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

Design and baseline characteristics of the finerenone in reducing cardiovascular mortality and morbidity in diabetic kidney disease trial

Background: Among people with diabetes, those with kidney disease have exceptionally high rates of cardiovascular (CV) morbidity and mortality and progression of their underlying kidney disease. Finerenone is a novel, nonsteroidal, selective mineralocorticoid receptor antagonist that has shown to reduce albuminuria in type 2 diabetes (T2D) patients with chronic kidney disease (CKD) while revealing only a low risk of hyperkalemia. However, the effect of finerenone on CV and renal outcomes has not yet been investigated in long-term trials. Patients and Methods: The Finerenone in Reducing CV Mortality and Morbidity in Diabetic Kidney Disease (FIGARO-DKD) trial aims to assess the efficacy and safety of finerenone compared to placebo at reducing clinically important CV and renal outcomes in T2D patients with CKD. FIGARO-DKD is a randomized, double-blind, placebo-controlled, parallel-group, event-driven trial running in 47 countries with an expected duration of approximately 6 years. FIGARO-DKD randomized 7,437 patients with an estimated glomerular filtration rate >= 25 mL/min/1.73 m(2) and albuminuria (urinary albumin-to-creatinine ratio >= 30 to <= 5,000 mg/g). The study has at least 90% power to detect a 20% reduction in the risk of the primary outcome (overall two-sided significance level alpha = 0.05), the composite of time to first occurrence of CV death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure. Conclusions: FIGARO-DKD will determine whether an optimally treated cohort of T2D patients with CKD at high risk of CV and renal events will experience cardiorenal benefits with the addition of finerenone to their treatment regimen. Trial Registration: EudraCT number: 2015-000950-39; ClinicalTrials.gov identifier: NCT02545049

Hypotension in the Emergency Department and Contrast Extravasation on Computerized Tomography Predict Blood Transfusion in Low-Energy Pelvic Fractures.

INTRODUCTION: Although low-energy pelvic fractures seldom present with significant hemorrhage, early recognition of at-risk patients is essential. We aimed to identify predictors of transfusion requirements in this cohort. METHODS: A 7-y retrospective chart review was performed. Low-energy mechanism was defined as falls of ≤5 feet. Fracture pattern was classified using the Orthopedic Trauma Association/Arbeitsgemeinschaft für Osteosynthesefragen system as A, B, or C. Primary outcome was transfusion of ≥2 units of packed red blood cells in the first 48 h. Univariable analysis and logistic regression analysis were performed. A P value ≤0.05 was considered significant. RESULTS: Five hundred forty six patients were included with median (interquartile range) age of 86 (79-91) and median (interquartile range) Injury Severity Score of 5 (4-8). Five hundred forty one (99%) had type A fractures. Twenty six (5%) had the primary outcome and 17 (3%) died. Logistic regression found that systolic blood pressureDepartment, Injury Severity Score, and pelvic angiography were predictors of the primary outcome. Seventeen percent of those who had the primary outcome died compared with 2% who did not (P = 0.0004). Three hundred sixty four (67%) received intravenous contrast for computerized tomography scans and of these, 44 (12%) had contrast extravasation (CE). CE was associated with the primary outcome but not mortality. CONCLUSIONS: Hypotension at any time in the Emergency Department and CE on computerized tomography predicted transfusion of ≥2 units packed red blood cells in the first 48 h in patients with low-energy pelvic fractures

Is clinician assessment accurate or is routine pan-body CT needed in the stable intoxicated trauma patient?

© 2019 Elsevier Inc. Background: We sought to determine if clinician suspicion of injury was useful in predicting injuries found on pan-body computed tomography (PBCT) in clinically intoxicated patients. Methods: We prospectively enrolled awake, intoxicated patients with low-energy mechanism of injury. For each of four body regions (head/face, neck, thorax and abdomen/pelvis), clinician suspicion for injury was recorded as “low index” or “more than a low index”. The reference standard was the presence of any pre-defined significant finding (SF) on CT. Sensitivity, specificity, positive (LR+) and negative (LR-) likelihood ratios were calculated. Results: Enrollment of 103 patients was completed. Sensitivity, specificity, LR+ and LR-for clinician index of suspicion were: 56%, 68%, 1.75, 0.64 (head/face), 50%, 92%, 6.18, 0.54 (neck), 10%, 96%, 2.60, 0.94 (thorax) and 67%, 93%, 9.56, 0.36 (abdomen/pelvis). Conclusion: Clinician judgement was most useful to guide need for CT imaging in the neck and abdomen/pelvis. Routine PBCT may not be necessary. For awake, stable intoxicated patients after falls and assaults, clinician index of suspicion was most useful to guide the need for CT imaging in the neck and abdomen/pelvis. Our findings support selective use of CT if the index of suspicion is low. Routine PBCT may not be necessary