Obeticholic acid for the treatment of non-alcoholic steatohepatitis: interim analysis from a multicentre, randomised, placebo-controlled phase 3 trial

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

The JaCa-Android Framework for\ua0Programming BDI-Based Personal Agents on Mobile Devices

Nowadays, smart mobile applications are a medium allowing more and more for developing (part of) complex software systems, featuring interactive behaviour and exhibiting different degrees of autonomy and flexibility. In agents and MAS literature, Personal Assistant Agents represent the area that mostly can benefit from the availability of frameworks allowing for easily developing native agent-based applications able to exploit features offered by smart mobile and wearable devices. This paper discusses the JaCa-Android framework, a version of JaCaMo redesigned to natively run over mobile devices equipped with Google Android operating system. Exposing native features to observe and perceive the real-time user context and act accordingly, the framework is oriented in particular to the development of smart mobile apps as BDI-based personal assistant agents offering a proper layer of abstraction for this specific purpose

Reliability analysis for radiographic measures of lumbar lordosis in adult scoliosis: a case–control study comparing 6 methods

Several methods are used to measure lumbar lordosis. In adult scoliosis patients, the measurement is difficult due to degenerative changes in the vertebral endplate as well as the coronal and sagittal deformity. We did the observational study with three examiners to determine the reliability of six methods for measuring the global lumbar lordosis in adult scoliosis patients. Ninety lateral lumbar radiographs were collected for the study. The radiographs were divided into normal (Cobb < 10°), low-grade (Cobb 10°–19°), high-grade (Cobb  ≥ 20°) group to determine the reliability of Cobb L1–S1, Cobb L1–L5, centroid, posterior tangent L1–S1, posterior tangent L1–L5 and TRALL method in adult scoliosis. The 90 lateral radiographs were measured twice by each of the three examiners using the six measurement methods. The data was analyzed to determine the inter- and intra-observer reliability. In general, for the six radiographic methods, the inter- and intra-class correlation coefficients (ICCs) were all ≥0.82. A comparison of the ICCs and 95% CI for the inter- and intra-observer reliability between the groups with varying degrees of scoliosis showed that, the reliability of the lordosis measurement decreased with increasing severity of scoliosis. In Cobb L1–S1, centroid and posterior tangent L1–S1 methods, the ICCs were relatively lower in the high-grade scoliosis group (≥0.60). And, the mean absolute difference (MAD) in these methods was high in the high-grade scoliosis group (≤7.17°). However, in the Cobb L1–L5 and posterior tangent L1–L5 method, the ICCs were ≥0.86 in all groups. And, in the TRALL method, the ICCs were ≥0.76 in all groups. In addition, in the Cobb L1–L5 and posterior tangent L1–L5 method, the MAD was ≤3.63°. And, in the TRALL method, the MAD was ≤3.84° in all groups. We concluded that the Cobb L1–L5 and the posterior tangent L1–L5 methods are reliable methods for measuring the global lumbar lordosis in adult scoliosis. And the TRALL method is more reliable method than other methods which include the L5–S1 joint in lordosis measurement