PCSK9 and Lipid Metabolism in Sepsis (PALMS) : a Two-center, Phase 1b Randomized, Placebo-controlled, Double-blind, Clinical Trial of Alirocumab in Patients with Sepsis
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- 入组人数
- 50
- 试验地点
- 2
- 主要终点
- Bacterial endotoxin level
研究概览
简要总结
The purpose of this study is to determine whether the drug alirocumab, which may lower cholesterol, can reduce the amount of inflammation caused by an infection that has caused either low blood pressure or difficulty breathing. Participants will be randomized to receive a single IV infusion of alirocumab or a placebo.
详细描述
Sepsis is an inflammatory syndrome with life threatening organ dysfunction resulting from a dysregulated host response to infection. The global burden is estimated to exceed 15 million cases annually. In the United States, the incidence is increasing and currently there are more 1,750,000 cases each year, with more than half requiring intensive care unit (ICU) admission. Further, sepsis cases account for 30%- 50% of all hospital deaths, making it the third leading cause of death in the United States, and is the most expensive reason for hospitalization with annual expenditures exceeding $20 billion. Notably, even among those that do survive, many endure significant reductions in physical, emotional and cognitive quality of life. New therapeutic approaches to reduce the high morbidity and mortality of sepsis are needed.
Current management strategies focus on early aggressive fluid resuscitation, blood pressure support with vasopressors, early appropriate antibiotics, and the identification and control of infected sites. Though outcomes have improved with the bundled deployment of these strategies, mortality remains high at 20 - 30%. Despite over a hundred phase 2 and phase 3 clinical trials of pharmacological agents with the potential to improve sepsis outcomes, only antibiotics have demonstrated reproducible benefits.
Despite decades of research, no specific treatment of the dysregulated host response has proven effective. There is strong biologic plausibility to modulate the PCSK9 pathway in sepsis patients. Alirocumab is a PCSK9 inhibitor that has been shown to reduce LDL cholesterol in normal volunteers and in patients with familial hypercholesterolemia.
Patients admitted to a study site hospital with sepsis or septic shock associated with cardiovascular or respiratory failure will be considered for enrollment. Those meeting eligibility criteria and providing consent for study participation will be randomized to receive alirocumab or a placebo, administered once via IV over an approximately 30 ± 10 minute infusion. Participants will be followed for 180 days.
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, Investigator)
入排标准
- 年龄范围
- 18 Years 至 90 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Suspected or confirmed infection as evidenced by ordering of blood cultures and administration of at least one antimicrobial agent
- •Acute respiratory or cardiovascular organ dysfunction attributed to sepsis as evidenced by at least one of the following requirements:
- •Vasopressor Requirement - Continuous infusion of norepinephrine, epinephrine, vasopressin, dopamine, phenylephrine or other vasopressor agents at any dose for greater than 1 hour and required to maintain a mean arterial pressure ≥ 65 mm Hg despite intravenous crystalloid infusion of at least 1000cc
- •Respiratory Support Requirement - Acute hypoxemic respiratory failure defined as persistent hypoxemia requiring (1) intubation and mechanical ventilation, or (2) positive pressure ventilation via tight-fitting face mask or (3) high flow nasal cannula ≥ 45 liters per minute (LPM) flow and fraction of inspired oxygen (FiO2) ≥ 0.40
- •Anticipated or confirmed intensive care unit (ICU) admission
排除标准
- •Organ dysfunction present > 24 hours at time randomization
- •Limitations of care (defined as refusal of cardiovascular and respiratory support described under inclusion criteria) including "do not intubate" (DNI) status
- •Development of sepsis while in the hospital ( i.e not present on admission to hospital)
- •Chronic hypoxemia requiring supplemental non-invasive oxygen or home mechanical ventilation
- •Chronic cardiovascular failure requiring home mechanical hemodynamic support or home chemical hemodynamic support
- •Known allergy or known contraindication to alirocumab
- •Chronic disease/illness that, in the opinion of the site investigator, have an expected lifespan of < 30 days unrelated to current sepsis diagnosis (e.g, stage IV malignancy, neurodegenerative disease, etc.)
- •Requirement of more than 6 liters (L) nasal cannula (NC) if not receiving invasive mechanical ventilation
- •Pregnancy
- •Prisoner or incarceration
- •Current participation in another interventional pharmaceutical research study for sepsis
- •Inability or unwillingness of subject or legal surrogate/representative to give written informed consent
研究组 & 干预措施
Alirocumab
Critically ill participants with sepsis leading to cardiovascular and/or respiratory failure who are randomized to receive alirocumab.
干预措施: Alirocumab (Drug)
Placebo
Critically ill participants with sepsis leading to cardiovascular and/or respiratory failure who are randomized to receive a placebo to match alirocumab.
干预措施: Placebo (Drug)
结局指标
主要结局
Bacterial endotoxin level
时间窗: Hour 120
Levels of bacterial endotoxin will be compared between study arms.
Lipoteichoic acid level
时间窗: Hour 120
Levels of lipoteichoic acid will be compared between study arms.
次要结局
- ICU Mortality(Up to Day 30)
- Days in Hospital(Up to Day 30)
- Days in ICU(Up to Day 30)
- Interleukin-10 (IL-10) Level(Hour 120)
- Interleukin-1 beta (IL-1 beta) Level(Hour 120)
- Interleukin-6 (IL-6) Level(Hour 120)
- Number of Vasopressor and Ventilation Free Days (VVFD)(Up to Day 30)
- Mortality(Up to Day 30)
- Tumor necrosis factor - alpha (TNF-alpha) Level(Hour 120)
研究者
Jonathan Sevransky
Professor
Emory University