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The Quest for an Acute Traumatic Brain Injury Treatment: Why Progesterone Could Be On Track To Become the First FDA-Approved Therapy

By Addison K. May, MD FACS, FCCM

Addison K. May ARTICLE IMAGE

Traumatic brain injury (TBI) is a leading cause of death and disability in the United States, contributing to as many as a third of injury-related deaths. When a patient presents to the emergency department with a TBI in isolation or as part of multi-system injury, he or she is stabilized, evaluated and a treatment plan is determined. Despite advances in medical technology and a greater understanding of TBI physiology over the past decades, treatment options remain relatively limited and are primarily directed towards the prevention of secondary brain injury through treatment and prevention of hypotension, hypoxia, and elevated intracranial pressure.

The failure to identify an effective acute TBI treatment has not been for lack of trying. During the past 16 years, the time which I have been a practicing trauma surgeon, more than 75 clinical trials have tested treatments for TBI, but none of the treatments studied has proven to safely and effectively reverse the damage brought on by the injury. (1)

TBIs occur across a spectrum of severity, in all age groups, and result from a wide variety of mechanisms. Severe, life-threatening TBI most commonly occur from assaults, motor vehicle accidents or as the result of a fall. (2) TBI also includes injuries that occur in both recreational and organized athletics. Most of the injuries suffered on the playing field, like those experienced by National Football League players, are a mild form of the condition called concussions. Impairment from concussions usually resolves in days to weeks but longer-lasting changes may persist, particularly if repetitive or recurrent concussions occur before full recovery. However, severe forms of brain injury can occur in these settings as well. The complex spectrum of TBI and its potential debilitating impact on a broad array of patients and their loved ones necessitates efforts to more effectively assure full recovery from this injury.

No One is Immune to TBI

TBI is defined as an alteration in brain function, or other evidence of brain pathology, caused by an external force. It can happen anywhere, to anyone, at any time. A major cause of death and disability worldwide, the U.S. Centers for Disease Control (CDC) has labeled TBI a “serious public health problem.” Data published by the CDC estimates that 3.5 million Americans suffer a TBI each year, roughly 1.7 million of which are seen in emergency departments, 325,000 hospitalized, and 52,000 die. Rates are higher for men than women across every age group. Incidence is highest among 20 to 24 year olds. Long-term effects include functional changes that affect thinking, sensation, language and/or emotion, as well as physical changes that alter overall mobility and motor skills.

TBI is grouped into three categories based upon severity: mild, moderate or severe. Mild TBI is characterized by a concussion and forms the majority of brain injuries that occur each year. Moderate TBI occurs when a person experiences changes in brain function for greater than 30 minutes but less than 24 hours following trauma. Severe TBI is defined as a brain injury resulting in a loss of consciousness of greater than 24 hours. While mild TBI usually results in good recovery, repetitive injury may produce long term impairment and the presence of even mild TBI in a multiply injured patient significantly increases the risk of death. (3)

Regardless of the cause, many TBI survivors may require long-term assistance in performing daily tasks, and are frequently left with significant cognitive, behavioral and communicative disabilities. Their caregivers also can face a host of economic and quality-of-life burdens.

TBI Treatment Would Be Revolutionary

Although advances in trauma systems have contributed to some improved outcomes following TBI, no specific therapies have been identified in decades of research. Research continues and recent progress supports optimism that the promising studies underway will yield a treatment that could prevent some of the permanent disability that the condition inflicts. An acute TBI treatment could improve the quality of life for the millions of people worldwide who suffer these injuries each year. Progesterone, now being studied in two Phase III clinical trials, currently provides the best hope for a potentially approvable TBI treatment in the near term.

Single Target for TBI Treatment Proves Elusive

The failure of previous TBI treatment clinical studies can be attributed in part to the fact that the agents targeted a single receptor or pathway or hit pathways that proved to have detrimental effects. TBI is in fact a very complex disease and while the initial blow takes its toll, it is followed by a cascade of events that lead to significant subsequent neuronal injury and loss.

In 2012 in the journal Brain Injury, Lu, et. al published an analysis of all randomized clinical trials in adults with traumatic brain injury over the past 30 years, including both acute and post-acute recovery Phase pharmacologic and non-pharmacologic trials. The table shown here includes a summary of 100 trials during this period. Despite the tremendous efforts and resources that have been devoted to study brain injury in search of effective treatment for the diverse symptoms of TBI, the majority of intervention trials targeting numerous injury mechanisms during this acute Phase have failed to show effectiveness of treatment.

Title: The Path to Treatment for Traumatic Brain Injury* (4)

Types of Intervention Number of Trials 1982-2012 Intervention Effectivenessa
No Effect
Acute phase post-TBI    
Pharmacological drug trials Total: 32 Total: 24
· Published trials 25 18

· Unpublished phase III trials

7

6

Non-pharmacological trials Total: 23 Total: 10
· Decompressive craniectomy 3 -
· Early nutritional supplement 2 -

· Hyperbaric oxygen therapy

2

2

· Hyperventilation 1 -
· Osmotic therapy 5 3
· Therapeutic hypothermia 9 5
· Pre-hospital rapid sequence intubation 1 -
Post-acute phase following TBI    
Cognitive rehabilitation Total: 24 Total: 2
- Comprehensive interdisciplinary models 9 1

- Cognitive or academic exercises and communication skill training

3

-

- Compensatory technique and computer-assisted training 4 -
- Education 5 1
- Psychotherapy and behavior modifications 3 -
Physical rehabilitation 8 2
Pharmacotherapy 11 4
Nutrition therapy 1 -
Alternative therapy 1 -

a Based on the study primary outcome defined by the original authors.

In 2010, Maas et al conducted an analysis of 33 past and current clinical trials of traumatic brain injuries published in Neurotherapeutics. Despite a peak in the mid-1990s, the initiation of Phase III clinical trials declined from 2000 to 2004, further highlighting the ongoing challenges that researchers face. A closer look (shown below) at a select number of Phase III studies completed over the past decade includes both those with neuroprotective agents and those using therapeutic strategies (e.g., hypothermia or decompressive craniectomy). (5) In contrast to previous decades, the number of investigations of neuroprotective agents taken forward into efficacy-oriented studies during the 2000s has remained low.

Traumatic Brain Injury Phase III Clinical Trials (2003 – Current)

Publication

Clinical Trial Sponsor

Study Population

Agent/Intervention

Results

Lu et al., 2003

Investigator initiated

GCS ≤ 8

Decompr.

craniectomy

Significant reduction of mortality

Cooper et al., (6) 2004

Investigator initiated. MRC_AUS

GCS ≤ 8

Hypertonic saline

No significant treatment effect

Jiang et al., (7) 2005

Investigator initiated

GCS ≤ 8 + refractory intracranial hypertension

Standard trauma craniectomy vs. limited craniectomy (raised intracranial pressure)

Better outcome with large craniectomy

Yurkewicz et al., (8) 2005

Pfizer

GCS 4-8

Traxoprodil

Higher mortality, no significant effect

Maas et al., (9) 2006

Pharmos

Motor Scale 2-5 + CT abnormalities

Dexanabinol (multiple processes)

No significant treatment effect

Jiang et al., (10) 2006

Investigator initiated

GCS ≤ 8

Long-term mild hypothermia (multiple mechanisms)

5-day mild hypothermia is more efficacious than 2-day short term

Clifton GL, et al. (11) 2011 (NIH-NINDS)

Investigator initiated

GCS 3-8

NABIS: H IIR hypothermia

Terminated for futility

Temkin et al., (12) 2007

Investigator initiated

GCS ≤ 12

Magnesium sulfate (multiple mechanisms)

Poor outcome in treated group

Progesterone Has Neuroprotective Properties

While progesterone is most commonly known for regulating a woman’s menstrual cycle and playing a key role in pregnancy, it has been proven to also be a potent neurosteroid produced by both the male and female brain. (13)

Animal and Phase II studies have shown progesterone to be critical for normal development of brain cells and to reduce swelling from trauma. More than 250 peer-reviewed studies from multiple labs substantiate the neuroprotective and regenerative properties of progesterone. (14, 15, 16) In addition, research has shown that a metabolite of progesterone which is preferentially produced in the CNS, allopregnanolone, is also an active neuroprotectant molecule. (17)

Discovery of progesterone's neuroprotective properties began with the observation of a gender difference in the model responses of mice to experimentally induced TBI. After noting anecdotal reports that female rats recovered better than male rats following a TBI, Donald Stein, PhD, a 30-year brain injury expert at Emory University, conducted studies that showed the hormone might account for this discrepancy in outcome. (18) Since the original observation, animal studies demonstrate protective effects of progesterone in male and female rats, with a reduction in cerebral edema (19) and an enhancement of cerebral recovery. (20) Overall, rats with brain contusions treated with progesterone performed significantly better than control rats in a water maze. Supporting the idea that the sooner you treat with progesterone the better, cerebral edema significantly decreased in progesterone-treated rats when treated within two to six hours post-injury, but not at 48 hours post-injury. (21) These findings are supported by other studies that have demonstrated that administering large doses of progesterone during the first few hours to days after injury significantly limits brain damage, reduces loss of neuronal tissue, and improves functional recovery. (22)

Progesterone Acts on Multiple Pathways

The insult from TBI results from a complex array of pathophysiologic changes brought on by the initial trauma and progesterone’s diverse pleiotropic affects may be the key difference for potential treatment success versus the previous "magic bullet" agents that target single pathways. Progesterone receptors are abundant and widely distributed in the central nervous system. And unlike other sex steroids such as estrogen, progesterone is not only synthesized in the gonads and adrenal glands but is produced by glial cells in the brain and by Schwann cells in the peripheral nervous system. Progesterone is the only investigative treatment for TBI to date that potentially hits multiple pathways, exerting its neuroprotective effects by protecting or rebuilding the blood-brain barrier, decreasing development of cerebral edema (brain swelling), down-regulating the inflammatory cascade and limiting cellular necrosis and apoptosis (programmed cell death). (23)

Progesterone Improved TBI Outcomes in Humans

Human data is also very promising. Two independently conducted, randomized, double-blind, placebo-controlled Phase II clinical trials assessed the efficacy of progesterone in TBI patients, and both demonstrated that progesterone improved outcomes. The ProTECT™ trial in the United States and Xiao et al in China each showed a roughly 50 percent reduction in mortality in the progesterone-treated group as compared to placebo and statistically significant functional improvement in survivors. (24, 25)

Two Phase III clinical trials are underway to test progesterone as an acute treatment for moderate-to-severe TBI. SyNAPSe® is a global trial studying BHR-100, a novel intravenous progesterone infusion, with the intent of bringing the first-ever FDA-approved TBI treatment to market. Sponsored by BHR Pharma, LLC, the trial randomized 1,180 patients who met the following criteria:

  • Non-penetrating head trauma
  • Infusion within 8 hours of the time of injury
  • Glasgow Coma Scale of 3 to 8
  • 16 - 70 years of age
  • At least 1 reactive pupil
  • Greater than 24 hours expected survival

With 154 participating sites in 21 countries, trial participants were randomized in a one-to-one allocation to receive progesterone or placebo. The treatment was administered as a five-day (120-hour), continuous intravenous infusion.  The study drug, BHR-100 was granted an orphan drug designation for treating moderate and severe TBI by the U.S. Food and Drug Administration, which placed the drug on Fast Track status designed to accelerate its potential approval.

The SyNAPSe® study’s independent data and safety monitoring board (DSMB) has released 6 analyses of the trial’s safety data over the course of the study, concluding each time that SyNAPSe® should continue to its intended completion. Additionally, the DSMB's conducted a formal interim analysis of primary six-month efficacy data from 400 SyNAPSe® patients in January 2013, concluding that the study should not be stopped for futility. Based on this analysis, the DSMB concluded that SyNAPSe® should continue to its intended enrollment and completion.  

SyNAPSe® completed patient enrollment in September 2013.   Study results are anticipated in spring 2014.

A second Phase III clinical trial, the NIH-sponsored multicenter trial known as ProTECT™ III at Emory University, is currently studying the safety and efficacy of progesterone for moderate-to-severe TBI patients. (26)

Additional Agents Being Investigated as TBI Treatment

Other clinical trials are enrolling patients worldwide to study a number of agents beyond progesterone and surgeries or applications to treat TBI:

Tranexamic acid, being studied in the CRASH-3 study, is an antifibrinolytic agent hypothesized to reduce intracranial bleeding after injury. In this study has enrolled nearly 500 of the 10,000 patients targeted world-wide. The study includes patients with moderate to severe TBI (GCS 3-12) within 8 hours of injury.

The recently completed DECRA trial examined bilateral decompressive craniectomy in TBI with intracranial hypertension refractory to first line therapies. It failed to demonstrate improved neurologic outcome. The RESCUE-ICP study related to decompressive craniectomy continues enrollment at present. This study does include higher ICP pressures.

Three Phase II studies are underway and may hold promise for the more distant future. INTREPID 2566is is examining a synthetic tripeptide analogue in moderate–to-severe TBI. RP-1127 is examining the ability of glyburide to limit swelling and edema following TBI. The DASH TBI Study is investigating whether decreasing adrenergic or sympathetic hyperactivity after TBI alters outcome after injury.

Finally, the POLAR Phase III study is currently enrolling patients to investigate whether early cooling of patients with severe TBI is associated with better outcomes.

TBI Treatment Could Be On the Horizon

General public recognition that TBI produces significant impairment and disability has been increased by coverage of the wars in Iraq and Afghanistan, and the incidence of grave head injuries suffered by National Football League players. Clinicians treating patients with severe TBI have long recognized the devastating effects of this injury. The lack of specific treatment for patients with severe TBI despite decades of study has been frustrating. Even long-held standards of management in these patients are not universally supported. A recent study, for example, found that ICP monitoring – the standard of care for severe traumatic brain injury – showed no significant difference in outcome than a treatment based on imaging and clinical examination. (28)

Researchers remain optimistic that a potential treatment could be relatively close.  Progesterone is the closest agent on the horizon with significant promise for possible FDA approval.  Definitive clinical data will be available in 2014. Multiple lab and clinical studies demonstrate that this neurosteroid hormone plays a critical role in brain health, and could meet an unmet medical need for gravely injured patients for whom no treatment currently exists.

About Addison K. May, MD FACS, FCCM

Addison K. May BIG IMAGEAddison K. May, MD FACS, FCCM is a professor of surgery and anesthesiology and Director, Surgical Critical Care, at Vanderbilt University. Dr. May leads the SyNAPSe® clinical trial site at Vanderbilt.

Sources

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Disclaimer: This article has not been subjected to peer review and is presented as the personal views of a qualified expert in the subject in accordance with the general terms and condition of use of the News-Medical.Net website.

Last Updated: Feb 3, 2014

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