Resuscitative Endocrinology:Single-dose Clinical Uses for Estrogen-Traumatic Brain Injury (RESCUE-TBI)
|The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.|
|ClinicalTrials.gov Identifier: NCT00973674|
Recruitment Status : Completed
First Posted : September 9, 2009
Results First Posted : November 12, 2019
Last Update Posted : November 12, 2019
|First Submitted Date ICMJE||July 14, 2009|
|First Posted Date ICMJE||September 9, 2009|
|Results First Submitted Date ICMJE||April 1, 2016|
|Results First Posted Date ICMJE||November 12, 2019|
|Last Update Posted Date||November 12, 2019|
|Study Start Date ICMJE||July 2009|
|Actual Primary Completion Date||January 2012 (Final data collection date for primary outcome measure)|
|Current Primary Outcome Measures ICMJE
||Percent Passing the Galveston Orientation Amnesia Test (GOAT) Within 28 Days Post Injury [ Time Frame: 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.
|Original Primary Outcome Measures ICMJE
||Short term neurological outcome [ Time Frame: Up to 2 months ]|
|Current Secondary Outcome Measures ICMJE
|Original Secondary Outcome Measures ICMJE
||Examine the effects of IV estrogen vs. placebo for treating patients with severe TBI: Mortality, GOSE, DRS, cognitive, neurological and functional outcomes, levels of injury markers and sex steroids, and safety [ Time Frame: Up to 6 months post-injury ]|
|Current Other Pre-specified Outcome Measures||Not Provided|
|Original Other Pre-specified Outcome Measures||Not Provided|
|Brief Title ICMJE||Resuscitative Endocrinology:Single-dose Clinical Uses for Estrogen-Traumatic Brain Injury|
|Official Title ICMJE||A Phase II Trial to Evaluate the Effects of A Single Dose of Intravenous Premarin for the Treatment of Severe Traumatic Brain Injury|
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.
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.
Finally, estrogen is not the only sex steroid implicated in resuscitation. While estrogen has been the most frequently studied sex steroid in animal resuscitation models, progesterone too is thought to have potential neuroprotective effects. There is a recently published clinical pilot trial of IV progesterone as an acute resuscitative therapy for TBI patients, which indicates potentially promising clinical results without negative safety findings, thereby also poising this sex steroid for future multi-center trials.
In summary, we believe that there are compelling reasons to evaluate estrogen as an acute intervention in patients with traumatic brain injury given the benefit demonstrated in animal studies of brain injury, and safety data in humans prescribed estrogen for other indications. But we are aware that there are no published data related to use of a single dose of IV estrogen in injured patients in the acute setting. Therefore we have conceptualized our trial with frequent evaluation of patient safety through an organized Data Safety Monitoring Committee.
Potential participants include patients between the ages of 18 and 55 years who are admitted to Parkland Memorial Hospital or Baylor University Medical Center with a presumed diagnosis of severe traumatic brain injury. This young population was chosen for several reasons:
For assessing length of time in coma and orientation, we will administer the Galveston Orientation and Amnesia Test (GOAT) daily until the patient successfully completes the test, for up to 2 months.
Longer-term neurological outcomes will be measured at discharge, 28 days, 3 and 6 months post-injury utilizing the Disability Rating Scale, Glasgow Outcome Score-Extended (GOSE), and Functional Status Examination. These outcomes measures will be collected by the research staff via telephone interviews if the patient has been discharged. The Disability Rating Scale (DRS), Glasgow Outcome Scale-Extended GOSE, and Functional Status Examination are well validated in the literature for follow-up in patients with TBI. These tests can be easily administered over the phone to either the patient or the caregiver.
|Study Type ICMJE||Interventional|
|Study Phase ICMJE||Phase 2|
|Study Design ICMJE||Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
|Condition ICMJE||Traumatic Brain Injury|
|Study Arms ICMJE||
|Publications *||Not Provided|
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
|Recruitment Status ICMJE||Completed|
|Actual Enrollment ICMJE
|Original Estimated Enrollment ICMJE||Same as current|
|Actual Study Completion Date ICMJE||May 2012|
|Actual Primary Completion Date||January 2012 (Final data collection date for primary outcome measure)|
|Eligibility Criteria ICMJE||
|Ages ICMJE||18 Years to 50 Years (Adult)|
|Accepts Healthy Volunteers ICMJE||No|
|Contacts ICMJE||Contact information is only displayed when the study is recruiting subjects|
|Listed Location Countries ICMJE||United States|
|Removed Location Countries|
|NCT Number ICMJE||NCT00973674|
|Other Study ID Numbers ICMJE||RESCUE-TBI|
|Has Data Monitoring Committee||Yes|
|U.S. FDA-regulated Product||Not Provided|
|IPD Sharing Statement ICMJE||
|Responsible Party||University of Texas Southwestern Medical Center|
|Study Sponsor ICMJE||University of Texas Southwestern Medical Center|
|PRS Account||University of Texas Southwestern Medical Center|
|Verification Date||October 2019|
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP