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Efficacy of DEXamethasone in Patients With Acute Hypoxemic REspiratory Failure Caused by INfEctions (DEXA-REFINE)

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ClinicalTrials.gov Identifier: NCT04545242
Recruitment Status : Not yet recruiting
First Posted : September 10, 2020
Last Update Posted : January 22, 2021
Sponsor:
Collaborators:
Li Ka Shing Knowledge Institute
Consorcio Centro de Investigación Biomédica en Red, M.P.
Information provided by (Responsible Party):
Jesus Villar, Dr. Negrin University Hospital

Brief Summary:

Background: There are no proven therapies specific for pulmonary dysfunction in patients with acute hypoxemic respiratory failure (AHRF) caused by infections (including Covid-19). The full spectrum of AHRF ranges from mild respiratory tract illness to severe pneumonia, acute respiratory distress syndrome (ARDS), multiorgan failure, and death. The efficacy of corticosteroids in AHRF and ARDS caused by infections remains controversial.

Methods: This is a multicenter, randomized, controlled, open-label clinical trial testing dexamethasone in mechanically ventilated adult patients with established AHRF (including ARDS) caused by confirmed pulmonary or systemic infections, admitted in a network of Spanish ICUs. Eligible patients will be randomly assigned to receive dexamethasone: either 6 mg/d x 10 days or 20 mg/d x 5 days followed by 10 mg/d x 5 days. The primary outcome is 60-day mortality. The secondary outcome is the number of ventilator-free days at 28 days. All analyses will be done according to the intention-to-treat principle.


Condition or disease Intervention/treatment Phase
Acute Hypoxemic Respiratory Failure Drug: Dexamethasone Phase 4

Detailed Description:

Acute hypoxemic respiratory failure (AHRF), and its more severe form termed the acute respiratory distress syndrome (ARDS), is a catastrophic illness of multifactorial etiology characterized by a severe inflammatory process of the lung leading to hypoxemic respiratory failure requiring mechanical ventilation (MV). Pulmonary infections are the leading causes of AHRF and ARDS. Translational research has established a strong association between dysregulated systemic and pulmonary inflammation and progression or delayed resolution of AHRF.2 Glucocorticoid receptor-mediated downregulation of systemic and pulmonary inflammation is essential to accelerate disease resolution and restore tissue homeostasis, and can be enhanced with glucocorticoid treatment.

The COVID-19 pandemic is a critical moment for the world, in which even industrially advanced countries have rapidly reached intensive care units (ICUs) saturation, and intensivists are forced to make difficult ethical decisions that are uncommon outside war zones. As with other bacterial or viral infections, severe pneumonia is the main condition leading to AHRF and ARDS requiring weeks of MV with high mortality (35-55%) in critically ill patients. There has been great interest in the role of corticosteroids to attenuate the pulmonary and systemic damage in ARDS patients because of their potent anti-inflammatory and antifibrotic properties.3 Corticosteroids have been off patent for greater than 20 years, they are cheap, and globally equitable. However, the efficacy of corticosteroids in AHRF (including ARDS) caused by infections remains controversial.

Only two large randomized clinical trials (RCT) have shown that the administration of dexamethasone is able to reduce mortality in patients with AHRF. Villar et al in Spain observed that moderate doses of dexamethasone (10-20 mg/d x 10 days) caused a 15% absolute reduction of 60-day mortality in patients with established moderate-to-severe ARDS from multiple etiologies. Horby et al in the RECOVERY trial in Great Britain reported that dexamethasone at low doses (6 mg/d x 10 days) reduced 28-day mortality in patients with AHRF caused by COVID-19. These findings confirmed that corticosteroid therapy is associated with a sizable reduction in duration of MV and hospital mortality. These two RCTs will change clinical practice for the management of AHRF and ARDS. However, there is a reasonable doubt whether dexamethasone at moderate doses (10-20 mg/d) would cause a greater reduction in mortality than 6 mg/d. Our goal in this study is to respond this question.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 980 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Multicenter, randomized, controlled, open-label trial involving mechanically ventilated adult patients with AHRF (including ARDS) caused by confirmed bacterial or viral infections.
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Efficacy of Higher vs. Lower Doses of Dexamethasone in Patients With Acute Hypoxemic Respiratory Failure (Including ARDS) Caused by Infections (Including COVID-19)
Estimated Study Start Date : February 8, 2021
Estimated Primary Completion Date : September 30, 2023
Estimated Study Completion Date : December 30, 2023

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Active Comparator: Dexamethasone (low dose)
Dexamethasone: 6 mg/iv/day during 10 days.
Drug: Dexamethasone
Intravenous dexamethasone (low vs. moderate doses) during 10 days
Other Names:
  • Decadron
  • Dexasone
  • Diodex

Active Comparator: Dexamethasone (moderate dose)
Dexamethasone: 20 mg/iv/ daily from day of randomization (day 1) during 5 days, followed by 10 mg/iv/ daily from Day 6 to Day 10 of randomization.
Drug: Dexamethasone
Intravenous dexamethasone (low vs. moderate doses) during 10 days
Other Names:
  • Decadron
  • Dexasone
  • Diodex




Primary Outcome Measures :
  1. 60-day mortality [ Time Frame: 60 days ]
    All-cause mortality at 60 days after randomization


Secondary Outcome Measures :
  1. Ventilator-free days [ Time Frame: 28 days ]
    Number of ventilator-free days (VFDs) at Day 28 (defined as days being alive and free from mechanical ventilation at day 28 after randomization. For patients ventilated 28 days or longer and for subjects who die, VFD is 0.



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • age 18 years or older;
  • intubated and mechanically ventilated;
  • acute onset of AHRF (as defined by a PaO2/FiO2 ≤300 mmHg during at least 6 hours from diagnosis. For the measurement of PaO2 and calculation of PaO2/FiO2 ratio, the minimum accepted value for PEEP is 5 cmH2O and for FiO2 is 0.3. ARDS is defined by Berlin criteria,4 which includes: (i) having pneumonia or worsening respiratory symptoms, (ii) bilateral pulmonary infiltrates on chest imaging (x-ray or CT scan), (iii) absence of left atrial hypertension or no clinical signs of left heart failure, and (iv) hypoxemia, as defined by a PaO2/FiO2 ≤300 mmHg on positive end-expiratory pressure (PEEP) of ≥5 cmH2O, regardless of FiO2.
  • Pulmonary or systemic infectious etiology of AHRF.

Exclusion Criteria:

  • Patients with a known contraindication to corticosteroids,
  • Patient included in another therapeutic clinical trial
  • Lack of informed consent

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04545242


Contacts
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Contact: Jesús Villar, MD +34606860027 jesus.villar54@gmail.com
Contact: Arthur Slutsky, MD +14168244000 Arthur.Slutsky@unityhealth.to

Locations
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Sponsors and Collaborators
Dr. Negrin University Hospital
Li Ka Shing Knowledge Institute
Consorcio Centro de Investigación Biomédica en Red, M.P.
Investigators
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Principal Investigator: Jesús Villar, MD Hospital Universitario Dr. Negrin
Publications:
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Responsible Party: Jesus Villar, Senior scientist, Dr. Negrin University Hospital
ClinicalTrials.gov Identifier: NCT04545242    
Other Study ID Numbers: ICI20-00062
First Posted: September 10, 2020    Key Record Dates
Last Update Posted: January 22, 2021
Last Verified: January 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Jesus Villar, Dr. Negrin University Hospital:
Acute respiratory failure
ARDS
Mechanical ventilation
Infection
Additional relevant MeSH terms:
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Infections
Respiratory Insufficiency
Respiration Disorders
Respiratory Tract Diseases
Dexamethasone
Anti-Inflammatory Agents
Antiemetics
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Gastrointestinal Agents
Glucocorticoids
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Antineoplastic Agents, Hormonal
Antineoplastic Agents