Atosiban versus placebo in the treatment of late threatened preterm birth
Go to the APOSTEL VIII website
The aim of this study is to investigate if tocolysis with atosiban in late preterm birth (30 to 34 weeks) is (cost-) effective compared with placebo in improving neonatal morbidity and mortality.
A nationwide multicenter, double-blind randomized placebo controlled clinical trial performed within the NVOG consortium. From July 2017 until August 2020 women presenting with threatened preterm birth between 30 and 34 weeks of gestation will be randomized to atosiban or placebo. Women with symptoms of preterm labour, defined as regular uterine contractions, and one of the following, a cervical length < 15 mm, a cervical length of 15-30 mm and a positive fibronectin test or ruptured membranes will be eligible for the trial and asked for informed consent.
Women with threatened preterm birth between 30 and 34 weeks of gestation are eligible for the trial. All 10 perinatal centers in The Netherlands to which women with threatened preterm delivery before 32 weeks are transferred as well as 25 teaching hospitals will participate in the trial. Threatened preterm birth is defined as regular uterine contractions, and one of the following: a cervical length < 15 mm, a cervical length of 15-30 mm and a positive fetal fibronectin test or ruptured membranes. Our previous APOSTEL III study showed that half of the women with these criteria deliver within seven days, validating this definition of women at high risk for preterm birth.
Gynaecologists, residents and midwives within our consortium network will counsel women, ask informed consent, perform randomisation and collect data. Randomisation will be centrally controlled using a computerised randomisation service with random block size of two or four, rendered by an independent data manager. Centres will be able to access the randomisation service 24hr/day. Women presenting between 30 and 34 weeks will be randomised to atosiban or placebo. Participants and investigators will be masked for allocation. To prevent any imbalance between groups in aspects of care that may differ between centres, randomisation will be stratified by centre. Furthermore, since multiple pregnancies and women with premature prelabour rupture of the membranes (PPROM) have a higher risk for poor neonatal outcome, we will also stratify randomisation by singleton or multiple pregnancy and intact membranes versus PPROM.
Main study parameter/endpoint
The primary outcome of the study will be a composite adverse perinatal outcome, consisting of bronchopulmonary dysplasia at 36 weeks postmenstrual age (PMA), periventricular leucomalacia > grade 1, intraventricular hemorrhage > grade 2, necrotizing enterocolitis ≥ stage 2, retinopathy of prematurity > grade 2 or need for laser therapy, culture proven sepsis and perinatal death. Neonatal outcome will be assessed by neonatologists according definitions in the Dutch perinatal registry.
Secondary study parameters/endpoints
Secondary outcomes will be birth within 48 hours, time to delivery, gestational age at delivery, birth weight, number of days on invasive mechanical ventilation, length of admission in NICU, convulsions, asphyxia, meningitis, pneumothorax and mortality until 3 months corrected age, maternal infection, maternal side effects and costs. The components of the composite adverse perinatal outcome will also be assessed separately. Maternal side effects are defined as admission to intensive care, anaphylactic shock, dyspnea, hypotension (leading to CTG abnormalities), liver test abnormalities (elevated ASAT or ALAT), and general side effects (nausea, vomiting, headache), post-partum haemorrhage defined as > 500 ml blood loss. Outcome parameters are in line with the core outcome set for studies on prevention of preterm birth defined by members of GONet and the Core Outcomes in Women’s health (CROWN) initiative (www.crown-initiative.org).
Based on the Apostel III data the proportion of adverse perinatal outcome in women randomized between 30 and 34 weeks gestation and treated with atosiban was 6%. To show a 40% reduction of 10% in the placebo group to 6% in the atosiban group we need to randomize 1438 women (beta-error 0.2; alpha error 0.05). Assuming a 5% drop-out rate, we need to randomize 1514 women (757 in each arm).
All statistical analyses will be done according to the intention-to treat principle. Missing cost and effect data will be imputed using multiple imputation according to the MICE algorithm developed by van Buuren. Rubin’s rules will be used to pool the results from the different multiply imputed datasets. Bivariate regression analyses will be used to estimate cost and effect differences between atosiban and placebo while adjusting for confounders if necessary. Incremental cost-effectiveness ratios (ICERs) will be calculated by dividing the difference in the mean total costs between the treatment groups by the difference in mean effect between the treatment groups. Bias-corrected and accelerated bootstrapping with 5000 replications will be used to estimate 95% confidence intervals around the cost differences and statistical uncertainty surrounding the ICERs. Uncertainty surrounding ICERs will be graphically presented on cost-effectiveness planes. Cost-effectiveness acceptability curves will also be estimated showing the probability that atosiban is cost-effective in comparison with placebo for a range of different ceiling ratios thereby showing decision uncertainty. Sensitivity analyses will be performed to assess the robustness of the results using different assumptions regarding costs and effects.
June 2017 – August 2020
Dr. M. Kok, gynaecologist, AMC
Dr. M.A. Oudijk, gynaecologist, AMC
Dr. C.A. Naaktgeboren, methodologist, UMC Utrecht
W. Breebaart, MD, PhD candidate
Academic Medical Center
Obstetrics & gynaecology, room H4-250
1105 AZ Amsterdam
Drs. K. Heida, UMCU