Dexamethasone Treatment for Sepsis-associated Acute Respiratory Distress Syndrome: a Multicenter, Randomised, Double-blinded, Controlled Trial (DEFEND)

Acute respiratory distress syndrome (ARDS) is a major cause of acute hypoxemic respiratory failure in critically ill patients and is associated with substantial mortality. Current management is largely supportive, and no pharmacologic therapy has been shown consistently to reduce mortality in a broad population of patients with ARDS. Inflammation plays a central role in the pathogenesis of ARDS. Excessive inflammatory activation contributes to alveolar-capillary injury, impaired gas exchange, and progression of organ dysfunction. Glucocorticoids may mitigate these processes and have been associated in some studies with improved clinical outcomes, including shorter duration of mechanical ventilation. However, the effect of glucocorticoids on survival remains uncertain.

ARDS is a heterogeneous syndrome with diverse etiologies, and treatment response may vary according to the underlying cause. A post hoc analysis of the Dex-ARDS trial suggested that the treatment effect of glucocorticoids may be greater in ARDS caused by pneumonia or extrapulmonary sepsis. In a cross-sectional survey of 135 patients with ARDS from 20 ICUs in China, pneumonia- and extrapulmonary sepsis-associated ARDS accounted for 77.6% of cases, indicating that these are the predominant etiologic subtypes encountered in clinical practice in China. More importantly, compared with ARDS attributable to other causes, pneumonia- and extrapulmonary sepsis-associated ARDS has been associated with higher mortality, suggesting a greater disease burden, worse prognosis, and a more urgent need for improved treatment strategies. On this basis, the present trial will enroll patients with ARDS caused by sepsis, including pneumonia and extrapulmonary sepsis.

The primary hypothesis of this study is that, among patients with sepsis-associated ARDS, dexamethasone plus usual care, as compared with placebo plus usual care, will reduce 90-day all-cause mortality. We therefore designed a multicenter, randomized, double-blind, controlled trial to evaluate the clinical efficacy of dexamethasone in patients with sepsis-associated ARDS. The primary objective is to compare dexamethasone plus usual care with placebo plus usual care with respect to 90-day all-cause mortality.

Study Overview

• Status: Not yet recruiting
• Conditions: Acute Respiratory Distress Syndrome (ARDS)
• Intervention / Treatment: Drug: Dexamethasone; Drug: Placebo

• Study Type: Interventional
• Enrollment (Estimated): 1474
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Hui Chen, MD; Phone Number: +86-18006138640; Email: huichen.icu@gmail.com

Study Locations

• China
  • Jiangsu
    • Nanjing, Jiangsu, China, 210009
      • Zhongda Hospital, School of Medicine, Southeast University
      • Contact: Jianfeng Xie, MD; Phone Number: +86-13770332331; Email: xie820405@126.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Age 18 years or older
2. Suspected or confirmed infection
3. Intubated and mechanically ventilated
4. Acute-onset ARDS, defined as PaO2/FiO2 of 300 mm Hg or less within at least 6 hours after diagnosis of ARDS, with all of the following criteria met in the same 24-hour period:

(1) New or worsening respiratory symptoms or respiratory failure within 1 week (2) Pulmonary infiltrates (patchy opacities/consolidation) on chest imaging not fully explained by pleural effusion, lobar or lung collapse, or pulmonary nodules; unilateral infiltrates are eligible (3) Respiratory failure not fully explained by cardiac failure or fluid overload (4) Hypoxemia defined as PaO2/FiO2 of 300 mm Hg or less at PEEP of at least 5 cm H2O and FiO2 of at least 0.3; for altitude greater than 1000 m, the threshold will be adjusted as [300 * (barometric pressure/760)]

Exclusion Criteria:

1. Pregnancy
2. Planned withdrawal of life-sustaining treatment within the next 24 hours
3. Current hospitalization for more than 7 days before screening;
4. Clinical improvement within the 48 hours before randomization, based on the investigator's overall assessment
5. Highly suspected or confirmed COVID-19 infection
6. Severe chronic obstructive pulmonary disease, defined as a PaCO₂ ≥ 60 mmHg in a stable condition, or the need for long-term oxygen therapy, excluding CPAP/BiPAP prescribed exclusively for sleep-disordered breathing.
7. Congestive heart failure (NYHA III-IV)
8. ARDS diagnosed more than 72 hours before screening
9. A definite clinical indication for high-dose corticosteroids at screening, defined as a maximum daily dose exceeding hydrocortisone 200 mg or an equivalent glucocorticoid dose
10. Contraindications to short-term dexamethasone, including untreated systemic fungal infection, active tuberculosis, active viral hepatitis, or major upper gastrointestinal bleeding
11. Known hypersensitivity to dexamethasone
12. Participation in another interventional clinical trial within the previous 30 days

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Dexamethasone Group; Dexamethasone plus usual care	Drug: Dexamethasone; Participants assigned to dexamethasone will receive 20 mg intravenously as soon as possible after randomization. Beginning after 10:00 am on the next calendar day following randomization, dexamethasone 20 mg will be administered once daily through day 5. From day 6 through day 10, dexamethasone 10 mg will be administered once daily or until liberation from invasive mechanical ventilation, whichever occurs first.; Other Names: Dexamethasone sodium phosphate injection, 5 mg/1 mL
Placebo Comparator: Placebo Group; Placebo plus usual care	Drug: Placebo; Participants assigned to the placebo group will receive 0.9% sodium chloride injection as matching placebo, administered according to the same schedule as dexamethasone

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
90-day all-cause mortality	The proportion of participants who die from any cause between randomization (day 0) and day 90 (inclusive)	From randomization (day 0) to day 90 (inclusive)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Ventilator-free days through day 28	The number of days from randomization (day 0) to day 28 (inclusive) during which the patient is alive and successfully liberated from invasive mechanical ventilation	From randomization (day 0) to day 28 (inclusive)
Vasopressor-free days through day 28	The number of days from randomization (day 0) to day 28 (inclusive) during which the patient is alive and successfully discontinued from vasopressor therapy	From randomization (day 0) to day 28 (inclusive)
Renal replacement therapy-free days through day 28	The number of days from randomization (day 0) to day 28 (inclusive) during which the patient is alive and does not require renal replacement therapy	From randomization (day 0) to day 28 (inclusive)
28-day all-cause mortality	The proportion of participants who die from any cause between randomization (day 0) and day 28 (inclusive)	From randomization (day 0) to day 28 (inclusive)
ICU mortality	The proportion of participants who die from any cause between randomization (day 0) and ICU discharge (inclusive). If a patient remains in the ICU for more than 90 days, 90-day mortality will be used as ICU mortality	From randomization (day 0) up to ICU discharge, assessed up to 90 days
In-hospital mortality	The proportion of participants who die from any cause between randomization (day 0) and hospital discharge (inclusive). If a patient remains hospitalized for more than 90 days, 90-day mortality will be used as in-hospital mortality	Time Frame: From randomization (day 0) up to hospital discharge, assessed up to 90 days
6-month all-cause mortality	The proportion of participants who die from any cause between randomization (day 0) and 6 months (inclusive)	From randomization (day 0) to 6 months (inclusive)
12-month all-cause mortality	The proportion of participants who die from any cause between randomization (day 0) and 12 months	From randomization(day 0) to 12 months
ICU-free days through day 28	The number of days from randomization (day 0) to day 28 (inclusive) during which the patient is alive and does not require ICU stay	From randomization (day 0) to day 28 (inclusive)
Hospital-free days through day 28	The number of days from randomization (day 0) to day 28 (inclusive) during which the patient is alive and does not require hospitalization	From randomization (day 0) to day 28 (inclusive)
Decision to withhold or withdraw active treatment during hospitalization	The proportion of participants in whom active treatment is withheld or withdrawn between randomization (day 0) and hospital discharge (inclusive)	Time Frame: From randomization (day 0) up to hospital discharge, assessed up to 90 days
Telephone Interview for Cognitive Status-Modified (TICS-m)	Cognitive status was assessed using a Chinese modified version of the Telephone Interview for Cognitive Status-modified (TICS-m). Higher scores indicate better cognitive performance	90 days, 6 months and 12 months after randomization
Post-Traumatic Stress Disorder (PTSD)	Psychological outcomes will be assessed with the Post-traumatic Stress Disorder Checklist-Civilian Version (PCL-C, Chinese version). Respondents indicate how much they have been bothered by a symptom over the past month using a 5-point scale, with higher scores indicating more severe levels of PTSD.	90 days, 6 months and 12 months after randomization
Health-related quality of life (EQ-5D-5L)	Health-related quality of life assessed using the EuroQol 5-Dimension 5-Level (EQ-5D-5L) instrument at 90 days, 6months and 12 months after randomization. The EQ-5D-5L measures health across five dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression.	90 days, 6 months and 12 months after randomization
Functional Activities Questionnaire (FAQ)	Caregiver-reported outcome, higher scores indicating worse impairment.	90 days, 6 months, 12 months after randomization
Activities of daily living (ADL) score	Assessed using the Barthel Index, including feeding, bathing, grooming, dressing, bowel control, bladder control, toileting, chair/bed transfer, ambulation, and stair climbing, higher scores indicate greater independence.	90 days, 6 months, 12 months after randomization

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of weaning success through day 28	For intubated patients, successful weaning was defined as survival without reintubation within 7 days after extubation, or liberation from invasive mechanical ventilation with ICU discharge within 7 days. For tracheostomized patients, successful weaning was defined as spontaneous breathing via tracheostomy without mechanical ventilation for at least 7 consecutive days, or liberation from invasive mechanical ventilation with ICU discharge within 7 days. Reintubation for diagnostic purposes (e.g., bronchoscopy) or planned surgical procedures (e.g., wound debridement, abdominal lavage, internal fixation of fractures, tracheostomy) was not considered weaning failure.	From randomization (day 0) to day 28 (inclusive)
Incidence of gastrointestinal bleeding through day 28	The proportion of participants who developed acute gastrointestinal bleeding requiring transfusion of more than 1 unit of packed red blood cells within 24 hours	From randomization (day 0) to day 28 (inclusive)
Incidence of secondary bloodstream infection through day 28	The proportion of participants who developed secondary bloodstream infection through day 28	From randomization (day 0) to day 28 (inclusive)
Incidence of VAP through day 28	The proportion of participants who developed ventilator-associated pneumonia through day 28	From randomization (day 0) to day 28 (inclusive)
Incidence of hyperglycemia events through day 28	The proportion of participants who had hyperglycemia events (blood glucose level >180 mg/dl) through day 28	From randomization (day 0) to day 28 (inclusive)

Collaborators and Investigators

• Sponsor: Southeast University, China
• Investigators: Principal Investigator: Jianfeng Xie, MD, Southeast University, Zhongda Hospital

Publications and helpful links

General Publications

• [1] MATTHAY M A, ARABI Y, ARROLIGA A C, et al. A New Global Definition of Acute Respiratory Distress Syndrome[J]. American Journal of Respiratory and Critical Care Medicine, 2024, 209(1): 37-47. [2] BELLANI G, LAFFEY J G, PHAM T, et al. Epidemiology, Patterns of Care, and Mortality for Patients With Acute Respiratory Distress Syndrome in Intensive Care Units in 50 Countries[J]. JAMA, 2016, 315(8): 788. [3] LIU L, YANG Y, GAO Z, et al. Practice of diagnosis and management of acute respiratory distress syndrome in mainland China: a cross-sectional study[J]. Journal of Thoracic Disease, 2018, 10(9): 5394-5404. [4] MATTHAY M A, ZEMANS R L, ZIMMERMAN G A, et al. Acute respiratory distress syndrome[J]. Nature Reviews Disease Primers, 2019, 5(1): 18. [5] MEDURI G U, GOLDEN E, FREIRE A X, et al. Methylprednisolone infusion in early severe ARDS[J]. Chest, 2007, 131(4): 954-963. [6] ANNANE D, SÉBILLE V, BELLISSANT E. Effect of low doses of corticosteroids in septic shock patients with or without early acute respiratory distress syndrome*:[J]. Critical Care Medicine, 2006, 34(1): 22-30. [7] TONGYOO S, PERMPIKUL C, MONGKOLPUN W, et al. Hydrocortisone treatment in early sepsis-associated acute respiratory distress syndrome: Results of a randomized controlled trial[J]. Critical Care, 2016, 20(1): 329. [8] GRASSELLI G, CALFEE C S, CAMPOROTA L, et al. ESICM guidelines on acute respiratory distress syndrome: definition, phenotyping and respiratory support strategies[J]. Intensive Care Medicine, 2023, 49(7): 727-759. [9] VILLAR J, FERRANDO C, MARTÍNEZ D, et al. Dexamethasone treatment for the acute respiratory distress syndrome: A multicentre, randomised controlled trial[J]. The Lancet Respiratory Medicine, 2020, 8(3): 267-276. [10] CHRIGUER R S, ROSELINO A M, DE CASTRO M. Glucocorticoid sensitivity and proinflammatory cytokines pattern in pemphigus[J]. Journal of Clinical Immunology, 2012, 32(4): 786-793.

Study record dates

Study Major Dates

• Study Start (Estimated): July 1, 2026
• Primary Completion (Estimated): September 30, 2029
• Study Completion (Estimated): September 30, 2030

Study Registration Dates

• First Submitted: April 25, 2026
• First Submitted That Met QC Criteria: May 4, 2026
• First Posted (Actual): May 8, 2026

Study Record Updates

• Last Update Posted (Actual): May 8, 2026
• Last Update Submitted That Met QC Criteria: May 4, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: Acute respiratory distress syndrome; Sepsis; Dexamethasone
• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Respiratory Tract Diseases; Systemic Inflammatory Response Syndrome; Inflammation; Lung Diseases; Respiration Disorders; Pathological Conditions, Signs and Symptoms; Respiratory Distress Syndrome; Sepsis; Polycyclic Compounds; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Steroids, Fluorinated; Pregnadienetriols; Dexamethasone; dexamethasone 21-phosphate
• Other Study ID Numbers: DEFEND Trial

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No