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Clinical Trial
. 2025 Jun;45(6):e70131.
doi: 10.1111/liv.70131.

Noninvasive Evaluation of Prolonged-Release Pirfenidone in Compensated Liver Cirrhosis. ODISEA Study, a Randomised Trial

Linda E Muñoz-Espinosa  1 , Aldo Torre  2 , Laura Cisneros  3 , Iaarah Montalvo  4 , René Malé  5 , Scherezada Mejía  6 , Juan Ramón Aguilar  7 , Javier Lizardi  7 , Jaime Zuñiga-Noriega  1 , María Eugenia Icaza  4 , Frida Gasca-Díaz  7 , Larissa Hernández-Hernández  7 , Paula Cordero-Pérez  1 , Luis Chi  4 , Lilian Torres  5 , Fátima Rodríguez-Alvarez  2 , Graciela Tapia  8 , Jorge Luis Poo  7
Affiliations
Clinical Trial

Noninvasive Evaluation of Prolonged-Release Pirfenidone in Compensated Liver Cirrhosis. ODISEA Study, a Randomised Trial

Linda E Muñoz-Espinosa et al. Liver Int. 2025 Jun.

Abstract

Background: Advanced liver fibrosis (ALF) predicts an adverse prognosis in chronic liver disease. In addition to etiological treatment, a new approach to stop or reverse residual fibrosis is desirable.

Objective: To assess the efficacy and safety of prolonged-release pirfenidone (PR-PFD) versus placebo in compensated cirrhosis.

Methods: 180 patients with ALF (F4) were randomly assigned to: placebo, 1200 mg/d, and 1800 mg/d PR-PFD, plus standardised care, for 24mo. Frequency of lab tests: (3mo), liver stiffness measurement (LSM), FibroTest, ultrasound (US) (6mo), and endoscopy (annually).

Results: Fibrosis evolution estimated from LSM was significantly lower only in the 1200 compared to placebo and 1800 groups (24.2 ± 2.4 vs. 15.4 ± 2.4; 27.6 ± 2.4 vs. 24.6 ± 2.4; 24.4 ± 2.3 vs. 23.3 ± 2.3 kPa, respectively, p < 0.001), in intergroup analysis, meeting the primary endpoint. Fibrotest was significantly lower only in the 1200 mg/d group, compared to baseline values (0.86 ± 0.02 vs. 0.83 ± 0.02 units, p < 0.001). Liver function test (LFT's) also improved as well as Model for End-Stage Liver Disease (MELD) score and quality of life (QoL). Decompensations occurred in 19 patients: 12 ascites (more frequent in placebo, p = 0.003), 5 variceal bleeding, 4 encephalopathies, 4 hepatocarcinomas. Adverse events were mainly mild gastrointestinal (n = 35, 48 and 46, p = 0.010) and cutaneous (n = 12, 15, and 22, p = 0.0001) in placebo, 1200 and 1800 mg/day, respectively.

Conclusion: PR-PFD at a dose of 1200 mg significantly decreased non-invasive liver fibrosis markers at 24 months and induced improvement in LFT's, MELD, and QoL in compensated cirrhosis, without safety concerns.

Trial registration: ClinicalTrials.gov identifier: NCT01046474.

Keywords: cirrhosis; fibrosis; prolonged‐release pirfenidone.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

FIGURE 1
FIGURE 1
ODISEA study population flow chart.
FIGURE 2
FIGURE 2
(A) Fibrosis evolution estimated by liver stiffness assessment (mean ± SE) shows a statiscally significant difference using the Mixed Model method (p < 0.001), for inter‐group analysis. Final values between the three groups showed also significant differences (placebo vs. 1200 mg, *p = 0.023; 1200 mg versus 1800 mg, *p = 0.012) in post hoc analysis with Bonferroni correction. Additionally, for intra‐group analisis only in the 1200 mg PR‐PFD group, compared to baseline values **p = 0.001, by Student's t test. (B) Fibrosis evolution estimated by Fibrotest assessment (mean ± SE). Statistical significance was analysed by Student's t‐test; **p = 0.001 in the 1200 mg, and *p = 0.045 in the 1800 mg PR‐PFD group, compared to baseline values.
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