Lumbar Disc Herniation
Conditions
Keywords
Lumbar disc herniation, Radiculopathy, Sciatica, Intradiscal injection, Chemonucleolysis
Brief summary
This study is to evaluate the effectiveness of a single-dose intervertebral disc injection of SI-6603 in subjects with lumbar disc herniation (LDH)
Interventions
DRUGSI-6603
SI-6603 will be injected into an intervertebral disc.
DRUGSham injection
The injection will be performed without needle placement into an intervertebral disc.
Sponsors
Seikagaku Corporation
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
30 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
* Subjects with single-level LDH (L4-L5 or L5-S1 (or L5-L6)) with clear, demonstrable nerve root impingement as assessed by magnetic resonance imaging (MRI) and clinical symptoms corresponding to position of the impaired nerve root. * Subjects with radiculopathy/radicular leg pain in the unilateral leg for 6 weeks or more but 1 year or less. * Subjects with positive result of Straight Leg Raise (SLR) test (≤70°) only on the ipsilateral leg having chief complaint of radiculopathy * Subjects with inadequate improvement in pain caused by LDH despite 6 weeks or more of conservative treatment.
Exclusion criteria
* Subjects who have 2 or more lumbar disc herniations as assessed by MRI. * Subjects who have undergone a lumbar operation, lumbar percutaneous nucleotomy, or lumbar intradiscal therapies at the affected level of lumbar spine. * Subjects who have received block procedure (e.g., spinal injection, epidural injection or nerve block) for treatment of LDH, oral or injectable corticosteroids within 28 days prior to randomization. * Subjects who have received opioids or cannabis by any route of administration, local anesthesia to the back, buttock, or posterior/lateral aspects of the affected leg within 7 days prior to randomization. * Subjects with a body mass index (BMI) ≥40. * Subjects who are receiving compensation according to the Workers' Compensation Act or are involved in personal injury litigation due to a lumbar-related injury.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline to Week 13 in Average Worst Leg Pain Score During the Past 24 Hours Over the Previous 7 Days | baseline and 13 weeks | The primary endpoint was the change from baseline to Week 13 in average worst leg pain score during the past 24 hours over the previous 7 days, as assessed by 100 mm Visual Analog Scale (VAS). VAS is a pain assessment tool with 0 mm representing an absence of pain, and 100 mm representing the worst pain patients have ever experienced. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline to Week 52 in Average Worst Leg Pain Score During the Past 24 Hours Over the Previous 7 Days | baseline and 52 weeks | One of the key secondary endpoints was the change from baseline to Week 52 in average worst leg pain score during the past 24 hours over the previous 7 days, as assessed by 100 mm Visual Analog Scale (VAS). VAS is a pain assessment tool with 0 mm representing an absence of pain, and 100 mm representing the worst pain patients have ever experienced. |
| Change From Baseline to Week 13 in Herniation Volume | baseline and 13 weeks | One of the key secondary endpoints was change from baseline to Week 13 in herniation volume. Herniation volumes were assessed with MRI by a central imaging facility. |
| Change From Baseline to Week 13 in Oswestry Disability Index (ODI) Score | baseline and 13 weeks | One of the key secondary endpioints was change from baseline to Week 13 in Oswestry Disability Index (ODI) score. The ODI questionnaire is designed to provide information as to how the patient's back (or leg) pain affects their ability to manage in everyday life. A higher score on the ODI indicates a more severe disability. The final index score is calculated as a percentage, with 0% indicating no disability and 100% indicating highest disability. |
Countries
United States
Participant flow
Recruitment details
Sixty sites screened at least 1 subject, and 41 of these sites enrolled at least 1 subject. The first participant was enrolled in November 2018 and the last participant was enrolled in March 2022.
Pre-assignment details
A total of 807 subjects were screened for enrollment. Of the 352 subjects randomized in the study, 176 were randomized to the SI-6603 group and 176 were randomized to the sham control group. Study drug was received by 169 SI-6603 subjects, and 172 subjects underwent sham control. The reasons for discontinuation from the study before injection were 'withdrawal of consent' (4), 'failure to meet randomization criteria' (3), 'other' (3) and 'physician decision' (1).
Participants by arm
| Arm | Count |
|---|---|
| SI-6603 Condoliase: 1.25U, intradiscal injection, one time
For patients in the active treatment group, a volume of 1.0 mL was administered into the intervertebral disc in a single dose. | 169 |
| Sham Sham injection
For patients in the control group, a solution was not prepared, and the needle was not placed in the intervertebral disc. | 172 |
| Total | 341 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 2 | 2 |
| Overall Study | Change of mind | 0 | 1 |
| Overall Study | Due to work | 1 | 0 |
| Overall Study | Failure to meet randomization criteria | 1 | 2 |
| Overall Study | Lack of Efficacy | 14 | 20 |
| Overall Study | Litigation | 0 | 1 |
| Overall Study | Lost to Follow-up | 6 | 11 |
| Overall Study | Physician Decision | 2 | 0 |
| Overall Study | Pregnancy | 1 | 0 |
| Overall Study | Protocol Violation | 1 | 0 |
| Overall Study | Temperature excursion for study drug | 0 | 1 |
| Overall Study | Withdrawal by Subject | 13 | 8 |
Baseline characteristics
| Characteristic | SI-6603 | Sham | Total |
|---|---|---|---|
| Age, Continuous | 46.8 years STANDARD_DEVIATION 9.36 | 45.9 years STANDARD_DEVIATION 9.84 | 46.3 years STANDARD_DEVIATION 9.6 |
| Body Mass Index (BMI) | 29.0 kilograms per square meter STANDARD_DEVIATION 4.92 | 28.4 kilograms per square meter STANDARD_DEVIATION 4.86 | 28.7 kilograms per square meter STANDARD_DEVIATION 4.89 |
| Days of Onset of Current Leg Pain | 161.9 days STANDARD_DEVIATION 83.57 | 172.2 days STANDARD_DEVIATION 79.65 | 167.1 days STANDARD_DEVIATION 81.66 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 47 Participants | 43 Participants | 90 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 122 Participants | 129 Participants | 251 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Herniation Site L4-L5 | 70 Participants | 71 Participants | 141 Participants |
| Herniation Site L5-S1 | 99 Participants | 101 Participants | 200 Participants |
| Occupation Heavy labor | 39 Participants | 49 Participants | 88 Participants |
| Occupation Light labor | 130 Participants | 123 Participants | 253 Participants |
| ODI score | 48.2 percentage of disability STANDARD_DEVIATION 11.77 | 49.1 percentage of disability STANDARD_DEVIATION 11.85 | 48.7 percentage of disability STANDARD_DEVIATION 11.8 |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 6 Participants | 9 Participants | 15 Participants |
| Race (NIH/OMB) Black or African American | 18 Participants | 14 Participants | 32 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 2 Participants | 3 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 6 Participants | 5 Participants | 11 Participants |
| Race (NIH/OMB) White | 137 Participants | 142 Participants | 279 Participants |
| Sex: Female, Male Female | 74 Participants | 83 Participants | 157 Participants |
| Sex: Female, Male Male | 95 Participants | 89 Participants | 184 Participants |
| Smoking History Current smoker | 29 Participants | 33 Participants | 62 Participants |
| Smoking History Never smoked | 106 Participants | 103 Participants | 209 Participants |
| Smoking History Past smoker | 34 Participants | 36 Participants | 70 Participants |
| Worst Back Pain (VAS) | 53.73 mm STANDARD_DEVIATION 25.25 | 52.45 mm STANDARD_DEVIATION 25.261 | 53.08 mm STANDARD_DEVIATION 25.227 |
| Worst Leg Pain (VAS) | 71.99 mm STANDARD_DEVIATION 9.554 | 71.82 mm STANDARD_DEVIATION 9.751 | 71.91 mm STANDARD_DEVIATION 9.64 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1 / 167 | 0 / 174 |
| other Total, other adverse events | 91 / 167 | 62 / 174 |
| serious Total, serious adverse events | 7 / 167 | 6 / 174 |
Outcome results
Primary
Change From Baseline to Week 13 in Average Worst Leg Pain Score During the Past 24 Hours Over the Previous 7 Days
The primary endpoint was the change from baseline to Week 13 in average worst leg pain score during the past 24 hours over the previous 7 days, as assessed by 100 mm Visual Analog Scale (VAS). VAS is a pain assessment tool with 0 mm representing an absence of pain, and 100 mm representing the worst pain patients have ever experienced.
Time frame: baseline and 13 weeks
Population: Modified intention-to-treat population
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| SI-6603 | Change From Baseline to Week 13 in Average Worst Leg Pain Score During the Past 24 Hours Over the Previous 7 Days | -41.7 units on a scale | Standard Error 2.38 |
| Sham | Change From Baseline to Week 13 in Average Worst Leg Pain Score During the Past 24 Hours Over the Previous 7 Days | -34.2 units on a scale | Standard Error 2.36 |
p-value: 0.026395% CI: [-14.1, -0.9]Mixed Models Analysis
Secondary
Change From Baseline to Week 13 in Herniation Volume
One of the key secondary endpoints was change from baseline to Week 13 in herniation volume. Herniation volumes were assessed with MRI by a central imaging facility.
Time frame: baseline and 13 weeks
Population: Modified intention-to-treat population
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| SI-6603 | Change From Baseline to Week 13 in Herniation Volume | -103.8 mm^3 | Standard Error 10.74 |
| Sham | Change From Baseline to Week 13 in Herniation Volume | -78.1 mm^3 | Standard Error 10.79 |
p-value: 0.09295% CI: [-55.7, 4.2]Mixed Models Analysis
Secondary
Change From Baseline to Week 13 in Oswestry Disability Index (ODI) Score
One of the key secondary endpioints was change from baseline to Week 13 in Oswestry Disability Index (ODI) score. The ODI questionnaire is designed to provide information as to how the patient's back (or leg) pain affects their ability to manage in everyday life. A higher score on the ODI indicates a more severe disability. The final index score is calculated as a percentage, with 0% indicating no disability and 100% indicating highest disability.
Time frame: baseline and 13 weeks
Population: Modified intention-to-treat population
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| SI-6603 | Change From Baseline to Week 13 in Oswestry Disability Index (ODI) Score | -29.6 percentage of disability | Standard Error 1.38 |
| Sham | Change From Baseline to Week 13 in Oswestry Disability Index (ODI) Score | -25.4 percentage of disability | Standard Error 1.38 |
p-value: 0.033695% CI: [-8, -0.3]Mixed Models Analysis
Secondary
Change From Baseline to Week 52 in Average Worst Leg Pain Score During the Past 24 Hours Over the Previous 7 Days
One of the key secondary endpoints was the change from baseline to Week 52 in average worst leg pain score during the past 24 hours over the previous 7 days, as assessed by 100 mm Visual Analog Scale (VAS). VAS is a pain assessment tool with 0 mm representing an absence of pain, and 100 mm representing the worst pain patients have ever experienced.
Time frame: baseline and 52 weeks
Population: Modified intention-to-treat population
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| SI-6603 | Change From Baseline to Week 52 in Average Worst Leg Pain Score During the Past 24 Hours Over the Previous 7 Days | -51.2 units on a scale | Standard Error 2.4 |
| Sham | Change From Baseline to Week 52 in Average Worst Leg Pain Score During the Past 24 Hours Over the Previous 7 Days | -44.7 units on a scale | Standard Error 2.41 |
p-value: 0.055895% CI: [-13.2, 0.2]Mixed Models Analysis