Randomized Trials of Retosiban Versus Placebo or Atosiban in Spontaneous Preterm Labor

Abstract

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.

Keywords

atosiban - efficacy - oxytocin antagonist - recruitment - retosiban - safety - spontaneous preterm labor - tocolysis

Note

Within 6 months of this publication, anonymized individual participant data, the annotated case report form, protocol, reporting and analysis plan, dataset specifications, raw dataset, analysis-ready dataset, and clinical study report will be available for research proposals approved by an independent review committee. Proposals should be submitted to www.clinicalstudydatarequest.com. A data access agreement will be required.

^* Kathleen Beach's and Jerry Snidow's affiliations are correct as at the time the study was completed.

^† Barbara V. Parilla's address at time of online publication: Rush Center for Maternal-Fetal Medicine, Aurora, IL. Feng Liu's address at time of online publication: AstraZeneca, Gaithersburg, MD. Yosuke Komatsu's address at time of online publication: Global Clinical Development, Mitsubishi Tanabe Pharma Development America, Jersey City, NJ. Laura McKain's address at time of online publication: Myovant Sciences, Brisbane, CA.

Publikationsverlauf

Eingereicht: 08. November 2019

Angenommen: 19. März 2020

Artikel online veröffentlicht:
07. Mai 2020

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