Clinical trial NCT04545242: Efficacy of DEXamethasone in Patients With Acute Hypoxemic REspiratory Failure Caused by INfEctions
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)
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE4
Conditions: Acute Hypoxemic Respiratory Failure
Keywords: Acute respiratory failure
ARDS
Mechanical ventilation
Infection
Lead sponsor: Dr. Negrin University Hospital
Sponsor class: OTHER
Collaborators: name: Li Ka Shing Knowledge Institute
name: Consorcio Centro de Investigación Biomédica en Red (CIBER)
First posted: 2020-09-10
Enrollment: 980
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
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.
Primary purpose: TREATMENT

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.

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.

Eligibility 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

Primary outcomes:
measure: 60-day mortality
timeFrame: 60 days
Secondary outcomes:
measure: Ventilator-free days
timeFrame: 28 days
Other outcomes:
Locations:
city: Terrassa
country: Spain
facility: Hospital Universitario Mutua Terrassa (ICU)
state: Barcelona
city: Alcazar de San Juan
country: Spain
facility: Hospital General La Mancha Centro (ICU)
state: Ciudad Real
city: Santiago De Compostela
country: Spain
facility: Complejo Hospitalario Universitario de Santiago (Anesthesia)
state: La Coruña
city: Ponferrada
country: Spain
facility: Hospital General El Bierzo (ICU)
state: León
city: Coslada
country: Spain
facility: Hospital Universitario del Henares (ICU)
state: Madrid
city: Getafe
country: Spain
facility: Hospital Universitario de Getafe (ICU)
state: Madrid
city: Leganés
country: Spain
facility: Hospital Universitario Severo Ochoa (ICU)
state: Madrid
city: Majadahonda
country: Spain
facility: Hospital Universitario Puerta de Hierro (ICU)
state: Madrid
city: Talavera De La Reina
country: Spain
facility: Hospital Nuestra Señora del Prado (ICU)
state: Toledo
city: Barakaldo
country: Spain
facility: Hospital Universitario de Cruces (Anesthesia)
state: Vizcaya
city: Barakaldo
country: Spain
facility: Hospital Universitario de Cruces (ICU)
state: Vizcaya
city: Albacete
country: Spain
facility: Complejo Hospitalario Universitario de Albacete (ICU)
city: Barcelona
country: Spain
facility: Hospital Clinic de Barcelona (AVI)
city: Barcelona
country: Spain
facility: Hospital Clinic de Barcelona (Cardiac ICU)
city: Barcelona
country: Spain
facility: Hospital Clínic (Hepatic ICU)
city: Barcelona
country: Spain
facility: Hospital Clínic de Barcelona (Anesthesia)
city: Ciudad Real
country: Spain
facility: Hospital General de Ciudad Real (ICU)
city: Cuenca
country: Spain
facility: Hospital Virgen de la Luz (ICU)
city: La Coruña
country: Spain
facility: Hospital Universitario de A Coruña (ICU)
city: León
country: Spain
facility: Complejo Asistencial Universitario de León (ICU)
city: Madrid
country: Spain
facility: Hospital Universitario La Princesa (ICU)
city: Madrid
country: Spain
facility: Hospital Universitario Ramón y Cajal (Anesthesia)
city: Madrid
country: Spain
facility: Hospital Clínico Universitario San Carlos (ICU)
city: Madrid
country: Spain
facility: Hospital Universitario Fundación Jiménez Díaz (ICU)
city: Madrid
country: Spain
facility: Hospital Universitario Doce de Octubre (ICU)
city: Madrid
country: Spain
facility: Hospital Universitario La Paz (Anesthesia)
city: Madrid
country: Spain
facility: Hospital Universitario La Paz (ICU)
city: Murcia
country: Spain
facility: Hospital Universitario Virgen de Arrixaca (Anesthesia)
city: Murcia
country: Spain
facility: Hospital Universitario Virgen de Arrixaca (ICU)
city: Málaga
country: Spain
facility: Hospital Universitario Regional de Malaga Carlos Haya (ICU)
city: Pamplona
country: Spain
facility: Clínica Universidad de Navarra
city: Pontevedra
country: Spain
facility: Hospital Universitario Montecelo (Anesthesia)
city: Santa Cruz De Tenerife
country: Spain
facility: Hospital Universitario Nuestra Señora de Candelaria (ICU)
city: Segovia
country: Spain
facility: Hospital General de Segovia (ICU)
city: Valencia
country: Spain
facility: Hospital Clinico Universitario de Valencia (Anesthesia)
city: Valencia
country: Spain
facility: Hospital Clinico Universitario de Valencia (ICU)
city: Valladolid
country: Spain
facility: Hospital Clínico Universitario de Valladolid (Anesthesia)
city: Valladolid
country: Spain
facility: Hospital Universitario Río Hortega (Anesthesia)
city: Valladolid
country: Spain
facility: Hospital Universitario Río Hortega (ICU)
city: Zamora
country: Spain
facility: Hospital Virgen de la Concha (ICU)
Study officials:
affiliation: Hospital Universitario Dr. Negrin
name: Jesús Villar, MD
role: PRINCIPAL_INVESTIGATOR
References:
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.
citation: 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.