Immunomodulatory Effect of Curcumin in Critically Ill Patients With Sepsis at the Antiguo Hospital Civil de Guadalajara "Fray Antonio Alcalde": A Randomized, Double-Blind, Placebo-Controlled Clinical Trial

Sepsis is a complex, dysregulated host response to infection characterized by systemic inflammation, immune dysfunction, endothelial injury, oxidative stress, microcirculatory alterations, and subsequent organ dysfunction. Despite adherence to guideline-directed management, including early antimicrobial therapy, hemodynamic optimization, and organ support, sepsis continues to be associated with high morbidity and mortality. Increasing evidence suggests that both hyperinflammatory and subsequent immunosuppressive phases contribute to adverse outcomes, highlighting the need for adjunctive immunomodulatory therapies. Curcumin is a bioactive polyphenol derived from Curcuma longa, and has demonstrated anti-inflammatory, antioxidant, and immunomodulatory properties in preclinical models. Curcumin has been shown to modulate multiple intracellular signaling pathways implicated in sepsis pathophysiology, including inhibition of NF-κB activation, downregulation of pro-inflammatory cytokines (e.g., TNF-α, IL-1β, IL-6), attenuation of oxidative stress via Nrf2 activation, and modulation of Toll-like receptor signaling. Additionally, curcumin may influence endothelial function, mitochondrial homeostasis, and apoptosis pathways. However, clinical data in critically ill septic patients remain limited, and robust randomized controlled trials are lacking. This study is designed as a prospective, randomized, double-blind, placebo-controlled clinical trial conducted in critically ill adult patients diagnosed with sepsis and admitted at the Antiguo Hospital Civil de Guadalajara "Fray Antonio Alcalde" in Guadalajara, Mexico. The primary objective is to evaluate whether adjunctive administration of a bioavailable formulation of curcumin, in addition to standard sepsis management, favorably modulates systemic inflammation and organ dysfunction. Participants will be randomly assigned in a 1:1 ratio to receive either curcumin or a matched placebo. Randomization will be performed using a computer-generated sequence with allocation concealment through sequentially numbered, opaque, sealed containers prepared by personnel not involved in patient care or outcome assessment. Blinding will be maintained for participants, treating clinicians, investigators, laboratory personnel, and data analysts. The investigational product and placebo will be identical in appearance, packaging, and administration schedule. All participants will receive standard-of-care management for sepsis according to institutional protocols aligned with international guidelines, including antimicrobial therapy, fluid resuscitation, vasopressor support, ventilatory support, renal replacement therapy, and other organ-support measures as clinically indicated. The intervention consists of adjunctive administration of a standardized, enhanced-bioavailability formulation of curcumin delivered enterally. The dosing regimen, duration of administration, and formulation characteristics are predefined in the protocol and selected based on prior safety data and pharmacokinetic considerations. Enteral administration will occur via oral route or feeding tube in patients receiving enteral nutrition. Treatment will begin within a defined time window after fulfillment of sepsis diagnostic criteria and admission. Adherence to the intervention will be documented daily. Curcumin is known to have limited bioavailability due to poor absorption, rapid metabolism, and systemic elimination. Therefore, the selected formulation incorporates strategies to enhance systemic exposure. The dosing schedule is designed to maintain sustained plasma concentrations within ranges associated with biological activity in prior human studies, while remaining within established safety parameters. Clinical and laboratory data will be collected at baseline and at prespecified time points during their stay. Data will include demographic information, comorbidities, infection source, hemodynamic parameters, organ support requirements, and relevant biochemical markers. Inflammatory and immunologic biomarkers will be measured using validated laboratory techniques. Blood samples will be processed according to standardized protocols to ensure reproducibility and minimize pre-analytical variability. Adverse events will be recorded and categorized according to severity and relatedness to the investigational product. Particular attention will be given to gastrointestinal intolerance, hepatotoxicity, bleeding risk, and allergic reactions. Routine laboratory monitoring will include liver function tests and coagulation parameters to ensure safety. Criteria for discontinuation of the intervention include predefined safety thresholds or clinical judgment by the treating team. Sample size calculation is based on detecting a clinically meaningful difference in predefined biological or clinical parameters between groups, with an appropriate power and two-sided alpha level. The calculation incorporates estimated variance derived from prior studies in similar populations. Statistical analysis will follow the intention-to-treat principle. Continuous variables will be assessed for normality and analyzed using parametric or non-parametric tests as appropriate. Categorical variables will be compared using chi-square or Fisher's exact test. Multivariable analyses will be performed to adjust for potential confounders such as baseline severity of illness, comorbid conditions, and infection source. The study protocol has been submitted to and approved by the institutional Research Ethics Committee. Written informed consent will be obtained from patients or legally authorized representatives prior to enrollment, in accordance with national (Mexican) regulations and the Declaration of Helsinki. Given the critical illness context, provisions are included for surrogate consent when patients lack decision-making capacity. Participants retain the right to withdraw at any time without affecting their standard medical care. Curcumin has an established safety profile in prior human studies at comparable doses, and the risk associated with participation is considered minimal beyond standard treatment. The potential benefit includes improved regulation of systemic inflammation and organ function. This study addresses an important gap in sepsis research by evaluating a multi-target immunomodulatory compound within a rigorous randomized controlled framework. Unlike single-pathway biologic agents that have historically failed in sepsis trials, curcumin exerts pleiotropic effects across inflammatory, oxidative, and endothelial pathways, which may be advantageous in a syndrome characterized by complex immune dysregulation. If adjunctive curcumin therapy demonstrates biological and clinical benefit without increased adverse events, it may represent a cost-effective and accessible strategy for resource-limited settings. Furthermore, this study may provide mechanistic insights into host-response modulation in sepsis and inform future translational research.