SCS with Closed-Loop System Superior to Open-Loop

SAN DIEGO — The next advance in spinal cord stimulation (SCS) could be a closed-loop system that uses evoked compound action potentials (ECAPs) to maintain therapeutic activation, results of the phase 2 EVOKE trial show. EVOKE is the first randomized, double-blind trial to evaluate outcomes for SCS.

EVOKE used ECAPs for programming and measuring activation in both the investigational closed-loop group and the open-loop control group, but only the closed-loop group used ECAPs to optimize spinal cord stimulation over time, explained Robert M. Levy, MD, PhD, of Northwestern University in Chicago, Illinois.

"We saw improved outcomes in both treatment arms, but closed-loop feedback further improved outcomes by maintaining activation within the therapeutic window and at the prescribed spinal cord activation levels," Levy said.

SCS is a well-established treatment for chronic pain but long-term success rates remain suboptimal. Evidence in SCS has evolved in recent years, but clinical trials have been largely unblinded and biased, he said. "The EVOKE study I'm presenting today was specifically designed to try to avoid these complications," he told attendees at the American Association of Neurological Surgeons (AANS) 2019 Annual Scientific Meeting.

Closed-Loop SCS and ECAPs

All commercially available SCS systems operate with an open-loop feature and have shortcomings: they do not measure or adjust for changes in the electrical field strength reaching the spinal cord (caused, for example, by movement); activation of the spinal cord and the pain inhibition pathway is unclear; and delivery of the therapy as prescribed is uncertain.

For these reasons, variability in spinal cord activation with open-loop systems results in unpredictable inhibition of pain-processing pathways and may limit SCS efficacy, Levy pointed out.

In contrast, closed-loop SCS is designed to give consistent spinal cord activation on every pulse, changing the stimulation output current as needed to maintain spinal cord activation within the therapeutic window.

The other novel component is ECAPs, which are the sum of the electrophysiologic response from multiple nerve fibers and a measure of spinal cord activation. ECAPs represent the synchronous firing of electrically stimulated nerve fibers. This technology allows the SCS device to communicate with the spinal cord neurons and adjust the dose of stimulation accordingly.

"What the closed-loop system does is to measure the ECAPs, and then register that measurement against a pre-programmed stimulation that has optimized the amount of spinal cord activation…The amplitude of the output device is changed with every single pulse to maintain the appropriate activation of the fibers in real time," he explained, noting that amplitude changes number in the millions.

In the study, ECAPs were used in the programming of both the open-loop and closed-loop groups and the measurements they produced helped to identify the optimal therapeutic window for each subject. For the open-loop group, ECAPs also maintained appropriate spinal cord activation.

EVOKE Potential

The EVOKE study enrolled 134 subjects with chronic intractable pain of the trunk and/or limbs, including unilateral or bilateral pain associated with failed back surgery syndrome, intractable low back pain, or leg pain. Patients were randomly assigned into closed-loop or open-loop feedback arms, both with ECAP measurements.

The procedures were equivalent, including lead placement/location and ECAP measurement for programming (in clinic) and tracking spinal cord activation (outside the clinic). Only the closed-loop group, however, allowed for the ECAP-controlled feedback mechanism to maintain spinal cord activation at the target level.

Participants and the clinical staff were blinded to the treatment assignment. A pain assessment and other patient-reported outcome measures were collected.

The primary objective was to show non-inferiority, and then to test the superiority, of closed-loop SCS compared to open-loop SCS. The primary endpoint was, at 3 months, a ≥ 50% reduction in overall trunk and limb pain as determined by the visual analog scale (VAS), with no increases in analgesics 4 weeks prior to the 3-month visit. There were a number of hierarchical secondary endpoints.

Pre-specified Endpoints Met

"Closed-loop SCS in EVOKE met all the pre-specified endpoints at 3 months," Levy reported, "including the unexpectedly high rate of patients with greater than 80% pain relief."

The primary composite endpoint, ≥ 50% overall pain reduction with no increase in analgesics in the intent-to-treat population, was achieved by 82.3% of the closed-loop group vs 60.3% of the open-loop group, a highly significant difference (P = .005).

Levy noted that a 60% rate of response in the control group is much higher than the rate of response seen in trials of traditional tonic stimulation. "We believe this is due to the fact that we used ECAPs to program the devices, but there is still a highly statistically significant benefit for having the closed-loop stimulation activated," he said.

All pre-specified hierarchical endpoints demonstrated better outcomes in the closed-loop, with superiority shown for closed-loop in both back pain reduction (P = .015) and back pain response (P = .003).

Table. Pre-specified Endpoints at 3 Months
Endpoint	Closed-Loop (%)	Open-Loop (%)
≥50% overall pain reduction	82.3	60.3
≥50% pain reduction in permanent implant subset	87.9	71.7
≥50% pain reduction by 7-day diary	75.4	52.4
≥80% reduction in overall pain reduction (high responders)	58.1	42.9
≥50% reduction in back pain	80.6	57.1
% change in leg pain	76.8	67.8
% change in back pain	72.1	57.5

Levy noted that pain reduction in the open-loop group was "on the high end, but not exceeding" that reported for commercially available open-loop systems in other studies, "whereas with closed-loop, all of the outcomes not only exceeded published trials but were statistically significantly better."

At 3 months, 91% of the closed-loop cohort remained within the therapeutic window, but only 59% of the control group did (P < .001). "Without the closed-loop feedback maintaining them within the therapeutic window, patients turned the device down to avoid episodes of shocking with overstimulation," he explained.

In both groups, subjects showed improvements across measures of disability, psychological health, sleep, quality of life, and satisfaction. There were no unexpected adverse events.

The investigators have just completed the primary outcome data analysis, which they will submit to the US Food and Drug Administration.

'Show This in Other SCS Modalities'

Ashwin Viswanathan, MD, assistant professor of neurosurgery at Baylor College of Medicine in Houston, Texas, highlighted that EVOKE is unique in being a randomized double-blind study of an SCS device and the first to evaluate closed-loop stimulation. "These are two very novel and important factors," he said.

"The outcomes were better than we’ve seen with not using closed-loop SCS," said Viswanathan, who was not involved with the current research, "but the study did not compare this method with other types of SCS, such as high-frequency stimulation."

Dirk de Ridder, MD, credited with inventing the burst SCS technology, called the results of the study "very impressive," but said he would like to see if they are "universally applicable" to all other kinds of SCS.

De Ridder, the Neurological Foundation Professor of Neurosurgery at Dunedin School of Medicine in New Zealand, told Medscape Neurology, "It would be interesting to see if they can extend this to other wave forms because the field is moving slowly away from paresthesia-based to paresthesia-free stimulation.

"If this can also be shown effective for paresthesia-free stimulation, then that would be a dramatic improvement for the system itself," he added.

Levy has consulted for Abbott, Mainstay Medical, Nalu, Nuvectra, Saluda, and Vertos and is a minority equity holder in Bioness, Nevro, Nalu, Saluda and Vertos. De Ridder holds a patent for a burst SCS device. Viswanathan has disclosed no relevant financial relationships.

American Association of Neurological Surgeons (AANS) 2019 Annual Scientific Meeting: Abstract 312. Presented April 16, 2019.

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