FDA Investigational Device Exemption Research Articles

Cervical Disk Arthroplasty: Updated Considerations of an Evolving Technology.

For years, anterior cervical diskectomy and fusion has been considered the benchmark for patients with cervical radiculopathy/myelopathy. However, concerns regarding adjacent segment pathology have promoted the popularity of cervical disk arthroplasty (CDA) with its motion-preserving properties. To replicate the natural cervical disk's six degrees of freedom and compressibility in cervical spine implants, designers need to carefully consider the level of constraint for stability and material selection. Recent CDA designs have incorporated strategies to facilitate unrestricted or semirestricted motion, deploying various articulating components and materials with distinct wear and compressibility properties. To optimize outcomes, patient selection considering additional degeneration of the cervical spine is critical. Clinical long-term studies have been reported in industry-funded FDA investigational device exemption and nonindustry-funded data for one-level and two-level CDA. There are limited data available on three-level and four-level CDA. Adverse events such as heterotopic ossification, osteolysis, migration, subsidence, and failure have been described, where analysis from explanted devices yields insight into in vivo wear and impingement performance. CDA has shown short-term cost advantages, such as decreased procedural expenses. Nonetheless, long-term analysis is necessary to assess possible economic tradeoffs. Advancements in designs may lead to improved implant longevity while evidence-based decision making will guide and responsibly manage the rapid advancement in CDA technology.

The fragility index and reverse fragility index of FDA investigational device exemption trials in spinal fusion surgery: a systematic review.

FDA investigational device exemption (IDE) studies are considered a gold standard of assessing safety and efficacy of novel devices through RCTs. The fragility index (FI) has emerged as a means to assess robustness of statistically significant study results and inversely, the reverse fragility index (RFI) for non-significant differences. Previous authors have defined results as fragile if loss to follow up is greater than the FI or RFI. The aim of this study was to assess the FI, RFI, and robustness of data supplied by IDE studies in spinal surgery. This was a systematic review of the literature. Inclusion criteria included randomized controlled trials with dichotomous outcome measures conducted under IDE guidelines between 2000 and 2023. FI and RFI were calculated through successively changing events to non-events until the outcome changed to non-significance or significance, respectively. The fragility quotient (FQ) and reverse fragility quotient (RFQ) were calculated by dividing the FI and RFI, respectively, by the sample size. Thirty-two studies met inclusion criteria with a total of 40 unique outcome measures; 240 outcomes were analyzed. Twenty-six studies reported 96 statistically significant results. The median FI was 6 (IQR: 3-9.25), and patients lost to follow up was greater than the FI in 99.0% (95/96) of results. The average FQ was 0.027. Thirty studies reported 144 statistically insignificant results and a median RFI of 6 (IQR: 4-8). The average RFQ extrapolated was 0.021, and loss to follow up was greater than the RFI in 98.6% (142/144) of results. IDE studies in spine surgery are surprisingly fragile given their reputations, large sample sizes, and intent to establish safety in investigational devices. This study found a median FI and RFI of 6. The number of patients lost to follow-up was greater than FIand RFI in 98.8% (237/240) of reported outcomes. FQ and RFQ tell us that changes of two to three patients per hundred can flip the significance of reported outcomes. This is an important reminder of the limitations of RCTs. Analysis of fragility in future studies may help clarify the strength of the relationship between reported data and their conclusions.

FLASH radiotherapy for the treatment of symptomatic bone metastases in the thorax (FAST-02): protocol for a prospective study of a novel radiotherapy approach

BackgroundFLASH therapy is a treatment technique in which radiation is delivered at ultra-high dose rates (≥ 40 Gy/s). The first-in-human FAST-01 clinical trial demonstrated the clinical feasibility of proton FLASH in the treatment of extremity bone metastases. The objectives of this investigation are to assess the toxicities of treatment and pain relief in study participants with painful thoracic bone metastases treated with FLASH radiotherapy, as well as workflow metrics in a clinical setting.MethodsThis single-arm clinical trial is being conducted under an FDA investigational device exemption (IDE) approved for 10 patients with 1–3 painful bone metastases in the thorax, excluding bone metastases in the spine. Treatment will be 8 Gy in a single fraction administered at ≥ 40 Gy/s on a FLASH-enabled proton therapy system delivering a single transmission proton beam. Primary study endpoints are efficacy (pain relief) and safety. Patient questionnaires evaluating pain flare at the treatment site will be completed for 10 consecutive days post-RT. Pain response and adverse events (AEs) will be evaluated on the day of treatment and on day 7, day 15, months 1, 2, 3, 6, 9, and 12, and every 6 months thereafter. The outcomes for clinical workflow feasibility are the occurrence of any device issues as well as time on the treatment table.DiscussionThis prospective clinical trial will provide clinical data for evaluating the efficacy and safety of proton FLASH for palliation of bony metastases in the thorax. Positive findings will support the further exploration of FLASH radiation for other clinical indications including patient populations treated with curative intent.RegistrationClinicalTrials.gov NCT05524064.

A prospective study of lumbar facet arthroplasty in the treatment of degenerative spondylolisthesis and stenosis: cost-effective assessment from the Total Posterior Spine system (TOPSTM) IDE Study: 2-year model revision and sensitivity analyses based on 305 subjects

BACKGROUND CONTEXTA previous cost-effectiveness analysis published in 2022 found that the Total Posterior Spine (TOPSTM) system was dominant over transforaminal lumbar interbody fusion (TLIF). This analysis required updating to reflect a more complete dataset and pricing considerations. PURPOSETo evaluate the cost-effectiveness of TOPSTM system as compared with TLIF based on an updated and complete FDA investigational device exemption (IDE) data set. STUDY DESIGN/SETTINGCost-utility analysis of the TOPSTM system compared to TLIF. PATIENT SAMPLEA multicenter, FDA IDE, randomized control trial (RCT) investigated the efficacy of TOPSTM compared to TLIF with a current population of n=305 enrolled and n=168 with complete 2-year follow-up. OUTCOME MEASURESCost and quality adjusted life years (QALYs) were calculated to determine our primary outcome measure, the incremental cost-effectiveness ratio. Secondary outcome measures included: net monetary benefit as well at willingness-to-pay (WTP) thresholds. METHODSThe primary outcome of cost-effectiveness is determined by incremental cost-effectiveness ratio. A Markov model was used to simulate the health outcomes and costs of patients undergoing TOPSTM or TLIF over a 2-year period. alternative scenario sensitivity analysis, one-way sensitivity analysis, and probabilistic sensitivity analysis were conducted to assess the robustness of the model results. RESULTSThe updated base case result demonstrated that TOPSTM was immediately and longitudinally dominant compared with the control with an incremental cost-effectiveness ratio of −9,637.37 $/QALY. The net monetary benefit was correspondingly $2,237, both from the health system's perspective and at a WTP threshold of 50,000 $/QALY at the 2-year time point. This remained true in all scenarios tested. The Alternative Scenario Sensitivity Analysis suggested cost-effectiveness irrespective of payer type and surgical setting. To remain cost-effective, the cost difference between TOPSTM and TLIF should be no greater than $1,875 and $3,750 at WTP thresholds of $50,000 and 100,000 $/QALY, respectively. CONCLUSIONSThis updated analysis confirms that the TOPSTM device is a cost-effective and economically dominant surgical treatment option for patients with lumbar stenosis and degenerative spondylolisthesis compared to TLIF in all scenarios examined.

Prospective, multicenter clinical trial comparing the M6-C compressible cervical disc with anterior cervical discectomy and fusion for the treatment of single-level degenerative cervical radiculopathy: 5-year results of an FDA investigational device exemption study

BACKGROUND CONTEXTVarious total disc replacement (TDR) designs have been compared to anterior cervical discectomy and fusion (ACDF) with favorable short and long-term outcomes in FDA-approved investigational device exemption (IDE) trials. The unique design of M6-C, with a compressible viscoelastic nuclear core and an annular structure, has previously demonstrated favorable clinical outcomes through 24 months. PURPOSETo evaluate the long-term safety and effectiveness of the M6-C compressible artificial cervical disc and compare to ACDF at 5 years. STUDY DESIGNProspective, multicenter, concurrently and historically controlled, FDA-approved IDE clinical trial. PATIENT SAMPLESubjects with one-level symptomatic degenerative cervical radiculopathy were enrolled and received M6-C (n=160) or ACDF (n=189) treatment as part of the IDE study. Safety outcomes were evaluated at 5 years for all subjects. The primary effectiveness endpoint was available at 5 years for 113 M6-C subjects and 106 ACDF controls. OUTCOME MEASURESThe primary endpoint of this analysis was composite clinical success (CCS) at 60 months. Secondary endpoints were function and pain (neck disability index, VAS), physical quality of life (SF-36, SF-12), safety, neurologic, and radiographic assessments. METHODSPropensity score subclassification was used to control for selection bias and match baseline covariates of the control group to the M6-C subjects. Sixty-month CCS rates were estimated for each treatment group using a generalized linear model controlling for propensity score. RESULTSAt 5 years postoperatively, the M6-C treatment resulted in 82.3% CCS while the ACDF group showed 67.0% CCS (superiority p=.013). Secondary endpoints indicated that significantly more M6-C subjects achieved VAS neck and arm pain improvements and showed maintained or improved physical functioning on quality-of-life measures compared to baseline assessments. The M6-C group-maintained flexion-extension motion, with significantly greater increases from baseline disc height and disc angle than observed in the control group. The rates of M6-C subsequent surgical interventions (SSI; 3.1%) and definitely device- or procedure-related serious adverse events (SAE failure; 3.1%) were similar to ACDF rates (SSI=5.3%, SAE failure=4.8%; p>.05 for both). CONCLUSIONSSubjects treated with the M6-C artificial disc demonstrated superior 5-year achievement of clinical success when compared to ACDF controls. In addition, significantly more subjects in the M6-C group showed improved pain and physical functioning scores than observed in ACDF subjects, with no difference in reoperation rates or safety outcomes.

Technical Infrastructure for Clinical Translation of Electron FLASH

For safe clinical translation of electron FLASH, hardware tools for real-time beam control and software tools for treatment planning are necessary. The purpose of this study is to prototype high-throughput hardware for real-time beam control, along with accurate beam modeling of a modern clinical Linac configured to deliver FLASH dose-rates. For real-time beam current monitoring, a beam current transformer (BCT) was initially coupled to a fast digitizer and its linearity was established by varying dose per pulse. The radiation pulse width was modified, and this change was measured using the BCT. The BCT was then used to measure the variability of dose per pulse and pulse width due to a mistuned linear accelerator system. Next, the BCT was interfaced with a field programmable gate array (FPGA) which provides the ability for high-throughput and deterministic control of the Linac based on dose accumulation. For beam modeling, the program, TOol for PArticle Simulation (TOPAS), was used to obtain beam parameters by using Bayesian optimization of the beam energy, source size, angular, and energy spread via comparison of simulated and representative dose profiles. The beam model would then be employed to calculate 3D dose distribution in a CT scan of a 3D-printed anatomically realistic mouse phantom. The area under the current-time curve from the BCT exhibited excellent linearity (response = 12.80 nC/Gy) up to 2.5 Gy/Pulse (R2 = 0.99). The peak beam current for the electron FLASH beam was measured to be ∼10 mA for an instantaneous dose-rate of ∼5×105 Gy/s. The measured radiation pulse width agreed with the expected value (3.7 μs). The pulse width was then shortened and the measurement by the BCT indicated pulse widths of 1.8 μs and 0.5 μs corresponding to 0.7 Gy/pulse and 0.3 Gy/pulse, respectively. The beamline exhibited a ramp-up in dose per pulse and pulse width when using the automatic frequency controller (AFC). For the first pulse, the dose delivered was ∼0.1-0.3 Gy and the pulse width was 0.6 μs. The output stabilized to nominal values of dose and pulse width after 3-4 pulses. This ramp-up was mitigated by manually tuning the RF resonance with the AFC disabled, after which the BCT exhibited constant output and pulse width. The beam modeling work is in progress. We demonstrated that a BCT can provide real-time measurement of per-pulse output suitable as input for FLASH beam control based on dose accumulation. The next steps are to quantify the accuracy of the dose control mechanism with the FPGA-based hardware. Potential failure modes will be identified and mitigated in parallel with the development of the hardware. A 3D-printed mouse phantom has been constructed to facilitate beam modeling work for treatment planning (in progress). On completion of this work, it is expected that we will have key infrastructure elements needed to move towards an eventual FDA investigational device exemption for clinical trials.

Validation of a 12-color flow cytometry assay for acute myeloid leukemia minimal/measurable residual disease detection.

Acute myeloid leukemia (AML) minimal/measurable residual disease (MRD) by multicolor flow cytometry is a complex laboratory developed test (LDT), challenging for implementation. We share our experience in the validation of a 12-color AML MRD flow cytometry assay to meet stringent regulatory requirements. We worked under the guidelines of the CLSI HL62 publication, illustrated the details of the validation process that was tailored to uniqueness of AML MRD, and tested its clinical validity in 61 patients. The "trueness" was determined by correlating with concurrent molecular genetic testing and follow-up bone marrow examinations. Under assay specificity, we shared the details of panel design, analysis, and criteria for interpretation and reporting. The assay accuracy was assessed by testing known positive and negative samples and correlating with molecular genetic testing and follow-up bone marrow examination. The limit of detection (LOD) and limit of quantification (LOQ) were validated to a level between 0.01% and 0.1%, varied from the leukemia-associated immunophenotypes (LAIP) and the numbers of events obtained for analysis. Assay linearity, precision and carry over studies all met acceptable criteria. In the clinical validity test, the concordance was 93%, specificity 98% and sensitivity 83%. The most challenging aspects of the assay were the discrimination of pre-leukemic cells (persistent clonal hematopoiesis) or underlying myelodysplastic clones from AML MRD with immunophenotypic switch or subclone selection. The validation met all criteria and obtained FDA IDE (investigational device exemption) approval. This study provides ample technical and professional details in setting up the AML MRD flow cytometry assay and illustrates through the example of the "fit for purpose" validation process. We also highlight the need for further characterization of abnormal blasts bearing the potential for AML relapse.

Abstract OT1-12-02: Preliminary report of the PRECISION Trial (Profiling Early Breast Cancer for Radiotherapy Omission): A Phase II Study of Breast-Conserving Surgery Without Adjuvant Radiotherapy for Favorable-Risk Breast Cancer

Abstract Background: Breast conserving surgery (BCS) is typically followed by adjuvant radiotherapy (RT) based on several landmark trials demonstrating improvements in disease control and survival. Since completion of these historical trials, the advent of molecular subtyping has revealed that breast cancer is not a single disease entity, but rather a class of cancers with differential risk profiles. We evaluated whether RT could be safely omitted following BCS for patients with the most favorable subtype as defined by the Prosigna PAM50 assay. Methods: We conducted a multicenter prospective single-arm cohort study with IRB approval and an FDA investigational device exemption (IDE). Eligible patients were women 50 to 75 years of age (inclusive) who had undergone BCS revealing tumors ≤2cm in size, that were estrogen or progesterone receptor positive (HR+), HER2 negative, grade 1-2, node negative (N0), with negative excision margins (no ink on tumor). Intent to take endocrine therapy was required. Upon registration, tumors were submitted for central Prosigna testing and those with Risk of Recurrence (ROR) score ≤40 were deemed eligible for the investigational omission of RT. The primary endpoint was the 5-year locoregional recurrence rate (LRR). Anticipating a total of 345 RT-omitting patients to enroll over 3.5 years, the study was designed with 90% power to exclude a 5-year LRR of 5% using a one-sample exponential test with one-sided type I error of 0.025. Results: From 2016 to 2020, 671 patients were registered from 13 centers, inclusive of affiliated regional network sites. Of these, 382 patients had a ROR Score ≤40 and opted to forego RT, comprising the main intention-to-treat (ITT) study population. Median age was 65 years (range 50 to 75), and median tumor size was 0.9 cm (range 0.1 to 2.0 cm). At a median follow-up of 26.9 months, 12 events were observed: 4 patients had ipsilateral in-breast recurrences, 7 had contralateral breast cancers, and 1 developed an unrelated melanoma. There were no regional-nodal or distant recurrences. The 2-year cumulative rate of LRR was 0.3% (95% CI: 0 – 1.0%). Of the 4 ipsilateral breast recurrences, 2 were in the same quadrant as the original primary tumor. Conclusion: In this preliminary report of the PRECISION trial, patients 50-75 years of age undergoing BCS and endocrine therapy for pT1N0 HR+ HER2-negative breast cancer with ROR score ≤40 had exceedingly low rates of LRR in the absence of adjuvant RT at a median follow-up of 26.9 months. Additional follow-up is required to determine whether these favorable results are durable. Citation Format: Lior Z. Braunstein, Julia Wong, Deborah A. Dillon, Yu-Hui Chen, Paul Catalano, Oren Cahlon, Mahmoud B. El-Tamer, Rachel Jimenez, Atif Khan, Carmen Perez, Rinaa Punglia, Ron Shiloh, Laura Warren, David Wazer, Jean Wright, Elizabeth Buckley, Tari King, Simon Powell, Eric Winer, Jennifer Bellon. Preliminary report of the PRECISION Trial (Profiling Early Breast Cancer for Radiotherapy Omission): A Phase II Study of Breast-Conserving Surgery Without Adjuvant Radiotherapy for Favorable-Risk Breast Cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr OT1-12-02.

Spatially selective stimulation of the pig vagus nerve to modulate target effect versus side effect

Electrical stimulation of the cervical vagus nerve using implanted electrodes (VNS) is FDA-approved for the treatment of drug-resistant epilepsy, treatment-resistant depression, and most recently, chronic ischemic stroke rehabilitation. However, VNS is critically limited by the unwanted stimulation of nearby neck muscles—a result of non-specific stimulation activating motor nerve fibers within the vagus. Prior studies suggested that precise placement of small epineural electrodes can modify VNS therapeutic effects, such as cardiac responses. However, it remains unclear if placement can alter the balance between intended effect and limiting side effect. We used an FDA investigational device exemption approved six-contact epineural cuff to deliver VNS in pigs and quantified how epineural electrode location impacts on- and off-target VNS activation. Detailed post-mortem histology was conducted to understand how the underlying neuroanatomy impacts observed functional responses. Here we report the discovery and characterization of clear neuroanatomy-dependent differences in threshold and saturation for responses related to both effect (change in heart rate) and side effect (neck muscle contractions). The histological and electrophysiological data were used to develop and validate subject-specific computation models of VNS, creating a well-grounded quantitative framework to optimize electrode location-specific activation of nerve fibers governing intended effect versus unwanted side effect.

FAST-01: Results of the First-in-Human Study of Proton FLASH Radiotherapy

<h3>Purpose/Objective(s)</h3> FLASH radiotherapy (RT) is delivered at ultra-high dose rates (>40 Gy/s), with preclinical animal data suggesting less toxicity to normal tissues. FAST-01 was a prospective, first-in-human study that evaluated the feasibility of a clinical workflow for proton FLASH RT in the treatment of painful extremity bone metastases. The treatment workflow was hypothesized to be feasible. In addition, this study intended to generate preliminary results regarding the safety and efficacy of this FLASH treatment. <h3>Materials/Methods</h3> FAST-01 was a single institution study under an FDA investigational device exemption (IDE) approved for 10 patients with >2 month life expectancy and 1-3 painful bone metastases in the extremities. Exclusion criteria included patients with fractures or prior RT in the treatment site(s), or lesions of the feet, hands, or wrists. Treatment was 8 Gy (RBE = 1.0) in a single fraction delivered at ≥40 Gy/s via a FLASH-enabled proton therapy system employing a single transmission proton beam. Primary study endpoints were workflow feasibility (time on the treatment table and FLASH-related treatment delays) and toxicity, and secondary endpoint was efficacy (validated pain questionnaires). Pain flare questionnaires were completed for 10 consecutive days post-RT. Pain response at each treatment site was evaluated at 3 months post-RT using the methodology of RTOG 9714. Pain, pain medication use, and adverse events (AEs) were evaluated on the day of treatment and at 15 days, 1, 2, and 3 months post-RT, and every 2 months thereafter. AEs were graded using CTCAE v5. Safety analysis included all events that were physician-attributed to be at least "possibly related" to FLASH. Photos of skin in the treatment site areas supported AE evaluations. <h3>Results</h3> Ten subjects aged 27-81 years received FLASH RT to 12 metastatic sites. No FLASH-related technical issues or delays occurred. Average time on the treatment table was 15.8 min per treated site (range 11-33 min). Follow-up ranged from 2.3-13 months (median 4.8 months). Transient pain flares occurred in 4 of 12 treated sites. Complete or partial pain relief following FLASH radiotherapy was seen in 8 of 12 sites (7 of the 10 subjects) for an overall response rate of 66.7%. Complete pain responses were 50% (6/12 sites), and partial responses were 17% (2/12 sites). AEs were mild: skin hyperpigmentation (G1, n=4), skin discoloration (G1, n=1), limb edema (G1, n=2), pruritis (G1, n=2), fatigue (G1, n=1), erythema (G1, n=1), and extremity pain (G2, n=1). <h3>Conclusion</h3> This first-in-human trial establishes the feasibility of FLASH proton radiotherapy. The treatment efficacy and the profile of AEs were favorable and were comparable to the published literature for conventional dose rate photon RT. AE and pain data collection continues for the evaluation of long-term results. These findings support the further exploration of FLASH radiation treatments for other clinical indications.

Prospective, multicenter study of 2-level cervical arthroplasty with a PEEK-on-ceramic artificial disc.

The purpose of this study was to evaluate the safety and efficacy of a PEEK-on-ceramic cervical total disc replacement (cTDR) device for the treatment of 2-level cervical disc disease with radiculopathy and/or myelopathy. The study was a prospective, nonrandomized, historically controlled FDA investigational device exemption trial evaluating the Simplify Cervical Artificial Disc for use at 2 levels. The anterior cervical discectomy and fusion (ACDF) control group was derived from a propensity score-matched (using subclassification) cohort of patients who participated in an earlier prospective trial in which similar indications were used. The follow-up duration was 24 months. The primary outcome was a 4-point composite success classification. Other validated clinical and radiographic assessments were also evaluated. The investigational group (n = 182) was compared with patients who underwent ACDF (n = 170) in a historical control group using propensity score analysis. The overall composite success rate was statistically significantly greater in the cTDR group compared with the ACDF group (86.7% vs 77.1%; p < 0.05). The mean Neck Disability Index scores improved significantly in both groups, with cTDR significantly lower at some follow-up points. At the 24-month follow-up, a minimum 15-point improvement in Neck Disability Index scores was achieved in 92.9% of the cTDR group and 83.5% of the ACDF group (p > 0.05). In both groups, neck and arm pain scores improved significantly (p < 0.05) by 6 weeks and improvement was maintained throughout follow-up. Segmental range of motion was maintained at both treated segments in the cTDR group. MRI performed in the cTDR group at 24 months postoperatively found minimal changes in facet joint degeneration. The rate of subsequent surgical intervention was 2.2% in the cTDR group and 8.8% in the ACDF group. This study adds to the growing body of literature supporting cTDR for 2-level cervical disc disease with radiculopathy or myelopathy. cTDR showed a superior overall success rate compared to ACDF, while maintaining motion. These results support that the Simplify disc is a viable alternative to ACDF in appropriately selected patients with 2-level cervical spondylosis.

29. Imaging outcome at 24-month follow-up in a prospective, multicenter study of two-level cervical arthroplasty with a PEEK on ceramic artificial disc

<h3>BACKGROUND CONTEXT</h3> The use of cervical total disc replacement (cTDR) continues to increase. The implants continually evolve with respect to design and materials. Imaging studies of these devices provides insight to their ability to provide and maintain range of motion (ROM), disc height, and depending on the implant materials, facet joint assessment. <h3>PURPOSE</h3> The purpose of this study was to evaluate the imaging outcome of a PEEK-on-ceramic artificial disc for the treatment of two-level cervical disc disease. <h3>STUDY DESIGN/SETTING</h3> Data for this study came from a prospective, multicenter, non-randomized, historically controlled FDA Investigational Device Exemption (IDE) trial evaluating the Simplify®Cervical Artificial Disc for use at two levels. <h3>PATIENT SAMPLE</h3> Two-level cTDR was performed in 182 patients treated for symptomatic cervical disc degeneration with radiculopathy/myelopathy. <h3>OUTCOME MEASURES</h3> The primary outcome measures were ROM, disc height, and heterotopic ossification (HO) of the treated levels. MRI was used to assess the facet joints. <h3>METHODS</h3> The cTDR is composed of PEEK endplates with a mobile ceramic core. Radiographic evaluations were performed preoperatively, at hospital discharge, and 6 weeks, and 3, 6, 12, and 24 months postoperatively. MRI was performed pre- and 24 months postoperatively. All images were evaluated by an independent core lab. HO was evaluated based on a 0 (normal) to 4 (bridging bone) scale. Facets joints were scored on a 4-point scale ranging from 0 (normal) to 3 (severe degeneration) based on the MRI performed pre- and 24 months postoperatively. <h3>RESULTS</h3> At the superior cTDR level, the mean ROM improved from 8.0° prior to surgery to 9.5° at 24-month follow-up. At the inferior level, the values were 6.6° and 8.9°, respectively. At both operated levels, mean disc height increased postoperatively and the increase was maintained through 24-month follow-up. At the superior index level, the preoperative mean height was 3.1 mm and at 24 months it was 4.3 mm. At the inferior index level, the preoperative height was 3.1 mm and was 4.0 at 24 months. HO rates at 24-month follow-up were, the superior index level, severe HO (Grade 3) occurred in 8 patients (5%). Bridging HO (Grade 4) was also seen in 8 patients (5%). At the inferior index level, severe and bridging HO was seen in 17 (10%) and 5 (3%) patients, respectively. There was a lack of facet degeneration progression assessed on MRI between pre- and 24-month follow-up. No patient had severe facet degeneration at either operated level at either time point. The percentage of patients with a grade of moderate facet degeneration did not change at either level 8% at the superior index level and 5% at the inferior index level. At both levels, there appeared to be patients changing from the "none" category to the "mild" category. At the superior level prior to surgery, the figures for "none" and "mild" were 62% and 30% respectively. At 24-month follow-up, the figures were 52% and 39%, respectively. A similar pattern was seen at the inferior index level. <h3>CONCLUSIONS</h3> This study adds to the expanding evidence that two-level cTDR increases and maintains ROM and disc height and through 24-month follow-up. The majority of cTDR patients did not experience bridging HO. This PEEK-on-ceramic cTDR produces minimal artifact, allowing for reliable MRI visualization. This was used to evaluate the facet joints and a lack of facet degeneration progression was found. <h3>FDA DEVICE/DRUG STATUS</h3> Simplify Cervical Artificial Disc 2-level (Approved for this indication).

11. Clinical outcome of a prospective, controlled, multicenter study evaluating two-level cervical arthroplasty with a PEEK-on-ceramic artificial disc

<h3>BACKGROUND CONTEXT</h3> Over the past two decades, there has been increasing use of cervical total disc replacement (cTDR) with designs and materials continually evolving. Nine devices have been FDA approved for 1-level use, and the current study led to the approval of a third device for two levels. <h3>PURPOSE</h3> The purpose of this study was to evaluate the safety and efficacy of a PEEK-on-ceramic artificial disc for the treatment of 2-level cervical disc disease. <h3>STUDY DESIGN/SETTING</h3> This was a prospective, non-randomized, historically controlled multicenter FDA Investigational Device Exemption (IDE) trial evaluating the Simplify®Cervical Artificial Disc (NuVasive, Inc). The anterior cervical discectomy and fusion (ACDF) control group was derived from a propensity score matched (using subclassification) cohort of patients who participated in an earlier prospective cTDR trial using similar indications. <h3>PATIENT SAMPLE</h3> The cTDR group (n=182) was compared with ACDF patients (n=170). All patients had 2-level, symptomatic cervical disc disease with radiculopathy and/or myelopathy. <h3>OUTCOME MEASURES</h3> The primary outcome measure was classification of success at 24-month follow-up based on 4 criteria (1) at least 15-point (of 100) improvement in Neck Disability Index (NDI) scores; (2) maintenance or improvement in neurological status; (3) no serious adverse event classified as implant associated or implant/surgical procedure associated; and (4) no additional index level surgery. Secondary evaluations included NDI scores, numeric rating scales assessing neck and arm pain intensity and frequency, and patient satisfaction. Safety was assessed by adverse events and subsequent surgery at an index level. <h3>METHODS</h3> Patients were evaluated preoperatively, at hospital discharge, 6 weeks, and 3, 6, 12, and 24 months after surgery. <h3>RESULTS</h3> The overall composite success rate was statistically significantly greater in the cTDR group compared with the ACDF group (86.7% vs 77.1%; p 15 points at 24-mo follow-up) occurred in 92.9% of the cTDR group and 83.5% of the ACDF group (0.05 < p < 0.10). Mean NDI scores improved significantly in both groups by 6 weeks with cTDR scores significantly lower at 6 weeks and 3 and 6 months. Mean NDI scores in the cTDR group were 58.6 preoperatively and 14.3 at 24 months. In the ACDF group, the values were 53.6 and 17.2, respectively. In both groups, neck and arm pain improved significantly (p <0.05) by 6 weeks with improvement maintained throughout follow-up. In the cTDR group, the mean preop neck pain intensity score was 7.9 and 1.8 at 24 months. In the ACDF group, the values were 7.7 and 2.5, respectively. Improvement in arm pain followed a similar pattern with a preoperative mean value of 7.5 in the cTDR group which improved to 1.8 at 24 months. In the ACDF group, the values were 7.0 and 1.6. The ACDF scores were not superior to those in the cTDR group on any of the outcome measures. There were four subsequent surgical interventions (2.2%) in the cTDR group and 15 (8.8%) in the ACDF group. <h3>CONCLUSIONS</h3> The cTDR group had a statistically significantly greater overall clinical success rate compared to ACDF as well as similar to superior scores on the NDI and pain scales at all follow-up points. These results add to the growing body of literature supporting cervical arthroplasty for treating 2-level cervical disc disease with radiculopathy and/or myelopathy. <h3>FDA DEVICE/DRUG STATUS</h3> Simplify Cervical Artificial Disc: 2-level (Approved for this indication).

128. A prospective study of lumbar facet arthroplasty in the treatment of degenerative spondylolisthesis and stenosis: results from the Total Posterior Spine System (TOPS) IDE study

<h3>PURPOSE</h3> The purpose of the present study is to report the 1-year clinical and radiographic outcomes as well as safety profiles of patients who underwent lumbar facet arthroplasty via implantation of the TOPS device as part of a prospective Investigational Device Exemption (IDE) trial. <h3>STUDY DESIGN/SETTING</h3> Prospective FDA IDE trial. <h3>METHODS</h3> We reviewed the prospectively collected clinical and radiographic outcomes of patients who underwent facet arthroplasty via implantation of the TOPS device in the investigational arm of a multicenter, prospective, randomized, controlled FDA IDE trial. Standard demographic information was collected for each patient, including surgical variables. Radiographic parameters and patient reported outcome measures (PROMs) including ODI, VAS back and leg, and ZCQ were assessed preoperatively and at 6 weeks, 3 months, 6 months, and 12 months postoperatively. Adverse event, complication and reoperation data were also collected for each patient. <h3>RESULTS</h3> At the time of this study, 153 patients had undergone implantation of the TOPS device as part of this ongoing clinical trial and were included in this study. The mean surgical time was 187.8 minutes and mean estimated blood loss was 205.7cc. The mean length of hospital stay was 3.0 days. Mean ODI, VAS leg and back, and ZCQ scores improved significantly at all postoperative time points (P>0.001). Greater than 79% of patients achieved MCID in all patient reported outcome measures at all postoperative time points. There were no clinically significant changes in radiographic parameters and all operative segments remained mobile at 1-year follow-up without evidence of worsening sagittal translation. Postoperative complications occurred in 11 patients out of the 153 patients (7.2%) who underwent implantation of the TOPS device, including two new neurological deficits, two dural tears, two retained drains, one misplaced pedicle screw, one screw loosening, one infection, one seroma and one hematoma. Nine patients (5.9%) underwent a total of 13 reoperations, eight for surgical complications (5.3%) and one (0.6%) of which was for device-related failure due to bilateral L4 pedicle screw loosening. <h3>CONCLUSIONS</h3> Lumbar facet arthroplasty with the TOPS device demonstrated a statistically significant improvement in all PROMs and the ability to maintain motion at the index level while limiting sagittal translation with a low complication rate. <h3>FDA DEVICE/DRUG STATUS</h3> Total Posterior Spine System (TOPS) device: Investigational.

Extended Use of The Spanner® Temporary Prostatic Stent in Catheter-Dependent Men with Comorbidities.

Purpose This US FDA investigational device exemption (IDE) study evaluated the extended use of The Spanner® Temporary Prostatic Stent in catheter-dependent men with urinary retention who were not deemed candidates for corrective surgery but demonstrated bladder contractility. Materials and Methods The Spanner was placed for 3 cycles of 30 days in catheter-dependent men with comorbid conditions, confirmed detrusor contractility, and catheter-associated discomfort. At each visit, postvoid residual, maximum flow rate, international prostate symptom score, quality of life, and adverse events were assessed. Voiding success was defined as PVR ≤ 150 ml at all visits. Results One hundred seven men were enrolled at 8 US sites; 82/107 (76.6%) completed the trial, and 79/107 (73.8%) successfully maintained PVR ≤ 150 ml for the trial duration. Patients were 77.1 ± 10.6 years old; 63/107 (58.9%) were dependent on Foley and 40/107 (37.4%) on intermittent catheterization for 36.0 ± 39.3 days and 30.2 ± 45.8 days, respectively. 25/107 (23.4%) discontinuations were primarily due to voluntary patient withdrawal 9/107 (8.4%), investigator-initiated withdrawal 8/107 (7.5%), or lack of effectiveness 4/107 (3.7%). During Spanner use, the mean Qmax was 11.2 ± 6.6, mean IPSS was 7.5 ± 6.4, and mean QOL was 2.0 ± 1.6. The most prevalent device-related adverse events were asymptomatic bacteriuria 25/107 (23.4%), discomfort 10/107 (9.4%), and urinary urgency 8/107 (7.5%). No device-related serious AEs were reported. Conclusions This study demonstrates that catheter-dependent men with sufficient bladder contractility can achieve volitional voiding and successful bladder drainage using The Spanner Temporary Prostatic Stent for extended periods of time.

P128. Six-year follow-up of i-FACTOR® peptide enhanced bone graft vs autograft in single level ACDF in a randomized single blinded FDA investigational device exemption study

<h3>BACKGROUND CONTEXT</h3> i-FACTOR is a composite bone substitute material consisting of a P-15 synthetic collagen fragment adsorbed onto an organic bone mineral and suspended in an inert biocompatible hydrogel carrier. Previous analyses of the US FDA IDE study demonstrated the benefits of i-FACTOR compared to local autograft bone in single-level ACDF at 12- and 24-months postoperative. <h3>PURPOSE</h3> We report 6-year clinical and radiological outcomes of post-approval study. <h3>STUDY DESIGN/SETTING</h3> Subjects from a completed, prospective, randomized, controlled, multicenter clinical trial that was conducted at 22 North American sites were enrolled in a post-approval study and we report 6-year outcomes. <h3>PATIENT SAMPLE</h3> Of 319 subjects that participated in the IDE study, 220 were enrolled into post-approval 6 years follow-up autograft (n = 114) or i-FACTOR (n = 105) in a cortical ring allograft. <h3>OUTCOME MEASURES</h3> Radiological, clinical, and patient-reported outcomes. <h3>METHODS</h3> Subjects completed prospective, randomized, controlled, multicenter clinical trial that was conducted at 22 North American sites were enrolled into post-approval study 6 years follow-up. <h3>RESULTS</h3> Fusion rates at 72 months were 99.0% in i-FACTOR subjects and 98.2% in autograft subjects, with a difference of 0.8% (95% C.I., (95% CI -2.3%, 4.0%). Mean improvement in NDI in i-FACTOR subjects was 28.56 (95% CI 24.79, 32.33) compared to 29.17 (95% CI 25.46, 32.88) in autograft subjects, with a difference of -0.61 (2.793) (95% CI -6.10, 4.88). Neurologic success rate at 72 months was 95.89% in i-FACTOR subjects and 93.33% in autograft subjects, with a difference of 2.6% (95% CI, -4.70%, 9.81%). Overall success rate was 68% in i-Factor and 62% in autograft subjects. Safety outcomes were similar between the 2 treatment groups. Secondary surgery at any cervical level occurred in 20 (18.9%) i-FACTOR subjects and 23 (20.2%) autograft subjects (p=0.866). Pain and SF-36 outcomes were similar between the groups at all study visits. There were no adverse reactions associated with i-FACTOR. <h3>CONCLUSIONS</h3> At 6 years, i-FACTOR in ACDF resulted in similar outcomes compared to local autograft. Safety outcomes are acceptable and clinical and functional outcomes for i-FACTOR in the previous studies are confirmed. <h3>FDA DEVICE/DRUG STATUS</h3> I-Factor (Approved for this indication)

Epilepsy Personal Assistant Device-A Mobile Platform for Brain State, Dense Behavioral and Physiology Tracking and Controlling Adaptive Stimulation.

Epilepsy is one of the most common neurological disorders, and it affects almost 1% of the population worldwide. Many people living with epilepsy continue to have seizures despite anti-epileptic medication therapy, surgical treatments, and neuromodulation therapy. The unpredictability of seizures is one of the most disabling aspects of epilepsy. Furthermore, epilepsy is associated with sleep, cognitive, and psychiatric comorbidities, which significantly impact the quality of life. Seizure predictions could potentially be used to adjust neuromodulation therapy to prevent the onset of a seizure and empower patients to avoid sensitive activities during high-risk periods. Long-term objective data is needed to provide a clearer view of brain electrical activity and an objective measure of the efficacy of therapeutic measures for optimal epilepsy care. While neuromodulation devices offer the potential for acquiring long-term data, available devices provide very little information regarding brain activity and therapy effectiveness. Also, seizure diaries kept by patients or caregivers are subjective and have been shown to be unreliable, in particular for patients with memory-impairing seizures. This paper describes the design, architecture, and development of the Mayo Epilepsy Personal Assistant Device (EPAD). The EPAD has bi-directional connectivity to the implanted investigational Medtronic Summit RC+STM device to implement intracranial EEG and physiological monitoring, processing, and control of the overall system and wearable devices streaming physiological time-series signals. In order to mitigate risk and comply with regulatory requirements, we developed a Quality Management System (QMS) to define the development process of the EPAD system, including Risk Analysis, Verification, Validation, and protocol mitigations. Extensive verification and validation testing were performed on thirteen canines and benchtop systems. The system is now under a first-in-human trial as part of the US FDA Investigational Device Exemption given in 2018 to study modulated responsive and predictive stimulation using the Mayo EPAD system and investigational Medtronic Summit RC+STM in ten patients with non-resectable dominant or bilateral mesial temporal lobe epilepsy. The EPAD system coupled with an implanted device capable of EEG telemetry represents a next-generation solution to optimizing neuromodulation therapy.

Demographic and radiographic predictors of patient reported outcomes and revision surgery after stemless total shoulder arthroplasty

BackgroundStemless total shoulder arthroplasty (TSA) is aimed at better re-creating native anatomy, facilitating revision, and preserving bone. The purpose of this study is to determine which pre-operative patient characteristics or radiographic parameters were predictive of outcomes following stemless TSA. MethodsThis was a retrospective review of prospectively collected data. One hundred fifty-seven patients with glenohumeral osteoarthritis were prospectively enrolled as part of a multi-center FDA Investigational Device Exemption protocol in July 2011-November 2012. In the present study, one hundred forty-nine patients with minimum 2-year follow-up had imaging available for review and were included (107 men, 42 women). Mean age 65 years (range,37-84). Pre-operative patient demographics, baseline ASES and Constant scores, deltoid tuberosity index (DTI), combined cortical thickness, and postoperative glenoid version were analyzed to predict treatment success. Treatment success was defined by no revision procedures and an adjusted Constant score of >85% at final follow-up. Statistical analyses were performed using student T-test, multiple logistic regression, and Pearson correlation with a p-value of 0.05 defining significance. Intraclass correlation and kappa values were calculated to determine interrater reliability for radiographic measurements. ResultsThree patients (2.0%) underwent revision or explant due to infection, unstable implant, or glenoid loosening. Eleven (7.4%) had an adjusted Constant score <85% at 2-year follow-up. These patients made up the suboptimal treatment outcome cohort (n = 13), with a mean age of 55.5 compared to 66.6(P <0.001). Relative risk for suboptimal outcome for patients <60 years was 1.32(95% CI:1.05-1.66). Baseline Constant was lower in the suboptimal treatment group (47.9 vs. 57.0, p=0.001). There were no differences between groups when comparing radiographic parameters. Older age correlated with lower combined cortical thickness (r = 0.32, P <0.05), lower DTI(r = 0.17, P <0.05), greater Constant(r = 0.47, P <0.05) and ASES(r = 0.29, P <0.05) scores at follow-up. ConclusionPatients younger than 60 years old had a 1.3x risk of suboptimal treatment outcome following stemless TSA, similar to what is seen with stemmed implants. Low radiographic bone density was not predictive of suboptimal constant score or reoperation at final follow-up. Older patients had decreased combined cortical thickness and deltoid tuberosity index, yet were more likely to have a successful outcome following stemless TSA compared to younger patients. Level of evidenceLevel III; Retrospective Cohort

Prospective, multicenter clinical trial comparing M6-C compressible six degrees of freedom cervical disc with anterior cervical discectomy and fusion for the treatment of single-level degenerative cervical radiculopathy: 2-year results of an FDA investigational device exemption study

BACKGROUND CONTEXTVarious designs of total disc replacement (TDR) devices have been compared to anterior cervical discectomy and fusion (ACDF) with favorable outcomes in FDA-approved investigational device exemption trials. The design of M6-C with a compressible viscoelastic nuclear core and an annular structure is substantially different than prior designs and has previously demonstrated favorable kinematics and clinical outcomes in small case series. PURPOSETo evaluate the safety and effectiveness of the novel M6-C compressible artificial cervical disc compared with ACDF for subjects with single-level degenerative cervical radiculopathy. STUDY DESIGN/SETTINGProspective, multicenter, concurrently and historically controlled, FDA-approved investigational device exemption clinical trial. PATIENT SAMPLESubjects with one-level symptomatic degenerative cervical radiculopathy were enrolled and assigned to receive M6-C or ACDF. OUTCOME MEASURESPain and function (Neck Disability Index, VAS), quality of life (SF-36), safety, neurologic, and radiographic assessments of motion (both flexion extension and lateral bending) were performed. The primary clinical endpoint was composite clinical success (CCS) at 24 months. METHODSUsing propensity score subclassification to control for selection bias, 160 M6-C subjects were compared to a matched subset of 189 ACDF controls (46 concurrent and 143 historical controls). RESULTSBoth ACDF and M6-C subjects reported significant improvements in patient-reported outcomes at all time points over baseline. Overall SF-36 Physical Component Score and neck and arm pain scores were significantly improved for M6-C as compared to ACDF treatment. CCS and mean Neck Disability Index improvements were similar between M6-C and ACDF. Correspondingly, there were significantly fewer subjects that utilized pain medication or opioids following M6-C treatment at 24 months relative to baseline. Range of motion was maintained in subjects treated with M6-C. Subsequent surgical interventions, dysphagia rates, and serious adverse events were comparable between groups. CONCLUSIONSM6-C treatment demonstrated both safety and effectiveness for the treatment of degenerative cervical radiculopathy. Treatment with M6-C demonstrated noninferiority for the primary endpoint, indicating a similar ability to achieve CCS at 24 months. However, for the secondary endpoints, M6-C subjects demonstrated significantly improved pain and function compared to ACDF subjects, while maintaining range of motion, improving quality of life, and decreasing analgesic and opioid usage at 2 years postoperatively relative to baseline.

162. Two-level cervical disc replacement using a PEEK-on-ceramic device: prospective outcome data from an FDA IDE trial

BACKGROUND CONTEXT While there have been several large-scale FDA investigational device exemption (IDE) studies on single-level cervical total disc replacement (TDR) such information is available for only two devices used for two-level disc replacement. One of these devices has metallic endplates and a plastic core, the other is a two-piece device machined from a titanium-ceramic composite. A TDR designed with titanium-coated PEEK endplates and a biconvex zirconia toughened alumina ceramic core is being evaluated in an IDE trial for two-level implantation. PURPOSE The purpose of this study was to investigate preliminary outcomes of the PEEK-on-ceramic TDR based on three sites participating in the two-level trial. STUDY DESIGN/SETTING This was a prospective study based on data from three of 18 centers participating in the TDR arm of a prospective study evaluating two-level cervical TDR using a nonconcurrent historical control. PATIENT SAMPLE These preliminary outcomes were based on 62 patients at 12 months postoperative following two-level cervical TDR. OUTCOME MEASURES Patient reported outcome measures included the neck disability index (NDI) and numerical rating scores (NRS) separately assessing neck and arm pain intensity. Radiographic measures made at the index levels included disc height and flexion/extension range of motion (ROM). METHODS Patients enrolled in the trial received the Simplify® PEEK-on-ceramic TDR. Evaluations were conducted prior to surgery and at 6 weeks, and 3, 6 and 12 months after surgery. All radiographs were analyzed by an independent lab specializing in image assessment. RESULTS The mean NDI score decreased significantly (p CONCLUSIONS Preliminary results of this IDE study found that two-level cervical TDR using the PEEK-on-ceramic implant was associated with significant decreases in pain and function scores, which were maintained during 12-month follow-up. Disc height of the operated segments were increased after surgery and remained increased through 12-month follow-up. ROM was increased, significantly at the superior level and nonsignificantly at the inferior level. These early results suggest that the device may be a future consideration for the treatment of symptoms arising from two-level degenerative conditions of the cervical spine. Patients from all centers continue to be followed annually. FDA DEVICE/DRUG STATUS Simplify disc (Investigational/Not approved)