Vaginal Progesterone to Prevent Spontaneous Preterm Birth in Women With a Sonographic Short Cervix: The Story of the PREGNANT Trial.

The PREGNANT trial was a randomized, placebo-controlled, multicenter trial designed to determine the efficacy and safety of vaginal progesterone (VP) to reduce the risk of birth < 33 weeks and of neonatal complications in women with a sonographic short cervix (10 to 20 mm) in the mid-trimester (19 to 23 6/7 wk). Patients allocated to receive VP had a 45% lower rate of preterm birth (8.9% vs 16.1%; relative risk = 0.55; 95% CI: 0.33-0.92). Neonates born to mothers allocated to VP had a 60% reduction in the rate of respiratory distress syndrome. This article reviews the background, design, execution, interpretation, and impact of the PREGNANT Trial.

Results of a phase 1, randomized, placebo-controlled first-in-human trial of griffithsin formulated in a carrageenan vaginal gel.

HIV pre-exposure prophylaxis (PrEP) is dominated by clinical therapeutic antiretroviral (ARV) drugs. Griffithsin (GRFT) is a non-ARV lectin with potent anti-HIV activity. GRFT's preclinical safety, lack of systemic absorption after vaginal administration in animal studies, and lack of cross-resistance with existing ARV drugs prompted its development for topical HIV PrEP. We investigated safety, pharmacokinetics (PK), pharmacodynamics (PD), and immunogenicity of PC-6500 (0.1% GRFT in a carrageenan (CG) gel) in healthy women after vaginal administration. This randomized, placebo-controlled, parallel group, double-blind first-in-human phase 1 study enrolled healthy, HIV-negative, non-pregnant women aged 24-45 years. In the open label period, all participants (n = 7) received single dose of PC-6500. In the randomized period, participants (n = 13) were instructed to self-administer 14 doses of PC-6500 or its matching CG placebo (PC-535) once daily for 14 days. The primary outcomes were safety and PK after single dose, and then after 14 days of dosing. Exploratory outcomes were GRFT concentrations in cervicovaginal fluids, PD, inflammatory mediators and gene expression in ectocervical biopsies. This trial is registered with ClinicalTrials.gov, number NCT02875119. No significant adverse events were recorded in clinical or laboratory results or histopathological evaluations in cervicovaginal mucosa, and no anti-drug (GRFT) antibodies were detected in serum. No cervicovaginal proinflammatory responses and no changes in the ectocervical transcriptome were evident. Decreased levels of proinflammatory chemokines (CXCL8, CCL5 and CCL20) were observed. GRFT was not detected in plasma. GRFT and GRFT/CG in cervicovaginal lavage samples inhibited HIV and HPV, respectively, in vitro in a dose-dependent fashion. These data suggest GRFT formulated in a CG gel is a safe and promising on-demand multipurpose prevention technology product that warrants further investigation.

Efficacy of the 1-year (13-cycle) segesterone acetate and ethinylestradiol contraceptive vaginal system: results of two multicentre, open-label, single-arm, phase 3 trials.

BACKGROUND: A ring-shaped, contraceptive vaginal system designed to last 1 year (13 cycles) delivers an average of 0·15 mg segesterone acetate and 0·013 mg ethinylestradiol per day. We evaluated the efficacy of this contraceptive vaginal system and return to menses or pregnancy after use. METHODS: In two identically designed, multicentre, open-label, single-arm, phase 3 trials (one at 15 US academic and community sites and one at 12 US and international academic and community sites), participants followed a 21-days-in, 7-days-out segesterone acetate and ethinylestradiol contraceptive vaginal system schedule for up to 13 cycles. Participants were healthy, sexually active, non-pregnant, non-sterilised women aged 18-40 years. Women were cautioned that any removals during the 21 days of cyclic use should not exceed 2 h, and used daily paper diaries to record vaginal system use. Consistent with regulatory requirements for contraceptives, we calculated the Pearl Index for women aged 35 years and younger, excluding adjunctive contraception cycles, as the primary efficacy outcome measure. We also did intention-to-treat Kaplan-Meier life table analyses and followed up women who did not use hormonal contraceptives or desired pregnancy after study completion for 6 months for return to menses or pregnancy. The trials are registered with ClinicalTrials.gov, numbers NCT00455156 and NCT00263341. FINDINGS: Between Dec 19, 2006, and Oct 9, 2009, at the 15 US sites, and between Nov 1, 2006, and July 2, 2009, at the 12 US and international sites we enrolled 2278 women. Our overall efficacy analysis included 2265 participants (1130 in the US study and 1135 in the international study) and 1303 (57·5%) participants completed up to 13 cycles. The Pearl Index for the primary efficacy group was 2·98 (95% CI 2·13-4·06) per 100 woman-years, and was well within the range indicative of efficacy for a contraceptive under a woman's control. The Kaplan-Meier analysis revealed the contraceptive vaginal system was 97·5% effective, which provided further evidence of efficacy. Pregnancy occurrence was similar across cycles. All 290 follow-up participants reported return to menses or became pregnant (24 [63%] of 38 women who desired pregnancy) within 6 months. INTERPRETATION: The segesterone acetate and ethinylestradiol contraceptive vaginal system is an effective contraceptive for 13 consecutive cycles of use. This new product adds to the contraceptive method mix and the 1-year duration of use means that women do not need to return to the clinic or pharmacy for refills every few months. FUNDING: Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health, the US Agency for International Development, and the WHO Reproductive Health Research Department.

Vaginal progesterone is as effective as cervical cerclage to prevent preterm birth in women with a singleton gestation, previous spontaneous preterm birth, and a short cervix: updated indirect comparison meta-analysis.

BACKGROUND: An indirect comparison meta-analysis published in 2013 reported that both vaginal progesterone and cerclage are equally efficacious for preventing preterm birth and adverse perinatal outcomes in women with a singleton gestation, previous spontaneous preterm birth, and a sonographic short cervix. The efficacy of vaginal progesterone has been challenged after publication of the OPPTIMUM study. However, this has been resolved by an individual patient-data meta-analysis (Am J Obstet Gynecol. 2018;218:161-180). OBJECTIVE: To compare the efficacy of vaginal progesterone and cerclage in preventing preterm birth and adverse perinatal outcomes in women with a singleton gestation, previous spontaneous preterm birth, and a midtrimester sonographic short cervix. DATA SOURCES: MEDLINE, EMBASE, LILACS, and CINAHL (from their inception to March 2018); Cochrane databases, bibliographies, and conference proceedings. STUDY ELIGIBILITY CRITERIA: Randomized controlled trials comparing vaginal progesterone to placebo/no treatment or cerclage to no cerclage in women with a singleton gestation, previous spontaneous preterm birth, and a sonographic cervical length <25 mm. STUDY APPRAISAL AND SYNTHESIS METHODS: Updated systematic review and adjusted indirect comparison meta-analysis of vaginal progesterone vs cerclage using placebo/no cerclage as the common comparator. The primary outcomes were preterm birth <35 weeks of gestation and perinatal mortality. Pooled relative risks (RRs) with 95% confidence intervals were calculated. RESULTS: Five trials comparing vaginal progesterone vs placebo (265 women) and 5 comparing cerclage vs no cerclage (504 women) were included. Vaginal progesterone, compared to placebo, significantly reduced the risk of preterm birth <35 and <32 weeks of gestation, composite perinatal morbidity/mortality, neonatal sepsis, composite neonatal morbidity, and admission to the neonatal intensive care unit (RRs from 0.29 to 0.68). Cerclage, compared to no cerclage, significantly decreased the risk of preterm birth <37, <35, <32, and <28 weeks of gestation, composite perinatal morbidity/mortality, and birthweight <1500 g (RRs from 0.64 to 0.70). Adjusted indirect comparison meta-analyses did not show statistically significant differences between vaginal progesterone and cerclage in the reduction of preterm birth or adverse perinatal outcomes. CONCLUSION: Vaginal progesterone and cerclage are equally effective for preventing preterm birth and improving perinatal outcomes in women with a singleton gestation, previous spontaneous preterm birth, and a midtrimester sonographic short cervix. The choice of treatment will depend on adverse events and cost-effectiveness of interventions and patient/physician's preferences.

Vaginal progesterone for preventing preterm birth and adverse perinatal outcomes in singleton gestations with a short cervix: a meta-analysis of individual patient data.

BACKGROUND: The efficacy of vaginal progesterone for preventing preterm birth and adverse perinatal outcomes in singleton gestations with a short cervix has been questioned after publication of the OPPTIMUM study. OBJECTIVE: To determine whether vaginal progesterone prevents preterm birth and improves perinatal outcomes in asymptomatic women with a singleton gestation and a midtrimester sonographic short cervix. STUDY DESIGN: We searched MEDLINE, EMBASE, LILACS, and CINAHL (from their inception to September 2017); Cochrane databases; bibliographies; and conference proceedings for randomized controlled trials comparing vaginal progesterone vs placebo/no treatment in women with a singleton gestation and a midtrimester sonographic cervical length ≤25 mm. This was a systematic review and meta-analysis of individual patient data. The primary outcome was preterm birth <33 weeks of gestation. Secondary outcomes included adverse perinatal outcomes and neurodevelopmental and health outcomes at 2 years of age. Individual patient data were analyzed using a 2-stage approach. Pooled relative risks with 95% confidence intervals were calculated. Quality of evidence was assessed using the GRADE methodology. RESULTS: Data were available from 974 women (498 allocated to vaginal progesterone, 476 allocated to placebo) with a cervical length ≤25 mm participating in 5 high-quality trials. Vaginal progesterone was associated with a significant reduction in the risk of preterm birth <33 weeks of gestation (relative risk, 0.62; 95% confidence interval, 0.47-0.81; P = .0006; high-quality evidence). Moreover, vaginal progesterone significantly decreased the risk of preterm birth <36, <35, <34, <32, <30, and <28 weeks of gestation; spontaneous preterm birth <33 and <34 weeks of gestation; respiratory distress syndrome; composite neonatal morbidity and mortality; birthweight <1500 and <2500 g; and admission to the neonatal intensive care unit (relative risks from 0.47-0.82; high-quality evidence for all). There were 7 (1.4%) neonatal deaths in the vaginal progesterone group and 15 (3.2%) in the placebo group (relative risk, 0.44; 95% confidence interval, 0.18-1.07; P = .07; low-quality evidence). Maternal adverse events, congenital anomalies, and adverse neurodevelopmental and health outcomes at 2 years of age did not differ between groups. CONCLUSION: Vaginal progesterone decreases the risk of preterm birth and improves perinatal outcomes in singleton gestations with a midtrimester sonographic short cervix, without any demonstrable deleterious effects on childhood neurodevelopment.

First-in-Human Trial of MIV-150 and Zinc Acetate Coformulated in a Carrageenan Gel: Safety, Pharmacokinetics, Acceptability, Adherence, and Pharmacodynamics.

OBJECTIVE: To evaluate the safety and pharmacokinetics of MIV-150 and zinc acetate in a carrageenan gel (PC-1005). Acceptability, adherence, and pharmacodynamics were also explored. DESIGN: A 3-day open-label safety run-in (n = 5) preceded a placebo-controlled, double-blind trial in healthy, HIV-negative, abstinent women randomized (4:1) to vaginally apply 4 mL of PC-1005 or placebo once daily for 14 days. METHODS: Assessments included physical examinations, safety labs, colposcopy, biopsies, cervicovaginal lavages (CVLs), and behavioral questionnaires. MIV-150 (plasma, CVL, tissue), zinc (plasma, CVL), and carrageenan (CVL) concentrations were determined with LC-MS/MS, ICP-MS, and ELISA, respectively. CVL antiviral activity was measured using cell-based assays. Safety, acceptability, and adherence were analyzed descriptively. Pharmacokinetic parameters were calculated using noncompartmental techniques and actual sampling times. CVL antiviral EC50 values were calculated using a dose-response inhibition analysis. RESULTS: Participants (n = 20) ranged from 19-44 years old; 52% were black or African American. Among those completing the trial (13/17, PC-1005; 3/3, placebo), 11/17 reported liking the gel overall; 7 recommended reducing the volume. Adverse events, which were primarily mild and/or unrelated, were comparable between groups. Low systemic MIV-150 levels were observed, without accumulation. Plasma zinc levels were unchanged from baseline. Seven of seven CVLs collected 4-hour postdose demonstrated antiviral (HIV, human papillomavirus) activity. High baseline CVL anti-herpes-simplex virus type-2 (HSV-2) activity precluded assessment of postdose activity. CONCLUSIONS: PC-1005 used vaginally for 14 days was well tolerated. Low systemic levels of MIV-150 were observed. Plasma zinc levels were unchanged. Postdose CVLs had anti-HIV and anti-human papillomavirus activity. These data warrant further development of PC-1005 for HIV and sexually transmitted infection prevention.

In Vitro Exposure to PC-1005 and Cervicovaginal Lavage Fluid from Women Vaginally Administered PC-1005 Inhibits HIV-1 and HSV-2 Infection in Human Cervical Mucosa.

Our recent phase 1 trial demonstrated that PC-1005 gel containing 50 µM MIV-150, 14 mM zinc acetate dihydrate, and carrageenan (CG) applied daily vaginally for 14 days is safe and well tolerated. Importantly, cervicovaginal lavage fluid samples (CVLs) collected 4 or 24 h after the last gel application inhibited HIV-1 and human papillomavirus (HPV) in cell-based assays in a dose-dependent manner (MIV-150 for HIV-1 and CG for HPV). Herein we aimed to determine the anti-HIV and anti-herpes simplex virus 2 (anti-HSV-2) activity of PC-1005 in human cervical explants after in vitro exposure to the gel and to CVLs from participants in the phase 1 trial. Single HIV-1BaL infection and HIV-1BaL-HSV-2 coinfection explant models were utilized. Coinfection with HSV-2 enhanced tissue HIV-1BaL infection. In vitro exposure to PC-1005 protected cervical mucosa against HIV-1BaL (up to a 1:300 dilution) in single-challenge and cochallenge models. CG gel (PC-525) provided some barrier effect against HIV-1BaL at the 1:100 dilution in a single-challenge model but not in the cochallenge model. Both PC-1005 and PC-525 at the 1:100 dilution inhibited HSV-2 infection, pointing to a CG-mediated protection. MIV-150 and CG in CVLs inhibited HIV (single-challenge or cochallenge models) and HSV-2 infections in explants in a dose-dependent manner (P < 0.05). Stronger inhibition of HIV-1 infection by CVLs collected 4 h after the last gel administration was observed compared to infection detected in the presence of baseline CVLs. The anti-HIV and anti-HSV-2 activity of PC-1005 gel in vitro and CVLs in human ectocervical explants supports the further development of PC-1005 gel as a broad-spectrum on-demand microbicide.

Vaginal progesterone in women with an asymptomatic sonographic short cervix in the midtrimester decreases preterm delivery and neonatal morbidity: a systematic review and metaanalysis of individual patient data.

OBJECTIVE: To determine whether the use of vaginal progesterone in asymptomatic women with a sonographic short cervix (≤ 25 mm) in the midtrimester reduces the risk of preterm birth and improves neonatal morbidity and mortality. STUDY DESIGN: Individual patient data metaanalysis of randomized controlled trials. RESULTS: Five trials of high quality were included with a total of 775 women and 827 infants. Treatment with vaginal progesterone was associated with a significant reduction in the rate of preterm birth <33 weeks (relative risk [RR], 0.58; 95% confidence interval [CI], 0.42-0.80), <35 weeks (RR, 0.69; 95% CI, 0.55-0.88), and <28 weeks (RR, 0.50; 95% CI, 0.30-0.81); respiratory distress syndrome (RR, 0.48; 95% CI, 0.30-0.76); composite neonatal morbidity and mortality (RR, 0.57; 95% CI, 0.40-0.81); birthweight <1500 g (RR, 0.55; 95% CI, 0.38-0.80); admission to neonatal intensive care unit (RR, 0.75; 95% CI, 0.59-0.94); and requirement for mechanical ventilation (RR, 0.66; 95% CI, 0.44-0.98). There were no significant differences between the vaginal progesterone and placebo groups in the rate of adverse maternal events or congenital anomalies. CONCLUSION: Vaginal progesterone administration to asymptomatic women with a sonographic short cervix reduces the risk of preterm birth and neonatal morbidity and mortality.

The impact of improved compliance with a weekly contraceptive transdermal system (Ortho Evra) on contraceptive efficacy.

OBJECTIVE: The contraceptive efficacy of perfect dosing cycles and imperfect dosing cycles has not been described previously. Method compliance determines the proportion of perfect and imperfect dosing cycles, and together can form the basis for evaluating differences in efficacy based on differences in compliance. MATERIALS AND METHODS: The transdermal contraceptive delivery system (Ortho Evra) has been studied in a North American randomized trial vs. an oral contraceptive (OC) and in total has been evaluated in 3319 women in contraceptive clinical trials. This article explores the impact of perfect vs. imperfect compliance with the contraceptive method on contraceptive efficacy. Previously published data for a transdermal system (Patch, n = 812) and OC (Triphasil, n = 605) users from the North American comparative study were reanalyzed to determine the effect of imperfect use on the contraceptive efficacy of the different methods. RESULTS: Contraceptive efficacy was significantly better (p = 0.007) in cycles with perfect dosing (Pearl Index = 0.83) compared to those with imperfect dosing (Pearl Index = 6.32) for both methods. This difference is homogeneous (p = 0.62) across the Patch and OC groups. Pooled data for all Patch users confirm that perfect dosing cycles are associated with significantly better efficacy than imperfect dosing cycles (p = 0.047). In addition, compliance did not vary by age in the pooled Patch data, which are in agreement with the previously published Patch data from the comparative study. In the comparative study, the percentage of cycles with perfect dosing was significantly higher with the Patch than with the OC (88.7% vs. 79.2%, p < 0.001), and was consistently high in all age groups (range, 89.6-91.8%). By contrast, among OC users, the percentage of cycles with perfect dosing increased with increasing age (p < 0.001) from 67.7% in users aged 18-20 years to more than 80% in those aged 30 years and older. CONCLUSION: In conclusion, deviations from perfect use (whether corrected or not) of a transdermal contraceptive system and of an OC increase contraceptive failures by approximately 5-10-fold when compared to perfect use. The weekly change schedule of the transdermal contraceptive delivery system is associated with a significantly greater proportion of cycles in which there is perfect dosing compared to an OC.

Ortho Evra/Evra versus oral contraceptives: follicular development and ovulation in normal cycles and after an intentional dosing error.

OBJECTIVE: To compare the effects of the contraceptive patch to oral contraceptives (OCs) on follicular size and incidence of ovulation in normal cycles and after dosing errors. DESIGN: Randomized, open-label. SETTING: Twelve centers. PATIENT(S): One hundred twenty-four ovulatory women. INTERVENTION(S): Subjects received either the patch (groups 1 and 2) or one of three OCs. Correct dosing occurred in cycles 1, 2, 3, and 5. The following dosing errors were planned during cycle 4, a shortened 10-day cycle: [1] patch group 1 subjects wore one patch for 10 consecutive days; [2] for patch group 2 and OC subjects, 7 dosing days were followed by 3 drug-free days. MAIN OUTCOME MEASURE(S): Follicular size, as determined at each cycle by the maximum mean follicular diameter. RESULT(S): After a 3-day dosing error, follicular size was significantly smaller in the patch group (mean, 7.0 mm) vs. each OC group (range of means, 11.8-17.1 mm). Similar results were seen after proper dosing. The incidence of ovulation was significantly lower for the patch users than for women using OCs. CONCLUSION(S): Follicular size and incidence of ovulation were significantly reduced among contraceptive patch users compared with women using OCs in normal cycles and after planned dosing errors.