Ibrexafungerp Versus Placebo for Vulvovaginal Candidiasis Treatment: A Phase 3, Randomized, Controlled Superiority Trial (VANISH 303).

BACKGROUND: Current treatment of vulvovaginal candidiasis (VVC) is largely limited to azole therapy. Ibrexafungerp is a first-in-class triterpenoid antifungal with broad-spectrum anti-Candida fungicidal activity. The objective of this study was to evaluate the efficacy and safety of ibrexafungerp compared with placebo in patients with acute VVC. METHODS: Patients were randomly assigned 2:1 to receive ibrexafungerp (300 mg twice for 1 day) or placebo. The primary endpoint was the percentage of patients with a clinical cure (complete resolution of vulvovaginal signs and symptoms [VSS] = 0) at test-of-cure (day 11 ± 3). Secondary endpoints included the percentage of patients with mycological eradication, overall success (clinical cure and mycological eradication), clinical improvement (VSS ≤ 1) at test-of-cure, and symptom resolution at follow-up (day 25 ± 4). RESULTS: Patients receiving ibrexafungerp had significantly higher rates of clinical cure (50.5% [95/188] vs 28.6% [28/98]; P = .001), mycological eradication (49.5% [93/188] vs 19.4% [19/98]; P < .001), and overall success (36.0% [64/178] vs 12.6% [12/95]; P < .001) compared with placebo. Symptom resolution was sustained and further increased with ibrexafungerp compared with placebo (59.6% [112/188] vs 44.9% [44/98]; P = .009) at follow-up. Post hoc analysis showed similar rates of clinical cure and clinical improvement at test-of-cure for Black patients (54.8% [40/73] and 63.4% [47/73], respectively) and patients with a body mass index >35 (54.5% [24/44] and 68.2% [30/44], respectively) compared with overall rates. Ibrexafungerp was well tolerated. Adverse events were primarily gastrointestinal and mild in severity. CONCLUSIONS: Ibrexafungerp provides a promising safe and efficacious oral treatment that mechanistically differs from current azole treatment options for acute VVC.

Effect of Immediate vs Delayed Pushing on Rates of Spontaneous Vaginal Delivery Among Nulliparous Women Receiving Neuraxial Analgesia: A Randomized Clinical Trial.

Importance: It is unclear whether the timing of second stage pushing efforts affects spontaneous vaginal delivery rates and reduces morbidities. Objective: To evaluate whether immediate or delayed pushing results in higher rates of spontaneous vaginal delivery and lower rates of maternal and neonatal morbidities. Design, Setting, and Participants: Pragmatic randomized clinical trial of nulliparous women at or beyond 37 weeks' gestation admitted for spontaneous or induced labor with neuraxial analgesia between May 2014 and December 2017 at 6 US medical centers. The interim analysis suggested futility for the primary outcome and recruitment was terminated with 2414 of 3184 planned participants. Follow-up ended January 4, 2018. Interventions: Randomization occurred when participants reached complete cervical dilation. Immediate group participants (n = 1200) began pushing immediately. Delayed group participants (n = 1204) were instructed to wait 60 minutes. Main Outcomes and Measures: The primary outcome was spontaneous vaginal delivery. Secondary outcomes included total duration of the second stage, duration of active pushing, operative vaginal delivery, cesarean delivery, postpartum hemorrhage, chorioamnionitis, endometritis, perineal lacerations (≥second degree), and a composite outcome of neonatal morbidity that included neonatal death and 9 other adverse outcomes. Results: Among 2414 women randomized (mean age, 26.5 years), 2404 (99.6%) completed the trial. The rate of spontaneous vaginal delivery was 85.9% in the immediate group vs 86.5% in the delayed group, and was not significantly different (absolute difference, -0.6% [95% CI, -3.4% to 2.1%]; relative risk, 0.99 [95% CI, 0.96 to 1.03]). There was no significant difference in 5 of the 9 prespecified secondary outcomes reported, including the composite outcome of neonatal morbidity (7.3% for the immediate group vs 8.9% for the delayed group; between-group difference, -1.6% [95% CI, -3.8% to 0.5%]) and perineal lacerations (45.9% vs 46.4%, respectively; between-group difference, -0.4% [95% CI, -4.4% to 3.6%]). The immediate group had significantly shorter mean duration of the second stage compared with the delayed group (102.4 vs 134.2 minutes, respectively; mean difference, -31.8 minutes [95% CI, -36.7 to -26.9], P < .001), despite a significantly longer mean duration of active pushing (83.7 vs 74.5 minutes; mean difference, 9.2 minutes [95% CI, 5.8 to 12.6], P < .001), lower rates of chorioamnionitis (6.7% vs 9.1%; between-group difference, -2.5% [95% CI, -4.6% to -0.3%], P = .005), and fewer postpartum hemorrhages (2.3% vs 4.0%; between-group difference, -1.7% [95% CI, -3.1% to -0.4%], P = .03). Conclusions and Relevance: Among nulliparous women receiving neuraxial anesthesia, the timing of second stage pushing efforts did not affect the rate of spontaneous vaginal delivery. These findings may help inform decisions about the preferred timing of second stage pushing efforts, when considered with other maternal and neonatal outcomes. Trial Registration: ClinicalTrials.gov Identifier: NCT02137200.

Factors Associated with Persistence with Teriparatide Therapy: Results from the DANCE Observational Study.

Purpose. Determine patient-reported reasons for discontinuation with teriparatide. Methods. Patients taking teriparatide in a multicenter, prospective, and observational study were given three questionnaires: baseline, follow-up questionnaire 1 (QF1, 2 to 6 months), and follow-up questionnaire 2 (QF2, 12 months). Discontinuation reported at QF1 and QF2 was defined as "early" and "late," respectively, and remaining patients were considered persistent. Cochran-Armitage trend test was used to identify factors associated with discontinuation. Results. Side effects, concern about improper use, injection difficulties, and several patient-perceived physician issues were associated with early discontinuation. Low patient-perceived importance of continuing treatment, side effects, difficulty paying, and low patient-perceived physician knowledge were associated with late discontinuation. The most common specific reasons selected for discontinuing treatment were "concerns about treatment outweighing the benefits" (n = 53) and "difficulty paying" (n = 47). Conclusions. Persistence with teriparatide is dependent on managing side effects, addressing financial challenges, proper training, and obtaining support from the healthcare provider.

Duloxetine in the treatment of women with stress urinary incontinence: results from DESIRE (Duloxetine Efficacy and Safety for Incontinence in Racial and Ethnic populations).

OBJECTIVE: To evaluate the effectiveness and safety of duloxetine for the treatment of African-American and Hispanic women with stress urinary incontinence. RESEARCH DESIGN AND METHODS: The 10-week (a 2-week lead in period followed by 8 weeks of active treatment), open-label, multicenter study of duloxetine 40 mg twice daily included women with stress urinary incontinence or stress predominant mixed incontinence. Efficacy was measured by the median percent change from baseline to endpoint of weekly incontinence episode frequency. The primary objective assessed the treatment response in a pre-specified group of women (n = 2960; 2321 Caucasian, 271 African-American, and 368 Hispanic) with similar baseline incontinence and comorbidity characteristics as the subjects enrolled in the placebo-controlled trials of duloxetine for the treatment of stress urinary incontinence. The efficacy in African-American and Hispanic women was compared with Caucasians using a predefined non-inferiority subpopulation analysis. Safety measures included adverse events, laboratory test results, and vital signs. RESULTS: All three subgroups reported significant (all p < 0.001) median percent decreases in weekly incontinence episode frequency: -65.7% (African-American), -73.0% (Hispanic), and -75.0% (Caucasian). Non-inferior efficacy was demonstrated for African-American and Hispanic women compared to the Caucasian women. Common adverse events included nausea (21.8%, 28.0%, 25.3%), dry mouth (7.7%, 11.4%, 11.9%), and fatigue (9.2%, 5.7%, 11.6%) for the African-American, Hispanic, and Caucasian groups, respectively. CONCLUSION: Duloxetine was efficacious and well tolerated for the treatment of African-American, Hispanic, and Caucasian women with stress urinary incontinence. The trial design was successful in enrolling a diverse population of patients. The most important limitations include the lack of placebo control, the short study duration, and the exclusion of patients with less than seven incontinence episodes per week.