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CLINICAL TRIALS INITIATIVE
The Clinical Trials Initiative is The Miami Project’s efforts to carefully take new discoveries to clinical trials. The Initiative was announced after Miami Project scientists had encouraging research findings in 2004 that showed a greater degree of recovery of locomotor function than normally experienced after spinal cord injury, in laboratory animals. These results were seen when Schwann cell transplants into the injured spinal cord were combined with injections of an anti-inflammatory drug Rolipram and cyclic AMP (a messenger molecule that stimulates nerve fibers to grow). The triple combination strategy prevented some nerve fibers in the spinal cord from dying, which resulted in spared function. In addition, some nerve cells in a specific region of the brain (the brainstem) grew their fibers not only into and across the injured area containing the Schwann cell grafts, but also beyond that and into the part of the spinal cord below the injury. With this evidence of functional recovery in laboratory animals, The Miami Project has focused on important preclinical activities needed to obtain approval from the Food and Drug Administration (FDA) to begin clinical trials with Schwann cells.
The Clinical Trials Initiative is also 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. The Miami Project is currently preparing for, or is involved in, several clinical trials.
These include:
SPINAL CORD INJURY CLINICAL TRIALS:
Autologous Schwann Cells for acute and chronic spinal cord injury (preclinical phase):
One of The Miami Project’s most anticipated human clinical trial initiatives is testing human Schwann cell transplants in humans with acute and chronic SCI. We are preparing our preliminary Investigational New Drug (IND) submission so as to gain approval from the Food and Drug Administration (FDA) to begin a Phase 1 trial. Specifically, we are working on the following preclinical processes:
Communications with the FDA
The Miami Project has secured the services of regulatory consultants at Biologics Consultant Group, Inc. Because of their familiarity with the FDA’s expectations, our consultants provided valuable guidance on the first documents we sent to the FDA to introduce our Schwann cell transplant project plan. They are well qualified to advise us on our project as they are experts in developing cell and tissue-based therapy products and are knowledgeable about the evolving area of regenerative medicine. Because of their advice, we have made significant progress in the preclinical processes necessary to support a successful IND application to the FDA.
Human Schwann Cell Manufacturing Process
One required preclinical process relates specifically to how the Schwann cells are prepared for transplantation. To get enough cells, Schwann cells from the trial participant will be used to grow more of their own cells in culture dishes. We must follow Good Manufacturing Process (GMP) when processing the cells to assure the safety and quality of the cells used for transplantation. GMP is a standard recognized internationally that requires documentation of every aspect of the procedures, activities, and operations involved in manufacturing the cells. To become compliant with this standard, we have been working with colleagues at the University of Miami’s Wallace H. Coulter Center for Translational Research, where a GMP laboratory is available. Miami Project staff have spent many hours in this laboratory receiving training from the Coulter Center staff on GMP procedures and establishing Schwann cell manufacturing steps for human cells that will meet the expectations of GMP and the FDA.
Human Schwann Cell Safety
Another preclinical process we must complete is a group of studies to test the safety of human Schwann cells. In our previous safety experiments, rat Schwann cells in rats with SCI did not cause tumors, travel to areas away from the transplant site or cause neuropathic pain. To support our IND application, our regulatory consultants have advised that we need to provide evidence to the FDA that our clinical product – the human Schwann cells – are safe. These studies, conducted under conditions similar to GMP studies, will be outsourced to a GLP (Good Laboratory Practice) laboratory and will test whether human Schwann cells produce tumors or cause toxic reactions in rats with acute and chronic SCI. Importantly, these studies will examine transplants of cells that have been processed in exactly the same way we intend to process human Schwann cells for the future clinical trial.
Miami Project neurosurgeons are conducting these crucial observational studies to identify biological markers for early diagnosis of TBI or SCI. Currently, there are no simple blood tests that enable physicians to identify the presence and severity of TBI or SCI 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 and SCI to facilitate earlier diagnosis of TBI/SCI and, thus, earlier intervention and management.
The Miami Project and UM Department of Neurological Surgery have become a 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. This information will help determine the design of SCI clinical trials.
NACTN will also conduct a clinical trial of the drug Riluzole. Riluzole has been approved for use in people diagnosed with amyotrophic lateral sclerosis (ALS). When Riluzole was tested in preclinical experimental SCI, it had a neuroprotective effect by blocking sodium from entering damaged nerve cells, which may prevent them from swelling and dying. The Miami Project/UM has received IRB approval for this Phase I trial and will begin enrolling subjects once the sponsor (Department of Defense) has provided the final approval.
The Miami Project/UM Department of Rehabilitation Medicine are participating in a Phase III trial evaluating the effectiveness of a drug called Pregabalin in treating chronic neuropathic pain in people living with SCI. Pregabalin, also known as Lyrica, is an anti-convulsant that has already been approved by the FDA for the treatment of pain associated with Fibromyalgia. The current study is a randomized, double-blind, placebo-controlled, multi-center clinical trial (the gold standard of clinical trial design) to identify whether Pregabalin can reduce the neuropathic pain symptoms caused by SCI as well as reduce pain-related sleep interference, functional limitations due to pain interference, and other pain-related symptoms.
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 Investigational New Drug application to the Food and Drug Administration to request approval to begin a Phase 1/2 clinical trial to test Rolipram’s safety and efficacy in acute human spinal cord injury.
The Miami Project and University of Miami (UM) Department of Neurological Surgery recently completed a Phase I clinical trial to learn if inducing hypothermia (cooling) within the first few hours of traumatic spinal cord or brain injury is neuroprotective and makes a difference in the severity of injury. When a person with a new injury is brought to the trauma center, doctors place 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). The cooling is maintained for a 48 hour period and then the participant is slowly re-warmed at one degree every eight hours. The researchers followed the participants for one year to compare outcomes. The details of the cooling method have been published in the Journal of Neurotrauma and the details of the clinical outcomes have been accepted for publication in the journal Neurosurgery.
TRAUMATIC BRAIN INJURY CLINICAL TRIALS:
Miami Project neurosurgeons are conducting these crucial observational studies to identify biological markers for early diagnosis of TBI or SCI. Currently, there are no simple blood tests that enable physicians to identify the presence and severity of TBI or SCI 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 and SCI to facilitate earlier diagnosis of TBI/SCI 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.
Miami Project neurosurgeons recently began enrolling participants in a Phase II clinical trial to test the safety and efficacy of SLV334 in people with moderate or severe traumatic brain injury (TBI). SLV334 is a drug that is thought to be neuroprotective by reducing blood vessel constriction and reducing edema (swelling) in the injured brain. The drug must be administered within 8 hours post-injury. This trial is evaluating the safety and efficacy of single and multiple doses of increasing concentration to determine the correct dose for the future pivotal Phase III trial.
The Miami Project and University of Miami (UM) Department of Neurological Surgery recently completed a Phase I clinical trial to learn if inducing hypothermia (cooling) within the first few hours of traumatic spinal cord or brain injury is neuroprotective and makes a difference in the severity of injury. When a person with a new injury is brought to the trauma center, doctors place 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). The cooling is maintained for a 48 hour period and then the participant is slowly re-warmed at one degree every eight hours. The researchers followed the participants for one year to compare outcomes. The details of the cooling method have been published in the Journal of Neurotrauma and the details of the clinical outcomes have been accepted for publication in the journal Neurosurgery.
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