Efficacy and Safety of Allogeneic Mesenchymal Precursor Cells With and Without Hyaluronic Acid for Treatment of Chronic Low Back Pain: A Prospective, Randomized, Double Blind, Concurrent-Controlled 36-Month Study.

Abstract

Background context: Low back pain (LBP) associated with degenerative disc disease (DDD) is a serious condition resulting in significant morbidity, disability, and reduced quality of life for millions of people each year. Patients who fail to improve with conservative/non-invasive treatments including physical therapy and non-opioid analgesic medications have limited options, which include opioid analgesics with their associated significant risks; epidural steroid injections with limited supporting evidence; or surgical interventions such as spine fusion or artificial disc replacement. A safe, minimally invasive, non-opioid treatment that provides prolonged improvement in pain, function, and quality of life is needed for such patients.

Purpose: Evaluate the efficacy and safety of a single injection of mesenchymal precursor cells (MPCs) with or without hyaluronic acid (HA) compared to an intradiscal saline injection through 36 months follow-up in subjects with chronic low back pain (CLBP) associated with moderate DDD (mDDD).

Study design/setting: A prospective, multicenter, randomized, double-blind, concurrent-controlled study conducted at 49 clinical sites.

Subject sample: A total of 404 subjects with CLBP associated with mDDD at one level from L1 to S1 received MPCs without HA (MPC), MPCs with HA (MPC+HA), or saline control (control) treatment.

Outcome measures: Subjects were clinically and radiographically evaluated at 1, 3, 6, 12, 18, 24, and 36 months post-injection. Clinical evaluation included adverse events, neurologic evaluation, laboratory tests, LBP intensity measured by Visual Analog Scale (VAS), Oswestry Disability Index (ODI) and EQ-5D-5L Index. Radiographic assessments used Magnetic Resonance (MR) imaging and X-ray imaging studies.

Methods: The primary efficacy endpoint was a composite responder analysis for overall treatment success at both 12 and 24 months that was comprised of:[1] at least a 50% reduction from baseline in low back pain VAS score (average pain over 24 hours);[2] at least a 15-point decrease from baseline in ODI score; and[3] no adjudicated post-treatment interventions at the treated level. To assess superiority, a Bayesian analysis used a probability threshold of 0.9875. Additional analyses were performed on a pre-specified subpopulation of subjects with CLBP duration at baseline less than the median baseline duration of 68 months (CLBPLTM). Statistical assessments included least squares (LS) mean, LS mean change from baseline (CFB) using the mixed model for repeated measures (MMRM) and categorical responder analyses using stratified Cochran Mantel Haenszel row means score test with p<0.05 defined as statistically significant. This study was conducted under a US Food and Drug Administration (FDA) Investigational New Drug (IND) application sponsored and funded by Mesoblast.

Results: All treatment groups showed substantial improvement from baseline in LS Mean LBP and ODI. The primary efficacy endpoint for the trial did not reach significance for either treatment group compared to control in all subjects. Furthermore, none of the secondary endpoints showed a significant difference between treatment and control in all subjects. While the primary and secondary responder efficacy endpoints were not reached, MPC+HA significantly reduced LS mean LBP compared to control at 12 and 24 months in all subjects. The results observed in all subjects were enhanced for MPC+HA and MPC in the pre-specified CLBPLTM subgroup with MPC+HA having significantly greater reduction in LBP at all time points compared to control and MPC having significantly greater reduction in LBP at 6, 12 and 36 months. In the CLBPLTM subgroup, MPC+HA also showed significantly greater proportion of pain responders at 12, 24 and 36 compared to control. MPC+HA also showed significantly greater function improvement at 12 and 18 months compared to control in the CLBPLTM subgroup. Furthermore, MPC+HA subjects in the CLBPLTM subgroup showed significantly greater improvement in quality of life (QOL) compared to control at 12, 24 and 36 months. MPC+HA baseline opioid users had greater reduction in daily average morphine equivalent dose (MED) compared to control at 6 through 36 months. Furthermore, significantly more MPC+HA baseline opioid users (27.8%) were not taking opioids at 36 months compared to (7.8%) control. The injection procedure and MPC treatment were well tolerated with no appreciable differences in Treatment Emergent Adverse Events (TEAEs). No Serious Adverse Events (SAEs) were related to the treatment or procedure. The number of subjects that received post-treatment interventions (PTI) at the treated level were comparable among groups.

Conclusions: While the primary and secondary efficacy endpoints were not met in all subjects, MPC+HA treatment showed a significant reduction in pain compared to control that was enhanced in subjects with CLBP duration less than 68 months. Intra-discal injection of MPC+HA is a minimally invasive non-opioid therapy that appears to be safe and demonstrates reduction in pain through 24 months compared to control with enhanced results in subjects with mDDD that have had CLBP less than 68 months.