Corticosteroids in Hyperinflammatory Phenotype of Critical Illness (CHIP)

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

Study Overview

• Status: Recruiting
• Conditions: Sepsis; Acute Respiratory Distress Syndrome
• Intervention / Treatment: Drug: Methylprednisolone (MP); Drug: Methylprednisolone (MP); Drug: Placebo

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Estimated): 150
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Bin Du; Phone Number: +86 6916 5643; Email: dubin98@gmail.com

Study Locations

• China
  • Beijing Municipality
    • Beijing, Beijing Municipality, China, 100730
      • Recruiting
      • Peking Union Medical College Hospital
      • Contact: Bin Du, MD; Phone Number: 8601069155036; Email: dubin98@gmail.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: high dose methylprednisolone group; Methylprednisolone 80 mg intravenously every 12 hours for the first 3 days. On day 4, prior to administration, patients will be reassessed; if the hyperinflammatory phenotype persists, the dose will be reduced to 40 mg every 12 hours and continued until day 7 or ICU discharge, whichever occurs first. Treatment will be discontinued if patients transition to a hypoinflammatory phenotype on day 4.	Drug: Methylprednisolone (MP); Methylprednisolone 80 mg intravenously every 12 hours for the first 3 days. On day 4, prior to administration, patients will be reassessed; if the hyperinflammatory phenotype persists, the dose will be reduced to 40 mg every 12 hours and continued until day 7 or ICU discharge, whichever occurs first. Treatment will be discontinued if patients transition to a hypoinflammatory phenotype on day 4.; Drug: Methylprednisolone (MP); Methylprednisolone 40 mg intravenously every 12 hours for the first 3 days. On day 4, prior to administration, patients will be reassessed; if the hyperinflammatory phenotype persists, the dose will be reduced to 20 mg every 12 hours and continued until day 7 or ICU discharge, whichever occurs first. Treatment will be discontinued if patients transition to a hypoinflammatory phenotype on day 4.
Experimental: low dose methylprednisolone group; Methylprednisolone 40 mg intravenously every 12 hours for the first 3 days. On day 4, prior to administration, patients will be reassessed; if the hyperinflammatory phenotype persists, the dose will be reduced to 20 mg every 12 hours and continued until day 7 or ICU discharge, whichever occurs first. Treatment will be discontinued if patients transition to a hypoinflammatory phenotype on day 4.	Drug: Methylprednisolone (MP); Methylprednisolone 80 mg intravenously every 12 hours for the first 3 days. On day 4, prior to administration, patients will be reassessed; if the hyperinflammatory phenotype persists, the dose will be reduced to 40 mg every 12 hours and continued until day 7 or ICU discharge, whichever occurs first. Treatment will be discontinued if patients transition to a hypoinflammatory phenotype on day 4.; Drug: Methylprednisolone (MP); Methylprednisolone 40 mg intravenously every 12 hours for the first 3 days. On day 4, prior to administration, patients will be reassessed; if the hyperinflammatory phenotype persists, the dose will be reduced to 20 mg every 12 hours and continued until day 7 or ICU discharge, whichever occurs first. Treatment will be discontinued if patients transition to a hypoinflammatory phenotype on day 4.
Placebo Comparator: placebo group; Normal saline (100 mL) will be administered intravenously every 12 hours for the first 3 days. On day 4, patients will be reassessed prior to dosing; if the hyperinflammatory phenotype persists, normal saline (100 mL) will continue to be administered every 12 hours until day 7 or ICU discharge, whichever occurs first. Treatment will be discontinued if patients transition to a hypoinflammatory phenotype on day 4.	Drug: Placebo; Normal saline (100 mL) will be administered intravenously every 12 hours for the first 3 days. On day 4, patients will be reassessed prior to dosing; if the hyperinflammatory phenotype persists, normal saline (100 mL) will continue to be administered every 12 hours until day 7 or ICU discharge, whichever occurs first. Treatment will be discontinued if patients transition to a hypoinflammatory phenotype on day 4.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of patients with a decrease in mean Sequential Organ Failure Assessment (SOFA) score ≥1.4 points from baseline to Day 9	The outcome is defined as the proportion of patients achieving a decrease of ≥1.4 points in mean SOFA score from baseline to Day 9. The mean change in SOFA score is calculated as the baseline SOFA score (Day 1) minus the average SOFA score from Days 2 through 9.The lowest possible SOFA score is 0, and the highest is 24. The higher the score, the more severe the organ dysfunction.	From baseline (Day 1) to Day 9

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
30-day Organ Support Free Days (OSFD)	Organ Support Free Days (OSFD) is defined as the number of days within 30 days where the patient survives without the need for any organ support, including respiratory support (mechanical ventilation and extracorporeal membrane oxygenation [ECMO]), circulatory support (vasopressors, positive inotropic agents, intra-aortic balloon pump [IABP], and ECMO), and renal replacement therapy. If the patient dies within 30 days, OSFD is recorded as 0 days.	From randomization to 30 days
30-day mortality	30-day mortality is defined as death from any cause within 30 days after randomization.	From randomization to 30 days
Incidence and severity of adverse events and serious adverse events during treatment	The outcome includes the incidence and severity of adverse events (AEs) and serious adverse events (SAEs) during the treatment period. Adverse events of interest include hyperglycemia (requiring insulin therapy in non-diabetic patients or increased insulin dosage in diabetic patients), gastrointestinal bleeding, muscle weakness, barotrauma (including pneumothorax, pneumomediastinum, subcutaneous emphysema, or imaging-confirmed findings), new-onset infection (hospital-acquired infections as determined by the treating physician), respiratory acidosis, severe acidosis (pH < 7.10), refractory hypoxemia (PaO₂ < 55 mmHg), severe hypotension (mean arterial pressure < 60 mmHg), new-onset arrhythmia (including atrial fibrillation or supraventricular tachycardia), cardiac arrest, and all reported serious adverse events.	During the treatment period (from randomization to Day 7 or ICU discharge, whichever occurs first)

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Length of ICU stay	Length of ICU stay is defined as the time from randomization to ICU discharge. Patients who remain in the ICU at 30 days after randomization or die during ICU stay will be assigned a value of 30 days.	From randomization to 30 days
Length of hospital stay	Length of hospital stay is defined as the time from randomization to hospital discharge. Patients who remain hospitalized at 30 days after randomization or die during hospitalization will be assigned a value of 30 days.	From randomization to 30 days
30-day ventilator-free days (VFD)	Ventilator-free days (VFD) are defined as the number of days from successful extubation to 30 days after randomization. Successful extubation is defined as liberation from mechanical ventilation for at least 48 hours without reintubation. Patients who remain ventilated at 30 days or die within 30 days will be assigned 0 ventilator-free days.	From randomization to 30 days
30-day vasopressor-free days	Vasopressor-free days are defined as the number of days from the last discontinuation of circulatory support to 30 days after randomization. Circulatory support includes vasopressors, inotropic agents, intra-aortic balloon pump (IABP), and extracorporeal membrane oxygenation (ECMO). Discontinuation is defined as cessation of vasopressors and inotropes for at least 48 hours without reinitiation. Patients who remain on circulatory support at 30 days or die within 30 days will be assigned 0 vasopressor-free days.	From randomization to 30 days
30-day renal replacement therapy-free days	Renal replacement therapy (RRT)-free days are defined as the number of days from the last discontinuation of RRT to 30 days after randomization. Discontinuation is defined as cessation of RRT for at least 48 hours without reinitiation. Patients who remain on RRT at 30 days or die within 30 days will be assigned 0 RRT-free days.	From randomization to 30 days
Probability of transition from hyperinflammatory to hypoinflammatory phenotype	The probability of transition from hyperinflammatory to hypoinflammatory phenotype is assessed at Days 4, 7, 9, and 15 after randomization.	At Days 4, 7, 9, and 15 after randomization
Biomarker levels after randomization	Levels of inflammatory biomarkers including C-reactive protein (CRP), procalcitonin (PCT), neutrophil-to-lymphocyte ratio (NLR), interleukin-6 (IL-6), IL-8, IL-10, tumor necrosis factor-alpha (TNF-α), protein C, soluble tumor necrosis factor receptor 1 (sTNFR1), ferritin, and HLA-DR expression on CD45+/CD14+ monocytes.	At Days 4, 7, 9, and 15 after randomization
Sequential Organ Failure Assessment (SOFA) score	SOFA scores are assessed longitudinally to evaluate organ dysfunction over time. The lowest possible SOFA score is 0, and the highest is 24. The higher the score, the more severe the organ dysfunction.	From Day 1 to Day 9 and Day 15 after randomization
Vasoactive-Inotropic Score (VIS)	VIS is calculated as: dopamine (μg/kg/min) + dobutamine (μg/kg/min) + 10 × milrinone (μg/kg/min) + 100 × epinephrine (μg/kg/min) + 100 × norepinephrine (μg/kg/min) + 10000 × vasopressin (U/kg/min). The minimum VIS score is 0, but there is no fixed maximum score. The higher the score, the greater the dose of vasoactive medications.	At Days 4, 7, 9, and 15 after randomization

Collaborators and Investigators

• Sponsor: Bin Du

Publications and helpful links

General Publications

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• Angus DC, Derde L, Al-Beidh F, Annane D, Arabi Y, Beane A, van Bentum-Puijk W, Berry L, Bhimani Z, Bonten M, Bradbury C, Brunkhorst F, Buxton M, Buzgau A, Cheng AC, de Jong M, Detry M, Estcourt L, Fitzgerald M, Goossens H, Green C, Haniffa R, Higgins AM, Horvat C, Hullegie SJ, Kruger P, Lamontagne F, Lawler PR, Linstrum K, Litton E, Lorenzi E, Marshall J, McAuley D, McGlothin A, McGuinness S, McVerry B, Montgomery S, Mouncey P, Murthy S, Nichol A, Parke R, Parker J, Rowan K, Sanil A, Santos M, Saunders C, Seymour C, Turner A, van de Veerdonk F, Venkatesh B, Zarychanski R, Berry S, Lewis RJ, McArthur C, Webb SA, Gordon AC; Writing Committee for the REMAP-CAP Investigators; Al-Beidh F, Angus D, Annane D, Arabi Y, van Bentum-Puijk W, Berry S, Beane A, Bhimani Z, Bonten M, Bradbury C, Brunkhorst F, Buxton M, Cheng A, De Jong M, Derde L, Estcourt L, Goossens H, Gordon A, Green C, Haniffa R, Lamontagne F, Lawler P, Litton E, Marshall J, McArthur C, McAuley D, McGuinness S, McVerry B, 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Study record dates

Study Major Dates

• Study Start (Actual): April 15, 2026
• Primary Completion (Estimated): April 1, 2028
• Study Completion (Estimated): June 1, 2028

Study Registration Dates

• First Submitted: March 30, 2026
• First Submitted That Met QC Criteria: March 30, 2026
• First Posted (Actual): April 6, 2026

Study Record Updates

• Last Update Posted (Actual): May 26, 2026
• Last Update Submitted That Met QC Criteria: May 21, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Keywords: Acute respiratory distress syndrome; Sepsis; Corticosteroids; Hyperinflammatory phenotype
• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Respiratory Tract Diseases; Systemic Inflammatory Response Syndrome; Inflammation; Lung Diseases; Respiration Disorders; Pathological Conditions, Signs and Symptoms; Respiratory Distress Syndrome; Sepsis; Polycyclic Compounds; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Pregnadienetriols; Prednisolone; Methylprednisolone
• Other Study ID Numbers: K10358

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No