A randomised controlled trial of losartan as an anti-fibrotic agent in non-alcoholic steatohepatitis

Lead Research Organisation: Newcastle University

Abstract

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Technical Summary

Scientific Abstract|Design: two-arm, parallel group, double blind, randomised, placebo-controlled trial|Setting: Five tertiary referral centres for the management of liver disease: Freeman Hospital, Newcastle upon Tyne (lead centre), Edinburgh, Nottingham, Birmingham and London (St. Marys).|Target population: Adults (aged 18+), with steatohepatitis and fibrosis, resulting from non alcoholic fatty liver disease.|Intervention: Angiotensin receptor blocker (Losartan) at a dose of 50 mg once a day vs. matched placebo for 24 months.|Measurement of outcomes and duration of follow-up: The primary outcome will be change in Kleiner fibrosis score, based on histological fibrosis stage (as judged by two independent blinded histopathologists from liver biopsies), from pre-treatment to end-of-study. Duration of treatment will be 24 months, with biopsies at month 0 (pre-treatment) and month 24 (end-of-study). Secondary outcomes will be a change in radiological (fibroscan) and serological (ELF) markers of fibrosis; both of which have been validated against the histological gold-standard. These will be performed at trial entry, 48 weeks and at end-of-study. A further secondary outcome is the change in NAFLD activity score (NAS) from baseline. This will be determined from trial entry and end-of-study liver biopsies. The NAS specifically includes only features of active injury that are traditionally reversible and is defined as the un-weighted sum of scores for steatosis (0-3), lobular inflammation (0-3) and hepatocyte ballooning (0-2). Responder rate for placebo vs. intervention will be compared. Responder rate is defined as end of treatment liver fibrosis stage less than baseline liver fibrosis stage. Fibroscan and serological markers of fibrosis will be measured at trial outset, at one year and on completion of the trial. On-trial patients will be reviewed on a three-monthly basis to determine whether there have been any clinical decompensation episodes, to look for side effects of the medication and to measure routine bloods and blood pressure for safety analyses.|Sample size: Natural history studies have suggested that, over a two year period, fibrosis progresses in around 25% of patients with NAFLD. Pilot data from small, one year trials of losartan in patients with NASH or transplanted with hepatitis C have suggested that the proportion that progress could be brought to nearly 0% with regression of fibrosis in up to 60% .No studies are available to inform us what may happen in the second year of treatment. Using available data, we have made what we feel to be conservative estimates of what we will see over two years with placebo (10% progress by 2 points, 15% progress by 1 point, 55% no change, 20% regress by 1 point) and drug (5% progress by 2 points, 5% progress by 1 point, 48% no change, 42% regress by 1 point, 0% regress by 2 points). These figures give us a difference in mean change of fibrosis score between drug and placebo of 0.42 with a standard deviation of 0.84. This give us an effect size (mean difference between placebo and intervention in change in fibrosis score/SD) of 0.5.|In order to detect this effect with 90% power with a significance of 0.05 (two tailed test), an achieved sample of 85 patients providing baseline and end-of-study biopsies will be required in each group, a total of 170. This achieved sample size would also provide 90% power, alpha = 0.05, to detect a difference in responder rate between placebo and intervention of 25% vs. 60%, and in rate of fibrosis progression of 25% vs. 3%.|Planned analyses: Analysis will be on the basis of intention to treat. There are no pre-planned interim or sub-group analyses. The primary analysis for efficacy will be based on change in fibrosis score, from baseline to end-of-treatment (month 0 to month 24). Differences between placebo and intervention groups will be assessed using analysis of covariance, with baseline fibrosis score as a covariate along with age, body mass

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