Selective Cytopheresis Therapy in Systemic Inflammatory Response Syndrome

全身炎症反应综合征的选择性细胞分离疗法

• 批准号: 8312409
• 负责人: DEBORAH Ann BUFFINGTON
• 金额: $ 73.96万
• 依托单位: INNOVATIVE BIOTHERAPIES, INC.
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-03-01 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8312409
• 关键词: Acute; Acute Kidney Failure; Acute Renal Failure with Renal Papillary Necrosis; Adult Respiratory Distress Syndrome; Affect; Animal Model; Antibiotics; Anticoagulation; Apoptosis; Area; Artificial Organs; Binding; Biological Response Modifier Therapy; Biomedical Engineering; Biomimetics; Blood; Blood Volume; Blood capillaries; Blood flow; Calcium; Cardiac; Cardiovascular system; Caring; Catheters; Cause of Death; Cells; Cessation of life; Characteristics; Chronic; Citrates; Clinical; Clinical Trials; Coagulation Process; Computer Simulation; Critical Illness; Custom; Data; Devices; Disease; Disease Progression; Environment; FDA approved; Family suidae; Fiber; Functional disorder; Future; Generations; Goals; Grant; Hospitals; Imagery; Immune response; In Vitro; Inflammation; Inflammation Mediators; Inflammatory; Innovative Therapy; Intensive Care Units; Investigation; Kidney; Kinetics; Knowledge; Leukocytes; Leukopenia; Liquid substance; Lung; Marketing; Medical; Membrane; Michigan; Modeling; Neutrophil Activation; Organ failure; Outcome; Pathogenesis; Patients; Phase; Pneumonia; Process; Proteins; Public Health; Randomized; Renal Replacement Therapy; Research Proposals; Resuscitation; Risk; Safety; Sepsis; Sepsis Syndrome; Septic Shock; Site; Surface; System; Testing; Therapeutic; Time; Tissues; Treatment Efficacy; United States; Universities; Variant; Venous; base; capillary; clinical effect; clinical research site; comparative efficacy; cytokine; density; design; hemodynamics; immunoregulation; improved; indexing; inflammatory modulation; innovation; mortality; neutrophil; novel therapeutic intervention; novel therapeutics; patient population; phase 1 study; polysulphone; pre-clinical; prototype; septic; simulation; therapy design

DESCRIPTION (provided by applicant): Leukocytes (LE) are major contributors to the pathogenesis and progression of many clinical inflammatory disorders, including the systemic inflammatory response syndrome, sepsis and acute respiratory distress syndrome. The need for new and innovative therapies to treat these inflammatory disease states presents a large commercial market opportunity. A large number of therapeutic approaches are under investigation to limit the activation and tissue accumulation of LE at sites of inflammation in order to minimize tissue destruction and disease progression. A therapeutic device within an extracorporeal blood circuit, called the selective cytopheretic device (SCD), sequesters activated LE in a low calcium environment and inhibits their release of inflammatory proteins and cytokines. This Phase II research proposal builds on the Phase I goals which successfully demonstrated the 1st generation SCD1G to have greater therapeutic efficacy with increasing surface area (SA) in a large animal model of septic shock, when compared to sham treated controls, in addition to establishing a simplified SCD extracorporeal circuit for ease of use under standard-of- care hospital settings. This Phase II proposal will determine the design and fabrication of a 2nd Generation SCD2G. Custom SCD2G designs will maintain the low shear force and low ionized calcium environment, shown to be efficacious for SCDG1, with variations to include flow path, flow rates, packing density, and SA, in addition to reduced blood fill volumes which were not achievable with the SCD1G commercially available hollow fiber cartridges. The lower blood fill volume and blood flow rate requirements, will allow SCD2G therapy to be administered via a peripherally inserted central catheter (PICC line) or to criticall ill patients with hemodynamic instability. SCD2G designs will be evaluated in silico via computational flow dynamics simulation to assess casing design and internal device geometry. Prototypes will be fabricated and flow visualization studies performed to determine designs with advantageous flow profiles (Aim 1). In vitro blood circuits with fresh blood will be used to evaluate SCD2G designs selected from in silico studies with respect to hemocompatibility and LE binding characteristics (Aim 2). Lastly, selected SCD2G designs will be evaluated in the porcine model of septic shock used in the Phase I studies. Various renal and cardiovascular parameters, pulmonary inflammation, cytokine levels, systemic neutrophil activation load and time to death will be compared between SCDG2 designs of varying SA and the SCDG1 (Aim 3). SCDG1 therapy has demonstrated an excellent safety profile and compelling efficacy impact in three exploratory clinical trials, reducing mortality rates from the control rate of 60% to 30%, in ICU patients with acute renal failure requiring continuous renal replacement therapy; 50-60% of these patients were also septic. This proposal will determine a finalized SCD2G design to treat a broad array of patients with sepsis, severe sepsis and septic shock and will provide data for an application to the FDA for IDE approval for the SCD to be used in the treatment of sepsis. PUBLIC HEALTH RELEVANCE: The goal of this proposal is to develop a Second Generation Selective Cytopheretic Device (SCD2G), an extracorporeal membrane device that can sequester activated leukocytes and inhibit their inflammatory activity in order to reduce tissue accumulation and resulting damage in patients. Inflammatory diseases such as sepsis and Systemic Inflammatory Response Syndrome (SIRS) are high impact medical indications, as severe sepsis with SIRS occurs in 200,000 patients annually in the U.S. and has a mortality rate of 30-40%, even with use of intensive care units and broad spectrum antibiotics. The relevance of this proposal to public health is that the SCD would greatly reduce the multiorgan effects of sepsis and SIRS, thus improving the clinical outcome of patients affected by these disease processes.

描述（由申请方提供）：白细胞（LE）是许多临床炎症性疾病（包括全身炎症反应综合征、脓毒症和急性呼吸窘迫综合征）发病机制和进展的主要贡献者。对治疗这些炎性疾病状态的新的和创新的疗法的需求带来了巨大的商业市场机会。大量的治疗方法正在研究中，以限制LE在炎症部位的激活和组织蓄积，从而最大限度地减少组织破坏和疾病进展。体外血液回路中的治疗装置，称为选择性细胞分离装置（SCD），在低钙环境中隔离活化的LE，并抑制其释放炎性蛋白和细胞因子。该II期研究提案建立在I期目标的基础上，该目标成功证明，与假治疗对照相比，第一代SCD 1G在感染性休克的大型动物模型中具有更大的治疗效果，表面积（SA）增加，此外还建立了简化的SCD体外回路，便于在 标准护理医院环境。该第二阶段提案将决定第二代SCD 2G的设计和制造。定制SCD 2G设计将保持低剪切力和低离子钙环境，这对SCDG 1有效，除了减少SCD 1G市售中空纤维笔芯无法实现的血液填充量外，还包括流路、流速、填充密度和SA。较低的血液填充量和血液流速要求，将允许通过外周插入中心导管（PICC管路）进行SCD 2G治疗，或用于血流动力学不稳定的危重患者。SCD 2G设计将通过计算流体动力学模拟进行计算机模拟评估，以评估套管设计和内部器械几何形状。将制造原型并进行流动可视化研究，以确定具有有利流动剖面的设计（目标1）。使用新鲜血液的体外血液回路将用于评价从计算机模拟研究中选择的SCD 2G设计的血液相容性和LE结合特性（目的2）。最后，将在I期研究中使用的感染性休克猪模型中评价选定的SCD 2G设计。将在不同SA的SCDG 2设计和SCDG 1之间比较各种肾脏和心血管参数、肺部炎症、细胞因子水平、全身中性粒细胞活化负荷和至死亡时间（目的3）。在三项探索性临床试验中，SCDG 1治疗显示出优异的安全性特征和令人信服的疗效影响，将死亡率从60%的控制率降低至30%， 需要连续性肾脏替代治疗的急性肾衰竭ICU患者;这些患者中有50-60%也是脓毒症患者。该提案将确定最终的SCD 2G设计，用于治疗各种脓毒症、严重脓毒症和脓毒性休克患者，并将为向FDA申请SCD用于脓毒症治疗的IDE批准提供数据。 公共卫生关系：该提案的目标是开发第二代选择性细胞移植装置（SCD 2G），这是一种体外膜装置，可以隔离活化的白细胞并抑制其炎症活性，以减少患者的组织蓄积和由此造成的损伤。炎症性疾病如脓毒症和全身炎症反应综合征（SIRS）是高影响医学指征，因为在美国每年有200，000名患者发生严重脓毒症伴SIRS，即使使用重症监护病房和广谱抗生素，死亡率也为30- 40%。该提议与公共卫生的相关性在于SCD将大大降低脓毒症和SIRS的多器官效应，从而改善受这些疾病过程影响的患者的临床结局。