Early Functional Outcomes in Low Back Pain Subjects with a Novel Interspinous Fusion Device: REFINE Study 6-Month Results

Introduction

Lumbar interlaminar decompression with interspinous fixation is an established safe and effective treatment for spinal stenosis. There are many reports on the longer term success of the procedure compared to nonoperative treatments, decompressive laminectomies, and interbody fusion. The landmark SPORT trial established longer term efficacy in spinal stenosis patients with decompressive laminectomy.¹ The study also establishes early improvement trajectory as a prognosticator for longer term success. In the SPORT trial, both group’s improvements were significantly related to the initial trajectory after treatment. In other words, if the patient improved substantially immediately after treatment they tended to stay significantly improved. Two other investigations of decompression supplemented with interspinous fixation for spinal stenosis patients exhibited this same trend of early improvement predicting longer term success.^2,3

Several important distinctions are appreciated in the longitudinal analysis of these lumbar stenosis patient outcomes after minimally invasive treatments. The first distinction is the treatment’s initial trajectory of success. Greater early improvement forecasts longer term success, starting as early as 3 months.² The second distinction is the maintenance, diminishment, or continued improvement in the success of the procedure after this early period. For example, the SPORT trial improvements diminished slightly over four years; the Schmidt trial improvements were maintained over two years; and the Kumar trial improvements increased over five years.^1–3 Both distinctions are related to an important but unmet need: early maintenance of improvements in pain intensity and function are critical for durability of symptom relief. The long-term efficacy of minimally invasive treatments for low back pain is somewhat understood; however, very little information exists on the early period after surgery and its ability to set the course for long-term success.

In addition to the aforementioned studies on the interspinous spacers, there are biomechanical investigations have been conducted on the stability of both fusion and non-fusion interspinous devices, which indicate increased range of motion and destabilization associated with non-fusion interspinous spacers.^4–6 There are, however, few studies which have assessed the safety, clinical efficacy, and fusion results of standalone interspinous fixation and fusion with bone graft 84% to 92%.^7,8 These studies showed fusion in 84% to 92% of cases, in addition to 52%, 64%, and 80% reduction in ODI, NRS back and NRS leg in patients with degenerative spondylolisthesis. While the Schmidt study showed a 57.5% reduction in ODI, only 22% of patients presented with degenerative spondylolisthesis.² Thus, there are no studies which currently report safety and efficacy in similar cohorts between fusion and non-fusion interspinous fixation construct.

This study utilized the ZIP^TM MIS Interspinous Fusion System (ZIP) by Aurora Spine (Carlsbad, CA) and bone graft material. The ZIP system provides an alternative to conservative treatment for patients suffering from DDD (defined as back pain of discogenic origin with degeneration of the disc confirmed by history and radiographic studies), spondylolisthesis, spinal stenosis, trauma, and/or tumor.⁹ The system utilizes a hollow central barrel which serves as a graft chamber, and interlaminar spacer to resist compressive motions such as extension. Superior and inferior spike features on bilateral locking plates connected by the barrel, serve to rigidly engage the spinous processes of the posterior noncervical spine (T1–S1) from an interlaminar approach, thus resisting distraction motions such as flexion. This biomechanical stabilization of the spinal column facilitates indirect decompression, and bony fusion when used in conjunction with autologous bone grafting via surgical decortication of the posterior elements and the use of exogenous allograft.

The current study reports 6-month outcomes from a prospective, non-randomized, multicenter study of patients with chronic low back pain with lower extremity symptoms, which present with degenerative disc disease (DDD) and concurrent neurogenic claudication. The specific aims of the study were to evaluate the effectiveness and safety of the interspinous fusion device and bone graft material in single or two-level DDD patients.

We anticipate the clinical efficacy and safety will be comparable to published studies on the minimally invasive interspinous devices. Future data will evaluate the rate of fusion resulting from rigid interlaminar fixation with the ZIP system, which is expected to be comparable to pedicle screw fixation.

Materials and Methods

Designs and Sites

This prospective, observational, open-label, non-randomized, multicenter study was performed under Western IRB approval (#20211168). The protocol and IRB were each also approved at each of the participating sites by the local governing entity. Clinical follow-up data was collected up to 6-months post operation on patients undergoing interspinous interlaminar fusion with bone graft performed on an ambulatory basis by neurosurgeons, orthopedic surgeons, and interventional pain physicians. Voluntary written informed consent was provided by each enrolled subject. Subjects were allowed to ask questions and were given a copy of the informed consent. Subject data was de-identified for confidentiality and compliance per the Declaration of Helsinki.

Patient Population

Patients above the age of 18 years were recruited from participating sites, and enrolled in the study, if they met all the inclusion and none of the exclusion criteria. Inclusion criteria included the presence of one or two symptomatic lumbar degenerative disc disease(s) at single or adjacent levels between T1 and S1, mild to moderate spinal stenosis at the index level on MRI, with or without grade I spondylolisthesis, and the presence of neurogenic claudication.^10,11 Patients must have completed at least 6 months of non-operative treatment, having a physical function Zurich Claudication Questionnaire (ZCQ) ≥2.0 at baseline as assessment, baseline Visual Analog Scale (VAS) ≥50 mm (100-mm scale). Key exclusion criteria included prior lumbar spine surgery, and ≥ grade II spondylolisthesis on flexion and extension films with 3-mm instability.

Interventions

Upon enrollment, interspinous fixation was performed on the patient in the prone position using the ZIP device as has been previously reported.¹² Final device placement, is as shown in Figure 1. Commercial or government payer insurance authorization was received prior to the prior to the procedure.

Figure 1 Image of the Device and its Placement in the Spine. AP Radiograph of the Deployment of the Device.

Follow-Up

Imaging and history of conservative treatment were reviewed prior to enrollment, to ensure recruited patients met the inclusion criteria as previously described. The goal of enrollment with 60 months of potential follow-up was set at 100 patients. All enrolled patients were approved by the medical monitor. Upon implantation, patients were followed-up immediately postoperatively as per standard of care by site, with scheduled visits occurring at 3 and 6 months.

Endpoints

Baseline demographic information and procedural detail were captured.

Primary

Clinical efficacy was evaluated via functional and neurological outcome measures. Meaningful improvements from baseline were defined as ≥20 mm pain reduction in VAS Back during walking or standing, ≥20 mm pain reduction in VAS Leg during walking or standing, ZCQ improvement ≥0.5 in two or three domains, Oswestry Disability Index (ODI) improvement ≥10 points and no reoperations or revisions at the index level(s). Safety was evaluated via the number of adverse events (infection, bleeding, worsening pain, and hardware malfunction) and their likelihood of relation to the device or procedure, were monitored through the study, as well as reoperation or revisions at the index level.

The ODI questionnaire quantifies the level to which back or leg pain affects the patient’s ability to conduct daily physical activity, as a measure of permanent functional disability.¹³ This quantification is assessed across 10 sections, each with a total possible score of 5. The ODI is reported as a percentage of the total possible score (Table 1). The ZCQ is self-administered post-operatively, by lumbar spinal stenosis (LSS) patients. It entails 12 questions to evaluate symptom severity (I–VII), and physical function (VIII–XII), and 6 questions to evaluate overall satisfaction, over the prior month.

Table 1 ODI Assessment

Secondary

Multidimensional pain and function assessment including opioid consumption related to study related pain, health-care consumption, global impression of change relative to baseline at 6 months (PGIC), Patient Reported Outcome Measurement Information System (PROMIS) 29 v2.1, and Pain Impact Score (PIS) (calculated from the PROMIS 29), were utilized as secondary endpoints.

The PROMIS 29 is a validated 29-item profile instrument that assesses eight universal domains. Seven of these non-disease specific domains, ie, anxiety, physical function, fatigue, depression, ability to participate in social roles and activities, sleep disturbance, and pain interference, are assessed with four questions each.^14–19 The final domain of pain intensity utilizes a single 11-point numeric rating scale (NRS) from 0 to 10 (no pain to worst imaginable pain). High scores represent more of the domain being measured. Symptom-oriented domains such as anxiety, fatigue, depression, sleep disturbance, and pain interference, are negatively worded, with higher scores representing worse symptomatology. Function-oriented domains such as physical function and social participation are positively worded with higher scores representing better functioning. The PIS is a derivative of the PROMIS 29, calculated by adding the raw scores for pain intensity from 0 to 10 and pain interference from 4 to 20 along with the inverted raw score for physical function from 4 to 20. It ranges from 8 to 50 (low to high impact).

Statistical Analysis

Statistical analysis was performed utilizing IBM SPSS statistics (Chicago, Illinois). Sample sizes were calculated assuming a 5% two-sided type 1 error rate and 85% power for a one-sided non-inferiority test. The ZIP MIS group will result in clinically relevant improvements in PROMIS score if the lower bound of the 95% confidence interval does not overlap 3.5. Ninety subjects were required (5% type 1 error rate, 85% power). The sample size was increased by 10% to allow for possible attrition. This gives a sample size of 99 which was rounded up to a total of 100 study subjects. Quantitative primary and secondary outcome measures were compared to baseline using paired t-tests, with analysis of variance (ANOVA) regression utilized to identify and verify reported correlations.

Results

Upon IRB approval, enrollment began on March 21, 2021, and is currently ongoing. Twelve centers participated in this study, spanning interventional pain management and neurosurgery specialties.

Patient Population

Baseline and demographic characteristics are summarized in Table 2. Age (mean ± stdev) was 70.3 ± 11.7 years, with 62% of patients being female. Baseline VAS Back, VAS Leg, and ODI were 77, 72, and 48, respectively.

Table 2 Baseline Characteristics of 42 Subjects Reporting on at 6 Months

Patient Activity

This is an ongoing study reporting a 6-month interim analysis of safety and efficacy. Currently, there are 100 active patients, 31 are pending implant, 7 withdrew from the study after implant, and 69 are active and implanted. Forty-two are examined here, representing nearly half of the goal enrollment. See Figure 2.

Figure 2 Study-related Activity.

Surgical Information

Surgical information is shown in Table 3. The neurosurgery specialty accounted for 60% of all cases, with treatment being predominantly single-level, and performed mostly at L3-4 and L4-5. All patients returned home on the same day.

Table 3 Surgical Characteristics of 42 Subjects Reporting on at 6 Months

Clinical Outcomes

Primary clinical outcomes are shown in Table 4. An average improvement of 34 was observed in VAS Back (Figure 3), while an average improvement of 38 was observed for VAS Leg (Figure 4). Mean ODI improvement was 15 (Figure 5), and improvement in mean ZCQ was noted in all 4 measures.

Table 4 Pain and Functional Outcome Measures as Primary Endpoints at 6 Months

Figure 3 Tornado Plot of Improvement of VAS Score at 6 Months for Back.

Figure 4 Tornado Plot of Improvement of VAS Score at 6 Months for Leg.

Figure 5 Tornado Plot of Improvement of ODI Score at 6 Months.

Secondary endpoints are shown in Table 5 and Table 6. There was statistically significant improvement in all PROMIS 29 v2.1 domains and 78% of patients on PGIC exhibited improvement at 6 months.

Table 5 PROMIS 29 v 2.1 Table of Mean Improvement in Scores at 6 Months from Baseline

Table 6 PGIC Assessment for Patient Cohort and Interim Analysis at 6 Months from Baseline

Safety Analysis

Safety Outcomes are shown in Table 7. One patient had post-operative bleeding that resolved after dressing re-application, another had worsening pain after surgery which resolved without surgical intervention, and a third patient had an exacerbation of symptoms of a known comorbidity. The episodes were controlled and completely resolved.

Table 7 Adverse Events

Discussion

This study presents a 6-month interim analysis, it is active and enrolling, with a goal of 100 patients at 3 and 12 months, and up to 5 years of planned follow-up. This analysis represents the first clinical evaluation of the safety and efficacy of a standalone interspinous fixation device for the treatment of degenerative disc disease in the presence of symptomatic spinal stenosis and neurogenic claudication. Other surgical treatments utilized to treat this condition include epidural injection, decompression with laminectomy, with or without fusion, percutaneous decompression, or interspinous spacer. The interspinous spacer (ISS) is a flexible interspinous device which aims to only decompress indirectly, while the interspinous fusion (ISF) implemented in this study decompresses and stabilizes the spine while facilitating fusion. Both options were presented to the patients during prior to surgical intervention.

The data represents significant improvement in pain, of 62% and 64% in VAS back and VA leg, respectively. The ZCQ improvement was 76% and at least 2 measures improved by 0.5, while at least 5-point improvement was demonstrated in all the seven domains in the PROMIS 29v 2.1, with 78% of patient demonstrating improvement in PGIC.

Regarding safety, 40% of these cases were done under MAC sedation and none required an overnight stay. Three adverse events were noted, all of which were resolved. One had increased pain at conclusion of the procedure, one had a hospitalization for exacerbation of multiple sclerosis, and had post-operative bleeding that resolved. The mortality event was unrelated to the procedure.

Three previous clinical trials included patient-reported outcomes in a similar population at early postoperative timepoints.^1–3 The SPORT trial reported outcomes from decompressive laminectomies as early as 6 weeks. The Schmidt trial and Kumar trial reported results of decompressions accompanied by interspinous stabilization as early as 3 months.^2,3 Pain improved in both populations by over 30 points in the early 3- to 6-month timeframe. Function improved by over 20 points in the same period. Afterwards, the improvements either remain consistent or increased slightly in the case of decompression with interspinous stabilization or the improvements diminished slightly in the case of decompression alone.^1–3 Our results to date corroborate these findings, providing further evidence that minimally invasive techniques for low back pain are effective and safe. We observed pain intensity improvement of 33 points after 3 months and sustained improvement to 34 points after 6 months. We observed function improvement of 17 points after 3 months and similar improvement of 15 points after 6 months.

Limitations to the study include the relatively short term of follow up as long-term robustness has not yet been evaluated. Anesthesia use was not controlled by the protocol and was decided per patient, based on provider preference. No imaging was conducted during follow-up to evaluate structural changes, stability, or fusion. These will be evaluated at 12-month follow-up. This study was not randomized and only included patients who were approved for the procedure, being a single-arm, prospective study.

Conclusion

This 6-month interim analysis of 42% of the intended patients aimed to provide insight into the procedure’s safety and efficacy profile. Our analysis revealed that in a non-randomized design, and amidst varied anesthesia use, improvements in pain, function, and quality of life remained stable and clinically meaningful when compared to their first 90 days. Thus, suggesting sustained safety and efficacy across the interventional pain and neurosurgery specialties.