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Abstract Details
Placebo Adverse Events in Non-alcoholic Steatohepatitis Clinical Trials: A Pooled Analysis of 2,944 Participants
1Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
2Department of Cardiology, National University Heart Centre, National University Hospital, Singapore.
3Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan.
4Division of Gastroenterology, Hepatology and Nutrition, Department of Internal Medicine, Virginia Commonwealth University, Richmond, Virginia, USA.
5Cedars-Sinai Fatty Liver Program, Division of Digestive and Liver Diseases, Department of Medicine, Comprehensive Transplant Center, Cedars-Sinai Medical Centre, Los Angeles, California, USA.
6Division of Gastroenterology and Hepatology, Department of Medicine, National University Hospital, Singapore, Singapore.
7National University Centre for Organ Transplantation, National University Health System, Singapore.
8NAFLD Research Center, Division of Gastroenterology and Hepatology, Department of Medicine, University of California San Diego, California, USA.
Abstract
Introduction: In the absence of an effective treatment for non-alcoholic steatohepatitis (NASH), a randomized, placebo-controlled trial (RCT) remains the current gold standard study design in NASH. As NASH is a largely asymptomatic disease, the side effects of potential therapies require careful evaluation, therefore a pooled rate of the adverse events (AEs) in placebo-treated patients serves as a useful comparator for safety. Therefore, we performed a systematic review and meta-analysis to estimate the rate of AEs among participants in the placebo arm of NASH RCTs.
Methods: Medline, Embase and Cochrane Central Register of Controlled Trials were searched to include clinical trials in phase 2-4 NASH RCTs with placebo treatment arms. A pooled proportions of AEs were analyzed using a generalized linear mixed model with Clopper-Pearson intervals.
Results: A total of 41 RCTs (2,944 participants on placebo) were included in this meta-analysis. A total of 68% (confidence interval [CI] 55%-77%) of participants on placebo experienced an AE, 7.8% (5.7%-10%) experienced serious AEs and 3.1% (CI: 1.9%-5.1%) experienced AEs leading to discontinuation. A significantly higher proportion of participants experienced serious AEs in phase 3 studies compared to in phase 2 studies ( P < 0.01) and in pharmaceutical funded studies as compared to studies which were federal-funded studies ( P < 0.01). An analysis of clinical trials evaluating bile acid modulating agents determined that 10% (CI: 5.5%-18%) of participants receiving placebo developed pruritus.
Discussion: The present study summarizes the AEs with NASH placebo. Among participants in the placebo arm in NASH, two-third experienced an AE, and nearly 10% experienced a serious AE.