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NCT Number: NCT07576660

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

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.

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Key information

Conditions

Acute Respiratory Distress Syndrome (ARDS) Infections Inflammation Lung Diseases Pathologic Processes Pathological Conditions, Signs and Symptoms Respiration Disorders Respiratory Distress Syndrome Respiratory Tract Diseases Sepsis Systemic Inflammatory Response Syndrome

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 3

Primary location

Zhongda Hospital, School of Medicine, Southeast University

Nanjing, Jiangsu, 210009, China

Location contact

Jianfeng Xie, MD

CONTACT

[email protected]

+86-13770332331

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

Inclusion criteria

  • Age 18 years or older
  • Suspected or confirmed infection
  • Receipt of invasive mechanical ventilation with a positive end-expiratory pressure (PEEP) of at least 5 cm H₂O, noninvasive positive-pressure ventilation with a PEEP of at least 5 cm H₂O, or high-flow nasal oxygen therapy with a flow rate of at least 30 L/min
  • Acute-onset ARDS, defined as ARDS diagnosed for at least 6 hours but no more than 72 hours, according to the following criteria:

(1) New or worsening respiratory symptoms or respiratory failure (2) Pulmonary infiltrates on chest radiography or computed tomography, or B-lines or consolidation on lung ultrasonography, not fully explained by pleural effusion, lobar or whole-lung collapse or atelectasis, or pulmonary nodules. Patients with unilateral pulmonary infiltrates, B-lines, or consolidation 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, or SpO₂/FiO₂ of 315 or less, with SpO₂ no greater than 97%.

Exclusion criteria

  • 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)
  • 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

Treatment and study plan

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, followed by dexamethasone 10 mg once daily from Day 6 to Day 10.

Other names: Dexamethasone sodium phosphate injection, 5 mg/1 mL

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

Primary outcomes

  1. 90-day all-cause mortality

    Time frame: From randomization (day 0) to day 90 (inclusive)

    The proportion of participants who die from any cause between randomization (day 0) and day 90 (inclusive)

Secondary outcomes

  1. Ventilator-free days through day 28

    Time frame: From randomization (day 0) to day 28 (inclusive)

    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

  2. Vasopressor-free days through day 28

    Time frame: From randomization (day 0) to day 28 (inclusive)

    The number of days from randomization (day 0) to day 28 (inclusive) during which the patient is alive and successfully discontinued from vasopressor therapy

  3. Renal replacement therapy-free days through day 28

    Time frame: From randomization (day 0) to day 28 (inclusive)

    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

  4. 28-day all-cause mortality

    Time frame: From randomization (day 0) to day 28 (inclusive)

    The proportion of participants who die from any cause between randomization (day 0) and day 28 (inclusive)

  5. In-hospital mortality

    Time frame: Time Frame: From randomization (day 0) up to hospital discharge, assessed up to 90 days

    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

  6. 6-month all-cause mortality

    Time frame: From randomization (day 0) to 6 months (inclusive)

    The proportion of participants who die from any cause between randomization (day 0) and 6 months (inclusive)

  7. 12-month all-cause mortality

    Time frame: From randomization(day 0) to 12 months

    The proportion of participants who die from any cause between randomization (day 0) and 12 months

  8. Hospital-free days through day 90

    Time frame: From randomization (day 0) to day 90 (inclusive)

    The number of days from randomization (day 0) to day 90 (inclusive) during which the patient is alive and does not require hospitalization

  9. Decision to withhold or withdraw active treatment during hospitalization

    Time frame: Time Frame: From randomization (day 0) up to hospital discharge, assessed up to 90 days

    The proportion of participants in whom active treatment is withheld or withdrawn between randomization (day 0) and hospital discharge (inclusive)

  10. Telephone Interview for Cognitive Status-Modified (TICS-m)

    Time frame: 90 days, 6 months and 12 months after randomization

    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

  11. Post-Traumatic Stress Disorder (PTSD)

    Time frame: 90 days, 6 months and 12 months after randomization

    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.

  12. Health-related quality of life (EQ-5D-5L)

    Time frame: 90 days, 6 months and 12 months after randomization

    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.

  13. Functional Activities Questionnaire (FAQ)

    Time frame: 90 days, 6 months, 12 months after randomization

    Caregiver-reported outcome, higher scores indicating worse impairment.

  14. Activities of daily living (ADL) score

    Time frame: 90 days, 6 months, 12 months after randomization

    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.

Other outcomes

  1. Incidence of weaning success through day 28

    Time frame: From randomization (day 0) to day 28 (inclusive)

    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.

  2. Incidence of gastrointestinal bleeding through day 28

    Time frame: From randomization (day 0) to day 28 (inclusive)

    The proportion of participants who developed acute gastrointestinal bleeding requiring transfusion of more than 1 unit of packed red blood cells within 24 hours

  3. Incidence of secondary bloodstream infection through day 28

    Time frame: From randomization (day 0) to day 28 (inclusive)

    The proportion of participants who developed secondary bloodstream infection through day 28

  4. Incidence of VAP through day 28

    Time frame: From randomization (day 0) to day 28 (inclusive)

    The proportion of participants who developed ventilator-associated pneumonia through day 28

  5. Incidence of hyperglycemia events through day 28

    Time frame: From randomization (day 0) to day 28 (inclusive)

    The proportion of participants who had hyperglycemia events (blood glucose level >180 mg/dl) through day 28

Study contacts

Contact information is provided by the study sponsor or research team.

Hui Chen, MD

CONTACT

[email protected]

+86-18006138640

Sponsors and collaborators

Lead sponsor

Southeast University, China

Other

Registry information

Acronym: DEFEND

Important dates

Study start
2026
Primary completion
2029
Study completion
2030
First posted
May 8, 2026
Registry last updated
Jun 30, 2026

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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