High rates of ineligibility for participation in trials of new therapies in non-alcoholic steatohepatitis: a systematic review

Abstract

Background and aims: Non-alcoholic fatty liver disease is common and there are a number of treatments in development. Patients with non-alcoholic steatohepatitis (NASH) and significant fibrosis are thought to be the population most in need of treatment. Identification of this group requires liver biopsy. The aim of this study was to identify the proportion of patients screened for phase 2 randomised controlled trials who subsequently entered these studies. Methods: Large, multicentre, phase 2 randomised controlled trials of pharmacological therapies for NASH were identified by systematic review. The pooled proportion of potential participants who entered the trials was estimated by meta-analysis. The reasons for trial ineligibility were separately extracted and analysed. Results: Thirteen reports of 14 trials were included. Overall, there were 4014 screened individuals included in the quantitative analyses and 53% were subsequently enrolled in a trial. Considering trials in which the entry criteria matched the current paradigm for treatment, that is, the presence of NASH and significant fibrosis, only 35% of screened individuals were eligible for trial entry. More than half of ineligible individuals were excluded on the basis of liver histology most often due to insufficient disease activity with or without insufficient fibrosis. Conclusion: The majority of patients considered at risk of NASH and fibrosis sufficient for treatment in randomised controlled trials are ineligible for trial entry. Most often, this is due to ineligible liver histology. These findings have implications for the design of future trials in NASH and for the applicability of treatments after licensing.

Histological Endpoints for Nonalcoholic Steatohepatitis Trials: Lights and Shadows

“…For instance, more than half of patients considered for entry into clinical trials for NASH do not enter those trials, most often due to ineligible liver histology. 24 Moreover, patients included in trials are different to those patients included in observational studies. 25 Use of treatments without biopsy risks the efficacy of these agents understanding that this will not be known amongst patients who did not meet the trial entry criteria and this is an issue that will need to be tackled as treatments that show efficacy within clinical trials are licensed for use.…”

Relevance of GLP-1 receptor agonists or SGLT-2 inhibitors on the recruitment for clinical studies in patients with NAFLD

“…Another relevant exclusion criterion for study participation may be the use of concomitant medications: So far, clinical NASH trial programs consisted of investigational monotherapies that excluded concomitant medications, which themselves can improve the underlying disease, for example, modern antidiabetics like glucagon-like peptide-1 receptor agonists (GLP-1 RA) or sodium-glucose co-transporter-1 inhibitors (SGLT2i) [14,[18][19][20][21]. Screening failure rates due to inappropriate biopsy results are often reported in study summaries, because they occur after informed consent during the screening process [17,22,23], while exclusion of patients due to prohibited concomitant medications is frequently not reported, because these study candidates can be excluded during the pre-screening process prior to obtaining informed study consent. German registry data indicate that 17% of NAFLD patients with type 2 diabetes mellitus receive GLP-1 RA or SGLT1i at secondary or tertiary referral centers [24].…”

“…A key inclusion criterion in phase III clinical trials is presence of an adequate liver biopsy that confirms NASH defined by NAS ≥ 4 and a fibrosis stage ≥ F2 according to the NASH CRN staging classification to investigate resolution of NASH without worsening of fibrosis or improvement of fibrosis without worsening of NASH [14]. However, only a small proportion of NAFLD patients undergoes liver biopsy and presents with a histology eligible for trial entry, so that liver biopsy is a major hurdle for study recruitment [16,17].…”