Idiosyncratic DILI, as the condition is known, is an adverse reaction that occurs in a small fraction of people exposed to drugs that are safe for most individuals. It can arise with a wide range of medications and, increasingly, with herbal and dietary supplements, and its severity ranges from asymptomatic liver enzyme elevations to acute liver failure and death. Most patients present with jaundice, abdominal pain or nausea. Despite the significant morbidity and mortality associated with the condition, no treatments with proven efficacy are currently available, leaving drug withdrawal and supportive care as the only standard management.

The rationale for testing corticosteroids rests on the immune-mediated nature of many DILI cases. The condition’s pathophysiology involves impaired hepatic drug transport, generation of reactive metabolites, mitochondrial and endoplasmic reticulum stress, and disruption of bile acid homeostasis, which can trigger innate and adaptive immune responses that drive clinically apparent liver damage. This immune component is supported by the recurrence of injury upon re-exposure to the offending drug and by associations between DILI risk and HLA alleles that modulate T-cell signaling. Corticosteroids are potent immunosuppressive agents that have demonstrated efficacy in immune-mediated liver inflammation such as autoimmune hepatitis, but they carry systemic adverse effects, and physicians have so far prescribed them for severe DILI cases only on an empirical basis.

The evidence base for this practice has been limited and contradictory. Retrospective data suggest corticosteroids may speed recovery of serum bilirubin in severe cases, while other retrospective series reported increased risk with high-dose prednisone above 40 milligrams per day. Those studies, however, did not adequately account for selection bias, since corticosteroids are more likely to be given to patients with more severe injury, meaning worse outcomes may reflect underlying disease severity rather than treatment failure. A recent international propensity score-matched analysis of 724 well-characterized DILI cases from the Spanish DILI Registry and Indiana University School of Medicine addressed this confounding: it found no association between corticosteroid use and acute liver failure, and patients receiving corticosteroids had a significantly higher rate of liver enzyme normalization than untreated patients, particularly in moderate-to-severe cases without early improvement. That study laid the groundwork for DILICORT.

The trial’s design reflects a deliberate effort to target patients most likely to benefit. Only adults with moderate-to-severe DILI, defined as ALT or AST elevations at least five times the upper limit of normal plus total bilirubin of at least 2.5 milligrams per deciliter, will be enrolled, and only if they show no 15 percent reduction in ALT or have persistently rising bilirubin five to ten days after the injury is recognized despite withdrawal of the culprit drug. This observation window filters out patients whose injury is resolving spontaneously, a common occurrence that would dilute any measurable treatment effect, while also allowing time for causality assessment before enrollment.

Because DILI lacks a gold-standard diagnostic test, diagnosis relies on clinical suspicion and exclusion of other causes, making misclassification a major threat to trial validity. DILICORT addresses this with an independent central adjudication committee of three DILI specialists who review all candidate cases using the same standardized methodology as the Spanish DILI Registry, blinded to treatment allocation. Patients who fail screening will be followed in a separate observational group rather than serving as comparators. Exclusion criteria also rule out immune-checkpoint inhibitor injury, active infection, established acute liver failure, MELD scores of 30 or above, pregnancy, viral co-infections, and patients already on immunosuppressants.

Participants will be randomized one-to-one to prednisone or matching placebo, starting at a daily dose of 40 milligrams in week one, followed by a four-week taper down to 5 milligrams daily. The tapering strategy is intended to provide sustained immunosuppression during the critical phase of liver injury while minimizing corticosteroid-related adverse effects, mirroring standard hepatology practice. The primary endpoints are the proportion of patients achieving at least a 50 percent reduction from peak total bilirubin by day 14, the time to bilirubin normalization, and safety measures including adverse events, serious adverse events and premature discontinuations. Secondary endpoints cover reductions in ALT, AST and the international normalized ratio, progression to acute liver failure, and health-related quality of life measured with validated questionnaires.

Beyond the clinical questions, DILICORT incorporates an unusually extensive mechanistic program. Researchers will track serum proteins including osteopontin, cytokeratin-18 and MCSFR1, circulating cell-free RNA, lymphocyte populations, gut microbiota diversity, serum metabolomics, mitochondrial dysfunction markers, magnesium levels and genetic variants, comparing profiles between treatment arms and between responders and non-responders. Bile acids, which have emerged as promising candidate biomarkers in previous studies, will be validated in a prospective randomized setting for the first time. The exploratory multi-omics analysis is intended to illuminate the biology of DILI and of corticosteroid response, potentially identifying biomarkers for earlier, non-invasive monitoring of disease progression and treatment response.

The statistical plan assumes a hazard ratio of 2.80 based on the prior observational study, requiring 47 patients to reach 30 primary events with 80 percent power, inflated to 52 after accounting for a 10 percent loss to follow-up. The investigators set a final target of 60 patients, 30 per group, reflecting the proof-of-concept nature of the study and the absence of prospective preliminary data. A futility analysis will be conducted once half the sample has completed the study, with a difference of 10 percent or less in maximum bilirubin reduction between groups serving as the cutoff for stopping. Efficacy will be analyzed on an intent-to-treat basis, and the statistical team will remain blinded throughout.

If prednisone demonstrates an acceptable benefit-risk profile, the trial could shift corticosteroid use in DILI from empirical practice to an evidence-based intervention, informing future clinical guidelines and larger confirmatory trials. The investigators caution that results should be interpreted as preliminary but essential evidence, and that the mechanistic findings will require validation in larger cohorts. Recruitment began in May 2024, and the trial, including follow-up, is expected to be completed by December 2028.

Subject of Research: A phase II placebo-controlled trial protocol testing prednisone for idiosyncratic drug-induced liver injury

Article Title: 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

Article References: Garrido-Rodríguez, V., Remesal-Doblado, Á., García-Cortés, M., Niu, H., Cárdenas-Quesada, J., Pinazo-Bandera, J. M., Toro-Ortiz, J. P., Pérez-López, E., Moreno-González, R., Bonilla-Toyos, E., Di Zeo-Sánchez, D. E., Matilla-Cabello, G., Villanueva-Paz, M., Andrade, R. J., Lucena, M. I., Alvarez-Alvarez, I., Sanabria-Cabrera, J., & Robles-Díaz, M. (2026). 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. Frontiers in Pharmacology, 17, Article 1963613. https://doi.org/10.3389/fphar.2026.1963613

Image Credits: AI Generated

DOI: 10.3389/fphar.2026.1963613

Keywords: drug-induced liver injury, DILICORT trial, prednisone, corticosteroids, clinical trial, hepatology, placebo-controlled, biomarkers, idiosyncratic hepatotoxicity, immunosuppression, liver injury, precision medicine