Randomized, Placebo-Controlled, Double-Blind Clinical Trial to Evaluate the Safety and Efficacy of Low-Dose Glucocorticoid Infusion in Acute Respiratory Distress Syndrome (ARDS)
试验速览
- 阶段
- 2 期
- 入组人数
- 400
- 试验地点
- 1
- 主要终点
- The primary aim is to determine if low-dose methylprednisolone infusion, compared to placebo, will reduce all cause 28-day mortality, defined as the proportion of patients alive in each group on study day 28 at midnight.
研究概览
简要总结
Scientific background. Dysregulated systemic inflammation is a key pathogenetic mechanism for morbidity and mortality in ALI/ARDS, and is associated with tissue insensitivity and/or resistance to inappropriately elevated endogenous glucocorticoids. In one study, prolonged methylprednisolone treatment of ARDS patients resulted in rapid and sustained reduction in circulating and pulmonary levels of pro-inflammatory cytokines, chemokines, and procollagen.
Preliminary work. Five randomized trials (N = 518) investigating prolonged glucocorticoid treatment in acute lung injury/ARDS reported a significant physiological improvement and a sizable reduction in duration of mechanical ventilation and ICU length of stay. Insufficient data is available on the effects of low dose prolonged methylprednisolone treatment initiated in early ALI/ARDS on mortality.
Hypothesis. We hypothesized that the anti-inflammatory activity associated with prolonged methylprednisolone administration improves pulmonary and extra-pulmonary organ dysfunction in early ALI/ARDS and reduces mortality.
Objective. To investigate the effects of prolonged low-dose methylprednisolone infusion on mortality and morbidity in early ALI/ARDS.
Study design. Multicenter, prospective randomized, placebo-controlled, double-blind clinical trial.
Entry criteria. Patients with ALI/ARDS of less than 72 hours duration.
Stratification. Patients are prospectively stratified prior to randomization as (1) intubated versus NPPV treated, and (2) ARDS versus severe ARDS. The purpose of stratification is to distribute equally in both arms intubated versus NPPV treated, and ARDS versus severe ARDS.
End-points. The primary end-point of trial is 28 days all cause mortality; the secondary end-points are (a) ventilator-free days at 28 days following study entry, (b) organ failure-free days at 28 days following study entry, and (c) duration of ICU stay.
详细描述
SCIENTIFIC BACKGROUND. Acute respiratory distress syndrome (ARDS) is a life-threatening form of acute hypoxemic respiratory failure that develops rapidly (12-48 hours), in the setting of an acute severe illness complicated by systemic inflammation.
Overall mortality in ARDS is 35-60%, with most nonsurvivors dying within two weeks of disease development. While a regulated inflammatory response is critical to survival, a major predictor of poor outcome in ARDS patients is persistence of pulmonary and systemic inflammation after one week of lung injury. Innate or treatment-induced downregulation of systemic inflammation is important to the resolution of ARDS.Failure to downregulate the production of inflammatory mediators (dysregulated inflammation) is associated with maladaptive lung repair and inability to improve ACM permeability, gas exchange, and lung mechanics over time.
In a phase II randomized controlled trial, Meduri and collaborators tested the hypothesis that prolonged administration of low dose methylprednisolone (1mg/Kg/day) initiated in early severe ARDS (within 72 h of diagnosis) downregulates systemic inflammation and leads to earlier resolution of pulmonary organ dysfunction and a reduction in duration of mechanical ventilation and ICU stay. The pre-defined primary end point to terminate the trial was a 1-point reduction in Lung Injury Score (LIS) or successful extubation by day 7. The duration of treatment was up to 28 days. In intention-to-treat analysis, the response of the two groups (63 treated and 28 control) clearly diverged by day 7 with twice the proportion of treated patients achieving a 1-point reduction in LIS (69.8% vs. 35.7%; P = 0.002) and breathing without assistance (53.9% vs. 25.0%; P = 0.01). Improvement by day 7 correlated with survival by day 7 (R = 0.41; P < 0.001) and hospital survival (R = 0.59; P < 0.001). Treatment was associated with a reduction in the duration of mechanical ventilation (5 vs. 9.5; P = 0.002), ICU stay (7 vs. 14.5; P = 0.007), and ICU mortality (79.4% vs. 57.4%; P = 0.03). At one year, the absolute difference in mortality was 17% (63.5% vs. 46.4%; P = 0.13).
The primary objective of the trial was to test the effect of treatment on lung function; a new larger trial is therefore needed to evaluate the effect of methylprednisolone treatment on survival. The primary aim of the proposed randomized trial is to determine if low-dose methylprednisolone infusion, compared to placebo, will reduce all cause 28-day mortality. Among patients admitted to the ICU with ALI/ARDS, we hypothesize that methylprednisolone infusion will reduce 28-day all cause mortality from 50% to 33% (aggregate data from five randomized studies).
SPECIFICS. In patients with ARDS, the administration of prolonged methylprednisolone treatment will decrease (in comparison to placebo):
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
- •Age. Patients age 18 years or older admitted to the intensive care unit.
- •ALI/ARDS criteria. The diagnosis of ALI/ARDS requires all of the following criteria:
- •Respiratory failure requiring mechanical ventilation - via endotracheal intubation or noninvasive positive pressure ventilation
- •Acute onset of bilateral pulmonary densities on chest radiograph in the contest of appropriate predisposing injury or illness with no evidence of left ventricular failure,
- •Static pulmonary compliance < 50 cm H2O
- •Ratio of partial pressure of arterial oxygen to partial pressure of alveolar oxygen (PaO2:FiO2 ) equal or less than 300 (criteria for ALI) or 200 (criteria for ARDS) with FiO2 1.
- •Severe ARDS. PaO2:FiO2 equal or less than 200 after 30 minutes of standardized ventilatory management on PEEP of 10 cm H2O with FiO2 1.0.
排除标准
- •Failure to obtain written informed consent from the patient or a next of kin.
- •Trauma-induced ARDS.
- •Major gastrointestinal bleeding requiring transfusion of 5 units or more of packed red blood cells (PRBC) within 3 months current hospitalization
- •Condition requiring > 0.5mg/Kg/day of prednisone equivalent (i.e., acute asthma or chronic obstructive pulmonary disease [COPD])
- •Patients enrolled in another experimental (interventional) protocol within the past 30 days, which might adversely impact on the results of this study as determined by the investigators
- •Pregnancy confirmed by urine or serum test
- •Weight is > 200% of ideal body weight
- •Non-ambulatory resident of long-term care facility
- •Primary care physician not committed to full, aggressive support of the patient at the time of randomization
- •Moribund patient (i.e., not expected to live more than 24 hr) or with recent (within 7 days or anytime during present hospitalization) cardiopulmonary arrest
- •Known or suspected irreversible cessation of all brain function
- •Presence of preexisting medical condition which is irreversible and expected to be fatal within 3 months
- •Immunosuppression including HIV+ status, history of bone marrow or solid organ transplantation, current malignancy, neutropenia, receiving cytotoxic therapy for any reason, and acute burn injury
- •Severe chronic liver disease (Child-Pugh Class C score > 10 points)
研究组 & 干预措施
1
Methylprednisolone
干预措施: Methylprednisolone (Drug)
2
干预措施: Normal saline intravenously and vitamin B1 per os (Other)
结局指标
主要结局
The primary aim is to determine if low-dose methylprednisolone infusion, compared to placebo, will reduce all cause 28-day mortality, defined as the proportion of patients alive in each group on study day 28 at midnight.
时间窗: one year
次要结局
- The secondary aims are the effects of treatment on: a. Systemic inflammation b. Duration of mechanical ventilation c. Multiple organ dysfunction syndrome d. Duration of ICU and hospital stay e. Cardiovascular morbidity-mortality f. Complications(one year)