Phase II, randomized controlled trial of brain tissue oxygen monitoring

描述（由申请人提供）：创伤性脑损伤（TBI）是死亡和残疾的主要原因。仅在美国，每年约有140万人遭受TBI，其中5万人死亡，超过20万人住院。TBI的急性处理旨在预防继发性神经元损伤，继发性神经元损伤由多种机制引起，其中突出的是组织缺血。最近，直接和连续监测脑组织中的氧分压（pBrO 2）已变得可行。几项观察性研究表明，低pBrO 2的发作很常见，并与不良结局相关，在临床实践中，医疗干预可有效改善pBrO 2。然而，由于没有进行随机对照试验来确定pBrO 2监测是否会改善严重TBI后的结局，因此该技术的使用迄今为止尚未在神经外科ICU中广泛采用。拟议的研究将是pBrO 2监测的第一个随机对照临床试验，旨在获得确定性III期研究所需的数据，例如旨在治疗pBrO 2的生理操作的有效性，以及在多个临床站点标准化复杂重症监护室管理方案的可行性。将通过ICP和pBrO 2监测对重度TBI患者进行监测，并将其随机分配至沿着ICP的治疗组（对照组）或基于ICP和pBrO 2值的治疗组（治疗组）。182名受试者将在4个临床研究中心入组，即德克萨斯大学西南医学中心/帕克兰纪念医院、华盛顿大学/Harborview医学中心、迈阿密大学/杰克逊纪念医院和宾夕法尼亚大学/宾夕法尼亚大学医院。功能结果将在损伤后6个月进行评估。本研究有一个主要假设和几个次要假设：（1）基于pBrO 2监测的治疗方案可减少组织缺氧。（二）、安全性假设：与pBrO 2监测相关的不良事件很少见（对于感染性、出血性或其他监测相关不良事件的组合，< 3%），并且pBrO 2定向治疗不会导致肺部或全身并发症（例如急性肺损伤/成人呼吸窘迫综合征（ALI/ARDS））的风险增加。（三）、可行性假设：可以识别pBrO 2降低的发作，并在4个临床研究中心制定治疗方案，方案违背率较低（<10%），并且在不同临床研究中心一致。（四）、非无效假设。由格拉斯哥预后量表-损伤后6个月扩展的2.0测量的良好预后的相对风险与该II期研究的结果一致。 公共卫生相关性：创伤性脑损伤（TBI）是导致死亡和残疾的主要原因，仅在美国每年估计花费450亿美元。每年约有140万人遭受TBI，其中5万人死亡，另有23.5万人住院并在受伤后幸存。因此，80，000 - 90，000人经历与TBI相关的永久性残疾。这对患者、其家庭和社会造成了巨大的心理负担。该项目旨在确定设计用于测量脑组织氧合并因此检测脑缺血的设备是否仍具有潜在的可治疗性，从而显示出减少脑缺血持续时间的前景，并获得进行明确的临床疗效试验所需的信息。

DESCRIPTION (provided by applicant): Traumatic brain injury (TBI) is a major cause of death and disability. In the United States alone approximately 1.4 million sustain a TBI each year, of which 50,000 people die, and over 200,000 are hospitalized. The acute management of TBI is aimed at preventing secondary neuronal injury, which results from a variety of mechanisms, prominently among them tissue ischemia. Recently, it has become feasible to directly and continuously monitor the partial pressure of oxygen in brain tissue (pBrO2). Several observational studies indicate that episodes of low pBrO2 are common and are associated with a poor outcome, and that medical interventions are effective in improving pBrO2 in clinical practice. However, as there have been no randomized controlled trials carried out to determine whether pBrO2 monitoring results in improved outcome after severe TBI, use of this technology has not so far been widely adopted in neurosurgical ICUs. The proposed study will be the first randomized, controlled clinical trial of pBrO2 monitoring, and is designed to obtain data required for a definitive phase III study, such as efficacy of physiologic maneuvers aimed at treating pBrO2, and feasibility of standardizing a complex intensive care unit management protocol across multiple clinical sites. Patients with severe TBI will be to be monitored with ICP and pBrO2 monitoring, and will be randomized to therapy based on ICP along (control group) or therapy based on ICP in addition to pBrO2 values (treatment group). 182 participants will be enrolled at four clinical sites, the University of Texas Southwestern Medical Center/Parkland Memorial Hospital, the University of Washington/Harborview Medical Center, the University of Miami/Jackson Memorial Hospital, and the University of Pennsylvania/Hospital of the University of Pennsylvania. Functional outcome will be assessed at 6-months after injury. This study has one primary and several secondary hypotheses: (1) Treatment protocol based on pBrO2 monitoring results in reduction of tissue hypoxia. (2). Safety hypotheses: Adverse events associated with pBrO2 monitoring are rare (< 3% for combination of infectious, hemorrhagic, or other monitoring-related adverse events) and pBrO2 directed therapy does not result in increased risk of pulmonary or systemic complications (such as acute lung injury/Adult Respiratory Distress Syndrome (ALI/ARDS). (3). Feasibility hypotheses: Episodes of decreased pBrO2 can be identified and treatment protocol instituted comparably across 4 Clinical sites, and protocol violations will be low (<10% and uniform across different clinical sites. (4). Non-futility hypothesis. A relative risk of good outcome measured by the Glasgow Outcome Scale-Extended 6-months after injury of 2.0 is consistent with the results of this phase II study. PUBLIC HEALTH RELEVANCE: Traumatic brain injury (TBI) is a major cause of death and disability, with an estimated cost of 45 billion dollars a year in the United States alone. Every year, approximately 1.4 million sustain a TBI, of which 50,000 people die, and another 235,000 are hospitalized and survive the injury. As a result, 80,000-90,000 people experience permanent disability associated with TBI. This results in an enormous psychosocial burden on patients, their families, and society. This project is designed to determine whether a device designed to measure brain tissue oxygenation and thus detect brain ischemia while it is still potentially treatable shows promise in reducing the duration of brain ischemia, and to obtain information required to conduct a definitive clinical trial of efficacy.