The Changing Face of Spinal Cord Injury Trials
Spine Summit 2016 Meeting Highlight: New research on interventions for spinal cord injury is emerging at a rapid pace.
New research on interventions for spinal cord injury is emerging at a rapid pace. From studies on neuroprotective approaches to novel biologics, these discoveries are anticipated to translate into breakthroughs in this field over the next 5 to 10 years, Michael G. Fehlings, MD, PhD, Professor of Neurosurgery at the University of Toronto and Chairman of AOSpine North America and the AOSpine Spinal Cord Injury Knowledge Forum, told attendees at Spine Summit 2016 in Orlando, Florida.
Dr. Fehlings gave the audience a brief snapshot of the current status of translationally relevant discoveries in spinal cord injuries.
“One of the important concepts that has emerged, is that any neuroprotective or reparative strategy applied to the spinal cord needs to be done in the context of an adequately decompressed and reconstructed spinal column,” Dr. Fehlings said. “It is quite clear that an early intervention for traumatic spinal cord injury can alter the trajectory.”
Studies such as the Surgical Timing in Acute Spinal Cord Study (STASCIS) indicate that patients who undergo surgical decompression within 24 hours of spinal cord injury have a markedly greater likelihood for improvement on the American Spinal Injury Association (ASIA) Impairment Scale.1
In addition, emerging neuroprotective strategies for acute spinal cord injury are being evaluated in randomized controlled trials, including minocycline, riluzole, and granulocyte-colony stimulating factor (G-CSF). Others, like hypothermia, epidural stimulation, and magnesium in polyethylene glycol are in earlier stages of research. Dr. Fehlings highlighted a few recent studies on some of these proposed treatments.
“Minocycline is a tetracycline analog and is commonly used to treat acne in children. So why is this being looked at in traumatic spinal cord injury? Well, it turns out it is antiinflammatory, and it is a matrix metalloproteinase inhibitor,” Dr. Fehlings explained.
In a phase II clinical trial by Casha et al, the overall findings did not show improved motor recovery with minocycline compared to placebo.2 However, in the subgroup of patients with cervical incomplete spinal cord injuries, a 14-point improvement in ASIA motor score was found that approached statistical significance (P=0.05).
“Based on this promising result, a phase III clinical trial in patients with acute cervical spinal cord injury is currently underway and is anticipated to be completed in 2018,” Dr. Fehlings said.
Smaller phase I studies of hypothermia have suggested safety and trends toward potential efficacy in spinal cord injury.3,4 A randomized, controlled, multicenter study examining the effects of moderate intravascular hypothermia for the treatment of acute traumatic cervical spinal cord injury—known as the ARCTIC trial (Acute Rapid Cooling for Traumatic Injuries of the Cord)—is currently seeking funding.
“Hypothermia, of course, needs to be applied very carefully; there have been negative trials in traumatic brain injury,” Dr. Fehlings noted.
Riluzole is a sodium channel blocker that is commonly used in amyotrophic lateral sclerosis to protect against nerve cell degeneration, Dr. Fehlings explained. The agent also has properties to block glutamatergic excitotoxicity.
In a prospective, multicenter, phase I matched-comparison trial, Dr. Fehlings and colleagues found an improved trajectory of outcome in patients with cervical spinal cord injury who took 50-mg riluzole twice daily within 12 hours of injury for 14 days. A significant improvement in mean motor scores was found in the riluzole group compared with the control group (mean difference, 15.5 points; P=0.021).5
Based on these findings, Dr. Fehlings and colleagues launched a phase III trial (funded by a partnership between AOSpine North America; North American Clinical Trials Network –NACTN; US Department of Defense; AOSpine International and the Rick Hansen Institute) to study the effects of riluzole in patients randomized to riluzole or placebo within 12 hours of injury.6 Riluzole is given at 100 mg BID for the first 24 hours followed by 50 mg BID for the next 13 days postinjury. Thus far, 44 patients have been randomized.
A case study by Harkema et al showed that epidural stimulation of the lumbosacral spinal cord enabled full weight-bearing standing in a 23-year-old man who had paraplegia from a C7-T1 subluxation.7
“What is not clear is whether epidural stimulation will be a practical solution and broadly applicable,” Dr. Fehlings said. He added that an early phase clinical trial of epidural stimulation is currently underway in patients with chronic cervical spinal cord injuries and is expected to be completed in December 2016.
A number of cell-based therapies for spinal cord injury are currently under investigation. Two of these—Schwann cells and neural stem cells—are currently approved by the FDA for clinical investigation in humans.
Cell-based therapies are believed to work through one of three principle mechanisms:
- tissue sparing—preserve tissue and halt degeneration
- cell replacement—remyelination and halt degeneration
- environmental modification—degrade scarring and trophic support
“One of the principle mechanisms by which both Schwann cells and neural stem cells are believed to work is through remyelination of residual axons, which are in the perilesional area,” Dr. Fehlings explained. “In the setting of traumatic spinal cord injuries, you have a central hematomyelia, a central hemorrhagic necrosis, and apoptotic cell death in the perilesional area,” he said. Oligodendrocytes are particularly sensitive to apoptosis, resulting in demyelination and incomplete remyelination.
In the molecular configuration, the axons are dramatically altered, resulting in axonal conduction block, Dr. Fehlings said. “What is being targeted in clinical trials is the use of cells to replace the oligodendrocytes or to simulate them in the setting of Schwann cells, and using the patients own spinal cord as an intrinsic scaffold,” he explained.
Currently, two phase I clinical trials of Schwann cells are currently underway: one in acute thoracic injuries and one in chronic thoracic and cervical injuries.
In terms of neural stem cells, “despite the cessation of the Geron trial, the stem cell era in spinal cord injury has started and will likely lead to a number of stem cell trials,” Dr. Fehlings said. He added that a phase I trial of adult neural stem cells has been completed in patients with severe thoracic spinal cord injury and that a cervical trial has commenced.
Use of bioengineered scaffolds that are conducive to cellular attachment and neurite outgrowth have shown promising results in rodent and primate models. In one study, neurospinal scaffolds seeded with neural stem cells appeared to reduce tissue loss from secondary injury processes as well as diminished glial scarring.8 A phase I/II trial of a neuro-spinal scaffold in the treatment of acute thoracic spinal cord injury is currently underway, with a potential investigation planned for cervical patients.
One of the challenges of spinal cord injury is lack of CNS regeneration. Among the key molecules that inhibit regeneration include myelin-derived factor Nogo, myelin associated glycoprotein (MAG), and oligodendrocytes myelin glycoprotein (OMgp).
All these inhibitory proteins bind with the Nogo receptor, “which triggers a small GTPase called Rho,” Dr. Fehlings said. “When these signals get activated, the growth cone (which is the attempt of the nerve cell to regenerate) collapses and retracts, resulting in failure of regeneration.”
Animal studies suggest that anti-Nogo-A antibody enhances axonal regrowth and compensatory sprouting of corticospinal tract, resulting in increased motor recovery.9 A phase I clinical trial of anti-Nogo-A is being planned.
In addition, an open-label phase I/II trial of Cethrin, a recombinant protein Rho GTPase inhibitor, showed improved motor recover particularly in patients with cervical spinal cord injury.10 Based on these findings, a phase III trial in patients with cervical spinal cord injury is being launched by Vertex Pharmaceuticals. The agent is intended to be added to a fibrin sealant and directly penetrates the spinal cord tissue after extradural delivery, Dr. Fehlings explained.