Title: Phase III trial in IntrahepaTic CHolestasis of pregnancy (ICP) to Evaluate urSodeoxycholic acid (UDCA) in improving perinatal outcomes
Funder: Department of Health and Social Care

Abstract: Background: Intrahepatic cholestasis of pregnancy (ICP), defined as gestational pruritus in association with raised maternal serum bile acids, affects approximately 1 in 150 pregnancies and is associated with increased rates of preterm labour, stillbirth and neonatal unit admission. Ursodeoxycholic acid (UDCA) is the most commonly used drug treatment for ICP. We and others have shown that UDCA improves maternal pruritus and biochemical abnormalities in ICP but there has been no adequately powered study to address the potential benefit of UDCA treatment in reducing adverse perinatal outcomes; this remains a novel research question. Aims: To evaluate the efficacy of ursodeoxycholic acid (UDCA) treatment on reduction of perinatal death, preterm delivery and neonatal unit admission in women with ICP, with the goal of establishing the potential benefit to the fetus. The secondary aim is to obtain samples in order to perform embedded studies to determine the mechanism(s) by which UDCA therapy may reduce the risk of adverse outcomes. Hypothesis: UDCA treatment for ICP reduces perinatal death, preterm delivery and neonatal unit admission with associated improvement in perinatal outcome. Design: Multi-centre randomised controlled trial to evaluate the efficacy of UDCA vs. placebo in women with ICP between 20+0 and 40+6 weeks' gestation. Population: Pregnant women with ICP (defined as pruritus together with a raised serum bile acid above the upper limit of normal) between 20+0 and 40+6 in a consultant-led maternity unit able to give informed consent. Intervention: UDCA or placebo tablets. The dose of UDCA will be 500mg bd, increased in increments of 500 mg per day every 3-14 days if there is no biochemical or clinical improvement, to a maximum of 2 grams per day. Outcomes: The primary outcome measure will be the proportion of infants affected by death (stillbirth or neonatal death) or preterm delivery (less than 37 weeks' gestation) or neonatal unit (NNU) admission. Each infant can only be counted once within this composite. Assessments: Women will be randomised at their first visit and then be seen weekly, coincident with routine follow-up within their consultant unit for biochemical monitoring, until delivery, together with one post-natal visit at six weeks as per usual protocol. Sample size: 582 pregnant women with ICP (291 per group) are required to have a 90% chance of detecting, as significant at the 5% level, a decrease in the composite primary outcome measure from 40% in the control group to 27% in the treated group. 612 women will be recruited to incorporate possible loss to follow-up. Statistical analysis: Trial analysis will follow the intention to treat principle, with women and infants analysed according to the original randomised allocation, irrespective of adherence and crossovers. We will estimate risk ratios and risk differences for yes/no outcomes using binary regression with a log-link (for risk ratios) and a linear link (for risk differences). Duration of the study: 1 January 2014 for four years Impact: This trial will provide definitive evidence for (or against) a role for UDCA in ameliorating adverse perinatal outcomes. If UDCA is beneficial, once published these results would be highly likely to lead to an immediate change in clinical practice, through individual choice of clinicians and pregnant women with ICP, and through changing national/ international guidelines.

Lay abstract: Intrahepatic cholestasis of pregnancy (ICP) is the commonest liver disease in pregnancy. Affected women itch and have abnormal liver blood tests. It is important to diagnose ICP because it is associated with risks for the unborn baby. Blood tests in the mother may show high levels of bile acids, which can increase the risk of the baby being born early and, in severe cases, being stillborn. At present the main drug used to treat ICP is ursodeoxycholic acid (UDCA). Our pilot study showed that women with ICP are willing to take part in a trial comparing UDCA with a placebo (an identical tablet not containing the drug). Our trial also suggested that UDCA may protect the unborn baby from poor outcomes, but the study was not large enough to be certain. A recent study that combined the results of several similar trials also showed that UDCA may improve the outcome for the baby in ICP. However, the current guideline from the Royal College of Obstetricians and Gynaecologists (RCOG) states, “Women should be informed of the lack of robust data concerning protection against stillbirth and safety to the fetus or neonate”. Lack of robust data means that the trials did not have a large enough number of women taking part. Our larger trial would address this problem. If it shows that UDCA protects babies, the RCOG could be clearer about its recommendations. The RCOG Guideline matters because this is what most doctors use as a guide for how to treat women with ICP. The main part of this study will be a clinical trial to compare the effect of UDCA or placebo treatment on the rate of adverse outcomes in ICP. As several studies have reported an increased rate of poor outcomes in ICP pregnancies with higher bile acid levels in the mother, we plan to make sure that at least a fifth of women who participate in the study have higher bile acid levels (>40µM/L). In the other part of the study we will collect samples from some of the mothers and babies to try and understand why ICP causes preterm birth and how it can cause the baby to be sick or die. We know that ICP babies have higher rates of breathing problems and spend longer on special care baby units. We do not know whether this is due to the mother and baby having high bile acid levels or because ICP pregnancies are often delivered early because doctors worry about the risk of stillbirth in this condition. This part of the study will try and find out why these problems happen and will also aim to find out how UDCA may prevent these complications. We will ask for some samples including blood, urine and faeces from the pregnant mother and placenta and umbilical cord blood (after the baby has been delivered). In a small number of women with severe disease we will ask for samples of amniotic fluid before delivery to allow measurement of bile acids and other substances that show how mature the baby’s lungs are. Women have told us that they are willing to give us these samples to help find out the answers. If we know that the baby’s lungs are not mature, we can give the mother a treatment to help reduce the chance of the baby having breathing problems when it is born. The fluid may also show whether the baby has opened its bowels (“passing meconium”) inside the womb which can mean that the baby is stressed and the doctors may want to deliver the baby sooner. This research will give vital information to help doctors understand and try and prevent the poor outcomes for the baby in ICP pregnancies.

Research activity codes: 5.1 PHARMACEUTICALS;6.1 PHARMACEUTICALS
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH