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Randomized Controlled Trial
. 2021 Oct 1;162(10):2486-2498.
doi: 10.1097/j.pain.0000000000002258.

An implantable restorative-neurostimulator for refractory mechanical chronic low back pain: a randomized sham-controlled clinical trial

Christopher Gilligan  1 , Willem Volschenk  2 , Marc Russo  2 , Matthew Green  3 , Christopher Gilmore  4 , Vivek Mehta  5 , Kristiaan Deckers  6 , Kris De Smedt  7 , Usman Latif  8 , Peter Georgius  9 , Jonathan Gentile  10 , Bruce Mitchell  11 , Meredith Langhorst  12 , Frank Huygen  13 , Ganesan Baranidharan  14 , Vikas Patel  15 , Eugene Mironer  16 , Edgar Ross  1 , Alexios Carayannopoulos  17 , Salim Hayek  18 , Ashish Gulve  19 , Jean-Pierre Van Buyten  20 , Antoine Tohmeh  21 , Jeffrey Fischgrund  22 , Shivanand Lad  23 , Farshad Ahadian  24 , Timothy Deer  25 , William Klemme  26 , Richard Rauck  27 , James Rathmell  1 , Robert Levy  28 , Jan Pieter Heemels  29 , Sam Eldabe  19 ; ReActiv8-B investigators
Affiliations
Randomized Controlled Trial

An implantable restorative-neurostimulator for refractory mechanical chronic low back pain: a randomized sham-controlled clinical trial

Christopher Gilligan et al. Pain. .

Abstract

Chronic low back pain can be caused by impaired control and degeneration of the multifidus muscles and consequent functional instability of the lumbar spine. Available treatment options have limited effectiveness and prognosis is unfavorable. We conducted an international randomized, double-blind, sham-controlled trial at 26 multidisciplinary centers to determine safety and efficacy of an implantable, restorative neurostimulator designed to restore multifidus neuromuscular control and facilitate relief of symptoms (clinicaltrials.gov identifier: NCT02577354). Two hundred four eligible participants with refractory mechanical (musculoskeletal) chronic LBP and a positive prone instability test indicating impaired multifidus control were implanted and randomized to therapeutic (N = 102) or low-level sham (N = 102) stimulation of the medial branch of the dorsal ramus nerve (multifidus nerve supply) for 30 minutes twice daily. The primary endpoint was the comparison of responder proportions (≥30% relief on the LBP visual analogue scale without analgesics increase) at 120 days. After the primary endpoint assessment, participants in the sham-control group switched to therapeutic stimulation and the combined cohort was assessed through 1 year for long-term outcomes and adverse events. The primary endpoint was inconclusive in terms of treatment superiority (57.1% vs 46.6%; difference: 10.4%; 95% confidence interval, -3.3% to 24.1%, P = 0.138). Prespecified secondary outcomes and analyses were consistent with a modest but clinically meaningful treatment benefit at 120 days. Improvements from baseline, which continued to accrue in all outcome measures after conclusion of the double-blind phase, were clinically important at 1 year. The incidence of serious procedure- or device-related adverse events (3.9%) compared favorably with other neuromodulation therapies for chronic pain.

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Conflict of interest statement

Mainstay Medical funded this pivotal regulatory trial and paid all investigators either directly or indirectly (payment to investigator employer). Trial agreements covering participant medical costs related to the trial were in place with all institutions. Travel expenses related to investigator meetings and training were reimbursed only with prior authorization.

All authors use the automated ICMJE Form for Disclosure of Potential Conflicts of Interest to generate their disclosure statements:

Study investigators: C. Gilligan discloses that Mainstay Medical pays part of his salary directly to his department. M. Russo reports personal fees from Mainstay Medical, outside the submitted work. M. Green reports other from Mainstay Medical, during the conduct of the study. C. Gilmore reports personal fees and other from SPR Therapeutics; personal fees from Nevro; personal fees from Abbott Neuromodulation; and personal fees from Medtronic Neuromodulation, outside the submitted work. V. Mehta is chief investigator in an ongoing investigator-initiated trial funded by Mainstay Medical and has received travel support to present in meetings from Mainstay Medical. K. Deckers served as a principal investigator for the trial described in this manuscript and received compensation as principal investigator from Mainstay Medical. K. De Smedt reports other from Mainstay Medical, during the conduct of the study, and personal fees from Mainstay Medical, outside the submitted work. U. Latif reports personal fees from Medtronic, outside the submitted work. P. Georgius reports personal fees from Boston Scientific, personal fees from Abbott, and personal fees from Spectrum Therapeutics, outside the submitted work. F. Huygen reports grants from Mainstay, during the conduct of the study; grants and personal fees from Abbott; grants and personal fees from the Saluda Advisory Board; and nonfinancial support from the Boston Scientific Advisory Board, outside the submitted work. G. Baranidharan reports grants and personal fees from Nevro Corporation, grants and personal fees from Abbott, grants and personal fees from Boston Scientific, and personal fees from Nalu Medical, outside the submitted work. V. Patel reports grants from Mainstay, during the conduct of the study, grants from Orthofix, grants from Pfizer, grants from Premia Spine, grants from Medicrea, grants from Globus, and grants from Aesculap, outside the submitted work. E. Ross reports personal fees and other from Mainstay Medical, during the conduct of this study. A. Carayannopoulos does not believe he has any conflicts of interest that would unduly influence him in participation nor in manuscript preparation/coauthorship. S. Hayek reports grants from Mainstay Medical during the conduct of the study. A. Gulve reports nonfinancial support from James Cook University Hospital, Middlesbrough; grants and nonfinancial support from Mainstay Medical International PLC; personal fees from Medtronic; grants and personal fees from Nevro; grants and personal fees from Abbott; and personal fees from Boston Scientific, during the conduct of the study. J.-P. Van Buyten received consultation fees from research grants from Medtronic, Nevro, Boston Scientific, Abbott, and Mainstay. A. Tohmeh has stock ownership and consulting as well as royalties arrangements with two spine companies but the products are not remotely similar to this project. Besides research fees received from Mainstay, he does not have any financial arrangements with this company or related to this work. F. Ahadian reports grants from Mainstay Medical, outside the submitted work. T. Deer reports grants and nonfinancial support from Mainstay Medical during the conduct of the study; grants, personal fees, and other from Abbott; other from Bioness; grants, personal fees, and other from Vertos; personal fees from Flowonix; personal fees and other from Axonics; personal fees and other from SpineThera; grants, personal fees, and other from Saluda; personal fees and other from Nalu; grants, personal fees and other from Vertiflex; personal fees and other from Cornerloc; personal fees and other from Ethos; grants, personal fees, and other from SPR Therapeutics; personal fees from Stimgenics; personal fees from SI Bone; personal fees from Nevro; and grants and personal fees from Boston Scientific, outside the submitted work; in addition, T. Deer has a patent pending with Abbott. S. Eldabe reports personal fees from Mainstay Medical, during the conduct of the study; grants from Medtronic, personal fees from Medtronic; personal fees from Saluda Medical; and other from Abbott, outside the submitted work.

Committee members: W. Klemme reports personal fees from Mainstay Medical, Inc, during the conduct of the study. J. Rathmell reports personal fees from Mainstay Medical during the conduct of the study, personal fees from the American Board of Anesthesiology, and personal fees from American Society of Anesthesiology, outside the submitted work. R. Levy is a consultant for Abbott, Saluda, Nalu, and Mainstay Medical. He has stock options <5% from Nalu and Saluda. J.P. Heemels is employee of Mainstay Medical. The remaining authors have no conflicts of interest to disclose.

Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.

Figures

Figure 1.
Figure 1.
Implanted restorative neurostimulation system. The call-out shows the distal fixation tines deployed on the anterior and posterior aspects of the intertransversarii.
Figure 2.
Figure 2.
CONSORT flow diagram for Participant Disposition.
Figure 3.
Figure 3.
Low back pain-VAS trajectory. Reduction in average LBP-VAS shows a significant mean group difference at 120 days (P = 0.032) and improvements in CLBP continue to accrue through 1 year. CLBP, chronic low back pain; VAS, visual analogue scale.
Figure 4.
Figure 4.
Primary outcome analysis. Proportion of participants with an improvement in LBP-VAS of ≥30% and no increase in analgesics (P = 0.138). Comparison of the cumulative proportion of responders shows significant separation (area between the curves) in favor of the treatment (P < 0.0499). This prespecified analysis was conducted with the primary endpoint and used Friedman regression analysis with multiple imputation to handle missing values, which is a comparison of ranks that preserves information over an endpoint based on dichotomization, thereby improving statistical power. LBP-VAS, low back pain visual analogue scale.
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