Sepsis is a life-threatening condition that occurs when the body's response to an infection becomes overwhelming and damages its own organs. It is one of the leading causes of death in critically ill (very sick) patients worldwide. Despite advances in antibiotics, intensive care, and life-support technologies, sepsis remains difficult to treat because much of the harm comes not only from the infection itself, but from an exaggerated and uncontrolled inflammatory response in the body. When a person develops sepsis, the immune system releases large amounts of inflammatory substances meant to fight infection. However, in many cases this response becomes excessive, leading to organ failure, prolonged stays in the intensive care unit (ICU), and increased risk of death. Current treatments focus mainly on controlling the infection and supporting failing organs, but there are limited therapies that directly help regulate this harmful immune overreaction. Curcumin is a natural compound found in turmeric, a spice commonly used in food. In laboratory studies and some clinical research, curcumin has shown anti-inflammatory and antioxidant properties. It appears to influence several pathways in the immune system that are involved in the inflammatory process. However, its potential benefits in patients with severe infections such as sepsis have not been fully studied in a rigorous clinical setting. The purpose of this clinical trial is to evaluate whether curcumin, when added to standard medical treatment, can help modulate (regulate) the immune response in critically ill patients with sepsis. This study will be conducted as a randomized, double-blind, placebo-controlled clinical trial at the Antiguo Hospital Civil de Guadalajara "Fray Antonio Alcalde" in Guadalajara, Mexico. "Randomized" means that participants will be assigned by chance to receive either curcumin or a placebo (a look-alike substance that contains no drug). "Double-blind" means that neither the patients nor the healthcare team will know who is receiving curcumin and who is receiving the placebo during the study. This design helps ensure that the results are objective and scientifically reliable. Participants in the study will continue to receive all standard treatments for sepsis, including antibiotics and intensive care support. The study will measure inflammatory markers in the blood, organ function, and important clinical outcomes such as the need for organ support and length of stay in the ICU. Safety will also be carefully monitored. Hypothesis: The investigators hypothesize that in critically ill patients with sepsis, the addition of curcumin to standard treatment will help regulate the excessive inflammatory response, leading to improved biological markers of inflammation and potentially better clinical outcomes, compared to standard treatment alone. If curcumin proves to be beneficial and safe in this population, it could represent an accessible and relatively low-cost complementary therapy to improve the management of sepsis. However, this study is necessary to determine scientifically whether these potential benefits are real and clinically meaningful. The ultimate goal of this research is to contribute new evidence that may improve the care and survival of patients suffering from one of the most severe and challenging conditions treated in intensive care medicine.
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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
TRIPLE
Enrollment
56
The investigational product consists of an oral, enhanced-bioavailability formulation of curcumin (Longvida®). Each capsule contains 500 mg of formulation standardized to 20% curcumin, providing 100 mg of active curcumin per capsule. Participants assigned to the experimental arm will receive 2 capsules three times daily (every 8 hours) for 10 consecutive days, for a total of 6 capsules per day and 600 mg of curcumin daily.
Participants randomized to this arm will receive standard-of-care treatment for sepsis plus a matched placebo administered enterally. The placebo consists of starch-based capsules identical in appearance to the active product. Patients will take 2 placebo capsules three times daily for 10 days (total 6 capsules/day), following the same schedule as the experimental arm, while all other treatment remains at the discretion of the treating team.
Antiguo Hospital Civil de Guadalajara "Fray Antonio Alcalde"
Guadalajara, Jalisco, Mexico
RECRUITINGChange in Interleukin-6 (IL-6) from baseline to Day 10 of treatment.
Serum concentrations of the pro-inflammatory cytokine interleukin-6 (IL-6, pg/mL) will be measured in peripheral venous blood samples collected at baseline (prior to initiation of the intervention) and on Day 10 of treatment. Samples will be processed under standardized laboratory conditions and analyzed using validated quantitative immunoassay techniques (enzyme-linked immunosorbent assay \[ELISA\]). Results will be reported in pg/mL. The primary endpoint will be defined as the change in cytokine levels from baseline to Day 10, comparing the curcumin and placebo groups. A greater reduction in circulating cytokine concentrations will be interpreted as evidence of a modulatory effect on the systemic inflammatory response associated with sepsis.
Time frame: Baseline to Day 10
Change in Interleukin-1 beta (IL-1β) from baseline to Day 10 of treatment.
Serum concentrations of the pro-inflammatory cytokine interleukin-1 beta (IL-1β, pg/mL), will be measured in peripheral venous blood samples collected at baseline (prior to initiation of the intervention) and on Day 10 of treatment. Samples will be processed under standardized laboratory conditions and analyzed using validated quantitative immunoassay techniques (enzyme-linked immunosorbent assay \[ELISA\]). Results will be reported in pg/mL. The primary endpoint will be defined as the change in cytokine levels from baseline to Day 10, comparing the curcumin and placebo groups. A greater reduction in circulating cytokine concentrations will be interpreted as evidence of a modulatory effect on the systemic inflammatory response associated with sepsis.
Time frame: Baseline to Day 10
Change in tumor necrosis factor-alpha (TNF-α) from baseline to Day 10 of treatment.
Serum concentrations of the pro-inflammatory cytokine tumor necrosis factor-alpha (TNF-α, pg/mL) will be measured in peripheral venous blood samples collected at baseline (prior to initiation of the intervention) and on Day 10 of treatment. Samples will be processed under standardized laboratory conditions and analyzed using validated quantitative immunoassay techniques (enzyme-linked immunosorbent assay \[ELISA\]). Results will be reported in pg/mL. The primary endpoint will be defined as the change in cytokine levels from baseline to Day 10, comparing the curcumin and placebo groups. A greater reduction in circulating cytokine concentrations will be interpreted as evidence of a modulatory effect on the systemic inflammatory response associated with sepsis.
Time frame: Baseline to Day 10
Change in high-sensitivity C-reactive protein (hs-CRP) from baseline to Day 10 of treatment.
Serum levels of high-sensitivity C-reactive protein (hs-CRP, mg/L) will be measured at baseline (prior to initiation of the intervention) and on Day 10 of treatment. hs-CRP will be quantified using standardized automated immunoassays. Results will be reported in mg/L. The secondary endpoint will be defined as the change in hs-CRP from baseline to Day 10, comparing the curcumin and placebo groups. A greater reduction in hs-CRP will be interpreted as evidence of attenuation of systemic inflammation.
Time frame: Baseline to Day 10
Change in procalcitonin (PCT) from baseline to Day 10 of treatment.
Serum levels of procalcitonin (PCT, ng/mL) will be measured at baseline (prior to initiation of the intervention) and on Day 10 of treatment. PCT will be quantified using standardized automated immunoassays. Results will be reported in ng/mL. The secondary endpoint will be defined as the change in PCT from baseline to Day 10, comparing the curcumin and placebo groups. A greater reduction in PCT will be interpreted as evidence of attenuation of systemic inflammation.
Time frame: Baseline to Day 10
Change in erythrocyte sedimentation rate (ESR) from baseline to Day 10 of treatment.
Serum levels of erythrocyte sedimentation rate (ESR, ng/mL), will be measured at baseline (prior to initiation of the intervention) and on Day 10 of treatment. ESR will be determined using conventional laboratory methodology (Westergren method). Results will be reported in ng/mL. The secondary endpoint will be defined as the change in ESR from baseline to Day 10, comparing the curcumin and placebo groups. A greater reduction in ESR will be interpreted as evidence of attenuation of systemic inflammation.
Time frame: Baseline to Day 10
Days of Hospital Length of Stay and Days of ICU Length of Stay
Clinical evolution will be evaluated by measuring total hospital length of stay, defined as the number of days from hospital admission to discharge, and ICU length of stay, defined as the number of days from ICU admission to ICU discharge, both reported in days. These outcomes will be compared between the curcumin and placebo groups to determine differences in clinical recovery.
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Time frame: From date of enrollment until the date of hospital discharge; assesed up to 52 weeks
Days of Mechanical Ventilation
Among patients who require mechanical ventilation, the duration of ventilatory support will be measured as the total number of days receiving invasive mechanical ventilation. This outcome will be compared between the curcumin and placebo groups to determine differences in clinical recovery.
Time frame: From date of intubation until the date of extubation; assesed up to 52 weeks
Number of Deaths (Mortality)
All-cause mortality will be assessed as the proportion of patients who die during hospitalization, expressed as a percentage. This outcome will be compared between the curcumin and placebo groups to determine differences in clinical recovery and overall prognosis.
Time frame: From date of enrollment until death; assesed up to 52 weeks
Change in "Sequential Organ Failure Assessment" (SOFA) score from baseline to Day 10 of treatment.
Clinical severity will be evaluated using the Sequential Organ Failure Assessment (SOFA) score. It will be calculated according to its validated criteria and reported as total score (0-24 points), higher scores mean a worse outcome. Comparisons between the curcumin and placebo groups will evaluate differences in SOFA score at baseline and Day 10.
Time frame: Baseline and Day 10
Change in "Sequential Organ Failure Assessment 2" (SOFA-2) score from baseline to Day 10 of treatment.
Clinical severity will be evaluated using the Sequential Organ Failure Assessment 2 (SOFA-2) score. It will be calculated according to its validated criteria and reported as total score (0-24 points), higher scores mean a worse outcome. Comparisons between the curcumin and placebo groups will evaluate differences in SOFA-2 score at baseline and Day 10.
Time frame: Baseline and Day 10
Change in "Acute Physiology and Chronic Health Evaluation IV" (APACHE IV) score from baseline to Day 10 of treatment
Clinical severity will be evaluated using the Acute Physiology and Chronic Health Evaluation IV (APACHE IV) score. It will be calculated according to its validated criteria and reported as total score (0-286 points), higher scores mean a worse outcome. Comparisons between the curcumin and placebo groups will evaluate differences in APACHE IV score at baseline and Day 10.
Time frame: Baseline and Day 10
Change in PaO2/FiO2 ratio from baseline to Day 10 of treatment.
Oxygenation status will be assessed using the PaO2/FiO2 ratio, calculated from arterial blood gas analysis and corresponding fraction of inspired oxygen. Results will be reported as unitless ratio, lower ratios mean a worse outcome. Comparisons between the curcumin and placebo groups will evaluate differences in PaO2/FiO2 ratio at baseline and Day 10.
Time frame: Baseline and Day 10
Change in neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) from baseline to Day 10 of treatment.
Inflammatory status will be evaluated using the neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR). These will be derived from complete blood count parameters. The results will be expressed as unitless ratios, higher ratios mean a worse outcome. Comparisons between the curcumin and placebo groups will evaluate differences in inflammatory indices at baseline and Day 10.
Time frame: Baseline and Day 10
Number of participants with adverse events
Safety and tolerability will be assessed by monitoring the incidence, type, and severity of adverse events occurring from the first dose of study medication through Day 10 and up to hospital discharge. Adverse events will be recorded and classified according to clinical severity (mild, moderate, severe) and relationship to the investigational product (unrelated, possibly related, probably related). Serious adverse events will be defined according to standard regulatory criteria, including events resulting in death, life-threatening conditions, prolonged hospitalization, significant disability, or other medically important events. Results will be reported as the total number of adverse events.
Time frame: From date of first dose until the date of hospital discharge; assesed up to 52 weeks