Am J Perinatol 2021; 38(S 01): e309-e317
DOI: 10.1055/s-0040-1710034
Original Article

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

George R. Saade
1  Department of Obstetrics and Gynecology, University of Texas Medical Branch, Galveston, Texas
,
Andrew Shennan
2  Department of Women and Children's Health, King's College London, St Thomas' Hospital, London, UK
,
Kathleen J. Beach*
3  Department of Maternal and Fetal Medicine, GSK, Research Triangle Park, North Carolina
,
Eran Hadar
4  Helen Schneider Hospital for Women, Rabin Medical Center, Petach-Tikva, Israel
5  Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
,
Barbara V. Parilla
6  Department of Obstetrics and Gynecology, Advocate Lutheran General Hospital, Park Ridge, Illinois
,
Jerry Snidow*
7  Alternative Discovery and Development, GSK, Research Triangle Park, North Carolina
,
Marcy Powell
8  Central Safety Department, GSK, Research Triangle Park, North Carolina
,
Timothy H. Montague
9  Clinical Statistics, Quantitative Sciences, GSK, Collegeville, Pennsylvania
,
Feng Liu
9  Clinical Statistics, Quantitative Sciences, GSK, Collegeville, Pennsylvania
,
Yosuke Komatsu
10  Maternal and Neonatal Health Unit, Alternative Discovery & Development, R&D, GSK, Research Triangle Park, North Carolina
,
Laura McKain
11  Pharmacovigilance, PPD, Wilmington, North Carolina
,
Steven Thornton
12  Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
› Author Affiliations
Funding This study received its funding from GlaxoSmithKline.

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 336/7 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.

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.


Supplementary Material



Publication History

Received: 08 November 2019

Accepted: 19 March 2020

Publication Date:
07 May 2020 (online)

© 2020. Thieme. All rights reserved.

Thieme Medical Publishers, Inc.
333 Seventh Avenue, 18th Floor, New York, NY 10001, USA