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Summary: Background: Seladelpar is a potent and selective peroxisome proliferator‐activated receptor‐δ agonist that targets multiple cell types involved in primary biliary cholangitis (PBC), leading to anti‐cholestatic, anti‐inflammatory and anti‐pruritic effects. Aims: To evaluate the long‐term safety and efficacy of seladelpar in patients with PBC. Methods: In an open‐label, international, long‐term extension study, patients with PBC completing seladelpar lead‐in studies continued treatment. Seladelpar was taken orally once daily at doses of 5 or 10 mg with dose adjustment permitted for safety or tolerability. The primary analysis was for safety and the secondary efficacy analysis examined biochemical markers of cholestasis and liver injury. The study was terminated early due to the unexpected histological findings in a concurrent study for non‐alcoholic steatohepatitis, which were subsequently found to predate treatment. Safety and efficacy data were analysed through 2 years. Results: There were no serious treatment‐related adverse events observed among 106 patients treated with seladelpar for up to 2 years. There were four discontinuations for safety, one possibly related to seladelpar. Among 53 patients who completed 2 years of seladelpar, response rates increased from years 1 to 2 for the composite endpoint (alkaline phosphatase [ALP] <1.67 × ULN, ≥15% decrease in ALP, and total bilirubin ≤ULN) and ALP normalisation from 66% to 79% and from 26% to 42%, respectively. In those with elevated bilirubin at baseline, 43% achieved normalisation at year 2. Conclusions: Seladelpar was safe, and markedly improved biochemical markers of cholestasis and liver injury in patients with PBC. These effects were maintained or improved throughout the second year. Clinicaltrials.gov: NCT03301506; Clinicaltrialsregister.eu: 2017‐003910‐16. [ABSTRACT FROM AUTHOR]

This document is a featured cover image for the journal Alimentary Pharmacology & Therapeutics. The image is based on a clinical trial extension study on the safety and efficacy of seladelpar in patients with primary biliary cholangitis. The study was conducted by a team of authors and provides two-year results. The document does not provide any specific details or findings from the study, but it serves as a visual representation of the research. [Extracted from the article]

Summary: Background: Palliative care remains suboptimal in end‐stage liver disease. Aim: To inform a definitive study, we assessed palliative long‐term abdominal drains in end‐stage liver disease to determine recruitment, attrition, safety/potential effectiveness, questionnaires/interview uptake/completion and make a preliminary cost comparison. Methods: A 12‐week feasibility nonblinded randomised controlled trial comparing large‐volume paracentesis vs long‐term abdominal drains in refractory ascites due to end‐stage liver disease with fortnightly home visits for clinical/questionnaire‐based assessments. Study success criteria were attrition not >50%, <10% long‐term abdominal drain removal due to complications, the long‐term abdominal drain group to spend <50% ascites‐related study time in hospital vs large‐volume paracentesis group and 80% questionnaire/interview uptake/completion. Results: Of 59 eligible patients, 36 (61%) were randomised, 17 to long‐term abdominal drain and 19 to large‐volume paracentesis. Following randomisation, median number (IQR) of hospital ascitic drains (long‐term abdominal drain group vs large‐volume paracentesis group) were 0 (0‐1) vs 4 (3‐7); week 12 serum albumin (g/L) and serum creatinine (μmol/L) were 29 (26.5‐32.5) vs 30 (25‐35) and 104.5 (81‐115.5) vs 127 (63‐158) respectively. Total attrition was 42% (long‐term abdominal drain group 47%, large‐volume paracentesis group 37%). Median (IQR) fortnightly community/hospital/social care ascites‐related costs and percentage study time in hospital were lower in the long‐term abdominal drain group, £329 (253‐580) vs £843 (603‐1060) and 0% (0‐0.74) vs 2.75% (2.35‐3.84) respectively. Self‐limiting cellulitis/leakage occurred in 41% (7/17) in the long‐term abdominal drain group vs 11% (2/19) in the large‐volume paracentesis group; peritonitis incidence was 6% (1/17) vs 11% (2/19) respectively. Questionnaires/interview uptake/completion were ≥80%; interviews indicated that long‐term abdominal drains could transform the care pathway. Conclusions: The REDUCe study demonstrates feasibility with preliminary evidence of long‐term abdominal drain acceptability/effectiveness/safety and reduction in health resource utilisation. Trial registration: ISRCTN30697116, date assigned: 07/10/2015. [ABSTRACT FROM AUTHOR]

Background & Aims Hepatitis C virus ( HCV) utilises cholesterol and lipoprotein metabolism for replication and infectivity. Statins and omega-3 (n-3) polyunsaturated fatty acids ( PUFA) have been shown to have antiviral properties in vitro. This open label pilot study evaluated the efficacy of fluvastatin (Lescol® 40-80 mg) and n-3 PUFA (Omacor®1 g and 2-4 g) on HCV- RNA and lipoviral particles ( LVP) in difficult to treat prior non-responders. Methods Patients ( n = 60) were randomly allocated in a factorial design to: no active drug; low-dose n-3 PUFA; high-dose n-3 PUFA; fluvastatin; low-dose n-3 PUFA + fluvastatin; or high-dose n-3 PUFA + fluvastatin. 50/60 completed study drugs for 12 weeks and followed up to week 24. Comparison was made between fluvastatin ( n = 24) vs no fluvastatin ( n = 26) and n-3 PUFA high-dose ( n = 17) vs low-dose ( n = 17) vs none ( n = 16). The primary outcomes were change in total HCV- RNA, LVP and ALT at week 12 compared with baseline. Secondary outcome was change in interferon-gamma-inducible protein-10 ( IP10) as a measure of interferon activation. Results 35% had compensated cirrhosis and 45% were prior null responders. There was no significant change in total HCV RNA, LVP, non-LVP or LVP ratio in patients receiving fluvastatin or n-3 PUFAs. ALT was not significantly different in those treated with fluvastatin or n-3 PUFAs. 12 weeks of low-dose n-3 PUFA decreased median IP10 concentration by −39 pg/ml (−111, 7.0 pg/ml Q1-Q3). Conclusions Fluvastatin and n-3 PUFAs have no effect on plasma HCV- RNA or LVP. The effect of low-dose n-3 PUFA on IP10 warrants further prospective evaluation as a supplemental therapy to enhance interferon sensitivity. [ABSTRACT FROM AUTHOR]

Background: Non-alcoholic steatohepatitis (NASH) is a common type of chronic liver disease that can lead to cirrhosis. Obeticholic acid, a farnesoid X receptor agonist, has been shown to improve the histological features of NASH. Here we report results from a planned interim analysis of an ongoing, phase 3 study of obeticholic acid for NASH.Methods: In this multicentre, randomised, double-blind, placebo-controlled study, adult patients with definite NASH, non-alcoholic fatty liver disease (NAFLD) activity score of at least 4, and fibrosis stages F2-F3, or F1 with at least one accompanying comorbidity, were randomly assigned using an interactive web response system in a 1:1:1 ratio to receive oral placebo, obeticholic acid 10 mg, or obeticholic acid 25 mg daily. Patients were excluded if cirrhosis, other chronic liver disease, elevated alcohol consumption, or confounding conditions were present. The primary endpoints for the month-18 interim analysis were fibrosis improvement (≥1 stage) with no worsening of NASH, or NASH resolution with no worsening of fibrosis, with the study considered successful if either primary endpoint was met. Primary analyses were done by intention to treat, in patients with fibrosis stage F2-F3 who received at least one dose of treatment and reached, or would have reached, the month 18 visit by the prespecified interim analysis cutoff date. The study also evaluated other histological and biochemical markers of NASH and fibrosis, and safety. This study is ongoing, and registered with ClinicalTrials.gov, NCT02548351, and EudraCT, 20150-025601-6.Findings: Between Dec 9, 2015, and Oct 26, 2018, 1968 patients with stage F1-F3 fibrosis were enrolled and received at least one dose of study treatment; 931 patients with stage F2-F3 fibrosis were included in the primary analysis (311 in the placebo group, 312 in the obeticholic acid 10 mg group, and 308 in the obeticholic acid 25 mg group). The fibrosis improvement endpoint was achieved by 37 (12%) patients in the placebo group, 55 (18%) in the obeticholic acid 10 mg group (p=0·045), and 71 (23%) in the obeticholic acid 25 mg group (p=0·0002). The NASH resolution endpoint was not met (25 [8%] patients in the placebo group, 35 [11%] in the obeticholic acid 10 mg group [p=0·18], and 36 [12%] in the obeticholic acid 25 mg group [p=0·13]). In the safety population (1968 patients with fibrosis stages F1-F3), the most common adverse event was pruritus (123 [19%] in the placebo group, 183 [28%] in the obeticholic acid 10 mg group, and 336 [51%] in the obeticholic acid 25 mg group); incidence was generally mild to moderate in severity. The overall safety profile was similar to that in previous studies, and incidence of serious adverse events was similar across treatment groups (75 [11%] patients in the placebo group, 72 [11%] in the obeticholic acid 10 mg group, and 93 [14%] in the obeticholic acid 25 mg group).Interpretation: Obeticholic acid 25 mg significantly improved fibrosis and key components of NASH disease activity among patients with NASH. The results from this planned interim analysis show clinically significant histological improvement that is reasonably likely to predict clinical benefit. This study is ongoing to assess clinical outcomes.Funding: Intercept Pharmaceuticals. [ABSTRACT FROM AUTHOR]