SECURE-C ARTIFICIAL CERVICAL DISC

{0} SUMMARY OF SAFETY AND EFFECTIVENESS DATA (SSED) I. GENERAL INFORMATION Device Generic Name: Artificial Cervical Disc Device Trade Name: SECURE®-C Cervical Artificial Disc Device Procode: MJO Applicant's Name and Address: Globus Medical, Inc. Valley Forge Business Center 2560 General Armistead Ave. Audubon, PA 19403 Date of Panel Recommendation: None Premarket Approval Application (PMA) Number: P100003 Date of FDA Notice of Approval: September 28, 2012 Expedited: Not Applicable II. INDICATIONS FOR USE The SECURE®-C Cervical Artificial Disc is indicated in skeletally mature patients for reconstruction of the disc at one level from C3-C7 following single-level discectomy for intractable radiculopathy (arm pain and/or a neurological deficit) with or without neck pain, or myelopathy due to a single-level abnormality localized to the disc space and at least one of the following conditions confirmed by radiographic imaging (CT, MRI, X-rays): herniated nucleus pulposus, spondylosis (defined by the presence of osteophytes), and/or visible loss of disc height as compared to adjacent levels. The SECURE®-C Cervical Artificial Disc is implanted using an anterior approach. Patients should have failed at least 6 weeks of conservative treatment prior to implantation of the SECURE®-C Cervical Artificial Disc. III. CONTRAINDICATIONS The SECURE®-C Cervical Artificial Disc should not be implanted in patients with the following conditions: - Active systemic infection or localized infection at the surgical site - Osteoporosis or osteopenia defined as a DEXA bone mineral density T-score ≤ -1 - Allergy or sensitivity to cobalt, chromium, molybdenum, titanium or polyethylene - Marked cervical instability on neutral resting lateral or flexion/extension radiographs; translation &gt;3mm and/or &gt;11° rotational difference from that of either adjacent level PMA P100003: FDA Summary of Safety and Effectiveness Data {1} - Severe spondylosis at the level to be treated, characterized by bridging osteophytes, loss of disc height $&gt;50\%$ , an absence of motion $(&lt;2^{\circ})$ as this may lead to a limited range of motion and may encourage bone formation (e.g. heterotopic ossification, fusion) - Severe facet joint arthropathy - Significant cervical anatomical deformity or clinically compromised vertebral bodies at the affected level due to current or past trauma (e.g., by radiographic appearance of fracture callus, malunion or nonunion) or disease (e.g., ankylosing spondylitis, rheumatoid arthritis) - Symptoms attributed to more than one vertebral level # IV. WARNINGS AND PRECAUTIONS The warnings and precautions can be found in the SECURE®-C Cervical Artificial Disc labeling. # V. DEVICE DESCRIPTION The SECURE®-C Cervical Artificial Disc (SECURE®-C) is an articulating intervertebral device comprised of two endplates and a central core, and is inserted using an anterior cervical approach. The superior and inferior cobalt-chrome alloy (CoCrMo per ISO 5832-12, ASTM F1537) endplates feature multiple serrated keels and a commercially pure titanium plasma spray coating (per ISO 5832-2, ASTM F1580, F1978, F1147, and C-633) on the bone contacting surfaces. The sliding core is composed of ultra-high molecular weight polyethylene (UHMWPE per ISO 5834-2, ASTM F648), with a spherical superior interface and a cylindrical inferior interface articulating with the endplates.  SECURE®-C implants are offered in a variety of configurations to accommodate varied patient anatomy. Implant footprints are as follows (AP depth x ML width): 11x12mm, 13x14mm, and 14x16mm. SECURE®-C provides $0^{\circ}$ or $6^{\circ}$ lordosis options in its neutral position. Implant heights range from 7mm to 12mm, in 1mm increments. A list of SECURE®-C implants is provided in Table 1. The SECURE®-C Cervical Artificial Disc is designed to allow motion in flexion and extension up to $30^{\circ}$ ( $\pm 15^{\circ}$ ), and in lateral bending to $20^{\circ}$ ( $\pm 10^{\circ}$ ). The design is intended to allow unlimited axial rotation, and is constrained by ligaments and posterior elements. The device is also designed to permit translation of $\pm 1.25\mathrm{mm}$ in the sagittal plane. PMA P100003: FDA Summary of Safety and Effectiveness Data {2} Table 1. SECURE®-C Cervical Artificial Disc Implants | Part Number | Description | | --- | --- | | 414.107S | SECURE®-C Core, 11x12, 7mm | | 414.108S | SECURE®-C Core, 11x12, 8mm | | 414.109S | SECURE®-C Core, 11x12, 9mm | | 414.110S | SECURE®-C Core, 11x12, 10mm | | 414.111S | SECURE®-C Core, 11x12, 11mm | | 414.112S | SECURE®-C Core, 11x12, 12mm | | 414.207S | SECURE®-C Core, 13x14, 7mm | | 414.208S | SECURE®-C Core, 13x14, 8mm | | 414.209S | SECURE®-C Core, 13x14, 9mm | | 414.210S | SECURE®-C Core, 13x14, 10mm | | 414.211S | SECURE®-C Core, 13x14, 11mm | | 414.212S | SECURE®-C Core, 13x14, 12mm | | 414.307S | SECURE®-C Core, 14x16, 7mm | | 414.308S | SECURE®-C Core, 14x16, 8mm | | 414.309S | SECURE®-C Core, 14x16, 9mm | | 414.310S | SECURE®-C Core, 14x16, 10mm | | 414.311S | SECURE®-C Core, 14x16, 11mm | | 414.312S | SECURE®-C Core, 14x16, 12mm | | 714.100S | SECURE®-C Endplate Assembly, 11x12, 0° | | 714.106S | SECURE®-C Endplate Assembly, 11x12, 6° | | 714.200S | SECURE®-C Endplate Assembly, 13x14, 0° | | 714.206S | SECURE®-C Endplate Assembly, 13x14, 6° | | 714.300S | SECURE®-C Endplate Assembly, 14x16, 0° | | 714.306S | SECURE®-C Endplate Assembly, 14x16, 6° | SECURE®-C devices are implanted using instruments specific to the device, as well as manual surgical instruments. Instruments specifically designed for implanting SECURE®-C consist of trials, milling guides, broaching chisels, keel chisels, a chisel endcap, an implant holding block, implant holders, and endplate positioners. Manual surgical instruments include instruments for cervical distraction, discectomy preparation, and milling. # VI. ALTERNATIVE PRACTICES AND PROCEDURES There are several other alternatives for the treatment of intractable radiculopathy or myelopathy due to a single-level abnormality localized to the disc space. - Nonoperative alternative treatments include, but are not limited to, physical therapy, medications, braces, chiropractic care, bed rest, spinal injections, or exercise programs. - Surgical alternatives include, but are not limited to, surgical decompression and/or fusion using various bone grafting techniques or interbody fusion devices, which may be used in conjunction with anterior cervical plating (e.g., plate and screws), or posterior spinal systems (e.g., rods, hooks, wires). Anterior cervical discectomy and fusion (ACDF) with an PMA P100003: FDA Summary of Safety and Effectiveness Data {3} interbody graft or spacer is the most commonly used method for decompression and fusion. Intractable radiculopathy or myelopathy due to a single-level abnormality localized to the disc space may also be treated surgically using another FDA approved artificial cervical disc. Each alternative has advantages and disadvantages. A patient should fully discuss these alternatives with his/her physician. ## VII. MARKETING HISTORY The SECURE®-C Cervical Artificial Disc has been commercially available outside of the United States since 2006. The device is available in the United Kingdom, Belgium, Germany, and India, and has not been withdrawn from the market for any reason. ## VIII. POTENTIAL ADVERSE EFFECTS OF THE DEVICE ON HEALTH Below is a list of the potential adverse effects (e.g., complications) associated with the use of the SECURE®-C Cervical Artificial Disc identified from the SECURE®-C Cervical Artificial Disc clinical study results, approved device labeling for other cervical total disc replacement devices, and published scientific literature including: (1) those associated with any surgical procedure; (2) those associated with anterior cervical spine surgery; and (3) those associated with a cervical artificial disc device, including the SECURE®-C Cervical Artificial Disc. In addition to the risks listed below, there is also the risk that surgery may not be effective in relieving symptoms, or may cause worsening of symptoms. Additional surgery may be required to correct some of the adverse effects. 1. Risks associated with any surgical procedure include: abscess; cellulitis; wound dehiscence; wound, local, and/or systemic infection; wound necrosis; edema; hematoma; heart and vascular complications; hypertension; thrombosis; ischemia; embolism; thromboembolism; hemorrhage; thrombophlebitis; adverse reactions to anesthesia; pulmonary complications; organ, nerve or muscular damage; gastrointestinal or genitourinary compromise; seizure, convulsion, or changes to mental status; complications of pregnancy including miscarriage and fetal birth defects; inability to resume activities of daily living; and death. 2. Risks associated with anterior cervical spine surgery include: dysphagia; dysphonia; hoarseness; vocal cord paralysis; laryngeal palsy; sore throat; recurring aspirations; tracheal, esophageal, or pharyngeal perforation; airway obstruction; warmth or tingling in the extremities; neurologic complications including damage to nerve roots, other nerves, or the spinal cord possibly resulting in weakness, pain or even paralysis; dural tears or leaks; cerebrospinal fistula; discitis, arachnoiditis, and other types of inflammation; loss of disc height; loss of anatomic sagittal plane curvature or vertebral listhesis; scarring, herniation or degeneration of adjacent discs; surrounding soft tissue damage, spinal stenosis; spondylolysis; fistula; vascular damage and/or rupture; and headache. 3. Risks associated with a cervical artificial disc device, including the SECURE®-C Cervical Artificial Disc, include: early or late loosening of the components; disassembly; bending or breakage of any or all of the components; implant migration; implant malpositioning; implant PMA P100003: FDA Summary of Safety and Effectiveness Data Page 4 of 50 {4} subsidence; loss of fixation; sizing issues with components; anatomical or technical difficulties; bone fracture; foreign body reaction to the implant including possible tumor formation, autoimmune disease, metallosis, and/or scarring; possible tissue reaction; bone resorption; bone formation (including heterotopic ossification) that may reduce spinal motion or result in a fusion, either at the treated level or at adjacent levels; development of new radiculopathy, myelopathy, or pain; tissue or nerve damage caused by improper positioning or placement of implants or instruments; bending or breakage of a surgical instrument, as well as the possibility of a fragment of a broken instrument remaining in the patient; loss of neurological function; decreased strength of extremities; decreased reflexes; cord or nerve root injury; loss of bowel and/or bladder control or other types of urological system compromise; interference with radiographic imaging because of the presence of the implant; and the need for subsequent surgical intervention. For the specific adverse events that occurred in the clinical study of the SECURE®-C Cervical Artificial Disc, please see Section X below. ## IX. SUMMARY OF PRECLINICAL STUDIES A variety of testing was conducted to characterize the performance of the SECURE®-C Cervical Artificial Disc, as follows: ### Laboratory Studies - Static Axial Compression - Dynamic Axial Compression - Static Compression-Shear - Dynamic Compression-Shear - Creep and Stress Relaxation - Device Pushout - Core Expulsion - Subsidence - Durability/Wear Testing ### Animal Studies - Particulate Animal Study ### Additional Studies - Sterilization Validation - Shelf Life and Packaging Validation - Biocompatibility PMA P100003: FDA Summary of Safety and Effectiveness Data Page 5 of 50 {5} # A. Laboratory Studies Table 2. Summary of Laboratory Studies | Test Name | Purpose | Method | Acceptance Criteria | Results | | --- | --- | --- | --- | --- | | Static Axial Compression | To evaluate the performance of the SECURE®-C device under static axial compressive loading, under worst case conditions. | Five (5) SECURE®-C specimens were tested under static compression in ambient air at a rate of 10mm/min until failure. | Yield load must be greater than the maximum compressive load that a cervical intervertebral disc can withstand (75N1). | The average 2% offset yield load was 1,677N ±129N, with an average displacement of 0.35mm ±0.1mm. SECURE®-C can withstand compressive loading that exceeds the anticipated physiologic loads on the cervical spine. | | Dynamic Axial Compression | To evaluate the performance of the SECURE®-C device under dynamic axial compressive loading, under worst case conditions. | Two (2) SECURE®-C specimens were tested under dynamic compression in ambient air to 10 million cycles, using a sinusoidal wave form with R=10 at 10Hz. | Fatigue load must be greater than the maximum compressive load that a cervical intervertebral disc can withstand (75N1). | Both specimens ran out to 10 million cycles under a 150N load. These results suggest that the SECURE®-C device can withstand dynamic compressive loading that exceeds the anticipated physiologic loads on the cervical spine. | | Static Compression-Shear | To evaluate the performance of the SECURE®-C device under static compression-shear, under worst case conditions. | Five (5) SECURE®-C specimens were tested under static compression-shear (45° angle) in ambient air at a rate of 10mm/min until failure. | Given that the shear failure load of the cervical intervertebral disc is 20N1, the yield load must be greater than the vertical component of shear loading, 28N (20N/cos45). | The average 2% offset yield load was 494N ±73N, with an average displacement of 0.93mm ±0.22mm. These results suggest that the SECURE®-C can withstand compressive-shear loading that exceeds the anticipated physiologic loads on the cervical spine. | | Dynamic Compression-Shear | To evaluate the performance of the SECURE®-C device under dynamic compressive-shear loading, under worst case | Two (2) SECURE®-C specimens were tested under dynamic compression shear in ambient air to 10 million cycles, using a sinusoidal wave form with R=10 at | Given that the shear failure load of the cervical intervertebral disc is 20N1, the yield load must be greater than the vertical | Both specimens ran out to 10 million cycles under a 106N load. These results suggest that the SECURE®-C device can withstand dynamic compressive-shear loading that | PMA P100003: FDA Summary of Safety and Effectiveness Data {6} PMA P100003: FDA Summary of Safety and Effectiveness Data Page 7 of 50 | Test Name | Purpose | Method | Acceptance Criteria | Results | | --- | --- | --- | --- | --- | | | conditions. | 10Hz. | component of shear loading, 28N (20N/cos45). | exceeds the anticipated physiologic loads on the cervical spine. | | Creep and Stress Relaxation | To evaluate the creep and stress relaxation characteristics of the SECURE®-C device, under worst case conditions. | Five (5) SECURE®-C specimens were tested under static compression in physiologic saline solution. Alternating static and dynamic axial loading was applied, with three progressive dynamic loads applied at 1 Hz over a 36 hour period. | The average residual deformation must be less than the 1.5mm normal diurnal disc height change^{2}. | The average residual deformation following creep and stress relaxation was 0.195mm. These results suggest that the SECURE®-C device exhibits creep behavior that is less than normal anticipated physiologic conditions in the cervical spine. | | Device Pushout | To evaluate the loads required to expulse the SECURE®-C device from the intervertebral disc space, under worst case conditions. | Five (5) SECURE®-C specimens were inserted into rigid polyurethane foam blocks, simulating bone, under a 50N pre-load, and tested to determine the amount of force required to displace the device by 3mm. Pushout load was applied at a rate of 10mm/min in ambient air. | Pushout load is greater than the shear failure load of the cervical intervertebral disc (20N^{1}). | The average pushout load was 289N ±101N. These results suggest that the SECURE®-C device can resist pushout forces that exceed the anticipated physiologic loads on the cervical spine. | | Core Expulsion | To evaluate the loads required to expulse the SECURE®-C core from the endplates, under worst case conditions. | Five (5) SECURE®-C specimens were pre-loaded with 50N and tested to determine the amount of force required to displace the core from the endplates by at least 3mm. Pushout load was applied at a rate of 10mm/min in ambient air. | Pushout load must be greater than the shear failure load of the cervical intervertebral disc (20N^{1}). | The average pushout load was 488N ±27N. These results suggest that the SECURE®-C core can resist pushout forces that exceed the anticipated physiologic loads on the cervical spine. | {7} | Test Name | Purpose | Method | Acceptance Criteria | Results | | --- | --- | --- | --- | --- | | Subsidence | To evaluate the SECURE®-C implant's resistance to subsidence into the vertebral endplate, under worst case conditions. | Five (5) SECURE®-C specimens were inserted into rigid polyurethane blocks simulating vertebral bone and loaded in compression to determine the amount of displacement resulting from a clinically relevant 150N load (2 x 75N). Compressive load was applied at a rate of 10mm/min in ambient air. | Subsidence at twice the maximum compressive load that a cervical intervertebral disc can withstand (2x75N¹) should be less than the thickness of the endplate (minimum 0.65mm³) | The average subsidence at 150N was 0.242mm ±0.156mm. These results suggest that the SECURE®-C device resists subsidence into the vertebral endplates. | | Durability/Wear Testing | To determine the wear and durability characteristics of the SECURE®-C device under complex physiologic loading and worst case conditions. | Six (6) SECURE®-C specimens were tested under physiologic conditions for 10 million cycles of complex loading at a frequency of 2Hz using combined flexion/extension (±7°), lateral bending (±7°), and axial rotation (±1.5°). An additional six specimens were tested with increased axial rotation (±6°). All specimens were subjected to a 150N constant compressive load for 10 million cycles. Specimens were placed in a calf serum and deionized water solution with EDTA, maintained at 37°C. Specimens were weighed and the solution was collected at each 1 million cycles. | The amount of wear debris should be similar to that reported for other cervical devices (2.59 ±0.36 mg per million cycles). | The average weight loss over the 10 million cycles was 2.57 mg ±1.21 mg per million cycles for the original testing. For the second round of testing, the average weight loss was 0.89 mg ±0.3 mg per million cycles. These results suggest that the SECURE®-C device demonstrates wear rates similar to that of other cervical devices. | 1,2,3 See Section XV References PMA P100003: FDA Summary of Safety and Effectiveness Data Page 8 of 50 {8} Note that during the course of the clinical trial, the endplate keels were modified slightly for ease of manufacture and for clearer demarcation of the keel boundaries for radiographic imaging. The outer dimensions and profile of the keels were not changed. There were no observed migrations of the original design or other difficulties encountered during the IDE study. Specifically, the modification was not the result of any clinical problems, safety issues or adverse events, product complaints, or surgeon requests from within or outside the United States. As this modification was minor, it did not affect the mechanical behavior of the device or the anticipated clinical outcome.  Original Design  New Design # B. Animal Studies Table 3. Summary of Animal Studies | Test Name | Purpose | Method | Acceptance Criteria | Results | | --- | --- | --- | --- | --- | | Particulate Debris Animal Study | To evaluate the local and systemic effect of UHMWPE particles implanted into the epidural space of New Zealand white rabbits. | The animals were injected with either 1 million particles, 10 million particles, or control saline, mixed with contrast media, into the epidural space. Animals were sacrificed at 3 months and 6 months. There were six animals per group, for a total of 36 animals. Gross anatomic, histopathologic and systemic analyses were used to assess neurotoxicity, systemic toxicity, and local effects of the debris. Tissues were evaluated using irritant ranking scores. | There should be no evidence of neurotoxicity, systemic toxicity, or local effects associated with the UHMWPE particulate debris, based on histopathologic assessment. Irritant ranking scores < 2.9 indicate that the test material is a non-irritant. | There was no evidence of neurotoxicity, systemic toxicity, or local effects associated with the UHMWPE particulate debris for either the 3 month or 6 month animals. Microscopic evaluation of tissues surrounding the particles (muscle, vertebral segments, lymph nodes) and organs did not reveal any remaining wear debris or local or system lesions that could be attributed to wear debris. Both the low and high dose particulate spinal injections were determined to be non-irritants (Irritant ranking scores <2.9). | PMA P100003: FDA Summary of Safety and Effectiveness Data {9} PMA P100003: FDA Summary of Safety and Effectiveness Data Page 10 of 50 ## C. Additional Studies ### Sterilization Validation Sterilization validation according to ANSI/AAMI/ISO 11137-2:2006 was conducted to confirm that the sterility of the device is maintained through a sterile barrier. ### Shelf Life and Packaging Validation Shelf life and packaging validation studies, including packaging seal and integrity, accelerated aging, and real-time aging testing, were conducted to demonstrate that the device packaging can maintain a sterile barrier, with a shelf life of 5 years. ### Biocompatibility The materials used in the SECURE®-C Cervical Artificial Disc are standard materials used in permanently implanted orthopaedic implants, including cobalt-chrome alloy (CoCrMo per ISO 5832-12, ASTM F1537), commercially pure titanium plasma spray coating (per ISO 5832-2, ASTM F1580, F1978, F1147, and C-633), and ultra-high molecular weight polyethylene (UHMWPE per ISO 5834-2, ASTM F648). ## X. SUMMARY OF PRIMARY CLINICAL STUDY The applicant performed a clinical study to establish a reasonable assurance of safety and effectiveness of reconstruction of the disc at one level from C3-C7 following single-level discectomy with the SECURE®-C Cervical Artificial Disc for intractable radiculopathy or myelopathy due to a single-level abnormality localized to the disc space in the United States under IDE #G050075. Data from this clinical study were the basis for the PMA approval decision. A summary of the clinical study is presented below. ### A. Study Design Patients were treated between July 7, 2005 and April 25, 2008. The database for this PMA reflected data collected through January 31, 2011 and included 380 patients. There were 18 investigational sites. The study was a prospective, multi-center, two-arm, randomized (1:1), unmasked, concurrently controlled, non-inferiority clinical study to compare the safety and effectiveness of the SECURE®-C Cervical Artificial Disc to the standard of care (a legally marketed alternative with similar indications for use), anterior cervical discectomy and fusion (ACDF) using a plate (ASSURE® Anterior Cervical Plate System) and structural allograft in treating patients with intractable symptomatic cervical disc disease (SCDD) at one level between C3 and C7. The first five subjects enrolled at each center were non-randomized subjects receiving the SECURE®-C Cervical Artificial Disc in order for the staff to become familiar with the implantation procedure for the device. Both the investigator and the patient were to be blinded to the randomization until immediately prior to surgery. Immediately before surgery, preferably while the patient was under anesthesia, the investigator or designee opened the treatment assignment envelope corresponding to the patient's clinical trial number. After assigning treatment, the {10} investigator was not blinded to the treatment. Data on whether a randomized patient was blinded was not captured on any case report form. Surgeons were instructed as to blinding the patient to their treatment prior to surgery. The applicant is not aware of any randomized patient who was unblinded to their treatment. Patients were evaluated preoperatively, intraoperatively, immediately postoperatively and then at 6 weeks, 3 months, 6 months, 12 months and 24 months and annually thereafter. The recommended postoperative care included use of an external orthosis for 3 weeks postoperatively, followed by a physical therapy program for active range of motion exercises. Patients were instructed to avoid lifting above their shoulders for 3 months, and to avoid athletic activities and repetitive bending or lifting for 6 months. Smokers were encouraged not to smoke. Patients were not treated with NSAIDs postoperatively in either treatment group. All adverse events (device-related or not) were monitored over the course of the study and radiographic assessments were done by an independent core laboratory. Overall success was determined by data collected during the initial 24 months of follow-up. For the PMA, all adverse events were independently adjudicated (for adverse event code, severity and relationship to the device and/or procedure) by a Clinical Events Committee comprised of two practicing spine surgeons. The study was designed as a non-inferiority trial with a margin (delta) of 15%. Bayesian statistical methods were used to obtain the posterior probabilities of non-inferiority and superiority, using a delta of 15%. Additional analyses using a delta of 10% as requested by FDA were also incorporated. The Bayesian model incorporated postoperative data from the 24 month time point and also the 6 month and 12 month time points for purposes of imputing incomplete or missing data. The protocol specified a sample size of 140 randomized patients per group based on an assumed 70% success rate in both treatment groups, a 20% drop out rate, and 80% power for a one-sided 0.05 significance level. With the addition of up to 5 non-randomized patients per site, the total planned sample size was 380 (100 non-randomized SECURE®-C, 140 randomized SECURE®-C, 140 ACDF). 1. Clinical Inclusion and Exclusion Criteria Enrollment in the SECURE®-C study was limited to patients who met the following inclusion criteria. - Symptomatic cervical disc disease (SCDD) in one vertebral level between C3-C7, defined as neck or arm (radicular) pain, or functional or neurological deficit and radiographic confirmation (by CT, MRI, X-ray, etc.) of any of the following: - Herniated nucleus pulposus; - Radiculopathy or myelopathy; - Spondylosis (defined by the presence of osteophytes); or - Loss of disc height. - Age between 18 and 60 years - Failed at least 6 weeks of conservative treatment - Neck Disability Index (NDI) Questionnaire score of at least 30 (as percentage of 50 point total) PMA P100003: FDA Summary of Safety and Effectiveness Data Page 11 of 50 {11} - Able to understand and sign informed consent form - Psychosocially, mentally and physically able to fully comply with this protocol including adhering to follow-up schedule and filling out forms - Able to meet the proposed follow-up schedule at 6 weeks, 3 months, 6 months, 12 months and 24 months - Able to follow postoperative management program Patients were not permitted to enroll in the SECURE®-C study if they met any of the following exclusion criteria. - More than one vertebral level requiring treatment - Prior fusion surgery adjacent to the vertebral level being treated - Prior surgery at the level to be treated - Clinically compromised vertebral bodies at the affected level(s) due to current or past trauma - Radiographic confirmation of facet joint disease or degeneration, defined as apparent sclerosis and/or hypertrophy of the facets demonstrated on AP radiographs as a disruption of the normally smooth facet curve - Marked cervical instability on resting lateral or flexion/extension radiographs: - Translation greater than 3mm, and/or - More than 11° of rotational difference from that of either adjacent level. - Severe spondylosis at the level to be treated as characterized by any of the following: - Bridging osteophytes; - A loss of disc height greater than 50%; or - Absence of motion (&lt;2°) - Neck or arm pain of unknown etiology - Osteoporosis, osteopenia, Paget’s disease, osteomalacia or any other metabolic bone disease - Pregnant or interested in becoming pregnant in the next 2 years - Active systemic or local infection - Known allergy to titanium, polyethylene, cobalt, chromium or molybdenum - Taking medications or any drug known to potentially interfere with bone/soft tissue healing (e.g., steroids) - Rheumatoid arthritis or other autoimmune disease - Systemic disease including AIDS, HIV, Hepatitis - Active malignancy: A patient with a history of any invasive malignancy (except non-melanoma skin cancer), unless he/she has been treated with curative intent and there has been no clinical signs or symptoms of the malignancy for at least 5 years - Neuromuscular disorders such as muscular dystrophy, spinal muscular atrophy, amyotrophic lateral sclerosis, etc. - Acute mental illness or substance abuse - Use of bone growth stimulator within past 30 days - Participation in other investigational device or drug clinical trials within 30 days of surgery - Prisoners PMA P100003: FDA Summary of Safety and Effectiveness Data Page 12 of 50 {12} PMA P100003: FDA Summary of Safety and Effectiveness Data Page 13 of 50 2. Follow-up Schedule All patients were scheduled to return for follow-up examinations at 6 weeks (±2 weeks), 3 months (±2 weeks), 6 months (±1 month), 12 months (±2 months), 24 months (±2 months), and annually thereafter (±2 months). The following parameters were measured: Table 4. Clinical Evaluation Schedule | Evaluation | Pre-op | Surgery/Hospital Discharge | 6 wks | 3 mo | 6 mo | 12 mo | 24 mo & annually | | --- | --- | --- | --- | --- | --- | --- | --- | | Neck Disability Index | X | | X | X | X | X | X | | Neck and Arm Pain (VAS) | X | | X | X | X | X | X | | Health Status (SF-36) | X | | X | X | X | X | X | | Neurological Status | X | | | | X | X | X | | Adverse Events* | X | X | X | X | X | X | X | | Demographic/Baseline Data | X | | | | | | | | Operative Data | | X | | | | | | | Medication Use | X | | | | X | X | X | | Imaging Studies: | | | | | | | | | AP & lateral | X | X | X | X | X | X | X | | Lateral flex/extension | X | | | | X | X | X | | CT and/or MRI | X | | | | | | | | Radiographic Outcomes: | | | | | | | | | Range of motion | X | | | | X | X | X | | Disc height | X | | | | X | X | X | | Device migration | | | X | X | X | X | X | | Fusion status | | | | | X | X | X | | Radiolucency | | | | | X | X | X | | Patient Satisfaction | | | | | | X | X | *Adverse events and complications were recorded at all visits (both scheduled and unscheduled). 3. Clinical Endpoints The safety of the SECURE®-C was assessed by comparing the nature and frequency of adverse events (overall and in terms of severity and relationship to the device and/or procedure) and secondary surgical procedures as well as maintenance or improvement in neurological status to the ACDF control group. The effectiveness of the SECURE®-C was assessed by evaluating improvement in the Neck Disability Index (NDI), neck and arm pain based on a Visual Analog Scale (VAS), and quality of life using the short-form 36 questionnaire (SF-36) as well as patient satisfaction compared to the ACDF control group. In addition, several radiographic endpoints were considered in evaluating both safety and effectiveness, including range of motion, disc height, device displacement or migration, radiolucency, spinal fusion status, and heterotopic ossification. Per the protocol, an individual patient was considered a success if the following criteria were met at 24 months: {13} - Pain/disability improvement of at least 25% in NDI compared to baseline; - No device failures requiring revision, removal, reoperation, or supplemental fixation; - Absence of major complications defined as major vessel injury, neurological damage, or nerve injury; and - For control fusion patients only, radiographic fusion, as defined by the presence of bridging trabecular bone, without evidence of pseudarthrosis (defined radiographically as no apparent bridging trabecular bone and range of motion &gt;3mm in translation and &gt;2° in rotation). In addition, FDA requested an additional analysis in which an individual patient was considered a success if the following criteria were met at 24 months: - Pain/disability improvement of at least 15 points in NDI compared to baseline; - No secondary surgery at the index level including revision, removal, reoperation or supplemental fixation; - No potentially device-related adverse events; - Maintenance or improvement in all components of neurologic status; and - No SECURE®-C intraoperative changes in treatment. Overall study success criteria were based on a comparison of individual patient success rates, such that the patient success rate for the SECURE®-C investigational group must be non-inferior to that of the ACDF fusion control group. Bayesian statistical methods were used to obtain the posterior probabilities of non-inferiority and superiority. The IDE study was approved using a non-inferiority margin (delta) of 15% with an advisory that a non-inferiority margin of 10% would be required to demonstrate a reasonable assurance of the device's effectiveness. According to the statistical analysis plan, if non-inferiority was demonstrated, then superiority would be evaluated as defined more specifically in the analysis plan. Of note, the statistical analysis plan pre-specified that the analysis technique would involve predicting 24 month outcomes for those without them, based on interim 6 month and 12 month observed outcomes, and integrating over the predictions to obtain posterior probabilities of non-inferiority and superiority. Secondary effectiveness evaluations specified in the protocol included comparisons of: - Components of the primary - Pain/Disability Improvement (NDI) - No device failures requiring revision, re-operation or removal - Absence of major complications - Neck Disability Index: 25% improvement from baseline - VAS pain scales (neck, right, and left arm): 20mm improvement from baseline - Health Status Survey SF-36 (mental and physical composite scores): 15% improvement from baseline - Neurological status (maintenance, worsening, or improvement): proportion of patients maintained or improved - Mean range of motion (angulation and translation) - Disc height on standard lateral radiograph: 2mm changes compared to baseline - No significant radiolucency for the SECURE®-C device: proportion of patients PMA P100003: FDA Summary of Safety and Effectiveness Data Page 14 of 50 {14} - Spinal fusion in the control arm - Patient satisfaction (definitely/mostly): proportion of patients - Device displacement or migration (&gt;3mm) - Operative time - Operative blood loss - Return to work ## B. Accountability of PMA Cohort At the time of database lock, of the 380 patients enrolled in the PMA study, all had reached the 24 month post-operative visit and 331 (87.1%) had data available for analysis at the completion of the study. Complete primary endpoint data (including fusion status for control group patients) was available for 215 investigational (77 non-randomized, 138 randomized) and 98 control patients at 24 months. A total of 5 investigational (2 non-randomized and 3 randomized) and 10 control patients had failures at or prior to the 24 month visit. 36 month follow-up data was also provided in the PMA for some of the study patients. A summary of patient accountability data for the 12 month, 24 month, and 36 month follow-up visits is provided in Table 5, and a summary of data available at 24 months for each specific evaluation is provided in Table 6. Table 5. Patient Accountability (based on treatment assignment*) | Number of Patients | 12 Months (±2 Months) | | | 24 Months (±2 Months) | | | 36 Months (±2 Months) | | | | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | | | NR SEC | R SEC | R ACDF | NR SEC | R SEC | R ACDF | NR SEC | R SEC | R ACDF | | Enrolled | 89 | 151 | 140 | 89 | 151 | 140 | 89 | 151 | 140 | | Theoretical | 89 | 151 | 140 | 89 | 151 | 140 | 89 | 151 | 140 | | Deaths¹ | 1 | 0 | 0 | 1 | 0 | 0 | 1 | 0 | 0 | | Failures¹ | 1 | 1 | 6 | 2 | 3 | 10 | 2 | 4 | 11 | | Not yet overdue | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 15 | 8 | | Expected² | 87 | 150 | 134 | 86 | 148 | 130 | 85 | 132 | 121 | | Actual, efficacy³ (% Follow-up) | 82 (94.3%) | 140 (93.3%) | 114 (85.1%) | 77 (89.5%) | 138 (93.2%) | 98 (75.4%) | 60 (70.6%) | 60 (45.5%) | 38 (31.4%) | | Actual, efficacy in window⁴ (% Follow-up) | 81 (93.1%) | 127 (84.7%) | 99 (73.9%) | 70 (81.4%) | 110 (74.3%) | 83 (63.8%) | 38 (44.7%) | 43 (32.6%) | 26 (21.5%) | | Actual, any data⁵ (% Follow-up) | 82 (94.3%) | 140 (93.3%) | 121 (90.3%) | 78 (90.7%) | 138 (93.2%) | 115 (88.5%) | 60 (70.6%) | 60 (45.5%) | 47 (38.8%) | NR SEC=Non-randomized SECURE®-C; R SEC=Randomized SECURE®-C; R ACDF=Control * A total of 380 patients at 18 sites were enrolled and treated in the IDE clinical trial; 236 received SECURE®-C (88 non-randomized, 148 randomized) and 144 received control treatment. Four patients intended to be treated with SECURE®-C (1 non-randomized and 3 randomized) were intraoperatively treated with ACDF; 1 was due to a randomization error by the site, 1 was due to inability to visualize the disc space due to the patient's large shoulders, and 2 were due to small patient anatomy. 1 Deaths and failures are cumulative 2 Theoretical patients minus the number of deaths, failures, and not yet overdue 3 Patients with complete efficacy data 4 Patients with complete efficacy data within the specified visit window 5 Patients with any information recorded at the visit PMA P100003: FDA Summary of Safety and Effectiveness Data Page 15 of 50 {15} Table 6. 24 Month Data Accounting | Parameter | NR SEC | R SEC | R ACDF | | --- | --- | --- | --- | | Intended to be implanted | 89 | 151 | 140 | | Expected* (As-randomized) | 86 | 148 | 131 | | Implanted | 88 | 148 | 144 | | Expected† (As-treated) | 85 | 145 | 133 | | NDI | 78 (90.7%) | 139 (93.9%) | 116 (88.5%) | | VAS Neck and Arm Pain‡ | 75 (87.2%) | 133 (89.9%) | 108 (82.4%) | | SF-36 | 78 (90.7%) | 138 (93.2%) | 115 (87.8%) | | Patient Survey | 78 (90.7%) | 139 (93.9%) | 116 (88.5%) | | Neurological Exam† | 75 (88.2%) | 123 (84.8%) | 101 (75.9%) | | Radiologic Assessments† | | | | | • Disc height | • 74 (87.1%) | • 119 (82.1%) | • 99 (74.4%) | | • Change in disc height | • 71 (83.5%) | • 118 (81.4%) | • 95 (71.4%) | | • Radiolucency | • 75 (88.2%) | • 122 (84.1%) | • 104 (78.2%) | | • Migration | • 75 (88.2%) | • 122 (84.1%) | • N/A | | • ROM | • 75 (88.2%) | • 120 (82.8%) | • 101 (75.9%) | | • Change in ROM from baseline | • 67 (78.8%) | • 113 (77.9%) | • 91 (68.4%) | | • Translation | • 74 (87.1%) | • 120 (82.8%) | • 99 (74.4%) | | • Change in translation from baseline | • 67 (78.8%) | • 113 (77.9%) | • 90 (67.7%) | NR SEC=Non-randomized SECURE®-C; R SEC=Randomized SECURE®-C; R ACDF=Control *3 randomized SECURE®-C subjects and 1 non-randomized SECURE®-C subject are included in their respective SECURE®-C group, but actually received ACDF. Expected is intended minus failures and deaths. † Neurologic and radiographic data are reported for subjects as-treated. Expected is treated minus failures/deaths. ‡Per FDA, VAS data excludes one site in which some scores were reported verbally. In the tables that follow throughout this summary, the as-treated population is used for safety analyses (88 non-randomized SECURE®-C, 148 randomized SECURE®-C, 144 ACDF) and the as-randomized population is used for efficacy analyses (89 non-randomized SECURE®-C, 151 randomized SECURE®-C, 140 ACDF). Statistical comparisons for efficacy are made between randomized groups, for patients as they were intended to be treated, referred to as the "As-Randomized" population. Safety comparisons such as adverse events and radiographic measurements are made between randomized groups, for patients as they were actually treated, referred to as the "As-Treated" population. ## C. Study Population Demographics and Baseline Parameters The demographics of the study population are typical for a cervical artificial disc study conducted in the US. Demographic data and preoperative evaluations for all patients enrolled and treated in the study are included in Table 7 and Table 8. Bayesian Credible Intervals (BCIs) for the difference (SECURE®-C – ACDF) between the randomized groups are presented. PMA P100003: FDA Summary of Safety and Effectiveness Data Page 16 of 50 {16} Table 7. Patient Demographics and Baseline Characteristics | Demographic Measure | Non-Randomized SECURE-C (N=89) | Randomized SECURE-C (N=151) | Randomized ACDF (N=140) | 95% BCI (Randomized Groups) | | --- | --- | --- | --- | --- | | Gender | | | | | | Male | 47 (52.8%) | 81 (53.6%) | 68 (48.6%) | (-6.4%, 16.3%) | | Female | 42 (47.2%) | 70 (46.4%) | 72 (51.4%) | | | Age (years) | 41.6 ±8.13 Range: 20 - 60 | 43.4 ±7.50 Range: 24 - 60 | 44.4 ±7.86 Range: 25 - 59 | (-2.7, 0.8) | | Race | | | | | | Caucasian | 79 (88.8%) | 136 (90.1%) | 126 (90.0%) | (-6.8%, 7.2%)* | | Black | 6 (6.7%) | 10 (6.6%) | 10 (7.1%) | | | Asian | 0 | 0 | 0 | | | Hispanic | 2 (2.2%) | 2 (1.3%) | 3 (2.1%) | | | Other | 2 (2.2%) | 3 (2.0%) | 1 (0.7%) | | | Height (in) | 67.3 ±4.03 Range: 59 - 76 | 68.1 ±3.68 Range: 60 - 76 | 67.3 ±4.07 Range: 60 - 77 | (-0.1, 1.7) | | Weight (lbs) | 181.6 ±46.05 Range: 110 - 330 | 191.6 ±45.87 Range: 104 - 365 | 187.1 ±40.32 Range: 107 - 320 | (-5.5, 14.4) | | BMI (kg/m²) | 27.9 ±5.36 Range: 19 - 43 | 28.9 ±5.53 Range: 18 - 48 | 29.0 ±5.47 Range: 20 - 45 | (-1.4, 1.2) | | Current tobacco use (yes)** | 21 (23.6%) | 51 (33.8%) | 53 (37.9%) | (-14.9%, 6.9%) | | Symptom duration (mo) | 25.4 ±44 Range: 1 - 304 | 16.6 ±27 Range: 0 - 189 | 19.8 ±40 Range: 0 - 272 | (-11.2, 4.7) | | History non-op care (yes) | 85 (95.5%) | 147 (97.4%) | 138 (98.6%) | (-5.0%, 2.5%) | | • Narcotics use | • 63 (70.8%) | • 108 (71.5%) | • 104 (74.3%) | | | • Injections | • 47 (52.8%) | • 57 (37.7%) | • 62 (44.3%) | | | • Physical therapy | • 53 (59.6%) | • 85 (56.3%) | • 77 (55.0%) | | | • Brace | • 13 (14.6%) | • 12 (7.9%) | • 14 (10.0%) | | | • Chiropractic | • 20 (22.5%) | • 35 (23.2%) | • 44 (31.4%) | | | • Other | • 13 (14.6%) | • 44 (29.1%) | • 37 (26.4%) | | | History prior surgery (yes) | 4 (4.5%) | 2 (1.3%) | 4 (2.9%) | (-5.6%, 2.1%) | | • Discectomy | • 0 | • 0 | • 2 (1.4%) | | | • Other | • 4 (4.5%) | • 2 (1.3%) | • 3 (2.1%) | | | Medication use in prior week for neck/arm pain (yes) | | | | | | • Non-narcotics | • 63 (70.8%) | • 109 (72.2%) | • 96 (68.6%) | (-6.8%, 14.0%) | | • Weak narcotics | • 41 (46.1%) | • 71 (47.0%) | • 62 (44.3%) | (-8.7%, 14.0%) | | • Strong narcotics | • 25 (28.1%) | • 50 (33.1%) | • 44 (31.4%) | (-9.0%, 12.3%) | | • Muscle relaxants | • 33 (37.1%) | • 51 (33.8%) | • 57 (40.7%) | (-17.9%, 4.2%) | | Preoperative pain status: | | | | | | • Arm and neck pain | • 82 (92.1%) | • 144 (95.4%) | • 134 (95.7%) | (-5.3%, 4.8%) | | • Arm pain only | • 2 (2.2%) | • 4 (2.6%) | • 5 (3.6%) | (-5.5%, 3.3%) | | • Neck pain only | • 4 (4.5%) | • 2 (1.3%) | • 1 (0.7%) | (-2.4%, 3.6%) | | Preoperative radiographic findings: | | | | | | • Herniated nucleus | • 62 (69.7%) | • 127 (84.1%) | • 123 (87.9%) | (-11.6%, 4.3%) | PMA P100003: FDA Summary of Safety and Effectiveness Data Page 17 of 50 {17} | Demographic Measure | Non-Randomized SECURE-C (N=89) | Randomized SECURE-C (N=151) | Randomized ACDF (N=140) | 95% BCI (Randomized Groups) | | --- | --- | --- | --- | --- | | pulposus | | | | | | • Spondylosis | • 55 (61.8%) | • 83 (55.0%) | • 79 (56.4%) | (-12.7%, 9.9%) | | • Loss of disc height | • 14 (15.7%) | • 16 (10.6%) | • 19 (13.6%) | (-10.6%, 4.5%) | *Caucasian vs. other; **Data on amount and length of tobacco use was not captured. Table 8. Preoperative Evaluation of Endpoints | Variable | Non-Randomized SECURE-C (N=89) | Randomized SECURE-C (N=151) | Randomized ACDF (N=140) | 95% BCI (Randomized Groups) | | --- | --- | --- | --- | --- | | NDI | 50.1 ±15.03 | 51.8 ±13.84 | 51.5 ±14.86 | (-3.0, 3.7) | | VAS Neck Pain* | 64.1 ±26.18 | 65.2 ±26.84 | 63.4 ±27.34 | (-4.8, 8.2) | | VAS Left Arm Pain* | 38.8 ±35.48 | 45.1 ±37.35 | 39.8 ±36.28 | (-3.5, 14.1) | | VAS Right Arm Pain* | 34.9 ±36.71 | 33.8 ±37.03 | 37.9 ±37.09 | (-12.9, 4.8) | | SF-36 PCS | 33.8 ±7.71 | 33.9 ±7.41 | 32.0 ±6.48 | (0.2, 3.4) | | SF-36 MCS | 42.9 ±11.01 | 44.0 ±13.16 | 44.4 ±11.97 | (-3.3, 2.5) | | Neurological Status (normal) | 22 (24.7%) | 31 (20.5%) | 28 (20.0%) | (-8.8%, 9.7%) | | • Motor | • 50 (56.2%) | • 68 (45.0%) | • 68 (48.6%) | | | • Sensory | • 59 (66.3%) | • 69 (45.7%) | • 66 (47.1%) | | | • Reflexes | • 60 (67.4%) | • 92 (60.9%) | • 95 (67.9%) | | | • Other assessments | • 58 (65.2%) | • 97 (64.2%) | • 86 (61.4%) | | | Baseline ROM angulation (°) | 9.5 ±5.2 Range: 0.3 – 23.4 | 8.5 ±4.8 Range: 0.1 – 23.3 | 7.2 ±4.3 Range: 0.1 – 19.3 | (0.2, 2.4) | | Baseline ROM translation (mm) | 1.0 ±0.75 Range: 0 – 3.4 | 0.9 ±0.62 Range: 0 – 3.4 | 0.8 ±0.59 Range: 0 – 2.7 | (0.0, 0.3) | * Per FDA, VAS data excludes one site in which some scores were reported verbally ## D. Safety and Effectiveness Results ### 1. Safety Results The analysis of safety was based on the as-treated cohort of 380 total patients (88 non-randomized SECURE®-C patients, 148 randomized SECURE®-C patients, and 144 ACDF patients). ### Adverse events that occurred in the PMA clinical study: A summary of the total number of adverse events, events classified by the Clinical Events Committee (CEC) as device-related, events classified by the CEC as surgery-related, events classified by the CEC as severe or life-threatening, events within 48 hours of the original procedure, and device failures (defined as a revision, removal, reoperation or supplemental fixation) are shown in Table 9. PMA P100003: FDA Summary of Safety and Effectiveness Data {18} Table 9. Adverse Event Summary | Adverse Event Type | Measure | NR SEC (N=88) | R SEC (N=148) | R ACDF (N=144) | Statistics* | | --- | --- | --- | --- | --- | --- | | All Adverse Events (AEs) | Patients (%) | 60 (68.2%) | 107 (72.3%) | 114 (79.2%) | (-17.0%, 2.4%) | | | Events (E/pt) | 130 (1.48) | 247 (1.67) | 294 (2.04) | 0.9978 | | Device-Related AEs | Patients (%) | 2 (2.3%) | 4 (2.7%) | 14 (9.7%) | (-13.0%, -1.5%) | | | Events (E/pt) | 2 (0.02) | 4 (0.03) | 17 (0.12) | 0.9990 | | Surgery-Related AEs | Patients (%) | 4 (4.5%) | 9 (6.1%) | 18 (12.5%) | (-13.3%, 0.2%) | | | Events (E/pt) | 4 (0.05) | 10 (0.07) | 20 (0.14) | 0.9789 | | Severe or Life-Threatening AEs | Patients (%) | 17 (19.3%) | 29 (19.6%) | 34 (23.6%) | (-13.6%, 5.3%) | | | Events (E/pt) | 23 (0.26) | 38 (0.26) | 44 (0.31) | 0.8378 | | AEs within 48 hrs of surgery | Patients (%) | 1 (1.1%) | 3 (2.0%) | 7 (4.9%) | Not provided | | | Events | 1 (0.01) | 4 (0.03) | 8 (0.06) | Not provided | | Device Failures (revision, reoperation, removal, or supplemental fixation) | | 2 | 4 | 17 | 0.9990 | NR SEC=Non-randomized SECURE®-C; R SEC=Randomized SECURE®-C; R ACDF=Control *For patient comparison: 95% BCI (lower, upper) for comparison of the difference (SECURE®-C - control) between randomized groups *For event comparison: Posterior probability that the event rate (E/pt) is lower in the SECURE®-C group than the ACDF group Note: For statistical comparisons of only randomized patients, ACDF group excludes 1 non-randomized patient, therefore N=143. This table includes data collected beyond 24 months. Table 10 provides data on the total number of adverse events in each treatment group stratified by level treated. The percentage of subjects with adverse events was similar for the SECURE®-C and ACDF groups, for all treated levels. Table 10. Total Adverse Events by Level Treated | Level Treated | NR SEC | R SEC | R ACDF | 95% BCI (lower, upper) | | --- | --- | --- | --- | --- | | C3-4 | 1/3 (33.3%) | 5/5 (100%) | 4/4 (100%) | (-35.3%, 42.4%) | | C4-5 | 5/7 (71.4%) | 5/8 (62.5%) | 11/11 (100%) | (-64.6%, -1.2%) | | C5-6 | 30/47 (63.8%) | 56/74 (75.7%) | 56/72 (77.8%) | (-16.5%, 10.5%) | | C6-7 | 24/31 (77.4%) | 41/61 (67.2%) | 43/57 (75.4%) | (-23.8%, 8.2%) | NR SEC=Non-randomized SECURE®-C; R SEC=Randomized SECURE®-C; R ACDF=Control Note: This table includes data collected beyond 24 months. The adverse events reported in the PMA clinical study from all 236 SECURE®-C patients and 144 ACDF patients are shown in Table 11. This table includes adverse events from all patients, randomized and non-randomized, to establish the safety profile of the device. Adverse events are listed in alphabetical order. Definitions of the adverse event categories are provided in Table 12. Adverse event rates are based on the number of patients having at least one occurrence of an adverse event, divided by the number of patients in that treatment group. Events per patient are based on the number of adverse events, divided by the number of patients. Note that patients with the same event reported within a window are counted once but may appear in multiple time points for the same event. The overall adverse event profile (percentage of patients experiencing at least one adverse event) is qualitatively lower PMA P100003: FDA Summary of Safety and Effectiveness Data Page 19 of 50 {19} for the randomized SECURE®-C group (70.8%) than the control ACDF group (79.2%), but is not statistically different. In addition, the overall number of adverse events per patient is lower for the SECURE®-C group(s) than the ACDF group (posterior probability 0.9978). In the SECURE®-C group, the most common adverse events were neck pain, upper extremity pain, back and/or lower extremity pain, and trauma. One non-randomized SECURE®-C patient died of cardiopulmonary arrest 210 days after surgery. The patient had poor cardiovascular fitness and the event was not considered to be associated with the device by the investigator or the Clinical Events Committee (CEC). One randomized ACDF patient died of unknown causes 1111 days after surgery. No other patients died during the study. Table 11. All Adverse Events (All Patients As Treated) | Adverse Event | Intra-Op(0-2 days) | | Peri-Op(>2days-6wks) | | Short Term(>6wks-12mo) | | Long Term(>12mo-24mo) | | Longer Term(>24mo) | | ALL SECURE-C(N=236) | | ACDF(N=144) | | | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | | | SEC | ACF | SEC | ACF | SEC | ACF | SEC | ACF | SEC | ACF | Patients(%) | Events(E/Pt) | Patients(%) | Events(E/Pt) | | All Adverse Events | | | | | | | | | | | 167 (70.8%) | 377 (1.60) | 114 (79.2%) | 294 (2.04) | | Cancer1 | 0 | 0 | 0 | 0 | 1 | 0 | 1 | 0 | 2 | 0 | 4 (1.7%) | 4 (0.02) | 0 (0.0%) | 0 (0.00) | | Cardiovascular | 0 | 0 | 1 | 0 | 4 | 0 | 4 | 0 | 0 | 1 | 8 (3.4%) | 10 (0.04) | 1 (0.7%) | 1 (0.01) | | Carpal Tunnel Syndrome (CTS) | 0 | 0 | 1 | 0 | 8 | 5 | 2 | 3 | 1 | 0 | 12 (5.1%) | 12 (0.05) | 8 (5.6%) | 8 (0.06) | | Cerebrovascular | 0 | 0 | 1 | 0 | 1 | 0 | 1 | 1 | 0 | 1 | 3 (1.3%) | 3 (0.01) | 2 (1.4%) | 3 (0.02) | | Compressive Peripheral Neuropathy (Non-CTS) | 0 | 0 | 2 | 0 | 2 | 0 | 2 | 0 | 1 | 0 | 7 (3.0%) | 7 (0.03) | 0 (0.0%) | 0 (0.00) | | Death | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 1 | 1 (0.4%) | 1 (0.01) | 1 (0.7%) | 1 (0.01) | | Dysesthesia - Lower Extremities | 0 | 0 | 0 | 0 | 2 | 1 | 0 | 0 | 0 | 0 | 2 (0.8%) | 2 (0.01) | 1 (0.7%) | 1 (0.01) | | Dysesthesia - Other | 0 | 0 | 2 | 1 | 0 | 2 | 0 | 0 | 0 | 0 | 2 (0.8%) | 2 (0.01) | 3 (2.1%) | 3 (0.02) | | Dysesthesia - Upper Extremities | 1 | 0 | 3 | 5 | 10 | 9 | 3 | 2 | 5 | 1 | 20 (8.5%) | 25 (0.11) | 15 (10.4%) | 18 (0.13) | | Dysphagia | 0 | 4 | 4 | 3 | 1 | 1 | 1 | 0 | 0 | 0 | 6 (2.5%) | 6 (0.02) | 8 (5.6%) | 8 (0.06) | | Dysphonia | 0 | 1 | 0 | 1 | 1 | 0 | 0 | 0 | 0 | 0 | 1 (0.4%) | 1 (0.01) | 2 (1.4%) | 2 (0.01) | | Gastrointestinal | 0 | 0 | 0 | 1 | 4 | 0 | 2 | 0 | 0 | 0 | 6 (2.5%) | 6 (0.02) | 1 (0.7%) | 1 (0.01) | | Headache | 0 | 0 | 1 | 2 | 4 | 5 | 1 | 3 | 2 | 1 | 8 (3.4%) | 8 (0.03) | 11 (7.6%) | 11 (0.08) | | Infection - Other | 0 | 0 | 0 | 1 | 2 | 2 | 1 | 0 | 0 | 0 | 3 (1.3%) | 3 (0.01) | 3 (2.1%) | 3 (0.02) | | Infection - Superficial Wound | 0 | 0 | 0 | 2 | 0 | 0 | 0 | 0 | 0 | 0 | 0 (0.0%) | 0 (0.00) | 2 (1.4%) | 2 (0.01) | | Muscle Spasms | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 (0.0%) | 0 (0.00) | 1 (0.7%) | 1 (0.01) | | Musculoskeletal | 0 | 0 | 4 | 1 | 16 | 5 | 8 | 2 | 3 | 2 | 30 (12.7%) | 36 (0.15) | 9 (6.3%) | 10 (0.07) | | Neurological | 0 | 0 | 1 | 1 | 1 | 2 | 0 | 1 | 1 | 0 | 3 (1.3%) | 3 (0.01) | 4 (2.8%) | 7 (0.05) | | Other* | 1 | 1 | 1 | 2 | 5 | 1 | 2 | 1 | 2 | 1 | 11 (4.7%) | 11 (0.05) | 4 (2.8%) | 6 (0.04) | | Pain - Back and/or Lower Extremities | 0 | 0 | 2 | 3 | 16 | 11 | 8 | 4 | 10 | 7 | 36 (15.3%) | 37 (0.16) | 23 (16.0%) | 28 (0.20) | | Pain - Neck | 1 | 0 | 13 | 17 | 21 | 21 | 6 | 5 | 12 | 4 | 50 (21.2%) | 53 (0.22) | 41 (28.5%) | 51 (0.35) | | Pain - Neck and Upper Extremities | 0 | 0 | 8 | 7 | 13 | 13 | 4 | 5 | 3 | 3 | 26 (11.0%) | 29 (0.12) | 28 (19.4%) | 28 (0.19) | | Pain - Neck and Upper Extremities with Dysesthesia | 0 | 0 | 1 | 0 | 0 | 3 | 0 | 0 | 0 | 0 | 1 (0.4%) | 1 (0.01) | 3 (2.1%) | 3 (0.02) | | Pain - Neck with Dysesthesia | 0 | 0 | 0 | 1 | 2 | 3 | 0 | 0 | 0 | 0 | 2 (0.8%) | 2 (0.01) | 4 (2.8%) | 4 (0.03) | | Pain - Other | 1 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 1 | 2 (0.8%) | 2 (0.01) | 1 (0.7%) | 1 (0.01) | | Pain - Upper Extremities | 1 | 2 | 10 | 9 | 12 | 8 | 9 | 3 | 6 | 5 | 32 (13.6%) | 43 (0.18) | 24 (16.7%) | 28 (0.20) | | Pain - Upper Extremities with Dysesthesia | 0 | 0 | 1 | 0 | 3 | 1 | 0 | 1 | 1 | 0 | 5 (2.1%) | 5 (0.02) | 2 (1.4%) | 3 (0.02) | | Psychological | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 1 (0.4%) | 1 (0.01) | 1 (0.7%) | 1 (0.01) | PMA P100003: FDA Summary of Safety and Effectiveness Data Page 20 of 50 {20} | Adverse Event | Intra-Op (0-2 days) | | Peri-Op (>2days-6wks) | | Short Term (>6wks-12mo) | | Long Term (>12mo-24mo) | | Longer Term (>24mo) | | ALL SECURE-C (N=236) | | ACDF (N=144) | | | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | | | SEC | ACF | SEC | ACF | SEC | ACF | SEC | ACF | SEC | ACF | Patients (%) | Events (E/Pt) | Patients (%) | Events (E/Pt) | | Surgery - Adjacent Level | 0 | 0 | 0 | 0 | 2 | 0 | 0 | 0 | 2 | 2 | 4 (1.7%) | 4 (0.02) | 2 (1.4%) | 3 (0.02) | | Surgery - Index Level | 0 | 0 | 1 | 4 | 2 | 4 | 2 | 2 | 2 | 4 | 6 (2.5%) | 7 (0.03) | 14 (9.7%) | 17 (0.00) | | Surgery - Lumbar Level | 0 | 0 | 0 | 2 | 4 | 2 | 1 | 0 | 1 | 1 | 6 (2.5%) | 6 (0.03) | 5 (3.5%) | 7 (0.05) | | Surgery - Other Cervical | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 (0.0%) | 0 (0.00) | 1 (0.7%) | 1 (0.00) | | Surgery - Thoracic Level | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 1 (0.4%) | 1 (0.01) | 0 (0.0%) | 0 (0.00) | | Trauma | 0 | 0 | 7 | 3 | 13 | 8 | 6 | 7 | 6 | 2 | 30 (12.7%) | 42 (0.18) | 17 (11.8%) | 28 (0.20) | | Urogenital | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 1 (0.4%) | 1 (0.01) | 0 (0.0%) | 0 (0.00) | | Weakness | 0 | 0 | 0 | 0 | 2 | 1 | 1 | 0 | 0 | 0 | 3 (1.3%) | 3 (0.01) | 1 (0.7%) | 1 (0.01) | | Wound Issue | 0 | 0 | 0 | 4 | 0 | 0 | 0 | 0 | 0 | 0 | 0 (0.0%) | 0 (0.00) | 4 (2.8%) | 4 (0.03) | SEC = all SECURE®-C Cervical Artificial Disc; ACDF = Anterior Cervical Discectomy and Fusion (Control) 3 non-randomized SEC: prostate cancer at 692 days, metastatic colon cancer at 959 days, metastatic esophageal cancer at 979 days; 1 randomized SEC: lymphoma at 358 days *Other: diabetes (SEC, ACDF), thyroid disease (2 SEC, ACDF), hemolytic syndrome (SEC), Wegener's granulomatosis (SEC), CSF leak after lumbar ESI (SEC), corneal abrasion (SEC), allergic reaction to medication (SEC) or to cervical collar material (2 ACDF), lightheadedness (SEC), flu symptoms (ACDF), occasional clicking (ACDF), mild lump in throat without dysphagia (SEC), and snoring (SEC). Note: This table includes data collected beyond 24 months. Table 12. Adverse Event Categories | Category | Definition | | --- | --- | | Cancer | A malignancy or malignant tumor/neoplasm | | Cardiovascular | Any condition of the heart and/or blood vessels (excluding the blood vessels that supply the brain) | | Carpal Tunnel Syndrome (CTS) | Condition with entrapment of the median nerve in the carpal tunnel | | Cerebrovascular | Any condition relating to the brain and the blood vessels that supply it | | Compressive Peripheral Neuropathy (Non-CTS) | Dysfunction of one or more nerves excluding Carpal Tunnel Syndrome | | Death | The termination of life | | Dysesthesia - Lower Extremities | Dysesthesia in the lower extremities including hips, buttocks, legs, knees, feet, toes | | Dysesthesia - Other | Dysesthesia in areas excluding the upper and lower extremities | | Dysesthesia - Upper Extremities | Dysesthesia in the upper extremities including include neck, shoulders, arms, elbows, hands, fingers | | Dysphagia | Difficulty in swallowing | | Dysphonia | Difficulty in speaking | | Gastrointestinal | Any condition pertaining to the stomach and intestines | | Headache | Pain in various parts of the head, but not confined to the area of distribution of any nerve | | Infection - Superficial Wound | An infection near the surface of the surgical incision | | Infection - Other | An infection in an area other than the surgical incision | | Muscle Spasms | A sudden contraction of muscle(s), excluding neck or upper extremity spasms which are considered to be pain | | Musculoskeletal | Any condition pertaining to the muscles and skeleton, such as fracture, ligament tear, arthritis of any kind, and degenerative conditions, excluding muscle spasms and events related to spinal degenerative conditions | | Neurological | Any condition pertaining to a disorder of the nervous system, e.g. Multiple Sclerosis, Parkinson's Disease, Alzheimer's | | Other | An adverse event not associated with any other term | | Pain - Back and/or Lower Extremities | Pain (including stiffness, strain, tightness) in back, and/or hip, leg, ankle, feet, or buttock; includes pain with or without dysesthesia | PMA P100003: FDA Summary of Safety and Effectiveness Data {21} Bayesian methods were used to analyze the primary endpoint, and were also used to compare adverse events in the randomized groups. The analysis results are provided in Table 13, with $95\%$ Bayesian Credible Intervals (BCI) for the difference in adverse event rates (SECURE-C - ACDF). BCIs that include zero indicate no statistical difference in proportions between randomized groups. Based on the BCIs, there were no differences between groups for all adverse events, except neck and upper extremity pain and surgery-index level, which is statistically lower for SECURE®-C, and musculoskeletal (which excludes spinal events), which is statistically higher for SECURE®-C. Table 13. Statistical Comparison of Adverse Events (Randomized Patients As Treated) | Adverse Event | Patients Experiencing Adverse Events (%) | | 95% BCI (lower, upper) | | --- | --- | --- | --- | | | SEC (N=148) | ACDF (N=144) | | | Any Adverse Event | 107 (72.3%) | 114 (79.7%) | (-17.0%, 2.4%) | | Cancer | 1 (0.7%) | 0 (0.0%) | (-1.6%, 3.2%) | | Cardiovascular | 2 (1.4%) | 1 (0.7%) | (-2.3%, 3.7%) | | Carpal Tunnel Syndrome (CTS) | 10 (6.8%) | 8 (5.6%) | (-4.6%, 6.9%) | | Cerebrovascular | 1 (0.7%) | 2 (1.4%) | (-3.9%, 2.2%) | | Compressive Peripheral Neuropathy | 4 (2.7%) | 0 (0.0%) | (-0.2%, 6.2%) | | Death | 0 (0.0%) | 1 (0.7%) | (-3.3%, 1.5%) | | Dysesthesia - Lower Extremities | 2 (1.4%) | 1 (0.7%) | (-2.3%, 3.7%) | PMA P100003: FDA Summary of Safety and Effectiveness Data {22} Table 14 provides a higher level comparison of all pain adverse events that occurred in the study. There were no statistical differences between randomized groups for all pain categories listed. Rates were higher for ACDF than for SECURE®-C in all categories, but the differences were not statistically significant. Table 14. Pain Adverse Events (All Treated Subjects) | Category | NR SEC (N=88) | R SEC (N=148) | R ACDF (N=144) | 95% BCI (lower, upper)* | | --- | --- | --- | --- | --- | | Subjects with ≥1 pain AE | 39 (44.3%) | 78 (52.7%) | 88 (61.1%) | (-19.9%, 2.5) | | Total pain AEs | 58 | 122 | 157 | -- | | Number of patients | 100 | 100 | 100 | -- | | Hypoalbuminemia | 100 | 100 | 100 | -- | | Diabetes | 100 | 100 | 100 | -- | | Hypertension | 100 | 100 | 100 | -- | | Diabetes | 100 | 100 | 100 | -- | | Hypertension | 100 | 100 | 100 | -- | | Diabetes | 100 | 100 | 100 | -- | | Hypertension | 100 | 100 | 100 | -- | | Diabetes | 100 | 100 | 100 | -- | *Other previously defined in Table 11 PMA P100003: FDA Summary of Safety and Effectiveness Data {23} | Category | NR SEC (N=88) | R SEC (N=148) | R ACDF (N=144) | 95% BCI (lower, upper)* | | --- | --- | --- | --- | --- | | Subjects with ≥1 cervical spine related pain AE | 30 (34.1%) | 68 (45.9%) | 81 (56.3%) | (-21.8%, 0.8%) | | Total cervical spine related pain AEs | 41 | 100 | 128 | -- | | Pain AEs by location: • Neck • Arm • Neck and arm • Headache • Back and/or LE • Other | • 26 (29.5%) • 17 (19.3%) • 30 (34.1%) • 1 (1.1%) • 16 (18.2%) • 0 | • 51 (34.5%) • 44 (29.7%) • 67 (45.3%) • 7 (4.7%) • 20 (13.5%) • 2 (1.4%) | • 63 (43.8%) • 50 (34.7%) • 76 (52.8%) • 11 (7.6%) • 23 (16.0%) • 1 (0.7%) | (-20.5%, 1.6%) (-15.8%, 5.5%) (-19.1%, 3.6%) (-8.8%, 2.7%) (-10.8%, 5.6%) (-2.3%, 3.7%) | NR SEC=Non-randomized SECURE®-C; R SEC=Randomized SECURE®-C; R ACDF=Control *For statistical comparisons of only randomized patients, ACDF group excludes 1 non-randomized patient, therefore N=143. Note: This table includes data collected beyond 24 months. Some adverse events resulted in surgical intervention at the index level, subsequent to the initial surgery. Secondary surgical interventions, classified as revisions, removals, reoperations or supplemental fixations at the index level, are study failures and are reported in Table 15, with details provided in Table 16. The percentage of patients experiencing secondary surgery at the index level was lower for the SECURE®-C group (2.5%) than the ACDF group (9.7%), and was statistically superior between randomized groups at 24 months (95% BCI: 0.3%, 10.8%). Table 15. Secondary Surgical Interventions at the Index Level (All Patients As Treated) | Adverse Event | Intra-Op (0-2 days) | | Peri-Op (>2days-6wks) | | Short Term (>6wks-12mo) | | Long Term (>12mo-24mo) | | Longer Term (>24mo) | | TOTAL Patients (%) | | | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | | | SEC | ACDF | SEC | ACDF | SEC | ACDF | SEC | ACDF | SEC | ACDF | SEC (N=236) | ACDF (N=144) | | Revision | 0 | 0 | 0 | 1 | 0 | 2 | 0 | 2 | 0 | 1 | 0 (0.0%) | 6 (4.2%) | | Removal | 0 | 0 | 0 | 0 | 2 | 2 | 1 | 2 | 1 | 3 | 4 (1.7%) | 7 (4.9%) | | Reoperation | 0 | 0 | 0 | 0 | 0 | 1 | 1 | 0 | 1 | 0 | 2 (0.8%) | 1 (0.7%) | | Suppl Fixation | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 (0.0%) | 0 (0.0%) | | Total | 0 | 0 | 0 | 1 | 2 | 5 | 2 | 4 | 2 | 4 | 6 (2.5%) | 14 (9.7%) | SEC = all SECURE®-C Cervical Artificial Disc; ACDF = Anterior Cervical Discectomy and Fusion (Control) Note: 1 SECURE®-C and 4 ACDF secondary surgeries occurred beyond the 24 month visit window (24 + 6 months) and therefore do not count as 24 month failures. This table includes data collected beyond 24 months. Table 16. Secondary Surgical Procedure Details | Group | Cause/Adverse Event | Action | Postop Days | | --- | --- | --- | --- | | NR SEC | Arm and parascapular pain | Removal C5-6, fusion same level | 880 | | NR SEC | Neck and shoulder pain; device not properly placed in disc space | Removal C5-6, fusion same level | 183 | PMA P100003: FDA Summary of Safety and Effectiveness Data {24} | Group | Cause/Adverse Event | Action | Postop Days | | --- | --- | --- | --- | | R SEC | Neck pain | Removal C5-6, fusion C5-7 | 507 | | R SEC | C5-6 foraminal stenosis | Posterior decompression C5-6; SECURE-C device remains implanted | 942 | | R SEC | C5-7 bilateral radiculopathy & foraminal stenosis | Posterior decompression C5-7; SECURE-C device remains implanted | 575 | | R SEC | Neck pain | Removal C6-7, fusion same level | 310 | | ACDF | C5-6 degenerated disc (adjacent level) | Removal C4-5, cervical arthroplasty inserted at C5-6 | 1576 | | ACDF | Continued neck pain, numbness, failure to fuse on CT and MRI | Removal C5-6, plate and spacer inserted same level | 441 | | ACDF | Neck pain and right arm pain | Removal C5-6 (fusion solid), plate and cage inserted C6-7 | 266 | | ACDF | Right shoulder pain, inadequate fusion | Removal C6-7, plate and autograft inserted same level | 400 | | ACDF | Neck pain, pseudoarthrosis on x-ray and CT | Removal C5-6 (no replacement; fusion intact on exploration, neck pain felt due to hardware) | 776 | | ACDF | Left C5 radiculopathy | Removal C5-6, 2-level plate/1 spacer inserted C4-6 | 54 | | ACDF | C4-5, C6-7 disc herniation | Removal C5-6, 3-level plate/spacers inserted C4-7 | 623 | | ACDF | C4-5 degenerated disc | Removal C5-6 (no evidence pseudoarthrosis on exploration), plate and spacer inserted C4-5 | 1216 | | ACDF | Neck pain, C5-6 disc herniation | Removal C4-5 (solid fusion on radiographs), plate and allograft inserted C5-6 | 1058 | | ACDF | Neck pain and thumb paresthesia | Posterior decompression and PLF C6-7; original plate remains implanted (non-study surgeon) | 418 | | ACDF | Myelopathy (not improved from baseline) | Removal C4-5, plate same level (non-study surgeon) | 263 | | ACDF | Left arm pain, numbness | Removal C6-7 (solid fusion on radiographs and exploration), plate and allograft at C5-6 | 1162 | | ACDF | Unknown (non-study surgeon) | Removal C4-5, 2-level plate inserted | 215 | | ACDF | Neck and left arm pain | Removal C6-7 (solid fusion on radiographs), plate and cage inserted C5-6 | 735 | NR SEC=Non-randomized SECURE®-C; R SEC=Randomized SECURE®-C; ACDF=Control The number and percentage of patients who experienced a device-related adverse event as determined by the Clinical Events Committee (CEC) is provided in Table 17. Note that the CEC used a relatively narrow definition in that device-related events were identified as having etiology, temporal association, or cause, that is related to the device, such as: revision, removal, reoperation, or supplemental fixation at the index level, surgery at the index level to remove or alter the device, fracture or mechanical failure of device(s), pseudarthrosis, radiolucency around device(s), migration, subsidence, loosening, etc. The CEC felt that it was not appropriate to broadly classify events such as neck or arm pain as potentially device related, as these are commonly reported symptoms for patients entering a study with preoperative neck and/or arm pain. PMA P100003: FDA Summary of Safety and Effectiveness Data {25} Based on the CEC's classification, the device-related adverse event profile is lower for the SECURE®-C (2.5%) group than the ACDF (9.7%) group because there were less secondary surgeries at the index level in the SECURE®-C group. The number of device-related adverse events per patient is also lower for SECURE®-C than ACDF, as previously described in Table 9. Table 17. Device-Related Adverse Events | Adverse Event | Intra-Op (0-2 days) | | Peri-Op (>2days-6wks) | | Short Term (>6wks-12mo) | | Long Term (>12mo -24mo) | | Longer Term (>24mo) | | Patients (%) | | | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | | | SEC | ACDF | SEC | ACDF | SEC | ACDF | SEC | ACDF | SEC | ACDF | SEC (N=236) | ACDF (N=144) | | Surgery - Index Level | 0 | 0 | 1 | 4 | 2 | 4 | 2 | 2 | 1 | 4 | 6 (2.5%) | 14 (9.7%) | SEC = all SECURE®-C Cervical Artificial Disc; ACDF = Anterior Cervical Discectomy and Fusion (Control) Note: This table includes data collected beyond 24 months. The total number and percentage of patients who experienced a surgery-related adverse event as determined by the Clinical Events Committee (CEC) is provided in Table 18. Surgery-related adverse events were defined as those identified as having etiology, temporal association, or cause that is related to the surgical procedure, such as: dysphagia, dysphonia, or postoperative infection. Based on the CEC's classification, the surgery-related adverse event profile is lower for the SECURE®-C (5.5%) group compared to the ACDF (12.5%) group, but is not statistically different. Table 18. Total Surgery-Related Adverse Events | Adverse Event | SEC (N=236) | | ACDF (N=144) | | | --- | --- | --- | --- | --- | | | Patients (%) | Events (E/Pt) | Patients (%) | Events (E/Pt) | | Surgery-Related Adverse Event | 13 (5.5%) | 14 (0.06) | 18 (12.5%) | 20 (0.14) | | Cardiovascular | 1 (0.4%) | 1 (0.01) | 0 (0.0%) | 0 (0.00) | | Cerebrovascular | 1 (0.4%) | 1 (0.01) | 0 (0.0%) | 0 (0.00) | | Dysesthesia – Other | 0 (0.0%) | 0 (0.00) | 1 (0.7%) | 1 (0.01) | | Dysesthesia – Upper Extremities | 1 (0.4%) | 1 (0.01) | 0 (0.0%) | 0 (0.00) | | Dysphagia | 5 (2.1%) | 5 (0.02) | 7 (4.9%) | 7 (0.05) | | Dysphonia | 0 (0.0%) | 0 (0.00) | 2 (1.4%) | 2 (0.01) | | Infection – Superficial Wound | 0 (0.0%) | 0 (0.00) | 2 (1.4%) | 2 (0.01) | | Musculoskeletal | 1 (0.4%) | 1 (0.01) | 0 (0.0%) | 0 (0.00) | | Other | 1 (0.4%) | 1 (0.01) | 0 (0.0%) | 0 (0.00) | | Pain – Other | 1 (0.4%) | 1 (0.01) | 0 (0.0%) | 0 (0.00) | | Pain – Upper Extremities | 3 (1.3%) | 3 (0.01) | 4 (2.8%) | 4 (0.03) | | Wound Issue | 0 (0.0%) | 0 (0.00) | 4 (2.8%) | 4 (0.03) | SEC = all SECURE®-C Cervical Artificial Disc; ACDF = Anterior Cervical Discectomy and Fusion (Control) Note: This table includes data collected beyond 24 months. The total number and percentage of patients who experienced a severe or life-threatening adverse event as determined by the CEC is provided in Table 19. A severe event was defined as an AE that significantly limits the patient's ability to perform routine activities despite PMA P100003: FDA Summary of Safety and Effectiveness Data Page 26 of 50 {26} symptomatic therapy, and a life-threatening event was defined as an AE that required removal of the implant or put the patient at immediate risk of death (including death). Based on the CEC's classification, the severe or life-threatening adverse event profile is similar for the SECURE®-C (19.5%) group and the ACDF (23.6%) group. Table 19. Total Severe or Life-Threatening Adverse Events | Adverse Event | SEC (N=236) | | ACDF (N=144) | | | --- | --- | --- | --- | --- | | | Patients (%) | Events (E/Pt) | Patients (%) | Events (E/Pt) | | Severe or Life-Threatening Event | 46 (19.5%) | 61 (0.26) | 34 (23.6%) | 44 (0.31) | | Cancer | 2 (0.8%) | 2 (0.01) | 0 (0.0%) | 0 (0.00) | | Cardiovascular | 5 (2.1%) | 6 (0.03) | 0 (0.0%) | 0 (0.00) | | Carpal Tunnel Syndrome (CTS) | 6 (2.5%) | 6 (0.03) | 3 (2.1%) | 3 (0.02) | | Cerebrovascular | 2 (0.8%) | 2 (0.01) | 0 (0.0%) | 0 (0.00) | | Compressive Periph Neuro (Non-CTS) | 3 (1.3%) | 3 (0.01) | 0 (0.0%) | 0 (0.00) | | Death | 1 (0.4%) | 1 (0.01) | 1 (0.7%) | 1 (0.01) | | Dysphagia | 0 (0.0%) | 0 (0.00) | 1 (0.7%) | 1 (0.01) | | Gastrointestinal | 4 (1.7%) | 4 (0.02) | 0 (0.0%) | 0 (0.00) | | Infection - Other | 0 (0.0%) | 0 (0.00) | 1 (0.7%) | 1 (0.01) | | Musculoskeletal | 13 (5.5%) | 14 (0.06) | 5 (3.5%) | 5 (0.03) | | Neurological | 0 (0.0%) | 0 (0.00) | 2 (1.4%) | 2 (0.01) | | Other | 1 (0.4%) | 1 (0.01) | 1 (0.7%) | 1 (0.01) | | Pain - Back and/or Lower Extremities | 2 (0.8%) | 2 (0.01) | 0 (0.0%) | 0 (0.00) | | Pain - Upper Extremities | 0 (0.0%) | 0 (0.00) | 1 (0.7%) | 1 (0.01) | | Psychological | 1 (0.4%) | 1 (0.01) | 0 (0.0%) | 0 (0.00) | | Surgery - Adjacent Level | 4 (1.7%) | 4 (0.02) | 2 (1.4%) | 3 (0.02) | | Surgery - Index Level | 6 (2.5%) | 7 (0.03) | 14 (9.7%) | 17 (0.12) | | Surgery - Lumbar Level | 6 (2.5%) | 6 (0.03) | 5 (3.5%) | 7 (0.05) | | Surgery - Other Cervical | 0 (0.0%) | 0 (0.00) | 1 (0.7%) | 1 (0.01) | | Surgery - Thoracic Level | 1 (0.4%) | 1 (0.01) | 0 (0.0%) | 0 (0.00) | | Trauma | 0 (0.0%) | 0 (0.00) | 1 (0.7%) | 1 (0.01) | | Urogenital | 1 (0.4%) | 1 (0.01) | 0 (0.0%) | 0 (0.00) | SEC = all SECURE®-C Cervical Artificial Disc; ACDF = Anterior Cervical Discectomy and Fusion (Control) Note: This table includes data collected beyond 24 months. ## Neurological Status: The change in neurologic status at each study timepoint is provided in Table 20 for all patient groups. If any one of the four neurologic assessments deteriorated, then the overall neurologic status is considered deteriorated. For overall neurologic status and for each of the four individual assessments, the percentage of patients with stable or improved status was similar for both groups. The randomized SECURE®-C group demonstrated numerically greater percentages of patients with stable/improved neurologic status than the control ACDF group at each time point, with statistical significance at 6 and 36 months; statistical comparisons of 24 month neurologic status success demonstrate non-inferiority with a posterior probability of 100%. PMA P100003: FDA Summary of Safety and Effectiveness Data {27} Table 20. Neurological Status | Timepoint | Status | Non-Randomized SECURE-C (N=88) | Randomized SECURE-C (N=148) | Randomized ACDF (N=144) | 95% BCI# (lower, upper) | | --- | --- | --- | --- | --- | --- | | 6 months | Improved | 49/83 (59.0%) | 81/139 (58.3%) | 71/130 (54.6%) | (0.7%, 12.6%) | | | Stable | 29/83 (34.9%) | 54/139 (38.8%) | 47/130 (36.2%) | | | | Deteriorated | 5/83 (6.0%) | 4/139 (2.9%) | 12/130 (9.2%) | | | 12 months | Improved | 47/81 (58.0%) | 78/136 (57.4%) | 67/124 (54.0%) | (-1.6%, 11.1%) | | | Stable | 28/81 (34.6%) | 52/136 (38.2%) | 46/124 (37.1%) | | | | Deteriorated | 6/81 (7.4%) | 6/136 (4.4%) | 11/124 (8.9%) | | | 24 months | Improved | 45/75 (60.0%) | 73/123 (59.3%) | 57/101 (56.4%) | (-2.9%, 9.2%) | | | Stable | 26/75 (34.7%) | 46/123 (37.4%) | 38/101 (37.6%) | | | | Deteriorated | 4/75 (5.3%) | 4/123 (3.3%) | 6/101 (5.9%) | | | 36 months | Improved | 34/52 (65.4%) | 35/53 (66.0%) | 23/43 (53.5%) | (0.9%, 20.6%) | | | Stable | 14/52 (26.9%) | 18/53 (34.0%) | 16/43 (37.2%) | | | | Deteriorated | 4/52 (7.7%) | 0/53 (0%) | 4/43 (9.3%) | | #95% Credible Interval on difference (SECURE-C randomized – ACDF) between proportions of improved/stable vs. deteriorated ## Adjacent Level Symptoms and Treatments: The incidence and progression of adjacent level disease was not collected prospectively, but was assessed in terms of symptoms, treatment, and surgery performed at the adjacent level by a thorough review of adverse event source documentation for adverse events coded as pain (neck and/or upper extremity), dysesthesia (neck and/or upper extremity), neurological, weakness, muscle spasms, surgery, pseudoarthrosis, or headache to isolate possible adjacent level symptoms, diagnoses, treatments, and surgeries. Based on this review, the percentage of patients with adjacent level symptoms was numerically higher for the control ACDF group (18.8%) than for the SECURE®-C group (11.5% randomized, 8% non-randomized). Some patients with adjacent level symptoms went on to receive postoperative treatment at the adjacent level; however, the percentage of patients with adjacent level treatment was low for all groups at all time points, with few patients receiving treatment. Some patients with adjacent level symptoms (with or without adjacent level treatment) went on to receive postoperative surgical treatment at the adjacent level. The percentage of patients having adjacent level surgery by 24 months was low for both groups (0% SECURE®-C non-randomized, 2.7% SECURE®-C randomized, 4.2% ACDF). ## Surgery and Hospitalization Data: Surgical data is provided in Table 21. The posterior probability that the mean or proportion is lower in the randomized SECURE®-C group than the ACDF group is included in the table. The most common treated surgical levels were C5-C6 and C6-C7. Mean surgery time was 15.6 min longer for the randomized investigational SECURE®-C group than for the control ACDF group, and was statistically different. Mean blood loss was also 9.6 ml more for the randomized SECURE®-C group, and this was borderline statistically significant although likely not clinically significant. Mean return to work time was 6 days shorter for the SECURE®-C group than the ACDF group, however this was not statistically different. Note that data on the amount/type of decompression and handling of the posterior longitudinal ligament for each procedure is not available. PMA P100003: FDA Summary of Safety and Effectiveness Data {28} Table 21. Surgical Data | Measure | Non-Randomized SECURE-C (N=89) | Randomized SECURE-C (N=151) | Randomized ACDF (N=140) | Posterior Probability * | Posterior Probability ** | | --- | --- | --- | --- | --- | --- | | Treated Level | | | | | | | C3-C4 (%) | 3 (3.4%) | 5 (3.3%) | 4 (2.9%) | 0.4230 | 0.5529 | | C4-C5 (%) | 7 (7.9%) | 8 (5.3%) | 11 (7.9%) | 0.8075 | 0.7977 | | C5-C6 (%) | 48 (53.9%) | 75 (49.7%) | 70 (50.0%) | 0.5226 | 0.7366 | | C6-C7 (%) | 31 (34.8%) | 63 (41.7%) | 55 (39.3%) | 0.3372 | 0.1482 | | Surgery Time (min) | 98.4 ±34.80 | 87.7 ±33.02 | 72.1 ±25.41 | <0.0001 | 0.9878 | | Blood Loss (mls) | 55.6 ±43.93 | 55.2 ±44.22 | 45.6 ±33.21 | 0.0254 | 0.4540 | | Classification | | | | | | | Inpatient (<23 hrs) | 62 (69.7%) | 92 (60.9%) | 87 (62.1%) | 0.5830 | 0.9112 | | Outpatient (>23 hrs) | 27 (30.3%) | 59 (39.1%) | 52 (37.9%) | | | | Hospitalization (days) | 1.2 ±0.56 | 1.0 ±0.46 | 0.9 ±0.46 | 0.4058 | 0.9878 | | Return to Work Time (days) | 46.4 ±32.40 | 44.0 ±74.47 | 50.0 ±72.21 | 0.5545 | 0.9934 | Mean $\pm$ standard deviation *Posterior probability that mean or proportion is lower in the randomized SECURE-C group compared to ACDF **Posterior probability that mean or proportion is lower in the randomized SECURE-C group compared to the non-randomized SECURE-C group A total of 236 SECURE®-C devices were implanted during the study. The design, footprint and height of the SECURE®-C devices used are presented in Table 22. Table 22. SECURE®-C Implants Used | Size/Option | Devices (%) | Size/Option | Devices (%) | |…