Baseline Parameters in Clinical Trials for Nonalcoholic Steatohepatitis: Recommendations From the Liver Forum

Imperial, Joanne C.; Anstee, Quentin M.; DeBrota, David J.; Dimick‐Santos, Lara; Filozof, Claudia; Mehta, Ruby; Sanyal, Arun J.; Schabel, Elmer; Neuschwander‐Tetri, Brent A.; Miller, Veronica; Bangma, Sander J.; Baxter, Melanie; Boulos, Sherif; Burgess, Gary; Chakravarthy, Manu V.; Christian, Rose; Coombs, Anthony; Gannedahl, G.; Herrmann, Richard; Hum, Dean W.; Kendrick, Stuart; MacConell, Leigh; Megnien, Sophie Jeannin; Muir, Andrew J.; Patel, Yuval A.; Peres, Dan; Rossi, Stephen J.; Shapiro, D. A.; Pierre, Timothy G. St.; Zemel, Michael B.

doi:10.1053/j.gastro.2017.07.024

Cited by 26 publications

(25 citation statements)

References 24 publications

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“…This point cannot be generalized. In clinical trial settings of NAFLD, the relationship between weight trends, duration of obesity, and fibrosis severity and treatment response is unknown …”

Section: Discussionmentioning

confidence: 99%

HOMA‐IR: An independent predictor of advanced liver fibrosis in nondiabetic non‐alcoholic fatty liver disease

Fujii

Imajo

Yoneda

et al. 2019

J of Gastro and Hepatol

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Background and Aim Although non‐alcoholic fatty liver disease (NAFLD) is common in the general population, identifying patients with advanced fibrosis remains a challenge. We investigated whether the homeostasis model assessment parameter of insulin resistance (HOMA‐IR), an index of IR and one of the most important metabolic factors, is an independent predictive factor for advanced fibrosis in nondiabetic patients with NAFLD. Methods This was a retrospective, cross‐sectional multicenter study. We included 361 patients with biopsy‐proven NAFLD who had not been diagnosed with type 2 diabetes mellitus: 175 (48%) were women and 48 (13%) had advanced fibrosis. We used simple random sampling; the sampling ratio of the estimation and validation groups was 7:3. A logistic model was constructed for both the estimation and validation groups. The explanatory variables were age ≥ 49 years, sex (women), body mass index ≥ 26.7 kg/m2, the presence of hypertension, presence of dyslipidemia, fasting plasma glucose level ≥ 98 mg/dL, fasting immune reactive insulin level ≥ 12.0 μU/mL, and HOMA‐IR ≥ 2.90. The median HOMA‐IR of the patients was 2.88 (interquartile range: 2.1–4.8). Results In the estimation group, univariate and multivariate analyses showed that age, dyslipidemia, and HOMA‐IR were independent predictors of advanced fibrosis. In the validation group, only age and HOMA‐IR were found to be independent predictors of advanced fibrosis. Conclusions Homeostasis model assessment parameter of insulin resistance was an independent predictor of advanced liver fibrosis in nondiabetic patients with NAFLD. Given that most patients with NAFLD are nondiabetic, it is important to set goals with respect to improving IR to subsequently reduce liver fibrosis.

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Section: Discussionmentioning

confidence: 99%

HOMA‐IR: An independent predictor of advanced liver fibrosis in nondiabetic non‐alcoholic fatty liver disease

Fujii

Imajo

Yoneda

et al. 2019

J of Gastro and Hepatol

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“…Nonalcoholic fatty liver disease (NAFLD) is a spectrum of disease that ranges from nonalcoholic fatty liver (NAFL) to nonalcoholic steatohepatitis (NASH) with progressive fibrosis . Table outlines currently accepted definitions and staging of NASH.…”

Section: Currently Accepted Scoring Systems To Grade and Stage Nash Imentioning

confidence: 99%

Report on the AASLD/EASL Joint Workshop on Clinical Trial Endpoints in NAFLD

et al. 2019

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Nonalcoholic fatty liver disease (NAFLD) is a global public health concern. Its natural history, the development of nonalcoholic steatohepatitis (NASH) and fibrosis, is highly variable, prone to endogenous (e.g., genetics, microbiota) and exogenous (e.g., nutrition, alcohol, physical activity) disease modifiers, and can fluctuate over time. The complexity of its pathophysiology is reflected by the multitude of pharmacological targets in development. NASH clinical trials have provided valuable insight that is applicable to future trial design. Endpoints for NASH have evolved over the past decade and will continue to be refined. Currently accepted endpoints for conditional approval include resolution of NASH without worsening of fibrosis and/or improvement in fibrosis without worsening of NASH by standardized evaluation of paired liver histology. In pediatric NASH, practical obstacles, pubertal hormonal changes, and stringent safety requirements mandate adaptations in trial design. In adult patients with NASH‐related cirrhosis, clinical events (e.g. decompensation, hepatocellular carcinoma, transplantation, death) are more prevalent and thereby are viable primary endpoints. Consideration of the natural fluctuation of disease, the clinical implication of the chosen primary endpoint, and factors that may affect placebo response will facilitate an accurate determination of efficacy of emerging therapeutics for NASH. Conclusion: The June 2018 American Association for the Study of Liver Diseases and European Association for the Study of the Liver joint workshop on NAFLD endpoints summarized important findings from ongoing and completed trials, defined the scientific evidence supporting distinct endpoints, and provided guidance for future trial design.

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“…Well‐defined endpoints are essential if therapeutic NASH trials are to robustly assess efficacy of treatment. These endpoints need to be accurate, reproducible, and clinically meaningful . Although noninvasive biomarkers, including imaging techniques, are promising tools to assess disease severity in NAFLD, none have yet been validated or qualified as trial endpoints, and none can accurately assess grade of steatosis, ballooning of hepatocytes, or liver inflammation.…”

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confidence: 99%

qFIBS: An Automated Technique for Quantitative Evaluation of Fibrosis, Inflammation, Ballooning, and Steatosis in Patients With Nonalcoholic Steatohepatitis

Goh²,

et al. 2020

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Background and Aims Nonalcoholic steatohepatitis (NASH) is a common cause of chronic liver disease. Clinical trials use the NASH Clinical Research Network (CRN) system for semiquantitative histological assessment of disease severity. Interobserver variability may hamper histological assessment, and diagnostic consensus is not always achieved. We evaluate a second harmonic generation/two‐photon excitation fluorescence (SHG/TPEF) imaging‐based tool to provide an automated quantitative assessment of histological features pertinent to NASH. Approach and Results Images were acquired by SHG/TPEF from 219 nonalcoholic fatty liver disease (NAFLD)/NASH liver biopsy samples from seven centers in Asia and Europe. These were used to develop and validate qFIBS, a computational algorithm that quantifies key histological features of NASH. qFIBS was developed based on in silico analysis of selected signature parameters for four cardinal histopathological features, that is, fibrosis (qFibrosis), inflammation (qInflammation), hepatocyte ballooning (qBallooning), and steatosis (qSteatosis), treating each as a continuous rather than categorical variable. Automated qFIBS analysis outputs showed strong correlation with each respective component of the NASH CRN scoring (P < 0.001; qFibrosis [r = 0.776], qInflammation [r = 0.557], qBallooning [r = 0.533], and qSteatosis [r = 0.802]) and high area under the receiver operating characteristic curve values (qFibrosis [0.870‐0.951; 95% confidence interval {CI}, 0.787‐1.000; P < 0.001], qInflammation [0.820‐0.838; 95% CI, 0.726‐0.933; P < 0.001), qBallooning [0.813‐0.844; 95% CI, 0.708‐0.957; P < 0.001], and qSteatosis [0.939‐0.986; 95% CI, 0.867‐1.000; P < 0.001]) and was able to distinguish differing grades/stages of histological disease. Performance of qFIBS was best when assessing degree of steatosis and fibrosis, but performed less well when distinguishing severe inflammation and higher ballooning grades. Conclusions qFIBS is an automated tool that accurately quantifies the critical components of NASH histological assessment. It offers a tool that could potentially aid reproducibility and standardization of liver biopsy assessments required for NASH therapeutic clinical trials.

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Baseline Parameters in Clinical Trials for Nonalcoholic Steatohepatitis: Recommendations From the Liver Forum

Cited by 26 publications

References 24 publications

HOMA‐IR: An independent predictor of advanced liver fibrosis in nondiabetic non‐alcoholic fatty liver disease

HOMA‐IR: An independent predictor of advanced liver fibrosis in nondiabetic non‐alcoholic fatty liver disease

Report on the AASLD/EASL Joint Workshop on Clinical Trial Endpoints in NAFLD

qFIBS: An Automated Technique for Quantitative Evaluation of Fibrosis, Inflammation, Ballooning, and Steatosis in Patients With Nonalcoholic Steatohepatitis

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