Abstract
Study Design.
An exploratory analysis of a randomized, double-blind, sham-controlled, phase three study.
Objective.
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).
Summary of Background Data.
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).
Methods.
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.
Results.
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.
Conclusions.
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.
Key Words: quality of life, productivity, condoliase, chemonucleolysis, lumbar disk herniation, radicular leg pain, radiculopathy, intradiscal injection, nonsurgical, randomized clinical trial, phase 3 treatments
Lumbar disk herniation (LDH) is a common spinal condition caused by localized displacement of disk material (primarily the nucleus pulposus) beyond the normal limits of the intervertebral disk space, often resulting in nerve root compression and debilitating pain.1,2 In many cases, LDH-associated radicular leg pain (often referred to as sciatica) resolves spontaneously or through conservative symptom management strategies such as rest, physical therapy, and pain-relieving medications.3 Epidural steroid injections (ESIs) are used to provide short-to-medium term symptomatic relief in certain cases, although they are not Food and Drug Administration (FDA)-approved for this indication.4,5 Individuals with persistent pain despite nonsurgical management have limited treatment options apart from surgery, perhaps contributing to the resurgence of interest in nonsurgical alternatives such as chemonucleolysis (recently reviewed elsewhere).5–7 In addition to pain relief, optimal LDH management should include restoration or maintenance of the individual’s quality of life (QoL) and productivity.
Health-related QoL (HRQoL) is a multi-dimensional assessment of health determined by the patient’s perception of their physical, mental, and socioeconomic well-being.8 Symptoms of LDH, including radicular leg pain and low back pain, are associated with impairments in HRQoL.9 Individuals with LDH-associated radicular leg pain or lumbar radiculopathy experience worse HRQoL outcomes, increased disability, greater health care utilization, and more missed work time than those with nonspecific back pain alone.2,10–12 Patient-reported HRQoL is vital for understanding disease severity and assessing the value of treatment options that improve or resolve symptoms of LDH.
SI-6603 (condoliase; chondroitin sulfate ABC endolyase) is a novel nonproteolytic mucopolysaccharidase with high substrate specificity for degrading glycosaminoglycan components in the nucleus pulposus (primarily chondroitin sulfate).13,14 Condoliase is thought to reduce water retention in the nucleus pulposus, thus decreasing intradiscal pressure and nerve root impingement, which in turn relieves radicular leg pain.15 Supporting this proposed mechanism of action, condoliase has been shown to reduce intradiscal pressure in the lumbar spine of sheep in a dose-dependent manner.16 Condoliase was approved in Japan in 2018 based on positive findings from a phase 2/3 (NCT00634946) dose-finding study and a phase 3 study assessing the safety and efficacy of condoliase (1.25 U) versus placebo.14,17 In the Japanese phase 3 trial (N=163), treatment with a single intradiscal injection of condoliase showed significantly greater improvements in worst leg pain, and change from baseline (CFB) in average worst leg pain at week 13 (least squares mean [LSM] CFB: −49.5) versus placebo (−34.3; LSM difference: −15.2; P=0.001) and at week 52 (−54.2) versus placebo (−42.3; LSM difference: −11.9; P=0.01).17 The condoliase group also showed significantly greater improvements in the Physical Component Summary (PCS) score of the 36-item Short Form Health Survey (SF-36) versus placebo, which were sustained through the end of the study at week 52. The Japanese phase 3 trial showed that condoliase was generally well tolerated, with the most common adverse event (AE) being back pain.17
The efficacy and safety of condoliase were recently confirmed in the pivotal United States (US) phase 3 Discovery 6603 study.18 The study met its primary end point, with participants who received condoliase showing significantly greater improvements in average worst leg pain, as assessed using the visual analogue scale (VAS), at week 13 (LSM CFB: −41.7) compared with sham (−34.2; LSM difference: −7.5; 95% confidence interval [CI]: −14.1, −0.9; P=0.0263). In addition, the treatment group differences in CFB in average worst leg pain at week 52, CFB in herniation volume at week 13, and CFB in Oswestry Disability Index (ODI) score at week 13 favored condoliase versus sham. As reported in Kim et al., condoliase was well tolerated, with no related serious AEs.18 The primary analysis did not comprehensively report and discuss QoL outcomes aside from ODI. In this second publication in a planned series of findings from this multicenter trial, we evaluated the impact of condoliase on HRQoL, patient and clinician impression of change in overall status, and work productivity in patients with LDH-associated radicular leg pain using results from the US phase 3 Discovery 6603 study.
MATERIALS AND METHODS
Study Design
The Discovery 6603 study (NCT03607838) was a randomized, double-blind, sham-controlled study conducted in the United States to evaluate the efficacy and safety of a single intradiscal injection of condoliase (1.25 U) compared with sham in individuals with LDH-associated radicular leg pain. Adults 30 to 70 years of age with the chief complaint of unilateral radicular leg pain, contained posterolateral LDH, demonstrable nerve root impingement as assessed by magnetic resonance imaging (MRI), and inadequate improvement in pain despite ≥6 weeks of conservative treatment were randomized 1:1 to receive condoliase or sham injections and observed for 52 weeks, with visits occurring at weeks 1, 2, 4, 6, 13, 26, 39, and 52. As detailed by Kim et al.,18 individuals who had previously undergone a lumbar surgery or intradiscal therapy at the affected level of the lumbar spine were excluded from the study; lumbar operation, percutaneous lumbar nucleotomy, or intradiscal lumbar therapies for the treatment of LDH symptoms were prohibited throughout the study. The administration procedures for condoliase and sham injections were comparable, but the sham injection did not require the preparation of a solution or penetration of the intervertebral disk.18 The study protocol was approved by the Institutional Review Board or Ethics Committee for each participating institution, and all participants provided written informed consent. The trial was conducted in accordance with International Council for Harmonisation guidelines and the ethical principles of the Declaration of Helsinki.
Endpoints
Supportive HRQoL endpoints included CFB in EuroQol group 5-Dimension Quality of Life instrument, 5-Level version (EQ-5D-5L) score and VAS (EQ-VAS) score assessed at week 13 and week 52. The EQ-5D-5L consists of five dimensions (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression) ranked from level 1 (no problems) to level five (extreme problems), and an EQ-VAS component, in which the patient ranks their health on a scale from 0 (worst imaginable health) to 100 (best imaginable health).19 The SF-36 questionnaire consists of eight scales that contribute to the PCS and Mental Component Summary (MCS) scores (normalized with a mean of 50 and an SD of 10).20 Specifically, the PCS score is comprised of the physical functioning, role-physical, bodily pain, and general health scales, while the MCS score includes the vitality, social functioning, role-emotional, and mental health scales.21 The CFB in SF-36 was assessed at week 0, week four, and at all remaining timepoints. The Patient Global Impression of Change (PGIC) and Clinical Global Impression of Change (CGIC) consist of a 7-point Likert scale ranging from “very much improved” to “very much worse.” The PGIC asks patients to rate their perceived change in overall status since beginning the treatment. For the CGIC, the clinician rates the patient’s change in overall clinical status since beginning the treatment. The PGIC and CGIC scores were assessed at week two and all remaining timepoints. The Work Productivity and Activity Impairment (WPAI) questionnaire measures the impact of lumbosacral radiculopathy on work and daily activities using four domains: activity impairment, impairment while working (ie, presenteeism), overall work impairment, and work time missed (ie, absenteeism). WPAI scores are expressed as percentages, and a negative change indicates improvement. WPAI was assessed at week 13 and week 52.22
Statistical Analysis
All analyses were performed on the modified intention-to-treat (mITT) population, which constituted all randomized participants who received the study injection. The mITT population was analyzed according to randomized treatment. A longitudinal analysis model was used for the analysis of CFB in EQ-5D-5L, EQ-VAS, and SF-36; it considered the baseline value as a fixed effect, as well as categorical effects of treatment, study week, and treatment by study week interaction. A difference-in-proportions Z test was used to compare the responder categories (ie, two highest categories) of the PGIC and CGIC scores, and the overall counts and percentages for responders/nonresponders were reported with 95% Wald CIs. Participants with missing values for the PGIC and CGIC scores were considered nonresponders. WPAI scores were analyzed using an analysis of covariance (ANCOVA) model that included the baseline value and duration of leg pain as covariates. All analyses were exploratory in nature and not α-controlled; therefore, P values do not denote statistical significance.
RESULTS
Baseline Characteristics
As detailed in Kim et al.,18 among 807 screened individuals, 352 were randomized 1:1 to receive condoliase (n=176) or sham (n=176). Of these, 311 participants completed up to week 13 (condoliase n=156; sham n=155), and 265 participants completed the study through week 52 (condoliase n=133; sham n=132). The mITT population consisted of 341 participants (condoliase: 169; sham: 172). To adhere to the ITT principle, two participants who were randomized to receive condoliase but instead received sham were analyzed as part of the condoliase group. Overall, the majority of participants were White (81.8%), and the average age was 46.3 years (Table 1). Participant baseline characteristics were generally similar across treatment groups. The condoliase group was more frequently male, was less likely to have an occupation requiring heavy labor, was more likely to be employed, and reported slightly less “activity impairment” and “impairment while working” versus the sham group (Table 1).
TABLE 1.
Baseline Participant Characteristics
| Condoliase (n=169) | Sham (n=172) | |
|---|---|---|
| Age, mean (SD), yr | 46.8 (9.4) | 45.9 (9.8) |
| Sex, n (%) | ||
| Male | 95 (56.2) | 89 (51.7) |
| Female | 74 (43.8) | 83 (48.3) |
| Race, n (%) | ||
| White | 137 (81.1) | 142 (82.6) |
| Black/African American | 18 (10.7) | 14 (8.1) |
| Asian | 6 (3.6) | 9 (5.2) |
| American Indian/Alaska Native | 1 (0.6) | 0 |
| Other | 7 (4.1) | 7 (4.1) |
| Ethnicity | ||
| Hispanic/Latino, n (%) | 47 (27.8) | 43 (25.0) |
| Not Hispanic or Latino, n (%) | 122 (72.2) | 129 (75.0) |
| Screening BMI, mean (SD), kg/m2 | 29.0 (4.9) | 28.4 (4.9) |
| Smoking status, n (%) | ||
| Never smoked | 106 (62.7) | 103 (59.9) |
| Past smoker | 34 (20.1) | 36 (20.9) |
| Current smoker | 29 (17.2) | 33 (19.2) |
| Currently employed, n (%) | ||
| Yes | 133 (78.7) | 127 (73.8) |
| No | 36 (21.3) | 45 (26.2) |
| Occupation, n (%) | ||
| Light labor | 130 (76.9) | 123 (71.5) |
| Heavy labor | 39 (23.1) | 49 (28.5) |
| Worst leg pain, mean (SD), VAS | 71.99 (9.6) | 71.82 (9.8) |
| ODI score, mean (SD) | 48.2 (11.8) | 49.1 (11.9) |
| Days since onset of current radicular leg pain, median (min, max) | 139.0 (31, 350) | 153.5 (44, 351) |
| EQ-5D-5L, mean (SD) | ||
| Mobility | 2.6 (0.8) | 2.6 (0.9) |
| Self-care | 2.2 (0.8) | 2.2 (0.9) |
| Usual activities | 2.8 (0.9) | 2.9 (0.8) |
| Pain/discomfort | 3.4 (0.6) | 3.5 (0.6) |
| Anxiety/depression | 1.7 (0.8) | 1.8 (0.9) |
| EQ-VAS | 68.6 (16.9) | 68.8 (17.6) |
| SF-36, mean (SD) | ||
| PCS | 34.3 (6.2) | 34.2 (6.9) |
| MCS | 48.1 (9.7) | 48.6 (10.5) |
| WPAI, mean (SD) | ||
| Activity impairment | 60.9 (22.2) | 65.6 (17.3) |
| Impairment while working | 56.1 (24.8) | 61.6 (18.3) |
| Overall work impairment | 14.2 (18.9) | 11.3 (15.0) |
| Work time missed | 13.7 (18.9) | 10.7 (15.1) |
BMI indicates body mass index; EQ-5D-5L, EuroQol group 5-Dimension Quality of Life instrument, 5-Level version; EQ-VAS, EuroQol-visual analogue scale; MCS, Mental Component Summary; ODI, Oswestry Disability Index; PCS, Physical Component Score; SF-36, 36-item Short Form Health Survey; VAS, visual analogue scale; WPAI, Work Productivity and Activity Impairment.
Quality of Life
At both week 13 and week 52, the condoliase group showed numerically greater improvements in all EQ-5D-5L dimensions versus sham with the exception of the anxiety/depression dimension. Notably, the condoliase group showed greater improvements in the self-care and pain/discomfort dimensions at week 13 (Fig. 1A) versus sham, and these differences persisted until week 52 (P<0.05; Fig. 1B). At week 13, LSM CFB in EQ-VAS started to favor condoliase (LSM CFB condoliase: 10.4; sham: 8.2; LSM difference: 2.1; 95% CI: −1.5, 5.8; P=0.2482), with the treatment effect increasing through week 52 compared with sham (LSM CFB condoliase: 14.0; sham: 10.5; LSM difference: 3.6; 95% CI: 0.0, 7.1; P=0.0487).
Figure 1.
CFB in EQ-5D-5L at week 13 (A) and week 52 (B). CFB indicates change from baseline; CI, confidence interval; EQ-5D-5L, EuroQol group 5-Dimension Quality of Life instrument, 5-Level version; EQ-VAS, EuroQol-visual analogue scale; LSM, least squares mean.
On the SF-36, the condoliase group showed numerically greater improvements versus sham in the PCS score at all measured timepoints, most notably at Week 6 (P=0.0228) and Week 52 (P=0.0341; Fig. 2A). There were no notable differences in MCS scores (Fig. 2B).
Figure 2.
CFB in SF-36 PCS (A) and MCS (B). CFB indicates change from baseline; CI, confidence interval; LSM, least squares mean; MCS, mental component summary; PCS, physical component summary; SF-36, 36-item Short Form Health Survey.
Participant-reported and Clinician-reported Global Impression of Change
Regarding PGIC scores, participants in the condoliase group more frequently reported that their overall status was “very much improved” at week 13 and week 52 versus the sham group (Fig. 3). Comparatively, sham-treated participants more frequently reported “no change” or “minimally worse” at week 13 and “no change” or “much worse” at week 52. A greater percentage of participants who received condoliase versus sham were considered responders based on PGIC scores at weeks 6, 13, and 52 (P<0.05; Table 2).
Figure 3.
PGIC Score: Percentage of participants in each category at week 13 and week 52. PGIC indicates Patient Global Impression of Change.
TABLE 2.
PGIC and CGIC Responder Rates
| Condoliase (n=169) n (%) | Sham (n=172) n (%) | Treatment effect % (95% CI)a | P b | |
|---|---|---|---|---|
| PGIC respondersc | ||||
| Week 2 | 54 (32.0) | 43 (25.0) | 7 (−2.6, 16.5) | 0.1548 |
| Week 4 | 69 (40.8) | 63 (36.6) | 4.2 (−6.1, 14.5) | 0.4259 |
| Week 6 | 95 (56.2) | 70 (40.7) | 15.5 (5.0, 26.0) | 0.0042 |
| Week 13 | 103 (60.9) | 81 (47.1) | 13.9 (3.4, 24.3) | 0.0103 |
| Week 26 | 101 (59.8) | 85 (49.4) | 10.3 (−0.2, 20.9) | 0.0551 |
| Week 39 | 97 (57.4) | 81 (47.1) | 10.3 (−0.2, 20.8) | 0.0569 |
| Week 52 | 103 (60.9) | 82 (47.7) | 13.3 (2.8, 23.8) | 0.0139 |
| CGIC respondersc | ||||
| Week 2 | 56 (33.1) | 44 (25.6) | 7.6 (−2.1, 17.2) | 0.1255 |
| Week 4 | 73 (43.2) | 61 (35.5) | 7.7 (−2.6, 18.1) | 0.1439 |
| Week 6 | 90 (53.3) | 67 (39.0) | 14.3 (3.8, 24.8) | 0.0081 |
| Week 13 | 104 (61.5) | 74 (43.0) | 18.5 (8.1, 28.9) | 0.0006 |
| Week 26 | 106 (62.7) | 83 (48.3) | 14.5 (4.0, 24.9) | 0.0072 |
| Week 39 | 101 (59.8) | 82 (47.7) | 12.1 (1.6, 22.6) | 0.0252 |
| Week 52 | 107 (63.3) | 82 (47.7) | 15.6 (5.2, 26.1) | 0.0037 |
Wald CI is reported.
P value is based on the difference-in-proportions Z test. Analyses were not alpha-controlled.
Responders included “very much improved” and “much improved” categories.
CGIC indicates Clinical Global Impression of Change; CI, confidence interval; PGIC, Patient Global Impression of Change.
For CGIC scores, clinicians more frequently rated the overall status of patients who received condoliase as “very much improved” or “much improved” at week 13 and week 52 versus sham (Fig. 4). Clinicians reported “no change” more frequently for participants in the sham-treated group compared with the condoliase-treated group at week 13 and week 52. According to CGIC scores, a greater percentage of participants were considered responders beginning at week 6 and throughout the duration of the study versus sham (P<0.05).
Figure 4.
CGIC Score: Percentage of participants in each category at week 13 and week 52. CGIC indicates Clinical Global Impression of Change.
Work Productivity
All four domains of the WPAI questionnaire favored the condoliase group at week 13 and week 52 compared with the sham group (Fig. 5A, B). While the treatment group differences were modest, the percent impairment while working domain showed the greatest improvement versus sham, which was maintained to week 52.
Figure 5.
CFB in WPAI at week 13 (A) and week 52 (B). CFB indicates change from baseline; CI, confidence interval; LSM, least squares mean; WPAI, Work Productivity and Activity Impairment.
DISCUSSION
The phase 3 Discovery 6603 study demonstrated the efficacy of condoliase in significantly improving average worst leg pain in adults with LDH, consistent with two previous Japanese clinical trials.14,17,18 Supporting the clinical efficacy results, the current HRQoL analysis showed that treatment with condoliase was associated with notable improvements in physical health (eg, SF-36 PCS, EQ-5D-5L pain/discomfort) across multiple measures of HRQoL and modest improvements in work productivity. Further, both patients and clinicians reported favorable changes in overall status more frequently following condoliase treatment versus sham. While the research in this area is still lacking, this work helps elucidate the impact of nonsurgical treatments for LDH on HRQoL.
Condoliase was associated with consistent and durable improvements in physical health across several assessments of HRQoL. Specifically, the condoliase group showed positive changes in the EQ-5D-5L self-care and pain/discomfort dimensions versus sham, which were maintained for one year following condoliase treatment. Correspondingly, patients treated with condoliase reported greater improvements in the physical component of the SF-36 (ie, PCS). The magnitude of improvement for condoliase versus sham in EQ-5D-5L mobility, self-care, and pain/discomfort domains (week 52 difference in LSM CFB: 0.2 in each domain) is considered clinically meaningful based on a reported minimal clinically important difference (MCID) of 0.17 to 0.2 for these domains in other orthopedic conditions.23 In addition, the magnitude of improvement for condoliase versus sham in SF-36 PCS (difference: 2.4) is comparable to the generally accepted MCID of 3 points.20,24,25
These results corroborate previous findings from the phase 2/3 and phase 3 Japanese clinical trials showing a treatment effect of condoliase on the SF-36 PCS. While the trend in SF-36 PCS improvements with condoliase (vs. placebo) did not achieve significance in the Japanese phase 2/3 trial,14 the Japanese phase 3 trial found that condoliase treatment resulted in significantly greater improvements in SF-36 PCS versus placebo at weeks 13 and 52.17 Consistent with the Japanese phase 3 study,17 the impact of condoliase on the mental component of the SF-36 (ie, MCS) was minimal. Traditional SF-36 scoring methods have been shown to inflate SF-36 MCS scores in orthopedic patient populations due to the assumption that the physical component and mental component are not correlated,20 which may contribute to the lack of treatment effect observed with condoliase.
Patients more frequently reported their overall status as “very much improved” following condoliase treatment versus sham, indicating that patients derive meaningful benefits from condoliase. PGIC score is considered a broad indicator of meaningful change over time in patients with chronic pain.26 Consistent with patients’ perceptions of treatment benefit, clinicians were also more likely to report their patient’s overall status as “very much improved” following condoliase versus sham treatment. While we did not directly assess patient satisfaction with treatment, a recent observational study reported high levels of treatment satisfaction with condoliase. Two years after receiving condoliase for radicular leg pain, 80% of patients were “satisfied” with their treatment and 85% “recommended” treatment with condoliase.27
We assessed the impact of condoliase on paid and unpaid work using the well-validated WPAI instrument.22,28 Overall, participants who received condoliase reported less work impairment than those who received sham treatment. The greatest treatment effect was seen for impairment while working, a measure of work presenteeism, in which the condoliase group showed less impairment in work performance versus sham at week 13 and week 52. Condoliase was also associated with a reduction in absenteeism versus sham, as measured by the percentage of work time missed due to LDH-associated radicular leg pain. To our knowledge, this is the first study to directly assess the impact of condoliase on work productivity outcomes. While the treatment effects were modest, these findings suggest that condoliase treatment could accelerate the return to work or lessen work impairment in some patients.
There is limited literature available on the impact of LDH treatments on QoL outcomes. Discectomy is associated with rapid improvements in QoL during the first year after surgery.29,30 A small number of studies have examined the impact of ESIs on HRQoL in patients with LDH. A retrospective longitudinal study comparing the impact of ESIs versus discectomy on HRQoL outcomes showed significantly greater improvements in the majority of the SF-36 domains following lumbar discectomy compared with ESI, including physical function, vitality, and social functioning.31 Interestingly, longer LDH symptom duration before treatment appears to be associated with worse HRQoL outcomes, regardless of whether the treatments were operative or nonoperative. An analysis of participants enrolled in the Spine Patient Outcomes Research Trial (SPORT) revealed that individuals with a shorter duration of symptomatic LDH (<6 mo) experienced greater improvements in physical health according to the SF-36 scales for bodily pain and physical functioning compared with those with symptoms lasting >6 months following either surgery or conservative treatment.32 In addition, a recent study evaluating the long-term effects of discectomy on HRQoL showed that individuals with symptoms for >12 months (vs. ≤12 mo) before the procedure reported worse scores on the EQ-5D-5L and EQ-VAS 2 decades after the initial surgery.30 Collectively, these findings suggest that timely treatment for LDH-related symptoms may be optimal for patients in maintaining long-term HRQoL.
The QoL analyses presented here have several strengths and limitations. As a double-blind randomized trial, neither the patients nor the investigators making evaluations are aware of the treatment received, which mitigates potential bias and placebo effect. Since the main objective of the US phase 3 Discovery 6603 study was to determine the efficacy of condoliase in improving average worst leg pain, the study was not adequately powered to determine statistical significance in the observed QoL assessments. Although exploratory, the majority of HRQoL outcomes favored condoliase versus sham and appeared to be meaningful to patients. While widely used in clinical trials for pain, PGIC and CGIC measures have not been as extensively validated as the SF-36 and EQ-5D-5L instruments. In addition, the patient population in this study had a median duration of radicular leg pain of ~5 months. Since long symptom duration is considered a negative prognostic indicator, it is unknown if this impacted the findings. Longer-term follow-up studies evaluating the impact of condoliase on HRQoL, work-related presenteeism/absenteeism, and treatment satisfaction are needed to better understand the value of treatment for individuals with LDH.
CONCLUSION
Supplementing previous findings on the efficacy of condoliase in improving worst leg pain, here we report that condoliase was associated with improvements in HRQoL-related outcomes, more favorable patient and clinician impressions of change in overall status, and modest benefits in measures of work productivity. This analysis adds to the limited data available on the HRQoL impact of nonsurgical LDH.
Key Points
SI-6603 (condoliase), a novel chemonucleolytic agent with high substrate specificity for chondroitin sulfate in the nucleus pulposus, has demonstrated efficacy and safety for the treatment of radicular leg pain in individuals with LDH.
In this exploratory analysis of the US phase three Discovery study, condoliase was associated with improvements in multiple patient-reported measures of HRQoL versus sham.
Patients with LDH who received condoliase showed numerically greater improvements versus sham in the SF-36 physical component score and the self-care and pain/discomfort dimensions of the EQ-5D-5L.
Both patients and clinicians more frequently reported the overall status of the patient as “very much improved” following condoliase versus sham.
In addition to improving worst leg pain, treatment with condoliase may positively impact patient quality of life and work productivity, further supporting its therapeutic potential as a nonsurgical treatment option for LDH.
ACKNOWLEDGMENTS
The authors thank the Medical writing support and publication assistance provided by SCIENT Health Care Communications (Cedar Knolls, NJ, USA).
Footnotes
The study protocol was approved by the Institutional Review Board (IRB) or Ethics Committee (EC) for each participating institution, and all participants provided written informed consent. The procedures set out in the study protocol were designed to ensure that the sponsor and the investigator abided by Good Clinical Practice and International Council for Harmonisation guidelines and directives, in compliance with the ethical principles described in the current revision of the Declaration of Helsinki and applicable local regulatory requirements and law.
This study was supported by Seikagaku Corporation (regulatory sponsor).
K.E.M. has been a speaker for Relievant, Inc. K.D.K. has received an institutional grant and consulting fees from Seikagaku Corporation, royalties from Zimmer Biomet and Precision Spine, Consulting fees from ZimVie and Globus, has served on the board of directors of Molecular Matrix, and has received grants from Medtronic, AbbVie, InVivo Therapeutics, Empirical Spine, Stryker, Cerapedics, and Mesoblast. A.P. has received consulting fees from and served on a scientific advisory board for Lexicon Pharmaceuticals. E.Z. is a salaried employee of Rho, a contract research organization that has been compensated for various work related to the conduct and analysis of this trial. K.C. is an employee of Ferring Pharmaceuticals. T.S. and J.W. are employees of Seikagaku Corporation. The remaining authors, J.R., K.D.C., and P.B.G., report no conflicts of interest.
Contributor Information
Kevin E. Macadaeg, Email: KMacadaeg@indianaspinegroup.com.
Kee D. Kim, Email: kdkim@ucdavis.edu.
Pragya B. Gupta, Email: pbgupta@aptcmd.com.
Jose Rivera, Email: joser1774@gmail.com.
Anand Patel, Email: anand.patel@conquestresearch.com.
Kinsuk Chauhan, Email: kinsuk.chauhan@ferring.com.
Jun Watanabe, Email: jun.watanabe@seikagaku-na.com.
Takayuki Seo, Email: takayuki.seo@seikagaku.co.jp.
Evan Zucker, Email: Evan_Zucker@rhoworld.com.
Kenneth Candido, Email: kdcandido1@gmail.com.
References
- 1. Kreiner DS, Hwang SW, Easa JE, et al. An evidence-based clinical guideline for the diagnosis and treatment of lumbar disc herniation with radiculopathy. Spine J. 2014;14:180–191. [DOI] [PubMed] [Google Scholar]
- 2. Vialle LR, Vialle EN, Suarez Henao JE, et al. Lumbar disc herniation. Rev Bras Ortop. 2010;45:17–22. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3. Schoenfeld AJ, Weiner BK. Treatment of lumbar disc herniation: evidence-based practice. Int J Gen Med. 2010;3:209–214. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4. Zhang J, Zhang R, Wang Y, et al. Efficacy of epidural steroid injection in the treatment of sciatica secondary to lumbar disc herniation: a systematic review and meta-analysis. Front Neurol. 2024;15:1406504. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5. Beall DP, Kim KD, Macadaeg K, et al. Treatment gaps and emerging therapies in lumbar disc herniation. Pain Physician. 2024;27:401–413. [PubMed] [Google Scholar]
- 6. Awadalla AM, Aljulayfi AS, Alrowaili AR, et al. Management of lumbar disc herniation: a systematic review. Cureus. 2023;15:e47908. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7. Schol J, Ambrosio L, Tamagawa S, et al. Enzymatic chemonucleolysis for lumbar disc herniation-an assessment of historical and contemporary efficacy and safety: a systematic review and meta-analysis. Sci Rep. 2024;14:12846. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8. Centers for Disease Control and Prevention . Measuring healthy days: population assessment of health-related quality of life. Updated November 2000. Accessed November 5, 2024. https://stacks.cdc.gov/view/cdc/6406/cdc_6406_DS1.pdf
- 9. Wong T, Patel A, Golub D, et al. Prevalence of long-term low back pain after symptomatic lumbar disc herniation. World Neurosurg. 2023;170:163–73 e1. [DOI] [PubMed] [Google Scholar]
- 10. Konstantinou K, Hider SL, Jordan JL, et al. The impact of low back-related leg pain on outcomes as compared with low back pain alone: a systematic review of the literature. Clin J Pain. 2013;29:644–654. [DOI] [PubMed] [Google Scholar]
- 11. Hider SL, Whitehurst DG, Thomas E, et al. Pain location matters: the impact of leg pain on health care use, work disability and quality of life in patients with low back pain. Eur Spine J. 2015;24:444–451. [DOI] [PubMed] [Google Scholar]
- 12. Samant P, Tawde P, Tawde DN. Understanding how patients with lumbar radiculopathy make sense of and cope with their symptoms. Cureus. 2024;16:e56987. [DOI] [PMC free article] [PubMed] [Google Scholar] [Retracted]
- 13. Hamai A, Hashimoto N, Mochizuki H, et al. Two distinct chondroitin sulfate ABC lyases. An endoeliminase yielding tetrasaccharides and an exoeliminase preferentially acting on oligosaccharides. J Biol Chem. 1997;272:9123–9130. [DOI] [PubMed] [Google Scholar]
- 14. Matsuyama Y, Chiba K, Iwata H, et al. A multicenter, randomized, double-blind, dose-finding study of condoliase in patients with lumbar disc herniation. J Neurosurg Spine. 2018;28:499–511. [DOI] [PubMed] [Google Scholar]
- 15. Matsuyama Y, Chiba K. Condoliase for treatment of lumbar disc herniation. Drugs Today (Barc). 2019;55:17–23. [DOI] [PubMed] [Google Scholar]
- 16. Sasaki M, Takahashi T, Miyahara K, et al. Effects of chondroitinase ABC on intradiscal pressure in sheep: an in vivo study. Spine (Phila Pa 1976). 2001;26:463–468. [DOI] [PubMed] [Google Scholar]
- 17. Chiba K, Matsuyama Y, Seo T, et al. Condoliase for the treatment of lumbar disc herniation: a randomized controlled trial. Spine (Phila Pa 1976). 2018;43:E869–E876. [DOI] [PubMed] [Google Scholar]
- 18. Kim KD Ahadian F Hassanzadeh H, et al. A phase 3, randomized, double-blind, sham-controlled trial of SI-6603 (condoliase) in patients with radicular leg pain associated with lumbar disc herniation. Spine J. 2024;24:2285–2296. [DOI] [PubMed] [Google Scholar]
- 19. van Hout B, Janssen MF, Feng YS, et al. Interim scoring for the EQ-5D-5L: mapping the EQ-5D-5L to EQ-5D-3L value sets. Value Health. 2012;15:708–715. [DOI] [PubMed] [Google Scholar]
- 20. Laucis NC, Hays RD, Bhattacharyya T. Scoring the SF-36 in orthopaedics: a brief guide. J Bone Joint Surg Am. 2015;97:1628–1634. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21. Ware JE, Kosinski M, Keller SD. Construction of summary measures. In: SF-36 Physical and Mental Health Summary Scales: A User’s Manual. 1993;3:2. [Google Scholar]
- 22. Reilly MC, Zbrozek AS, Dukes EM. The validity and reproducibility of a work productivity and activity impairment instrument. Pharmacoeconomics. 1993;4:353–365. [DOI] [PubMed] [Google Scholar]
- 23. Langenberger B, Schrednitzki D, Halder AM, et al. Predicting whether patients will achieve minimal clinically important differences following hip or knee arthroplasty. Bone Joint Res. 2023;12:512–521. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24. Frendl DM, Ware JE, Jr. Patient-reported functional health and well-being outcomes with drug therapy: a systematic review of randomized trials using the SF-36 health survey. Med Care. 2014;52:439–445. [DOI] [PubMed] [Google Scholar]
- 25. Copay AG, Glassman SD, Subach BR, et al. Minimum clinically important difference in lumbar spine surgery patients: a choice of methods using the Oswestry Disability Index, Medical Outcomes Study questionnaire Short Form 36, and pain scales. Spine J. 2008;8:968–974. [DOI] [PubMed] [Google Scholar]
- 26. Dworkin RH, Turk DC, Wyrwich KW, et al. Interpreting the clinical importance of treatment outcomes in chronic pain clinical trials: IMMPACT recommendations. J Pain. 2008;9:105–121. [DOI] [PubMed] [Google Scholar]
- 27. Banno T Hasegawa T Yamato Y, et al. Condoliase therapy for lumbar disc herniation -2 year clinical outcome. J Orthop Sci. 2022. [DOI] [PubMed]
- 28. Zhang W, Bansback N, Boonen A, et al. Validity of the work productivity and activity impairment questionnaire--general health version in patients with rheumatoid arthritis. Arthritis Res Ther. 2010;12:R177. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 29. Farzanegan G, Alghasi M, Safari S. Quality-of-life evaluation of patients undergoing lumbar discectomy using Short Form 36. Anesth Pain Med. 2011;1:73–76. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 30. Roiha M, Marjamaa J, Siironen J, et al. Favorable long-term health-related quality of life after surgery for lumbar disc herniation in young adult patients. Acta Neurochir (Wien). 2023;165:797–805. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 31. Pazhouhande F, Bazmi S, Taheri R, et al. Comparing quality of life: discectomy surgery versus epidural corticosteroid injection for lumbar disc herniation. World Neurosurg. 2024;185:e1309–e1320. [DOI] [PubMed] [Google Scholar]
- 32. Rihn JA, Hilibrand AS, Radcliff K, et al. Duration of symptoms resulting from lumbar disc herniation: effect on treatment outcomes: analysis of the Spine Patient Outcomes Research Trial (SPORT). J Bone Joint Surg Am. 2011;93:1906–1914. [DOI] [PMC free article] [PubMed] [Google Scholar]