A Phase 1 pharmacokinetic study of a single-dose bioadhesive clindamycin 2% gel for bacterial vaginosis.

OBJECTIVES: To evaluate pharmacokinetics (PK) of a single dose of an investigational 2% clindamycin phosphate vaginal gel in healthy women by assessment of plasma and vaginal clindamycin concentrations over 7 days, and assess safety. METHODS: Single-centre, Phase 1, single-dose PK study. Blood and vaginal samples were collected daily and safety was evaluated through to Day 7. RESULTS: Twenty-one subjects were enrolled; 20 completed the study. Plasma clindamycin concentrations demonstrated quantifiable values in all subjects through to 24 h post-dose, remaining above the limits of quantification (LOQ) through to 48 h for the majority of subjects. Systemic exposure (AUC0-t) was 1179 (range 62-3822) h·ng/mL. Arithmetic mean AUC0-24 was 818 (range 51-3287) h·ng/mL. Vaginal clindamycin phosphate levels were relatively high 24 h following administration in 15/21 subjects (6 subjects had values >400 µg/g and 9 had values of 100-400 µg/g). The levels dropped in most participants to below the LOQ 2 days following dosing. In a few participants, levels remained elevated for several days. Maximal amounts of vaginal clindamycin occurred on Day 2 with a mean value of 30.3 µg. One treatment-emergent adverse event (TEAE) of moderate-severity headache not related to study drug was reported and resolved on Day 1. No TEAEs were related to physical examinations, pelvic examinations, laboratory values or vital signs. CONCLUSIONS: The vaginal concentrations of clindamycin phosphate plus the clindamycin plasma profile over time are consistent with release of drug from the investigational gel over 24 to 72 h. A single dose was well tolerated.

Successful postcoital testing of Ovaprene: An investigational non-hormonal monthly vaginal contraceptive.

OBJECTIVE: Evaluate reduction in progressively motile sperm per high power field (HPF) in midcycle cervical mucus after intercourse with Ovaprene: an investigational monthly non-hormonal vaginal contraceptive consisting of a vaginal ring and mechanical barrier, releasing spermiostatic ferrous gluconate. STUDY DESIGN: Open-label, multicenter study enrolling heterosexually-active women with previous permanent contraception. Participants underwent a baseline postcoital test cycle with no device to confirm the presence of sperm, followed by one diaphragm postcoital test cycle, one Ovaprene safety cycle, and two Ovaprene postcoital test cycles. In each postcoital test cycle, participants underwent a midcycle cervical mucus evaluation to confirm an Insler score ≥10 and absence of sperm, and then returned two to four hours after vaginal intercourse for repeat cervical mucus evaluation. We considered <5 progressively motile sperm/HPF indicative of preliminary contraceptive effectiveness. RESULTS: We enrolled 38 participants; 23 completed the study. All participants had ≥5 progressively motile sperm/HPF in the baseline cycle and <5 progressively motile sperm/HPF in all 49 Ovaprene cycles and all 35 diaphragm cycles, meeting the definition of a successful postcoital test. This was true regardless of examiner blinding, prior vaginal delivery or vaginal ring use, body mass index, or dislodgements noted by the participant or investigator. The mean of 27.2 (±17.9) progressively motile sperm/HPF in baseline postcoital test cycles was reduced to 0.5 (±1.1) and 0.5 (±1.3) progressively motile sperm/HPF in the first and second Ovaprene cycles, respectively. Ovaprene fit all participants and all could insert, position, and remove it. CONCLUSION: Use of Ovaprene resulted in meeting the prespecified criterion for contraceptive effect by all participants during all postcoital test cycles. IMPLICATIONS: The finding that use of Ovaprene, an investigational monthly non-hormonal vaginal contraceptive, resulted in postcoital testing of cervical mucus that met the pre-specified definition of success (<5 progressively motile sperm/HPF) supports further evaluation of contraceptive efficacy of the device in users at risk for pregnancy.

Safety testing of Ovaprene: An investigational nonhormonal monthly vaginal contraceptive.

OBJECTIVES: Evaluate the safety of Ovaprene, an investigational nonhormonal vaginal contraceptive designed for monthly use. STUDY DESIGN: Open-label, multicenter study enrolling heterosexually-active women with previous permanent contraception who underwent assessments during five menstrual cycles: baseline postcoital test cycle, diaphragm postcoital test cycle, Ovaprene safety cycle, and two Ovaprene postcoital test cycles. Safety outcomes included treatment-emergent adverse events, systemic laboratory findings, pelvic examinations, colposcopies, Nugent scores, determination of community state types of vaginal microbiota, and anti-Escherichia coli activity and inflammatory markers in cervicovaginal fluids. RESULTS: We enrolled 38 participants. Of these, 33 used Ovaprene and completed 77 Ovaprene cycles. The most common product-related urogenital treatment-emergent adverse events were bacterial vaginosis and vaginal odor. The frequency of transitioning from Lactobacillus-dominated community state type to community state type IV (not Lactobacillus-dominated) was similar before Ovaprene use and afterwards. Mean Nugent scores were <4 at each visit without a discernible upward trend. Inflammatory markers showed wide variation but no upward trend, and E. coli inhibitory activity of cervical secretions did not change. We found no Staphylococcus aureus, the causative agent in toxic shock syndrome, on used Ovaprenes or in vaginal samples. No clinically important changes in systemic laboratory findings, pelvic examinations, or colposcopies occurred during Ovaprene use. CONCLUSIONS: Ovaprene use did not result in cervicovaginal irritation or adverse effects on resident vaginal microbiota and did not impact transitions from a Lactobacillus-dominated community state type to community state type IV. IMPLICATIONS: The finding that the use of Ovaprene, an investigational monthly user-controlled nonhormonal vaginal contraceptive, does not appear to result in adverse changes in vaginal health during short-term use supports further evaluation of the contraceptive potential of the device.

Evaluation of 28-day estradiol and progesterone vaginal rings in a phase 1 clinical pharmacokinetic study.

OBJECTIVE: The aim of this work is to develop a combination of 17ß-estradiol (E2) and progesterone (P4) in a single-dose intravaginal ring (IVR) for the treatment of vasomotor symptoms (VMS) and genitourinary syndrome of menopause while providing endometrial protection. The objective of this study was to evaluate DARE-HRT1, a 28-day IVR that continuously delivers E2 and P4, in a phase 1 clinical trial to assess its pharmacokinetics. METHODS: This was an open-label, three-arm (group) study. Thirty-two (32) healthy postmenopausal women were recruited at two Australian sites. The average age was 57.2 years (47-69 y). The first arm received one ring for 28 days designed to release E2 at a rate of 80 µg/d and P4 at 4 mg/d (80/4 IVR); the second arm received a ring releasing E2 at 160 µg/d and P4 at 8 mg/d (160/8 IVR). The third arm received oral Estrofem (1 mg E2) and Prometrium (100 mg P4) both daily for 29 days. Blood samples were taken predose then intensively over the first day (day 1) and periodically thereafter over the remaining 27 days. After removal of the rings on the morning of day 29, intensive samples were collected. Similar procedures were conducted with women enrolled in the oral group. The plasma samples were analyzed for E2, estrone (E1), and P4 using validated bioanalytical methods. RESULTS: The baseline-adjusted steady-state plasma levels of E2 and P4 from 80/4 IVR were 20.4 ± 17.1 pg/mL and 1.32 ± 0.19 ng/mL (n = 10), respectively. The baseline-adjusted steady-state plasma levels of E2 and P4 from 160/8 IVR were 30.9 ± 8.7 pg/mL and 2.08 ± 0.50 ng/mL (n = 10), respectively. The baseline-adjusted average plasma concentrations of E2 and P4 at day 29 of the oral group were 35.4 ± 11.2 pg/mL and 0.79 ± 0.72 ng/mL (n = 11), respectively. The baseline-adjusted steady state of E1 from the 80/4 IVR and the 160/8 IVR were 22.1 ± 16.6 pg/mL (n = 10) and 25.2 ± 12.3 pg/mL (n = 10), respectively. The baseline-adjusted concentration of E1 in the oral arm was 209 ± 67.7 ng/mL (n = 11). The IVR were well tolerated, and no serious adverse events were reported. CONCLUSIONS: The 80/4 IVR and 160/8 IVR gave similar steady-state concentrations of E2 as seen with drug products approved by the US Food and Drug Administration for treatment of VMS and genitourinary symptoms of menopause. The E2 concentrations of this study support the potential of DARE-HRT1, a promising new option for hormone therapy for treatment of VMS and vaginal symptoms associated with menopause.

A phase 1/2, open-label, parallel group study to evaluate the safety and pharmacokinetics of DARE-HRT1 (80 µg estradiol/4 mg progesterone and 160 µg estradiol/8 mg progesterone intravaginal rings) over 12 weeks in healthy postmenopausal women.

OBJECTIVES: Primary objectives were to evaluate the safety and systemic pharmacokinetics (PK) of DARE-HRT1, an intravaginal ring (IVR), which releases 17ß2-Estradiol (E2) with progesterone (P4) for 28 days in healthy postmenopausal women. METHODS: This was a randomized, open-label, 2-arm, parallel group study in 21 healthy postmenopausal women with an intact uterus. Women were randomized (1:1) to either DARE-HRT1 IVR1 (E2 80 µg/d with P4 4 mg/d) or DARE-HRT1 IVR2 (E2 160 µg/d with P4 8 mg/d). They used the IVR for three 28-day cycles, inserting a new IVR monthly. Safety was measured by treatment emergent adverse events and changes in systemic laboratories and the endometrial bilayer width. Baseline adjusted plasma PK of E2, P4, and estrone (E1) was described. RESULTS: Both DARE-HRT1 IVR were safe. All treatment emergent adverse events were mild or moderate and were distributed similarly among IVR1 versus IVR2 users. Month 3 median maximum plasma ( Cmax ) P4 concentrations were 2.81 and 3.51 ng/mL and Cmax E2 was 42.95 and 77.27 pg/mL for IVR1 and IVR2 groups, respectively. Month 3 median steady state ( Css ) plasma P4 concentrations were 1.19 and 1.89 ng/mL, and Css E2 was 20.73 and 38.16 pg/mL for IVR1 and IVR2 users, respectively. CONCLUSIONS: Both DARE-HRT1 IVRs were safe and released E2 in systemic concentrations, which were in the low, normal premenopausal range. Systemic P4 concentrations predict endometrial protection. Data from this study support further development of DARE-HRT1 for the treatment of menopausal symptoms.

A phase 1/2, open-label, parallel group study to evaluate the preliminary efficacy and usability DARE-HRT1 (80 µg estradiol/4 mg progesterone and 160 µg estradiol/8 mg progesterone intravaginal RinGSM) over 12 weeks in healthy postmenopausal women.

OBJECTIVES: The exploratory objectives of this study were to evaluate the usability and acceptability and to conduct a preliminary evaluation of the efficacy of DARE-HRT1. DARE-HRT1 is an intravaginal ring (IVR) that releases 17ß2-estradiol (E2) with progesterone (P4) over 28 days. It is the first combination E2 and P4 IVR being developed for the treatment of vasomotor symptoms (VMS) in healthy postmenopausal women with an intact uterus. METHODS: This was a randomized, open-label, 2-arm, parallel group study in 21 healthy postmenopausal women. Women were randomized (1:1) to either DARE-HRT1 IVR1 (E2 80 µg/d with P4 4 mg/d) or DARE-HRT1 IVR2 (E2 160 µg/d with P4 8 mg/d). They used the assigned IVR for three 28-day cycles, inserting a new IVR monthly. Preliminary genitourinary syndrome of menopause (GSM) treatment efficacy was estimated by measuring changes from baseline in vaginal pH, vaginal maturation index (VMI), and changes in the severity of GSM symptoms. Preliminary systemic VMS efficacy was measured by changes in responses to the Menopause-Specific Quality of Life (MENQOL) questionnaire. Acceptability was assessed by product experience surveys. RESULTS: Preliminary local GSM treatment efficacy was supported by significant decreases in vaginal pH and % parabasal cells, and significant increases in the overall VMI and % superficial cells for both IVR groups (all P values <0.01). Preliminary VMS efficacy was supported by significant decreases in all domains of the MENQOL questionnaire from baseline for both dosing groups (all P values <0.01). CONCLUSIONS: Data from this study support further development of DARE-HRT1 for the treatment of menopausal symptoms.

Acceptability of Single-dose Clindamycin Gel for Bacterial Vaginosis: A Randomized Controlled Trial.

PURPOSE: The goal of this study was to assess the acceptability of a single-dose bioadhesive 2% clindamycin vaginal gel for bacterial vaginosis (BV). METHODS: This double-blind, placebo-controlled, randomized study compared a new clindamycin gel with placebo gel (2:1 ratio). The primary objective was efficacy; secondary objectives were safety and acceptability. Subjects were evaluated at screening, days 7 to 14 (Day 7-14), and days 21 to 30 (test-of-cure [TOC]). An acceptability questionnaire with 9 questions was administered at the Day 7-14 visit, and a subset of questions (#7-#9) was asked again at the TOC visit. At Visit 1, subjects were provided with a daily electronic diary (e-Diary) to collect information regarding study drug administration, vaginal discharge, odor, itching, and any other treatments used. Study site staff reviewed e-Diaries at the Day 7-14 and TOC visits. FINDINGS: A total of 307 women with BV were randomized to treatment (204 to the clindamycin gel group and 103 to the placebo gel group). Most (88.3%) reported at least one previously diagnosed BV episode, and more than one half (55.4%) had experience with other vaginal treatments for BV. At the TOC visit, almost all (91.1%) of the clindamycin gel subjects described their overall experience with the study drug as "satisfied" or "very satisfied," 95.8% indicated that they would be "likely" or "very likely" to use the product again if it became available after the study and they had BV again, and 93.7% would be "likely" or "very likely" to recommend their treatment to a friend who had BV. Almost all (90.2%) clindamycin-treated subjects responded that application was "clean" or "fairly clean," as opposed to "neither clean nor messy," "fairly messy," or "messy." Although 55.4% experienced leakage in the days after application, only 26.9% of those indicated that it was bothersome. Subjects receiving clindamycin gel also reported improvement in both odor and discharge, commencing shortly after dosing and continuing through the assessment period, regardless of whether they met the critical cure criteria. IMPLICATIONS: A single dose of a new bioadhesive 2% clindamycin vaginal gel showed rapid resolution of symptoms and was highly acceptable as a treatment for bacterial vaginosis. CLINICALTRIALS: gov identifier: NCT04370548.

Single-Dose, Bioadhesive Clindamycin 2% Gel for Bacterial Vaginosis: A Randomized Controlled Trial.

OBJECTIVE: To assess efficacy and safety of a single-dose vaginal clindamycin gel for bacterial vaginosis treatment. METHODS: We conducted a double-blind, placebo-controlled, randomized study comparing clindamycin gel with placebo (2:1 ratio). Entry required clinical diagnosis of bacterial vaginosis, that is, all four Amsel's criteria, without other genital infections. Nugent scores of 7-10 were required for efficacy assessment, per updated 2019 U.S. Food and Drug Administration guidance. Patients were evaluated at screening, day 7-14, and day 21-30 (test of cure). Clinical cure was defined as resolution of three of four Amsel's criteria. Bacteriologic cure was defined as Nugent score lower than 4. Therapeutic cure was both clinical and bacteriologic cure. Primary outcome was clinical cure at the test-of-cure visit. Secondary endpoints were clinical cure at day 7-14, and bacteriologic and therapeutic cures at day 7-14 and test of cure. A sample size of 188 patients in the clindamycin group compared with 94 patients in the placebo group had 90% power to detect statistically significant difference (P=.05, 2-tailed). RESULTS: Participants were seen between July 9, 2020, and November 12, 2020. Of 307 randomized women, 56.0% were Black and 88.3% reported one or more previous bacterial vaginosis episodes. In the modified intention-to-treat population, 70.5% of patients in the clindamycin group and 35.6% in the placebo group achieved clinical cure at test of cure (primary outcome) (difference of 34.9, 95% CI 19.0-50.8), as did 77.5% of patients in the clindamycin group and 42.6% of patients in the placebo group in the per-protocol population (difference of 34.9, 95% CI 17.0-52.7). Statistically significant differences between groups were seen for all secondary endpoints. Clinical cure rate in patients in the clindamycin group with more than three bacterial vaginosis episodes in the prior year was 70.0%. Approximately 15% (15.3%) of patients in the clindamycin group experienced one or more treatment-emergent adverse events related to study treatment, as did 9.7% of patients in the placebo group. The most frequent treatment-related, treatment-emergent adverse event was vulvovaginal candidiasis. CONCLUSION: A new, single-dose clindamycin vaginal gel was highly effective, with excellent safety, in women disproportionately affected by bacterial vaginosis, with Nugent scores of 7-10 at study entry. FUNDING SOURCE: The study was funded by Daré Bioscience, Inc. CLINICAL TRIALS REGISTRATION: ClinicalTrials.gov, NCT04370548.

Assessment of the test-retest reliability of laboratory polysomnography.

STATEMENT OF THE PROBLEM: When conducting a treatment intervention study, it is assumed that a level of reliability can be obtained from the measurement tool such that the outcome can be reasonably assessed. PURPOSE OF STUDY: Investigate the reliability of laboratory polysomnography, the gold standard for assessment of treatment outcomes for obstructive sleep apnea, at a 1-month interval. MATERIALS AND METHODS: In a clinical trial of 118 patients recruited to assess the effects of a pharmaceutical treatment intervention, a subset of 20 patients designated as placebo controls completed two polysomnography studies, one at baseline and one at least one month later. RESULTS: The correlation between the overall Apnea/Hypopnea indices from the two polysomnography (PSG) studies was poor (r = 0.44) and the results were biased, with a mean increase of seven events per hour on night 2. Twenty-five percent of the subjects had an increase greater than 20 events/hour on night 2 and only 45% of participants had a night-to-night difference of < or =5 events/hour. The correlation between overall apnea indexes for nights 1 and 2 (r = 0.61) was improved, compared to the overall apnea/hypopnea indexes. The correlation in sleep efficiency across the two nights was relatively week (r = 0.52) but significant. The correlations between nights 1 and 2 for the percentage of time supine (r = 0.70) and the supine apnea-hypopnea index (AHI) (r = 0.69) were similar and highly significant. The correlation for the non-supine AHI was only 0.25 CONCLUSIONS: In this study, the reliability of a single-night PSG in measuring treatment outcome was compromised as a result of the large night-to-night variability of subjects' obstructive sleep apnea (OSA). Studies employing the AHI as an outcome need to be adequately powered with respect to the inherent night-to-night variability in the measurement. When assessing treatment intervention outcomes, there may be benefit from the acquisition and averaging of multiple nights of data in order to mitigate the inherent night-to-night variability of OSA and improve the accuracy of the outcome assessment.

Two randomized placebo-controlled trials to evaluate the efficacy and tolerability of mirtazapine for the treatment of obstructive sleep apnea.

OBJECTIVE: Mirtazapine is an a2A antagonist and mixed 5-HT2/5-HT3 antagonist that has been proposed as a potential treatment for obstructive sleep apnea (OSA). A small, randomized, controlled trial has previously found an approximate halving in the severity of OSA with daily doses of 4.5 and 15 mg. We aimed to confirm and extend these findings in 2 randomized placebo-controlled, proof-of-concept trials. METHODS: Two randomized, double-blind, placebo-controlled trials of mirtazapine for OSA (apnea-hypopnea index 10-40/h). Study 1: 3-way crossover, dose-finding study testing the self-administration of mirtazapine (7.5, 15, 30, and/or 45 mg) or placebo 30 minutes prior to bedtime for 2 weeks at each dose. Twenty patients were randomly assigned to 1 of 6 different dose-sequence groups, with each patient exposed to a maximum of 3 doses. Study 2: 3-arm, randomized, parallel-group trial of mirtazapine at 15 mg or mirtazapine 15 mg + Compound CD0012 or placebo for 4 weeks in 65 patients with OSA. RESULTS: Two patients withdrew from Study 1 after complaints of unacceptable lethargy. Fifteen patients were withdrawn from study 2, 7 after complaints of unacceptable lethargy or other side-effects. No measurement of sleep apnea improved due to mirtazapine in either study. Weight gain was significantly greater on mirtazapine than on placebo in both trials. CONCLUSIONS: Mirtazapine did not improve sleep apnea in either trial. Mirtazapine caused weight gain, which may further worsen OSA. Therefore, mirtazapine is not recommended for the treatment of OSA.