A Phase II Trial of Inhaled Carbon Monoxide for the Treatment of Acute Respiratory Distress Syndrome (ARDS)
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 4
- 试验地点
- 13
- 主要终点
- Primary Safety Outcome: Number of pre-specified administration-related adverse events.
研究概览
简要总结
This study will be a multi-center, prospective, randomized, partially double-blind, placebo-controlled Phase II clinical trial of inhaled CO (iCO) for the treatment of ARDS. The trial will be conducted at 7 tertiary care medical centers including Weill Cornell Medicine/NewYork-Presbyterian Hospital, Brigham and Women's Hospital (BWH), Massachusetts General Hospital (MGH), Duke University Hospital, Durham Veterans Administration Medical Center, New York-Presbyterian Brooklyn Methodist Hospital, and Duke Regional Hospital. The purpose of this study is to evaluate the safety, tolerability, and efficacy of inhaled carbon monoxide (iCO) for the treatment of ARDS and to examine the biologic readouts of low dose iCO therapy in patients with ARDS
详细描述
Acute respiratory distress syndrome (ARDS) is a devastating disease affecting military, veteran, and civilian populations. ARDS is a syndrome of severe acute lung inflammation and hypoxemic respiratory failure with an incidence of 180,000 cases annually in the United States. Despite recent advances in critical care management and lung protective ventilation strategies, ARDS morbidity and mortality remain unacceptably high. The lack of specific effective therapies for ARDS indicates a need for new treatments that target novel pathways. Carbon monoxide (CO) represents a novel therapeutic modality in ARDS based on data obtained in experimental models of ARDS over the past decade.
CO has been shown to be protective in experimental models of acute lung injury (ALI) and sepsis. Furthermore, multiple human studies have demonstrated that experimental administration of several different concentrations of CO is well tolerated and that low dose inhaled CO can be safely administered to subjects in a controlled research environment. The investigators have previously conducted a Phase I trial of low dose iCO in ARDS which demonstrated that precise administration of low dose iCO (100 and 200 ppm) is feasible, well-tolerated, and safe in patients with sepsis-induced ARDS.
The purpose of this study is to assess the safety and efficacy of low dose inhaled carbon monoxide (iCO) therapy in mechanically ventilated patients with ARDS.
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
- Double (Participant, Care Provider)
盲法说明
The study drug will be blinded to the study staff using identical tanks containing either CO or placebo air. The administering respiratory therapist (RT) and a physician study staff member will be unblinded to the treatment assignments.
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
- •All intubated patients ≥ 18 years old with ARDS
- •ARDS is defined when all four of the following criteria are met:
- •A PaO2/FiO2 ratio ≤ 300 with at least 5 cm H2O positive end-expiratory airway pressure (PEEP)
- •Bilateral opacities on frontal chest radiograph (not fully explained by effusions, lobar/lung collapse, or nodules) within 1 week of a known clinical insult or new or worsening respiratory symptoms
- •A need for positive pressure ventilation by an endotracheal or tracheal tube
- •Respiratory failure not fully explained by cardiac failure or fluid overload; need objective assessment (e.g., echocardiography) to exclude hydrostatic edema if no risk factor present.
- •ARDS onset is defined as the time the last of criteria 1-4 are met. ARDS must persist through the enrollment time window of 168 hours.
排除标准
- •An individual who meets any of the following criteria will be excluded from participation in this study:
- •Age less than 18 years
- •Greater than 168 hours since ARDS onset
- •Pregnant or breastfeeding
- •Patient, surrogate, or physician not committed to full support (exception: a patient will not be excluded if he/she would receive all supportive care except for attempts at resuscitation from cardiac arrest)
- •No consent/inability to obtain consent or appropriate legal representative not available
- •Physician refusal to allow enrollment in the trial
- •Moribund patient not expected to survive 24 hours
- •No arterial or central line/no intent to place an arterial or central line
- •No intent/unwillingness to follow lung protective ventilation strategy
- •Severe hypoxemia defined as SpO2 < 95 or PaO2 < 90 on FiO2 ≥ 0.9
- •Hemoglobin < 7.0 g/dL
- •Subjects who are Jehovah's Witnesses or are otherwise unable or unwilling to receive blood transfusions during hospitalization
- •Acute myocardial infarction (MI) or acute coronary syndrome (ACS) within the last 90 days
- •Coronary artery bypass graft (CABG) surgery within 30 days
- •Angina pectoris or use of nitrates with activities of daily living
- •Cardiopulmonary disease classified as NYHA class IV
- •Stroke (ischemic or hemorrhagic) within the prior 1 month, cardiac arrest requiring CPR within the prior 72 hours, or inability to assess mental status following cardiac arrest
- •Burns > 40% total body surface area (TBSA)
- •Severe airway inhalational injury
- •Use of high frequency oscillatory ventilation
- •Use of extracorporeal membrane oxygenation (ECMO)
- •Concomitant use of inhaled pulmonary vasodilator therapy (eg. nitric oxide [NO] or prostaglandins)
- •Diffuse alveolar hemorrhage from vasculitis
- •Concurrent participation in other investigational drug study
研究组 & 干预措施
Inhaled Carbon Monoxide
Inhaled Carbon Monoxide at 200 ppm for up to 90 minutes daily for 3 days.
干预措施: Inhaled Carbon Monoxide at 200 ppm (Drug)
Medical air
Inhaled Medical Air for up to 90 minutes daily for 3 days.
干预措施: Inhaled Medical air (Other)
结局指标
主要结局
Primary Safety Outcome: Number of pre-specified administration-related adverse events.
时间窗: 7 days
Safety of inhaled CO, defined by the incidence of pre-specified administration-related AEs (as defined below) and spontaneously reported AEs through study day 7. 1. Acute MI within 48 hours of study drug administration 2. Acute cerebrovascular accident (CVA) within 48 hours of study drug administration 3. New onset atrial or ventricular arrhythmia requiring DC cardioversion within 48 hours of study drug administration 4. Increased oxygenation requirements defined as: an increase in FiO2 of ≥ 0.2 AND increase in PEEP ≥ 5 cm H2O within 6 hours of study drug administration 5. Increase in COHb ≥ 10% 6. Increase in lactate by ≥ 2 mmol/L within 6 hours of study drug administration
Primary Efficacy Outcome: Change in Mitochondrial DNA (mtDNA) level from day 1 to day 5
时间窗: 5 days
Mitochondrial DNA (mtDNA) plasma levels will be measured by quantitative PCR of human NADH dehydrogenase 1.
Primary Safety Outcome: Number of Pre-specified Administration-related Adverse Events.
时间窗: 7 days
Safety of inhaled CO, defined by the incidence of pre-specified administration-related AEs (as defined below) and spontaneously reported AEs through study day 7. 1. Acute MI within 48 hours of study drug administration 2. Acute cerebrovascular accident (CVA) within 48 hours of study drug administration 3. New onset atrial or ventricular arrhythmia requiring DC cardioversion within 48 hours of study drug administration 4. Increased oxygenation requirements defined as: an increase in FiO2 of ≥ 0.2 AND increase in PEEP ≥ 5 cm H2O within 6 hours of study drug administration 5. Increase in COHb ≥ 10% 6. Increase in lactate by ≥ 2 mmol/L within 6 hours of study drug administration
Primary Efficacy Outcome: Change in Mitochondrial DNA (mtDNA) Level From Day 1 to Day 5
时间窗: 5 days
Mitochondrial DNA (mtDNA) plasma levels will be measured by quantitative PCR of human NADH dehydrogenase 1. The number presented is the percentage average difference from beginning to end of treatment. Limited number of measurements prevents variance analyses; therefore we present the data from the subjects available in each group and report as "Mean" without standard deviation, where measures of dispersion cannot be calculated.
次要结局
- Lung injury score (LIS) on days 1-5, and on day 7(7 days)
- Oxygenation Index (OI) on days 1-5, and day 7(7 days)
- PaO2/FiO2 ratio on days 1-5, and on day 7(7 days)
- Change in biomarkers of mitochondrial quality control(5 days)
- Dead Space Fraction (Vd/Vt) on days 1-3, and day 7(7 days)
- Sequential Organ Failure Assessment (SOFA) score on days 1-5, 7, 14, 28(28 days)
- Change in biomarkers of autophagy(5 days)
- Change in biomarkers of inflammation and inflammasome activation(5 days)
- Change in lipid mediators(5 days)
- Lung Injury Score (LIS) on Days 1-5, and on Days 1-7(7 days)
- Percent Change in PaO2/FiO2 Ratio on Days 1-5, and on Days 1-7(7 days)
- Percent Change in Oxygenation Index (OI) on Days 1-5, and Days 1-7(7 days)
- Percent Change in Dead Space Fraction (Vd/Vt) on Days 1-3, and Days 1-7(7 days)
- Percent Change in Sequential Organ Failure Assessment (SOFA) Score on Days 1-5, and Days 1-7.(1-5 and 1-7 days)
- Absolute Value of Biomarkers of Inflammation and Inflammasome Activation(4 days)
- Percent Change in Lipid Mediators(4 days)
研究者
Rebecca Baron
Associate Professor of Medicine
Brigham and Women's Hospital