PMID- 29424676 OWN - NLM STAT- MEDLINE DCOM- 20190523 LR - 20190523 IS - 1547-5646 (Electronic) IS - 1547-5646 (Linking) VI - 28 IP - 5 DP - 2018 May TI - A multicenter, randomized, double-blind, dose-finding study of condoliase in patients with lumbar disc herniation. PG - 499-511 LID - 2017.7.SPINE161327 [pii] LID - 10.3171/2017.7.SPINE161327 [doi] AB - OBJECTIVE 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. METHODS 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. RESULTS 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 (< 100 muU/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. CONCLUSIONS 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. Clinical trial registration no.: NCT00634946 (clinicaltrials.gov). FAU - Matsuyama, Yukihiro AU - Matsuyama Y AD - 1Department of Orthopaedic Surgery, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka. FAU - Chiba, Kazuhiro AU - Chiba K AD - 2Department of Orthopaedic Surgery, Keio University School of Medicine, Tokyo. FAU - Iwata, Hisashi AU - Iwata H AD - 3Department of Orthopaedic Surgery, Nagoya Kyoritsu Hospital, Nagoya, Aichi; and. FAU - Seo, Takayuki AU - Seo T AD - 4Biostatistics & Data Management Group, Clinical Development, Research & Development Division, Seikagaku Corporation, Tokyo, Japan. FAU - Toyama, Yoshiaki AU - Toyama Y AD - 2Department of Orthopaedic Surgery, Keio University School of Medicine, Tokyo. LA - eng SI - ClinicalTrials.gov/NCT00634946 PT - Case Reports PT - Journal Article PT - Multicenter Study PT - Randomized Controlled Trial PT - Research Support, Non-U.S. Gov't DEP - 20180209 PL - United States TA - J Neurosurg Spine JT - Journal of neurosurgery. Spine JID - 101223545 RN - EC 4.2.2.20 (Chondroitin ABC Lyase) SB - IM MH - Adult MH - Chondroitin ABC Lyase/blood/*therapeutic use MH - Double-Blind Method MH - Female MH - Humans MH - *Intervertebral Disc Chemolysis MH - Intervertebral Disc Displacement/complications/diagnostic imaging/*therapy MH - Lumbar Vertebrae MH - Male MH - Pain/etiology MH - Pain Management MH - Treatment Outcome OTO - NOTNLM OT - ADR = adverse drug reaction OT - AE = adverse event OT - ALT = alanine aminotransferase OT - AUClast = area under the serum concentration-time curve from baseline to last sampling time OT - Cmax = maximum serum concentration OT - IgE = immunoglobulin E OT - LDH = lumbar disc herniation OT - ODI = Oswestry Disability Index OT - SLR = straight leg raise OT - Tmax = time to reach maximum serum concentration OT - VAS = visual analog scale OT - chemonucleolysis OT - condoliase OT - dose-finding study OT - leg pain OT - less invasive OT - lumbar disc herniation EDAT- 2018/02/10 06:00 MHDA- 2019/05/24 06:00 CRDT- 2018/02/10 06:00 PHST- 2018/02/10 06:00 [pubmed] PHST- 2019/05/24 06:00 [medline] PHST- 2018/02/10 06:00 [entrez] AID - 2017.7.SPINE161327 [pii] AID - 10.3171/2017.7.SPINE161327 [doi] PST - ppublish SO - J Neurosurg Spine. 2018 May;28(5):499-511. doi: 10.3171/2017.7.SPINE161327. Epub 2018 Feb 9.