Title: An open randomised trial of the Arabin pessary to prevent preterm birth in twin pregnancy - STOPPIT - 2
Funder: Chief Scientist Office, Scotland

Abstract: DESIGN. A multicentre open randomised trial of the Arabin cervical pessary versus conventional treatment in women with twin pregnancy and a short cervix with two phases for each participant (i) a SCREENING phase to determine cervical length and (ii) a TREATMENT phase in which those with a short cervix (less than or equal to 35mm) are randomized to the Arabin pessary or standard care. SETTING. Antenatal clinics in the UK NHS. TARGET POPULATION. Women with twin pregnancy at less than 20+6 weeks gestation. HEALTH TECHNOLOGIES BEING ASSESSED. The cervical (Arabin) pessary, which appears effective in preventing preterm birth in singletons (Goya et al. 2012) and whose efficacy in twins has been suggested in a subgroup analysis of the ProTwin trial (Liem 2013). There are no alternative therapies (drug or non-drug) that prevent preterm birth in twins. MEASUREMENTS OF COSTS. A cost-effectiveness analysis of the Arabin pessary will be undertaken from the perspective of the UK NHS. MEASUREMENT OF OUTCOMES: The primary obstetric outcome is spontaneous onset of labour leading to delivery before 34+0 weeks gestation, measured at the mother level. The primary neonatal outcome is a composite of stillbirth, periventricular leucomalacia, early respiratory morbidity, intraventricular haemorrhage, necrotising enterocolitis, proven sepsis, and neonatal death, on either or both twins, very similar to the primary neonatal outcome in ProTwin (Liem 2013). Secondary outcomes will include acceptability, health economics, and outcomes likely to facilitate meta-analyses (Alfirevic 2014) – and will be informed by work ongoing under the COMET initiative (PI Duley). We will also calculate preterm birth before 34 weeks gestation for a variety of cervical lengths. SAMPLE SIZE: 2500 having consented to ultrasound screening and 500 randomised 1:1 to Arabin pessary or standard care there is 89% power at the 5% significance level to detect a difference in the primary obstetric outcome between the groups, assuming standard care event rate of 32% in the short cervix group and an (Arabin) treatment effect (RR) of 0.6. For the primary neonatal outcome, the study has 88% power for a treatment effect (RR). TIMETABLE. Set up - 4 months, pilot recruitment over 10 months / 28 centres (112 centre-months recruitment with randomization of 51 women – see case for support for assumptions) initiation of remaining 30 centres over next 14 months, during the recruitment period of a further 36 months, final outcomes collected - 7 months, data cleaning - 1 month, analysis - 2 months. EXPERTISE IN TEAM: Twin pregnancy and prevention of preterm birth, clinical trials, neonatal outcomes, health economics, social science (acceptability) and PPI (each of leading consumer organizations and regional level PPI groups). The team have experience of conducting large multicentre pregnancy studies in the UK (eg STOPPIT, OPPTIMUM and EMPOWaR – all whose recruitment targets have now been achieved).

Lay abstract: This study aims to confirm whether the Arabin cervical pessary prevents preterm birth in women with a twin pregnancy and a short cervix. Women with a twin pregnancy are at high risk of preterm labour. The extra risk of preterm labour in twin pregnancy is the main reason why twin babies are five times more likely to die both within the first one month or the first one year of life. Preterm babies who survive are at increased risk of long term disability, and require a lot of expensive health care – so if preterm birth could be prevented in twins this would be a very good thing. The Arabin cervical pessary is used to reduce preterm birth in women with a singleton pregnancy (one baby). A Dutch study which finished late last year has suggested that the cervical pessary might also prevent preterm birth in twins. Although the pessary did not work in all twins, it appeared to reduce preterm birth in those women with a twin pregnancy who had a short cervix (neck of the womb). However, before all UK women with twin pregnancy and a short cervix are offered this treatment in the NHS, we need to be certain about the benefits and the risks of this approach. Importantly, the number of women evaluated in the Dutch study was small, and the average length of the cervix was different from that found in a previous UK study. So we cannot yet be sure that the pessary will work in the UK, nor the threshold of cervical length below which the pessary might be beneficial. The study we propose here will resolve uncertainty around whether the Arabin pessary reduces spontaneous preterm birth in twins and improves outcomes for babies, define any adverse effects for mother and baby, ascertain whether women find the treatment acceptable and will calculate the costs for the NHS. We plan to involve at least 45 UK NHS centres. We will ask women with a twin pregnancy if they will have an ultrasound scan to measure their cervix at the same time as they have a fetal anomaly scan. The cervical scan is done through the vagina and is not painful. Women who are in the lowest 30% of cervical length measurements will be asked if they want to join the treatment phase of the study. Women who agree will be treated with either the Arabin pessary, or standard treatment. The pessary will be inserted between the beginning of the 18th to the end of the 20th week of pregnancy, and then removed at 36 weeks. We will look at the proportion of babies who are born before 34 weeks, and the complications that happen to babies and we will compare these between the two groups. If we find that the Arabin pessary improves outcomes and is acceptable to women, it could be used in the NHS straight away. The Arabin pessary is relatively cheap (£40 for one pessary for the entire pregnancy). It if works it will probably reduce health care costs, but we will perform an economic analysis to confirm this. We believe we will need to scan 2500women, and randomise 500 women with a short cervix to show a difference between the two groups, if one truly exists. The trial team is experienced in preterm birth and twin pregnancy and has relevant patient advocates involved who are helping us design and carry out our study and will make sure that the study is acceptable to, and of relevance to, pregnant women with twins. The team has experience of conducting large trials with pregnant women, so we are confident that we can carry out this study in the time we have requested.

Research activity codes: 6.3 MEDICAL DEVICES
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH