TOPS™ System

{0} SUMMARY OF SAFETY AND EFFECTIVENESS DATA (SSED) I. GENERAL INFORMATION Device Generic Name: Prosthesis, posterior spinal elements Device Trade Name: TOPS™ System Device Procode: QWK Applicant’s Name and Address: Premia Spine, Ltd. 7 Giborey Israel Street Ramat Poleg, Netanya HaMerkaz, Israel 4250407 Date(s) of Panel Recommendation: None Premarket Approval Application (PMA) Number: P220002 Date of FDA Notice of Approval: June 15, 2023 Breakthrough Device: Granted breakthrough device status on October 26, 2020, because the device and proposed indication for use met the criteria. II. INDICATIONS FOR USE The TOPS™ System is a motion-preserving spinal implant that is inserted into the lumbar spine via pedicle screws. The TOPS™ System is intended to stabilize the spine following a lumbar decompression without rigid fixation. The TOPS™ System is indicated for patients between 35 and 80 years of age with symptomatic degenerative spondylolisthesis up to Grade I, with moderate to severe lumbar spinal stenosis and either the thickening of the ligamentum flavum and/or scarring of the facet joint capsule at one level from L3 to L5. III. CONTRAINDICATIONS The TOPS™ System is contraindicated in patients with: - Presence of extruded or free fragment disc herniation at the index level - Spondylolisthesis greater than Grade I - Traumatic, dysplastic or lytic spondylolisthesis - Back or non-radicular leg pain of unknown etiology - Stenosis where the etiology is considered to be congenital, iatrogenic, post-traumatic, or metabolic PMA P220002: FDA Summary of Safety and Effectiveness Data 1 of 69 {1} - Known allergy or sensitivity to PEEK, titanium, and/or polyurethane - Scoliosis greater than 10 degrees by major Cobb angle (both angular and rotational) - Morbid obesity defined as a body mass index greater than 40 - Lumbar spine T-score less than -2.0 - Active infection - systemic or local - Cauda equina syndrome or neurogenic bowel/bladder dysfunction ## IV. WARNINGS AND PRECAUTIONS The warnings and precautions can be found in the TOPS™ System labeling. ## V. DEVICE DESCRIPTION The TOPS™ System presented in Figure 1 below is a motion-preserving spinal implant that is inserted into the lumbar spine via pedicle screws. The device is implanted via a posterior surgical approach to replace the degenerated skeletal elements such as the lamina and the facet joints that are removed during the decompression.  Figure 1: The TOPS™ System (TOPS™ Motion Implant and Pedicle Screws) The TOPS™ System is comprised of a motion device ("TOPS™ Motion Implant") and four pedicle screws. The TOPS™ Motion Implant is comprised of two Titanium Endplates connected by a polycarbonate urethane (PcU) Boot. Housed between the Titanium Endplates is an internal motion mechanism comprised of titanium and PcU articulating parts and an interlocking woven Polyether Ether Ketone (PEEK) ribbon (see Figure 2). The Top Articulating and Bottom Articulating parts are attached to their respective upper and lower Titanium Endplates. The flexible Boot and the internal articulating parts allow relative movement between the endplates. The device is designed to maintain motion in axial rotation, lateral bending, extension, and flexion, and to block translation when implanted into the human spine. PMA P220002: FDA Summary of Safety and Effectiveness Data 2 of 69 {2}  Figure 2: Illustration of the TOPS™ Motion Implant The TOPS™ Motion Implant is available in various sizes to meet a range of human anatomy, as depicted in Table 1. Table 1: TOPS™ Motion Implant Configurations | | Version | α (deg | A (mm) | B (mm) | C (mm) | | --- | --- | --- | --- | --- | --- | | 1 | TOPS™ - 21 L | 0 | 21 | 87 | 93 | | 2 | TOPS™ - 30 L | 14 | 30 | | | | 3 | TOPS™ - 38 L | 26 | 38 | | | | 4 | TOPS™ - 21 M | 0 | 21 | 77 | 83 | | 5 | TOPS™ - 30 M | 14 | 30 | | | | 6 | TOPS™ - 38 M | 26 | 38 | | | | 7 | TOPS™ - 21 S | 0 | 21 | 67 | 73 | | 8 | TOPS™ - 30 S | 14 | 30 | | | | 9 | TOPS™ - 38 S | 26 | 38 | | |  $\alpha =$ The angle between the arms (Top plate and Bottom plate); $\mathrm{A} =$ Inter-Pedicular Distance (IPD), defined by the configuration of the Top Plate.  B= Top Plate length C= Bottom plate length Note: *All dimensions indicated in the table are rounded and for reference only. **The IPD (21,30,38) is defined by the configuration of the Top Plate, which is available in 9 configurations: 21(L,M,S), 30(L,M,S) and 38(L,M,S), while the Bottom and Top Plates are available in 3 length configurations - L,M,S PMA P220002: FDA Summary of Safety and Effectiveness Data 3 of 69 {3} The TOPS™ System utilizes four polyaxial pedicle screws for fixation to the vertebrae. The Pedicle Screws are made of titanium alloy (Ti-6AI-4V in compliance with ASTM F136). Each polyaxial pedicle screw consists of a screw body, an insert, a screw Tulip, and a locking Set Screw. The Set Screw is threaded into the pedicle screw Tulip to secure the interconnection of the TOPS™ Motion Implant's arm and lock the polyaxial orientation in place. The Pedicle Screws are available in diameters of 5.5 mm, 6.5 mm and 7.5 mm. Their lengths vary in 5 mm increments from 25 to 60 mm. The heads of the pedicle screws are color anodized to allow for easy identification of screw diameter (5.5 mm - green, 6.5 mm - magenta, and 7.5 mm - blue). The assembled TOPS™ Motion Implant, and each pedicle screw are packaged in a Polyethylene Terephthalate Glycol (PETG) double blister, sealed with a Tyvek® lid, and sterilized by gamma radiation. All implants have a shelf life of five years. ## VI. ALTERNATIVE PRACTICES AND PROCEDURES There are several other alternatives for the correction of lumbar spinal stenosis (LSS), degenerative spondylolisthesis (DS) and facet joint osteoarthritis (FJ OA). Non-operative treatments include, but are not limited to, physical therapy, chiropractic care, medications, and spinal injections are the first treatment approaches. When non-operative treatments cease to be effective, there are several surgical alternatives, which include but are not limited to, surgical decompression alone and surgical decompression with spinal instrumentation and fusion. Each option has advantages and disadvantages. Patients should discuss risks, benefits and alternatives to all treatment options with their physicians. ## VII. MARKETING HISTORY The TOPS™ System has been marketed outside of the United States since 2012. The TOPS™ System is commercially available in several European Union countries, in Australia, and in several Asian countries. The TOPS™ System has not been withdrawn from any distribution/marketing in any country for safety or effectiveness reasons. ## 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 device. The adverse effects are sub-divided into three categories: (1) those commonly associated with any surgical procedure; (2) those associated with lumbar spinal surgery procedures using a posterior approach; and (3) those associated with posterior spinal implants, including those pertaining to the TOPS™ System. In addition to the risks listed below, there is also the risk that the procedure may not be effective and may not relieve or may cause worsening of pre-operative symptoms. Additional surgery may be required to correct some of the potential adverse effects. Possible risks associated with any surgical procedure include: - Anesthesia complications including allergic reaction, anaphylaxis, or other reactions to anesthesia PMA P220002: FDA Summary of Safety and Effectiveness Data 4 of 69 {4} - Reactions to transfused blood - Anemia - Blood loss/ hemorrhage - Heart or vascular complications including: - excessive bleeding or injury to blood vessels - edema - hematoma or seroma - hypotension or hypertension - ischemia - cardiac event - myocardial infarction, - embolism including pulmonary embolism - thrombosis - thromboembolism - thrombophlebitis - phlebitis - stroke - hemorrhage or vascular damage resulting in catastrophic or potentially fatal bleeding - Septicemia - Cerebral Vascular Accident (Stroke) - Pulmonary complications including atelectasis, pneumothorax or pneumonia, pulmonary edema and respiratory distress - Blindness secondary to pressure on the eye during surgery - False aneurysm - Headache - Infection (wound, local, and/or systemic) abscess, or cellulitis - Soft tissue damage or fluid collections, including edema, hematoma or seroma, which may require drainage, aspiration, or debridement or other intervention - Surgical wound dehiscence, necrosis, or scarring of tissue around the wound - Post-surgical pain, bruising, tenderness or discomfort at the surgical site or incision and/or skin or muscle sensitivity over the incision which may result in skin breakdown, pain, and/or irritation - Impairment of the gastrointestinal system including ileus or bowel obstruction, nausea or vomiting - Impairment of the genitourinary system including incontinence, bladder dysfunction, urinary tract infection, or reproductive system complications - Neurological complications including nerve damage, paralysis, seizures or convulsions, changes to mental status, or reflex sympathetic dystrophy - Psychological illness - Injury to muscles, or organs - Insomnia - Narcotic addiction - Numbness - Complications of pregnancy including miscarriage or congenital defects - Inability to resume activities of daily living PMA P220002: FDA Summary of Safety and Effectiveness Data 5 of 69 {5} - Death Possible risks associated with the posterior lumbar spinal surgery procedure include: - Risks to neurological structures: - dural tear dural leak and/or dural injury with or without CSF leakage - arachnoiditis - compressive neuropathy - neurologic deterioration - injury to nerves or nerve roots associated with the spinal cord (resulting in pain, weakness, paralysis (partial or complete), paresthesia, altered reflexes, numbness, tingling, or other changes in sensation) - coordination abnormalities - dysphasia - gait disturbance - headache - otitis media - tremors - cerebrospinal fluid leakage - cerebrospinal fistula - Reflex Sympathetic Dystrophy (RSD) - Cauda equina syndrome - Damage to nerves, blood vessels, and nearby tissues - Impaired muscle or nerve function - Epidural bleeding, hematoma, or fibrosis - Bone necrosis - Degenerative changes in adjacent segment - Surgery at incorrect level - Osteolysis - Loss of bowel or bladder function - Incontinence (loss of bowel or bladder control) - Fracture of the vertebrae, spinous process, or other damage to bony structures during or after surgery - Postoperative muscle and tissue pain - Development of disc degeneration at adjacent levels - Inflammatory conditions - Loss of disc height - Disc herniation - Undesirable change in lordosis - Scarring or soft tissue damage - Spinal instability - Spondylolisthesis acquisita (vertebral slippage) - Retrolisthesis - Spinal stenosis (narrowing of the spinal canal) - Spondylosis - Facet joint deterioration - Infection of the bone, or surrounding soft tissue - Musculoskeletal spasms (back or leg) PMA P220002: FDA Summary of Safety and Effectiveness Data 6 of 69 {6} - Perineural fibrosis - Surgery may not reduce the preoperative pain experienced - Pain and discomfort associated with the presence of implants - Pain and discomfort associated with the surgical procedure (e.g., cutting of muscles, ligaments, and tissue) and healing - The spine may undergo adverse changes or deterioration including loss of proper spinal curvature, correction, height, and/or reduction, or malalignment, and another surgery may be required - Adverse bone/implant interface reaction ## Possible risks associated with posterior lumbar spinal implants including the TOPS™ System: - Adverse reaction or allergy to the device materials [Titanium, Polycarbonate Urethane (PCU), and Polyether Ether Ketone (PEEK)], or device wear debris which may lead to an adverse reaction of the local tissues or chronic inflammation that may lead to implant loosening or failure of the device, adverse tissue reaction, osteolysis, tumor formation, autoimmune disease, metallosis, scarring, or other symptoms - Interference with radiographic imaging because of the presence of the device - Adverse reaction or allergy to contrast media - Herniated nucleus pulposus - Heterotopic ossification - Risks directly related to the device position and condition, including - implants malposition - implant breakage - implant degradation - implant disassembly - implant displacement - implant migration, subsidence, loosening or dislocation - implant separation - improper sizing - anatomical difficulties during the surgery - Misplaced screws in pedicle - Nerve root or spinal cord impingement or injury - Neurologic deterioration - cauda equina - clumsiness - foot drop - limp - numbness - paralysis - short step - slow moving gait - weakness - Osteophyte resorption - Osteolysis or vertebral inflammation PMA P220002: FDA Summary of Safety and Effectiveness Data 7 of 69 {7} - Reoperation including revision, removal, or supplemental fixation - Vertebral overload resulting in device failure and the need for additional surgery - Development of new 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 - Implantation at the wrong spinal level - Issues with the device instruments (e.g., bending/damage or breakage) including the possibility that a fragment of a broken instrument may remain in the patient after implantation, and improperly cleaned/disinfected instruments - Device/joint noise - 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 - Development of a new or recurrent spinal problem at the surgery level, or at levels above or below the treated spinal level - Fracture of the vertebrae, spinous process, or other damage to bony structures during or after surgery - Unintended bone formation (i.e., heterotopic ossification, annular 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 at the treated spinal level or at levels above or below the treated spinal level (including removal of the TOPS™ System, revision, re-operation or supplemental fixation - Additional radiography and contrast media may be used during the subsequent surgical intervention For the specific adverse events (AEs) that occurred in the clinical study, please see Section X below. ## IX. SUMMARY OF NON-CLINICAL STUDIES A variety of non-clinical tests were conducted to characterize the properties and performance of the TOPS™ System. These non-clinical evaluations included mechanical testing and animal studies to evaluate safety and performance, as well as biocompatibility testing, sterilization, shelf life and packaging validation, and magnetic resonance (MR) compatibility testing. The testing is summarized in the following table and described further below. Table 2: Summary of Non-clinical Studies | Test | Purpose | Acceptance Criteria | Results | | --- | --- | --- | --- | | Mechanical Testing of the TOPS™ Motion Implant | To evaluate the TOPS™ Motion Implant for the following endpoints: flexion loading, extension loading, | See Table 3 for acceptance criteria for each test | Pass | PMA P220002: FDA Summary of Safety and Effectiveness Data 8 of 69 {8} | Test | Purpose | Acceptance Criteria | Results | | --- | --- | --- | --- | | | lateral bending rotation, axial rotation loading, sagittal translation, flexion / extension fatigue, lateral bending fatigue, axial rotation fatigue, coupled motion fatigue, axial compression fatigue, shear fatigue, and wear particulate of PcU | | | | Mechanical Testing of the TOPS™ System Pedicle Screws | To evaluate the pedicle screws for the following endpoints: ultimate compression bending load, compression bending fatigue, ultimate flexion bending load, axial gripping load, and axial pull-out strength | See Table 3 for acceptance criteria for each test | Pass | | Animal Testing | To evaluate possible histopathologic effects (acute neural, local and systemic inflammatory responses) to particulate wear debris of the TOPS™ System materials when implanted within the epidural space | No histopathologic or other evidence of acute neural, local or systemic inflammatory response during 3-month and 6-month follow-up periods | Pass | | Biocompatibility | To assess the following endpoints: Cytotoxicity, Sensitization, Irritation, Acute Systemic Toxicity, Material-Mediated Pyrogenicity, Subacute/Subchronic Toxicity, Genotoxicity (Bacterial Gene Mutation Assay, Mammalian Chromosomal Aberration, and Mouse Bone Marrow Micronucleus), and Implantation | In combination with toxicological risk evaluation, the testing demonstrates biocompatibility in line with the requirements of ISO 10993-1 for a permanent implant in contact with bone. Test-specific acceptance criteria were defined per the applicable part of ISO 10993. | Pass | | Sterilization Validation | To establish 25 kGy as the sterilization dose | Acceptance criteria defined per ISO 11137 to ensure a Sterility Assurance Level of at least 10^{-6} | Pass | | Shelf-Life and Packaging Validation | To determine the effect of transportation simulation and aging (accelerated real-time) | Seal strength testing was conducted per ASTM F88/F88M-15 and bubble | Pass | PMA P220002: FDA Summary of Safety and Effectiveness Data 9 of 69 {9} | Test | Purpose | Acceptance Criteria | Results | | --- | --- | --- | --- | | | on packaging integrity, sterile seal, and device functionality | leak testing was conducted per ASTM F2096-11. | | | MR Compatibility | To evaluate the safety and compatibility of the TOPS™ System in the MR environment Non-clinical testing and MRI simulations, that included in vivo, clinically relevant modelling, were performed. | Demonstrate TOPS™ System is MR Conditional and define the conditions for safe MR scanning in patients implanted with the device. | Pass; see Section IX.C.4 below for MR scanning conditions | ## A. Laboratory Studies A summary of the conducted mechanical testing on the TOPS™ System is provided below. The tests were conducted on the TOPS™ System (TOPS™ Motion Implant and 4 Pedicle Screws). In addition, the Pedicle Screws were tested according to ASTM-F1717 and ASTM F1798 with Premia Spine’s ProMIS Fixation Systems (K150388 and K170061) and VersaLink Fixation Systems (K182598) that use the same pedicle screws. Table 3: Summary of Laboratory Studies | Test | Method | Acceptance Criteria | Results | | --- | --- | --- | --- | | Static Flexion to Failure | Each TOPS™ Motion Implant was held by 4 pedicle screws in a flexion test jig connected to tensile machine. Constant displacement rate of 10 mm/min is applied until failure or testing fixture’s limit is reached. | 20 Nm moment static load testing for flexion. | All samples exceeded 20 Nm flexion moment with no failure. | | Static Extension to Failure | Each TOPS™ Motion Implant was held by 4 pedicle screws in an extension test jig connected to tensile machine. Constant displacement rate of 10 mm/min is applied until failure or testing fixture’s limit is reached. | 25 Nm moment static load testing for extension. | All samples exceeded 80 Nm extension moment with no failure, thus exceeding the acceptance criteria of 25 Nm moment static load testing for extension. Test was stopped after a displacement of 16°. | | Static Lateral Bending to Failure | Each TOPS™ Motion Implant was held by 4 pedicle screws in a lateral bending test. | 8° lateral bending rotation per side shall be exceeded. | All samples exceeded 8° lateral bending rotation. | PMA P220002: FDA Summary of Safety and Effectiveness Data 10 of 69 {10} | Test | Method | Acceptance Criteria | Results | | --- | --- | --- | --- | | | bending test jig connected to tensile machine. Constant displacement rate of 10 mm/min is applied until failure or testing fixture’s limit is reached. | | bending rotation per side with no failure. | | Static Axial Rotation to Failure | Each TOPS™ Motion Implant was held by 4 pedicle screws in an axial rotation test jig connected to tensile machine. Constant displacement rate of 10 mm/min was applied until failure or testing fixture’s limit is reached. | 25 Nm moment load testing for axial rotation. | All samples exceeded criteria of 25 Nm axial rotation moment. | | Static Sagittal Translation to Failure | TOPS™ Motion Implant in a sagittal translation test jig connected to tensile machine. Constant displacement rate of 10 mm/min is applied until failure. | Exceeds shear force of 500 N. | All samples exceeded 500N shear force static load acceptance criteria. | | Monoaxial Flexion Extension Test | Based on ASTM WK7479, a dedicated fatigue motion control tester and test fixture were used to apply cyclic 7.5° Flexion and 2° Extension, accompanied with constant 150 N shear force, at frequency of 2Hz for 10 million cycles. | All samples should remain functional, no visible failures (breaks or cracks) in the metal parts. No side-to-side tear in PcU boot larger than 2.1 cm, PEEK ribbon shall not be broken or torn over 50% of its cross section, stiffness of samples should not change by more than 50%, overall PcU wear shall be less than 75 mg (over 10 MC). | All the samples tested remained functional in the end of the test. No visible failures were found: no tear in PcU Boot was observed and no damage to PEEK ribbon was observed. The stiffness of the samples did not change by more than 50%. The overall wear was 6 mg per 10 MC. | PMA P220002: FDA Summary of Safety and Effectiveness Data 11 of 69 {11} | Test | Method | Acceptance Criteria | Results | | --- | --- | --- | --- | | Monoaxial Lateral Bending Test | Based on ASTM-WK7479, a dedicated fatigue motion control tester and test fixture were used to apply cyclic lateral bending of 6° bending (right and left), accompanied with constant 150 N shear force, at frequency of 2Hz for 10 million cycles. | All samples should remain functional, no visible failures (breaks or cracks) in the metal parts. No side-to-side tear in PcU boot larger than 2.1 cm, PEEK ribbon shall not be broken or torn over 50% of its cross section, stiffness of samples should not change by more than 50%, overall PcU wear shall be less than 75 mg (over 10 MC). | All the samples tested remained functional in the end of the test. No visible failures were found: no tear in PcU Boot and no damage to PEEK ribbon. The stiffness of the samples did not change by more than 50%. The overall wear was 10.9 mg per 10 MC. | | Monoaxial Axial Rotation Test | Based on ASTM F2624-12, a dedicated fatigue load control tester and test fixture were used to apply cyclic Axial- Rotation of 10 Nm (right and left), accompanied with constant 300 N shear force, at frequency of 1Hz for 10 million cycles. | All samples should remain functional. No visible failures (breaks or cracks) in the metal parts. No side-to-side tear in PcU boot larger than 2.1 cm. PEEK ribbon shall not be broken or torn over 50% of its cross section. Stiffness of samples should not change by more than 50%. Overall PcU wear shall be less than 75 mg (over 10 MC). | All the samples tested remained functional in the end of the test. No visible failures were found: no tear in PcU Boot and no damage to PEEK ribbon. The stiffness of the samples did not change by more than 50%. The overall wear was 48.5 mg per 10 MC. | | Coupled Motion Simulator Test | A dedicated fatigue motion control tester and test fixture were used to apply cyclic motion of 4° Flexion, 2° Extension, 3° right and left lateral bending, and 1° right and left axial rotation, accompanied with constant 150 N shear force, at frequency of 1.2Hz. for 5 million cycles. | Wear results should be similar to the monoaxial tests wear results. | Overall wear was 7.3 mg per 5 MC; or 14.6 mg for 10 MC (extrapolated), which is comparable to the monoaxial wear test results. | PMA P220002: FDA Summary of Safety and Effectiveness Data 12 of 69 {12} | Test | Method | Acceptance Criteria | Results | | --- | --- | --- | --- | | Axial Compression Fatigue Test | Per ASTM F1717, with a dedicated fixture and jig to accommodate the TOPS™ System. 600 N applied force divided to 2 implants that bear 300 N each. Load control test: Metal core was assembled instead of polycarbonate urethane internal core to test the outer plates. Test conducted at a frequency of 5 Hz, for 10 MC. | No visible breaks or cracks in metal parts. No loosening of the pedicle screws connection with the TOPS™ arms. | All specimens reached a run-out of 10 MC without failure and passed the acceptance criteria successfully. | | Shear Fatigue Test | Based on ASTM F1717, with a dedicated fixture, cyclic shear load of 15 N-150 N, frequency of 5 Hz, for 10 MC. | Reaching a run-out of 10 MC without failure. No visual breaks, or cracks in metal parts | All specimens reached a run-out of 10 MC without failure and passed the acceptance criteria successfully. | | Pedicle Screws Static Compression Bending Test | Per ASTM F1717-15 | Ultimate bending load per all systems shall exceed 400 N | All samples exceeded ultimate bending load of 600 N, thus exceeded acceptance criteria. | | Pedicle Screws Compression Bending Fatigue Test | Per ASTM F1717-15, frequency 3 Hz, 5 million cycles. In maximum load of 190 N, 210 N, 230 N and 250 N for runout. | At least 2 specimens should pass the test with at least 185 N load without breaks or cracks in the rods and the pedicle screws, and no loosening in the connection between the pedicle screws and the rods. | All 4 specimens completed the test successfully with 190 N, 210 N, 230 N and 250 N, respectively, for runout, thus exceeded the acceptance criteria. | | Pedicle Screw Static Flexion Bending Test | Per ASTM F1798-13 | Ultimate Bending load shall exceed 560 N. | All 5 specimens exceeded ultimate bending load of 1,134 N, yield bending moment of 25.8 Nm. | | Pedicle Screws Static Axial Gripping Test | Per ASTM F1798-13. Axial load was carried on this interconnection of screw-rod until failure or until exceeds 50% of acceptance criteria. | Gripping load shall exceed 1180 N. | All specimens exceeded the acceptance criteria. | PMA P220002: FDA Summary of Safety and Effectiveness Data 13 of 69 {13} | Test | Method | Acceptance Criteria | Results | | --- | --- | --- | --- | | Pedicle Screws Static Axial Pull-Out Test | Per ASTM F543 | Pull-out strength of 307 ± 61 N | All screws exceeded the acceptance criteria. | | Polycarbonate Urethane (PcU) Gravimetric Wear | Per ASTM F1877, particles of different loading directions and loading cycles were analyzed in respect to particle size and shape. | Particle size and shape and particle size distribution are comparable to the results of the in-vivo rabbit study. | Wear particulate characterization was consistent with prior in vivo evaluation, supporting safety. | ## B. Animal Studies An in vivo study was performed to evaluate local and systemic inflammatory responses to particulate wear debris, using New Zealand White Rabbits as the experimental model. The study was undertaken to investigate the possible histopathologic effects of particulate wear debris of the TOPS™ System materials implanted within the epidural space. The study provides an experimental model and technique to assess the local/systemic histologic response to two materials – Titanium Alloy (Ti Alloy) and Polycarbonate Urethane (PcU) – used in dynamic spinal stabilization. 30 skeletally mature New Zealand White Rabbits were divided into the following 3 groups: - Control Group Surgical Control (Sham); - Group - Particulate #1 (Ti Alloy); - Group - Particulate #2 (PcU). The particle size, concentration and methods of sterilization were based on studies published in the literature that examined the effects of particulate wear debris in the lumbar spine. A dosage was selected for the test that, when normalized from a 5kg rabbit to a 70kg human, the implanted materials are the equivalent of a 112mg dosage in humans. Moreover, this application is a one-time acute dose applied directly to the spinal cord while wear is generated gradually during clinical use. The animals were evaluated for inflammatory reaction at 12 and 24 weeks. All cases were also monitored for signs of severe pain, neurologic complications and other adverse events throughout the course of the study. Overall, based on the 3 and 6-month post-operative time periods, there was no evidence of an acute neural, local or systemic histopathologic response to the materials of the TOPS™ System. PMA P220002: FDA Summary of Safety and Effectiveness Data 14 of 69 {14} C. Additional Studies 1. Biocompatibility Biocompatibility of the device was evaluated according to International Organization for Standardization (ISO) 10993-1:2018 and FDA Guidance Document “Use of International Standard ISO 10993-1, Biological evaluation of medical devices – Part 1: Evaluation and testing within a risk management process.” The TOPS™ System (TOPS™ Motion Implant and Pedicle Screws) is manufactured from Titanium alloy (Ti-6Al-4V), Polycarbonate Urethane (PcU), and Polyether Ether Ketone (PEEK). All implant materials are well characterized, have a long history of successful orthopedic clinical use and well-established biocompatibility. There are no color additives in the TOPS™ System. The following tests were performed per their respective ISO 10993 standards on representative sterile subassemblies that were manufactured according to final manufacturing methods: - Cytotoxicity - Sensitization - Irritation - Acute Systemic Toxicity - Material-Mediated Pyrogenicity - Subacute/subchronic Toxicity - Genotoxicity (bacterial reverse mutation, mammalian chromosomal aberration, and mouse bone marrow micronucleus) - Implantation Results of testing in combination with toxicological risk evaluation demonstrated biocompatibility in line with the requirements of ISO 10993-1 for a permanent implant in contact with bone. Biocompatibility assessments were also performed on the surgical instruments. 2. Sterilization Validation Sterilization validation was conducted for the TOPS™ System per ISO 11137 to establish 25kGy as the sterilization dose to achieve a Sterility Assurance Level (SAL) of at least 10⁻⁶. Separate validations were performed for the TOPS™ Motion Implant and for the Pedicle Screws. Sterilization validation was conducted for the TOPS™ System instruments per ANSI/AAMI ST79, AAMI TIR12, and ISO 17665-1. 3. Shelf Life and Packaging Validation Shelf life and packaging studies, including accelerated and real-time aging and simulated distribution (shipping and handling), were conducted to determine the effect of transportation simulation on the packaging integrity and demonstrate that the device packaging can maintain a sterile barrier over a 5-year shelf life. Seal strength PMA P220002: FDA Summary of Safety and Effectiveness Data 15 of 69 {15} testing was conducted per ASTM F88/F88M-15 and bubble leak testing was conducted per ASTM F2096-11. Continued functionality testing was also performed. ## 4. MR Compatibility Non-clinical testing and MRI simulations, that included in vivo, clinically relevant modelling, were performed to evaluate the safety and compatibility of the TOPS™ System in the MR environment. The non-clinical testing demonstrated that the TOPS™ System is MR Conditional. A person with the TOPS™ System may be safely scanned under the following conditions: Table 4: MR Compatibility Conditions | Static Magnetic Strength (B0) | 1.5 or 3.0 T | | --- | --- | | Maximum Spatial Field Gradient | 20 T/m | | RF Excitation | Circularly Polarized | | RF Transmit Coil Type | There are no Transmit Coil Restrictions | | Operating Mode | Normal Operating Mode | | Maximum Whole-Body SAR | 2 W/kg (Normal Operating Mode) | | Scan Duration | 2 W/kg whole-body average SAR for 60 minutes of continuous RF (a sequence or back-to-back series/scan without breaks) | | MR Image Artifact | The presence of this implant may produce an image artifact. Some manipulation of scan parameters may be needed to compensate for the artifact. In non-clinical testing, the image artifact caused by the TOPS™ (Total Posterior Spine) System extends approximately 10 mm from this device when imaged with a gradient echo pulse sequence and a 3T MRI system. | ## X. SUMMARY OF PRIMARY CLINICAL STUDY The applicant performed a clinical study to establish a reasonable assurance of safety and effectiveness of the TOPS™ System for treatment of degenerative spondylolisthesis up to Grade I, with moderate to severe lumbar spinal stenosis and either the thickening of the ligamentum flavum and/or scarring of the facet joint capsule at one level from L2 to L5 in the US under IDE # G160168. 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 in the TOPS™ System pivotal study were treated between 2017 and 2022. Enrollment included 321 patients at 37 investigational sites in the US. The database for this PMA reflected data collected through July 2022 and included 306 patients who had been randomized and had undergone surgery. The regulatory decision for PMA P220002: FDA Summary of Safety and Effectiveness Data 16 of 69 {16} this PMA relied primarily on a subset of 168 patients who had theoretically reached 24-month follow-up after the operative intervention (Month 24). The study was a prospective, multi-center randomized, concurrently controlled pivotal study of the TOPS™ System. Subjects were randomized in a 2:1 ratio to the TOPS™ System or the control treatment, a lumbar spinal fusion. The study pre-specified an initial interim analysis after 240 subjects were enrolled and a second interim analysis after 300 subjects were enrolled, in order to assess sample size as well as safety and effectiveness. The first interim analysis evaluated the primary endpoint for non-inferiority, and the second interim analysis evaluated the primary endpoint for superiority. The objective of the study was to evaluate the safety and effectiveness of the TOPS™ System compared to lumbar spinal fusion in subjects undergoing decompression surgery and instrumentation at a single lumbar level between L2 and L5 to alleviate leg pain, with or without back pain, stemming from all of the following conditions: (1) degenerative spondylolisthesis or retrolisthesis up to Grade I; (2) moderate to severe spinal stenosis (LSS); and (3) thickening of the ligamentum flavum and/or scaring of the facet joint capsule. The primary endpoint for this study was the composite clinical success (CCS) at Month 24. The following hypotheses pertaining to clinical non-inferiority were planned to be tested: Ho: $\pi_{\mathrm{I}} - \pi_{\mathrm{C}} \leqslant -0.10$ (the CCS rate of investigational device was clinically inferior to control) Ha: $\pi_{\mathrm{I}} - \pi_{\mathrm{C}} &gt; -0.10$ (the CCS rate of investigational device was not clinically inferior to control), where $\pi_{\mathrm{I}}$, $\pi_{\mathrm{C}}$ are CCS rate at Month 24 for the investigational device and control respectively. In all circumstances, non-inferiority hypotheses were based on the a priori selected non-inferiority margin, $\delta = -0.10$. Hypotheses pertaining to clinical superiority were tested after the null hypothesis of non-inferiority was successfully rejected: Ho: $\pi_{\mathrm{I}} - \pi_{\mathrm{C}} = 0$ (the CCS rate investigational device was the same with that of control) Ha: $\pi_{\mathrm{I}} - \pi_{\mathrm{C}} &gt; 0$ (the CCS rate of investigational device was superior to that of control). Bayesian posterior distribution with a non-informative prior (Beta(1,1)) were used to test the study hypotheses. The adaptive trial design allowed a minimum of 300 subjects and up to a maximum number of 500 subjects to be randomized, with interim analyses. The interim analyses allowed for sample size adjustment (including early stopping of the trial for futility) and for claiming early study success on non-inferiority and superiority. Driven by the superiority test, the minimum sample size was based on at least $80\%$ power for testing superiority assuming the true CCS rates are 0.80 and 0.65 for the PMA P220002: FDA Summary of Safety and Effectiveness Data 17 of 69 {17} investigational and control arm respectively. This sample size also allowed higher than 80% power for non-inferiority test. ## 1. Clinical Inclusion and Exclusion Criteria To be eligible for the TOPS™ System IDE study, subjects had to meet all of the following inclusion criteria: - Be between 35 to 80 years of age; - Must demonstrate at the level to be treated (L2/3, L3/4 or L4/5) all three of the following; - Degenerative spondylolisthesis or retrolisthesis up to Grade I, as determined by the investigator based on flexion/extension X-rays, and - At least moderate lumbar spinal stenosis, defined as greater than a 33% reduction in either the central canal, the lateral recess space, and/or the foramen when compared to an adjacent level, as determined by the investigator based on MRI, and - Thickening of the ligamentum flavum and/or scarring of the facet joint capsule as identified by the investigator based on MRI. - At least six (6) months of failed conservative treatment prior to surgery (e.g., physical therapy, use of anti-inflammatory medications at maximum recommended dosage; administration of epidural/facet injections and/or nerve block); - Oswestry Disability Index (ODI) score of at least 40/100 at baseline; - Leg pain with a Visual Analog Scale (VAS) score of at least 40/100 for at least one leg at baseline¹; - Neurogenic claudication (as defined by worsening leg/buttock symptoms when walking or standing, which is reduced when sitting or bending forward); - Demonstrate worse symptoms (e.g., pain, numbness, burning sensation, pin prick sensation, etc.) in the legs/buttock than in the lower back; - Be psychosocially, mentally, and physically able to fully comply with the clinical protocol; - Be willing to adhere to the follow-up schedule and protocol requirements; - Be willing and able to understand and sign study-specific, IRB-approved consent form. Subjects were not permitted to enroll in the IDE study if they met any of the following exclusion criteria: - More than one motion segment involved in the degenerative pathology that requires a surgical procedure; - Presence of free fragment disc herniation or prior discectomy at the index level or either adjacent level; - Less than 4mm of disc height at the index level; - Spondylolisthesis greater than Grade I; - Traumatic or dysplastic spondylolisthesis; - Lytic spondylolisthesis; ¹ The leg with the higher pain score was considered “Worst Leg.” PMA P220002: FDA Summary of Safety and Effectiveness Data 18 of 69 {18} - Back or non-radicular leg pain of unknown etiology; - Stenosis caused by an extruded spinal disc fragment (e.g., herniation) or where the etiology is considered congenital, iatrogenic, post-traumatic, or metabolic; - Known allergy or sensitivity to Polyether Ether Ketone (PEEK), titanium, cobalt chrome, and/or polyurethane; - Prior surgery at any lumbar vertebral level with instrumentation; - Prior surgery at the index vertebral level or either adjacent lumbar vertebral level without instrumentation [exception – prior intervention of posterior elements at index level (e.g. rhizotomy, laminectomy, foraminotomy and/or facetectomy)]²; Clinically compromised vertebral bodies at the affected level due to any traumatic, neoplastic, metabolic or infectious pathology; - Scoliosis greater than 10 degrees by major Cobb angle (both angular and rotational); - Morbid obesity defined as a body mass index greater than 40; - Lumbar spine T-score less than -2.0³; - Paget's disease, gout, osteomalacia, osteogenesis imperfecta, thyroid and/or parathyroid gland disorder and/or any other metabolic bone disease not stabilized with ongoing medication for at least 1 year; - Active infection - systemic or local; - Active hepatitis; - AIDS, HIV, Rheumatoid arthritis or other autoimmune disease; - Tuberculosis - active or in the past 3 years; - Active malignancy - history of any invasive malignancy (except non-melanoma skin cancer) unless prior treatment with curative intent and no clinical signs or symptoms of the malignancy for at least 5 years; - Any medical condition requiring treatment with any drug known to potentially interfere with bone/soft tissue healing or receiving radiation therapy that is expected to continue for the duration of the study; - Cauda equina syndrome or neurogenic bowel/bladder dysfunction; - Vascular claudication due to severe arterial insufficiency of the legs (Prospective subjects screened by physical examination for diminution or absence of dorsalis pedis or posterior tibialis pulses. If diminished or absent by palpation, then arterial ultrasound is required with vascular plethysmography. If the absolute arterial pressure is below 50 mm Hg at the calf or ankle level, then patient has severe arterial insufficiency and must be excluded.); - Sustained pathologic lumbar fractures of the vertebra or multiple lumbar fractures of the vertebra or hip; PMA P220002: FDA Summary of Safety and Effectiveness Data 19 of 69 {19} - Significant peripheral neuropathy causing decreased sensation in a stocking-like or non-radicular and non-dermatomal distribution in the lower extremities; - Insulin-dependent diabetes mellitus (unless well-controlled defined as HbA1c less than 7%)⁴; - Immunologically suppressed, receiving steroids for greater than 1 month out of the past year; - Currently taking anticoagulants other than aspirin unless subject can be taken off of anticoagulant prior to and during surgery; - Life expectancy of less than 3 years; - Currently experiencing an episode of major mental illness (psychosis, major affective disorder, or schizophrenia), or manifesting physical symptoms without a diagnosable medical condition to account for the symptoms, which may indicate symptoms of psychological rather than physical origin; - History of or current chemical/alcohol dependency⁵; - Smoking habit of more than 1 pack of cigarettes per week and/or frequent users (greater than 1/week) of chewing tobacco; - Pregnant or interested in becoming pregnant in the next 3 years (due to need for X-rays)⁶; - Currently involved in active spinal litigation; - Currently having a workman's compensation claim; - Currently incarcerated; - Participation in any other investigational drug, biologic or medical device study within the 30 days prior to the study surgery. ## 2. Follow-up Schedule All subjects 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), and 24 months (±3 months) post-operatively. Follow-up evaluations at scheduled visits included obtaining x-rays, neurological assessments, ODI, VAS (back and both legs), Zurich Claudication Questionnaire (ZCQ), study-related medications since the prior visit, and adverse events. At 24 months, subjects also underwent an MRI and completed the 12-Item Short Form, version 2 (SF-12v2) Health Survey. The key ⁴ HbA1c value must be within 3 months of screening. ⁵ A maladaptive pattern of substance use leading to clinically significant impairment or distress, as manifested by one (or more) of the following, occurring within a 12-month period: 1. Recurrent substance use resulting in a failure to fulfill major role obligations at work, school, home (e.g. repeated absences or poor work performance related to substance use; substance-related absences, suspensions, or expulsions from school; neglect of children or household) 2. Recurrent substance use in situations in which it is physically hazardous (e.g. driving as automobile or operating a machine when impaired by substance use) 3. Recurrent substance-related legal problems (e.g. arrests for substance-related disorderly conduct) 4. Continued substance use despite having persistent or recurrent social or interpersonal problems caused or exacerbated by the effects of the substance (e.g. arguments with spouse about consequences of intoxication, physical fights) ⁶ However, pregnancies occurring during the study will not be considered protocol deviations. Additionally, if a subject does become pregnant, no X-ray or MRI should be taken during the pregnancy. PMA P220002: FDA Summary of Safety and Effectiveness Data 20 of 69 {20} follow-up timepoints are shown in Table 5 below. Conventional naming of visits was utilized to reflect time elapsed since the operative intervention. PMA P220002: FDA Summary of Safety and Effectiveness Data 21 of 69 {21} Table 5: Study Schedule | Time Point | Pre-op^{1d} | Rx | Post-op | 6 wks | 3, 6 & 12 mo^{3} | 24 mo | 36 & 48 mo | 60 mo | D/C or Termination | | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | | Informed Consent | X | | | | | | | | | | Bone Quality Assessment^{1a} | X | | | | | | | | | | Medical History & Physical Examination | X | | | | | | | | | | Pregnancy Screening (within 30 days of surgery)^{1b} | X | | | | | | | | | | MRI^{1c} | X | | | | | X | | X | X | | Standing AP & Lateral X-rays^{4} | X | | X^{5} | X | X | X | X | X | X | | Standing Flexion & Extension X-rays^{4} | X | | | | X | X | X | X | X | | Standing Lateral Bending^{4} | X | | | | X | X | X | X | X | | Radiographic Core Lab Assessments | X | | X^{5} | X | X | X | X | X | X | | Neurologic Exam | X | | | X | X | X | X | X | X | | ODI | X | | | X | X | X | X | X | X | | VAS | X | | | X | X | X | X | X | X | | ZCQ | X | | | X | X | X | X | X | X | | Treatment Satisfaction | | | | X | X | X | X | X | X | | Medications Taken^{2} | X | | X^{5} | X | X | X | X | X | X | | SF-12v2 Health Survey | X | | | | | X | | X | | | Adverse Event Assessment | N/A | As needed | | | | | | | | | Study Completion / Termination | N/A | | As needed | | | | | | | | 1. Pre-treatment evaluations; a. All subjects will be screened for osteoporosis using an osteoporosis risk score (SCORE). Subjects with a SCORE value greater than 6 will be referred for DEXA Scan. DEXA must be performed within the 6 months prior to surgery. b. All female prospective subjects that are of child-bearing potential must undergo a pregnancy test. Results must be within 30 days prior to surgery. c. MRI may be taken up to 6 months prior to surgery. d. All other pre-treatment measurements must be done within 90 days of surgery. 2. Record only study-related medications. 3. Follow up visit evaluations will be taken at 6 weeks (± 2 weeks), 3 months (± 2 weeks), 12 months (± 2 months), and 24, 36, 48, and 60 months thereafter (± 3 months). 4. Radiographic films should be taken with the subject standing to the extent clinically possible. If subject is not able to stand, the films should be taken as clinically possible. 5. Postoperative evaluations are taken between 12 hours and 4 weeks postoperatively. Post-operative standing AP and lateral films must be taken prior to discharge. If a subject does become pregnant, no X-ray or MRI should be taken during the pregnancy. | | | | | | | | | | ## 3. Clinical Endpoints The safety and effectiveness of the TOPS™ System were assessed using a composite endpoint, as described below. Outcomes of the TOPS™ System investigative group were compared to the outcomes of the control group undergoing fusion operative treatment. Study success was based on the hypothesis that the TOPS™ System is PMA P220002: FDA Summary of Safety and Effectiveness Data 22 of 69 {22} superior to the lumbar spinal fusion control in achieving Month 24 composite clinical success (CCS). ## Primary Endpoint The primary endpoint was evaluated using a CCS endpoint at Month 24. Each subject was determined to have achieved CCS only if they met all of the following criteria: - A reduction of 15 points or more in ODI; - No new neurologic deficit, nor worsening and persistent neurologic deficit (see description of neurological failure below); - No epidural steroid injection, facet joint injections, nerve block procedures or implantable spinal cord stimulator to treat back or leg pain symptoms at any lumbar level; - Any TOPS™ subject was considered a failure if fusion occurred. Any control subject was considered a failure if fusion did not occur (see definitions of fusion and non-fusion below); - No revision or removal of implants; 7 - No supplemental fixation at the index level or at the immediately adjacent levels; 7 - No occurrence of a major device related adverse event (see definition of major device-related adverse event below). A subject was considered a neurological failure if they were categorized as a failure for any of the following: - Sensory (SN): A subject was considered an SN failure if he/she had an increase in sensory deficit in his/her Worst Leg pain at any dermatomal level at 24 months compared to baseline. - Muscle Strength (MS): A subject was considered an MS failure if his/her 24-month minimum value is a two-grade or more decrease in motor strength at any muscle group evaluated, compared to baseline. A one-grade decrease is not considered a significant change with the exception of a decrease from 1 to zero. - Straight leg raising (SLR): The summary endpoint for SLR was defined as positive (bad) if Worst Leg pain is positive. A subject was considered an SLR failure if he/she had a positive 24-month summary endpoint but negative SLR summary endpoint prior to index surgery. - Side Lying Femoral Stretch (FS): The summary endpoint for FS was defined as positive (bad) if Worst Leg pain is positive. A subject was considered an FS failure if he/she had a positive 24-month summary endpoint but negative FS summary endpoint prior to index surgery. ## Fusion vs. Non-Fusion Fusion was defined as: PMA P220002: FDA Summary of Safety and Effectiveness Data 23 of 69 {23} - Presence of bridging trabecular bone across the involved motion segment, and - Angular motion &lt; 3° from flexion to extension, and - Translational motion &lt; 2 mm from flexion to extension. Non-fusion was defined as: - Absence of bridging trabecular bone across the involved motion segment, or - Angular motion ≥ 3° from flexion to extension, or - Translational motion ≥ 2 mm from flexion to extension. ## Major Device-Related Adverse Events A major device-related AE was defined as any of the following, which were related to the device system or to a device component: - Device component degradation or breakage; - Device component separation or disassembly; - Device component loosening including screw loosening; - An increase in spondylolisthesis by one grade or more at the operative level. ## Highlighted Secondary Endpoints With Control of Type I Error Five secondary endpoints were selected a priori to be tested in the following sequence following demonstration of superiority based on the primary CCS endpoint. 1. Range-of-Motion: Greater range-of-motion through flexion-extension at the index level at Month 24; 2. Fusion success: Any TOPS™ investigational subject was considered a failure if fusion occurs as defined in the radiographic protocol. Any control subject was considered a failure if fusion (as defined in the radiographic protocol) did not occur. This assessment was made by a core lab; 3. No Month 24 narcotics use and no epidural steroid injection, facet joint injections, nerve block procedures, or spinal cord stimulators to treat back or leg pain symptoms at any lumbar level up to Month 24; 4. No new neurologic deficit nor worsening and persistent neurological deficit at Month 24; 5. Time to revision or removal or supplemental fixation at either the index level or adjacent level (based on log-rank statistic). ## Additional Secondary Endpoints (No Type I Error Control) In addition, the following additional secondary endpoints were pre-specified to evaluate general device performance for purposes of evaluating the two treatment groups and superiority of the investigational device relative to control: - Individual components of Month 24 CCS; - 20 mm improvement in VAS scores for back pain and Worst Leg pain as compared to baseline (the higher of the two leg scores at baseline was designated the Worst Leg for analysis purposes); - ZCQ findings; PMA P220002: FDA Summary of Safety and Effectiveness Data 24 of 69 {24} Improvement of ≥0.5 in ZCQ physical function score and symptom severity, and subject satisfaction score of ≤2.5 at Month 24 where 1 is very satisfied and 4 is very dissatisfied, Two component ZCQ success defined as meeting ≥2 individual ZCQ success criteria. Three component ZCQ success defined as meeting all three individual ZCQ success criteria. - Reduction in physical component score on SF-12; - Length of hospital stay, surgery time (skin-to-skin), blood loss and narcotic use for lower back pain and leg pain. - Range of motion in flexion/extension were evaluated at the index and immediately adjacent levels at Month 24 to evaluate the effect of the treatment. This result was monitored as an additional outcome and was separately compared with the subject’s physical functioning (ODI, ZCQ and VAS) scores. ## B. Accountability of PMA Cohort Pursuant to the design of this IDE study, interim analysis for early study success was conducted before all randomized subjects had reached the Month 24 visit (the final visit evaluated for safety and effectiveness as the basis for the PMA submission). At the time of database lock, 321 subjects were enrolled in the IDE study and 52.3% (168/321) had theoretically reached the Month 24 visit (at least 730 days post-surgery). Of the subjects who theoretically reached Month 24, 91.7% (154/168) were available for the primary endpoint analysis of CCS. Subject enrollment and accounting are illustrated in the figure and table below, followed by descriptions of the analysis populations. PMA P220002: FDA Summary of Safety and Effectiveness Data 25 of 69 {25}  Figure 3: Subject Accountability Tree PMA P220002: FDA Summary of Safety and Effectiveness Data 26 of 69 {26} Table 6: Subject Accounting at the Time of Database Lock | | TOPS™ | Fusion | Total | | --- | --- | --- | --- | | [1] All randomized subjects (ITT) | 219 | 102 | 321 | | [1a] Randomized and underwent surgery (mITT/AT)¹ | 210 | 96 | 306 | | [1b] Withdrawn prior to surgery | 8 | 4 | 12 | | [1c] Not yet treated | 1 | 2 | 3 | | | | | | | A. Randomized in mITT Analysis Set and Theoretically Due for Month 24 Visit (TDmITT)² | 115 | 53 | 168 | | A1. Excluded from Per Protocol Analysis Set | 2 | 2 | 4 | | A1a. Eligibility violation identified by CEC | 2 | 1 | 3 | | A1b. Intraoperative change to non-study treatment | 0 | 1 | 1 | | A2. Included in Per Protocol Analysis Set³ | 113 | 51 | 164 | | A2a. Death by Month 24 and not terminal CCS failures | 1 | 0 | 1 | | A2b. Not yet overdue for Month 24 and not terminal CCS failures | 3 | 1 | 4 | | A2c. Known Month 24 CCS Status | 106 | 44 | 150 | | A2d. Missing ≥1 CCS component or LTF and not a known failure | 3 | 6 | 9 | | | | | | | B. Randomized in mITT Analysis Set and Not Theoretically Due for Month 24 Visit | 95 | 43 | 138 | | B1. Excluded from Per Protocol Analysis Set | 2 | 1 | 3 | | B1a. Eligibility Violation Identified by CEC | 0 | 0 | 0 | | B1b. Intraoperative Change to Non-Study Treatment | 2 | 1 | 3 | | B2. Included in Per Protocol Analysis Set³ | 93 | 42 | 135 | | B2a. Early failures (have not reached Month 24 visit but known CCS terminal failure) | 3 | 0 | 3 | | B2b. Death by Month 24 and not terminal CCS failures | 0 | 0 | 0 | | B2c. Have not reached Month 24 visit and not failure (CCS pending) | 86 | 38 | 124 | | B2d. Observed Month 24 visit prior to day 730 and non-missing CCS | 4 | 3 | 7 | | B2e. Observed Month 24 visit prior to day 730 missing ≥1 CCS component and not a known failure | 0 | 1 | 1 | | | | | | | C. Month 24 CCS Status in TDmITT Analysis Set | 115 | 53 | 168 | | C1. Known Month 24 CCS Status | 108 | 46 | 154 | | C2. Missing Month 24 CCS Status | 7 | 7 | 14 | | Notes: ¹ Full safety analysis set (AT) includes all patients in [1a], also equal to A + B ² Primary endpoint analysis set (TDmITT) includes all patients in A. As shown in C, within TDmITT, 108 TOPS™ and 46 Fusion have a known Month 24 CCS status. ³ Per Protocol analysis set includes all patients in A2 + B2 | | | | PMA P220002: FDA Summary of Safety and Effectiveness Data 27 of 69 {27} Intent-to-Treat (ITT) Analysis Set – 321 subjects: Subjects in this group were randomized and are classified according to their assigned treatment. This analysis set includes all randomized subjects, including subjects who withdrew prior to surgery and subjects who were waiting to undergo their study procedure at the time of database lock. Modified Intent-to-Treat (mITT) Analysis Set – 306 subjects: Subjects in this group underwent surgery and were classified according to their assigned treatment, regardless of whether the subject was intraoperatively changed to another a non-study treatment or failure to complete any required follow-up examinations; it did not include subjects who were not yet treated or who withdrew prior to surgery. In Table 6 above, the mITT population includes all patients in row [1a]. As-Treated (AT) Analysis Set – 306 subjects: The AT analysis set included patients in the mITT analysis set, classified according to the treatment received by the patient. Since surgery for the assigned study treatment was initiated in all subjects, the AT analysis set is identical to the mITT analysis set. For clarity, four subjects began surgery for their assigned study treatment but were intra-operatively changed to a non-study treatment; since the surgery for the study treatment was initiated, these subjects are classified according to their attempted study treatment. The AT analysis set was the pre-specified primary safety analysis population. Per Protocol (PP) Analysis Set – 299 subjects: The PP analysis set included patients in the AT analysis set who were a part of the intended target population. The PP analysis set excluded patients who were randomized in error or were subsequently found to not meet clinically important inclusion or exclusion criteria that are objectively determined. In total, 7 subjects were excluded: 2 TOPS™ and 2 Fusion subjects who were changed intra-operatively to a non-study treatment, and 2 TOPS™ and 1 Fusion subject who were subsequently found to not meet clinically important inclusion or exclusion criteria that were objectively determined. The PP analysis set was the pre-specified primary efficacy analysis population. In Table 6 above, the PP analysis set includes all patients in rows A2 + B2. Modified Intent-to-Treat Analysis Set Theoretically Due Month 24 Visit (TDmITT) – 168 subjects: The TDmITT analysis set included patients in the mITT population who were theoretically due for the Month 24 visit (at least 730 days post-surgery) at the time of the interim analysis. In coordination with FDA, the TDmITT analysis set was designated the primary endpoint analysis population for basis of PMA approval. In Table 6 above, the TDmITT analysis set includes all patients in row A. C. Study Population Demographics and Baseline Parameters Demographics and baseline parameters are provided for the full mITT analysis set (210 TOPS™; 96 Fusion) (all randomized subjects in whom a study treatment was attempted) and the TDmITT analysis set (115 TOPS™; 53 Fusion) (randomized subjects in whom a study treatment was attempted and who were theoretically due for PMA P220002: FDA Summary of Safety and Effectiveness Data 28 of 69 {28} their Month 24 visit at the time of interim analysis). All available demographics and baseline data are presented. The tables below summarize the following information: - Baseline and Demographic Continuous Variables (Tables 7-8) - Baseline and Demographic Categorical Variables (Tables 9-10) - Summary of Operative Continuous Variables (Tables 11-12) - Summary of Operative Categorical Variables (Tables 13-14) As shown in Tables 7-10 below, overall in both analysis sets, the treatment groups had similar gender distribution, mean age, BMI, smoking history, race, and ethnicity. In addition, the treatment groups had a comparable proportion of patients in both groups who underwent prior lumbar surgery. In addition to the similarities in demographics, the TOPS™ and Fusion groups in both analysis sets had similar baseline scores, including mean VAS Worst Leg score, VAS low back pain, VAS right leg pain, VAS left leg pain, VAS Other Leg pain, ZCQ, ODI scores, and SF-12 physical scores. In summary, randomization was effective in providing a well-balanced study population, with similar demographic, baseline, and clinical characteristics between the TOPS™ and control groups. Table 7: Baseline and Demographic Continuous Variables - mITT Analysis Set | | TOPS™ | | | | | | Fusion | | | | | | TOPS™ - Fusion¹ | | | | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | | Demographics - All | N | Mean | SD | Med | Min | Max | N | Mean | SD | Med | Min | Max | Diff | LB | UB | | Age (yrs) | 210 | 63.4 | 8.2 | 64.0 | 38.0 | 80.0 | 96 | 64.0 | 8.5 | 66.0 | 43.0 | 80.0 | -0.5 | -2.6 | 1.5 | | Height (in) | 210 | 66.9 | 4.0 | 66.7 | 58.0 | 80.5 | 96 | 66.9 | 4.3 | 66.3 | 53.8 | 74.0 | 0.1 | -0.9 | 1.0 | | Weight (lbs) | 210 | 188.6 | 38.0 | 187.0 | 105.0 | 280.0 | 96 | 190.0 | 39.4 | 187.5 | 118.0 | 295.0 | -1.4 | -10.7 | 7.9 | | BMI (kg/m²) | 210 | 29.5 | 4.9 | 28.9 | 17.4 | 40.3 | 96 | 29.8 | 5.3 | 29.3 | 19.6 | 39.7 | -0.3 | -1.6 | 0.9 | | Demographics - Male | N | Mean | SD | Med | Min | Max | N | Mean | SD | Med | Min | Max | Diff | LB | UB | | Age (yrs) | 93 | 64.7 | 8.0 | 66.0 | 43.0 | 79.0 | 46 | 64.4 | 8.3 | 66.0 | 43.0 | 78.0 | 0.3 | -2.5 | 3.2 | | Height (in) | 93 | 70.4 | 2.7 | 70.0 | 65.0 | 80.5 | 46 | 70.2 | 2.7 | 70.8 | 64.0 | 74.0 | 0.2 | -0.7 | 1.2 | | Weight (lbs) | 93 | 210.5 | 32.9 | 209.0 | 132.0 | 280.0 | 46 | 205.6 | 38.2 | 206.5 | 128.0 | 295.0 | 4.8 | -7.5 | 17.2 | | BMI (kg/m²) | 93 | 29.9 | 4.5 | 30.0 | 19.1 | 40.0 | 46 | 29.3 | 4.7 | 29.1 | 21.7 | 39.3 | 0.6 | -1.0 | 2.2 | | Demographics - Female | N | Mean | SD | Med | Min | Max | N | Mean | SD | Med | Min | Max | Diff | LB | UB | | Age (yrs) | 117 | 62.4 | 8.4 | 63.0 | 38.0 | 80.0 | 50 | 63.6 | 8.8 | 64.5 | 46.0 | 80.0 | -1.2 | -4.0 | 1.7 | | Height (in) | 117 | 64.2 | 2.4 | 64.0 | 58.0 | 69.0 | 50 | 63.8 | 3.0 | 64.3 | 53.8 | 70.0 | 0.4 | -0.5 | 1.2 | | Weight (lbs) | 117 | 171.2 | 32.5 | 166.0 | 105.0 | 250.0 | 50 | 175.6 | 35.0 | 176.5 | 118.0 | 242.3 | -4.4 | -15.5 | 6.7 | | BMI (kg/m²) | 117 | 29.2 | 5.2 | 28.0 | 17.4 | 40.3 | 50 | 30.3 | 5.8 | 30.8 | 19.6 | 39.7 | -1.1 | -2.9 | 0.7 | | Baseline Functional Status | N | Mean | SD | Med | Min | Max | N | Mean | SD | Med | Min | Max | Diff | LB | UB | | VAS Low Back Pain Score | 210 | 68.5 | 23.1 | 72.5 | 0.0 | 100.0 | 96 | 69.7 | 21.9 | 75.0 | 0.0 | 100.0 | -1.2 | -6.7 | 4.3 | | VAS Right Leg Pain Score | 210 | 64.8 | 29.9 | 74.0 | 0.0 | 100.0 | 96 | 67.4 | 30.6 | 78.0 | 0.0 | 100.0 | -2.7 | -10.0 | 4.6 | PMA P220002: FDA Summary of Safety and Effectiveness Data 29 of 69 {29} Table 8: Summary of Baseline and Demographic Continuous Variables (TDmITT) | Demographics - All | N | Mean | SD | Med | Min | Max | N | Mean | SD | Med | Min | Max | Diff | LB | UB | | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | | Age (yrs) | 115 | 63.1 | 8.0 | 64.0 | 38.0 | 79.0 | 53 | 64.3 | 8.3 | 66.0 | 43.0 | 80.0 | -1.2 | -3.9 | 1.5 | | Height (in) | 115 | 67.1 | 4.1 | 67.0 | 58.0 | 80.5 | 53 | 66.8 | 4.3 | 66.0 | 53.8 | 74.0 | 0.3 | -1.1 | 1.6 | | Weight (lbs) | 115 | 194.2 | 38.5 | 196.2 | 106.1 | 280.0 | 53 | 194.4 | 41.9 | 190.0 | 123.0 | 295.0 | -0.2 | -13.2 | 12.8 | | BMI (kg/m²) | 115 | 30.2 | 5.0 | 30.0 | 17.4 | 40.3 | 53 | 30.5 | 5.4 | 29.7 | 20.8 | 39.7 | -0.3 | -2.0 | 1.4 | | Demographics - Male | N | Mean | SD | Med | Min | Max | N | Mean | SD | Med | Min | Max | Diff | LB | UB | | Age (yrs) | 53 | 64.1 | 8.1 | 66.0 | 43.0 | 79.0 | 27 | 64.5 | 7.7 | 66.0 | 43.0 | 78.0 | -0.4 | -4.1 | 3.4 | | Height (in) | 53 | 70.6 | 2.7 | 71.0 | 65.0 | 80.5 | 27 | 69.8 | 2.9 | 71.0 | 64.0 | 74.0 | 0.8 | -0.5 | 2.1 | | Weight (lbs) | 53 | 217.4 | 29.6 | 218.0 | 149.0 | 280.0 | 27 | 209.2 | 43.3 | 209.0 | 128.0 | 295.0 | 8.2 | -8.2 | 24.6 | | BMI (kg/m²) | 53 | 30.6 | 4.1 | 30.3 | 22.0 | 39.4 | 27 | 30.0 | 5.1 | 29.3 | 21.7 | 39.3 | 0.6 | -1.5 | 2.7 | | Demographics - Female | N | Mean | SD | Med | Min | Max | N | Mean | SD | Med | Min | Max | Diff | LB | UB | | Age (yrs) | 62 | 62.2 | 8.0 | 62.0 | 38.0 | 76.0 | 26 | 64.0 | 9.0 | 65.5 | 46.0 | 80.0 | -1.9 | -5.7 | 2.0 | | Height (in) | 62 | 64.1 | 2.4 | 64.0 | 58.0 | 68.5 | 26 | 63.7 | 3.2 | 64.3 | 53.8 | 70.0 | 0.4 | -0.9 | 1.6 | | Weight (lbs) | 62 | 174.3 | 34.0 | 166.5 | 106.1 | 250.0 | 26 | 179.0 | 35.0 | 180.5 | 123.0 | 242.3 | -4.7 | -20.7 | 11.2 | | BMI (kg/m²) | 62 | 29.9 | 5.7 | 29.1 | 17.4 | 40.3 | 26 | 31.0 | 5.8 | 32.4 | 20.8 | 39.7 | -1.2 | -3.8 | 1.5 | | Baseline Functional Status | N | Mean | SD | Med | Min | Max | N | Mean | SD | Med | Min | Max | Diff | LB | UB | | VAS Low Back Pain Score | 115 | 65.8 | 25.3 | 70.0 | 6.0 | 100.0 | 53 | 66.0 | 23.8 | 75.0 | 0.0 | 98.0 | -0.1 | -8.3 | 8.0 | | VAS Right Leg Pain Score | 115 | 63.9 | 31.2 | 74.0 | 0.0 | 100.0 | 53 | 64.6 | 30.5 | 75.0 | 0.0 | 100.0 | -0.7 | -10.9 | 9.4 | | VAS Left Leg Pain Score | 115 | 66.3 | 30.2 | 76.0 | 0.0 | 100.0 | 53 | 62.7 | 34.0 | 75.0 | 0.0 | 100.0 | 3.5 | -6.8 | 13.8 | PMA P220002: FDA Summary of Safety and Effectiveness Data 30 of 69 {30} Table 9: Baseline and Demographic Categorical Variables - mITT Analysis Set | | TOPS™ | | | | | | Fusion | | | | | | TOPS™ - Fusion¹ | | | | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | | | N | % | n | % | Diff (%) | LB | UB | | | | | | | | | | Number of subjects | 210 | | 96 | | | | | | | | | | | | | | Males | 93 | 44.3 | 46 | 47.9 | -3.6 | -15.7 | 8.4 | | | | | | | | | | Females | 117 | 55.7 | 50 | 52.1 | . | . | . | | | | | | | | | | Race | N | % | n | % | . | . | | | | | | | | | | | White | 195 | 92.9 | 89 | 92.7 | . | . | | | | | | | | | | | Black | 3 | 1.4 | 3 | 3.1 | . | . | | | | | | | | | | | Asian | 3 | 1.4 | 2 | 2.1 | . | . | | | | | | | | | | | Pacific Islander | 0 | 0.0 | 0 | 0.0 | . | . | | | | | | | | | | | American Indian or Alaskan Native | 1 | 0.5 | 1 | 1.0 | . | . | | | | | | | | | | | Other | 5 | 2.4 | 1 | 1.0 | . | . | | | | | | | | | | | Unknown | 3 | 1.4 | 0 | 0.0 | . | . | | | | | | | | | | | Hispanic or Latino | N | % | n | % | Diff (%) | LB | UB | | | | | | | | | | Yes | 6 | 2.9 | 2 | 2.1 | -0.8 | -4.4 | 2.9 | | | | | | | | | | No | 204 | 97.1 | 94 | 97.9 | . | . | . | | | | | | | | | | Use of nicotine products | N | % | n | % | . | . | | | | | | | | | | | No, never smoked | 128 | 61.0 | 62 | 64.6 | . | . | | | | | | | | | | | No, but prior history | 76 | 36.2 | 32 | 33.3 | . | . | | | | | | | | | | | Current smoker | 6 | 2.9 | 2 | 2.1 | . | . | | | | | | | | | | | Prior Lumbar Surgery | N | % | n | % | Diff (%) | LB | UB | | | | | | | | | | Yes | 12 | 5.7 | 6 | 6.3 | -0.5 | -6.3 | 5.2 | | | | | | | | | | No | 198 | 94.3 | 90 | 93.8 | . | . | . | | | | | | | | | | Index Leg (Worst VAS at Baseline) | N | % | n | % | . | . | | | | | | | | | | | Right Leg | 90 | 42.9 | 45 | 46.9 | . | . | | | | | | | | | | | Left Leg | 98 | 46.7 | 44 | 45.8 | . | . | | | | | | | | | | | Both Legs | 22 | 10.5 | 7 | 7.3 | . | . | | | | | | | | | | PMA P220002: FDA Summary of Safety and Effectiveness Data 31 of 69 {31} | | TOPS™ | | Fusion | | TOPS™ - Fusion¹ | | | | --- | --- | --- | --- | --- | --- | --- | --- | | Index Leg (Right Assigned if Equal) | N | % | n | % | Diff (%) | LB | UB | | Right Leg | 112 | 53.3 | 52 | 54.2 | -0.8 | -12.9 | 11.2 | | Left Leg | 98 | 46.7 | 44 | 45.8 | . | . | . | | Notes: ¹ Device group differences in proportions and 95% confidence intervals (CI) for group differences (95% CI not adjusted for multiplicity) | | | | | | | | Table 10: Summary of Baseline and Demographic Categorical Variables (TDmITT) | | TOPS™ | | Fusion | | TOPS™ - Fusion¹ | | | | --- | --- | --- | --- | --- | --- | --- | --- | | | n | % | n | % | Diff (%) | LB | UB | | Number of subjects | 115 | | 53 | | | | | | Males | 53 | 46.1 | 27 | 50.9 | -4.9 | -21.1 | 11.4 | | Females | 62 | 53.9 | 26 | 49.1 | . | . | . | | Race | n | % | n | % | . | . | | | White | 110 | 95.7 | 51 | 96.2 | . | . | | | Black | 1 | 0.9 | 1 | 1.9 | . | . | | | Asian | 1 | 0.9 | 0 | 0.0 | . | . | | | Pacific Islander | 0 | 0.0 | 0 | 0.0 | . | . | | | American Indian or Alaskan Native | 0 | 0.0 | 1 | 1.9 | . | . | | | Other | 2 | 1.7 | 0 | 0.0 | . | . | | | Unknown | 1 | 0.9 | 0 | 0.0 | . | . | | | Hispanic or Latino | n | % | n | % | Diff (%) | LB | UB | | Yes | 5 | 4.3 | 1 | 1.9 | -2.5 | -7.7 | 2.8 | | No | 110 | 95.7 | 52 | 98.1 | . | . | . | | Use of nicotine products | n | % | n | % | . | . | | | No, never smoked | 72 | 62.6 | 35 | 66.0 | . | . | | | No, but prior history | 42 | 36.5 | 17 | 32.1 | . | . | | | Current smoker | 1 | 0.9 | 1 | 1.9 | . | . | | | Prior Lumbar Surgery | n | % | n | % | Diff (%) | LB | UB | | Yes | 7 | 6.1 | 5 | 9.4 | -3.3 | -12.3 | 5.7 | | No | 108 | 93.9 | 48 | 90.6 | . | . | . | | Index Leg (Worst VAS at Baseline) | n | % | n | % | . | . | | | Right Leg | 47 | 40.9 | 23 | 43.4 | . | . | | | Left Leg | 56 | 48.7 | 26 | 49.1 | . | . | | | Both Legs | 12 | 10.4 | 4 | 7.5 | . | . | | | Index Leg (Right Assigned if Equal) | n | % | n | % | Diff (%) | LB | UB | | Right Leg | 59 | 51.3 | 27 | 50.9 | 0.4 | -15.9 | 16.6 | | Left Leg | 56 | 48.7 | 26 | 49.1 | . | . | . | | Notes: ¹ Device group differences in proportions and 95% confidence intervals (CI) for group differences (95% CI not adjusted for multiplicity) | | | | | | | | PMA P220002: FDA Summary of Safety and Effectiveness Data 32 of 69 {32} As shown in Tables 11-14 below, there were no apparent differences in operative characteristics between the TOPS™ and Fusion control groups in the mITT analysis set (210 TOPS™; 96 Fusion) or TDmITT analysis set (115 TOPS™; 53 Fusion). Note that Table 13 indicates a single Fusion group subject within the mITT was treated at L5/S1 (this subject was not due for Month 24 and thus is not included in the TDmITT analysis set); however, the subject is among the Intraoperative Change to Non-Study Treatment group because the fusion procedure was extended to a second level. Table 11: Summary of Operative Continuous Variables - mITT Analysis Set | | TOPS™ | | | | | | Fusion | | | | | | TOPS™ - Fusion¹ | | | | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | | Demographics - All | N | Mean | SD | Med | Min | Max | N | Mean | SD | Med | Min | Max | Diff | LB | UB | | Time in Surgery (min) | 210 | 183.7 | 58.1 | 173.0 | 74.0 | 359.0 | 96 | 176.9 | 56.9 | 167.5 | 77.0 | 357.0 | 6.8 | -7.2 | 20.8 | | Length of Hospital Stay (days) | 208 | 2.9 | 3.60 | 2.0 | 0.0 | 51.0 | 94 | 2.9 | 1.7 | 2.0 | 0.00 | 14.0 | 0.00 | -0.7 | 0.8 | | Estimated Blood Loss (cc) | 210 | 202.0 | 146.5 | 162.5 | 0.0 | 900.0 | 96 | 212.7 | 133.2 | 200.0 | 0.0 | 550.0 | -10.7 | -45.3 | 23.8 | | Demographics - Male | N | Mean | SD | Med | Min | Max | N | Mean | SD | Med | Min | Max | Diff | LB | UB | | Time in Surgery (min) | 93 | 194.5 | 54.1 | 193.0 | 89.0 | 332.0 | 46 | 174.7 | 61.6 | 160.0 | 84.0 | 357.0 | 19.9 | -0.3 | 40.0 | | Length of Hospital Stay (days) | 91 | 2.7 | 1.4 | 2.0 | 0.0 | 9.0 | 44 | 2.7 | 2.0 | 2.0 | 0.0 | 14.0 | 0.0 | -0.6 | 0.6 | | Estimated Blood Loss (cc) | 93 | 223.4 | 146.7 | 200.0 | 35.0 | 800.0 | 46 | 215.4 | 130.5 | 200.0 | 0.0 | 520.0 | 8.0 | -42.4 | 58.5 | | Demographics - Female | N | Mean | SD | Med | Min | Max | N | Mean | SD | Med | Min | Max | Diff | LB | UB | | Time in Surgery (min) | 117 | 175.0 | 60.0 | 159.0 | 74.0 | 359.0 | 50 | 178.9 | 52.7 | 184.5 | 77.0 | 304.0 | -3.9 | -23.2 | 15.5 | | Length of Hospital Stay (days) | 117 | 3.0 | 4.6 | 2.0 | 0.0 | 51.0 | 50 | 3.0 | 1.5 | 3.0 | 0.0 | 7.0 | 0.0 | -1.3 | 1.4 | | Estimated Blood Loss (cc) | 117 | 184.9 | 144.7 | 150.0 | 0.0 | 900.0 | 50 | 210.3 | 136.9 | 175.0 | 0.0 | 550.0 | -25.4 | -72.9 | 22.2 | | Notes: ¹Estimated mean difference and 95% confidence interval between TOPS™ and Fusion (95% CI not adjusted for multiplicity). | | | | | | | | | | | | | | | | Table 12: Summary of Operative Continuous Variables (TDmITT) | | TOPS™ | | | | | | Fusion | | | | | | TOPS™ - Fusion¹ | | | | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | | Demographics - All | N | Mean | SD | Med | Min | Max | N | Mean | SD | Med | Min | Max | Diff | LB | UB | | Time in Surgery (min) | 115 | 193.3 | 61.4 | 182.0 | 74.0 | 332.0 | 53 | 177.2 | 61.5 | 174.0 | 77.0 | 357.0 | 16.2 | -4.0 | 36.3 | PMA P220002: FDA Summary of Safety and Effectiveness Data 33 of 69 {33} | | TOPS™ | | | | | | Fusion | | | | | | TOPS™ - Fusion¹ | | | | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | | Length of Hospital Stay (days) | 115 | 3.06 | 4.67 | 2.00 | 0.00 | 51.00 | 52 | 3.21 | 2.15 | 3.00 | 0.00 | 14.00 | -0.15 | -1.49 | 1.19 | | Estimated Blood Loss (cc) | 115 | 223.6 | 166.2 | 200.0 | 0.0 | 900.0 | 53 | 231.2 | 139.0 | 200.0 | 0.0 | 550.0 | -7.6 | -59.4 | 44.3 | | Demographics - Male | N | Mean | SD | Med | Min | Max | N | Mean | SD | Med | Min | Max | Diff | LB | UB | | Time in Surgery (min) | 53 | 205.0 | 54.2 | 204.0 | 102.0 | 332.0 | 27 | 174.6 | 65.6 | 163.0 | 84.0 | 357.0 | 30.4 | 3.0 | 57.8 | | Length of Hospital Stay (days) | 53 | 2.62 | 1.18 | 2.00 | 0.00 | 6.00 | 26 | 2.96 | 2.51 | 3.00 | 0.00 | 14.00 | -0.34 | -1.16 | 0.48 | | Estimated Blood Loss (cc) | 53 | 238.2 | 154.2 | 200.0 | 50.0 | 800.0 | 27 | 230.9 | 125.7 | 200.0 | 0.0 | 520.0 | 7.4 | -61.0 | 75.8 | | Demographics - Female | N | Mean | SD | Med | Min | Max | N | Mean | SD | Med | Min | Max | Diff | LB | UB | | Time in Surgery (min) | 62 | 183.3 | 65.8 | 165.5 | 74.0 | 329.0 | 26 | 179.8 | 58.1 | 186.5 | 77.0 | 304.0 | 3.5 | -26.1 | 33.1 | | Length of Hospital Stay (days) | 62 | 3.4 | 6.3 | 3.0 | 1.0 | 51.0 | 26 | 3.5 | 1.7 | 3.0 | 0.0 | 7.0 | 0.0 | -2.5 | 2.5 | | Estimated Blood Loss (cc) | 62 | 211.1 | 176.2 | 150.0 | 0.0 | 900.0 | 26 | 231.5 | 154.2 | 200.0 | 50.0 | 550.0 | -20.4 | -99.4 | 58.6 | | Notes: ¹Estimated mean difference and 95% confidence interval between TOPS™ and Fusion (95% CI not adjusted for multiplicity) | | | | | | | | | | | | | | | | Table 13: Summary of Operative Categorical Variables - mITT Analysis Set | | TOPS™ | | Fusion | | | --- | --- | --- | --- | --- | | | n | % | n | % | | Number of subjects | 210 | | 96 | | | Level Implanted | n | % | n | % | | L1/L2 | 0 | 0.0 | 0 | 0.0 | | L2/L3 | 0 | 0.0 | 0 | 0.0 | | L3/L4 | 10 | 4.8 | 6 | 6.3 | | L4/L5 | 200 | 95.2 | 89 | 92.7 | | L5/S1 | 0 | 0.0 | 1 | 1.0 | | Operative Blood Loss | n | % | n | % | | <100 cc | 34 | 16.2 | 12 | 12.5 | | 100 - <250 cc | 106 | 50.5 | 49 | 51.0 | | 250 - <400 cc | 46 | 21.9 | 20 | 20.8 | | ≥400 cc | 24 | 11.4 | 15 | 15.6 | PMA P220002: FDA Summary of Safety and Effectiveness Data 34 of 69 {34} Table 14: Summary of Operative Categorical Variables (TDmITT) | | TOPS™ | | Fusion | | | --- | --- | --- | --- | --- | | | n | % | n | % | | Number of subjects | 115 | | 53 | | | Level Implanted | n | % | n | % | | L1/L2 | 0 | 0.0 | 0 | 0.0 | | L2/L3 | 0 | 0.0 | 0 | 0.0 | | L3/L4 | 5 | 4.3 | 3 | 5.7 | | L4/L5 | 110 | 95.7 | 50 | 94.3 | | L5/S1 | 0 | 0.0 | 0 | 0.0 | | Operative Blood Loss | n | % | n | % | | <100 cc | 19 | 16.5 | 4 | 7.5 | | 100 - <250 cc | 53 | 46.1 | 28 | 52.8 | | 250 - <400 cc | 25 | 21.7 | 11 | 20.8 | | ≥400 cc | 18 | 15.7 | 10 | 18.9 | D. Safety and Effectiveness Results The safety results below are presented for the AT analysis set (N=210 TOPS™ and 96 Fusion) and TDmITT analysis set (N=115 TOPS™ and 53 Fusion); the effectiveness results below are presented for the TDmITT analysis set (N=115 TOPS™ and 53 Fusion). The safety endpoint evaluated the rate of AEs, categorized by severity (mild, moderate or severe), relationship to the implant or procedure, and serious adverse events (SAEs). All adverse events were reviewed by a convened Clinical Events Committee (CEC) and adjudicated for severity and relationship to the implant or procedure based on the following definitions: Severity - Mild - An experience that is noticeable to the patient but does not impede routine activity. - Moderate - An experience that impedes the patient’s routine activity but responds to symptomatic therapy or rest. - Severe - An experience that significantly limits the patient’s ability to perform routine activities despite symptomatic therapy. Causality (relation to device and to procedure) - Not Related - A temporal relationship to device implantation or with ongoing use of the device, which makes a causal relationship clearly due to extraneous causes, such as other drugs, other devices, chemicals, underlying diseases, environment, etc. The event is clearly not-related to the device implanted or to a function/malfunction. - Possibly Related - Occurring within a reasonable period of time relative to device implantation or with ongoing use of the device, which makes a causal relationship possible, but plausible explanations can likely be PMA P220002: FDA Summary of Safety and Effectiveness Data 35 of 69 {35} attributed to other causes, such as other drugs, products, chemicals, underlying disease, environment, etc. - Probably Related - Occurring within a reasonable period of time relative to device implantation or with ongoing use of the device, which makes a causal relationship prob…