Ma Ai Thanda Han1, Osama Altayar2, Shadi Hamdeh3, Varun Takyar4, Yaron Rotman4, Ohad Etzion4, Eric Lefebvre5, Rifaat Safadi6, Vlad Ratziu7, Larry J Prokop8, Mohammad Hassan Murad9, Mazen Noureddin10. 1. Division of Digestive and Liver Diseases, Cedars-Sinai Medical Center, Los Angeles, California. 2. Division of Gastroenterology, Washington University School of Medicine, St. Louis, Missouri. 3. Division of Gastroenterology, Hepatology and Motility, University of Kansas Medical Center, Kansas City, Kansas. 4. Liver & Energy Metabolism Unit, Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Health, Bethesda, Maryland. 5. Allergan, PLC, South San Francisco, California. 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, Minnesota. 9. Evidence-based Practice Center, Mayo Clinic Robert D. and Patricia E. Kern Center for the Science of Health Care Delivery, Mayo Clinic, Rochester, Minnesota. 10. Fatty Liver Program, Division of Digestive and Liver Diseases, Comprehensive Transplant Program, Cedars-Sinai Medical Center, Los Angeles, California. Electronic address: mazen.noureddin@cshs.org.
Abstract
BACKGROUND & AIMS: It is important to know the extent of the placebo effect in designing randomized controlled trials for patients with nonalcoholic steatohepatitis (NASH), to accurately calculate sample size and define treatment endpoints. METHODS: We performed a systematic review and meta-analysis of the placebo groups from randomized controlled trials of adults with NASH that provided histologic and/or magnetic resonance image-based assessments. 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 nonalcoholic 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 a small amount of heterogeneity (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 moderate 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 a large amount of heterogeneity (I2 = 96%). Univariate and multivariate meta-regression showed that trials with a higher baseline NAS, those conducted in South America, and those in which patients had a decrease in body mass index, 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). CONCLUSIONS: 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.
BACKGROUND & AIMS: It is important to know the extent of the placebo effect in designing randomized controlled trials for patients with nonalcoholic steatohepatitis (NASH), to accurately calculate sample size and define treatment endpoints. METHODS: We performed a systematic review and meta-analysis of the placebo groups from randomized controlled trials of adults with NASH that provided histologic and/or magnetic resonance image-based assessments. 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 nonalcoholic 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 a small amount of heterogeneity (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 moderate 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 a large amount of heterogeneity (I2 = 96%). Univariate and multivariate meta-regression showed that trials with a higher baseline NAS, those conducted in South America, and those in which patients had a decrease in body mass index, 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). CONCLUSIONS: 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.
Authors: Nidhi P Goyal; Mary Catherine Sawh; Patricia Ugalde-Nicalo; Jorge E Angeles; James A Proudfoot; Kimberly P Newton; Michael S Middleton; Claude B Sirlin; Jeffrey B Schwimmer Journal: J Pediatr Gastroenterol Nutr Date: 2020-01 Impact factor: 2.839
Authors: Rish K Pai; David E Kleiner; John Hart; Oyedele A Adeyi; Andrew D Clouston; Cynthia A Behling; Dhanpat Jain; Sanjay Kakar; Mayur Brahmania; Lawrence Burgart; Kenneth P Batts; Mark A Valasek; Michael S Torbenson; Maha Guindi; Hanlin L Wang; Veeral Ajmera; Leon A Adams; Claire E Parker; Brian G Feagan; Rohit Loomba; Vipul Jairath Journal: Aliment Pharmacol Ther Date: 2019-10-03 Impact factor: 8.171
Authors: Fateh Bazerbachi; Eric J Vargas; Monika Rizk; Daniel B Maselli; Taofic Mounajjed; Sudhakar K Venkatesh; Kymberly D Watt; John D Port; Rita Basu; Andres Acosta; Ibrahim Hanouneh; Naveen Gara; Meera Shah; Manpreet Mundi; Matthew Clark; Karen Grothe; Andrew C Storm; Michael J Levy; Barham K Abu Dayyeh Journal: Clin Gastroenterol Hepatol Date: 2020-04-30 Impact factor: 11.382