Efficacy, Safety, and Tolerability of Methylprednisolone in Critically Ill Patients With the Hyperinflammatory Phenotype: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Phase II Trial
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 发起方
- 入组人数
- 150
- 试验地点
- 1
- 主要终点
- Proportion of patients with a decrease in mean SOFA score ≥1.4 points from baseline to Day 9
研究概览
简要总结
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
详细描述
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:
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Participants must meet all of the following criteria:
- •Age ≥18 years.
- •Diagnosis of acute respiratory distress syndrome (ARDS) or sepsis.
- •ARDS will be defined according to standard criteria:
- •acute onset within 1 week of a known clinical insult or new/worsening respiratory symptoms;
- •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;
- •respiratory failure not fully explained by cardiac failure or fluid overload;
- •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.
- •Admission to the intensive care unit (ICU).
- •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.
- •Provision of written informed consent by the patient or their legally authorized representative.
排除标准
- •Participants meeting any of the following criteria will be excluded:
- •Requirement for high-dose vasopressor support, defined as norepinephrine ≥0.5 μg/kg/min or epinephrine ≥0.25 μg/kg/min.
- •Post-cardiac surgery patients (e.g., coronary artery bypass grafting or valve replacement).
- •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).
- •Long-term systemic corticosteroid use within the past 6 months.
- •Pregnancy or lactation.
- •Brain death.
- •Advanced malignancy or other end-stage disease with an expected survival of less than 6 months, or anticipated death within 24 hours.
- •Known hypersensitivity to methylprednisolone, including but not limited to urticaria, eczema, angioedema, bronchospasm, or anaphylaxis.
- •History of solid organ transplantation or allogeneic hematopoietic stem cell transplantation.
- •Active life-threatening fungal infection or tuberculosis.
- •Neuromuscular disorders affecting spontaneous respiration.
- •Severe inherited or acquired immunodeficiency (e.g., human immunodeficiency virus infection, chronic granulomatous disease, or severe combined immunodeficiency).
- •Do-not-resuscitate (DNR) orders or withdrawal of life-sustaining treatment.
- •Concurrent participation in another interventional clinical trial.
- •Any other condition that, in the opinion of the treating physician or investigator, would make participation in the study inappropriate.
研究组 & 干预措施
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.
干预措施: Placebo (Drug)
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.
干预措施: Methylprednisolone (MP) (Drug)
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.
干预措施: Methylprednisolone (MP) (Drug)
结局指标
主要结局
Proportion of patients with a decrease in mean SOFA score ≥1.4 points from baseline to Day 9
时间窗: From baseline (Day 1) 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.
Proportion of patients with a decrease in mean Sequential Organ Failure Assessment (SOFA) score ≥1.4 points from baseline to Day 9
时间窗: From baseline (Day 1) 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.
次要结局
- 30-day Organ Support Free Days (OSFD)(From randomization to 30 days)
- 30-day mortality(From randomization to 30 days)
- Incidence and severity of adverse events and serious adverse events during treatment(During the treatment period (from randomization to Day 7 or ICU discharge, whichever occurs first))
研究者
Bin Du
Senior Consultant Physician; Professor
Peking Union Medical College Hospital