A Phase II Trial to Evaluate the Effects of A Single Dose of Intravenous Premarin for the Treatment of Severe Traumatic Brain Injury
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 50
- 试验地点
- 2
- 主要终点
- Percent Passing the Galveston Orientation Amnesia Test (GOAT) Within 28 Days Post Injury
研究概览
简要总结
Each year in the United States alone, a third of a million persons are hospitalized for traumatic brain injury (TBI), of whom approximately 1/4 die. Most are less than 30 years of age. Not only are the health care costs staggering for both initial care and rehabilitation, but the societal loss in terms of economic impact reaches into the billions of dollars annually in the U.S. alone. Despite advances in neurosurgical interventions and intensive care management, many survivors do not fully recover. A significant cause of this mortality and morbidity is thought due to potentially preventable secondary injury, namely oxidant injury, inflammation, and apoptosis in the penumbra (the area of brain surrounding the primary lesion, which is at-risk, but potentially salvageable), beginning in the first few hours after the severe traumatic event.
Despite the current bleak outlook for many of these patients, a series of animal investigations have uncovered a promising solution to the problem of the secondary injury seen in severe TBI and other similar processes, namely the early administration of estrogen, a strong anti-oxidant, anti-inflammatory and anti-apoptotic compound. Based on these encouraging results from animal studies, the investigators hypothesize that early administration of IV Premarin® in patients with severe TBI will safely reduce secondary brain injury, improve neurological outcomes, and improve survival.
详细描述
Early estrogen treatment has been tested in a myriad of animal models of resuscitation ranging from TBI and stroke to spinal cord injury, trauma-related hemorrhage, and sepsis. In these scenarios, studies using old and young, male and female animals found estrogen to be a strikingly effective therapy. Importantly, various animal studies examining brain injury sizes via radiological imaging and sophisticated immunofluorescent techniques have revealed significant protective effects of IV estrogen given post-injury, noting decreases in injury size of up to 65% in those receiving estrogen compared with those not receiving it. Furthermore, this beneficial effect is seen in all body tissues in both males and females. Only one identified TBI study to date did not show similar efficacy. A rodent model of TBI found that all females, in all three groups (those receiving no treatment, placebo, and estrogen) inexplicably died.
Mechanisms of Estrogen's Neuroprotection The use of estrogen as an acute resuscitation drug for severe brain injury has been extensively investigated in animal models. The mechanisms of estrogen's protective effects are numerous, including prevention of propogation of oxidant injury, anti-inflammatory properties in all major organs in the body, and mitochondria stabilization.
Importantly, the following studies find that estrogen exerts significant neuroprotective effects aimed at many of the mechanisms implicated in devastating secondary brain injury in TBI, including:
Brain Ischemia and Reperfusion Intracerebral Hemorrhage (a frequent component of traumatic brain injury) Impaired Cerebral Blood Flow Cerebral Vasospasm Cerebral Metabolic Dysfunction, including mitochondrial dysfunction with reduction of ATP production Cerebral Excitotoxicity and Blood Brain Barrier Preservation Cerebral Oxidant Injury Cerebral Edema Cerebral Inflammation Apoptosis
The protective effects of estrogen may initially appear counterintuitive in light of the recent WHI and HERS trials which studied long-term, oral, low-dose administration of estrogen in older, significantly-post menopausal women. In contrast, the proposed study utilizes a one-time resuscitative dose of IV estrogen administered rapidly following the injury. From a safety standpoint, there are a hundred-million women years of safety data for estrogen's clinical use, and safe use has been documented in men with prostate cancer, uremic bleeding, liver transplantation, and spine surgery. Any safety concerns, such as clotting effects found with long-tem, orally administered estrogen would not be expected when administered one time through an IV dose. Estrogen, when administered IV, avoids the first pass effect in the liver, and does not trigger the ER-α mediated pro-thrombotic effects seen with oral administration. Therefore, it is felt that this acute, IV single-dose administration of estrogen will convey the protective benefits seen in animal studies without side effects implicated with long-term oral use in humans.
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
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 50 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Suspected blunt head injury
- •Estimated age of 18 - 50 years
- •Estimated time to study drug administration < 2 hours post-trauma
- •Glasgow Come Scale (GCS) score of between 3 and 8 prior to intubation and/or sedation, due to difficulty of patient's cooperation in assessment after these interventions.
- •Systolic blood pressure > 90 mm Hg
- •Receiving medical treatment in the Emergency Department (ED) of Parkland Hospital, or Baylor University Medical Center Emergency Department, Level I Trauma Centers in Dallas,Texas
排除标准
- •Legal Do Not Resuscitate (DNR) orders in place prior to randomization.
- •Known incarcerated individuals
- •Status epilepticus prior to study drug administration
- •Penetrating head trauma
- •Estimated time to study drug administration > 2 hours post-trauma
- •Injury time unknown
- •Cardiopulmonary Resuscitation (CPR) prior to study drug administration
- •Severe hypothermia (suspected T <28C)
- •Drowning or asphyxia due to hanging
- •Burns TBSA > 20% in adults
- •Known inclusion in another interventional trial related to this traumatic event prior to randomization
- •Systolic blood pressure < or = 90 mm Hg
- •Known indication for IV estrogen
- •Known contraindication for estrogen (male sex is NOT a contraindication)
- •Sustained pulse oximeter < 90
- •Recognized spinal cord injury prior to study drug administration
研究组 & 干预措施
Premarin IV
Patients randomized to receive a single dose of 0.5 mg/kg Premarin® IV
干预措施: Premarin IV (Drug)
Placebo
Patients randomized to receive a single dose of placebo IV. Due of the faint yellow color of the reconstituted Premarin®, the placebo dose will be prepared with 0.14 ml of Vial 1 of Infuvite Adult Multivitamin and 14 ml of sterile water to generate a similar color and volume. This aliquot will be used only for those study patients who are randomized to the placebo arm. The placebo volume will be approximately equal to the volume which the patient would have received had the patient been randomized to the Premarin arm Considering the small amount of IV multivitamin needed for fluid tinting, it is not expected that the IV multivitamin will have any effect on patients with traumatic brain injury.
干预措施: Placebo (Drug)
结局指标
主要结局
Percent Passing the Galveston Orientation Amnesia Test (GOAT) Within 28 Days Post Injury
时间窗: 28 Days
The GOAT is a measure of early cognitive recovery following a severe traumatic injury. The score is determined after examination by health professionals with respect to orientation to person, place and time. On a scale 0 to 100, 76-100 represents normal recovery. The trial measures the percentage of patients who pass the Galveston Orientation Amnesia Test (GOAT) within 28 days post injury.
次要结局
- Acute Respiratory Distress Syndrome (ARDS) Free Survival(Days 0-28)
- 28-day Mortality(28 Days)
- 6-month Glasgow Outcomes Scale- Extended (GOSE) Score(Up to 6 months post-injury)