Proof-of-concept phase II study protocol to evaluate the efficacy and safety of prednisone in the treatment of idiosyncratic hepatotoxicity and its mechanistic pathways through an integrative analysis: the DILICORT clinical trial

Introduction Idiosyncratic drug-induced liver injury (DILI) is an unpredictable adverse reaction ranging from mild liver enzyme elevations to acute liver failure, with management largely limited to withdrawal of the causative drug. An international propensity score-matched study of 724 DILI cases associated corticosteroid therapy with a higher liver enzyme normalization rate, particularly in moderate-to-severe cases without early improvement. These findings informed the design and selection f endpoints for the DILICORT trial, which aims to evaluate the efficacy and safety of prednisone in patients with DILI. The trial will also investigate the effects of treatment on liver function recovery and identify biomarkers associated with therapeutic response. Methods DILICORT (EUCT 2024-513004-33–00; NCT06251232) is a national, randomized, double-blind, placebo-controlled phase II proof-of-concept trial. Sixty patients with moderate-to-severe DILI who show no ≥ 15% reduction in alanine aminotransferase (ALT) or have persistently increasing total bilirubin levels within 5–10 days will be recruited across 15 Spanish centers and followed for 12 weeks. Participants will be randomized to receive a 5-week course of prednisone or matching placebo. The primary objectives are to evaluate prednisone efficacy, assessed by the time to bilirubin reduction or normalization, and its safety and tolerability. Secondary objectives include changes in ALT, aspartate aminotransferase and international normalized ratio, progression to acute liver failure, and health-related quality of life. In addition, there are mechanistic objectives focused on elucidating DILI pathogenesis and biomarker discovery. Discussion DILICORT is the first multicenter, randomized, double-blind, placebo-controlled trial of prednisone in acute idiosyncratic DILI, designed to provide the highest evidence for this therapeutic approach. It specifically targets patients with moderate-to-severe DILI who do not show a favorable early clinical course and incorporates centralized adjudication of suspected DILI cases. Its integrated mechanistic approach may improve understanding of DILI pathophysiology, identify prognostic and treatment-response biomarkers, and facilitate the development of precision medicine strategies and evidence-based clinical guidelines. Clinical Trial Registration https://www.clinicaltrialsregister.eu/ctr-search/search , identifier EUCT 2024-513004-33-00; https://clinicaltrials.gov/ , identifier NCT06251232.