Simplify® Cervical Artificial Disc

P200022 · Nuvasive, Inc. · MJO · Sep 18, 2020 · Orthopedic

Device Facts

• Record ID: P200022
• Device Name: Simplify® Cervical Artificial Disc
• Applicant: Nuvasive, Inc.
• Product Code: MJO · Orthopedic
• Decision Date: Sep 18, 2020
• Decision: APPR
• Device Class: Class 3
• Attributes: Therapeutic

Intended Use

Simplify® Cervical Artificial Disc 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 manifested by at least one of the following conditions confirmed by radiographic imaging (e.g., X-rays, computed tomography (CT), magnetic resonance imaging (MRI)): herniated nucleus pulposus, spondylosis (defined by the presence of osteophytes), and/or visible loss of disc height as compared to adjacent levels. Patients receiving Simplify® Cervical Artificial Disc should have failed at least six weeks of non-operative treatment or have the presence of progressive symptoms (e.g., numbness or tingling) prior to implantation. Simplify® Cervical Artificial Disc is implanted via an open anterior approach.

Device Story

Simplify® Cervical Artificial Disc is a motion-preserving intervertebral device for single-level cervical disc replacement. It consists of two PEEK endplates with plasma-sprayed titanium coating and a mobile zirconia-toughened alumina ceramic core. The device is implanted via an open anterior approach by a surgeon. It provides range of motion in flexion-extension, lateral bending, and axial rotation, allowing patient anatomy to dictate kinematic profiles. By replacing the degenerated disc, the device aims to relieve radiculopathy or myelopathy symptoms, restore disc height, and potentially reduce adjacent segment degeneration compared to fusion. Clinical outcomes include improved NDI scores, reduced neck/arm pain (VAS), and high patient satisfaction. The device is MR Conditional.

Clinical Evidence

Prospective, non-randomized, historically controlled multi-center study (IDE #G140154) comparing 150 Simplify® subjects to 117 propensity-score matched historical ACDF controls. Primary endpoint: 24-month composite clinical success (NDI improvement ≥15 points, neurological maintenance/improvement, no device failure/SSI/major AE). Simplify® demonstrated superiority to ACDF (93.0% vs 73.6% success rate; p<0.001). Secondary endpoints (NDI, VAS, SF-12, Odom's criteria) favored Simplify®. Safety profile comparable to ACDF; no device failures reported in Simplify® group.

Technological Characteristics

Materials: PEEK endplates with plasma-sprayed titanium coating (ISO 5832-2, ASTM F1580) and zirconia-toughened alumina (ZTA) ceramic core. Design: Mobile core, three footprints, three heights (4-6mm), two lordosis angles (0°, 5°). Connectivity: None. Sterilization: ISO 11137. MR Conditional (1.5T/3.0T).

Indications for Use

Indicated for skeletally mature patients with intractable radiculopathy or myelopathy at one cervical level (C3-C7) due to herniated nucleus pulposus, spondylosis, or disc height loss. Requires failure of 6 weeks non-operative treatment or progressive symptoms. Contraindicated in patients with active infection, multi-level disease, osteoporosis (T-score < -1.5), material allergy, severe facet disease, bridging osteophytes, cervical instability, or significant anatomical deformity.

Submission Summary (Full Text)

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SUMMARY OF SAFETY AND EFFECTIVENESS DATA (SSED)

I. GENERAL INFORMATION

Device Generic Name: Artificial Cervical Disc
Device Trade Name: Simplify® Cervical Artificial Disc
Device Product Code: MJO
Applicant’s Name/Address: Simplify Medical, Inc.
685 North Pastoria Avenue
Sunnyvale, CA 94085
Date of Panel Recommendation: None
Premarket Approval Application: P200022 (PMA Number)
Date of FDA Notice of Approval: September 18, 2020

II. INDICATIONS FOR USE

Simplify® Cervical Artificial Disc 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 manifested by at least one of the following conditions confirmed by radiographic imaging (e.g., X-rays, computed tomography (CT), magnetic resonance imaging (MRI)): herniated nucleus pulposus, spondylosis (defined by the presence of osteophytes), and/or visible loss of disc height as compared to adjacent levels. Patients receiving Simplify® Cervical Artificial Disc should have failed at least six weeks of non-operative treatment or have the presence of progressive symptoms (e.g., numbness or tingling) prior to implantation. Simplify® Cervical Artificial Disc is implanted via an open anterior approach.

III. CONTRAINDICATIONS

Simplify® Cervical Artificial Disc should not be implanted in patients with the following conditions:

- An active systemic infection or an infection at the operative site.
- Intractable radiculopathy or myelopathy necessitating surgical treatment at more than one cervical level.
- Osteoporosis or osteopenia defined as DEXA bone mineral density T-score less than -1.5.
- Known allergy to the implant materials (PEEK, ceramic, titanium).
- Severe facet disease or facet degeneration.
- Bridging osteophytes.

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- Marked cervical instability on neutral lateral or flexion/extension radiographs (e.g., radiographic signs of subluxation $&gt;3.0\mathrm{mm}$ or angulation of the disc space more than $11^{\circ}$ greater than adjacent segments).
- Significant cervical anatomical deformity at the index level or clinically compromised cervical vertebral bodies at the index level due to current or past trauma (e.g., by radiographic appearance of fracture callus, malunion, or nonunion) or disease (e.g., ankylosing spondylitis, rheumatoid arthritis).

# IV. WARNINGS AND PRECAUTIONS

The warnings and precautions can be found in the Simplify® Cervical Artificial Disc Instructions for Use.

# V. DEVICE DESCRIPTION

The Simplify® Cervical Artificial Disc is a cervical artificial intervertebral device manufactured from PEEK endplates and a mobile, zirconia-toughened alumina ceramic core. The PEEK endplates have a plasma-sprayed titanium coating per ISO 5832-2 and ASTM F1580. The articulating surfaces on the endplates have a concave surface and the core has two convex surfaces. The device is pictured in the figures below (Figure 1 and Figure 2).

Figure 1: Schematic of Simplify® Cervical Artificial Disc: assembly (left) and mid-sagittal section (right).


For the Simplify® Cervical Artificial Disc family, two core options (i.e., either small or large) are used for all assemblies. The articulating features of superior and inferior endplates are identical and congruent with the appropriate core. Superior and inferior endplates are available in three footprints (Small, Medium, Large), three thicknesses resulting in three device heights (4 mm, 5 mm, 6 mm), and two lordosis angles $(0^{\circ}$ and $5^{\circ})$ , as shown in Figure 3 and Table 1 below. The superior endplates have a retention ring feature. All endplates are titanium coated on the bone interfacing surfaces, with two options available for coating thickness (80 μm or 160μm). All endplate components, regardless of configuration, have identical manufacturing process flow, including packaging and sterilization.

The Simplify® Cervical Artificial Disc is designed to provide a theoretical maximum of $\pm 12^{\circ}$ in any combination of flexion-extension and lateral bending, unlimited axial rotation, and $1 - 2\mathrm{mm}$ translation. These ranges of motion are intended to permit the patient's anatomy to determine actual range of motion without imposing an artificial limit that may be restrictive to the patient's

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kinematic profile. The maximum range of motion in vivo will be dictated by the patient's anatomical boundaries or the device limits, whichever is smaller.

Figure 2: Exploded Schematic of the Simplify® Cervical Artificial Disc

Figure 3: Simplify® Cervical Artificial Disc Heights and Sizes

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Table 1: Simplify® Cervical Artificial Disc Part Listing and Size Overview

| Disc Sizes | Catalog Number | A/P Width (mm) | Lateral Width (mm) | Height (mm) | Lordosis (°) |
| --- | --- | --- | --- | --- | --- |
| 80 Micron Coating | | | | | |
| Simplify® Cervical Artificial Disc Size SM, Height 4 | SM-4-T | 12 | 15 | 4 | 0 |
| Simplify® Cervical Artificial Disc Size SM, Height 4, 5° Lordosis | SM-4L-T | 12 | 15 | 4 | 5 |
| Simplify® Cervical Artificial Disc Size SM, Height 5 | SM-5-T | 12 | 15 | 5 | 0 |
| Simplify® Cervical Artificial Disc Size SM, Height 5, 5° Lordosis | SM-5L-T | 12 | 15 | 5 | 5 |
| Simplify® Cervical Artificial Disc Size SM, Height 6 | SM-6-T | 12 | 15 | 6 | 0 |
| Simplify® Cervical Artificial Disc Size MD, Height 4 | MD-4-T | 14 | 16 | 4 | 0 |
| Simplify® Cervical Artificial Disc Size MD, Height 5 | MD-5-T | 14 | 16 | 5 | 0 |
| Simplify® Cervical Artificial Disc Size MD, Height 5, 5° Lordosis | MD-5L-T | 14 | 16 | 5 | 5 |
| Simplify® Cervical Artificial Disc Size MD, Height 6 | MD-6-T | 14 | 16 | 6 | 0 |
| Simplify® Cervical Artificial Disc Size MD, Height 6, 5° Lordosis | MD-6L-T | 14 | 16 | 6 | 5 |
| Simplify® Cervical Artificial Disc Size LG, Height 5 | LG-5-T | 16 | 18 | 5 | 0 |
| Simplify® Cervical Artificial Disc Size LG, Height 5, 5° Lordosis | LG-5L-T | 16 | 18 | 5 | 5 |
| Simplify® Cervical Artificial Disc Size LG, Height 6 | LG-6-T | 16 | 18 | 6 | 0 |
| Simplify® Cervical Artificial Disc Size LG, Height 6, 5° Lordosis | LG-6L-T | 16 | 18 | 6 | 5 |
| 160 Micron Coating | | | | | |
| Simplify® Cervical Artificial Disc Size SM, Height 4 | SM-4 | 12 | 15 | 4 | 0 |
| Simplify® Cervical Artificial Disc Size SM, Height 4, 5° Lordosis | SM-4L | 12 | 15 | 4 | 5 |
| Simplify® Cervical Artificial Disc Size SM, Height 5 | SM-5 | 12 | 15 | 5 | 0 |
| Simplify® Cervical Artificial Disc Size SM, Height 5, 5° Lordosis | SM-5L | 12 | 15 | 5 | 5 |
| Simplify® Cervical Artificial Disc Size SM, Height 6 | SM-6 | 12 | 15 | 6 | 0 |
| Simplify® Cervical Artificial Disc Size MD, Height 4 | MD-4 | 14 | 16 | 4 | 0 |
| Simplify® Cervical Artificial Disc Size MD, Height 5 | MD-5 | 14 | 16 | 5 | 0 |
| Simplify® Cervical Artificial Disc Size MD, Height 5, 5° Lordosis | MD-5L | 14 | 16 | 5 | 5 |
| Simplify® Cervical Artificial Disc Size MD, Height 6 | MD-6 | 14 | 16 | 6 | 0 |
| Simplify® Cervical Artificial Disc Size MD, Height 6, 5° Lordosis | MD-6L | 14 | 16 | 6 | 5 |
| Simplify® Cervical Artificial Disc Size LG, Height 5 | LG-5 | 16 | 18 | 5 | 0 |
| Simplify® Cervical Artificial Disc Size LG, Height 5, 5° Lordosis | LG-5L | 16 | 18 | 5 | 5 |
| Simplify® Cervical Artificial Disc Size LG, Height 6 | LG-6 | 16 | 18 | 6 | 0 |
| Simplify® Cervical Artificial Disc Size LG, Height 6, 5° Lordosis | LG-6L | 16 | 18 | 6 | 5 |

# VI. ALTERNATIVE PRACTICES AND PROCEDURES

There are several other alternatives available for the treatment of symptomatic degeneration of the cervical spine at a single-level presenting with arm pain and/or neurological deficit (intractable radiculopathy), with or without neck pain or myelopathy and radiographic abnormality.

- Nonoperative alternative treatments, which include, but are not limited to, physical therapy, medications, braces, chiropractic care, bed rest, spinal injections, or exercise programs.
- Surgical alternatives, which include, but are not limited to:

Surgical decompression alone
Surgical decompression using intervertebral cages or bone grafting techniques, with or without supplemental anterior plating
$\mathrm{O}$ Decompression with posterior spinal systems (e.g., rods, hooks, wires)
Another FDA-approved artificial cervical disc

Each option has advantages and disadvantages. Patients should fully discuss the available alternatives with his or her physician to select the option that best meets their clinical condition, lifestyle and expectations.

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# VII. MARKETING HISTORY

The Simplify® Cervical Artificial Disc has been marketed outside of the United States since 2016. The Simplify® Cervical Artificial Disc is currently distributed in the United Kingdom and Germany. The Simplify® Cervical Artificial Disc 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) identified from the Simplify® Cervical Artificial Disc clinical study results, approved device labeling for other cervical total disc replacement devices, and published scientific literature including: (1) those associated with any general surgical procedure; (2) those associated with anterior cervical spine surgery; and (3) those associated with a cervical artificial disc device, including the Simplify® Cervical Artificial Disc. In addition to the risks listed below, there is also the risk that surgery may not be effective in relieving symptoms or may cause worsening of symptoms. Additional surgery may be required to correct some of the adverse effects.

## General Surgery Risks

General surgical risks are, but may not be limited to:

- Infection/abscess/cyst, localized or systemic
- Blood clots, including pulmonary emboli
- Medication and anesthesia reactions
- Phlebitis
- Pneumonia
- Atelectasis
- Soft tissue damage
- Septicemia
- Hemorrhage possibly requiring a blood transfusion, with possible transfusion reaction
- Myocardial infarction
- Paralysis
- Poor tissue healing
- Cerebrovascular accident (CVA)
- Death

## Anterior Cervical Surgery Risks

Anterior cervical surgical risks are, but may not be limited to:

- Infection/abscess/cyst, localized or systemic
- Injury or damage to the trachea, esophagus, nerves or blood vessels
- Dysphagia
- Hoarseness
- Vocal cord paralysis
- Paresis
- Recurrent laryngeal nerve palsy

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- Soft tissue damage
- Spinal cord damage
- Dural tear with cerebrospinal fluid leakage
- Arm weakness or numbness
- Bowel, bladder or sexual dysfunction
- Nerve root injury
- Airway obstruction
- Epidural hematoma or bleeding
- Epidural fibrosis
- Vertebral body fracture
- Dysesthesia or numbness
- Paresthesia
- Unresolved pain
- Surgical intervention at incorrect level
- Need for supplemental fixation
- Spinal instability
- Death

## Cervical Artificial Disc Risks

Risks specific to cervical artificial discs, including the Simplify® Cervical Artificial Disc, are but may not be limited to:

- Infection/abscess/cyst, localized or systemic
- Allergic reaction to the implant materials
- Implant failure
- Device migration
- Device subsidence
- Device fatigue or fracture or breakage
- Device instability
- Separation of device components
- Placement difficulties, device malposition
- Improper device sizing
- Excessive device height loss
- Wear debris
- Disc space collapse
- Material degradation
- Excessive facet loading
- Kyphosis or hyper-extension
- Loss of flexibility
- Asymmetric range of motion
- Vertebral body fracture
- Spinal cord damage,
- Dural tear with cerebrospinal fluid leakage
- Soft tissue damage

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- Epidural fibrosis
- Nerve injury, paralysis or weakness that is temporary or permanent
- Injury or damage to the trachea, esophagus, or blood vessels
- Epidural hematoma or bleeding
- Dysesthesia or numbness
- Paresthesia
- Failure to relieve symptoms including unresolved pain
- Additional surgery due to loss of fixation, infection or injury
- Spontaneous fusion due to heterotopic ossification, development of bridging bone or osteophytes
- Periarticular calcification and fusion
- Development of spinal conditions, including but not limited to spinal stenosis, spondylolisthesis, or retrolisthesis
- Removal, revision, reoperation or supplemental fixation of the disc
- Osteolysis, bone loss, or bone resorption
- Death

For the specific adverse events (AEs) that occurred in the Simplify® Cervical Artificial Disc 1-Level clinical study, please see Section X.

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IX. SUMMARY OF NON-CLINICAL STUDIES

A variety of testing was conducted to characterize the performance of the Simplify® Cervical Artificial Disc, as follows:

Laboratory Studies
- Static Axial Compression
- Dynamic Axial Compression
- Static Compression Shear
- Dynamic Compression Shear
- Static Peripheral Supported Compression
- Dynamic Peripheral Supported Compression
- Subluxation/ Expulsion
- Subsidence
- Wear (Mode I Wear)
- Third Body Wear (Mode 3 Wear)
- Impingement (Mode 4 Wear)
- Range of Motion
- Coating Testing

Additional Studies
- MR Compatibility
- Biocompatibility/ Pyrogenicity/ Neurotoxicity
- Device Sterilization
- Shelf Life and Transit Validation

A. Laboratory Studies

A summary of the conducted laboratory testing is presented in the following table, stratified by the above classifications (Table 2).

Table 2: Non-Clinical Study Summary

| Test Name | Purpose | Test Method | Acceptance Criteria | Results |
| --- | --- | --- | --- | --- |
| Static and Dynamic Strength | | | | |
| Static and Fatigue under Axial Compression | Verify static and fatigue performance under simulated physiologic conditions are sufficient to withstand in vivo compressive loads | Six (6) Simplify® Cervical Artificial Disc specimens were tested under static compression in 37°C deionized water at a rate of 25mm/min until failure or ≈10 kN (capacity of load cell) was reached.
Three (3) Simplify® Cervical Artificial Disc specimens were tested | Must withstand ≥300 N static load without functional failure
Fatigue load (10 x 10^{6} cycles runout) ≥150 N | Static strength: ≥10 kN
Static stiffness: 2317 N/mm (for information only)
Dynamic strength: 375 N
Change in disc height: 0.24 mm
All acceptance criteria were met. |

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| Test Name | Purpose | Test Method | Acceptance Criteria | Results |
| --- | --- | --- | --- | --- |
| | | under dynamic compression in 37°C 0.9% saline to 10 x 106cycles, using a sinusoidal wave form with R=10 at 2 Hz. Testing per ASTM F2346 | Average residual height loss after runout ≤ 1.5mm | |
| Static and Fatigue Shear Strength | Verify that the static and fatigue performance are sufficient to withstand anticipated in vivo shear compressive loads | Six (6) Simplify® Cervical Artificial Disc specimens were tested under static compression-shear (27°) in 37°C deionized water at a rate of 25 mm/min until failure.Three (3) Simplify® Cervical Artificial Disc specimens were tested under dynamic compression-shear in 37°C 0.9% saline to 10 x 106cycles, using a sinusoidal wave form with R=10 at 2 Hz. Testing per ASTM F2346 | Must withstand ≥ 20 N static shear without functional failureFatigue load (10 x106cycles runout) ≥ 20 N | Static compressive shear strength: 284 NDynamic compressive shear strength: ≥ 123 NAll acceptance criteria were met. |
| Endplate Strength under Peripheral Support | Characterize the strength of the Simplify® Cervical Artificial Disc under the special case of a peripherally supported endplate | Five (5) Simplify® Cervical Artificial Disc specimens were tested under static compression in 37°C deionized water at a rate of 25mm/min until failure.Custom fixturing left the central 14 mm diameter region unsupported.Seven (7) Simplify® Cervical Artificial Disc specimens were tested under dynamic compression in 37°C 0.9% saline at various loads using a sinusoidal wave form with R=10 at 2 Hz. Runout was considered 2 x 106cycles,Testing was based on ASTM F2346 | N/A (for characterization purposes) | Ultimate static strength was 1253 N.Linear regression analysis of dynamic tests indicates fatigue strength ≈388 N.Results compare favorably to static strength requirements. |
| Subluxation/ Expulsion | | | | |
| Subluxation/ Expulsion | Verify ability of Simplify® Cervical Artificial Disc to | Simplify® Cervical Artificial Discs implanted in Grade 15 polyurethane | Force ≥ 20 N required to cause subluxation or | Resistance to expulsion at 0°: 223 N; at 12°: 193 N. |
| | in situ | in situ | in situ | |

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| Test Name | Purpose | Test Method | Acceptance Criteria | Results |
| --- | --- | --- | --- | --- |
| | resist expulsion and subluxation using simulated physiologic conditions | foam with 100N static axial preload were subjected to 6 mm/min anterior shear. Load was applied to both endplates (expulsion) or one endplate (subluxation) with endplate parallel or in 12° extension. Twenty test specimens, five (5) per test configuration, were tested. | expulsion (defined as movement ≥ 3 mm) | Resistance to subluxation at 0°: 117N; at 12°: 154 N
All acceptance criteria were met. |
| Subsidence | | | | |
| Subsidence | Verify the ability of the Simplify® Cervical Artificial Disc to resist subsidence using simulated physiologic conditions | Five (5) Simplify® Cervical Artificial Disc specimens were compressed between Grade 15 polyurethane foam blocks at a rate 0.1 mm/sec per ASTM F2267. | Subsidence force ≥ 300 N | Subsidence force: 768.0 N. Acceptance criterion was met. |
| Wear | | | | |
| Device Wear, Mode I | Characterize in vitro wear properties | Six (6) Simplify® Cervical Artificial Disc test specimens were subjected to 10 x 10^6 cycles of combined 50-150 N axial load, ±7.5° flexion/extension, ±6° axial rotation, and ±6° lateral bending at 1 Hz per ISO 18192-1 and ASTM F2423 while submerged in bovine serum solution with a protein concentration of 5 g/L Two (2) test specimens served as load soak controls. | Wear rate ≤ 7 mg/MC (70 mg total)
No fracture, functional failure or impingement | Cumulative mass loss: 9.0 mg
Average gravimetric wear rate: 0.9 mg/MC
(Average volumetric wear rate: 0.7 mm³/MC)
No devices demonstrated signs of fracture, functional failure, or impingement.
All acceptance criteria were met. |
| Wear, Mode III (Third Body) | To characterize in vivo wear properties under third-body abrasive wear conditions (Mode III) | A titanium scar was created on both articulating surfaces of the core in Simplify® Cervical Artificial Disc test specimens. Six (6) specimens were then subjected to 5 x 10^6 cycles of combined 50-150 N axial load, ±7.5° flexion/extension, ±6° axial rotation, and ±6° lateral bending at 1 Hz per ISO 18192-1 and ASTM F2423 while submerged in bovine serum solution with a protein concentration of 5 | N/A (for characterization purposes) | Average mass wear rate: 2.8 mg/MC
No devices demonstrated signs of fracture or functional failure. |

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| Test Name | Purpose | Test Method | Acceptance Criteria | Results |
| --- | --- | --- | --- | --- |
| | | g/L. Two (2) test specimens served as load soak controls. | | |
| Wear, Mode IV (Impingement) | Characterize the impingement properties using simulated physiologic conditions (Mode IV wear) | Six (6) Simplify® Cervical Artificial Disc test specimens, three (3) SM and three (3) LG, were subjected to 1 x 10^6 cycles of combined 150 N axial load, 17-18° extension, and ±6° axial rotation at 1 Hz per ASTM F3295 while submerged in bovine serum solution with a protein concentration of 5 g/L. Two (2) test specimens, one per size, served as load soak controls. | N/A (for characterization purposes) | Gravimetric wear rates: Size SM: 1.0 mg/MC Size LG: 1.9 mg/MC No devices demonstrated signs of fracture or functional failure. |
| Range of Motion | | | | |
| Range of Motion | Characterize range of motion of Simplify® Cervical Artificial Disc using finite element techniques. | Finite Element (FE) methods compared range of motion for an intact spine and the same spine with a Simplify® Cervical Artificial Disc implanted at C5/C6 subjected to 100 N axial load and various 1.5 Nm moments (flexion, extension, lateral bending, and axial rotation). | N/A (for characterization purposes) | The range of motion for the Simplify® Cervical Artificial Disc is similar to the intact spine model and generally falls within the range of previously published finite element models and cadaver tests. |
| Coating Testing | | | | |
| Coating Shear Fatigue | Evaluate coating in shear fatigue testing | Six (6) test specimens were subjected to sinusoidal tensile stress of 10 MPa for 10 x 10^6 cycles per ASTM F1160 | No failure of the coating | None of the test specimens showed any evidence of coating failure. The acceptance criterion was met. |
| Coating Static Shear Strength | Evaluate coating in static shear testing | Twenty (20) test specimens were tested per ASTM F1044 | ≥20 MPa | 32.04 MPa. The acceptance criterion was met. |
| Coating Static Tensile Strength | Evaluate coating in tensile testing | Twenty (20) test specimens were tested per ASTM F1147 | ≥22 MPa | 36.2 MPa. The acceptance criterion was met. |
| Coating Abrasion | Coating taper abrasion testing | Six (6) test specimens were tested per ASTM F1978 | ≤65 mg mass loss after 100 cycles | 49 mg mass loss. The acceptance criterion was met. |
| Coating Characterization | Characterize coating morphology | Coating thickness per ASTM F1854, n=60 | 160 ± 20 μm | 156.3 μm. Acceptance criterion was met. |
| | | Roughness Ra per DIN EN ISO 4288 & DIN EN ISO 4287, n=20 | 20 ± 5 μm | 19.4 μm. Acceptance criterion was met. |
| | | Porosity per ASTM F1854, n=59 | 20-40% | 36.54%. Acceptance criterion was met. |

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| Test Name | Purpose | Test Method | Acceptance Criteria | Results |
| --- | --- | --- | --- | --- |
| | | Visual appearance, n=59 | Uniform | Uniform. Acceptance criterion was met. |
| Coated Endplate Characterization | Demonstrate that titanium coating does not degrade or adversely affect the PEEK substrate | Three (3) coated PEEK endplates were characterized per ASTM F2026 using FTIR (chemical composition), DSC (thermal transitions and crystallinity), and GPC (molecular weight and polydispersity), with results compared to those from the original PEEK bar stock used to manufacture the endplates. The PEEK-coating interface was evaluated with optical microscopy for signs of polymer degradation. | N/A (for characterization purposes only) | Coated endplates showed no discernable physiochemical differences from original bar stock and no visual evidence of degradation. |

## B. Additional Studies

### Magnetic Resonance (MR) Imaging

The safety and compatibility of the Simplify® Cervical Artificial Disc in the Magnetic Resonance (MR) environment was evaluated. Specifically, it was tested for magnetic field interactions, heating, and artifacts associated with clinically relevant magnetic resonance imaging.

The magnetic field interaction evaluations consisted of displacement and torque assessments. For the assessment of displacement, an induced displacement force test was performed in accordance with ASTM F2052. The evaluation of magnetic torque was performed in accordance with ASTM F2052. The Simplify® Cervical Artificial Disc was tested for MRI-related heating in accordance with ASTM F2182. MR imaging artifacts were assessed in accordance with ASTM F2119.

The results of the assessments demonstrated that the Simplify® Cervical Artificial Disc is MR Conditional. A patient with the Simplify® Cervical Artificial Disc can be scanned safely in an MR system under the following conditions:

- Static magnetic field of 1.5 Tesla (1.5T) or 3.0 Tesla (3.0T).
- Maximum spatial gradient field less than or equal to 5990 Gauss/cm (59.9 T/m).
- Maximum whole-body specific absorption rate (SAR) of 2.0 W/kg for 15 minutes of scanning in Normal Operating Mode.
- Transmit/receive body coil.

Under the scan conditions defined, the Simplify® Cervical Artificial Disc is expected to produce a maximum temperature rise of less than 3.0°C after 15 minutes of continuous scanning.

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In non-clinical testing per ASTM F2119, the image artifact caused by the Simplify® Cervical Artificial Disc extends approximately 5-mm at 1.5T and 8 mm at 3.0T from Simplify® Cervical Artificial Disc when imaged using a gradient echo pulse sequence.

## Biocompatibility

The Simplify® Cervical Artificial Disc is manufactured from PEEK, zirconia-toughened alumina (ZTA) ceramic, and commercially pure titanium plasma spray (TPS). All implant materials have a long history of successful orthopedic clinical use and well-established biocompatibility. There are no color additives in the Simplify® Cervical Artificial Disc.

Biocompatibility testing was performed on the Simplify® Cervical Artificial Disc in its final sterilized state in accordance with ISO 10993-1, ISO 10993-12, ISO 10993-17, and ISO 10993-18, for the level of contact duration of a permanent implant contacting tissue and bone. The battery of biocompatibility tests conducted included: Cytotoxicity (ISO 10993-5), Pyrogenicity (ISO 10993-11), Bacterial Endotoxin Evaluation (ANSI/AAMI ST72, USP&lt;85&gt;, USP&lt;161&gt;), Neurotoxicity Assessment (ASTM F2423, ISO 18192-1, ASTM WK33006), and Biological Risk Assessment (ISO 10993-1, -12, -17, -18). All test results met the acceptance criteria demonstrating biocompatibility in line with the requirements of ISO 10993-1.

## Sterilization Validation

Full sterilization validation has been conducted for the Simplify® Cervical Artificial Disc implants per ISO 11137. Full sterilization validation has been conducted for the Simplify® Cervical Artificial Disc Instruments per ANSI/AAMI ST79, AAMI TIR12, and ISO 17665-1.

## Shelf Life and Transit Validation

Shelf life and transit validation studies, including assessments of packaging seal integrity and real-time aging testing, were conducted to demonstrate that the device packaging can maintain a sterile barrier over a 4-year shelf life.

## X. SUMMARY OF PRIMARY CLINICAL STUDIES

The applicant conducted a clinical study to establish a reasonable assurance of safety and effectiveness of replacement of the degenerated native disc with the Simplify® Cervical Artificial Disc 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 manifested by at least one of the following conditions confirmed by radiographic imaging (e.g., X-rays, computed tomography (CT), magnetic resonance imaging (MRI)): herniated nucleus pulposus, spondylosis (defined by the presence of osteophytes), and/or visible loss of disc height as compared to adjacent levels. The study was performed in the United States under IDE #G140154 with additional control anterior cervical discectomy and fusion (ACDF) data from a separate IDE study performed in the United States. A summary of the clinical study is presented below.

## A. Study Design

Subjects in the Simplify® Cervical Artificial Disc pivotal study (“Simplify® Cervical Artificial Disc IDE study”) were treated between February 2016 and February 2018. The database for this

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PMA reflects data collected through March 2020 and included 150 Simplify® Cervical Artificial Disc subjects (166 including training subjects) at 16 sites and 133 historical ACDF control subjects treated at 21 sites. Control subjects were treated between July 2005 and August 2007.

The prospective, non-randomized, historically controlled, multi-center study was performed in the United States under IDE #G140154 combined with additional control ACDF data from a previous multi-center, prospective, randomized concurrently-controlled cervical disc IDE study performed in the United States. This previous study incorporated a similar study design, indications for use, study entry criteria, study endpoints, and data collected. The two studies were not identical, and differences were identified in some categories and are discussed below.

A statistical plan utilizing propensity score (PS) modeling was developed to incorporate both the concurrent control and historical control and to match the baseline covariates to the Simplify® Cervical Artificial Disc group. The resultant PS Selected study cohort used for the primary analysis population thus included all investigational Simplify® Cervical Artificial Disc subjects (excluding training subjects) and historical control subjects (excluding trimmed subjects) and is termed the "Primary Analysis Set."

# 1. Clinical Inclusion and Exclusion Criteria

To be eligible for the Simplify® Cervical Artificial Disc IDE study, subjects had to be eligible for a fusion procedure and meet all of the inclusion criteria and none of the exclusion criteria (Table 3):

Table 3: Study Inclusion/Exclusion Criteria

| Study Inclusion Criteria | Study Exclusion Criteria |
| --- | --- |
| ·Be between 18 and 60 years of age; ·Have symptoms of cervical degenerative disc disease (DDD) at one cervical level from C3 to C7 defined as 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 radiographic evidence of at least one of the following; ·Spondylosis (defined by the presence of osteophytes or dark disc) on CT or MRI or; ·Disc height decreased by ≥ 1 mm when compared to adjacent levels on radiographic film, CT, or MRI or ·Disc herniation on CT or MRI; ·Have at least one of the following radiculopathy or myelopathy symptoms in neck and/or arm; ·Pain or paresthesias in a specific nerve root distribution from C3 to C7, ·Decreased muscle strength of at least one level on the 0-5 scale, or ·Abnormal sensation, including hyperesthesia or hypoesthesia. ·Have at least one of the following: | ·Marked cervical instability on resting lateral or flexion/ extension X-ray (translation > 3 mm or > 11 degrees rotation to that of either adjacent non-treatment level); ·Non discogenic neck pain or non-discogenic source of symptoms (e.g., tumor, rotator cuff injury, etc.); ·Radiographic confirmation of severe facet disease or facet degeneration; ·Bridging osteophytes; ·Less than 2 degrees of motion at index level; ·Prior surgery at the level to be treated, except laminotomy without accompanying facetectomy; ·Prior fusion or artificial disc replacement at any cervical level; ·More than one neck surgery via anterior approach; ·Previous trauma to the C3-C7 levels resulting in compression or bursting; ·Documented presence of a free nuclear fragment at cervical levels other than the study level; ·Axial neck pain only (no radicular or myelopathy symptoms); |

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| Study Inclusion Criteria | Study Exclusion Criteria |
| --- | --- |
| • At least six weeks of prior conservative treatment (e.g., physical therapy and/or use of anti-inflammatory medications and muscle relaxants at the manufacturer's recommended therapeutic dose);
• The presence of progressive symptoms (e.g., increasing numbness or tingling) or
• Signs of nerve root compression.
• Have a Neck Disability Index (NDI) greater than or equal to 40 on a scale of 100 (moderate disability);
• Be appropriate for treatment using an anterior surgical approach;
• Be likely to return for all follow-up visits¹ and
• Be willing and able to provide Informed Consent for study participation.

Muscle strength will be graded for the deltoid (C5), biceps (C6), and triceps (C7) according to a 6-point scale where 0 = no movement, 1 = trace of muscle contraction; 2 = active movement without gravity; 3 = active movement against gravity; 4 = active movement against gravity/resistance; and 5 = normal response.²

For the purpose of this study, conservative therapy may include, but is not limited to, injections of steroids, physical therapy, bracing, traction, acupuncture, yoga, life style changes, neck support or massage chairs, exercise, ice, heat, massage, water therapy, chiropractic, and medications prescribed for pain, muscle tightness, muscle cramping or inflammation of muscles or nerves or other symptoms typically involved with chronic neck conditions such as DDD. | • Symptomatic DDD at more than one cervical level;
• Severe myelopathy (less than 3/5 muscle strength);
• Any paralysis;
• Recent history (within previous six months) of chemical or alcohol dependence;
• Active systemic infection;
• Infection at the site of surgery;
• Prior disc space infection or osteomyelitis in the cervical spine;
• Any terminal, systemic or autoimmune disease;
• Metabolic bone disease (e.g., osteoporosis/osteopenia³, gout, osteomalacia, Paget’s disease);
• Any disease, condition or surgery which might impair healing, such as;
• Diabetes mellitus requiring daily insulin management,
• Active malignancy,
• History of metastatic malignancy.
• Current or extended use (> 6 months) of any drug known to interfere with bone or soft tissue healing;
• Known PEEK, ceramic, titanium allergy;
• Arachnoiditis;
• Significant cervical anatomical deformity at the index level or clinically compromised cervical vertebral bodies at the index level due to current or past trauma (e.g., by radiographic appearance of fracture callus, malunion, or nonunion) or disease (e.g., ankylosing spondylitis, rheumatoid arthritis);
• 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; |

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| Study Inclusion Criteria | Study Exclusion Criteria |
| --- | --- |
| | • Pregnancy at time of enrollment, or planning to become pregnant, since this would contraindicate surgery^{4};
• Use of spinal stimulator at any cervical level prior to surgery;
• Currently a prisoner;
• Currently involved in spinal litigation which may influence the subjects reporting of symptoms or
• Participation in any other investigational drug, biologic or medical device study within the last 30 days prior to study surgery. |

## 2. Control

Control subjects received ACDF. The historical control was collected from the control arm of a previously completed multi-center, prospective, randomized non-inferiority clinical trial.

Comparison of the data collected from the Simplify® Cervical Artificial Disc Pivotal IDE study and historical ACDF control demonstrated that the cohorts were comparable, though not identical.

- A detailed comparison of the indications and inclusion/exclusion criteria of the historical ACDF cohort and the Simplify® Cervical Artificial Disc IDE study protocol was conducted to determine if the historical data were adequate to serve as comparator and support a PMA application. The sponsor reviewed the protocol and case report forms as submitted to the FDA. Based on this review and discussion with FDA, it was determined that the historical study was similar to the IDE study in its Indications for Use and Inclusion/Exclusion criteria.
- The historical study collected the parameters used to calculate overall success, success of the individual components of the composite primary endpoint, secondary endpoints, and safety assessments per the defined assessments in the Simplify® Cervical Artificial Disc IDE study protocol.

A PS method was used to address selection bias in the observational study design when pooling data from the historical control and actively enrolled Simplify® Cervical Artificial Disc group. The objective of the observational design was to select from the candidate pool of historical controls those subjects whose baseline covariate distribution was approximately the same as Simplify® Cervical Artificial Disc subjects within PS subclasses. The final Primary Analysis set included all 150 Simplify® Cervical Artificial Disc subjects (166 including training subjects) and 117 of 133 historical control subjects. Rigorous statistical criteria and graphical analyses demonstrated that within PS subclasses, Simplify® Cervical Artificial Disc subjects and PS-selected historical controls had approximately the same multivariate baseline covariate distribution.

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# 3. Follow-up Schedule

All subjects were evaluated preoperatively, postoperatively (up to 2-weeks post-treatment) and postoperatively at 6 weeks ( $\pm$ 2 weeks), 3 months ( $\pm$ 2 weeks), 6 months ( $\pm$ 1 month), 1 year ( $\pm$ 2 months), 2 years ( $\pm$ 2 months), and annually thereafter ( $\pm$ 2 months). The following parameters (Table 4) were measured throughout the study:

Table 4: Simplify® Cervical Artificial Disc IDE Study Assessment Schedule

| Evaluation | Pre-op | Treatment | Post-op | 6 Weeks | 3 Months | 6 Months | 12 Months | 24 Months |
| --- | --- | --- | --- | --- | --- | --- | --- | --- |
| Informed Consent | X | | | | | | | |
| Medical History & Physical Examination | X | | | | | | | |
| DXA (as described in protocol) | X | | | | | | | |
| AP & Lateral X-rays | X | | X | X | X | X | X | X |
| Flexion & Extension X-rays | X | | | | X | X | X | X |
| Lateral bending X-rays | X | | | | | X | X | X |
| MRI (Simplify® Cervical Artificial Disc Subjects only) | X | | | | | | | X |
| Radiographic Core Lab Assessments | X | | X | X | X | X | X | X |
| Dysphagia Handicap Index (Simplify® Cervical Artificial Disc Subjects only) | X | | | X | X | X | X | X |
| Neck Disability Index (NDI) | X | | | X | X | X | X | X |
| SF-12v2 Health Survey (Simplify® Cervical Artificial Disc Subjects only) | X | | | | | X | X | X |
| Visual Analog Scale (VAS) | X | | X | X | X | X | X | X |
| Odom's Criteria | | | X | X | X | X | X | X |
| Neurologic Exam | X | | X | X | X | X | X | X |
| Medications Taken | X | | X | X | X | X | X | X |
| Work Status | X | | | | X | X | X | X |
| Treatment Assessments | | X | | | | | | |
| Treatment Satisfaction Assessment | | | | | | | X | X |
| Adverse Event Assessment | N/A | As Needed | | | | | | |

# 4. Clinical Endpoints

The effectiveness of the Simplify® Cervical Artificial Disc was assessed using a composite endpoint, as described below. Effectiveness was further evaluated by assessing improvement in the Neck Disability Index (NDI), neck and arm pain based on a Visual Analog Scale (VAS), and health-related quality of life using the short-form questionnaire (SF-12v2), work status, as well as patient satisfaction of the Simplify® Cervical Artificial Disc group compared to the historical ACDF control group. Similar criteria were used to measure success in both groups.

The safety of the Simplify® Cervical Artificial Disc was assessed by comparison to the historical ACDF control group with respect to the nature and frequency of AEs (overall and in terms of

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seriousness and relationship to the implant), secondary index level surgical procedures and maintenance or improvement in neurological status.

## Primary Endpoints

The study hypothesis for the Simplify® Cervical Artificial Disc IDE study was that the Month 24 (i.e., 24 months post-operatively) composite clinical success (CCS) rate of the Simplify® Cervical Artificial Disc would be no worse than conventional ACDF when success of ACDF is evaluated at Month 24 in patients with 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 at one level from C3 to C7 that are unresponsive to conservative management or have presence of progressive symptoms.

- Individual success for the investigational Simplify® Cervical Artificial Disc is defined as at least a 15 point (out of 100) improvement in NDI percentage at Month 24 compared with baseline; maintenance or improvement in neurologic status at Month 24 compared with baseline; no device failures or revision, reoperation, removal and/or supplemental fixation within 24 months of index procedure; and, the absence of major AEs within 24 months as defined below.
- Individual success for the historical control ACDF device is defined as at least a 15 point (out of 100) improvement in NDI percentage at Month 24 compared with baseline; maintenance or improvement in neurologic status at Month 24 compared with baseline; no device failures or revision, reoperation, removal and/or supplemental fixation within 24 months; and the absence of major AEs within 24 months as defined below.

Device failure is defined as breakage, migration, or mechanical failure of the components. For purpose of determining individual patient success, a major AE is defined as any of the following which are definitely-related to the device system or to a device component as determined by the Clinical Events Committee (CEC):

- Permanent neurologic damage or permanent nerve root injury related to a level at or below the level treated;
- Implant or component breakage or migration that does not require revision, reoperation or removal, but causes persistent or moderate to severe dysphagia and/or
- Patient death.

Per the FDA Guidance for the Preparation of IDEs for Spinal Systems, the following definitions apply:

- Reoperation – Any surgical procedure at the index level that does not involve modification, addition or removal of any components of the device in the postoperative or follow-up period.
- Revision – Any procedure in the postoperative or follow-up period that adjusts, modifies, or removes part of the original implant configuration with or without replacement of a

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component – may include adjusting the position of the original configuration in the postoperative or follow-up period.

- Removal – A procedure where the entire device is removed with or without replacement of the device in the postoperative or follow-up period.
- Supplemental fixation – A procedure in which additional instrumentation not under study is implanted (e.g., supplemental placement of a rod/ screw system).

## Secondary Endpoints

Secondary objectives, measured in both groups (except as noted), included:

- Clinically significant improvement in one or more radicular symptoms or myelopathy at Month 24 compared to baseline for the investigational Simplify® Cervical Artificial Disc and the historical ACDF control subjects. The data collected reflect the number of subjects who improved (numbers are stratified to reflect clinical improvement), who remain unchanged, and who deteriorated at each study timepoint. These endpoints are graded and defined as follows:

- VAS for the following pain locations:
- Neck and arm pain (to allow comparison to historical ACDF control);
- Neck, Arm (Right/Left) pain (Simplify® Cervical Artificial Disc group only);

Changes of at least 20 mm on a 100 mm scale is regarded as clinically significant.

- Motor status - A change of one or more grade levels in muscle strength is regarded as clinically significant.
- Sensory status - Sensation is graded as normal or abnormal (diminished or absent). Any changes from abnormal to normal or absent to diminished is regarded as clinically significant improvement.

- Time to recovery (earliest time at which a minimum 15-point (out of 100) NDI improvement is reached).
- Disc height at Month 24 compared to baseline.
- Adjacent level deterioration at Month 24 compared to baseline.
- Displacement or migration of the device defined as a change of 3 mm or greater compared to the position at implantation.
- Treatment satisfaction at Month 24.
- Health-related Quality of Life Survey (SF-12v2) at Month 24 compared to baseline (Simplify® Cervical Artificial Disc group only).
- Dysphagia Handicap Index (DHI scale) at Month 24 compared to baseline (Simplify® Cervical Artificial Disc group only).
- Facet deterioration at Month 24 compared to baseline (Simplify® Cervical Artificial Disc group only).
- Results at Month 24 as categorized by the physician according to Odom’s Criteria.

## 5. Clinical Events Committees

A CEC was utilized for the Simplify® Cervical Artificial Disc IDE study, including the historical ACDF control population, to mitigate reporting bias of safety-related events. The CEC was comprised of three (3) independent spine surgeons, and a CEC charter was used to define the role of the CEC. The committee was responsible for adjudication of AE (i.e., AE code, relationship to device/procedure, seriousness, severity, determination of major AE and unanticipated adverse

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device effects), secondary surgical intervention (SSI) (i.e., classification of revision, removal, reoperation or supplemental fixation), protocol deviations (i.e., classification as Major or Minor), and neurological success criterion (classification of neurologic status at Month 24 as compared to baseline).

## B. Accountability of PMA Cohort

One-hundred sixty-six (166) subjects were enrolled in the Simplify® Cervical Artificial Disc population. Of these, 16 Simplify® Cervical Artificial Disc subjects were training subjects. The historical ACDF control population included 133 subjects.

The 283 available subjects (150 Simplify® Cervical Artificial Disc (excluding training subjects) and 133 historical ACDF control) were assessed via the PS subclassification sequential model-building process. After applying an established heuristic for 3 iterations, a total of 150 Simplify® Cervical Artificial Disc and 117 historical ACDF control subjects were retained in the final PS designed sample. Inclusion into a PS subclass is the observational study analogue to randomized treatment allocation. When accounting for the PS design, there was excellent balance across all considered baseline covariates. For subjects at Month 24, the visit compliance rates were 97% for Simplify® Cervical Artificial Disc subjects and 86% for the PS Selected ACDF subjects.

The subject accountability for Month 12 and Month 24 clinical evaluations is presented in Table 5 and Figure 4.

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Table 5: Subject Accounting Summary (Primary Analysis Population)

| | Month 12 | | Month 24 | |
| --- | --- | --- | --- | --- |
| | I | C | I | C |
| Accounting | | | | |
| (1) Theoretical follow-up | 150 | 117 | 150 | 117 |
| (2) Cumulative Death | 0 | 0 | 0 | 0 |
| (3a) Intra-Op Deviations | 2 | 0 | 2 | 0 |
| (3b) Cumulative SSI Failures | 1 | 2 | 4 | 5 |
| (4) Not Yet Overdue | 0 | 0 | 0 | 0 |
| (5) Deaths+SSI failures+Intra-Op Deviations among theoretically due | 3 | 2 | 6 | 5 |
| (6) Expected Due [(6)=(1)-(4)-(5)] | 147 | 115 | 144 | 112 |
| (7) SSI failures+Intra-Op Deviations among theoretically due | 3 | 2 | 6 | 5 |
| (8) Expected due+SSI failures+Intra-Op Deviations among theoretically Due [(8)=(6)+(7)] | 150 | 117 | 150 | 117 |
| All Evaluated Accounting (Actual b) Among Expected Due Procedures | | | | |
| (9) Procedures with any clinical data in interval† | 144 | 101 | 139 | 96 |
| (10) Visit Compliance (%) | 98% | 88% | 97% | 86% |
| (11) Change in NDI | 143 | 100 | 138 | 96 |
| (12) Change in VAS | 142 | 100 | 139 | 95 |
| (13) Neuro evaluations | 143 | 100 | 139 | 95 |
| (14) Composite Clinical Success (CCS) | | 136 | 91 | |
| (15) Actualb % Follow-up for CCS | | | 94% | 81% |
| Within Window Accounting (Actual A) Among Expected Due Procedures | | | | |
| (16) Procedures with any clinical data in interval† | 141 | 89 | 128 | 79 |
| (17) Visit Compliance (%) | 96% | 77% | 89% | 71% |
| (18) Change in NDI | 140 | 88 | 127 | 79 |
| (19) Change in VAS | 139 | 88 | 128 | 79 |
| (20) Neuro evaluations | 140 | 88 | 128 | 78 |
| (21) Composite Clinical Success (CCS) | | 125 | 74 | |
| (22) ActualA % Follow-up for CCS | | | 87% | 66% |
| †Change in NDI, change in VAS, or Neuro overall status;Source: Table Follow-up Compliance.sas; Analyzed: 27AUG2020 | | | | |

Actual: Patients with complete data for each endpoint, within window.
Actual: Patients with any follow-up data reviewed or evaluated by investigator ("all evaluated" accounting).

(1) Theoretical follow-up: The theoretical follow-up is the number of devices at one level that would have been examined if all subjects returned on the exact anniversary of their respective initial surgery dates. The date of database closure for these analyses was March $27^{\text{th}}$ , 2020. All subjects were theoretically due for Month 12 and Month 24 follow-up at the date of database closure.
(2) Cumulative deaths: Cumulative deaths up to the date of the exact anniversary defining the current interval. Deaths occurring after the exact anniversary are recorded in the next interval.
(3a) Intra-Op Deviations: Subjects who were to be treated with Simplify® Cervical Artificial Disc but converted to alternate treatment intra-operatively. Intra-operative deviation subjects are considered a treatment failure in the CCS primary endpoint calculation and censored at day 0 for SSI and device survivorship. At the time of surgery, due to anatomical challenges, the surgeons could not implant the TDR for 2 subjects enrolled to be treated with Simplify® Cervical Artificial Disc and performed an ACDF surgery. Since these 2 subjects do not meet the definition of an SSI, they are accounted for separately. They will be considered a treatment failure in the CCS primary endpoint calculation and censored at day 0 for SSIs and device survivorship.

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(3b) Cumulative SSI Failures: Failures are defined as any result that removes the subject from further evaluation of effectiveness, that is, these Failures are "terminal failures". As per FDA Guidance (2004), failure includes SSIs categorized as reoperations, revisions, removals, reoperations or supplemental fixation. It also includes other severe AEs or other parameters that would define the device as ineffective or unsafe from that point on. Failures are counted up to the date of the exact anniversary defining the current interval. Terminal failures occurring after the exact anniversary are recorded in the next interval. Terminal failures on this row do not include radiographic failure since radiographic failure does not remove a subject from the study. It also does not include clinical failures determined on the basis of clinical scores such NDI, VAS, or deteriorating neurological status because these types of failure do not remove the subject from further follow-up. Although the cumulative number of failures is recorded on this row, only failures among devices that are theoretically due for that interval are subtracted from theoretically due to determine the number expected due for clinical indices.

(4) Not Yet Overdue: Includes subjects whose surgical anniversary has occurred; however, clinical data has not yet been collected (i.e., NDI or VAS/NRS is currently unavailable) but the subject is still in the protocol specified follow-up window. Such subjects may yet be observed and so follow-up compliance estimates account for this by removing such subjects from the denominator as well as from the numerator when determining compliance ratios.

(5) Deaths+SSI Failures+Intra-Op Deviations among theoretically due: This row records the sum of deaths, SSI Failures, and Intra-Op Deviations among those theoretically due for follow-up according to the exact anniversary of the scheduled follow-up visit. Only deaths, SSI Failures, and Intra-Op Deviations among procedures that are theoretically due for that interval are subtracted from theoretically due to determine the number expected due for clinical index evaluation.

(6) Expected due for clinic visit: This row is the number of subjects expected for a given time interval. These include the theoretical number of subjects who were due to be evaluated, less the number of subjects who died or who were considered failures by that time interval and less the subjects in the "Not yet overdue" category. Expected = Theoretical - [Deaths + Failures + Not yet overdue] where the counts of the numbers of Deaths, Failures, and Not yet overdue are determined from among the theoretically due subjects. This row serves as denominator for evaluation % follow-up for clinical indices (e.g., NDI, VAS/NRS). The Expected row includes subjects lost to follow-up, and major protocol violations are included in the expected group for all time points.

(7) SSI Failures + Intra-Op Deviations among theoretical due: SSI failures and intra-op deviations among theoretically due is the count of theoretically due Failures that need to be "added back" to the number of expected due to serve as the correct denominator for CCS counts when determining CCS follow-up compliance.

(8) Expected due + SSI Failures + Intra-Op Deviations among theoretical due: Expected due plus theoretical due Failures is computed by adding expected due in row (6) to the number of cumulative Failures among theoretically due devices in row (7). This row serves as the denominator for composite clinical success (CCS) outcomes since CCS status is known for subjects with a Failure as defined in row (3).

(9) and (16) Procedures with any clinical data in interval: These rows indicate the number of subjects with any clinical data that report a change in NDI, VAS, or neurological status for all evaluated subjects among expected due subjects (9) and for all subjects that are within window among expected due subjects (16).

(10) and (17) Visit Compliance (%): These rows indicate the percentage of subjects compliant with the specified visit scheduled for all evaluated subjects among expected due subjects (10) and for all subjects that are within window among expected due subjects (17).

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(11) and (18) Change in NDI: These rows indicate the number of subjects reporting a change in NDI for all evaluated subjects among expected due procedures (11) and for all subjects that are within window among expected due procedures (18).
(12) and (19) Change in VAS: These rows indicate the number of subjects reporting a change in VAS for all evaluated subjects among expected due procedures (12) and for all subjects that are within window among expected due procedures (19).
(13) and (20) Neuro evaluations: These rows indicate the number of subjects reporting a change in neurological status for all evaluated subjects among expected due procedures (13) and for all subjects that are within window among expected due procedures (20).
(14) and (21) Composite Clinical Success: These rows indicate the number of subjects with enough data available for evaluation of clinical composite success for all evaluated subjects among expected due procedures (14) and for all subjects that are within window among expected due procedures (21).
(15) and (22) Actual Follow-up for CCS: These rows indicate the percentage of subjects with follow-up data available used to evaluate CCS for all evaluated subjects among expected due procedures (15) and for all subjects that are within window among expected due procedures (22).

Figure 4. Subject Accountability Tree

# C. Study Population Demographics and Baseline Parameters

After adjusting for PS subclass, the demographic data appear to demonstrate that the treatment groups were well-balanced and no statistically significant differences were noted in the demographic characteristics and categorical values (Table 6 and Table 7). The mean baseline preoperative assessments for NDI, VAS Neck and Arm, and baseline radiographic parameters were also similar between treatment groups. Baseline VAS Neck and Arm were significantly higher in

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the Simplify® Cervical Artificial Disc group; however, when adjusting for PS subclass, there was no significant difference between groups, indicating similar neck pain and function.

Table 6: Summary of Demographic and Baseline Continuous Variables (Clinical) (Primary Analysis Population)

| | Simplify Disc | | | | | | ACDF | | | | | | Group Difference* | | | |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| | N | Mean | SD | Med | Min | Max | N | Mean | SD | Med | Min | Max | p | Δ | LB | UB |
| All | | | | | | | | | | | | | | | | |
| Age (years) | 150 | 43.0 | 8.9 | 43.2 | 18.1 | 60.9 | 117 | 44.1 | 7.0 | 43.9 | 23.6 | 59.3 | 0.765 | -0.3 | -2.5 | 1.8 |
| BMI (kg/m2) | 150 | 27.5 | 5.2 | 26.6 | 18.2 | 40.3 | 117 | 28.7 | 5.6 | 27.3 | 19.5 | 48.4 | 0.914 | 0.1 | -1.3 | 1.5 |
| Height (inches) | 150 | 67.7 | 4.0 | 67.0 | 59.0 | 76.0 | 117 | 67.3 | 4.1 | 67.0 | 57.0 | 79.0 | 0.927 | -0.1 | -1.1 | 1.0 |
| Weight (pounds) | 150 | 180.3 | 42.9 | 178.5 | 103.0 | 308.0 | 117 | 185.3 | 41.4 | 180.0 | 103.0 | 298.0 | 0.855 | 1.1 | -10.4 | 12.5 |
| Female | | | | | | | | | | | | | | | | |
| Age (years) | 91 | 43.0 | 8.7 | 43.1 | 18.1 | 60.4 | 68 | 44.7 | 6.8 | 45.6 | 30.5 | 58.8 | 0.678 | -0.6 | -3.3 | 2.1 |
| BMI (kg/m2) | 91 | 26.7 | 5.5 | 25.5 | 18.2 | 40.3 | 68 | 28.9 | 6.5 | 27.1 | 19.5 | 48.4 | 0.404 | -0.8 | -2.8 | 1.1 |
| Height (inches) | 91 | 65.3 | 2.5 | 65.0 | 59.0 | 72.0 | 68 | 65.0 | 3.0 | 66.0 | 57.0 | 72.0 | 0.416 | -0.4 | -1.3 | 0.5 |
| Weight (pounds) | 91 | 162.2 | 36.2 | 160.0 | 103.0 | 265.0 | 68 | 173.7 | 40.9 | 167.0 | 103.0 | 292.0 | 0.343 | -6.3 | -19.4 | 6.8 |
| Male | | | | | | | | | | | | | | | | |
| Age (years) | 59 | 42.8 | 9.2 | 43.9 | 22.1 | 60.9 | 49 | 43.2 | 7.2 | 43.7 | 23.6 | 59.3 | 0.797 | -0.5 | -4.1 | 3.2 |
| BMI (kg/m2) | 59 | 28.7 | 4.5 | 27.4 | 21.5 | 39.5 | 49 | 28.4 | 4.0 | 27.5 | 20.5 | 38.3 | 0.177 | 1.3 | -0.6 | 3.2 |
| Height (inches) | 59 | 71.4 | 2.9 | 72.0 | 64.0 | 76.0 | 49 | 70.4 | 3.1 | 70.0 | 66.0 | 79.0 | 0.440 | 0.5 | -0.8 | 1.9 |
| Weight (pounds) | 59 | 208.2 | 37.4 | 195.0 | 150.0 | 308.0 | 49 | 201.4 | 36.7 | 200.0 | 127.0 | 298.0 | 0.171 | 11.7 | -5.1 | 28.4 |
| Clinical Scores | | | | | | | | | | | | | | | | |
| Neck Disability Index | 150 | 63.3 | 12.5 | 61.0 | 40.0 | 94.0 | 117 | 62.4 | 12.6 | 64.0 | 40.0 | 90.0 | 0.950 | 0.1 | -3.3 | 3.5 |
| VAS Neck and Arm | 150 | 81.6 | 12.4 | 84.0 | 41.0 | 100.0 | 117 | 77.6 | 13.5 | 79.0 | 42.0 | 100.0 | 0.717 | 0.6 | -2.7 | 4.0 |
| VAS Neck | 150 | 77.1 | 18.2 | 81.0 | 0.0 | 100.0 | | | | | | | | | | |
| VAS Left Arm | 150 | 54.3 | 36.3 | 67.5 | 0.0 | 100.0 | | | | | | | | | | |
| VAS Right Arm | 150 | 48.8 | 39.4 | 60.0 | 0.0 | 100.0 | | | | | | | | | | |
| DHI Score | 150 | 6.2 | 8.8 | 3.0 | 0.0 | 50.0 | | | | | | | | | | |
| SF12 PCS | 150 | 31.1 | 7.4 | 30.3 | 11.2 | 56.1 | | | | | | | | | | |
| SF12 MCS | 150 | 42.4 | 12.2 | 42.3 | 15.6 | 67.5 | | | | | | | | | | |
| Radiography | | | | | | | | | | | | | | | | |
| Disc Angle | 148 | 2.1 | 4.5 | 2.4 | -8.2 | 14.0 | 116 | 2.6 | 4.4 | 2.4 | -8.4 | 14.0 | 0.249 | -0.7 | -1.9 | 0.5 |
| Average Disc Height | 148 | 3.3 | 0.7 | 3.3 | 1.1 | 5.7 | 115 | 3.3 | 0.8 | 3.2 | 1.4 | 5.2 | 0.813 | 0.0 | -0.2 | 0.2 |
| Anterior Disc Height | 148 | 3.6 | 1.0 | 3.5 | 1.6 | 6.5 | 115 | 3.6 | 1.1 | 3.5 | 1.4 | 6.9 | 0.419 | -0.1 | -0.4 | 0.2 |
| Posterior Disc Height | 148 | 3.0 | 0.9 | 3.1 | 0.6 | 5.4 | 115 | 2.9 | 0.9 | 2.8 | 0.9 | 5.2 | 0.537 | 0.1 | -0.2 | 0.3 |
| Rotation | 143 | 7.3 | 4.2 | 6.4 | 0.0 | 21.4 | 110 | 7.3 | 4.4 | 6.8 | -0.8 | 19.0 | 0.588 | -0.3 | -1.5 | 0.9 |
| Translation (mm) | 143 | 0.7 | 0.5 | 0.6 | 0.0 | 2.4 | 109 | 0.8 | 0.6 | 0.7 | -0.1 | 2.7 | 0.061 | -0.1 | -0.3 | 0.0 |
| Translation (%) | 143 | 4.6 | 3.1 | 3.9 | 0.0 | 13.9 | 110 | 5.2 | 3.9 | 4.6 | -0.7 | 16.0 | 0.090 | -0.8 | -1.8 | 0.1 |
| AP Rotation | 144 | 6.1 | 2.8 | 5.6 | 0.3 | 15.4 | 106 | 5.2 | 3.1 | 4.7 | 0.0 | 12.9 | 0.211 | 0.5 | -0.3 | 1.4 |
| Spondylolisthesis (mm) | 148 | 0.9 | 1.0 | 0.9 | -1.8 | 3.9 | 115 | 1.2 | 0.9 | 1.0 | -0.5 | 3.8 | 0.078 | -0.2 | -0.5 | 0.0 |
| Spondylolisthesis (%) | 148 | 6.0 | 6.1 | 5.7 | -10.5 | 24.9 | 116 | 7.4 | 5.8 | 6.1 | -4.1 | 25.7 | 0.091 | -1.4 | -3.1 | 0.2 |
| *Device group mean differences and 95% CI adjusting for propensity score (PS) subclass using two-way analysis of variance. Source: Tables Baseline Demo.sas; Analyzed: 14MAY2020 | | | | | | | | | | | | | | | | |

Table 7: Summary of Baseline Categorical Variables - (Primary Analysis Population)

| | Simplify® Cervical Artificial Disc | | | ACDF | | | Group Difference* | | | |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| | N | n | %** | N | n | %** | p | Δ | LB | UB |
| Conservative Therapy with Injection | 150 | 70 | 46.7% | 117 | 52 | 44.4% | 0.953 | 0.4% | -12.6% | 13.4% |
| Conservative Therapy with Narcotics | 150 | 66 | 44.0% | 117 | 67 | 57.3% | 0.994 | 0.1% | -13.5% | 13.6% |
| Neurological Motor Deficit | 150 | 53 | 35.3% | 117 | 62 | 53.0% | 0.772 | 0.2% | -15.7% | 11.5% |
| Neurological Sensory Deficit | 150 | 66 | 44.0% | 117 | 66 | 49.6% | 0.855 | -0.1% | -14.2% | 11.7% |
| Work Status = Employed | 150 | 120 | 80.0% | 117 | 82 | 70.1% | 0.617 | 2.9% | -8.1% | 13.9% |
| *Device group differences and 95% CI adjusting for propensity score (PS) subclass using two-way generalized linear model. **Unadjusted proportions calculated as x/n. Source: Table Clinical Follow-up.sas; Analyzed: 19JUN2020 | | | | | | | | | | |

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Table 8 summarizes the available race and ethnicity data. Please note, complete race and ethnicity data were not collected.

Table 8: Summary of Demographic and Baseline Variables – Race and Ethnicity (Primary Analysis Population)

| | Simplify Disc | | | ACDF | | | |
| --- | --- | --- | --- | --- | --- | --- | --- |
| | N | n | % | N | n | % | p* |
| Race and Ethnicity | 150 | | | 117 | | | 0.822 |
| Caucasian | | 131 | 87.3% | | 103 | 88.0% | |
| Black | | 10 | 6.7% | | 7 | 6.0% | |
| Hispanic | | 4 | 2.7% | | 6 | 5.1% | |
| Other | | 5 | 3.3% | | 1 | 0.9% | |
| *p-value adjusted for PS subclass using two-way analysis of variance with race dichotomized as Caucasian vs. Non-Caucasian. Source: Tables Baseline Demo.sas; Analyzed: 27FEB2020 | | | | | | | |

The radiographic findings used to qualify a subject for enrollment are provided with post-hoc nominal measures of significance are presented in Table 9.

Table 9: Summary of Baseline Variables – Radiographic Data (Primary Analysis Population)

| | Simplify Disc | | | ACDF | | | Group Difference* | | | |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| | N | n | % | N | n | % | p** | Δ | LB | UB |
| Spondylosis (defined by the presence of osteophytes or dark disc on CT/MRI† | 150 | 72 | 48.0% | 117 | 66 | 56.4% | 0.490 | -5.7% | -18.6% | 7.2% |
| Decrease disc height ≥1mm compared to adjacent levels on x-rays, CT, or MRI | 150 | 59 | 39.3% | 117 | 53 | 45.3% | 0.490 | -4.7% | -17.4% | 8.0% |
| Disc herniation on CT or MRI | 150 | 139 | 92.7% | 117 | 98 | 83.8% | 0.117 | 8.0% | -0.6% | 16.6% |
| *Post-hoc nominal Device group differences and 95% CI adjusting for propensity score (PS) subclass using two-way generalized linear model. **PS adjusted Hochberg p-values corrected for multiplicity (3 tests). †Historical control criterion wording reads ‘degenerated / dark disc on MRI’. Source: IR3 - Question 7c.sas; Analyzed: 10JUN2020 | | | | | | | | | | |

Table 10: Summary of Operative Continuous Variables (Primary Analysis Population)

| | Simplify Disc | | | | | | ACDF | | | | | | Group Difference* | | |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| | N | Mean | SD | Med | Min | Max | N | Mean | SD | Med | Min | Max | p | Δ | LB |
| Operative Time (minutes) | 150 | 73.6 | 21.8 | 70.0 | 32.0 | 170.0 | 117 | 74.0 | 27.1 | 69.0 | 29.0 | 157.0 | 0.987 | -0.05 | -6.66 |
| Blood Loss (cc) | 150 | 31.2 | 38.6 | 20.0 | 0.0 | 250.0 | 117 | 42.4 | 33.9 | 30.0 | 0.0 | 200.0 | 0.013 | -12.62 | -22.55 |
| Length of Stay (days) | 150 | 0.6 | 1.9 | 0.0 | 0.0 | 23.0 | 117 | 1.1 | 0.5 | 1.0 | 0.0 | 3.0 | 0.134 | -0.31 | -0.71 |
| *Device group mean differences and 95% CI adjusting for propensity score (PS) subclass using two-way analysis of variance. Source: Tables Intra-op.sas; Analyzed: 09JAN2020 | | | | | | | | | | | | | | | |

As evidenced by Table 10, a statistically significant difference was observed in blood loss, favoring the Simplify® Cervical Artificial Disc subjects. The mean blood loss for the Simplify® Cervical Artificial Disc subjects was 31.2cc while the mean blood loss for the historical ACDF control subjects was 42.4cc. The operative time and length of stay were not significantly different.

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Table 11: Summary of Operative Categorical Variables (Primary Analysis Population)

| | Simplify Disc (N=150) | | ACDF (N=117) | |
| --- | --- | --- | --- | --- |
| | n | % | n | % |
| C3/C4 | 3 | 2% | 3 | 3% |
| C4/C5 | 7 | 5% | 6 | 5% |
| C5/C6 | 80 | 53% | 71 | 61% |
| C6/C7 | 60 | 40% | 37 | 32% |
| Posterior Ligament Cut | | | | |
| No | 6 | 4% | 17 | 15% |
| Yes | 144 | 96% | 91 | 78% |
| Not available | 0 | 0% | 9 | 8% |
| Device Size | | | | |
| Height 4 | 58 | 39% | | |
| SM-4 | 22 | 15% | | |
| MD-4 | 36 | 24% | | |
| Height 5 | 78 | 53% | | |
| SM-5 | 9 | 6% | | |
| SM-5S | 18 | 12% | | |
| MD-5 | 20 | 14% | | |
| MD-5L | 12 | 8% | | |
| LG-5 | 10 | 7% | | |
| LG-5L | 9 | 6% | | |
| Height 6 | 12 | 8% | | |
| SM-6 | 1 | 1% | | |
| MD-6 | 1 | 1% | | |
| MD-6L | 0 | 0% | | |
| LG-6 | 8 | 5% | | |
| LG-6L | 2 | 1% | | |
| Source: Tables Intra-op.sas; Analyzed: 09JAN2020 | | | | |

As evidenced by Table 11, the majority of procedures occurred in C5/C6 and C6/C7 for both the Simplify® Cervical Artificial Disc subjects and historical ACDF control subjects.

# D. Safety and Effectiveness Results

Please note: The counts and percentages provided for the Simplify® Cervical Artificial Disc and ACDF control groups correspond to the values unadjusted for PS subclass. The device group difference and $95\%$ confidence interval lower bound (LB) and upper bound (UB) are calculated controlling for PS subclass, accounting for why the reported difference does not match the difference between the presented unadjusted percentages.

# 1. Safety Results

Similar rates of any AE and any SAE occurred in the Simplify® Cervical Artificial Disc cohort and the historical ACDF control cohort through Month 24 (safety results shown through postoperative day 790, the end of the Month 24 visit window). Over the same timecourse, a similar

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rate of device- and procedure-related AEs occurred in both groups. While not significantly different, the Simplify® Cervical Artificial Disc subjects experienced a numerically greater number of AEs (245 events in 98 subjects) than the historical ACDF control subjects (192 events in 69 subjects) (Table 12).

Table 12: Comparisons of Summary AE Rates between Simplify® Cervical Artificial Disc and ACDF Groups (Primary Analysis Population through Day 790)

| | Simplify Disc (N=150) | | | ACDF (N=117) | | | Group Difference* | | | |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| | Events | Subjs | % | Events | Subjs | % | p | Δ | LB | UB |
| Adverse Events | | | | | | | | | | |
| All | 245 | 98 | 65.3% | 192 | 69 | 59.0% | 0.234 | 8.0% | -4.5% | 20.5% |
| Device Related† | 77 | 54 | 36.0% | 86 | 46 | 39.3% | 0.364 | -6.1% | -18.6% | 6.4% |
| Device Related - Definitely | 2 | 1 | 0.7% | 1 | 1 | 0.9% | 0.663 | -0.5% | -2.7% | 1.7% |
| Procedure Related† | 108 | 64 | 42.7% | 93 | 49 | 41.9% | 0.823 | -1.5% | -14.2% | 11.2% |
| Procedure Related - Definitely | 24 | 16 | 10.7% | 7 | 6 | 5.1% | 0.298 | 3.4% | -3.1% | 9.9% |
| Serious Adverse Events | | | | | | | | | | |
| All | 26 | 16 | 10.7% | 24 | 16 | 13.7% | 0.686 | 1.5% | -6.5% | 9.5% |
| Device Related† | 5 | 5 | 3.3% | 9 | 5 | 4.3% | 0.825 | 0.5% | -4.0% | 5.0% |
| Major | 0 | 0 | 0.0% | 0 | 0 | 0.0% | | | | |
| Device Related - Definitely | 1 | 1 | 0.7% | 0 | 0 | 0.0% | | | | |
| Procedure Related† | 11 | 5 | 3.3% | 9 | 5 | 4.3% | 0.825 | 0.5% | -4.0% | 5.0% |
| Procedure Related - Definitely | 6 | 1 | 0.7% | 0 | 0 | 0.0% | | | | |
| AE by Severity | | | | | | | | | | |
| Mild | 112 | 58 | 38.7% | 68 | 43 | 36.8% | 0.912 | 0.7% | -11.7% | 13.2% |
| Moderate | 103 | 59 | 39.3% | 99 | 40 | 34.2% | 0.307 | 6.8% | -5.5% | 19.1% |
| Severe | 30 | 21 | 14.0% | 22 | 15 | 12.8% | 0.241 | 4.9% | -3.3% | 13.2% |
| Life Threatening | 0 | 0 | 0.0% | 3 | 2 | 1.7% | | | | |
| SAE by Severity | | | | | | | | | | |
| Mild | 1 | 1 | 0.7% | 0 | 0 | 0.0% | | | | |
| Moderate | 2 | 2 | 1.3% | 7 | 7 | 6.0% | 0.155 | -3.4% | -8.3% | 1.5% |
| Severe | 23 | 15 | 10.0% | 14 | 10 | 8.5% | 0.230 | 4.0% | -3.0% | 10.9% |
| Life Threatening | 0 | 0 | 0.0% | 3 | 2 | 1.7% | | | | |
| Death | | | | | | | | | | |
| All | 0 | 0 | 0.0% | 0 | 0 | 0.0% | | | | |
| *Device group differences and 95% CI adjusting for propensity score (PS) subclass using two-way generalized linear model; Comparisons with less than 6 subjects in each group includes PS as a continuous variable (df=1) for model stability; |Percentage of subjects experiencing specific event; †Definite, probable, possibly, and unknown; ‡Subjects censored at Index level secondary surgical interventions. Source: Tables Safety - AE Summary - Primary.sas; Analyzed: 28APR2020 | | | | | | | | | | |

Counts and percentages of subjects with specific AEs are presented in Table 13 and counts of AEs by timecourse are presented in Table 14. The most commonly occurring events reported to have occurred in the Simplify® Cervical Artificial Disc cohort include radiculopathy (n=35), spasm (n=24), and inflammation conditions, such as discitis, joint and other types of inflammation (n=17). In the historical ACDF control cohort, the most commonly reported AEs include radiculopathy (n=29), pain with narcotic given (n=29), and pain with no narcotic given (n=18). Through Month 24, the nature and incidence of specific AEs were comparable in the two study groups.

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Table 13. Counts and Percentages of Subjects with Specific AEs – (Primary Analysis Population through Day 790)

| | Simplify Disc (N=150) | | | ACDF (N=117) | | | Group Difference* | | | |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| | Events | Subjs | % | Events | Subjs | % | p | Δ | LB | UB |
| All Events | 245 | 98 | 65.3% | 192 | 69 | 59.0% | 0.234 | 8.0% | -4.5% | 20.5% |
| Spasm | 24 | 23 | 15.3% | 6 | 5 | 4.3% | 0.012 | 10.8% | 3.6% | 18.1% |
| Trauma | 11 | 11 | 7.3% | 8 | 7 | 6.0% | 0.271 | 3.2% | -2.6% | 9.0% |
| Other | 15 | 13 | 8.7% | 8 | 6 | 5.1% | 0.381 | 3.0% | -3.3% | 9.2% |
| Infection (All Other Infections - NOT at cervical surgical site) | 13 | 9 | 6.0% | 7 | 5 | 4.3% | 0.377 | 2.6% | -2.8% | 8.0% |
| Dysphagia | 9 | 8 | 5.3% | 3 | 3 | 2.6% | 0.342 | 2.6% | -2.3% | 7.4% |
| Injury To Muscles Or Organs | 4 | 4 | 2.7% | 1 | 1 | 0.9% | 0.164 | 2.3% | -0.7% | 5.4% |
| Psychological Illness | 5 | 5 | 3.3% | 2 | 2 | 1.7% | 0.432 | 1.7% | -2.2% | 5.6% |
| Allergic Reaction | 6 | 5 | 3.3% | 1 | 1 | 0.9% | 0.400 | 1.6% | -1.8% | 5.0% |
| Soft Tissue Damage | 3 | 3 | 2.0% | 1 | 1 | 0.9% | 0.161 | 1.4% | -1.1% | 4.0% |
| Pneumonia | 2 | 2 | 1.3% | 1 | 1 | 0.9% | 0.258 | 0.7% | -1.2% | 2.6% |
| Surgical Wound Dehiscence | 2 | 2 | 1.3% | 1 | 1 | 0.9% | 0.979 | 0.0% | -2.5% | 2.6% |
| Tingling - increased from pre-op or prior visit | 1 | 1 | 0.7% | 2 | 2 | 1.7% | 0.935 | -0.1% | -2.0% | 1.9% |
| Implant/Joint Noise | 1 | 1 | 0.7% | 1 | 1 | 0.9% | 0.848 | -0.2% | -2.5% | 2.0% |
| Cardiac Event | 1 | 1 | 0.7% | 1 | 1 | 0.9% | 0.848 | -0.2% | -2.5% | 2.0% |
| Spinal Stenosis | 1 | 1 | 0.7% | 1 | 1 | 0.9% | 0.663 | -0.5% | -2.7% | 1.7% |
| Facet Joint Deterioration | 1 | 1 | 0.7% | 2 | 2 | 1.7% | 0.635 | -0.6% | -3.4% | 2.1% |
| Inflammation Conditions, Such As Discitis, Joint And Other Types Of Inflammation | 17 | 15 | 10.0% | 14 | 12 | 10.3% | 0.856 | -0.7% | -8.4% | 6.9% |
| Numbness - increased from pre-op or prior visit | 8 | 7 | 4.7% | 8 | 5 | 4.3% | 0.748 | -0.9% | -6.2% | 4.4% |
| Adjacent Segment Degeneration | 11 | 10 | 6.7% | 8 | 8 | 6.8% | 0.791 | -0.9% | -7.4% | 5.5% |
| Weakness - increased from pre-op or prior visit | 2 | 2 | 1.3% | 2 | 2 | 1.7% | 0.429 | -1.1% | -4.2% | 1.9% |
| Radiculopathy | 35 | 29 | 19.3% | 29 | 21 | 17.9% | 0.753 | -1.7% | -11.8% | 8.4% |
| Pseudoarthrosis | 1 | 1 | 0.7% | 4 | 4 | 3.4% | 0.161 | -2.8% | -6.7% | 1.1% |
| Pain (No Narcotic Given) | 15 | 14 | 9.3% | 18 | 15 | 12.8% | 0.305 | -4.4% | -12.5% | 3.8% |
| Compressive Neuropathy | 4 | 4 | 2.7% | 10 | 9 | 7.7% | 0.035 | -6.4% | -12.4% | -0.4% |
| Headache | 8 | 6 | 4.0% | 14 | 12 | 10.3% | 0.008 | -9.1% | -16.1% | -2.1% |
| Pain (Narcotic Given) | 11 | 11 | 7.3% | 29 | 21 | 17.9% | 0.011 | -11.6% | -20.4% | -2.8% |
| Gastrointestinal Complications Including Ileus, Nausea and Vomiting | 8 | 7 | 4.7% | 0 | 0 | 0.0% | | | | |
| Infection Localized To Cervical Surgical Site | 5 | 5 | 3.3% | 0 | 0 | 0.0% | | | | |
| Surgery At A Location Other than the Spine | 8 | 4 | 2.7% | 0 | 0 | 0.0% | | | | |
| Hematoma or Seroma | 2 | 2 | 1.3% | 0 | 0 | 0.0% | | | | |
| Tremors | 2 | 2 | 1.3% | 0 | 0 | 0.0% | | | | |
| Difficulty With Urination | 2 | 2 | 1.3% | 0 | 0 | 0.0% | | | | |
| Otitis Media | 1 | 1 | 0.7% | 0 | 0 | 0.0% | | | | |
| Stroke | 1 | 1 | 0.7% | 0 | 0 | 0.0% | | | | |
| Esophageal Perforation | 1 | 1 | 0.7% | 0 | 0 | 0.0% | | | | |
| Hypertension | 1 | 1 | 0.7% | 0 | 0 | 0.0% | | | | |
| Ischemia | 1 | 1 | 0.7% | 0 | 0 | 0.0% | | | | |
| Deep wound infection localized to cervical surgical site | 1 | 1 | 0.7% | 0 | 0 | 0.0% | | | | |
| Skin disorders | 1 | 1 | 0.7% | 0 | 0 | 0.0% | | | | |
| Airway Obstruction | 0 | 0 | 0.0% | 1 | 1 | 0.9% | | | | |
| Dural Injury | 0 | 0 | 0.0% | 1 | 1 | 0.9% | | | | |
| Dysphonia | 0 | 0 | 0.0% | 1 | 1 | 0.9% | | | | |
| Implant Collapse Or Subsidence | 0 | 0 | 0.0% | 1 | 1 | 0.9% | | | | |
| Pulmonary Embolism | 0 | 0 | 0.0% | 1 | 1 | 0.9% | | | | |
| Thrombosis | 0 | 0 | 0.0% | 1 | 1 | 0.9% | | | | |
| Swelling (Edema) | 0 | 0 | 0.0% | 1 | 1 | 0.9% | | | | |
| Hypotension | 0 | 0 | 0.0% | 1 | 1 | 0.9% | | | | |
| Cancer | 0 | 0 | 0.0% | 2 | 2 | 1.7% | | | | |
| *Device group differences and 95% CI adjusting for propensity score (PS) subclass using two-way generalized linear model;Comparisons with less than 6 subjects in each group includes PS as a continuous variable (df=1) for model stability;Percentage of subjects experiencing specific event; †Definite, probable, possibly, and unknown;‡Subjects censored at Index level secondary surgical interventions.Source: Tables Safety - All AEs - Primary aas; Analyzed: 11JUN2020 | | | | | | | | | | |

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Table 14: Counts of Specific AEs by Time of Occurrence – (Primary Analysis Population through Day 790) (I = Simplify® Cervical Artificial Disc, C = ACDF)

| | Days Post-Op | | | | | | | | | | | | | | | |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| | Missing | | 0-2 | | 2-30 | | 30-90 | | 90-180 | | 180-365 | | 365-730 | | 730-790 | |
| | I | C | I | C | I | C | I | C | I | C | I | C | I | C | I | C |
| All Events | 0 | 0 | 8 | 8 | 35 | 16 | 50 | 30 | 51 | 43 | 51 | 41 | 48 | 44 | 2 | 10 |
| Radiculopathy | 0 | 0 | 0 | 2 | 5 | 1 | 6 | 6 | 6 | 8 | 9 | 3 | 9 | 6 | 0 | 3 |
| Spasm | 0 | 0 | 0 | 0 | 2 | 0 | 3 | 2 | 9 | 3 | 6 | 1 | 4 | 0 | 0 | 24 |
| Inflammation Conditions, Such As Discitis, Joint And Other Types Of Inflammation | 0 | 0 | 0 | 0 | 2 | 0 | 4 | 1 | 3 | 1 | 1 | 5 | 7 | 7 | 0 | 17 |
| Pain (No Narcotic Given) | 0 | 0 | 0 | 0 | 2 | 3 | 3 | 2 | 7 | 5 | 1 | 3 | 2 | 5 | 0 | 15 |
| Other | 0 | 0 | 0 | 1 | 1 | 0 | 4 | 1 | 1 | 1 | 6 | 4 | 2 | 0 | 1 | 15 |
| Infection (All Other Infections - NOT at cervical surgical site) | 0 | 0 | 0 | 0 | 2 | 3 | 3 | 1 | 2 | 1 | 2 | 2 | 4 | 0 | 0 | 13 |
| Pain (Narcotic Given) | 0 | 0 | 0 | 0 | 1 | 1 | 3 | 4 | 3 | 9 | 1 | 7 | 3 | 5 | 0 | 3 |
| Trauma | 0 | 0 | 0 | 0 | 0 | 1 | 3 | 1 | 1 | 0 | 3 | 4 | 4 | 2 | 0 | 11 |
| Adjacent Segment Degeneration | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 2 | 2 | 0 | 3 | 0 | 4 | 4 | 1 | 2 |
| Dysphagia | 0 | 0 | 0 | 0 | 3 | 0 | 3 | 1 | 2 | 2 | 1 | 0 | 0 | 0 | 0 | 9 |
| Numbness - increased from pre-op or prior visit | 0 | 0 | 1 | 0 | 2 | 0 | 3 | 3 | 1 | 2 | 1 | 2 | 0 | 1 | 0 | 8 |
| Surgery At A Location Other than the Spine | 0 | 0 | 1 | 0 | 1 | 0 | 3 | 0 | 0 | 0 | 2 | 0 | 1 | 0 | 0 | 8 |
| Gastrointestinal Complications Including Ileus, Nausea and Vomiting | 0 | 0 | 0 | 0 | 1 | 0 | 2 | 0 | 0 | 0 | 3 | 0 | 2 | 0 | 0 | 8 |
| Headache | 0 | 0 | 0 | 0 | 1 | 0 | 1 | 1 | 4 | 6…