Optimising primary therapy in primary biliary cholangitis
| ISRCTN | ISRCTN17176388 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN17176388 |
| EudraCT/CTIS number | 2022-000050-28 |
| IRAS number | 1006087 |
| Secondary identifying numbers | NIHR131359, 10077, IRAS 1006087, CPMS 54589 |
- Submission date
- 08/11/2022
- Registration date
- 10/07/2023
- Last edited
- 17/02/2025
- Recruitment status
- Recruiting
- Overall study status
- Ongoing
- Condition category
- Digestive System
Plain English Summary
Background and study aims
Primary biliary cholangitis (PBC) is a rare liver disease. A number of treatments exist, which slow the rate that liver disease gets worse. However, at the moment, doctors have to wait for one treatment to fail before adding in a second. As a result, many people with PBC develop symptoms and some go on to need a liver transplant. The aim of the OPERA trial is to see if people who are newly/recently diagnosed with PBC have a better outcome if they receive two medicines from the start rather than one. Importantly, this trial will recruit people who are at risk of not responding to the one therapy alone (ursodeoxycholic acid, UDCA or “urso”). The second, additional medicine offered as part of this study is called obeticholic acid (OCA). OCA is already licenced for the treatment of PBC in people who have not responded to urso, and it has a well-known safety profile.
Who can participate?
Adults with a recent diagnosis of PBC
What does the study involve?
People who meet trial criteria and want to take part will be treated with either OCA or placebo ("dummy drug"), in addition to urso (the current standard care) for up to 6 months. After this time point, people will be followed up as part of the trial for an additional 6 months thereafter. The trial will recruit at hospitals across the UK, and aims to recruit 106 people with PBC.
What are the possible benefits and risks of participating?
We cannot promise the trial will help you directly. We hope the information we get from this trial will help to improve the treatment for PBC patients in the future who are at high risk of progression of their disease to cirrhosis. By being part of this trial you will also be more closely monitored and have follow up visits and calls which would not happen as part of your normal care.
OCA is currently licensed for the treatment of PBC in the UK. The treating clinicians in the study have clinical experience with OCA and there is no reason to suspect a different safety profile in treating patients with PBC at an earlier stage of their disease course. However as with any medication there is potential for side effects to occur. Patients will be advised of the known side effects and will be provided with contact details of their local study team should they have any safety concerns. If side effects are reported, participant dosage may be reduced or withheld or they may treated with additional medication until side effects have resolved. Clinicians will refer to the British Society of Gastroenterology/UK-PBC Primary Biliary Cholangitis Treatment and Management Guidelines.
The safety profile of pregnant women taking OCA is not known. All participants will be asked to use acceptable contraception (e.g. barrier/ hormonal/ sterilisation) or to practice sexual abstinence for the entire duration of the treatment period. If a participant were to become pregnant during the course of the study, the patient will be withdrawn from study treatment but will be followed up until completion of pregnancy (i.e. termination, miscarriage, stillbirth or live birth) and for a year after birth. We will also follow up on any pregnancies of partners of participants who become pregnant while the participant is on the trial.
Where is the study run from?
Newcastle University (UK) and trial sites across the UK
When is the study starting and how long is it expected to run for?
November 2022 to February 2026
Who is funding the study?
National Institute for Health and Care Research (NIHR) (UK). This project (NIHR131359) is funded by the Efficacy and Mechanism Evaluation (EME) Programme, an MRC and NIHR partnership.
Who is the main contact?
opera@newcastle.ac.uk
Contact information
Scientific
1-4 Claremont Terrace
Newcastle upon Tyne
NE2 4HH
United Kingdom
| opera@newcastle.ac.uk |
Principal Investigator
Framlington Place
Newcastle-Upon-Tyne
NE2 4HH
United Kingdom
| Phone | +44 (0)191 208 7572 |
|---|---|
| david.jones@ncl.ac.uk |
Study information
| Study design | Randomized placebo-controlled double-blind parallel-group superiority study |
|---|---|
| Primary study design | Interventional |
| Secondary study design | Randomised controlled trial |
| Study setting(s) | Hospital |
| Study type | Treatment, Safety, Efficacy |
| Participant information sheet | Not available in web format, please use the contact details to request a participant information sheet |
| Scientific title | Optimising primary therapy in primary biliary cholangitis |
| Study acronym | OPERA |
| Study hypothesis | To assess the impact of first-line obeticholic acid therapy combined with ursodeoxycholic acid (UDCA) standard of care therapy compared to placebo in achieving biochemical remission of disease in new-onset PBC patients with enhanced disease risk. 1. To assess whether biochemical remission is sustained following discontinuation of experimental therapy and reversion to UDCA standard of care therapy 2. To assess the degree of biochemical improvement with obeticholic acid therapy combined with UDCA (or urso) standard of care therapy compared to placebo 3. To assess the impact of obeticholic acid therapy combined with UDCA standard of care therapy compared to placebo using conventional therapy response criteria (as used in current clinical practice) 4. To assess the safety and tolerability of obeticholic acid as first-line therapy in PBC 5. To assess the impact of the intervention compared to placebo on symptom severity and participant quality of life Experimental: 1. To assess whether biochemical remission is sustained following discontinuation of experimental therapy and reversion to UDCA standard of care therapy in those participants who are in remission at 26 weeks 2. To assess changes in chemokine levels in the blood potentially associated with bile duct senescence 3. To assess the impact of intervention compared to placebo on the degree of liver inflammation and bile duct senescence |
| Ethics approval(s) |
Approved 31/05/2023, London - Riverside Research Ethics Committee (Ground Floor Temple Quay House, 2 The Square, Bristol, BS1 6PN, United Kingdom; None available; riverside.rec@hra.nhs.uk), ref: 22/LO/0878 |
| Condition | Primary biliary cholangitis |
| Intervention | The trial is a double-blinded, superiority, placebo-controlled, randomised, multi-centre trial of an investigational medicinal product (CTIMP). Participants will be randomised using a Sealed Envelope online tool. The trial comprises a 26-week treatment phase in a cohort of 106 participants (Obeticholic Acid n=53; Placebo n=53), followed by a 26-week follow-up period. The study drug is taken orally at a dose of 5mg per day and titrated up to a maximum of 10mg/day after 12 weeks according to tolerability. All participants will continue to receive standard-of-care background treatment with UDCA throughout the trial. The study population will be newly diagnosed, non-cirrhotic patients, with less than 3 months of treatment with UDCA at the time of consent and at an enhanced risk of not achieving biochemical disease remission with UDCA 1st-line therapy alone. |
| Intervention type | Drug |
| Pharmaceutical study type(s) | Pharmacodynamic |
| Phase | Not Applicable |
| Drug / device / biological / vaccine name(s) | Obeticholic acid, ursodeoxycholic acid |
| Primary outcome measure | Percentage of participants showing normalisation of serum alkaline phosphatase and total bilirubin levels, measured using blood samples at 26 weeks (visit 5) |
| Secondary outcome measures | 1. Percentage of participants in each study group showing sustained normalisation of serum alkaline phosphatase and total bilirubin levels, measured using blood samples at 52 weeks (visit 6) 2. Magnitude of alkaline phosphatase and bilirubin reduction, measured using blood samples, from baseline to 26 weeks (visit 5), assessed as a continuous variable 3. Percentage of participants attaining serum alkaline phosphatase values lower than 1.67x the upper limit of normal and a bilirubin <1x the upper limit of normal, measured using blood samples at 26 weeks (visit 5). These are termed the POISE criteria, and are widely applied as outcome measures in conventional clinical trials of 2nd-line PBC therapy 4. Change in liver stiffness assessed by Transient Elastography (FibroScan) from screening to week 26 5. Safety and tolerability assessed by AE and SAE Reporting up to 26 weeks (visit 5) 6. Symptom severity and participant quality of life measured using the Quality of Life for Primary Biliary Cirrhosis (PBC-40) questionnaire (change from baseline to 26 weeks (visit 5) and 52 weeks (visit 6)) 7. Symptom severity and participant quality of life measured using EQ-5D-5L questionnaire (change from baseline to 26 weeks (visit 5) and 52 weeks (visit 6)) 8. Symptom severity and participant quality of life measured using Patient Health Questionnaire (26 and 52 weeks) Experimental outcome measures 1. Percentage of participants in each study group who remain in remission at 52 weeks (visit 6) as a proportion of those who showed normalisation of serum alkaline phosphatase and total bilirubin levels, measured using blood samples at primary end-point assessment at 26 weeks (visit 5) 2. Serum levels of putative senescence-associated chemokines, demonstrated to be elevated in high-risk disease and UDCA non-responders in underpinning UK-PBC studies as outlined earlier, will be quantified using a bespoke multiplex assay and evaluated as dynamic risk and response markers. The combination of CCL20 and CXCL11 will be specifically explored as a baseline and early response predictive biomarker and validated against liver biopsy findings. Assessment of the capacity for ongoing elevation of chemokine biomarkers at 26 weeks to predict biochemical relapse at 52 weeks. 3. Change in liver fibrosis stage on liver histology and the degree of bile duct senescence assessed using p16 and p21 immunohistochemistry in a biopsy sub-study (n approx. 15 in each group). p16 and p21 are established and well-validated cellular markers of senescence. Biopsies will be centrally read by two pathologists blinded to treatment allocation and findings correlated with serum chemokine marker values. |
| Overall study start date | 03/11/2022 |
| Overall study end date | 28/02/2026 |
Eligibility
| Participant type(s) | Patient |
|---|---|
| Age group | Mixed |
| Lower age limit | 18 Years |
| Sex | Both |
| Target number of participants | 106 |
| Participant inclusion criteria | 1. Established diagnosis of PBC based on the presence of at least 2 out of the 3 key disease characteristics, specifically: 1.1. AMA or PBC-specific ANA at a clinically diagnostic level 1.2. Elevated alkaline phosphatase (above the upper limit of normal (ULN) for the relevant laboratory) 1.3. Compatible or diagnostic liver biopsy 2. Ongoing elevation of alkaline phosphatase (≥15% above ULN) at screening 3. Disease duration of <6 months from date of diagnosis at the time of consent 4. Use of UDCA for <3 months at the time of consent 5. Pre-treatment Ursodeoxycholic Acid Response Score with a predicted risk of future non-remission of liver biochemistry (ie ALP>ULN) with UDCA alone of >20% 6. For people of childbearing potential: an agreement to use at least an acceptable effective method contraception or to practise sexual abstinence to avoid pregnancy for entire duration of the study period. 7. Willing to complete the study assessment protocols 8. Ability to consent, able to comply with study protocol and attend clinic visits 9. Age ≥ 18 years at the time of consent |
| Participant exclusion criteria | 1. Clinical contraindication to obeticholic acid use 2. Untreated, clinically significant pruritus (patients with effectively treated pruritus are eligible for inclusion) 3. Concomitant use of fibric acid derivatives (e.g. bezafibrate or fenofibrate) within 14 days prior to screening 4. Clinical suspicion of cirrhosis evidenced by a history of one or more of the following: 4.1. ascites requiring diuretic therapy or percutaneous drainage 4.2. endoscopically-confirmed varices 4.3. liver biopsy suggesting cirrhosis 4.4. platelet count <150 x109/L 4.5. transient elastography score >16.9 kPa within 3 months prior to or at screening 4.6. hepatocellular carcinoma confirmed by biopsy or 2 imaging modalities 4.7. hepatic encephalopathy 5. Bilirubin >twice the upper limit of normal 6. Evidence of complete biliary obstruction 7. Previous exposure to obeticholic acid (either in clinical trials or in clinical practice) or other potential PBC-modifying therapy 8. Regular (more than one week per month) alcohol consumption in excess of recommended safe limits (14 units per week) 9. Active participation in another interventional trial or exposure to another experimental drug within 5 half-lives 10. Pregnancy or planning to get pregnant within duration of participation in the trial 11. Currently breastfeeding 12. Overlapping features of an additional liver disease, including autoimmune hepatitis (using the Paris criteria for autoimmune hepatitis overlap) 13. Hypersensitivity to the active substance or to any of the excipients 14. If the participant’s treating clinician deems the patient is not suitable to participate in the trial based on other criteria apparent during screening or from medical history 15. Previous liver transplantation |
| Recruitment start date | 30/09/2023 |
| Recruitment end date | 31/08/2025 |
Locations
Countries of recruitment
- England
- Scotland
- United Kingdom
Study participating centres
Mindelsohn Way
Edgbaston
Birmingham
B15 2GW
United Kingdom
Hills Road
Cambridge
CB2 0QQ
United Kingdom
91 Wishart Street
Glasgow
G31 2HT
United Kingdom
Freeman Road
High Heaton
Newcastle upon Tyne
NE7 7DN
United Kingdom
E Floor, West Block
Derby Road
Nottingham
NG7 2UH
United Kingdom
Southwick Hill Road
Cosham
Portsmouth
PO6 3LY
United Kingdom
Pond Street
London
NW3 2QG
United Kingdom
Aberdeen
AB25 2ZN
United Kingdom
Brixton
London
SW9 8RR
United Kingdom
Headington
Oxford
OX3 9DU
United Kingdom
Beckett Street
Leeds
LS9 7TF
United Kingdom
Sponsor information
University/education
Level 1, Regent Point
Regent Farm Road
Gosforth
Newcastle upon Tyne
Newcastle upon Tyne
NE3 3HD
England
United Kingdom
| Phone | None provided |
|---|---|
| tnu-tr.sponsormanagement@nhs.net | |
| Website | http://www.ncl.ac.uk/ |
"ROR" |
https://ror.org/05p40t847 |
Funders
Funder type
Government
Government organisation / National government
- Alternative name(s)
- National Institute for Health Research, NIHR Research, NIHRresearch, NIHR - National Institute for Health Research, NIHR (The National Institute for Health and Care Research), NIHR
- Location
- United Kingdom
Results and Publications
| Intention to publish date | 28/02/2027 |
|---|---|
| Individual participant data (IPD) Intention to share | Yes |
| IPD sharing plan summary | Published as a supplement to the results publication |
| Publication and dissemination plan | 1. Peer reviewed scientific journals 2. Internal report 3. Conference presentation 4. Publication on website 5. Other publication 6. Submission to regulatory authorities Access to raw data and right to publish freely by all investigators in study or by Independent Steering Committee on behalf of all investigators. Until publication of the trial results, access to the full dataset will be restricted to the Trial Management Group and to authors of the publication. Participants will be asked to consent to sharing of anonymised study data with other researchers. Anonymised data from this trial/study may be available to the scientific community subject to appropriate ethical approval. Requests for data should be directed to the lead author/Chief Investigator and NCTU in line with any applicable data sharing policies. |
| IPD sharing plan | The datasets generated and/or analysed during the current study will be published as a supplement to the results publication. |
Editorial Notes
17/02/2025: The recruitment end date was changed from 31/12/2024 to 31/08/2025.
15/11/2023: The study participating centres Aberdeen Royal Infirmary, Kings College Hospital, John Radcliffe Hospital and St James’s University Hospital were added.
07/09/2023: The following has been changed:
1. The study website was added.
2. The Individual participant data (IPD) sharing plan and summary were added.
08/08/2023: Internal review.
01/06/2023: ISRCTN received notification of combined HRA/MHRA approval for this trial on 01/06/2023
08/11/2022: Trial’s existence confirmed by the HRA.
