The experimental use of hypothermia in people with nervous system trauma came about after years of laboratory research conducted by W. Dalton Dietrich, Ph.D., and his colleagues.  Their work, beginning in the 1980s, showed that cooling the body temperature a couple of degrees resulted in improved recovery of walking in paralyzed rats.  Currently, they continue their work to gain a better understanding of the biochemical, histological and physiological effects of hypothermia.
 
It took some years to begin testing this therapy in people partly because reliable methods to cool patients still needed to be developed.  By the year 2000, several companies had developed devices to control a patient’s temperature.  An initial goal of using cooling devices was to counteract fever in patients with stroke, heart attacks, head trauma and spinal cord injury. Fever is common in these patients and studies by various investigators, including Helen Bramlett, Ph.D., at The Miami Project, report that small increases in body temperature can worsen neurological outcome.

Today’s very sophisticated cooling devices now allow clinicians to accurately record and manipulate a patient’s body temperature.  With this degree of control, it appears possible to safely cool injured patients and, with further study, potentially give them a chance for better neurological recovery.

CLINICAL TRIALS INITIATIVE UPDATE

Recent Accomplishments

~ Completed an initial Hypothermia clinical study in 14 patients with acute spinal cord injury

~ Gained U.S. Department of Defense funding to support a Phase 2 Oxycyte trial

~ Established a Clinical Trials Unit

~ Organized a working team to assemble an IND (Investigational New Drug) application for a Phase 1 trial of autologous human Schwann cell transplantation
~ Had a pre-pre IND discussion with the FDA (Food and Drug Administration) that provided guidance for the design and implementation of FDA-required safety studies to assess the potential risks of Schwann cell transplantation prior to approval for human trial

"By establishing the Clinical Trials Unit, an infrastructure has been set in place to fuel more than just one clinical trial"

Research That’s Making A Difference
Is it luck? Or are a handful of patients treated at the University of Miami/Jackson Health System Medical Center the beneficiaries of a new therapy for acute spinal cord injury; a therapy that’s based on laboratory experiments done years before?

Therapeutic hypothermia has been the focus of much attention after Kevin Everett, National Football League player, experienced a remarkable recovery after his severe spinal cord injury. Mild hypothermia for patients who suffer certain types of heart attacks is becoming a standard treatment. In fact, the American Heart Association has published guidelines for the use of hypothermia in this patient population. Could this up-and-coming therapy also ease the degree of disability for those suffering spinal cord injury?

Over the last two years, clinical scientists at The Miami Project and the Department of Neurological Surgery have examined the use of therapeutic hypothermia in 14 patients with acute cervical spinal cord injury. Their initial experience with the clinical application of modest hypothermia after spinal cord injury has been accepted for publication in an upcoming issue of the Journal of Neurotrauma.

Summarizing their preliminary findings, Allan Levi, M.D., Ph.D., a neurosurgeon and lead investigator, said, "I think there’s enough information here to be excited about doing a prospective trial. It looks like the treatment, if used correctly, is pretty safe." The group has prepared another article that will undergo review by their peers and will describe the clinical results of the 10 males and 4 females who participated in the study.

So far with respect to safety, the researchers have noted a few complications, most commonly pneumonia and acute respiratory distress syndrome as well as lower heart rates. In this study, none of the participants experienced life threatening complications such as deep venous thrombosis, pulmonary embolism or myocardial infarction.

The investigators will continue evaluating the treatment’s effectiveness, and are working on overcoming a challenge with the timing of the treatment. "We would like to see a major improvement in the time between the injury and the initiation of hypothermia," says Dr. Levi. It took an average of 9 hours to begin the hypothermia treatment and another 3 hours to reach the target body temperature. "We need to do better," says Barth A. Green, M.D., who believes cooling is likely to be most effective if prehospital treatment protocols can be developed and tested. "We know early cooling is better," comments W. Dalton Dietrich, Ph.D., whose findings in preclinical studies show that cooling immediately after injury improves outcomes.

For hypothermia to become a standard treatment for acute spinal cord injury, more evidence than what this preliminary study can generate will be needed. The study included just a small number of patients whose results were not compared with a control group of newly injured patients not receiving the treatment. To more clearly determine the neuroprotective benefits of hypothermia, the investigators are planning a prospective multicenter trial with a larger group of patients. Neurosurgeon Michael Wang, M.D., is currently heading an effort to move this study to the next phase. He and fellow investigators are negotiating a plan to conduct this trial with the Neurological Emergencies Treatment Trials group, a network of 17 academic medical centers with emergency personnel available to conduct large multicenter clinical trials.

Better Than Blood?

With traumatic brain injuries so prevalent in the Iraq war, the U.S. Department of Defense has agreed to fund $1.9 million of the cost of the trials on Oxycyte at the University of Miami and Virginia Commonwealth University. Oxycyte is a perfluorocarbon-based oxygen therapeutic that has shown the ability to deliver four times more oxygen than red blood cells to damaged brain tissue.
 

M. Ross Bullock, M.D., Ph.D., professor of neurological surgery and director of clinical neurotrauma and principal investigator of Phase II clinical trials for the therapeutic oxygen carrier, expects to begin the trials this winter. If Oxycyte, developed by Synthetic Blood International, is successful in civilian trials, it could be used in the battlefields in a year or two. Beyond that, there are other potential uses. W. Dalton Dietrich, Ph.D., says he and other researchers will be taking a closer look at Oxycyte for use in spinal cord injury.

The Phase II trial is expected to last two years, involving 200 patients at hospitals in the U.S., including Jackson Memorial Hospital, the University of Pennsylvania, Virginia Commonwealth University, Fairfax Hospital in Virginia, and possibly hospitals in Toronto, Germany, and Switzerland.

Clinical Trials Unit

The Clinical Trials Unit also includes administrative personnel who work behind the scenes to secure trial funding, facilitate communications with the University of Miami Institutional Review Board (IRB), and create and monitor each clinical trial budget. For the four impending drug trials, they have been responsible for negotiating with trial sponsors and have shepherded the clinical trial protocols through the UM IRB approval process.

"By establishing the Clinical Trials Unit, an infrastructure has been set in place to fuel more than just one clinical trial," says Dr. Levi. In addition to the upcoming drug trials, the Clinical Trials Unit will be ready when the development of human Schwann cell transplants is completed and we receive FDA approval to begin that trial.

Working Toward Approval for a Phase 1 Clinical Trial To Test Autologous Human Schwann Cells in People with Spinal Cord Injury

The Miami Project had a pre-pre Investigational New Drug (IND) discussion with the Food and Drug Administration (FDA) and received guidance on some aspects of the preclinical safety studies that need to be completed. These studies, vital for a successful IND application, are carried out under conditions that must satisfy Good Laboratory Practice (GLP) regulations. One of the goals of these studies is to establish that human Schwann cells do not form tumors or cause other toxic effects. Another goal is to generate evidence that establishes survival time of the transplanted Schwann cells. To clearly understand the potential risks associated with Schwann cell transplantation, the FDA made it clear that the duration of the tumorgenicity study should be at least six months. Before we initiate the IND-enabling GLP studies, we need to be confident that our study specific protocols and regimen are feasible and will provide the required data. Therefore, The Miami Project is currently carrying out a feasibility study to understand how long human Schwann cells can survive when transplanted into a rat spinal cord lesion and what measures can be taken to enhance survival of the transplanted cells. This information is vital to assure the success of the large and expensive GLP safety studies that we will outsource to a Contract Research Organization.

It’s a new frontier for SCI researchers as well as FDA officials with respect to a cellular transplantation for spinal cord injury. So far, only one complete IND application of this kind has ever been submitted, one in which the investigators sought approval for human embryonic stem cell transplantation. Other research groups, including The Miami Project, are undertaking the IND process to bring new treatments to clinical trial.

Reaching the goal of submitting a successful IND application takes a team with dedicated members responsible for the various aspects of the regulatory and therapy development process. The Miami Project continues to build the team that will succeed in accomplishing this goal. Those currently involved with planning and conducting the ongoing preclinical studies, and preparing all the written materials that describe and support every step of producing, administering and testing the treatment are: Basic Scientists: W. Dalton Dietrich, Ph.D., Mary Bartlett Bunge, Ph.D., Damien Pearse, Ph.D., Patrick Wood, Ph.D., Gagani Athauda, M.D., Alex Marcillo, M.D., Roozbeh Golshani, Ph.D., Yerko Berrocal, M.D.; Physician Researchers: Allan Levi, M.D., Ph.D., James Guest, M.D., Ph.D., Diana Cardenas, M.D., MHA; Project Coordinators: Anil Lalwani, Maria Amador, Zsuzsanna Nemeth; Wallace H. Coulter Center for Translational Research. Cell Processing Facility Administrators: Norma Kenyon, M.D., Jose DeSilva, Ph.D., Aisha Khan, Elina Linetsky.