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Randomized Controlled Trial
. 2022 Mar 1;79(3):251-260.
doi: 10.1001/jamaneurol.2021.4998.

Durability of Clinical and Quality-of-Life Outcomes of Closed-Loop Spinal Cord Stimulation for Chronic Back and Leg Pain: A Secondary Analysis of the Evoke Randomized Clinical Trial

Nagy Mekhail  1 , Robert M Levy  2 , Timothy R Deer  3 , Leonardo Kapural  4 , Sean Li  5 , Kasra Amirdelfan  6 , Corey W Hunter  7 , Steven M Rosen  8 , Shrif J Costandi  1 , Steven M Falowski  9 , Abram H Burgher  10 , Jason E Pope  11 , Christopher A Gilmore  12 , Farooq A Qureshi  13 , Peter S Staats  5 , James Scowcroft  14 , Tory McJunkin  15 , Jonathan Carlson  16 , Christopher K Kim  3 , Michael I Yang  17 , Thomas Stauss  18 , Julie Pilitsis  19 , Lawrence Poree  20 ; Evoke Study Group; Dan Brounstein  21 , Samuel Gilbert  21 , Gerrit E Gmel  21 , Robert Gorman  21 , Ian Gould  21 , Erin Hanson  21 , Dean M Karantonis  21 , Abeer Khurram  21 , Angela Leitner  21 , Dave Mugan  21 , Milan Obradovic  21 , Zhonghua Ouyang  21 , John Parker  21 , Peter Single  21 , Nicole Soliday  21
Affiliations
Randomized Controlled Trial

Durability of Clinical and Quality-of-Life Outcomes of Closed-Loop Spinal Cord Stimulation for Chronic Back and Leg Pain: A Secondary Analysis of the Evoke Randomized Clinical Trial

Nagy Mekhail et al. JAMA Neurol. .

Erratum in

  • Error in Figure.
    [No authors listed] [No authors listed] JAMA Neurol. 2022 Apr 1;79(4):420. doi: 10.1001/jamaneurol.2022.0022. JAMA Neurol. 2022. PMID: 35156999 Free PMC article. No abstract available.

Abstract

Importance: Chronic pain is debilitating and profoundly affects health-related quality of life. Spinal cord stimulation (SCS) is a well-established therapy for chronic pain; however, SCS has been limited by the inability to directly measure the elicited neural response, precluding confirmation of neural activation and continuous therapy. A novel SCS system measures the evoked compound action potentials (ECAPs) to produce a real-time physiological closed-loop control system.

Objective: To determine whether ECAP-controlled, closed-loop SCS is associated with better outcomes compared with fixed-output, open-loop SCS at 24 months following implant.

Design, setting, and participants: The Evoke study was a double-blind, randomized, controlled, parallel arm clinical trial with 36 months of follow-up. Participants were enrolled from February 2017 to 2018, and the study was conducted at 13 US investigation sites. SCS candidates with chronic, intractable back and leg pain refractory to conservative therapy, who consented, were screened. Key eligibility criteria included overall, back, and leg pain visual analog scale score of 60 mm or more; Oswestry Disability Index score of 41 to 80; stable pain medications; and no previous SCS. Analysis took place from October 2020 to April 2021.

Interventions: ECAP-controlled, closed-loop SCS was compared with fixed-output, open-loop SCS.

Main outcomes and measures: Reported here are the 24-month outcomes of the trial, which include all randomized patients in the primary and safety analyses. The primary outcome was a reduction of 50% or more in overall back and leg pain assessed at 3 and 12 months (previously published).

Results: Of 134 randomized patients, 65 (48.5%) were female and the mean (SD) age was 55.2 (10.6) years. At 24 months, significantly more closed-loop than open-loop patients were responders (≥50% reduction) in overall pain (53 of 67 [79.1%] in the closed-loop group; 36 of 67 [53.7%] in the open-loop group; difference, 25.4% [95% CI, 10.0%-40.8%]; P = .001). There was no difference in safety profiles between groups (difference in rate of study-related adverse events: 6.0 [95% CI, -7.8 to 19.7]). Improvements were also observed in health-related quality of life, physical and emotional functioning, and sleep, in parallel with opioid reduction or elimination. Objective neurophysiological measurements substantiated the clinical outcomes and provided evidence of activation of inhibitory pain mechanisms.

Conclusions and relevance: ECAP-controlled, closed-loop SCS, which elicited a more consistent neural response, was associated with sustained superior pain relief at 24 months, consistent with the 3- and 12-month outcomes.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Mekhail reported personal fees from as independent medical monitor for the EVOKE study and grants from Cleveland Clinic for participating as a research site for the EVOKE study (of which they were not involved) during the conduct of the study. Dr Levy reported stock options from Saluda Medical outside the submitted work. Dr Deer reported personal fees from Saluda Medical during the conduct of the study; personal fees from Abbott, Vertos, Flowonix, SpineThera, Mainstay, Nalu, Cornerloc, Ethos, SPR Therapeutics, Stimgenics, SI Bone, Nevro, Medtronic, Boston Scientific, PainTEQ, Tissue Tech, and Avanos outside the submitted work; and had a patent for Abbott pending (dorsal root ganglion surgical leads). Dr Kapural reports consulting relationships with Saluda Medical, Medtronic, Nevro, and Biotronik outside the submitted work. Dr Li reports research grants and personal consulting fees from Saluda Medical during the conduct of the study; personal consulting fees from Abbott, Boston Scientific, Averitas Pharma, Avanos, Nalu, Nevro, Vertos, Scilex Pharma, PainTEQ, SPR Therapeutics, and Biotronik outside the submitted work; grants from Boston Scientific, Averitas Pharma, Avanos, Nalu, Nevro, PainTEQ, SGX Medical, SPR Therapeutics, and Biotronik outside the submitted work; and stock options from Nalu. Dr Amirdelfan reports grants from IPM Medical Group during the conduct of the study. Dr Hunter reports grants from Saluda Medical during the conduct of the study and personal fees from Abbott, Mainstay, and Nalu outside the submitted work. Dr Costandi reports grants from Cleveland Clinic during the conduct of the study. Dr Falowski reports personal research fees from Abbott, Medtronic, and Vertiflex, and personal fees from SPR Equity outside the submitted work. Dr Pope reports research and consulting fees from Saluda Medical during the conduct of the study; research fees from Abbott, Saluda, Medtronic, Flowonix, SpineThera, PainTEQ, Vertos, Vertiflex, SPR Therapeutics, Aurora, Ethos, Spark Biotronik, Boston Scientific, and Thermaquil outside the submitted work; consulting fees from Abbott, Medtronic, Saluda, Flowonix, SpineThera, PainTEQ, Vertos, Vertiflex, SPR Therapeutics, Tersera, Aurora, Spark, Ethos, Biotronik, Mainstay, WISE, Boston Scientific, and Thermaquil outside the submitted work; grants from Abbott, Flowonix, Saluda, Aurora, PainTEQ, Ethos, Muse, Boston Scientific, SPR Therapeutics, Mainstay, Vertos, AIS, and Thermaquil outside the submitted work; and reports being a shareholder of Vertos, SPR Therapeutics, PainTEQ, Aurora, Spark, Celeri Health, Neural Integrative Solutions, Pacific Research Institute, and Thermaquil. Dr Gilmore reports clinical trial funding from Saluda Medical during the conduct of the study; is an advisory board member of Saluda Medical, Boston Scientific Neuromodulation, SPR Therapeutics, and Biotronik; a speaker bureau member of Nevro and Nalu; and reports consulting fees from SPR Therapeutics, Nevro, and Nalu outside the submitted work. Dr Staats reports consulting fees from Saluda Medical outside the submitted work, consulting fees from Saluda, Medtronic, SPR Therapeutics, and Nalu outside the submitted work; is an advisory board member of AIS; is cofounder and chief medical officer of electroCore; receives royalties from Averitas and Grünenthal for the Qutenza patch as the patent owner; and is president of the World Institute of Pain. Dr Scowcroft reports personal fees from Nevro during the conduct of the study and personal fees from Saluda Medical and Boston Scientific outside the submitted work. Dr McJunkin reports research fees from Saluda Medical during the conduct of the study and personal fees from Nevro outside the submitted work. Dr Carlson reports personal fees from Saluda Medical during the conduct of the study; personal fees from Abbott, Boston Scientific, Nevro, Medtronic, Mainstay, SPR Therapeutics, CornerLoc, PillNurse, Biotronik, and Vivex outside the submitted work; and stock from Mainstay, CornerLoc, and PillNurse. Dr Pilitsis reports grants from Boston Scientific, Nevro, Medtronic, Abbott, and the National Institutes of Health; personal fees from Saluda Medical and Aim Medical Robotics outside the submitted work; and has a patent for a head clamp and robotics platform (issued US 10,182,897 B2) and for a system and method for robotic surgical intervention (issued US 2011/0077504 A1). Dr Poree reports personal fees from Saluda Medical; is a member of the data monitoring board of Saluda Medical during the conduct of the study; and reports personal consulting fees from Medtronic and Nalu outside the submitted work. Messrs Brounstein, Single, Gilbert, Mugan, and Obradovic; Mss Soliday, Hanson, Khurram, and Leitner; and Drs Gmel, Gorman, Gould, Karantonis, and Ouyang report being an employee of Saluda Medical. Dr Parker reports personal fees from Saluda Medical during the conduct of the study and outside the submitted work and holds US Patents 10,568,559, 10,278,600, 9,974,455, and 9,381,356, all issued to Saluda Medical. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. CONSORT Diagram
AE indicates adverse event. aCOVID-19 resulted in 2 missed 24-month visits in the open-loop group. bAll randomized patients (67 in the closed-loop group and 67 in the open-loop group) were included in the analysis of the primary outcome, visual analog scale pain, using a last value carried forward approach to account for missing data. Patients who completed the 24-month visit (50 in the closed-loop group and 42 in the open-loop group) were included in the analysis of secondary outcomes.
Figure 2.
Figure 2.. Individual Patient Percent Change From Baseline in Overall Back and Leg Pain at 24 Months
Positive change indicates improvement. A significantly greater proportion of closed-loop patients were responders and high responders in overall back and leg pain compared with open-loop patients.
Figure 3.
Figure 3.. Additional Patient-Reported Outcomes
A, Mean change in profile of mood states (POMS) total mood disturbance (TMD) from baseline to 24 months was approximately double in the closed-loop compared with open-loop group, a significant difference (closed-loop group: 18.6; open-loop group: 9.4; difference, 9.2 [95% CI, 1.8-16.5]; P = .02; repeated-measures model: estimate of the difference, 10.7 [95% CI, 3.9-17.6]; P = .002). Additionally, 68.0% of closed-loop compared with 42.9% of open-loop patients had a minimum clinically important difference (MCID) of ≥10 points (difference, 25.1% [95% CI, 5.4%-44.9%]; P = .02). B, For study inclusion, patients were required to be classified as having a severe disability or as “crippled” on the Oswestry Disability Index (ODI) (score, 41-80). At 24 months, 78.0% closed-loop vs 59.5% open-loop patients improved to minimum or moderate disability (score, 0-40). C, The mean improvement in the European Quality of Life Five-Dimensional Five-Level (EQ-5D-5L) index score was greater than 3 times the MCID (MCID = 0.074) in the closed-loop group (mean [SD], 0.254 [0.157]) and greater than 2 times the MCID in the open-loop group (mean [SD], 0.208 [0.163]). aSignificant difference between treatment groups (P < .05).
Figure 4.
Figure 4.. Device Performance, Dose-Response Relationship, and Therapeutic Window Differences Between Closed- and Open-Loop SCS
A, Device performance is defined as the ability of the spinal cord stimulation (SCS) device to adhere to the prescribed neural response. Owing to the ever-changing coupling of the electrical field to the target neural tissue, open-loop systems are not capable of continuously adhering to the prescribed neural response. A consistent neural response at the prescribed level may only be achieved with a physiological closed-loop control system that continually adjusts on every stimulation pulse. This figure depicts the neural response of an Evoke study patient performing the same series of postures in clinic in both the open-loop and closed-loop stimulation modes and demonstrates how closed-loop minimizes the error between the prescribed target neural response and the observed elicited neural response pulse by pulse. In this patient, the elicited neural response deviated 22.1 times more from the target neural response with open-loop compared with closed-loop (66.4 μV deviation vs 3.0 μV deviation, respectively). B, In pharmacology, the importance of characterizing the dose-response relationship has long been understood because the concentration of a drug at its site of action controls its effect. In SCS, the charge (stimulation dose [μC/pulse]) produces a neural response (evoked compound action potentials [ECAP]; μV), which results in a clinical effect. ECAP amplitude (ie, a measure of the number of fibers activated) increases with increasing charge. In this study, dose-response data (ie, ECAP amplitude and charge) were collected during scheduled programming visits in a sitting position at patients’ perception threshold, comfort, and maximum. Patient perception threshold to maximum defined the patients’ therapeutic window. The mean (standard error) dose-response for the Evoke study patients at 24 months is presented. C, On average, closed-loop patients were nearly always within the therapeutic window (median [IQR], 93.9% [48.0%-98.9%]), while open-loop patients were only with the window half of the time (median [IQR], 46.1% [25.9%-71.9%]), and half of the time below threshold (median [IQR], 49.3% [22.7%-74.1%]); the differences in time spent with, below, and above the therapeutic window were significant between groups (P < .05). aSignificant difference between treatment groups (P < .05).
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