- Category: An Emissary Clinical Trial Success Story
Without urgent pressure-relieving surgery, the chance of survival drops quickly for head trauma patients having a severe intracerebral hematoma (bleeding inside the skull). Sadly, the condition is too often not diagnosed in time. A technology with the potential to change that might have languished in the halls of academia if not for the dedication of a creative entrepreneur and an experienced contract research organization (CRO) committed to advancing lifesaving solutions for unmet medical needs.
It has been called the “signature injury” of the war in Iraq, afflicting an estimated 7,500 soldiers and countless thousands of civilians, including in a widely-televised first, Bob Woodruff, the American news anchor.
It was the cause of death for Kurt Vonnegut, author of Slaughterhouse Five which in a strange coincidence opened with the bombing of Dresden in WW2 where thousands of people undoubtedly died from it, and in which the main character’s time travels may have been a mental manifestation of it.
Each year in the U.S. alone, one million people are seen in emergency departments because of it. Eighty-thousand Americans will end up with significant disabilities due to it and some 50,000 less fortunate will die from it.
"It" is traumatic brain injury.
Tramatic brain injury or TBI is often simply called head injury, and it occurs from bleeding, tearing and swelling of the brain following a traumatic event (as opposed to something spontaneous like a stroke). The injury causing it may be as dramatic as a war-zone explosion or a piercing bullet, but more than half of the time it is a transportation accident. However, in the elderly, as was the case with Kurt Vonnegut, traumatic brain injury is most often the result of a fall, sometimes just a trivial bump on the head.
It doesn’t take much to cause brain injury. Even without an actual impact, any sudden acceleration or deceleration can be enough when the rigid skull abruptly stops the inertia of the jelly-like brain floating inside. Perhaps surprisingly, the initial damage can be both in, and opposite to, the direction of force as the brain first slams into the skull and then recoils back hard against the opposite side causing a contre-coup injury. Beyond the surface injury, such sheering forces can also cause stretching and tearing deeper within the brain or at connection points such as the optic nerves, a heartbreaking characteristic of shaken baby syndrome.
Unfortunately, there is little that can be done to reverse the damage caused by the initial trauma so the primary focus is on stabilizing the patient and minimizing further injury. In about half of the serious cases of head injury, neurosurgeons must burr a hole or cut a flap in the skull (a craniotomy) to evacuate bleeding. This bleeding within the skull is called an intracranial hematoma, or brain hematoma. Emergency surgery hopefully prevents further crushing of the brain tissue caused by the pooling blood and relieves the high intracranial pressure (ICP). An untreated elevation in intracranial pressure restricts the flow of blood to the brain, leading quickly to death or serious morbidity.
The Classification & Diagnosis of Intracranial Hematoma
A subdural hematoma (SDH) occurs in about a third of head traumas when blood vessels, usually low-pressure veins, rupture between the brain and the dura mater, the tough outermost of the three membranes called the meninges, that surround the brain and spinal column. A subdural hematoma can be acute (symptom onset within 48 hours) which is often fatal even with emergency medical treatment, sub-acute (symptom onset after 48 hours), or chronic. The latter type is sometimes seen in the elderly two weeks or more after a fall, as appears to be the case in the April 2007 death of that 84-year-old counterculture novelist with the famous acerbic wit.
An epidural hematoma (EDH) occurs when a blood vessel, usually a high-pressure artery, ruptures between the outer layer of the dura mater and the skull. It is usually the result of a focused blow from a blunt object such as a baseball bat, and is typically associated with a skull fracture. Epidural hematomas are present in 1-3% of head injuries and tragically end in death between 15-20% of the time.
Intracerebral hematomas (ICH), sometimes called intra-axial hemorrhages, are caused by direct damage within the brain tissue. In these cases, it is generally believed that surgery is less likely to restore function than when the brain is damaged by extra-axial compression, as occurs with epidural and subdural hematomas. However Emissary is also involved with MISTIE, a groundbreaking trial lead by Johns Hopkins University's Brain Injury Outcomes Service. The MISTIE researchers, at most of the top neurology hospitals worldwide, are evaluating new techniques for removing intracerebral blood clots (ICH) using tiny stereotactically-placed catheters and tissue plasminogen activator (a clot dissolving drug called tPA or alteplase) or alternatively endoscopic techniques.
Emissary is a key part of a second large phase III multicenter international trial, CLEAR III, which is evaluating surgical and pharmacologic approaches to treat bleeding within the brain's ventricular system (called intraventricular hemorrhage or IVH). The ventricular system is where cerebrospinal fluid circulates between the brain and spinal column. Both MISTE-ICH and CLEAR-IVH are enrolling patients with bleeding from a spontaneous stroke, usually due to uncontrolled hypertension, but IVH can occur as well in about 35% of moderate to severe traumatic brain injuries.
No single physical symptom reliably indicates the presence of a hematoma. Head trauma patients that do NOT have a significant hematoma may still experience a coma 56% of the time. A unilaterally-dilated pupil is found not only in patients with surgical-grade hematoma, but also in those with diffuse brain injuries. Diagnosis of a hematoma, therefore, requires access to expensive and bulky imaging equipment, usually a computed tomography (CT) scan, to view the actual pooling of blood within the skull.
Particularly in the case of a subdural hematoma, bleeding may re-occur long after the initial trauma, or new hematomas may suddenly and unexpectedly start in other locations. Head injury patients therefore must usually undergo repeated CT scans for a period of days even after they are stabilized. Due to the expense and the necessity of moving the patient to centrally-located equipment, repeat CT scans are usually only done once a day unless the patient loses consciousness or has an intracranial pressure spike.
The Golden Hour for Emergency Treatment
There is debate among emergency medicine experts as to the validity of the first “golden hour” as an appropriate target, but it is clear that the chance of survival falls off precipitously for an intracerebral hematoma patient with severely elevated intracranial pressure that does not undergo pressure-relieving surgery within perhaps as little as 60 minutes or less. The developed countries usually have elaborate emergency response systems for rapid transport and a network of tertiary medical centers (trauma centers) with dedicated CT equipment and specialized staff in the emergency department that can get a hematoma patient into surgery within that critical first hour. But, there are definite gaps, particularly in rural areas. Even across the developed countries, estimates are that, because of inaccessibility and high cost, as many as half of all head trauma patients will not get a diagnostic CT scan.
A recent study by a 280-bed community hospital in Massachusetts showed the lag time between when the emergency department (ED) requested an urgent CT and the completion of the scan was about 39 minutes. After a new “portable” (750-pound, albeit battery-powered) CT machine was installed in the ED, that lag time dropped to around 17 minutes. Adding in the time required to transport the patient to the hospital, assess the need for a CT, prep for surgery and so forth, it is clear that getting a hematoma patient to surgery in that first golden hour is a difficult challenge even at American hospitals having an extra half-million bucks to spend on a second CT machine.
For poorly-funded hospitals in developing countries, it’s damn near impossible. The sharply accelerating number of vehicles in these emerging counties, particularly in Asia, means ever more head trauma cases racing into ill-prepared government-run hospitals. The World Health Organization predicts that by 2020 deaths from traffic accidents will increase by 92% in China, 147% in India and an average of 80% across other developing countries, from a current average of 3,000 worldwide auto-related deaths each day. As a closely-related consequence, the worldwide incidence of brain hematoma, currently around ten million each year, is growing rapidly as well.
Emissary and Infrascan Collaborate on a Possible Solution
In summary, there exists a significant unmet medical need. Emissary International is proud to be helping one of its clients to address this critical need! Infrascan, Inc. is a start-up medical device company based in Philadelphia. The company’s flagship product — the Infrascanner™ — is a hand-held, battery-powered device for the detection of intracerebral hematoma in head trauma patients.
The Infrascanner was designed specifically to meet this unmet medical need for a portable, low cost device that could help triage head injury cases. In other words, the Infrascanner is designed to quickly and inexpensively identify patients who have a high likelihood of having a hematoma and thus should be urgently sent for a CT scan to obtain a definitive diagnosis.
In practice, should it receive regulatory approval, an Infrascanner might be carried by first responders to aid in selecting the best destination (primary or tiertary hospital) and means of transport (air or ground). It might be used in emergency departments to prioritize patients needing a CT. It might be used in ICU or on the hospital floor for a quick interim check between routine follow-up CT scans. An Infrascanner might even be used on the battlefield when weighting the risk/benefit of bringing in a medivac helicopter versus using armored ground-based transport. Although, it is not intended to replace a CT, it might ultimately be the only viable option for confirming a surgical intervention decision at remote health facilities in poor countries where imaging equipment is cost-prohibitive.
The Infrascanner works by projecting light, at a specific near-infrared (NIR) frequency, through the skull, meninges, and a few centimeters into the brain. In something akin to looking at your hand while held over a flashlight, an optical sensor then reads the absorption and alteration of frequency of the light as it traverses the tissue (something called reflectance spectroscopy); the hemoglobin pooled in an intracranial hematoma absorbs more light than healthy tissue. In the current design, the comb-like sensor then transmits wirelessly to sophisticated software running on a personal digital assistant (PDA); a forthcoming model will combine these into a single lightweight device. An asymmetric optical density reading when comparing opposite sides of the head (a high delta-OD), indicates a strong likelihood of a hematoma. Thus, in a simple, 5-minute procedure, the user “scans” left and right sides of the head across four sectors (frontal, parietal, temporal, and occipital) and gets back an immediate yes/no answer to the question: does this patient have a likely hematoma? A positive reading means the patient should be prioritized as a candidate for likely neurosurgery after getting an urgent CT to pinpoint the exact location and extent of the bleeding.
Coincidence and Serendipity
The Infrascanner investigational medical device is based on patented discoveries by Dr. Britton Chance, the groundbreaking biophysicist, biochemist, Olympic medalist, and all-around medical imaging guru. The software in the Infrascanner uses complex signal analysis algorithms first pioneered in early radar systems.
Here again lies a strange coincidence. In 1950, Dr. Chance received the Presidential Certificate of Merit for leading a top-secret group that during WW2 developed the H2X radar. While historians credit the H2X radar for much of the Allied success in winning the war, critics claim the reliance on the H2X radar contributed to the massive number of civilian deaths during the bombing of Dresden, the highly controversial event witnessed firsthand by then prisoner-of-war Kurt Vonnegut which so profoundly influenced his writings.
A decade ago, experiments using an early prototype device showed that near-infrared spectroscopy (NIRS) had promise. But, the technology behind the Infrascanner might have languished in the ivory halls of academia had it not been for the entrepreneurial perseverance of Infrascan’s founder and the personal dedication of Emissary’s president to advancing life-saving research.
Taking a new technology from invention to a commercially-viable medical device and then on through clinical testing and regulatory submission is an enormous challenge. But, it was just the challenge that Infrascanner’s founder, Baruch Ben Dor, was seeking. With a doctorate in physics and 17 years experience in the field of electro-optics, Dr. Ben Dor immediately recognized the potential of this new technology after meeting Dr. Chance back in 2004. But the sad reality of medical research is that a start-up company with an unproven technology is unlikely to ever get funding through conventional sources. Venture capitalists understand MPR and ROI but they just don’t get GCP and delta-OD.
Undaunted, Dr. Ben Dor, having assembled a small but renowned team of supporters, turned to unconventional sources, first winning a business plan competition from Wharton and then a small grant from the U.S. Navy. These successes allowed the company to design and build the first few devices, but the next step of validating the Infrascanner in a large multicenter clinical trial would require help from an experienced contract research organization (CRO) which looked to be prohibitively expensive.
Proving the Infrascanner has the accuracy needed for such a critical diagnostic role would require collecting and analyzing scores of measurements from a couple hundred patients scattered across geographically-dispersed trauma centers. To achieve statistically analyzable data, patients entered into the trial would have to meet strict criteria including a subsequently confirmed diagnosis of hematoma by a CT scan conducted within 30 minutes of the NIRS scan (as discussed above, obtaining a CT within an hour is already tough). Ultimately, only one out of every 8-10 subjects entered into the trial would meet these evaluation criteria, greatly expanding the total number of head trauma patients required.
Although head trauma is relatively common on an epidemiologic scale, the typical emergency department actually only sees a handful of cases each week, and the cases are mostly at night or on the weekends, notably coinciding with the higher incidence of alcohol-related auto accidents at these times. You won’t find many experienced clinical study coordinators working at those odd hours. Yet, the alternative, having emergency department physicians and nurses collect clinical trial data on a trauma patient being rushed off to a CT scan would be formidable as well.
Consequently, for the typical contract research organization, this looked to be a large, complex and expensive trial with possibly insurmountable challenges, not the least of which was a sponsor that ultimately might not be able to afford it. But Emissary is not the typical CRO! In the words of our founder, this is exactly the type of noble quest for which our company was founded: helping to bring innovative life-saving medical products to people that so desperately need them.
Emissary's Illuminating Solution
The first challenge was to distill the study down to a manageable size. In the hectic rush to get a head trauma patient to surgery within that first golden hour, there just isn’t much time to collect clinical trial data. So, Emissary staff worked closely with Infrascan and the clinical investigators to identify the minimal amount of data needed to answer the scientific questions, and then to devise a means to collect data from the emergency department within no more than 3 to 5 minutes.
An important set of data consisted of the many optical density (OD) readings generated by the Infrascanner and stored in a file on the PDA. Originally, it was assumed that this information would have to be transcribed by hand to paper data collection forms. Instead, Emissary utilized its proprietary Electronic Data Capture (EDC) technology, adding custom programming to upload and parse the data file, thereby allowing an automated immediate calculation of certain study endpoints. Having the device data files attached to the patient record solved a regulatory retention and source-validation problem as well.
Additionally, clickable diagrams of the skull were added to allow the investigators to easily and rapidly document the scan points and the location of any scalp bruising or laceration.. This was to ensure that the NIRS scans were not inadvertently affected by the presence of surface blood from extra-cranial (scalp) injuries, and to correlate with the confirming CT scans. Granted, many other CROs have now adopted EDC software, but few competing systems have the power and flexibility to so easily handle unusual situations like this.
The second challenge was the need to keep the Infrascan operators blinded to the CT results, and the CT readers blinded to the Infrascanner results. This basic tenet of clinical research would normally have been extremely hard to accomplish in the emergency room setting where rapid dissemination of information is critical. Thankfully, it was a relatively easy thing to accomplish using the field-level access controls available in Emissary’s EDC system. This was also an opportunity for Emissary to help two of its clients work together: a group at Johns Hopkins served as the central CT reading center.
On the regulatory side, another challenge was that head trauma patients are often unconscious and incapable of granting informed consent or a HIPAA waiver allowing access to records. This required working with the institutional review boards at each hospital to obtain a formal waiver of informed consent requirements, as well as devising unique ways to eliminate any patient identifiers (date of birth, initials, etc.) from both the collected data and the source documents.
As many of the staff at the clinical sites would have little to no prior experience with clinical trials, Emissary focused much attention on the training and support challenges. Due to the budget restraints, on-site monitoring visits had to be kept to a minimum, so worksheets, regulatory forms, and similar study materials needed to be user-friendly, easy to maintain, and self-explanatory. Emissary developed effective online training programs and supporting educational materials. The sophistication of Emissary’s EDC system played an important role here by making hundreds of calculations for on-the-fly entry validation to ensure the data would be complete and accurate with only a minimal amount of monitoring oversight.
Yet Another Success!
Overcoming a series of such obstacles over the last 18 months, Emissary successfully conducted this international multicenter clinical trial of the Infrascanner, working with neuro-specialists, radiologists, emergency medicine physicians, and their staffs from such renowned organizations as Baylor University, Drexel University, The University of Pennsylvania, The University of Cincinnati, Johns Hopkins University, and Lokmanya Tilak Medical College in Mumbai, India. Data from this study was recently submitted in an application for marketing clearance to the U.S. Food and Drug Administration. I think Kurt Vonnegut would be very pleased!
 Weinreb, David B. and Schwamm, Lee. Use of a Portable CT Scanner associated with 58% Reduction in Request-to-Scan Times. Stroke. Vol 39, No 2, Feb 2008, pg. 101.
 2007 World HealthReport. Chapter 6: Neglected Global Epidemics – Three Growing Threats.
 MPR is an abbreviation for Market Penetration Rate. ROI is short for Return on Investment. Delta-OD refers to the mathematical difference in optical density. GCP is an acronym for Good Clinical Practice regulations governing investigational medical products, but if you are reading this article, you probably already know that one.