A Clinical Trial of Progesterone for Severe Traumatic Brain Injury

Skolnick, Brett E.; Maas, Andrew I.R.; Narayan, Raj K.; Hoop, R. Gerritsen van der; MacAllister, Thomas W.; Ward, John D.; Nelson, Neta R.; Stocchetti, Nino; Investigators, Synapse Trial

doi:10.1056/nejmoa1411090

Cited by 411 publications

(296 citation statements)

References 26 publications

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“…Clinical [24][25][26] Anti-inflammatory treatments have had no success thus far either, and the Corticosteroid Randomisation After Significant Head Injury (CRASH) study showed increased risk of death in patients who received methylprednisolone for 48 hours after TBI. 27 Even treatments with multifarious drugs, such as erythropoietin and progesterone, intended to target the pathology through multiple mechanisms of action have failed in phase III clinical trials.…”

Section: Discussionmentioning

confidence: 99%

Acute or Delayed Treatment with Anatabine Improves Spatial Memory and Reduces Pathological Sequelae at Late Time-Points after Repetitive Mild Traumatic Brain Injury

Ferguson

Mouzon

Paris

et al. 2017

Journal of Neurotrauma

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(2017) Acute or delayed treatment with anatabine improves spatial memory and reduces pathological sequelae at late time-points after repetitive mild traumatic brain injury. Journal of Neurotrauma, 34(8), pp. 1676Neurotrauma, 34(8), pp. -1691Neurotrauma, 34(8), pp. . (doi:10.1089Neurotrauma, 34(8), pp. /neu.2016 This is the author's final accepted version.There may be differences between this version and the published version. You are advised to consult the publisher's version if you wish to cite from it.http://eprints.gla.ac.uk/131662/ Abstract Traumatic brain injury (TBI) has chronic and long term consequences for which there are currently no approved pharmacological treatments. We have previously characterized the chronic neurobehavioral and pathological sequelae of a mouse model of repetitive mild TBI (r-mTBI) through to two years post-TBI. Despite the mild nature of the initial insult, secondary injury processes are initiated which involve neuroinflammatory and neurodegenerative pathways persisting and progressing for weeks and months post-injury and providing a potential window of opportunity for therapeutic intervention. In this study we examined the efficacy of a novel anti-inflammatory compound, anatabine, in modifying outcome after TBI.Our model of r-mTBI involves a series of 5 mild impacts (midline impact at 5 m/s, 1mm strike depth, 200ms dwell time)with an interval of 48 hours. Anatabine treatment was administered starting 30 minutes after injury and delivered continuously through in the water. At 6 months after TBI, anatabine treatment improved spatial memory in injured mice. Nine months after TBI, a cohort of mice were euthanized for pathological analysis which revealed reductions in astroglial (GFAP) and microglial (IBA1) responses in treated, injured animals. Treatments for the remaining mice were then crossed-over to assess the effects of late treatment administration and effects of treatment termination. 9 months following crossover the remaining mice showed no effect of injury on their spatial memory, and while pathological analysis showed improvements in mice who had received delayed treatment, corpus callosum IBA1 increased in postcrossover placebo r-mTBI mice.These data demonstrate efficacy of both early and late initiation of treatment with anatabine in improving long term behavioral and pathology outcomes after mild TBI. Future studies will characterize the treatment window, the time course of treatment needed, and the dose needed to achieve therapeutic levels of anatabine in humans after injury.

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Section: Discussionmentioning

confidence: 99%

Acute or Delayed Treatment with Anatabine Improves Spatial Memory and Reduces Pathological Sequelae at Late Time-Points after Repetitive Mild Traumatic Brain Injury

Ferguson

Mouzon

Paris

et al. 2017

Journal of Neurotrauma

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“…13,14 There have been other recent large interventional ED-based trials of progesterone for TBI in adults (ProTECT III and SyNAPSe) worth noting (and both were stopped for futility). 15,16 In ProTECT III, study drug was administered to adult patients within a 4-hour window using EFIC. 15 There are several examples of pediatric TBI trials that failed to accrue sufficient numbers of children due to several factors such as limited numbers of eligible children at any one site, difficulties with informed consent, and arrival of subjects outside the therapeutic window of the study intervention.…”

Section: Discussionmentioning

confidence: 99%

“…For example, progesterone has been shown to have several different mechanisms of action and, therefore, adult progesterone trials have typically enrolled patients with all types of intracranial injuries that could theoretically benefit from the actions of progesterone (recent negative trials notwithstanding). 15,16 However, future trials of targeted therapies may need to enroll children with specific injury types, such as TXA for intracranial hemorrhage. [33][34][35][36][37] In our cohort, intracranial hemorrhage was the most common type of brain injury on CT, accounting for approximately one-half of enrolled patients.…”

Section: Discussionmentioning

confidence: 99%

Challenges Enrolling Children Into Traumatic Brain Injury Trials: An Observational Study

Stanley

Johnson

Vance

et al. 2017

Academic Emergency Medicine

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Objectives: In preparation for a clinical trial of therapeutic agents for children with moderate-to-severe blunt traumatic brain injuries (TBIs) in emergency departments (EDs), we conducted this feasibility study to (1) determine the number and clinical characteristics of eligible children, (2) determine the timing of patient and guardian arrival to the ED, and (3) describe the heterogeneity of TBIs on computed tomography (CT) scans. Methods:We conducted a prospective observational study at 16 EDs of children ≤ 18 years of age presenting with blunt head trauma and Glasgow Coma Scale scores of 3-12. We documented the number of potentially eligible patients, timing of patient and guardian arrival, patient demographics and clinical characteristics, severity of injuries, and cranial CT findings.

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“…In addition, the findings on phase-III RCTs for TBI management challenged the former evidence of neuroprotective agent use (i.e., CRASH 2005 for Corticosteroid (4), COR-BIT 2012 for Citicoline (17), SYNAPSE 2014 (18) and ProTECT 2014 (19) for progesterone, and EPO-TBI 2015 for erythropoietin (9)). Despite the current process of phase-I to phase-III (IV) drug evaluation for use in human-beings, it is recommended to skip phase-II trials for TBI related studies.…”

Section: Discussionmentioning

confidence: 99%

Erythropoietin for Traumatic Brain Injury: A Systematic Review and Meta-Analysis

Meshkini¹,

Meshkini²,

Sadeghi‐Bazargani³

2016

Trauma Mon

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Context: Traumatic brain injury (TBI) is a leading cause of mortality and morbidity; despite the use of neuroprotective agents for TBI management, no evidence-based recommendation for any particular neuroprotective agent with favorable outcomes and less adverse effects has been made in TBI management. Objectives: We aimed to assess the efficacy of erythropoietin (EPO) use for TBI management. Data Sources: This study is part of a review on neuroprotective agents used for traumatic brain injury: A systematic review and meta-analyses was done, based on a wide search strategy incorporating information from Cochrane CENTRAL, MedLine/PubMed, SCOPUS, Thomson Reuters Web of Science, SID.ir, Barekat Foundation, and clinicaltrials.gov databases up to September 06, 2015. Study Selection: The present study limited the retrieved search results only to those using EPO for TBI management. Data Extraction: The retrieved randomized clinical trials (RCTs) were assessed for their quality of reporting according to the consolidated standards of reporting trials (CONSORT) checklist prior to extracting the data for meta-analysis. The meta-analyses in this review was conducted using the extended Glasgow outcome scale (GOS-E) for acute TBI patients, mortalities, and adverse-effects. Results: Four RCTs were retrieved on EPO use for acute TBI, and two of them were kept for the final analysis. The analysis of the enrolled 645 participants in these studies showed insignificant but slightly better outcomes in the placebo group, while a significant reduction in mortality rates among EPO users was observed. Slightly better outcomes in vascular and non-vascular side-effects were also observed in the intervention group. Conclusions: EPO may be considered as effective in reducing TBI mortality and vascular side-effects, while there is no evidence to support any benefits in other outcomes or for the elimination of non-vascular side-effects. Further studies, especially well-designed phase-III dose-controlled trials, are needed for building a stronger body of evidence for recommending the use of EPO for acute TBI.Keywords: Head Injury, Traumatic Brain Injury, Neuroprotective Agent, Erythropoietin, Review ContextTraumatic brain injury (TBI), which is also known as head injury (1-3), is a leading cause of mortality and morbidity (1, 4-6), especially among those of young ages (1).Epidemiological studies have demonstrated the following facts about TBI in the U.S. (1, 4): -There is an incidence rate of 558 cases per 100,000 people each year.-TBI-related disability cases are estimated as rising by 33 new cases per 100,000 people each year.-They cause more than 50,000 deaths each year.-Motor vehicle collisions (MVC) are responsible for 50% of TBI cases.TBI costs more than $48 billion a year, and between 2.5 and 6.5 million Americans alive today have been victims of a TBI-related assault. Survivors of TBI are often left with significant cognitive, behavioral, and communicative disabilities (7).Erythropoietin (EPO) is a glycoprotein hormone of the cy...

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A Clinical Trial of Progesterone for Severe Traumatic Brain Injury

Cited by 411 publications

References 26 publications

Acute or Delayed Treatment with Anatabine Improves Spatial Memory and Reduces Pathological Sequelae at Late Time-Points after Repetitive Mild Traumatic Brain Injury

Acute or Delayed Treatment with Anatabine Improves Spatial Memory and Reduces Pathological Sequelae at Late Time-Points after Repetitive Mild Traumatic Brain Injury

Challenges Enrolling Children Into Traumatic Brain Injury Trials: An Observational Study

Erythropoietin for Traumatic Brain Injury: A Systematic Review and Meta-Analysis

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