2009 5th Annual Scientific Meeting – Methodological Issues in Traumatic Brain Injury – Session Summary
A Plenary Symposium of the International Society for CNS Drug Trials Methodology (ISCTM),
Arlington, VA, 3 March 2009
Chairmen: Tom Macek, PharmD, PhD, Takeda Global Research and Development, Deerfield IL and Alan Faden, MD, Georgetown University Medical Center, Washington, D.C.
Speakers:
Mark Lovell, PhD, University of Pittsburgh Medical Center, Pittsburgh, PA,
Col. Michael S. Jaffee, MD, and Karen Schwab, PhD, Defense and Veterans Brain Injury Center, Washington, D.C.,
Douglas Smith, MD, University of Pennsylvania, Philadelphia, PA,
M. Ross Bullock, MD, PhD, University of Miami, Miami, FL.
Summary
Although mild traumatic brain injury (mTBI) or “concussion” affects over 1 million victims each year in the United States (reference), it is not generally recognized as a major health issue. However, this ‘mild’ form of injury induces persisting neurocognitive and psychiatric dysfunction in many of these patients, exacting an enormous emotional and financial toll on society. The symptoms of post-concussive injury, as measured by the Post-concussion Symptom Scale, include emotional, sleep, somatic, and cognitive disturbances (Pardini, Lovell et al 2004).
Thus far, pharmacological treatments for mTBI are elusive, as well as mechanistic or interventional studies for exploring the pathophysiological consequences that translate from animal to human or human to animal. In understanding mTBI as a distinct consequence of injury, it must also be recognized that there exists tremendous range of symptomatology and situations within the mTBI patient population that contribute to the disparity of these outcomes. Moreover, systematic methods of the study of mTBI may be confounded by additional factors, which, as in the example of military populations, have life-threatening consequences for not only the patient, but also those conducting such investigation. These methodological issues may contribute to the limited therapeutic treatments for this trauma, as well as limited pharmacological or interventional treatments to improve outcome.
On March 5, 2009, a joint meeting was held between the American Society of Experimental NeuroTherapeutics (ASENT) and the International Society of CNS Clinical Trials Methodology to review and discuss the etiological and methodological issues facing this patient population. Both organizations are committed to the advancement and development of improved therapies for CNS disorders, as well as the methodological challenges in the development of these improved therapies. Experts in the nosology, clinical research, and translational medicine were gathered in Arlington, VA for these purposes and identify and discuss areas in which such advances may be made. This session was chaired by Alan Faden, MD (Georgetown University) and Tom Macek, PharmD, PhD (Takeda Global Research and Development). Speakers included Mark Lovell, PhD (University of Pittsburgh Medical Center), Col. Michael S. Jaffee, MD, and Karen Schwab, PhD (Defense and Veterans Brain Injury Center), Douglas Smith, MD (University of Pennsylvania), and M. Ross Bullock, MD, PhD, University of Miami, Miami, FL.
mTBI – A diversity of patient populations
While some similarity of the clinical course of patients suffering from mTBI may be common to patients with mTBI, the diversity of injurious situations that lead to the clinical course of mTBI is highly heterogeneous. The consequence of this diversity is that a universal, systematic approach to the study of mTBI is not currently feasible. Within both civilian and military populations, there are commonalities as well as divergences in clinical course, the situations leading to injury and a multitude of other confounding variables that contribute to the difficulty in studying this heterogeneous population.
In the realm of athletics and sport, mTBI is a common occurrence, particularly in children. In his talk, entitled “mTBI in the Civilian Population: New Frontiers in Diagnosis and Treatment”, Dr. Lovell described the pervasiveness of mTBI in the civilian population. To this, it is estimated that approximately 1 million children per year, in the US, have mTBI, accounting for approximately 10% of all pediatric evaluations. The CDC estimates that 1.6-3.8 million sports-related mTBIs annually.
Sports-related injuries offer a unique opportunity to study the effects of mTBI, in that, there is a unique opportunity to conduct baseline and post-injury assessments, in an at-risk population, as well as the longitudinal course of recovery.
Within athletes, poorer outcome is associated with repetitive injury, younger age, and also female gender. In sports played by both sexes, it was noted that the rate of mTBI is higher in females, than in males and that high school athletes have prolonged time to recovery when compared to college or professional athletes.
Because athletes may face pressure to return to competition prematurely, methods for evaluation of severity of injury and recovery are necessary to objectively assess readiness for athletes to compete.
Like athletes, members of the military also face situations or scenarios that lead to high prevalence of mTBI. Col. Michael Jaffee, MD, presented “Characterization and Study of Acute Military Mild Traumatic Brain Injury in the War-Zone”. The ongoing conflicts in which the United States military is engaged – Operation Iraqi Freedom and Operation Enduring Freedom – have unfortunately shed light on the high prevalence in combat troops. Studies in which troops returning from Iraq or Afghanistan were screened for mTBI, approximately 15- 23% of returning soldiers and 18.5% of veterans at VA medical centers screened positive for mTBI (refs). Ironically, due to improvements in body armor and combat lifesaving techniques, the incidence of mTBI may be relatively higher than in previous conflicts.
Understandably, the theater of battle does not lend itself well to the clinical study of this population, as troops face potential lethal consequences during enemy engagement. Not only the emergent consequences of injury, but the long-term risks of unresolved mTBI in military theater – slower reaction time, decreased concentration, and slowed thinking – may have residual consequences if the soldier is not fully recovered.
To this, the Military Acute Concussion Evaluation (MACE) has been developed for the screening of mTBI as soon as possible after injurious events such as blast, fall, vehicle crash, or impact. The components of the MACE include description of injury, the Standardized Assessment of Concussion (SAC), and brief neurologic and cognitive evaluations.
While tools and instruments have been developed for the acute assessment of mTBI, the methodological challenges to the clinical study are unique. During combat, the mission supersedes all other activities. The injury may occur great distances from study sites. Also, as with athletes, there may be pressures to participate or a general unwillingness to seek treatment. In addition, due to the nature of their activities, the combat soldier is drastically unique from the general population. These men and women may face constant sleep deprivation, hyper-arousal, psychiatric or other physical comorbidities that make direct comparisons to a “control” population virtually impossible.
Like the acute study of mTBI in combat troops, the longitudinal study of mTBI in combat troops is equally challenging. In her talk entitled “Studies of Chronic Problems after Mild TBI in Military Populations: Challenges in the Characterization of Chronic Problems and Design of Treatment Trials”, these methodological challenges were described by Karen Schwabb, PhD.
Returning combat troops may have undetected or misdiagnosed mTBI. The identification and diagnosis of injury in is paramount to adequate treatment and recovery from injury. In one study, 51% of 47 patients seen in a British trauma center with a TBI did not have a diagnosis of TBI recorded (ref). To address the difficulty in identifying mTBI, a post-deployment screening instrument which assesses injury and consequences of injury, which may be suggestive of mTBI. A number of personality, psychiatric, and psychosocial consequences of mTBI contribute to the difficult transition from military theater to recovery.
As most mTBI improve with time, there is very little class I evidence to support different treatment methods or modalities in the returning military population. Therefore, well-controlled, randomized, clinical trials are desperately needed to address these issues.
Clinical trials in this population face the added challenges of perceptions that they are resource intensive, the lengthiness of well-designed studies, challenges in IRB approval in multi-center studies, issues in blinding, as well as financial incentive for sponsors of pharmacotherapy trials in which the perception that such pharmaceutical studies are, in effect, futile. Add to this the more-traditional issues with recruitment, randomization, and the added complexities of multiple deployments, comorbidities and concomitant pharmacotherapy and the complexity becomes even greater. It is, however, in the name of military readiness that such trials are conducted to more effectively treat these patients.
Lost in translation – Human to animal and animal to human
A number of animal models exist to explore potential therapies for the treatment of mTBI. In nonclinical studies, numerous agents with diverse pharmacological properties have been described which predicted potential therapeutic benefit. Unfortunately, in clinical studies of these agents, none have demonstrated the promise in phase 3 trials which observed in either early clinical trials (phase 2) or in nonclinical studies. To this point, many of the models utilized in nonclinical studies may be somewhat too precise to be utilized for accurate prediction of potential therapeutic benefit in a tremendously heterogeneous and variable patient population.
Douglas Smith, MD, described in his talk “mild TBI: Animal to human translation” newer techniques to help explore and understand the pathology associated with mTBI. Dr. Smith described the hypothesis that mTBI may be most accurately described as Diffuse Axonal Injury (DAI), the most important and most common underlying pathology of mTBI. In addition, DAI is difficult to detect and difficult to model. To address the difficulty in modeling mTBI, a porcine gyrenecephalic model of head rotational acceleration has been developed. Unlike other animal models of mTBI, this model results in diffuse axonal injury observed in parallel studies in humans post-injury by diffusion tensor imaging (DTI) fiber tractography (ref). Histopathological changes in pig post-injury confirm regional edema or hemorrhage and surrogate protein markers of brain pathology were identified after mTBI in the serum of both patients and swine. In addition, an in vitro model of axonal stretch injury of cultured neurons is used to explore the biochemical changes associated with insult. Post-injury, these cultured neurons display many of the properties associated with DAI – delayed elasticity, interruption of protein transport, and swelling of axons. At the core of the pathological insult following injury is an acute disruption of sodium channel function. A consequence of injury is damage to the inactivation gate of sodium channels, leading to an acute increase in intracellular sodium. The electrochemical imbalance caused by this increase in sodium and reversal of the sodium-calcium exchanger and activation of voltage-sensitive calcium channels and an increase in calcium influx. The increased intracellular calcium activates proteases such as calpain which target the inactivation gate of the sodium channel. In addition, an acute increase in sodium channel expression is noted post-injury, which may be a compensatory mechanism to restore normal sodium channel function. Models such as these employed by Dr. Smith add to the understanding of the underlying pathological changes post-mTBI and may add greater predictability of potential human therapies utilized in clinical trials.
It is this failure of the translation from animal to human studies that has plagued this area of research, as no treatment has been approved for mTBI. There are, however, a number of examples of clinical studies that have been conducted in TBI or related disorders (eg, stroke), but a multitude of failures – particularly in phase 3 – have been reported in recent years after very promising nonclinical and early clinical results.
M. Ross Bullock, MD, PhD, addressed this difficulty in his talk entitled “How do we optimize neurotrauma trial design: where do we go from here?”. In it, Dr. Bullock described the large number of clinical studies that have been conducted in mTBI and in related disorders such as stroke. Despite promising early results and large investments by both pharmaceutical companies and governmental organizations, the results in late-stage clinical trials have been disappointing. In stroke research, the high degree of failures has resulted in a collaborative effort between industry and academia (Stroke and Industry-Academia Roundtable or STAIR) to specifically identify methodological approaches to improving potential outcomes or optimization of study design to improve chances of success (ref). The outcome of STAIR has been a call for the utilization of sensitive and less variable outcome measures, the development of new methods of analysis of study data, and improvements in homogeneity through the use of novel study designs and more focused patient populations.
In the realm of mTBI, application of staged, strategic clinical development for novel therapies is imperative for improving success. That is, in the development of compounds for treatment of mTBI, it is imperative that the pharmacokinetic parameters of the compound are well characterized and adequately penetrate to CSF to ensure effective delivery to the target organ (brain). In addition, mechanistic studies to better understand the mechanism of action and incorporation of biomarkers into clinical trials are essential to fully elucidate the potential effectiveness of experimental therapies or for effective, strategic decision-making.
Clinical development programs have also suffered from the common pressures to quickly move from phase 2 to phase 3, without fully understanding phase 2 results. In addition, due to the modest nature of magnitude of improvement in TBI and mTBI trials, Dr. Bullock contended that many of these studies may have been adequately powered to detect the true difference between treatments. The need for larger sample sizes (~3000) should be considered to detect these small differences. And, comparable to other CNS disease areas, there are needs to also improve the quality of data reported in clinical trials and there may be a limited number of “quality” research centers to conduct these complicated assessments and evaluations. Lastly, Dr. Bullock called for greater public/private collaborative efforts to expand our understanding of mTBI.
Discussion and Take-home Messages
” mTBI comprises a great unmet medical need in the general population, particularly in specific at-risk groups (such as athletes and military)
” The consequences of mTBI are potentially significant, causing disruptions in a number of emotional, sleep, somatic, and cognitive disturbances
” Difficulties in developing new therapies for treatment of mTBI are confounded by the lack of predictability of animal to human outcomes in this heterogeneous population
” Instruments and measures of greater sensitivity are needed to improve signal detection in clinical trials; novel study designs and alternative methodological approaches should be utilized to improve signal detection
” As with stroke and the STAIR initiative, the collective understanding of mTBI and potential therapies would greatly benefit from a formal partnering between governmental, academic, and pharmaceutical institutions