Primary biliary cholangitis (PBC) is a rare chronic cholestatic disease that despite current therapy has significant ongoing unmet needs, including risks of cirrhosis and life-impairing symptoms. The current treatment approach is a step-up model, wherein first-line therapy, ursodeoxycholic acid (UDCA), is given for a minimum of 12 months before the addition of second-line therapy is considered for non-responding patients. This ‘waiting to fail’ approach, focused on the needs of low-risk patients, allows, we postulate, a key process of biliary epithelial cell (BEC) senescence to become established, driving accelerated bile duct loss and aggressive disease. Preclinical mouse modelling has shown that early use of the farnesoid X receptor agonist obeticholic acid (OCA), currently only used as second-line therapy following UDCA failure, reverses BEC senescence, changing the clinical course of disease. Here, we describe the design of the Optimising Primary thErapy in pRimAry biliary cholangitis (OPERA) trial. The aim of OPERA is to explore a new paradigm for disease-modifying treatment of PBC: risk-informed early treatment stratification, with patients at increased risk offered UDCA and OCA combination with the goal of complete biochemical remission.

OPERA is a multicentre, randomised, double-blind, placebo-controlled trial of OCA in combination with UDCA, as first-line treatment for high-risk PBC. This is a multicentre trial in England, which will be undertaken in specialist clinics in secondary/tertiary referral centres (or as per local set up). These centres will be specialists in the area of PBC management and will manage patients from across their local region. OPERA will recruit and randomise 106 adults, within 6 months of PBC diagnosis, who are at an enhanced risk of non-response to standard first-line therapy, between either: (1) UDCA and OCA or (2) UDCA and matched placebo in a 1:1 ratio. The primary efficacy outcome measure is the percentage of participants showing normalisation of serum alkaline phosphatase and total bilirubin values at 26 weeks (disease remission).

Favourable ethical opinion was received from London – Riverside Research Ethics Committee (reference: 22/LO/0878). Potential participants will be fully informed of their rights and the benefits and harms of the trial by the research team before giving informed consent to participate in the trial. Results will be disseminated in peer-reviewed publications, at national and international conferences, in peer-reviewed journals and to participants and the public (using lay language).

ISRCTN17176388.

Perinatal healthcare providers need access to accurate and current outcome data to counsel parents facing the birth of extremely premature infants. Parents want to know their infant’s risk of mortality, as well as the risk of hospital morbidities and neurodevelopmental outcomes, if their infant survives. Such data must be personalised to the precise infant-specific circumstances, including antenatal and perinatal risk factors unique to that infant.

The evidence-based preterm outcome calculator (EB-POC) cohort study uses linked population data to design, model, construct and validate an EB-POC to predict outcomes of premature birth (mortality, hospital complications and neurodisability).

Information from eight routinely collected administrative databases will be linked for all births registered in the Australian Capital Territory (ACT) and New South Wales, Australia, between 1 January 2007 and 31 December 2022 (or the latest available at the time of linkage). Key outcome measures will include an EB-POC to predict mortality, hospital morbidities and neurodisability. Data analysis will be conducted using Minitab and R software.

Approval was obtained from the ACT Human Research Ethics Committee (2022.LRE.00164 and 2024.LRE.00188), ACT Aboriginal and Torres Strait Islander Consumer Reference Group and the eight data custodians. The results are expected to be released in December 2025. The results will be presented at medical conferences and published in peer-reviewed academic journals. The calculator will be available free of charge through a user-friendly website and a mobile app, enabling prospective parents of premature babies and clinicians to make evidence-based, personalised, precision-based decisions.