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.
Panoramica dello studio
Stato
Intervento / Trattamento
Tipo di studio
Iscrizione (Stimato)
Fase
- Fase 3
Contatti e Sedi
Contatto studio
- Nome: hui chen, MD
- Numero di telefono: +86-18006138640
- Email: huichen.icu@gmail.com
Luoghi di studio
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Nanjing, Cina
- Reclutamento
- Zhongda Hospital, School of Medicine, Southeast University
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Contatto:
- hui chen, MD
- Numero di telefono: +86-18006138640
- Email: huichen.icu@gmail.com
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Jiangsu
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Nanjing, Jiangsu, Cina, 210009
- Non ancora reclutamento
- Zhongda Hospital, School of Medicine, Southeast University
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Contatto:
- Jianfeng Xie, MD
- Numero di telefono: +86-13770332331
- Email: xie820405@126.com
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Criteri di partecipazione
Criteri di ammissibilità
Età idonea allo studio
- Bambino
- Adulto
- Adulto più anziano
Accetta volontari sani
Descrizione
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
Piano di studio
Come è strutturato lo studio?
Dettagli di progettazione
- Scopo principale: Trattamento
- Assegnazione: Randomizzato
- Modello interventistico: Assegnazione parallela
- Mascheramento: Quadruplicare
Armi e interventi
Gruppo di partecipanti / Arm |
Intervento / Trattamento |
|---|---|
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Sperimentale: Dexamethasone Group
Dexamethasone plus usual care
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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.
Altri nomi:
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Comparatore placebo: Placebo Group
Placebo plus usual care
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Participants assigned to the placebo group will receive 0.9% sodium chloride injection as matching placebo, administered according to the same schedule as dexamethasone
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Cosa sta misurando lo studio?
Misure di risultato primarie
Misura del risultato |
Misura Descrizione |
Lasso di tempo |
|---|---|---|
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90-day all-cause mortality
Lasso di tempo: From randomization (day 0) to day 90 (inclusive)
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The proportion of participants who die from any cause between randomization (day 0) and day 90 (inclusive)
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From randomization (day 0) to day 90 (inclusive)
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Misure di risultato secondarie
Misura del risultato |
Misura Descrizione |
Lasso di tempo |
|---|---|---|
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Ventilator-free days through day 28
Lasso di tempo: From randomization (day 0) to day 28 (inclusive)
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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
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From randomization (day 0) to day 28 (inclusive)
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Vasopressor-free days through day 28
Lasso di tempo: From randomization (day 0) to day 28 (inclusive)
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The number of days from randomization (day 0) to day 28 (inclusive) during which the patient is alive and successfully discontinued from vasopressor therapy
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From randomization (day 0) to day 28 (inclusive)
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Renal replacement therapy-free days through day 28
Lasso di tempo: From randomization (day 0) to day 28 (inclusive)
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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
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From randomization (day 0) to day 28 (inclusive)
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28-day all-cause mortality
Lasso di tempo: From randomization (day 0) to day 28 (inclusive)
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The proportion of participants who die from any cause between randomization (day 0) and day 28 (inclusive)
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From randomization (day 0) to day 28 (inclusive)
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In-hospital mortality
Lasso di tempo: Time Frame: From randomization (day 0) up to hospital discharge, assessed up to 90 days
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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
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Time Frame: From randomization (day 0) up to hospital discharge, assessed up to 90 days
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6-month all-cause mortality
Lasso di tempo: From randomization (day 0) to 6 months (inclusive)
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The proportion of participants who die from any cause between randomization (day 0) and 6 months (inclusive)
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From randomization (day 0) to 6 months (inclusive)
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12-month all-cause mortality
Lasso di tempo: From randomization(day 0) to 12 months
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The proportion of participants who die from any cause between randomization (day 0) and 12 months
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From randomization(day 0) to 12 months
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Decision to withhold or withdraw active treatment during hospitalization
Lasso di tempo: Time Frame: From randomization (day 0) up to hospital discharge, assessed up to 90 days
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The proportion of participants in whom active treatment is withheld or withdrawn between randomization (day 0) and hospital discharge (inclusive)
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Time Frame: From randomization (day 0) up to hospital discharge, assessed up to 90 days
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Telephone Interview for Cognitive Status-Modified (TICS-m)
Lasso di tempo: 90 days, 6 months and 12 months after randomization
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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
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90 days, 6 months and 12 months after randomization
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Post-Traumatic Stress Disorder (PTSD)
Lasso di tempo: 90 days, 6 months and 12 months after randomization
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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.
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90 days, 6 months and 12 months after randomization
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Health-related quality of life (EQ-5D-5L)
Lasso di tempo: 90 days, 6 months and 12 months after randomization
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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.
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90 days, 6 months and 12 months after randomization
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Functional Activities Questionnaire (FAQ)
Lasso di tempo: 90 days, 6 months, 12 months after randomization
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Caregiver-reported outcome, higher scores indicating worse impairment.
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90 days, 6 months, 12 months after randomization
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Activities of daily living (ADL) score
Lasso di tempo: 90 days, 6 months, 12 months after randomization
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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.
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90 days, 6 months, 12 months after randomization
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Hospital-free days through day 90
Lasso di tempo: From randomization (day 0) to day 90 (inclusive)
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The number of days from randomization (day 0) to day 90 (inclusive) during which the patient is alive and does not require hospitalization
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From randomization (day 0) to day 90 (inclusive)
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Altre misure di risultato
Misura del risultato |
Misura Descrizione |
Lasso di tempo |
|---|---|---|
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Incidence of weaning success through day 28
Lasso di tempo: From randomization (day 0) to day 28 (inclusive)
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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)
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Incidence of gastrointestinal bleeding through day 28
Lasso di tempo: From randomization (day 0) to day 28 (inclusive)
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The proportion of participants who developed acute gastrointestinal bleeding requiring transfusion of more than 1 unit of packed red blood cells within 24 hours
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From randomization (day 0) to day 28 (inclusive)
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Incidence of secondary bloodstream infection through day 28
Lasso di tempo: From randomization (day 0) to day 28 (inclusive)
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The proportion of participants who developed secondary bloodstream infection through day 28
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From randomization (day 0) to day 28 (inclusive)
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Incidence of VAP through day 28
Lasso di tempo: From randomization (day 0) to day 28 (inclusive)
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The proportion of participants who developed ventilator-associated pneumonia through day 28
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From randomization (day 0) to day 28 (inclusive)
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Incidence of hyperglycemia events through day 28
Lasso di tempo: From randomization (day 0) to day 28 (inclusive)
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The proportion of participants who had hyperglycemia events (blood glucose level >180 mg/dl) through day 28
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From randomization (day 0) to day 28 (inclusive)
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Collaboratori e investigatori
Sponsor
Investigatori
- Investigatore principale: Jianfeng Xie, MD, Southeast University, Zhongda Hospital
Pubblicazioni e link utili
Pubblicazioni generali
- [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.
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Inizio studio (Effettivo)
Completamento primario (Stimato)
Completamento dello studio (Stimato)
Date di iscrizione allo studio
Primo inviato
Primo inviato che soddisfa i criteri di controllo qualità
Primo Inserito (Effettivo)
Aggiornamenti dei record di studio
Ultimo aggiornamento pubblicato (Effettivo)
Ultimo aggiornamento inviato che soddisfa i criteri QC
Ultimo verificato
Maggiori informazioni
Termini relativi a questo studio
Parole chiave
Termini MeSH pertinenti aggiuntivi
- Processi patologici
- Infezioni
- Malattie delle vie respiratorie
- Sindrome da risposta infiammatoria sistemica
- Infiammazione
- Malattie polmonari
- Disturbi respiratori
- Condizioni patologiche, segni e sintomi
- Sindrome da stress respiratorio
- Sepsi
- Composti policiclici
- Incinta
- In gravidanza
- Steroidi
- Composti anelli fusi
- Steroidi, fluorurati
- Incintadienetrioli
- Desametasone
- desametasone 21-fosfato
Altri numeri di identificazione dello studio
- DEFEND Trial
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