This study was approved by the Vice-Chancellor in Research Affairs -Medical University of Isfahan (Biomedical Research Ethics Committee) (approval code: IR.MUI.RESEARCH.REC.1400.037, March 2021). The Ethics Committee was responsible for monitoring the trial. Audits on accuracy were carried out twice during the trial.

Patients gave written informed consent and this trial was conducted by the Declaration of Helsinki principles [16]. This trial was also registered in the Iranian Registry of Clinical Trials (ID: IRCT20201129049534N1, May 2021, https://fa.irct.ir/trial/55874).

The full study protocol was previously published [17]. In summary, it was a parallel randomized, double-blinded, and clinical controlled trial and was conducted et al.-Zahra Hospital, Isfahan, Iran. Recruitment of participants was carried out between September 2021 and February 2023 in the general ICU.

Eligibility criteria for participating in the study were: Septic ICU resident patients (diagnosed by sepsis-3 criteria), older than 18 years, having provided written informed consent, and being nourished enterally. Pregnant women, extremely low-weight persons (body mass index (BMI) < 18.5 kg/m2), patients who required frequent blood transfusions, septic shock patients, and those patients having any unwanted side effects after taking a supplement or placebo were excluded.

This trial was conducted et al.-Zahra Hospital, Isfahan, Iran.

For included participants, after hemodynamic resuscitation and stabilization, nutritional support with enteral tube feeding (25 kcal/kg of energy) was begun. Nutritional feeding was administered via bolus method (7 times in 24 h).

At first, the principal investigator (MK) explained the potential benefits of the current trial and obtained informed consent from their patients or their legal representatives. Then, they were randomized to receive a high dosage of LC (3 g/day, 1 gr t.i.d, in capsule form) or placebo which contained maltodextrin (3 g/day, 1 gr t.i.d, in capsule form) for 7 days.

Sealed and opaque envelopes were provided by the supplement manufacturer which determined A or B box content (LC or placebo).

Standard protocol treatment was implemented for all patients, our intervention added to those and did not need to alter the usual treatment strategy. Intervention and control capsules had similar shapes, sizes, colors, odors, and tastes. Capsules were packaged in pill boxes that were tagged A and B for blinding. Intervention and placebo capsules and blinded pillboxes were made by Karen Pharma and Food Supplement Company, Tehran, Iran.

At baseline, disease severity status was evaluated using acute physiology and chronic health evaluation II (APACHE II), SOFA, quick SOFA (qSOFA), and nutrition risk in the critically ill (NUTRIC) score. Variations in inflammatory mediators were monitored by serum CRP and erythrocyte sedimentation rate (ESR) as principal outcomes at baseline and 7th day. The 28-mortality rate, oxidative status including total antioxidant capacity (TAC), malondialdehyde (MDA), SOD, and usual monitoring variables in the ICU monitoring were also appraised at baseline and endpoint of the study as secondary outcomes.

About 10 ml volume of fasting blood sample was drained before and after the study and then centrifuged, with the serum separated from the sediment, and preserved at a temperature of -80 °C. Laboratory personnel were unaware of intervention allocation.

The ELISA assay method has been used for assessing CRP, ESR, TAC, SOD activity, and MDA. Complete blood count (CBC) diff, blood urea nitrogen (BUN), creatinine (Cr), albumin (Alb), total bilirubin (Bill-T), direct bilirubin (Bil-D), prothrombin time (PT), and partial prothrombin time (PTT), were measured at the Clinical Chemistry Laboratory in Al-Zahra Hospital, according to a standardized protocol. Anthropometric variables also were evaluated by MK using a tape meter. Because of the limitations in the ICU weight and height were calculated using the Chumlea I formula [18] and an equation by Tarnowski, et al. [19] respectively. The 28-day mortality rate was collected and calculated by follow-up of patients after intervention by telephone contacting their families.

The sample size was calculated according to the results of a previous study [20] using the following equation and data:

$$n=\frac_+_)}^}^}+\frac_^}$$

mean of group 1 = 47.01.

mean of group 2 = 78.43.

σ = 42.

α = 0.05.

β = 0.2

Z(1-α⁄2) = 1.96.

z(1-β) = 0.84.

power = 80%

Intervention allocation was done by using a random number list and eligible patients were randomly allocated to trial groups in a ratio of 1:1.

Sealed and opaque envelopes were provided by the supplement manufacturer which determined A or B box content (LC or placebo).

Intervention or control capsules were administered orally or with enteral nutrition (enteral tube feeding) three times a day at 9:00, 15:00, and 21:00.

The interventions were prescribed to participants using a double-blind method. It is noteworthy that patients or their legal guardians, all investigators, and data analysts were blinded.

All statistical analyses were performed based on the intention-to-treat (ITT) principle, in which missing values were imputed using multiple imputations. We used the expectation–maximization (EM) algorithm for missing data estimation. The data were entered into SPSS software version 21 and Stata software for analysis. The skewness test and Q–Q plots were applied to assess the normal distribution of variables. Quantitative and qualitative variables were reported as mean ± standard deviation (SD) and number (percentage), respectively. Baseline characteristics of the participants were compared between the groups, using the independent-sample t-test and Pearson’s chi-square test, where applicable. ANCOVA (Analysis of covariance) was used to detect any differences between the two groups at the end of the study and adjust for baseline values and the other confounders. The logarithmic transformation approach was applied to those variables with an abnormal distribution. For the 28-day mortality rate, we used a univariate and multivariable (adjusted for CRP and ESR values) logistic regression model. p-value < 0.05 was considered as significant.