Efficacy of DEXamethasone in Patients With Acute Hypoxemic REspiratory Failure Caused by INfEctions

Acute Hypoxemic Respiratory Failure Clinical Trial

— DEXA-REFINE  

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)

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04545242
• Other study ID #: ICI20-00062
• Status: Recruiting
• Phase: Phase 4
• Start date: July 6, 2021
• Est. completion date: December 30, 2024

Study information

• Verified date: February 2024
• Source: Dr. Negrin University Hospital
• Contact: Jesús Villar, MD
• Phone: +34606860027
• Email: jesus.villar54[@]gmail.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 980
• Est. completion date: December 30, 2024
• Est. primary completion date: December 30, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Acute Hypoxemic Respiratory Failure
• Infections
• Respiratory Insufficiency

Intervention

Drug:
• Dexamethasone
Intravenous dexamethasone (low vs. moderate doses) during 10 days

Locations

Country	Name	City	State
Spain	Complejo Hospitalario Universitario de Albacete (ICU)	Albacete
Spain	Hospital General La Mancha Centro (ICU)	Alcazar de San Juan	Ciudad Real
Spain	Hospital Universitario de Cruces (Anesthesia)	Barakaldo	Vizcaya
Spain	Hospital Universitario de Cruces (ICU)	Barakaldo	Vizcaya
Spain	Hospital Clínic (Hepatic ICU)	Barcelona
Spain	Hospital Clínic de Barcelona (Anesthesia)	Barcelona
Spain	Hospital Clinic de Barcelona (AVI)	Barcelona
Spain	Hospital Clinic de Barcelona (Cardiac ICU)	Barcelona
Spain	Hospital General de Ciudad Real (ICU)	Ciudad Real
Spain	Hospital Universitario del Henares (ICU)	Coslada	Madrid
Spain	Hospital Virgen de la Luz (ICU)	Cuenca
Spain	Hospital Universitario de Getafe (ICU)	Getafe	Madrid
Spain	Hospital Universitario de A Coruña (ICU)	La Coruña
Spain	Hospital Universitario Severo Ochoa (ICU)	Leganés	Madrid
Spain	Complejo Asistencial Universitario de León (ICU)	León
Spain	Hospital Clínico Universitario San Carlos (ICU)	Madrid
Spain	Hospital Universitario Doce de Octubre (ICU)	Madrid
Spain	Hospital Universitario Fundación Jiménez Díaz (ICU)	Madrid
Spain	Hospital Universitario La Paz (Anesthesia)	Madrid
Spain	Hospital Universitario La Paz (ICU)	Madrid
Spain	Hospital Universitario La Princesa (ICU)	Madrid
Spain	Hospital Universitario Ramón y Cajal (Anesthesia)	Madrid
Spain	Hospital Universitario Puerta de Hierro (ICU)	Majadahonda	Madrid
Spain	Hospital Universitario Regional de Malaga Carlos Haya (ICU)	Málaga
Spain	Hospital Universitario Virgen de Arrixaca (Anesthesia)	Murcia
Spain	Hospital Universitario Virgen de Arrixaca (ICU)	Murcia
Spain	Clínica Universidad de Navarra	Pamplona
Spain	Hospital General El Bierzo (ICU)	Ponferrada	León
Spain	Hospital Universitario Montecelo (Anesthesia)	Pontevedra
Spain	Hospital Universitario Nuestra Señora de Candelaria (ICU)	Santa Cruz De Tenerife
Spain	Complejo Hospitalario Universitario de Santiago (Anesthesia)	Santiago De Compostela	La Coruña
Spain	Hospital General de Segovia (ICU)	Segovia
Spain	Hospital Nuestra Señora del Prado (ICU)	Talavera De La Reina	Toledo
Spain	Hospital Universitario Mutua Terrassa (ICU)	Terrassa	Barcelona
Spain	Hospital Clinico Universitario de Valencia (Anesthesia)	Valencia
Spain	Hospital Clinico Universitario de Valencia (ICU)	Valencia
Spain	Hospital Clínico Universitario de Valladolid (Anesthesia)	Valladolid
Spain	Hospital Universitario Río Hortega (Anesthesia)	Valladolid
Spain	Hospital Universitario Río Hortega (ICU)	Valladolid
Spain	Hospital Virgen de la Concha (ICU)	Zamora

Sponsors (3)

Lead Sponsor	Collaborator
Dr. Negrin University Hospital	Consorcio Centro de Investigación Biomédica en Red (CIBER), Li Ka Shing Knowledge Institute

Country where clinical trial is conducted

Spain, 

References & Publications (2)

RECOVERY Collaborative Group; Horby P, Lim WS, Emberson JR, Mafham M, Bell JL, Linsell L, Staplin N, Brightling C, Ustianowski A, Elmahi E, Prudon B, Green C, Felton T, Chadwick D, Rege K, Fegan C, Chappell LC, Faust SN, Jaki T, Jeffery K, Montgomery A, Rowan K, Juszczak E, Baillie JK, Haynes R, Landray MJ. Dexamethasone in Hospitalized Patients with Covid-19. N Engl J Med. 2021 Feb 25;384(8):693-704. doi: 10.1056/NEJMoa2021436. Epub 2020 Jul 17. — View Citation

Villar J, Ferrando C, Martinez D, Ambros A, Munoz T, Soler JA, Aguilar G, Alba F, Gonzalez-Higueras E, Conesa LA, Martin-Rodriguez C, Diaz-Dominguez FJ, Serna-Grande P, Rivas R, Ferreres J, Belda J, Capilla L, Tallet A, Anon JM, Fernandez RL, Gonzalez-Martin JM; dexamethasone in ARDS network. Dexamethasone treatment for the acute respiratory distress syndrome: a multicentre, randomised controlled trial. Lancet Respir Med. 2020 Mar;8(3):267-276. doi: 10.1016/S2213-2600(19)30417-5. Epub 2020 Feb 7. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	60-day mortality	All-cause mortality at 60 days after randomization	60 days
Secondary	Ventilator-free 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.	28 days