Baseline Parameters in Clinical Trials for Nonalcoholic Steatohepatitis: Recommendations From the Liver Forum.
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SUBMITTER: Patel YA
PROVIDER: S-EPMC5861348 | biostudies-literature | 2017 Sep
REPOSITORIES: biostudies-literature
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Baseline Parameters in Clinical Trials for Nonalcoholic Steatohepatitis: Recommendations From the Liver Forum.
Patel Yuval A YA Imperial Joanne C JC Muir Andrew J AJ Anstee Quentin M QM DeBrota David D Dimick-Santos Lara L Filozof Claudia C Mehta Ruby R Sanyal Arun J AJ Schabel Elmer E Neuschwander-Tetri Brent A BA Miller Veronica V
Gastroenterology 20170727 3
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Project description:Tremendous effort has been put forth over the past 2 decades in understanding the pathophysiology of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis (NAFLD/NASH). Although multiple potential targets for drug development exist, there have been no approved therapies for NAFLD/NASH. Lipotoxicity, owing to increased delivery of fatty acids to the liver, and hepatic de novo lipogenesis are key drivers of disease pathogenesis. Moreover, genetics, environmental factors, and comorbid conditions converge to determine disease progression in individual patients. Given the complexity and heterogeneity of disease pathogenesis, numerous therapeutic targets have emerged and have been tested in clinical trials. Early trial failures have provided key lessons and foundational insights to move the field forward. Current ongoing phase 3 trials and emerging phase 2 trials are reasons for optimism, and 2 drugs, obeticholic acid and resmetirom, are being evaluated for accelerated approval by the US Food and Drug Administration this year. This article highlights key features of NASH pathophysiology and drug targets, the lessons learned from completed trials, and the current landscape of phase 2 and 3 clinical trials in NASH.
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Project description:Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in the United States. The association between NAFLD and quality of life (QOL) remains unclear. These data are important to estimate the burden of illness in NAFLD. The aim was to report QOL scores of adults with NAFLD and examine the association between NAFLD severity and QOL. QOL data were collected from adults with NAFLD enrolled in the Nonalcoholic Steatohepatitis Clinical Research Network using the Short Form 36 (SF-36) survey, and scores were compared with normative U.S. population scores. Liver biopsy histology was reviewed by a central pathology committee. A total of 713 subjects with NAFLD (male = 269, female = 444) were included. Mean age of subjects was 48.3 years; 61% had definite nonalcoholic steatohepatitis (NASH), and 28% had bridging fibrosis or cirrhosis. Diabetes was present in 27% of subjects. Subjects with NAFLD had worse physical (mean, 45.2) and mental health scores (mean, 47.6) compared with the U.S. population with (mean, 50) and without (physical, 55.8; mental, 52.5) chronic illness. Subjects with NASH reported lower physical health compared with subjects with fatty liver disease without NASH (44.5 versus 47.1, P = 0.02). Subjects with cirrhosis had significantly (P < 0.001) poorer physical health scores (38.4) than subjects with no (47.6), mild (46.2), moderate (44.6), or bridging fibrosis (44.6). Cirrhosis was associated with poorer physical health after adjusting for potential confounders. Mental health scores did not differ between participants with and without NASH or by degree of fibrosis.Adults with NAFLD have a significant decrement in QOL. Treatment of NAFLD should incorporate strategies to improve QOL, especially physical health.
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Project description:Nonalcoholic fatty liver disease (NAFLD) is the primary cause of chronic liver disease in the United States, afflicting an estimated 80 to 100 million Americans. Nonalcoholic fatty liver disease is a spectrum of liver diseases composed of nonalcoholic fatty liver and nonalcoholic steatohepatitis (NASH). Although nonalcoholic fatty liver has a negligible risk of progression, patients with NASH often develop cirrhosis or hepatocellular carcinoma. Although liver biopsy is required to diagnose NASH, only patients with a high risk of NASH or advanced fibrosis require this evaluation. Despite the high prevalence of NAFLD, well-defined screening recommendations are currently lacking. In this review, suggestions for screening, diagnosis, and initial work-up of NAFLD are given on the basis of established guidelines and recent publications. Proposed drug treatments of NASH are also discussed, highlighting the study outcomes, as well as proposed uses and limitations of these drugs. The literature was searched in PubMed using search terms nonalcoholic fatty liver disease and nonalcoholic steatohepatitis, with filters of "English language." A date range of January 1, 2000, to May 1, 2015, was used for the search. The bibliographies of key references were also searched manually, and seminal publications before the year 2000 were included.
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Project description:Background Several early-phase clinical trials for the treatment of nonalcoholic steatohepatitis (NASH) use liver fat content as measured with the MRI-derived proton density fat fraction (PDFF) for a primary outcome. These trials have shown relative reductions in liver fat content with placebo treatment alone, a phenomenon termed "the placebo effect." This phenomenon confounds the results and limits generalizability to future trials. Purpose To quantify the effect of placebo treatment on change in the absolute PDFF value and to identify variables associated with this observed change. Materials and Methods This is a secondary analysis of prospectively collected data from seven early phase clinical trials that included participants with a diagnosis of NASH based on MRI and/or liver biopsy who received placebo treatment. The primary outcome was a greater than or equal to 30% relative reduction in PDFF after placebo treatment. Normalization of PDFF, relative change in alanine aminotransferase (ALT) level, and normalization of ALT level were also examined. An exploratory linear mixed-effects model was used to estimate an overall change in absolute PDFF and to explore parameters associated with this response. Results A total of 187 participants (median age, 52 years [IQR, 43-60 years]; 114 women) who received placebo treatment were evaluated. A greater than or equal to 30% relative reduction in baseline PDFF was seen in 20% of participants after 12 weeks of placebo treatment (10 of 49), 9% of participants after 16 weeks (two of 22), and 28% of participants after 24 weeks (34 of 122). A repeated-measures linear mixed-effects model estimated a decrease of 2.3 units (median relative reduction of 13%) in absolute PDFF values after 24 weeks of placebo treatment (95% CI: 3.2, 1.4; P < .001). Conclusion In this analysis of 187 participants, a clinically relevant decrease in PDFF was observed with placebo treatment. Based on the study model, assuming an absolute PDFF decrease of approximately 3 units (upper limit of 95% CI) to account for this "placebo effect" in sample size calculations for future clinical trials is suggested. Clinical trial registration nos. NCT01066364, NCT01766713, NCT01963845, NCT02443116, NCT02546609, NCT02316717, and NCT02442687 © RSNA, 2022 Online supplemental material is available for this article. See also the editorial by Yoon in this issue.
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Project description:Nonalcoholic fatty liver (NAFL) is an emerging global epidemic which progresses to nonalcoholic steatohepatitis (NASH) and cirrhosis in a subset of subjects. Various reviews have focused on the etiology, epidemiology, pathogenesis and treatment of NAFLD. This review highlights specifically the triggers implicated in disease progression from NAFL to NASH. The integrating role of genes, dietary factors, innate immunity, cytokines and gut microbiome have been discussed.
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Project description:BackgroundChildhood obesity is a global problem associated with metabolic abnormalities. The gut-liver axis is thought to play a major role in its pathogenesis. Probiotics are known to alter the gut microbiota and, therefore, could be a therapeutic option in the management of childhood obesity-related complications.PurposeThis double-blind randomized placebo-controlled trial evaluated the effects of probiotics on metabolic derangement in obese children with nonalcoholic fatty liver disease/ nonalcoholic steatohepatitis (NAFLD/NASH).MethodsObese children with NAFLD/NASH treated at the nutrition clinic of the University Paediatric Unit at Lady Ridgeway Hospital, Colombo, were recruited. Anthropometry, body fat, metabolic derangement, and liver ultrasound scan (USS) results were evaluated at baseline and after 6 months. Transient elastography (FibroScan) was performed on a subsample of these patients. Eighty-four patients were recruited and randomized into the probiotics (n=43) and placebo (n= 41) groups. The mean age was 11.3±1.9 versus 12.1±1.5 years in the probiotic and placebo groups, respectively. Baseline parameters including liver disease stage on USS, body fat percentage, fasting blood sugar, lipid profile, liver function, and C-reactive protein showed no significant intergroup differences.ResultsIn the probiotic group, a statistically significant reduction in body mass index was noted from the baseline value. However, the reduction was not significant compared with the placebo group. There was a significant reduction in triglycerides, aspartate transaminase (AST), alanine aminotransferase (ALT), AST/ALT ratio, and alkaline phosphatase in the placebo group over the treatment period. Although the liver disease stage on USS improved from stage II-III to stage I in a small number of patients in the probiotic-treated group, transient elastography performed in a subsample did not demonstrate significant improvement in either group.ConclusionOur results indicate that probiotics have no advantage over lifestyle modification for improving obesityassociated metabolic derangement in children.
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Project description:Background and aim: Diagnosing nonalcoholic steatohepatitis (NASH) is challenging. This study intended to explore the diagnostic value of multiple technical acoustic measurements in the diagnosis of NASH, and to establish a diagnostic model combining technical acoustic measurements with clinical parameters to improve the diagnostic efficacy of NASH. Methods: We consecutively enrolled 75 patients with clinically suspected nonalcoholic fatty liver disease (NAFLD) who underwent percutaneous liver biopsy in our hospital from June 2020 to December 2021. All cases underwent multiple advanced acoustic measurements for liver such as shear wave dispersion (SWD), shear wave speed (SWS), attenuation imaging (ATI), normalized local variance (NLV), and liver-kidney intensity ratio (Ratio) examination before liver biopsies. A nomogram prediction model combining the technical acoustic measurements and clinical parameters was established and the model is proposed to improve the diagnostic performance of NASH. Results: A total of 75 cases were included in this study. The classification of pathological grade for NASH was as follows: normal liver, (n = 15, 20%), nonalcoholic fatty liver (NAFL), (n = 44, 58.7%), and NASH, (n = 16, 21.3%). There were statistically significant differences in SWS (p = 0.002), acoustic coefficient (AC) (p = 0.018), NLV (p = 0.033), age (p = 0.013) and fasting blood glucose (Glu) (p = 0.049) between NASH and non-NASH. A nomogram model which includes SWS, AC, NLV, age and Glu was built to predict NASH, and the calibration curves showed good calibrations in both training and validation sets. The AUCs of the combined nomogram model for the training set and validation set were 0.8597 and 0.7794, respectively. Conclusion: There were statistically significant differences in SWS, AC, NLV, age and Glu between NASH and non-NASH. A nomogram model which includes SWS, AC, NLV, age and Glu was built to predict NASH. The predictive model has a higher diagnostic performance than a single factor model in the diagnosis of NASH and has good clinical application prospects.
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Project description:Hepatocellular injury and inflammation are believed to be the primary drivers of fibrogenesis that ultimately lead to cirrhosis in patients with nonalcoholic steatohepatitis (NASH). This study sought associations between observed improvements in fibrosis with improvement in specific histologic features, nonalcoholic fatty liver disease activity score (NAS) ≥2, diagnostic category, and primary histologically based outcomes of two adult NASH treatment trials. The primary outcome for the study was fibrosis improvement from baseline to end of treatment, defined as a 1-point or more improvement in fibrosis stage. This is a retrospective analysis of biopsy data collected from the NASH Clinical Research Network Pathology Committee of Pioglitazone versus Vitamin E versus Placebo for the Treatment of Nondiabetic Patients with NASH Trial (PIVENS) and Farnesoid X Receptor Ligand Obeticholic Acid in NASH Treatment Trial (FLINT) baseline and final biopsies. Treatment group-adjusted univariable and multivariable logistic regression models related improvement in fibrosis to improvements in other histologic variables, resolution of steatohepatitis, and improvement in the NAS ≥2. In PIVENS 221 subjects had baseline and 96-week biopsies, and in FLINT 200 subjects had baseline and 72-week biopsies. Improvement in fibrosis was found in 38% of PIVENS and 29% of FLINT biopsies; fibrosis improvement was more likely in treated than placebo subjects in both studies. Controlling for treatment group, fibrosis improvement was associated most strongly with resolution of NASH (PIVENS, odds ratio [OR], 3.9; 95% confidence interval [CI] 2.0-7.6; P < 0.001; FLINT, OR, 8.0; 95% CI 3.1-20.9; P < 0.001), and improved NAS by ≥2 (PIVENS, OR, 2.4; 95% CI 1.3-4.3; P = 0.003; FLINT, OR, 4.2; 95% CI 2.1-8.3; P < 0.001). Improvement in histologic features associated with improved fibrosis for both studies included steatosis, ballooning, Mallory-Denk bodies, and portal, but not lobular, inflammation. Conclusion: These findings support a strong link between histologic resolution of steatohepatitis with improvement in fibrosis in NASH.
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Project description:Nonalcoholic fatty liver disease is the leading cause of liver disease in western society. It is a cause of end-stage liver disease, with increased mortality secondary to cirrhosis and its complications. It is also recognized that cardiovascular disease is a significant cause of death in these patients. Significant work evaluating various treatments has been performed in recent years; however, to date, no ideal therapy exists. Lifestyle modification remains the cornerstone of management. The present article reviews the current status of various treatment modalities evaluated in nonalcoholic fatty liver disease.
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Project description:Nonalcoholic fatty liver disease (NAFLD) is common in children and may progress to nonalcoholic steatohepatitis (NASH), advanced fibrosis, and even cirrhosis in childhood or early adulthood, indicating the need for pharmacologic treatment in this age group. Multiple trials are evaluating different therapeutic targets for NASH with fibrosis in adults, and the U.S. Food and Drug Administration has recently provided clear guidance to the pharmaceutical industry on developing drugs for the treatment of noncirrhotic NASH with liver fibrosis. Pediatric NAFLD has several unique aspects that distinguish it from the adult disease in terms of histology, our understanding of the natural history, and the utility of noninvasive tests. These differences have the potential to impact the design of clinical trials to test different drugs in the pediatric population. The aim of this article is to provide a review of common misconceptions regarding pediatric NAFLD and key differences from adult NAFLD. We have provided our recommendations on the design of early proof-of-concept and late phase 2 trials based on lessons learned from previous clinical trials. We believe that clinical drug development for children with NAFLD should happen in parallel with ongoing adult trials.
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