M6-C Artificial Cervical Disc

P170036 · Spinal Kinetics, LLC · MJO · Feb 6, 2019 · Orthopedic

Device Facts

• Record ID: P170036
• Device Name: M6-C Artificial Cervical Disc
• Applicant: Spinal Kinetics, LLC
• Product Code: MJO · Orthopedic
• Decision Date: Feb 6, 2019
• Decision: APPR
• Device Class: Class 3
• Attributes: Therapeutic

Intended Use

The M6-C™ Artificial Cervical Disc is indicated for reconstruction of the disc following single level discectomy in skeletally mature patients with intractable degenerative cervical radiculopathy with or without spinal cord compression at one level from C3 – C7. Degenerative cervical radiculopathy is defined as arm pain and/or a neurological deficit (numbness, weakness, deep tendon reflexes changes) with or without neck pain due to disc herniation and/or osteophyte formation and confirmed by radiographic imaging (CT, MRI, x-rays). The M6-C™ Artificial Cervical Disc is implanted via an anterior approach. Patients should have failed at least 6 weeks of conservative treatment or exhibit progressive neurological symptoms which could lead to permanent impairment prior to implantation of the M6-C™ Artificial Cervical Disc.

Device Story

The M6-C™ Artificial Cervical Disc is an intervertebral disc prosthesis for single-level cervical spine reconstruction. It replaces a degenerated native disc to maintain functional spinal unit motion. The device consists of an UHMWPE fiber matrix (artificial annulus) wound around a PCU core (artificial nucleus), housed between two Ti6Al4V titanium alloy inner endplates. Outer Ti6Al4V endplates with titanium plasma spray (TPS) coating and low-profile fins provide fixation to vertebral bodies. The device allows motion in six degrees of freedom, replicating physiological progressive resistance. It is implanted via an anterior approach by a surgeon. The device is designed to maintain natural biomechanics, potentially reducing adjacent segment degeneration compared to fusion. Clinical output is assessed via patient-reported outcomes (NDI, VAS) and radiographic imaging. Benefits include pain relief, functional improvement, and motion preservation.

Clinical Evidence

Pivotal prospective, non-randomized, concurrently controlled study (IDE #G050254) with pooled historical control data (ACDF). ITT (PS Selected) cohort included 160 M6-C™ and 189 ACDF subjects. Primary endpoint: composite success at 24 months (no serious device/procedure-related AE, no index-level reoperation, neurological maintenance/improvement, NDI improvement ≥15 points). M6-C™ success rate 86.8% vs. 79.3% for ACDF (p-value not provided, but non-inferiority met with lower bound of 90% CI > -10%). M6-C™ showed lower pain medication usage and maintained range of motion compared to ACDF.

Technological Characteristics

Materials: Ti6Al4V titanium alloy, UHMWPE fiber, PCU core, TPS coating. Design: Multi-layer fiber matrix annulus, PCU nucleus, titanium endplates with fins. Motion: 6 degrees of freedom. Connectivity: None. Sterilization: Ethylene oxide (implants), moist heat (instruments). MR Conditional (1.5T/3T).

Indications for Use

Indicated for skeletally mature patients (18-75 years) with intractable degenerative cervical radiculopathy (C3-C7) due to disc herniation or osteophyte formation, failing 6 weeks of conservative treatment. Contraindicated in patients with advanced cervical deformity, symptomatic facet arthrosis, advanced spondylosis (bridging osteophytes, >11° kyphosis), active infection, osteoporosis (T-score ≤ -2.5), or known allergy to titanium, stainless steel, PCU, or UHMWPE.

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: M6-C™ Artificial Cervical Disc
Device Product Code: MJO
Applicant’s Name/Address: Spinal Kinetics LLC
501 Mercury Drive
Sunnyvale, CA 94085
Date of Panel Recommendation: None
Premarket Approval Application: P170036 (PMA Number)
Date of FDA Notice of Approval: February 6, 2019

II. INDICATIONS FOR USE

The M6-C™ Artificial Cervical Disc is indicated for reconstruction of the disc following single level discectomy in skeletally mature patients with intractable degenerative cervical radiculopathy with or without spinal cord compression at one level from C3 – C7. Degenerative cervical radiculopathy is defined as arm pain and/or a neurological deficit (numbness, weakness, deep tendon reflexes changes) with or without neck pain due to disc herniation and/or osteophyte formation and confirmed by radiographic imaging (CT, MRI, x-rays). The M6-C™ Artificial Cervical Disc is implanted via an anterior approach. Patients should have failed at least 6 weeks of conservative treatment or exhibit progressive neurological symptoms which could lead to permanent impairment prior to implantation of the M6-C™ Artificial Cervical Disc.

III. CONTRAINDICATIONS

The M6-C™ Artificial Cervical Disc should not be implanted in patients with the following conditions:

- Advanced cervical anatomical deformity (e.g., ankylosing spondylitis, scoliosis) at the operative or adjacent levels
- Symptomatic facet arthrosis defined as pain in the neck that is worse when in extension and/or rotation and/or stiffness or the inability to move part of the neck attributable to the facets as confirmed by imaging (x-ray, CT, MRI, bone scan)
- Advanced degenerative changes (e.g., spondylosis) at the index vertebral level as evidenced by bridging osteophytes, excessive translation or kyphotic deformity > 11° on neutral x-rays
- Active systemic infection or infection at the operative site

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- Osteoporosis defined as DEXA bone mineral density T-score $\leq -2.5$
- Known allergy to titanium, stainless steel, polyurethane, polyethylene, or ethylene oxide residuals

# IV. WARNINGS AND PRECAUTIONS

The warnings and precautions can be found in the M6-CTM Artificial Cervical Disc Instructions for Use.

# V. DEVICE DESCRIPTION

The M6-CTM Artificial Cervical Disc is an intervertebral disc prosthesis designed to permit motion of a functional spinal unit in the cervical spine when replacing a degenerated native disc. The device is comprised of ultra-high molecular weight polyethylene (UHMWPE) fiber wound in a specific pattern, with multiple redundant layers, creating a fiber matrix (artificial annulus). The fiber is wound around a polycarbonate urethane polymer (PCU) core (artificial nucleus) and through the slots in two Ti6Al4V titanium alloy inner endplates (see Figure 1). The core is situated between and in contact with the two inner endplates, but not affixed to them. A PCU sheath surrounds the fiber matrix and is retained by two Ti6Al4V weld bands that are welded to the inner endplates. Two Ti6Al4V outer endplates are also welded to the inner endplates. The exterior surfaces of the outer endplates include low profile fins and are coated with titanium plasma spray (TPS).

Figure 1: Cross-Section View of the M6-CTM Artificial Cervical Disc

The M6-CTM Artificial Cervical Disc is designed to maintain the natural behavior of a functional spinal unit by replicating the biomechanical characteristics of the native disc. This design enables the M6-CTM Artificial Cervical Disc to move in all six degrees of freedom, with independent angular rotations (flexion-extension, lateral bending and axial rotation) along with independent translational motions (anterior-posterior and lateral translations as well as axial compression). The device is intended to replicate the physiological phenomenon of progressive resistance to motion in all six degrees of freedom. The sheath is designed to minimize any tissue ingrowth as well as the migration of wear debris. The serrated fins provide acute fixation to the superior and inferior vertebral bodies. The TPS coating increases the bone contact surface area.

The M6-CTM Artificial Cervical Disc is currently offered in four different footprint sizes and two heights, as shown below in Figure 2 and Table 1.

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Figure 2: M6-CTM Artificial Cervical Disc Heights and Footprint Sizes

Table 1: M6-CTM Part Listing and Size Overview

| Catalog Number | Description | Provided Sterile |
| --- | --- | --- |
| CDM-625 | Cervical Disc – 6 Medium (15mm W x 12.5mm D x 6mm H) | Yes |
| CDM-725 | Cervical Disc – 7 Medium (15mm W x 12.5mm D x 7mm H) | Yes |
| CDL-627 | Cervical Disc – 6 Large (17mm W x 14mm D x 6mm H) | Yes |
| CDL-727 | Cervical Disc – 7 Large (17mm W x 14mm D x 7mm H) | Yes |
| CDM-635L | Cervical Disc – 6 Medium-Long (15mm W x 15mm D x 6mm H) | Yes |
| CDM-735L | Cervical Disc – 7 Medium-Long (15mm W x 15mm D x 7mm H) | Yes |
| CDL-637L | Cervical Disc – 6 Large-Long (17mm W x 16mm D x 6mm H) | Yes |
| CDL-737L | Cervical Disc – 7 Large-Long (17mm W x 16mm D x 7mm H) | Yes |

# VI. ALTERNATIVE PRACTICES AND PROCEDURES

There are several other alternatives for the treatment of intractable radiculopathy due to a single-level abnormality localized to the level of the disc space.

- 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

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- Surgical decompression via an anterior approach with fusion using various bone grafting and anterior plating techniques
- Surgical decompression using intervertebral cages, with various bone grafting techniques, with or without supplemental anterior plating
- Decompression with posterior spinal systems (e.g., rods, hooks, wires)
- Another FDA-approved artificial cervical disc

Each alternative 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.

## VII. MARKETING HISTORY

The M6-C™ Artificial Cervical Disc has been marketed outside of the United States since 2006. The M6-C™ Artificial Cervical Disc has not been withdrawn from distribution/ marketing in any country for any safety or effectiveness reasons. The M6-C™ Artificial Cervical Disc has been, and/or currently is, distributed in the following countries: Argentina, Australia, Austria, Belgium, Brazil, Canada, Chile, Czech Republic, France, Germany, Greece, Italy, Mexico, Netherlands, Poland, Portugal, Russia, South Africa, Spain, Sweden, Switzerland, Turkey, United Arab Emirates, and the United Kingdom.

## VIII. POTENTIAL ADVERSE EFFECTS OF THE DEVICE ON HEALTH

Below is a list of the potential adverse effects (e.g., complications) identified from the M6-C™ Artificial Cervical 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 M6-C™ Artificial Cervical 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:

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- 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
- 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 M6-C™ Artificial Cervical 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

- 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

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These conditions do not include all potential adverse events that may occur, but are important considerations in relation to the use of the M6-C™ Artificial Cervical Disc. For the specific adverse events that occurred in the M6-C™ clinical study, please see Section X.

# IX. SUMMARY OF NON-CLINICAL STUDIES

A variety of testing was conducted to characterize the performance of the M6-CTM Artificial Cervical Disc, as follows:

# Laboratory Studies

Static Axial Compression
- Dynamic Axial Compression
Static Compression-Shear
- Dynamic Compression-Shear
Static Torsion
Dynamic Torsion
- Functional and Kinematic Wear Assessment
Clinical Experience Testing
Migration/Expulsion
- Compressive Creep
- Subsidence
- Cadaveric Biomechanics Assessment
- Sheath Retention
Translation
- Finite Element Modeling
- Instrument Testing

# Animal Studies

- Caprine Studies
- Rabbit Particulate Studies

# Additional Studies

- Magnetic Resonance (MR) Imaging
TPS Coating Assessment
Biocompatibility
Sterilization Validation
- Shelf Life and Packaging Validation

# A. Laboratory Studies

Table 2: Overview of Laboratory Studies

| Test Name | Purpose | Method | Acceptance Criteria | Results |
| --- | --- | --- | --- | --- |
| M6-CTM | M6-CTM | M6-CTM | Slightly high sensitivity and specificity | Sensitivity to toxicity |
| M6-CTM | M6-CTM | M6-CTM | Slightly high specificity and specificity | Sensitivity to toxicity |
| M6-CTM | M6-CTM | M6-CTM | Slightly high specificity and specificity | Sensitivity to toxicity |

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| Test Name | Purpose | Method | Acceptance Criteria | Results |
| --- | --- | --- | --- | --- |
| Static Axial Compression | To evaluate the performance of the M6-C™ Artificial Cervical Disc under static axial compressive loading | Five (5) M6-C™ specimens were tested under static compression in 37°C phosphate buffered saline at a rate of 0.2mm/sec until failure or approximately 25,000N (capacity of largest available load cell) was reached. Testing per ASTM F2346. | Ultimate load must be ≥ 3200N | No mechanical failure could be achieved under axial compressive loading to approximately 25,000N. The acceptance criteria were met. |
| Dynamic Axial Compression | To evaluate the performance of the M6-C™ Artificial Cervical Disc under dynamic axial compressive loading | Two (2) M6-C™ specimens were tested under dynamic compression in 37°C phosphate buffered saline to 10 million cycles, using a sinusoidal wave form with R=10 at 2 Hz. Testing per ASTM F2346. | The minimum total runout load for compression was 150N. | Two samples were tested to 10 million cycles from 15 to 150 N of axial compression. No mechanical or functional failures were observed; the acceptance criteria were met. |
| Static Compression-Shear | To evaluate the performance of the M6-C™ Artificial Cervical Disc under static compression-shear loading | Five (5) M6-C™ specimens were tested under static compression-shear (45°), with the devices in 7.5° of extension, in 37°C phosphate buffered saline at a rate of 0.01mm/sec until failure. Testing per ASTM F2346. | The ultimate compression shear load must be ≥ 845N. | The average load at failure for the 5 samples tested in compression shear (including a full extension angle of 7.5°) to failure was 6714 ± 113N. The acceptance criteria were met. |
| Dynamic Compression-Shear | To evaluate the performance of the M6-C™ Artificial Cervical Disc under dynamic compression-shear loading | Two (2) M6-C™ specimens were tested under dynamic compression-shear in 37°C phosphate buffered saline to 10 million cycles, using a sinusoidal wave form with R=10 at 2 Hz. Testing per ASTM F2346. | The minimum total runout load for compression-shear was 150 N. | Two samples were tested to 10 million cycles from 15 to 150N of compression shear with full extension. No mechanical or functional failures were observed; the acceptance criteria were met. |

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| Test Name | Purpose | Method | Acceptance Criteria | Results |
| --- | --- | --- | --- | --- |
| Static Torsion | To evaluate the performance of the M6-CTM Artificial Cervical Disc under static torsional loading | Five (5) M6-CTM specimens were tested under static torsion in 37°C phosphate buffered saline at a rate of 0.5°/sec until failure. Testing per ASTM F2346. | Ultimate load must be ≥ 4 Nm. | The maximum torque was 10.26 ± 1.23 Nm. The acceptance criteria were met. |
| Dynamic Torsion | To evaluate the performance of the M6-CTM Artificial Cervical Disc under dynamic torsion loading | Two (2) M6-CTM specimens were tested under dynamic torsion in 37°C phosphate buffered saline to 10 million cycles, using a sinusoidal wave form with R=-1 at 2 Hz. Testing per ASTM F2346. | The minimum total runout moment for torsion was ±0.35 Nm. | Two devices were tested to 10 million cycles at ±0.35 Nm. No mechanical or functional failures were observed; the acceptance criteria were met. |
| Functional & Kinematic Wear Assessment | To evaluate the functional and kinematic wear properties of the M6-CTM Artificial Cervical Disc to ensure that the structural integrity of the device is sufficient for the projected life of the implant and that the device does not generate excessive wear debris | Testing per ASTM F2423 for 10 million cycles of flexion/extension and 10 million cycles of coupled lateral bending and axial rotation at 2 Hz. Six (6) samples were tested in Bovine Calf Serum (BCS) and six (6) were tested in DI water. | The total wear debris mass must be less than 40 mg. | The M6-CTM Artificial Cervical Disc met the acceptance criterion as defined in the test protocol. In BCS, the debris mass at 20 million cycles was 0.54 ± 0.08 mg, or 0.03 mg/MC. In DI water, the debris mass at 20 million cycles was 12.27 ± 4.41 mg, or 0.61 mg/MC. These results suggest that the M6-CTM Artificial Cervical Disc generates an acceptable level of wear debris for clinical use. |

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| Test Name | Purpose | Method | Acceptance Criteria | Results |
| --- | --- | --- | --- | --- |
| Functional & Kinematic Wear Assessment | To evaluate the functional and kinematic wear properties of the M6-CTM Artificial Cervical Disc to ensure that the structural integrity of the device is sufficient for the projected life of the implant and that the device does not generate excessive wear debris | Testing per ISO 18192-1 for 10 million cycles of clinically derived coupled flexion/extension, lateral bending, and torsion at 1 Hz. Six (6) samples were tested in Bovine Calf Serum and six (6) were tested in DI water. | The total wear debris mass must be less than 40 mg. | The M6-CTM Artificial Cervical Disc met the acceptance criterion as defined in the test protocol. In BCS, the debris mass at 10 million cycles was 3.36 ± 0.54 mg, or 0.34 mg/MC. In DI water, the debris mass at 10 million cycles was 9.38 ± 3.30 mg, or 0.94 mg/MC. These results suggest that the M6-CTM Artificial Cervical Disc generates an acceptable level of wear debris for clinical use. |
| Clinical Experience Testing | To assess the functional and kinematic wear properties of the M6-CTM Artificial Cervical Disc under clinically derived atypical conditions | Twelve (12) samples were tested in total under 3 different sets of conditions. Six (6) samples (primary test) were tested under three clinically derived atypical conditions. Three (3) samples were tested under two clinically derived typical conditions. Three (3) samples were tested under one clinically derived atypical condition. All samples were tested in Bovine Calf Serum (BCS) for 2 million cycles at 1 Hz. | This test was performed for characterization only. | Testing under more clinically derived atypical conditions resulted in varying degrees of device wear. The M6-CTM Artificial Cervical Disc is robust when subjected to clinically derived atypical conditions. |

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| Test Name | Purpose | Method | Acceptance Criteria | Results |
| --- | --- | --- | --- | --- |
| Migration and Expulsion | To evaluate the acute migration potential of the M6-C™ Artificial Cervical Disc | Nine (9) M6-C™ specimens were implanted into a cadaveric model and tested in monotonic axial compression (4) to a load of 3000N with the spinal segment at 7.5° of extension, and in cyclic fatigue (5) at ±7.5° of flexion/extension to 20,000 cycles. | The device must not migrate or subluxate over the course of the test (defined as superior or inferior endplate moving ≥3.5mm or 20% from its initial position. | Monotonic compression: The average migration was 0.4 ± 0.5mm. The normalized subluxation was 5.5 ± 3.5%.
Cyclic fatigue: The average migration was 0.3 ± 0.5mm. The normalized subluxation was 1.3 ± 2.5%.
All acceptance criteria were met. |
| Compressive Creep | To evaluate the compressive creep characteristics of the M6-C™ Artificial Cervical Disc | Six (6) M6-C™ specimens were tested per ASTM D2990-01 and loaded at an axial compressive load of 100N for 42 days followed by a simulated sleep/wake cycle (100N for 16hr and 53N for 8hr) for an additional 10 days. | Maintenance of inter-endplate distance of 1.0mm at 100 N extrapolated to 100 years, and maintain appropriate stiffness. | All samples were met the acceptance criteria for height loss and resulting inter-endplate distance when evaluated at 1000 hours, a calculated 100 years, and after 10 days of sleep/wake cycling. All samples exhibited acceptable axial compressive stiffness. |
| Subsidence | To characterize the M6-C™ implant’s resistance to subsidence into the vertebral endplate, under worst case conditions | Six (6) M6-C™ specimens were tested per ASTM F2267. | N/A: for characterization purposes. | The M6-C™ Artificial Cervical Disc had a mean yield load of 1147 ± 9.7N. These results of the subsidence testing can be correlated with the available clinical data and will constitute a baseline that can be used to assess the possible impact on subsidence potential of any future design iteration. |
| Cadaveric Biomechanics Assessment | To characterize the biomechanical behavior of the M6-C™ Artificial Cervical Disc and to compare to native disc biomechanics | Six (6) M6-C™ specimens were tested in three scenarios: a follower load model with 150N preload and a 1.5 Nm F/E bending moment; a ±1.5 Nm axial rotation moment; and a 1.5 Nm lateral bending moment | N/A: for characterization purposes. | The results of the testing indicate that the M6-C™ Artificial Cervical Disc has similar biomechanical performance to that of a native human disc. |

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| Test Name | Purpose | Method | Acceptance Criteria | Results |
| --- | --- | --- | --- | --- |
| Sheath Retention | To evaluate the sheath retention mechanism in a worst-case scenario | Six (6) M6-CTM specimens were tested from neutral to 18° of extension for 30,000 cycles at 2 Hz. | The sheath must be retained. | The results of the testing indicated that all sheaths were retained. The acceptance criteria were met. |
| Translation | To characterize the static translation behavior of the M6-CTM Artificial Cervical Disc | M6-CTM Artificial Cervical Disc was tested in static lateral translation to 2000 N, the limit of the test machine, while under a physiologic axial load (100N). Because the device is symmetric, this assessment is also applicable to AP translation. | N/A: for characterization purposes. | At the highly non-physiologic (>10x) shear load of 2000N, the device translated while remaining intact with no fiber breakage. Non-physiologic shear loads were required to achieve 3.5 mm of translation, the level at which a natural disc is considered unstable. Therefore, the M6-CTM design provides for significant patient safety with regard to device translation. |
| Finite Element Modeling | To characterize the biomechanical response of total disc arthroplasty with the M6-CTM Artificial Cervical Disc | Both an intact C5-C6 model and a model with a 6 mm Medium M6-CTM replacement were assessed under a compressive load of 150N alone as well as under a compressive load of 150N in combination with 1.5 Nm of each of the following: flexion, extension, torsion, and lateral bending. | N/A: for characterization purposes. | The results indicated a close correlation between the intact model and the M6-CTM replacement was obtained for all loading conditions; the M6-CTM Artificial Cervical Disc had performance commensurate with an intact disc, and no excessive loads beyond material strengths. |
| Instrument Testing | To verify and validate the functionality of the M6-CTM Surgical Instruments | Various verification and validation activities. | Various | The instruments met all acceptance criteria. |

Two minor design changes have been made to the M6-CTM Artificial Cervical Disc and have been evaluated via the appropriate verification and validation activities to supplement the original testing.

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# B. Animal Studies

Table 3: Overview of Animal Studies

| Test Name | Purpose | Method | Acceptance Criteria | Results |
| --- | --- | --- | --- | --- |
| Caprine Studies | To evaluate the biological response of the implant | The M6-CTM Artificial Cervical Disc was implanted in a goat cervical spine and evaluated histologically for the biological response at 0, 3, 6, and 12 months. | N/A: for characterization purposes | The following concerns were observed. However, these results were attributed to inadequate implantation technique and the use of skeletally immature goats. a. Relatively thick periprosthetic fibrous membrane indicative of a host inflammatory response/immune response that prevented adequate device fixation. b. Osteoclastic activity that shows bone remodeling and bone resorption (osteolysis). c. At 12 months, macrophages with hemosiderin were still evident which is indicative of hemorrhage. d. Macrophages associated with hemosiderin, bone wax, and occasional polyethylene fibers or metallic particles were observed suggesting a local inflammatory response; however, there was no evidence of adaptive immune response or unexpected inflammatory reaction to the particles. There was wear particulate at the final time point (12 months) in this study; however, it is not clear how this observation can be extrapolated to humans given the limitations of this study. e. Fixation and stability were not completely achieved. Despite the sources of uncertainty discussed above, there was no histologic evidence of systemic |

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| Test Name | Purpose | Method | Acceptance Criteria | Results |
| --- | --- | --- | --- | --- |
| | | | | toxicity at one year. There was no evidence of an adaptive immune reaction to the implants or debris. |
| Rabbit Particulate Study | To evaluate the local and systemic responses to the potential wear debris in an animal model | Potential wear debris particles with material proportions representative of the device were implanted into rabbits. The amount and number of particles were chosen based on the worst case kinematic wear assessment debris profile with added margin of safety. Two different doses (low and high) along with sham control were injected into the epidural space of the lumbar region (L4-L6) of each rabbit (n=54). The animals were evaluated for clinical and neurological observations as well as hematological, histological, and gross pathologic methods. These evaluations occurred at 2, 3, and 6 months. | N/A: for characterization purposes | The following issues added uncertainty to the study results:
a. The presence of certain liver and brain related pathology in the treated 3-month rabbit group (4 out of 12 animals), that were attributed to a parasitic infection confounded the test data interpretation.
b. In the 6-month group, the particles injected into the animals were contaminated with other inorganic matter.

With these sources of uncertainty in mind, the measured systemic toxicity and inflammatory responses did not identify significant biocompatibility concerns with the device. |

## C. Additional Studies

### Magnetic Resonance (MR) Imaging

The safety and compatibility of the M6-C™ Artificial Cervical 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.

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The magnetic field interaction evaluations consisted of translational attraction and torque assessments. For the assessment of translational attraction, an angular deflection test was performed in accordance with ASTM F2052-15, Standard Test Method for Measurement of Magnetically Induced Displacement Force on Medical Devices in the Magnetic Resonance Environment. The evaluation of magnetic torque was performed in accordance with ASTM F2213-06 (2011), Standard Test Method for Measurement of Magnetically Induced Torque on Medical Devices in the Magnetic Resonance Environment. The M6-C™ Artificial Cervical Disc was tested for MRI-related heating in accordance with ASTM F2182-11a, Standard Test Method for Measurement of Radio Frequency Induced Heating On or Near Passive Implants During Magnetic Resonance Imaging. MR imaging artifacts were assessed in accordance with ASTM F2119-07 (Reapproved 2013), Standard Test Method for Evaluation of MR Image Artifacts from Passive Implants.

The results of the assessments demonstrated that the M6-C™ Artificial Cervical Disc is MR Conditional. A patient with the M6-C™ Artificial Cervical Disc can be scanned safely in an MR system under the following conditions:

- Static magnetic field of 1.5-Tesla or 3-Tesla, only
- Maximum spatial gradient magnetic field of 4,000-Gauss/cm (40-T/m)
- Maximum MR system reported whole body averaged specific absorption rate (SAR) of 2-W/kg for 15 minutes of scanning (i.e., per pulse sequence) in the Normal Operating Mode.

Under the scan conditions defined, the M6-C™ Artificial Cervical Disc is expected to produce a maximum temperature rise of 2.2°C after 15-minutes of continuous scanning (i.e., per pulse sequence).

In non-clinical testing, the image artifact caused by the M6-C™ Artificial Cervical Disc extends approximately 10-mm from this device when imaged using a gradient echo pulse sequence and a 3-Tesla MR system.

## Biocompatibility

The M6-C™ Artificial Cervical Disc is manufactured from titanium alloy, polycarbonate urethane (PCU), UHMWPE 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 M6-C™ Artificial Cervical Disc.

Biocompatibility testing was performed on the M6-C™ Artificial Cervical Disc in its final sterilized state in accordance with ISO 10993-1, 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), Sensitization (ISO 10993-10), Irritation/Intracutaneous Reactivity (ISO 10993-10), Systemic Toxicity (10993-11), Genotoxicity (10993-3), Implantation (ISO 10993-6), Subchronic Toxicity (10993-11), and Pyrogen Testing (ISO 10993-11). All test results met the acceptance criteria demonstrating biocompatibility in line with the requirements of ISO 10993-1.

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# Sterilization Validation

Full sterilization validation has been conducted for the M6-C™ implants per BS-EN-ISO 11135 - Sterilization of health-care products- Ethylene oxide -Requirements for the development, validation and routine control of a sterilization process for medical devices.

Full sterilization validation has been conducted for the M6-C™ instruments per BS-EN-ISO 17665 - Sterilization of health care products - Moist heat, Part 1: Requirements for the development, validation and routine control of a sterilization process for medical devices.

# 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 5-year shelf life.

# X. SUMMARY OF PRIMARY CLINICAL STUDIES

The applicant performed a clinical study to establish a reasonable assurance of safety and effectiveness of replacement of the diseased native disc with the M6-C™ Artificial Cervical Disc following single level discectomy in skeletally mature subjects with intractable degenerative cervical radiculopathy (arm pain and/or a neurological deficit) with or without spinal cord compression at one level from C3 – C7. Degenerative cervical radiculopathy is defined as discogenic neck and/or arm pain and is demonstrated by signs and/or symptoms (e.g., numbness, weakness, pathologic reflexes, etc.) of disc herniation and/or osteophyte formation and is confirmed by subject history and radiographic imaging (CT, MRI, x-rays). The study was performed in the United States under IDE #G050254 with additional control 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 M6-C™ pivotal study (“M6-C™ IDE study”) were treated between May 2014 and June 2016. The database for this PMA reflects data collected through May 2018 and included 160 M6-C™ subjects at 12 sites and 72 ACDF subjects treated at 11 sites. An additional 192 ACDF treated subjects were available from a previously conducted cervical disc IDE study, with subjects treated between November 2005 and October 2007.

The prospective, non-randomized, concurrently controlled study was performed in the United States under IDE #G050254 combined with additional control ACDF data from a previous multicenter, 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 M6-C™ group. The resultant PS Selected study cohort used for the primary analysis population thus included all investigational M6-C™ subjects and the pooled concurrent and historical control subjects and is termed the “ITT (PS Selected) Cohort.”

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# 1. Clinical Inclusion and Exclusion Criteria

To be eligible for the M6-CTM 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 4: Study Inclusion/Exclusion Criteria

| Study Inclusion Criteria | Study Exclusion Criteria |
| --- | --- |
| 1. Diagnosis of degenerative cervical radiculopathy with or without spinal cord compression requiring surgical treatment at one level from C3 to C7 demonstrated by signs and/or symptoms of disc herniation and/or osteophyte formation (e.g. neck and/or arm pain, radiculopathy, etc.) and is confirmed by patient history and radiographic studies (e.g. MRI, CT, x-rays, etc.)2. Inadequate response to conservative medical care over a period of at least 6 weeks3. Neck Disability Index score of ≥ 30% (raw score of ≥ 15/50)4. Neck or arm pain VAS ≥ 4 on a scale of 0 to 105. Willing and able to comply with the requirements of the protocol including follow-up requirements6. Willing and able to sign a study specific informed consent7. Skeletally mature and ≥ 18 years old and ≤ 75 years old | 1. More than one cervical level requiring surgery2. Previous anterior cervical spine surgery3. Axial neck pain as the solitary symptom4. Previous posterior cervical spine surgery (e.g., posterior element decompression) that destabilizes the cervical spine5. Advanced cervical anatomical deformity (e.g., ankylosing spondylitis, scoliosis) at the operative or adjacent levels6. Symptomatic facet arthrosis7. Less than 4° of motion in flexion/extension at the index level8. Instability as evidenced by subluxation > 3 mm at the index or adjacent levels as indicated on flexion/extension x-rays9. Advanced degenerative changes (e.g., spondylosis) at the index vertebral level as evidenced by bridging osteophytes, central disc height < 4mm and/or < 50% of the adjacent normal intervertebral disc, or kyphotic deformity > 11° on neutral x-rays10. Severe cervical myelopathy (i.e., Nurick's Classification > 2)11. Active systemic infection or infection at the operative site12. Co-morbid medical conditions of the spine or upper extremities that may affect the cervical spine neurological and/or pain assessment13. Metabolic bone disease such as osteoporosis that contradicts spinal surgery (for females over 50 and males over 55 years old, or if the score on the Osteoporosis Self-Assessment Test is < 2, a dual energy x-ray absorptiometry [DEXA scan] of the spine is required; if the bone mineral density T-score in the spine is = -2.5 the patient must be excluded)14. History of an osteoporotic fracture of the spine, hip or wrist15. History of an endocrine or metabolic disorder (e.g., Paget's disease) known to affect bone and mineral metabolism16. Taking medications that may interfere with bony/soft tissue healing including chronic steroid use17. Known allergy to titanium, stainless steels, polyurethane, polyethylene, or ethylene oxide residuals |

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| Study Inclusion Criteria | Study Exclusion Criteria |
| --- | --- |
| | 18. Rheumatoid arthritis or other autoimmune disease or a systemic disorder such as HIV, active hepatitis B or C or fibromyalgia
19. Insulin-dependent type 1 or type 2 diabetes
20. Medical condition (e.g., unstable cardiac disease, cancer) that may result in patient death or have an effect on outcomes prior to study completion
21. Pregnant, or intend to become pregnant, during the course of the study
22. Severe obesity (Body Mass Index > 40)
23. Physical or mental condition (e.g., psychiatric disorder, senile dementia, Alzheimer's disease, alcohol or drug addiction) that would interfere with patient self-assessment of function, pain or quality of life.
24. Involved in current or pending spinal litigation where permanent disability benefits are being sought
25. Incarcerated at the time of study enrollment
26. Current participation in other investigational study that may impact study outcomes |

## 2. Control

Control subjects received Anterior Cervical Discectomy and Fusion (ACDF). The M6-C™ IDE study was not randomized and the study sites were device-specific (i.e. performed either ACDF or implantation with the M6-C™ Artificial Cervical Disc). This concurrent control was supplemented with subjects from the control arm (ACDF) of a historical IDE study in the cervical spine.

Comparison of the data from the two control sources demonstrated that the cohorts were comparable, though not identical. There were some differences in the study protocols, the patient population, and the resulting data. Specifically:

- A detailed comparison of the inclusion/exclusion criteria of the two cohorts 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 and remained blinded to the aggregate study results. Based on this review, the sponsor determined that the historical study was similar to the IDE study in its Indications for Use and Inclusion/Exclusion criteria. As clinical confirmation of the comparability of the study populations, 3 independent surgeons who also serve on the Clinical Events Committee (CEC) for the M6-C™ IDE study reviewed the inclusion and exclusion criteria for both the M6-C™ IDE study and the historical control study. The independent surgeons concluded that although some of the criteria are worded differently, and some are written in more detail than their comparable criteria, the result of both sets of inclusion/exclusion criteria describe a similar population: patients presenting with single level symptomatic degenerative cervical radiculopathy qualifying for single level surgery from C3-C7.

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- 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 M6-CTM IDE study protocol.
- In some cases, the data was inadequate for analysis explicitly per the M6-CTM IDE study protocol. In these instances, the results were harmonized.

A PS method was used to address selection bias in the observational study design when pooling data from the concurrent and historical controls. The objective of the observational design was to select from the candidate pool of concurrent and historical controls those subjects whose baseline covariate distribution was approximately the same as M6-CTM subjects within five PS subclasses. The final ITT (PS Selected) analysis set included all 160 M6-CTM subjects, 46 of 72 available concurrent control subjects and 143 of 192 historical control subjects for a total control sample size of 189 subjects. Rigorous statistical criteria and graphical analyses demonstrated that within PS subclasses, M6-CTM subjects and selected controls had approximately the same multivariate baseline covariate distribution. Consequently, controlling for PS subclass, selection bias was eliminated for a rich set of observed demographic and baseline covariates.

# 3. Follow-up Schedule

All subjects were evaluated preoperatively (within 30 days prior to surgery), postoperatively (prior to discharge) 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 were measured throughout the study:

Table 5: M6-CTM IDE Study Assessment Schedule

| Evaluation | Pre-op | Operative/Discharge | 6 Weeks | 3 Months | 6 Months | 1 Year | 2+ Years |
| --- | --- | --- | --- | --- | --- | --- | --- |
| Demographics | X | | | | | | |
| Work Status | X | | X | X | X | X | X |
| Medications | X | | X | X | X | X | X |
| Neurological Examination | X | X | X | X | X | X | X |
| Neck Disability Index (NDI) | X | | X | X | X | X | X |
| Neck and Arm Pain (VAS) | X | | X | X | X | X | X |
| SF-36 | X | | | | X | X | X |
| Patient Satisfaction | | | | | | | X |
| Odom's Criteria | | | | | | | X |
| Surgery Data | | X | | | | | |
| Adverse Event Assessment | | X | X | X | X | X | X |
| AP & Lateral X-rays | X | X | X | X | X | X | X |
| Flexion/Extension X-rays | X | | | X | X | X | X |
| L & R Lateral Bending X-rays | M6-CTM | | | M6-CTM | M6-CTM | M6-CTM | M6-CTM |
| MRI within 3 Months | X | | | | | | |

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## 4. Clinical Endpoints

The effectiveness of the M6-C™ Artificial Cervical Disc was assessed using a composite endpoint. 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 quality of life using the short-form questionnaire as well as patient satisfaction of the investigational group compared to the ACDF control group. Similar criteria were used to measure success in both groups.

The safety of the M6-C™ Artificial Cervical Disc was assessed by comparison to the ACDF control group with respect to the nature and frequency of adverse events (overall and in terms of seriousness and relationship to the implant), additional index level surgical procedures and maintenance or improvement in neurological status.

## Primary Endpoint (Overall Subject Success)

All subjects were assessed for overall success using the parameters defined in the M6-C™ IDE study protocol including the safety components. A subject was considered a study success at two years follow-up if he/she met all of the following criteria:

- No serious adverse event(s) classified as device or device procedure related (as determined by the Clinical Events Committee),
- No supplemental surgical procedure at the index level (including revision, removal, reoperation, or supplemental fixation),
- Maintenance or improvement in neurological function compared to baseline, and
- Improvement of the NDI of at least 15 points (on a 100-point scale).

The parameters needed to assess subjects for overall success as defined in the M6-C™ IDE study were collected on a patient level basis in the historical control study. As such, pooling of the control data from the two studies did not interfere with the ability to assess the M6-C™ primary endpoint and provide an assessment of the safety and effectiveness of the M6-C™ Artificial Cervical Disc compared to the control subjects selected via the propensity score method. The statistical team utilized the patient level adverse event, surgical intervention, and neurological data from both study datasets for each of the above criteria to determine a subject's success or failure.

## Secondary Endpoints and Assessments

Secondary objectives, measured in both groups, included:

- Neck Pain and Arm Pain as assessed using a 10-cm Visual Analog Scale (VAS)
- Health-Related Quality of Life (SF-12 or SF-36v2)
- Radiographic assessment including assessment of fusion status
- Pain Medication Use
- Surgery Time
- Length of Hospital Stay
- Return to Work
- Patient Satisfaction
- Odom's Criteria
- Adverse Events

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In addition, quantitative and qualitative radiographic measurements were performed in the M6-C™ IDE study by an independent core laboratory and included range of motion, center of rotation, disc angle, disc height, device condition, device subsidence, device migration, radiolucency, spinal fusion status, heterotopic ossification, neural impingement, and soft tissue impingement. Independent radiographic assessments were performed in the historical controls at a temporal distance, and included angular and translational motion (range of motion), center of rotation, disc angle, disc height, device condition, device subsidence, device migration, radiolucency, and spinal fusion status.

## 5. Clinical Events Committees (CEC)

A CEC was utilized for the M6-C™ IDE study 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 adverse events (i.e., relationship to device/procedure, seriousness, and unanticipated adverse device effects), protocol deviations (i.e., classification as Major or Minor), and neurological success criterion (assessment if any neurological deficits reported from baseline vs. two years were clinically relevant).

An independent CEC was also used in the historical control study at the time of that study and reviewed all cervical spine post-operative surgical interventions and made the final determination of whether the intervention was considered device-related or serious. All reports of serious adverse events (whether or not device related), serious adverse device effects (SADEs), and unanticipated adverse device effects (UADEs) were reviewed by the CEC. Additionally, the CEC assessed changes in individual neurological parameters to determine whether the change in the individual neurological parameter is a sustained neurological deficit.

## B. Accountability of PMA Cohort

Two hundred fifty-eight (258) subjects were consented under the M6-C™ IDE study. Twenty-six (26) subjects were withdrawn prior to surgery resulting in 232 subjects treated, comprising 160 M6-C™ and 72 ACDF subjects. The historical control population resulted in an additional 192 available control subjects.

The 424 available subjects (160 M6-C™, 72 concurrent ACDF, and 192 historical ACDF) were assessed via the Propensity Score (PS) sub-classification process. After applying an established heuristic for 9 iterations (18 models), a total of 160 M6-C™ investigational subjects and 189 pooled control subjects (46 concurrent ACDF and 143 historical ACDF) were retained in the final PS designed sample. Inclusion into a PS subclass is the observational study analogue to randomized treatment allocation. For subjects at 24 months, the follow-up rates are 95.0% for the M6-C™ subjects and 87.7% for the PS Selected ACDF subjects.

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Table 6: Subject Accounting and Follow-up Compliance of the M6-C™ and PS Selected Pooled Controls Subjects (ACDF) – ITT (PS Selected) Cohort

| | Pre-Op | | Month 12 | | Month 24 | |
| --- | --- | --- | --- | --- | --- | --- |
| | M6-C™ | ACDF | M6-C™ | ACDF | M6-C™ | ACDF |
| [1] Theoretical Due | 160 | 189 | 160 | 189 | 160 | 189 |
| [2] Cumulative Deaths | 0 | 0 | 1 | 0 | 1 | 0 |
| [3] Cumulative Terminal Failures¹ | 0 | 0 | 4 | 6 | 5 | 10 |
| [4] Not Yet Overdue | 0 | 0 | 0 | 0 | 0 | 2 |
| [5] Expected² | 160 | 189 | 156 | 183 | 155 | 177 |
| [6] Expected + Terminal Failures among Theoretical Due | 160 | 189 | 160 | 189 | 160 | 187 |
| [7] Actual % Follow-Up for Overall Success³ | 160 (100%) | 189 (100%) | 153 (95.6%) | 175 (92.6%) | 152 (95.0%) | 164 (87.7%) |
| [8] Actual % Within Window⁴ | 160 (100%) | 189 (100%) | 140 (87.5%) | 167 (88.4%) | 136 (85.0%) | 151 (80.7%) |

¹Subsequent surgical intervention and definitely device- or procedure- related SAEs
²Expected = [1] - [4] - ([2] + [3])
³The number of subjects with overall success (denominator = [6])
⁴The number of subjects with overall success within window (denominator = [6])

The subject accountability for Month 12 and Month 24 clinical evaluations is presented in Table 7.

Table 7: Data Accounting and Follow-up Compliance for Month 12 and Month 24 Outcomes - ITT (PS Selected) Cohort

| | Month 12 | | | | Month 24 | | | |
| --- | --- | --- | --- | --- | --- | --- | --- | --- |
| | M6-C™ | | ACDF | | M6-C™ | | ACDF | |
| | n | % | n | % | n | % | n | % |
| ITT (PS Selected Cohort) | 160 | -- | 189 | -- | 160 | -- | 189 | -- |
| Deaths (not surgery-related) | 0 | -- | 0 | -- | 0 | -- | 0 | -- |
| Not Yet Overdue/Not Yet Due | 0 | -- | 0 | -- | 0 | -- | 2 | -- |
| Expected Due | 160 | -- | 189 | -- | 160 | -- | 187 | -- |
| • Overall Success Evaluation | 153 | 95.6 | 175 | 92.6 | 152 | 95.0 | 164 | 87.7 |
| • Neurological Evaluation | 152 | 95.0 | 175 | 92.6 | 150 | 93.8 | 164 | 87.7 |
| Terminal Failures¹ | 4 | -- | 6 | -- | 5 | -- | 10 | -- |
| Expected for Clinical Evaluation | 156 | -- | 183 | -- | 155 | -- | 177 | -- |
| • NDI Evaluation | 149 | 95.5 | 168 | 92.8 | 147 | 94.8 | 154 | 87.0 |
| • VAS Neck Pain Evaluation | 148 | 94.9 | 168 | 92.8 | 147 | 94.8 | 154 | 87.0 |
| • VAS Arm Pain Evaluation | 148 | 94.9 | 168 | 92.8 | 147 | 94.8 | 154 | 87.0 |
| • SF-12/36 Evaluation | 148 | 94.9 | 164 | 89.6 | 147 | 94.8 | 150⁵ | 84.7 |
| • Radiographic Evaluation | 143 | 91.7 | 162 | 88.5 | 141 | 91.0 | 140 | 79.1 |
| • Odom's Criteria | - | - | - | - | 150 | 93.8 | 164 | 86.8 |
| • Patient Satisfaction | - | - | - | - | 150 | 93.8 | 162 | 85.7 |

¹Subsequent surgical intervention and definitely device- or procedure- related SAEs
²Two subjects did not have baseline SF-12/36 measurement. Change from baseline scores in PMA Results section use 148 subjects.

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Figure 3: Subject Accountability Tree

# C. Study Population Demographics and Baseline Parameters

The demographics of the study population are consistent with demographics reported for prior cervical artificial disc studies conducted in the US. Demographic data showed that the treatment groups were well-balanced and no statistically significant differences were noted in the demographic characteristics and categorical values (Table 8 and Table 9). The mean baseline pre-operative assessments for NDI, VAS neck pain, VAS arm pain, the MCS component of SF-12/SF-36, and baseline radiographic parameters were also similar between treatment groups. The Short Form Physical Function scores were slightly higher in the M6-CTM group; however, when adjusting for PS subclass, there was no significant difference between groups in baseline NDI, indicating similar neck pain and function.

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Table 8: Summary of Demographic and Baseline Continuous Variables (Clinical) with Two-Sided 95% CI's – ITT (PS Selected) Cohort

| | M6-C™ | | | | | | ACDF | | | | | | M6-C™ - ACDF† | | | Unadj‡ |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| Demographics - All | N | Mean | SD | Med | Min | Max | N | Mean | SD | Med | Min | Max | Diff | LB | UB | Diff |
| Age at surgery (yrs) | 160 | 43.64 | 9.10 | 42.35 | 21.8 | 68.4 | 189 | 44.74 | 7.87 | 44.60 | 24.0 | 65.4 | -0.22 | -2.18 | 1.74 | -1.10 |
| Height (inches) | 160 | 67.86 | 3.98 | 68.00 | 58.0 | 83.0 | 189 | 67.93 | 3.85 | 68.00 | 59.0 | 77.0 | -0.04 | -0.95 | 0.86 | -0.07 |
| Weight (lbs) | 160 | 178.93 | 38.03 | 183.00 | 85.0 | 283.0 | 189 | 183.67 | 39.33 | 183.00 | 104.0 | 315.0 | -0.94 | -9.91 | 8.03 | -4.75 |
| BMI (k/m²) | 160 | 27.18 | 4.77 | 26.85 | 17.8 | 39.6 | 189 | 27.84 | 4.86 | 27.30 | 19.1 | 47.8 | -0.05 | -1.16 | 1.07 | -0.66 |
| Osteo Self Assessment Test | 160 | 80.73 | 18.84 | 81.46 | 34.4 | 132.1 | 189 | 82.89 | 19.42 | 82.00 | 43.4 | 146.3 | -0.43 | -4.86 | 4.01 | -2.15 |
| Duration of Symptoms | 153 | 18.21 | 36.77 | 8.00 | 0.5 | 360.0 | 178 | 21.32 | 32.17 | 9.00 | 0.9 | 253.0 | 0.02 | -8.21 | 8.25 | -3.11 |
| Demographics - Male | N | Mean | SD | Med | Min | Max | N | Mean | SD | Med | Min | Max | Diff | LB | UB | Diff |
| Age at surgery (yrs) | 82 | 45.47 | 8.89 | 43.75 | 28.2 | 68.4 | 93 | 45.07 | 7.51 | 45.00 | 26.0 | 65.4 | 0.12 | -2.47 | 2.72 | 0.41 |
| Height (inches) | 82 | 70.43 | 3.06 | 70.00 | 61.0 | 83.0 | 93 | 70.80 | 2.63 | 71.00 | 63.0 | 77.0 | -0.12 | -1.02 | 0.78 | -0.37 |
| Weight (lbs) | 82 | 199.68 | 28.95 | 195.00 | 140.0 | 283.0 | 93 | 202.82 | 33.31 | 200.00 | 130.0 | 315.0 | -1.68 | -11.63 | 8.26 | -3.14 |
| BMI (k/m²) | 82 | 28.35 | 4.08 | 28.00 | 20.9 | 38.4 | 93 | 28.38 | 3.97 | 28.10 | 20.4 | 42.3 | -0.04 | -1.32 | 1.25 | -0.03 |
| Osteo Self Assessment Test | 82 | 90.75 | 14.57 | 89.26 | 62.9 | 132.1 | 93 | 92.40 | 16.31 | 91.60 | 57.2 | 146.3 | -0.87 | -5.78 | 4.04 | -1.65 |
| Duration of Symptoms | 78 | 13.05 | 16.55 | 7.00 | 1.0 | 107.0 | 85 | 18.31 | 23.75 | 9.00 | 1.0 | 119.0 | -1.89 | -8.48 | 4.71 | -5.26 |
| Demographic - Female | N | Mean | SD | Med | Min | Max | N | Mean | SD | Med | Min | Max | Diff | LB | UB | Diff |
| Age at surgery (yrs) | 78 | 41.71 | 8.96 | 41.00 | 21.8 | 60.5 | 96 | 44.42 | 8.23 | 44.25 | 24.0 | 63.0 | -0.02 | -2.85 | 2.81 | -2.71 |
| Height (inches) | 78 | 65.17 | 2.92 | 66.00 | 58.0 | 71.0 | 96 | 65.15 | 2.59 | 66.00 | 59.0 | 71.0 | 0.00 | -0.95 | 0.96 | 0.02 |
| Weight (lbs) | 78 | 157.10 | 34.12 | 152.50 | 85.0 | 246.0 | 96 | 165.13 | 35.78 | 155.00 | 104.0 | 270.0 | 0.02 | -11.92 | 11.97 | -8.02 |
| BMI (k/m²) | 78 | 25.96 | 5.14 | 24.70 | 17.8 | 39.6 | 96 | 27.32 | 5.56 | 26.40 | 19.1 | 47.8 | 0.02 | -1.80 | 1.84 | -1.36 |
| Osteo Self Assessment Test | 78 | 70.21 | 17.04 | 67.84 | 34.4 | 112.2 | 96 | 73.68 | 17.73 | 69.37 | 43.4 | 128.2 | 0.02 | -5.96 | 5.99 | -3.47 |
| Duration of Symptoms | 75 | 23.58 | 49.34 | 8.00 | 0.5 | 360.0 | 93 | 24.08 | 38.20 | 9.00 | 0.9 | 253.0 | 2.30 | -13.15 | 17.76 | -0.50 |
| Baseline Functional Status† | N | Mean | SD | Med | Min | Max | N | Mean | SD | Med | Min | Max | Diff | LB | UB | Diff |
| Neck Disability Index (NDI) | 160 | 54.83 | 14.08 | 54.00 | 26.0 | 96.0 | 189 | 51.86 | 14.47 | 50.00 | 30.0 | 90.0 | -0.09 | -3.31 | 3.13 | 2.96 |
| VAS Neck Pain | 160 | 7.25 | 1.86 | 7.60 | 0.00 | 10.0 | 189 | 7.05 | 1.95 | 7.40 | 0.40 | 10.0 | -0.01 | -0.46 | 0.43 | 0.20 |
| VAS Left Arm/Shoulder Pain | 160 | 4.63 | 3.74 | 5.57 | 0.00 | 10.0 | 189 | 4.48 | 3.56 | 5.10 | 0.00 | 10.0 | 0.46 | -0.38 | 1.31 | 0.16 |
| VAS Right Arm/Shoulder Pain | 160 | 4.19 | 3.61 | 4.51 | 0.00 | 10.0 | 189 | 4.63 | 3.65 | 5.00 | 0.00 | 10.0 | -0.55 | -1.39 | 0.29 | -0.44 |
| VAS Worst Arm Pain | 160 | 7.26 | 2.19 | 7.60 | 0.15 | 10.0 | 189 | 7.46 | 1.91 | 7.70 | 0.10 | 10.0 | -0.07 | -0.54 | 0.40 | -0.21 |
| PCS (SK SF-36v2 / CC SF-12v2)‡ | 160 | 34.88 | 7.71 | 34.56 | 16.1 | 55.0 | 187 | 32.66 | 8.04 | 32.37 | 10.8 | 56.9 | 2.84 | 1.01 | 4.67 | 2.22 |
| MCS (SK SF-36v2 / CC SF-12v2)‡ | 160 | 41.38 | 13.88 | 42.08 | 7.7 | 66.6 | 187 | 42.47 | 12.77 | 42.04 | 16.0 | 73.6 | 0.47 | -2.58 | 3.53 | -1.09 |

Notes:
1 Device group differences and 95% confidence intervals (CI) for group differences controlling for propensity score (PS) subclass using two-way analysis of variance. The PS model included main effects and important interactions and squared terms for the following baseline variables: age; BMI; height; gender; NDI; VAS neck pain; VAS worst arm pain; narcotics use (Y vs N); workers compensation/disability (Y vs N); work status (not working due to neck problems); smoking status (never, past, current); treated level (C3-C4, C4-C5, C5-C6 or C6-C7); and symptom duration (&lt;9 mo. vs. ≥9 mo.).
2 Comparison of the PS adjusted group differences to the unadjusted group differences in this column demonstrate the covariate balance obtained using the PS model. The adjusted mean differences are always smaller than unadjusted values for variables in the PS model, and for some variables, the difference is very large.
3 VAS Worst Arm/Shoulder Pain was included in PS modeling but not individual Left and Right VAS scores.
4 PCS and MCS were not included in PS model due to uncertainty concerning comparability between SF-36 and SF-12 versions.

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Table 9: Summary of Demographic and Baseline Categorical Variables – ITT (PS Selected) Cohort

| | M6-C™ | | ACDF | | M6-C™ - ACDF¹ | | |
| --- | --- | --- | --- | --- | --- | --- | --- |
| | n | % | n | % | Diff (%) | LB | UB |
| Number of subjects | 160 | | 189 | | | | |
| Males | 82 | 51.3 | 93 | 49.2 | -0.2 | -11.6 | 11.1 |
| Females | 78 | 48.8 | 96 | 50.8 | | | |
| Use of Nicotine Products | n | % | n | % | p² | | |
| No, never smoked | 103 | 64.4 | 107 | 56.6 | 0.789 | | |
| No, but prior history | 40 | 25.0 | 56 | 29.6 | | | |
| Current smoker | 17 | 10.6 | 26 | 13.8 | | | |
| Narcotics Use³,⁴ | n | % | n | % | Diff (%) | LB | UB |
| Yes | 88 | 55.0 | 117 | 62.2 | -2.3 | -13.7 | 9.2 |
| No | 72 | 45.0 | 71 | 37.8 | | | |
| Prior Cervical Surgery⁵ | n | % | n | % | Diff (%) | LB | UB |
| Yes | 3 | 1.9 | 1 | 0.5 | 1.4 | -10.6 | 13.4 |
| No | 157 | 98.1 | 188 | 99.5 | | | |
| Notes: ¹ Device group differences and 95% confidence intervals (CI) for group differences controlling for propensity score (PS) subclass using two-way generalized linear model for dichotomous variables. The PS model included main effects and important interactions and squared terms for the following baseline variables: age; BMI; height; gender; NDI; VAS neck pain; VAS worse arm pain; narcotics use (Y vs N); workers compensation/disability (Y vs N); work status (not working due to neck problems); smoking status (never, past, current); treated level (C3-C4, C4-C5, C5-C6 or C6-C7); and symptom duration (<9 mo. vs. ≥9 mo.). ² P-values are from Mantel-Haenszel PS subclass stratified comparisons between device groups. ³ For M6-C™ and concurrent controls based on yes/no narcotics use variables. For supplemental controls based on collapsing "INTERMITTENT SHORT-ACTING NARCOTICS", "CHRONIC DAILY SHORT-ACTING NARCOTICS", "CHRONIC DAILY LONG-ACTING NARCOTICS", and "IV OR INJECTED NARCOTICS". ⁴ One supplemental control value missing was set to "Yes" in in PS modeling. ⁵ Variable not included as covariate in PS modeling due to insufficient sample size. | | | | | | | |

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Table 10: Summary of Operative Continuous Variables with Two-Sided 95% CI's – ITT (PS Selected) Cohort

| | M6-C™ | | | | | | ACDF | | | | | | M6-C™ - ACDF¹ | | |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| Demographics - All | N | Mean | SD | Med | Min | Max | N | Mean | SD | Med | Min | Max | Diff | LB | UB |
| Time in Surgery in mins | 160 | 74.5 | 23.2 | 75.0 | 28.0 | 146.0 | 188 | 120.2 | 39.4 | 116.5 | 27.0 | 275.0 | -45.7 | -53.3 | -38.1 |
| Length of Hospital Stay in days | 160 | 0.61 | 0.62 | 1.00 | 0.00 | 5.00 | 189 | 1.10 | 0.58 | 1.00 | 0.00 | 4.00 | -0.53 | -0.66 | -0.39 |
| Demographics - Male | N | Mean | SD | Med | Min | Max | N | Mean | SD | Med | Min | Max | | | |
| Time in Surgery in mins | 82 | 77.2 | 24.7 | 77.5 | 28.0 | 146.0 | 93 | 125.0 | 41.2 | 119.0 | 39.0 | 275.0 | -46.7 | -57.6 | -35.7 |
| Length of Hospital Stay in days | 82 | 0.67 | 0.72 | 1.00 | 0.00 | 5.00 | 93 | 1.11 | 0.50 | 1.00 | 0.00 | 3.00 | -0.47 | -0.66 | -0.27 |
| Demographic - Female | N | Mean | SD | Med | Min | Max | N | Mean | SD | Med | Min | Max | | | |
| Time in Surgery in mins | 78 | 71.7 | 21.4 | 72.5 | 28.0 | 127.0 | 95 | 115.5 | 37.1 | 113.0 | 27.0 | 216.0 | -44.7 | -55.4 | -34.1 |
| Length of Hospital Stay in days | 78 | 0.55 | 0.50 | 1.00 | 0.00 | 1.00 | 96 | 1.08 | 0.64 | 1.00 | 0.00 | 4.00 | -0.58 | -0.78 | -0.38 |
| Notes:¹ Device group differences and 95% confidence intervals (CI) for group differences controlling for propensity score (PS) subclass using two-way generalized linear model for dichotomous variables.. The PS model included main effects and important interactions and squared terms for the following baseline variables: age; BMI; height; gender; NDI; VAS neck pain; VAS worse arm pain; narcotics use (Y vs N); workers compensation/disability (Y vs N); work status (not working due to neck problems); smoking status (never, past, current); treated level (C3-C4, C4-C5, C5-C6 or C6-C7); and symptom duration (<9 mo. vs. ≥9 mo.). | | | | | | | | | | | | | | | |

Table 11: Summary of Operative Categorical Variables – ITT (PS Selected) Cohort

| | M6-C™ | | ACDF | | |
| --- | --- | --- | --- | --- | --- |
| | n | % | n | % | |
| Number of Subjects | 160 | | 187 | | |
| Operative Blood Loss | n | % | n | % | p¹ |
| <25 cc | 72 | 45.0 | 85 | 45.5 | 0.490 |
| 25-<50 cc | 46 | 28.8 | 61 | 32.6 | |
| 50-<100 cc | 40 | 25.0 | 38 | 20.3 | |
| >=100 cc | 2 | 1.3 | 3 | 1.6 | |
| Treated Levels | n | % | n | % | p¹ |
| C3-C4 | 4 | 2.5 | 4 | 2.1 | 0.887 |
| C4-C5 | 10 | 6.3 | 10 | 5.3 | |
| C5-C6 | 82 | 51.3 | 102 | 54.0 | |
| C6-C7 | 64 | 40.0 | 73 | 38.6 | |
| Note:¹ P-value is from Mantel-Haenszel PS subclass stratified comparisons between device groups. The PS model included main effects and important interactions and squared terms for the following baseline variables: age; BMI; height; gender; NDI; VAS neck pain; VAS worse arm pain; narcotics use (Y vs N); workers compensation/disability (Y vs N); work status (not working due to neck problems); smoking status (never, past, current); treated level (C3-C4, C4-C5, C5-C6 or C6-C7); and symptom duration (<9 mo. vs. ≥9 mo.). | | | | | |

## D. Safety and Effectiveness Results

Statistically significant differences were observed in both surgery time and length of hospital stay. The mean surgery time for the M6-C™ subjects was 74.5 minutes compared to 120.2 minutes for the ACDF group. Length of stay was significantly shorter in the M6-C™ group (0.61 days) compared to the ACDF group (1.10 days). Similar trends were observed when these operative details were evaluated by gender. There was no statistically significant difference between the two groups in operative blood loss or level treated.

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# 1. Safety Results

At the 24-month time-point, higher rates of any adverse event, any serious adverse event, and device related adverse events occurred in the ACDF group. At the same time-point, a higher rate of procedure-related adverse events occurred in the M6-CTM group. The combined device and procedure-related adverse event rate for each study arm is also higher in the control arm, although this difference is small. Adverse events rates were comparable in the two study arms. These data should be viewed in the context of the different classification categories and definitions used in the two studies. Specifically, adverse events were not classified as procedure related in the historical study. To harmonize the data, patient level adverse event data were reviewed by the sponsor, at which time 49 adverse events in 32 subjects were identified as procedure related. These events were adjudicated by the CEC and subsequently classified for procedure-relatedness.

In summary, there were 358 adverse events in 108 M6-CTM subjects and 594 adverse events in 157 control subjects (Table 12).

Table 12: Comparisons of Summary Adverse Event Rates between M6-CTM and ACDF Groups with Two-Sided 95% CI's – ITT (PS Selected) Cohort through 24 Months

| | M6-CTM (I) (N=160) | | ACDF (C) (N=189) | | I vs. C1 | | |
| --- | --- | --- | --- | --- | --- | --- | --- |
| | n | % | n | % | Diff (%) | LB | UB |
| Any adverse event (per patient)4 | 108 | 67.5 | 157 | 83.1 | -13.7 | -23.3 | -4.2 |
| Any device related AE2 | 4 | 2.5 | 26 | 13.8 | -11.9 | -17.6 | -6.1 |
| Any procedure related AE2 | 59 | 36.9 | 51 | 27.0 | 11.6 | 1.2 | 21.9 |
| Any AE related to device or procedure2 | 60 | 37.5 | 69 | 36.5 | 1.9 | -8.8 | 12.6 |
| Any serious AE | 15 | 9.4 | 28 | 14.8 | -6.3 | -13.3 | 0.8 |
| Serious AE that is either device or procedure related2 | 6 | 3.8 | 12 | 6.3 | -2.7 | -7.3 | 1.9 |
| Deaths3 | 1 | 0.6 | 0 | 0.0 | 0.7 | -0.7 | 2.1 |
| Notes: 1 Device group differences and 95% confidence intervals (CI) for group differences controlling for propensity score (PS) subclass using two-way generalized linear model for dichotomous variables. The PS model included main effects and important interactions and squared terms for the following baseline variables: age; BMI; height; gender; NDI; VAS neck pain; VAS worse arm pain; narcotics use (Y vs N); workers compensation/disability (Y vs N); work status (not working due to neck problems); smoking status (never, past, current); treated level (C3-C4, C4-C5, C5-C6 or C6-C7); and radicular symptom duration (<9 mo. vs. ≥9 mo.). 2 Includes possible, probable, or definite. 3 The very low event rates for these variables required that PS subclass be included in the generalized linear model as a continuous variable (df=1) rather than as a stratification variables (df=4). 4 Historical control follow-up exceed two-years in many cases. Therefore, in order to provide meaningful comparisons between groups, AEs with onset dates more than 790 days (24 months + 60 days) post index surgery were excluded from primary safety tables for all subjects. | | | | | | | |

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Table 13: Counts of Specific Adverse Events by Time of Occurrence – ITT (PS Selected) Cohort through 24 Months (I = M6-C™, C = ACDF)

| | Day of Surgery | | Immed. Posit. Op to Month 6 (Day 1-90) | | >Mo. 3 to Mo 6 (Day 91-100) | | >Mo. 6 to Mo. 12 (Day 101-365) | | >Mo. 12 to Mo. 24 (Day 365-730) | | Pos 1 Month 24 (Day>730) | | Totals | |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| | I | C | I | C | I | C | I | C | I | C | I | C | I | C |
| ANATOMY/TECHNICAL DIFFICULTY | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 2 |
| Cervical - Non-StudySurgery | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 1 |
| Cervical - StudySurgery | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 |
| CANCER | 0 | 0 | 0 | 0 | 1 | 0 | 2 | 1 | 4 | 0 | 1 | 2 | 8 | 3 |
| CARDIOVASCULAR | 0 | 0 | 1 | 3 | 0 | 1 | 0 | 1 | 2 | 2 | 0 | 2 | 3 | 9 |
| DEATH | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 |
| DYSPHAGA/DYSPHONIA | 0 | 0 | 14 | 9 | 1 | 0 | 2 | 2 | 0 | 1 | 0 | 0 | 17 | 12 |
| Dysphagia | 0 | 0 | 13 | 8 | 1 | 0 | 2 | 2 | 0 | 0 | 0 | 0 | 16 | 10 |
| Dysphonia | 0 | 0 | 1 | 1 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 1 | 2 |
| GA STRONTESTINAL | 0 | 0 | 6 | 12 | 2 | 1 | 0 | 3 | 2 | 8 | 0 | 2 | 10 | 26 |
| INFECTION | 0 | 0 | 4 | 9 | 1 | 1 | 1 | 1 | 2 | 11 | 0 | 0 | 8 | 26 |
| Local | 0 | 0 | 1 | 2 | 1 | 1 | 1 | 4 | 1 | 8 | 0 | 0 | 4 | 15 |
| Superficial Wound - Cervical | 0 | 0 | 3 | 5 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 3 | 5 |
| Deep Wound - Cervical | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 1 | 0 |
| Systemic | 0 | 0 | 0 | 2 | 0 | 0 | 0 | 1 | 0 | 2 | 0 | 0 | 0 | 5 |
| Other Wound - Non StudySurgery | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 1 |
| NECKAND/ORARIM PAIN | 0 | 0 | 17 | 22 | 14 | 11 | 12 | 15 | 16 | 27 | 3 | 5 | 62 | 80 |
| Arm Pain | 0 | 0 | 6 | 7 | 3 | 3 | 4 | 6 | 4 | 7 | 1 | 3 | 18 | 26 |
| Neck Pain | 0 | 0 | 9 | 14 | 10 | 8 | 5 | 8 | 10 | 19 | 1 | 2 | 35 | 51 |
| Neck and Arm Pain | 0 | 0 | 2 | 1 | 1 | 0 | 3 | 1 | 2 | 1 | 1 | 0 | 9 | 3 |
| NEUROLOGICAL | 0 | 0 | 17 | 35 | 10 | 16 | 16 | 26 | 21 | 34 | 4 | 4 | 68 | 115 |
| Neck | 0 | 0 | 4 | 11 | 3 | 2 | 5 | 1 | 3 | 2 | 0 | 0 | 15 | 16 |
| Back | 0 | 0 | 0 | 3 | 1 | 0 | 0 | 3 | 3 | 0 | 0 | 1 | 4 | 7 |
| Gait Disturbance | 0 | 0 | 0 | 1 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 1 | 1 |
| Spinal Cord Disturbance | 0 | 0 | 2 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 2 | 0 |
| Upper Extremity | 0 | 0 | 9 | 19 | 4 | 9 | 8 | 15 | 10 | 21 | 3 | 3 | 34 | 67 |
| Lower Extremity | 0 | 0 | 1 | 1 | 2 | 5 | 1 | 6 | 3 | 7 | 1 | 0 | 8 | 19 |
| Non-Specific | 0 | 0 | 1 | 0 | 0 | 0 | 1 | 0 | 2 | 0 | 0 | 0 | 4 | 0 |
| Other | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 4 | 0 | 0 | 0 | 5 |
| NON-UNION | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 5 | 0 | 5 | 0 | 0 | 0 | 11 |
| OTHER PAIN | 0 | 0 | 27 | 42 | 20 | 20 | 20 | 28 | 19 | 33 | 5 | 4 | 91 | 127 |
| Back | 0 | 0 | 2 | 14 | 7 | 5 | 4 | 10 | 9 | 8 | 1 | 3 | 23 | 40 |
| Headache | 0 | 0 | 5 | 7 | 5 | 3 | 7 | 4 | 3 | 3 | 3 | 1 | 23 | 18 |
| Lower Extremity | 0 | 0 | 2 | 5 | 3 | 3 | 3 | 4 | 4 | 10 | 1 | 0 | 13 | 22 |
| Shoulder | 0 | 0 | 11 | 12 | 5 | 7 | 5 | 9 | 2 | 10 | 0 | 0 | 23 | 38 |
| Torsio | 0 | 0 | 1 | 1 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 1 | 2 |
| Other | 0 | 0 | 6 | 3 | 0 | 2 | 1 | 0 | 1 | 1 | 0 | 0 | 8 | 6 |
| RESPIRATORY | 0 | 0 | 2 | 1 | 0 | 1 | 1 | 3 | 1 | 3 | 0 | 0 | 4 | 8 |
| SPINAL DISORDER | 0 | 0 | 1 | 2 | 0 | 3 | 1 | 5 | 5 | 16 | 0 | 2 | 7 | 28 |
| "No subcategory for CervicCorse" | 0 | 0 | 0 | 1 | 0 | 1 | 0 | 0 | 0 | 3 | 0 | 2 | 0 | 7 |
| Cervical - Non-StudySurgery | 0 | 0 | 0 | 1 | 0 | 1 | 0 | 1 | 3 | 5 | 0 | 0 | 3 | 8 |
| Cervical - StudySurgery | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 1 | 0 | 0 | 0 | 1 | 1 |
| Non Cervical | 0 | 0 | 1 | 0 | 0 | 0 | 1 | 4 | 1 | 8 | 0 | 0 | 3 | 12 |
| TRAUMA | 0 | 0 | 3 | 7 | 2 | 7 | 4 | 13 | 7 | 16 | 0 | 2 | 16 | 45 |
| UPPER EXTREMITY NERVE ENTRAPMENT | 0 | 0 | 5 | 4 | 1 | 0 | 0 | 5 | 1 | 6 | 0 | 0 | 7 | 15 |
| UROGENITAL | 0 | 0 | 1 | 3 | 0 | 2 | 0 | 2 | 2 | 2 | 1 | 0 | 4 | 9 |
| WOUND ISSUE NON-INFECTION | 0 | 0 | 21 | 6 | 0 | 0 | 0 | 3 | 0 | 1 | 0 | 0 | 21 | 10 |
| OTHER | 0 | 0 | 10 | 23 | 9 | 6 | 8 | 10 | 4 | 19 | 0 | 10 | 31 | 68 |
| Total IAE Categories | 0 | 0 | 130 | 179 | 61 | 70 | 67 | 128 | 86 | 184 | 14 | 33 | 358 | 594 |

At 24 months, the nature and incidence of specific adverse events were comparable in the two study arms. In both study arms, the highest counts of adverse events were dysphagia/dysphonia, neck and arm pain, neurological events and wound complications. In each of these categories, the counts were numerically higher for the control group, with the exception of dysphagia and dysphonia and wound complications, which were higher for the M6-C™ group.

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# Definitely Device Related Adverse Events

There was 1 event in the M6-CTM group (in 1 subject, $0.6\%$ rate) and 13 events in the ACDF group (in 7 subjects, $3.7\%$ rate) that were determined to be definitely related to the device (Table 14). The event categories where the ACDF rate is higher than the M6-CTM rate included neurological (upper extremity). The non-union adverse event rate for the ACDF group was $2.6\%$ . Adverse events related to non-union were not expected in the M6-CTM group since it is a motion-sparing technology. There were no categories where the M6-CTM rate was higher than the ACDF rate. These data should be interpreted in the context of different adverse event categorizations and definitions for device-related adverse events between the two studies.

Table 14: Counts and Percentages of Subjects with Specific Definitely Device Related Adverse Event Sub-Categories with Two-Sided $95\%$ CI's - ITT (PS Selected) Cohort through 24 Months

| | M6-CTM (I) (N=160) | | | ACDF (C) (N=189) | | | I vs C1 | | |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| Adverse Event Category/Sub Category | No. of Events | No. of Pts. | % of Pts. | No. of Events | No. of Pts. | % of Pts. | Diff | LB | UB |
| ANATOMY:TECHNICAL DIFFICULTY | 0 | 0 | 0.0 | 1 | 1 | 0.5 | -0.5 | -11.0 | 10.0 |
| Cervical - Study Surgery | 0 | 0 | 0.0 | 1 | 1 | 0.5 | -0.5 | -11.0 | 10.0 |
| DYSPHAGIA:DYSPHONIA | 0 | 0 | 0.0 | 1 | 1 | 0.5 | -0.5 | -11.0 | 10.0 |
| Dysphagia | 0 | 0 | 0.0 | 1 | 1 | 0.5 | -0.5 | -11.0 | 10.0 |
| INFECTION | 1 | 1 | 0.6 | 0 | 0 | 0.0 | 0.6 | -9.9 | 11.1 |
| Deep Wound - Cervical | 1 | 1 | 0.6 | 0 | 0 | 0.0 | 0.6 | -9.9 | 11.1 |
| NECK AND/OR ARM PAIN | 0 | 0 | 0.0 | 1 | 1 | 0.5 | -0.5 | -11.0 | 10.0 |
| Arm Pain | 0 | 0 | 0.0 | 1 | 1 | 0.5 | -0.5 | -11.0 | 10.0 |
| NEUROLOGICAL | 0 | 0 | 0.0 | 4 | 4 | 2.1 | -2.1 | -12.6 | 8.4 |
| Upper Extremity | 0 | 0 | 0.0 | 4 | 4 | 2.1 | -2.1 | -12.6 | 8.4 |
| NON-UNION | 0 | 0 | 0.0 | 5 | 5 | 2.6 | -2.6 | -13.1 | 7.9 |
| RESPIRATORY | 0 | 0 | 0.0 | 1 | 1 | 0.5 | -0.5 | -11.0 | 10.0 |
| Subjects with at least 1 adverse event | | 1 | | | 7 | | | | |
| Notes: 1 Exact 95% binomial confidence interval without PS adjustment. | | | | | | | | | |

# Serious Adverse Events (SAEs)

There were a total of 25 SAEs in the M6-CTM group in 15 subjects and 62 SAEs in 28 subjects in the control group (Table 15). Categories where the rates were higher in the ACDF control included gastrointestinal $(2.6\%)$ and other pain $(4.2\%)$ . The non-union adverse event rate for the ACDF control was $3.2\%$ . Adverse events related to non-union were not expected in the M6-CTM group since it is a motion-sparing technology. There was one category where the M6-CTM group had a higher rate than the ACDF group (Infection, deep wound - cervical; $0.6\%$ ).

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Table 15: Counts and Percentages of Subjects with Specific Serious Adverse Event Sub-Categories with Two-Sided 95% CI's – ITT (PS Selected) Cohort through 24 Months

| | M6-C™ (I)
(N=160) | | | ACDF (C)
(N=189) | | | I vs C¹ | | |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| Adverse Event Category/Sub Category | No. of Events | No. of Pts. | % of Pts. | No. of Events | No. of Pts. | % of Pts. | Diff | LB | UB |
| ANATOMY:TECHNICAL DIFFICULTY | 0 | 0 | 0.0 | 1 | 1 | 0.5 | -0.5 | -11.0 | 10.0 |
| Cervical - Study Surgery | 0 | 0 | 0.0 | 1 | 1 | 0.5 | -0.5 | -11.0 | 10.0 |
| CANCER | 7 | 3 | 1.9 | 1 | 1 | 0.5 | 1.3 | -9.2 | 11.8 |
| CARDIOVASCULAR | 0 | 0 | 0.0 | 1 | 1 | 0.5 | -0.5 | -11.0 | 10.0 |
| DEATH | 1 | 1 | 0.6 | 0 | 0 | 0.0 | 0.6 | -9.9 | 11.1 |
| DYSPHAGIA:DYSPHONIA | 0 | 0 | 0.0 | 2 | 2 | 1.1 | -1.1 | -11.5 | 9.4 |
| Dysphagia | 0 | 0 | 0.0 | 2 | 2 | 1.1 | -1.1 | -11.5 | 9.4 |
| GASTROINTESTINAL | 1 | 1 | 0.6 | 6 | 5 | 2.6 | -2.0 | -12.5 | 8.5 |
| INFECTION | 1 | 1 | 0.6 | 3 | 3 | 1.6 | -1.0 | -11.5 | 9.5 |
| Local | 1 | 1 | 0.6 | 3 | 3 | 1.6 | -1.0 | -11.5 | 9.5 |
| NECK AND/OR ARM PAIN | 1 | 1 | 0.6 | 3 | 3 | 1.6 | -1.0 | -11.5 | 9.5 |
| Arm Pain | 1 | 1 | 0.6 | 0 | 0 | 0.0 | 0.6 | -9.9 | 11.1 |
| Neck Pain | 0 | 0 | 0.0 | 3 | 3 | 1.6 | -1.6 | -12.1 | 8.9 |
| NEUROLOGICAL | 5 | 4 | 2.5 | 8 | 8 | 4.2 | -1.7 | -12.2 | 8.8 |
| Neck | 0 | 0 | 0.0 | 1 | 1 | 0.5 | -0.5 | -11.0 | 10.0 |
| Back | 1 | 1 | 0.6 | 0 | 0 | 0.0 | 0.6 | -9.9 | 11.1 |
| Spinal Cord Disturbance | 1 | 1 | 0.6 | 0 | 0 | 0.0 | 0.6 | -9.9 | 11.1 |
| Upper Extremity | 3 | 2 | 1.3 | 3 | 3 | 1.6 | -0.3 | -10.8 | 10.2 |
| Lower Extremity | 0 | 0 | 0.0 | 2 | 2 | 1.1 | -1.1 | -11.5 | 9.4 |
| Other | 0 | 0 | 0.0 | 2 | 2 | 1.1 | -1.1 | -11.5 | 9.4 |
| NON-UNION | 0 | 0 | 0.0 | 7 | 6 | 3.2 | -3.2 | -13.6 | 7.3 |
| OTHER PAIN | 1 | 1 | 0.6 | 9 | 8 | 4.2 | -3.6 | -14.1 | 6.9 |
| Back | 1 | 1 | 0.6 | 3 | 3 | 1.6 | -1.0 | -11.5 | 9.5 |
| Headache | 0 | 0 | 0.0 | 1 | 1 | 0.5 | -0.5 | -11.0 | 10.0 |
| Lower Extremity | 0 | 0 | 0.0 | 2 | 2 | 1.1 | -1.1 | -11.5 | 9.4 |
| Shoulder | 0 | 0 | 0.0 | 2 | 2 | 1.1 | -1.1 | -11.5 | 9.4 |
| RESPIRATORY | 2 | 2 | 1.3 | 1 | 1 | 0.5 | 0.7 | -9.8 | 11.2 |
| SPINAL DISORDER | 4 | 4 | 2.5 | 9 | 5 | 2.6 | -0.1 | -10.6 | 10.4 |
| "No subcategory for CerviCore" | 0 | 0 | 0.0 | 1 | 1 | 0.5 | -0.5 | -11.0 | 10.0 |
| Cervical - Non-Study Surgery | 2 | 2 | 1.3 | 2 | 2 | 1.1 | 0.2 | -10.3 | 10.7 |
| Cervical - Study Surgery | 1 | 1 | 0.6 | 0 | 0 | 0.0 | 0.6 | -9.9 | 11.1 |
| Non Cervical | 1 | 1 | 0.6 | 6 | 3 | 1.6 | -1.0 | -11.5 | 9.5 |
| TRAUMA | 0 | 0 | 0.0 | 4 | 4 | 2.1 | -2.1 | -12.6 | 8.4 |
| UPPER EXTREMITY NERVE ENTRAPMENT | 1 | 1 | 0.6 | 1 | 1 | 0.5 | 0.1 | -10.4 | 10.6 |
| UROGENITAL | 1 | 1 | 0.6 | 1 | 1 | 0.5 | 0.1 | -10.4 | 10.6 |
| WOUND ISSUE NON-INFECTION | 0 | 0 | 0.0 | 2 | 2 | 1.1 | -1.1 | -11.5 | 9.4 |
| OTHER | 0 | 0 | 0.0 | 3 | 2 | 1.1 | -1.1 | -11.5 | 9.4 |
| Subjects with at least 1 adverse event | | 15 | | | 28 | | | | |
| Notes:
¹ Exact 95% binomial confidence interval without PS adjustment. | | | | | | | | | |

## Definitely Device- or Procedure- Related Serious Adverse Events

There were 3 M6-C™ subjects (1.88%) and 8 control subjects (4.23%) with at least one SAE definitely related to the device or procedure. Based on the lower and upper bounds, there were no notable observed differences in the reported device- and procedure- related SAEs between the two study groups.

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Table 16: Counts and Percentages of Subjects with Specific Serious, Definitely Device/Procedure Related Adverse Event Sub-Categories with Two-Sided 95% CI's – ITT (PS Selected) Cohort through 24 Months

| | M6-CTM (I) (N=160) | | | ACDF (C) (N=189) | | | I vs C¹ | | |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| Adverse Event Category/Sub Category | No. of Events | No. of Pts. | % of Pts. | No. of Events | No. of Pts. | % of Pts. | Diff | LB | UB |
| ANATOMY:TECHNICAL DIFFICULTY | 0 | 0 | 0.0 | 1 | 1 | 0.5 | -0.5 | -11.0 | 10.0 |
| Cervical - Study Surgery | 0 | 0 | 0.0 | 1 | 1 | 0.5 | -0.5 | -11.0 | 10.0 |
| DEATH | 1 | 1 | 0.6 | 0 | 0 | 0.0 | 0.6 | -9.9 | 11.1 |
| DYSPHAGIA:DYSPHONIA | 0 | 0 | 0.0 | 1 | 1 | 0.5 | -0.5 | -11.0 | 10.0 |
| Dysphagia | 0 | 0 | 0.0 | 1 | 1 | 0.5 | -0.5 | -11.0 | 10.0 |
| NEUROLOGICAL | 3 | 2 | 1.3 | 3 | 3 | 1.6 | -0.3 | -10.8 | 10.2 |
| Spinal Cord Disturbance | 1 | 1 | 0.6 | 0 | 0 | 0.0 | 0.6 | -9.9 | 11.1 |
| Upper Extremity | 2 | 1 | 0.6 | 3 | 3 | 1.6 | -1.0 | -11.5 | 9.5 |
| NON-UNION | 0 | 0 | 0.0 | 5 | 5 | 2.6 | -2.6 | -13.1 | 7.9 |
| RESPIRA…