Liraglutide efficacy and action in non-alcoholic steatohepatitis (LEAN): study protocol for a phase II multicentre, double-blinded, randomised, controlled trial

Abstract

Introduction: Non-alcoholic steatohepatitis (NASH) is now the commonest cause of chronic liver disease. Despite this, there are no universally accepted pharmacological therapies for NASH. Liraglutide (Victoza), a human glucagon-like peptide-1 (GLP-1) analogue, has been shown to improve weight loss, glycaemic control and liver enzymes in type 2 diabetes. There is currently a lack of prospective-controlled studies investigating the efficacy of GLP-1 analogues in patients with NASH.

Methods and analysis: Liraglutide efficacy and action in NASH (LEAN) is a phase II, multicentre, double-blinded, placebo-controlled, randomised clinical trial designed to investigate whether a 48-week treatment with 1.8 mg liraglutide will result in improvements in liver histology in patients with NASH. Adult, overweight (body mass index ≥25 kg/m(2)) patients with biopsy-confirmed NASH were assessed for eligibility at five recruitment centres in the UK. Patients who satisfied the eligibility criteria were randomly assigned (1:1) to receive once-daily subcutaneous injections of either 1.8 mg liraglutide or liraglutide-placebo (control). Using A'Hern's single stage phase II methodology (significance level 0.05; power 0.90) and accounting for an estimated 20% withdrawal rate, a minimum of 25 patients were randomised to each treatment group. The primary outcome measure will be centrally assessed using an intention-to-treat analysis of the proportion of evaluable patients achieving an improvement in liver histology between liver biopsies at baseline and after 48 weeks of treatment. Histological improvement will be defined as a combination of the disappearance of active NASH and no worsening in fibrosis.

Ethics and dissemination: The protocol was approved by the National Research Ethics Service (East Midlands-Northampton committee; 10/H0402/32) and the Medicines and Healthcare products Regulatory Agency. Recruitment into the LEAN started in August 2010 and ended in May 2013, with 52 patients randomised. The treatment follow-up of LEAN participants is currently ongoing and is due to finish in July 2014. The findings of this trial will be disseminated through peer-reviewed publications and international presentations.

Trial registration: clinicaltrials.gov NCT01237119.

Keywords: Clinical Pharmacology; Histopathology.

Figure 1

Schematic of liraglutide efficacy and action in non-alcoholic steatohepatitis trial design. Eligible participants are randomly assigned to a 48-week treatment of once daily subcutaneous injections of either 1.8 mg liraglutide or placebo control. Both the trial investigators and the participants are blinded to drug allocation.

Figure 2

Histological inclusion criteria for liraglutide efficacy and action in non-alcoholic steatohepatitis (LEAN) trial. Liver biopsy sections (actual magnification ×400). (A and B) ‘Uncertain’ non-alcoholic steatohepatitis (NASH)—not eligible for LEAN: (A) H&E stain highlights fat, inflammation and some pale cells, however (B) ubiquitin immunohistochemistry does not identify any Mallory Denk bodies (no confirmed ballooning). (C and D) ‘Uncertain’ NASH—eligible for LEAN: (C) H&E stain highlights fat, inflammation and pale cells, but with no obvious Mallory Denk bodies. However, ubiquitin staining (D) is positive (confirming ballooned hepatocytes). (E,F) ‘Definite’ NASH—eligible for LEAN: both H&E and ubiquitin staining highlight fat, lobular inflammation and widespread ballooned hepatocytes. Black arrows highlight Mallory Denk bodies.