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Comparison of self-reported female condom failure and biomarker-confirmed semen exposure

Walsh, Terri L; Snead, Margaret C; St Claire, Breione J; Schwartz, Jill L; Mauck, Christine K; Frezieres, Ron G; Blithe, Diana L; Archer, David F; Barnhart, Kurt T; Jensen, Jeffrey T; Nelson, Anita L; Thomas, Michael A; Wan, Livia S; Weaver, Mark A
OBJECTIVE:To investigate whether rates of self-reported Woman's Condom (WC) clinical failure and semen exposure from a functionality study are comparable to results from a contraceptive efficacy substudy. STUDY DESIGN/METHODS:We structured our comparative analysis to assess whether functionality studies might credibly supplant contraceptive efficacy studies when evaluating new female condom products. Couples not at risk of pregnancy in the functionality (breakage/slippage/invagination/penile misdirection) study and women in the contraceptive efficacy study completed condom self-reports and collected pre and postcoital vaginal samples for up to four uses of the WC. Both studies used nearly identical self-report questions and the same self-sampling procedures and laboratory for prostatic specific antigen (PSA), a well-studied semen biomarker. We compared condom failure and semen exposure proportions using generalized estimating equations methods accounting for within-couple correlation. RESULTS:Ninety-five (95) efficacy substudy participants used 334 WC and 408 functionality participants used 1572 WC. Based on self-report, 19.2% WC (64 condoms) clinically failed in the efficacy substudy compared to 12.3% WC (194 condoms) in the functionality study (p-value=0.030). Of the 207 WC efficacy uses with evaluable post-coital PSA levels, 14.5% (30 uses) resulted in semen exposure compared to 14.2% (184 uses) of the 1293 evaluable WC functionality study uses. CONCLUSIONS:When evaluating the ability of an experimental condom to prevent semen exposure, the rate of clinical condom failure reported by participants risking pregnancy in an efficacy substudy was significantly higher than the rate reported by participants not risking pregnancy in a functionality study. The rate of semen exposure, assessed by an objective biomarker was nearly identical for the two studies. IMPLICATIONS/CONCLUSIONS:Our results suggest that an objective marker of semen exposure in functionality studies could provide a reasonable alternative to contraceptive efficacy studies in evaluating risk of unintended pregnancy and inferring protection from sexually transmitted infection than condom failure rates based on self-report.
PMID: 31381878
ISSN: 1879-0518
CID: 4055242

Continuous dosing of a novel contraceptive vaginal ring releasing Nestorone® and estradiol: pharmacokinetics from a dose-finding study

Jensen, J T; Edelman, A B; Chen, B A; Archer, D F; Barnhart, K T; Thomas, M A; Burke, A E; Westhoff, C L; Wan, L S; Sitruk-Ware, R; Kumar, N; Variano, B; Blithe, D L
BACKGROUND:As part of a program to develop a novel estradiol-releasing contraceptive vaginal ring (CVR), we evaluated the pharmacokinetic (PK) profile of CVRs releasing segesterone acetate (Nestorone® (NES)) combined with one of three different estradiol (E2) doses. STUDY DESIGN/METHODS:A prospective, double-blind, randomized, multi-centered study to evaluate a 90-day CVR releasing NES [200μg/day] plus E2, either 10μg/day, 20μg/day, or 40μg/day in healthy reproductive-age women with regular cycles. Participants provided blood samples twice weekly for NES and E2 levels during the first 60days (ring 1) and the last 30days (ring 2) of use. A subset underwent formal PK assessments at ring initiation, ring exchange (limited PK), and study completion. RESULTS:The main study enrolled 197 women; 22 participated in the PK substudy. Baseline characteristics between the main and PK participants were comparable, with an average BMI of 25.8kg/m2 (SD 4.3). In the PK substudy, all three rings showed similar NES PK: mean area under the curve (AUC(0-72)) 34,181pg*day/mL; concentration maximum (Cmax) 918pg/mL; time to maximum concentration (Tmax) 3.5h. For E2, the Cmax occurred at 2h, and was significantly higher with the 20 ug/day ring (mean 390pg/mL); 10ug/day, 189pg/mL, p=.003; 40 ug/day, 189pg/mL, p<.001), and declined rapidly to≤50pg/mL for all doses by 24h. For all subjects, the median E2 levels remained under 35pg/mL during treatment. CONCLUSION/CONCLUSIONS:PK parameters of NES were not affected when paired with different doses of E2, but E2 levels from all three doses were lower than anticipated and no dose response was observed. IMPLICATIONS/CONCLUSIONS:While these novel estradiol-releasing combination contraceptive vaginal rings provided sustained release of contraceptive levels of Nestorone over 90days, the E2 levels achieved were not consistent with bone protection, and a dose-response was not observed.
PMCID:5948142
PMID: 29409834
ISSN: 1879-0518
CID: 2948132

Magnetic Resonance Imaging (MRI) of hormone-induced breast changes in young premenopausal women

Clendenen, Tess V; Kim, Sungheon; Moy, Linda; Wan, Livia; Rusinek, Henry; Stanczyk, Frank Z; Pike, Malcolm C; Zeleniuch-Jacquotte, Anne
OBJECTIVES: We conducted a pilot study to identify whether MRI parameters are sensitive to hormone-induced changes in the breast during the natural menstrual cycle and whether changes could also be observed during an oral contraceptive (OC) cycle. MATERIALS AND METHODS: The New York University Langone Medical Center Institutional Review Board approved this HIPAA-compliant prospective study. All participants provided written informed consent. Participants were aged 24-31 years.We measured several non-contrast breast MRI parameters during each week of a single menstrual cycle (among 9 women) and OC cycle (among 8 women). Hormones were measured to confirm ovulation and classify menstrual cycle phase among naturally cycling women and to monitor OC compliance among OC users. We investigated how the non-contrast MRI parameters of breast fibroglandular tissue (FGT), apparent diffusion coefficient (ADC), magnetization transfer ratio (MTR), and transverse relaxation time (T2) varied over the natural and the OC cycles. RESULTS: We observed significant increases in MRI FGT% and ADC in FGT, and longer T2 in FGT in the luteal vs. follicular phase of the menstrual cycle. We did not observe any consistent pattern of change for any of the MRI parameters among women using OCs. CONCLUSIONS: MRI is sensitive to hormone-induced breast tissue changes during the menstrual cycle. Larger studies are needed to assess whether MRI is also sensitive to the effects of exogenous hormones, such as various OC formulations, on the breast tissue of young premenopausal women.
PMID: 22898693
ISSN: 0730-725x
CID: 179985

Endometrial brush biopsy device vs. traditional aspiration sampler [Meeting Abstract]

Lynch, C; Hamed, AHassan; Wan, L; Mohammed, K; Yang, G; Del Priore, G
ISI:000303227600173
ISSN: 0090-8258
CID: 2737022

Contraceptive efficacy, acceptability, and safety of C31G and nonoxynol-9 spermicidal gels: a randomized controlled trial

Burke, Anne E; Barnhart, Kurt; Jensen, Jeffrey T; Creinin, Mitchell D; Walsh, Terri L; Wan, Livia S; Westhoff, Carolyn; Thomas, Michael; Archer, David; Wu, Hongsheng; Liu, James; Schlaff, William; Carr, Bruce R; Blithe, Diana
OBJECTIVE: To estimate whether a gel containing the spermicide C31G was noninferior to a commercially available product containing nonoxynol-9. METHODS: Participants were healthy, sexually active women aged 18-40 years. Measured outcomes included pregnancy rates, continuation rates, adverse events, and acceptability. The primary study outcome was contraceptive efficacy. Sample size was calculated at a 2.5% significance level using a one-sided test based on assumed 6-month pregnancy probability of 15% in the nonoxynol-9 group. Sample size was sufficient to reject, with 80% power, the null hypothesis that pregnancy probability in the C31G arm would be more than 5% higher. RESULTS: Nine hundred thirty-two women were randomized in the C31G group and 633 in the nonoxynol-9 group. For randomized patients with at least one episode of coitus (modified intent-to-treat group), 6-month pregnancy probabilities were 12.0% (95% confidence interval [CI] 9.3-14.7%) and 12.0% (95% CI 8.7-15.3%) for C31G and nonoxynol-9,respectively. Twelve-month pregnancy probabilities were 13.8% (95% CI 7.6-20%) for C31G and 19.8% (95% CI 10.9-28.7%) for nonoxynol-9. Two serious adverse events were deemed possibly related to study product and neither occurred in the C31G group. Three fourths of users in either group reported that they liked their assigned study product. Approximately 40% of patients discontinued prematurely for reasons other than pregnancy with 11% lost to follow-up. CONCLUSION: C31G demonstrated noninferior contraceptive efficacy compared with nonoxynol-9. C31G may provide another marketable option for women seeking spermicidal contraception. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.ClinicalTrials.gov, NCT00274261
PMCID:3332092
PMID: 21099590
ISSN: 1873-233x
CID: 120713

Determining the feasibility of utilizing the microbicide applicator compliance assay for use in clinical trials (vol 76, pg 53, 2007) [Correction]

Wallace, Andrea R; Teitelbaum, Aaron; Wan, Livia; Mulima, Maria Gloria; Guichard, Laura; Skoler, Stephanie; Vilakazi, Hlengiwe; Mapula, Fridda S; Rossier, Jasmine; Govender, Sumen N; Lahteenmaki, Pekka; Maguire, Robin A; Phillips, David M
ISI:000250029700018
ISSN: 0010-7824
CID: 2734002

Contraceptive efficacy of a novel spermicidal microbicide used with a diaphragm: a randomized controlled trial

Barnhart, Kurt T; Rosenberg, Michael J; MacKay, H Trent; Blithe, Diana L; Higgins, Jim; Walsh, Terri; Wan, Livia; Thomas, Michael; Creinin, Mitchell D; Westhoff, Carolyn; Schlaff, William; Archer, David F; Ayers, Charletta; Kaunitz, Andrew; Das, Sutapa; Moench, Thomas R
OBJECTIVE: Women need products that protect against both pregnancy and sexually transmitted infections, including human immunodeficiency virus (HIV). The acid buffering gel is a nondetergent spermicide that may provide this dual protection by reinforcing normal vaginal acidity to inactivate both sperm and acid-sensitive sexually transmitted pathogens. The objective of this study was to assess the gel's contraceptive effects, safety, and acceptability. METHODS: We conducted a multicenter, randomized, double-masked, noninferiority study at 11 centers, comparing 621 women who used an acid buffering gel plus diaphragm with 300 women who used a nonoxynol-9 spermicide plus diaphragm for 6 months. A double-masked study extension followed 234 women for an additional 6 months of use. RESULTS: The 6-month pregnancy rate per hundred women was 10.1% (95% confidence interval [CI] 7.1-13.1%) for acid buffering gel and 12.3 (95% CI 7.7-16.9) for nonoxynol-9 spermicide users. The difference in rates was -2.2% with a 95% CI -7.7 to 3.3%. Consistent and correct use 6-month pregnancy rates were 4.7% for acid buffering gel and 6.1% for nonoxynol-9 spermicide users, calculated from those cycles where diary entries indicated such use. Adverse events and acceptability were similar between the two groups. Pregnancy probabilities were similar between groups participating in the 12-month study extension. CONCLUSION: An acid buffering gel used with a diaphragm is a safe, acceptable contraceptive with efficacy comparable to that of a common commercial spermicide with diaphragm. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.ClinicalTrials.gov, NCT00065858 LEVEL OF EVIDENCE: I
PMID: 17766603
ISSN: 0029-7844
CID: 120709

Determining the feasibility of utilizing the microbicide applicator compliance assay for use in clinical trials

Wallace, Andrea R; Teitelbaum, Aaron; Wan, Livia; Mulima, Maria Gloria; Guichard, Laura; Skoler, Stephanie; Vilakazi, Hlengiwe; Mapula, Fridda S; Rossier, Jasmine; Govender, Sumen N; Lahteenmaki, Pekka; Maguire, Robin A; Phillips, David M
INTRODUCTION: Participant's adherence to use of study product is a major concern in microbicide clinical trials, which can impact on proving product efficacy. In a previously described assay, single-use microbicide applicators exposed to the vagina were tested by spraying the applicator with trypan blue dye, resulting in vaginal mucus staining on inserted applicators. As subjects in our Phase 3 trials return applicators only at quarterly visits, often mixing inserted and not-inserted applicators together in the same bag, cross-contamination could confound results. In addition, trypan blue is carcinogenic and thus potentially hazardous to technicians spraying daily. METHODS: Applicators that were exposed to the vagina were placed in the same bag as unexposed applicators and shaken daily for up to 4 months. Validation was carried out in three clinical sites in South Africa. RESULTS: Trypan blue was replaced with FD&C Blue #1 granular food dye. Cross-contamination did not occur, nor did the length of time affect reaction to dye. In South Africa, the assay was validated with an accuracy of over 95%. CONCLUSION: Applicator assay modifications render the test safe and suitable for use in clinical trials
PMID: 17586138
ISSN: 0010-7824
CID: 120708

Progesterone receptor modulator for emergency contraception: a randomized controlled trial

Creinin, Mitchell D; Schlaff, William; Archer, David F; Wan, Livia; Frezieres, Ron; Thomas, Michael; Rosenberg, Michael; Higgins, James
OBJECTIVE: Compare the efficacy and adverse effects of CDB-2914, a new progesterone receptor modulator, to levonorgestrel for emergency contraception. METHODS: We performed a randomized, double-blinded noninferiority trial, enrolling healthy women seeking emergency contraception within 72 hours of unprotected intercourse. Participants were randomly assigned to receive a single dose of 50 mg of CDB-2914, plus a placebo 12 hours later or two doses of 0.75 mg of levonorgestrel taken 12 hours apart. Follow-up was scheduled 5 to 7 days after the expected onset of the next menstrual period. Posttreatment pregnancy was established by a positive urine test at follow-up and confirmed by quantitative serum beta-hCG. Daily diaries were used from the time of emergency contraception use until next menses to record adverse effects and sexual activity. RESULTS: Product efficacy was evaluable in 775 of CDB-2914 users and 774 of levonorgestrel users. Pregnancies occurred in 7 (0.9%, 95% confidence interval 0.2-1.6%) and 13 (1.7%, 95% confidence interval 0.8-2.6%) women, respectively. Based on the estimated cycle day of unprotected intercourse, 85% and 69% of anticipated pregnancies, respectively, were averted. Nausea was reported by a somewhat greater percentage of CDB-2914 than levonorgestrel users (29% compared with 24%, P=.03), but the distribution of other adverse effects was similar in both groups. Women in both groups experienced considerable variation in menstrual cycle length as compared with their reported individual normal cycle lengths. CONCLUSION: CDB-2914 is at least as effective as levonorgestrel in preventing pregnancies after unprotected intercourse and has a similar side effect profile. LEVEL OF EVIDENCE: I
PMCID:2853373
PMID: 17077229
ISSN: 0029-7844
CID: 102586

Acceptability of five nonoxynol-9 spermicides

Raymond, Elizabeth G; Chen, Pai Lien; Condon, Sean; Luoto, Joanne; Barnhart, Kurt T; Creinin, Mitchell D; Poindexter, Alfred; Wan, Livia; Martens, Mark; Schenken, Robert; Blackwell, Richard
OBJECTIVE: To examine the acceptability of five nonoxynol-9 (N-9) spermicides. METHODS: We analyzed data from a randomized trial of five products, including three gels containing different amounts of N-9 per dose, a film and a suppository. In the trial, 1536 participants were asked to use the assigned spermicide for 7 months and to complete questionnaires 4 weeks after admission and at discontinuation. RESULTS: Overall, 43% of participants liked their spermicide 'very much.' This proportion was higher in the three gel groups than in the suppository and film groups. Difficulty with insertion, messiness and discontent with timing of insertion were common complaints in all groups. After adjustment for selected baseline factors, acceptability on the first questionnaire was not related to duration or consistency of subsequent spermicide use or to subsequent time to pregnancy. CONCLUSIONS: In this study, all five spermicides were considered acceptable by most users. Acceptability did not appear to influence spermicide use or pregnancy risk
PMCID:2861722
PMID: 15914133
ISSN: 0010-7824
CID: 120707