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

Outcome of live and deceased donor renal transplantation in patients aged ≥55 years: A single-center experience

Renal transplantation (RTx) has now become an accepted therapeutic modality of choice for elderly ESRD patients. This single-center study was undertaken to evaluate the outcome of RTx in ESRD patients ≥55 years. A total of 103 patients underwent RTx 79 living related living donors [LD], 24 deceased donors [DD]) at our center. Post-transplant immunosuppression consisted of calcineurin inhibitor–based regimen. The mean donor age was 58.3 years in the LD group and 59.5 years in the DD group. Male recipients constituted 92% in LD and 75% in DD group. In living donor renal transplantation, 1- and 5-year patient survival was 93% and 83.3% respectively and death-censored graft survival was 97.3% and 92.5% respectively. There were 12.6% biopsy proven acute rejection (BPAR) episodes and 12.6% patients were lost, mainly due to infections. In deceased donor renal transplantation, 1- and 5-year patient survival was 79.1% and 74.5% respectively and death-censored graft survival was 95.8% and 85.1% respectively. There were 12.5% BPAR episodes and 25% of patients were lost, mainly due to infections. RTx in ESRD (≥55 years) patients has acceptable patient and graft survival if found to have cardiac fitness and therefore should be encouraged

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