Clinical trial NCT06496997: A Comparative Study of Glucocorticoids Efficacy in Acute Respiratory Distress Syndrome
Official title: A Comparative Study of Glucocorticoids Efficacy in Acute Respiratory Distress Syndrome
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
PHASE3
Conditions: Acute Respiratory Distress Syndrome
Lead sponsor: Fayoum University
Sponsor class: OTHER
First posted: 2024-07-11
Enrollment: 300
Sex: ALL
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The aim of the work is to compare the efficacy of equivalent doses of methylprednisolone, dexamethasone and hydrocortisone in patients with ARDS

Detailed description: Acute respiratory distress syndrome (ARDS) is a secondary disease that follows-usually within 6-48 h-a primary disease of multifactorial etiology (most frequently pneumonia and extrapulmonary sepsis) associated with severe systemic inflammation. Inflammatory mediators released into the systemic circulation (systemic inflammation) from the site of infection reach the broad pulmonary capillary surface, producing severe and diffuse inflammatory exudate of the pulmonary lobules and resulting in hypoxemic respiratory failure.

In ARDS, systemic inflammation is activated by the nuclear factor-κB (NF-κB) signaling system and downregulated by activated glucocorticoid receptor α (GRα). In these patients, inadequate (endogenous glucocorticoid-activated) GRα-mediated downregulation of proinflammatory transcription factor NF-κB in circulating and tissue cells leads to higher initial levels and persistent elevation over time of plasma and bronchoalveolar lavage markers of inflammation, hemostasis, and tissue repair. Inadequate intracellular GRα-mediated anti-inflammatory activity for the severity of the patient's illness was recently termed critical illness-related corticosteroid insufficiency (CIRCI). Experimental and clinical research shows that CIRCI can be improved with quantitatively and temporally adequate glucocorticoid administration.

Glucocorticoids are commonly used in patients with acute respiratory distress syndrome (ARDS) or at-risk for ARDS with proposed mechanisms including reduction of local lung inflammation and dampening of systemic immune responses.

Clinical trials of glucocorticoids in patients with ARDS or at-risk from a pulmonary infection have had mixed results with some studies suggesting benefit and others showing no beneficial effects. Notably, the glucocorticoid agent, dose, and duration has varied widely between studies increasing the challenge of interpreting discordant findings.

In animal models of ARDS, glucocorticoids decreased the expression of pro-inflammatory mediators in lung tissue, including TNF-a, IL-1a, IL-1b, IL-6 and IL-12 p40, and reduces lung injury through the reduction of oxygen radicals produced by neutrophils. Beyond their anti-inflammatory effects during the acute phase of inflammation, glucocorticoids also contributed to the resolution of inflammation, trough reprogramming effects on macrophages.

Glucocorticoids have been administered during two distinct phases of ARDS, during the early stage of ARDS when inflammation is expected to be most important and during late phase of ARDS, when lung fibrosis predominates. The biological and pathological characteristics of these two entities differ greatly, explaining the observed conflicting results in the effects of glucocorticoids in these two distinct conditions.

The early phase of ARDS is characterized by major alveolar inflammation. Thus, glucocorticoids, potent anti-inflammatory agents, are theoretically expected to be relevant treatment for ARDS.

Late-stage ARDS is characterized histologically by ongoing inflammation with fibroproliferation, presence of hyaline membranes, and persistent diffuse alveolar damage, leading to prolonged mechanical ventilation and a higher risk of death. The largest multicenter placebo-controlled trial, found no evidence for beneficial effects of glucocorticoids initiated for late-stage ARDS.

Eligibility criteria: Inclusion Criteria:

We include patients receiving mechanical ventilation for hypoxemic respiratory failure if they met the diagnostic criteria for ARDS according to the American-European Consensus definition, as later reclassified on the basis of the 2012 Berlin criteria for the diagnosis of ARDS, defined as:

1. Presence of acute hypoxemic respiratory failure (an arterial oxygen partial pressure to fraction of inspired oxygen ratio (PaO2/FiO2) of ≤ 300 mm Hg, requiring supplemental oxygen administrated by simple face mask, nasal cannula, or other similar oxygen-delivery device to maintain oxygen saturation at greater than 93% within the first 48 h of the onset of ARDS)
2. Onset within 7 days of insult, or new (within 7 days) or worsening respiratory symptoms
3. Bilateral opacities on chest x-ray or CT not fully explained by effusions, lobar or lung collapse, or nodules
4. Cardiac failure not the primary cause of acute respiratory failure

Exclusion Criteria:

We exclude patients with acute hypoxemic respiratory failure caused by congestive heart failure

Primary outcomes:
measure: 28-day mortality after enrolment
timeFrame: From enrollment to the end of treatment at 28 days
Secondary outcomes:
measure: The number of patients needing invasive mechanical ventilation
timeFrame: From enrollment to the end of treatment at 28 days
measure: The Number of ventilator-free days
timeFrame: From enrollment to the end of treatment at 28 days
measure: Duration of the ICU stay
timeFrame: From enrollment to the end of treatment at 28 days
measure: Duration of hospitalization
timeFrame: From enrollment to the end of treatment at 28 days
measure: Incidence of serious adverse events, including secondary infections, hyperglycemia, clinically important gastrointestinal bleeding, and hypertension
timeFrame: From enrollment to the end of treatment at 28 days
Other outcomes:
Locations:
city: Fayoum
country: Egypt
facility: Fayoum University
Study officials:
affiliation: Faculty of Pharmacy - Fayoum University
name: Mahmoud Ezzat Elkmash, Teaching Assistant
role: PRINCIPAL_INVESTIGATOR
affiliation: Faculty of Pharmacy - Beni Suef University
name: Raghda Roshdy Hussein, Assistant Professor
role: STUDY_DIRECTOR
affiliation: Faculty of Pharmacy - Fayoum University
name: Marwa Kamal Tolba, Assistant Professor
role: STUDY_DIRECTOR
affiliation: Faculty of Pharmacy - Beni Suef University
name: Marian Sobhi Saeed, Lecturer
role: STUDY_DIRECTOR
affiliation: Faculty of Medicine - Fayoum University
name: Mona Ibrahim Ahmed, Lecturer
role: STUDY_DIRECTOR
References: