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

Southeast University, China

Status and phase: Begins enrollment this month; Phase 3

Conditions: Acute Respiratory Distress Syndrome (ARDS)

Treatments: Drug: Placebo; Drug: Dexamethasone

Study type: Interventional

Funder types: Other

Identifiers

NCT07576660

DEFEND Trial

Details and patient eligibility

About

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.

Enrollment: 1,474 estimated patients

Sex: All

Volunteers: No Healthy Volunteers

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

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Quadruple Blind

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1,474 participants in 2 patient groups, including a placebo group

Dexamethasone Group

Experimental group

Description:

Dexamethasone plus usual care

Treatment:

Drug: Dexamethasone

Placebo Group

Placebo Comparator group

Description:

Placebo plus usual care

Treatment:

Drug: Placebo