Treatment of spontaneous preterm labour with retosiban: a phase 2 proof-of-concept study

Abstract

Aim: The aim was to investigate the efficacy and safety of intravenous retosiban in women with spontaneous preterm labour.

Methods: This was a randomized, double-blind, placebo-controlled, phase 2 trial. Retosiban was administered intravenously for 48 h to women in spontaneous preterm labour between 30(0/7) and 35(6/7) weeks' gestation with an uncomplicated singleton pregnancy in an in-patient obstetric unit. Outcome measures were uterine quiescence (primary endpoint), days to delivery, preterm delivery and safety.

Results: Uterine quiescence was achieved in 62% of women who received retosiban (n = 30) compared with 41% who received placebo (n = 34). The relative risk (RR) was 1.53 (95% credible interval [CrI] 0.98, 2.48; NS). Retosiban resulted in a significant increase in time to delivery compared with placebo (mean difference 8.2 days, 95% CrI 2.7, 13.74). This difference was consistent across all gestational ages. The proportion of preterm births in the retosiban and placebo groups was 18.7% (95% CrI 7.4%, 33.7%) and 47.2% (95% CrI 31.4%, 63.4%), respectively. The RR of preterm birth in women treated with retosiban was 0.38 (95% CrI 0.15, 0.81). There were no deliveries within 7 days in the retosiban group, but there were six (17.6%) births in the placebo group. The maternal, fetal and neonatal adverse events were comparable in the retosiban and placebo groups.

Conclusions: Intravenous administration of retosiban in women with spontaneous preterm labour was associated with a greater than 1 week increase in time to delivery compared with placebo, a significant reduction in preterm deliveries, a non-significant increase in uterine quiescence and a favourable safety profile.

Keywords: preterm birth; preterm labour; proof-of-concept study; retosiban; uterine quiescence.

Figure 1

Disposition of women in proof-of-concept study (IP, investigational product)

Figure 2

Mean uterine contraction frequency. , retosiban, (n = 30); , placebo (n = 34)

Figure 3

Scatter plot of days to delivery vs. gestational age at randomization. The solid line represents the time in days to achieve 37 weeks. Women falling below the solid line delivered before 37 weeks and those above the line delivered after 37 weeks. The dashed red and blue lines display the linear fit for time to delivery for the retosiban and placebo groups, respectively. The difference between the red and blue lines represents the difference between retosiban and placebo in mean days to delivery, which was consistent across gestational ages. , retosiban; , placebo

Figure 4

Maternal blood pressure (mean and 95% CrI) following administration of retosiban or placebo (0–48 h). , retosiban, systolic; , placebo, systolic; , retosiban, diastolic; , placebo, diastolic

Figure 5

Maternal and fetal heart rate (mean and 95% CrI) following maternal treatment with retosiban or placebo (0–48 h). , retosiban, fetal; , placebo, fetal; , retosiban, mother; , placebo, mother