P285. Radiographic predictors of instability vs composite clinical success of spondyloplasty of TLIF for degenerative spondylolisthesis. Analysis of results from a prospective FDA IDE trial

Blumenthal et al (2013) found that segmental facet joint angle (FJA) >50°, disc height (DH) >6.5mm and segmental translation (ST) >1.25mm were associated with higher rates of reoperation in patients who had decompression only, without fusion, for symptomatic degenerative spondylolisthesis (DS). An ongoing FDA IDE study (NCT03115983) is comparing spondyloplasty (decompression and dynamic sagittal tether (DST) stabilization vs decompression and transforaminal lumbar interbody fusion (TLIF) for symptomatic DS. Radiographic measures including those identified by Blumenthal may identify signals among subgroups with clinical success or failure. The purpose of this analysis is to assess composite clinical success (CCS) among spondyloplasty and TLIF subjects having a PDI. Post-hoc analysis of data from a multi-center, prospective IDE study of spondyloplasty vs TLIF for symptomatic DS (NCT03115983). A total of 299 subjects enrolled in the IDE trial of spondyloplasty (N=140) vs TLIF (N=159). Full study inclusion criteria provided at clinicaltrials.gov (NCT03115983). Primary outcome measure CCS was defined as patients meeting all of the following through 24-months: successful index implantation; 15-point improvement on the Oswestry Disability Index (ODI); no device integrity failure defined as device breakage, separation, dislocation or disassembly; no subsequent surgical intervention (SSI) at the index or adjacent segments; and no decrease in neurologic status unless attributable to a concurrent medical condition or other unrelated cause. PDI were defined as ST>1.25mm, FJA>50° or DH>6.5mm as measured on preoperative radiographs. CCS rates were calculated for each subgroup of patients having or not having each individual PDI, all PDI, any PDI or no PDI in each of the two treatment arms. Influence of each PDI was assessed using student's t-test to compare subjects with and without the PDI. Too Long Text characters = 69300 max allowed in xls 32,250. There was no identifiable relationship between any of the preoperative radiographic parameters and clinical success in either the spondyloplasty or TLIF groups. Notably, failures in the spondyloplasty group were not associated with higher preoperative mobility, disc height, anterolisthesis or FJ angle, as has been seen in decompression alone. LimiFlex Dynamic Sagittal Tether (Investigational/Not Approved), Standard of Care TLIF instrumentation and graft materials (Approved for this indication

P110. Primary outcomes of an FDA IDE trial of Spondyloplasty vs TLIF for degenerative spondylolisthesis

Durable outcome for patients with DS usually requires decompression and fusion. Spondyloplasty is an investigational procedure utilizing a dynamic sagittal tether (DST) for segmental stabilization after decompression for DS as an alternative to fusion. Evaluate propensity score (PS) adjusted outcomes comparing decompression and DST stabilization versus decompression and TLIF for symptomatic grade I DS at 2 years after surgery. Concurrently enrolled multi-center IDE trial with propensity score matching of groups. All patients had Grade I DS on a lateral radiograph at one level and spinal canal stenosis at one or two levels with ODI≥35 and VAS-leg/hip≥50. Full inclusion criteria are detailed at clinicaltrials.gov (NCT03115983). Primary outcome measure was composite clinical success (CCS) where a patient had to satisfy 5 criteria at 24-months follow-up: successful index implantation; improvement of at least 15 points on the Oswestry Disability Index (ODI); no decrease in neurologic status at 24 months compared to baseline unless attributable to a concurrent medical condition or other unrelated cause; no subsequent surgical intervention (SSI) at the index or adjacent levels; and no device integrity failure (breakage, separation/disassembly or dislocation). Secondary outcomes included individual components of the CCS. Patients were enrolled into the trial at either investigational spondyloplasty or control TLIF sites. A propensity score (PS) model was developed, achieving excellent balance between trial groups. Differences between groups were calculated using average treatment effect of the treated (ATT) weighted analyses of the PS subclasses per FDA requirements. The trial was designed as a noninferiority study, with a -12.5% noninferiority margin as tested with a 95% single sided confidence interval (CI) of the between-group difference. All 140 spondyloplasty and 125 TLIF subjects were selected into the PS model, the equivalent of randomization. Mean±SD preoperative age of the spondyloplasty/TLIF subjects was 65.8±7.7/64.5±8.9yrs, BMI 28.1±4.7/29.3±5.3kg/m2, ODI 52.6±11.9/51.7±13.5, 42.1%/29.6% male. CCS, individual component success, between-group differences and 95% and 97.5% single-sided CI are presented in the table below. The spondyloplasty group demonstrated a 15.9% higher overall success rate, with 95% CI +2.9% > -12.5%, demonstrating noninferiority. With a 97.5% single sided lower CI of +0.4%, superiority of the spondyloplasty group was also demonstrated for the primary CCS (p=0.022). The spondyloplasty group demonstrated higher success rates on each of the individual components, however none of these differences were significant. Reoperation rates (SSI) at index or adjacent levels at 24 months were 7.8% in the spondyloplasty group and 10.1% in the TLIF group. Spondyloplasty – comprising surgical decompression and segmental stabilization with a dynamic sagittal tether – demonstrated superiority over TLIF at 24 months in the treatment of symptomatic degenerative spondylolisthesis. More durable outcomes, including lower reoperation rates, is the primary motivation to add instrumented fusion to surgical decompression for DS, and in this study, the spondyloplasty group had a lower reoperation rate vs TLIF. Longer-term follow-up will demonstrated if this benefit is maintained. LimiFlex Dynamic Sagittal Tether (Investigational/Not Approved), Standard of Care TLIF instrumentation and graft materials (Approved for this indication)

207. FDA trial of decompression and dynamic sagittal tether for degenerative spondylolisthesis: 24 months clinical and radiographic follow-up

Degenerative spondylolisthesis (DS) with lumbar spinal stenosis (LSS) is commonly treated with decompression and fusion. The LimiFlex Dynamic Sagittal Tether (DST) is an investigational stabilization device for patients with DS and LSS. The purpose of this study is to assess the clinical and radiographic outcomes of decompression and DST compared to transforaminal lumbar interbody fusion (TLIF) for patients with DS and LSS. Multicenter prospective concurrently controlled study. Patients undergoing treatment (decompression and DST or TLIF stabilization) of Grade I Meyerding lumbar degenerative spondylolisthesis. Patients undergoing treatment (decompression and DST or TLIF stabilization) of Grade I Meyerding lumbar degenerative spondylolisthesis. Patients with single-level Grade I DS with LSS were enrolled in the FDA-IDE study (NCT03115983) comparing decompression with DST and decompression with TLIF. Clinical and radiographic outcomes were assessed at baseline and 6-week, 3, 6, 12 and 24-month follow-up. All propensity score (PS) selected patients who had 24-month follow-up were included in this interim analysis. Summary statistics are reported, as well as paired t-tests to assess within-group changes. At 24 months, 228 PS-selected patients (129DST/99TLIF) had clinical follow-up and 197 (117DST/80TLIF) had radiographic follow-up. Mean characteristics of DST and TLIF groupswere: age 65.5/64.1 yrs; BMI 28.1/30.5; CCI 0.43/0.41, respectively. Mean perioperative outcomes for DST/TLIF were: procedure time 112/189 min; EBL 53/232 mL; LOS 0.7/3.2 nights. A significant reduction at 24 months for mean VAS-leg/hip (79.5 to 22.9), VAS-back (66.8 to 19.0) and ODI (52.8 to 13.2) was reported for DST patients (all p < 0.01) with 91% achieving 15-point ODI improvement. TLIF patients demonstrated similar improvements for VAS-leg (80.6 to 24.4), VAS-back (68.1 to 26.1) and ODI (52.3 to 20.9) (all p < 0.01), with 80% achieving 15-point ODI improvement. While there was no difference at baseline, the DST group had lower ODI at all postoperative timepoints. Within the 24 months, 9% of each group had additional surgery at the index or adjacent level. At 24 months, the DST group had mean reductions of 1.7° ROM and 0.4mm translation in flexion/extension images compared to 3.8° and 1.0mm reductions in the TLIF group. Considering the index and adjacent segments together (IAS), the index segment accounted for 30% of IAS ROM at baseline and 27% at 24 months in the DST group compared to 29% at baseline and 13% at 24 months in the TLIF group. These results suggest that decompression with DST stabilization for spondylolisthesis can achieve significant clinical improvement as is expected with fusion, without an increase in reoperations during the 24 months postoperative period. Similarly, statistically significant improvements in patient-reported outcomes were demonstrated in each group, with lower disability scores in the DTB group at all postoperative timepoints. Imaging demonstrated no increased instability in the DST group with maintained distribution of motion between the index and adjacent segments. While these groups were PS-selected, further analyses should include quantitative comparison between groups with PS-adjusted differences per the predefined composite clinical success criteria for a definitive comparison of outcomes. LimiFlex Dynamic Sagittal Tether (Investigational/Not Approved)

24. Return to work, activities of daily living and disability improvement: twelve-month outcomes of an FDA IDE trial of decompression and tension band stabilization for degenerative spondylolisthesis

Degenerative spondylolisthesis (DS) with lumbar spinal stenosis (LSS) is commonly treated with decompression and fusion. The LimiFlex Dynamic Sagittal Tether (DST) is an investigational stabilization device for patients with DS and LSS. Assess return to work (RTW) and activities of daily living (ADL) receiving either decompression and DST stabilization (D+DST) or decompression and transforaminal lumbar interbody fusion (D+TLIF). Interim analysis from a multicenter, concurrently controlled study. Patients undergoing treatment (D+DST or D+TLIF) of Grade I Meyerding lumbar DS. Propensity score (PS) selected patients with 12-month follow-up were included. Time to RTW and activities of daily living, as well as Oswestry disability index (ODI). PS-selected IDE study subjects with 12 months of follow-up were included in this analysis. Study records queried for work status preoperatively and at 12 months, as well as time to RTW and ADL, and change in disability (Oswestry Disability Index; ODI) at 12 months vs preop. Outcomes were compared using student's t-tests. PS-selected subjects totaled 267 (136 D+DST, 131 D+TLIF). Preoperatively, 49% of D+DST and 43% of D+TLIF subjects were working (p=0.14) and 7% D+DST and 11% D+TLIF were not working due to spinal condition (NWSC) (p=0.13). At 12 months postop, 44% of D+DST and 34% of D+TLIF subjects were working (p=0.05) and 2% D+DST and 10% D+TLIF were NWSC (p<0.01). Proportion of D+DST NWSC was significantly lower 12 months postop compared to preop (p=0.02). Mean±SD RTW time for D+DST/D+TLIF subjects was 5.4±6.6/11.8±9.6 weeks (p<0.01) and return to ADL time was 5.5±6.5/10.0±9.5 weeks (p<0.01). Mean±SD reduction in disability at 12 months from baseline was 38.1±18.4 for the D+DST group and 31.8±20.7 for the D+TLIF group (p<0.01) with effect sizes of -2.1 and -1.5, respectively. The primary objective of surgery for symptomatic DS is resolution of symptoms so patients can return to their normal ADL and work. Both D+DST and D+TLIF treated patients demonstrated a significant reduction in disability at 12-month follow-up. Significantly faster RTW and ADL were observed for D+DST compared to D+TLIF patients, by an average of more than 5 weeks. The proportion of D+DST patients NWSC was significantly less than at 12 months. Results indicate a significant advantage of earlier recovery for the D+DST patients allowing earlier RTW and earlier increase in ADLs compared to D+TLIF, with similar or greater improvements in disability after one year for patients treated with decompression and stabilization for symptomatic DS. Longer-term follow-up assessment with propensity score-adjusted outcomes will demonstrate whether this advantage and long-term outcomes are durable and generalizable. This abstract does not discuss or include any applicable devices or drugs

Hypoglycemic neuronal death is triggered by glucose reperfusion and activation of neuronal NADPH oxidase

Hypoglycemic coma and brain injury are potential complications of insulin therapy. Certain neurons in the hippocampus and cerebral cortex are uniquely vulnerable to hypoglycemic cell death, and oxidative stress is a key event in this cell death process. Here we show that hypoglycemia-induced oxidative stress and neuronal death are attributable primarily to the activation of neuronal NADPH oxidase during glucose reperfusion. Superoxide production and neuronal death were blocked by the NADPH oxidase inhibitor apocynin in both cell culture and in vivo models of insulin-induced hypoglycemia. Superoxide production and neuronal death were also blocked in studies using mice or cultured neurons deficient in the p47(phox) subunit of NADPH oxidase. Chelation of zinc with calcium disodium EDTA blocked both the assembly of the neuronal NADPH oxidase complex and superoxide production. Inhibition of the hexose monophosphate shunt, which utilizes glucose to regenerate NADPH, also prevented superoxide formation and neuronal death, suggesting a mechanism linking glucose reperfusion to superoxide formation. Moreover, the degree of superoxide production and neuronal death increased with increasing glucose concentrations during the reperfusion period. These results suggest that high blood glucose concentrations following hypoglycemic coma can initiate neuronal death by a mechanism involving extracellular zinc release and activation of neuronal NADPH oxidase