A Phase Ib Trial of Inhaled Carbon Monoxide for the Treatment of Pneumonia and Sepsis-Induced Acute Respiratory Distress Syndrome (ARDS)
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 入组人数
- 5
- 试验地点
- 6
- 主要终点
- Accuracy of the Coburn-Forster-Kane (CFK) equation-based personalized iCO dosing algorithm to achieve a COHb level of 6-8%
研究概览
简要总结
This study is a multi-center, randomized, partially double-blind, and placebo-controlled Phase Ib clinical trial of inhaled CO (iCO) for the treatment of sepsis-induced acute respiratory distress syndrome (ARDS). The purpose of this study is to evaluate the safety and accuracy of a Coburn-Forster-Kane (CFK) equation-based personalized iCO dosing algorithm to achieve a target carboxyhemoglobin (COHb) level of 6-8% in patients with sepsis-induced ARDS. We will also examine the biologic readouts of low dose iCO therapy in patients with sepsis-induced ARDS.
详细描述
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. Furthermore, no specific effective pharmacologic therapies currently exist. Sepsis, life-threatening organ dysfunction caused by a dysregulated host response to infection, represents a major risk for the development of ARDS and multi-organ dysfunction syndrome (MODS). In recent years, the number of patients with severe sepsis has risen to 750,000 per year in the U.S., which bears an alarming forecast for critically ill patients in the intensive care unit with significant risk for the development of ARDS. 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 sepsis-induced ARDS based on data obtained in experimental models of sepsis and 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 sepsis-induced 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 accuracy of a CFK equation-based iCO personalized dosing algorithm of inhaled carbon monoxide (iCO) to achieve a target COHb level of 6-8% in mechanically ventilated patients with sepsis-induced 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 assignment will be blinded to the subject, clinical team, study coordinators, and other study staff with the exception of the administering study staff (respiratory therapist and physician or physician alone), who will be unblinded to the treatment assignment to ensure subject safety.
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 patients (age 18 and older) will be eligible for inclusion if they meet all of the following consensus criteria for sepsis and ARDS3,4 or if they meet the criteria for pneumonia as described below.
- •Patients with sepsis are defined as those with life-threatening organ dysfunction caused by a dysregulated host response to infection:
- •Suspected or proven infection: Sites of infection include thorax, urinary tract, abdomen, skin, sinuses, central venous catheters, and central nervous system
- •Increase in Sequential Organ Failure Assessment (SOFA) Score ≥ 2 over baseline
- •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 is present
- •Pneumonia (without ARDS or sepsis) will be defined as a unilateral or bilateral lung infiltrate on chest X-ray or chest CT (not fully explained by effusions, lobar/lung collapse or nodules) in the setting of receiving mechanical ventilation, a new suspected respiratory infection, an increase in SOFA score less than 2 at the time of randomization (baseline).
- •Pneumonia (with sepsis, without ARDS) will be defined as a unilateral or bilateral lung infiltrate on chest X-ray or chest CT (not fully explained by effusions, lobar/lung collapse or nodules) in the setting of receiving mechanical ventilation and a new suspected respiratory infection with an increase in SOFA score of ≥ 2 over baseline at the time of randomization. Pneumonia with bilateral opacities, PaO2/FiO2 ratio ≤ 300, or an increase in SOFA score greater than or equal to 2 over baseline will continue to be considered ARDS and sepsis.
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 line 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
- •Severe cardiopulmonary disease classified as New York Heart Association (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
- •Severe airway inhalational injury
- •Use of high frequency oscillatory ventilation
- •Use of extracorporeal membrane oxygenation (ECMO)
- •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 CFK equation-determined personalized dose (200-500 ppm to achieve a COHb level of 6-8%) for up to 90 minutes daily for 3 days.
干预措施: Inhaled Carbon Monoxide at CFK equation-determined personalized dose (200-500 ppm to achieve a COHb level of 6-8%) (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
Accuracy of the Coburn-Forster-Kane (CFK) equation-based personalized iCO dosing algorithm to achieve a COHb level of 6-8%
时间窗: day 1, day 2, and day 3
This will be assessed by comparing the measured 90-minute COHb level and the target COHb level of 6-8% daily on days 1-3.
Primary Safety Outcome: Number of pre-specified administration-related adverse events (AEs).
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 myocardial infarction 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
次要结局
- 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)
- Lung injury score (LIS) on days 1-5 and day 7(7 days)
- PaO2/FiO2 ratio on days 1-5 and day 7(7 days)
- Oxygenation Index (OI) on days 1-5 and day 7(7 days)
- Hospital mortality to day 28 and 60(60 days)
- Montreal Cognitive Assessment- MoCA-Blind(3 months, 6 months)
- Hayling Sentence Completion Test(3 months, 6 months)
- Hospital-free days at day 60(60 days)
- Ventilator-free days at day 28(28 days)
- ICU-free days at day 28(28 days)
研究者
Rebecca Baron
Associate Professor
Brigham and Women's Hospital