By Sam Maddox
The Reeve Foundation's North American Clinical Trials Network (NACTN) recently completed a multi-center Phase I safety trial for the drug Riluzole for acute spinal cord injury; 36 patients were enrolled in the study. Data is being compiled and has not yet been published but there are hopes the drug can move to a larger, randomized trial. "The data are not complete but we feel the agent has provided some neuroprotection after spinal cord injury," said Charles Tator, M.D., Ph.D., who chairs what might be called a pipeline committee for the NACTN. The committee hopes to identify which drug agents or cell therapies might be next in the network's trials.
The advantage of testing a drug or cell therapy in the NACTN framework is clear, says Dr. Tator. "By running a trial in a formal, organized way, with top clinical centers and expertise involved, you gain the most value from it. Protocols are rigorously followed and there is consistent treatment and careful measurement across all centers."
Over the past few years NACTN has clearly established its credibility. "We have really gained stature in the field," said Dr. Tator. "More companies, individual investigators and clinical centers are coming to us, either wanting help with testing compounds, or to join the network."
More Progress in Research
There are four areas of interest in possible clinical trials, said Dr. Tator: drugs, especially related to neuroprotection; cellular therapies, including stem cells; physical agents, such as epidural stimulation; and bioengineering, including support structures or scaffolds that might enhance axon growth across the injury site.
The Riluzole trial falls in the area of neuroprotection; it is given within hours of injury with the hopes it will protect surviving spinal cord neurons from further damage. Several other neuroprotective trials are being considered. No decisions have been made but the pipeline has many interesting possibilities.
Cethrin is a drug that neutralizes inhibitors to growth. It was reported last year that it increased neurological recovery after complete SCI in a small clinical trial. Lisa McKerracher, Ph.D., who discovered the drug, has been in contact with NACTN about continuing a larger trial.
Another drug candidate for treatment of acute injury is a magnesium chloride in polyethylene glycol (PEG). The compound is called AC105 by Acorda Therapeutics, which recently obtained the license to it. In preclinical animal studies, intravenously administered AC105 was neuroprotective and improved motor function in SCI and cognitive function in traumatic brain injury when therapy was initiated within four hours of injury.
A drug that neutralizes the inhibitory molecule called Nogo might be a candidate for a NACTN trial. The anti-Nogo drug, from Novartis, recently completed a safety trial in Europe. Said Dr. Robert Grossman, NACTN's lead principal investigator, "There were no serious safety issues in the trial. We have had discussions with Novartis but the company has not made a decision on moving forward."
Glibenclamide is a drug that has been used for many years for diabetes. In the spinal cord it blocks ion channels, preventing influx of sodium and calcium into endothelial cells, glia and neurons. Marc Simard, M.D., Ph.D., at the University of Maryland, has data to show the drug may help in both central nervous system trauma and stroke. Experiments indicate that the drug may have long-term protective effects after mild-to-moderate TBI. Clinical trials for brain injury and stroke are currently underway.
Another drug, chondroitinase, has been effective in animal experiments to facilitate nerve regeneration through the glial scar that develops in the traumatized spinal cord. Most experiments have been in acute injury although there is some evidence ch'ase, as it is known, can be of benefit in chronic SCI.
Cellular therapies might include olfactory ensheathing glial cells. These cells, harvested from the nasal mucosa have been used clinically in Europe and China. They have been tested in a small human trial in Australia. OEGs seem safe, said Dr. Tator. More rigorous testing is needed to affirm results from these trials.
Schwann cells will be implanted in a trial planned by the Miami Project. Autologous (from one's own body) Schwann cells, found in the peripheral nervous system, promote nerve growth and survival and will be used for implantation in the trial. Animal studies have shown that Schwann cells assist axon growth in the injured spinal cord.
NACTN has had contact with Stem Cells, Inc., a Palo Alto, CA company currently recruiting patients for a trial of fetal stem cells. The trial, being conducted in Switzerland, is enrolling patients in the subacute/early chronic phase of injury.
NACTN is not just about running trials. The organization has created an important database to quantify the natural history of human SCI. "We are also building a multi-center SCI registry," said Dr. Tator, "to document a representative sample of all SCI cases, with data on age, gender, nature of injury, mechanism of injury and so on. This gives us a statistical baseline upon which we can compare any potential therapy." So far over 500 detailed cases are in the registry.
Dr. Grossman notes that the registry will help with outcome prediction, by stratifying SCI cases more carefully. "In the past it has been hard to demonstrate the effect of a therapy. If you lump all the patients together you blur the differences in outcome that are characteristic of each neurological level of injury."
NACTN is also studying better ways to measure return of function. A group of tests called GRASSP (Graded Redefined Assessment of Strength Sensibility and Prehension) has been developed by Dr. Kalsi-Ryan at the University of Toronto to capture information after cervical SCI for any level at any point during recovery (acute, sub acute, chronic). Current measures are not sensitive enough to pick up subtle changes in the hand and upper limb. "This more sensitive measure will enable researchers to better understand how beneficial new treatments can be," said Dr. Grossman. A large multicenter trial is being planned to test and refine the new tool.