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Randomized Controlled Trial
. 2022 Aug;76(2):429-444.
doi: 10.1002/hep.32403. Epub 2022 Feb 28.

Randomized placebo-controlled trial of losartan for pediatric NAFLD

Miriam B Vos  1 , Mark L Van Natta  2 , Niviann M Blondet  3 , Srinivasan Dasarathy  4 , Mark Fishbein  5 , Paula Hertel  6 , Ajay K Jain  7 , Saul J Karpen  1 , Joel E Lavine  8 , Saeed Mohammad  5 , Laura A Miriel  2 , Jean P Molleston  9 , Marialena Mouzaki  10 , Arun Sanyal  11 , Emily P Sharkey  2 , Jeffrey B Schwimmer  12 , James Tonascia  2 , Laura A Wilson  2 , Stavra A Xanthakos  10 ; NASH Clinical Research Network
Affiliations
Randomized Controlled Trial

Randomized placebo-controlled trial of losartan for pediatric NAFLD

Miriam B Vos et al. Hepatology. 2022 Aug.

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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Conflict of interest statement

Dr. Karpen consults for Albireo, Mirum, and Vertex. Dr. Lavine consults for Intercept and Novo Nordisk. Dr. Mohammad advises Albireo. Dr. Molleston received grants from Abbvie, Albireo, and Mirum. Dr. Sanyal consults and received grants from Conatus, Gilead, Mallinckrodt, Immuron, Boehringer Ingelheim, Novartis, Bristol Myers Squibb, Merck, Lilly, Novo Nordisk, Fractyl, Siemens, Madrigal, Inventiva, and Covance. He owns stock in and consults for Genfit and Hemoshear. He consults for Intercept, Pfizer, Salix, Galectin, Sequana, Terns, Albireo, Sanofi, Janssen, Takeda, Northsea, AMRA, Perspectum, Poxel, 89 Bio, AstraZeneca, NGM Bio, Amgen, Regeneron, Genentech, Roche, Albireo, Prosciento, Histoindex, Path AI, and Biocellvia. He received grants from Echosens‐Sandhill, OWL, and Second Genome. He received royalties from Elsevier and UptoDate. He owns stock in Sanyal Bio, Exhalenz, Durect, Indalo, Tiziana, and Rivus. Dr. Schwimmer received grants from Intercept and Genfit. Dr. Vos consults for Novo Nordisk, Boehringer Ingelheim, and Eli Lilly. She received grants from Bristol Myers Squibb. Dr. Xanthakos received grants from Target RWE.

Figures

FIGURE 1
FIGURE 1
Consolidated Standards of Reporting Trials flow diagram. ALT, alanine aminotransferase; and COVID, 2019 coronavirus pandemic
FIGURE 2
FIGURE 2
Liver measures and metabolic characteristics over time
See this image and copyright information in PMC

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