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Diseases of liver
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Primary biliary cirrhosis (PBC) is a chronic, cholestatic liver disease that occurs in approximately 1/1000 women over the age of 40 in the UK. It is characterised by autoimmune destruction of the intrahepatic bile ducts. In patients with active disease, PBC may progress to cirrhosis and liver failure with attendant need for liver transplantation (LT).
The only medication licensed for treatment of PBC is ursodeoxycholic acid (UDCA). By convention, the therapeutic response to UDCA is defined in terms of the liver biochemistry (LFT) measured 12 months after starting treatment. It has been shown that survival in patients who respond to UDCA is comparable to that of the general population
whereas LT-free survival in UDCA non-responders is substantially reduced. It has also been shown that earlier age-at-presentation
is a risk factor for UDCA non-response and progressive liver disease.
The pharmaceutical industry has a major interest in finding novel medications for UDCA non-responders.However, the biological mechanisms of UDCA responsiveness are unknown, which impedes drug discovery and precludes an informed decision about which medications should be prioritised for clinical trials. In the UKPBC
Nested Cohort Study, we aim to elucidate the biological mechanisms of UDCA responsiveness. To do this, we will recruit known UDCA non-responders and matched UDCA responders from the UKPBC Research Cohort, a cohort of approximately 4500 PBC patients that has been established for population-level studies of PBC. We will also recruit treatment-naive PBC patients who presented before the age of 50. All patients recruited to the UK-PBC Nested Cohort Study will undergo detailed cell-and tissue-based study with correlation to biological and clinical outcomes. By exploring the biological mechanisms of UDCA responsiveness, we hope to identify optimal therapeutic approaches. We aspire to targeted clinical intervention by the end of the funding period.
Start dates may differ between countries and research sites. The research team are responsible for keeping the information up-to-date.
The recruitment start and end dates are as follows:
Observational type: Cohort study;
You can take part if:
You may not be able to take part if:
The principal exclusion criteria in the Nested Cohort Study are as follows: 1. Cohort A Cohort A of the Nested Cohort Study consists of PBC patients who are UDCA non-responders or UDCA responders matched by sex, age and region. Exclusion criteria i. An established diagnosis or clinical suspicion of a liver disease other than PBC; ii. End-stage liver disease; iii. Hepatocellular carcinoma; iv. Liver transplant for any indication; v. Poorly managed diabetes mellitus, defined by HbA1c ≥7.5% (or the equivalent); vi. Current treatment with immunosuppressants (including glucocorticoids); vii. Alcohol excess; viii. Pregnancy; ix. Inability to give informed consent. 2. Cohort B Cohort B of the Nested Cohort Study consists of treatment-naïve PBC patients who first presented with the disease before the age of 50 years. Exclusion criteria i. An established diagnosis or clinical suspicion of a liver disease other than PBC; ii. End-stage liver disease; iii. Hepatocellular carcinoma; iv. Liver transplant for any indication; v. Poorly managed diabetes mellitus, defined by HbA1c ≥7.5% (or the equivalent); vi. Current treatment with immunosuppressants (including glucocorticoids); vii. Alcohol excess; viii. Pregnancy; ix. Inability to give informed consent; x. Previous treatment with UDCA at any dose. 3. Cohort C Cohort C of the Nested Cohort Study consists of patients with a liver disease other than PBC, who require a liver biopsy for a clinical indication (e.g. diagnosis or staging). Exclusion criteria i. Established diagnosis of PBC; ii. Treatment with UDCA for any reason; iii. End-stage liver disease; iv. Hepatocellular carcinoma; v. Liver transplant for any indication; vi. Poorly managed diabetes mellitus, defined by HbA1c ≥7.5% (or the equivalent); vii. Current treatment with immunosuppressants (including glucocorticoids); viii. Alcohol excess; ix. Pregnancy; x. Inability to give informed consent. 4. Cohort D Cohort D consists of patients without an underlying liver disease who require liver surgery for a clinical indication (e.g. partial hepatectomy for resection of a solitary liver metastasis). Exclusion criteria i. An established diagnosis or clinical suspicion of any underlying liver disease; ii. Liver transplant for any indication; iii. Poorly managed diabetes mellitus, defined by HbA1c ≥7.5% (or the equivalent); iv. Current treatment with immunosuppressants (including glucocorticoids); v. Alcohol excess; vi. Pregnancy; vii. Inability to give informed consent; viii. Treatment with UDCA at any dose. 5. Cohort E Cohort E consists of healthy, disease-free volunteers recruited from the NIHR Cambridge BioResource (CBR). Exclusion criteria i. An established diagnosis or clinical suspicion of an underlying liver disease; ii. Hepatocellular carcinoma; iii. Liver transplant for any indication; iv. An established diagnosis or clinical suspicion of an autoimmune condition; v. Poorly managed diabetes mellitus, defined by HbA1c ≥7.5% (or the equivalent); vi. Current treatment with immunosuppressants (including glucocorticoids); vii. Alcohol excess, defined as regular consumption of >8 units/day or >50 units/week for a man, or regular consumption of >6 units/day or >35 units/week for a woman; viii. Pregnancy; ix. Inability to give informed consent; x. Treatment with UDCA at any dose.
Below are the locations for where you can take part in the trial. Please note that not all sites may be open.
The study is sponsored by THE NEWCASTLE UPON TYNE HOSPITALS NHS FOUNDATION TRUST and funded by Medical Research Council (MRC) .
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for Trial ID: CPMS 17542
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