Primary biliary cholangitis Digestive System
Conditions
Interventions
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
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 pa
Sponsors
Newcastle upon Tyne Hospitals NHS Foundation Trust
Eligibility
Sex/Gender
All
Age
18 Years to 120 Years
Inclusion criteria
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 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
Exclusion criteria
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 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
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Percentage of participants showing normalisation of serum alkaline phosphatase and total bilirubin levels, measured using blood samples at 26 weeks (visit 5) | — |
Secondary
| Measure | Time frame |
|---|---|
| 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 | — |
Countries
England, Scotland, United Kingdom
Outcome results
None listed