PRESTIGE LP(TM) CERVICAL DISC

{0} # SUMMARY OF SAFETY AND EFFECTIVENESS DATA (SSED) ## I. GENERAL INFORMATION | Device Generic Name: | Artificial Cervical Disc | | --- | --- | | Device Trade Name: | PRESTIGE LPT™ Cervical Disc | | Device Procode: | MJO | | Applicant's Name and Address: | Medtronic Sofamor Danek 1800 Pyramid Place Memphis, TN 38132 | | Date of Panel Recommendation: | None | | Premarket Approval Application (PMA) Number: | P090029 / S003 | | Date of FDA Notice of Approval: | July 7, 2016 | The original PMA (P090029) was approved on July 24, 2014 and is indicated for use 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 level of the disc space and at least one of the following conditions confirmed by 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 PRESTIGE LPT™ Cervical Disc is implanted using an anterior approach. Patients should have failed at least 6 weeks of non-operative treatment or have had the presence of progressive symptoms or signs of nerve root/spinal cord compression in the face of continued non-operative management prior to implantation of the PRESTIGE LPT™ Cervical Disc. The SSED to support the previously approved one level indication is available on the CDRH website (http://www.accessdata.fda.gov/cdrh\\_docs/pdf9/P090029B.pdf) and is incorporated by reference here. The current supplement was submitted to expand the indication for the PRESTIGE LPT™ Cervical Disc to include use of the device at two (2) contiguous levels and to add a 5 mm device height option. ## II. INDICATIONS FOR USE The PRESTIGE LPT™ Cervical Disc is indicated in skeletally mature patients for reconstruction of the disc from C3-C7 following discectomy at one level or two contiguous levels for intractable radiculopathy (arm pain and/or a neurological deficit) with or without neck pain, or myelopathy due to abnormality localized to the level of the disc space and at least one of the following conditions confirmed by 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 PRESTIGE LPT™ Cervical Disc is implanted using an anterior PMA P090029/S003: FDA Summary of Safety and Effectiveness Data Page 1 of 94 {1} approach. Patients should have failed at least 6 weeks of non-operative treatment or have had the presence of progressive symptoms or signs of nerve root/spinal cord compression in the face of continued non-operative management prior to implantation of the PRESTIGE LP™ Cervical Disc. ### III. CONTRAINDICATIONS The PRESTIGE LP™ Cervical 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 ≤ -1.0; - Allergy or sensitivity to titanium, aluminum or vanadium; - Marked cervical instability on neutral resting lateral or flexion/extension radiographs; translation >3.5mm and/or >11° rotational difference from that of either level adjacent to the treated levels; - Severe spondylosis at the level to be treated, characterized by bridging osteophytes, loss of disc height >50%, or an absence of motion (<2°) 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(s) 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), or - Significant kyphotic deformity or significant reversal of lordosis. ### IV. WARNINGS AND PRECAUTIONS The warnings and precautions can be found in the PRESTIGE LP™ Cervical Disc labeling. ### V. DEVICE DESCRIPTION The PRESTIGE LP™ Cervical Disc is a two-piece articulating device that is inserted into the intervertebral disc space as a pre-assembled unit at one or two contiguous cervical levels using an anterior approach. The device is manufactured from a titanium ceramic composite (Titanium-6Aluminum-4Vanadium with 10% Titanium Carbide) and consists of two metal plates which function via a ball and trough mechanism. The superior component of the implant contains the ball portion of the mechanism, and the inferior component contains the trough portion. These two features engage to create an interface designed to allow for motion after implantation. Each component is affixed to the adjacent vertebral body by two rail geometries incorporating anti-migration teeth, which are press fit into two pre-drilled holes in the vertebral bone. The portion of the flat surface between the rails that contacts the vertebral endplate has a commercially pure titanium (CP Ti) plasma thermal sprayed coating per ASTM F1580, designed to permit bony on-growth for additional device incorporation. The remaining portion of the flat surface is titanium ceramic roughened to enhance fixation. Each component also contains two anterior tab features PMA P090029/S003: FDA Summary of Safety and Effectiveness Data Page 2 of 94 {2} designed to aid in device insertion and to minimize the risk of implanting the device too far into the intervertebral space. Figure 1: PRESTIGE LP™ Cervical Disc  Figure 2: PRESTIGE LP™ Cervical Disc at two contiguous levels  The PRESTIGE LP™ Cervical Disc is offered in a variety of configurations to accommodate varied patient anatomy. The available components are shown in Table 1 below. Table 1: PRESTIGE LP™ Cervical Disc Device Sizes | Catalog Number | Size (Height x AP Dimension x ML Dimension) | | --- | --- | | 6972250 | 5mm x 12mm x 15mm | | 6972450 | 5mm x 14mm x 15mm | | 6972650 | 5mm x 16mm x 15mm | | 6972260 | 6mm x 12mm x 17.8mm | | 6972460 | 6mm x 14mm x 17.8mm | PMA P090029/S003: FDA Summary of Safety and Effectiveness Data Page 3 of 94 {3} | 6972660 | 6mm x 16mm x 17.8mm | | --- | --- | | 6972860 | 6mm x 18mm x 17.8mm | | 6972470 | 7mm x 14mm x 17.8mm | | 6972670 | 7mm x 16mm x 17.8mm | | 6972870 | 7mm x 18mm x 17.8mm | | 6972480 | 8mm x 14mm x 17.8mm | | 6972680 | 8mm x 16mm x 17.8mm | | 6972880 | 8mm x 18mm x 17.8mm | The PRESTIGE LP™ Cervical Disc is designed to allow a minimum of 10 degrees lateral bending (from neutral) and a minimum of 10 degrees flexion/extension (from neutral). The design is also intended to allow unlimited axial rotation (constrained by ligaments and posterior elements) and translation of ±2 mm in the sagittal plane. The PRESTIGE LP™ Cervical Disc is implanted using instruments specific to the device, as well as manual surgical instruments. Instruments specifically designed for implanting the PRESTIGE LP™ Cervical Disc consist of trials, trial cutter guides, rail punches, and implant inserters. General purpose instruments include instruments for cervical distraction and discectomy preparation. The PRESTIGE LP™ Cervical Disc approved in this supplement is identical to the PRESTIGE LP™ Cervical Disc approved in P090029 with the exception of the addition of 5mm device height options (5mm x 12mm, 5mm x 14mm, 5mm x 16mm) and their corresponding instruments (which were included in the 2-level IDE study, G050202) to the system. ## **VI. ALTERNATIVE PRACTICES AND PROCEDURES** There are several other alternatives for the treatment of intractable radiculopathy or myelopathy due to a single-level or multi-level abnormality localized to the level of the disc space at one or two contiguous levels. - 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 (e.g., Cloward bone dowels, Smith Robinson trico-cortical wedges, and Keystone grafts) or interbody fusion devices, which may or may not 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 interbody graft or spacer is the most commonly used method for decompression and fusion. Intractable radiculopathy or myelopathy due to a single-level or multi-level abnormality localized to the level of the disc space at one or two contiguous levels may also be treated surgically using another FDA approved artificial cervical disc. Each alternative has its own advantages and disadvantages. A patient should fully discuss these alternatives with his/her physician to select the method that best meets expectations and lifestyle. ## **VII. MARKETING HISTORY** PMA P090029/S003: FDA Summary of Safety and Effectiveness Data Page 4 of 94 {4} The device has been marketed outside of the United States since 2004, and has not been withdrawn from the market in any country, for any reason. The PRESTIGE LP™ Cervical Disc is marketed in: Argentina, Australia, Austria, Belgium, Brazil, Canada, Czech Republic, Chile, China, Costa Rica, Denmark, Finland, France, Germany, Greece, Hong Kong, Hungary, India, Israel, Italy, Jamaica, Malaysia, Mexico, Netherlands, New Zealand, Norway, Pakistan, Poland, Portugal, Saudi Arabia, Singapore, Slovakia, South Africa, South Korea, Spain, Sweden, Switzerland, Taiwan, Turkey and the United Kingdom. ## **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 PRESTIGE LP™ Cervical Disc identified from the PRESTIGE LP™ Cervical Disc clinical study results, use of the PRESTIGE LP™ Cervical Disc outside of the United States, 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 PRESTIGE LP™ Cervical Disc. These risks may occur singly or in combination. In addition to the risks listed below, there is also the risk that the procedure may not be effective and may not relieve symptoms or may cause worsening of symptoms. Additional surgery may be required to correct some of the adverse effects. 1. 1. Risks associated with any surgical procedure: - • Anesthesia complications including an allergic reaction or anaphylaxis; - • Infection (wound, local, and/or systemic) or abscess; - • Wound dehiscence or necrosis; - • Edema; - • Soft tissue damage or fluid collections, including hematoma or seroma; - • Pain/discomfort at the surgical incision and/or skin or muscle sensitivity over the incision which may result in skin breakdown, pain, and/or irritation; - • Heart or vascular complications including bleeding, hemorrhage or vascular damage resulting in catastrophic or potentially fatal bleeding, ischemia, myocardial infarction, abnormal blood pressure, venous thromboembolism including deep vein thrombosis and pulmonary embolism, thrombophlebitis, or stroke; - • Pulmonary complications including atelectasis or pneumonia; - • Impairment of the gastrointestinal system including ileus or bowel obstruction; - • Impairment of the genitourinary system including incontinence, bladder dysfunction, or reproductive system complications; - • Neurological complications including nerve damage, paralysis, seizures, changes to mental status, or reflex sympathetic dystrophy; - • Complications of pregnancy including miscarriage or congenital defects; - • Inability to resume activities of daily living; and - • Death. 2. 2. Risks associated with anterior cervical spine surgery: PMA P090029/S003: FDA Summary of Safety and Effectiveness Data Page 5 of 94 {5} - Injury to surrounding organs and structures including the spinal cord, nerve roots, other neurologic structures adjacent to the spinal column, vocal cords, adjacent vertebrae, lymphatic vessels, blood vessels, soft tissue, dura, the trachea, the esophagus, the larynx, or the pharynx; - Dysphagia, dysphonia, hoarseness, vocal cord paralysis, laryngeal palsy; or sore throat; - Tracheal, esophageal, or pharyngeal perforation, fistula, recurrent aspiration, or airway obstruction; - Neurological complications, including damage to nerve roots, the spinal cord, or other nerves possibly resulting in muscle weakness or paralysis, changes in sensation (including numbness, dysesthesias, or paresthesias), bowel/bladder dysfunction, or pain; - Neck pain, arm pain, or headache; - Dural tear or leak or cerebrospinal fistula; - Discitis, arachnoiditis, or other type of inflammation; - Loss of disc height; loss of anatomic sagittal plane curvature or vertebral listhesis, spinal stenosis, or spondylolysis; and - Scarring, herniation or degeneration of adjacent discs. 3. Risks associated with a cervical artificial disc device, including the PRESTIGE LP™ Cervical Disc: - Risks directly related to the device including malposition, migration/displacement, subsidence/loss of disc height, device breakage, device disassembly, or early or late loosening of the device. Any of these issues may cause pain or injury to surrounding organs and structures including the spinal cord, nerve roots, or other neurologic structures adjacent to the spinal column (which could cause pain, paralysis, or numbness) or blood vessel damage or erosion (which could cause catastrophic or fatal bleeding); - Deterioration in neurologic status including muscle weakness or paralysis, changes in sensation (including numbness, dysesthesias, or paresthesias), decreased reflexes, or loss of bowel and/or bladder control; - Development of new radiculopathy, myelopathy, or pain; - Failure of the device to improve symptoms or function; - Problems during placement of the device including trouble sizing the device, anatomical or technical difficulties implanting the device, or issues with the device instruments (e.g., bending or breakage) including the possibility that a fragment of a broken instrument may remain in the patient after implantation; - Adverse reaction or allergy to the device materials (titanium, aluminum or vanadium), device wear debris or metal ions which may lead to a systemic reaction or a local adverse tissue reaction or chronic inflammation which may lead to implant loosening or failure of the device, osteolysis, bone resorption, tumor formation, autoimmune disease, metallosis, scarring, or other symptoms; - Change in the alignment of the spine or loss of proper anatomic curvature, correction, height or reduction of the spine including spondylolisthesis, change in lordosis, or instability of the spine; - Degeneration of other parts of the spine including the facet joints or adjacent discs; - Fracture of the surrounding vertebrae; PMA P090029/S003: FDA Summary of Safety and Effectiveness Data Page 6 of 94 {6} • Unintended bone formation (i.e., heterotopic ossification) that may result in bridging trabecular bone and may reduce spinal motion or result in unintended fusion at either the treated level or adjacent levels; • Device failure which may require a subsequent surgical intervention (including removal of the PRESTIGE LP™ Cervical Disc, revision, re-operation, or supplemental fixation); and • Interference with radiographic imaging because of the presence of the implant. Some of the adverse effects listed above were observed in the 2-level PRESTIGE LP™ Cervical Disc clinical study. For more detailed information on the specific adverse events that occurred during the clinical study, please refer to Section X (Summary of Primary Clinical Study). Some of the most common adverse effects experienced by study subjects were cervical arm pain, cervical neck pain, and cervical neurological events. ## IX. SUMMARY OF NONCLINICAL STUDIES A variety of preclinical testing was conducted to characterize the performance of the PRESTIGE LP™ Cervical Disc, as follows: ### A. Laboratory Studies - Subluxation Testing - Subsidence Testing - Push-Out - Static Compression - Compression Fatigue - Static Compression Shear - Compression Shear Fatigue - Durability and Wear Testing - Impingement Testing - MRI Testing ### B. Animal Testing - Wear Particulate Injection Analysis ### C. Additional Studies - Biocompatibility - Sterilization, Packaging, and Shelf Life Testing PMA P090029/S003: FDA Summary of Safety and Effectiveness Data Page 7 of 94 {7} # A. Laboratory Studies Table 2: Mechanical Testing | Test Description | Purpose | Methods | Medtronic's Acceptance Criteria | Results | | --- | --- | --- | --- | --- | | Subluxation 1 | To determine the amount of shear force applied to the inferior component required to dislocate (subluxate) the superior "ball" feature from the "trough" feature in multiple directions and lordotic angulations. | Under 100N preload, Components (n=1 assembly test puck) were tested in both the M-L and AP directions. M-L specimens were held in two relative positions 0° and 10°. A-P specimens were held in 10° flexion. In both configurations, the inferior component of each specimen was displaced laterally in multiple directions until the superior component (ball) was displaced from the inferior component (trough). | The subluxation force must be greater than the maximum in vivo shear load in the cervical spine (20N).^{1} | The mean maximum subluxation force was 357±8.3 N at 0°; 321±17.6 N at 10° positive lateral bending and 769±82 N at 10° negative lateral bending; 683±116.0 N at 10° flexion and 276±43.6 N at 10° extension. In all instances, the PRESTIGE LP™ disc subluxation values exceeded the clinically acceptable value of 20 N. These results suggest that the device can resist subluxation loads that exceed anticipated physiologic loads on the cervical spine. | | Subluxation 2 | To determine what amount of shear force applied to the inferior component required to dislocate (subluxate) the superior "ball" feature from the "trough" feature in multiple directions and angulations. | Under 100N preload, n=6 (6mm x 16 mm) device assemblies were tested in both the M-L and AP directions. M-L specimens were held in two relative positions 0° and 10°. A-P specimens were held in 10° flexion. In both configurations, the inferior component of each specimen was displaced laterally in positive and negative directions until the superior component (ball) was displaced from the inferior component (trough). | The medial-lateral and flexion-extension subluxation forces must exceed 20N.^{1} | The mean maximum medial-lateral subluxation force was 246.2±16.0N at 0°; 360.5±21.0N at 10° positive lateral bending, and 73.7±4.5N at 10° negative lateral bending; 406.9±37.9N at 10° flexion and 93.2±11.9N at 10° extension. In all instances, the PRESTIGE LP™ disc subluxation values exceeded the clinically acceptable value of 20 N. These results suggest that the device can resist subluxation loads that exceed anticipated physiologic loads on the cervical spine. | $^{1}$ White A, Panjabi M. Clinical Biomechanics of the Spine. J.B Lippincott, Philadelphia. 2$^{nd}$ Edition, p. 9. PMA P090029/S003: FDA Summary of Safety and Effectiveness Data Page 8 of 94 {8} | Test Description | Purpose | Methods | Medtronic's Acceptance Criteria | Results | | --- | --- | --- | --- | --- | | Subsidence 1 | To determine whether the PRESTIGE LP™ implant can effectively withstand a static axial compressive load without subsiding (sinking) into the vertebral body endplates, which in vivo would potentially cause endplate fracture, instability, and/or pain at the implanted level. | n=1 (5mm x 12mm) device assembly was assembled to mating foam blocks and axial load was applied at 0.1 mm/sec until the blocks contacted. Load/displacements were recorded for 5 repetitions of the test. | The subsidence force must be greater than the maximum in vivo compressive load in the cervical spine (74N) due to head weight¹ and equivalent to the stiffness of the previously approved PRESTIGE® Cervical Disc (363 N/mm). | The mean ultimate load was 793±28.3N. The average subsidence values were higher than the clinically acceptable value of 74N and PRESTIGE® Cervical Disc (363 N/mm). These results suggest that the device can resist subsidence loads that exceed anticipated physiologic loads on the cervical spine. | | Subsidence 2 | To determine whether the PRESTIGE LP™ implant can effectively withstand a static axial compressive load without subsiding (sinking) into the vertebral body endplates, which in vivo would potentially cause endplate fracture, instability, and/or pain at the implanted level. | n=1 (6mm x 12mm) device assembly was assembled to mating foam blocks and axial load was applied at 0.1 mm/sec until the blocks contacted. Load/displacements were recorded for 5 repetitions of the test. | The subsidence force must be greater than the maximum in vivo compressive load in the cervical spine (74N) due to head weight¹ and equivalent to the stiffness of the previously approved PRESTIGE® Cervical Disc (363 N/mm). | The mean ultimate load was 513±28.6N with a stiffness value of 442± 19.1 N/mm. The average subsidence values were higher than the clinically acceptable value of 74N and PRESTIGE® Cervical Disc (363 N/mm). These results suggest that the device can resist subsidence loads that exceed anticipated physiologic loads on the cervical spine. | | Push-Out 1 | To determine overall resistance to push-out for the PRESTIGE LP™ device | A 100 N preload was applied to n=1 (5mm x 12mm) device assembly while an axial force was applied in the anterior/posterior and medial lateral directions at 6 mm/min until failure was obtained. | The pushout force must be greater than the maximum in vivo intervertebral shear force in the cervical spine (20N).¹ | The mean ultimate load was 156±4N. The results exceeded the clinically acceptable load of 20N. These results suggest that the device can resist push-out loads that exceed anticipated physiologic loads on the cervical spine. | PMA P090029/S003: FDA Summary of Safety and Effectiveness Data Page 9 of 94 {9} | Test Description | Purpose | Methods | Medtronic's Acceptance Criteria | Results | | --- | --- | --- | --- | --- | | Push-Out 2 | To determine overall resistance to push-out for the PRESTIGE LP™ device | A 100 N preload was applied to n=1 (6mm x 12mm) device assembly while an axial force was applied in the anterior/posterior and medial lateral directions at 6mm/min until failure was obtained. | The pushout force must be greater than the maximum in vivo intervertebral shear force in the cervical spine (20N).^{1} | The mean ultimate load was 127.4±3.2N. The results exceeded the clinically acceptable load of 20N. These results suggest that the device can resist push-out loads that exceed anticipated physiologic loads on the cervical spine. | | Static Compression 1 | To characterize the 5mm x 12mm PRESTIGE LP™ device's ability to withstand axial compressive loads by determining the ultimate failure load of the construct over multiple specimens | n=1 (5mm x 12mm) device assemblies were tested in accordance with ASTM Standard F2346 "Standard Test Method for Static and Dynamic Characterization of Spinal Artificial Discs" | The axial compressive failure load must exceed the clinically acceptable value of 74N.^{1} | The mean failure load was 8070N. The result of the static compression test far exceeded the clinically acceptable load of 74N. This result suggests that the device can resist compressive loading that exceeds anticipated physiologic loads on the cervical spine. | | Static Compression 2 | To characterize the 5mm x 16mm PRESTIGE LP™ device's ability to withstand axial compressive loads by determining the ultimate failure load of the construct over multiple specimens | n=1 (5mm x 16mm) device assemblies were tested in accordance with ASTM Standard F2346 "Standard Test Method for Static and Dynamic Characterization of Spinal Artificial Discs" | The axial compressive failure load must exceed the clinically acceptable value of 74N.^{1} | The mean failure load was 6494N. The result of the static compression test far exceeded the clinically acceptable load of 74N. This result suggests that the device can resist compressive loading that exceeds anticipated physiologic loads on the cervical spine. | PMA P090029/S003: FDA Summary of Safety and Effectiveness Data Page 10 of 94 {10} | Test Description | Purpose | Methods | Medtronic's Acceptance Criteria | Results | | --- | --- | --- | --- | --- | | Static Compression 3 | To characterize the 6mm x18mm PRESTIGE LP™ device's ability to withstand axial compressive loads by determining the ultimate failure load of the construct over multiple specimens | n=6 (6mm x 18mm) device assemblies were tested in accordance with ASTM Standard F2346 "Standard Test Method for Static and Dynamic Characterization of Spinal Artificial Discs" | The mean ultimate load for the 6x18mm PRESTIGE LP™ implant was greater than or equal to 550N. This load is twice the acceptance criterion of the fatigue load and a factor of safety six times the compression load in the cervical spine due to the weight of the head (74N).^{1} | The maximum load was 7992±748N and a stiffness of 21,096N/mm. The results of the static compression test exceeded the clinically acceptable load of 74N as well as the 550N load. These results suggest that the device can resist compressive loading that exceeds anticipated physiologic loads on the cervical spine. | | Static Compression 4 | To characterize the 7mm x 18mm PRESTIGE LP™ device's ability to provide resistance to axial compressive loading | n=5 (7mm x 18mm) device assemblies were placed between two unsupported stainless steel test blocks, and an axial compressive load was applied at 3mm/min until functional failure occurred. | The axial compressive failure load must exceed the clinically acceptable value of 74N.^{1} | The mean failure load was 8808±2233N. The results of the static compression test far exceeded the clinically acceptable load of 74N. These results suggest that the device can resist compressive loading that exceeds anticipated physiologic loads on the cervical spine. | | Compression Fatigue 1 | To characterize the 7mm x 18mm PRESTIGE LP™ device's ability to provide resistance to axial compressive loading throughout the device's life cycle. | n=3 (7mm x 18mm) devices assemblies were placed between two polyethylene test blocks. They were then tested on an MTS machine in load control with an R-value of 10 and a cyclical load of 225N until attainment of 5M cycles or failure of the component. | The compression fatigue force must exceed the clinically acceptable value of 74N.^{1} | All three specimens ran out at 10 million cycles at an applied load of 225N. Results from the compression fatigue tests exceeded the clinically acceptable load of 74N. These results suggest that the device can resist dynamic compressive loading that exceeds anticipated physiologic loads on the cervical spine. | PMA P090029/S003: FDA Summary of Safety and Effectiveness Data Page 11 of 94 {11} | Test Description | Purpose | Methods | Medtronic's Acceptance Criteria | Results | | --- | --- | --- | --- | --- | | Compression Fatigue 2 | To characterize the 5x12mm and 5x16mm PRESTIGE LP™ device's ability to provide resistance to axial compressive loading throughout a device's life cycle. | n=2 (5mm x 12mm) device assemblies were tested in accordance with ASTM Standard F2193 "Standard Specifications and Test Methods for Components Used in the Surgical Fixation of the Spinal Skeletal System." | The assemblies must attain two run outs at 10 million cycles at a compressive fatigue load of 225N without functional failure which represents a three times factor of safety of the compression load in the cervical spine due to the weight of the head (74N).^{1} | All assemblies ran out at 10 million cycles at an applied load of 225N. Results from the compression fatigue tests far exceeded the clinically acceptable load of 74N and met the acceptance criterion as defined in the test protocol. These results suggest that the device can resist compressive loading that exceeds anticipated physiologic loads on the cervical spine. | | Compression Fatigue 3 | To characterize the 6x18mm PRESTIGE LP™ device's ability to provide resistance to axial compressive loading throughout a device's life cycle. | n=2 (6mm x 18mm) device assemblies were tested in accordance with ASTM Standard F2346 "Standard Test Method for Static and Dynamic Characterization of Spinal Artificial Discs." | The assemblies must attain two run outs at 10 million cycles at a compressive fatigue load of 225N without functional failure which represents a three times factor of safety of the compression load in the cervical spine due to the weight of the head (74N).^{1} | Both assemblies ran out at 10 million cycles at an applied load of 225N. Results from the compression fatigue tests far exceeded the clinically acceptable load of 74N and met the acceptance criterion as defined in the test protocol. These results suggest that the device can resist compressive loading that exceeds anticipated physiologic loads on the cervical spine. | PMA P090029/S003: FDA Summary of Safety and Effectiveness Data Page 12 of 94 {12} | Test Description | Purpose | Methods | Medtronic's Acceptance Criteria | Results | | --- | --- | --- | --- | --- | | Static Compression Shear | To characterize the device's ability to resist shear compressive loads found during day-to-day physiologic loading of the cervical spine. | n=6 (5mm x 16mm) device assemblies were tested in accordance with ASTM Standard F2346 "Standard Test Method for Static and Dynamic Characterization of Spinal Artificial Discs." | The assemblies must attain at least a 550N compressive load prior to functional failure for all six samples which represents a six times factor of safety of the compression load in the cervical spine due to the weight of the head (74N).^{1} | The mean maximum static compression shear load was 4962±674N with a mean stiffness of 6058±762N. The average ultimate load for all PRESTIGE LP™ components exceeds the clinically acceptable load of 74N and the defined acceptance criteria of 550N. These results suggest that the device can resist compressive shear loading that exceeds anticipated physiologic loads on the cervical spine. | | Compression Shear Fatigue | To characterize the device's ability to resist shear compressive loads found during day-to-day physiologic loading of the cervical spine. | n=2 (5mm x 12mm) device assemblies were tested in accordance with ASTM Standard F2346 "Standard Test Method for Static and Dynamic Characterization of Spinal Artificial Discs." | The assemblies must attain two run outs at 10 million cycles without functional failure at a minimum compressive load of 225N which represents a three times factor of safety of the compression load in the cervical spine due to the weight of the head (74N).^{1} | The assemblies ran out at 10 million cycles at a maximum compression shear axial load of 225N and maximum calculated shear load of 159N. Results from the compression fatigue tests far exceeded the clinically acceptable load of 74N and met the acceptance criterion as defined in the test protocol. These results suggest that the device can resist dynamic compressive shear loading that exceeds anticipated physiologic loads on the cervical spine. | PMA P090029/S003: FDA Summary of Safety and Effectiveness Data Page 13 of 94 {13} **Table 3: Wear Testing** | Test Description | Purpose | Methods | Medtronic's Acceptance Criteria | Results | | --- | --- | --- | --- | --- | | Wear Test 1 (Lateral bending coupled with axial rotation followed by flexion/extension) | To characterize the wear behavior for the PRESTIGE LP™ family of implants. | n=6 (6mm x 16mm) device assemblies were tested in accordance with ASTM 2423 'Functional, Kinematic, and Wear Assessment of Total Disc Prostheses.' | The wear rate under combined motion for the PRESTIGE LP™ device must not be statistically higher than wear rate for hard bearing cervical disc replacements (1.10±0.09mm³/MC). | The steady-state wear rate under combined motion for the PRESTIGE LP™ Device was 0.35±0.03mm³/MC with a mean particle diameter of <0.2µm. The total wear at 20MC was 4.22±0.21mm³. The overall steady-state wear rate for the PRESTIGE LP™ device was lower than that of other hard bearing cervical disc replacements, and met the acceptance criterion as defined in the test protocol. The wear rate, volume, and size of particulate wear debris are similar to other legally-marketed hard bearing cervical disc replacements. | | Wear Test 2 (Lateral bending combined with axial rotation and flexion/extension) | To characterize the wear behavior for the PRESTIGE LP™ family of implants | n=6 (6mm x 16mm) device assemblies were tested at 2 Hz in accordance with ISO 18192-1 'Implants for Surgery – Wear of Total Intervertebral Spinal Disc Prostheses – Part 1: Loading and Displacement Parameters for Wear Testing and Corresponding Environmental Conditions for Test. | This test was used to generate benchmark volumetric wear and wear rate data under the ISO standard, and there was no acceptance criteria quantified. | The steady-state wear rate was 0.25±0.04mm³/MC The total accumulated wear was 2.74±0.38mm³ Characterization only. | PMA P090029/S003: FDA Summary of Safety and Effectiveness Data Page 14 of 94 {14} | Test Description | Purpose | Methods | Medtronic's Acceptance Criteria | Results | | --- | --- | --- | --- | --- | | Wear Test 3 (Lateral bending combined with axial rotation and flexion extension) | To characterize the wear behavior for the PRESTIGE LP™ family of implants | n=6 (6mm x 16mm) device assemblies were tested at 1 Hz in accordance with ISO 18192-1 “Implants for Surgery – Wear of Total Intervertebral Spinal Disc Prostheses – Part 1: Loading and Displacement Parameters for Wear Testing and Corresponding Environmental Conditions for Test. | This test was used to generate benchmark volumetric wear and wear rate data under the ISO standard, and there was no acceptance criteria quantified. | The steady-state wear rate was 0.25±0.03mm³/MC The total accumulated wear was 2.81±0.14mm³ Characterization only. | PMA P090029/S003: FDA Summary of Safety and Effectiveness Data Page 15 of 94 {15} | Test Description | Purpose | Methods | Medtronic's Acceptance Criteria | Results | | --- | --- | --- | --- | --- | | Wear Test 4 (Lateral bending coupled with axial rotation followed by flexion/extension; Flexion/extension followed by lateral bending coupled with axial rotation) | To characterize the wear behavior for the PRESTIGE LP™ family of implants under simulated loading of the cervical spine. | n=6 device test coupons (three in each sequence) were tested in coupled Lateral Bending and axial rotation followed by flexion/extension, and three were tested in reverse order with flexion/extension cycles first. Coupled motion was tested to 5.0 million cycles (MC) with a compressive load of 49N. Flexion/extension of 9.7° was tested to 10.0 MC with a compressive load of 148N. Combined motion testing was conducted in lateral bending at 4.7° and axial rotation at 3.8°. All specimen were tested in a temperature controlled both with a fluid medium of 25% alpha calf fraction. | All implants must be functional by allowing a total of ±4.7° lateral bending (LB) coupled with ±3.8° axial rotation (AR) followed by ±9.7° flexion/extension (FE). Furthermore, none of the inferior side components must wear through from the bottom of the trough feature to the test coupon. | All test components remained functional after 15.0 MC in all three motions. Therefore, the acceptance criteria were met. The total volumetric wear after 15 MC when testing first in lateral bending plus axial rotation and then flexion-extension was 1.25±0.89mm³. The total volumetric wear after 15 MC when testing in flexion-extension first and then lateral bending plus axial rotation was 1.32±0.71mm³. The mean steady-state wear rate when testing first in lateral bending plus axial rotation and then flexion-extension was 0.27±0.31mm³/MC for lateral bending plus axial rotation and was 0.01mm³±0.00mm³/MC in flexion-extension. The mean steady-state wear rate when testing when testing in flexion-extension first and then lateral bending plus axial rotation was 0.21±0.18mm³/MC for lateral bending plus axial rotation and was 0.01mm³±0.01mm³/MC in flexion-extension. These results suggest that the device will not wear through during expected physiological use. | PMA P090029/S003: FDA Summary of Safety and Effectiveness Data Page 16 of 94 {16} | Test Description | Purpose | Methods | Medtronic's Acceptance Criteria | Results | | --- | --- | --- | --- | --- | | Wear Test 5 (Lateral bending coupled with axial rotation for high and low radial clearances) | To characterize the influence of radial clearance on the wear behavior of the PRESTIGE LP™ Cervical Disc. | n=6 (n=3 high clearance; n=3 low clearance) device assemblies were tested in accordance with ASTM 2423 "Functional, Kinematic, and Wear Assessment of Total Disc Prostheses" | The steady-state wear rate for both the high and low clearances are statistically equivalent or lower than the specimen's nominal steady-state wear rate. (0.41±0.06.mm³/MC). | The steady-state wear rate at low clearance was 0.45±0.05 mm³/MC and 0.28±0.17 mm³/MC at high clearance. The volumetric wear for 5 MC at low clearance was 2.41±0.38 mm³ and 1.52±0.92 mm³ at high clearance. There was no statistically significant difference between the steady-state wear rate of the low-clearance and the nominal specimens (p = 0.381) and between the high-clearance specimens and the nominal specimens (p = 0.107). These results suggest that the device has similar wear rates as other legally-marketed hard bearing cervical disc replacements. | PMA P090029/S003: FDA Summary of Safety and Effectiveness Data Page 17 of 94 {17} | Test Description | Purpose | Methods | Medtronic's Acceptance Criteria | Results | | --- | --- | --- | --- | --- | | Impingement Testing | To determine the wear and durability characteristics of the PRESTIGE LP™ Device under conditions simulating device impingement. | n=6 (6mm x 16mm) device assemblies using a set of custom test fixtures. Each device assembly underwent combined flexion-extension (FE) and axial rotation (AR) motions for 1 million cycles (MC) under static load of 150N. | This test was used to generate benchmark impingement data, and there was no acceptance criteria quantified. | The total volumetric wear after 1 MC was 0.17±0.04mm³ (0.83±0.18mg). All endplate impingement patterns observed were aligned with the median plane at the anterior endplate edge of the male components and at the anterior edge of the trough for female components. There was no evidence of structural damage due to endplate impingement. The average surface roughness of the female specimens. | PMA P090029/S003: FDA Summary of Safety and Effectiveness Data Page 18 of 94 {18} **Table 4: MRI Testing** | Test Description | Purpose | Methods | Medtronic's Acceptance Criteria | Results | | --- | --- | --- | --- | --- | | MRI Characterization | To evaluate the safety and compatibility of the PRESTIGE LP™ Cervical Disc System in a 1.5 Tesla and 3.0 Tesla MRI environment | n=4 (5mm x 12mm, 6mm x 12mm, 6mm x 16mm, and 8mm x 18mm) devices assemblies were tested in accordance with ASTM F2052 'Standard Test Method for Measurement of Magnetically Induced Displacement Force on Medical Devices in the Magnetic Resonance Environment,' ASTM F2182 'Standard Test Method for Measurement of Radio Frequency Induced Heating on or Near Passive Implants During Magnetic Resonance Imaging,' and ASTM F2119, 'Standard Test Method for Evaluation of MR Image Artifacts from Passive Implants' | All tests were for characterization purposes and acceptance criteria were not established. | 1.) Magnetic field interactions: Implant does not present an additional risk or hazard to the patient in a 1.5 Tesla or 3.0-Tesla MRI environment with regard to translational attraction, migration, or torque. 2.) MRI-related heating: Highest temperature change recorded was not considered physiologically consequential for a human subject. 3.) Artifact test: Worst case artifacts that appeared on MR images were localized signal voids graded as 'small' in comparison to the size and shape of the device. | ## **B. Animal Testing** Two particulate injection studies were conducted in rabbit models to evaluate potential toxicity associated with debris and particulates obtained from Ti6Al4V/TiC particulates when placed in direct contact with the spinal column via epidural injection. Summary data for the studies are provided in the following table. PMA P090029/S003: FDA Summary of Safety and Effectiveness Data Page 19 of 94 {19} Table 5: Animal Testing | Test Description | Purpose | Methods | Medtronic's Acceptance Criteria | Results | | --- | --- | --- | --- | --- | | Injection Study | To evaluate the host response to PRESTIGE LP™ Cervical Disc's Ti6Al4V/TiC material | Rabbits were injected in the epidural space of the spinal canal with a control solution or a mixture of solution (contrast solution mixed with 10% Ti-6Al-4V/TiC particulate injected into n=20 total rabbits) representative of wear debris. Test groups were divided into low and high doses and represented an equivalent dose of 18.9 and 57.7 million cycles of use based upon wear test data. Rabbits were terminated at 12 and 24 weeks. Local and distant tissues were harvested and examined for gross pathology (if present) and the tissue was analyzed histologically. | The test was for characterization purposes and acceptance criteria were not established. | Characterization of response to wear particles near the spine. The lungs, spleen, thymus, and lymph nodes were all observed to be unaffected by either the high or low dose. The particles generally elicited no tissue reaction or mild tissue reaction in both 12 and 24-week dose groups. | PMA P090029/S003: FDA Summary of Safety and Effectiveness Data Page 20 of 94 {20} | Test Description | Purpose | Methods | Medtronic's Acceptance Criteria | Results | | --- | --- | --- | --- | --- | | Injection Study | To evaluate the potential toxicity associated with wear particulate generated from the Ti6Al4V/TiC material from which the PRESTIGE LP™ Cervical Disc is manufactured | Rabbits were injected in the epidural space of the spinal canal with a control solution or a mixture of solution (contrast solution mixed with 10% Ti-6Al-4V/TiC particulate injected into n=36 total rabbits) representative of wear debris. Test groups were divided into low and high doses representing an equivalent dose of 20 and 60 million cycles of use based upon wear test data. Rabbits were terminated at 3 and 6 months. Local and distant tissues were harvested and examined for gross pathology (if present) and the tissue was analyzed histologically. | The test was for characterization purposes and acceptance criteria were not established. | Characterization of response to wear near the spine. There were no adverse tissue effects such as necrosis or excessive inflammation. | ### C. Additional Studies #### Biocompatibility Testing Per the requirements of ISO 10993-1, PRESTIGE LP™ Cervical Disc device is classified as a permanent contact, tissue/bone-contacting implant. The following biocompatibility tests were undertaken on the complete device (or extract, as required): Cytotoxicity, sensitization, intracutaneous reactivity, and systemic toxicity. Data are also available for genotoxicity and implantation. All standard acceptance criteria were met. The test results support the biocompatibility of the device materials. Therefore, the Ti-6Al-4V/TiC material is considered to be safe for use in the cervical spine. #### Sterilization, Packaging and Shelf Life Validation The PRESTIGE LP™ Cervical Disc is provided in a sterile package ready for use. The PRESTIGE LP™ Cervical Disc is sterilized using gamma radiation at a minimum dosage of 25 kGy, at a sterilization assurance level (SAL) of 10⁻⁶. 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 studies, including PMA P090029/S003: FDA Summary of Safety and Effectiveness Data Page 21 of 94 {21} packaging seal and integrity, accelerated aging, and real-time aging testing, were conducted to demonstrate the device packaging can maintain a sterile barrier with a shelf life of 8 years. ## **X. SUMMARY OF PRIMARY CLINICAL STUDY** The applicant performed a clinical study within the United States under IDE #G050202 to establish a reasonable assurance of safety and effectiveness of the PRESTIGE LP™ Cervical Disc for reconstruction of the disc from C3-C7 following discectomy at two contiguous levels in skeletally mature subjects with intractable radiculopathy (arm pain and/or a neurological deficit) with or without neck pain or myelopathy localized to the two disc space levels. The subjects had been unresponsive to at least 6 weeks of non-operative treatment or had the presence of progressive symptoms or signs of nerve root/spinal cord compression in the face of continued non-operative management. 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** Subjects were treated between June 20, 2006 and November 29, 2007. The database for this PMA reflected data collected through September 29, 2014 and included a total of 397 subjects treated (209 investigational subjects and 188 control subjects) at 30 investigational sites in the United States. The study was a prospective, multi-center, randomized (1:1), unmasked, concurrently controlled, non-inferiority study. The study was designed to compare the safety and effectiveness of the 2-level PRESTIGE LP™ Cervical Disc to the standard of care, 2-level anterior cervical discectomy and fusion (ACDF) using cortical ring allograft and stabilization with an ATLANTIS® Anterior Cervical Plate, in reconstruction of the disc from C3-C7 following discectomy at two contiguous levels in skeletally mature subjects with intractable radiculopathy or myelopathy localized to the two disc space levels who had been unresponsive to at least 6 weeks of non-operative treatment or had the presence of progressive symptoms or signs of nerve root/spinal cord compression in the face of continued non-operative management. Subjects were evaluated pre-operatively, intra-operatively, immediately post-operatively and at 6 weeks, 3 months, 6 months, 12 months, 24 months and annually thereafter until the last subject in the study had completed his/her 24-month follow-up evaluation. The recommended post-operative care in both treatment groups included avoidance of overhead lifting, heavy lifting, repetitive neck bending, high-impact exercise and athletic activity for 60 days post-operatively. Avoidance of prolonged (beyond 2 weeks post-op) non-steroidal anti-inflammatory drug (NSAID) use was specified in the post-operative regimen, although the use of NSAIDs was recommended for the first two weeks post-operatively in the 2-level PRESTIGE LP™ group. Post-operative bracing requirements were left to the discretion of the investigators and included the option for use of a soft collar as needed. The use of electrical bone growth stimulators was not recommended during the 24-month follow-up period. Subjects who smoked were encouraged to discontinue smoking. PMA P090029/S003: FDA Summary of Safety and Effectiveness Data Page 22 of 94 {22} 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. All adverse events were independently adjudicated (for severity and relationship to the device and/or procedure) by a Clinical Adjudication Committee (CAC) composed of three independent, practicing spine surgeons. Overall success was a composite endpoint which required the following for success: - Neck Disability Index (NDI) score improvement of at least 15 points from pre-operative; - Maintenance or improvement in neurological status; - No serious adverse event classified as implant associated or implant/surgical procedure associated; and - No additional surgical procedure classified as a “failure.” Overall success was determined based on data collected during the initial 24 months of follow-up. The study was designed as a non-inferiority study with a margin (delta) of 10%. The protocol specified a sample size of 209 2-level PRESTIGE LP™ IDE subjects and 188 2-level ACDF control subjects, based on assumed success rates of 75% in the investigational group and 70% in the control group, a 15% lost-to-follow-up rate, and 80% power for a one-sided 0.05 significance level. The protocol also specified secondary superiority evaluations of the primary endpoint if non-inferiority was demonstrated. For the secondary endpoints and other measurements, multiple comparisons were carried out without adjusting for multiplicity. The statistical plan pre-defined that the data would initially be analyzed after approximately 250 subjects (investigational and control subjects combined) had reached the 24-month evaluation timepoint at which time all subjects would have reached the 12-month timepoint. The applicant then also planned to analyze the data when the entire cohort had reached the 24-month timepoint. Due to rapid study enrollment and timing considerations, the pre-defined interim analysis was not performed. ### 1. Clinical Inclusion and Exclusion Criteria Enrollment in the 2-level PRESTIGE LP™ Cervical Disc study was limited to subjects who met the following inclusion criteria: - Cervical degenerative disc disease at two (2) adjacent cervical levels (from C3-C7) requiring surgical treatment and involving intractable radiculopathy, myelopathy, or both; - Herniated disc and/or osteophyte formation at each level to be treated that is producing symptomatic nerve root and/or spinal cord compression. The condition is documented by patient history (e.g., neck and/or arm pain, functional deficit and/or neurological deficit), and the requirement for surgical treatment is evidenced by radiographic studies (e.g., CT, MRI, x-rays, etc.); - Unresponsive to non-operative treatment for approximately six weeks or has the presence of progressive symptoms or signs of nerve root/spinal cord compression in the face of continued non-operative management; - No previous surgical intervention at the involved levels or any subsequent, planned/staged surgical procedure at the involved or adjacent levels; - At least 18 years of age and skeletally mature at the time of the surgery; PMA P090029/S003: FDA Summary of Safety and Effectiveness Data Page 23 of 94 {23} - Pre-operative Neck Disability Index (NDI) score ≥ 30; - Pre-operative neck pain score ≥ 8 on Pre-operative Neck and Arm Pain Questionnaire; - If a female of child-bearing potential, subject is non-pregnant, non-nursing, and agrees not to become pregnant during the study period; - Willing to comply with the study plan and sign the Patient Informed Consent Form. Subjects were not permitted to enroll in the 2-level PRESTIGE LP™ Cervical Disc study if they met any of the following exclusion criteria: - A cervical spinal condition other than symptomatic cervical degenerative disc disease requiring surgical treatment at the involved levels; - Documented or diagnosed cervical instability relative to adjacent segments at either level, defined by dynamic (flexion/extension) radiographs showing sagittal plane translation > 3.5 mm or sagittal plane angulation > 20°; - More than two cervical levels requiring surgical treatment; - A fused level adjacent to the levels to be treated; - Severe pathology of the facet joints of the involved vertebral bodies; - Previous surgical intervention at either one or both of the involved levels or at adjacent levels; - Previously diagnosed with osteopenia or osteomalacia; - Any of the following that may be associated with a diagnosis of osteoporosis (if “Yes” to any of the below risk factors, a DEXA Scan was required to determine eligibility): - Postmenopausal non-Black female over 60 years of age who weighs less than 140 pounds. - Postmenopausal female who has sustained a non-traumatic hip, spine, or wrist fracture. - Male over the age of 70; - Male over the age of 60 who has sustained a non-traumatic hip or spine fracture; If the level of bone mineral density (BMD) was a T score of -3.5 or lower (i.e., -3.6, -3.7, etc.) or a T score of -2.5 or lower (i.e., -2.6, -2.7, etc.) with vertebral crush fracture, then the subject was excluded from the study; - Presence of spinal metastases; - Overt or active bacterial infection, either local or systemic; - Insulin dependent diabetes; - A tobacco user who does not agree to suspend smoking prior to surgery; - Chronic or acute renal failure or prior history of renal disease; - A documented allergy or intolerance to stainless steel, titanium, or a titanium alloy; - Mentally incompetent (If questionable, obtain psychiatric consult); - A prisoner; - Pregnant; - An alcohol and/or drug abuser currently undergoing treatment for alcohol and/or drug abuse; - Involved with current or pending litigation regarding a spinal condition; - Received drugs that may interfere with bone metabolism within two weeks prior to the planned date of spinal surgery (e.g. steroids or methotrexate) excluding routine perioperative anti-inflammatory drugs; PMA P090029/S003: FDA Summary of Safety and Effectiveness Data Page 24 of 94 {24} - A history of an endocrine or metabolic disorder known to affect osteogenesis (e.g., Paget's Disease, renal osteodystrophy, Ehlers-Danlos Syndrome, or osteogenesis imperfecta); - A condition that requires post-operative medications that interfere with the stability of the implant, such as steroids. (This does not include low dose aspirin for prophylactic anticoagulation and routine perioperative anti-inflammatory drugs); - Received treatment with an investigational therapy within 28 days prior to implantation surgery or such treatment is planned during the 16 weeks following implantation with the PRESTIGE LP™ device. ## 2. Follow-up Schedule Subjects were evaluated pre-operatively (within 6 months of surgery), intra-operatively, and post-operatively. All subjects were scheduled to return for post-operative 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 until the last subject enrolled in the study had been seen for his/her 24-month evaluation. Additional evaluations were approved by FDA for 36 months (±2 months), 60 months (±3 months), 84 months (±3 months), and 120 months (±3 months). Evaluations were done according to the visit schedule below. Adverse events and complications were recorded at all visits. Table 6: Schedule of Study Assessments | Procedure | Pre-/Peri-operative | | Post-operative | | | | | | --- | --- | --- | --- | --- | --- | --- | --- | | | Pre-op | Surgery/Hospital Discharge | 6 wks (±2 wks) | 3 mos (±2 wks) | 6 mos (±1 mo) | 12 mos, 24 mos 36 mos, (±2 mos) | 60 mos, 84 mos, 120 mos (±3 mos) | | Clinical Evaluations: | | | | | | | | | Inclusion/Exclusion Determination | X | | | | | | | | Osteoporosis/Osteopenia Screen | X | | | | | | | | Informed Consent and HIPAA Authorization | X | | | | | | | | Baseline Medical History/Physical Exam | X | | | | | | | | Surgery and Hospital Discharge Data | | X | | | | | | | Neck Disability Index (NDI) | X | | X | X | X | X | X | | Neck and Arm Pain Questionnaire | X | | X | X | X | X | X | | Health Status Questionnaire (SF-36) | X | | | | X | X | X | | Neurological Status | X | | X | X | X | X | X | | Preoperative Gait Assessment and Foraminal Compression Test | X | | X | X | X | X | X | | Medication Use | X | | X | X | X | X | X | | Work Status | X | | X | X | X | X | X | | Satisfaction and Perceived Effect (subject & physician) | X | | X | X | X | X | X | PMA P090029/S003: FDA Summary of Safety and Effectiveness Data Page 25 of 94 {25} | Procedure | Pre-/Peri-operative | | Post-operative | | | | | | --- | --- | --- | --- | --- | --- | --- | --- | | | Pre-op | Surgery/ Hospital Discharge | 6 wks (±2 wks) | 3 mos (±2 wks) | 6 mos (±1 mo) | 12 mos, 24 mos 36 mos, (±2 mos) | 60 mos, 84 mos, 120 mos (±3 mos) | | Radiologic Review | X | X | X | X | X | X | X | | Adverse Events | | X | X | X | X | X | X | | Subject Disposition* | X | X | X | X | X | X | X | | **Radiographic Procedures:** | | | | | | | | | Anterior/Posterior and Lateral Neutral X-rays | X | X | X | X | X | X | X | | Lateral Flexion/Extension X-rays | X | | X | X | X | X | X | | CT and/or MRI | X | | | | | | | | DEXA Scan ** | X | | | | | | | * While the Subject Disposition CRF could be filled out at any time, it was only filled out once for each subject. ** A DEXA Scan was only required if the subject had a risk factor that may be associated with a diagnosis of osteoporosis as outlined in the clinical protocol. ### 3. Clinical Endpoints The safety of the 2-level PRESTIGE LP™ Cervical Disc was assessed by comparing the nature and frequency of adverse events (overall and in terms of seriousness and relationship to the device and/or procedure) and subsequent surgical procedures as well as maintenance or improvement in neurological status to the 2-level ACDF control group. The effectiveness of the 2-level PRESTIGE LP™ Cervical Disc was assessed by evaluating improvement in NDI score, improvement in neck and arm pain measured at rest using a neck and arm pain questionnaire, improvement in quality of life measured using the Short-Form 36 (SF-36) questionnaire, subject satisfaction, medication usage, and work status compared to the 2-level ACDF control group. In addition, several radiograph endpoints were considered in evaluating both safety and effectiveness including range of motion, functional spinal unit (FSU) height maintenance, implant condition, and heterotopic ossification. Per the protocol, an individual subject in either treatment group was considered a success if the following criteria were met at 24 months post-operative: 1. Improvement (reduction) of at least 15 points in NDI score at 24 months compared to pre-operative baseline; 2. Maintenance or improvement in neurological status at 24 months compared to pre-operative baseline as measured based on motor function, sensory function, and reflexes; 3. No serious adverse event classified as implant associated, or implant/surgical procedure associated; and 4. No additional surgical procedure classified as a “failure.” Note that because the additional surgical procedure component of the primary endpoint did not consider all subsequent surgeries at the index level as failures, FDA requested an additional analysis of overall success in which all subsequent surgeries at the index level and all intra-operative treatment conversions were considered failures. PMA P090029/S003: FDA Summary of Safety and Effectiveness Data Page 26 of 94 {26} Overall study success criteria were based on a comparison of individual subject success rates, such that the subject success rate for the 2-level PRESTIGE LP™ group was required to be non-inferior to that of the 2-level ACDF control group. The study was designed as a non-inferiority study with a margin (delta) of 10%. For the analysis of overall success, individual effectiveness variables and neurological status, the Bayesian model incorporated data from both the 12-month and 24-month follow-up visits, including data from the 12-month only or 24-month only visits, to statistically compare the outcomes at the 24-month visit between the two treatment groups. The study hypothesis was that the success rate of the 2-level PRESTIGE LP™ group was statistically non-inferior to the success rate in the 2-level ACDF control group by a margin of 10%. Non-inferiority was to be claimed if the posterior probability that the success rate in the 2-level PRESTIGE LP™ group was not lower than the success rate in the 2-level ACDF control group by more than 10% was greater than 95%. The protocol also specified secondary superiority evaluations if non-inferiority was demonstrated. For comparison of adverse events and subsequent surgical procedures, a beta-binomial model was used. Secondary endpoints, measured in both treatment groups, included neck pain, arm pain, quality of life (SF-36 Physical Component Score [PCS] and Mental Component Score [MCS]), gait assessment (Nurick's classification), subject satisfaction, subject perceived effect, physician perception of results, radiographic success (defined differently in the two treatment groups), range of motion, Functional Spinal Unit (FSU) height, implant condition, heterotopic ossification, and return to work. For the secondary endpoints and other measurements, multiple comparisons were carried out without adjusting for multiplicity. ### B. Accountability of PMA Cohort A total of 397 subjects (209 2-level PRESTIGE LP™, 188 2-level ACDF control) were treated in the 2-level PRESTIGE LP™ Cervical Disc study at 30 sites. At the time of database lock (September 29, 2014), of the 397 subjects enrolled in the PMA study, all had reached the 24 month post-operative visit and 363 of the 396 expected subjects (92%) had any 24-month data available for analysis. Complete 24-month overall success (primary endpoint) data was available for 199 2-level PRESTIGE LP™ subjects (95.2%) and 160 2-level ACDF control subjects (88.9%). A summary of subject accountability data for the 12-month, 24-month, 36-month, 60-month, and 84-month follow-up visits is provided in Table 7. PMA P090029/S003: FDA Summary of Safety and Effectiveness Data Page 27 of 94 {27} Table 7: Subject Accountability | | 12 Months | | 24 Months | | 36 Months | | 60 Months | | 84 Months | | | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | | | INV | CTR | INV | CTR | INV | CTR | INV | CTR | INV | CTR | | Enrolled and treated | 209 | 188 | 209 | 188 | 209 | 188 | 209 | 188 | 209 | 188 | | Deaths (cumulative) | 0 | 0 | 0 | 1 | 0 | 1 | 1 | 1 | 1 | 2 | | Not Yet Overdue | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 21 | 15 | | Expected^{1} | 209 | 188 | 209 | 187 | 209 | 187 | 208 | 187 | 187 | 171 | | Withdrawn (cumulative) | 0 | 4 | 0 | 7 | 1 | 10 | 5 | 12 | 5 | 16 | | Actual, primary endpoint data (% follow-up)^{2} | 202 (97%) | 166 (88%) | 199 (95%) | 160 (86%) | 185 (89%) | 149 (80%) | 166 (80%) | 138 (74%) | 126 (67%) | 99 (58%) | | Actual, primary endpoint data in window (% follow-up)^{3} | 191 (91%) | 162 (86%) | 181 (87%) | 140 (75%) | Not Available | | | | | | | Actual, any data (% follow-up)^{4} | 203 (97%) | 168 (89%) | 199 (95%) | 164 (88%) | 187 (89%) | 152 (81%) | 167 (80%) | 139 (74%) | 126 (67%) | 101 (59%) | INV=2-level PRESTIGE LP™ (N=209); CTR = 2-level ACDF control (N=188) $^{1}$ Treated subjects – (Deaths + Not yet overdue). $^{2}$ Subjects with complete data for the primary endpoint (overall success), regardless of in-window status. $^{3}$ Subjects with complete data for the primary endpoint (overall success), evaluated in-window. $^{4}$ Subjects with any follow-up data reviewed or evaluated. In addition to the study subjects described above, 17 investigational subjects and 42 control subjects were consented but declined participation in the study prior to receiving the assigned treatment. The demographic and pre-operative characteristics of the subjects who declined to participate in the study were comparable to the characteristics of the subjects who participated in the study. A summary of data availability for specific study assessments at 24 months is provided in Table 8 below. Table 8: 24-Month Data Accounting For Specific Study Assessments | Parameter | INV | CTR | | --- | --- | --- | | Treated | 209 | 188 | | Expected | 209 | 187 | | Primary Endpoint: | | | | NDI (% of Expected) | 199 (95%) | 159 (85%) | | Neurological assessment (% of Expected) | 199 (95%) | 159 (85%) | | Device failure (% of Expected) | 209 (100%) | 187 (100%) | | SD AE (% of Expected) | 209 (100%) | 187 (100%) | | All primary endpoint components (% of Expected) | 199 (95%) | 160 (89%) | | Secondary Clinical Endpoints: | | | | SF-36 Physical Component Summary (% of Expected) | 197 (94%) | 156 (83%) | | SF-36 Mental Component Summary (% of Expected) | 197 (94%) | 156 (83%) | | Neck Pain (% of Expected) | 199 (95%) | 159 (85%) | | Arm Pain (% of Expected) | 199 (95%) | 159 (85%) | | Subject Perceived Effect (% of Expected) | 199 (95%) | 159 (85%) | | Doctor's Perception (% of Expected) | 199 (95%) | 159 (85%) | | Subject Satisfaction (% of Expected) | 199 (95%) | 159 (85%) | | Gait (% of Expected) | 199 (95%) | 159 (85%) | | Foraminal Compression Test (% of Expected) | 199 (95%) | 157 (84%) | | Adverse events (% of Expected) | 209 (100%) | 187 (100%) | PMA P090029/S003: FDA Summary of Safety and Effectiveness Data Page 28 of 94 {28} | Parameter | INV | CTR | | --- | --- | --- | | Secondary Radiographic Endpoints: | | | | Disc height superior level (% of Expected) | 199 (95%) | 155 (83%) | | Disc height inferior level (% of Expected) | 190 (91%) | 151 (81%) | | Angulation superior level (% of Expected) | 198 (95%) | 154 (82%) | | Angulation inferior level (% of Expected) | 196 (94%) | 151 (81%) | | Translation superior level (% of Expected) | 198 (95%) | 154 (82%) | | Translation inferior level (% of Expected) | 196 (94%) | 151 (81%) | | Device subsidence (FSU Height) (% of Expected) | 170 (11%) | 132 (70%) | | Device migration (% of Expected) | 195 (93%) | 159 (85%) | | Heterotopic Ossification Evaluation (% of Expected) | 198 (95%) | N/A | INV=2-level PRESTIGE LP™ (N=209); CTR = 2-level ACDF control (N=188) The primary analysis dataset (209 2-level PRESTIGE LP™, 188 2-level ACDF control) included all subjects who completed the surgical procedure and received a study device in either treatment group according to the treatment received (as-treated). Subjects who had subsequent surgical procedures classified as “failure”, were deemed “failures” for overall success, and since these subsequent surgical procedures had potential to alter the original study treatment’s outcomes, for all neurological status and all individual effectiveness variables, the last observation obtained before the subsequent surgery occurred was carried forward. Primary statistical comparisons were based on the observed data, and missing data due to lost-to-follow-ups were not imputed. Therefore, the denominators varied for the primary study endpoint (overall success) and individual effectiveness variables such as NDI and neurological status. ### C. Study Population Demographics and Baseline Parameters The demographics of the study population are typical for a cervical artificial disc device study performed in the United States. Table 9 presents the summary statistics for demographic and baseline characteristics for the 2-level PRESTIGE LP™ group and the 2-level ACDF control group. The investigational and control treatment groups were similar demographically, and there were no statistically significant differences (p<0.05) for any of the variables except for pre-operative work status (70% working pre-operatively in the 2-level PRESTIGE LP™ group as compared to 60% in the 2-level ACDF control group). PMA P090029/S003: FDA Summary of Safety and Effectiveness Data Page 29 of 94 {29} Table 9: Study Population Demographics and Baseline Characteristics | Demographic Measure/ Baseline Characteristic | INV (N=209) | CTR (N=188) | p-value (INV - CTR) | | --- | --- | --- | --- | | Age (years; mean ± standard deviation) | 47.1 ± 8.3 Range: 22 – 75 | 47.3 ± 7.7 Range: 25 – 69 | 0.844 | | Gender (n(%)) | | | 0.480 | | Male | 92 (44.0%) | 90 (47.9%) | | | Female | 117 (56.0%) | 98 (52.1%) | | | Race (n(%)) | | | 0.879 | | Caucasian | 195 (93.3%) | 172 (91.5%) | | | Black | 8 (3.8%) | 8 (4.3%) | | | Asian | 1 (0.5%) | 3 (1.6%) | | | Hispanic | 4 (1.9%) | 4 (2.1%) | | | Other | 1 (0.5%) | 1 (0.5%) | | | BMI (kg/m²; mean ± standard deviation) | 28.2 ± 5.6 Range: 16 – 46 | 28.6 ± 4.9 Range: 18 – 43 | 0.481 | | Marital Status (n(%)) | | | 0.698 | | Single | 25 (12.0%) | 29 (15.4%) | | | Married | 146 (69.9%) | 133 (70.7%) | | | Divorced | 32 (15.3%) | 23 (12.2%) | | | Separated | 4 (1.9%) | 2 (1.1%) | | | Widowed | 2 (1.0%) | 1 (0.5%) | | | Education Level (n(%)) | | | 0.652 | | < High School | 21 (10.0%) | 20 (10.6%) | | | High School | 63 (30.1%) | 64 (34.0%) | | | > High School | 125 (59.8%) | 104 (55.3%) | | | Previous Neck Surgery (n(%)) | | | 0.224 | | Yes | 0 (0.0%) | 2 (1.1%) | | | No | 209 (100.0%) | 186 (98.9%) | | | Pre-operative Medication Use | | | | | Non-Narcotics | 138/208 (66.3%) | 133/185 (71.9%) | 0.275 | | Weak Narcotics | 83/208 (39.9%) | 78/186 (41.9%) | 0.758 | | Strong Narcotics | 52/207 (25.1%) | 44/188 (23.4%) | 0.725 | | Muscle Relaxants | 75/208 (36.1%) | 73/188 (38.8%) | 0.604 | | Pre-operative Pain Status^{1} | | | 0.078 | | Arm and Neck Pain | 180 (86.1%) | 173 (92.0%) | | | Arm Pain Only | 0 (0.0%) | 0 (0.0%) | | | Neck Pain Only | 29 (13.9%) | 15 (8.0%) | | | Pre-operative Diagnosis (n(%)) | | | 0.837 | | Radiculopathy and myelopathy | 54 (25.8%) | 45 (23.9%) | | | Radiculopathy only | 150 (71.8%) | 137 (72.9%) | | | Myelopathy only | 5 (2.4%) | 6 (3.2%) | | | Duration of Symptoms | | | 0.340 | | < 6 wks. | 5 (2.4%) | 8 (4.3%) | | | 6 wks. – 6 mos. | 56 (26.8%) | 58 (30.9%) | | | > 6 mos. | 148 (70.8%) | 122 (64.9%) | | | Working pre-operatively | 146 (69.9%) | 113 (60.1%) | 0.045 | | Worker's Compensation | 26 (12.4%) | 19 (10.1%) | 0.527 | | Unresolved Spinal Litigation | 0 (0.0%) | 1 (0.5%) | 0.474 | | Smoking Status | Not provided. Protocol excluded tobacco users who did not agree to stop smoking prior to surgery. | | | | Current Alcohol Use | 116 (55.5%) | 88 (46.8%) | 0.088 | INV=2-level PRESTIGE LP™ (N=209); CTR = 2-level ACDF control (N=188) $^{1}$ Pre-operative arm and neck pain defined as both arm and neck pain scores ≥ 8/10; pre-operative neck pain only defined as neck pain score ≥ 8/10 and arm pain score < 8/10. There were no subjects with only arm pain because neck pain score ≥ 8/10 was a study inclusion criterion. PMA P090029/S003: FDA Summary of Safety and Effectiveness Data Page 30 of 94 {30} The mean baseline pre-operative assessments for the 2-level PRESTIGE LP™ group and the 2-level ACDF control group are presented in Table 10. There were no statistical differences between the 2-level PRESTIGE LP™ group and the 2-level ACDF control group for any of the variables identified in the table. Table 10: Pre-operative Evaluation of Endpoints | Variable | INV (N=209) | CTR (N=188) | p-value (INV - CTR) | | --- | --- | --- | --- | | NDI; mean ± standard deviation | 52.1 ± 13.4 Range: 30 – 84 | 53.2 ± 14.8 Range: 30 – 94 | 0.441 | | SF-36 PCS; mean ± standard deviation | 31.8 ± 7.8 Range: 11.7 – 55.5 | 30.8 ± 7.4 Range: 11.1 – 51.1 | 0.189 | | SF-36 MCS; mean ± standard deviation | 43.9 ± 11.8 Range: 16.7 – 70.6 | 43.8 ± 12.2 Range: 15.9 – 67.1 | 0.930 | | Neck Pain Score; mean ± standard deviation | 16.2 ± 2.9 Range: 8 – 20 | 16.3 ± 2.6 Range: 8 – 20 | 0.720 | | Arm Pain Score; mean ± standard deviation | 13.8 ± 5.6 Range: 0 – 20 | 14.4 ± 4.3 Range: 0 – 20 | 0.208 | | Neurological Status Normal (n(%)) Motor Sensory Reflexes Overall^{1} | 97 (46.4%) 85 (40.7%) 90 (43.1%) 42 (20.1%) | 88 (46.8%) 66 (35.1%) 75 (39.9%) 31 (16.5%) | 1.000 0.257 0.542 0.367 | | ROM flexion/extension angulation (°) Superior Target Level; mean ± standard deviation | 6.75 ± 4.16 Range: 0.08 – 18.15 | 7.12 ± 4.14 Range: 0.45 – 19.72 | 0.387 | | ROM flexion/extension angulation (°) Inferior Target Level; mean ± standard deviation | 5.56 ± 3.89 Range: 0.37 – 18.20 | 5.37 ± 3.26 Range: 0.37 – 18.51 | 0.637 | | ROM flexion/extension translation (mm) Superior Target Level; mean ± standard deviation | 1.48 ± 1.08 Range: 0.13 – 9.17 | 1.57 ± 1.14 Range: 0.03 – 8.96 | 0.446 | | ROM flexion/extension translation (mm) Inferior Target Level; mean ± standard deviation | 1.04 ± 0.74 Range: 0.06 – 3.42 | 1.14 ± 0.93 Range: 0.00 – 6.60 | 0.267 | | Baseline radiographic findings – superior target level (n(%)) Herniated disc Osteophyte formation Both | 63 (30.1%) 48 (23.0%) 98 (46.9%) | 54 (28.7%) 32 (17.0%) 102 (54.3%) | 0.240 | | Baseline radiographic findings – inferior target level (n(%)) Herniated disc Osteophyte formation Both | 67 (32.1%) 42 (20.1%) 100 (47.8%) | 62 (33.0%) 29 (15.4%) 97 (51.6%) | 0.480 | INV=2-level PRESTIGE LP™ (N=209); CTR = 2-level ACDF control (N=188) $^{1}$ If at least one of the three components (motor, sensory, reflexes) is not normal, then overall is defined as not normal. If all components are normal, then overall is defined as normal. ### D. Safety and Effectiveness Results #### 1. Safety Results The analysis of safety was based on the as-treated cohort of 397 total subjects which included all subjects who completed the surgical procedure and received a study device in either treatment group according to the treatment received (209 2-level PRESTIGE LP™ subjects PMA P090029/S003: FDA Summary of Safety and Effectiveness Data Page 31 of 94 {31} and 188 2-level ACDF control subjects). The key safety outcomes for this study are presented below in Tables 11 to 27. # Summary of adverse events that occurred in the PMA clinical study A summary of the adverse event (AE) data is presented in Table 11. Adverse events were classified by an independent Clinical Adjudication Committee (CAC) for severity and relationship to the device and/or surgical procedure. The severity of an AE was assessed as mild (grade 1), moderate (grade 2), severe (grade 3), or life-threatening (grade 4) according to the World Health Organization (WHO) Recommendations for Grading of Acute and Subacute Toxic Effects. The relationship between an AE and the device/surgical procedure was assessed based on the following definitions: - Implant Associated: AE for which there is a reasonable possibility that the AE may have been caused primarily by the device; - Implant/Surgical Procedure Associated AE: AE for which there is a reasonable possibility that the AE may have been caused both by the device and the surgical procedure; - Surgical Procedure Associated AE: AE for which there is a reasonable possibility that the AE may have been caused primarily by the surgical procedure; - Undetermined: AE for which sufficient information is not available at the time of the AE to determine its causality; - Not Related: AE for which sufficient information exists to indicate that the etiology is unrelated to the device or surgical procedure. The overall AE rates were similar in the 2-level PRESTIGE LP™ group (93.3%) and in the 2-level ACDF control group (92.0%) through 24 months. Table 11: Summary of Adverse Events (AEs) Through 24-Month Interval (≤30 Months) | | INV (N=209) | | CTR (N=188) | | Posterior Mean and 95% BCI* of the Difference of Event Rate between INV and CTR** | | --- | --- | --- | --- | --- | --- | | | Events | Subjects (n (%)) | Events | Subjects (n (%)) | | | All Adverse Events | 1477 | 195 (93.3%) | 1593 | 173 (92.0%) | 1.3% (-3.9%, 6.6%) | | Subsequent Surgeries at Index Level | 6 | 5 (2.4%) | 17 | 15 (8.0%) | -5.6% (-10.2%, -1.1%) | | Device Related AEs | 38 | 16 (7.7%) | 35 | 16 (8.5%) | -0.9% (-6.4%, 4.6%) | | Device/Surgical Procedure Related AEs | 57 | 19 (9.1%) | 80 | 26 (13.8%) | -4.7% (-11.1%, 1.6%) | | Device or Device/Surgical Procedure Related AEs | 95 | 33 (15.8%) | 115 | 39 (20.7%) | -4.9% (-12.6%, 2.6%) | | Surgical Procedure Related AEs | 127 | 60 (28.7%) | 106 | 45 (23.9%) | 4.7% (-3.9%, 13.3%) | | Severe AEs (Grade 3 or 4) | 293 | 72 (34.4%) | 430 | 90 (47.9%) | -13.3% (-22.8%, -3.7%) | | Severe Device or Device/Surgical Procedure Related AEs (Grade 3 or 4) | 8 | 4 (1.9%) | 28 | 11 (5.9%) | -3.9% (-8.1%, 0.0%) | INV=2-level PRESTIGE LP™ (N=209); CTR = 2-level ACDF control (N=188) * BCI = Bayesian HPD Credible Interval **95% BCI of the difference of the event rate between the investigational group and control group was only determined for the “All Adverse Events” category because the analysis was pre-defined. All other analyses were not pre-defined. PMA P090029/S003: FDA Summary of Safety and Effectiveness Data Page 32 of 94 {32} ### *Timecourse of all Adverse Events* The timecourse of adverse events reported in the PMA clinical study from all 397 total subjects (209 2-level PRESTIGE LP™ subjects and 188 2-level ACDF control subjects) through all available follow-up are shown in Table 12. This table includes adverse events from all subjects to establish the safety profile of the device. Adverse events are listed in alphabetical order by main category with clinically relevant subcategories also detailed. Definitions of the adverse event categories and subcategories are provided in Table 13. Subject adverse event rates are based on the number of subjects having at least one occurrence of an adverse event, divided by the number of subjects in that treatment group. Subjects experiencing adverse events in more than one category are represented in each category in which they experienced an adverse event. The percentage of subjects experiencing at least one adverse event is comparable in the 2-level PRESTIGE LP™ group and the 2-level ACDF control group. Some of the more commonly reported clinically relevant adverse events through all available follow-up were cervical neck and/or arm pain (in 62.7% of 2-level PRESTIGE LP™ subjects and 63.3% of 2-level ACDF control subjects), cervical neurological adverse events (in 39.7% of 2-level PRESTIGE LP™ subjects and 38.8% of 2-level ACDF control subjects), cervical study surgery spinal events (in 19.1% of 2-level PRESTIGE LP™ subjects and 10.6% of 2-level ACDF control subjects), cervical Heterotopic Ossification (in 15.8% of 2-level PRESTIGE LP™ subjects and 13.3% of 2-level ACDF control subjects), dysphagia/dysphonia (in 8.6% of 2-level PRESTIGE LP™ subjects and 12.2% of 2-level ACDF control subjects), non-infectious wound adverse events (in 8.6% of 2-level PRESTIGE LP™ subjects and 7.4% of 2-level ACDF control subjects), and implant adverse events (in 7.2% of 2-level PRESTIGE…