Randomized, Double-blind, Placebo-controlled Phase 2a Trial of Efficacy and Safety of Evolocumab for PCSK9 Lowering in Early Acute Sepsis
试验速览
- 阶段
- 2 期
- 入组人数
- 36
- 试验地点
- 3
- 主要终点
- Area under the plasma LTA and LPS curves
研究概览
简要总结
This study evaluates using evolocumab, a currently approved and marketed biologic drug, in a novel way. Patients who present to the emergency room or intensive care unit (ICU) with severe infection are eligible. Either the patient or their designated decision maker will be approached for consent. If they choose to participate they will be given either a single dose of evolocumab, a higher single dose of evolocumab,or a single dose of placebo. Participants will be followed during their stay in the ICU and will receive follow up phone calls at Day 28 and 90.
详细描述
Evolocumab is currently approved and marketed in USA and Canada for lowering cholesterol levels. Evolocumab is an anti-PSCK9 monoclonal antibody, and functions by binding PSCK9 (an inhibitor of LDL removal) and blocking its function. Evidence suggests that since evolocumab increases the removal rate of low-density lipoproteins from the body, it might also help increase the removal of bacterial components that are attached to circulating lipids during sepsis. Quickly removing these bacterial components could prevent a strong and rapid immune response that often leads to organ failure and death in sepsis patients.
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
- Triple (Participant, Care Provider, Outcomes Assessor)
入排标准
- 年龄范围
- 19 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Signed informed consent
- •At least 19 years of age
- •Known or suspected infection
- •AND one or more of the following organ dysfunctions judged due to sepsis:
- •Cardiovascular- refractory hypotension (a systolic blood pressure (SBP) < 90 mm Hg or mean arterial pressure (MAP) < 60 mm Hg despite an IV fluid challenge of at least 30 ml/kg fluids), or use of vasopressor(s) to maintain SAP > 90 mm Hg or MAP > 60 mm Hg, or;
- •Respiratory: PaO2/FiO2 < 300 or PaO2/FiO2 < 200 if lung is the only organ dysfunction or SaO2:FiO2 150
排除标准
- •Known pregnancy
- •Underlying severe congestive heart failure (New York Heart Association (NYHA) IV), severe COPD (need for chronic oxygen or mechanical ventilation), severe liver disease (Child-Pugh Class C), cancer requiring chemotherapy, or transplantation (bone marrow, heart, lung, liver, pancreas, or small bowel) in the past 6 months or likely within the next 6 months
- •Previous episode of sepsis during that hospital admission
- •Absolute Neutrophil Count < 500/mm³
- •CD4 count < 50/mm³
- •Treating physician deems aggressive care unsuitable (i.e. no commitment to active care)
- •Participation in another interventional drug study within previous 1 month
- •Allergic to the study drug or any of its components
- •Lactation
- •Have signed a Do No Resuscitate (DNR) Form
研究组 & 干预措施
Low Dose
This treatment arm will receive the highest dose of evolocumab currently marketed and approved: 420mg. The dose will be given at a single time point within 4 hours of randomization. The dose will be administered through three subcutaneous injections, each in a different quadrant of the abdomen.
干预措施: Evolocumab (Drug)
High Dose
This treatment arm will receive double the highest dose of evolocumab currently marketed and approved: 840mg. The dose will be given at a single time point within 4 hours of randomization. The dose will be administered through three subcutaneous injections, each in a different quadrant of the abdomen.
干预措施: Evolocumab (Drug)
Placebo
This treatment arm will receive saline solution. The dose will be given at a single time point within 4 hours of randomization. The dose will be administered through three subcutaneous injections, each in a different quadrant of the abdomen.
干预措施: Placebo (Drug)
结局指标
主要结局
Area under the plasma LTA and LPS curves
时间窗: 7 days or less (as data is collected from participants only while they are admitted to critical care, they may be discharged or moved to a different ward before day 7 and therefore subsequent time points would be not be collected)
Determine whether evolocumab decreases plasma levels of bacterial LPS and LTA, at 6, 24, 48 and 72 hours, and day 7 by comparing the area under the operating curve between arms.
次要结局
- Changes in 28-day mortality(28 days)
- Level of organ support(28 days or less (may be discharged from critical care before day 28))
- Changes in Vitals: norepinephrine dose(28 days or less (may be discharged from critical care before day 28))
- Levels of LDL-C(7 days or less (as data is collected from participants only while they are admitted to critical care, they may be discharged or moved to a different ward before day 7 and therefore subsequent time points would be not be collected))
- Levels of cytokines IL-6, TNF-alpha and IL-8(7 days or less (as data is collected from participants only while they are admitted to critical care, they may be discharged or moved to a different ward before day 7 and therefore subsequent time points would be not be collected))
- Concentration of circulating evolocumab and circulating free PCSK9 in septic patients(7 days or less (may be discharged from critical care before day 7))
- Safety outcomes: changes in urine density(28 days or less (may be discharged from critical care before day 28))
- Safety outcomes: changes in urine pH(28 days or less (may be discharged from critical care before day 28))
- Cmax of circulating evolocumab and circulating free PCSK9 in septic patients(7 days or less (may be discharged from critical care before day 7))
- Days alive(28 days or less (may be discharged from critical care before day 28))
- Level of organ dysfunction(28 days or less (may be discharged from critical care before day 28))
- Changes in Vitals: lactate(28 days or less (may be discharged from critical care before day 28))
- Changes in Vitals: heart rate(28 days or less (may be discharged from critical care before day 28))
- Safety outcomes: changes in concentration of ketones in urine(28 days or less (may be discharged from critical care before day 28))
- Changes in Vitals: temperature(28 days or less (may be discharged from critical care before day 28))
- Safety outcomes: changes in blood cell counts(28 days or less (may be discharged from critical care before day 28))
- Changes in Vitals: mean arterial pressure(28 days or less (may be discharged from critical care before day 28))
- Changes in Vitals: respiratory rate(28 days or less (may be discharged from critical care before day 28))
- Changes in Vitals: urine output(28 days or less (may be discharged from critical care before day 28))
- Safety outcomes: Number of treatment-related adverse events as ranked by severity(Day 1 to Day 90)
- Changes in Vitals: fluid balance(28 days or less (may be discharged from critical care before day 28))
- Safety outcomes: changes in coagulation(28 days or less (may be discharged from critical care before day 28))
- Safety outcomes: changes in blood analytes(28 days or less (may be discharged from critical care before day 28))
- Safety outcomes: document other urine abnormalities if required(28 days or less (may be discharged from critical care before day 28))
研究者
john boyd
Associate Professor
University of British Columbia