Hepatitis B virus (HBV) infection frequently leads to liver fibrosis and is the leading cause of hepatocellular carcinoma (HCC) and cirrhosis in Asia Pacific. Pirfenidone is approved by FDA for treatment of idiopathic pulmonary fibrosis and hydronidone is a novel structural modification of pirfenidone with the aim of reducing hepatoxicity. We aimed to investigate the safety and efficacy of hydronidone in patients with chronic hepatitis B (CHB) associated liver fibrosis.This was a 52-week multicenter, randomized, double-blind, placebo-controlled, phase 2 study at 8 centers in China. CHB patients with biopsied documented liver fibrosis were eligible and were randomly assigned into receiving daily placebo or hydronidone orally (180 mg/day ,270 mg/day or 360 mg/day). All enrolled subjects also received entecavir 0.5 mg/day. A second liver biopsy was performed at week 52. The primary endpoint was defined as fibrosis improvement (reduction of at least one Ishak score at week 52 of treatment).From June 25, 2015, to September 5, 2019, 168 CHB patients with liver fibrosis met the inclusion/exclusion criteria and were subsequently randomized, 43 in the placebo group and 125 in the hydronidone groups (42 in the 180mg group, 42 in the 270mg group, and 41 in the 360mg group). The fibrosis improvement endpoint was achieved by 11 (25.6%) patients in placebo group and 17 (40.5%) patients in the 180 mg group (p=0.12), 23 (54.8%)patients in the 270 mg group (p=0.006) and 18 (43.90%) patients in the 360 mg group (p=0.08). The improvement rate was 58/125 (46.4%) in the combined hydronidone group (p=0.014). The overall safety profile and incidence of serious adverse events were similar among the groups.Hydronidone plus entecavir showed clinically significant histological improvement of liver fibrosis in CHB patients and the dose of 270 mg showed best efficacy of fibrosis regression. Further studies are required to assess the long-term effectiveness of hydronidone in regression of hepatic fibrosis.gov number, NCT02499562.Copyright © 2022 AGA Institute. Published by Elsevier Inc. All rights reserved.