A multi-centre, open label, randomised, parallel-group, superiority Trial to compare the efficacy of URsodeoxycholic acid with RIFampicin in the management of women with severe early onset Intrahepatic Cholestasis of pregnancy: the TURRIFIC randomised trial

William Hague ,Dorothy Graham,Michael Peek,Antonia Shand,Marloes Dekker,Jennifer Chambers,Susan Walker,Jim Thornton,Oskari Heikinheimo,Ben Willem J Mol ,Caroline Ovadia,Lucy C Chappell ,Angela Makris,Risto Kaaja,David Warrilow,Philippa Middleton,Jonathan M Morris ,Laura Lampio,Leonie K Callaway ,John P Newnham,Maria Fuller,Michael J Stark ,Annemarie Hennessy,Jennie Louise,Suzette Coat,Susanna Timonen,Peter H Dixon ,Sanne J Gordijn ,C Markus ,H.-U Marschall ,T Yee Khong ,Jiska De Haan-Jebbink,Jodie M Dodd ,Catherine Williamson

doi:10.1186/s12884-020-03481-y

Abstract

BackgroundSevere early onset (less than 34 weeks gestation) intrahepatic cholestasis of pregnancy (ICP) affects 0.1% of pregnant women in Australia and is associated with a 3-fold increased risk of stillbirth, fetal hypoxia and compromise, spontaneous preterm birth, as well as increased frequencies of pre-eclampsia and gestational diabetes. ICP is often familial and overlaps with other cholestatic disorders.Treatment options for ICP are not well established, although there are limited data to support the use of ursodeoxycholic acid (UDCA) to relieve pruritus, the main symptom. Rifampicin, a widely used antibiotic including in pregnant women, is effective in reducing pruritus in non-pregnancy cholestasis and has been used as a supplement to UDCA in severe ICP. Many women with ICP are electively delivered preterm, although there are no randomised data to support this approach.MethodsWe have initiated an international multicentre randomised clinical trial to compare the clinical efficacy of rifampicin tablets (300 mg bd) with that of UDCA tablets (up to 2000 mg daily) in reducing pruritus in women with ICP, using visual pruritus scores as a measuring tool.DiscussionOur study will be the first to examine the outcomes of treatment specifically in the severe early onset form of ICP, comparing “standard” UDCA therapy with rifampicin, and so be able to provide for the first-time high-quality evidence for use of rifampicin in severe ICP. It will also allow an assessment of feasibility of a future trial to test whether elective early delivery in severe ICP is beneficial.Trial identifiersAustralian New Zealand Clinical Trials Registration Number (ANZCTR): 12618000332224p (29/08/2018). HREC No: HREC/18/WCHN/36.EudraCT number: 2018–004011-44.IRAS: 272398.NHMRC registration: APP1152418 and APP117853.

Highlights

Severe early onset intrahepatic cholestasis of pregnancy (ICP) affects 0.1% of pregnant women in Australia and is associated with a 3-fold increased risk of stillbirth, fetal hypoxia and compromise, spontaneous preterm birth, as well as increased frequencies of pre-eclampsia and gestational diabetes
Our study will be the first to examine the outcomes of treatment in the severe early onset form of ICP, comparing “standard” ursodeoxycholic acid (UDCA) therapy with rifampicin, and so be able to provide for the first-time highquality evidence for use of rifampicin in severe ICP
It will allow an assessment of feasibility of a future trial to test whether elective early delivery in severe ICP is beneficial

Summary

Methods

We have initiated an international multicentre randomised clinical trial to compare the clinical efficacy of rifampicin tablets (300 mg bd) with that of UDCA tablets (up to 2000 mg daily) in reducing pruritus in women with ICP, using visual pruritus scores as a measuring tool

Discussion

Background

Methods/design

Findings