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CLINICAL TRIALS INITIATIVE
The Clinical Trials Initiative is The Miami Project’s efforts to carefully take new discoveries from the laboratory to clinical trials. The Clinical Trials Initiative was started in 2004 and is aimed at creating the infrastructure needed to gain approval for and to conduct clinical trials at the University of Miami affiliated hospitals. The Miami Project is pursuing various preclinical and clinical trial activities that fall under the umbrella of the Initiative. We anticipate these activities will bring new and potentially life-changing treatments to people with central nervous system trauma. As a result of the infrastructure created as part of the Initiative, The Miami Project is already involved with several clinical trials, as described below.
SPINAL CORD INJURY CLINICAL TRIALS:
One of The Miami Project’s most anticipated clinical trials involves the testing of autologous Schwann cell transplants in humans with acute and chronic SCI. The first step, generating all of the preclinical safety and efficacy data to justify the testing of Schwann cell transplantation in humans, has been completed. The Food and Drug Administration (FDA) has approved our Investigational New Drug (IND) application to allow us to begin a Phase I clinical trial to evaluate the safety of autologous human Schwann cell transplantation a few weeks after a spinal cord injury has occurred.
This first trial will purely test safety, because we have to do surgery on people and actually stick a needle into their spinal cord injury site in order to put their Schwann cells inside. It will only involve about 8 people and they will all be new injuries. The main reason we are doing new injuries first is because we have more animal data in that setting and it allows us to seek FDA approval faster. Obtaining faster FDA approval means going into people faster; this means finding out about safety faster. As soon as we know it is safe to inject, we can then request approval to start additional trials such as expanding into chronic injuries, incomplete injuries, and even combination therapies. We are continuing to generate animal data in the chronic injury setting to be used for future trials in people with chronic injury. So think of this as our building block to developing the most effective treatments for people living with SCI. The best way to get access to these treatments fastest is to keep yourself healthy and in very good condition so that you qualify for clinical trials as they become available and for which you qualify.
So think of this as our building block to developing the most effective treatments for people living with SCI. The best way to get access to these treatments fastest is to keep yourself healthy and in very good condition so that you qualify for clinical trials as they become available and for which you qualify.
One of the great advances in modern medicine has been the development of biomarkers for specific human diseases. In medicine, a biomarker is typically a protein that can be measured from bodily fluid, such as blood, whose concentration levels can be used to predict the severity or presence of a diseased state. Biomarkers allow doctors to detect a disease early, monitor its progress, predict its severity, and tailor treatments to any specific patient’s problem. In the spinal cord injury (SCI) arena, early predictors of injury may have important diagnostic and prognostic significance, helping to detect the presence and severity of injury within the first few hours and to aid physicians in directing the best patient care in a timely manner. For researchers, a SCI biomarker may give early insight into the effects of experimental treatments, speeding study results and reducing the research subjects sample sizes needed. Over the past two years, a team of Miami Project and Neurosurgery Department researchers (Drs. Ross Bullock, Michael Wang, Helen Bramlett, Dalton Dietrich, Robert Keane, Pablo de Rivero Vaccari, and Stephanie Adamczak) have been investigating the use of surrogate biomarkers to predict the outcome of acute SCI in a study sponsored by Banyan Biomarkers.
In this study, blood and spinal fluid samples were obtained from 7 newly injured people who were already undergoing spinal fluid drainage as a part of their necessary clinical treatment. The presence of several breakdown products from spinal cords tissue or inflammatory mediators were found to be elevated in blood and cerebrospinal fluid at early time points after injury. Similar results were observed in a rat model of SCI. Samples indicating severe neural damage were found to be correlated with the degree of neurological impairment as well as native recovery. In other words, higher levels of these breakdown products circulating in the blood or cerebrospinal fluid were predictive of less recovery. The team’s preliminary results, and that of others, suggests that a panel of spinal tissue structural protein breakdown products have potential as promising biomarkers in an animal SCI model and in humans with SCI.
This study is still enrolling participants that are admitted to the Ryder Trauma Center at Jackson Memorial Hospital and with increasing numbers may reveal keys to early interventions for acute SCI. Ultimately, biomarkers may be used to tailor the intervention (surgical, pharmacologic, rehabilitation) to each individual person with SCI, much as cancer phenotyping is beginning to be used to target chemo- and immunotherapies, as well as to identify candidates for clinical trials targeting acute neuroprotection.
The Miami Project and UM Department of Neurological Surgery are part of the North American Clinical Trials Network (NACTN). The Miami Project and UM Department of Neurological Surgery are part of the North American Clinical Trials Network (NACTN). NACTN is a network of institutions that is developing the infrastructure, methods, and skilled personnel needed to conduct trials for SCI. Presently, the collaborative centers are collecting natural history data from newly injured people to determine the medical and rehabilitative outcomes and complications that occur in people receiving standard of care. Participants are evaluated for one year post-injury. The Miami Project has already enrolled more than 35 people to this registry. This information will help determine the design of SCI clinical trials because we will better understand complications that are risky for interventions at specific times post-injury and what degree of spontaneous recovery would be considered normal for different types of injuries.
NACTN also recently completed enrollment for a Phase I open label multi-center safety trial of a drug (Riluzole) that reduces secondary damage after SCI in animals. In humans, Riluzole has been associated with improved life span in Lou Gehrig’s disease. In the Phase I trial for SCI, several aspects of Riluzole’s effects are being tested, hopefully as a prelude to a Phase II study testing the efficacy of Riluzole in a blinded manner, which is a more powerful clinical test. In Phase I the amount of drug that enters the blood stream and how quickly it is metabolized is being measured over 14 days. This is essential information to understand how to predict the dose that has the best chance to reduce secondary damage. Also, complications related to the drug’s administration are being carefully monitored, again enabling more effective dosing in future trials. This trial is the first to carefully study the metabolism of Riluzole in acute SCI, an important step forward given the many changes in organ function that follow SCI. Finally, although not the primary aim of the study, efficacy measures such motor and sensory changes and changes in daily key functions are being acquired and compared to the NACTN registry database, acquired from the same clinical centers.
The Miami Project is conducting pre-clinical studies to identify the optimal methods for delivering Rolipram as a neuroprotective therapy for acute spinal cord injury. The goal of these studies is to determining the best dose, route, and timing of administration of Rolipram to achieve maximal tissue protection. These studies are producing critical data needed to submit an IND application to the FDA to request approval to begin a Phase I/II clinical trial to test Rolipram’s safety and efficacy in acute spinal cord injury.
ARCTIC is the acronym for our next clinical trial testing the safety and efficacy of therapeutic hypothermia (cooling) in SCI, Acute Rapid Cooling Therapy for Injuries of the Spinal Cord. We have already completed a Phase I clinical trial to start learning whether inducing hypothermia within the first few hours of traumatic SCI is safe and makes a difference in the severity of injury. When people with new cervical SCI were brought to the trauma center, doctors placed a cooling catheter in a large blood vessel (vena cava) that allows them to cool the body a few degrees to 33 degrees Celsius (or 92 degrees Fahrenheit). In that trial the cooling was started within 9 hours post-injury, on average, and was maintained for 48 hours. After which, participants were slowly re-warmed at one degree every eight hours and then proceeded with standard medical care. In that initial trial there were no serious safety concerns and there was a trend for more people to recovery more function after 1 year post-injury than would normally occur spontaneously.
ARCTIC will be a Phase II/III clinical trial where we will evaluate the safety of different durations of hypothermia, initiated within 6 hours post-injury, and then confirm the efficacy of the best duration. We have taken what may seem like a long time to plan this clinical trial, but for many good reasons. One, predicting whether someone has a “complete” or “incomplete” SCI within the first 6 hours is VERY difficult and unreliable. In fact, it is not reliable until after 72 hours post-injury. However, because we have such a short time window in which to intervene with hypothermia, it is a complication we must deal with. Two, this trial will involve more than 200 people with acute SCI and cost several million dollars. We have been working with the National Institutes of Health sponsored Neurologic Emergencies Treatment Trials (NETT) network for review and, hopefully, funding. Three, we have to get this right, the SCI field needs it! There have been too many “failed” Phase III clinical trials because of design issues. Drs. Michael Wang and Dalton Dietrich have been working with several experts in clinical trial design and statistics to develop the most appropriate design to capture clinically meaningful improvements yet still be responsive to unknown safety issues. If this pivotal trial gets funded and the data positively demonstrate that the benefits significantly outweigh the risks, we could change the standard of care for SCI medicine worldwide.
TRAUMATIC BRAIN INJURY CLINICAL TRIALS:
Biomarkers for acute traumatic brain injury
Miami Project neurosurgeons are conducting these crucial observational studies to identify biological markers for early diagnosis of TBI. Currently, there are no simple blood tests that enable physicians to identify the presence and severity of TBI in the emergency setting. In these trials, cerebrospinal fluid and blood serum samples will be analyzed in people immediately post-injury and compared with brain injury/spinal injury severity and outcome. The goal of this study is to identify biomarkers of TBI to facilitate earlier diagnosis of TBI and, thus, earlier intervention and management.
BOOST for acute traumatic brain injury
Miami Project neurosurgeons recently received funding from the National Institutes of Health (NIH) to begin a Phase II clinical trial of brain tissue oxygen monitoring in people with severe TBI. TBI can lower the concentration of oxygen in brain tissue and this has been observed to be associated with poor functional outcome. This trial will use a brain oxygen monitoring device to guide clinical decision making for therapy. Participants will be randomized to therapy based on the current standard of care monitoring (intracranial pressure) or standard of care plus brain oxygen monitoring. The results will be used to develop a pivotal Phase III trial to test the efficacy of interventions designed to prevent low concentration of oxygen in brain tissue.
A new multi-center trial being conducted at The Miami Project/UM is to evaluate whether the occurrence or severity of a secondary injury phenomenon called spreading depression is related to worse neurologic recovery following TBI. Spreading depression is a process of short-circuits in brain function, which arise spontaneously from an injury. These “short-circuits” spread repeatedly as waves into neighboring brain tissue and have been shown to cause secondary damage in animal studies. It is known that spreading depression occurs in a large proportion of people with acute TBI during the first week post-injury. The information gained from this study will help neurosurgeons determine whether monitoring of spreading depression is a useful guide for medical management of TBI or is a target for therapeutic intervention.
Another study that Miami Project neurosurgeons are participating in is a trial to evaluate a neuroprotective drug for acute TBI called NNZ-2566. NNZ-2566 is a synthetic analog of a trophic factor called Insulin-like growth factor (IGF-1). This drug has multiple functions. It has been shown to reduce inflammation in injured brain tissue, reduce cell death, protect neurons, and inhibit non-convulsive seizures that occur in the acute, post-injury period. This is a multi-center, randomized, placebo-controlled trial designed to identify the best dose of the drug that reduces side effects and improves brain function.
This trial will test the safety and efficacy of “Oxycyte,” a perfluorocarbon that improves brain oxygenation. Oxycyte is an oxygen transport enhancer, capable of carrying four times the normal amount of oxygen than a normal human red blood cell. By introducing Oxycyte to the brain or spinal cord after injury, the investigators hope this will increase the oxygen delivered to the injured tissue and reduce the amount of permanent damage to nerve tissue. The Oxycyte trial is currently enrolling subjects in Switzerland and Israel and is scheduled to begin enrolling subjects at UM by 2012.