{
  "abstract": "Introduction 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.Methods and analysis 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).Ethics and dissemination 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).Trial registration number ISRCTN17176388.",
  "authors": [
    {
      "affiliations": [
        "Newcastle Clinical Trials Unit, Newcastle University, Newcastle upon Tyne, UK"
      ],
      "name": "Sarah Dunn"
    },
    {
      "affiliations": [
        "Newcastle University, Newcastle upon Tyne, UK"
      ],
      "name": "Lysbeth Evans"
    },
    {
      "affiliations": [
        "Newcastle Clinical Trials Unit, Newcastle University, Newcastle upon Tyne, UK"
      ],
      "name": "Ciara Kennedy"
    },
    {
      "affiliations": [
        "Newcastle University, Newcastle upon Tyne, UK"
      ],
      "name": "Rebecca Wafer"
    },
    {
      "affiliations": [
        "Newcastle University, Newcastle upon Tyne, UK"
      ],
      "name": "Sam Moody"
    },
    {
      "affiliations": [
        "Newcastle University, Newcastle upon Tyne, UK"
      ],
      "name": "Faye Wolstenhulme"
    },
    {
      "affiliations": [
        "Newcastle University, Newcastle upon Tyne, UK"
      ],
      "name": "Emma Burton"
    },
    {
      "affiliations": [
        "Newcastle University, Newcastle upon Tyne, UK"
      ],
      "name": "Ann Breeze Konkoth"
    },
    {
      "affiliations": [
        "Population Health Sciences Institute, Newcastle University Faculty of Medical Sciences, Newcastle upon Tyne, UK"
      ],
      "name": "Holly Fisher"
    },
    {
      "affiliations": [
        "Newcastle University Institute for Health and Society, Newcastle upon Tyne, UK"
      ],
      "name": "Thomas Chadwick"
    },
    {
      "affiliations": [
        "PPIE, Newcastle upon tyne, UK"
      ],
      "name": "Annie Banham"
    },
    {
      "affiliations": [
        "PPIE, Newcastle upon tyne, UK"
      ],
      "name": "Fiona Hale"
    },
    {
      "affiliations": [
        "PBC Foundation, Edinburgh, UK"
      ],
      "name": "Mo Christie"
    },
    {
      "affiliations": [
        "Glasgow Royal Infirmary, Glasgow, UK"
      ],
      "name": "Stephen T Barclay"
    },
    {
      "affiliations": [
        "Newcastle Upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK"
      ],
      "name": "Jessica Dyson"
    },
    {
      "affiliations": [
        "Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK"
      ],
      "name": "Rachel Smith"
    },
    {
      "affiliations": [
        "Wofson Digestive Disease Centre, Queens Medical Centre University Hospital, Nottingham, UK"
      ],
      "name": "Guruprasad Aithal"
    },
    {
      "affiliations": [
        "Oxford University Hospitals NHS Foundation Trust, Oxford, UK"
      ],
      "name": "Emma Culver"
    },
    {
      "affiliations": [
        "Portsmouth Hospitals University NHS Trust, Portsmouth, UK"
      ],
      "name": "Richard Aspinall"
    },
    {
      "affiliations": [
        "Department of Hepatology, Royal Free London NHS Trust, London, UK"
      ],
      "name": "Doug Thorburn"
    },
    {
      "affiliations": [
        "Institute of Liver Studies, King’s College London, London, UK"
      ],
      "name": "Michael Heneghan"
    },
    {
      "affiliations": [
        "Newcastle Clinical Trials Unit, Newcastle University, Newcastle upon Tyne, UK"
      ],
      "name": "Helen C Hancock"
    },
    {
      "affiliations": [
        "University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK"
      ],
      "name": "Palak Trivedi"
    },
    {
      "affiliations": [
        "Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK"
      ],
      "name": "George Mells"
    },
    {
      "affiliations": [
        "Population Health Sciences Institute, Newcastle University, Newcastle upon Tyne, UK",
        "MRC Biostatistics Unit, University of Cambridge, Cambridge, UK"
      ],
      "name": "James Wason"
    },
    {
      "affiliations": [
        "NIHR Newcastle Biomedical Research Centre and Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK"
      ],
      "name": "David E J Jones"
    }
  ],
  "title": "Optimising Primary thErapy in pRimAry biliary cholangitis (OPERA): protocol for a randomised, double-blind, placebo-controlled trial of enhanced primary therapy with obeticholic acid",
  "uid": "aa3b2247-d703-50ab-b5f0-ac378ff28e23"
}