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 oneaccompanying 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 endpointsfor 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

Hemoglobin E Hemoglobinopathy in an Adult from Assam with Unusual Presentation: A Diagnostic Dilemma

Hemoglobin E (HbE) is estimated to affect at least one million people around the world. Carrier frequency of hemoglobin E/β-thalassemia (HbE/β-thalassemia) is highest in Southeast Asia, reaching as high as 60% in parts of Thailand, Laos, and Cambodia. In the Indian subcontinent, highest frequency is observed in The Northeast regions, but relatively rare in rest of the country. Increasing migration of population from highly affected areas is resulting in rising prevalence in The South and other parts of India. HbE/β-thalassemia is characterized by marked clinical diversity, phenotypic instability, and age-related changes in adaptation to anemia. This paper reports a case of HbE disease in an adult immigrant from Assam and documents the difficulties encountered in the definitive subtyping of HbE hemoglobinopathy. Distinguishing between homozygous HbE disease and HbE/β-thalassemia is a challenge to hematopathologist as both are clinically and hematologically similar

INFLUENCE OF VIBRATIONS DURING DIRECTIONAL SOLIDIFICATION ON MICROSTRUCTURE, HARDNESS AND STRENGTH OF Al-Si-GRAPHITE FG COMPOSITE

The present work aims to synthesize functionally Graded (FG) composites through directional solidification (DS) in combination with lateral vibrations. Directional solidification is one of the effective processing techniques to synthesize FG composite. Due to the advancements in developing new class of materials, DS has become one of the important processing techniques in order to attain the gradation in properties. To achieve the better gradation of properties in Al-Si alloy, Chill was placed at the bottom of the mold which is subjected to lateral vibrations. FG composites produced showed that better hardness was obtained towards the region where primary Silicon (Si) is precipitated. In contrast diametrical compression strength results revealed that the Si rich region is brittle in nature when compared to the other end of the cast which is ductile in nature. Microstructural study also revealed that gradation in properties has taken place from bottom to top portion due to precipitation of Si

Strength evaluation of flake and spheroidal graphite cast irons using diametral compression test

AbstractThe diametral compression test also known as the Brazilian test is an old and unique method of measuring tensile strength of brittle materials owing to simple specimen geometry test conditions and quickness of testing. However, its practice in measuring the strength of the metals is quite limited. This work therefore attempts to apply diametral compression test with specimens of thickness to diameter ratio equal to 0.2, 0.4 and 0.6 in determining the tensile and compressive strengths of Flake Graphite (FG) and Spheroidal Graphite (SG) types of cast iron. Cracks developed in the FG and SG specimens indicate that the failures were caused by tensile and shear stress respectively. In case of FG cast iron specimens at lower t/d ratio, the stress state becomes biaxial and influence of tensile stress was found to be higher than the compressive stress. Whereas the biaxial stress condition violates in SG cast iron specimens. The present work concludes the suitability of diametral compression test at any t/d ratio of FG cast iron specimens and only at lower t/d ratios of SG cast iron specimens

The Study of Functionally Graded Al-Si Alloy Fabricated by Centrifuge Casting Technique

Functionally graded materials are plays very important role in engineering and other applications. They are class of designed materials described by a spatial variety of organization and microstructure going for controlling comparing utilitarian properties(i.e. mechanical, thermal, electrical, etc). In this paper describes comparison of FGMs of Al-Si alloys fabricated through centrifuge casting technique. Al-Si alloys are characterized good strength, less weight, low corrosive and wear resistance, good weldability etc. Here we are fabricating Al-12%Si and Al-18%Si alloys through centrifuge casting (vertical centrifugal technique) for different pouring temperature of molten metal and constant mould rotation speed. For that we conclude results based on varying the addition of silicon percentage in base metal and increases pouring temperature, for that we got better mechanical properties and good microstructure features. These alloys are useful wherever good strength, light weight of materials is required