.
From the *CONRAD, Arlington, VA; †Women's Health and Fertility Branch, Division of Reproductive Health, Centers for Disease Control and Prevention, Atlanta, Georgia; ‡CONRAD Clinical Research Center, Eastern Virginia Medical School, Norfolk, Virginia; §University of Pittsburgh and the Magee Womens Research Institute, Pittsburgh, Pennsylvania; |Departments of Obstetrics and Gynecology and the Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania Medical Center, Philadelphia, Pennsylvania; ¶Family Health International, Research Triangle Park, North Carolina
The Acidform gel was donated by Instead, Inc., LA Jolla, CA, and the BufferGel was donated by ReProtect, Inc., Baltimore, MD. The authors gratefully acknowledge the excellent study coordination by Sharon Long (EVMS), Lorie Maloney (University of Pennsylvania), and Lynne Reid (University of Pittsburgh). The authors also thank the following individuals: Jaim-Jou Lai for his work on the study analysis; Dr. Katherine M. Stone for her assistance in the analysis and preparation of this manuscript; and Angela Prince and Jennifer Legardy-Williams for administrative support of the study.
This subproject (MSA-03-360) was supported by CONRAD, Eastern Virginia Medical School, under a Cooperative Agreement with the United States Agency for International Development (USAID) (HRN-A-00-98-00020-00), which in turn receives funds for AIDS research from an interagency agreement with the Division of Reproductive Health, Centers for Disease Control and Prevention (CDC). The study was also funded in part by NIH General Clinic Research Center Grants (MO1RR000056) at the University of Pittsburgh.
The findings and conclusions in this article are those of the authors and do not necessarily represent the views of the CDC, USAID, or CONRAD. Use of trade names is for identification purposes only and does not constitute endorsement by the CDC or the US Department of Health and Human Services.
Correspondence: D'Nyce Williams, 4770 Buford Highway, Mailstop K34, Atlanta, GA 30341. E-mail address: firstname.lastname@example.org.
Received for publication November 29, 2006, and accepted June 3, 2007.
THE WORLDWIDE EPIDEMIC OF HIV and other sexually transmitted infections (STIs) among women has led to an increased interest in female-controlled methods of STI prevention that also provide contraception.1,2 Condom use is currently the only contraceptive method that has been shown to provide protection against HIV and other STIs.1,3–5 Many women, however, are unable to negotiate condom use with their male partners. Therefore, a female-controlled product with dual protection against pregnancy and STI could significantly reduce HIV, STI, and unintended pregnancies.1,6 A variety of potential female-controlled solutions are currently under investigation, including several microbicides 7–10 for use alone or with a barrier contraceptive method such as the diaphragm.
Nonoxynol-9 (N-9), a commercially available detergent-type spermicide with a long history as a contraceptive, was one of the first products evaluated for its potential use as protection against both pregnancy and STIs. Recent research, however, found that frequent use of N-9 by sex workers increased the risk of HIV transmission, compared with placebo, possibly by increasing mucosal irritation and epithelial disruption.11–14 Acidform and BufferGel are two candidate microbicides that show in vitro spermicidal and antibacterial activity against certain STI pathogens such as Neisseria gonorrheoae and Chlamydia trachomatis.15–17 Their mechanism of action is very different from that of N-9. Both Acidform18 and BufferGel15,19 are acidic buffers, with a pH of 3.5 and 3.9, respectively. Both products maintain low vaginal pH in the presence of relatively alkaline semen. Low vaginal pH has been shown to inactivate most STI pathogens, including HIV, as well as sperm.17,20,21 In addition, when mixed with semen, the viscosity of both Acidform and BufferGel creates a matrix that impedes sperm mobility.7,15
The use of the diaphragm has declined as hormonal contraceptives have become popular and widely available.22 The diaphragm (used with a spermicidal gel) works as a contraceptive by covering the cervical os and blocking the entry of sperm into the uterus. By acting as a physical barrier to the cervix, the diaphragm also has promise for protection against cervical STIs, because the cervical mucosa is the primary portal of entry for Chlamydia trachomatis, Neisseria gonorrhoeae, and possibly HIV.2 Observational studies have found a reduced risk of STIs among diaphragm users when compared with nonusers.2,5,23–25 Randomized controlled trials (RCTs) are currently underway to evaluate the effectiveness of the diaphragm when used with nonspermicidal vaginal lubricants against the acquisition of HIV and other STIs.26
Phase I clinical safety trials have suggested that vaginal application of Acidform7,27 and BufferGel15,19 is safe. Although studies have evaluated the effectiveness of vaginal microbicides alone and the use of the diaphragm alone against STIs, to date the diaphragm has not been studied in combination with buffering microbicides.1 Commercially available vaginal lubricants are not known to be spermicidal, and commercially available spermicides are not known to have significant microbicidal activity. Therefore, a diaphragm used with an effective spermicidal microbicide may provide cost-effective, female-controlled protection against STIs and conception. The combination of a barrier method and a chemical method may provide superior protection than either product used alone, and may potentially have synergistic effects. The US Food and Drug Administration (FDA) granted clearance for Acidform to be marketed as a personal lubricant (Amphora) in 2004. This study evaluates the safety of 2 candidate vaginal microbicides, Acidform and BufferGel used with a diaphragm. Information obtained in this study will also guide the microbicide selection for use in a planned RCT to evaluate the efficacy of the microbicide with the diaphragm in reducing the transmission of gonorrhea and chlamydia.
Materials and Methods
The study was a randomized double-masked Phase I safety trial that compared the safety of 2 microbicides, Acidform (Instead Inc., LA Jolla, CA) and BufferGel (ReProtect Inc., Baltimore, MD) with that of KY Jelly (Personal Products, Raritan, NJ) when used with a diaphragm nightly for 14 consecutive nights. The study was conducted at 3 sites: Eastern Virginia Medical School (Norfolk, VA), the University of Pennsylvania Medical Center (Philadelphia, PA), and the University of Pittsburgh (Pittsburgh, PA) - from May to December 2004. All participants were informed and provided written consent before participating in the study. The study protocol was approved by local Institutional Review Boards at each of the 3 sites and at the Centers for Disease Control and Prevention (CDC).
Healthy, sexually active women aged 18 to 48 years old with regular menstrual cycles (average, 26–30 days) or amenorrheic on hormonal contraceptives for at least 3 months, who were willing to abstain from intercourse during the study period were eligible. Women were excluded if they were unable or unwilling to participate in the study and attend all study visits; currently used an intrauterine device for contraception; were allergic to silicone, KY Jelly, or latex; had a history of toxic shock syndrome; currently had gonorrhea, chlamydia, or trichomoniasis; were currently pregnant or planning to become pregnant within the next 2 months; had a total hysterectomy; had a history of cervical cytopathology within the past 12 months; had cervical or vaginal lesions suspicious for dysplasia or neoplasia; had irregular vaginal bleeding; reported douching within 30 days of enrollment; were unwilling to refrain from douching or from using non–study-related intravaginal products; or were unable to comply with the study protocol.
At the screening visit, women provided urine samples for urinalysis and pregnancy testing. If the urinalysis indicated a urinary tract infection, women were treated and allowed to participate in the study after completing therapy. A pelvic examination was performed that included a wet mount, gonorrhea and chlamydia testing by DNA amplification, and an evaluation of vaginal pH. If bacterial vaginosis (BV) was identified by Amsel's criteria, the women received a prescription for 7 days of oral medication and were considered eligible for enrollment within 5 days of the end of their subsequent menstrual cycle. Women who were diagnosed with trichomoniasis by wet mount or whose gonorrhea or chlamydia test was positive were not enrolled. Instead, they were counseled and given appropriate treatment. After the pelvic examination, the women were fitted for a Milex Wideseal Arcing diaphragm (CooperSurgical, Chicago, IL) and were given verbal and written information on correct diaphragm use and cleaning. They were then asked to demonstrate proper insertion and removal before leaving the clinic. Women who were unable to correctly insert the diaphragm were considered screen failures.
Study participants were enrolled in the study within 5 days after the end of their next menstrual period to avoid menstrual bleeding during the study. At the enrollment visit, a pelvic examination was performed, including a wet mount and Gram stain. A colposcopic examination of the lower genital tract was performed according to the CONRAD/WHO Manual for the Standardization of Colposcopy for the Evaluation of Vaginal Products (2004).
Eligible women were randomly assigned to 1 of the 3 treatment groups: Acidform, BufferGel, or KY Jelly in equal ratios. Block randomization was used to ensure an equal number of participants in each treatment group for each study site. The study gels were packaged in identical multiuse tubes labeled with a participant number by an independent supplier. Study participants and all study personnel were masked to the study gel assignments.
Study participants were instructed to insert 5 mL of the assigned study gel into the concave portion of the diaphragm with a reusable plastic applicator, and to then insert the diaphragm into the vagina. They were asked to wear the diaphragm and gel for 6 to 10 hours each night for 14 consecutive nights, and to record insertion and removal times along with comments and problems in a daily diary. Women were asked to abstain from sexual activity during the study and were instructed not to use any vaginal products other than the study gel and diaphragm for the duration of the study.
Follow-up assessments were scheduled on study Days 8 and 15, although study participants could return for unscheduled visits if they experienced problems. At Day 8, the women arrived for their follow-up visit having removed their diaphragms 3 to 6 hours before the visit. On Day 15, women arrived for their visit with their diaphragms in place to enable the study clinician to identify any immediate effects of the diaphragm and study gel on the cervical and vaginal epithelium. At each follow-up visit, the study staff reviewed the participant's diary, administered an acceptability questionnaire, performed a pelvic examination including a Gram stain specimen, and performed a colposcopic evaluation. Women diagnosed with BV or a vaginal infection requiring medical treatment at any time after enrollment were discontinued from the study. Similarly, any study participant who was diagnosed with any other medical condition which required antibiotic therapy was discontinued from the study, as the vaginal microflora would be expected to be altered.28
Cervico-vaginal lavage (CVL) was performed using normal saline for cytokine evaluation at enrollment, Day 8 and Day 16. The results of the cytokine analyses are discussed in another publication29 and, therefore, are not presented here.
The primary endpoints were designed to assess the safety and acceptability of Acidform or BufferGel used with a diaphragm compared to KY Jelly used with a diaphragm. The endpoints included proportions of women and frequencies of vaginal or cervical mucosal irritation or disruption identified by pelvic examination and colposcopy, changes in occurrence of BV as measured by vaginal smear Gram stain, and adverse events (AE). Participant acceptability and adherence were secondary endpoints.
The occurrence of vaginal/cervical mucosal irritation or disruption was evaluated by pelvic examination and colposcopy (CONRAD/ WHO Manual for the Standardization of Colposcopy for the Evaluation of Vaginal Products, 2004). Mild colposcopic findings were those in which both the epithelium and blood vessels were intact. Moderate colposcopic findings included those in which the epithelium was superficially disrupted and/or blood vessels were disrupted (but not bleeding). Severe findings were those with deep disruption of the epithelium, meaning disruption that extended into the subepithelial layer (for example, an area of bleeding epithelium was considered deeply disrupted). In addition to this classification, other clinical information was recorded, such as size, location, and color of the finding, and whether the finding was judged to be related to the study products. Relatedness was determined by the study clinicians based on the known effects of the microbicides (per investigators' brochures) and their clinical judgment. Iatrogenic colposcopic findings were excluded from analysis. A finding was considered iatrogenic if the investigator directly observed the new onset of the finding during the examination (e.g., during speculum insertion or manipulation, probing with cotton swab, or after using pH paper).
Gram stain specimens were collected, batched and sent to a central laboratory where they were assessed for BV using Nugent scoring.30 A score between 0 and 3 represents normal vaginal flora, and between 7 and 10 represents BV. A score between 4 and 6 is intermediate.
Based on Guidelines for Good Clinical Practice (GCP), an AE was defined as “any untoward medical occurrence in a study participant administered a study treatment, which does not necessarily have a causal relationship to the treatment.”31 A serious adverse event (SAE) was defined as any experience that was fatal or life-threatening, required hospitalization or prolongation of an existing hospitalization, resulted in persistent or significant disability or incapacity, was a congenital anomaly or brain defect, or any other event deemed serious by the clinical investigator(s). AEs were categorized by severity, expectedness, and relationship to the study treatment based on Investigator's Brochures, package inserts and/or and previous research findings. Based on the safety profiles of the diaphragm and study gels, only mild AEs were expected.
If a woman had at least one scheduled or unscheduled follow-up visit, she was included in the endpoint analyses. Study participants were considered adherent if they used the study products for at least 13 nights. Clinical findings were summarized for the entire follow-up period and the acceptability measures were summarized by visit. Data were managed using Clintrial version 4.3 (Clinsoft Corporation, Nashua, NH). Statistical analyses for this paper were conducted by CDC using The SAS System version 8.2 (SAS Institute, Cary, NC). Fisher's Exact Tests were used to assess differences in proportions across treatment groups, pooling sites. All reported P values were 2-sided and P <0.05 was considered to be statistically significant. P values were not adjusted for multiple comparisons. Because the sample size was not based on statistical considerations, all p-values were exploratory and the results of statistical tests serve only as supplementary information to guide clinical interpretation. The tests have power to detect only large differences between groups.
A total of 120 women were screened, of which 81 (27 per study group) were enrolled in the study (Fig. 1). The most common reasons for ineligibility were irregular/long cycle length (8 women), current STI (5 women), bladder infection (5 women) and inability to comply with study visits (5 women). The mean age of the enrolled women was 30.6 years. More than two-thirds of the study participants identified themselves as white, 28.4% as black, 2.5% as Asian; 2.5% identified themselves as Hispanic/Latina (Table 1). All of the study participants had completed high school, and 40% were college graduates. Fifty-six percent of the study participants were single, and 37% were married. One-fourth of study participants had prior experience with a diaphragm.
Twelve women did not complete all of the study visits (Fig. 1). Of the 7 women in the Acidform group who discontinued, only 2 did so for medical reasons related to the study (urinary tract infection and yeast infection, respectively). Two additional women discontinued for medical reasons unrelated to the study (shaving abrasion and infected tattoo, respectively). The other 3 women discontinued for personal reasons (couldn't keep appointments/job termination). One woman in the BufferGel group discontinued because she disliked the study gel, and one woman was involved in a car accident. In the KY Jelly group, one woman discontinued because she was unable to remove the diaphragm at home, and another was uncomfortable touching her genitals. The remaining woman was unable to keep study appointments. No women in the study were lost to follow-up.
Abnormal pelvic examination findings (seen with the naked eye) were infrequent at both baseline and follow-up (Table 2). The most frequent abnormal finding at both baseline and during follow-up physical examination finding was vulvar/vaginal erythema, which was seen in less than 15% of each group at baseline and during follow-up. No occurrences of edema, excoriations, or abrasions were identified at baseline. During follow-up, however, 1 occurrence each of edema (Acidform), vulvar excoriation (BufferGel) and cervical abrasion (BufferGel) was identified among the study participants.
At baseline, 23 study participants had a total of 38 colposcopic findings. Table 2 categorizes the study participants according to each woman's worst colposcopic finding that was identified at baseline or follow-up. The number of women at baseline with mild versus moderate findings was approximately equally distributed across the 3 treatment groups. During the follow-up period, 42 women were found to have 74 new colposcopic findings. The proportions of women with mild colposcopic findings during the follow-up period were similarly distributed across the 3 treatment groups. The proportions of women with moderate colposcopic findings, and the total number of moderate colposcopic findings was approximately twice as high in the Acidform and BufferGel groups than in the KY Jelly group, but sample sizes were small and the differences were not statistically significant. Two women with severe colposcopic findings were identified at the Day 15 visit in the Acidform group. One woman had a small external genital abrasion, and the other had a small lesion (<5 mm) on the face of cervix. The frequency of women with multiple colposcopic findings was approximately twice as high in the Acidformgroup as in the KY Jelly and BufferGel groups (9 compared to 5 and 5, respectively). None of the colposcopic findings was associated with clinical complaints from the study participants.
None of the women in the study was diagnosed with BV by clinical (Amsel's) criteria at baseline or during follow-up. However, review of vaginal smears for Nugent scoring at baseline identified 4 women in the KY Jelly group with BV. In addition, 3 women—2 in the Acidform group and 1 in the KY Jelly group—developed incident BV by Nugent scoring during the follow-up period. All but 1 of the BV cases identified during the study resolved spontaneously by the end of the study. One of the incident BV cases (KY Jelly group) was identified at the Day 15 visit.
There were 45 AEs among 26 women. Twenty-six of the AEs, which occurred among 18 women (6, 7, and 5 women in the Acidform, BufferGel and KY Jelly groups, respectively), were at least possibly related to the study products (Table 3). The most frequent of these, vaginal itching (7 AEs), was reported 6 times among 4 women in the BufferGel group. The unrelated AEs included headache, tendonitis, diarrhea, abdominal pain, and bronchitis. The highest number of AEs reported for a single study participant was 4. Two study participants each had 4 AEs—1 study participant (BufferGel group) had 4 AE which were deemed unrelated to the study products (cold, diarrhea, pulled neck muscle, and tendonitis), and the other study participant (Acidform group) had 1 AE which was considered unrelated (intermittent abdominal cramping) and 3 which were thought to be probably related to the study products (intermittent suprapubic discomfort, vaginal discharge and vaginal odor). There were no study-related SAEs, and the overall frequency of AEs was similar for all 3 treatment groups.
Approximately 80% of the study participants liked the diaphragm and gel or had no opinion at Day 8 and at Day 15 (Table 4). The differences between groups at Day 15 (among those who completed) approached statistical significance (P = 0.051) with more women liking the diaphragm with KY Jelly or BufferGel than with Acidform. In general, opinions about the diaphragm appeared to remain consistent across time whereas the proportion of women who liked their assigned gel changed with time. The percentages of women who reported that they liked the study gel were similar at Day 8 (although slightly lower in the BufferGel group), but the differences were statistically significant at Day 15, with more women in the KY Jelly group liking the study gel than the women in either the Acidform (P = 0.02) or BufferGel (P = 0.03) groups.
Over 93% of the women reported that the diaphragm and gel were comfortable, and only 17% of study participants reported problems inserting or removing the diaphragm and gel. When asked specifically about their experience with the diaphragm, however, 63% of the study participants disliked something about it (Table 4). The most common complaints were insertion/removal, messiness and discomfort. Overall, 42% of study participants disliked something about their study gel, but 64% still reported that they liked the gel at Day 8. The overall frequency of complaints was similar for all treatment groups. Women in each group reported messiness, whereas other complaints were group-specific. All of the reports of odor (n = 3) and stinging (n = 2) occurred in the Acidform group. All reports of clumpiness (n = 6) and most complaints of vaginal itching (n = 6) occurred in the BufferGel group. Reports of discharge/excess moisture occurred primarily in the KY Jelly group (n = 5). Because the daily use of an intravaginal gel could be expected to result in increased vaginal discharge, this observation was not considered an AE—it more likely represents a difference in the physical properties of KY Jelly compared to the 2 microbicide gels.
All 69 women who completed the study used the study products for at least 13 days. None of the study participants used the diaphragm without the study gel; however, 1 study participant (KY Jelly group) used the study gel once without the diaphragm. Within the BufferGel group, 1 study participant used another lubricant (KY Jelly) 3 times during the study due to vaginal dryness, and 1 study participant did not remain sexually abstinent (1 act of intercourse).
This study evaluated the safety, acceptability, and adherence of Acidform or BufferGel used with a diaphragm compared with KY Jelly used with a diaphragm for 14 nights among low-risk, sexually abstinent women. Our analyses found very few statistically significant or clinically meaningful differences between the 3 treatment groups during follow-up, but the study was powered to detect only large differences. Because the sample size in this study was not based on statistical considerations, the results of the statistical tests were provided only as supplementary information to guide clinical review.
The primary endpoints, in general, were more frequent in the 2 microbicide groups than in the KY Jelly group. Genital irritation was measured by the presence of vaginal or cervical mucosal irritation or disruption, seen by “naked eye” or colposcopic examination. In our study, naked eye findings were infrequent at baseline and during follow-up, and in the majority of the findings, both the epithelium and blood vessels were intact. Only 2 epithelial disruptions (1 vulvar excoriation and 1 cervical abrasion) were seen with the naked eye during follow-up (both were in the BufferGel group, only 1 was thought related to product use, and neither involved deep epithelial disruption).
Colposcopically detected lesions of moderate severity were seen nearly twice as frequently in the 2 microbicide groups as in the KY Jelly group, and the Acidform group had the most women with multiple findings and the only severe findings. Similar to observations in previous studies, the colposcopic findings observed in this study were not associated with clinical complaints from the study participants.14,32,33 Although these data suggest that Acidform may be less safe than BufferGel or KY Jelly, and studies have reported an association between HIV transmission and ulcerative lesions, there is no compelling evidence that superficial microscopic epithelial disruptions (e.g., moderate colposcopic findings) increase HIV risk.11,34,35 Superficial epithelial disruptions are present following intercourse, tampon use, and speculum examinations.36,37 Over 28% of our study participants had mild or moderate colposcopic findings identified at baseline (similarly distributed across treatment groups), compared to 53% during follow-up. The 2 severe colposcopic findings (both in Acidform group) were seen only via colposcopy. One of the findings was an external genital abrasion located on the inferior area of the right labia minora near the introitus, and the second lesion was a small lesion on the surface of the cervix. Both of these lesions could have been caused by diaphragm insertion or removal.
Colposcopic assessment has become a required component of microbicide safety studies conducted under FDA guidance, but the clinical relevance of colposcopic lesions seen in the absence of naked-eye findings remains unclear.38 It is possible that at least some of the epithelial disruptions observed during this study were related to the insertion and removal of the diaphragm. Because all study participants used the diaphragm, this theory could not be evaluated.
The AEs that were at least possibly related to the study products were mild in nature and expected, based on information from previous Acidform and BufferGel studies.15,19,39 Additionally, the numbers of women with AEs in each treatment group appeared to be similar. Only 2 AEs, both in the Acidform group, resulted in product discontinuation (yeast infection and urinary tract infection). Both yeast infection and UTI have been associated with the use of the diaphragm, so it is not possible to determine whether these observations are associated with use of the microbicide gels as well. The most commonly reported AE that was at least possibly related to product use was vaginal itching, which was observed primarily in the BufferGel group.
Overall, women liked the diaphragm/gel combination or had no opinion about it; only 20% disliked it. The complaints about the diaphragm related primarily to insertion and removal. Although nearly half of the study participants reported that they disliked inserting/removing the diaphragm, few reported difficulty doing so. We hypothesized that because the diaphragm used in this study had an arcing spring that was compressible in only 2 discrete locations on the rim, insertion and removal could be difficult. Removal could be especially challenging because the compressible areas on the rim are not palpable, and could be difficult to locate intravaginally, making removal uncomfortable, especially if the diaphragm was removed without compressing the rim. Difficulty inserting or removing the diaphragm may increase the chance of epithelial injury. Future studies should use nondirectional spring diaphragms that compress at any 2 points along the rim, and thus are easier to use. Complaints about the study gels, although somewhat varied by group, fell into 3 categories. One group of complaints related to the physical properties of the gels such as odor (Acidform) and clumpiness (BufferGel). Another group of complaints appeared to be related to volume, such as messiness/excessive moisture and discharge (mostly among KY Jelly users). A third group included clinical symptoms such as itching (mostly BufferGel) and stinging (Acidform).
Adherence was high among study participants. All of the women who completed the study used the study products for at least 13 days. Even when including study participants who discontinued from the study, 81%, 93%, and 96% of women in the Acidform, BufferGel and KY Jelly groups, respectively, used the study product for at least 10 nights. Although more women discontinued from the Acidform group (7 women), than the BufferGel (2 women) or KY Jelly groups (3 women), the frequency of study participants who discontinued for reasons related to the study was similar across product groups.
Based on the mechanisms of action of Aciform and BufferGel, we expected to see fewer cases of BV in the active gel arms than in the KY Jelly group.40,41 Only 1 of the 3 women with incident BV identified by Nugent scoring during the current study occurred in the KY Jelly group, compared to 2 in the Acidform group and no cases in the BufferGel group. The 4 baseline BV cases identified by Nugent score in the KY Jelly group make interpretation of the results more difficult, although the comparisons of the treatment groups at baseline showed no statistically significant differences. The detection of these baseline findings by Nugent and not by clinical diagnosis (Amsel's), supports the superior sensitivity of the Nugent score.30 All but one of the BV cases identified during the study resolved by the end of the study without treatment (1 of the incident BV cases occurred at the Day 15 visit). It is unknown whether the study gels had activity against the BV pathogens or whether the resolution was simply a function of time and healthy immune systems. A recent Acidform study found that only 23% of women treated for 5 days with Acidform for BV were cured at the first follow-up visit, compared to 88% who were treated with metronidazole gel.41 Although the 2 cases of BV in the Acidform group in this study may be suggestive of less activity against BV pathogens, the numbers are too small to be conclusive.
This study had several strengths. First, 2 different buffering microbicides were compared to the KY Jelly, allowing more information on this class of microbicides to be collected than would have occurred from studying either microbicide alone. Second, the study design enabled the researchers to examine the vaginal and cervical epithelium at different time points relative to the removal of the diaphragm, which allowed for the identification of transient effects on the vaginal or cervical epithelium. Approximately 20% more moderate colposcopic findings were noted at Day 15 when the diaphragm was removed during the study visit (compared to the Day 8 visit). The Day 15 findings were similarly distributed with 8, 5, and 5 findings among the Acidform, BufferGel, and KY Jelly groups, respectively. It is unknown, however, whether the increase was related to timing of diaphragm removal, the cumulative effect of study product use, statistical chance or other factors. Third, masking of the study products to study participants and study staff, along with the use of identical packaging minimized bias. Fourth, no participants were lost to follow-up.
This Phase I study also had some limitations. Phase I studies often restrict enrollment to healthy participants. Because the participants in this study were well educated (e.g., all completed high school and 40% were college graduates), had a low STI risk, and were sexually abstinent, the results of this study may not be generalizable to less educated, higher-risk, sexually active populations. This study was designed to assess general safety; therefore, the sample size was small and the trial was unable to detect small to moderate differences between products. This means that distributions and proportions that did not seem to be statistically significant in this study might have been significant if the study population was larger. Finally, as would also be expected with a Phase I study of this nature, the requirement for sexual abstinence during product use and the study's short duration did not allow a thorough assessment of adherence and acceptability in “real world” conditions. For such answers, Phase II and III studies are needed.
The findings from this study suggest that Acidform and BufferGel have sufficient safety and acceptability profiles in Phase I testing when combined with a contraceptive diaphragm to warrant further investigation as candidate microbicides in STI/HIV prevention trials. Future research should evaluate vaginal microbicide gels used with a diaphragm among sexually active women, for longer time periods, for effectiveness against STI, including HIV, and for pregnancy prevention. A recent acceptability study in Madagascar among high-risk, sexually active women evaluated continuous use of a diaphragm with KY Jelly and reported favorable results.42 Gel-only study arms will also allow for the assessment of the effects of the diaphragm separate from the study gels. A RCT in Madagascar is planned among high risk, sexually active women to evaluate the long-term safety and efficacy of the diaphragm (worn continuously) with a microbicide gel in reducing the acquisition of gonorrhea and chlamydia. Secondary endpoints will include pregnancy rates and HIV acquisition. The results of the current study suggest that either of the 2 microbicides evaluated in this study could be used in the planned RCT. If the diaphragm/microbicide combination is found to be effective in future studies, the diaphragm with a microbicide gel could represent a commercially available, female-controlled method of protection against pregnancy and STIs for women worldwide.
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