Trial design and participants
NASH, cirrhosis, hepatic steatosis
CIRRHOSIS, LIVER FIBROSIS, HEPATIC STEATOSIS, CHRONIC LIVER DISEASE
All patients provided written informed consent before entering the trial and this trial was conducted in accordance with Good Clinical Practice, the ethical principles laid down in the Declaration of Helsinki and applicable regulatory requirements. The full study protocol is available as a supplementary file. Five global protocol amendments were implemented to the study protocol with Amendments 3, 4 and 5 implemented following the approval of version 3.0 of the study protocol. Details and rationale for the implemented protocol amendments are provided in the supplementary materials. The Institutional Review Boards and Independent Ethics Committees that approved each version of the study protocol are listed in Supplementary Table This multicentre, parallel-group, randomised, double-blind, placebo-controlled Phase IIa trial (ClinicalTrials.gov: NCT03166735) was conducted at 44 centres across the US, Germany, Spain, Belgium, the UK, Netherlands, Canada, France and Ireland between 27 July 2017 and 14 June 2019. Eligible patients were adults (aged 18–75 years), with either clinical evidence of NASH defined as histological evidence no more than 3 years prior to screening or clinical imaging suggestive of NASH (evidence of hepatic steatosis by magnetic resonance imaging of proton density fat fraction or ultrasound and evidence of liver fibrosis defined by stiffness >3.64 kPa with magnetic resonance elastography or >7.2 kPa with transient elastography) no more than 3 years prior to screening or within the screening phase. Patients were also required to have an ALT level >1.5 to ≤5.0 × the upper limit of normal (ULN) or historic ALT > 1.25 × ULN within 1 week to 3 months prior to screening and two consecutive ALT > 1.5 × ULN measurements at least one week apart during the screening period to be included in the trial.Patients were excluded if they had cirrhosis; other causes of chronic liver disease; a current or recent (within 5 years) history of significant alcohol consumption (>210 g or >140 g per week in men or women, respectively); a bilirubin level >ULN; or glycosylated haemoglobin ≥9.5% or a change in body weight ≥5% in the 3 months prior to screening. A prior risk evaluation using a mechanistic static model suggested that BI 1467335 concentrations in man following 10 mg once daily could potentially inhibit MAO-B irreversibly. Due to this potential risk, concomitant medications, such as antidepressants, MAO inhibitors and serotonergic compounds, were prohibited.