Primary Biliary Cholangitis (PBC)

The participants of this study will have confirmed Primary Biliary Cholangitis (PBC) and cirrhosis (scarring of the liver). PBC is a slowly progressive disease, characterised by damage to the bile ducts in the liver, leading to a build-up of bile acids which causes further damage. The liver damage in PBC may lead to cirrhosis. PBC may also be associated with multiple symptoms. Many patients with PBC may require liver transplant or may die if the disease progresses and a liver transplant is not done. This study will compare a daily dose of elafibranor (the study drug) to a daily dose of placebo (a dummy treatment) and will last up to 3.5 years for each participant. The main aim of this study is to determine if elafibranor is better than placebo in preventing clinical outcome events showing disease worsening (including progression of disease leading to liver transplant or death). This study will also study the safety of long-term treatment with elafibranor, as well as the impact on symptoms such as itching and tiredness.

Cholestatic liver diseases are characterized by jaundice, pruritus, and elevated levels of alkaline phosphatase (ALP) and gamma-glutamyl transferase (GGT). Primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) represent the major autoimmune-driven entities within this category. Without effective intervention, these conditions may progress to liver failure and even death. Ursodeoxycholic acid (UDCA), the first-line therapy for PBC, has been shown to improve prognosis; however, 20%-40% of patients exhibit an inadequate biochemical response. For PSC, no clearly effective pharmacologic agent is currently available. In refractory patients, pruritus often progressively worsens, severely impairing quality of life and treatment adherence, underscoring an urgent need for novel therapeutic approaches that simultaneously address disease control and itch relief. Autoimmune-associated cholangitis frequently coexists with atopic dermatitis, and in a subset of patients, pruritus may be compounded by dermatologic factors. The pruritus of atopic dermatitis involves the JAK-STAT signaling pathway, which not only serves as a convergent node for pruritic signals but also constitutes a key downstream hub in the immune dysregulation characteristic of cholangitis. Inhibition of this pathway is therefore hypothesized to alleviate pruritus and modulate aberrant immune responses. Case reports have suggested that upadacitinib, a selective JAK inhibitor, may improve biochemical parameters in refractory PBC and exhibit potential anti-fibrotic effects. To this end, investigators plan to conduct an exploratory clinical study to systematically evaluate the safety and efficacy of upadacitinib in patients with atopic dermatitis complicated by moderate-to-severe pruritus and refractory autoimmune-associated cholangitis.

The present phase 1b/2 randomised, double-blind, placebo-controlled, two-part study is designed to evaluate the safety, tolerability, pharmacokinetic characteristics and preliminary efficacy of two dose levels of golexanolone compared with placebo among subjects with a history of non-cirrhotic or Child-Pugh class A cirrhotic Primary Biliary Cholangitis (PBC) with clinically significant fatigue and cognitive symptoms on stable background standard of care (SoC) PBC medication. The objectives of this research study are to assess the safety and tolerability as well the pharmacokinetic (PK) characteristics of golexanolone administered 40 mg BID for 5 days in the target population (part A) and to assess the safety and tolerability, the effects of golexanolone on health-related quality of life (HRQoL), including fatigue, day-time sleepiness and cognitive function as well as Investigator's overall impression of treatment effect of 28 days twice per day (BID) treatment with two dose levels of golexanolone versus placebo (part B).

This study is a bidirectional cohort study. The investigators conduct a bidirectional cohort study utilizing a database in mainland China, continuously collecting demographics, clinical symptoms, and biochemical characteristics of diagnosed PBC patients. The study aims to analyze the association between varying post-treatment alkaline phosphatase (AKP) levels and complication-free survival rates, with the objective to develop and validate a predictive survival model.

An Open Label Long-Term Study to Evaluate the Safety and Tolerability of Fenofibrate in Combination with Ursodeoxycholic Acid in Subjects with Primary Biliary Cholangitis (PBC)

An Open Label Long-Term Study to Evaluate the Safety and Tolerability of Fenofibrate in Combination with Ursodeoxycholic Acid in Subjects with Primary Biliary Cholangitis (PBC)

The goal of this clinical trial is to learn if the drug Fenofibrate works to treat adults with a liver disease called Primary Biliary Cholangitis (PBC) who have not received previous treatment. It will also learn about the safety of Fenofibrate. The main questions it aims to answer are: Is Fenofibrate better at helping the liver return to normal function (measured by a blood test called ALP) than the standard medication, Ursodeoxycholic What kind of medical problems do participants have when taking Fenofibrate compared to those taking UDCA? Researchers will compare Fenofibrate to the active drug UDCA (the current standard treatment) to see which one works better.\*\* Participants will: Be randomly assigned to take either Fenofibrate plus a UDCA placebo, or UDCA plus a Fenofibrate placebo, every day for 12 months. (Neither they nor their doctor will know which group they are in.) Visit the clinic 5 times over the year (at 1, 3, 6, 9, and 12 months) for check-ups, blood tests, and questionnaires. Undergo a special scan (like FibroScan) to measure liver stiffness at some visits. Be encouraged to have a liver biopsy at the start and end of the study to provide detailed information about liver health (this is optional).

The goal of this observational study is to achieve early diagnosis of Primary Biliary Cholangitis (PBC) in patients with positive Anti-Mitochondrial Antibodies (AMA) and Normal Alkaline Phosphatase (ALP) in adults aged 18-80 years with positive AMA and normal ALP. The main question it aims to answer is: • Are there any predictive factors for histological PBC in patients with positive AMA and normal ALP? Participants will undergo a liver biopsy and specific blood tests if eligible based on inclusion and exclusion criteria.

The implementation of a non-pharmacological multimodal intervention program-including physical exercise, nutritional counseling, and psychological support-is expected to improve fatigue in patients with primary biliary cholangitis. Consequently, this improvement is anticipated to enhance quality of life and cognitive symptoms, while also positively impacting emotional, social, and occupational aspects. From a pathophysiological perspective, it is hypothesized that chronic cholestasis and/or immune system activation, with the release of pro-inflammatory cytokines, leads to both central and peripheral alterations causing fatigue. At the central level, systemic inflammation may induce neuronal senescence in the basal ganglia, resulting in altered functional connectivity networks dependent on these regions and/or structural and connectivity changes in areas involved in interoception, such as the insula and anterior cingulate cortex. At the peripheral level, the hypothesis is that chronic inflammation mediated by anti-mitochondrial antibodies causes mitochondrial metabolic dysfunction in muscle cells, which would be reflected in changes observed in the gene expression analysis of these cells. Improvement in fatigue following the multimodal intervention program is expected to be associated with normalization of the immunological profile, enhanced functional brain connectivity, and improved mitochondrial metabolism in muscle.

Primary biliary cholangitis (PBC) is an autoimmune liver disease predominantly affecting middle-aged women. While historically it was deemed rare, advancements in specific auto-antibody tests have led to increased recognition of PBC. The long-term survival of PBC patients in China is not yet fully understood. Several studies have investigated the prognosis of PBC in China. While these studies provide valuable insights into the disease characteristics and prognostic factors of PBC in China, they are all single-center studies with limitations. They lack consideration of the impact of symptoms, varying disease stages, and second-line treatments on prognosis. Therefore, there is a pressing need for multicenter and large-scale studies to further elucidate the characteristics and long-term survival of PBC patients in China. Biochemical response to ursodeoxycholic acid (UDCA) is an independent factor associated with long-term survival. Unfortunately, approximately 30-40% of PBC patients demonstrate insufficient biochemical response to UDCA. In our cohort, we reported a higher nonresponse rate, with about 44% according to the Paris I criteria. These patients remain at risk for disease progression to advanced stages and may benefit from additional second-line drug therapies. With significant advancements in the development of new drugs for PBC, a comprehensive understanding of patients with suboptimal responses to UDCA-including long-term prognosis, the distribution of different disease stages, and the prevalence of pruritus-will provide a basis for individualized treatment strategies. Additionally, fatigue and pruritus are prevalent symptoms for PBC patients and fluctuates independently of disease activity or stage, which significantly diminishing health-related quality of life. However, the incidence and impact of fatigue and pruritus on long-term outcomes for PBC patients in China need further clarification. Therefore, we would like to conduct this multicenter study to estimate the prevalence of PBC in China and to evaluate the symptomatic burden, treatment, and long-term outcomes among PBC patients in China.

An Open Label Long-Term Study to Evaluate the Safety and Tolerability of Fenofibrate in Subjects with Primary Biliary Cholangitis (PBC)

The purpose of the registry is to know the status of primary biliary colgantis, autoimmune hepatitis, primary sclerosing cholagitis and genetic cholestatic diseases in Spain.