Effect of early dexamethasone on major complications and all-cause mortality in severe burns (DEXA-BURN): A multicenter, randomized, placebo-controlled, double-blind trial

Effect of early dexamethasone on major complications and all-cause mortality in severe burns (DEXA-BURN): A multicenter, randomized, placebo-controlled, double-blind trial | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Effect of early dexamethasone on major complications and all-cause mortality in severe burns (DEXA-BURN): A multicenter, randomized, placebo-controlled, double-blind trial Alexandre Bourdiol, Nicolas Bruder, François Dépret, Delphine Flattres, and 14 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7759180/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 4 You are reading this latest preprint version Abstract Background Severe burns lead to intense and prolonged systemic inflammation and high rates of organ failure and major complications such as acute respiratory distress syndrome (ARDS), acute kidney injury (AKI) and mortality. Although corticosteroids have shown benefits in various critical care settings, no adequately powered randomized controlled trial has yet evaluated their effect in burn patients. Objectives The DEXA-BURN trial aims to assess whether early administration of dexamethasone reduces the incidence of major complications (moderate-to-severe ARDS or stage 2-3 AKI) and all-cause mortality in adults with severe burns. Methods DEXA-BURN is a multicenter, randomized, placebo-controlled, double-blind trial conducted in 10 French intensive care units. Adult patients with ≥20% total body surface area (TBSA) burns, admitted within 24 hours of injury and requiring mechanical ventilation, will be randomized (1:1) to receive either dexamethasone (0.2 mg/kg/day IV for 5 days) or placebo. The hierarchical primary endpoint includes: (1) major complications within 28 days (moderate to severe ARDS or AKI stage 2–3); and, if positive, (2) all-cause mortality at Day 90. Secondary endpoints include nosocomial infections, ventilator-free days, ICU/hospital stay, CRP trajectory, and steroid-related adverse events. A total of 478 patients will be enrolled. Analyses will follow the ITT and mITT principle. Discussion This trial will provide for the first time high-quality evidence on the effectiveness and safety of corticosteroid therapy in the acute management of severely burned patients. Findings may inform future guidelines and improve critical care practices for this understudied population with a high-risk of mortality. Trial registration: EudraCT: 2024-517708-12-00; ClinicalTrials.gov: NCT06968559 Figures Figure 1 Administrative information Note: the numbers in curly brackets in this protocol refer to SPIRIT checklist item numbers. The order of the items has been modified to group similar items (see http://www.equator-network.org/reporting-guidelines/spirit-2013-statement-defining-standard-protocol-items-for-clinical-trials/). Title {1} Effect of early dexamethasone on major complications and all-cause mortality in severe burns (DEXA-BURN): A multicenter, randomized, placebo-controlled, double-blind trial Trial registration {2a and 2b}. EudraCT Number: 2024-517708-12-00 Sponsor Protocol Number: RC24_0442 ClinicalTrials.gov identifier : NCT06968559 Protocol version {3} Version:20250331 Date: 31 March 2025 Funding {4} Sponsored by Nantes University Hospital, Medical Affairs and Research Department, 5 allée de l'île Gloriette, 44093 Nantes Cedex 01, France. Funded by the French Ministry of Health – National - PHRC Grant Author details {5a} Dr. Bourdiol Alexandre, Principal Investigator, Nantes Université, CHU de Nantes, Service d’Anesthésie Réanimation Chirurgicale, INSERM CIC 0004 Immunologie et Infectiologie, Nantes France Pr Bruder Nicolas, Principal Investigator, Dept of Anesthesiology and Critical Care Medicine, La Conception Hospital, APHM, Marseille Pr Dépret François, Dept of Anesthesiology and Surgical Critical Care and Burn Unit, Saint-Louis Hospital, AP-HP, Paris, Université de Paris Flattres Delphine Chief Coordinating Research Assistant, Nantes Université, CHU de Nantes, Service d’Anesthésie Réanimation Chirurgicale, INSERM CIC 0004 Immunologie et Infectiologie, Nantes France Dr. Flet Laurent, Coordinating Pharmacist, Nantes Université, CHU de Nantes, Pharmacie Hospitalière de Nantes, Nantes France Fortin June, Project Manager, Direction de la Recherche et de l’Innovation, CHU de Nantes Dr. Gaufichon Anne-Emmanuelle, Dept of Anesthesiology and Critical Care Medicine, CHU de Bordeaux Dr Glavnik Boris, Dept of Anesthesiology and Critical Care Medicine, CHR Metz Pr. Jeanne Mathieu, M.D., Ph.D. ULR 7365 - GRITA - Groupe de Recherche sur les Formes Injectables et les Technologies Associees, Univ. Lille, Lille, France ; Anesthesiology and Critical Care Medicine, CHU Lille, Lille, France Jobert Alexandra, Pharmacovigilance expert, CHU de Nantes Pr. Jung Boris, Dept of Anesthesiology and Critical Care Medicine, CHU de Montpellier Pr. Lukaszewicz Anne-Claire, Dept of Anesthesiology and Critical Care Medicine, HCL, Lyon Mathelier Noëline, Coordinating Research Assistant, Nantes Université, CHU de Nantes, Service d’Anesthésie Réanimation Chirurgicale, INSERM CIC 0004 Immunologie et Infectiologie, Nantes France Péré Morgane, Methodologist, Direction de la Recherche, Plateforme de Méthodologie et de Biostatistiques, CHU de Nantes Dr. Pichon Xavier, Dept of Anesthesiology and Critical Care Medicine, CHU de Toulouse Dr. Ravaux Hugues, Dept of Anesthesiology and Critical Care Medicine, CHU de Tours Dr. Mahe Pierre-Joachim, Nantes Université, CHU de Nantes, Service d’Anesthésie Réanimation Chirurgicale, INSERM CIC 0004 Immunologie et Infectiologie, Nantes France Pr. Asehnoune Karim, Coordinating Investigator, Nantes Université, CHU de Nantes, Service d’Anesthésie Réanimation Chirurgicale, INSERM CIC 0004 Immunologie et Infectiologie, Nantes France Corresponding author {5a} Dr. Bourdiol Alexandre, Principal Investigator, Nantes Université, CHU de Nantes, Service d’Anesthésie Réanimation Chirurgicale, INSERM CIC 0004 Immunologie et Infectiologie, Nantes France [email protected] Name and contact information for the trial sponsor {5b} Sponsored by Nantes University Hospital, Medical Affairs and Research Department, 5 allée de l'île Gloriette, 44093 Nantes Cedex 01, France. Tel : + 33 (0)2 53 48 28 35 Role of sponsor {5c} The sponsor is responsible for the allocation of the funding, oversight, and organization of the study. It does not influence data interpretation or publication decisions. Funding comes exclusively from a grant from the French Ministry of Health Introduction Background and rationale {6a} Burn injuries are among the most devastating forms of trauma, associated with huge local and systemic inflammatory response as well as a high mortality rate. While this inflammation is a physiological phenomenon that favors the healing of tissues, the overproduction of inflammatory mediators in severe burn patients, well correlated to the total body surface area burned (1), leads to an exacerbated Systemic Inflammatory Response Syndrome (SIRS). In turn, SIRS contributes to an enhanced risk of sepsis, ARDS (2) and organ failures in general such as AKI, most of those occurring within the first week of admission (3). Despite improvements in clinical care in ICU, patients’ outcomes with severe burns remain poor. There is growing evidence from other areas of critical care medicine—such as septic shock (4), community-acquired pneumonia (CAP) (5), and ARDS (6) that low-to-moderate dose corticosteroid therapy improves clinical outcomes, including time to recovery and mortality. Moreover low-to-moderate dose corticosteroid therapy decreases severe complications such as AKIs or the need for mechanical ventilation in major surgery (7). Severe burn patients lie at the crossroads between critical care and major surgery, yet preliminary data are scarce in this population and result from two case control studies (8,9) and one small RCT (10) suggesting that corticosteroids may modulate the excessive inflammatory response and contribute to improved organ function. However, to date, robust prospective randomized studies are lacking in this population. The DEXA-BURN trial was designed to address this critical knowledge gap by assessing the effect of early dexamethasone administration on major complications and mortality in patients with severe burns. Objectives {7} · Primary : To evaluate whether early administration of dexamethasone reduces the incidence of major complications (ARDS, AKI) and all-cause mortality in adults with severe burns. · Secondary : To assess effects on nosocomial infections, ventilator-free days at Day 28, duration of mechanical ventilation, ICU and hospital length of stay, CRP trajectory, and tolerance of dexamethasone. Trial design {8} This is a multicenter, randomized, placebo-controlled, double-blind, parallel-group superiority trial conducted in French intensive care burn units. Patients will be randomized in a 1:1 ratio, stratified by presence of smoke inhalation and TBSA >30%. The intervention period is 5 days, and patients will be followed up until Day 90. Methods: Participants, interventions and outcomes Study setting {9} The study will be conducted in 10 specialized intensive care units in France. All centers have extensive experience in clinical trials and follow national and international standards for burn care. The list of study sites is available on Appendix 1. Eligibility criteria {10} Inclusion criteria: · Age ≥ 18 years · Severe burns ≥ 20% of total body surface area (TBSA) · Admission to a participating ICU within 48 hours of injury · Invasive mechanical ventilation · Obtained informed consent (next-of kin consent or emergency procedure) Exclusion criteria: · Known allergy or contraindication to corticosteroids · Immunosuppressive therapy or chronic corticosteroid use · Pregnancy or breastfeeding · Patient under legal protection · Moribund state or decision to withhold/withdraw life support Who will take informed consent? {26a} Due to the critical condition of eligible patients, written consent will be obtained from the patient’s legally authorized representative. If no representative is available, we will apply emergency procedure for deferred consent under French emergency inclusion regulations, with confirmation from representatives as soon as possible. The patient will be informed and his written consent will be obtained as soon as his state allows. Additional consent provisions for collection and use of participant data and biological specimens {26b} No additional biological sampling is planned beyond routine care. No samples will be stored or used for ancillary studies. Patient and public involvement The French Burn Survivors Association (Association des Brûlés de France) gave their agreement on the trial objectives and outcome relevance during the design phase of the trial. No direct involvement is planned during conduct or data analysis but patient representatives will be informed of the results. Interventions Explanation for choice of comparators {6b} A placebo-controlled design was selected to rigorously assess the efficacy of dexamethasone. The placebo consists of 0.9% NaCl and is identical in appearance and volume to the investigational product. Interventions {11a} Eligible patients will be randomized to receive either: · Dexamethasone group : 0.2 mg/kg (ideal body weight), once daily IV, for 5 consecutive days (maximum dose: 20 mg/day) · Placebo group : volume-matched 0.9% sodium chloride IV, once daily, for 5 consecutive days All other aspects of burn care (e.g., fluid resuscitation, antimicrobial therapy, wound care, respiratory support) will follow standard practices at each site, in accordance with national or international guidelines. Criteria for discontinuing or modifying allocated interventions {11b} Study treatment may be discontinued in the event of: · Life-threatening adverse reactions suspected to be linked to dexamethasone · Participant or legal representative withdrawal of consent · Medical decision to withdraw or withhold life support Strategies to improve adherence to interventions {11c} Administration of the study drug will be managed by ICU clinical staff and documented in the electronic case report form (eCRF). Hospital pharmacy at each site will supervise dose preparation and administration. Relevant concomitant care permitted or prohibited during the trial {11d} Systemic corticosteroids not specified in the protocol are prohibited during the first 5 days post-randomization, unless used as rescue therapy in critical situations. Other treatments are authorized in accordance with the rules for dexamethasone use. Provisions for post-trial care {30} Participants will receive standard care throughout and after the trial period. No additional post-trial care or compensation is planned. Outcomes {12} Primary outcomes: Hierarchical primary outcome including: 1. Incidence of major complications within 28 days, defined as: o Moderate-to-severe ARDS (Berlin definition) (11) o AKI KDIGO stages 2–3 (12) 2. All-cause mortality by Day 90 Secondary outcomes: · Incidence of nosocomial infections during ICU stay · Number of ventilator-free days at Day 28 · Duration of invasive mechanical ventilation · Length of ICU stay and total hospital stay · CRP levels on Days 1, 3, 5, and 7 · Incidence of hyperglycemia or other corticosteroid-related adverse effects Participant timeline {13} Schedule of enrolment, interventions, and assessments {13} See spirit figure below. Sample size {14} We assume that the primary endpoint (all-cause 90-day mortality and major complications defined as KDIGO stage ≥ 2 to 3 AKI and moderate-to-severe ARDS within 28 days after admission) will be 15 % less frequent in the intervention group. Based on previous works on the study population we were able to pinpoint a mortality incidence on day 90 of 13% (13), an incidence of KDIGO stage 2 to 3 AKI of 20% (3), an incidence of moderate to severe ARDS of 35% (2) and an incidence of 45% of patients with moderate-to-severe ARDS and/or KDIGO stage 2 to 3. To demonstrate a decrease of major complications and/or mortality of 15%, we thus hypothesize that 434 patients are needed to ensure a power of 90% with an alpha risk of 5% (215 per randomization arm). Assuming 10% non-analyzable patients (death, loss to follow-up or consent withdrawal), 478 patients are needed (239 per randomization arm). There will be no patient replacement. Recruitment {15} All consecutive patients meeting inclusion criteria can be included provided they meet the inclusion criteria and do not meet the exclusion criteria. 10 specialized French intensive burn units will participate in the study. Given the study recruitment period of 36 months, recruitment per center will be less than 1.5 patient/center/month. Most of these centers have recently collaborated to achieve effective recruitment in at least one large French interventional trial (NCT04292054). Moreover, the allowance for co-enrollment in our study may further enhance participant recruitment. Assignment of interventions: allocation Sequence generation {16a} Randomization will be performed centrally using a secure web-based system. The allocation sequence will be computer-generated using random permuted blocks of variable size and stratified by site, presence of smoke inhalation injury, and TBSA >30%. Concealment mechanism {16b} Allocation will be concealed using sequentially numbered containers prepared and labeled by the hospital pharmacy. The treatment assignment will remain blinded to the clinical staff, participants, or outcome assessors. Implementation {16c} After verifying eligibility criteria, investigators will log into the electronic randomization system to obtain treatment allocation. Hospital pharmacies will prepare the blinded study drug accordingly. Assignment of interventions: blinding Blinding {17a} The trial will be double-blinded. Participants, clinical staff, investigators, pharmacists, and statisticians will remain blinded to group assignment. Placebo and dexamethasone vials will be indistinguishable in appearance, labeling, and packaging. Procedure for unblinding if needed {17b} Dexamethasone is a commonly used drug and we do not anticipate there will be any need for unblinding, also because there is no antidote available. If toxicity is suspected, the attending physician should contact the coordinating centre, where the steering committee will assess and validate the need for unblinding In case of unblinding because of suspected toxicity, every drug from the same shipment will be destroyed. Data collection and management {19, 18a, 18b, 18c} Study data will be collected via a secure electronic Case Report Form (eCRF) designed for this trial. Data entry will be performed by trained research staff at each site. All protocol-required information must be recorded in the eCRF; source documents must be maintained at the site to support the data entered. Data will be anonymized using a unique participant identification number. The eCRF will include built-in edit checks and logic rules to enhance data quality. Data queries will be resolved in collaboration with the study monitor. Data will be hosted and managed by the Nantes University Hospital’s Clinical Research Unit in compliance with French data protection regulations and the General Data Protection Regulation (GDPR). A detailed data management plan (DMP) will be developed and approved prior to database lock. The DMP will describe data validation, audit trails, coding standards, and database security procedures. Only authorized personnel will have access to the full dataset before the study is completed. Statistical methods Statistical methods for primary and secondary outcomes {20a} All variables will be described globally and by treatment arm. The description will include the number and percentage of the modalities for the qualitative variables and the minimum, maximum, average, standard deviation, median, 1st and 3rd quartile for the quantitative variables. Analyses will be conducted, on data from the modified intention-to-treat (mITT) population. Primary outcome will also be analysed on the intention-to-treat (ITT) population as well as in the per-protocol (PP) population. The criteria for including patients in the mITT and in the PP populations, respectively, are as follows: ● Intention-to treat (ITT): All randomized patients ● Modified intention-to-treat (mITT) or Full Analyse Set (FAS): All randomized patients except patients who ● Would not have been eligible for randomization according to the major inclusion/non-inclusion criteria (administrative censoring as presence of a consent, minor patient) OR ● Would never had any of the interventions (dexamethasone or placebo) ● Per-protocol: All randomized patients except patients having one or more major protocol violations defined as: ● patients not included in the mITT population OR ● Patients who would not be eligible for randomization according to inclusion/non-inclusion criteria OR ● Patients who accidentally would have received the wrong intervention (Dexamethasone or placebo and vice versa) OR ● Would not have the first dose within 6 hours of randomization OR ● Would not have the 5 consecutive doses between Day1 and Day 5 OR ● Patients who would have received out-of-protocol corticosteroids OR ● primary endpoint not met All statistical analyses will take into account stratified randomization. Primary outcome Co-primary hierarchical endpoints: · The composite primary endpoint includes two components tested hierarchically: 1. Major complications within 28 days, defined as moderate to severe ARDS (Berlin definition (11)) or AKI stage 2–3 (KDIGO criteria (12)) 2. All-cause mortality at Day 90 First, we will test the superiority of dexamethasone on composite criterion of major complications within 28 days after randomisation (binary qualitative variable: presence or absence of major complications) with the use of mixed effects logistic regression adjusted on stratification factors (smoke inhalation injury and TBSA > 30%) as fixed effects and on center as random effect. Second, if the superiority criterion is met, the superiority of dexamethasone on all-cause mortality at day 90 will be tested. If the superiority composite criterion of major complications on day 28 is not demonstrated, all-cause mortality on day 90 will be considered as an exploratory secondary outcome. All-cause mortality at day 90 will be analysed with frailty survival models adjusted on stratification factors (smoke inhalation injury and TBSA > 30%) as fixed effects and on center as random effect. Time to death is defined from randomisation date to time of death. If no event, a censor will be applied at the last news date or at day 90. A group-dependent Kaplan Meier curve will also be performed. Secondary outcomes Subgroup analyses of the primary endpoint will be performed according to each of the stratification factors (smoke inhalation injury and TBSA > 30%). Categorical data (e.g., proportion of patients who experience adverse events as pneumonia, infection, KDIGO stages 2 and 3 AKI, RRT, hyperglycemia...) will be analyzed with mixed effects logistic regression adjusted for stratification factors as fixed effects and center as random effect. Longitudinal continuous data will be analyzed with linear mixed models with random effects models adjusted for stratification factors as fixed effects and center to take into account the repeated measurements within patients. Assumptions of normality and homoscedasticity associated with these models will be evaluated. Mortality, ICU LOS and Hospital LOS (censored at 90 days) will be analysed with frailty survival model adjusted for stratification factors as fixed effects and center as random effect. Antibiotic-free days and invasive ventilator-free days will be analyzed using competitive risks models to take into account the informative censoring and the competing risk due to death, adjusted for stratification factors. The cumulative incidence functions of each competing event (death/extubation or death/discontinuation of antibiotic therapy) will be estimated as well as the area under curve between the two treatment arms to obtain the difference in Restricted Mean Survival Times (mean survival time of all subjects in the study population followed up to a given time) as well as its 95% confidence interval for inference. Interim analyses {21b} No interim analysis is planned and no formal criteria will be set for stopping the study. Nevertheless, for safety reasons, a safety analysis will be planned with the Data and Safety Monitoring Board (at 200 patients included). Recommendations for pausing or stopping the study will be made by the DSMB in case of SAEs or SUSAEs. The steering committee will be responsible to continue, hold or stop the study based on the DSMB recommendations. Methods for additional analysis (e.g. subgroup analysis) {20b} Estimands strategies will be considered for the two primary outcomes. 1) Major complications within 28 days Population: Randomized adult severe burn patients admitted to an intensive burn unit and presenting with a burn ≥ 20% of TBSA Variable s : major complications defined as moderate to severe ARDS (using Berlin definition criteria) within 28 days or AKI KDIGO 2 to 3 within 28 days Study intervention: dexamethasone plus standard of care (SOC) versus placebo plus SOC Population-level summary : difference in the percentages of major complications within 28 days between the two study groups, with IC95%. Intercurrent events (IE) and their corresponding strategies: Intercurrent Events before D28 Strategy for Addressing Intercurrent Events · ICU discharge Treatment Policy strategy: The observed value is used regardless of whether the intercurrent event occurs. · Death Composite strategy: Patients are considered as major complication – treatment failure · Missing data - Study data are not available for the evaluation of complications - Administrative censuring (such as consent withdrawal or lost to follow-up) Treatment Policy strategy: Data will be censured at the date of last evaluation. Missing primary criterion will be analyzed by multiple imputation or worst clinical scenario (treatment success in arm 2 and treatment failure in arm 1) as a sensitivity analysis. · Study treatment dropouts - No allocated treatment administration - Delay for the first administration not respected (> 6 hours from randomization) - Administration of allocated treatment stopped for toxicity adverse events Treatment Policy strategy: The observed value is used regardless of whether the intercurrent event occurs. · Concomitant or additional treatments - Any steroids administration as rescue therapy before day 28 - Unauthorized treatments (cf. 3.4.2) Treatment Policy strategy: The observed value is used regardless of whether the intercurrent event occurs. And Hypothetical strategy: All data collected after administration of additional treatment will be erased and imputed as worst clinical scenario (treatment success in arm 2 and treatment failure in arm 1) as sensitivity analyses. 2) All-cause mortality at D90 Population: Randomized adult severe burn patients admitted to an intensive burn unit and presenting with a burn ≥ 20% of TBSA Variable : all-cause mortality on Day 90 Study intervention: dexamethasone plus standard of care (SOC) versus placebo plus SOC Population-level summary : Hazard ratio of all-cause mortality at D90 Intercurrent events (IE) and their corresponding strategies: Intercurrent Events Strategy for Addressing Intercurrent Events · Missing data - Administrative censure (such as consent withdrawal or lost-to-follow-up) Treatment Policy strategy: Data will be censored at the date of last news. · Study treatment dropouts - No allocated treatment administration - Delay of the first administration not respected (> 6 hours from randomization) - Administration of allocated treatment stopped for toxicity adverse events - Dexamethasone or any steroid administration as rescue therapy. - Medical decision of care withdrawal before day 28 Treatment Policy strategy: Mortality will be used regardless of whether or not the intercurrent event occurs. Hypothetical strategy: All data collected after administration of additional treatment will be erased and imputed under the hypothetical strategy where no patient had had a study treatment dropout. Methods in analysis to handle protocol non-adherence and any statistical methods to handle missing data {20c} There should not be missing data for the primary outcome measure and the missing data rate should be low for the other outcomes as well. Missing data will be described by treatment arms. According to the presence of missing data on the primary outcome, sensitivity analyses will be performed (see 20b) using multiple imputation methods as well as worst case scenario (missing data considered as the most unfavourable case) and maximum bias scenario (missing data considered as the most favourable or unfavourable case in the placebo and experimental arms respectively). Plans to give access to the full protocol, participant level-data and statistical code {31c} Full protocol will be available through publication and appears on clinicaltrials.gov (NCT06968559). The results of this trial will be submitted for publication in a peer-reviewed medical journal, regardless of the direction or magnitude of the findings. Trials results will also be communicated through scientific conferences and reported on clinical trial registries. The datasets generated and/or analyzed during the current study will not be publicly available at the time of publication of this protocol because recruitment and follow-up are ongoing. After completion of the trial and publication of the primary results, anonymized individual participant data (IPD) underlying the published results, along with the statistical analysis code, will be available upon reasonable request to the corresponding author (subject to approval by the steering committee and in accordance with French and European data protection regulations, including GDPR). Access will be granted for academic research purposes only, following signature of a data-sharing agreement, and for a period of 5 years after publication of the main trial results. Oversight and monitoring Composition of the coordinating centre and trial steering committee {5d} The steering committee encompasses the coordinating centre team including the coordinating investigator, coordinating center principal investigator, coordinating pharmacist, methodologist, project manager and clinical research associates. They will coordinate efforts to ensure patient enrollment, issue queries to the other centers and assist in any way they can to ensure smooth proceedings and the safety of patients enrolled in the study. The steering committee will be responsible to continue, hold or stop the study based on the recommendations from the data monitoring committee. Only the steering committee may allow unblinding upon request from a treating physician or investigator. The steering committee will be consulted should a request for an ancillary or side study be made. Composition of the data and safety monitoring board, its role and reporting structure {21a} The DSMB is an advisory committee that advises the sponsor and steering committee on the safety of a clinical trial. Its members have expertise in clinical trials (pathology and methodology) and are not involved in the trial. They are appointed for the duration of the trial and commit themselves to their participation as well as to the respect of data confidentiality. The choice of the DSMB members is made in a collegial manner by the coordinator and the sponsor. The DSMB and can be called upon by the monitor if a Suspected Unexpected Serious Adverse Reaction (SUSAR) or a Serious Adverse Event (SAE) presents a particular difficulty in analysis or if a doubt about the benefit/risk balance arises during the trial. The DSMB is an independent group consisting of clinicians or experts that collectively has experience in the management of severe burn patients and/or use of dexamethasone, the use of CS in critical care medicine and specific expertise in the conduct, monitoring and analysis of randomized clinical trials. Adverse events reporting and harms {22} All adverse events (AEs) and SAEs occurring from the time of study drug administration until Day 28 will be recorded. Known adverse effects of corticosteroids, such as hyperglycemia, secondary infections, gastrointestinal bleeding, and neuromuscular complications will be particularly tracked. Monitoring {21a, 23} Monitoring will be conducted by the sponsor or its delegate in accordance with Good Clinical Practice (GCP) and regulatory requirements. A clinical research associate (CRA) will perform on-site visits and remote monitoring to verify: · Compliance with the protocol and regulatory requirements · Accuracy and completeness of the data recorded in the eCRF · Proper documentation of informed consent · Storage and accountability of study drugs Monitoring frequency and intensity will be described in a monitoring plan and adjusted based on site performance and risk assessment. All findings will be documented in monitoring reports. Independent audits may be conducted by the sponsor’s Quality Assurance Unit to assess protocol compliance, trial conduct, and data integrity. Results of audits will remain confidential but may be shared with regulatory authorities upon request. SAEs will be reported to the sponsor within 24 hours of awareness. Events will be assessed for severity, seriousness, and relationship to study treatment by the investigator. The sponsor will ensure timely notification to regulatory authorities and ethics committees, in compliance with applicable regulations. An independent Data Safety Monitoring Board (DSMB) will regularly review unblinded safety data (after 100 and 250 patients enrolled). The DSMB may recommend study continuation, modification, or early termination based on predefined stopping rules. Suspected unexpected serious adverse reactions (SUSARs) will be reported according to national pharmacovigilance laws and guidelines. A final safety report will be submitted at study completion. Plans for communication important protocol amendments to relevant parties (e.g. trial participants, ethical committees) {25} Any substantial modifications to the protocol will be submitted by the sponsor to the Agence Nationale de Sécurité du Médicament (ANSM, French National Agency for the Safety of Medicines and Health Products) and the relevant Personal Protection Committee for authorization or information, in accordance with applicable laws and implementing decrees. Once authorized, these amendments will be communicated to all relevant stakeholders, including investigators, clinical site staff, and trial participants (when possible). The protocol will be reissued as an updated, dated version, and patient information and consent forms will be revised and re-signed if necessary, prior to implementation of the changes. Dissemination plans {31a} The results of this trial will be submitted for publication in a peer-reviewed medical journal, regardless of the direction or magnitude of the findings. Authorship will follow ICMJE guidelines. Trial results will also be communicated through scientific conferences and reported on clinical trial registries. Complete data will be made available upon reasonable request. Ethics This study has been approved by the relevant Ethical Review Board for the European Medicines Agency (EMA) (Assessment part II) through the French National Agency for the Safety of Medicines and Health Products (ANSM). All participants or their legally authorized representatives will provide written informed consent as soon as possible, including in case of emergency procedures. The trial will be conducted in compliance with the Declaration of Helsinki, ICH-Good Clinical Practices (GCP) guidelines, and French regulations. Confidentiality of participant data will be strictly maintained. Access to personal data will be limited to authorized research personnel and monitors. Trial status Trial protocol current version is 20250331. It has been approved by the relevant Ethical Review Board by the EMA through the ANSM and funded through a PHRC grant by the French ministry of Health after being peer-reviewed by experts of the field. The trial will be conducted in compliance with the Declaration of Helsinki, ICH-GCP guidelines, and French regulations. The first inclusion could be made as early as October the 10th, 2025. Recruitment should be complete around October the 31 st 2028. Abbreviations AE Adverse Event AKI Acute Kidney Injury ANSM Agence Nationale de Sécurité du Médicament et des produits de santé AR Adverse Reaction ARDS Acute Respiratory Distress Syndrome CAP Community-acquired Pneumonia CNIL Commission Nationale de l’Informatique et des Libertés CRA Clinical Research Associate (monitor) CRF Case Report Form CRP C-Reactive Protein CS Corticosteroids DSMB Data and Safety Monitoring BOARD eCRF Electronic Case Report Form EMA European Medicines Agency ERB Ethical Review Board GCP Good Clinical Practice IBW Ideal Body Weight ICU Intensive Care Unit KDIGO Kidney Disease Improving Global Outcomes MA Marketing Authorisation SAE Serious Adverse Event SAR Serious Adverse Reaction SUSAR Suspected Unexpected Serious Adverse Reaction SIRS Systemic Inflammatory Response Syndrome SUSAR Suspected Unexpected Serious Adverse Reaction TBSA Total Burn Surface Area Declarations Author’s contributions {31b} PJM, AB and KA conceived the study. AB, KA and JF led the proposal through funding, protocol development and regulatory authorities. MP is the trial methodologist who led the design and statistical plan. KA, AB and MP drafted the manuscript. LF is the coordinating pharmacist led the pharmaceutical plan, including drug management and delivery to the centers. AEG, MJ, ACL, BG, BJ, FD, XP, HR, NB are principal investigators in each associate center and provided assistance in proofreading the trial protocol. DF and NM are CRA in the coordinating center and helped design the protocol, and proofread the trial protocol. AJ is our pharmacovigilance expert. Acknowledgments The authors wish to thank the CIC immuno-infectiology of Nantes teaching hospital for their contributions to the design and development of this study protocol. We acknowledge the support of the Department of Research and Innovation and Nantes Teaching Hospital. We are grateful to the French Ministry of Health for the exhaustive funding of this trial. We are also grateful to the members of the Steering Committee and Data Monitoring Board for their ongoing advice. Special thanks to every investigator, clinician and research assistant from our fellow intensive burn units for their valuable input and support during protocol development as well as their involvement in the proceedings of the trial. Funding {4} DEXA-BURN is funded through a PHRC grant by the French ministry of Health after being peer-reviewed by experts of the field. Availability of data and material {29} There are no contractual limitations on the availability of data after the study is completed to investigators. Complete data will be made available through reasonable request. Ethics approval and consent to participate {24} It has been approved by the relevant Personal Protection Committee and the French National Agency for the Safety of Medicines and Health Products (ANSM) through the European Medicines Agency (EMA) (2024-517708-12-00) and funded through a PHRC grant by the French ministry of Health after being peer-reviewed by experts of the field. The trial will be conducted in compliance with the Declaration of Helsinki, ICH-GCP guidelines, and French regulations Consent for publication {32} Consent forms and related patient information sheet are provided as appendixes. Competing interests {28} The authors declare no competing interests. References Bergquist M, Hästbacka J, Glaumann C, Freden F, Huss F, Lipcsey M. The time-course of the inflammatory response to major burn injury and its relation to organ failure and outcome. Burns J Int Soc Burn Inj. 2019 Mar;45(2):354–63. Cartotto R, Li Z, Hanna S, Spano S, Wood D, Chung K, et al. The Acute Respiratory Distress Syndrome (ARDS) in mechanically ventilated burn patients: An analysis of risk factors, clinical features, and outcomes using the Berlin ARDS definition. Burns J Int Soc Burn Inj. 2016 Nov;42(7):1423–32. Stoppe C, Hill A, Day AG, Kristof AS, Hundeshagen G, Kneser U, et al. The initial validation of a novel outcome measure in severe burns- the Persistent Organ Dysfunction +Death: Results from a multicenter evaluation. Burns. 2021 June 1;47(4):765–75. Annane D, Renault A, Brun-Buisson C, Megarbane B, Quenot JP, Siami S, et al. Hydrocortisone plus Fludrocortisone for Adults with Septic Shock. N Engl J Med. 2018 Mar 1;378(9):809–18. Dequin PF, Meziani F, Quenot JP, Kamel T, Ricard JD, Badie J, et al. Hydrocortisone in Severe Community-Acquired Pneumonia. N Engl J Med. 2023 May 25;388(21):1931–41. Villar J, Ferrando C, Martínez D, Ambrós A, Muñoz T, Soler JA, et al. Dexamethasone treatment for the acute respiratory distress syndrome: a multicentre, randomised controlled trial. Lancet Respir Med. 2020 Mar;8(3):267–76. Asehnoune K, Le Moal C, Lebuffe G, Le Penndu M, Josse NC, Boisson M, et al. Effect of dexamethasone on complications or all cause mortality after major non-cardiac surgery: multicentre, double blind, randomised controlled trial. BMJ. 2021 June 2;373:n1162. Fuchs PCh, Bozkurt A, Johnen D, Smeets R, Groger A, Pallua N. Beneficial effect of corticosteroids in catecholamine-dependent septic burn patients. Burns. 2007 May 1;33(3):306–11. de Leeuw K, Niemeijer AS, Eshuis J, Nieuwenhuis MK, Beerthuizen GIJM, Janssen WMT. Effect and mechanism of hydrocortisone on organ function in patients with severe burns. J Crit Care. 2016 Dec;36:200–6. Venet F, Plassais J, Textoris J, Cazalis MA, Pachot A, Bertin-Maghit M, et al. Low-dose hydrocortisone reduces norepinephrine duration in severe burn patients: a randomized clinical trial. Crit Care. 2015 Dec 1;19(1):21. ARDS Definition Task Force, Ranieri VM, Rubenfeld GD, Thompson BT, Ferguson ND, Caldwell E, et al. Acute respiratory distress syndrome: the Berlin Definition. JAMA. 2012 June 20;307(23):2526–33. Kellum JA, Lameire N. Diagnosis, evaluation, and management of acute kidney injury: a KDIGO summary (Part 1). Crit Care. 2013;17(1):204. Heyland DK, Wibbenmeyer L, Pollack JA, Friedman B, Turgeon AF, Eshraghi N, et al. A Randomized Trial of Enteral Glutamine for Treatment of Burn Injuries. N Engl J Med. 2022 Sept 15;387(11):1001–10. Supplementary Files Appendix.docx SPIRITChecklistDEXABURN.docx Cite Share Download PDF Status: Under Review Version 1 posted Reviewers agreed at journal 10 Dec, 2025 Reviewers invited by journal 10 Dec, 2025 Editor assigned by journal 19 Oct, 2025 First submitted to journal 17 Oct, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7759180","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":558457723,"identity":"ae24e178-c985-48df-bc3a-36e8bf3a0778","order_by":0,"name":"Alexandre 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Infusion must begin within 6 hours of randomization\u003c/p\u003e\n\u003cp\u003e\u003csup\u003e1\u003c/sup\u003e Patient informed consent will be recorded as soon as possible\u003c/p\u003e\n\u003cp\u003e\u003csup\u003e2 \u003c/sup\u003eRoutine clinical examination includes screening for ARDS and staging AKI\u003c/p\u003e\n\u003cp\u003e\u003csup\u003e3 \u003c/sup\u003eSOFA scores is collected only during ICU stay\u003c/p\u003e\n\u003cp\u003e\u003csup\u003e4\u003c/sup\u003e Routine laboratory tests are defined as follows: arterial blood gases, creatinine, urea, bilirubin, hemoglobin, white blood cells count and platelet count\u003c/p\u003e\n\u003cp\u003e\u003csup\u003e5\u003c/sup\u003e ICU outcomes refers to most clinical endpoints linked to the primary and secondary objectives including infections, ventilator-free days, antibiotic-free days, ICU length-of-stay, etc.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp; * D28 or ICU discharge, whichever comes first\u003c/p\u003e\n\u003cp\u003e** Day 90 : final visit, vital status and hospital LOS collected over the phone\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-7759180/v1/272bde7fb51e38ac127e3123.png"},{"id":98445700,"identity":"a03e4573-e585-492b-b347-b50f891b51ee","added_by":"auto","created_at":"2025-12-17 17:20:57","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1917899,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7759180/v1/fcdd0546-e3b7-4776-84ed-b76900cd5ebd.pdf"},{"id":98376977,"identity":"7a306171-5b41-4f94-acca-e8179b085861","added_by":"auto","created_at":"2025-12-17 07:09:22","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":200412,"visible":true,"origin":"","legend":"","description":"","filename":"Appendix.docx","url":"https://assets-eu.researchsquare.com/files/rs-7759180/v1/e5d720651c6d8b5f81b6c0f9.docx"},{"id":98377045,"identity":"71aa809b-0c11-4171-b5b4-f717941005c8","added_by":"auto","created_at":"2025-12-17 07:09:28","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":28852,"visible":true,"origin":"","legend":"","description":"","filename":"SPIRITChecklistDEXABURN.docx","url":"https://assets-eu.researchsquare.com/files/rs-7759180/v1/59e0956aa5dad2148158a51f.docx"}],"financialInterests":"","formattedTitle":"Effect of early dexamethasone on major complications and all-cause mortality in severe burns (DEXA-BURN): A multicenter, randomized, placebo-controlled, double-blind trial","fulltext":[{"header":"Administrative information","content":"\u003cp\u003eNote: the numbers in curly brackets in this protocol refer to SPIRIT checklist item numbers. The order of the items has been modified to group similar items (see http://www.equator-network.org/reporting-guidelines/spirit-2013-statement-defining-standard-protocol-items-for-clinical-trials/).\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"639\" class=\"fr-table-selection-hover\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 218px;\"\u003e\n \u003cp\u003eTitle {1}\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 421px;\"\u003e\n \u003cp\u003eEffect of early dexamethasone on major complications and all-cause mortality in severe burns (DEXA-BURN): A multicenter, randomized, placebo-controlled, double-blind trial\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 218px;\"\u003e\n \u003cp\u003eTrial registration {2a and 2b}.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 421px;\"\u003e\n \u003cp\u003eEudraCT Number:\u0026nbsp;2024-517708-12-00\u003c/p\u003e\n \u003cp\u003eSponsor Protocol Number: RC24_0442\u003c/p\u003e\n \u003cp\u003eClinicalTrials.gov identifier : NCT06968559\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 218px;\"\u003e\n \u003cp\u003eProtocol version {3}\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 421px;\"\u003e\n \u003cp\u003eVersion:20250331\u003cbr\u003e\u0026nbsp;Date: 31 March 2025\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 218px;\"\u003e\n \u003cp\u003eFunding {4}\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 421px;\"\u003e\n \u003cp\u003eSponsored by Nantes University Hospital, Medical Affairs and Research Department, 5 all\u0026eacute;e de l\u0026apos;\u0026icirc;le Gloriette, 44093 Nantes Cedex 01, France.\u003c/p\u003e\n \u003cp\u003eFunded by the French Ministry of Health \u0026ndash; National - PHRC Grant\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 218px;\"\u003e\n \u003cp\u003eAuthor details {5a}\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 421px;\"\u003e\n \u003cul type=\"disc\"\u003e\n \u003cli\u003eDr. Bourdiol Alexandre, Principal Investigator, Nantes Universit\u0026eacute;, CHU de Nantes, Service d\u0026rsquo;Anesth\u0026eacute;sie R\u0026eacute;animation Chirurgicale, INSERM CIC 0004 Immunologie et Infectiologie, Nantes France\u003c/li\u003e\n \u003cli\u003ePr Bruder Nicolas, Principal Investigator, Dept of Anesthesiology and Critical Care Medicine, La Conception Hospital, APHM, Marseille\u003c/li\u003e\n \u003cli\u003ePr D\u0026eacute;pret Fran\u0026ccedil;ois, Dept of Anesthesiology and Surgical Critical Care and Burn Unit, Saint-Louis Hospital, AP-HP, Paris, Universit\u0026eacute; de Paris\u003c/li\u003e\n \u003cli\u003eFlattres Delphine Chief Coordinating Research Assistant, Nantes Universit\u0026eacute;, CHU de Nantes, Service d\u0026rsquo;Anesth\u0026eacute;sie R\u0026eacute;animation Chirurgicale, INSERM CIC 0004 Immunologie et Infectiologie, Nantes France\u003c/li\u003e\n \u003cli\u003eDr. Flet Laurent, Coordinating Pharmacist, Nantes Universit\u0026eacute;, CHU de Nantes, Pharmacie Hospitali\u0026egrave;re de Nantes, Nantes France\u003c/li\u003e\n \u003cli\u003eFortin June, Project Manager, Direction de la Recherche et de l\u0026rsquo;Innovation, CHU de Nantes\u003c/li\u003e\n \u003cli\u003eDr. Gaufichon Anne-Emmanuelle, Dept of Anesthesiology and Critical Care Medicine, CHU de Bordeaux\u003c/li\u003e\n \u003cli\u003eDr Glavnik Boris, Dept of Anesthesiology and Critical Care Medicine, CHR Metz\u003c/li\u003e\n \u003cli\u003ePr. Jeanne Mathieu, M.D., Ph.D. ULR 7365 - GRITA - Groupe de Recherche sur les Formes Injectables et les Technologies Associees, Univ. Lille, Lille, France\u0026nbsp;; Anesthesiology and Critical Care Medicine, CHU Lille, Lille, France\u003c/li\u003e\n \u003cli\u003eJobert Alexandra, Pharmacovigilance expert, CHU de Nantes\u003c/li\u003e\n \u003cli\u003ePr. Jung Boris, Dept of Anesthesiology and Critical Care Medicine, CHU de Montpellier\u003c/li\u003e\n \u003cli\u003ePr. Lukaszewicz Anne-Claire, Dept of Anesthesiology and Critical Care Medicine, HCL, Lyon\u003c/li\u003e\n \u003cli\u003eMathelier No\u0026euml;line, Coordinating Research Assistant, Nantes Universit\u0026eacute;, CHU de Nantes, Service d\u0026rsquo;Anesth\u0026eacute;sie R\u0026eacute;animation Chirurgicale, INSERM CIC 0004 Immunologie et Infectiologie, Nantes France\u003c/li\u003e\n \u003cli\u003eP\u0026eacute;r\u0026eacute; Morgane, Methodologist, Direction de la Recherche, Plateforme de M\u0026eacute;thodologie et de Biostatistiques, CHU de Nantes\u003c/li\u003e\n \u003cli\u003eDr. Pichon Xavier, Dept of Anesthesiology and Critical Care Medicine, CHU de Toulouse\u003c/li\u003e\n \u003cli\u003eDr. Ravaux Hugues, Dept of Anesthesiology and Critical Care Medicine, CHU de Tours\u003c/li\u003e\n \u003cli\u003eDr. Mahe Pierre-Joachim, Nantes Universit\u0026eacute;, CHU de Nantes, Service d\u0026rsquo;Anesth\u0026eacute;sie R\u0026eacute;animation Chirurgicale, INSERM CIC 0004 Immunologie et Infectiologie, Nantes France\u003c/li\u003e\n \u003cli\u003ePr. Asehnoune Karim, Coordinating Investigator, Nantes Universit\u0026eacute;, CHU de Nantes, Service d\u0026rsquo;Anesth\u0026eacute;sie R\u0026eacute;animation Chirurgicale, INSERM CIC 0004 Immunologie et Infectiologie, Nantes France\u003c/li\u003e\n \u003c/ul\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 218px;\"\u003e\n \u003cp\u003eCorresponding author {5a}\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 421px;\"\u003e\n \u003cul type=\"disc\"\u003e\n \u003cli\u003eDr. Bourdiol Alexandre, Principal Investigator, Nantes Universit\u0026eacute;, CHU de Nantes, Service d\u0026rsquo;Anesth\u0026eacute;sie R\u0026eacute;animation Chirurgicale, INSERM CIC 0004 Immunologie et Infectiologie, Nantes France\u003c/li\u003e\n \u003cli\[email protected]\u003c/li\u003e\n \u003c/ul\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 218px;\"\u003e\n \u003cp\u003eName and contact information for the trial sponsor {5b}\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 421px;\"\u003e\n \u003cp\u003eSponsored by Nantes University Hospital, Medical Affairs and Research Department, 5 all\u0026eacute;e de l\u0026apos;\u0026icirc;le Gloriette, 44093 Nantes Cedex 01, France.\u003c/p\u003e\n \u003cp\u003eTel : + 33 (0)2 53 48 28 35\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 218px;\"\u003e\n \u003cp\u003eRole of sponsor {5c}\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 421px;\"\u003e\n \u003cp\u003eThe sponsor is responsible for the allocation of the funding, oversight, and organization of the study. It does not influence data interpretation or publication decisions.\u003c/p\u003e\n \u003cp\u003eFunding comes exclusively from a grant from the French Ministry of Health\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e"},{"header":"Introduction","content":"\u003cp\u003e\u003cstrong\u003eBackground and rationale {6a}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eBurn injuries are among the most devastating forms of trauma, associated with huge local and systemic inflammatory response as well as a high mortality rate. While this inflammation is a physiological phenomenon that favors the healing of tissues, the overproduction of inflammatory mediators in severe burn patients, well correlated to the total body surface area burned (1), leads to an exacerbated Systemic Inflammatory Response Syndrome (SIRS). In turn, SIRS contributes to an enhanced risk of sepsis, ARDS (2) and organ failures in general such as AKI, most of those occurring within the first week of admission (3). Despite improvements in clinical care in ICU, patients’ outcomes with severe burns remain poor. There is growing evidence from other areas of critical care medicine—such as septic shock (4), community-acquired pneumonia (CAP) (5), and ARDS (6) that low-to-moderate dose corticosteroid therapy improves clinical outcomes, including time to recovery and mortality. Moreover low-to-moderate dose corticosteroid therapy decreases severe complications such as AKIs or the need for mechanical ventilation in major surgery (7). Severe burn patients lie at the crossroads between critical care and major surgery, yet preliminary data are scarce in this population and result from two case control studies (8,9) and one small RCT (10) suggesting that corticosteroids may modulate the excessive inflammatory response and contribute to improved organ function. However, to date, robust prospective randomized studies are lacking in this population. The DEXA-BURN trial was designed to address this critical knowledge gap by assessing the effect of early dexamethasone administration on major complications and mortality in patients with severe burns.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eObjectives {7}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e· \u003cstrong\u003ePrimary\u003c/strong\u003e: To evaluate whether early administration of dexamethasone reduces the incidence of major complications (ARDS, AKI) and all-cause mortality in adults with severe burns.\u003c/p\u003e\n\u003cp\u003e· \u003cstrong\u003eSecondary\u003c/strong\u003e: To assess effects on nosocomial infections, ventilator-free days at Day 28, duration of mechanical ventilation, ICU and hospital length of stay, CRP trajectory, and tolerance of dexamethasone.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTrial design {8}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis is a multicenter, randomized, placebo-controlled, double-blind, parallel-group superiority trial conducted in French intensive care burn units. Patients will be randomized in a 1:1 ratio, stratified by presence of smoke inhalation and TBSA \u0026gt;30%. The intervention period is 5 days, and patients will be followed up until Day 90.\u003c/p\u003e"},{"header":"Methods: Participants, interventions and outcomes","content":"\u003cp\u003e\u003cstrong\u003eStudy setting {9}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study will be conducted in 10 specialized intensive care units in France. All centers have extensive experience in clinical trials and follow national and international standards for burn care. The list of study sites is available on Appendix 1.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEligibility criteria {10}\u003c/strong\u003e\u003cbr\u003e\u003cstrong\u003eInclusion criteria:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u0026middot; Age \u0026ge; 18 years\u003c/p\u003e\n\u003cp\u003e\u0026middot; Severe burns \u0026ge; 20% of total body surface area (TBSA)\u003c/p\u003e\n\u003cp\u003e\u0026middot; Admission to a participating ICU within 48 hours of injury\u003c/p\u003e\n\u003cp\u003e\u0026middot; Invasive mechanical ventilation\u003c/p\u003e\n\u003cp\u003e\u0026middot; Obtained informed consent (next-of kin consent or emergency procedure)\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eExclusion criteria:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u0026middot; Known allergy or contraindication to corticosteroids\u003c/p\u003e\n\u003cp\u003e\u0026middot; Immunosuppressive therapy or chronic corticosteroid use\u003c/p\u003e\n\u003cp\u003e\u0026middot; Pregnancy or breastfeeding\u003c/p\u003e\n\u003cp\u003e\u0026middot; Patient under legal protection\u003c/p\u003e\n\u003cp\u003e\u0026middot; Moribund state or decision to withhold/withdraw life support\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eWho will take informed consent? {26a}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDue to the critical condition of eligible patients, written consent will be obtained from the patient\u0026rsquo;s legally authorized representative. If no representative is available, we will apply emergency procedure for deferred consent under French emergency inclusion regulations, with confirmation from representatives as soon as possible. The patient will be informed and his written consent will be obtained as soon as his state allows.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAdditional consent provisions for collection and use of participant data and biological specimens {26b}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo additional biological sampling is planned beyond routine care. No samples will be stored or used for ancillary studies.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePatient and public involvement\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe French Burn Survivors Association (Association des Br\u0026ucirc;l\u0026eacute;s de France) gave their agreement on the trial objectives and outcome relevance during the design phase of the trial. No direct involvement is planned during conduct or data analysis but patient representatives will be informed of the results.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eInterventions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eExplanation for choice of comparators {6b}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA placebo-controlled design was selected to rigorously assess the efficacy of dexamethasone. The placebo consists of 0.9% NaCl and is identical in appearance and volume to the investigational product.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eInterventions {11a}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eEligible patients will be randomized to receive either:\u003c/p\u003e\n\u003cp\u003e\u0026middot; \u003cstrong\u003eDexamethasone group\u003c/strong\u003e: 0.2 mg/kg (ideal body weight), once daily IV, for 5 consecutive days (maximum dose: 20 mg/day)\u003c/p\u003e\n\u003cp\u003e\u0026middot; \u003cstrong\u003ePlacebo group\u003c/strong\u003e: volume-matched 0.9% sodium chloride IV, once daily, for 5 consecutive days\u003c/p\u003e\n\u003cp\u003eAll other aspects of burn care (e.g., fluid resuscitation, antimicrobial therapy, wound care, respiratory support) will follow standard practices at each site, in accordance with national or international guidelines.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCriteria for discontinuing or modifying allocated interventions {11b}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eStudy treatment may be discontinued in the event of:\u003c/p\u003e\n\u003cp\u003e\u0026middot; Life-threatening adverse reactions suspected to be linked to dexamethasone\u003c/p\u003e\n\u003cp\u003e\u0026middot; Participant or legal representative withdrawal of consent\u003c/p\u003e\n\u003cp\u003e\u0026middot; Medical decision to withdraw or withhold life support\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStrategies to improve adherence to interventions {11c}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAdministration of the study drug will be managed by ICU clinical staff and documented in the electronic case report form (eCRF). Hospital pharmacy at each site will supervise dose preparation and administration.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eRelevant concomitant care permitted or prohibited during the trial {11d}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSystemic corticosteroids not specified in the protocol are prohibited during the first 5 days post-randomization, unless used as rescue therapy in critical situations. Other treatments are authorized in accordance with the rules for dexamethasone use.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eProvisions for post-trial care {30}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eParticipants will receive standard care throughout and after the trial period. No additional post-trial care or compensation is planned.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eOutcomes {12}\u003c/strong\u003e\u003cbr\u003e\u003cstrong\u003ePrimary outcomes:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eHierarchical primary outcome including:\u003c/p\u003e\n\u003cp\u003e1.\u0026nbsp; \u0026nbsp;Incidence of major complications within 28 days, defined as:\u003c/p\u003e\n\u003cp\u003eo Moderate-to-severe ARDS (Berlin definition) (11)\u003c/p\u003e\n\u003cp\u003eo AKI KDIGO stages 2\u0026ndash;3 (12)\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e2.\u0026nbsp; \u0026nbsp;All-cause mortality by Day 90\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSecondary outcomes:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u0026middot; Incidence of nosocomial infections during ICU stay\u003c/p\u003e\n\u003cp\u003e\u0026middot; Number of ventilator-free days at Day 28\u003c/p\u003e\n\u003cp\u003e\u0026middot; Duration of invasive mechanical ventilation\u003c/p\u003e\n\u003cp\u003e\u0026middot; Length of ICU stay and total hospital stay\u003c/p\u003e\n\u003cp\u003e\u0026middot; CRP levels on Days 1, 3, 5, and 7\u003c/p\u003e\n\u003cp\u003e\u0026middot; Incidence of hyperglycemia or other corticosteroid-related adverse effects\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eParticipant timeline\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003e{13}\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSchedule of enrolment, interventions, and assessments {13}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSee spirit figure below.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSample size {14}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe assume that the primary endpoint (all-cause 90-day mortality and major complications defined as KDIGO stage\u0026nbsp;\u0026ge;\u0026nbsp;2 to 3 AKI and moderate-to-severe ARDS within 28 days after admission) will be 15 % less frequent in the intervention group. Based on previous works on the study population we were able to pinpoint a mortality incidence on day 90 of 13%\u0026nbsp;(13), an incidence of KDIGO stage 2 to 3 AKI of 20%\u0026nbsp;(3), an incidence of moderate to severe ARDS of 35%\u0026nbsp;(2)\u0026nbsp;and an incidence of 45% of patients with moderate-to-severe ARDS and/or KDIGO stage 2 to 3. To demonstrate a decrease of major complications and/or mortality of 15%, we thus hypothesize that 434 patients are needed to ensure a power of 90% with an alpha risk of 5% (215 per randomization arm). Assuming 10% non-analyzable patients (death, loss to follow-up or consent withdrawal), 478 patients are needed (239 per randomization arm).\u003c/p\u003e\n\u003cp\u003eThere will be no patient replacement.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eRecruitment\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003e{15}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll consecutive patients meeting inclusion criteria can be included provided they meet the inclusion criteria and do not meet the exclusion criteria. 10 specialized French intensive burn units will participate in the study. Given the study recruitment period of 36 months, recruitment per center will be less than 1.5 patient/center/month. Most of these centers have recently collaborated to achieve effective recruitment in at least one large French interventional trial (NCT04292054).\u0026nbsp;Moreover, the allowance for co-enrollment in our study may further enhance participant recruitment.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAssignment of interventions: allocation\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSequence generation {16a}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eRandomization will be performed centrally using a secure web-based system. The allocation sequence will be computer-generated using random permuted blocks of variable size and stratified by site, presence of smoke inhalation injury, and TBSA \u0026gt;30%.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConcealment mechanism {16b}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAllocation will be concealed using sequentially numbered containers prepared and labeled by the hospital pharmacy. The treatment assignment will remain blinded to the clinical staff, participants, or outcome assessors.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eImplementation {16c}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAfter verifying eligibility criteria, investigators will log into the electronic randomization system to obtain treatment allocation. Hospital pharmacies will prepare the blinded study drug accordingly.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAssignment of interventions: blinding\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eBlinding {17a}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003eThe trial will be double-blinded. Participants, clinical staff, investigators, pharmacists, and statisticians will remain blinded to group assignment. Placebo and dexamethasone vials will be indistinguishable in appearance, labeling, and packaging.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eProcedure for unblinding if needed {17b}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDexamethasone is a commonly used drug and we do not anticipate there will be any need for unblinding, also because there is no antidote available.\u0026nbsp;If toxicity is suspected, the attending physician should contact the coordinating centre, where the steering committee will assess and validate the need for unblinding\u003c/p\u003e\n\u003cp\u003eIn case of unblinding because of suspected toxicity, every drug from the same shipment will be destroyed.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData collection and management {19, 18a, 18b, 18c}\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eStudy data will be collected via a secure electronic Case Report Form (eCRF) designed for this trial. Data entry will be performed by trained research staff at each site. All protocol-required information must be recorded in the eCRF; source documents must be maintained at the site to support the data entered.\u003c/p\u003e\n\u003cp\u003eData will be anonymized using a unique participant identification number. The eCRF will include built-in edit checks and logic rules to enhance data quality. Data queries will be resolved in collaboration with the study monitor.\u003c/p\u003e\n\u003cp\u003eData will be hosted and managed by the Nantes University Hospital\u0026rsquo;s Clinical Research Unit in compliance with French data protection regulations and the General Data Protection Regulation (GDPR).\u003c/p\u003e\n\u003cp\u003eA detailed data management plan (DMP) will be developed and approved prior to database lock. The DMP will describe data validation, audit trails, coding standards, and database security procedures. Only authorized personnel will have access to the full dataset before the study is completed.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatistical methods\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatistical methods for primary and secondary outcomes {20a}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll variables will be described globally and by treatment arm. The description will include the number and percentage of the modalities for the qualitative variables and the minimum, maximum, average, standard deviation, median, 1st and 3rd quartile for the quantitative variables.\u003c/p\u003e\n\u003cp\u003eAnalyses will be conducted, on data from the modified intention-to-treat (mITT) population. Primary outcome will also be analysed on the intention-to-treat (ITT) population as well as in the per-protocol (PP) population. The criteria for including patients in the mITT and in the PP populations, respectively, are as follows:\u003c/p\u003e\n\u003cp\u003e● \u003cstrong\u003eIntention-to treat (ITT):\u003c/strong\u003e All randomized patients\u003c/p\u003e\n\u003cp\u003e● \u003cstrong\u003eModified intention-to-treat (mITT) or Full Analyse Set (FAS):\u0026nbsp;\u003c/strong\u003eAll randomized patients except patients who\u003c/p\u003e\n\u003cp\u003e● Would not have been eligible for randomization according to the major inclusion/non-inclusion criteria (administrative censoring as presence of a consent, minor patient)\u003c/p\u003e\n\u003cp\u003eOR\u003c/p\u003e\n\u003cp\u003e● Would never had any of the interventions (dexamethasone or placebo)\u003c/p\u003e\n\u003cp\u003e● \u003cstrong\u003ePer-protocol:\u003c/strong\u003e All randomized patients except patients having one or more major protocol violations defined as:\u003c/p\u003e\n\u003cp\u003e● patients not included in the mITT population\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eOR\u003c/p\u003e\n\u003cp\u003e●\u0026nbsp; \u0026nbsp;\u0026nbsp;Patients who would not be eligible for randomization according to inclusion/non-inclusion criteria\u003c/p\u003e\n\u003cp\u003eOR\u003c/p\u003e\n\u003cp\u003e● Patients who accidentally would have received the wrong intervention (Dexamethasone or placebo and vice versa)\u003c/p\u003e\n\u003cp\u003eOR\u003c/p\u003e\n\u003cp\u003e● Would not have the first dose within 6 hours of randomization\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eOR\u003c/p\u003e\n\u003cp\u003e● Would not have the 5 consecutive doses between Day1 and Day 5\u003c/p\u003e\n\u003cp\u003eOR\u003c/p\u003e\n\u003cp\u003e● Patients who would have received out-of-protocol corticosteroids\u003c/p\u003e\n\u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;OR\u003c/p\u003e\n\u003cp\u003e● primary endpoint not met\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAll statistical analyses will take into account stratified randomization.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePrimary outcome\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eCo-primary hierarchical endpoints:\u003c/p\u003e\n\u003cp\u003e\u0026middot; The composite primary endpoint includes two components tested hierarchically:\u003c/p\u003e\n\u003cp\u003e1.\u0026nbsp; \u0026nbsp;Major complications within 28 days, defined as moderate to severe ARDS (Berlin definition (11)) or AKI stage 2\u0026ndash;3 (KDIGO criteria (12))\u003c/p\u003e\n\u003cp\u003e2.\u0026nbsp; \u0026nbsp;All-cause mortality at Day 90\u003c/p\u003e\n\u003cp\u003eFirst, we will test the superiority of dexamethasone on composite criterion of major complications within 28 days after randomisation (binary qualitative variable: presence or absence of major complications) with the use of mixed effects logistic regression\u0026nbsp;adjusted on stratification factors (smoke inhalation injury and TBSA \u0026gt; 30%) as fixed effects and on center as random effect.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eSecond, if the superiority criterion is met, the superiority of dexamethasone on all-cause mortality at day 90 will be tested. If the superiority composite criterion of major complications on day 28 is not demonstrated, all-cause mortality on day 90 will be considered as an exploratory secondary outcome. All-cause mortality at day 90 will be analysed with frailty survival models adjusted on stratification factors (smoke inhalation injury and TBSA \u0026gt; 30%) as fixed effects and on center as random effect. Time to death is defined from randomisation date to time of death. If no event, a censor will be applied at the last news date or at day 90. A group-dependent Kaplan Meier curve will also be performed.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSecondary outcomes\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSubgroup analyses of the primary endpoint will be performed according to each of the stratification factors (smoke inhalation injury and TBSA \u0026gt; 30%).\u003c/p\u003e\n\u003cp\u003eCategorical data (e.g., proportion of patients who experience adverse events as pneumonia, infection, KDIGO stages 2 and 3 AKI, RRT, hyperglycemia...) will be analyzed with mixed effects logistic regression adjusted for stratification factors as fixed effects and center as random effect. Longitudinal continuous data will be analyzed with linear mixed models with random effects models adjusted for stratification factors as fixed effects and center to take into account the repeated measurements within patients. Assumptions of normality and homoscedasticity associated with these models will be evaluated.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eMortality, ICU LOS and Hospital LOS (censored at 90 days) will be analysed with frailty survival model adjusted for stratification factors as fixed effects and center as random effect.\u003c/p\u003e\n\u003cp\u003eAntibiotic-free days and invasive ventilator-free days will be analyzed using competitive risks models to take into account the informative censoring and the competing risk due to death, adjusted for stratification factors. The cumulative incidence functions of each competing event (death/extubation or death/discontinuation of antibiotic therapy) will be estimated as well as the area under curve between the two treatment arms to obtain the difference in Restricted Mean Survival Times (mean survival time of all subjects in the study population followed up to a given time) as well as its 95% confidence interval for inference.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eInterim analyses {21b}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo interim analysis is planned and no formal criteria will be set for stopping the study. Nevertheless, for safety reasons, a safety analysis will be planned with the Data and Safety Monitoring Board (at 200 patients included). Recommendations for pausing or stopping the study will be made by the DSMB in case of SAEs or SUSAEs. The steering committee will be responsible to continue, hold or stop the study based on the DSMB recommendations.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods for additional analysis (e.g. subgroup analysis)\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003e{20b}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eEstimands strategies will be considered for the two primary outcomes.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e1) \u0026nbsp;Major complications within 28 days\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePopulation:\u003c/strong\u003e Randomized adult severe burn patients admitted to an intensive burn unit and presenting with a burn \u0026ge; 20% of TBSA\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eVariable\u003c/strong\u003e\u003cstrong\u003es\u003c/strong\u003e\u003cstrong\u003e:\u0026nbsp;\u003c/strong\u003emajor complications defined as\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003emoderate to severe ARDS (using Berlin definition criteria) within 28 days or AKI KDIGO 2 to 3 within 28 days\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStudy intervention:\u0026nbsp;\u003c/strong\u003edexamethasone plus standard of care (SOC) versus placebo plus SOC\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePopulation-level summary\u003c/strong\u003e: difference in the percentages of major complications within 28 days between the two study groups, with IC95%.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eIntercurrent events (IE) and their corresponding strategies:\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 300px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eIntercurrent Events before D28\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 324px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eStrategy for Addressing Intercurrent Events\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 300px;\"\u003e\n \u003cp\u003e\u0026middot; \u003cstrong\u003eICU discharge\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 324px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTreatment Policy strategy:\u0026nbsp;\u003c/strong\u003eThe observed value is used regardless of whether the intercurrent event occurs.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 300px;\"\u003e\n \u003cp\u003e\u0026middot; \u003cstrong\u003eDeath\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 324px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eComposite strategy:\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003ePatients are considered as major complication \u0026ndash; \u003cem\u003etreatment failure\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 300px;\"\u003e\n \u003cp\u003e\u0026middot; \u003cstrong\u003eMissing data\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e- \u0026nbsp;Study data are not available for the evaluation of complications\u003c/p\u003e\n \u003cp\u003e- \u0026nbsp;Administrative censuring (such as consent withdrawal or lost to follow-up)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 324px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTreatment Policy strategy:\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003eData will be censured at the date of last evaluation. Missing primary criterion will be analyzed by multiple imputation or worst clinical scenario (treatment success in arm 2 and treatment failure in arm 1) as a sensitivity analysis.\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 300px;\"\u003e\n \u003cp\u003e\u0026middot; \u003cstrong\u003eStudy treatment dropouts\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e- No allocated treatment administration\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e- Delay for the first administration not respected (\u0026gt; 6 hours from randomization)\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e- Administration of allocated treatment stopped for toxicity adverse events\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 324px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTreatment Policy strategy:\u0026nbsp;\u003c/strong\u003eThe observed value is used regardless of whether the intercurrent event occurs.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 300px;\"\u003e\n \u003cp\u003e\u0026middot; \u003cstrong\u003eConcomitant or additional treatments\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e- \u0026nbsp;Any steroids administration as rescue therapy before day 28\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e- \u0026nbsp;Unauthorized treatments (cf. 3.4.2)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 324px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTreatment Policy strategy:\u0026nbsp;\u003c/strong\u003eThe observed value is used regardless of whether the intercurrent event occurs.\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eAnd\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eHypothetical strategy:\u003c/strong\u003e All data collected after administration of additional treatment will be erased and imputed as worst clinical scenario (treatment success in arm 2 and treatment failure in arm 1) as sensitivity analyses.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e2)\u0026nbsp;All-cause mortality at D90\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePopulation:\u003c/strong\u003e Randomized adult severe burn patients admitted to an intensive burn unit and presenting with a burn \u0026ge; 20% of TBSA\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eVariable\u003c/strong\u003e: all-cause mortality on Day 90\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStudy intervention:\u0026nbsp;\u003c/strong\u003edexamethasone plus standard of care (SOC) versus placebo plus SOC\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePopulation-level summary\u003c/strong\u003e: Hazard ratio of all-cause mortality at D90\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eIntercurrent events (IE)\u003c/strong\u003e and their corresponding strategies:\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 300px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eIntercurrent Events\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 324px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eStrategy for Addressing Intercurrent Events\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 300px;\"\u003e\n \u003cp\u003e\u0026middot; \u003cstrong\u003eMissing data\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e- \u0026nbsp;Administrative censure (such as consent withdrawal or lost-to-follow-up)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 324px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTreatment Policy strategy:\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003eData will be censored at the date of last news.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 300px;\"\u003e\n \u003cp\u003e\u0026middot; \u003cstrong\u003eStudy treatment dropouts\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e- No allocated treatment administration\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e- Delay of the first administration not respected (\u0026gt; 6 hours from randomization)\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e- Administration of allocated treatment stopped for toxicity adverse events\u003c/p\u003e\n \u003cp\u003e- Dexamethasone or any steroid administration as rescue therapy.\u003c/p\u003e\n \u003cp\u003e- Medical decision of care withdrawal before day 28\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 324px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTreatment Policy strategy:\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003eMortality will be used regardless of whether or not the intercurrent event occurs.\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eHypothetical strategy:\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003eAll data collected after administration of additional treatment will be erased and imputed under the hypothetical strategy where no patient had had a study treatment dropout.\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods in analysis to handle protocol non-adherence and any statistical methods to handle missing data\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003e{20c}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThere should not be missing data for the primary outcome measure and the missing data rate should be low for the other outcomes as well. Missing data will be described by treatment arms. According to the presence of missing data on the primary outcome, sensitivity analyses will be performed (see 20b) using multiple imputation methods as well as worst case scenario (missing data considered as the most unfavourable case) and maximum bias scenario (missing data considered as the most favourable or unfavourable case in the placebo and experimental arms respectively).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePlans to give access to the full protocol, participant level-data and statistical code {31c}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFull protocol will be available through publication and appears on clinicaltrials.gov (NCT06968559). The results of this trial will be submitted for publication in a peer-reviewed medical journal, regardless of the direction or magnitude of the findings. Trials results will also be communicated through scientific conferences and reported on clinical trial registries.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe datasets generated and/or analyzed during the current study will not be publicly available at the time of publication of this protocol because recruitment and follow-up are ongoing. After completion of the trial and publication of the primary results, anonymized individual participant data (IPD) underlying the published results, along with the statistical analysis code, will be available upon reasonable request to the corresponding author (subject to approval by the steering committee and in accordance with French and European data protection regulations, including GDPR). Access will be granted for academic research purposes only, following signature of a data-sharing agreement, and for a period of 5 years after publication of the main trial results.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eOversight and monitoring\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eComposition of the coordinating centre and trial steering committee {5d}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe steering committee encompasses the coordinating centre team including the coordinating investigator, coordinating center principal investigator, coordinating pharmacist, methodologist, project manager and clinical research associates. They will coordinate efforts to ensure patient enrollment, issue queries to the other centers and assist in any way they can to ensure smooth proceedings and the safety of patients enrolled in the study. The steering committee will be responsible to continue, hold or stop the study based on the recommendations from the data monitoring committee. Only the steering committee may allow unblinding upon request from a treating physician or investigator.\u003c/p\u003e\n\u003cp\u003eThe steering committee will be consulted should a request for an ancillary or side study be made.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eComposition of the data and safety monitoring board, its role and reporting structure {21a}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe DSMB is an advisory committee that advises the sponsor and steering committee on the safety of a clinical trial. Its members have expertise in clinical trials (pathology and methodology) and are not involved in the trial. They are appointed for the duration of the trial and commit themselves to their participation as well as to the respect of data confidentiality. The choice of the DSMB members is made in a collegial manner by the coordinator and the sponsor. The DSMB and can be called upon by the monitor if a Suspected Unexpected Serious Adverse Reaction (SUSAR) or a Serious Adverse Event (SAE) presents a particular difficulty in analysis or if a doubt about the benefit/risk balance arises during the trial.\u003c/p\u003e\n\u003cp\u003eThe DSMB is an independent group consisting of clinicians or experts that collectively has experience in the management of severe burn patients and/or use of dexamethasone, the use of CS in critical care medicine and specific expertise in the conduct, monitoring and analysis of randomized clinical trials.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAdverse events reporting and harms\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003e{22}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;All adverse events (AEs) and SAEs occurring from the time of study drug administration until Day 28 will be recorded. Known adverse effects of corticosteroids, such as hyperglycemia, secondary infections, gastrointestinal bleeding, and neuromuscular complications will be particularly tracked.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMonitoring {21a, 23}\u003c/strong\u003e Monitoring will be conducted by the sponsor or its delegate in accordance with Good Clinical Practice (GCP) and regulatory requirements. A clinical research associate (CRA) will perform on-site visits and remote monitoring to verify:\u003c/p\u003e\n\u003cp\u003e\u0026middot; Compliance with the protocol and regulatory requirements\u003c/p\u003e\n\u003cp\u003e\u0026middot; Accuracy and completeness of the data recorded in the eCRF\u003c/p\u003e\n\u003cp\u003e\u0026middot; Proper documentation of informed consent\u003c/p\u003e\n\u003cp\u003e\u0026middot; Storage and accountability of study drugs\u003c/p\u003e\n\u003cp\u003eMonitoring frequency and intensity will be described in a monitoring plan and adjusted based on site performance and risk assessment. All findings will be documented in monitoring reports.\u003c/p\u003e\n\u003cp\u003eIndependent audits may be conducted by the sponsor\u0026rsquo;s Quality Assurance Unit to assess protocol compliance, trial conduct, and data integrity. Results of audits will remain confidential but may be shared with regulatory authorities upon request.\u003c/p\u003e\n\u003cp\u003eSAEs will be reported to the sponsor within 24 hours of awareness. Events will be assessed for severity, seriousness, and relationship to study treatment by the investigator. The sponsor will ensure timely notification to regulatory authorities and ethics committees, in compliance with applicable regulations.\u003c/p\u003e\n\u003cp\u003eAn independent Data Safety Monitoring Board (DSMB) will regularly review unblinded safety data (after 100 and 250 patients enrolled). The DSMB may recommend study continuation, modification, or early termination based on predefined stopping rules.\u003c/p\u003e\n\u003cp\u003eSuspected unexpected serious adverse reactions (SUSARs) will be reported according to national pharmacovigilance laws and guidelines. A final safety report will be submitted at study completion.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePlans for communication important protocol amendments to relevant parties (e.g. trial participants, ethical committees) {25}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAny substantial modifications to the protocol will be submitted by the sponsor to the Agence Nationale de S\u0026eacute;curit\u0026eacute; du M\u0026eacute;dicament (ANSM, French National Agency for the Safety of Medicines and Health Products) and the relevant Personal Protection Committee for authorization or information, in accordance with applicable laws and implementing decrees.\u003cbr\u003e\u0026nbsp;Once authorized, these amendments will be communicated to all relevant stakeholders, including investigators, clinical site staff, and trial participants (when possible).\u003cbr\u003e\u0026nbsp;The protocol will be reissued as an updated, dated version, and patient information and consent forms will be revised and re-signed if necessary, prior to implementation of the changes.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDissemination plans\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003e{31a}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe results of this trial will be submitted for publication in a peer-reviewed medical journal, regardless of the direction or magnitude of the findings. Authorship will follow ICMJE guidelines. Trial results will also be communicated through scientific conferences and reported on clinical trial registries. Complete data will be made available upon reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study has been approved by the relevant Ethical Review Board for the European Medicines Agency (EMA) (Assessment part II) through the French National Agency for the Safety of Medicines and Health Products (ANSM). All participants or their legally authorized representatives will provide written informed consent as soon as possible, including in case of emergency procedures. The trial will be conducted in compliance with the Declaration of Helsinki, ICH-Good Clinical Practices (GCP) guidelines, and French regulations.\u003c/p\u003e\n\u003cp\u003eConfidentiality of participant data will be strictly maintained. Access to personal data will be limited to authorized research personnel and monitors.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTrial status\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTrial protocol current version is 20250331. It has been approved by the relevant Ethical Review Board by the EMA through the ANSM and funded through a PHRC grant by the French ministry of Health after being peer-reviewed by experts of the field. The trial will be conducted in compliance with the Declaration of Helsinki, ICH-GCP guidelines, and French regulations.\u003c/p\u003e\n\u003cp\u003eThe first inclusion could be made as early as October the 10th, 2025. Recruitment should be complete around October the 31\u003csup\u003est\u003c/sup\u003e 2028.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"601\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eAE\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eAdverse Event\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eAKI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eAcute Kidney Injury\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eANSM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eAgence Nationale de Sécurité du Médicament et des produits de santé\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eAR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eAdverse Reaction\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eARDS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eAcute Respiratory Distress Syndrome\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eCAP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eCommunity-acquired Pneumonia\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eCNIL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eCommission Nationale de l’Informatique et des Libertés\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eCRA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eClinical Research Associate (monitor)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eCRF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eCase Report Form\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eCRP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eC-Reactive Protein\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eCS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eCorticosteroids\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eDSMB\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eData and Safety Monitoring BOARD\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eeCRF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eElectronic Case Report Form\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eEMA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eEuropean Medicines Agency\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eERB\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eEthical Review Board\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eGCP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eGood Clinical Practice\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eIBW\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eIdeal Body Weight\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eICU\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eIntensive Care Unit\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eKDIGO\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eKidney Disease Improving Global Outcomes\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eMA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eMarketing Authorisation\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eSAE\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eSerious Adverse Event\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eSAR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eSerious Adverse Reaction\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eSUSAR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eSuspected Unexpected Serious Adverse Reaction\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eSIRS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eSystemic Inflammatory Response Syndrome\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eSUSAR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eSuspected Unexpected Serious Adverse Reaction\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eTBSA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eTotal Burn Surface Area\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAuthor’s contributions {31b}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePJM, AB and KA conceived the study. AB, KA and JF led the proposal through funding, protocol development and regulatory authorities. MP is the trial methodologist who led the design and statistical plan. KA, AB and MP drafted the manuscript. LF is the coordinating pharmacist led the pharmaceutical plan, including drug management and delivery to the centers. AEG, MJ, ACL, BG, BJ, FD, XP, HR, NB are principal investigators in each associate center and provided assistance in proofreading the trial protocol. DF and NM are CRA in the coordinating center and helped design the protocol, and proofread the trial protocol. AJ is our pharmacovigilance expert.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgments\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors wish to thank the CIC immuno-infectiology of Nantes teaching hospital for their contributions to the design and development of this study protocol.\u003cbr\u003e\u0026nbsp;We acknowledge the support of the Department of Research and Innovation and Nantes Teaching Hospital.\u003c/p\u003e\n\u003cp\u003eWe are grateful to the French Ministry of Health for the exhaustive funding of this trial.\u003cbr\u003e\u0026nbsp;We are also grateful to the members of the Steering Committee and Data Monitoring Board for their ongoing advice.\u003c/p\u003e\n\u003cp\u003eSpecial thanks to every investigator, clinician and research assistant from our fellow intensive burn units for their valuable input and support during protocol development as well as their involvement in the proceedings of the trial.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding {4}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDEXA-BURN is funded through a PHRC grant by the French ministry of Health after being peer-reviewed by experts of the field.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and material\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003e{29}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThere are no contractual limitations on the availability of data after the study is completed to investigators.\u0026nbsp;Complete data will be made available through reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003e{24}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIt has been approved by the relevant Personal Protection Committee and the French National Agency for the Safety of Medicines and Health Products (ANSM) through the European Medicines Agency (EMA) (2024-517708-12-00)\u0026nbsp;and funded through a PHRC grant by the French ministry of Health after being peer-reviewed by experts of the field. The trial will be conducted in compliance with the Declaration of Helsinki, ICH-GCP guidelines, and French regulations\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003e{32}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eConsent forms and related patient information sheet are provided as appendixes.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests {28}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no competing interests.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eBergquist M, H\u0026auml;stbacka J, Glaumann C, Freden F, Huss F, Lipcsey M. The time-course of the inflammatory response to major burn injury and its relation to organ failure and outcome. Burns J Int Soc Burn Inj. 2019 Mar;45(2):354\u0026ndash;63. \u003c/li\u003e\n\u003cli\u003eCartotto R, Li Z, Hanna S, Spano S, Wood D, Chung K, et al. The Acute Respiratory Distress Syndrome (ARDS) in mechanically ventilated burn patients: An analysis of risk factors, clinical features, and outcomes using the Berlin ARDS definition. Burns J Int Soc Burn Inj. 2016 Nov;42(7):1423\u0026ndash;32. \u003c/li\u003e\n\u003cli\u003eStoppe C, Hill A, Day AG, Kristof AS, Hundeshagen G, Kneser U, et al. The initial validation of a novel outcome measure in severe burns- the Persistent Organ Dysfunction +Death: Results from a multicenter evaluation. Burns. 2021 June 1;47(4):765\u0026ndash;75. \u003c/li\u003e\n\u003cli\u003eAnnane D, Renault A, Brun-Buisson C, Megarbane B, Quenot JP, Siami S, et al. Hydrocortisone plus Fludrocortisone for Adults with Septic Shock. N Engl J Med. 2018 Mar 1;378(9):809\u0026ndash;18. \u003c/li\u003e\n\u003cli\u003eDequin PF, Meziani F, Quenot JP, Kamel T, Ricard JD, Badie J, et al. Hydrocortisone in Severe Community-Acquired Pneumonia. N Engl J Med. 2023 May 25;388(21):1931\u0026ndash;41. \u003c/li\u003e\n\u003cli\u003eVillar J, Ferrando C, Mart\u0026iacute;nez D, Ambr\u0026oacute;s A, Mu\u0026ntilde;oz T, Soler JA, et al. Dexamethasone treatment for the acute respiratory distress syndrome: a multicentre, randomised controlled trial. Lancet Respir Med. 2020 Mar;8(3):267\u0026ndash;76. \u003c/li\u003e\n\u003cli\u003eAsehnoune K, Le Moal C, Lebuffe G, Le Penndu M, Josse NC, Boisson M, et al. Effect of dexamethasone on complications or all cause mortality after major non-cardiac surgery: multicentre, double blind, randomised controlled trial. BMJ. 2021 June 2;373:n1162. \u003c/li\u003e\n\u003cli\u003eFuchs PCh, Bozkurt A, Johnen D, Smeets R, Groger A, Pallua N. Beneficial effect of corticosteroids in catecholamine-dependent septic burn patients. Burns. 2007 May 1;33(3):306\u0026ndash;11. \u003c/li\u003e\n\u003cli\u003ede Leeuw K, Niemeijer AS, Eshuis J, Nieuwenhuis MK, Beerthuizen GIJM, Janssen WMT. Effect and mechanism of hydrocortisone on organ function in patients with severe burns. J Crit Care. 2016 Dec;36:200\u0026ndash;6. \u003c/li\u003e\n\u003cli\u003eVenet F, Plassais J, Textoris J, Cazalis MA, Pachot A, Bertin-Maghit M, et al. Low-dose hydrocortisone reduces norepinephrine duration in severe burn patients: a randomized clinical trial. Crit Care. 2015 Dec 1;19(1):21. \u003c/li\u003e\n\u003cli\u003eARDS Definition Task Force, Ranieri VM, Rubenfeld GD, Thompson BT, Ferguson ND, Caldwell E, et al. Acute respiratory distress syndrome: the Berlin Definition. JAMA. 2012 June 20;307(23):2526\u0026ndash;33. \u003c/li\u003e\n\u003cli\u003eKellum JA, Lameire N. Diagnosis, evaluation, and management of acute kidney injury: a KDIGO summary (Part 1). Crit Care. 2013;17(1):204. \u003c/li\u003e\n\u003cli\u003eHeyland DK, Wibbenmeyer L, Pollack JA, Friedman B, Turgeon AF, Eshraghi N, et al. A Randomized Trial of Enteral Glutamine for Treatment of Burn Injuries. N Engl J Med. 2022 Sept 15;387(11):1001\u0026ndash;10. \u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":true,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"trials","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"trls","sideBox":"Learn more about [Trials](http://trialsjournal.biomedcentral.com/)","snPcode":"13063","submissionUrl":"https://www.editorialmanager.com/trls","title":"Trials","twitterHandle":"MedicalEvidence","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-7759180/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7759180/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground \u003c/strong\u003eSevere burns lead to intense and prolonged systemic inflammation and high rates of organ failure and major complications such as acute respiratory distress syndrome (ARDS), acute kidney injury (AKI) and mortality. Although corticosteroids have shown benefits in various critical care settings, no adequately powered randomized controlled trial has yet evaluated their effect in burn patients.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eObjectives \u003c/strong\u003eThe DEXA-BURN trial aims to assess whether early administration of dexamethasone reduces the incidence of major complications (moderate-to-severe ARDS or stage 2-3 AKI) and all-cause mortality in adults with severe burns.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods \u003c/strong\u003eDEXA-BURN is a multicenter, randomized, placebo-controlled, double-blind trial conducted in 10 French intensive care units. Adult patients with ≥20% total body surface area (TBSA) burns, admitted within 24 hours of injury and requiring mechanical ventilation, will be randomized (1:1) to receive either dexamethasone (0.2 mg/kg/day IV for 5 days) or placebo. The hierarchical primary endpoint includes: (1) major complications within 28 days (moderate to severe ARDS or AKI stage 2–3); and, if positive, (2) all-cause mortality at Day 90. Secondary endpoints include nosocomial infections, ventilator-free days, ICU/hospital stay, CRP trajectory, and steroid-related adverse events. A total of 478 patients will be enrolled. Analyses will follow the ITT and mITT principle.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDiscussion \u003c/strong\u003eThis trial will provide for the first time high-quality evidence on the effectiveness and safety of corticosteroid therapy in the acute management of severely burned patients. Findings may inform future guidelines and improve critical care practices for this understudied population with a high-risk of mortality.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTrial registration: \u003c/strong\u003eEudraCT: 2024-517708-12-00; ClinicalTrials.gov: NCT06968559\u003c/p\u003e","manuscriptTitle":"Effect of early dexamethasone on major complications and all-cause mortality in severe burns (DEXA-BURN): A multicenter, randomized, placebo-controlled, double-blind trial","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-12-17 07:08:29","doi":"10.21203/rs.3.rs-7759180/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"reviewerAgreed","content":"","date":"2025-12-10T21:41:05+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-12-10T21:33:43+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-10-19T09:19:56+00:00","index":"","fulltext":""},{"type":"submitted","content":"Trials","date":"2025-10-17T10:11:42+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"trials","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"trls","sideBox":"Learn more about [Trials](http://trialsjournal.biomedcentral.com/)","snPcode":"13063","submissionUrl":"https://www.editorialmanager.com/trls","title":"Trials","twitterHandle":"MedicalEvidence","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"86dc06f7-82f3-4f0b-8000-96b610ec2cd9","owner":[],"postedDate":"December 17th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-01-31T10:17:54+00:00","versionOfRecord":[],"versionCreatedAt":"2025-12-17 07:08:29","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7759180","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7759180","identity":"rs-7759180","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}