High Or Low Dose Syntocinon for delay in labour (HOLDS)

HOLDS PROTOCOL SUMMARY DESIGN: A multicentre, double blind, randomised controlled trial. SETTING: Delivery Suites in approximately 30 Maternity Units. TARGET POPULATION: Nulliparous women with a singleton cephalic pregnancy at term (37+0 - 41+6 weeks gestation) with confirmed delay in the first stage of labour (using NICE definitions). Those with a significant maternal condition or contra-indication to oxytocin will be excluded. Confirmed delay in labour (as defined per NICE Guidelines 2014): Labour is established when there are regular painful contractions and progressive cervical dilation from 4 cm. Delay is suspected when cervical dilatation of <2 cm in 4 hours occurs. Delay is confirmed when progress of <1 cm in 2 hours is found on repeat vaginal examination. HEALTH TECHNOLOGIES ASSESSED: Standard dose regimen of oxytocin (2mU/min increasing every 30 minutes to a maximum 32mU/min) compared to high dose regimen of oxytocin (4mU/min increasing every 30 minutes to a maximum of 64mU/min). OUTCOMES: Primary Outcome: Caesarean Section (CS). Secondary maternal outcomes: Clinical outcomes: Epidural use during labour, duration of first, second and third stages of labour, time to birth from randomisation, mode of birth (spontaneous vaginal birth (SVB), instrumental or CS), degree of perineal trauma, reason for CS and decision to delivery interval for CS, positive confirmed urinary retention requiring catheterisiation and pulmonary oedema, tachysystole (uterine contractions greater than 5 in 10 mins for 20 minutes) requiring reduction in oxytocin and/or tocolysis, hyperstimulation (uterine contractions greater than 5 in 10 mins for 20 minutes resulting in non-reassurring or abnormal fetal heart rate), fetal blood sampling (FBS) during labour or significant STAN event, abnormal cardiotocogram leading to immediate birth without fetal blood sample, incidence of possible maternal morbidity (anaphylaxis, pulmonary oedema, postpartum haemorrhage, shoulder dystocia, chorioamnionitis, uterine rupture/hysterectomy, active management of third stage of labour, length of time after birth in hospital, admission to HDU/ITU, maternal death. Process outcomes: Time from randomisation to commencement of allocation, total oxytocin dose, time to maximum oxytocin rate, maximum oxytocin dose reached. Neonatal secondary outcomes: Gender and birthweight, Apgar score at 5 minutes, arterial cord blood gases (when collected), breastfeeding rates on discharge from hospital, length of time after birth in hospital, resuscitation, reason for neonatal review on ward (excluding routine baby check), admission to neonatal unit (NNU) and level of care received including intensive care, duration of respiratory support, days to full suck feeds, seizures, neonatal encephalopathy, the need for therapeutic hypothermia (cooling), intrapartum still birth, early neonatal death (within seven days of birth). ANALYSIS: The analysis will be by intention to treat. Point estimates and two-sided 95% confidence intervals will be calculated for all main outcome measures. P-values will be reported from two-sided tests at the 5% significant level for the primary outcome and Serious Adverse Events only. A Statistical Analysis Plan will be drawn up prior to any analysis and agreed by the Trial Steering Committee (TSC) and Data Monitoring Committee (DMC). SAMPLE SIZE: 1500 women will be recruited. The sample size is informed by the pilot study [Kenyon 2013], and survey of practice and Cochrane review [Kenyon 2013]. The pilot study indicated a CS rate of 32% in the standard dose group (95%CI: 19% to 45%), whilst responses from the survey of practice (n=60 responses) indicate that a 25% relative reduction would be considered an important clinical difference to change practice. Detecting a difference of this size assuming a standard dose group rate of 32% (i.e. 8% absolute reduction down to 24%) with 90% power (p=0.05) will require 1320 women. If the control group rate is lower, e.g. 24%, recruiting 1500 women would give 80% power to detect the same relative difference. The independent Data Monitoring Committee (DMC) will review the event rate to monitor the control rate on a six-monthly basis throughout the recruitment period. TIMESLINES: Months 0-9: Regulatory and R&D applications to obtain approvals for the first 20 sites, development of telephone randomisation system, designating of HOLDS Midwives in sites, data collection forms and database finalised. Months 9-16: Recruitment of participants to pilot study. Months 17-24: Pilot assessment by TSC and DMC and decision to continue to the main trial. Setup of a further 10 sites to complete recruitment in month 24. Months 25-29: Completion of data collection, data cleaning, analysis, write-up of report and publication. Submission of draft trial report to the HTA in month 29. Following publication, results to be posted on the website for women and distributed widely. SITES: 30 maternity sites will collaborate. Each site will receive funding towards HOLDS Midwife time. Contracts will only be continued if pre-specified numbers of women have been recruited. For this trial having Research Midwives who are clinically active and part of Delivery Suite culture is particularly important. The HOLDS Midwife will be responsible for training staff, actively promoting the trial and maintaining the profile within each unit, troubleshooting challenges and collecting outcome data to minimise the impact on busy clinical staff, maintaining oversight of IMP accountability and active temperature monitoring, including submission of daily temperature logs on a monthly basis, receiving, acting upon and distribution information received via HOLDS updates and newsletters, representing the site at training and progress meetings.