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（由申请人提供）：白细胞（LE）是许多临床炎症性疾病的发病和进展的主要因素，包括全身性炎症反应综合征，败血症和急性呼吸窘迫综合征。需要新的创新疗法来治疗这些炎症性疾病状态，这是一个巨大的商业市场机会。正在研究大量的治疗方法，以限制LE在炎症部位的激活和组织积累，以最大程度地减少组织破坏和疾病进展。体外血回路中的一种治疗装置，称为选择性细胞生成器械（SCD），在低钙环境中激活了LE，并抑制了它们释放炎症蛋白和细胞因子。该第二阶段的研究建议建立在I期目标基础上，该目标成功证明了第一代SCD1G在与假治疗的对照组相比，在大型化粪池震动的大动物模型中，表面积（SA）具有更大的治疗功效，此外还可以建立简化的SCD外室外电路，以便于使用下的SCD外电路。 护理医院的环境。该II期建议将确定第二代SCD2G的设计和制造。自定义的SCD2G设计将保持低剪切力和低离子化钙环境，该环境对SCDG1有效，除了减少血液填充量以外，还包括流动路径，流速，包装密度和SA，这些变化是可通过SCD1G市售空心纤维盒可实现的。较低的血液填充体积和血流量要求，将允许通过外围插入的中央导管（PICC系）或批评患有血液动力学不稳定的患者患者进行SCD2G治疗。 SCD2G设计将通过计算流动动力学模拟在计算机中进行评估，以评估壳体设计和内部设备几何形状。原型将是制造的，并进行了流动可视化研究，以确定具有有利流量曲线的设计（AIM 1）。带有新鲜血液的体外血液回路将用于评估在硅研究中选择的SCD2G设计，这些设计在血液相容性和LE结合特征方面（AIM 2）。最后，选定的SCD2G设计将在I期研究中使用的败血性休克模型中进行评估。在变化的SA和SCDG1的SCDG2设计之间，将比较各种肾脏和心血管参数，肺部炎症，细胞因子水平，全身性嗜中性粒细胞活化负荷以及死亡时间（AIM 3）。在三项探索性临床试验中，SCDG1治疗表现出了出色的安全性和引人注目的功效影响，使死亡率从60％降低到30％，在 ICU急性肾衰竭患者需要连续肾脏替代疗法；这些患者中有50-60％也是败血症。该提案将确定最终的SCD2G设计，以治疗败血症，严重败血症和败血性休克的广泛患者，并将为FDA提供数据，以供IDE批准用于治疗败血症的SCD。 公共卫生相关性：该提案的目的是开发第二代选择性细胞生殖器（SCD2G），这是一种可以隔离活化的白细胞并抑制其炎症活性的体外膜装置，以减少组织积累并在患者中造成损害。败血症和全身性炎症反应综合征（SIRS）等炎症性疾病是高影响医学上的指示，因为siRS的严重败血症每年在美国的200,000例患者中发生，即使使用重症监护病房和广泛的频谱抗生素，也具有30-40％的死亡率。该提议与公共卫生的相关性是，SCD将大大减少败血症和SIR的多器官作用，从而改善受这些疾病过程影响的患者的临床结果。