Award Title: Atosiban versus placebo in the treatment of late threatened preterm birth.APOSTEL VIII study
Funder: Department of Health and Social Care

Abstract: Background  Preterm birth affects over 60,000 pregnancies annually in the UK (1). It causes more than half of all perinatal deaths and is the leading cause of neonatal morbidity, mostly due to respiratory and gastro-intestinal problems, brain damage and infection (2-4). Overall it is one of the largest single contributors to the Global Burden of Disease (5). Although there are three evidence-based obstetric treatments, namely steroids to promote lung maturity (9), magnesium sulphate to reduce cerebral palsy (10) and delayed cord clamping which reduces perinatal mortality (11), there is no evidence-based prevention. Obstetricians often prescribe uterine relaxants, or tocolytics, to delay birth, but no trial has ever shown that these reduce any substantive adverse outcome compared with placebo or no treatment. The World Health Organisation has recently stated that the use of tocolytics should be re-evaluated.  Aim  The APOSTEL-8 trial seeks to determine whether the most promising tocolytic agent, the oxytocin antagonist atosiban, reduces adverse baby outcomes. It will test the hypothesis that in women with threatened preterm birth between 30 and 34 weeks, tocolysis with atosiban reduces a composite of poor neonatal outcome (combined morbidity and mortality) compared to placebo.  Project plan  The present application is for funding to recruit 600 UK participants to the ongoing international multi-centre randomised, double-blind, placebo controlled, APOSTEL-8 trial, led from the Netherlands.  Population - Women, aged ≥ 18 years, with threatened preterm birth & gestational age between 30+0 and 33+6 weeks. Threatened preterm birth defined as uterine contractions plus either a cervical length of ≤ 15 mm or a positive fibronectin test or insulin-like growth factor binding protein-1 (Actim-Partus test), or ruptured membranes  Intervention - Atosiban intravenously by a bolus injection of 6.75 mg/0.9 ml in one minute followed by a continuous infusion of 18 mg/hour for 3 hours followed by a continuous infusion of 6 mg/hour for 45 hours.  Comparator - Placebo (intravenous normal saline) at the same rate.  Outcome - The primary outcome is a composite of perinatal in-hospital mortality or bronchopulmonary dysplasia at 36 weeks postmenstrual age, periventricular leucomalacia > grade 1, intraventricular haemorrhage > grade 2, necrotizing enterocolitis ≥ stage 2, retinopathy of prematurity > grade 2 or needing laser therapy, or culture proven sepsis.  Secondary outcome measures include: birth   Sample size - The full trial will recruit 1,514 participants (757 in each arm). Assuming 5% drop-out/loss-to follow-up, this is sufficient to show a 40% reduction (10% placebo to 6% atosiban) in the primary endpoint (alpha 0.05; beta 0.2). In the UK part of the trial we propose to recruit in twenty large centres over three years. This amounts to 10 participants per centre per year.

Lay Abstract: Premature birth is the leading cause of baby death and disability related to pregnancy. Drugs to stop uterine contractions (tocolytics) when a woman is in premature labour are widely used. However, although they delay birth, none have ever been shown to actually improve baby outcomes. They may even do harm if the placenta is not working well, or there is uterine infection, such that the baby would be safer delivered.   Previous trials have shown that the safest tocolytic for the mother is a drug called atosiban. This is licensed for use in pregnancy and already used in many hospitals. It is not a new drug. However many other hospitals don t use it, because of the fear that it might do more harm than good. This is why we need a proper research trial to test whether it really improves baby outcomes or not.  The trial needs to be randomised to give an unbiased answer. This means that women in preterm labour will be asked to consent to have their treatment chosen at random, like by tossing a coin. Half will be given the drug atosiban, and half will get salt water. Neither the parents, nor the doctors caring for them, will know which treatment they get.  Every mother and baby will still get all the other treatments which have been proven effective in previous trials. These include steroids to help the lungs work, magnesium to protect the baby s brain, and delayed cord clamping, which has been shown to improve survival. So no-one will miss out on an effective treatment.  Parents of preterm babies, their doctors, and others involved in their care have all indicated that this trial is a priority. The preterm baby charity, BLISS, supports the trial and one of their members is a co-applicant.  To give a clear answer the trial needs to be large, 1514 participants, and international. The APOSTEL-8 trial obtained funding and started in 2018 in the Netherlands, but it will take many years to complete in such a small country.  The APOSTEL-8 researchers therefore sought help from UK doctors to recruit. At least twenty UK centres are keen to join, and the UK part of the trial has been approved by the UK research ethics committee, and will start soon. However, the funding from the Netherlands is insufficient to cover all the UK costs.   The present grant is to fund trial organisation and follow-up for 600 participants in the UK.  Separate funding is also being sought for centres from other countries.

Research Activity Codes: 6.1 PHARMACEUTICALS
Health Categories: REPRODUCTIVE HEALTH AND CHILDBIRTH