Corticosteroids in Hyperinflammatory Phenotype of Critical Illness

Efficacy, Safety, and Tolerability of Methylprednisolone in Critically Ill Patients With the Hyperinflammatory Phenotype: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Phase II Trial

The goal of this clinical trial is to learn whether methylprednisolone improves outcomes in critically ill patients with a hyperinflammatory phenotype. It will also evaluate the safety of methylprednisolone at different doses.

The main questions it aims to answer are:

• Does methylprednisolone improve organ function compared with placebo?
• Does methylprednisolone reduce the risk of mortality within 30 days?

Researchers will compare high-dose methylprednisolone (160mg/d), low-dose methylprednisolone (80mg/d), and placebo (normal saline) to evaluate effectiveness and safety.

Participants will:

• Receive high-dose methylprednisolone, low-dose methylprednisolone, or placebo every 12 hours for the first 3 days
• Be reassessed on Day 4 based on their inflammatory status If the hyperinflammatory phenotype persists, the treatment dose will be reduced by half and continued until Day 7 or ICU discharge, whichever occurs first If the patient transitions to a hypoinflammatory phenotype, the study treatment will be discontinued
• Be monitored daily in the intensive care unit for organ function, inflammatory status, and need for organ support
• Be followed for up to 30 days after randomization to assess survival and recovery

Background: Acute respiratory distress syndrome (ARDS) and sepsis are common critical illnesses associated with persistently high mortality. The lack of improvement in overall outcomes despite multiple interventions may be attributable to substantial biological heterogeneity. Both ARDS and sepsis can be classified into hyperinflammatory and hypoinflammatory phenotypes based on clinical variables and/or biomarkers. Previous retrospective and target trial emulation studies suggest differential treatment responses, with hyperinflammatory patients potentially benefiting from corticosteroid therapy.

Objective: The primary objective is to evaluate the preliminary efficacy signal of intravenous methylprednisolone, compared with placebo, in critically ill patients with a hyperinflammatory phenotype. The primary endpoint is the proportion of patients achieving a ≥1.4-point reduction in mean Sequential Organ Failure Assessment (SOFA) score from baseline to Day 9. Secondary objectives include evaluation of 30-day mortality, organ support-free days, safety, and tolerability, and to inform endpoint selection and dose optimization for a future phase III trial.

Study Design: This is a multicenter, randomized, double-blind, placebo-controlled phase II trial. Participants will be randomized using a centralized system with stratified permuted block randomization by study site, with varying block sizes to minimize predictability. Eligible participants will be assigned in a 1:1:1 ratio to high-dose methylprednisolone, low-dose methylprednisolone, or placebo.

Participants:

Inclusion Criteria: Participants must meet all of the following criteria:

① Age ≥18 years; ② Diagnosis of ARDS or sepsis; ③ ARDS defined according to standard criteria: acute onset within 1 week, bilateral opacities, respiratory failure not fully explained by cardiac causes, and PaO₂/FiO₂ ≤300 mmHg or SpO₂/FiO₂ ≤315 under PEEP ≥5 cmH₂O. Sepsis defined according to Sepsis-3 criteria (suspected or confirmed infection with SOFA increase ≥2); ④ Receiving invasive mechanical ventilation; ⑤ Admission to ICU; ⑥ Hyperinflammatory phenotype (predicted probability ≥0.5 using a clinical classifier); ⑦Randomization within 72 hours of ARDS or sepsis onset; ⑧Written informed consent from patient or legally authorized representative.

Exclusion Criteria: Participants meeting any of the following will be excluded:

① High-dose vasopressor requirement (norepinephrine ≥0.5 μg/kg/min or epinephrine ≥0.25 μg/kg/min); ② Recent cardiac surgery; ③ Conditions requiring high-dose corticosteroids; ④ Long-term systemic corticosteroid use within 6 months; ⑤ Pregnancy or lactation; ⑥ Brain death; ⑦ Advanced malignancy or expected survival <6 months; ⑧Known hypersensitivity to methylprednisolone; ⑨ Organ transplantation or hematopoietic stem cell transplantation; ⑩ Active life-threatening fungal infection or tuberculosis; ⑪ Neuromuscular disease affecting respiration; ⑫ Severe immunodeficiency (e.g., HIV, SCID); ⑬ Do-not-resuscitate (DNR) orders or withdrawal of care; ⑭ Participation in another interventional trial; ⑮ Any condition deemed unsuitable by investigator.

Sample Size: This phase II exploratory trial aims to estimate clinically meaningful effect sizes rather than formally test hypotheses. A total of 150 participants (50 per group) will be enrolled. Assuming a 10% dropout rate, approximately 45 evaluable participants per group are expected. Based on prior data, the control group is expected to have a 20% response rate, with treatment potentially increasing this to 40%. The 95% confidence interval half-width is estimated at ±18.5%, providing sufficient precision to inform a phase III trial.

Interventions: Participants will be randomized to: High-dose group: methylprednisolone 80 mg IV every 12 hours; Low-dose group: methylprednisolone 40 mg IV every 12 hours; or Placebo group: normal saline (100 mL) IV every 12 hours. All treatments will be identical in volume, appearance, and administration. At Day 4, inflammatory phenotype will be reassessed; treatment will be discontinued if phenotype transitions to hypoinflammatory. Otherwise, dose will be halved and continued until Day 7 or ICU discharge. All patients will receive standard ICU care according to guidelines.

Blinding: Double-blind design. Drug preparation will be performed by unblinded personnel, while investigators, clinicians, and patients remain blinded.

Outcomes: Primary outcome is proportion of patients achieving a ≥1.4-point reduction in mean SOFA score from baseline to Day 9. Mean SOFA change is calculated as baseline SOFA minus the average SOFA from Days 2-9. For patients who die before Day 9, SOFA is imputed as 24 thereafter; for discharged patients, last observation carried forward (LOCF) is applied. Secondary outcomes include 30-day all-cause mortality, 30-day organ support-free days (OSFD) and Incidence and severity of adverse events. Exploratory outcomes include ICU and hospital length of stay; ventilator-, vasopressor-, and RRT-free days; phenotype transition rates; biomarkers (CRP, PCT, IL-6, etc.); SOFA score trajectory; Vasoactive-Inotropic Score (VIS); incidence of new infections Statistical Analysis: Analyses will follow the intention-to-treat principle. Primary outcome will be reported as proportions with risk differences and 95% confidence intervals. Secondary and exploratory outcomes will be analyzed descriptively. Results will inform effect size estimation and design of a future phase III trial.

Inclusion Criteria:

Participants must meet all of the following criteria:

1. Age ≥18 years.
2. Diagnosis of acute respiratory distress syndrome (ARDS) or sepsis.

ARDS will be defined according to standard criteria:

1. acute onset within 1 week of a known clinical insult or new/worsening respiratory symptoms;
2. bilateral pulmonary opacities on chest imaging (X-ray or CT) or bilateral B-lines and/or consolidation on lung ultrasound, not fully explained by effusion, atelectasis, or nodules;
3. respiratory failure not fully explained by cardiac failure or fluid overload;
4. hypoxemia defined as PaO₂/FiO₂ ≤300 mmHg or SpO₂/FiO₂ ≤315 (with SpO₂ ≤97%) under a minimum positive end-expiratory pressure (PEEP) of 5 cmH₂O.

Sepsis will be defined according to the Sepsis-3 criteria as suspected or confirmed infection with an acute increase in SOFA score ≥2 points, assuming a baseline SOFA score of 0 in patients without known prior organ dysfunction.

Sepsis-associated ARDS will be defined as ARDS occurring in patients with sepsis.

3. Receiving invasive mechanical ventilation. 4. Admission to the intensive care unit (ICU). 5. Hyperinflammatory phenotype, defined as a predicted probability ≥0.5 using a validated AI clinical classifier based on clinical data.

6. Randomization within 72 hours of ARDS or sepsis onset. 7. Provision of written informed consent by the patient or their legally authorized representative.

Exclusion Criteria:

Participants meeting any of the following criteria will be excluded:

1. Requirement for high-dose vasopressor support, defined as norepinephrine ≥0.5 μg/kg/min or epinephrine ≥0.25 μg/kg/min.
2. Post-cardiac surgery patients (e.g., coronary artery bypass grafting or valve replacement).
3. Conditions requiring systemic corticosteroid therapy exceeding 1 mg/kg methylprednisolone or an equivalent dose (e.g., acute asthma exacerbation, acute exacerbation of chronic obstructive pulmonary disease, or autoimmune diseases).
4. Long-term systemic corticosteroid use within the past 6 months.
5. Pregnancy or lactation.
6. Brain death.
7. Advanced malignancy or other end-stage disease with an expected survival of less than 6 months, or anticipated death within 24 hours.
8. Known hypersensitivity to methylprednisolone, including but not limited to urticaria, eczema, angioedema, bronchospasm, or anaphylaxis.
9. History of solid organ transplantation or allogeneic hematopoietic stem cell transplantation.
10. Active life-threatening fungal infection or tuberculosis.
11. Neuromuscular disorders affecting spontaneous respiration.
12. Severe inherited or acquired immunodeficiency (e.g., human immunodeficiency virus infection, chronic granulomatous disease, or severe combined immunodeficiency).
13. Do-not-resuscitate (DNR) orders or withdrawal of life-sustaining treatment.
14. Concurrent participation in another interventional clinical trial.
15. Any other condition that, in the opinion of the treating physician or investigator, would make participation in the study inappropriate.