Medtronic PRESTIGE LP User Manual

Instructions for Use

PRESTIGE LP™ CERVICAL DISC

Medtronic Sofamor Danek USA, Inc.

1800 Pyramid Place Memphis, TN 38132 Tel. 800 933 2635 (In U.S.A.)

901 396 3133 (Outside of U.S.A.)

Fax 901 396 0356

CAUTION: Federal (United States) law restricts this device to sale by or on the order of a

Physician.

HOW SUPPLIED

PRESTIGE LP™ Cervical Disc Implants – Sterile Surgical Instruments – Non-sterile (unless otherwise noted on the package label)

DEVICE DESCRIPTION

The PRESTIGE LP™ Cervical Disc is a two-piece articulating device that is inserted into the intervertebral disc space as a pre-assembled unit at one or two contiguous cervical levels using an anterior approach. The device is manufactured from a titanium ceramic composite (Titanium6Aluminum-4Vanadium with 10% Titanium Carbide) and consists of two metal plates which function via a ball and trough mechanism. The superior component of the implant contains the ball portion of the mechanism, and the inferior component contains the trough portion. These two features engage to create an interface designed to allow for motion after implantation. Each component is affixed to the adjacent vertebral body by two rail geometries incorporating antimigration teeth, which are press fit into two pre-drilled holes in the vertebral bone. The portion of the flat surface between the rails that contacts the vertebral endplate has a commercially pure titanium (CP Ti) plasma thermal sprayed coating per ASTM F1580, designed to permit bony ongrowth for additional device incorporation. The remaining portion of the flat surface is titanium ceramic roughened to enhance fixation. Each component also contains two anterior tab features designed to aid in device insertion and to minimize the risk of implanting the device too far into the intervertebral space.

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Catalog Number

Size (Height x AP Dimens ion x ML Dimension)

6972250

5mm x 12mm x 15mm

6972450

5mm x 14mm x 15mm

6972650

5mm x 16 mm x 15mm

6972260

6mm x 12mm x 17.8mm

6972460

6mm x 14mm x 17.8mm

6972660

6mm x 16mm x 17.8mm

6972860

6mm x 18mm x 17.8mm

6972470

7mm x 14mm x 17.8mm

6972670

7mm x 16mm x 17.8mm

6972870

7mm x 18mm x 17.8mm

6972480

8mm x 14mm x 17.8mm

6972680

8mm x 16mm x 17.8mm

6972880

8mm x 18mm x 17.8mm

Figure 1a: PRESTIGE LP™ Cervical Disc Figure 1b: PRESTIGE LP™

Cervical Disc at two contiguous levels

The PRESTIGE LP™ Cervical Disc is offered in a variety of configurations to accommodate varied patient anatomy. The available components are shown in Table 1 below.

The PRESTIGE LP™ Cervical Disc is designed to allow a minimum of 10 degrees lateral bending (from neutral) and a minimum of 10 degrees flexion/extension (from neutral). The design is also intended to allow unlimited axial rotation (constrained by ligaments and posterior elements) and translation of ±2mm in the sagittal plane.

Table 1: PRESTIGE LP™ Cervical Disc Device Sizes

The PRESTIGE LP™ Cervical Disc is implanted using instruments specific to the device, as well as manual surgical instruments. Instruments specifically designed for implanting

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PRESTIGE LP™ Cervical Disc consist of trials, trial cutter guides, rail punches, and implant inserters. General purpose instruments include instruments for cervical distraction and discectomy preparation.

No warranties, express or implied, are made. Implied warranties of merchantability and fitness for a particular purpose or use are specifically excluded.

INDICATIONS FOR USE

The PRESTIGE LP™ Cervical Disc is indicated in skeletally mature patients for reconstruction of the disc from C3-C7 following discectomy at one level or two contiguous levels for intractable radiculopathy (arm pain and/or a neurological deficit) with or without neck pain, or myelopathy due to abnormality localized to the level of the disc space and at least one of the following conditions confirmed by imaging (CT, MRI, X-rays): herniated nucleus pulposus, spondylosis (defined by the presence of osteophytes), and/or visible loss of disc height as compared to adjacent levels. The PRESTIGE LP™ Cervical Disc is implanted using an anterior approach. Patients should have failed at least 6 weeks of non-operative treatment or have had the presence of progressive symptoms or signs of nerve root/spinal cord compression in the face of continued non-operative management prior to implantation of the PRESTIGE LP™ Cervical Disc.

CONTRAINDICATIONS

The PRESTIGE LP™ Cervical Disc should not be implanted in patients with the following conditions:

• Active systemic infection or localized infection at the surgical site;

• Osteoporosis or osteopenia defined as a DEXA bone mineral density T-score ≤ -1.0;

• Allergy or sensitivity to titanium, aluminum or vanadium;

• Marked cervical instability on neutral resting lateral or flexion/extension radiographs;

translation >3.5mm and/or >11° rotational difference from that of either level adjacent to the treated levels;

• Severe spondylosis at the level to be treated, characterized by bridging osteophytes, loss

of disc height >50%, an absence of motion (<2°) as this may lead to a limited range of motion and may encourage bone formation (e.g. heterotopic ossification, fusion);

• Severe facet joint arthropathy;

• Significant cervical anatomical deformity or clinically compromised vertebral bodies at

the affected level(s) due to current or past trauma (e.g., by radiographic appearance of fracture callus, malunion or nonunion) or disease (e.g., ankylosing spondylitis, rheumatoid arthritis); or

• Significant kyphotic deformity or significant reversal of lordosis.

WARNINGS

The PRESTIGE LP™ Cervical Disc should only be used by surgeons who are experienced with anterior cervical spinal procedures and have undergone adequate hands-on training in the use of this specific device. Only surgeons who are familiar with the implant components, instruments, procedure, clinical applications, biomechanics, adverse events, and risks associated with the PRESTIGE LP™ Cervical Disc should use this device. Medtronic will offer hands-on training to physicians prior to their first use of the device. A lack of adequate experience and/or training may lead to a higher incidence of adverse events, including neurological complications.

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Correct sizing and placement of the device is essential to optimal performance. Information regarding proper implant size selection, implant site preparation, and the use of instrumentation before, during and after PRESTIGE LP™ surgery is provided in the PRESTIGE LP™ Cervical Disc Surgical Technique manual. Users are advised to read and understand the surgical technique manual and instructions for use prior to surgery.

Due to the proximity of vascular and neurological structures to the implantation site, there are risks of serious or fatal hemorrhage and risks of neurological damage with the use of this device. Serious or fatal hemorrhage may occur if the great vessels are eroded or punctured during implantation or are subsequently damaged due to breakage of implants, migration of implants, or if pulsatile erosion of the vessels occurs because of close apposition of the implants. Care must be taken to identify and protect these structures.

Heterotopic Ossification (HO) is a potential complication associated with artificial cervical discs and could lead to reduced cervical motion.

Devices with metal-on-metal articulating surfaces (such as the Prestige LP Cervical Disc) may release wear debris, metallic particles or metal ions locally near the device and/or systemically. The short and long term effects of the wear debris, metallic particles and metal ions on the body are not known, but certain groups of patients may be at a higher risk including patients who are pregnant, patients who are planning to get pregnant, and patients who have renal disease.

PRECAUTIONS

The safety and effectiveness of this device has not been established in patients with the following conditions:

• Axial neck pain as the solitary symptom;

• Skeletally immature patients, pediatric or adolescent children (<21 years old), or those

over the age of 78;

• Prior cervical spine surgery, including prior surgery at the index level or adjacent levels;

• More than two cervical discs or two non-adjacent cervical discs that require surgical

treatment;

• Facet joint pathology of involved vertebral bodies;

• Spinal metastases;

• An endocrine or metabolic disease that affects bones such as Paget’s disease,

osteomalacia, renal osteodystrophy, Ehlers-Danlos Syndrome, or osteogenesis imperfecta;

• Chronic or acute renal failure or history of renal disease;

• Taking medications known to potentially interfere with bone/soft tissue healing (e.g.,

steroids);

• Diabetes mellitus requiring daily insulin management;

• Serious mental illness;

• Being treated for alcohol and/or drug abuse; and

• Pregnant.

Pre-operative

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Patient selection is extremely important. In selecting patients for a total disc replacement, the following factors may negatively affect the success of the procedure: the patient’s occupation or activity level; prior injury or ongoing illness (e.g., Alzheimer’s disease, emphysema); alcoholism or drug abuse; and certain degenerative diseases (e.g., degenerative scoliosis, ankylosing spondylitis) that may be so advanced at the time of implantation that the expected useful life of the device is substantially diminished.

In order to minimize the risk of periprosthetic vertebral fractures, surgeons must consider all comorbidities, past and present medications, previous treatments, etc. Surgeons should screen patients to determine if a DEXA bone mineral density measurement is necessary. If DEXA is performed, the patient should not receive the PRESTIGE LP™ Cervical Disc (per the contraindications listed above) if the DEXA bone mineral density T-score is ≤ -1.0, as the patient may be osteoporotic or osteopenic.

The patient should be informed of the potential adverse effects (risk/complications) contained in this insert (see POTENTIAL ADVERSE EFFECTS OF THE DEVICE ON HEALTH).

Preoperative planning may be used to estimate the required implant size and to assure that the appropriate range of sizes is available for surgery. Specific preoperative planning is necessary when performing a two-level procedure. The procedure should not take place if the appropriate range of sizes will not be available.

Inspect all instruments prior to surgery and replace any worn or damaged items. Instruments which have been used excessively may be more likely to break.

Intra-operative

Correct selection of the appropriate implant size is extremely important to ensure the placement and function of the disc. When performing a two-level procedure, to ensure sufficient access to the two affected disc spaces, make the skin incision centered at the middle vertebral body. A standard incision for the exposure of two levels is required. See the surgical technique manual for step-by-step instructions on the surgical technique, including determining the correct implant size.

Use aseptic technique when removing the PRESTIGE LP™ Cervical Disc components from the innermost packaging. Carefully inspect each component and its packaging for any signs of damage, including damage to the sterile barrier. Do not use PRESTIGE LP™ Cervical Disc components if the packaging is damaged or the implant shows signs of damage.

Use care when handling a PRESTIGE LP™ Cervical Disc component to ensure it does not come in contact with objects that could damage the implant. Exercise care to ensure implantation instruments do not contact the highly polished articulating surfaces of the endplates. Damaged implants are no longer functionally reliable. Visual inspection of the PRESTIGE LP™ Cervical Disc assembly is recommended prior to implantation. If any part of the assembly appears damaged, do not use the device.

When preparing the disc space, remove anterior or posterior osteophytes as needed, taking care to

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perform a complete discectomy while minimizing bone removal, as excessive bone removal may weaken the vertebral endplates or vertebral body.

Correct positioning of the rail punch is critical prior to performing the rail preparation step. Care should be taken to correctly position the rail punch during this step.

Ensure proper alignment and placement of the PRESTIGE LP™ Cervical Disc as misalignment may cause excessive wear and/or early failure of the device.

In a two-level procedure, when placing the first implant, pay special attention to implant height selection. The goal is to balance the discs to achieve normal sagittal balance and disc space height. Before placing the first implant, it is important to verify normal sagittal balance and disc space height by using the Implant Trials. Achieve this by preoperative templating, careful trialing under lateral fluoroscopy, and comparing the facet and intradiscal heights in healthy adjacent levels. Implant Trials should fit snugly without distracting the disc spaces.

The PRESTIGE LP™ Cervical Disc components should not be used with components or instruments of spinal systems from other manufacturers. See the surgical technique manual for step-by-step instructions.

The PRESTIGE LP™ Cervical Disc implants are designed for single patient use only. Do not reuse, re-process, or re-sterilize the implants. Even if the device appears undamaged, re-use, reprocessing, or re-sterilization may compromise the structural integrity of the implant and the intended function of the device which could result in patient injury.

Post-operative

Patients in the clinical study of the PRESTIGE LP™ Cervical Disc were instructed to use nonsteroidal anti-inflammatory drugs (NSAIDs) for two weeks postoperatively. It has been reported in the literature that short-term postoperative use of NSAIDs may reduce the instance of heterotopic ossification (HO). To reduce the instance of HO, it is recommended that the PRESTIGE LP™ device be implanted in subjects able to tolerate the use of NSAIDs for two weeks post-operatively.

Patients should be instructed in postoperative care procedures and should be advised of the importance of adhering to these procedures for successful treatment with the device. Patients should be advised to avoid any activities that require repeated bending or twisting, heavy lifting, and challenging activities such as athletic activities. Gradual increase in physical activity will depend on individual patient progress.

MRI Safety Information

In non-clinical testing the PRESTIGE LP™ Cervical Disc implanted at either a single level or two contiguous levels was determined to be MR-conditional. A patient with this device can be scanned safely, immediately after placement, under the following conditions:

• Static magnetic field of 1.5-Tesla and 3.0-Tesla.

• Maximum spatial gradient magnetic field of 3000-Gauss/cm or less.

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• Maximum whole body average specific absorption rate (SAR) of 4.0 -W/kg or less under

Normal Operating Mode or first level controlled operating mode.

• Body Coil only.

Under the scan conditions defined above, the PRESTIGE LP™ Cervical Disc is expected to produce a maximum temperature rise of less than 4.0°C after 15 minutes of continuous scanning.

In non-clinical testing, the image artifact caused by the device extends approximately 20 mm from the PRESTIGE LP™ Cervical Disc when imaged with a gradient echo pulse sequence in a

3.0 Tesla MRI system. If the PRESTIGE LP™ Cervical Disc is used in connection with any device which is not

MR Conditional, please be advised that this combination has not been tested in the MR environment and, therefore, higher heating and possible injury to the patient may occur.

The presence of other implants or the health state of the patient may require a modification of the MR conditions.

POTENTI AL AD VERSE EFFECTS OF THE D EVI CE ON HEALTH

Below is a list of the potential adverse effects (e.g., complications) associated with the use of the PRESTIGE LP™ Cervical Disc identified from the PRESTIGE LP™ Cervical Disc clinical study results, approved device labeling for other cervical total disc replacement devices, and published scientific literature including: (1) those associated with any surgical procedure; (2) those associated with anterior cervical spine surgery; and (3) those associated with a cervical artificial disc device, including the PRESTIGE LP™ Cervical Disc. In addition to the risks listed below, there is also the risk that surgery may not be effective in relieving symptoms, or may cause worsening of symptoms. Additional surgery may be required to correct some of the adverse effects.

1. Risks associated with any surgical procedure include:

• Anesthesia complications including an allergic reaction or anaphylaxis;

• Infection (wound, local, and/or systemic) or abscess;

• Wound dehiscence or necrosis;

• Edema;

• Soft tissue damage or fluid collections, including hematoma or seroma;

• Pain/discomfort at the surgical incision and/or skin or muscle sensitivity over the incision

which may result in skin breakdown, pain, and/or irritation;

• Heart or vascular complications including bleeding, hemorrhage or vascular damage

resulting in catastrophic or potentially fatal bleeding, ischemia, myocardial infarction, abnormal blood pressure, venous thromboembolism including deep vein thrombosis and pulmonary embolism, thrombophlebitis, or stroke;

• Pulmonary complications including atelectasis or pneumonia;

• Impairment of the gastrointestinal system including ileus or bowel obstruction;

• Impairment of the genitourinary system including incontinence, bladder dysfunction, or

reproductive system complications;

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• Neurological complications including nerve damage, paralysis, seizures, changes to

mental status, or reflex sympathetic dystrophy;

• Complications of pregnancy including miscarriage or congenital defects;

• Inability to resume activities of daily living; and

• Death.

2. Risks associated with anterior cervical spine surgery include:

• Injury to surrounding organs and structures including the spinal cord, nerve roots, other

neurologic structures adjacent to the spinal column, vocal cords, adjacent vertebrae, lymphatic vessels, blood vessels, soft tissue, dura, the trachea, the esophagus, the larynx, or the pharynx;

• Dysphagia, dysphonia, hoarseness, vocal cord paralysis, laryngeal palsy; or sore throat;

• Tracheal, esophageal, or pharyngeal perforation, fistula, recurrent aspiration, or airway

obstruction;

• Neurological complications, including damage to nerve roots, the spinal cord, or other

nerves possibly resulting in muscle weakness or paralysis, changes in sensation (including numbness, dysesthesias, or paresthesias), bowel/bladder dysfunction, or pain;

• Neck pain, arm pain, or headache;

• Dural tear or leak or cerebrospinal fistula;

• Discitis, arachnoiditis, or other type of inflammation;

• Loss of disc height; loss of anatomic sagittal plane curvature or vertebral listhesis, spinal

stenosis, or spondylolysis; and

• Scarring, herniation or degeneration of adjacent discs.

3. Risks associated with a cervical artificial disc device, including the PRESTIGE LP™

Cervical Disc, include:

• Risks directly related to the device including malposition, migration/displacement,

subsidence/loss of disc height, device breakage, device disassembly, or early or late loosening of the device. Any of these issues may cause pain or injury to surrounding organs and structures including the spinal cord, nerve roots, or other neurologic structures adjacent to the spinal column (which could cause pain, paralysis, or numbness) or blood vessel damage or erosion (which could cause catastrophic or fatal bleeding);

• Deterioration in neurologic status including muscle weakness or paralysis, changes in

sensation (including numbness, dysesthesias, or paresthesias), decreased reflexes, or loss of bowel and/or bladder control;

• Development of new radiculopathy, myelopathy, or pain;

• Failure of the device to improve symptoms or function;

• Problems during placement of the device including trouble sizing the device, anatomical

or technical difficulties implanting the device, or issues with the device instruments (e.g., bending or breakage) including the possibility that a fragment of a broken instrument may remain in the patient after implantation;

• Adverse reaction or allergy to the device materials (titanium, aluminum or vanadium),

device wear debris or metal ions which may lead to a systemic reaction or a local adverse tissue reaction or chronic inflammation which may lead to implant loosening or failure of

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the device, osteolysis, bone resorption, tumor formation, autoimmune disease, metallosis, scarring, or other symptoms;

• Change in the alignment of the spine or loss of proper anatomic curvature, correction,

height or reduction of the spine including spondylolisthesis, change in lordosis, or instability of the spine;

• Degeneration of other parts of the spine including the facet joints or adjacent discs;

• Fracture of the surrounding vertebrae;

• Unintended bone formation (i.e., heterotopic ossification) that may result in bridging

trabecular bone and may reduce spinal motion or result in unintended fusion at either the treated level or adjacent levels;

• Device failure which may require a subsequent surgical intervention (including removal

of the PRESTIGE LP™ Cervical Disc, revision, re-operation, or supplemental fixation); and

• Interference with radiographic imaging because of the presence of the implant.

NOTE: Some of the adverse effects listed above were observed in the PRESTIGE LP™ Cervical Disc clinical studies. For detailed information on the specific adverse events that occurred in the clinical studies of the PRESTIGE LP™ Cervical Disc, please see Tables 8-10b and 12 for the single-level study and Tables 31-33 and 35 for the two-level study.

PHYSICIAN NOTE: Although the physician is the learned intermediary between the company and the patient, the important medical information given in this document should be conveyed to the patient.

CLINICAL STUDIES

Two IDE studies were conducted to support the safety and effectiveness of the PRESTIGE LP™ Cervical Disc for reconstruction of the disc from C3-C7 following discectomy at one level (G040086) or two contiguous levels (G050202) for the indications outlined above. The IDE studies are summarized separately below.

Single-Level Clinical Study (G040086)

The clinical investigation of the PRESTIGE LP™ Cervical Disc was conducted under an approved IDE #G040086. The study was a prospective, multi-center, non-randomized, unmasked, non-inferiority clinical trial conducted in the United States to compare the safety and effectiveness of the PRESTIGE LP™ Cervical Disc to the standard of care (a legally marketed alternative with similar indications for use) anterior cervical discectomy and fusion (ACDF) using structural allograft and plate stabilization. The control group consisted of a nonrandomized historical control group that received treatment with ACDF for reconstruction of the disc from C3-C7 following single-level discectomy for intractable radiculopathy and/or myelopathy in the previous IDE randomized trial of the PRESTIGE® Cervical Disc (#G010188).

The study consisted of 280 patients treated with the investigational device at 20 investigational centers in the clinical trial, and 265 patients received the control treatment under a previous IDE study. Fifty-four additional subjects were enrolled at the same investigational sites, including: 30 patients enrolled into a Metal Ion Cohort (MI) for which metal ion analysis was conducted based on blood draws at each follow-up time point; and, 24 Continued Access (CA) patients.

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Clinical Inclusion and Exc lusi on C ri te r ia

To qualify for enrollment in the study, subjects met all of the following inclusion criteria and none of the following exclusion criteria.

Clinical Inclusion Criteria

Enrollment in the PRESTIGE LP™ study was limited to patients who met the following inclusion criteria:

• Cervical degenerative disc disease defined as: intractable radiculopathy and/or

myelopathy with at least one of the following items producing symptomatic nerve root and/or spinal cord compression documented by patient history [e.g., pain, func tiona l deficit, and/ o r n eurologic deficit and radio gra p hic studies (e.g., computed tomography (CT), magnetic resonance imaging (MRI), x-rays, etc.)]

o Herniated disc; o Osteophyte formation

• One level requiring surgical treatment;

• C3-C4 disc to C6-C7 disc level of involvement;

• Unresponsive to non-operative treatment for approximately six weeks or has the presence

of progressive symptoms or signs of nerve root/spinal cord compression in the face of continued non-operative management;

• No previous surgical intervention at involved level or any subsequent, planned/staged

surgical procedure at the involved or adjacent level(s);

• Is at least 18 years of age, inclusive, at the time of the surgery;

• Preoperative Neck Disability Index score of ≥ 30;

• Has a preoperative neck pain score of ≥ 20 on Preoperative Neck and Arm Pain

Questionnaire;

• If a female of child-bearing potential, patient is not pregnant at the time of surgery;

• Is willing to comply with the study plan and sign the Patient Informed Consent Form.

Clinical Exclusion Criteria

Patients were not permitted to enroll in the PRESTIGE LP™ study if any of the following exclusion criteria were present:

• Has a cervical spinal condition other than symptomatic cervical disc disease requiring

surgical treatment at the involved level;

• Documented or diagnosed cervical instability defined by dynamic (flexion/extension)

radiographs showing sagittal plane translation > 3.5mm or sagittal plane angulation > 20°;

• More than one cervical level requiring surgical treatment;

• Has a fused level adjacent to the level to be treated;

• Has severe pathology of the facet joints of the involved vertebral bodies;

• Previous surgical intervention at the involved level;

• Has previous diagnosis of osteopenia or osteomalacia;

• Has any of the following that may be associated with a diagnosis of osteoporosis (if

“Yes” to any of the below risk factors, a DEXA Scan will be required to determine

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eligibility):

o Postmenopausal non-Black female over 60 years of age and weighs less than 140

pounds

o Postmenopausal female that has sustained a non-traumatic hip, spine, or wrist

fracture

o Male over the age of 70 o Male over the age of 60 that has sustained a non-traumatic hip or spine fracture

If the level of bone mineral density (BMD) is a T score of -3.5 or a T score of -2.5 with vertebral crush fracture, the patient is excluded from the study

• Has presence of spinal metastases;

• Has overt or active bacterial infection, either local or systemic;

• Has severe insulin dependent diabetes;

• Has chronic or acute renal failure or prior history of renal disease;

• Has fever (temperature > 101°F oral) at the time of surgery;

• Has a documented allergy or intolerance to stainless steel, titanium, or a titanium alloy;

• Is mentally incompetent (if questionable, obtain psychiatric consult);

• Is a prisoner;

• Is pregnant;

• Is an alcohol and/or drug abuser currently undergoing treatment for alcohol and/or drug

abuse

• Has received drugs which may interfere with bone metabolism within two weeks prior to

the planned date of spinal surgery (e.g., steroids or methotrexate) excluding routing perioperative anti-inflammatory drugs;

• Has a history of an endocrine or metabolic disorder known to affect osteogenesis (e.g.,

Paget’s Disease, renal osteodystrophy, Ehlers-Danlos Syndrome, or osteogenesis imperfecta);

• Has a condition that requires postoperative medications that interfere with the stability of

the implant, such as steroids. (This does not include low dose aspirin for prophylactic anticoagulation), excluding routine perioperative anti-inflammatory drugs;

• Has received treatment with an investigational therapy within 28 days prior to

implantation surgery or such treatment is planned during the 16 weeks following implantation with the PRESTIGE LP™ device.

Postoperative Care

The recommended post-operative care included avoidance of overhead lifting, heavy lifting, repetitive bending, and high-impact exercise or athletic activity for 60 days postoperatively. Avoidance of prolonged (beyond 2 weeks post-op) non-steroidal anti-inflammatory drug (NSAID) use was specified in the postoperative regimen, although the use of NSAIDs was recommended for the first two weeks post-operatively. Post-operative bracing requirements were left to the discretion of the investigators and included the option for use of a soft collar as needed. The use of electrical bone growth stimulators was not recommended during the 24month follow-up period. However, in a few cases where an electrical bone growth stimulator was utilized due to specific patient presentation, they were considered a supplemental form of therapy for spinal fusion surgery, and deemed failures included in the “Supplemental Fixation” Adverse Event category. Patients who smoked were encouraged to discontinue smoking.

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Pre-/Peri-Operative

Postoperative

24 mo.

Beyond

Preoperative Information

Confirm Patient Eligibility

Obtain Informed Consent

Obtain HIPAA Authorization

Case Report Forms

Patient Enrollment

Patient Qualification

Preoperative Data

Prior History Questionnaire

Neurological Status

X X X X X X

Preoperative Gait Assessment and

Foraminal Compression Test

Preoperative Patient Survey

Preoperative Neck Disability Index

Preoperative Neck and Arm Pain

Questionnaire

Health Status Questionnaire (SF-36)

X X X X

Surgery Data

Hospital Discharge

Postoperative Data

X X X X X

Postoperative Patient Survey

X X X X X

Neck Disability Index

X X X X X

Postoperative Neck and Arm Pain

Questionnaire

X X X X X

Postoperative Gait Assessment and

Foraminal Compression Test

X X X X X

Adverse Event Form (if any)

X X X X X X

Outstanding (Unresolved) Adverse E v e nt

(if any)

X X X X X X

Patient Disposition

X X X X X

Imaging – Radiographs and Scans*

Anterior/Posterior X-ray

X X X X X X X

Lateral X-ray

X X X X X X X

Right/Left Lateral Bend X-rays

X X X X X X

Flexion/Extension X-rays

X X X X X X

CT and/or MRI

DEXA Scan **

Follow-Up Schedule

Patients were evaluated preoperatively (within 6 months of surgery), intraoperatively, and postoperatively at 6 weeks (±2 weeks), 3 months (±2 weeks), 6 months (± one month), 12 months (± two months), 24 months (± two months), and annually thereafter until the last subject enrolled in the study had been seen for their 24-month evaluation, as shown in Table 2. Complications and adverse events were evaluated over the course of the clinical trial. At each evaluation timepoint, the primary and secondary clinical and radiographic outcome parameters were evaluated. Success was determined from data collected during the initial 24 months of follow-up.

Table 2: Schedule of Study Assessments

Procedure

Pre-OP

Surgery/ Hospital

Discharge

6 w ks ±2

wks

3 mo. ±2

wks

6 mo.

1 mo.

12 mo. ±

2mo.

2 mo.

* Patients w ho sign consent and are screened el igible, but who do not receive the PRESTIGE LP™ device, were not required to have the preoperative radiographs obtained and forwarded to Medtronic.

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** A DEXA S can was only required if the patient had a risk factor that may be associated with a diagnosis of osteoporosis.

Clinical Endpoints

The safety of the PRESTIGE LP™ Cervical Disc was assessed by comparison to the historical control group with respect to the nature and frequency of adverse events, secondary surgical procedures, as well as maintenance or improvement in neurological status.

The effectiveness of the PRESTIGE LP™ Cervical Disc device was assessed using a composite definition of study success. The primary endpoint used for assessment of effectiveness was improvement in Neck Disability Index (NDI) pain/disability scores.

In addition, several radiograph-assisted assessments were considered in evaluating both safety and effectiveness including device subsidence, functional spinal unit (FSU) height maintenance, device migration, and device breakage.

According to the final IDE protocol, an individual patient in either treatment group was considered an overall success if the following criteria were met at 24 months:

1. An improvement (reduction) of at least 15 points from the baseline Neck Disability Index

score;

2. Maintenance or improvement in neurological status;

3. Disc height (Functional Spinal Unit Height) success (FSU success)

4. No severe adverse event classified as implant-associated, surgical procedure-associated, or

implant/surgical procedure-associated; and

5. No additional surgical procedure classified as “Failure”

An alternative analysis of the primary endpoint analysis was also conducted without the addition of FSU height as a success criterion.

Secondary endpoints, measured in both treatment groups, included Radiographic Success, neck pain (VAS), arm pain (VAS), quality of life (SF-36 PCS and MCS scores), patient satisfaction, patient global perceived effort, gait assessment (Nurick’s classification), and foraminal compression test. Additional measurements recorded were adjacent level stability, return to work, and doctor’s perception of results. Radiographic Succcess for maintenance of motion is defined as >4° but <20° of angular motion based on lateral flexion/extension radiographs and no radiographic evidence of bridging trabecular bone that forms a continuous bony connection with the vertebral bodies (bridging bone).

Criteria for the success of the control group was defined in a previous IDE study (G010188). Briefly, the same success criteria for the primary endpoints exist for the control group as the investigational group, with the exception that the secondary endpoint for radiographic success was defined by radiographic evidence of bone spanning the two vertebral bodies, existence of angular motion stability <4°, and no radiolucent lines covering more than 50% of the implant surface.

Accountability of PMA Cohort

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Number of Patients:

12 Months (±2 Months)

24 Months (±2 Months)

Enrolled

280

265

333

280

265

333

Theoretical FU

280

265

333

280

265

333

Cumulative Deaths 1

0 2 0 0 2

Patients Evaluated Early 2

0 0 0 0 0

Patients Not Yet Overdue

0 0 0 0 0

Expected3

280

263

333

280

263

333

Evaluable for Overall Success (% of Total Expected)

274

(97.9%)

223

(84.8%)

326

(97.9%)

271

(96.8%)

220

(83.7%)

322

(96.7%)

Evaluable for Overall Success, In

(% of Total Expected)

Percent Follow-up

98.2%

87.1%

98.5%

97.1%

84.0%

97.3%

The subject accountability data are summarized in Table 3. Please note that Continued Access Cohort (CA) and the Metal Ion Cohort (MI) were enrolled separately from the IDE Cohort at the same study sites. Safety and effectiveness data were collected for the IDE, Safety (IDE+CA+MI), and ACDF Control Cohorts while the statistical analyses were performed with the IDE Cohort in comparison to the control group.

Table 3: Subject Accountability

PRESTIGE LP™

IDE Cohort

ACDF Control

PRESTIGE LP™

Safety Cohort

PRESTIGE LP™

IDE Cohort

ACDF Control

PRESTIGE LP™

Safety Cohort

Window

In addition to the study subjects described above, nineteen (19) subjects were consented but declined participation in the study prior to receiving the assigned treatment. The demographic and preoperative characteristics of the subjects who declined to participate in this study were comparable to the patients included in this study.

Study Population Demographics and Baseline Parameters Table 4 presents the summary statistics for demographic and baseline characteristics for the

PRESTIGE LP™ IDE Cohort, the ACDF Control, and PRESTIGE LP™ Safety Cohort. The demographics of the study population are consistent with the demographics reported for prior cervical artificial disc studies conducted in the U.S.

The investigational and control treatment groups were very similar demographically, and there were no statistically significant differences (p<0.05) for any of the variables except for the use of tobacco and race. Current tobacco use was higher in the control group (34.7% versus 26.4%) as

Cumulative deaths are the total number of deaths of study patients at the 12- and 24-month time points. However, none of the

deaths were believed to be in any way related to the study treatment .

Patients that completed follow-up visits early before the visit window

Expected = Theoretical min us Cumulative Deaths minus Patients Not Yet Overdue plus Patients Evaluated Early for Visit

271

(96.8%)

206

(78.3%)

321

(96.4%)

262

(93.6%)

201

(76.4%)

309

(92.8%)

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Variables

PRESTIGE LP™ IDE

(N=280)

(N=265)

PRESTIGE LP™

(N=333)

p-value

Control)

Age (years)

44.5 ± 8.8

Range: 23 - 78

43.9 ± 8.8

Range: 22 - 73

43.8 ± 9.0

Range: 23 – 78

Height (inches)

67.7 ± 4.1

Range: 60.0 – 77.0

67.5 ± 4.2

Range: 58.0 – 80.0

67.7 ± 4.0

Range: 60.0 – 77.0

Weight (lbs.)

186.9 ± 45.0

Range: 100.0 – 340.0

184.7 ± 41.5

Range: 98.0 – 328.0

187.3 ± 45.2

Range: 100.0 – 340.0

BMI (kg/m2)

28.5 ± 5.6

Range: 17.2 – 48.2

28.3 ± 5.1

Range: 19.0 – 53.6

28.5 ± 5.6

Range: 17.2 – 48.2

Sex

Female (%)

151 (53.9%)

143 (54.0%)

178 (53.5%)

Race

Other

1 (0.4%)

1 (0.3%)

Marital Status

Widowed

2 (0.7%)

2 (0.8%)

3 (0.9%)

Education Level

> High School

206 (74.1%)

173 (65.5%)

236 (71.3%)

277 (98.9%)

263 (99.2%)

330 (99.1%)

Preoperative Medication

Muscle Relaxants

100/279 (35.8%)

114/264 (43.2%)

123/332 (37.0%)

0.095

compared to the IDE Cohort. However, tobacco use was established through use of patient questionnaires which utilized a binary response (i.e., yes or no), and quantification of the extent or history of tobacco use was not established. Therefore, it is not possible to definitively ascertain whether there were any substantial confounding effects from tobacco use on patient outcomes. Regarding race differences among cohorts, there was a higher percentage of Caucasian subjects in the IDE Cohort compared to the control group (96.8% versus 91.7%).

Table 4: Study Patient Demographics and Baseline Characteristics

Male (%)

Caucasian Black Asian Hispanic

Single Married Divorced Separated

Cohort

129 (46.1%)

271 (96.8%)

7 (2.5%) 0 (0.0%) 1 (0.4%)

40 (14.3%)

189 (67.5%)

42 (15.0%)

7 (2.5%)

ACDF Control

122 (46.0%)

243 (91.7%)

13 (4.9%)

2 (0.8%) 6 (2.3%)

32 (12.1%)

204 (77.0%)

24 (9.1%)

3 (1.1%)

Safety Cohort

155 (46.5%)

320 (96.1%)

10 (3.0%)

1 (0.3%) 1 (0.3%)

47 (14.1%)

224 (67.3%)

51 (15.3%)

8 (2.4%)

(IDE vs.

0.369

0.622

0.567

0.722

1.000

0.043

0.096

< High School High School

Previous Ne ck Surgery Yes

use Non-Narcotics Weak Narcotics Strong Narcotics

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208/280 (74.3%) 133/279 (47.7%)

15 (5.4%)

57 (20.5%)

3 (1.1%)

62/279 (22.2%)

14 (5.3%)

77 (29.2%)

2 (0.8%)

187/263 (71.1%) 127/263 (48.3%)

58/264 (22.0%)

17 (5.1%)

78 (23.6%)

3 (0.9%)

246/333 (73.9%) 152/332 (45.8%)

68/332 (20.5%)

0.062

1.000

0.441

0.931

1.000

Neck Pain Only

25 (8.9%)

26 (9.8%)

34 (10.2%)

Worker’s Compensation

32/280 (11.4%)

35/365 (13.2%)

54/333 (16.2%)

0.602

Unresolved S pinal Litigation

Current Tobacco Use

74/280 (26.4%)

92/265 (34.7%)

94/333 (28.2%)

0.041

Current Alcoho l Use

150/280 (53.6%)

141/265 (53.2%)

172/333 (51.7%)

1.000

Preoperative Work Status

188/280 (67.1%)

166/265 (62.6%)

217/333 (65.2%)

0.282

> 6 mos.

173 (61.8%)

161 (60.8%)

212 (63.7%)

Preoperative Pain Status4 Arm and Neck Pain Arm Pain Only

34/280 (12.1%) 32/265 (12.1%) 61/333 (18.3%) 1.000

Duration of Symptoms < 6 wks. 6 wks. – 6 mos.

255 (91.1%)

0 (0.0%)

22 (7.9%)

85 (30.4%)

238 (90.2%)

0 (0.0%)

15 (5.7%)

89 (33.6%)

299 (89.8%)

0 (0.0%)

24 (7.2%)

97 (29.1%)

0.769

0.494

The mean baseline pre-operative assessments for the PRESTIGE LP™ IDE Cohort, Control Group, and PRESTIGE Safety Cohort are presented in Table 5. There were no statistical differences between the PRESTIGE LP™ IDE Cohort and Control for NDI, SF-36 PCS, SF-36 MCS, neck pain, and arm pain. There were statistically significant differences in baseline motor neurologic status (38.2% - PRESTIGE LP™ IDE Cohort; 59.5% - Control) and mean cervical range of motion (5.67º - PRESTIGE LP™ IDE Cohort; 7.87º - Control). However, after propensity score adjustments, the variables appeared balanced between groups. Thus, differences in baseline symptoms were adjusted for in the analysis and are therefore unlikely to have led to significant bias in the reported results.

Arm pain is defined as a subject having an arm pain score ≥20 and neck pain is defined as a subject having a neck pain score

≥20. If a subject has both an arm pain score ≥20 and a neck pain score ≥20, then this subject is considered as having “Arm and Neck Pain”; if a subject has a neck pain score ≥20 and an arm pain score < 20, then this subject is considered as having “Neck Pain Only”; if a subject has an arm pain score ≥20 and a neck pain score < 20, then this subject is considered as having “Arm Pain Only”. Since neck pain score ≥20 is an inclusion criteria, there are no subjects with “Arm Pain Only”. LP™ Cervical Disc is indicated in skeletally mature patients for reconstruction of the disc at one level from C3-C7 following single-level discectomy for intractable radiculopathy (arm pain and/or a neurological deficit) with or without neck pain and is not indicated for treatment of isolated neck pain. No patients were included into the study with neck pain without any other symptoms.

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The PRESTIGE

p-value (IDE

Control)

55.5 ± 14.7

Range: 30.0 – 98.0

56.4 ± 15.9

Range: 26.0 – 100.0

56.6 ± 15.0

Range: 30.0 – 98.0

32.2 ± 7.4

Range: 14.3 – 57.9

32.0 ± 7.5

Range: 7.9 – 56.0

32.3 ± 7.1

Range: 14.3 – 57.9

44.5 ± 11.5

Range: 16.5 – 68.3

42.7 ± 12.4

Range: 14.1 – 70.8

43.8 ± 11.9

Range: 16.5 – 68.3

67.0 ± 20.8

Range: 20.0 – 100.0

69.3 ± 21.5

Range: 20.0 – 100.0

68.0 ± 20.8

Range: 20.0 – 100.0

59.6 ± 26.3

Range: 0.0 – 100.0

62.4 ± 28.5

Range: 0.0 – 100.0

59.0 ± 27.1

Range: 0.0 – 100.0

Neurological Status

• Overall5

64/280 (22.9%)

79/264 (29.9%)

73/333 (21.9%)

0.065

Baseline ROM angulation (º)

5.67 ± 3.69

Range: 0.27 – 18.10

7.87 ± 4.32

Range: 0.74 – 21.34

5.88 ± 3.78

Range: 0.27 – 19.47

Baseline ROM translation (mm)

0.26 ± 0.25

Range: 0.00 – 1.64

Table 5: Preoperative Evaluation of Endpoints

Variables

NDI

SF-36 PCS

SF-36 MCS

Neck Pain Score

Arm Pain Score

(normal)

• Motor

• Sensory

• Reflexes

PRESTIGE LP™ IDE Cohort (N=280)

107/280 (38.2%) 117/280 (41.8%) 186/280 (66.4%)

N/A

ACDF Control

(N=265)

157/264 (59.5%) 134/264 (50.8%) 161/264 (61.0%)

PRESTIGE LP™

Safety Cohort

(N=333)

135/333 (40.5%) 147/333 (44.1%) 200/333 (60.1%)

N/A N/A

Cohort vs

ACDF

0.498

0.777

0.079

0.191

0.236

< 0.001

0.039

0.212

< 0.001

Surgery and Hospitalization Table 6 summarizes the information related to the surgical procedures and postoperative

hospitalizations of subjects. The most common treated surgical levels were C5-C6 and C6C7.The mean operative times for the IDE and control treatment groups were 1.5 hours and 1.4 hours, respectively, which is a mean difference of 0.1 hours, or 6 minutes and is unlikely to represent any significant clinical difference. Additionally, investigational subjects were found to have similar estimated blood loss to the control group subjects (50.5 ml for IDE cohort and 49.4 ml for Safety cohort versus 57.5 ml for control group). The median blood loss was 35 ml for the IDE cohort versus 50 ml for both the Safety and control groups. The mean hospital stays of subjects in all treatment groups were similar (1.0 days for all groups). Table 7 summarizes the PRESTIGE LP™ device implanted by size and level.

If at least one of the three components (motor, sensory, reflexes) is not normal, then overall is defined as “not normal”, if all the

components are normal, then overall is defined as “normal”

Medtronic Page 17 of 91

(N=280)

(N=265)

(N=333)

Posterior Mean

(lower, upper)

Spinal Level Treated

C34 (%)

4 (1.4%)

10 (3.8%)

4 (1.2%)

N/A

C45 (%)

21 (7.5%)

15 (5.7%)

28 (8.4%)

N/A

C56 (%)

147 (52.5%)

149 (56.2%)

178 (53.5%)

N/A

C67 (%)

108 (38.6%)

91 (34.3%)

123 (36.9%)

N/A

Operative time (hrs)

1.5 ± 0.6

(n=280)

1.4 ± 0.5

(n=265)

1.4 ± 0.5

(n=333)

Blood Loss (ml)

50.5 ± 73.5

(n=278)

57.5 ± 68.1

(n=263)

49.4 ± 67.9

(n=333)

Hospitalization (days)

1.0 ± 0.5

(n=280)

1.0 ± 0.5

(n=265)

1.0 ± 0.4

(n=333)

Median Return to Work Time (days)

6mm x 12mm Disc (%)

6mm x 14mm Disc (%)

6mm x 16mm Disc (%)

6mm x 18mm Disc (%)

7mm x 12mm Disc (%)7

7mm x 14mm Disc (%)

7mm x 16mm Disc (%)

7mm x 18mm Disc (%)

8mm x 12mm Disc (%)

8mm x 14mm Disc (%)

8mm x 16mm Disc (%)

8mm x 18mm Disc (%)

(1.4%)

(7.5%)

147

(52.5%

108

(38.6%)

280

(100.0%)

(1.2)

(8.4%)

178

(53.5%)

123

(36.9%)

333

(100.0%)

Table 6: Surgical Data

and 95% BCI6 of

the Difference of

Mean between

PRESTIGE LP™

IDE Cohort

ACDF Control

PRESTIGE LP™

Safety Cohort

IDE Cohort and

Control Group

Range: 0.7 – 3.4

Range: 3.0 – 700.0

Median: 35.0

Range: 0.0 – 3.0

Range: 0.6 – 3.4

Range: 0.0 – 700.0

Median: 50.0

Range: 0.0 – 4.0

Range: 0.7 – 3.4

Range: 3.0 – 700.0

Median 50.0

Range: 0.0 – 3.0

0.11 (0.02, 0.22)

-4.7 (-16.8, 7.9)

0.03 (-0.05, 0.11)

40 60 42 N/A

Table 7: All PRESTIGE LP™ Devices Implanted by Size and Level

PRESTIGE LP™ IDE Cohort PRESTIGE LP™ Safety Cohort C3-C4 C4-C5 C5-C6 C6-C7 Total C3-C4 C4-C5 C5-C6 C6-C7 Total

1 4 15 11 1 10 65 37 2 1 35 23 0 0 0 0 0 0 1 1 0 2 5 8 0 4 16 9 0 0 9 11 0 0 0 0 0 0 0 3 0 0 1 4 0 0 0 1

31 (11.1%)

113 (40.4%)

61 (21.8%)

0 (0.0%) 2 (0.7%)

15 (5.4%)

29 (10.4%)

20 (7.1%)

0 (0.0%) 3 (1.1%) 5 (1.8%) 1 (0.4%)

1 8 28 12 1 13 76 42 2 1 37 23 0 0 0 0 0 0 1 2 0 2 9 11 0 4 17 12 0 0 9 11 0 0 0 0 0 0 0 4 0 0 1 5 0 0 0 1

49(14.7%)

132 (39.6%)

63 (18.9%)

0 (0.0%)

3 (0.9%) 22 (6.6%) 33 (9.9%) 20 (6.0%)

0 (0.0%)

4 (1.2%)

6 (1.8%)

1 (0.3%)

Total (%)

BCI = Bayesian HPD Credible Interval

Th e 7 mm x 12mm PRESTIGE LP™ Cervical Dis c was a part of the size offerings in the IDE study, but is no t a part o f

the size offerings availabl e for market.

Medtronic Page 18 of 91

Adverse Event Type

Posterior Mean and

Control10

Patients (%)

257 (91.8%)

219 (82.6%)

306 (91.9%)

Events (Events/Patient)

Patients (%)

72 (25.7%)

71 (26.8%)

78 (23.4%)

Events (Events/Patient)

Severe Adverse

(Grade 3 or 4)

Patients (%)

133 (47.5%)

98 (37.0%)

163 (48.9%)

Events (Events/Patient)

Severe Device or

(Grade 3 or 4)

Events (Events/Patient)

Safety and Effectiveness Results

Safety Results

The analysis of safety was based on the as-treated cohort of 598 total patients with surgery (333 PRESTIGE LP™ “Safety” subjects consisting of 280 PRESTIGE LP™ IDE Cohort subjects, as well as 54 subjects from the Continued Access (CA) and Metal Ion (MI) Cohorts8; and 265 ACDF control subjects). This was a non-randomized study and the ACDF group was a historical control. A summary of the total number of adverse events is shown in Table 8. Adverse events were classified by the independent Clinical Adjudication Committee (CAC) for severity and relationship to the device and/or surgical procedure.

Table 8: Summary of Adverse Events Up to the 24-Month Time Interval

All Adverse Events (AEs)

Device or Device/Surgical Procedure Related AEs

Surgical Procedure Related AEs Only

Events

Device/ProcedureRelated AEs

PRESTIGE LP™

Measure

Patients (%)

Patients (%) 14 (5.0%) 13 (4.9%) 16 (4.8%)

IDE Cohort

(N=280)

1559 (5.57) 1198 (4.52) 1863 (5.59)

34 (12.1%) 41 (15.5%) 44 (13.2%)

61 (0.22) 60 (0.23) 76 (0.23)

132 (0.47) 121 (0.46) 140 (0.42)

433 (1.55) 267 (1.01) 518 (1.56)

33 (0.12) 22 (0.08) 40 (0.12)

ACDF Control

(N=265)

PRESTIGE LP™

Safety Cohort

(N=333)

95% BCI9 of the

Difference of Event

Rate between IDE

Cohort and ACDF

10.2% (4.1%, 16.2%)

-2.9% (-9.2%, 3.3%)

-0.5% (-8.6%, 7.4%)

13.3% (3.5%, 21.8%)

0.7% (-3.0%, 4.6%)

Table 9 provides summary data on the number of adverse events in each treatment group by treatment level, including post-hoc statistical anal ysis and comparison between the PRESTIGE LP™ IDE Cohort and the ACDF control group through the 24-month time point using Frequentist methods. The percentage of subjects with adverse events was not statistically different between the two groups for all levels except for C5-C6; however, this difference was not clinically meaningful.

One Metal Ion Cohort subject was also an IDE Cohort subject.

BCI = Bayesian HPD Credible Interval

95% BCI of the difference of the event rate between the investigational group and control group was only determined for the

“All Adverse Events” category because the analysis was pre-defined. All other analyses were not pre-defined.

Medtronic Page 19 of 91

Level

(N=280)

(N=265)

(N=333)

Point Estimate and 95%

Cohort

C3-C4

4/4 (100%)

9/10 (90.0%)

4/4 (100.0%)

10.0% (-19.9%, 39.9%)

C4-C5

20/21 (95.2%)

12/15 (80.0%)

27/28 (96.4%)

15.2% (-5.6%, 36.1%)

C5-C6

135/147 (91.8%)

124/149 (83.2%)

163/178 (91.6%)

8.6% (1.1%, 16.2%)

C6-C7

98/108 (90.7%)

74/91 (81.3%)

112/123 (91.1%)

9.4% (-0.1%, 19.0%)

Table 9: Summary o f Total Advers e Events by Level Treated thro ug h Month 24- IDE

and Safety Population

Confidence Interval11 of

Difference of Adverse

Treatment

PRESTIGE LP™

IDE Cohort

ACDF Control

PRESTIGE LP™

Safety Cohort

Rate between IDE Cohort

and ACDF Control

Table 10 reports adverse events from all patients to establish the safety profile of the device.

Adverse events are listed in alphabetical order. Adverse event rates are based on the number of patients having at least one occurrence of an adverse event, divided by the number of patients in that treatment group. Subjects experiencing adverse events in more than one category are represented in each category in which they experienced an adverse event.

The overall adverse event rate was higher for subjects treated with the PRESTIGE LP™ device (IDE Cohort, 91.8%; Safety Cohort, 91.9%) compared to the Control (82.6%) through 24 months. The adverse event rate between the PRESTIGE LP™ IDE Cohort and the Control was statistically different with the 95% BCI for the difference of adverse events rates between the PRESTIGE LP™ IDE Cohort and the ACDF Control Cohort being (4.1%, 16.2%), excluding 0. However, when comparing device-related adverse events, the rates are comparable (see Table 10b below). Although the rate of PRESTIGE LP™ IDE subjects having at least one adverse event was statistically higher than the control group rate, the difference in adverse event rates was not considered to be clinically meaningful and this finding may be attributable to the higher follow-up rates (and potentially, higher reporting of events) for investigational subjects as compared to the ACDF control subjects. Specifically, note that the 24-month follow-up rates are

97.1% and 84.0% respectively for the PRESTIGE LP™ IDE Cohort and ACDF Control Cohort. Table 11 lists the brief definitions for all adverse events.

There were a total of three deaths in the investigational group and five deaths in the control group, of which two deaths occurred in the control group prior to 24 months (at the 12-month time point) and none in the investigational group prior to 24 months. Deaths were evaluated based upon available information and none of the deaths were believed to be in any way related to the study treatment.

The 95% CI was provided using Frequentist Farrington and Manning methods

Medtronic Page 20 of 91

≥

PRESTIGE LP™ IDE

Total # Events

Anatomi cal /

Difficulty

3 (1.1) 5 2 (0.8)

5 (1.5)

Cardiac Disorders

16 (5.7)

18 (6.8)

19 (5.7)

0 (0.0) 0 0 (0.0)

0 (0.0)

Dysphagia / Dysphonia

26 (9.3)

22 (8.3)

30 (9.0)

35 (12.5)

38 (14.3)

43 (12.9)

Heterotopic Ossification

27 (9.6)

15 (5.7)

31 (9.3)

16 (5.7)

5 (1.9)

21 (6.3)

34 (12.1)

27 (10.2)

40 (12.0)

Neck and / or Arm Pain

144 (51.4)

275

124 (46.8)

213

184 (55.3)

353

136 (48.6)

242

108 (40.8)

217

162 (48.6)

289

0 (0.0) 0 29 (10.9)

0 (0.0)

93 (33.2)

177

81 (30.6)

133

110 (33.0)

207

146 (52.1)

278

132 (49.8)

231

175 (52.6)

328

24 (8.6)

17 (6.4)

27 (8.1)

83 (29.6)

172

55 (20.8)

103

106 (31.8)

212

61 (21.8)

35 (13.2)

69 (20.7)

26 (9.3)

9 (3.4)

31 (9.3)

12 (4.3)

4 (1.5)

13 (3.9)

Wound (NonInfectious)

25 (8.9)

13 (4.9)

27 (8.1)

Any Adverse Event

257 (91.8)

1559

219 (82.6)

1198

306 (91.9)

1863

Table 10: Adverse Events in Pivotal Study Through 24 Months

Surgery

4 Weeks)

Postoperative

(1 day -

9 Weeks)

6 Weeks

4 Wks (

5 Months)

3 Months

9 Wks (

9 Months)

6 Months

5 Mos(

12 Months

12, 13

19 Months)

9 Mos(

30 Months))

24 Months

19 Mos((

Adverse

Events

ACDF Contro

PRESTIGE LP™ IDE Cohort

Technical

Cancer 0 0 0 1 1 1 0 0 0 0 0 0 1 0 1 3 0 3 0 1 2

Death

2 0 2 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0

0 0 0 2 2 2 2 1 3 0 2 0 3 3 3 4 3 5 10 9 11

0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0

1 4 1 16 11 17 4 4 6 5 3 5 5 0 5 0 1 1 2 0 3

PRESTIGE LP™ Safety Cohor t

ACDF C ontrol

PRESTIGE LP™ IDE Cohort

PRESTIGE LP™ Safety Cohor t

ACDF C ontrol

PRESTIGE LP™ IDE Cohort

PRESTIGE LP™ Safety Cohor t

ACDF C ontrol

PRESTIGE LP™ IDE Cohort

PRESTIGE LP™ Safety Cohort

ACDF C ontrol

PRESTIGE LP™ IDE Cohort

PRESTIGE LP™ Safety Cohor t

ACDF C ontrol

PRESTIGE LP™ IDE Cohort

PRESTIGE LP™ Safety Cohor t

ACDF C ontrol

PRESTIGE LP™ IDE Cohort

Total adverse events

Total ( Up to 24 Month)

# of Patients Reporting &

Cohort

# Patients

(% of 280)

# Patients

(% of 265)

Total # Events

ACDF Control

PRESTIGE LP™ Safety Cohor t

2 (0.7)

0 (0.0)

PRESTIGE LP™ Safety Cohort

2 (0.6)

# Patients

(% of 333)

Total # Events

Gastrointestinal 2 7 2 8 7 8 1 3 2 4 4 7 3 2 7 20 21 22 17 24 20

0 0 0 2 1 2 6 4 6 1 2 1 4 1 5 7 2 9 11 11 12

Implant Events 6 0 6 1 1 1 2 1 3 3 0 3 1 0 3 0 2 1 4 1 5

Infection 1 2 1 5 3 5 6 5 7 6 2 9 11 1 12 16 10 16 12 14 13

3 1 4 31 16 35 43 19 57 57 49 77 37 40 50 68 50 84 36 38 46

Neurological 2 6 2 18 21 20 34 19 42 47 35 55 31 16 39 73 60 88 37 60 43

Non-Union 0 0 0 0 0 0 0 1 0 0 3 0 0 8 0 0 8 0 0 10 0

Other 5 3 8 19 14 22 12 13 14 24 16 28 29 9 38 55 21 58 33 57 39

Other Pain15 3 6 3 22 19 23 32 11 39 49 45 65 57 30 69 65 57 71 50 63 58

Respiratory 0 0 0 7 4 7 0 4 1 1 1 1 10 5 10 3 1 6 13 8 14

Spinal Event 0 0 0 19 8 22 22 6 34 20 25 25 26 15 31 44 20 53 41 29 47

Trauma 0 0 0 6 2 7 5 4 6 12 12 13 11 5 12 19 9 20 18 12 21

Urogenital 1 0 1 1 0 1 2 0 2 1 1 1 9 3 9 12 5 13 16 2 20

Vascular 3 1 4 1 0 1 1 0 1 0 1 0 2 1 2 2 1 2 4 0 4

0 2 1 14 4 15 3 2 3 4 2 4 4 1 4 5 2 5 4 0 4

Based on 24-month cohort.

Some adverse events may lead to additional surgeries or interventions. Refer to Table 4 for more information.

Control=Single-level anterior interbody fusion procedure with allograft and plate stabilization. Non-randomized control arm

from IDE study of PRESTIGE® Cervical Disc.

Back and/or lower extremity (LE) pain adverse events (AEs) and Headache AE’s were classified as “Other Pain ” AEs

for the PRESTIGE LP™ IDE study.

Medtronic Page 21 of 91

PRESTIGE LP™

(N=280)

PRESTIGE LP™

(N=333)

Device Relationship

Determined by CAC

Wound (NonInfectious)

Table 10b: Adverse Events Classified as Device-Related or Device/Surgical Procedure-

Related According to the Clinical Adjudication Committee through Month 24 – Safety

Population

of Adverse Event

Dysphagia / Dysphonia 0 0 (0. 0) 1 1 (0.4) 0 0 (0.0) Heterotopic Ossification 4 4 (1.4) 3 2 (0.8) 6 6 (1.8) Implant Events 16 15 (5.4) 5 5 (1.9) 20 19 (5.7) Neck and / or Arm Pain 9 7 (2.5) 6 4 (1.5) 13 11 (3.3) Neurological 11 9 (3.2) 7 7 (2.6) 14 11 (3.3) Non-Union 0 0 (0.0) 27 27 (10.2) 0 0 (0.0) Other 2 2 (0.7) 2 2 (0.8) 3 3 (0.9) Other Pain 5 5 (1.8) 4 3 (1.1) 5 5 (1.5%) Spinal Event 13 8 (2.9) 4 2 (0.8) 13 8 ( 2.4%) Trauma 1 1 (0.4) 0 0 (0.0) 2 2 (0.6)

Any Adverse Event 61 34 (12.1) 60 41 (15.5) 76 44 (13.2)

IDE Cohort

Events

0 0 (0.0) 1 1 (0.4) 0 0 (0.0)

Patients

N (%)

ACDF Control

(N=265)

Events

Patients

N (%)

Safety Cohort

Events

Patients

N (%)

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Adverse Event Category

Definition

Anatomical/Technical Difficulty – Cervical Study Surgery

Anatomical or technical difficulty encountered during the original implantation of the PRESTIGE LP™ device or control treatment device

Anatomical or technical difficulty encountered during an additiona l surgery involving

control treatment device

Anatomical/

Cervical

Technical problem encountered during an additional surgery that involved a region

Cancer

A malignancy or malignant tumor/neoplasm

Cardiac Disorders

Any condition of the heart

Death

Termination of life due to any cause

Dysphagia

Difficulty in swallowing

Dysphonia

Difficulty in speaking

Gastrointestinal

Any condition pertaining to the stomach and intestines

Heterotopic Ossification Cervical

Event involving heterotopic ossification at any region of the cervical spine

Heterotopic Ossification - NonCervical

Event involving heterotopic ossification at any region of the spine that is not cervical or any other region of the body.

Implant Events - Malpositioning

Poor or inappropriate placement of the implant

Implant Events - Displacement

Incomplete or partial dislocation of the implant

Implant Events - Loosening

Wear around the implant and/or loosening o f t he implant surface

Implant Events - Breakage

Breakage of any implant or implant component

Event that is implant-related, but does not meet the definition of malpositioned implant, implant displacement, implant loosening, or implant breaking

Infection - Superficial

An infection near the surface of the surgical incision

Infection - Deep

An infection below the fascia at the surgical incision

Infection - Other Wound

Infection occurring in other surgical wound not involving the study

Infection - Hematoma

Swelling or mass of blood that has become infected

Infection - CSF Leak

Infection resulting from the leakage of CSF

Infection - Systemic

Infection pertaining to the whole body

Infection - Urinary Tract

Infection of any part of the urinary system

Infection - Other

Any infection not listed above

Pain - Neck

Pain (includ ing stiffness, strain, t ightness) in the neck

Pain - Upper Extremities

Pain (includ ing stiffness, strain, t ightness) in the shoulder, arm, wrist or hand

Pain - Neck and Upper Extremities

Pain (includ ing stiffness, strain, t ightness) in the neck and shoulder, a rm, wrist, or hand

Pain (including stiffness, strain, tightness) in an area that is not of cervical spine etiology (e.g., abdominal pain of unknown etiology, hea dache, flank pai n, bursitis).

Other

Event not associated with any other categories (e.g., weight loss, tinnitus, substance abuse, insomnia).

Respiratory

Ailments or symptoms associated with respiration or the respirato ry system

Spinal Event – Cervical Study Surgery

Event involving the treated level of cervical spine

Spinal Event – Cervical NonStudy Surgery

Event involving one or more cervical spine level(s), with the exception of the treated level

Spinal Event - Non-Cervical

Event involving one or more spine levels other than cervical spine

Trauma

Physical injury caused by a physical force or traumatic event (e.g. motor vehicle accident, fall, etc.)

Urogenital

Any condition of, relating to, affecting, treating, or being the organs or functions o f excretion and reproduction

Table 11: Adverse Event Categories

Anatomical/Technical Difficulty – Cervical Non-Study Surgery

Technical Difficulty Non-

Implant Events - Other

the cervical region, but did not involve the PRESTIGE LP™ device or original

other than the cervical spine

Pain - Other

Medtronic Page 23 of 91

Injury to a vasc ular structure that is sustained during the course of the operative procedure

Vascular – Vertebral artery

Injury to vertebral artery occurring at any time

Vascular - Other

Disorder or condition in which the vascular system is affected

Wound (Non-Infectious)

Any issue of surgical inci s i on, such as hematoma, excluding infection

Vascular – injury (intraoperative)

Bayesian analyses were conducted on all adverse events using non-informative priors. The results are presented in Table 12 with 95% Bayesian Credible Intervals (BCI) for the difference in adverse event rates (PRESTIGE LP™ IDE – ACDF). BCIs that exclude zero indicate statistical differences in the adverse event rates between the PRESTIGE LP™ IDE cohort and the ACDF Control group while the BCIs that include zero fail to conclude that this is a statistical difference in the adverse event rates between the two groups. Based on the BCIs, statistical differences were noted between groups for the adverse event rates in the following categories: heterotopic ossification, implant events, neurological, non-union, spinal events, trauma, urogenital, vascular, and wound (non-infectious). All are statistically higher for the PRESTIGE LP™ IDE Cohort except for non-union which was statistically higher for the control group.

Medtronic Page 24 of 91

Posterior Mean and 95%

Control

ACDF

Control

Safety

Cohort

Anatomical /

Difficulty

Cancer

3 (1.1%)

2 (0.8%)

5 (1.5%)

1.0 (0.1%, 2.3%)

0.6% (0.0%. 1.6%)

0.4% (-1.2% , 2.0%)

Cardiac Disorders

16 (5.7%)

18 (6.8%)

19 (5.7%)

5.4% (2.8%, 8.2%)

7.0% (4.0%, 10.4%)

-1.6% (-6.0%, 2.9%)

Dysphagia / Dysphonia

Gastrointestinal

35 (12.5%)

38 (14.3%)

43 (12.9%)

12.9% (9.0% , 17.3%)

13.7% (9.3%, 17.9%)

-0.8% (-7.2%, 5.1%)

Heterotopic Ossification

Implant Events

16 (5.7%)

5 (1.9%)

21 (6.3%)

5.7% (3.0%, 8.7%)

1.8% (0.4%, 3.4%)

3.9% (0.6%, 7.4%)*

Infection

34 (12.1%)

27 (10.2%)

40 (12.0%)

12.0% (8.2%. 16.1%)

10.3% (6.6%, 14.2%)

1.7% (-3.8%, 7.5%)

Neck and / or Arm Pain

Neurological

136 (48.6%)

108 (40.8%)

162 (48.6%)

49.4% (43.2%, 55.6%)

39.8% (33.7%, 46.1%)

9.6% (0.6%, 18.9%)*

Non-Union

0 (0.0%)

29 (10.9%)

0 (0.0%)

0.0%

11.4% (7.3%, 15.4%)

-11.3% (-15.4%, -7.3%)*

Other

93 (33.2%)

81 (30.6%)

110 (33.0%)

33.6% (27.9%, 39.5%)

30.1% (24.4%, 36.0%)

3.5% (-4.9%, 12.1%)

Other Pain

146 (52.1%)

132 (49.8%)

175 (52.6%)

51.3% (45.3%, 57.4%)

50.7% (44.2%, 56.8%)

0.6% (-8.5%, 9.7%)

Respiratory

24 (8.6%)

17 (6.4%)

27 (8.1%)

8.3% (4.9%, 11.7%)

6.5% (3.6%, 9.7%)

1.9% (-2.9%, 6.7%)

Spinal Event

83 (29.6%)

55 (20.8%)

106 (31.8%)

31.4% (25.7%, 37.2%)

19.0% (13.8%, 23.8%)

12.4% (4.5%, 20.3%)*

Trauma

61 (21.8%)

35 (13.2%)

69 (20.7%)

21.2% (16.4%, 26.3%)

13.5% (9.4%, 17.9%)

7.6% (0.7%, 14.4%)*

Urogenital

26 (9.3%)

9 (3.4%)

31 (9.3%)

8.7% (5.2%, 12.2%)

3.5% (1.4%, 5.8%)

5.2% (1.1%, 9.9%)*

Vascular

12 (4.3%)

4 (1.5%)

13 (3.9%)

4.6% (2.3%, 7.3%)

1.2% (0.2%, 2.5%)

3.4% (0.6%, 6.5%)*

Wound (NonInfectious)

Any adverse Event

Table 12: Bayesian Comparison of Posterior Probabilities of Adverse Events

Adverse Event

Technical

Patients Experiencing Adverse Events (%)

IDE Cohort

2 (0.7%) 0 (0.0%) 2 (0.6%) 0.5% (0.0%, 1.4%) 0.0% (0.0%, 0.1%) 0.5% (0.0%, 1.4%)

26 (9.3%) 22 (8.3%) 30 (9.0%) 9.3% (5.9%, 12.9% ) 8.2% (4.8%, 11.6%) 1.0% (-4.2%, 6.1%)

27 (9.6%) 15 (5.7%) 31 (9.3%) 10.2% (6.7%, 14.0%) 5.0% (2.5%, 7.7%) 5.2% (0.5%, 10.1%)*

144 (51.4%) 124 (46.8%) 184 (55.3%) 51.9% (45.9%, 57.9%) 46.2% (39. 7%, 52.3%) 5.7% (-3.3%, 15.0%)

Posterior Mean and 95% HPD of Adverse

Event Rate

IDE Cohort ACDF Control IDE - ACDF

BCI16 of Difference of

Adverse Event Rate between

LP IDE Cohort and ACDF

25 (8.9%) 13 (4.9%) 27 (8.1%) 9.6% (6.0%, 13.1% ) 4.2% (1.9% , 6.6%) 5.3% (0.7%, 9.7%)*

257 (91.8%) 219 (82.6%) 306 (91.9%) 92.3% (89.0%, 95.4%) 82.0% (77. 2%, 86.9%) 10.2% (4.1%, 16.2%)*

*Asterisk denotes statistical difference.

BCI = Bayesian HPD Credible Interval

Medtronic Page 25 of 91

Table 13 summarizes the secondary interventions in the PRESTIGE LP™ device and control treatment groups that occurred at or before the 24-month post-operative interval. Revisions, removals, and supplemental fixations were considered second surgery failures in the clinical study. Reoperations were not considered second surgery failures in the study. Table 13 also presents the Bayesian statistical comparison of secondary surgeries between the PRESTIGE LP™ IDE device and control treatment groups.

Overall, there were a greater number of subjects undergoing secondary surgical procedures at the index level in the ACDF control group [21 (7.9 %)] compared to the PRESTIGE LP™ IDE [14 (5.0%)] and Safety Cohorts [15 (4.5%)]. Bayesian statistical comparison of secondary surgeries between the PRESTIGE LP™ IDE Cohort and ACDF control treatment groups were performed (if zero is excluded from the 95% BCI of the difference of the event rates, the event rates are considered to be statistically different between the two groups). The only statistical difference between the control and PRESTIGE LP™ Safety Cohort occurred in the Supplemental Fixation category, with the investigational cohort requiring fewer supplemental fixation procedures than the control cohort. However, this category also included use of external bone stimulators as “supplemental fixation,” which may inflate the numbers in the ACDF control group, as all “supplemental fixation” patients were considered failures due to secondary surgery. Among the eight ACDF control subjects who had supplemental fixation, two had supplemental fixation without using any external bone stimulators, one had “supplemental fixation” with and without using an external bone stimulator and 5 subjects had “supplemental fixation” with external bone stimulators only. Excluding the 5 subjects only using external bone stimulators, the supplemental fixation rates are comparable between the two treatment groups.

Medtronic Page 26 of 91

Medtronic Page 27 of 91

Table 13. Secondary Interventions and Surgical Procedures Up to the 24-Month Visit.

Surgery

Postoperative

(1 day -

4 Weeks)

6 Weeks

(

≥

4 Wks -

9 Weeks)

3 Months

(

≥

9 Wks -

5 Months)

6 Months

(

≥

5 Mos-

9 Months)

12 Months

(

≥

9 Mos-

19 Months)

24 Months

((

≥

19 Mos-

30 Months))

Total 24 Month

# of Patients Reporting &

Total adverse events

Posterior Mean and

95% HPD of Secondary

Surgery Rate

Posterior Mean and 95%

BCI

of Difference of Secondary Surgery Rate between LP IDE Coho rt

and ACDF Control

Complication

IDE

Contro

Safety Cohort

IDE Control

Safety Cohort

IDE

Control

Safety Cohort

IDE

Control

Safety Cohort

IDE

Control

Safety Cohort

IDE

Control

Safety Cohort

IDE Control

Safety Cohort

IDE # Patients

(% of 280)

IDE Total # Even ts

Control # Patients

(% of 265)

Control Total # Events

Safety Cohort # Patients

(% of 333

Safety Cohort Total #

Events

PRESTIGE

LP™

IDE Cohort

ACDF

Control

PRESTIGE™ LP IDE –

ACDF Control

Revisions18

0 0 0 0 1 0 1 0 1 0 3 0 0 0 0 0 1 0 0 0 0

(0.4)

(1.9)

(0.3)

0.4%

(0.0%, 1.1%)

1.6%

(0.3%, 3.3%)

-1.3%

(-3.2%, 0.4%)

Removals

0 0 0 1 0 1 1 0 1 1 1 1 3 2 3 3 6 4 1 2 1

(3.6)

(4.2)

(3.3)

3.7%

(1.6%, 6.0%)

3.8%

(1.6%, 6.2%)

-0.1%

(-3.7%, 3.2%)

Supplemental Fixations

0 0 0 0 0 0 0 0 0 0 0 0 1 3 1 1 5 1 0 1 0

(0.7)

(3.0)

(0.6)

0.5%

(0.0%, 1.3%)

3.2%

(1.3%, 5.5%)

-2.7%

(-5.0%, -0.5%)

Reoperations

0 0 0 0 0 0 0 1 0 0 0 0 0 0 0 1 1 1 2 0 2

(1.1)

(0.8)

(0.9)

1.1%

(0.1%, 2.3%)

0.6%

(0.0%, 1.6%)

0.4%

(-1.2%, 2.1%)

Total

0 0 0 1 1 1 2 1 2 1 4 1 4 5 4 5 13 6 3 3 3

(5.0)

(7.9)

(4.5)

5.3%

(2.8%, 8.2%)

7.1%

(4.1%, 10.4%)

-1.9%

(-6.4%, 2.3%)

BCI = Bayesian HPD Credible Interval

A procedure that adjusts or in any way modifies the original implant configuration (e.g., adjusting position of the original configuration, removal with replacement with the same

type of study implant).

A procedure that removes one or more components of the original implant configuration without replacement with the same type of trial implant. Removals include elective

removals.

A procedure at the involved level in which additional spinal devices not approved as part of the protocol are placed. This categorization of Supplemental Fixations includes

supplemental therapies (i.e. external bone growth stimulators). There were a total of six (6) external bone growth stimulators used in the ACDF Control group. Three (3) occurred at six (6) months, and three (3) occurred at 12 months. No external bone growth stimulators were used in the IDE or Safety Cohorts. Please note that since this additional device was used, and included as a supplemental fixation, these patients were considered failures in the Primary Endpoint.

A procedure that involves any surgical procedure at the involved level that does not remove, modify, or add any components and that is not considered a Removal. Revision, or

Supplemental Fixation.

Group

Cause/Adverse Event

Action

Secondary

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