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

NCT07576660 | Not Yet Recruiting Phase 3 DMC

• 1 other identifier: DEFEND Trial
• Study Type: interventional
• Target: 1,474
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Acute Respiratory Distress Syndrome (ARDS)

Keywords

Acute respiratory distress syndrome; Sepsis; Dexamethasone

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (16)

• Ventilator-free days through day 28

  From randomization (day 0) to day 28 (inclusive)

• Vasopressor-free days through day 28

  From randomization (day 0) to day 28 (inclusive)

• Renal replacement therapy-free days through day 28

  From randomization (day 0) to day 28 (inclusive)

• 28-day all-cause mortality

  From randomization (day 0) to day 28 (inclusive)

• ICU mortality

  From randomization (day 0) up to ICU discharge, assessed up to 90 days

Other Outcomes (5)

• Incidence of weaning success through day 28

  From randomization (day 0) to day 28 (inclusive)

• Incidence of gastrointestinal bleeding through day 28

  From randomization (day 0) to day 28 (inclusive)

• Incidence of secondary bloodstream infection through day 28

  From randomization (day 0) to day 28 (inclusive)

Study Arms (2)

Dexamethasone Group

EXPERIMENTAL

Dexamethasone plus usual care

Drug: Dexamethasone

Placebo Group

PLACEBO COMPARATOR

Placebo plus usual care

Drug: Placebo

Interventions

Dexamethasone DRUG

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.

Also known as: Dexamethasone sodium phosphate injection, 5 mg/1 mL

Dexamethasone Group

Placebo DRUG

Participants assigned to the placebo group will receive 0.9% sodium chloride injection as matching placebo, administered according to the same schedule as dexamethasone

Placebo Group

Eligibility Criteria

• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• Age 18 years or older
• Suspected or confirmed infection
• Intubated and mechanically ventilated
• 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 \[300 \* (barometric pressure/760)\]

You may not qualify if:

• Pregnancy
• Planned withdrawal of life-sustaining treatment within the next 24 hours
• Current hospitalization for more than 7 days before screening;
• Clinical improvement within the 48 hours before randomization, based on the investigator's overall assessment
• Highly suspected or confirmed COVID-19 infection
• 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.
• Congestive heart failure (NYHA III-IV)
• ARDS diagnosed more than 72 hours before screening
• 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
• Contraindications to short-term dexamethasone, including untreated systemic fungal infection, active tuberculosis, active viral hepatitis, or major upper gastrointestinal bleeding
• Known hypersensitivity to dexamethasone
• Participation in another interventional clinical trial within the previous 30 days

Sponsors & Collaborators

• Southeast University, China: lead

Study Sites (1)

Zhongda Hospital, School of Medicine, Southeast University

Nanjing, Jiangsu, 210009, China

Location

Related Publications (1)

• [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.

  BACKGROUND

MeSH Terms

Conditions

Respiratory Distress Syndrome; Sepsis

Interventions

Dexamethasone; dexamethasone 21-phosphate

Condition Hierarchy (Ancestors)

Lung Diseases; Respiratory Tract Diseases; Respiration Disorders; Infections; Systemic Inflammatory Response Syndrome; Inflammation; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Pregnadienetriols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Steroids, Fluorinated

Study Officials

• Jianfeng Xie, MD

  Southeast University, Zhongda Hospital

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Hui Chen, MD

CONTACT

+86-18006138640; huichen.icu@gmail.com

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: Double blind, placebo controlled
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Prof

Study Record Dates

• First Submitted: April 25, 2026
• First Posted: May 8, 2026
• Study Start (Estimated): July 1, 2026
• Primary Completion (Estimated): September 30, 2029
• Study Completion (Estimated): September 30, 2030
• Last Updated: May 8, 2026

Record last verified: 2026-04

Data Sharing

• IPD Sharing: Will not share

Locations

CN (1)