Placebo Adverse Events in Non-alcoholic Steatohepatitis Clinical Trials: A Pooled Analysis of 2,944 Participants

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.

Hepatic steatosis and advanced hepatic fibrosis are independent predictors of long‐term mortality in acute myocardial infarction

“…Strategies in the management of fatty liver disease should target the root cause of energy surplus and excess adiposity early on in the spectrum of liver disease, before the development of an advanced form of liver disease. 60 The presence of hepatic steatosis and fibrosis is associated with previous cardiovascular events, as well as the increased prevalence of obesity and diabetes. These individuals with fatty liver disease are already at very high cardiovascular risk conferred by these metabolic risk factors, and the additive or synergistic effect of the presence of fatty liver disease on prognostic outcomes remains unclear.…”

“…The metabolic dysfunction results from chronic energy surplus and associated lipotoxicity, cell death, inflammation and fibrosis within the liver. Strategies in the management of fatty liver disease should target the root cause of energy surplus and excess adiposity early on in the spectrum of liver disease, before the development of an advanced form of liver disease 60 …”

Editorial: The heart of NAFLD

“…The concerted approach to the reduction of the NAFLD and CVD burden was succinctly consolidated by the study, with the continued medical education program on NAFLD that encompass the best clinical practices tailored to primary care setting, that can improve confidence in the management of NAFLD-related conditions (Papadakis et al). With the plethora of upcoming NASH therapeutic options (33-35) in the pipeline, treatment strategies in improving both liver-related outcomes and concomitant cardiometabolic profile are promising (32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42)(43).…”

Applying Placebo and Nocebo Effects From Randomized Trials to Clinical Care and Future Studies

“…Jones et al demonstrated that patients with functional dyspepsia were more likely to respond to placebo if they had higher baseline symptom scores and coexisting irritable bowel syndrome (1). Tay et al and Glissen Brown et al assessed adverse events (AEs) occurring in patients with NASH or DGBI, respectively, who received placebo (2,3). These authors showed that approximately two-thirds of patients with NASH receiving placebo experienced an AE, whereas 4% of patients with DGBI withdrew from an RCT due to AEs, despite not receiving a neuromodulator during the study.…”

“…In this issue of The American Journal of Gastroenterology , 3 separate analyses evaluated the positive placebo response or the negative nocebo effect in patients with disorders of gut–brain interaction (DGBI), functional dyspepsia, or nonalcoholic steatohepatitis (NASH), participating in placebo-controlled RCTs (1–3). Jones et al demonstrated that patients with functional dyspepsia were more likely to respond to placebo if they had higher baseline symptom scores and coexisting irritable bowel syndrome (1).…”