NEW ORLEANS — The chance that a patient with acute thoracic complete spinal cord injury (SCI) will have a neurologic status “conversion” from complete paraplegia to incomplete injury appears to be improved by implantation of an investigational scaffold device, results of the INSPIRE study show.
The primary endpoint of the trial, American Spinal Injury Association Impairment Scale (AIS) conversion at 6 months, was achieved in 44% of patients, greater than the 25% objective performance criterion of the study design, reported Stuart Lee, MD, from Vidant Health in Greenville, North Carolina.
“Large, multinational natural history databases consistently indicate that only 12% to 16% of subjects with complete thoracic injury will convert to an improved AIS grade by 6 months after injury,” Lee said.
The investigational scaffold device (Neuro-Spinal, InVivo Therapeutics), which is 2 to 3 cm in diameter and 1 cm in length, is implanted into the spinal cord at the site of injury.
“Obviously, this was a unique and very bold study,” said Sanjay S. Dhall, MD, associate professor of neurosurgery at the University of California San Francisco (UCSF) and director of Spinal Neurotrauma at the Zuckerberg San Francisco General Hospital in California, commenting on the findings.
“They were actually cutting the spinal cord open and placing the scalpel into the intramedullary cavity.”
The findings were presented here at the American Association of Neurological Surgeons (AANS) 2018 Annual Meeting.
The scaffold is a small porous biodegradable structure made of polyglycolic acid and polylysine. In rat models, polylisine has enhanced neural sprouting, and the device has reduced cyst volume, spared white matter, and promoted generation of remodeled tissue, Lee said.
Lee presented data for the complete 6-month primary endpoint of the prospective INSPIRE (INvivo study of Probable Benefit of the Neuro-SPInal Scaffold for Safety and Neurologic REcovery in Subjects with Complete Thoracic AIS A Spinal Cord Injury) study, which evaluated the device in 19 patients from 11 study sites.
The objective performance criterion was that at least 25% of patients would convert from complete paraplegia (AIS A) to incomplete injury (AIS B, C, or D) within 6 months. Additional endpoints of sensory and motor scores, bladder and bowel function, Spinal Cord Independence Measure, pain, and quality of life will be reported later.
INSPIRE Study Details
All patients, aged 16 to 70 years, had complete SCI (AIS A), with T2 to T12 neurologic levels of injury. They had visible contusions on MRI but no cord transections or traumatic brain injuries. All were undergoing open stabilization surgery less than 96 hours after injury.
By the inclusion criteria, this population “seems pretty simple,” he noted, “but as we all know, these patients usually have multiple injuries and are quite sick, so this actually proved to be a very difficult trial in which to enroll patients.”
At the time of stabilization surgery, a decompression laminectomy was done at the site of injury and the maximal damage was determined by ultrasonography. Surgeons exposed the contusion through durotomy/myelotomy, used gentle irrigation to remove the necrotic tissue, and exposed the intramedullary cavity. The scaffold was selected by size to fit the cavity and gently implanted lengthwise, then the dura was closed.
“As a side note, this gave us an opportunity to look at the pathology of acute SCI in humans, something that is generally only possible at autopsy,” Lee added. From debris that exuded from the cord, they saw significant disruption of neuropil, acute hemorrhage, and acute inflammation.
The outcomes were actually better than investigators had hypothesized in the study design. While a 25% conversion rate was the goal, 44% of patients converted, he reported.
Conversion at 6 months was observed in 7 of 16 patients; no predictors of conversion were identified. Interestingly, at longer follow-up, 3 patients who were AIS B at 6 months had late conversion to AIS C at 12 or 24 months.
“Three of the responders in the INSPIRE trial had late conversion in AIS grade, which is very unusual and possibly related to prolonged repair,” Lee commented.
While opening of the dura posed the risk for “potential complications,” the procedure proved to be safe, he said.
Three patients died within 2 weeks, but none of the deaths was related to the spinal surgery or the device. All three had other significant injuries, he reported.
INSPIRE investigators recently conducted the CONTEMPO Registry Study to have a benchmark for comparison of their results with the standard of care. CONTEMPO included neurologic recovery data from registries of 170 patients with SCI who had baseline characteristics similar to those of patients in the INSPIRE study, injured between 2006 and 2016.
The patients were enrolled in the North American Clinical Trials Network (NACTN), European Multicenter Study about Spinal Cord Injury (EMSCI), and Spinal Cord Injury Model Systems (SCIMS).
AIS conversion rates were lower in these registries than in the INSPIRE study. “The INSPIRE AIS conversion rate exceeds modern-day standard-of-care conversion rates,” Lee noted.
Table. INSPIRE AIS Conversion Rate vs Comparators (CONTEMPO)
| Endpoint | INSPIRE (n = 16) | NACTN (n = 12) | EMSCI (n = 64) | SCIMS (n = 94) |
|---|---|---|---|---|
| Conversion rate (%) | 43.8 | 16.7 | 18.8 | 23.4 |
On the basis of the encouraging findings for the device, the US Food and Drug Administration recently approved the single-blind INSPIRE 2.0 trial. The study will randomly assign 10 patients to surgical stabilization, which is the standard of care, and another 10 to stabilization plus the scaffold. The study is slated to begin sometime in 2018.
Other Explanations?
Dhall, the study’s formal discussant, considered the most interesting finding to be the “very delayed” conversion of three severely injured patients. “This is unique for a thoracic injury and invokes questions about what is happening in the spinal cord at this later date,” he said.
But despite the encouraging outcomes, Dhall found some issues with the study. For one thing, he said, the timing of surgery varied, ranging from 9 hours to 3.5 days.
“We have pretty robust data at UCSF that the timing of surgery has a profound impact on neurological recovery after spinal cord injury,” he said. “We have found that patients having surgery within 12 hours have significantly greater neurologic recovery.”
In his database, 89% of patients having surgery within 12 hours have improved by 1.3 AIS grades. Their data include cervical as well as thoracic SCI, “so it’s a bit of a confounder,” he acknowledged, “but it’s still a much higher conversion rate than in the literature.”
He also pointed out that patients with acute SCI are a heterogeneous group, according to motor evoked potentials (MEPs).
“We have been able to show that patients who appear to be clinically complete — no motor or sensory function, no voluntary anal contraction — are not all the same,” he said. “There are patients we take to surgery in whom we are actually able to elicit MEPs. Those patients all go on to recover, compared to patients without MEPs, who tend not to recover.”
Finally, it is possible, he suggested, that simply opening the dura can lead to better outcomes because the use of expansive duroplasty has been shown to improve cord perfusion. “The question is whether the scaffold is benefitting the patient, or is it the expansive duroplasty?” A study comparing duraplasty and duraplasty plus scaffold would be informative, he suggested.
“Nonetheless, I think the authors deserve congratulations on pursuing this very bold, very aggressive trial,” Dhall said. “I applaud them, and I look forward to hearing their long-term data.”
Lee disclosed a relationship with InVivo Therapeutics. Dhall has received teaching honoraria from DePuy Spine and Globus Spine.
American Association of Neurological Surgeons (AANS) 2018 Annual Meeting. Late-Breaking Abstract. Presented May 1, 2018.
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