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A prospective, randomized, multicenter study of intraosseous basivertebral nerve ablation for the treatment of chronic low back pain

  • Jad G. Khalil
    Correspondence
    Corresponding author. William Beaumont Hospital, Department of Orthopedic Surgery, 3811 West 13 Mile Road, Royal Oak, MI, 48073, USA. Tel.: (248) 663-1900.
    Affiliations
    William Beaumont Hospital, Department of Orthopaedic Surgery, 3811 West 13 Mile Rd, Royal Oak, MI 48073, USA
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  • Matthew Smuck
    Affiliations
    Stanford Orthopedic Surgery, 450 Broadway St, Pavillion C, Redwood City, CA 94063, USA
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  • Theodore Koreckij
    Affiliations
    Saint Luke's Hospital, Medical Plaza Bldg 1, Ste. 610, 4320 Wornall Rd, Kansas City, MO 64111, USA
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  • John Keel
    Affiliations
    Emory Orthopedics/Spine Center, 59 Executive Park South NE, Atlanta, GA 30329, USA
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  • Douglas Beall
    Affiliations
    Clinical Investigations, LLC, 1800 S. Renaissance Blvd, Ste 110, Edmond, OK 73013, USA
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  • Bradly Goodman
    Affiliations
    Alabama Clinical Therapeutics, LLC, 52 Medical Park East Drive, Suite 203, Birmingham, Alabama 35235, USA
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  • Paul Kalapos
    Affiliations
    Penn State Hershey Medical Center, 500 University Drive, H066, Hershey, PA 17033, USA
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  • Dan Nguyen
    Affiliations
    Oklahoma Spine Hospital, 14100 Parkway Commons Drive, Ste 103, Oklahoma City, OK 73134, USA
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  • Steven Garfin
    Affiliations
    University of California San Diego, 9500 Gilman Drive, #0602, La Jolla, CA 92093-0602, USA
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  • on behalf of theINTRACEPT Trial Investigators
    Author Footnotes
    1 On behalf of the INTRACEPT Trial Investigators:Douglas Beall, MD, Clinical Investigations, LLC; Scott Bainbridge, M.D., Denver Back Pain Specialists; Jad Khalil, M.D., William Beaumont Hospital; Theodore Koreckij, M.D., Saint Luke's Hospital; Paul Kalapos, M.D., Penn State Hershey Medical Center; Frank Phillips, M.D., Rush University Medical Center; John Keel, M.D., Emory University; Jeffrey Wang, M.D., Keck Hospital of USC; Matthew Smuck, M.D., Stanford Hospital; Charles Munyon, M.D., Temple University; John Markman, M.D., University of Rochester; Bruce Vrooman, M.D., Dartmouth Hitchock Medical Center; Neel Anand, M.D., Cedars Sinai Spine Center; Daniel Lieberman, M.D., Phoenix Spine; Larry Shannon II, M.D., Bassett Medical Center; Scott Kreiner, M.D., Barrow Brain and Spine; Aaron Calodney, M.D., Precision Spine Care; Ken Yonemura, M.D., Salt Lake Center for Spine and Peripheral Nerve Surgery; Bradly Goodman, M.D., Alabama Clinical Therapeutics, LLC; Gregory Moore, M.D., NeuroSpine Institute; Michael Schaufele, M.D., Drug Studies America; Al Rhyne, M.D., OrthoCarolina; Dan Nguyen, M.D., Oklahoma Spine Hospital; Steven Garfin, M.D., University of California San Diego.
  • Author Footnotes
    1 On behalf of the INTRACEPT Trial Investigators:Douglas Beall, MD, Clinical Investigations, LLC; Scott Bainbridge, M.D., Denver Back Pain Specialists; Jad Khalil, M.D., William Beaumont Hospital; Theodore Koreckij, M.D., Saint Luke's Hospital; Paul Kalapos, M.D., Penn State Hershey Medical Center; Frank Phillips, M.D., Rush University Medical Center; John Keel, M.D., Emory University; Jeffrey Wang, M.D., Keck Hospital of USC; Matthew Smuck, M.D., Stanford Hospital; Charles Munyon, M.D., Temple University; John Markman, M.D., University of Rochester; Bruce Vrooman, M.D., Dartmouth Hitchock Medical Center; Neel Anand, M.D., Cedars Sinai Spine Center; Daniel Lieberman, M.D., Phoenix Spine; Larry Shannon II, M.D., Bassett Medical Center; Scott Kreiner, M.D., Barrow Brain and Spine; Aaron Calodney, M.D., Precision Spine Care; Ken Yonemura, M.D., Salt Lake Center for Spine and Peripheral Nerve Surgery; Bradly Goodman, M.D., Alabama Clinical Therapeutics, LLC; Gregory Moore, M.D., NeuroSpine Institute; Michael Schaufele, M.D., Drug Studies America; Al Rhyne, M.D., OrthoCarolina; Dan Nguyen, M.D., Oklahoma Spine Hospital; Steven Garfin, M.D., University of California San Diego.
Open AccessPublished:June 20, 2019DOI:https://doi.org/10.1016/j.spinee.2019.05.598

      Abstract

      BACKGROUND CONTEXT

      Current literature suggests that degenerated or damaged vertebral endplates are a significant cause of chronic low back pain (LBP) that is not adequately addressed by standard care. Prior 2-year data from the treatment arm of a sham-controlled randomized controlled trial (RCT) showed maintenance of clinical improvements at 2 years following radiofrequency (RF) ablation of the basivertebral nerve (BVN).

      PURPOSE

      The purpose of this RCT was to compare the effectiveness of intraosseous RF ablation of the BVN to standard care for the treatment of chronic LBP in a specific subgroup of patients suspected to have vertebrogenic related symptomatology.

      STUDY DESIGN/SETTING

      A prospective, parallel, open label RCT was conducted at 20 U.S. sites.

      PATIENT SAMPLE

      A total of 140 patients with chronic LBP of at least 6 months duration, with Modic Type 1 or 2 vertebral endplate changes between L3 and S1, were randomized 1:1 to undergo either RF ablation of the BVN or continue standard care.

      OUTCOME MEASURES

      Oswestry Disability Index (ODI) was collected at baseline, 3, 6, 9, and 12-months postprocedure. Secondary outcome measures included a 10-point Visual Analog Scale (VAS) for LBP, ODI and VAS responder rates, SF-36, and EQ-5D-5L. The primary endpoint was a between-arm comparison of the mean change in ODI from baseline to 3 months post-treatment.

      METHODS

      Patients were randomized 1:1 to receive RF ablation or to continue standard care. Self-reported patient outcomes were collected using validated questionnaires at each study visit. An interim analysis to assess for superiority was prespecified and overseen by an independent data management committee when a minimum of 60% of patients had completed their 3-month primary endpoint visit.

      RESULTS

      The interim analysis showed clear statistical superiority (p<.001) for all primary and secondary patient-reported outcome measures in the RF ablation arm compared with the standard care arm. This resulted in a data management committee recommendation to halt enrollment in the study and offer early cross-over to the control arm. These results are comprised of the outcomes of the 104 patients included in the intent-to-treat analysis of the 3-month primary endpoint, which included 51 patients in the RF ablation arm and 53 patients in the standard care arm. Baseline ODI was 46.1, VAS was 6.67, and mean age was 50 years. The percentage of patients with LBP symptoms ≥5 years was 67.3%. Comparing the RF ablation arm to the standard care arm, the mean changes in ODI at 3 months were −25.3 points versus −4.4 points, respectively, resulting in an adjusted difference of 20.9 points (p<.001). Mean changes in VAS were −3.46 versus −1.02, respectively, an adjusted difference of 2.44 cm (p<.001). In the RF ablation arm, 74.5% of patients achieved a ≥10-point improvement in ODI, compared with 32.7% in the standard care arm (p<0.001).

      CONCLUSIONS

      Minimally invasive RF ablation of the BVN led to significant improvement of pain and function at 3-months in patients with chronic vertebrogenic related LBP.

      Keywords

      Introduction

      Chronic low back pain (CLBP) affects 10%–13% of the adult U.S. population, or more than 30 million people [
      • Freburger JK
      • Holmes GM
      • Agans RP
      • Jackman AM
      • Darter JD
      • Wallace AS
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      The rising prevalence of chronic low back pain.
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      • Shmagel A
      • Foley R
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      Epidemiology of chronic low back pain in US adults: data from the 2009-2010 National Health and Nutrition Examination Survey.
      ]. Often, a specific diagnosis is lacking, making it difficult to establish validated care pathways [
      • Deyo RA
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      Overtreating chronic back pain: time to back off?.
      ,
      • Dagenais S
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      A systematic review of low back pain cost of illness studies in the United States and internationally.
      ]. This results in over- or undertreatment, suboptimal outcomes, and high costs. Furthermore, clinical guidelines and payer policies governing nonoperative and surgical treatments for CLBP are inconsistent and have a high degree of heterogeneity [
      • Cheng JS
      • Lee MJ
      • Massicotte E
      • Ashman B
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      • Pilcher LE
      • et al.
      Clinical guidelines and payer policies on fusion for the treatment of chronic low back pain.
      ].
      Although the diagnosis of vertebrogenic pain is a relatively new clinical concept, there is a substantial body of basic science evidence supporting the vertebral endplates as a significant source of LBP [
      • Lotz JC
      • Fields AJ
      • Liebenberg EC
      The role of the vertebral end plate in low back pain.
      ,
      • Dudli S
      • Fields AJ
      • Samartzis D
      • Karppinin J
      • Lotz JC
      Pathobiology of Modic changes.
      ,
      • Munir S
      • Freidin MB
      • Rade M
      • Määttä J
      • Livshits G
      • Williams FMK
      Endplate defect is heritable, associated with low back pain and triggers intervertebral disc degeneration: a longitudinal study from twins UK.
      ,
      • Dudli S
      • Sing DC
      • Hu SS
      • Berven SH
      • Burch S
      • Deviren V
      • et al.
      ISSLS PRIZE IN BASIC SCIENCE 2017: intervertebral disc/bone marrow cross-talk with Modic changes.
      ,
      • Fras C
      • Kravetz P
      • Mody DR
      • Heggeness MH
      Substance P-containing nerves within the human vertebral body. an immunohistochemical study of the basivertebral nerve..
      ,
      • Bailey JF
      • Liebenberg E
      • Degmetich S
      • Lotz JC
      Innervation patterns of PGP 9.5-positive nerve fibers within the human lumbar vertebra.
      ]. Immunohistochemical studies have demonstrated nociceptors at the endplates that trace back to the basivertebral nerve (BVN), a branch of the sinuvertebral nerve that was first described by Antonacci et al. in 1998 [
      • Antonacci MD
      • Mody DR
      • Heggeness MH
      Innervation of the human vertebral body: a histologic study.
      ]. The endplates’ dual role of nutritional support for the disc and structural support for the spine are at odds, making them vulnerable to damage. Endplate damage can lead to cellular communication between the immunologically privileged disc nucleus and vertebral bone marrow, triggering chronic inflammation, a process that is visible as Modic changes on magnetic resonance imaging (MRI) [
      • Dudli S
      • Sing DC
      • Hu SS
      • Berven SH
      • Burch S
      • Deviren V
      • et al.
      ISSLS PRIZE IN BASIC SCIENCE 2017: intervertebral disc/bone marrow cross-talk with Modic changes.
      ]. This leads to endplate nerve proliferation that, in the presence of chemical sensitization and mechanical stimulation, can result in pain signals transmitted to the central nervous system by the BVN that are perceived as LBP [
      • Lotz JC
      • Fields AJ
      • Liebenberg EC
      The role of the vertebral end plate in low back pain.
      ]. These findings led to interest in utilizing therapeutic radiofrequency (RF) ablation of the BVN in a specific subgroup of the chronic LBP population suspected of having vertebrogenic pain.
      Following a pilot study [
      • Becker S
      • Hadjipavlou A
      • Heggeness MH
      Ablation of the basivertebral nerve for treatment of back pain: a clinical study.
      ], a randomized, double-blind, sham-controlled trial of 225 patients demonstrated the efficacy of intraosseous RF ablation of the BVN to treat chronic LBP in patients with Modic type 1 or 2 changes of the vertebral endplates [
      • Fischgrund JS
      • Rhyne A
      • Franke J
      • Sasso R
      • Kitchel S
      • Bae H
      • et al.
      Intraosseous basivertebral nerve ablation for the treatment of chronic low back pain: a prospective randomized double-blind sham-controlled multi-center study.
      ]. A follow-up study of the treatment arm of the sham-controlled trial demonstrated durability of those results at 24 months [
      • Fischgrund J.S.
      • Rhyne A.
      • Franke J.
      • Sasso R.
      • Kitchel S.
      • Bae H.
      • et al.
      Intraosseous basivertebral nerve ablation for the treatment of chronic low back pain: two-year results from a prospective randomized double-blind sham-controlled multi-center Study.
      ]. Based on these findings, a new study was designed and undertaken to evaluate the clinical effectiveness of BVN RF ablation compared to standard care of chronic LBP.

      Methods

      Trial design

      The INTRACEPT trial reported here (registered on ClinicalTrials.gov as NCT03246061) is a prospective, parallel, randomized, controlled, open label, multicenter clinical trial of 140 patients with suspected vertebrogenic chronic low back pain randomized to either RF Ablation of the BVN or continuation of standard care. These study subjects were consecutively recruited at 20 investigative sites in the U.S. from September 2017 to January 2019. Since an earlier and separate sham-controlled trial that ended recruitment in 2014 (registered with ClinicalTrials.gov as NCT01446419) revealed that 3-month treatment outcomes were maintained at 2 years [
      • Fischgrund JS
      • Rhyne A
      • Franke J
      • Sasso R
      • Kitchel S
      • Bae H
      • et al.
      Intraosseous basivertebral nerve ablation for the treatment of chronic low back pain: a prospective randomized double-blind sham-controlled multi-center study.
      ,
      • Fischgrund J.S.
      • Rhyne A.
      • Franke J.
      • Sasso R.
      • Kitchel S.
      • Bae H.
      • et al.
      Intraosseous basivertebral nerve ablation for the treatment of chronic low back pain: two-year results from a prospective randomized double-blind sham-controlled multi-center Study.
      ], the primary endpoint for this new trial was set at the 3-month follow-up. In addition, a prespecified interim analysis for superiority assessment was conducted (per protocol) when 60% of randomized subjects completed 3-month follow-up. An independent Data Management Committee (DMC) oversaw the interim analysis and study decisions. This is a report on the prespecified interim analysis at the 3-month primary endpoint.
      The INTRACEPT trial was sponsored by Relievant Medsystems, Inc. (Minneapolis, MN, USA). The study was HIPAA compliant and conducted under Institutional Board Review approval and participant informed consent was obtained. Enrolled patients were assigned a unique participant ID number, and all submitted patient information was deidentified. Data submitted by the study sites was source-verified to the medical record and patient-completed questionnaires by study monitors. A third-party statistician (QST Consultations, Grand Rapids, MI, USA) prepared the computer-generated randomization scheme using permuted blocks of four or six and stratified by study site.

      Participants

      Eligibility was adjudicated by an independent medical monitor based on each patient's medical, clinical, and radiographic presentation. The primary inclusion criteria included skeletally mature patients with ≥6 months of CLBP who had not responded to at least 6 months of conservative care and had Type 1 or Type 2 Modic changes on an MRI at one or more vertebral bodies from L3 through S1. Primary exclusion criteria included radicular pain, symptomatic spinal stenosis, disc protrusion >5 mm, spondylolisthesis >2 mm at any level, or Beck Depression Inventory of greater than 24. See Table 1 for a complete listing of inclusion and exclusion criteria for this study.
      Table 1Listing of the inclusion and exclusion criteria for the study
      Inclusion criteriaExclusion criteria
      • Skeletally mature patients with chronic (≥6 months) isolated lumbar back pain, who had not responded to at least 6 months of nonoperative management.

      • Type 1 or Type 2 Modic changes at one or more vertebral body for levels L3–S1.

      • Minimum ODI of 30 points (100-point scale).

      • Minimum VAS of 4 cm (10 cm scale).

      • Ability to provide informed consent, read and complete questionnaires.
      • MRI evidence of Modic at levels other than L3–S1.

      • Radicular pain (defined as nerve pain following a dermatomal distribution and that correlates with nerve compression in imaging).

      • Previous lumbar spine surgery (discectomy/laminectomy allowed if >6 months before baseline and radicular pain resolved).

      • Symptomatic spinal stenosis (defined as the presence of neurogenic claudication and confirmed by imaging).

      • Metabolic bone disease, spine fragility fracture history, or trauma/compression fracture, or spinal cancer.

      • Spine infection, active systemic infection, bleeding diathesis.

      • Radiographic evidence of other pain etiology

       • Disc extrusion or protrusion >5 mm.

       • Spondylolisthesis > 2 mm at any level

       • Spondylolysis at any level.

       • Facet arthrosis / effusion correlated with facet-mediated LBP.

      • Beck Depression Inventory >24 or 3 or > Waddell's signs.

      • Compensated injury or litigation.

      • Currently taking extended release narcotics with addiction behaviors.

      • BMI >40.

      • Bedbound or neurological condition that prevents early mobility or any medical condition that impairs follow up.

      • Contraindication to MRI, allergies to components of the device, or active implantable devices, pregnant or lactating.
      ODI, Oswestry Disability Index; VAS, Visual Analog Scale; MRI, magnetic resonance scale; BMI, body mass index.
      Upon confirmation of eligibility, baseline measurements were collected and entered by the study site research personnel into the online clinical database (iMedNet, Mednet Solutions, Minneapolis, MN, USA). An electronic randomization assignment was provided by the clinical database if the minimum thresholds for ODI (>30 points) and VAS (>4 cm) were met. Patients were electronically randomized 1:1 to either RF ablation treatment or standard care.

      Study interventions

      Patients in the treatment arm received intraosseous RF ablation of the BVN using a unilateral transpedicular delivery system (Intracept System, Relievant Medsystems, Minneapolis, MN, USA). Treatment of up to four vertebrae in nonconsecutive levels from L3 to S1 was allowed. The procedure was performed under image guidance with moderate conscious sedation or general anesthesia, per investigator discretion, in an outpatient setting. The electrode was advanced to the targeted location proximal to the terminus of the BVN, approximately 30%–50% across the sagittal vertebral body width (Fig. 1). Following imaging confirmation, thermal ablation was delivered for 15 minutes at 85°C to create an approximately 1 cm spherical lesion within each treated vertebral body (Fig. 2). Detailed information about the surgical technique was previously described in the literature [
      • Fischgrund JS
      • Rhyne A
      • Franke J
      • Sasso R
      • Kitchel S
      • Bae H
      • et al.
      Intraosseous basivertebral nerve ablation for the treatment of chronic low back pain: a prospective randomized double-blind sham-controlled multi-center study.
      ]. All of the study investigators had training and previous experience with percutaneous transpedicular cannulation, such as pedicle screw placement, vertebroplasty, and/or kyphoplasty; all received cadaver training on the BVN RF ablation procedure before study initiation.
      Fig. 1
      Fig. 1Fluoroscopic images showing probe placement at S1. (Left) AP Image. (Right) lateral image with target zone.
      Fig. 2
      Fig. 2Example of pre and post treatment T2-weighted MRI. (Left) Baseline MRI showing Modic changes at L5–S1 vertebral endplates. Arrow points to terminus of BVN at L5. (Right) Six-week post-treatment MRI arrows showing RF ablation lesion.
      Patients randomized to standard care continued treatment, including, but not limited to, pain medications, physical therapy, exercise, chiropractic treatment, acupuncture, and spinal injections. Standard care was provided in a shared decision-making process between the patient and the treating investigator, according to the investigator's medical judgment and the patient's clinical presentation and experiences with prior treatments.

      Study follow-up

      The primary endpoint of the study is collected at 3 months postrandomization (standard care) or post-treatment (RF ablation). In addition, all RF ablation patients are followed at 6 weeks, and 3, 6, 9, 12, and 24 months. Standard care patients are followed at 3, 6, 9, and 12 months. Here, results from the 3-month primary endpoint are reported.

      Target success

      Magnetic resonance imaging (T1, T2, and STIR time constants) was performed at 6 weeks post RF ablation. Measurements of the degree of overlap between the RF ablation lesion and the terminus of the BVN for each vertebral body were performed by an independent, blinded neuroradiologist reviewer. Targeting success was based on a defined threshold of observed overlap.

      Outcome measures

      Patient-reported clinical outcomes were evaluated at baseline and 3, 6, 9, and 12 months using validated questionnaires, with 3-month outcomes reported here. Functional impact was measured using the Oswestry Disability Index (ODI) questionnaire [
      • Roland M
      • Fairbank J.
      The Roland Morris disability questionnaire and the Oswestry disability questionnaire.
      ]. Low back pain was assessed using a Visual Analog Scale (VAS) [
      • Price DD
      • McGrath PA
      • Rafii A
      • Buckingham B
      The validation of visual analogue scales as ratio scale measures for chronic and experimental pain.
      ] ranging from 0 (no pain) to 10 (worst pain imaginable). Health Status and Quality of Life were measured at each follow-up using the SF-36 [
      • Ware JE
      • Kosinski M
      • Keller SK
      SF-36 physical and mental health summary scales: a user's manual.
      ] and EQ-5D-5L [
      • Herdman M
      • Gudex C
      • Lloyd A
      • Janssen M
      • Kind P
      • Parkin D
      • et al.
      Development and preliminary testing of the new five-level version of EQ-5D (EQ-5D-5L).
      ,
      • Janssen MF
      • Pickard AS
      • Golicki D
      • Gudex C
      • Niewada M
      • Scalone L
      • et al.
      Measurement properties of the EQ-5D-5L compared to the EQ5D-3L across eight patient groups: a multi-country study.
      ] questionnaires. Physical and neurological examinations were performed by the site investigator(s) at each follow-up study visit. Spinal and neurological adverse events (AEs) were collected at each study visit. All reported AEs were adjudicated by an independent clinical event committee for relatedness to device therapy and procedure.
      The predefined primary endpoint of this study is the 3-month follow-up, and the primary outcome is a between-arm comparison of the least squares (LS) mean change in ODI from baseline to 3 months post-treatment, adjusted for baseline ODI.

      Sample calculations

      The full study was over-powered at 95% power to detect a 10-point difference in ODI with a two-sided overall alpha level of 0.05, requiring 150 randomized participants (approximately 75 participants per arm) with an estimated attrition rate of 15%. The actual attrition rate was much lower, thereby requiring less participants to be enrolled. At 100 randomized participants (approximately 50 per arm), the study was 80% powered to detect a 10-point difference with a two-sided overall alpha level of 0.05. The study had a group-sequential design with one planned interim analysis for primary endpoint superiority testing after 60% of the randomized participants completed their 3-month follow-up visit. These results are presented herein. Statistical significance was defined as p <.025 for this interim analysis for an overall alpha level of 0.05.

      Statistical analysis

      All study outcomes data were analyzed as intent to treat. Statistical analysis was performed with SAS version 9.3 software (SAS Institute Inc, Cary, NC, USA), using an analysis of covariance (ANCOVA) with a factor of treatment group and a covariate of baseline ODI score for the primary endpoint, producing LS means for statistical comparison. Values were adjusted for multiple imputation. Missing values were imputed using multiple imputations, and only one participant had missing data for the primary outcome. Responder rates were analyzed using Fischer's Exact test without imputation for missing values. Secondary endpoint estimates and p values were analyzed using an ANCOVA with a factor of treatment group and covariate of the baseline scores for each of the endpoints for between arms comparisons.

      Study revisions

      The protocol was revised to allow treatment of up to four vertebrae in nonconsecutive levels from L3 to S1 upon receiving Food & Drug Administration 501k clearance. Inclusion of patients at least 6 months from laminectomy or discectomy, with moderate symptomatic spinal stenosis, and taking extended-release opioids was also allowed. All subjects met the inclusion/exclusion criteria of the final protocol for the analysis. An evaluation of the impact of protocol revisions to the primary endpoint was conducted with no significant differences detected, and no adjustment for differences was required.

      Results

      Planned interim analysis and DMC decision to halt enrollment

      As per the study protocol, interim analysis was undertaken when 60% of patients reached the 3-month follow-up, the primary endpoint of the study. At the time of the independent DMC's review of the prespecified interim analysis, a total of 140 patients were randomized, with 104 patients (n=51 RF ablation and n=53 standard care) having completed their 3-month follow-up. Thus, there was <1% attrition at the primary endpoint (Fig. 3). The interim analysis showed statistical superiority (p<.001) for all patient-reported outcome measures favoring the RF ablation arm. This resulted in a recommendation from the DMC to halt enrollment in the study and offer patients in the standard care arm early cross-over to the RF ablation arm.
      Fig. 3
      Fig. 3Consort flow of study patients at the time of the predetermined 3-month interim analysis.
      There were three members of the DMC—1 independent statistician and 2 independent physicians (an interventional radiologist and an anesthesiologist). The physician qualifications to serve on the DMC were: independence from the sponsoring company with no current or previous financial relationships; international recognition in spine care with clinical expertise in invasive spine treatments; extensive experience with scientific studies, including acting as principle investigators of studies, acting on the editorial board of journals, and in-depth understanding of statistics.
      To make their recommendations the DMC reviewed the same outcomes reported in this study. The DMC Charter and statistical analysis plan prespecified effectiveness superiority as p<.025. There were no safety concerns noted by the DMC. However, the DMC noted the overwhelming degree of superiority in the treatment arm combined with the requirement that subjects have chronic LBP for a minimum of 6 months with conservative treatment and determined that it was not ethical to continue the control arm and that further enrollment into the treatment arm was not needed.

      Patient demographics & baseline characteristics

      Demographics and baseline characteristics were similar between the two groups (Table 2). Baseline ODI was 46.1 (p=.064); VAS was 6.67 (p=.231); mean age was 50 years (p=.098). The percentage of patients with LBP symptoms ≥5 years was 67.3% (p=.404). Over 70% (p=.831) of patients had previously undergone at least one trial of physical therapy or a formal exercise program; 42% (p=.692) had received chiropractic care; 70% (p=.054) had undergone spinal injections, with 16% (p=.434) having undergone prior RF ablation of a facet or sacroiliac joint(s). Prior usage of medications was also similar.
      Table 2Depicts the demographics and baseline characteristics of the ITT interim study population
      Interim Total

      (N=104)
      RF Ablation

      (N=51)
      Standard Care (N=53)p Value
      Mean Age (years), SD (Range)50.0, 10.1 (26–70)50.0, 9.0 (32–68)50.0, 11.1 (26–70).0977
      p value from a two sample t test with a factor of treatment group.
      Male, n (%)51 (49.0%)26 (51.0%)25 (47.2%).845
      p value from Fischer's Exact test.
      Mean BMI (kg/m
      p value from Fischer's Exact test.
      ), SD (Range)
      28.1, 4.7 (18.9–39.5)27.9, 4.5 (18.9–38.4)28.2, 5.0 (19.6–39.5).720
      p value from a two sample t test with a factor of treatment group.
      Current tobacco use – n (%)9 (8.7%)6 (11.8%)3 (5.7%).589
      p value from a two sample t test with a factor of treatment group.
      Caucasian n (%)97 (93.3%)49 (96.1%)48 (90.6%).437
      p value from Fischer's Exact test.
      Married n (%)74 (71.2%)33 (64.7%)41 (77.4%).195
      p value from Fischer's Exact test.
      College degree or higher n (%)52 (50.0%)28 (54.9%)24 (45.3%).842
      p value from Fischer's Exact test.
      Working before procedure n (%)82 (78.8%)43 (84.3%)39 (73.6%).232
      p value from Fischer's Exact test.
      Not working due to back pain n (%)4 (3.8%)3 (5.9%)1 (1.9%).358
      p value from Fischer's Exact test.
      Mean BDI, SD (Range)5.9, 4.84 (0–20)6.0, 5.08 (0–20)5.8, 4.64 (0–16).858
      p value from a two sample t test with a factor of treatment group.
      Duration low back symptoms n (%)
       ≥6 months to <1 year6 (5.8%)4 (7.8%)2 (3.8%)
       ≥1 year to <2 years3 (2.9%)3 (5.9%)0 (0.0%)
       ≥2 years to <3 years12 (11.5%)5 (9.8%)7 (13.2%)
       ≥3 years to <5 years13 (12.5%)7 (13.7%)6 (11.3%)
       ≥5 years70 (67.3%)32 (62.7%)38 (71.7%).404
      p value from Fischer's Exact test.
      Treatment history n (%)
       Opioid use at baseline33 (32%)18 (35.3%)15 (28.3%).529
      p value from Fischer's Exact test.
       Injections73 (70.2%)31 (60.8%)42 (79.2%).054
      p value from Fischer's Exact test.
       Past lower pack surgeries12 (11.5%)6 (11.8%)6 (11.3%)1.000
      p value from Fischer's Exact test.
      Disc protrusion (1 or more levels), n %60 (57.7%)30 (58.8%)30 (56.6%).845
      p value from Fischer's Exact test.
       Grade 1 spondylolithesis n (%)8 (7.7%)6 (11.8%)2 (3.8%).157
      p value from Fischer's Exact test.
      Type of Modic by subject n (%)
       Type 1,38 (36.5%)18 (35.3%)20 (37.7%).634
      p value from Fischer's Exact test.
       Type 255 (52.9%)29 (56.9%)26 (49.1%)
       Mixed (Type 1 & Type 2)11(10.6%)4 (7.8%)7 (13.2%)
      Baseline mean ODI, SD (Range)46.1, 11.30 (30–88)44.0, 11.08 (30–70)48.1, 11.24 (32–88).064
      p value from a two sample t test with a factor of treatment group.
      Baseline mean VAS, SD (Range)6.67, 1.33 (4.0–10.0)6.51, 1.31 (4.0–10.0)6.82, 1.34 (4.0–10.0).231
      p value from a two sample t test with a factor of treatment group.
      Baseline mean SF-36 PCS, (Range)32.04 (17.23–47.64)32.79 (18.43–46.93)31.33 (17.23–47.64).301
      p value from a two sample t test with a factor of treatment group.
      Baseline mean EQ-5D-5L, (Range).6207 (0.252–0.827).6322 (0.270–0.827).6095 (0.252–0.827).378
      p value from a two sample t test with a factor of treatment group.
      BDI, Beck Depression Inventory; PCS, physical component summary; EQ-5D-5L, EuroQual Group 5 Dimension five-Level Quality of Life.
      low asterisk p value from Fischer's Exact test.
      p value from a two sample t test with a factor of treatment group.

      Treatment results

      Treatment was completed in all 51 RF ablation patients. Two-vertebral bodies were treated in 40 subjects and three vertebral bodies in the remaining 11 subjects. The most commonly treated segment was L5–S1 (24 patients, 47%), followed by L4–L5 (29%), and L4–L5–S1 (18%). Mean procedure duration was 92.5 minutes (SD 38.82) from incision to closure. In regard to health-care utilization, no RF ablation patients received a spinal injection before the 3-month end-point, whereas in the standard care arm, six standard care patients (11%) received injections across five study sites. Opioid pain medications were used by 32% (p=.529) of patients at baseline and no significant difference in opioid reduction was observed between the two treatment arms at 3-months.

      ODI (primary outcome)

      The primary outcome was a between-arm comparison of the LS mean change in ODI from baseline to 3 months post-treatment, adjusted for baseline ODI. At 3-months, the mean change in ODI from baseline was −25.3 points in the RF ablation arm, compared with −4.4 points in the standard care arm (Fig. 4). The difference between arms was −20.9 points as shown in Table 3 (p<.001). Using a 10-point improvement threshold for success, 74.5% of patients in the RF ablation arm reached clinical success compared with 32.7% of patients in the standard care arm as shown in Fig. 5 (p<.001). An ODI improvement of ≥20 points was reported by 62.7% of RF ablation patients compared with 13.5% in standard care patients (p<.001).
      Table 3ODI was the primary outcome of the pre-planned interim analysis at 3 months, the primary endpoint of the study. This table depicts the details of the primary outcome
      RF Ablation

      (N=51)
      Standard Care

      (N=53)
      p Value
      Baseline ODI (0–100 points)
      Mean, SD,44.0, 11.0848.1, 11.24.064
      p value from a two sample t test with a factor of treatment group.
      Median (Range)40.0 (30–70)36.0 (32–88)
      3-month ODI (0–100 points)
      3 month visit is computed as post-treatment for the RF Ablation Arm, and postrandomization for the Control Arm. Multiple imputation used to impute missing values.
      Mean, SD,19.9, 16.5942.5, 15.83
      Median (Range)18.0 (0–62)40.0 (10–74)
      Mean change in ODI baseline to 3-months
      Mean, SD,−24.1, 18.97−5.6, 14.33
      Median (Range)−26.0, (−70 to 12)−2.0, (−64–20)
      LS Mean change in ODI baseline to 3-months
      LS mean−25.3−4.4
      95% confidence interval
      Estimates and p value from an ANCOVA with a factor of treatment group and a covariate of baseline score. Values have been adjusted for multiple imputation.
      (−29.6 to −21.0)(−8.7 to −0.2)
      Mean difference between arms
      LS mean adjusted for baseline ODI−20.9<.001
      Estimates and p value from an ANCOVA with a factor of treatment group and a covariate of baseline score. Values have been adjusted for multiple imputation.
      Confidence intervals
      Estimates and p value from an ANCOVA with a factor of treatment group and a covariate of baseline score. Values have been adjusted for multiple imputation.
      −27.0 to −14.7
      low asterisk p value from a two sample t test with a factor of treatment group.
      3 month visit is computed as post-treatment for the RF Ablation Arm, and postrandomization for the Control Arm. Multiple imputation used to impute missing values.
      Estimates and p value from an ANCOVA with a factor of treatment group and a covariate of baseline score. Values have been adjusted for multiple imputation.

      VAS

      Visual Analog Scale and other secondary outcomes are displayed in Table 4. The LS mean change in VAS from baseline was −3.46 in the RF ablation arm, compared with −1.02 in the standard care arm (Fig. 6). The mean difference between arms was −2.44 (p<.001). Using a threshold of 2.0 cm improvement, 72.5% of patients in the RF ablation arm reached clinical success compared with 34.0% of patients in the standard care arm as shown in Fig. 7 (p<.001).
      Table 4The secondary outcomes of the preplanned interim analysis at 3 months. The table depicts the details of the secondary outcomes; all showed a statistically significant difference between arms (p<.001)
      RF ablation

      (N=51)
      Standard care

      (N=53)
      p Value
      ODI responder rates
      ≥10-point reduction in ODI, n (%)38 (74.5%)17 (32.7%)<.001
      p Value from a Fisher's exact test.
      ≥20-point reduction in ODI, n (%)32 (62.7%)7 (13.5%)<.001
      p Value from a Fisher's exact test.
      Baseline VAS (0–10 cm)
      Mean, SD,6.51, 1.3106.82, 1.339
      Median, (Range)6.50, (4–10)7.00, (4–10)
      3-month VAS (0–10 cm)
      Mean, SD,3.11, 2.6365.73, 2.155
      Median, (Range)2.00, (0–10)6.00, (0–10)
      Mean change in VAS baseline to 3-months
      Mean, SD,−3.40, 2.586−1.08, 2.082
      Median, (Range)−4.00, (−8.0–2.0)−1.00, (−6.5–3.0)
      LS mean change in VAS baseline to 3-months
      LS Mean−3.46−1.02
      95% confidence interval
      Estimates and p value from an ANCOVA with a factor of treatment group and a covariate of baseline score.
      (−4.10 to −2.82)(−1.66 to −0.37)
      Mean difference between arms
      LSM mean adjusted for baseline VAS−2.44<.001
      Estimates and p value from an ANCOVA with a factor of treatment group and a covariate of baseline score.
      Confidence intervals
      Estimates and p value from an ANCOVA with a factor of treatment group and a covariate of baseline score.
      (−3.36 to −1.53)
      VAS responder rates
      ≥1.5 cm reduction in VAS, n (%)38 (74.5%)18 (36.0%)<.001
      p Value from a Fisher's exact test.
      ≥2.0 cm reduction in VAS, n (%)37 (72.5%)17 (34.0%)<.001
      p Value from a Fisher's exact test.
      Baseline SF-36 (PCS)
      Mean, SD,32.78, 6.8331.33, 7.48
      Median range32.42 (18.43 –46.93)30.18 (17.23–47.64)
      LS mean change in SF36 (PCS)

      Baseline to 3-months
      LS mean14.0212.114
      95% Confidence interval
      Estimates and p value from an ANCOVA with a factor of treatment group and a covariate of baseline score.
      (11.995–16.048)(0.088–4.140)
      Mean difference between arms SF-36 (PCS)
      LSM mean adjusted for baseline SF-36 PCS11.907<.001
      Estimates and p value from an ANCOVA with a factor of treatment group and a covariate of baseline score.
      Confidence intervals
      Estimates and p value from an ANCOVA with a factor of treatment group and a covariate of baseline score.
      (9.035–14.780)
      Baseline SF-36 (MCS)
      Mean, SD,53.51, 9.3952.31, 9.51
      Median Range54.76 (22.24–69.80)54.46 (29.43–64.67)
      LS mean change in SF36 (MCS)

      Baseline to 3-months
      LS mean2.615−2.786
      95% Confidence interval
      Estimates and p value from an ANCOVA with a factor of treatment group and a covariate of baseline score.
      (0.450–4.781)(−4.952 to −0.620)
      Mean difference between arms SF-36 (MCS)
      LSM mean adjusted for baseline SF-36 MCS5.401<.001
      Estimates and p value from an ANCOVA with a factor of treatment group and a covariate of baseline score.
      Confidence intervals
      Estimates and p value from an ANCOVA with a factor of treatment group and a covariate of baseline score.
      (2.333–8.469)
      Baseline EQ-5D-5L
      Mean, SD,0.6322, 0.12900.6095, 0.13227
      Median range0.6430 (0.270–0.827)0.6340 (0.252–0.827)
      LS mean change in EQ-5D-5L baseline to

      3-months
      LS mean0.18030.0135
      95% Confidence interval
      Estimates and p value from an ANCOVA with a factor of treatment group and a covariate of baseline score.
      (0.1469–0.2137)(−0.0203–0.0472)
      Mean difference between arms
      LS mean adjusted for baseline EQ-5D-5L0.1668<.001
      Estimates and p value from an ANCOVA with a factor of treatment group and a covariate of baseline score.
      Confidence intervals
      Estimates and p value from an ANCOVA with a factor of treatment group and a covariate of baseline score.
      (0.1193–0.2144)
      PCS, physical component summary; MCS, mental component summary; EQ-5D-5L EuroQual Group 5 Dimension 5-Level Quality of Life.
      low asterisk p Value from a Fisher's exact test.
      Estimates and p value from an ANCOVA with a factor of treatment group and a covariate of baseline score.

      SF-36 and EQ-5D-5L

      The LS mean change from baseline between the RF ablation and standard care arms, respectively, in SF-36 (mental) were 2.615 versus −2.786; and SF-36 (physical) were 14.021 versus 2.114. The difference between arms in adjusted means were both statistically significant (p<.001). Similarly, LS mean change from baseline in EQ-5D-5L was 0.1803 in the RF ablation arm and 0.0135 in the standard care arm, resulting in an adjusted mean difference between arms of 0.1668 (p<.001).

      Patient satisfaction

      Fifty of the 51 RF ablation arm patients responded to a series of questions related to satisfaction following the procedure. Thirty-nine patients (78%) rated their condition as improved; 8 patients (16%) reported no change; and 3 patients (6%) indicated worsened condition. Thirty-seven patients (74%) felt the treatment was a success and were satisfied with the results of surgery; Forty patients (80%) would have the surgery again for the same condition, and 44 (88%) would recommend the procedure to a loved one with the same condition.

      Target success

      Targeting was adjudicated as successful in 96% of patients (49 of 51 subjects) and in 98% of treated vertebral bodies (111 of 113 vertebral bodies). Targeting failure was observed in two patients. The first demonstrated failure in one of two treated vertebrae, and the second in one of three treated vertebrae. With only two target failures in the study, a statistical comparison is not possible. However, a qualitative comparison does suggest a potential impact on outcomes, with outcomes below the treatment group mean and proportional to the individual target failure rate. Specifically, worse outcomes occurred in the first participant with the higher failure rate (ODI +10 points and VAS +1 point) relative to the second participant with the lower failure rate (ODI -10 points, and VAS -4 points).

      Adverse events

      Adverse events that were musculoskeletal, neurological, device or procedure related were collected in this study. Of the 22 AEs reported and adjudicated, 15 were in 13 RF ablation treated patients. Regarding AEs in the RF ablation arm, none were deemed device related. Three were categorized as general procedure related (incisional pain, urinary retention, and lateral femoral cutaneous neurapraxia). Seven were felt to be procedure related. One patient had back pain in a new location and the remaining 6 patients had either leg pain or paresthesia. All were categorized as mild, requiring no interventions beyond oral medication. Five of the seven AEs resolved before the 3-month follow-up visit (mean of 41 days). Two are ongoing at the time of this report (one mild paresthesia, one new leg pain that was reported 6-months postprocedure). There were no broken devices, no pedicle fractures, and no infections. One patient in the RF ablation arm was rescheduled due to inadequate analgesia under monitored anesthesia care. That patient was successfully treated at a later date without incident under general anesthesia.

      Discussion

      This report details the results from a preplanned interim analysis of outcomes at the 3-month primary endpoint comparing BVN ablation to standard nonoperative care in patients with CLBP and Modic Type 1 or Type 2 changes from L3 to S1. The primary outcome was determined by changes in patient-reported function on the ODI and was strongly in favor of the RF ablation treatment group with a mean improvement of −25.3 points, and an adjusted difference between means of −20.9 points compared with the usual care group (Table 3). These differences were statistically significant and well above established thresholds for clinical significance. The same is true of the study's secondary outcomes including pain, health status, quality of life, and patient satisfaction (Table 4).
      Although this study reports the 3-month primary outcomes from the planned interim analysis, and enrollment has stopped, long-term follow-up continues. Results of this interim analysis were compelling enough to halt study enrollment and initiate an early crossover option for patients in the control arm, based on the recommendations of the independent data management committee. It is surprising for a LBP treatment study to be halted early due to better than expected results. In fact, the authors are unaware of another instance in recent decades. We speculate that this highly successful outcome is due to a combination of factors. Most importantly, our protocol included the treatment of a well-defined subpopulation of CLBP patients using a novel intervention that targets a radiographically identifiable pathoanatomic process elucidated by ample basic science.
      By contrast, common therapies aimed at chronic nonspecific LBP are limited by small effect size [
      • Dagenais S
      • Caro J
      • Haldeman S
      A systematic review of low back pain cost of illness studies in the United States and internationally.
      ] leaving many patients dissatisfied [
      • Silvis WL
      • Lakke SE
      • Stegeman P
      • Speijer BL
      • Vroomen PC
      • Coppes MH
      • et al.
      Can patients with low back pain be satisfied with less than expected?.
      ]. Clinicians and researchers in the spine care community have long recognized these challenges and have identified the heterogeneous nature of the large CLBP population as an important contributor. Accordingly, better identifying subgroups of CLBP might result in more targeted and effective treatments. The results of this study highlight the benefits of such an approach.
      Magnetic resonance imaging is commonly used to identify potential sources of CLBP, however few MRI findings have proven reliable to improve CLBP treatment outcomes. The correlation between vertebral endplate (Modic) changes and LBP has been extensively investigated and the pathoanatomic basis of vertebrogenic back pain established [
      • Maatta JH
      • Wadge S
      • MacGregor A
      • Karppinen J
      • Williams FM
      ISSLS Prize Winner: Vertebral endplate (Modic) change is an independent risk factor for episodes of severe and disabling low back pain.
      ,
      • Luoma K
      • Vehmas T
      • Kerttula L
      • Gronblad M
      • Rinne E
      Chronic low back pain in relation to Modic changes, bony endplate lesions, and disc degeneration in a prospective MRI study.
      ,
      • Chung CB
      • Vande Berg BC
      • Tavernier T
      • Cotton A
      • Laredo JD
      • Vallee C
      • et al.
      End plate marrow changes in the asymptomatic lumbosacral spine: frequency, distribution and correlation with age and degenerative changes.
      ,
      • Kaapa E
      • Luoma K
      • Pitkaniemi J
      • Kerttula L
      • Gronblad M
      Correlation of size and type of Modic types 1 and 2 lesions with clinical symptoms: a descriptive study in a subgroup of patients with chronic low back pain on the basis of a university hospital patient sample.
      ,
      • Albert HB
      • Manniche C
      Modic changes following lumbar disc herniation.
      ,
      • Kjaer P
      • Korsholm L
      • Bendix T
      • Sorensen JS
      • Leboeuf-Yde C
      Modic changes and their associations with clinical findings.
      ,
      • Weishaupt D
      • Zanetti M
      • Hodler J
      • Min K
      • Fuchs B
      • Pfirrmann CW
      • et al.
      Painful lumbar disk derangement: relevance of endplate abnormalities at MR imaging.
      ,
      • Mok FP
      • Samartzis D
      • Karppinen J
      • Fong DY
      • Luk KD
      • Cheung KM
      Modic changes of the lumbar spine: prevalence, risk factors, and association with disc degeneration and low back pain in a large-scale population-based cohort.
      ,
      • Schroeder GD
      • Markova DZ
      • Koerner JD
      • Rihn JA
      • Hilibrand AS
      • Vaccaro AR
      • et al.
      Are Modic changes associated with intervertebral disc cytokine profiles?.
      ,
      • Jensen OK
      • Nielsen CV
      • Sørensen JS
      • Stengaard-Pedersen K
      Type 1 Modic changes was a significant risk factor for 1-year outcome in sick-listed low back pain patients: a nested cohort study using magnetic resonance imaging of the lumbar spine.
      ,
      • Jensen RK
      • Leboeuf-Yde C.
      Is the presence of Modic changes associated with the outcomes of different treatments? A systematic critical review.
      ]. Ample histologic, anatomic and immunohistochemical evidence supports the nociceptive role of the BVN in the pathogenesis of LBP [
      • Fras C
      • Kravetz P
      • Mody DR
      • Heggeness MH
      Substance P-containing nerves within the human vertebral body. an immunohistochemical study of the basivertebral nerve..
      ,
      • Bailey JF
      • Liebenberg E
      • Degmetich S
      • Lotz JC
      Innervation patterns of PGP 9.5-positive nerve fibers within the human lumbar vertebra.
      ]. In addition, a recent review concluded that Modic changes are more likely to be a reflection of a pathologic process than a coincidental finding, thus segments with Modic changes are a potential target for therapy [
      • Dudli S
      • Fields AJ
      • Samartzis D
      • Karppinin J
      • Lotz JC
      Pathobiology of Modic changes.
      ]. Accordingly, this study enrolled subjects based on specific MRI findings, including Type 1 or Type 2 Modic changes (Table 1).

      Comparison to the previously published RCT of BVN ablation

      Both this study and the previous RCT on BVN ablation used the same clinical and radiographic inclusion and exclusion criteria and primary endpoint [
      • Fischgrund JS
      • Rhyne A
      • Franke J
      • Sasso R
      • Kitchel S
      • Bae H
      • et al.
      Intraosseous basivertebral nerve ablation for the treatment of chronic low back pain: a prospective randomized double-blind sham-controlled multi-center study.
      ]. Still, some caution should be exercised in directly comparing the results of the current study with that of the previous sham-controlled RCT of BVN ablation, since different study designs and different control groups were used. Notwithstanding this caution, the 3-month outcomes in the BVN ablation treatment arms of both studies are similar with somewhat greater improvements in ODI and VAS in the current RCT relative to the previous sham-controlled trial. In addition to the trial design differences, this may be due to modifications of the access instruments that improved RF probe placement resulting in greater target success in the current study (96% vs. 89%). The 12-month and the 24-month results from the prior sham-controlled trial demonstrated that 3-month outcomes were maintained in the treatment arm [
      • Fischgrund J.S.
      • Rhyne A.
      • Franke J.
      • Sasso R.
      • Kitchel S.
      • Bae H.
      • et al.
      Intraosseous basivertebral nerve ablation for the treatment of chronic low back pain: two-year results from a prospective randomized double-blind sham-controlled multi-center Study.
      ]. It also revealed that opioid usage was reduced at 12-months in participants with improved pain and function [

      Markman JD, Rhyne A, Sasso R, Patel A, Hsu W, Fischgrund J, et al. Association between opioid use and patient reported outcomes in a randomized trial evaluating basivertebral nerve ablation for the relief of chronic low back pain. Neurosurgery. In Press.

      ]. Although the current study did not show a difference in opioid reduction at 3 months, this is not surprising given the different time points and the complexity of changing opioid habits.

      Comparison to other treatments for chronic LBP

      A strength of the current study is that it provides direct comparison to standard nonoperative care of CLBP, and thus demonstrates the potential benefits of BVN ablation relative to currently available alternatives for qualifying patients. The use of a standard care control arm is common in randomized trials of LBP treatments since the optimal care for CLBP remains unknown. Weinstein et al. suggested that variability in conservative treatment as prescribed by the treating physicians is a better reflection of actual clinical practice than a highly structured care program [
      • Weinstein JN
      • Tosteson TD
      • Lurie JD
      • Tosteson AN
      • Hanscom B
      • Skinner JS
      • et al.
      Surgical vs nonoperative treatment for lumbar disk herniation: the spine patient outcomes research trial (SPORT): a randomized trial.
      ]. Fortunately, the existence of many studies using a standard care control provides the opportunity for additional insights through comparisons. It is important to note that such comparisons should be interpreted cautiously. By definition, standard care is intended to mimic real-world treatment and is not structured. Thus, differences in standard care between studies may influence comparisons.
      When compared with a standard care control, treatment of patients with CLBP failed to demonstrate a statistically significant difference or failed to exceed established thresholds of clinical relevance using acupuncture [
      • Cherkin DC
      • Sherman KJ
      • Avins AL
      • Erro JH
      • Ichikawa L
      • Barlow WE
      • et al.
      A randomized trial comparing acupuncture, simulated acupuncture, and usual care for chronic low back pain.
      ], cognitive behavioral therapy [
      • Cherkin DC
      • Anderson ML
      • Sherman KJ
      • Balderson BH
      • Cook AJ
      • Hansen KE
      • et al.
      Two-year follow-up of a randomized clinical trial of mindfulness-based stress reduction vs cognitive behavioral therapy or usual care for chronic low back pain.
      ], massage [
      • Cherkin DC
      • Sherman KJ
      • Kahn J
      • Wellman R
      • Cook AJ
      • Johnson E
      • et al.
      A comparison of the effects of 2 types of massage and usual care on chronic low back pain: a randomized, controlled trial.
      ], multidisciplinary rehabilitation [
      • Kamper SJ
      • Apeldoorn AT
      • Chiarotto A
      • Smeets RJ
      • Ostelo RW
      • Guzman J
      • et al.
      Multidisciplinary biopsychosocial rehabilitation for chronic low back pain: Cochrane systematic review and meta-analysis.
      ], and yoga [
      • Tilbrook HE
      • Cox H
      • Hewitt CE
      • Kang'ombe AR
      • Chuang LH
      • Jayakody S
      • et al.
      Yoga for chronic low back pain: a randomized trial.
      ]. The observed treatment outcomes in the current study are much better than the nonoperative treatments detailed above. Perhaps it is more appropriate to compare the treatment effect size of BVN ablation to other surgical treatments for CLBP. In this regard, a recent meta-analysis of seven studies comparing segmental fusion to different types of structured and unstructured care for CLBP revealed a weighted mean difference in ODI of 5.13 points (95% confidence interval 0.19–10.07) in favor of fusion surgery [
      • Yavin D
      • Casha S
      • Wiebe S
      • Feasby TE
      • Clark C
      • Isaacs A
      • et al.
      Lumbar fusion for degenerative disease: a systematic review and meta-analysis.
      ]. In comparison, the current study achieved a mean difference of 20.9 points.
      Although these comparisons help provide perspective on the strength of the current study's results, they do not suggest that BVN ablation is a better treatment for all people with CLBP. Rather this study, and these comparisons, reveal that BVN ablation is a highly effective treatment only for a specific subgroup of patients with CLBP characterized by the clinical and radiographic criteria outlined in this study's methods.
      Previous novel CLBP treatments have been associated with indiscriminant patient selection and overuse. This is partially explained by a scarcity of objective diagnostic standards, and further motivated by a lack of highly effective and available treatment options for the CLBP population at large. The authors believe that the success observed in the current study is a direct result of meticulous patient selection based on rigorous clinical and radiographic criteria and they caution against the broad application of this procedure to the general population with CLBP.
      Limitations include use of a nonstructured standard care control and open label design. In addition, industry funding is a potential source of study bias. This report only provides short-term 3-month outcomes from the planned interim analysis and long-term results from the complete study cohort are underway. Although this study was designed to collect longer-term data from both randomized groups, a review of the study results from the planned interim analysis led to the independent DMC's recommendation to halt enrollment and offer early crossover to patients in the standard care group. It was noted that the Informed Consent regulations and the Declaration of Helsinki require that study participants be advised of any new information from the study that may impact their willingness to continue, and the results of the interim analysis would have such an impact, especially on the control group. Ultimately, the DMC determined that is was not ethical to continue the control arm, and that further enrollment into the treatment arm was not needed. As a result, follow-up will be limited in the standard care patients in the final analysis to results collected up to the point of cross-over or study exit. Further follow-up of the treatment arm patients for 5 years is underway as a single arm study, and control subjects that elect to crossover to treatment are being followed at 3 and 6 months postprocedure. Finally, another important limitation of this study is a lack of generalizability to the broader CLBP population who do not meet the strict clinical and radiographic criteria of this study.

      Conclusions

      The present study further defines the role of radiofrequency ablation of the BVN. We report on a large randomized controlled trial of patients with chronic LBP and type 1 or 2 Modic changes. Patients treated with RF ablation of the BVN exhibited significant improvement in ODI, VAS, SF-36, and EQ-5D-5L at 3 months. In addition, patients in the treatment arm were found to have higher satisfaction than in the control arm. This further demonstrates the role of this novel therapy in the treatment of a specific subtype of chronic LBP.

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