Many interventional strategies are commonly used to treat chronic low back pain (CLBP), though few are specifically intended to target the distinct underlying pathomechanisms causing low back pain. Restorative neurostimulation has been suggested as a specific treatment for mechanical CLBP resulting from multifidus dysfunction. In this randomized controlled trial, we report outcomes from a cohort of patients with CLBP associated with multifidus dysfunction treated with restorative neurostimulation compared to those randomized to a control group receiving optimal medical management (OMM) over 1 year. RESTORE is a multicenter, open-label randomized controlled trial. Candidates were assessed for CLBP associated with multifidus dysfunction, with no indication for or history of lumbar spine surgery. Participants were randomized to either restorative neurostimulation with the ReActiv8 system or OMM. The primary endpoint was a comparison of the mean change in the Oswestry Disability Index (ODI) between the treatment and control arms at 1 year, and secondary endpoints included pain (numeric rating scale [NRS]) and health-related quality of life (EuroQol Five-Dimension [EQ-5D-5L]). A total of 203 patients, average age 47 years, and with an average 11-year history of low back pain, were included in the analysis. The primary endpoint was a statistically significant demonstration of a clinically relevant mean improvement in the Oswestry Disability Index (ODI) between restorative neurostimulation and OMM arms: ODI (−19.7 ± 1.4 vs. −2.9 ± 1.4; p < 0.001). Additionally, improvements in both the numeric rating scale (NRS) (−3.6 ± 0.2 vs. −0.6 ± 0.2; p < 0.001) and EuroQol Five-Dimension (EQ-5D-5L) (0.155 ± 0.012 vs. 0.008 ± 0.012; p < 0.001) were statistically and clinically significant in the restorative neurostimulation arm compared to the OMM arm. The RESTORE trial demonstrates that restorative neurostimulation is a safe, reversible, clinically effective, and highly durable option for patients suffering with nonoperative CLBP associated with multifidus dysfunction. This demonstration of treatment superiority over OMM through 1 year is a significant milestone in addressing a major health burden and unmet clinical need. ClinicalTrials.gov Identifier: NCT04803214. Chronic low back pain can occur as a consequence of dysfunction in the key stabilizing muscles of the spine, the multifidi. This type of low back pain is difficult to treat, with many interventions resulting in limited improvement or short-term relief for a significant proportion of patients. Despite this limitation, these approaches still represent the best available care in most practices. Restorative neurostimulation is a technique that stimulates dysfunctional multifidi, overriding muscle inhibition to improve spinal function, reduce disability, and alleviate pain. The hypothesis was that this treatment is appropriate for a specific subset of patients who have failed to respond to best available conservative and interventional care. The goal of this study was to compare the effect of restorative neurostimulation to standard-of-care interventions (optimal medical management) for patients with chronic mechanical low back pain. Patients with an average 11-year history of chronic low back pain and diagnosed with multifidus dysfunction were randomly assigned to either ongoing optimal medical management or restorative neurostimulation. At 1 year, disability, pain, and healthcare-related quality of life were assessed. Patients treated with restorative neurostimulation demonstrated significant improvements in their clinical outcomes compared to those receiving optimal medical management alone. Device-related adverse events were rare, reinforcing the safety profile of this technique. This study demonstrated that without restorative neurostimulation, patients with chronic low back pain and multifidus dysfunction have very few effective options and obtained little clinical benefit from ongoing optimal medical management. Restorative neurostimulation is an important advancement for this difficult-to-treat population.
An exploratory analysis of a randomized, double-blind, sham-controlled, phase three study. To evaluate the impact of SI-6603 (condoliase) on health-related quality of life (HRQoL)-related outcomes in patients with lumbar disk herniation (LDH)-associated radicular leg pain from the Discovery 6603 study (NCT03607838). Condoliase is a novel chemonucleolytic agent that selectively degrades chondroitin sulfate in the nucleus pulposus. Condoliase is approved in Japan for the treatment of radicular leg pain associated with LDH. Recently, the Discovery 6603 study demonstrated the efficacy and tolerability of condoliase in the United States (US). Adults with LDH and unilateral radicular leg pain were randomized to receive a single intradiscal injection of condoliase (1.25 units) or sham, followed by 52 weeks of observation. Exploratory HRQoL-related outcomes included change from baseline (CFB) in EuroQol Group 5-Dimension Quality of Life instrument, 5-Level version (EQ-5D-5L), and visual analogue scale (EQ-VAS), CFB in the 36-item Short Form Health Survey (SF-36), Patient Global Impression of Change (PGIC), Clinical Global Impression of Change (CGIC), and CFB in Work Productivity and Activity Impairment (WPAI) scores. EQ-5D-5L and SF-36 measures were assessed using a longitudinal analysis model. Of 352 randomized participants, 341 constituted the modified intention-to-treat population (condoliase: 169; sham: 172). Condoliase showed numerically greater improvements in EQ-5D-5L self-care and pain/discomfort dimensions at week 13 and week 52 compared with sham (P<0.05). The SF-36 physical component and WPAI scores numerically favored condoliase compared with sham. Patients and clinicians more frequently reported “very much improved” in overall status following condoliase treatment versus sham. Previous findings confirmed the efficacy and tolerability of condoliase for LDH management. Condoliase showed notable improvements in exploratory HRQoL-related outcomes, which were consistent across multiple patient-reported measures. Condoliase has the potential to enhance QoL and work productivity in individuals with LDH.
Prospective, multicenter, single-blind, randomized, and controlled pivotal study. Compare time-to-fusion in patients treated with P-15L (PearlMatrix TM P-15 peptide enhanced bone graft) versus local autograft over 24 months and evaluate changes in pain and quality of life at 24 months relative to baseline. P-15L, an FDA-designated breakthrough device, is a composite bone graft with P-15, a 15-amino acid polypeptide that promotes cellular adhesion, proliferation, and differentiation to support bone formation. Patients (22–80 y) with degenerative disc disease were randomized to the investigational (P-15L) or control (local autograft) group during single-level transforaminal lumbar interbody fusion (TLIF) with a PEEK cage and supplemental pedicle screw fixation. Fusion assessments occurred at 6, 12, and 24 months. Time-to-fusion was tested for superiority as compared with the control using Kaplan-Meier survival analysis. Back and leg pain were measured using the Visual Analog Scale (VAS) and quality of life was assessed using the Short Form Survey (SF-12). The analysis included 290 patients from 33 sites; 141 (48.6%) received P-15L and 149 (51.3%) received local autograft. At randomization, at least one risk factor for pseudoarthrosis (obesity, nicotine use, or diabetes) was reported in 58.9% (83/141) of the investigational group and 60.4% (90/149) of the control group. More patients in the investigational group than the control group achieved fusion at 6 months (Kaplan-Meier fusion rates 57.6% vs. 26.9%, respectively), 12 months (68.8% vs. 41.5%, respectively), and 24 months (81.1% vs. 54.9%, respectively). P-15L was statistically superior to autograft for time-to-fusion (hazard ratio=1.87, 95% CI: 1.47–2.38; P < 0.0001). There was marked improvement in VAS and SF-12 relative to baseline in both groups at 24 months. P-15L promotes statistically superior earlier time-to-fusion than local autograft in instrumented TLIF. Both treatments resulted in clinically meaningful improvements in pain and quality of life at 24 months. Level I.
Prospective, multicenter, single-blind, randomized, controlled pivotal study. To evaluate whether P-15L (PearlMatrix P-15 Peptide Enhanced Bone Graft) is noninferior in effectiveness to local autograft when applied in single-level instrumented transforaminal lumbar interbody fusion (TLIF). P-15L, an FDA-designated Breakthrough Drug-Device, is a composite drug-device combination bone graft containing P-15, a 15-amino acid polypeptide, which enhances cell binding, proliferation, and differentiation, resulting in bone formation. Skeletally mature patients, aged 22 to 80 years, with degenerative disc disease (DDD) were randomized 1:1 to P-15L (investigational) or to the local autograft (control) during single-level TLIF with a polyetheretherketone (PEEK) cage and supplemental pedicle screw fixation. The primary outcome was composite clinical success (CCS) at 24 months, defined as: no index level secondary surgical procedures; achievement of fusion; ≥15-point improvement in Oswestry low back pain disability questionnaire (ODI) from baseline; no new or worsening persistent neurological deficit relative to baseline; and no device-related serious adverse events (SAEs). A total of 290 patients were enrolled at 33 sites: 141 (48.6%) received P-15L, and 149 (51.3%) received local autograft. P-15L was noninferior ( P <0.0001) and superior ( P =0.002) to autograft with respect to CCS, with 55.5% of the investigational group achieving composite clinical success compared with 37.5% of the control group. P-15L had a 25.8% higher fusion rate as compared with autograft for the CCS at 24 months (84.3% vs. 58.5%, respectively). Device-related SAE rates were similar in both groups. P-15L was superior to local autograft in achieving clinical success at 24 months. Furthermore, P-15L produced a significantly higher fusion rate as compared with autograft. No meaningful clinical differences were found in the incidence of device-related SAEs. P-15L appears to be a safe and effective option for TLIF. Level I.
