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Clinical Trial
. 2024 Jun 3;7(6):e2415643.
doi: 10.1001/jamanetworkopen.2024.15643.

Riluzole for Degenerative Cervical Myelopathy: A Secondary Analysis of the CSM-PROTECT Trial

Michael G Fehlings  1   2   3 , Karlo M Pedro  1   2   3 , Mohammed Ali Alvi  1   2   3 , Jetan H Badhiwala  2 , Henry Ahn  4 , H Francis Farhadi  5 , Christopher I Shaffrey  6 , Ahmad Nassr  7 , Praveen Mummaneni  8 , Paul M Arnold  9 , W Bradley Jacobs  10 , K Daniel Riew  11 , Michael Kelly  12 , Darrel S Brodke  13 , Alexander R Vaccaro  14 , Alan S Hilibrand  15 , Jason Wilson  16 , James S Harrop  14 , S Tim Yoon  17 , Kee D Kim  18 , Daryl R Fourney  19 , Carlo Santaguida  20 , Eric M Massicotte  1   2 , Peng Huang  21   22
Affiliations
Clinical Trial

Riluzole for Degenerative Cervical Myelopathy: A Secondary Analysis of the CSM-PROTECT Trial

Michael G Fehlings et al. JAMA Netw Open. .

Abstract

Importance: The modified Japanese Orthopaedic Association (mJOA) scale is the most common scale used to represent outcomes of degenerative cervical myelopathy (DCM); however, it lacks consideration for neck pain scores and neglects the multidimensional aspect of recovery after surgery.

Objective: To use a global statistical approach that incorporates assessments of multiple outcomes to reassess the efficacy of riluzole in patients undergoing spinal surgery for DCM.

Design, setting, and participants: This was a secondary analysis of prespecified secondary end points within the Efficacy of Riluzole in Surgical Treatment for Cervical Spondylotic Myelopathy (CSM-PROTECT) trial, a multicenter, double-blind, phase 3 randomized clinical trial conducted from January 2012 to May 2017. Adult surgical patients with DCM with moderate to severe myelopathy (mJOA scale score of 8-14) were randomized to receive either riluzole or placebo. The present study was conducted from July to December 2023.

Intervention: Riluzole (50 mg twice daily) or placebo for a total of 6 weeks, including 2 weeks prior to surgery and 4 weeks following surgery.

Main outcomes and measures: The primary outcome measure was a difference in clinical improvement from baseline to 1-year follow-up, assessed using a global statistical test (GST). The 36-Item Short Form Health Survey Physical Component Score (SF-36 PCS), arm and neck pain numeric rating scale (NRS) scores, American Spinal Injury Association (ASIA) motor score, and Nurick grade were combined into a single summary statistic known as the global treatment effect (GTE).

Results: Overall, 290 patients (riluzole group, 141; placebo group, 149; mean [SD] age, 59 [10.1] years; 161 [56%] male) were included. Riluzole showed a significantly higher probability of global improvement compared with placebo at 1-year follow-up (GTE, 0.08; 95% CI, 0.00-0.16; P = .02). A similar favorable global response was seen at 35 days and 6 months (GTE for both, 0.07; 95% CI, -0.01 to 0.15; P = .04), although the results were not statistically significant. Riluzole-treated patients had at least a 54% likelihood of achieving better outcomes at 1 year compared with the placebo group. The ASIA motor score and neck and arm pain NRS combination at 1 year provided the best-fit parsimonious model for detecting a benefit of riluzole (GTE, 0.11; 95% CI, 0.02-0.16; P = .007).

Conclusions and relevance: In this secondary analysis of the CSM-PROTECT trial using a global outcome technique, riluzole was associated with improved clinical outcomes in patients with DCM. The GST offered probability-based results capable of representing diverse outcome scales and should be considered in future studies assessing spine surgery outcomes.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Fehlings reported receiving financial support from the Robert Campeau Family Foundation/Dr C.H. Tator Chair in Brain and Spinal Cord Research at UHN. Dr Farhadi reported receiving budget support from AO Spine North America during the conduct of the study. Dr Shaffrey reported receiving personal fees from Medtronic, NuVasive, SI-BONE, and Proprio outside the submitted work. Dr Nassr reported receiving grants from AO Spine North America during the conduct of the study; grants from Premia Spine, 3Spine, and AO Spine North America outside the submitted work; and personal fees from AlloSource outside the submitted work. Dr Mummaneni reported receiving grants from the Patient-Centered Outcomes Research Institute during the conduct of the study and receiving personal fees from DePuy Synthes, Globus, BK Medical, SI-BONE, and Brainlab; receiving grants from AO Spine, the National Institutes of Health, the Neurosurgery Research & Education Foundation, the International Spine Study Group, SLIP II, and Pacira; having stock in DiscGenics; and receiving book royalties from Thieme Medical Publishers and Springer outside the submitted work. Dr Jacobs reported having consulting agreements with Cerapedics, Stryker, and DePuy-Synthes outside the submitted work. Dr Riew reported receiving grants from AO Spine North America during the conduct of the study and receiving royalties from Biomet; having stock or stock options in AxioMed, Expanding Orthopedics, Spineology, Spinal Kinetics, CTL Amedica, Vertiflex, Benvenue, Paradigm Spine, and HAPPE Spine; receiving nonfinancial personal fees from HAPPE Spine and NuVasive for consulting; receiving personal fees from NuVasive for travel support; and receiving nonfinancial support from Global Spine Journal for serving as a journal board member outside the submitted work. Dr Kelly reported receiving grants from AO Spine to the institution during the conduct of the study and travel fees from AO Spine outside the submitted work. Dr Brodke reported receiving personal fees from Orthofix and CTL Amedica outside the submitted work. Dr Vaccaro reported receiving royalties from Medtronic, Stryker Spine, Thieme Medical Publishers, Jaypee, Elsevier, Taylor Francis/Hodder & Stoughton, SpineWave, ATEC, Harvard MedTech, and Wolters Kluwer; receiving consulting fees, royalties, and stocks from Globus; receiving royalties and stocks from Stout Medical and Atlas Spine; having stock in Progressive Spinal Technologies, Advanced Spinal Intellectual Properties, Flagship Surgical, Cytonics, electroCore, AVKN Patient Driven Care, Flow Pharma, the Rothman Institute and Related Properties, Innovative Surgical Designs, Orthobullets, Avaz Surgical, Dimension Orthotics, Surgalign, NuVasive, Parvizi Surgical Innovation, Jushi, DeepHealth, and ViewFi Health; serving as an independent contractor for AO Spine; serving on a committee for Sentryx; receiving stocks from and serving on a committee for the National Spine Health Foundation and Accelus; and consulting for and receiving royalties from Spinal Elements outside the submitted work. Dr Hilibrand reported receiving royalties from ZimVie and CTL Amedica outside the submitted work. Dr Harrop reported being an advisor for DePuy-Ethicon outside the submitted work. Dr Yoon reported receiving grants from AO Spine during the conduct of the study and receiving personal fees from Alphatec; serving as chairman of the Degenerative Knowledge Forum of AO Spine; owning stock in Medyssey; and receiving royalties from Spineart outside the submitted work. Dr Kim reported receiving research grants or contracts paid to the University of California, Davis, from Medtronic, Empirical Spine, Mesoblast, In ViVo, Seikagaku, Stryker, and AbbVie; serving as a consultant for ZimVie and Globus; receiving royalties from ZimVie and Precision Spine; and having equity in Molecular Matrix. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Flowchart Depicting the Patient Recruitment and Randomization Strategy in the CSM-PROTECT Trial
CSM-PROTECT indicates Efficacy of Riluzole in Surgical Treatment of Cervical Spondylotic Myelopathy; GST, global statistical test. aIncludes 1 patient who missed the 35-day follow-up visit. bIncludes 5 patients who missed the 6-month follow-up visit. cIncludes 4 patients who missed the 6-month follow-up visit.
Figure 2.
Figure 2.. Application of the Global Statistical Test in the Estimation of Global Treatment Effect (GTE)
Each θ value (θv) quantifies the difference between the probability that treatment is better than control (A) and the probability that control is better than treatment (B) (ie, θv = [A − B]). ASIA indicates American Spinal Injury Association; NRS, numeric rating scale; SF-36 PCS, 36-Item Short Form Health Survey Physical Component Summary.
Figure 3.
Figure 3.. Components of the Global Statistical Test (GST) Used in the Secondary Analysis of the CSM-PROTECT Trial
The mean change from baseline to 1 year is presented for each of the 5 components (A) and the GST (B). Error bars indicate 95% CIs. CSM-PROTECT indicates Efficacy of Riluzole in Surgical Treatment of Cervical Spondylotic Myelopathy. aP = .80 by Wilcoxon test; P = .42 by t test. bP = .02 by Wilcoxon test; P = .01 by t test. cP = .05 by Wilcoxon test; P = .04 by t test. dP = .42 by Wilcoxon test; P = .23 by t test. eP = .45 by Wilcoxon test; P = .20 by t test. fP = .02, calculated using a 2-sample t test comparing the mean rank sum between riluzole and placebo groups.
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Comment in

  • Riluzole for Cervical Myelopathy.
    Ghogawala Z. Ghogawala Z. JAMA Netw Open. 2024 Jun 3;7(6):e2415616. doi: 10.1001/jamanetworkopen.2024.15616. JAMA Netw Open. 2024. PMID: 38904966 No abstract available.

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