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Abstract
Introduction A novel, spinal cord stimulation (SCS) system with a physiologic closed-loop (CL) feedback mechanism controlled by evoked compound action potentials (ECAPs) enables the optimization of physiologic neural dose and the accuracy of the stimulation, not possible with any other commercially available SCS systems. The report of objective spinal cord measurements is essential to increase the transparency and reproducibility of SCS therapy. Here, we report a cohort of the EVOKE double-blind randomized controlled trial treated with CL-SCS for 36 months to evaluate the ECAP dose and accuracy that sustained the durability of clinical improvements.
Methods 41 patients randomized to CL-SCS remained in their treatment allocation and were followed up through 36 months. Objective neurophysiological data, including measures of spinal cord activation, were analyzed. Pain relief was assessed by determining the proportion of patients with ≥50% and ≥80% reduction in overall back and leg pain.
Results The performance of the feedback loop resulted in high-dose accuracy by keeping the elicited ECAP within 4µV of the target ECAP set on the system across all timepoints. Percent time stimulating above the ECAP threshold was >98%, and the ECAP dose was ≥19.3µV. Most patients obtained ≥50% reduction (83%) and ≥80% reduction (59%) in overall back and leg pain with a sustained response observed in the rates between 3-month and 36-month follow-up (p=0.083 and p=0.405, respectively).
Conclusion The results suggest that a physiological adherence to supra-ECAP threshold therapy that generates pain inhibition provided by ECAP-controlled CL-SCS leads to durable improvements in pain intensity with no evidence of loss of therapeutic effect through 36-month follow-up.
- Spinal Cord Stimulation
- CHRONIC PAIN
- Treatment Outcome
Data availability statement
Data are available upon request. Saluda Medical is committed to responsible data sharing regarding the clinical trials we sponsor. This includes access to anonymized, individual, and trial-level data (analysis data sets), as well as other information (eg, protocols and clinical study reports), provided the trials are not part of an ongoing or planned regulatory submission. This includes requests for clinical trial data for unlicensed products and indications. These clinical trial data can be requested by any qualified researchers who engage in rigorous, independent scientific research and will be provided after review and approval of a research proposal and statistical analysis plan and execution of a data sharing agreement. Data requests can be submitted at any time, and the data will be accessible for 12 months, with possible extensions considered. For more information on the process or to submit a request, visit https://www.saludamedical.com/us/contact-us/.
This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, an indication of whether changes were made, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.
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WHAT IS ALREADY KNOWN ON THIS TOPIC
Spinal cord stimulation (SCS) can provide long-term benefits to patients with chronic pain; however, patients may experience a loss of therapeutic effect over time.
WHAT THIS STUDY ADDS
Evoked compound action potential (ECAP)-controlled closed-loop (CL) SCS enables the collection of objective neurophysiological measurements that can be used to confirm continuous therapy delivery over time.
This study represents one of the longest assessments of efficacy in the SCS literature and the longest for ECAP-controlled CL-SCS.
HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE, OR POLICY
An objective physiologic approach to SCS is essential to enable a reproducible therapy and outcomes.
Patients who received ECAP-controlled CL-SCS obtained durable improvements in chronic pain with no evidence of loss of therapeutic effect to 3 years.
Introduction
Spinal cord stimulation (SCS) using a closed-loop (CL) system informed by the elicited neural response as measured by evoked compound action potentials (ECAPs) represents a novel paradigm in the field of neuromodulation.1 2 ECAP-controlled CL-SCS enables continuous and automatic real-time adjustment of the output of each electrical pulse to optimize the ECAP dose and accuracy of the stimulation. The dynamic environment between the electrodes and spinal cord requires real-time physiologic assessment via ECAPs and stimulation adjustments to ensure that the dose accuracy is maintained despite continuous variation in the distance between the electrodes and the spinal cord. The SCS system used in the current study is the only FDA-approved system for chronic pain that meets the FDA definition of a physiologic CL control system.3 4 Fixed-output, open-loop SCS (OL-SCS) systems deliver a constant electrical output without consideration of these dynamic changes, which can result in variations in spinal cord activation.
The loss of the therapeutic effect over time has been a major limitation of SCS therapy. While often described in the SCS literature as tolerance or habituation, these pharmacodynamic mechanisms5 do not accurately describe the loss of therapeutic effect observed with SCS. ECAP-controlled CL-SCS enables the collection of objective neurophysiological measurements which can be assessed over time to detect signs of the loss of therapeutic effect. We operationally define the loss of therapeutic effect as the deterioration over time in pain relief or other biopsychosocial components contributing to a patient’s chronic pain experience with the same neural dose of stimulation delivered.
The effects of OL-SCS for chronic pain have been evaluated in randomized controlled trials (RCTs), systematic reviews, and numerous observational studies.6–15 Most OL-SCS data derived from RCTs are limited to 6 months before patients in the comparator arm are allowed to cross over to the intervention arm.6–8 11 16 In these RCTs, the data analysis at later timepoints considered only those patients that completed the last follow-up assessment.
Previous publications of the EVOKE participant, investigator, and outcome assessor-blinded, parallel-arm RCT have reported the efficacy and safety of CL-SCS compared with OL-SCS for the full cohort through 36 months of follow-up.17–19 The 36-month analysis of the EVOKE RCT comparing CL-SCS to OL-SCS that followed best practices using the intention-to-treat (ITT) principle with imputation for missing data has been previously published.19 Presented here is the analysis of the subjects who were randomized to CL-SCS and chose to remain in CL-SCS following the self-selected crossover through 36 months to elucidate the neurophysiological data that sustained the durability of physiologic CL-SCS therapy when received, as intended, over the long-term. The analysis in the current study of patients who completed the follow-up is consistent with other previous reports of SCS.20–24
Materials and methods
Study design, participants, trial procedure, and SCS system
Study design, participants, and trial procedure to 36 months of follow-up are reported in detail elsewhere19 and presented in online supplemental material 1 for completion. The neuromodulation system, physiologic CL controller (Evoke System, Saluda Medical, Artarmon, Australia), provided ECAP-controlled CL-SCS and the ability to measure neural activation. All patients included in the current analysis were initially randomized to and completed the 36-month follow-up visit in the CL-SCS arm.
Supplemental material
Outcomes
Objective device data
Objective device data collected provide information on device settings, system utilization, dose, and system performance.
Device settings (stimulation frequency and pulse width)
Programming parameters including frequency (Hz) and pulse width (µs) were collected.
System utilization
System utilization was defined as the proportion of time the system was on for the week prior to the scheduled visit.
Dose (ECAP dose, electrical dose, dose ratio, dose-response, and dose sensitivity)
The time period for these data includes the out-of-clinic neural activation for the week leading up to the scheduled visit that produced the clinical outcomes reported.
ECAP dose or neural dose is defined by the median ECAP level (normalized ECAP amplitude (µV)). The electrical dose is defined by the charge (µC/pulse), the product of pulse width(µs), and the current amplitude (mA) (µC=current amplitude (mA) × pulse width (µs) × 1A/1000mA). Dose-response and dose sensitivity were defined as the relationship between electrical dose (ie, charge) and neural activation levels (ECAPs (µV)) at perception threshold, comfort, and maximum (ie, discomfort threshold). Dose sensitivity is the slope of the dose-response curve (µV/µC).
The dose ratio is determined by the estimated current (mA) at the median ECAP level divided by the current (mA) at the ECAP threshold. The dose ratio allows individualization of a patient’s neural dose using their spinal cord sensitivity (slope of the ECAP amplitude to current curve) and their ECAP threshold, such that it is transferable across patients. This metric normalizes for electrode-cord distance and distances between stimulation and recording electrodes.
Dose accuracy
The ability of the system to minimize the error between the ECAP target and measured ECAP was assessed in clinic. The dose accuracy is defined by the root mean square error of recorded ECAPs compared with the ECAP target and is based on µV of deviation from the ECAP target.
Holistic treatment response
The assessment of pain relief and patient-reported outcome measures used are reported elsewhere19 and presented in online supplemental material 1 for completion. The treatment response was assessed by attaining minimal clinically important differences (MCIDs) for the visual analog scale (VAS), Oswestry Disability Index (ODI), Profile of Mood States (POMS), Pittsburgh Sleep Quality Index (PSQI), and generic health-related quality of life (HRQoL, EuroQol 5-Dimension 5-level (EQ-5D-5L)). The breadth of treatment response refers to the number of domains in which at least one MCID was achieved while the depth of treatment response refers to the number of MCIDs obtained in each domain. Holistic treatment response was determined for each patient based on attaining at least one MCID improvement in all domains that were impaired at baseline when compared with normative US values.25 26 In addition, the total amount of MCIDs achieved was calculated for each domain and pooled for all domains to derive a cumulative responder score. The holistic MCID considered the cumulative responder score adjusted for the number of impaired domains at baseline for each patient.
Adverse events
All adverse events (AEs) were reported by the investigators throughout the study and reviewed and adjudicated by a blinded, independent clinical events committee.
Statistical analysis
Descriptive statistics were provided as mean (SD), median (IQR), or number of observations (percentage), as appropriate. Paired-sample t-tests were used to compare differences in outcome measures between baseline and follow-up. Mean difference (MD) and 95% CIs were reported. Wilcoxon signed-rank test was used to compare differences between medians. Cochran-Mantel-Haenszel test was used to compare differences in matched categorical data. Additionally, a longitudinal mixed effect quantile regression for electrical dose changes over time was performed.27 Statistical significance was judged at the 5% level. Statistical analyses were conducted using SAS statistical softwareV.9.4 (SAS Institute) and R V.4.3.1.
Results
67 patients were randomized to CL-SCS and underwent a screening trial procedure (figure 1). 59 patients reported ≥50% reduction in overall back and leg pain VAS score and proceeded to implantation of the SCS leads and pulse generator. Baseline demographics and other characteristics were largely similar between the patients initially randomized to CL-SCS and those that completed 36-month follow-up with this intervention (online supplemental table S1). There was a slightly greater proportion of patients taking opioids at baseline in the initial group randomized to CL-SCS. The most common etiology was radiculopathy both for the patients initially randomized to CL-SCS (61/67, 91%) and those that completed the 36-month follow-up (37/41, 90%).
Patient disposition in the ECAP-controlled CL-SCS arm through 36 months.
16 of 50 (32%) CL-SCS patients self-selected to cross over to OL-SCS at the 24-month timepoint. The most common reason to try the other stimulation mode was curiosity of experiencing the other mode of therapy (13/16 (81%)). 13 of the 16 patients who chose to try the other stimulation mode returned to CL-SCS (7 patients after 1 month and 6 patients after 3 months). 41 CL-SCS patients, including the patients who did not cross over and those who crossed and returned to CL-SCS, completed the 36-month follow-up visit. None of the reasons for withdrawal were due to a lack of therapeutic effect or an AE that was related to the device or stimulation (a study flow diagram with detailed reasons for withdrawals is presented in online supplemental figure S1). All patients were blinded to the mode of stimulation administered from randomization through to the last assessment at 36 months.
Neural activation
The performance of the feedback loop resulted in high dose accuracy by keeping the elicited ECAP within 4µV of the target ECAP set on the system across all timepoints (table 1). The median stimulation frequency was 40 Hz (IQR 30–50 Hz) across all timepoints. SCS system utilization was >77%, percent time stimulating above ECAP threshold was >98%, ECAP dose was ≥19.3µV, and the dose ratio was >1.3 (ie, 30% above ECAP threshold) on average at all timepoints. While the clinical effect was maintained through 36 months, there was a gradual decrease in the dose requirements over time, with less system utilization (p<0.001), percent time stimulating above ECAP threshold, and ECAP dose observed at 36 months compared with 3 months. Additionally, there was a significant left shift in the dose-response curves at perception, comfort, and maximum (discomfort) threshold from 3 months to 36 months (figure 2). A longitudinal mixed effect quantile regression for electrical dose changes over time demonstrated a statistically significant left shift in the dose-response curve (ie, a reduction in median stimulation dose) from 3-month to 12-month, 24-month, and 36-month follow-up at perception and comfort dose and from 3-month to 36-month follow-up at a maximum dose (online supplemental table S2). Spinal cord sensitivity values (µV/µC), the slope of the dose-response curve which describes the sensitivity of the spinal cord to stimulation, did not significantly change over time from 3 months to 36 months.
Objective measures of program parameters and neural activation with CL-SCS through 36 months
Dose-response curves for CL-SCS through 36 months. The dose-response curves showed a significant left shift from a 3-month to 36-month visit. The dose-response relationship was characterized by assessing the amplitude of the ECAP response in relation to the electrical dose, measured in microcoulombs per pulse (µC/pulse). To illustrate this relationship, median dose values and corresponding responses were plotted at three distinct levels: perception, comfort, and maximum (discomfort threshold). CL-SCS, closed-loop spinal cord stimulation; ECAP, evoked compound action potential.
Holistic treatment assessment
Overall back and leg pain intensity reduction, additional patient-reported outcomes collected including ODI, POMS, EQ-5D-5L, and PSQI and treatment response for individual domains are presented in online supplemental material 5 and 6.
The average improvement in each domain was greater than the clinically meaningful threshold (ie, 1 MCID) at all timepoints through 36 months (online supplemental figure S5). For VAS, ODI, and POMS, >2 MCIDs were reported, and for EQ-5D-5L, >3 MCIDs were observed at all timepoints (online supplemental table S4, figure 3). The cumulative responder score which reflects the total number of MCIDs obtained across all domains was >11 MCIDs at all timepoints (online supplemental table S4, online supplemental figure S6). No differences were observed in the cumulative responder score and components between 3-month and 36-month timepoints (all p≥0.05). The holistic MCID, which adjusts the cumulative responder score by the number of impaired baseline domains, was ≥2.5 at all timepoints (online supplemental table S4, figure 3).
Cumulative MCIDs for each domain and for holistic MCID through 36 months. No significant differences were observed in the number of MCIDs achieved in the holistic domains between the 3-month and 36-month timepoints (p>0.05 for all). ECAP dose requirements were significantly less between the 3-month and 36-month timepoints (3 months (32.3 µV), 12 months (29.7 µV), 24 months (23.9 µV), 36 months (19.3 µV); p=0.001). HRQoL, health-related quality of life; MCID, minimal clinically important difference; ODI, Oswestry Disability Index; POMS, Profile of Mood States; PSQI, Pittsburgh Sleep Quality Index; SEM, SE error of mean; TMD, total mood disorder; VAS, visual analog scale.
All patients were responders for at least one domain at each timepoint, with 93% and 85% of patients at 36-month follow-up considered responders for ≥2 and ≥3 domains, respectively (online supplemental table S5). Holistic treatment response characterized by the improvement of ≥1 MCID in all domains impaired at baseline was reported by 54% of patients at 36-month follow-up.
Adverse events
Over the course of 36 months, 17 study-related AEs were observed in 11/41 (26.8%) patients (online supplemental table S6). The most common AE was lead migration (four events in four (9.8%) patients) followed by implantable pulse generator pocket pain (three events in three (7.3%) patients). There were no study-related serious AEs in this group through 36-month follow-up.
Discussion
A sustained response to CL-SCS between 3 months and 36 months in the proportion of patients who obtained ≥50% and ≥80% reduction in pain and in the cumulative responder score was observed. Furthermore, the durability of ECAP-controlled CL-SCS over 36 months was evidenced by no degradation of the performance of the physiologic CL controller to maintain dose accuracy. While the clinical effect was maintained at the same level, the ECAP dose requirements were significantly less at 36 months compared with 3 months. The stability of therapeutic effect while requiring reduced ECAP dose discredits the notion previously discussed in SCS publications that consistent activation may lead patients to develop a tolerance to SCS over time and that habituation may explain the loss of therapeutic effect in SCS. Patients received stimulation above ECAP threshold more than 98% of this time with an average frequency of 40 Hz. Therefore, the ECAP-controlled CL-SCS system was activating nerve axons 40 times a second for the majority of the time over 3 years. If a loss of therapeutic effect were an issue for ECAP-controlled CL-SCS, we would expect to see increased usage and/or higher ECAP dosages, but in fact, we found the opposite, that less activation was needed to maintain pain relief over time. Additionally, this phenomenon could manifest itself as a reduced level of neural activation for a given input stimulus over time (other things being equal) which would cause the dose-response curves shown in figure 2 to move to the right over time as more current would be required to achieve the same degree of activation. In fact, these dose-response curves appear to be remarkably stable between 12 and 36 months and actually moved left between 3 months and 12 months. Some care should be taken when interpreting these data as factors such as programming parameter alterations, and medication usage can affect these curves. These data strongly suggest that if a patient uses their ECAP-controlled CL-SCS system as intended, they may require less therapy over time to achieve the same results, and therefore, the loss of therapeutic effect (usually described as tolerance or habituation) is not a failure mode for ECAP-controlled CL-SCS.
Neurophysiological data may also tell us something about the functioning of the dorsal column fibers. We saw no differences in the sensitivity of the spinal cord to stimulation over time. That is, for a given increase in stimulation (µC), an equivalent increase in the number of fibers activated was seen, manifested by the increasing ECAP size (µV). Furthermore, there were no reports of neurological deficit for ECAP-controlled CL-SCS. The type, nature, and rate of AEs for ECAP-controlled CL-SCS were comparable with reports of other SCS modalities. In fact, CL-SCS AE rates even at 36 months were at the low end of the range reported in the literature (online supplemental figure S7). 40 Hz ECAP-controlled CL-SCS does not appear to cause neurophysiological changes that could affect its efficacy or cause patient harm.
The study results show that ECAP-controlled CL-SCS can lead to clinically significant improvements in the long term. At 36 months, a large majority of patients (83%) obtained ≥50% reduction, and 59% obtained a ≥80% reduction in overall back and leg pain. For those patients who obtained ≥50% response at 3 months (88%), there was a >90% chance that they would maintain this response through 36 months. This is an important finding for patient and clinician confidence in the therapy. In addition to pain intensity, statistically and clinically significant improvements were observed in physical function, emotional function, sleep, and HRQoL. All patients obtained a clinically meaningful change in at least one of the five outcome domains at all timepoints through 36-month follow-up, and >50% of patients were holistic treatment responders with a clinically meaningful change in all outcomes assessed. The holistic MCID score was ≥2.5 MCIDs, that is, more than double the threshold for a clinically meaningful response across the individual baseline impaired domains at all timepoints. In parallel with the pain reduction and multimodal improvement observed, voluntary opioid reduction or elimination was observed in 55% of patients at 36 months. Comparative results of ECAP-controlled CL-SCS versus OL-SCS are presented elsewhere.19
Reports of SCS outcomes at 36 months or longer show that this therapy can provide long-term benefits to patients with chronic pain.20 22 28 29 The pain intensity observed in the current study at 36 months was lower (2.06), and the reduction in pain was greater (6.14) than that reported in other studies at the same timepoint (table 2). A greater proportion of patients that received ECAP-controlled CL-SCS obtained ≥50% and ≥80% reduction in pain at 36 months when compared with OL-SCS systems including high-frequency, burst, and paresthesia-based stimulation (online supplemental figure S8, table 2).
36-month evidence for SCS
Strengths and weaknesses
To the authors’ knowledge, the observation that less stimulation therapy may be needed to achieve the same therapeutic effect over time with ECAP-controlled CL-SCS is the first such neurophysiological evidence of this with any SCS therapy. ECAP-controlled CL-SCS enables the measurement of the neural dose from which the dose-response can be observed and understood. Future studies are needed to confirm this finding.
We report the longest follow-up of patients who received ECAP-controlled CL-SCS. Although a single-arm report of an RCT, the outcomes reported by those patients who completed the study receiving the intervention as intended merit consideration. The results of the current report of CL-SCS patients who completed the 36-month follow-up was performed to evaluate the durability of the therapy when received as intended and shows greater improvements for all outcomes for patients who received CL-SCS than those reported in the EVOKE RCT ITT analysis.
Conclusions
Physiological adherence to the prescribed neural activation level provided by ECAP-controlled CL-SCS demonstrates the potential for sustainable and durable improvements in pain intensity and the multimodal domains impacted by the chronic pain experience. We found no evidence of the loss of therapeutic effect through 36-months of follow-up which suggests that the loss of therapeutic effect (usually described as tolerance or habituation) is not a failure mode for ECAP-controlled CL-SCS. These findings call into question the previously held beliefs that tolerance or habituation occurs with long-term use of SCS. This objective physiologic approach to SCS enables a reproducible therapy that results in long-term improvements in the biopsychosocial aspects of chronic pain as experienced by the individual. At 36-month follow-up, most patients reported high levels of pain relief, more than 50% were holistic treatment responders, and all patients reported at least one clinically meaningful change in an impaired domain at baseline.
Data availability statement
Data are available upon request. Saluda Medical is committed to responsible data sharing regarding the clinical trials we sponsor. This includes access to anonymized, individual, and trial-level data (analysis data sets), as well as other information (eg, protocols and clinical study reports), provided the trials are not part of an ongoing or planned regulatory submission. This includes requests for clinical trial data for unlicensed products and indications. These clinical trial data can be requested by any qualified researchers who engage in rigorous, independent scientific research and will be provided after review and approval of a research proposal and statistical analysis plan and execution of a data sharing agreement. Data requests can be submitted at any time, and the data will be accessible for 12 months, with possible extensions considered. For more information on the process or to submit a request, visit https://www.saludamedical.com/us/contact-us/.
Ethics statements
Patient consent for publication
Ethics approval
This study involves human participants and was approved by the Western Institutional Review Board (IRB IDs 1168219, 1168118, 1168713, 1174388, 1171961, 1172489, 1169008, 1173993, 1178269, 1180823), Forsyth Medical Center IRB (IRB ID 16-518), St. Luke’s University Health Network IRB (IRB ID SLUHN 2016-92), and Cleveland Clinic Foundation IRB (IRB ID 16-1465). Participants gave informed consent to participate in the study before taking part.
Acknowledgments
The authors are grateful to Sam Eldabe (The James Cook University Hospital, Middlesbrough, UK) for the access to individual patient outcome data from the TRIAL-STIM RCT 36-month follow-up and for the comments on an early version of this manuscript.
References
Supplementary materials
Supplementary Data
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Footnotes
Twitter @doctdeer, @CAGPain
Contributors All authors made substantial contributions to the study design, data analysis, and data interpretation, actively participated in drafting and critically revising the manuscript, provided final approval of the submitted version, and agreed to be held accountable for the accuracy and integrity of the finished publication. NAM is a guarantor who accepts full responsibility for the finished work and the conduct of the study as well as having access to the data and controlling the decision to publish.
Funding This work was supported by Saluda Medical.
Competing interests NM reports personal fees from Saluda Medical for acting as independent medical monitor for the EVOKE study during the conduct of the study; he reports receiving research grants from Neuros, Mesoblast, and Vivex Biologics, as well as consulting as a medical monitor of Nevro, Vivex Biologics, Mainstay, Sollis Therapeutics, and Vertos outside the submitted work. RL is an uncompensated consultant of Biotronik, Abbott, Nalu, Saluda, and Mainstay Medical and has stock options from Nalu and Saluda Medical. TD reports personal fees from Saluda Medical during the conduct of the study and consultancy for Axonics, Abbott, Nalu, Vertos, SpineThera, Mainstay, CornerLoc, Ethos, SPR Therapeutics, Medtronic, Boston Scientific, PainTEQ, Tissue Tech, Spinal Simplicity, and Avanos outside the submitted work. He is a minor equity holder of Saluda Medical, Nalu, SpineThera, Stimgenics, Vertiflex, Vertos, and Bioness and an advisory board member of Abbott, Vertos, Nalu, SPR Therapeutics, and Tissue Tech. LK reports receiving grants from Nevro, Neuros, Avanos, Medtronic, Neuralace, and Xalud Therapeutics and financial support from Nevro, Avanos, and Saluda Medical outside the submitted work. SL reports receiving grants and personal fees from Saluda Medical during the conduct of the study; he reports grants from Avanos, Boston Scientific, Nalu Medical, SPR Therapeutics, Averitas Pharma, Biotronik, SGX Therapeutics, and PainTEQ, as well as consultancy for Abbott, Avanos, Boston Scientific, Nevro, SPR Therapeutics, Averitas Pharma, Biotronik, Nalu Medical, and PainTEQ, outside the submitted work, as well as holding stock options for Nalu Medical. KA reports consultancy for Medtronic, Nevro, Boston Scientific, Nalu, Presidio, Biotronik, Mesoblast, and Vivex Laboratories outside the submitted work. CH reports grants from Saluda Medical during the conduct of the study and consultancy fees from Genecentrix outside the submitted work. SC reports research grants from Saluda Medical to the Cleveland Clinic during the conduct of the study and grants from Vertos, Mainstay, and Vivex outside the submitted work. SMF reports consulting fees from Abbott, Medtronic, Saluda, VertiFlex, Vertos, Surgentec, CornerLoc, Mainstay, and Relievant outside the submitted work; has received grant for research funding from Mainstay, Relievant, Medtronic, Abbott, VertiFlex, Saluda, Nalu, CornerLoc, Aurora, Biotronik, and Stimgenics outside the submitted work; and has an equity position in SynerFuse, Aurora Spine, Thermaquil, SPR Therapeutics, Saluda, CornerLoc, PainTEQ, Stimgenics, Anesthetic Gas Reclamation, Neural Integrative Solutions, SpineThera, and Celeri Health. JP reports research and consulting fees from Saluda Medical during the conduct of the study and consultancy for Abbott, Medtronic, Saluda Medical, Flowonix, SpineThera, Vertos, Vertiflex, SPR Therapeutics, Tersera, Aurora, Spark, Ethos, Biotronik, Mainstay, WISE, Boston Scientific, and Thermaquil outside the submitted work; has received grant and research support from Abbott, Flowonix, Aurora, PainTEQ, Ethos, Muse, Boston Scientific, SPR Therapeutics, Mainstay, Vertos, AIS, and Thermaquil outside the submitted work; and is a shareholder of Vertos, SPR Therapeutics, PainTEQ, Aurora, Spark, Celeri Health, Neural Integrative Solutions, Pacific Research Institute, Thermaquil, and Anesthetic Gas Reclamation. CG reports clinical trial funding from Saluda Medical during the conduct of the study and reports personal fees and others from SPR and personal fees from Nevro, Nalu, Biotronik, and Boston Scientific outside the submitted work. PSS has received consultancy fees from Medtronic, Saluda Medical, Nalu, and Biotronic outside the submitted work and has stock options from Saluda Medical and Nalu. JS reports personal fees from Nevro during the conduct of the study and personal fees from Saluda Medical and Boston Scientific outside the submitted work. TM reports research fees from Saluda Medical during the conduct of the study and personal fees from Nevro outside the submitted work. RR reports grants from SPR, Nalu, and Nevro outside the submitted work, personal fees from Presidio, and grants and personal fees from Boston Scientific and Saluda Medical outside the submitted work. RD, NS, AL, EH, ZO, and DM report being employees of Saluda Medical. LP 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. No other disclosures were reported.
Provenance and peer review Not commissioned; externally peer reviewed.
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