Author information
1
Division of Digestive and Liver Diseases, Cedars-Sinai Medical Center, Los Angeles, California, United States.
2
Division of Gastroenterology, Washington University School of Medicine, St. Louis, Missouri, United States.
3
Division of Gastroenterology, Hepatology and Motility, University of Kansas Medical Center, Kansas City, Kansas, United States.
4
Liver & Energy Metabolism Unit, Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Health, Bethesda, Maryland, United States.
5
Allergan, Plc, South San Francisco, CA, United States.
6
Liver and Gastroenterology Unit, Division of Medicine, Hadassah University Medical Center, Jerusalem, Israel.
7
Institute for Cardiometabolism and Nutrition, Université Pierre et Marie Curie, Paris, France.
8
Mayo Clinic Libraries, Mayo Clinic, Rochester, MN, United States.
9
Evidence-based Practice Center, Mayo Clinic Robert D. and Patricia E. Kern Center for the Science of Health Care Delivery, Mayo Clinic, Rochester, MN, United States.
10
Fatty Liver Program, Division of Digestive and Liver Diseases, Comprehensive Transplant Program, Cedars-Sinai Medical Center, Los Angeles, California, United States. Electronic address: mazen.noureddin@cshs.org.
Abstract
BACKGROUND & AIMS:
Understanding the extent of the placebo effect in randomized controlled trials of studying nonalcoholic steatohepatitis (NASH) is important for optimal trial design, including sample size calculations and treatment endpoint definition.
METHODS:
We performed a systematic review and meta-analysis of the placebo groups from randomized controlled trials of adults with NASH that provided histological and/or magnetic resonance image-based measurements of intrahepatic triglyceride. We identified trials through a comprehensive search of MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, and Scopus, from each database's inception through January 2, 2018.
RESULTS:
We identified 39 randomized controlled trials, comprising 1463 patients who received placebo. Histologic assessment data (the non-alcoholic fatty liver disease activity scores, NAS) were available from 956 patients; magnetic resonance spectroscopy data were available from 295 patients and magnetic resonance proton density fat fraction measurements from 61 patients. Overall, 25% of patients given placebo had an improvement in NAS by 2 or more points (95% CI, 21%-29%) with moderate (I2 = 27%). There were improvements by at least 1 point in steatosis scores of 33%±3% of patients, in hepatocyte ballooning scores of 30%±3% of patients, in lobular inflammation scores of 32%±3% of patients, and in fibrosis scores of 21%±3% of patients, with a substantial amount of heterogeneity among trials (I2 range, 51%-63%). Patients given placebo had a statistically significant improvement in NAS (by 0.72±0.19), with substantial heterogeneity (I2 = 96%). Univariate and multivariate meta-regression showed that trials with a decrease in body mass index, with a higher baseline NAS, and conducted in South America were associated with greater improvements in NAS among patients given placebo. Patients given placebo had significant reductions in intrahepatic triglyceride, measured by magnetic resonance spectroscopy (by 1.45%±0.54%) with moderate heterogeneity (I2 = 40%), and in magnetic resonance proton density fat fraction (by 2.43±0.89), without heterogeneity (I2 = 0). Mean serum levels of alanine and aspartate aminotransferases decreased significantly (by 11.7±3.8 U/L and 5.9±2.1 U/L, respectively; P<.01 for both).
CONCLUSION:
In a meta-analysis of randomized controlled trials of NASH, patients given placebo have significant histologic, radiologic, and biochemical responses. The placebo response should be considered in designing trials of agents for treatment of NASH.