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Case study: Finding a new treatment option for Primary Biliary Cholangitis with POISE trial

POISE trial enabled obeticholic acid to be licensed as a treatment option for Primary Biliary Cholangitis patients when there was previous only one treatment option that did not always work to control the disease. The drug was subsequently approved and commissioned for NHS use in patients improving care.

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Phase 3 double blind placebo controlled trial and long term safety extension of obeticholic acid in patients with primary biliary cirrhosis

Primary Biliary Cholangitis (PBC), previously called Primary Biliary Cirrhosis, is a life-long rare autoimmune liver disease affecting more than 15,000 people in the UK which affects mostly women.

Bile is a liquid produced inside the liver that’s used to help digest fats and remove waste products from the body. It passes out of the liver through small tubes called bile ducts. In PBC, the immune system mistakenly attacks the bile ducts and leads to a build up of bile in the liver. Left untreated or as the disease progresses with treatment, it can lead to scarring of the liver (cirrhosis) and eventual tranplant or early death.

Standard treatment for PBC is ursodeoxycholic acid therapy, a bile acid that helps to remove bile from the liver. Commonly people with PBC have high alkaline phosphatase and bilirubin levels that increase as the disease progresses. Obeticholic acid had shown potential benefit in patients with PBC and reduces alkaline phosphatase and bilirubin levels. However the dose response, safety and efficacy of obeticholic acid at 5mg and 10mg was unknown and POISE trial was designed to provide the evidence to these questions.

216 participants were recruited into the trial and were patients who had seen an inadequate response to ursodeoxycholic acid therapy. Patients were randomised to one of three arms, to receive obeticholic acid at a dose of 10 mg, obeticholic acid at a dose of five mg with adjustment to 10 mg if applicable, or placebo for 12 months. The majority of the trial participants also received the standard ursodeoxycholic acid treatment. The primary end point was an alkaline phosphatase level of less than 1.67 times the upper limit of the normal range, with a reduction of at least 15 per cent from baseline, and a normal total bilirubin level.

Key features

• March 2012 - December 2013.
• Funded by Intercept Pharmaceuticals.
• 22 patients recruited, with support from the NIHR Clinical Research Network. Global Recruitment was 216.
• Chief Investigator: Professor Douglas Thorburn Consultant hepatologist and clinical director for liver transplantation at Royal Free London NHS Foundation Trust.
• POISE trial enabled primary biliary cholangitis patients with high alkaline phosphatase levels to access a new treatment option that did not exist before and provided the evidence for the drug to be licensed internationally.

Outcomes and findings

Obeticholic acid administered with ursodeoxycholic acid or as monotherapy for 12 months in patients with primary biliary cholangitis, resulted in decreases from baseline in alkaline phosphatase and total bilirubin levels that differed significantly from the changes observed with placebo. These effects were sustained for 2 years.

Itchy skin was the most common reaction found in both five mg or 10mg groups, although less occurred in the five mg group. There were no other changes in quality of life among patients who were treated with obeticholic acid.

Value to the NHS

POISE trial enabled obeticholic acid to be licensed as a treatment option for PBC patients when there was previous only one treatment option that did not always work to control the disease. The drug was subsequently approved and commissioned for NHS use in patients improving care. NICE changed guidelines in 2017 recommending the use of obeticholic acid as a treatment option for PBC patients.

“The UK made a significant contribution to this study which ensured the licensing of obeticholic acid as the only current approved second line therapy for the 30% of people who do not have an adequate response to ursodeoxycholic acid therapy. This is an important development for such patients who are recognised to be at risk of progressive liver disease.”
Professor Douglas Thorburn, Chief Investigator on the POISE trial, Consultant Hepatologist and Clinical Director for liver transplantation at Royal Free London NHS Foundation Trust.

Key publications