A clinical trial of progesterone for severe traumatic brain injury

Does this invalidate this research?

Progesterone Changes VEGF and BDNF Expression and Promotes Neurogenesis After Ischemic Stroke

 Who the fuck is going to answer that question and write up a stroke protocol?
http://www.mdlinx.com/internal-medicine/medical-news-article/2014/12/15/traumatic-brain-injury/5803762/?

Progesterone has been associated with robust positive effects in animal models of traumatic brain injury (TBI) and with clinical benefits in two phase 2 randomized, controlled trials. Authors investigated the efficacy and safety of progesterone in a large, prospective, phase 3 randomized clinical trial. Primary and secondary efficacy analyses showed no clinical benefit of progesterone in patients with severe TBI. These data stand in contrast to the robust preclinical data and results of early single–center trials that provided the impetus to initiate phase 3 trials.

Methods

• Authors conducted a multinational placebo–controlled trial, in which 1195 patients, 16 to 70 years of age, with severe TBI (Glasgow Coma Scale score, <=8 [on a scale of 3 to 15, with lower scores indicating a reduced level of consciousness] and at least one reactive pupil) were randomly assigned to receive progesterone or placebo.
• Dosing began within 8 hours after injury and continued for 120 hours.
• The primary efficacy end point was the Glasgow Outcome Scale score at 6 months after the injury. The Extended Glasgow Outcome Scale may be widely used and accepted but it still has no objective measurement except for the death answer.

Results

• Proportional–odds analysis with covariate adjustment showed no treatment effect of progesterone as compared with placebo (odds ratio, 0.96; confidence interval, 0.77 to 1.18).
• The proportion of patients with a favorable outcome on the Glasgow Outcome Scale (good recovery or moderate disability) was 50.4% with progesterone, as compared with 50.5% with placebo.
• Mortality was similar in the two groups.
• No relevant safety differences were noted between progesterone and placebo.

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Very early administration of progesterone for acute traumatic brain injury

A negative trial that was published. The Extended Glasgow Outcome Scale may be widely used and accepted but it still has no objective measurement except for the death answer.
Does this invalidate this research?

Progesterone Changes VEGF and BDNF Expression and Promotes Neurogenesis After Ischemic Stroke

With NO stroke leadership or strategy we will never know that answer.

Very early administration of progesterone for acute traumatic brain injury

 

Wright DW, Yeatts SD, Silbergleit R, Palesch YY, Hertzberg VS, Frankel M, Goldstein FC, Caveney AF, Howlett-Smith H, Bengelink EM, Manley GT, Merck LH, Janis LS, Barsan WG; NETT Investigators.

Collaborators (299)

Abstract

BACKGROUND:

Traumatic brain injury (TBI) is a major cause of death and disability worldwide. Progesterone has been shown to improve neurologic outcome in multiple experimental models and two early-phase trials involving patients with TBI.

METHODS:

We conducted a double-blind, multicenter clinical trial in which patients with severe, moderate-to-severe, or moderate acute TBI (Glasgow Coma Scale score of 4 to 12, on a scale from 3 to 15, with lower scores indicating a lower level of consciousness) were randomly assigned to intravenous progesterone or placebo, with the study treatment initiated within 4 hours after injury and administered for a total of 96 hours. Efficacy was defined as an increase of 10 percentage points in the proportion of patients with a favorable outcome, as determined with the use of the stratified dichotomy of the Extended Glasgow Outcome Scale score at 6 months after injury. Secondary outcomes included mortality and the Disability Rating Scale score.

RESULTS:

A total of 882 of the planned sample of 1140 patients underwent randomization before the trial was stopped for futility with respect to the primary outcome. The study groups were similar with regard to baseline characteristics; the median age of the patients was 35 years, 73.7% were men, 15.2% were black, and the mean Injury Severity Score was 24.4 (on a scale from 0 to 75, with higher scores indicating greater severity). The most frequent mechanism of injury was a motor vehicle accident. There was no significant difference between the progesterone group and the placebo group in the proportion of patients with a favorable outcome (relative benefit of progesterone, 0.95; 95% confidence interval [CI], 0.85 to 1.06; P=0.35). Phlebitis or thrombophlebitis was more frequent in the progesterone group than in the placebo group (relative risk, 3.03; CI, 1.96 to 4.66). There were no significant differences in the other prespecified safety outcomes.

CONCLUSIONS:

This clinical trial did not show a benefit of progesterone over placebo in the improvement of outcomes in patients with acute TBI. (Funded by the National Institute of Neurological Disorders and Stroke and others; PROTECT III ClinicalTrials.gov number, NCT00822900.).

Erythropoietin in traumatic brain injury (EPO-TBI): a double-blind randomised controlled trial

The Glasgow Outcome Scale is way too crude to be of any use in determining effectiveness of an intervention.  So this research told us nothing.  Do we not have anyone that knows how to do proper research?

Erythropoietin in traumatic brain injury (EPO-TBI): a double-blind randomised controlled trial

Erythropoietin might have neurocytoprotective effects. In this trial, authors studied its effect on neurological recovery, mortality, and venous thrombotic events in patients with traumatic brain injury. Following moderate or severe traumatic brain injury, erythropoietin did not reduce the number of patients with severe neurological dysfunction (GOS–E level 1–4) or increase the incidence of deep venous thrombosis of the lower limbs. The effect of erythropoietin on mortality remains uncertain.

Methods

• Erythropoietin in Traumatic Brain Injury (EPO–TBI) was a double–blind, placebo–controlled trial undertaken in 29 centres (all university–affiliated teaching hospitals) in seven countries (Australia, New Zealand, France, Germany, Finland, Ireland, and Saudi Arabia).
• Within 24 h of brain injury, 606 patients were randomly assigned by a concealed web–based computer–generated randomisation schedule to erythropoietin (40 000 units subcutaneously) or placebo (0•9% sodium chloride subcutaneously) once per week for a maximum of three doses.
• Randomisation was stratified by severity of traumatic brain injury (moderate vs severe) and participating site.
• With the exception of designated site pharmacists, the site dosing nurses at all sites, and the pharmacists at the central pharmacy in France, all study personnel, patients, and patients' relatives were masked to treatment assignment.
• The primary outcome, assessed at 6 months by modified intention–to–treat analysis, was improvement in the patients' neurological status, summarised as a reduction in the proportion of patients with an Extended Glasgow Outcome Scale (GOS–E) of 1–4 (death, vegetative state, and severe disability).
• Two equally spaced preplanned interim analyses were done (after 202 and 404 participants were enrolled).

Results

• Between May 3, 2010, and Nov 1, 2014, 606 patients were enrolled and randomly assigned to erythropoietin (n=308) or placebo (n=298).
• Ten of these patients (six in the erythropoietin group and four in the placebo group) were lost to follow up at 6 months; therefore, data for the primary outcome analysis was available for 596 patients (302 in the erythropoietin group and 294 in the placebo group).
• Compared with placebo, erythropoietin did not reduce the proportion of patients with a GOS–E level of 1–4 (134 [44%] of 302 patients in the erythropoietin group vs 132 [45%] of 294 in the placebo group; relative risk [RR] 0•99 [95% CI 0•83–1•18], p=0•90).
• In terms of safety, erythropoietin did not significantly affect 6–month mortality versus placebo (32 [11%] of 305 patients had died at 6 months in the erythropoietin group vs 46 [16%] of 297 [16%] in the placebo group; RR 0•68 [95% CI 0•44–1•03], p=0•07) or increase the occurrence of deep venous thrombosis of the lower limbs (48 [16%] of 305 vs 54 [18%] of 298; RR 0•87 [95% CI 0•61–1•24], p=0•44).

Hypothermia for intracranial hypertension after traumatic brain injury

I decided to look at this again since it is still coming up in my news feeds. This research is incredibly flawed. The measurement endpoints of using the Extended Glasgow Outcome Scale are totally worthless. Nothing in them is objective at all except for the death category. These people need to be retrained in valid research techniques. Whatever conclusions they came up with can't be supported by their research. This research is not repeatable due to no objective starting or ending points. Once again stroke medical leadership needs to be fired.
http://www.mdlinx.com/internal-medicine/medical-news-article/2015/10/13/intracranial-hypertension/6359648/?
In patients with traumatic brain injury, hypothermia can reduce intracranial hypertension. The benefit of hypothermia on functional outcome is unclear. In patients with an intracranial pressure of more than 20 mm Hg after traumatic brain injury, therapeutic hypothermia plus standard care to reduce intracranial pressure did not result in outcomes better than those with standard care alone.

Methods

• Authors randomly assigned adults with an intracranial pressure of more than 20 mm Hg despite stage 1 treatments (including mechanical ventilation and sedation management) to standard care (control group) or hypothermia (32 to 35°C) plus standard care.
• In the control group, stage 2 treatments (e.g., osmotherapy) were added as needed to control intracranial pressure.
• In the hypothermia group, stage 2 treatments were added only if hypothermia failed to control intracranial pressure.
• In both groups, stage 3 treatments (barbiturates and decompressive craniectomy) were used if all stage 2 treatments failed to control intracranial pressure.
• The primary outcome was the score on the Extended Glasgow Outcome Scale (GOS–E; range, 1 to 8, with lower scores indicating a worse functional outcome) at 6 months.
• The treatment effect was estimated with ordinal logistic regression adjusted for prespecified prognostic factors and expressed as a common odds ratio (with an odds ratio <1.0 favoring hypothermia).

Results

• They enrolled 387 patients at 47 centers in 18 countries from November 2009 through October 2014, at which time recruitment was suspended owing to safety concerns.
• Stage 3 treatments were required to control intracranial pressure in 54% of the patients in the control group and in 44% of the patients in the hypothermia group.
• The adjusted common odds ratio for the GOS–E score was 1.53 (95% confidence interval, 1.02 to 2.30; P=0.04), indicating a worse outcome in the hypothermia group than in the control group.
• A favorable outcome (GOS–E score of 5 to 8, indicating moderate disability or good recovery) occurred in 26% of the patients in the hypothermia group and in 37% of the patients in the control group (P=0.03).

Is TBI recovery based on genetics?

Well, what is the similar answer for stroke? Is your stroke association going to do anything about this?

Cytokine Gene Polymorphisms and Outcome after Traumatic Brain Injury

To cite this article:
Ryan J. Waters, Gordon D. Murray, Graham M. Teasdale, Janice Stewart, Ian Day, Robert J. Lee, and James A.R. Nicoll. Journal of Neurotrauma. October 15, 2013, 30(20): 1710-1716. doi:10.1089/neu.2012.2792.
Published in Volume: 30 Issue 20: October 10, 2013

ABSTRACT

Clinical outcome after traumatic brain injury (TBI) is variable and cannot easily be predicted. There is increasing evidence to suggest that there may be genetic influences on outcome. Cytokines play an important role in mediating the inflammatory response provoked within the central nervous system after TBI. This study was designed to identify associations between cytokine gene polymorphisms and clinical outcome 6 months after head injury. A prospectively identified cohort of patients (n=1096, age range 0–93 years, mean age 37) was used. Clinical outcome at 6 months was assessed using the Glasgow Outcome Scale. In an initial screen of 11 cytokine gene single nucleotide polymorphisms (SNPs) previously associated with disease susceptibility or outcome (TNFA −238 and −308, IL6 −174, −572 and −597, IL1A −889, IL1B −31, −511 and +3953, and TGFB −509 and −800), TNFA −308 was identified as having a likely association. The TNFA −308 SNP was further evaluated, and a significant association was identified, with 39% of allele 2 carriers having an unfavorable outcome compared with 31% of non-carriers (adjusted odds ratio 1.67, confidence interval 1.19–2.35, p=0.003). These findings are consistent with experimental and clinical data suggesting that neuroinflammation has an impact on clinical outcome after TBI and that tumor necrosis factor alpha plays an important role in this process.