In 1982, chymopapain was approved by the United States Food and Drug Administration as a less-invasive intermediate treatment for lumbar disc herniation (LDH), positioned between conservative treatment and surgery. Chymopapain was widely used in a large number of patients in the United States and Europe, with many studies showing an improvement of up to 80% in symptoms, and a significantly higher response rate in patients who had definite radiological evidence of nerve root compression by LDH.1 However, because of its low substrate specificity, chymopapain also acts on tissues surrounding the intervertebral disc, and coupled with lack of training of some surgeons (e.g., inappropriate patient selection or poor intradiscal injection technique), these have resulted in anaphylactic reactions or serious neurological complications (paraplegia, transverse myelitis, discitis, etc.) in rare cases. Despite more than 135,000 United States patients receiving this treatment, in 1999 the manufacturer eventually discontinued production and sale of chymopapain, thereby making it unavailable for use.2,3
Condoliase (chondroitin sulfate ABC endolyase) is a pure mucopolysaccharidase derived from Proteus vulgaris, a Gram-negative rod.4 Condoliase has high substrate specificity for chondroitin sulfate and hyaluronic acid, which are glycosaminoglycans (GAGs) of proteoglycans abundant in the nucleus pulposus of the intervertebral disc, and, unlike chymopapain, lacks protease activity.5
We already conducted a randomized, double-blind, placebo-controlled, multicenter combined phase II/III clinical study to evaluate the safety, pharmacokinetics of condoliase, and pharmacodynamics of keratan sulfate and to determine suitable therapeutic dose for later studies.6 The purpose of the present phase III study was to verify the efficacy and safety of chemonucleolysis with condoliase in patients with LDH.
MATERIALS AND METHODS
The study was a randomized, double-blind, placebo-controlled, multicenter phase III clinical trial conducted at 35 medical institutions in Japan. Patients were recruited via a rigorous selection processes and received an intradiscal injection of condoliase or placebo. The efficacy and safety of condoliase were evaluated up to 52 weeks after the injection. The study protocol was approved by the institutional review board at each study site.
All patients provided written informed consent. Patients aged 20 to 70 years were included if they had: (1) unilateral leg pain and positive straight leg raise (SLR) test (≤70°); (2) a contained LDH (i.e., protrusion or subligamentous extrusion) at L4/L5, L5/L6, or L5/S1 verified on magnetic resonance imaging (MRI); (3) neurological signs consistent with the distribution of the compressed nerve root; (4) no improvement after conservative treatment for 6 weeks or more; and (5) mean visual analogue scale (VAS) of 50 mm or more for worst leg pain on 7 consecutive days before enrolment.
Patients were excluded if they: (1) had LDH at two or more levels on MRI; (2) had a noncontained LDH (i.e., transligamentous extrusion or sequestration); (3) had a history of previous lumbar surgery; (4) had a nerve root block within 3 weeks before the time of informed consent; (5) had severe and rapidly progressive neurologic deficits (e.g., cauda equina syndrome); (6) had other lumbar spine diseases; (7) were pregnant or breast-feeding; (8) had a body mass index of 35.0 kg/m2 or more; and (9) were receiving workers’ compensation.
Randomization and Blinding
An independent organization used a minimization protocol to randomly assign all eligible patients to receive condoliase or placebo on a 1:1 basis. The stratification factors, i.e., the duration of leg pain and worst leg pain at baseline, were balanced between groups. The patients in each group were stratified into two subgroups by duration of leg pain, less than 180 days and 180 days or more; and by worst leg pain at baseline, 50 to 70 mm and more than 70 to 100 mm, because the mean VAS at baseline was 70 mm in the previous study.6 Key codes were broken after all patients remaining in the study had completed evaluations at week 13.
Both condoliase and placebo were lyophilized white powders of identical appearance in a vial, with the latter containing all components except for condoliase. Each vial was reconstituted with 1.2 mL of saline to prepare a solution for injection containing 1.25 U/mL of condoliase or placebo. There were no differences in color and viscosity between condoliase and placebo after reconstitution.
Under fluoroscopic guidance, a single 1 mL dose of condoliase or placebo was injected into the nucleus pulposus of an intervertebral disc using a 21- to 23-gauge disc puncture needle, with the patient lying in a lateral recumbent or prone position. All injections were performed by registered board-certified spine surgeons who were well trained in the intradiscal injection technique. The use of general anesthesia, contrast medium, and midline transdural puncture was prohibited.
All patients were hospitalized on the day of administration to carefully monitor the immediate safety after the injection. The patients were discharged the next day and followed up in outpatient clinics at weeks 1, 2, 4, 6, 13, 26, 39, and 52. Patients withdrawn from the study were also followed up at week 52 to determine whether they underwent lumbar disc surgery.
All patients continued to receive the same conservative treatment that they were receiving at the time of informed consent. If necessary, additional conservative treatment was allowed if pain and/or neurological symptoms were exacerbated after injection of the investigational drug (condoliase or placebo) at the discretion of the investigators. Patients who underwent nerve root blocks or surgery after treatment administration were withdrawn from the study.
The primary endpoint was the change in worst leg pain7 during the past 24 hours from baseline to week 13. Patients assessed their own pain levels before going to bed. The intensity of pain was measured on a horizontal 100 mm VAS, with 0 mm representing “no pain” and 100 mm representing the “worst pain ever experienced.” The VAS at baseline was measured on the last 7 consecutive days before patient enrolment; those from the day of administration to week 6 were consecutively measured; that at week 13 was measured on the last 7 consecutive days before observation; and those at weeks 26, 39, and 52 were measured on the day before observation.
The secondary endpoints were responder rate (percentage of patients with ≥50% improvement in worst leg pain [i.e., substantial change in pain]8) and changes from baseline up to week 52 in the following measures: worst back pain (VAS); Oswestry Disability Index (ODI)9; 36-Item Short-Form Health Survey (SF-36)10; neurologic examinations (SLR test, hypesthesia, muscle weakness, deep-tendon hyporeflexia); volumes of the intervertebral disc and herniated mass on MRI; disc height on X-rays; and any lumbar surgery performed before week 52.
The safety endpoints were adverse events (AEs), vital signs, laboratory parameters, anticondoliase antibody titers, X-rays changes (disc height, posterior intervertebral angle, vertebral translation), and MRI changes using Modic and Pfirrmann classifications.11–13 All AE data were collected until week 13. Data on leg pain, back pain, abnormal neurological findings, and imaging parameters were collected until week 52 to evaluate the long-term safety of condoliase. Imaging parameters were tabulated as frequency of the positive findings based on the following criteria; (1) 30% or more decrease in disc height; (2) posterior intervertebral angle of 5° or more; (3) vertebral translation of 3 mm or more; (4) endplate and vertebral body signal changes in Modic classification; and (5) intervertebral signal changes in Pfirrmann classification.
Measurement of Imaging Parameters
X-rays and MRIs were obtained at each study site according to the protocol provided by the central imaging facility. Acquired images were sent to, and processed and evaluated at the central imaging facility. The measurement of the volumes of the intervertebral disc and herniated mass, disc height, posterior intervertebral angle, vertebral translation, and Modic and Pfirrmann classification changes were performed using the same procedures as in our previous study.6
Based on the result of the previous study, a power analysis revealed that a sample size of 80 patients per treatment group was necessary to detect a substantial difference between the condoliase and placebo group of approximately 15 mm in the worst leg pain at week 13 with 90% power and a two-sided significance of 0.05.
Efficacy analyses were undertaken on an intention-to-treat basis in all randomized patients who received the investigational drug and had at least one postadministration efficacy assessment. The primary endpoint and secondary endpoints were analyzed using the analysis of covariance model including the baseline value and duration of leg pain as covariates. The binary secondary endpoints were analyzed using logistic regression with adjustment for the baseline value and duration of leg pain. Missing values were imputed using the last observation carried forward method. In addition, patients’ unbalanced characteristics were included as covariates in the analysis of covariance of the primary endpoint to confirm their covariate effects. Safety analyses were carried out on all randomized patients who received the investigational drug. All analyses were carried out using SAS version 9.2 (SAS Institute, Cary, NC).
The flow of the patients is shown in Figure 1. A total of 204 patients were assessed for eligibility between March 5, 2012 and February 28, 2013. Of these patients, 166 were eligible and were randomized to the two groups. Subsequently, 82 and 81 patients received an injection of condoliase and placebo, respectively. A total of 76 patients in the condoliase group and 70 patients in the placebo group completed the evaluations at week 13. The baseline characteristics of the patients are shown in Table 1. With respect to baseline characteristics, the smoking history, posterior intervertebral angle, vertebral translation, and Modic type were unbalanced between the two groups.
With respect to the primary endpoint, the mean VAS scores at baseline and week 13 were 72.4 and 22.9 mm in the condoliase group, and 74.6 and 39.2 mm in the placebo group. The changes in worst leg pain from baseline to week 13, the primary endpoint, were −49.5 mm in the condoliase group and −34.3 mm in the placebo group. The difference was −15.2 mm (95% confidence interval, −24.2 to −6.2; P = 0.001) and was statistically significant (Table 2). The difference in the degree of improvement in worst leg pain was already detectable between the two groups by week 1 and became significant by week 2, and remained significant thereafter (Figure 2). The results of the analysis of covariance revealed that the primary endpoint was not affected by the patient characteristics that were not equally distributed between the two groups.
With respect to secondary endpoints, the responder rate was significantly higher in the condoliase group (72.0% vs. 50.6%; P = 0.008) at week 13. Condoliase also provided significantly better improvements in the SLR test, ODI, and the physical component score (PCS) of SF-36 compared with placebo. These improvements were maintained until week 52. In addition, decreases in the volumes of the intervertebral disc and herniated mass, and disc height were found significantly more frequently in the condoliase group (Table 2).
The percentage of patients who underwent surgery was 9.8% in the condoliase group and 9.9% in the placebo group. In all cases, the reason for surgery was lack of efficacy.
No patient died or developed anaphylactic shock or any neurologic sequelae. No patient in the condoliase group and five patients in the placebo group dropped out from the study due to AEs. Ten serious AEs occurred in 10 patients (four in the condoliase group and six in the placebo group). All serious AEs resolved. Severe AEs were observed in six patients in the condoliase group (Table 3). One case each of serious AE (exacerbation of low back pain) and severe AE (toxic skin eruption) were considered by the investigators to be possibly related to condoliase.
Back pain occurred more frequently in the condoliase group and was observed in 36.6% of patients. Most cases of back pain occurred within a week after administration. Severity was mild to moderate in all patients, and clinical symptoms resolved or abated in most patients without treatment. Allergy-like symptoms, i.e., rash, urticaria, pruritus, and toxic skin eruption, were reported in four patients, all in the condoliase group. The symptoms occurred within 1 day after administration and all resolved with standard dermatologic treatment. Recurrence of LDH causing leg pain in the opposite side was reported in one patient in the condoliase group; however, surgical treatment was not necessary.
No significant changes were observed in vital signs or laboratory parameters. No patients had elevated serum anticondoliase immunoglobulin E (IgE) antibody titers, but one patient in the condoliase group had an elevated serum anticondoliase IgG antibody titer; however, no allergy-like symptoms were observed in this patient.
Regarding imaging findings, the incidence of Modic type 1 change and decrease of 30% or more in disc height was higher in the condoliase group (26.8% and 8.5%) compared to the placebo group (17.3% and 0%). The mean change in disc height from baseline to week 52 was significantly greater in the condoliase group than the placebo group (−17.0% vs. −8.0%). The Pfirrmann classification grades changed more frequently in the condoliase group (53.7% vs. 2.5%). There were no significant changes in the posterior intervertebral angle or vertebral translation from baseline to week 52 in both groups. No image findings were associated with clinical symptoms.
In this study, safety and efficacy of condoliase was verified in patients with LDH and this study showed consistent results in the efficacy and tolerability with previous studies.
The efficacy results showed that the change in the worst leg pain was greater in the condoliase group than in the placebo group, verifying that condoliase provided a significantly better clinical improvement than placebo. With respect to the secondary endpoints, condoliase produced significantly better improvements in SLR test, ODI, and SF-36 PCS at weeks 13 and 52, showing that condoliase was highly effective for improving neurological findings, physical function, and quality of life.
In the imaging analyses, the volumes of the herniated mass decreased significantly in the condoliase group compared with the placebo group. Condoliase may reduce the size of the intervertebral disc by degrading GAGs of proteoglycans in the nucleus pulposus, thereby reducing water content, intradiscal pressure, and in turn the herniated mass compressing the nerve root.
Back pain was the most common AE and occurred relatively early after drug administration in most patients. Intense and acute back pain (back spasm), often seen with chymopapain,14 was not reported in this study. In the condoliase group, Modic type 1 change and a decrease in disc height were observed frequently. McGirt et al15 reported a decrease in disc height of 21% and 26% at 6 months and 2 years after discectomy, similar to the decrease (17.0%) observed at 52 weeks after administration of condoliase. Ohtori et al16 reported that Modic changes were observed in 15.6% of patients during the 2 years of follow-up after discectomy. After administration of condoliase, Modic changes were observed in 28.0% of patients, a prevalence higher than that reported by Ohtori. Similar imaging findings were also observed frequently in the condoliase group in the present study; however, they were not accompanied by clinical symptoms and resulted in no clinical consequences. Therefore, we believe that the benefits from condoliase injection are greater than the risks related to imaging changes, such as Modic change and decrease in disc height. However, there are several reports that indicate association of Modic change and decrease in disc height with back pain.16–21 Therefore, further studies are needed to confirm the clinical relevance of these imaging findings after condoliase administration.
Allergy-like symptoms were observed in the condoliase group only, suggesting that any sign of hypersensitivity should be monitored carefully. Anaphylactic shock occurred in 0.5% of patients after chymopapain administration.2,22 Because condoliase is a foreign protein,4 the risk of anaphylactic shock cannot be ignored. However, no elevation in the serum level of anticondoliase IgE antibody titer was observed, and there were no cases of anaphylactic shock in the present study.
This study has several limitations. First, patients with uncontained herniation, that is, sequestration and transligamentous extrusions, were excluded from the study. Condoliase may reach the transligamentously extruded mass through the pedicle of the nucleus pulposus and exert its effect; however, both types are likely to regress spontaneously with time.23 Second, the 1-year follow-up period of this study was relatively short, and we therefore plan to follow the patients for further evaluation.
In the present study, there were no clinically significant AEs, such as paraplegia, transverse myelitis, or discitis, that were previously associated with chymopapain treatment.2,3,24 Unlike chymopapain, condoliase specifically degrades GAGs and has no protease activity.5 It has been reported that condoliase has little effect on the tissues surrounding the disc after intradiscal or intrathecal administration.25–27 Therefore, condoliase is less likely to cause symptoms related to damage of the tissues, including nerves and vessels, surrounding the disc. However, further safety information needs to be collected from a larger number of patients to fully prove its safety.
In general, LDH is treated conservatively, and surgery has been the only therapeutic option available to patients who had a poor response to conservative treatment.28,29 Invasive surgical treatments impose tremendous physical and mental burdens on patients. Thus, less invasive surgical treatments have been developed and are favored options. Chemonucleolysis with condoliase is a minimally invasive treatment of LDH not requiring general anesthesia, which is a major advantage over any surgical treatment. Condoliase administration is much less physically and mentally burdensome than surgery and should contribute to patients’ early return to normal daily and social activities.
Condoliase significantly improved symptoms, physical functions, and quality of life in patients with LDH. Condoliase was well tolerated by patients and did not cause clinically important AEs. Condoliase is a novel and potent chemonucleolytic drug for the treatment of LDH.
- At present, no chemonucleolytic drugs are available.
- Condoliase showed significantly better improvements in leg pain and other clinical end points, including the SLR test, ODI, and the PCS of SF-36 compared with placebo. These improvements were maintained until week 52.
- No clinically significant AEs were reported, including death, anaphylactic shock and neurologic sequelae in the condoliase group.
- Changes in imaging findings were frequently observed in the condoliase group than in the placebo group; however, these findings were not accompanied by any clinical symptoms.
- Condoliase significantly improved symptoms in patients with LDH and was well tolerated.
The authors thank the following participating investigators for their contributions to data acquisition: M. Yamagata, S. Ito, N. Kawakami, K. Shigenobu, M. Takemitsu, M. Shioda, E. Okada, T. Tokioka, K. Sato, F. Kato, M. Deguchi, K. Shirasawa, S. Satoh, H. Hyodo, Y. Ito, M. Takahashi, M. Kamata, A. Harada, H. Okai, T. Yonekura, H. Hashiguchi, T. Shima, M. Hoshino, N. Sha, H. Konishi, I. Shiina, N. Mamizuka, S. Isefuku, H. Sato, Y. Fujimoto, H. Katoh, A. Yoshida, S. Ishikawa, K. Chino, H. Inanami, I. Nakamura, and H. Gen.
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