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Objective  The aim of this study is to assess the efficacy and safety of retosiban in spontaneous preterm labor (sPTL). Study Design  Two multicenter, randomized, and double-blind trials compared retosiban with placebo and retosiban with atosiban in women with a singleton pregnancy and intact membranes in sPTL at 24 to 33 6/7 weeks' gestation. Coprimary endpoints in the placebo-controlled trial were time to delivery (TTD) or treatment failure (whichever occurred first) and neonatal composite morbidity and mortality. The primary endpoint of the atosiban comparator trial was TTD. Results  The trials were terminated early because of slow recruitment. The placebo-controlled trial enrolled 23 participants (February 2016–July 2017; 2.6% of target);the atosiban-comparator trial enrolled 97 (March 2015–August 2017; 29% of target). Baseline participant characteristics were similar between treatments. In the placebo-controlled trial, mean gestational ages at randomization were 30.8 (retosiban, n  = 10) and 30.5 weeks (placebo, n  = 13), and mean times to delivery/treatment failure were 18.9 days (retosiban) and 11.1 days (placebo). Two and four neonates in the retosiban and placebo groups, respectively, had ≥1 component of the neonatal composite endpoint. In the atosiban-comparator trial, mean gestational age at randomization was 31.5 weeks (for both retosiban, n  = 47, and atosiban, n  = 50), and adjusted mean TTDs were 32.51 days (retosiban) and 33.71 days (atosiban; p  > 0.05). Adverse events were no more common with retosiban than placebo or atosiban. Conclusion  Despite considerable efforts to conduct two adequate and well-controlled studies in patients with sPTL, both studies were unable to recruit effectively and consequently terminated prematurely. Key factors negatively affecting participation were patient and physician resistance to use of a placebo comparator, lack of investigator consensus on diagnostic criteria and acceptance of protocol procedures, and ethics committee decisions. Meaningful cooperation between pharmaceutical companies, regulatory authorities, and the obstetric community is essential for future development of drugs to treat sPTL. [ABSTRACT FROM AUTHOR]

In prior works, this group demonstrated the feasibility of valid adaptive sequential designs for crossover bioequivalence studies. In this paper, we extend the prior work to optimize adaptive sequential designs over a range of geometric mean test/reference ratios (GMRs) of 70-143% within each of two ranges of intra-subject coefficient of variation (10-30% and 30-55%). These designs also introduce a futility decision for stopping the study after the first stage if there is sufficiently low likelihood of meeting bioequivalence criteria if the second stage were completed, as well as an upper limit on total study size. The optimized designs exhibited substantially improved performance characteristics over our previous adaptive sequential designs. Even though the optimized designs avoided undue inflation of type I error and maintained power at [ABSTRACT FROM AUTHOR]

Objective  To propose and assess a composite endpoint (CE) of neonatal benefit based on neonatal mortality and morbidities by gestational age (GA) for use in preterm labor clinical trials. Study Design  A descriptive, retrospective analysis of the Medical University of South Carolina Perinatal Information System database was conducted. Neonatal morbidities were assessed for inclusion in the CE based on clinical significance/risk of childhood neurodevelopmental impairment, frequency, and association with GA in a mother-neonate linked cohort, comprising women with uncomplicated singleton pregnancies delivered at ≥24 weeks' GA. Results  Among 17,912 mother-neonate pairs, neonates were at a risk of numerous severe but infrequent morbidities. Clinically important, predominantly rare events were combined into a CE comprising neonatal mortality and morbidities, which decreased in frequency with increasing GA. The highest CE frequency occurred at <31 weeks. High frequency of respiratory distress syndrome, bronchopulmonary dysplasia, and sepsis drove the CE. Median length of hospital stay was longer at all GAs in those with the CE compared with those without. Conclusions  Descriptive epidemiological assessment and clinical input were used to develop a CE to measure neonatal benefit, comprising clinically meaningful outcomes. These empirical data and CE allowed trials investigating tocolytics to be sized appropriately.