A multicenter, randomized, double-blind, dose-finding study of condoliase in patients with lumbar disc herniation

Abstract

<jats:sec><jats:title>OBJECTIVE</jats:title><jats:p>Chemonucleolysis with condoliase has the potential to be a new, less invasive therapeutic option for patients with lumbar disc herniation (LDH). The aim of the present study was to determine the most suitable therapeutic dose of condoliase.</jats:p></jats:sec><jats:sec><jats:title>METHODS</jats:title><jats:p>Patients between 20 and 70 years of age with unilateral leg pain, positive findings on the straight leg raise test, and LDH were recruited. All eligible patients were randomly assigned to receive condoliase (1.25, 2.5, or 5 U) or placebo. The primary end point was a change in the worst leg pain from preadministration (baseline) to week 13. The secondary end points were changes from baseline in the following items: worst back pain, Oswestry Disability Index (ODI), SF-36, and neurological examination. For pharmacokinetic and pharmacodynamic analyses, plasma condoliase concentrations and serum keratan sulfate concentrations were measured. The safety end points were adverse events (AEs) and radiographic and MRI parameters. Data on leg pain, back pain, abnormal neurological findings, and imaging parameters were collected until week 52.</jats:p></jats:sec><jats:sec><jats:title>RESULTS</jats:title><jats:p>A total of 194 patients received an injection of condoliase or placebo. The mean change in worst leg pain from baseline to week 13 was −31.7 mm (placebo), −46.7 mm (1.25 U), −41.1 mm (2.5 U), and −47.6 mm (5 U). The differences were significant at week 13 in the 1.25-U group (−14.9 mm; 95% CI −28.4 to −1.4 mm; p = 0.03) and 5-U group (−15.9 mm; 95% CI −29.0 to −2.7 mm; p = 0.01) compared with the placebo group. The dose-response improvement in the worst leg pain at week 13 was not significant (p = 0.14). The decrease in the worst leg pain in all 3 condoliase groups was observed from week 1 through week 52. Regarding the other end points, the worst back pain and results of the straight leg raise test, ODI, and SF-36 showed a tendency for sustained improvement in each of the condoliase groups until week 52. In all patients at all time points, plasma condoliase concentrations were below the detectable limit (&lt; 100 μU/ml). Serum keratan sulfate concentrations significantly increased from baseline to 6 hours and 6 weeks after administration in all 3 condoliase groups. No patient died or developed anaphylaxis or neurological sequelae. Five serious AEs occurred in 5 patients (3 patients in the condoliase groups and 2 patients in the placebo group), resolved, and were considered unrelated to the investigational drug. Severe AEs occurred in 10 patients in the condoliase groups and resolved or improved. In the condoliase groups, back pain was the most frequent AE. Modic type 1 change and decrease in disc height were frequent imaging findings. Dose-response relationships were observed for the incidence of adverse drug reactions and decrease in disc height.</jats:p></jats:sec><jats:sec><jats:title>CONCLUSIONS</jats:title><jats:p>Condoliase significantly improved clinical symptoms in patients with LDH and was well tolerated. While all 3 doses had similar efficacy, the incidence of adverse drug reactions and decrease in disc height were dose dependent, thereby suggesting that 1.25 U would be the recommended clinical dose of condoliase.</jats:p><jats:p>Clinical trial registration no.: NCT00634946 (clinicaltrials.gov)</jats:p></jats:sec>

Characterization of chondroitinase-induced lumbar intervertebral disc degeneration in a sheep model intended for assessing biomaterials

“…Specifically, C-ABC has been previously evaluated for its therapeutic potential to degrade tissue fragments impinging on nerves in patients with herniated IVDs. (45) The administration of C-ABC enzyme initiates the targeted degradation of NP tissue to provide an accelerated degeneration cascade similar to conditions observed in humans as a result of increased levels of matrix metalloproteinases (MMPs) and a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) observed within increasing levels of IVDD; thus, intradiscal injection of C-ABC has been used as a method of initiating IVDD in large animals to serve as models for studying pathological mechanisms and preclinical assessments of potential therapeutics. (21), (22), (29), (30) .…”

Chemonucleolysis with Chondroitin Sulfate ABC Endolyase for Treating Lumbar Disc Herniation: Exploration of Prognostic Factors for Good or Poor Clinical Outcomes

“…Chymopapain was introduced in July 1963 and was widely used throughout Europe, North America, and Australia [8][9][10]. Following reports of severe adverse events, including fatal anaphylaxis, bleeding, and neurologic complications [11][12][13][14][15][16], the production of chymopapain (Chymodiactin® , Smith Laboratories Inc., MN, USA) was discontinued for nonscientific and commercial reasons in 2002. The first clinical study on collagenase (nucleolysin) was reported in 1981 [7].…”

“…Phase 1-3 clinical trials of condoliase were conducted in Japan. Matsuyama et al reported the results of phases 2 and 3 trials of chemonucleolysis for the treatment of LDH (Clinical trial registration no.NCT00634946) [11]. In this study, 194 patients received three different doses of condoliase (1.25, 2.5, or 5 U) or placebo injections, and the appropriate dose of injection was determined (1.25 U).…”

Two Cases of Lateral Lumbar Disc Herniation Successfully Treated with Intradiscal Condoliase Injection

“…The JOA score had improved to 21/29 points. Condoliase injected into an intervertebral disc specifically dissolves glycosaminoglycans, which constitute proteoglycans, the main component of the nucleus pulposus 6) . This restricts the proteoglycans' water-holding capacity, reducing pressure inside the intervertebral disc, lowering the pressure on the nerve root from the hernia, and improving lower extremity and low back pain 6) .…”

“…Condoliase injected into an intervertebral disc specifically dissolves glycosaminoglycans, which constitute proteoglycans, the main component of the nucleus pulposus 6) . This restricts the proteoglycans' water-holding capacity, reducing pressure inside the intervertebral disc, lowering the pressure on the nerve root from the hernia, and improving lower extremity and low back pain 6) . A previous study observed significant analgesic effects, improved lumbar function, and improved quality of life compared to a placebo in cases of protrusion-type or subligamentous-type lumbar disc herniation inside the spinal canal 7) .…”