Endpoints and clinical trial design for nonalcoholic steatohepatitis

Abstract

Nonalcoholic fatty liver disease (NAFLD) is a common cause of chronic liver disease in the general population. Nonalcoholic steatohepatitis (NASH), the aggressive form of NAFLD, is associated with an increased risk of liver-related mortality and cardiovascular disease. Currently, a liver biopsy is the only generally acceptable method for the diagnosis of NASH and to assess its progression towards cirrhosis. While several treatments have shown evidence of efficacy in clinical trials of varying design, there are no approved treatments for NASH and published trials are often too divergent to allow meaningful comparisons. There is thus a lack of established non-invasive, point of care diagnostics and approved treatment on one hand and a substantial population burden of disease on the other. These provide the rationale to develop consensus on key endpoints and clinical trial design for NASH. This paper summarizes the consensus arrived at a meeting of the American Association for Study of Liver Diseases on the key endpoints and specific trial design issues that are germane for development of diagnostic biomarkers and treatment trials for NASH.

Metabolic risk factors are associated with non‐hepatitis B non‐hepatitis C hepatocellular carcinoma in Taiwan, an endemic area of chronic hepatitis B

“…A nonsmoker was defined as an individual who had never smoked or who had smoked fewer than 100 cigarettes in his or her life. Positive alcoholic history was defined as alcohol consumption over 30 g/day for male patients and 20 g/day for female patients when converted to ethanol 35. Cirrhosis was diagnosed mainly by a histopathological examination (82% for patients with HBV‐HCC, 77% for HCV‐HCC, and 74% for NBNC‐HCC).…”

The diagnosis and management of non-alcoholic fatty liver disease: Practice Guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association

“…However, the precise definition of significant alcohol consumption in patients with suspected NAFLD is uncertain. A recent consensus meeting 58 concluded that, for NASH clinical trials candidate eligibility purposes, significant alcohol consumption be defined as >21 drinks per week in men and >14 drinks per week in women over a 2-year period prior to baseline liver histology. Furthermore, this group recommended that validated questionnaires should be used to quantify the amount of alcohol consumption in the context of clinical trials.…”

52-Year-Old Man With Liver Enzyme Abnormalities and Elevated Ferritin Level

“…As the US population ages and becomes more obese, the prevalence of NAFLD will continue to increase, and NAFLD will become the most important cause of chronic liver disease. 9 Although the results of a recent study using vitamin E treatment for NASH are promising, 4 it is unlikely that the problems with NAFLD will be resolved with medication alone. The management of NAFLD is currently limited to weight reduction by means of diet and exercise and to treatment of the individual components of the metabolic syndrome.…”

“…In a recent controlled trial, vitamin E therapy, as compared with placebo, was associated with a significantly higher rate of improvement in NASH. 4 The clinical significance of this finding has not been determined, and long-term effects of this therapy have not been studied.…”