Congress Proceedings: COGI

US PLACEBO-CONTROLLED TRIALS OF ATOSIBAN IN THE TREATMENT OF PRETERM LABOUR 

T Murphy Goodwin, MD 
Division of Maternal-Fetal Medicine, Women's and Children's Hospital, Los Angeles, USA 

Dr T Murphy Goodwin was educated at the Medical School of the University of Southern California and was involved in both the phase II and phase III clinical trials of atosiban. His research interests include diagnosis, prediction and treatment of preterm birth, and thyroid disease in pregnancy. Over the past five years Dr Goodwin has published more than 15 papers on the subject of preterm birth and related topics. Dr (Goodwin is currently Associate Professor in the Department of Obstetrics and Gynecology at the University of Southern California Medical School, and Head of the Maternal-Fetal Medicine division. 

Two randomised, double-blind, placebo-controlled trials, PTL-096 (acute) and PTL-098 (main tenance), evaluated the efficacy and safety of the oxytocin receptor antagonist atosiban in the treatment of preterm labour (PTL). 

In PTL-0961, 501 women with documented PTL remait (based on contraction and cervical findings) at 20-33 6/7 weeks were randomised and received either atosiban (n=246) or placebo (n=255). Atosiban was given for up to 48 hours by i.v. infusion followed by a maintenance dose via subcutaneous pump until 36 completed weeks. Although there was no significant difference between atosiban and placebo for median time to delivery or therapeutic failure (25.6 days vs 21.0 days, respectively), the proportion of women remaining undelivered and not requiring alternative tocolysis after 24 hours, 48 hours and 7 days was significantly higher following atosiban administration than placebo (73% vs 58%, 67% vs 56% and 62% vs 49%, respectively) (Figure 1). 

In PTL-O982, following successful uterine quiescence with i.v. atosiban, 512 women were randomised to maintenance (as above); 261 atosiban and 251 placebo. The median time to first recurrence of PTL was 32.6 days with atosiban and 27.6 days with placebo (P=O.O2). Also, 23% of women given atosiban and 31% on placebo had at least one subsequent i.v. therapy for recurrent PTL. 

The reported incidence of both maternal and fetal adverse events following atosiban administration was comparable to placebo, except for an increase in injection-site reactions (Table 1)³. Neonatal morbidity and mortality were similar in neonates = 28 weeks, but these outcomes were inconclusive in neonates < 24 weeks due to complications of prematurity.

In total, 73% and 81% of infants returned for 6-month follow-up, and 65% and 74% of infants returned for 12-month follow-up in Studies PTL-O96 and PTL-O98, respectively³. Infant 6- and 12-month follow-up showed no unexpected safety or developmental findings in either trial (Table 2) .

The results of the placebo-controlled trials indicate that i.v. atosiban is associated with a significantly higher proportion of women remaining undelivered and not requiring alternative tocolysis up to 7 days of starting treatment. Following successful i.v. treatment with atosiban, subcutaneous maintenance therapy was also associated with prolonging the time interval to first recurrence of labour and reducing the need for subsequent i.v. therapy for recurrent PTL. Safety outcomes were particularly encouraging, since both maternal/fetal adverse events and 12-month infant follow-up were comparable in the atosiban and placebo groups. These findings, which were dependent on gestational age, suggest a role for atosiban in the treatment of PTL.

References 

1. Sibai BM, Romero R, Sanchez-Ramos L et al. A double-blind placebo-controlled trial of an oxytocin-receptor antagonist (Antocin) in the treatment of preterm labor. Am J Obstet Gynecol 1997; 176 (1 Pt 2): S2. 

2. Sanchez-Ramos L, Valenzuela G, Romero R et al. A double-blind placebo-controlled trial of oxytocin receptor antagonist (Antocin) maintenance therapy in patients with preterm labor. Am J Obstet Gynecol 1997; 176 (1 Pt 2): S30. 

3. Goodwin TM, Randall H, Perry K et al. A report on infant outcomes at 6 and 12 months after the use of atosiban in the management of preterm labor. Presented at the AGOG meeting, New Orleans, USA, May 1998.