Randomized Placebo-Controlled Trial of Losartan for Pediatric NAFLD

Authors

Miriam B Vos
Mark L Van Natta
Niviann M Blondet
Srinivasan Dasarathy
Mark Fishbein
Paula Hertel
Ajay K Jain
Saul J Karpen
Joel E Lavine
Saeed Mohammad
Laura A Miriel
Jean P Molleston
Marialena Mouzaki
Arun Sanyal
Emily P Sharkey
Jeffrey B Schwimmer
James Tonascia
Laura A Wilson
Stavra A Xanthakos
NASH Clinical Research Network

Publication Date

8-1-2022

Journal

Hepatology

DOI

10.1002/hep.32403

PMID

35133671

PMCID

PMC9288975

PubMedCentral® Posted Date

2-28-2022

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes

Keywords

Adolescent, Angiotensin Receptor Antagonists, Blood Pressure, Child, Double-Blind Method, Female, Humans, Hypertension, Losartan, Male, Non-alcoholic Fatty Liver Disease, Treatment Outcome

Abstract

BACKGROUND AND AIMS: To date, no pharmacotherapy exists for pediatric NAFLD. Losartan, an angiotensin II receptor blocker, has been proposed as a treatment due to its antifibrotic effects.

APPROACH AND RESULTS: The Nonalcoholic Steatohepatitis Clinical Research Network conducted a multicenter, double-masked, placebo-controlled, randomized clinical trial in children with histologically confirmed NAFLD at 10 sites (September 2018 to April 2020). Inclusion criteria were age 8-17 years, histologic NAFLD activity score ≥ 3, and serum alanine aminotransferase (ALT) ≥ 50 U/l. Children received 100 mg of losartan or placebo orally once daily for 24 weeks. The primary outcome was change in ALT levels from baseline to 24 weeks, and the preset sample size was n = 110. Treatment effects were assessed using linear regression of change in treatment group adjusted for baseline value. Eighty-three participants (81% male, 80% Hispanic) were randomized to losartan (n = 43) or placebo (n = 40). During an enrollment pause, necessitated by the 2019 coronavirus pandemic, an unplanned interim analysis showed low probability (7%) of significant group difference. The Data and Safety Monitoring Board recommended early study termination. Baseline characteristics were similar between groups. The 24-week change in ALT did not differ significantly between losartan versus placebo groups (adjusted mean difference: 1.1 U/l; 95% CI = -30.6, 32.7; p = 0.95), although alkaline phosphatase decreased significantly in the losartan group (adjusted mean difference: -23.4 U/l; 95% CI = -41.5, -5.3; p = 0.01). Systolic blood pressure decreased in the losartan group but increased in placebo (adjusted mean difference: -7.5 mm Hg; 95% CI = -12.2, -2.8; p = 0.002). Compliance by pill counts and numbers and types of adverse events did not differ by group.

CONCLUSIONS: Losartan did not significantly reduce ALT in children with NAFLD when compared with placebo.

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