Instructions for Use PRESTIGE LP™ CERVICAL DISC … LP™ CERVICAL DISC . Medtronic Sofamor Danek...

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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 (Titanium-6Aluminum-4Vanadium with 10% Titanium Carbide) and consists of two metal plates which function via a ball and trough mechanism. The superior component of the implant contains the ball portion of the mechanism, and the inferior component contains the trough portion. These two features engage to create an interface designed to allow for motion after implantation. Each component is affixed to the adjacent vertebral body by two rail geometries incorporating anti-migration teeth, which are press fit into two pre-drilled holes in the vertebral bone. The portion of the flat surface between the rails that contacts the vertebral endplate has a commercially pure titanium (CP Ti) plasma thermal sprayed coating per ASTM F1580, designed to permit bony on-growth for additional device incorporation. The remaining portion of the flat surface is titanium ceramic roughened to enhance fixation. Each component also contains two anterior tab features 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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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 Catalog Number

Size (Height x AP Dimension x M L Dimension)

6972250 5mm x 12mm x 15mm 6972450 5mm x 14mm x 15mm 6972650 5mm x 16mm x 15mm 6972260 6mm x 12mm x 17.8mm 6972460 6mm x 14mm x 17.8mm 6972660 6mm x 16mm x 17.8mm 6972860 6mm x 18mm x 17.8mm 6972470 7mm x 14mm x 17.8mm 6972670 7mm x 16mm x 17.8mm 6972870 7mm x 18mm x 17.8mm 6972480 8mm x 14mm x 17.8mm 6972680 8mm x 16mm x 17.8mm 6972880 8mm x 18mm x 17.8mm

The PRESTIGE LP™ Cervical Disc is 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 co-morbidities, 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 re-use, re-process, or re-sterilize the implants. Even if the device appears undamaged, re-use, re-processing, 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 non-steroidal 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. POTENTIAL ADVERSE EFFECTS OF THE DEVICE ON HEALTH Below is a list of the potential adverse effects (e.g., complications) associated with the use of the PRESTIGE LP™ Cervical Disc identified from the PRESTIGE LP™ Cervical Disc clinical study results, 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 non-randomized 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 Exclusion Criteria 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, functional deficit, and/ or neurologic deficit and radiographic 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 24-month 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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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

Pre-/Peri-Operative Postoperative

Procedure Pre-OP

Surgery/ Hospital

Discharge

6 wks ±2 wks

3 mo. ±2 wks

6 mo. ± 1 mo.

12 mo. ± 2mo.

24 mo. ± 2 mo.

& Beyond

Preoperative Information Confirm Patient Eligibility X Obtain Informed Consent X

Obtain HIPAA Authorization X Case Report Forms Patient Enrollment X

Patient Qualification X Preoperative Data X

Prior History Questionnaire X Neurological Status X X X X X X

Preoperative Gait Assessment and Foraminal Compression Test

X

Preoperative Patient Survey X Preoperative Neck Disability Index X Preoperative Neck and Arm Pain

Questionnaire X

Health Status Questionnaire (SF-36) X X X X Surgery Data X

Hospital Discharge X 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 Event

(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 X DEXA Scan ** X

* Patients who sign consent and are screened eligible, 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 Scan 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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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 Number of Patients: 12 Months

(±2 Months) 24 Months (±2 Months)

PRE

STIG

E L

P™

IDE

Coh

ort

AC

DF

Con

trol

PRE

STIG

E L

P™

Safe

ty C

ohor

t

PRE

STIG

E L

P™

IDE

Coh

ort

AC

DF

Con

trol

PRE

STIG

E L

P™

Safe

ty C

ohor

t

Enrolled 280 265 333 280 265 333 Theoretical FU 280 265 333 280 265 333 Cumulative Deaths 1 0 2 0 0 2 0 Patients Evaluated Early 2 0 0 0 0 0 0 Patients Not Yet Overdue 0 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 Window (% of Total Expected)

271 (96.8%)

206 (78.3%)

321 (96.4%)

262 (93.6%)

201 (76.4%)

309 (92.8%)

Percent Follow-up 98.2% 87.1% 98.5% 97.1% 84.0% 97.3% 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

1 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. 2 Patients that completed follow-up visits early before the visit window 3 Expected = Theoretical minus Cumulative Deaths minus Patients Not Yet Overdue plus Patients Evaluated Early for Visit

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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

Variables

PRESTIGE LP™ IDE Cohort

(N=280) ACDF Control

(N=265)

PRESTIGE LP™ Safety Cohort

(N=333)

p-value (IDE vs. Control)

Age (years) 44.5 ± 8.8

Range: 23 - 78 43.9 ± 8.8

Range: 22 - 73 43.8 ± 9.0

Range: 23 – 78 0.369

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 0.622

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 0.567

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 0.722

Sex Male (%) Female (%)

129 (46.1%) 151 (53.9%)

122 (46.0%) 143 (54.0%)

155 (46.5%) 178 (53.5%)

1.000

Race Caucasian Black Asian Hispanic Other

271 (96.8%)

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

243 (91.7%)

13 (4.9%) 2 (0.8%) 6 (2.3%) 1 (0.4%)

320 (96.1%)

10 (3.0%) 1 (0.3%) 1 (0.3%) 1 (0.3%)

0.043

Marital Status Single Married Divorced Separated Widowed

40 (14.3%)

189 (67.5%) 42 (15.0%)

7 (2.5%) 2 (0.7%)

32 (12.1%)

204 (77.0%) 24 (9.1%) 3 (1.1%) 2 (0.8%)

47 (14.1%)

224 (67.3%) 51 (15.3%)

8 (2.4%) 3 (0.9%)

0.096

Education Level < High School High School > High School

15 (5.4%)

57 (20.5%) 206 (74.1%)

14 (5.3%)

77 (29.2%) 173 (65.5%)

17 (5.1%)

78 (23.6%) 236 (71.3%)

0.062

Previous Neck Surgery Yes No

3 (1.1%)

277 (98.9%)

2 (0.8%)

263 (99.2%)

3 (0.9%) 330 (99.1%)

1.000

Preoperative Medication use Non-Narcotics Weak Narcotics Strong Narcotics Muscle Relaxants

208/280 (74.3%) 133/279 (47.7%) 62/279 (22.2%)

100/279 (35.8%)

187/263 (71.1%) 127/263 (48.3%) 58/264 (22.0%)

114/264 (43.2%)

246/333 (73.9%) 152/332 (45.8%) 68/332 (20.5%)

123/332 (37.0%)

0.441 0.931 1.000 0.095

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Preoperative Pain Status4 Arm and Neck Pain Arm Pain Only Neck Pain Only

255 (91.1%) 0 (0.0%)

25 (8.9%)

238 (90.2%) 0 (0.0%)

26 (9.8%)

299 (89.8%) 0 (0.0%)

34 (10.2%)

0.769

Worker’s Compensation 32/280 (11.4%) 35/365 (13.2%) 54/333 (16.2%) 0.602 Unresolved Spinal Litigation 34/280 (12.1%) 32/265 (12.1%) 61/333 (18.3%) 1.000

Current Tobacco Use 74/280 (26.4%) 92/265 (34.7%) 94/333 (28.2%) 0.041 Current Alcohol 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

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

22 (7.9%) 85 (30.4%)

173 (61.8%)

15 (5.7%) 89 (33.6%)

161 (60.8%)

24 (7.2%) 97 (29.1%)

212 (63.7%)

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.

4 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”. The PRESTIGE 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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Table 5: Preoperative Evaluation of Endpoints

Variables PRESTIGE LP™ IDE Cohort (N=280)

ACDF Control (N=265)


(N=333)

p-value (IDE Cohort vs

ACDF Control)

NDI 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 0.498

SF-36 PCS 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 0.777

SF-36 MCS 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 0.079

Neck Pain Score 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 0.191

Arm Pain Score 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 0.236

Neurological Status (normal) • Motor • Sensory • Reflexes • Overall5

107/280 (38.2%) 117/280 (41.8%) 186/280 (66.4%) 64/280 (22.9%)

157/264 (59.5%) 134/264 (50.8%) 161/264 (61.0%) 79/264 (29.9%)

135/333 (40.5%) 147/333 (44.1%) 200/333 (60.1%) 73/333 (21.9%)

< 0.001 0.039 0.212 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 < 0.001

Baseline ROM translation (mm) N/A 0.26 ± 0.25

Range: 0.00 – 1.64 N/A N/A

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 C6-C7.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.

5 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”

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Table 6: Surgical Data



(N=265)


(N=333)

Posterior Mean and 95% BCI6 of the Difference of Mean between

IDE Cohort and Control Group (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

Range: 0.7 – 3.4 (n=280)

1.4 ± 0.5 Range: 0.6 – 3.4

(n=265)

1.4 ± 0.5 Range: 0.7 – 3.4

(n=333) 0.11 (0.02, 0.22)

Blood Loss (ml) 50.5 ± 73.5 Range: 3.0 – 700.0

Median: 35.0 (n=278)

57.5 ± 68.1 Range: 0.0 – 700.0

Median: 50.0 (n=263)

49.4 ± 67.9 Range: 3.0 – 700.0

Median 50.0 (n=333)

-4.7 (-16.8, 7.9)

Hospitalization (days) 1.0 ± 0.5 Range: 0.0 – 3.0

(n=280)

1.0 ± 0.5 Range: 0.0 – 4.0

(n=265)

1.0 ± 0.4 Range: 0.0 – 3.0

(n=333) 0.03 (-0.05, 0.11)

Median Return to Work Time (days) 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

6mm x 12mm Disc (%) 1 4 15 11 31 (11.1%) 1 8 28 12 49(14.7%)

6mm x 14mm Disc (%) 1 10 65 37 113 (40.4%) 1 13 76 42 132 (39.6%)

6mm x 16mm Disc (%) 2 1 35 23 61 (21.8%) 2 1 37 23 63 (18.9%)

6mm x 18mm Disc (%) 0 0 0 0 0 (0.0%) 0 0 0 0 0 (0.0%)

7mm x 12mm Disc (%)7 0 0 1 1 2 (0.7%) 0 0 1 2 3 (0.9%)

7mm x 14mm Disc (%) 0 2 5 8 15 (5.4%) 0 2 9 11 22 (6.6%)

7mm x 16mm Disc (%) 0 4 16 9 29 (10.4%) 0 4 17 12 33 (9.9%)

7mm x 18mm Disc (%) 0 0 9 11 20 (7.1%) 0 0 9 11 20 (6.0%)

8mm x 12mm Disc (%) 0 0 0 0 0 (0.0%) 0 0 0 0 0 (0.0%)

8mm x 14mm Disc (%) 0 0 0 3 3 (1.1%) 0 0 0 4 4 (1.2%)

8mm x 16mm Disc (%) 0 0 1 4 5 (1.8%) 0 0 1 5 6 (1.8%)

8mm x 18mm Disc (%) 0 0 0 1 1 (0.4%) 0 0 0 1 1 (0.3%)

Total (%) 4 (1.4%)

21 (7.5%)

147 (52.5%

108 (38.6%)

280 (100.0%)

4 (1.2)

28 (8.4%)

178 (53.5%)

123 (36.9%)

333 (100.0%)

6 BCI = Bayesian HPD Credible Interval 7 The 7mm x 12mm PRESTIGE LP™ Cervical Disc was a part of the size offerings in the IDE study, but is not a part of

the size offerings available for market.

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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

Adverse Event Type

Measure PRESTIGE LP™

IDE Cohort (N=280)



(N=333)

Posterior Mean and 95% BCI9 of the

Difference of Event Rate between IDE Cohort and ACDF

Control10

All Adverse Events (AEs)

Patients (%) 257 (91.8%) 219 (82.6%) 306 (91.9%) 10.2% (4.1%, 16.2%) Events

(Events/Patient) 1559 (5.57) 1198 (4.52) 1863 (5.59)

Device or Device/Surgical Procedure Related AEs

Patients (%)

34 (12.1%) 41 (15.5%) 44 (13.2%) -2.9% (-9.2%, 3.3%)

Events (Events/Patient) 61 (0.22) 60 (0.23) 76 (0.23)

Surgical Procedure Related AEs Only

Patients (%) 72 (25.7%) 71 (26.8%) 78 (23.4%) -0.5% (-8.6%, 7.4%) Events

(Events/Patient) 132 (0.47) 121 (0.46) 140 (0.42)

Severe Adverse Events (Grade 3 or 4)

Patients (%) 133 (47.5%) 98 (37.0%) 163 (48.9%) 13.3% (3.5%, 21.8%) Events

(Events/Patient) 433 (1.55) 267 (1.01) 518 (1.56)

Severe Device or Device/Procedure-Related AEs (Grade 3 or 4)

Patients (%) 14 (5.0%) 13 (4.9%) 16 (4.8%) 0.7% (-3.0%, 4.6%) Events

(Events/Patient) 33 (0.12) 22 (0.08) 40 (0.12)

Table 9 provides summary data on the number of adverse events in each treatment group by treatment level, including post-hoc statistical analysis 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.

8 One Metal Ion Cohort subject was also an IDE Cohort subject. 9 BCI = Bayesian HPD Credible Interval 10 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.

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Table 9: Summary of Total Adverse Events by Level Treated through M onth 24- IDE and Safety Population

Treatment Level



(N=265)


(N=333)

Point Estimate and 95% Confidence Interval11 of

Difference of Adverse Rate between IDE Cohort

and ACDF Control 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 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.

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

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Table 10: Adverse Events in Pivotal Study Through 24 Months12, 13

Su

rger

y

Posto

pera

tive

(1 d

ay - <4

Wee

ks)

6 Wee

ks

(≥4 W

ks - <9

Wee

ks)

3 Mon

ths

(≥9 W

ks - <5

Mon

ths)

6 Mon

ths

(≥5 M

os- <

9 Mon

ths)

12 M

onth

s (≥

9 Mos

- <19

Mon

ths)

24 M

onth

s ((≥

19 M

os- <

30 M

onth

s))

Tota

l ( U

p to

24 M

onth

) #

of P

atien

ts R

epor

ting &

To

tal a

dver

se e

vent

s

Adverse Events

PRES

TIG

E LP

™ ID

E Co

hort

ACD

F Co

ntro

l14

PRE

STIG

E LP

™ S

afety

Coh

ort

PRES

TIG

E LP

™ ID

E Co

hort

ACD

F Co

ntro

l

PRE

STIG

E LP

™ S

afety

Coh

ort

PRES

TIG

E LP

™ ID

E Co

hort

ACD

F Co

ntro

l

PRE

STIG

E LP

™ S

afety

Coh

ort

PRES

TIG

E LP

™ ID

E Co

hort

ACD

F Co

ntro

l

PRE

STIG

E LP

™ S

afety

Coh

ort

PRES

TIG

E LP

™ ID

E Co

hort

ACD

F Co

ntro

l

PRE

STIG

E LP

™ S

afety

Coh

ort

PRES

TIG

E LP

™ ID

E Co

hort

ACD

F Co

ntro

l

PRE

STIG

E LP

™ S

afety

Coh

ort

PRES

TIG

E LP

™ ID

E Co

hort

ACD

F Co

ntro

l

PRE

STIG

E LP

™ S

afety

Coh

ort

PRES

TIG

E LP

™ ID

E C

ohor

t #

Patie

nts

(% o

f 280

) To

tal #

Eve

nts

A

CD

F C

ontr

ol

# Pa

tient

s (%

of 2

65)

Tota

l # E

vent

s

PR

ESTI

GE

LP™

Saf

ety

Coh

ort

# Pa

tient

s (%

of 3

33)

Tota

l # E

vent

s

Anatomical / Technical Difficulty

2 0 2 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 2 (0.7) 2

0 (0.0) 0

2 (0.6) 2

Cancer 0 0 0 1 1 1 0 0 0 0 0 0 1 0 1 3 0 3 0 1 2 3 (1.1) 5

2 (0.8) 2

5 (1.5) 7

Cardiac Disorders 0 0 0 2 2 2 2 1 3 0 2 0 3 3 3 4 3 5 10 9 11 16 (5.7)

21 18 (6.8)

20 19 (5.7)

24

Death

0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 (0.0) 0

0 (0.0) 0

0 (0.0) 0

Dysphagia / Dysphonia 1 4 1 16 11 17 4 4 6 5 3 5 5 0 5 0 1 1 2 0 3 26 (9.3)

33 22 (8.3)

23 30 (9.0)

38

Gastrointestinal 2 7 2 8 7 8 1 3 2 4 4 7 3 2 7 20 21 22 17 24 20 35 (12.5) 55

38 (14.3) 68

43 (12.9) 68

Heterotopic Ossification 0 0 0 2 1 2 6 4 6 1 2 1 4 1 5 7 2 9 11 11 12 27 (9.6)

31 15 (5.7)

21 31 (9.3)

35

Implant Events 6 0 6 1 1 1 2 1 3 3 0 3 1 0 3 0 2 1 4 1 5 16 (5.7) 17

5 (1.9) 5

21 (6.3) 22

Infection 1 2 1 5 3 5 6 5 7 6 2 9 11 1 12 16 10 16 12 14 13 34 (12.1) 57

27 (10.2) 37

40 (12.0) 63

Neck and / or Arm Pain 3 1 4 31 16 35 43 19 57 57 49 77 37 40 50 68 50 84 36 38 46 144 (51.4)

275 124 (46.8)

213 184 (55.3)

353

Neurological 2 6 2 18 21 20 34 19 42 47 35 55 31 16 39 73 60 88 37 60 43 136 (48.6) 242

108 (40.8) 217

162 (48.6) 289

Non-Union 0 0 0 0 0 0 0 1 0 0 3 0 0 8 0 0 8 0 0 10 0 0 (0.0) 0

29 (10.9) 30

0 (0.0) 0

Other 5 3 8 19 14 22 12 13 14 24 16 28 29 9 38 55 21 58 33 57 39 93 (33.2) 177

81 (30.6) 133

110 (33.0) 207

Other Pain15 3 6 3 22 19 23 32 11 39 49 45 65 57 30 69 65 57 71 50 63 58 146 (52.1) 278

132 (49.8) 231

175 (52.6) 328

Respiratory 0 0 0 7 4 7 0 4 1 1 1 1 10 5 10 3 1 6 13 8 14 24 (8.6) 34

17 (6.4) 23

27 (8.1) 39

Spinal Event 0 0 0 19 8 22 22 6 34 20 25 25 26 15 31 44 20 53 41 29 47 83 (29.6) 172

55 (20.8) 103

106 (31.8) 212

Trauma 0 0 0 6 2 7 5 4 6 12 12 13 11 5 12 19 9 20 18 12 21 61 (21.8) 71

35 (13.2) 44

69 (20.7) 79

Urogenital 1 0 1 1 0 1 2 0 2 1 1 1 9 3 9 12 5 13 16 2 20 26 (9.3) 42

9 (3.4) 11

31 (9.3) 47

Vascular 3 1 4 1 0 1 1 0 1 0 1 0 2 1 2 2 1 2 4 0 4 12 (4.3) 13

4 (1.5) 4

13 (3.9) 14

Wound (Non-Infectious) 0 2 1 14 4 15 3 2 3 4 2 4 4 1 4 5 2 5 4 0 4 25 (8.9)

34 13 (4.9)

13 27 (8.1)

36 Any Adverse Event 257 (91.8)

1559 219 (82.6)

1198 306 (91.9)

1863

12 Based on 24-month cohort. 13 Some adverse events may lead to additional surgeries or interventions. Refer to Table 4 for more information. 14 Control=Single-level anterior interbody fusion procedure with allograft and plate stabilization. Non-randomized control arm

from IDE study of PRESTIGE® Cervical Disc. 15 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.

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Table 10b: Adverse Events Classified as Device-Related or Device/Surgical Procedure-Related According to the Clinical Adjudication Committee through Month 24 – Safety

Population

PRESTIGE LP™

IDE Cohort (N=280)



(N=333) Device Relationship of Adverse Event Determined by CAC

Events N

Patients N (%)

Events N

Patients N (%)

Events N

Patients N (%)

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) Wound (Non-Infectious) 0 0 (0.0) 1 1 (0.4) 0 0 (0.0)

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

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Table 11: Adverse Event Categories 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/Technical Difficulty – Cervical Non-Study Surgery

Anatomical or technical difficulty encountered during an additional surgery involving the cervical region, but did not involve the PRESTIGE LP™ device or original control treatment device

Anatomical/ Technical Difficulty Non-Cervical

Technical problem encountered during an additional surgery that involved a region other than the cervical spine

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 - Non-Cervical

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 of the implant surface Implant Events - Breakage Breakage of any implant or implant component

Implant Events - Other 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 (including stiffness, strain, tightness) in the neck Pain - Upper Extremities Pain (including stiffness, strain, tightness) in the shoulder, arm, wrist or hand Pain - Neck and Upper Extremities

Pain (including stiffness, strain, tightness) in the neck and shoulder, arm, wrist, or hand

Pain - Other Pain (including stiffness, strain, tightness) in an area that is not of cervical spine etiology (e.g., abdominal pain of unknown etiology, headache, flank pain, 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 respiratory system Spinal Event – Cervical Study Surgery

Event involving the treated level of cervical spine

Spinal Event – Cervical Non-Study 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 of excretion and reproduction

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Vascular – injury (intraoperative) Injury to a vascular 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 incision, such as hematoma, excluding infection 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.

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Table 12: Bayesian Comparison of Posterior Probabilities of Adverse Events

Adverse Event Patients Experiencing Adverse Events (%) Posterior Mean and 95% HPD of Adverse

Event Rate

Posterior Mean and 95% BCI16 of Difference of

Adverse Event Rate between LP IDE Cohort and ACDF

Control

IDE Cohort ACDF Control

Safety Cohort IDE Cohort ACDF Control IDE - ACDF

Anatomical / Technical Difficulty

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%)

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 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%)

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 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%)*

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 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%)

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 (Non-Infectious) 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%)*

Any adverse Event 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.

16 BCI = Bayesian HPD Credible Interval

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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.

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

Surg

ery

Posto

pera

tive

(1 d

ay - <4

Wee

ks)

6 Wee

ks

(≥4 W

ks - <9

Wee

ks)

3 Mon

ths

(≥9 W

ks - <5

Mon

ths)

6 Mon

ths

(≥5 M

os- <

9 Mon

ths)

12 M

onth

s (≥

9 Mos

- <19

Mon

ths)

24 M

onth

s ((≥

19 M

os- <

30 M

onth

s))

Tota

l 24 M

onth

#

of P

atien

ts R

epor

ting &

To

tal a

dver

se e

vent

s

Posterior Mean and 95% HPD of Secondary

Surgery Rate

Posterior Mean and 95% BCI17 of Difference of

Secondary Surgery Rate between LP IDE Cohort

and ACDF Control

Complication IDE

Cont

rol

Safe

ty C

ohor

t ID

E Co

ntro

l

Safe

ty C

ohor

t ID

E Co

ntro

l

Safe

ty C

ohor

t ID

E Co

ntro

l

Safe

ty C

ohor

t ID

E Co

ntro

l

Safe

ty C

ohor

t ID

E Co

ntro

l

Safe

ty C

ohor

t ID

E Co

ntro

l

Safe

ty C

ohor

t

IDE

# P

atien

ts (%

of 2

80)

IDE

Tot

al #

Eve

nts

C

ontr

ol #

Pat

ients

(% o

f 265

) C

ontr

ol T

otal

# E

vent

s

Safe

ty C

ohor

t # P

atien

ts (%

of 3

33

Safe

ty C

ohor

t Tot

al #

E

vent

s

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 1 (0.4) 1 5

(1.9) 5 1 (0.3) 1 0.4%

(0.0%, 1.1%) 1.6%

(0.3%, 3.3%) -1.3%

(-3.2%, 0.4%)

Removals19 0 0 0 1 0 1 1 0 1 1 1 1 3 2 3 3 6 4 1 2 1 10 (3.6) 10 11

(4.2) 11 11 (3.3) 11 3.7%

(1.6%, 6.0%) 3.8%

(1.6%, 6.2%) -0.1%

(-3.7%, 3.2%)

Supplemental Fixations20

0 0 0 0 0 0 0 0 0 0 0 0 1 3 1 1 5 1 0 1 0 2 (0.7) 2 8

(3.0) 9 2 (0.6) 2 0.5%

(0.0%, 1.3%) 3.2%

(1.3%, 5.5%) -2.7%

(-5.0%, -0.5%)

Reoperations21 0 0 0 0 0 0 0 1 0 0 0 0 0 0 0 1 1 1 2 0 2 3

(1.1) 3 2 (0.8) 2 3

(0.9) 3 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 14 (5.0) 16 21

(7.9) 27 15 (4.5) 17 5.3%

(2.8%, 8.2%) 7.1%

(4.1%, 10.4%) -1.9%

(-6.4%, 2.3%)

17 BCI = Bayesian HPD Credible Interval 18 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). 19 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. 20 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.

21 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.

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Table 14: Secondary Surgical Interventions at the Index Level– Procedure Details

Group Cause/Adverse Event Action

Secondary Surgical

Intervention Category

Time to Index Level

Surgery Safety Cohort

IDE C4-C5 displaced device with

fractured vertebrae; subject's bone scan was positive for osteopenia

C4-C5 explant of PRESTIGE LP™ artificial disc followed by

anterior cervical fusion

Removal 01 Day- <4 Weeks

(01 day) Safety Cohort

IDE C4-C5 PRESTIGE LP™ artificial disc compressed into the vertebral body and rotated within the disc

space secondary to a fall



Removal 06 Weeks (49 days)

Safety Cohort IDE

C5-C6 device extrusion C5-C6 explant of PRESTIGE LP™ artificial disc and replacement with new

PRESTIGE LP™ artificial disc; different size

Revision 06 Weeks (56 days)

Safety Cohort IDE

C6-C7 large recurrent disc herniation with cord compression and severe

stenosis

C6-C7 explant of PRESTIGE LP™ artificial disc with

anterior cervical discectomy and fusion

Removal 03 Months (150 days)

Safety Cohort IDE

Severe neck pain C5-C6 explant of PRESTIGE LP™ artificial disc followed by



Safety Cohort IDE

C6-C7 cervical radiculopathy with cervical stenosis

C6-C7 explant PRESTIGE LP™ artificial disc,C5-C7



Safety Cohort IDE

C5-C6 artificial disc dislodging posteriorly




Safety Cohort IDE

C3-C4 foraminal stenosis; possible C4 impingement; C4-C5 foraminal

disc protrusion

C3-C4 posterior cervical fusion Supplemental Fixation

06 Months (262 days)

Safety Cohort IDE

C5-C6 herniated disc with right upper extremity radiculopathy

C6-C7 explant PRESTIGE LP™ artificial disc, C5-C7



Safety Cohort IDE

Radiating paracervical pain and right shoulder pain

C4-C5 explant of PRESTIGE LP™ artificial disc, followed

by anterior cervical fusion


Safety Cohort

IDE Neck pain radiating to shoulders C6-C7 explant of PRESTIGE

LP™ artificial disc; anterior cervical fusion


Safety Cohort IDE

C3-C4, C5-C6 foraminal stenosis C3-C4, C5-C6 left posterior laminectomy

Reoperation 12 Months (528 days)

Safety Cohort Continued

Access

C7 subsidence into the vertebral body and lucency as a result of traumatic

event

C6-C7 explant of PRESTIGE LP™ artificial disc, anterior microdiscectomy and fusion


Safety Cohort IDE

C6-C7 cervical radiculopathy with cervical stenosis. Additionally, the

patient had removal due to the same diagnosis at 215 days as referenced

above.

C5-C7 posterior cervical fusion; C6-C7 posterior cervical foraminotomy

Supplemental Fixation


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Secondary Surgical


Time to Index Level

Surgery Safety Cohort

IDE C4-C5, C5-C6 left-sided neural

foraminal narrowing as a result of a fall

C4-C5, C5-C6 left posterior foraminotomy


Safety Cohort IDE

C6-C7 disc herniation; C5-C6 osteophyte

C5-C6 explant of PRESTIGE LP™ artificial disc; C5-C7 partial vertebrectomy and



Safety Cohort IDE

C5-C6 radiculopathy C5-C6 left foraminotomy Reoperation 24 Months (743 days)

Safety Cohort IDE

Lifting injury; C5-C6 changes (not specified, pre-existing) bilateral upper

extremity radiculopathy; axial neck pain

C5-C6 explant of PRESTIGE LP™ artificial disc with fusion,

C6-C7 artificial disc replacement


Safety Cohort IDE

Subsidence into C6, C4-C5 facet arthropathy, C4-C6 osteophytic

spurring and stenosis, C6-C7 herniated nucleus pulposus

C5-C6 explant of PRESTIGE LP™ artificial disc; C4-C7 anterior cervical discectomy

and fusion


Safety Cohort IDE

C4-C6 foraminal stenosis C6-C7 explant PRESTIGE LP™ artificial disc, C4-C6



Safety Cohort IDE

Shortened muscle syndrome resulting in shoulder and arm pain aggravated

by altercation at work

C6-C7 explant of PRESTIGE LP™ artificial disc, C5-C6

anterior decompression; C5-C7 anterior cervical fusion


Control C5-C6 residual foraminal stenosis; hematoma

C5-C6 left forminatomy and hematoma removal

Revision 01 Day- <4 Weeks

(02 days) Control C5 small piece of disc material or

hematoma per MRI, deltoid weakness C5-C6 posterior

microforaminotomy (C5) Reoperation 06 Weeks

(43 days) Control Esophageal perforation/fistula,

abscess C5-C6 removal of the cervical plate and allograft; exploration

and debridement of an esophageal abscess, repair of

an esophageal fistula


Control C5-C6 herniated nucleus pulposus C5-C7 anterior cervical discectomy

and fusion

Revision 03 Months (88 days)

Control C7 distribution pain and numbness C5-C7 fusion Revision 03 Months (98 days)

Control C6-C7 disc herniation C5-C6 Removal of cervical plate, exploration of fusion at

C5-C6; C6-C7 anterior cervical discectomy and fusion


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Secondary Surgical


Time to Index Level

Surgery Control C5-C6 Delayed nonunion C5-C6 bone growth stimulator Supplemental

Fixation-External

Bone Growth Stimulator


Control C5-C6 nonunion C5-C6 bone growth stimulator Supplemental Fixation-External



Control C6-C7 pseudoarthrosis C6-C7 bone growth stimulator Supplemental Fixation-External



Control C5-C6 nonunion, failed fusion with motion present

C5-C6 removal of the cervical plate and allograft; partial

corpectomy C5 with anterior cervical fusion


Control Posterior cervical region and trapezius pain, spasms, and bilateral

arm pain

C5-C6 removal of the cervical plate and allograft; anterior

cervical fusion; bilateral foraminotomies


Control C5-C6, C6-C7 nonunion

C5-C7 bone growth stimulator Supplemental Fixation-External



Control C5-C6 nonunion C5-C6 removal of the cervical plate and allograft; partial

corpectomy at C6, microdissection, and fusion


Control C5-C6 pseudoarthrosis C5-C6 removal of the cervical plate and allograft; allograft

and plate replaced


Control C5-C6, C6-C7 nonunion; wound infection

C5-C7 removal of the cervical plate and allograft; revision

anterior arthrodesis


Control C5-C6 pseudoarthrosis C5-C6 external bone growth stimulator

Supplemental Fixation-External



Control C6-C7 nonunion C6-C7 bone growth stimulator Supplemental Fixation-External



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Secondary Surgical


Time to Index Level

Surgery Control C5-C6 possible facet disease; neck

pain with right posterior scapular pain C6-C7 removal of the cervical

plate to facilitate C5-C6 anterior cervical discectomy

and fusion

Elective Removal


Control C6-C7 non-union with motion present, neck and shoulder pain

C6-C7 removal of the cervical plate and allograft; C4-C7



Control Shoulder pain and numbness in fingers

C5-C6 removal of the cervical plate to facilitate C6-C7

cervical discectomy and fusion

Elective Removal


Control Neck and arm pain; possible recurrent nerve compression

C5-C6 posterior cervical fusion Supplemental Fixation


Control Involuntary movements thumb; gait abnormalities; upper and lower extremity deficits and findings

suggestive of upper motor neuron lesion; body "jumps" when lays

down; urinary incontinence

C4, C5, C6, C7, T1 laminectomies


Control Cervical spondylosis, neck pain, glenohumeral joint



Elective Removal


Control C5-C6, C6-C7 nonunion

C5-C7 posterior fusion Supplemental Fixation


Control C5-C6 pseudoarthrosis C5-C6 posterolateral cervical fusion



Control C5-C6 discogenic pain confirmed via discogram



Elective Removal


Control C5-C6 lucency C5-C6 removal of the cervical plate and allograft; anterior

cervical fusion with autologous stem cells, and bone marrow aspiration (left anterior ilium)


Control C5-C6, C6-C7 lateral stenosis C5-C6, C6-C7 right foraminotomies with C6-C7 nerve root decompression


Control C6-C7 delayed fusion; possibly work related



Control C6-C7 osteophytes, cord edema, herniated nucleus pulposus, spinal

stenosis, radiating neck pain, motor vehicle accident



Elective Removal


Control C6-C7 pseudoarthrosis; resorption of graft



Control C6-C7 pseudoarthrosis; resorption of graft

Supplemental Fixation-C6-C7 bone growth stimulator

Supplemental Fixation-External

Bone Grown Stimulator


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Secondary Surgical


Time to Index Level

Surgery Control C6-C7 herniation, foramen

impingement, osteophyte compression

C5-C6 removal of the cervical plate to facilitate C6-C7 anterior discectomy and

osteophytectomy with anterior interbody fusion

Elective Removal


Control Neck and left arm pain C5-C6 removal of the cervical plate to facilitate C6-C7

foraminotomy with arthrodesis

Elective Removal


Control C3-C4 severe spondylitic changes with bilateral spurring, left

paracentral disc osteophyte complex, bilateral foraminal encroachment, and

C4-C5 severe spondylitic changes



Elective Removal


Control C5-C6 herniation, C4-C6 foraminal stenosis


discectomy with anterior plate

Elective Removal


Control C5-C6 degenerative changes possible small disc protrusion, osteophytes



Elective Removal


Control C3-C4 protrusion, hypertrophy; C5-C6 mild stenosis, protrusion, segment

degeneration

C4-C5 removal of the cervical plate to facilitate C3-C4, C5-

C6 anterior cervical discectomy and fusion

Elective Removal


Control C6-C7 spondylosis, disc bulge C5-C6 removal of the cervical plate to facilitate C6-C7

artificial disc replacement

Elective Removal


Control C5-C6 osteophytosis and arthropathy C6-C7 removal of the cervical plate to facilitate C5-C6


Elective Removal


Control C6 right radiculopathy, C6-C7 foraminal narrowing

C5-C6 right anterolateral foraminotomy


Control C5-C6 epidural abscess C5-C6 laminectomy with evacuation of epidural abscess


Neurological status was evaluated by assessment of motor function, sensory function, and reflexes. Overall neurological status at 6 weeks, 3 months, 6 months, 12 months and 24 months is provided for the PRESTIGE LP™ and Control subjects in Table 15 below. Neurologic success was defined as maintenance or improvement in neurologic status at 24 months compared to baseline. The success rates at 24 months postoperative were 93.3%, 94.0% and 83.6% for the PRESTIGE LP™ IDE Cohort, PRESTIGE LP™ Safety Cohort and Control group, respectively. As shown in Table 16, the neurological success rate in the PRESTIGE LP™ IDE Cohort is statistically superior to that of the ACDF Control group with the posterior probability of superiority being 99.9%.

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Table 15: Neurological Success Time Point

Variable PRESTIGE LP™ IDE Cohort

(N=280) Success (%)


Success (%)


(N=333) Success (%)

6 Weeks Overall Improved 187 (67.3%) 144 (56.7%) 228 (69.1%) Stable 65 (23.4%) 78 (30.7%) 74 (22.4%) Deteriorated 26 (9.4%) 32 (12.6%) 28 (8.5%)

3 Months Overall Improved 194 (70.3%) 136 (56.4%) 237 (72.3%) Stable 63 (22.8%) 74 (30.7%) 72 (22.0%) Deteriorated 19 (6.9%) 31 (12.9%) 19 (5.8%)




Effectiveness Results

Primary Effectiveness Analysis

The effectiveness variables represent those measurements that describe the clinical outcomes of the study subjects. The primary endpoint is a composite endpoint that takes into account the success of NDI, Neurological Status, FSU height and the absence of serious implant related adverse events or secondary surgeries. Additional secondary endpoints include radiographic success, indicators of pain relief, general health status, and doctor and subject perceptions of outcomes. Please note that this was a non-randomized study with a historical control. Study success was expressed as the number of individual subjects categorized as a success divided by the total number of subjects evaluated. Table 16 describes the observed success rates and Bayesian analyses for individual outcome parameters and overall success. Observed success rates are the 24-month outcomes of the clinical trial. Posterior means for each group can be interpreted as the average chance of success at 24 months, and the posterior mean of the difference can be interpreted as the average difference in the chance of success at 24 months. When a patient receives the PRESTIGE LP™ device, the average chance of overall success (without FSU) as defined in the clinical study at 24 months is 78.9%. Given the results of the trial, there is a 95% probability that the chance of success ranges from 74.1% to 84.0%. When a patient receives the control treatment, the average chance of overall success (without FSU) at 24

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months is 67.8%. Given the results of the trial, there is a 95% probability that the chance of success ranges from 61.2% to 74.0%. The average difference in the change of success (without FSU) between the IDE cohort and the ACDF control is 11.1% with 95% probability that this difference will fall in range of 2.7% to 19.6%. For overall success (without FSU) the posterior probability of non-inferiority of the IDE cohort to the ACDF control group is essentially 100%, reaching the primary objective.

All success probabilities were for the 24-month outcomes, and posterior probabilities of success were calculated using Bayesian statistical methods and are presented in Table 16.

Table 16: Observed Success Rates and Posterior Probabilities of Success at 24 Months

Primary Outcome Variable

24-Month Observed Success Rate 24-Month Posterior Mean (95% HPD Credible Interval) 24-Month Posterior Probabilities

(IDE vs Control) IDE

Cohort ACDF

Control IDE Cohort ACDF Control IDE Cohort –

ACDF Control Non-Inferiority Superiority

NDI 237/270 (87.8%)

177/219 (80.8%)

87.2% (83.1%, 91.2%)

82.4% (77.0%, 87.5%)

4.8% (-2.0%, 11.8%) ~100.0% 91.2%

Neurological Status

252/270 (93.3%)

184/220 (83.6%)

93.4% (90.3%, 96.2%)

83.6% (78.2%, 88.5%)

9.9% (3.8%, 16.1%) ~100.0% 99.9%

FSU 205/224 (91.5%)

156/164 (95.1%)

91.7% (87.8%, 95.2%)

95.1% (91.6%, 98.3%)

-3.4% (-8.5%, 2.1%) 99.2% 9.7%

Overall Success (without FSU)22

215/271 (79.3%)

147/220 (66.8%)

78.9% (74.1%, 84.0%)

67.8% (61.2%, 74.0%)

11.1% (2.7%, 19.6%) ~100.0% 99.5%

Overall Success (with FSU)23

159/226 (70.4%)

108/171 (63.2%)

68.9% (62.7, 75.1%)

65.7% (58.3%, 73.4%)

3.2% (-7.0%, 13.4%) 99.5% 73.6%

Statistical superiority of the PRESTIGE LP™ Cervical Disc group was demonstrated for overall success (when not including FSU data) and the neurological component for the population studied in the clinical trial at 24 months postoperatively since the posterior probability of superiority for both endpoints are over 99.0%, exceeding the threshold of 95.0%. With FSU data included, the average chance of overall success, as defined in the clinical study at 24 months, is 68.9%. These results are lower than when excluding FSU data. Given the results of the trial, there is a 95% probability that the chance of success ranges from 62.7% to 75.1%. However, the average chance of success for the control group (with FSU) is also lower, at 65.7%, with a 95% probability that the chance of success ranges from 58.3% to 73.4%. The average difference in the chance of success between the IDE cohort and the ACDF control group is 3.2% with 95% probability that this difference will fall in range of -7.0% to 13.4%. Thus, while the rates of success were lower for the investigational device when including FSU data, the success rates were also lower for the control group, and the probability of non-inferiority for the investigational device was statistically achieved. Thus it can be stated that the investigational

22 A success is a patient who had successes in NDI and neurological status and had no additional surgery classified as ‘failure’ and no serious device or device/ surgery associated adverse event. 23 A success is a patient who had successes in NDI, neurological status, and FSU and had no additional surgery classified as ‘failure’ and no serious device or device/ surgery associated adverse event.

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device is statistically non-inferior to the control procedure as the posterior probability of non-inferiority is 99.5%. The NDI, FSU, and overall success (with FSU) variables were found to be statistically non-inferior at 24 months postoperatively. The time course of overall success for each treatment group is shown in Table 17. Table 17: Time Course of Observed Success Rates

Primary Outcome Variable

3-Month Observed Success Rate




IDE Cohort

ACDF Control

IDE Cohort

ACDF Control

IDE Cohort

ACDF Control

IDE Cohort

ACDF Control

NDI 241/276 (87.3%)

174/235 (74.0%)

241/271 (88.9%)

173/224 (77.2%)

241/272 (88.6%)

176/222 (79.3%)

237/270 (87.8%)

177/219 (80.8%)

Neurological Status

257/276 (93.1%)

210/241 (87.1%)

254/270 (94.1%)

205/228 (89.9%)

257/272 (94.5%)

194/226 (85.8%)

252/270 (93.3%)

184/220 (83.6%)

FSU 229/235 (97.4%)

182/182 (100%)

227/230 (98.7%)

174/175 (99.4%)

225/233 (96.6%)

164/172 (95.3%)

205/224 (91.5%)

156/164 (95.1%)

Overall Success (without FSU) 24

223/277 (80.5%)

154/239 (64.4%)

224/271 (82.7%)

158/224 (70.5%)

227/274 (82.8%)

150/223 (67.3%)

215/271 (79.3 %)

147/220 (66.8%)

Overall Success (with FSU) 25

187/238 (78.6%)

113/181 (62.4%)

189/233 (81.1%)

119/174 (68.4%)

187/234 (79.9%)

110/173 (63.6%)

159/226 (70.4 %)

108/171 (63.2 %)

Table 18 provides overall success data for each treatment group stratified by the treated level including post-hoc statistical analysis and comparisons between the PRESTIGE LP™ IDE Cohort and the ACDF Control group through the 24-month time point using Frequentist methods. Overall success rates (without FSU) were not significantly different between the PRESTIGE LP™ IDE Cohort and ACDF Control group at any treatment level except for at the C6-C7 level, in which the IDE cohort had a significantly higher success rate compared to the control group. Overall success rates (with FSU) at 24 months were not significantly different between the IDE cohort and control group at any treatment level.

24 A success is a patient who had successes in NDI and neurological status and had no additional surgery classified as ‘failure’ and no severe device or device/surgery associated adverse event. 25 A success is a patient who had successes in NDI, neurological status, and FSU and had no additional surgery classified as ‘failure’ and no severe device or device/surgery associated adverse event.

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Table 18: Overall Success by Level Treated at 24 Months

PRESTIGE LP™ IDE Cohort (N = 280)

ACDF Control (N = 265)

Point Estimate and 95% Confidence Interval26 of Difference of Success Rate between IDE Cohort and ACDF Control Cohort

Overall Success (without FSU) 27 • C3-C4 • C4-C5 • C5-C6 • C6-C7

• 3/4 (75.0%) • 16/20 (80.0%) • 106/140 (75.7%) • 90/107 (84.1%)

• 4/8 (50.0%) • 6/11 (54.5%) • 84/125 (67.2%) • 53/76 (69.7%)

• 25.0% (-34.2%, 84.2%) • 25.5% (-7.9%, 58.9%) • 8.5% (-2.4%, 19.4%) • 14.4% (2.2%, 26.5%)

Overall Success (with FSU) 28 • C3-C4 • C4-C5 • C5-C6 • C6-C7

• 2/3 (66.7%) • 12/19 (63.2%) • 93/133 (69.9%) • 52/71 (73.2%)

• 4/5 (80.0%) • 5/10 (50.0%) • 72/115 (62.6%) • 27/41 (65.9%)

• -13.3% (-75.3%, 48.6%) • 13.2% (-24.6%, 50.9%) • 7.3% (-4.5%, 19.1%) • 7.3% (-10.1%, 24.9%)

Overall success data stratified by patient race at the 24-month time point is also provided in Table 19. Due to the relatively small numbers of non-Caucasians treated in the IDE, statistical conclusion for outcomes based on race cannot be reliably made and will be evaluated further as part of an Enhanced Surveillance Study Medtronic Sofamor Danek will conduct for 10 years postmarket.

Table 19: Overall Success by Patient Race at 24 months

Overall Success PRESTIGE LP™ IDE Cohort ACDF Control PRESTIGE LP™ Safety

Cohort Caucasian (N = 271)

Non-Caucasian (N = 9)

Caucasian (N = 243)


Caucasian (N = 320)


Overall Success (without FSU) 29

209/263 (79.5%)

6/8 (75.0%)

140/205 (68.3%)

7/15 (46.7%)

248/311 (79.7%)

10/12 (83.3%)

Overall Success (with FSU) 30

155/219 (70.8%)

4/7 (57.1%)

103/159 (64.8%)

5/12 (41.7%)

190/262 (72.5%)

8/11 (72.7%)

Secondary Effectiveness Analysis Table 20 describes the results of the secondary effectiveness endpoints at 24 months.

26 The 95% CI was provided using Frequentist Farrington and Manning methods 27 A success is a patient who had successes in NDI and neurological status and had no additional surgery classified as ‘failure’ and no severe device or device/surgery associated adverse event. 28 A success is a patient who had successes in NDI, neurological status, and FSU and had no additional surgery classified as ‘failure’ and no severe device or device/surgery associated adverse event. 29 A success is a patient who had successes in NDI and neurological status and had no additional surgery classified as ‘failure’ and no severe device or device/surgery associated adverse event. 30 A success is a patient who had successes in NDI, neurological status, and FSU and had no additional surgery classified as ‘failure’ and no severe device or device/surgery associated adverse event.

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Table 20: Secondary Endpoints and Other Measurements31

24-Month Observed Success

Rate 24-Month Posterior Mean (95% HPD Credible

Interval)

Variable

PRESTIGE LP™ IDE

Cohort ACDF

Control IDE Cohort ACDF Control IDE Cohort –

ACDF Control Neck pain Success Failure

260 (96.3%) 10 (3.7%)

213 (97.3%) 6 (2.7%)

96.4%

(94.0%, 98.4%)

97.3%

(95.1%, 99.2%)

-1.0%

(-4.3%, 2.3%) Arm pain Success Failure

258 (96.3%) 10 (3.7%)

208 (95.0%) 11 (5.0%)

96.7%

(94.4%, 98.6%)

94.7%

(91.6%, 97.5%)

1.9%

(-1.8%, 5.8%) SF-36 PCS Success Failure

221 (83.7%) 43 (16.3%)

186 (86.1%) 30 (13.9%)

82.8%

(78.0%, 87.4%)

87.6%

(82.7%, 91.8%)

-4.7% (-11.3%, 2.1%)

SF-36 MCS Success Failure

205 (77.7%) 59 (22.3%)

150 (69.4%) 66 (30.6%)

78.7%

(73.5%, 83.6%)

68.2%

(61.7%, 74.7%)

10.5%

(2.0%, 19.0%) Patient Perceived Effect Complete recovery Much improved

127 (47.0%) 107 (39.6%)

88 (40.2%) 89 (40.6%) Not Available Not Available Not Available

Doctor Perception Excellent Good

194 (71.6%) 62 (22.9%)


Gait Success Failure

268 (99.3%) 2 (0.7%)


Work Status Median days until return to work

40 60 Not Available Not Available Not Available

For patients receiving the PRESTIGE LP™ Cervical Disc device, the mean angular motion values at 12 and 24 months postoperative, respectively, were 7.85° (n=266) and 7.51° (n=264) as compared to a preoperative value of 5.67° (n=260). The range of motion values measured from flexion/extension radiographs at 24 months for the PRESTIGE LP™ Cervical Disc patients are presented in the histogram below. This histogram uses values obtained by rounding the recorded range of motion for each subject to the nearest integer.

31 Patient accounting in this table is affected by subjects lost to follow up and/or missing data.

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Figure 2: Histogram of PRESTIGE LP™ Cervical Disc Angular Range of Motion at 24 Months Table 21 presents data on change in range of motion from the preoperative baseline for each time point by treatment group. Table 21: Time Course of Radiographic Change in Range of Motion

1. 2. 3.

Time Point Change in Angular Range of Motion

PRESTIGE LP™ IDE (N =280)

Control (N=265)

6 Weeks Increased (≥2º) 120 (48.0%) 2 (1.4%) No Change(-2º to 2º) 70 (28.0%) 5 (3.4%) Decreased ≤-2º) 60 (24.0%) 138 (95.2%)

3 Months Increased (≥2º) 128 (51.0%) 0 (0.0%) No Change(-2º to 2º) 71 (28.3%) 10 (6.4%) Decreased ≤-2º) 52 (20.7%) 146 (93.6%)




0

2

4

6

8

10

12

14

16

18

20

22

24

26

Num

ber o

f Pat

ient

s

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26

Degrees of Motion

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Table 22 presents radiographic disc height success at each time point for each treatment group. Disc height success is achieved when the change in the six-week post-operative height from the post-operative height is greater than or equals -2mm in either the anterior or posterior measurements. Disc height success was similar between the two treatment groups with greater than 90% of the patients in both groups achieving success at each time point.

Table 22: Time Course of Radiographic Disc Height Success32

Time Point PRESTIGE LP™

IDE (N = 280) Control

(N = 265)

3 Months 229/235 (97.4%)

182/182 (100.0%)

6 Months 227/230 (98.7%)

174/175 (99.4%)

12 Months 225/233 (96.6%)

164/172 (95.3%)

24 Months 205/224 (91.5%)

156/164 (95.1%)

Available radiographs for the PRESTIGE LP™ study patients were assessed for bridging bone (Criteria was comparable to Class IV assessment on the McAfee and Mehren classification system for Heterotopic Ossification) between the vertebral bodies of the implanted motion segment. Bridging was defined as evidence of a continuous bony connection from the superior vertebral body to the inferior vertebral body laterally, anteriorly, and/or posteriorly. The radiographic results are shown in Table 23. More than 90% of the PRESTIGE LP™ IDE patients displayed no signs of bridging bone at each time point, with 94.1% of the patients exhibiting no bridging bone at 24 months.

Table 23: Time Course of Bridging Bone

Bridging Bone PRESTIGE LP™

IDE (N = 280)

6 Weeks No 278 (100.0%) Yes 0 (0%)

3 Months No 274 (99.6%) Yes 1 (0.4%)

6 Months No 268 (99.3%) Yes 2 (0.7%)

12 Months No 269 (98.2%) Yes 5 (1.8%)

24 Months No 253 (94.1%) Yes 16 (5.9%)

32 Disc height success is defined as Postoperative Height minus Six-Week Postoperative Height ≥ -2mm either at the anterior or posterior measurements

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The percentage of PRESTIGE LP™ patients with range of motion >4º and ≤ 20º for patients with and without bridging bone at 24 months is described in Table 24.

Table 24: Range of Motion (ROM) at 24 Months by Patients with Bridging Bone PRESTIGE LP™ IDE Cohort PRESTIGE LP™ Safety Cohort

No Bridging

Bone (N=253)

Bridging Bone

(N=16)

Total (N=269

)

No Bridging

Bone (N=303)

Bridging Bone

(N=18)

Total (N=321)

Patients w/ 4º < ROM ≤ 20º

179/248 (72.2%)

2/16 (12.5%)

181/264 (68.6%)

219/298 (73.5%)

3/18 (16.7%)

222/316 (70.3%)

% Patients ROM ≤ 4º

67/248 (27.0%)

14/16 (87.5%)

81/264 (30.7%)

77/298 (25.8%)

15/18 (83.3%)

92/316 (29.1%)

% Patients ROM > 20º

2/248 (0.8%)

0/16 (0.0%)

2/264 (0.8%)

2/298 (0.7%)

0/18 (0.0%)

2/316 (0.6%)

An analysis of the correlation between the degree of segmental motion, NDI, neck and arm pain scores was also performed, and statistically significant correlations were noted, but the magnitudes of the correlations were small. Conclusions Drawn from the Study Data The clinical results from the use of the investigational device, the PRESTIGE LP™ Cervical Disc, were shown to be statistically non-inferior to the control group results. The scientific evidence that has been presented here supports the safety and effectiveness of the PRESTIGE LP™ Cervical Disc in the treatment of intractable radiculopathy and/or myelopathy at a single-level from C3 to C7. The study demonstrated that the treatment of intractable radiculopathy and/or myelopathy with the PRESTIGE LP™ Cervical Disc was as effective as the control treatment (fusion with bone graft and plate stabilization). The results for the primary effectiveness outcome parameters for the investigational group were non-inferior to the control group. The investigational group demonstrated superiority to the control group for the neurological component and overall success (without FSU). The PRESTIGE LP™ Cervical Disc was able to achieve comparable or better clinical performance while maintaining motion at the involved cervical level.

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Two-Level Clinical Study (G050202) The clinical investigation of the PRESTIGE LP™ Cervical Disc for use at two contiguous levels was conducted under an approved IDE #G050202. The study was a prospective, multi-center, randomized (1:1), unmasked, concurrently controlled, non-inferiority clinical trial conducted in the United States to compare the safety and effectiveness of the 2-level PRESTIGE LP™ Cervical Disc to the standard of care, 2-level anterior cervical discectomy and fusion (ACDF) using structural allograft and stabilization with an ATLANTIS® Anterior Cervical Plate. The primary objective of the study was to evaluate the overall success rate of the investigational device through 24 months as compared to the control in reconstruction of the disc from C3-C7 following discectomy at two contiguous levels in skeletally mature subjects with intractable radiculopathy or myelopathy localized to the two disc space levels, The subjects had been unresponsive to at least 6 weeks of non-operative treatment or had the presence of progressive symptoms or signs of nerve root/spinal cord compression in the face of continued non-operative management. The study included a total of 397 subjects (209 investigational subjects and 188 control group subjects) at 30 investigational sites in the United States. Clinical Inclusion and Exclusion Criteria To qualify for enrollment in the study, subjects had to meet all of the following inclusion criteria and none of the following exclusion criteria. Clinical Inclusion Criteria

Enrollment in the 2-level PRESTIGE LP™ Cervical Disc study was limited to subjects who met the following inclusion criteria:

• Cervical degenerative disc disease at two (2) adjacent cervical levels (from C3-C7) requiring surgical treatment and involving intractable radiculopathy, myelopathy, or both;

• Herniated disc and/or osteophyte formation at each level to be treated that is producing symptomatic nerve root and/or spinal cord compression. The condition is documented by patient history (e.g., neck and/or arm pain, functional deficit and/or neurological deficit), and the requirement for surgical treatment is evidenced by radiographic studies (e.g., CT, MRI, x-rays, etc.);

• Unresponsive to non-operative treatment for approximately six weeks or has the presence of progressive symptoms or signs of nerve root/spinal cord compression in the face of continued non-operative management;

• No previous surgical intervention at the involved level or any subsequent, planned/staged surgical procedure at the involved or adjacent level(s);

• At least 18 years of age and be skeletally mature at the time of the surgery; • Pre-operative Neck Disability Index (NDI) score ≥ 30; • Pre-operative neck pain score ≥ 8 on Preoperative Neck and Arm Pain

Questionnaire; • If a female of child-bearing potential, subject is non-pregnant, non-nursing, and

agrees not to become pregnant during the study period;

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

Clinical Exclusion Criteria

Subjects were not permitted to enroll in the 2-level PRESTIGE LP™ Cervical Disc study if they met any of the following exclusion criteria:

• A cervical spinal condition other than symptomatic cervical disc disease requiring surgical treatment at the involved levels;

• Documented or diagnosed cervical instability relative to adjacent segments at either level, defined by dynamic (flexion/extension) radiographs showing sagittal plane translation > 3.5 mm or sagittal plane angulation > 20°;

• More than two cervical levels requiring surgical treatment; • A fused level adjacent to the level to be treated; • Severe pathology of the facet joints of the involved vertebral bodies; • Previous surgical intervention at either one or both of the involved levels or at

adjacent levels; • Previously diagnosed with osteopenia or osteomalacia; • Any of the following that may be associated with a diagnosis of osteoporosis (if

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

o Postmenopausal non-Black female over 60 years of age who 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) was a T score of -3.5 or lower (i.e., -3.6, -3.7, etc.) or a T score of -2.5 or lower (i.e., -2.6, -2.7, etc.) with vertebral crush fracture, then the subject was excluded from the study;

• Presence of spinal metastases; • Overt or active bacterial infection, either local or systemic; • Insulin dependent diabetes; • A tobacco user who does not agree to suspend smoking prior to surgery; • Chronic or acute renal failure or prior history of renal disease; • A documented allergy or intolerance to stainless steel, titanium, or a titanium

alloy; • Mentally incompetent (If questionable, obtain psychiatric consult); • A prisoner; • Pregnant; • An alcohol and/or drug abuser currently undergoing treatment for alcohol and/or

drug abuse; • Involved with current or pending litigation regarding a spinal condition;

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• 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 routine perioperative anti-inflammatory drugs;

• A history of an endocrine or metabolic disorder known to affect osteogenesis (e.g., Paget’s Disease, renal osteodystrophy, Ehlers-Danlos Syndrome, or osteogenesis imperfecta);

• A condition that requires postoperative medications that interfere with the stability of the implant, such as steroids. (This does not include low dose aspirin for prophylactic anticoagulation and routine perioperative anti-inflammatory drugs);

• Received treatment with an investigational therapy within 28 days prior to implantation surgery or such treatment is planned during the 16 weeks following implantation with the PRESTIGE LP™ device.

Post-operative Care The recommended post-operative care included avoidance of overhead lifting, heavy lifting, repetitive neck bending, and high-impact exercise or athletic activity for 60 days post-operatively. Avoidance of prolonged (beyond 2 weeks post-op) non-steroidal anti-inflammatory drug (NSAID) use was specified, although the use of NSAIDs was recommended for the first two weeks post-operatively in the 2-level PRESTIGE LP™ Cervical Disc group. Post-operative bracing requirements were left to the discretion of the investigators and included the option for use of a soft collar as needed. Subjects who smoked were encouraged to discontinue smoking. The use of electrical bone growth stimulators was not recommended during the 24-month follow-up period. However, in the few control group cases where an electrical bone growth stimulator was used, the subjects were deemed treatment failures.

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Follow-Up Schedule All subjects were evaluated pre-operatively (within 6 months of surgery), intra-operatively, immediately post-operatively (prior to discharge) and then at 6 weeks (±2 weeks), 3 months (±2 weeks), 6 months (±1 month), 12 months (±2 months), 24 months (±2 months), and annually thereafter until the last subject enrolled in the study had completed his or her 24-month follow-up evaluation. Additional evaluations were approved by FDA for 36 months (±2 months), 60 months (±3 months), 84 months (±3 months), and 120 months (±3 months). Effectiveness parameters assessed during follow-up included pain and function measured by the Neck Disability Index (NDI), neck pain, arm pain, and quality of life as measured by the Medical Outcomes Study 36-Item Short Form Health Survey (SF-36). Other parameters assessed during follow-up included neurological assessment and radiologic outcomes. Complications and adverse events, device-related or not, were evaluated over the course of the study. Evaluations were done according to the visit schedule below:

Table 25: Schedule of Study Assessments Procedure

Pre-/Peri-operative Post-operative Pre-op Surgery/

Hospital Discharge

6 wks (±2 wks)

3 mos (±2 wks)

6 mos (±1 mo)

12 mos, 24 mos 36 mos, (±2 mos)

60 mos, 84 mos, 120 mos (±3 mos)

Clinical Evaluations: Inclusion/Exclusion Determination

X

Osteoporosis/Osteopenia Screen X Informed Consent and HIPAA Authorization

X

Baseline Medical History/Physical Exam

X

Surgery and Hospital Discharge Data

X

Neck Disability Index (NDI) X X X X X X Neck and Arm Pain Questionnaire

X X X X X X

Health Status Questionnaire (SF-36)

X X X X

Neurological Status X X X X X X Preoperative Gait Assessment and Foraminal Compression Test

X X X X X X

Medication Use X X X X X X Work Status X X X X X X Satisfaction and Perceived Effect (subject & physician)

X X X X X X

Radiologic Review X X X X X X X Adverse Events X X X X X X Subject Disposition* X X X X X X X Radiographic Procedures Anterior/Posterior and Lateral Neutral X-rays

X X X X X X X

Lateral Flexion/Extension X-rays

X X X X X X

CT and/or MRI X

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Procedure

Pre-/Peri-operative Post-operative Pre-op Surgery/

Hospital Discharge

6 wks (±2 wks)

3 mos (±2 wks)

6 mos (±1 mo)

12 mos, 24 mos 36 mos, (±2 mos)

60 mos, 84 mos, 120 mos (±3 mos)

DEXA Scan ** X * While the Subject Disposition CRF could be filled out at any time, it was only filled out once for each subject. ** A DEXA Scan was only required if the subject had a risk factor that may be associated with a diagnosis of osteoporosis as outlined in the clinical protocol.

Clinical Endpoints The safety of the 2-level PRESTIGE LP™ Cervical Disc was assessed by comparing the nature and frequency of adverse events (overall and in terms of seriousness and relationship to the device and/or procedure) and subsequent surgical procedures as well as maintenance or improvement in neurological status to the 2-level ACDF control group. The effectiveness of the 2-level PRESTIGE LP™ Cervical Disc was assessed by evaluating improvement in NDI score, improvement in neck and arm pain measured at rest using a neck and arm pain questionnaire, improvement in quality of life measured using the Short-Form 36 (SF-36) questionnaire, subject satisfaction, medication usage, and work status compared to the 2-level ACDF control group. In addition, several radiographic endpoints were considered in evaluating both safety and effectiveness including range of motion, functional spinal unit (FSU) height maintenance, implant condition, and heterotopic ossification. Per the protocol, an individual subject in either treatment group was considered a success if the following criteria were met at 24 months post-operative.

1. Improvement (reduction) of at least 15 points in NDI score compared to pre-operative baseline;

2. Maintenance or improvement in neurological status at 24 months compared to pre-operative baseline as measured based on motor function, sensory function, and reflexes;

3. No serious adverse event classified as implant associated, or implant/surgical procedure associated; and

4. No additional surgical procedure classified as a “failure.”

Note that because the additional surgical procedure component of the primary endpoint did not consider all subsequent surgeries at the index level as failures, FDA requested an additional analysis of overall success in which all subsequent surgeries at the index level and all intra-operative treatment conversions were considered failures. Overall study success criteria were based on a comparison of individual subject success rates, such that the subject success rate for the 2-level PRESTIGE LP™ group was required to be non-inferior to that of the 2-level ACDF control group. The study was designed as a non-inferiority study with a margin (delta) of 10%. For the analysis of overall success, individual effectiveness variables and neurological status, a Bayesian analysis model incorporated data from both the 12-month and 24-month follow-up visits, including data from the 12-month only or 24-month only

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visits, to statistically compare the outcomes at the 24-month visit between the two treatment groups. The study hypothesis was that the success rate of the 2-level PRESTIGE LP™ group was statistically non-inferior to the success rate in the 2-level ACDF control group by a margin of 10%. Non-inferiority was to be claimed if the posterior probability that the success rate in the 2-level PRESTIGE LP™ group was not lower than the success rate in the 2-level ACDF control group by more than 10% was greater than 95%. For comparison of adverse events and subsequent surgical procedures, a beta-binomial model was used. Secondary endpoints, measured in both treatment groups, included neck pain, arm pain, quality of life (SF-36 Physical Component Score [PCS] and Mental Component Score [MCS]), gait assessment (Nurick’s classification), subject satisfaction, subject perceived effect, physician perception of results, radiographic success (defined differently in the two treatment groups), range of motion, Functional Spinal Unit (FSU) height, implant condition, heterotopic ossification, and return to work. For these endpoints, multiple comparisons were carried out without adjusting for multiplicity. Accountability of PMA Cohort A total of 397 subjects (209 2-level PRESTIGE LP™, 188 2-level ACDF control) were treated in the IDE study. At the time of database lock, of the 397 subjects enrolled in the study, complete 24-month overall success (primary endpoint) data was available for 199 2-level PRESTIGE LP™ subjects (95%) and 160 2-level ACDF control subjects (86%). A summary of subject accountability data for the 12 month, 24 month, 36 month, 60 month, and 84 month follow-up visits is provided in Table 26.

Table 26: Subject Accountability

12 Months 24 Months 36 Months 60 Months 84 Months

INV CTR INV CTR INV CTR INV CTR INV CTR Enrolled and treated 209 188 209 188 209 188 209 188 209 188 Deaths (cumulative) 0 0 0 1 0 1 1 1 1 2 Not Yet Overdue 0 0 0 0 0 0 0 0 21 15 Expected1 209 188 209 187 209 187 208 187 187 171 Withdrawn (cumulative) 0 4 0 7 1 10 5 12 5 16 Actual, primary endpoint data (% follow-up)2

202 (97%)

166 (88%)

199 (95%)

160 (86%)

185 (89%)

149 (80%)

166 (80%)

138 (74%)

126 (67%)

99 (58%)

Actual, primary endpoint data in window (% follow-up)3

191 (91%)

162 (86%)

181 (87%)

140 (75%)

Not Available

Actual, any data (% follow-up)4

203 (97%)

168 (89%)

199 (95%)

164 (88%)

187 (89%)

152 (81%)

167 (80%)

139 (74%)

126 (67%)

101 (59%)

INV=2-level PRESTIGE LP™ (N=209); CTR = 2-level ACDF control (N=188) 1 Treated subjects – (Deaths + Not yet overdue). 2 Subjects with complete data for the primary endpoint (overall success), regardless of in-window status. 3 Subjects with complete data for the primary endpoint (overall success), evaluated in-window. 4 Subjects with any follow-up data reviewed or evaluated.

In addition to the study subjects described above, there were an additional 59 subjects (17 2-level PRESTIGE LP™ subjects and 42 2-level ACDF control subjects) who were consented and randomized 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 characteristics of the subjects who participated in the study.

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Throughout this summary, the primary analysis dataset (209 2-level PRESTIGE LP™ subjects, 188 2-level ACDF control subjects) includes all subjects who completed the surgical procedure and received a study device in either treatment group classified according to the treatment received (as-treated). Subjects who had subsequent surgical procedures classified as “failures” were deemed “failures” for overall success, and since these subsequent surgical procedures had the potential to alter the original study treatment’s outcomes, for all neurological status and all individual effectiveness variables, the last observation obtained before the subsequent surgery occurred was carried forward. Primary statistical comparisons were based on the observed data, and missing data due to lost-to-follow-ups were not imputed. Therefore, the denominators varied for the primary study endpoint (overall success) and individual effectiveness variables such as NDI and neurological status. Study Population Demographics and Baseline Parameters Table 27 presents the summary statistics for demographic and baseline characteristics for the 2-level PRESTIGE LP™ group and the 2-level ACDF control group. 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 similar demographically. Although p-values were obtained without any adjustment for multiplicity, there were no statistically significant differences (p<0.05) for any of the variables except for preoperative work status (70% working pre-operatively in the 2-level PRESTIGE LP™ group as compared to 60% in the 2-level ACDF control group).

Table 27: Study Population Demographics and Baseline Characteristics

Demographic Measure/ Baseline Characteristic

INV (N=209)

CTR (N=188)

p-value (INV - CTR)

Age (years; mean ± standard deviation)

47.1 ± 8.3 Range: 22 – 75

47.3 ± 7.7 Range: 25 – 69

0.844

Gender (n(%)) Male Female

92 (44.0%)

117 (56.0%)

90 (47.9%) 98 (52.1%)

0.480

Race (n(%)) Caucasian Black Asian Hispanic Other

195 (93.3%)

8 (3.8%) 1 (0.5%) 4 (1.9%) 1 (0.5%)

172 (91.5%)

8 (4.3%) 3 (1.6%) 4 (2.1%) 1 (0.5%)

0.879

BMI (kg/m2; mean ± standard deviation)

28.2 ± 5.6 Range: 16 – 46

28.6 ± 4.9 Range: 18 – 43

0.481

Marital Status (n(%)) Single Married Divorced Separated Widowed

25 (12.0%)

146 (69.9%) 32 (15.3%)

4 (1.9%) 2 (1.0%)

29 (15.4%)

133 (70.7%) 23 (12.2%)

2 (1.1%) 1 (0.5%)

0.698

Education Level (n(%)) < High School High School > High School

21 (10.0%) 63 (30.1%)

125 (59.8%)

20 (10.6%) 64 (34.0%)

104 (55.3%)

0.652

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Previous Neck Surgery (n(%)) Yes No

0 (0.0%)

209 (100.0%)

2 (1.1%)

186 (98.9%)

0.224

Pre-operative Medication Use Non-Narcotics Weak Narcotics Strong Narcotics Muscle Relaxants

138/208 (66.3%) 83/208 (39.9%) 52/207 (25.1%) 75/208 (36.1%)

133/185 (71.9%) 78/186 (41.9%) 44/188 (23.4%) 73/188 (38.8%)

0.275 0.758 0.725 0.604

Pre-operative Pain Status1 Arm and Neck Pain Arm Pain Only Neck Pain Only

180 (86.1%)

0 (0.0%) 29 (13.9%)

173 (92.0%)

0 (0.0%) 15 (8.0%)

0.078

Pre-operative Diagnosis (n(%)) Radiculopathy and myelopathy Radiculopathy only Myelopathy only

54 (25.8%)

150 (71.8%) 5 (2.4%)

45 (23.9%)

137 (72.9%) 6 (3.2%)

0.837

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

5 (2.4%)

56 (26.8%) 148 (70.8%)

8 (4.3%)

58 (30.9%) 122 (64.9%)

0.340

Pre-operative Work Status 146 (69.9%) 113 (60.1%) 0.045 Worker’s Compensation 26 (12.4%) 19 (10.1%) 0.527 Unresolved Spinal Litigation 0 (0.0%) 1 (0.5%) 0.474 Smoking Status Not provided. Protocol excluded tobacco users who did not

agree to stop smoking prior to surgery. Current Alcohol Use 116 (55.5%) 88 (46.8%) 0.088

INV=2-level PRESTIGE LP™ (N=209); CTR = 2-level ACDF control (N=188) 1 Pre-operative arm and neck pain defined as both arm and neck pain scores ≥ 8/10; pre-operative neck pain only defined as neck pain score ≥ 8/10 and arm pain score < 8/10. There were no subjecs with only arm pain because neck pain score ≥ 8/10 was a study inclusion criterion.

The mean baseline pre-operative assessments for the 2-level PRESTIGE LP™ group and the 2-level ACDF control group are presented in Table 28. Although p-values were obtained without any adjustment for multiplicity, there were no statistical differences between the 2-level PRESTIGE LP™ group and the 2-level ACDF control group for any of the variables identified in the table.

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Table 28: Preoperative Evaluation of Clinical Endpoints

Variable INV (N=209)

CTR (N=188)

p-value (INV - CTR)

NDI; mean ± standard deviation 52.1 ± 13.4 Range: 30 – 84

53.2 ± 14.8 Range: 30 – 94

0.441

SF-36 PCS; mean ± standard deviation 31.8 ± 7.8 Range: 11.7 – 55.5

30.8 ± 7.4 Range: 11.1 – 51.1

0.189

SF-36 MCS; mean ± standard deviation 43.9 ± 11.8 Range: 16.7 – 70.6

43.8 ± 12.2 Range: 15.9 – 67.1

0.930

Neck Pain Score; mean ± standard deviation 16.2 ± 2.9 Range: 8 – 20

16.3 ± 2.6 Range: 8 – 20

0.720

Arm Pain Score; mean ± standard deviation 13.8 ± 5.6 Range: 0 – 20

14.4 ± 4.3 Range: 0 – 20

0.208

Neurological Status Normal (n(%)) Motor Sensory Reflexes Overall1

97 (46.4%) 85 (40.7%) 90 (43.1%) 42 (20.1%)

88 (46.8%) 66 (35.1%) 75 (39.9%) 31 (16.5%)

1.000 0.257 0.542 0.367

ROM flexion/extension angulation (º) Superior Target Level; mean ± standard deviation

6.75 ± 4.16

Range: 0.08 – 18.15

7.12 ± 4.14

Range: 0.45 – 19.72

0.387

ROM flexion/extension angulation (º) Inferior Target Level; mean ± standard deviation

5.56 ± 3.89

Range: 0.37 – 18.20

5.37 ± 3.26

Range: 0.37 – 18.51

0.637

ROM flexion/extension translation (mm) Superior Target Level; mean ± standard deviation

1.48 ± 1.08

Range: 0.13 – 9.17

1.57 ± 1.14

Range: 0.03 – 8.96

0.446

ROM flexion/extension translation (mm) Inferior Target Level; mean ± standard deviation

1.04 ± 0.74

Range: 0.06 – 3.42

1.14 ± 0.93

Range: 0.00 – 6.60

0.267

Baseline radiographic findings – superior target level (n(%))

Herniated disc Osteophyte formation Both

63 (30.1%) 48 (23.0%) 98 (46.9%)

54 (28.7%) 32 (17.0%) 102 (54.3%)

0.240

Baseline radiographic findings – inferior target level (n(%))

Herniated disc Osteophyte formation Both

67 (32.1%) 42 (20.1%) 100 (47.8%)

62 (33.0%) 29 (15.4%) 97 (51.6%)

0.480

INV=2-level PRESTIGE LP™ (N=209); CTR = 2-level ACDF control (N=188) 1 If at least one of the three components (motor, sensory, reflexes) is not normal, then overall is defined as not normal. If all components are normal, then overall is defined as normal.

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Surgery and Hospitalization Data Table 29 summarizes the information related to the surgical procedures and postoperative hospitalizations of subjects. The most common treated surgical levels were the C5-C6 and C6-C7 levels. The mean operative times for the 2-level PRESTIGE LP™ and 2-level ACDF control groups were 2.1 hours and 1.7 hours, respectively, which is a mean difference of 0.4 hours (24 minutes) when not adjusting for multiplicity. Additionally, 2-level PRESTIGE LP™ subjects were found to have more estimated blood loss compared to the 2-level ACDF control group subjects (67.2 ml for 2-level PRESTIGE LP™ group versus 55.7 ml for 2-level ACDF control group) when not adjusting for multiplicity. The mean hospital stays for subjects in both treatment groups were similar (1.2 days versus 1.3 days for the 2-level PRESTIGE LP™ and 2-level ACDF control groups, respectively). Data regarding the amount/type of decompression and handling of the posterior longitudinal ligament for each procedure was not systematically collected. Table 30 summarizes the PRESTIGE LP™ devices implanted during the 2-level clinical study by size and treatment level.

Table 29: Surgical Data Procedural Characteristic INV CTR Posterior Mean and 95% BCI of

the Difference of Mean between INV and CTR (lower, upper)

Treated Level (n(%) C3-C4 and C4-C5 C4-C5 and C5-C6 C5-C6 and C6-C7

3 (1.4%)

43 (20.6%) 163 (78.0%)

3 (1.6%)

44 (23.4%) 141 (75.0%)

N/A

Operative time (hrs); mean ± standard deviation

2.1 ± 0.8 Range: 0.8 – 5.0

1.7 ± 0.7 Range: 0.7 – 4.9

0.4 (0.25, 0.55)

Blood Loss (ml); mean ± standard deviation

67.2 ± 64.1 Range: 0.0 – 600

(n=208)

55.7 ± 46.3 Range: 0.0 – 250.0

11.5 (0.56, 22.44)

Hospitalization (days); mean ± standard deviation

1.2 ± 0.5 Range: 0.0 – 4.0

1.3 ± 1.0 Range: 0.0 – 8.0

-0.1 (-0.26, 0.06)

Median Return to Work Time (days) 49 55 N/A

INV=2-level PRESTIGE LP™ (N=209); CTR = 2-level ACDF control (N=188) BCI = Bayesian HPD Credible Interval

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Table 30: PRESTIGE LP™ Devices Implanted by Size and Treatment Level

Superior Level PRESTIGE LP™ Size

Inferior Level PRESTIGE LP™ Size

C3-C4, C4-C5

C4-C5, C5-C6

C5-C6, C6-C7

Total (N=209)

5mm x 12mm 5mm x 12mm 0 1 0 1 (0.5%) 5mm x 12mm 5mm x 14mm 0 0 1 1 (0.5%) 5mm x 12mm 6mm x 14mm 0 1 0 1 (0.5%) 5mm x 14mm 5mm x 14mm 1 5 13 19 (9.1%) 5mm x 14mm 5mm x 16mm 0 0 3 3 (1.4%) 5mm x 14mm 6mm x 12mm 0 1 0 1 (0.5%) 5mm x 14mm 6mm x 14mm 0 1 9 10 (4.8%) 5mm x 14mm 6mm x 16mm 0 0 2 2 (1.0%) 5mm x 14mm 8mm x 14mm 0 0 1 1 (0.5%) 5mm x 16mm 5mm x 14mm 0 2 0 2 (1.0%) 5mm x 16mm 5mm x 16mm 2 6 15 23 (11.0%) 5mm x 16mm 6mm x 16mm 0 2 10 12 (5.7%) 6mm x 12mm 5mm x 14mm 0 1 0 1 (0.5%) 6mm x 12mm 6mm x 12mm 0 0 3 3 (1.4%) 6mm x 12mm 6mm x 14mm 0 1 0 1 (0.5%) 6mm x 12mm 7mm x 12mm 0 0 3 3 (1.4%) 6mm x 14mm 5mm x 14mm 0 0 2 2 (1.0%) 6mm x 14mm 5mm x 16mm 0 1 0 1 (0.5%) 6mm x 14mm 6mm x 12mm 0 0 1 1 (0.5%) 6mm x 14mm 6mm x 14mm 0 6 23 29 (13.9%) 6mm x 14mm 6mm x 16mm 0 1 8 9 (4.3%) 6mm x 14mm 7mm x 16mm 0 0 2 2 (1.0%) 6mm x 14mm 8mm x 14mm 0 0 1 1 (0.5%) 6mm x 14mm 8mm x 16mm 0 0 1 1 (0.5%) 6mm x 16mm 5mm x 16mm 0 1 1 2 (1.0%) 6mm x 16mm 6mm x 14mm 0 0 1 1 (0.5%) 6mm x 16mm 6mm x 16mm 0 6 25 31 (14.8%) 6mm x 16mm 7mm x 16mm 0 0 4 4 (1.9%) 6mm x 16mm 7mm x 18mm 0 0 2 2 (1.0%) 7mm x 12mm 6mm x 12mm 0 0 2 2 (1.0%) 7mm x 14mm 5mm x 14mm 0 0 1 1 (0.5%) 7mm x 14mm 6mm x 14mm 0 2 0 2 (1.0%) 7mm x 14mm 6mm x 16mm 0 0 1 1 (0.5%) 7mm x 14mm 7mm x 14mm 0 1 0 1 (0.5%) 7mm x 14mm 7mm x 16mm 0 0 1 1 (0.5%) 7mm x 16mm 5mm x 16mm 0 1 0 1 (0.5%) 7mm x 16mm 6mm x 16mm 0 0 7 7 (3.3%) 7mm x 16mm 7mm x 16mm 0 2 5 7 (3.3%)

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7mm x 16mm 7mm x 18mm 0 0 1 1 (0.5%) 7mm x 18mm 7mm x 16mm 0 0 1 1 (0.5%) 7mm x 18mm 7mm x 18mm 0 1 12 13 (6.2%) 7mm x 18mm 8mm x 18mm 0 0 1 1 (0.5%)

Total (%) 3 (1.4%) 43 (20.6%) 163 (78.0%) 209 (100%)

Safety and Effectiveness Results Safety Results The analysis of safety was based on the as-treated cohort of 397 total subjects which included all subjects who completed the surgical procedure and received a study device in either treatment group classified according to the treatment received (209 2-level PRESTIGE LP™ subjects and 188 2-level ACDF control subjects). Summary of Adverse Event Data: A summary of the adverse event data is presented in Table 31. Adverse events were classified by an independent Clinical Adjudication Committee (CAC) for severity and relationship to the device and/or surgical procedure. The severity of an AE was assessed as mild (grade 1), moderate (grade 2), severe (grade 3), or life-threatening (grade 4) according to the World Health Organization (WHO) Recommendations for Grading of Acute and Subacute Toxic Effects.

The relationship between an AE and the device/surgical procedure was assessed based on the following definitions: • Implant Associated: AE for which there is a reasonable possibility that the AE may have been

caused primarily by the device; • Implant/Surgical Procedure Associated AE: AE for which there is a reasonable possibility

that the AE may have been caused both by the device and the surgical procedure; • Surgical Procedure Associated AE: AE for which there is a reasonable possibility that the AE

may have been caused primarily by the surgical procedure; • Undetermined: AE for which sufficient information is not available at the time of the AE to

determine its causality; • Not Related: AE for which sufficient information exists to indicate that the etiology is

unrelated to the device or surgical procedure. The overall AE rates were similar in the 2-level PRESTIGE LP™ group (93.3%) and in the 2-level ACDF control group (92.0%) through 24 months.

Table 31: Summary of Adverse Events (AEs) Up to the 24-Month Time Interval (≤30 Months)

INV (N=209) CTR (N=188) Posterior Mean and 95% BCI* of the Difference of Event Rate

between INV and CTR** Events Subjects

(n (%)) Events Subjects

(n (%)) All Adverse Events 1477 195 (93.3%) 1593 173 (92.0%) 1.3% (-3.9%, 6.6%) Subsequent Surgeries at Index Level 6 5 (2.4%) 17 15 (8.0%) -5.6% (-10.2%, -1.1%)

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INV (N=209) CTR (N=188) Posterior Mean and 95% BCI* of the Difference of Event Rate

between INV and CTR** Events Subjects

(n (%)) Events Subjects

(n (%)) Device Related AEs 38 16 (7.7%) 35 16 (8.5%) -0.9% (-6.4%, 4.6%) Device/Surgical Procedure Related AEs 57 19 (9.1%) 80 26 (13.8%) -4.7% (-11.1%, 1.6%) Device or Device/Surgical Procedure Related AEs

95 33 (15.8%) 115 39 (20.7%) -4.9% (-12.6%, 2.6%)

Surgical Procedure Related AEs 127 60 (28.7%) 106 45 (23.9%) 4.7% (-3.9%, 13.3%) Severe AEs (Grade 3 or 4) 293 72 (34.4%) 430 90 (47.9%) -13.3% (-22.8%, -3.7%) Severe Device or Device/Surgical Procedure Related AEs (Grade 3 or 4)

8 4 (1.9%) 28 11 (5.9%) -3.9% (-8.1%, 0.0%)

INV=2-level PRESTIGE LP™ (N=209); CTR = 2-level ACDF control (N=188) * BCI = Bayesian HPD Credible Interval **95% BCI of the difference of the event rate between the investigational group and control group was only determined for the “All Adverse Events” category because the analysis was pre-defined. All other analyses were not pre-defined.

Adverse Event Data by Treatment Level: Table 32 provides summary adverse event data in each treatment group by treatment level, including post-hoc statistical analysis and comparison between the 2-level PRESTIGE LP™ group and the 2-level ACDF control group through the 24-month time point using Frequentist methods.

Table 32: Summary of Total Adverse Events by Level Treated through Month 24-IDE and Safety Population

Superior C3-C4 Inferior C4-C5



INV CTR INV CTR INV CTR All Adverse Events

Statistics*

3/3 (100%)

2/3 (66.7%)

41/43 (95.3%)

40/44 (90.9%)

151/163 (92.6%)

131/141 (92.9%)

33.3% (-26.3%, 93.0%) 4.4% (-6.2%, 15.1%) -0.3% (-6.1%, 5.6%) Device or Device/Surgical Procedure Related AEs

0/3 (0.0%)

0/3 (0.0%)

9/43 (20.9%)

9/44 (20.5%)

24/163 (14.7%)

30/141 (21.3%)

Surgical Procedure Related AEs

0/3 (0.0%)

1/3 (33.3%)

13/43 (30.2%)

10/44 (22.7%)

47/163 (28.8%)

34/141 (24.1%)

Severe AEs (Grade 3 or 4)

2/3 (66.7%)

0/3 (0.0%)

16/43 (37.2%)

20/44 (45.5%)

54/163 (33.1%)

70/141 (49.6%)

Severe Device or Device/Surgical Procedure Related AEs (Grade 3 or 4)

0/3 (0.0%)

0/3 (0.0%)

1/43 (2.3%)

3/44 (6.8%)

3/163 (1.8%)

8/141 (5.7%)

INV=2-level PRESTIGE LP™ (N=209); CTR = 2-level ACDF control (N=188) * Point Estimate and 95% Confidence Interval of Difference of Adverse Rate between INV and CTR. The 95% CI was provided using Frequentist Farrington and Manning methods.

Timecourse of All Adverse Events: The timecourse of adverse events reported in the PMA clinical study from all 397 total subjects (209 2-level PRESTIGE LP™ subjects and 188 2-level ACDF control subjects) through all available follow-up are shown in Table 33. This table includes adverse events from all subjects to establish the safety profile of the device. Adverse events are listed in alphabetical order by main category with clinically relevant subcategories also detailed. Definitions of the adverse event categories and subcategories are provided in Table 34. Subject adverse event rates are

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

The percentage of subjects who experienced at least one adverse event is similar in the 2-level PRESTIGE LP™ group (93.3%) and the 2-level ACDF control group (92.0%). Some of the more commonly reported clinically relevant adverse events through all available follow-up were cervical neck and/or arm pain (in 62.7% of 2-level PRESTIGE LP™ subjects and 63.3% of 2-level ACDF control subjects), cervical neurological adverse events (in 39.7% of 2-level PRESTIGE LP™ subjects and 38.8% of 2-level ACDF control subjects), cervical study surgery spinal events (in 19.1% of 2-level PRESTIGE LP™ subjects and 10.6% of 2-level ACDF control subjects), cervical Heterotopic Ossification (in 15.8% of 2-level PRESTIGE LP™ subjects and 13.3% of 2-level ACDF control subjects), dysphagia/dysphonia (in 8.6% of 2-level PRESTIGE LP™ subjects and 12.2% of 2-level ACDF control subjects), non-infectious wound adverse events (in 8.6% of 2-level PRESTIGE LP™ subjects and 7.4% of 2-level ACDF control subjects), and implant adverse events (in 7.2% of 2-level PRESTIGE LP™ subjects and 8.5% of 2-level ACDF control subjects).

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Table 33: Adverse Events Through All Available Follow-up

Surgery Peri-Op

(1 day - <4 Weeks)

Short Term Long Term Longer Term

6 Weeks (≥4 Wks - < 9 Weeks)

3 Months (≥9 Wks – <5 Mo)

6 Months (≥5 Mo- <9 Mo)


24 Months (≥19 Mo- <30 Mo)

# of Patients Reporting & Total adverse events

(≤ 24 Months)


(≤ 84 Months)

Adverse Event

Inve

st

Cont

rol

Inve

st

Cont

rol

Inve

st

Cont

rol

Inve

st

Cont

rol

Inve

st

Cont

rol

Inve

st

Cont

rol

Inve

st

Cont

rol INV Subj.

(% of 209)

INV Events

(N)

CTR Subj.

(% of 188)

CTR Events

(N)

INV Subj.

(% of 209)

INV Events

(N)

CTR Subj.

(% of 188)

CTR Events

(N)

Total Adverse Events 54 38 166 221 116 119 228 266 245 240 372 390 296 319 195 (93.3%) 1477 173 (92.0%) 1593 204 (97.6%) 2146 179 (95.2%) 2147

Cancer 0 0 0 0 0 1 0 0 0 0 0 1 0 1 0 (0.0%) 0 3 (1.6%) 3 3 (1.4%) 3 8 (4.3%) 10 Cardiac Disorders 2 3 2 0 3 0 1 1 8 3 8 8 4 3 18 (8.6%) 28 16 (8.5%) 18 27 (12.9%) 40 27 (14.4%) 43 Death 0 0 0 0 0 0 0 0 0 0 0 1 0 0 0 (0.0%) 0 1 (0.5%) 1 1 (0.5%) 1 2 (1.1)% 2 Dysphagia / Dysphonia • Dysphagia • Dysphonia

1

1 0

2

1 1

5

4 1

11

9 2

2

1 1

4

3 1

1

0 1

5

4 1

0

0 0

0

0 0

4

3 1

3

3 0

1

1 0

2

2 0

14 (6.7%)

10 (4.8%) 4 (1.9%)

14

10 4

21 (11.2%)

20 (10.6%) 5 (2.7%)

27

22 5

18 (8.6%)

14 (6.7%) 4 (1.9%)

18

14 4

23 (12.2%)

22 (11.7%) 5 (2.7%)

29

24 5

Gastrointestinal 5 2 13 16 0 3 12 7 16 6 38 28 17 17 43 (20.6) 101 38 (20.2%) 79 58 (27.8%) 142 45 (23.9%) 97 Heterotopic Ossification • Cervical • Non-Cervical

0

0 0

0

0 0

1

1 0

2

2 0

0

0 0

2

2 0

3

3 0

5

4 1

3

3 0

5

3 2

9

8 1

3

2 1

11

11 0

7

2 5

22 (10.5%)

21 (10.0%)` 1 (0.5%)

27

26 1

21 (11.2%)

14 (7.4%) 8 (4.3%)

24

15 9

33 (15.8%)

32 (15.3%) 2 (1.0%)

40

38 2

32 (17.0%)

25 (13.3%) 10 (5.3%)

37

26 11

Implant Events • Breakage • Displacement • Displacement -

Subsidence • Loosening • Malpositioning • Other

4

1 1

0

0 2 0

0

0 0

0

0 0 0

2

0 0

0

0 1 1

2

1 0

0

1 0 0

1

0 1

0

0 0 0

2

0 0

2

0 0 0

0

0 0

0

0 0 0

2

1 0

0

1 0 0

3

0 1

2

0 0 0

2

0 0

2

0 0 0

0

0 0

0

0 0 0

4

0 1

2

1 0 0

5

0 3

1

0 0 1

0

0 0

0

0 0 0

13 (6.2%)

1 (0.5%) 6 (2.9%)

2 (1.0%)

0 (0.0%)

3 (1.4%) 2 (1.0%)

15

1 6

3

0 3 2

10 (5.3%)

2 (1.1%) 1 (0.5%)

6 (3.2%)

3 (1.6%) 0 (0.0%) 0 (0.0%)

12

2 1

6

3 0 0

15 (7.2)

2 (1.0%) 7 (3.3%)

3 (1.4%)

0 (0.0%) 3 (1.4%) 2 (1.0%)

18

2 7

4

0 3 2

16 (8.5%)

4 (2.1%) 2 (1.1%)

6 (3.2%)

6 (3.2%) 0 (0.0%)

0 (0.0%)

18

4 2

6

6 0 0

Infection* 0 1 5 6 3 3 3 7 8 3 20 11 9 9 35 (16.9%) 47 31 (16.5%) 40 39 (18.7) 60 37 (19.7%) 54 Cervical Neck and / or Arm Pain • Cervical Neck

Pain • Cervical Arm

Pain

13

6

7

2

1

1

37

16

21

49

23

26

28

13

15

24

14

10

49

25

24

41

19

22

33

17

16

41

22

19

44

25

19

47

20

27

43

21

22

40

24

16

112 (53.6%)

83 (39.7%)

76 (36.4%)

247

123

124

104 (55.3%)

80 (42.6%)

76 (40.4%)

244

23

121

131 (62.7)

105(50.2)

89(42.6)

325

167

158

119 (63.3%)

97 (51.6%)

88 (46.8%)

314

165

149

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Surgery Peri-Op

(1 day - <4 Weeks)






24 Months (≥19 Mo- <30 Mo)


(≤ 24 Months)


(≤ 84 Months)

Adverse Event

Inve

st

Cont

rol

Inve

st

Cont

rol

Inve

st

Cont

rol

Inve

st

Cont

rol

Inve

st

Cont

rol

Inve

st

Cont

rol

Inve

st

Cont

rol INV

Subj. (% of 209)

INV Events

(N)

CTR Subj.

(% of 188)

CTR Events

(N)

INV Subj.

(% of 209)

INV Events

(N)

CTR Subj.

(% of 188)

CTR Events

(N)

Non-Cervical Arm and/ or Neck Pain

0 0 1 3 8 4 10 15 11 9 8 11 9 7 36 (17.2%) 47 36 (19.1%) 49 55 (26.3) 73 49 (26.1) 74

Cervical Neurological • Spinal Cord

Disturbance • Upper

Extremity-Motor

• Upper Extremity-Sensory

5

0

0

5

4

0

1

3

16

0

2

14

16

0

0

16

13

0

3

10

16

1

4

11

26

1

2

23

20

0

7

13

23

0

3

20

10

0

4

6

21

0

4

17

21

1

1

19

23

0

4

19

14

0

1

13

66 (31.6%)

1 (0.5%)

15 (7.2%)

60(28.7%)

127

1

18

108

59 (31.4%)

2 (1.1%)

13 (6.9%)

52(27.7%)

101

2

18

81

83 (39.7%)

1(0.5%)

21 (10.0%)

75 (35.9%)

1167

1

25

141

73 (38.8%)

3 (1.6%)

19 (10.1%)

65 (34.6%)

2133

3

27

103

Non-Cervical Neurological

2 4 7 9 8 7 19 21 14 12 12 23 10 15 54 (25.8%) 72 50 (26.6%) 91 62 (29.7%) 100 60 (31.9%) 115

Non-Union 0 0 0 1 0 1 0 7 0 6 0 2 0 1 0 (0.0%) 0 18 (9.6%) 18 1 (0.5%) 1 21 (11.2%) 22 Other 8 6 27 24 13 9 20 27 34 22 52 71 41 57 97 (46.4%) 195 87 (46.3%) 216 114 (54.5%) 281 103 (54.8%) 299 Other Pain** 4 6 26 36 23 21 45 40 44 57 68 74 49 61 125 (59.8%) 259 113 (60.1%) 295 147 (70.3%) 401 127 (67.6%) 392 Respiratory 4 5 8 6 1 2 3 8 3 10 14 13 14 8 29 (13.9%) 47 34 (18.1%) 52 38 (18.2%) 68 43(22.9%) 66 Spinal Event • Cervical (Study

Surgery) • Cervical (Non-

Study Surgery) • Non-Cervical

2

2

0

0

0

0

0

0

3

0

1

2

26

12

9

5

7

0

0

7

12

1

3

8

20

2

3

15

45

7

8

30

32

9

4

19

38

4

12

22

45

9

17

19

47

4

15

28

40

13

13

14

29

2

7

20

74 (35.4%)

29 (13.9%)

26 (12.4%)

38 (18.2%)

149

35

38

76

80 (42.6%)

17 (9.0%)

34(18.1%)

52 (27.7%)

197

30

54

113

97 (46.4%)

40 (19.1%)

38 (18.2%)

58 (27.8%)

2231

52

56

123

96 (51.1%)

20 (10.6%)

59 (31.4%)

56 (29.8%)

2267

33

109

125

Trauma 0 0 0 6 5 2 8 6 8 8 15 14 9 24 37 (17.7%) 45 39 (20.7%) 60 57 (27.3%) 83 55 (29.3%) 88 Urogenital 1 1 5 4 0 5 6 3 2 4 9 5 8 14 25 (12.0%) 31 19 (10.1%) 36 42 (20.1%) 60 28 (14.9%) 53 Vascular • Injury Intra-op • Other

1

1 0

0

0 0

0

0 0

1

1 0

0

0 0

1

0 1

1

0 1

2

0 2

0

0 0

0

0 0

3

1 2

1

0 1

1

0 1

9

0 9

5 (2.4%)

2 (1.0%) 3(1.4%)

6

2 4

8 (4.3%)

1 (0.5%) 7 (3.7%)

14

1 13

10 (4.8%)

2 (1.0%) 8 (3.8%)

12

2 10

10 (5.3%)

1 (0.5%) 9 (4.8%)

16

1 15

Wound 2

2

8

3

2

0

1

4

3

4

2

2

2

1

16 (7.7%)

20

12 (6.4%)

16

18 (8.6%)

22

14 (7.4%)

18

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Surgery Peri-Op

(1 day - <4 Weeks)






24 Months (≥19 Mo- <30 Mo)


(≤ 24 Months)


(≤ 84 Months)

Adverse Event

Inve

st

Cont

rol

Inve

st

Cont

rol

Inve

st

Cont

rol

Inve

st

Cont

rol

Inve

st

Cont

rol

Inve

st

Cont

rol

Inve

st

Cont

rol INV

Subj. (% of 209)

INV Events

(N)

CTR Subj.

(% of 188)

CTR Events

(N)

INV Subj.

(% of 209)

INV Events

(N)

CTR Subj.

(% of 188)

CTR Events

(N)

(Non-Infectious) • CSF Leak • Dehiscence • Hematoma • Cervical

superficial surgical site

• Other

0 0 0 0

2

1 0 0 0

1

0 1 2 0

5

0 0 0 1

2

0 0 0 1

1

0 0 0 0

0

0 0 1 0

0

2 0 0 0

2

0 2 1 0

0

0 1 0 0

3

0 0 1 0

1

0 0 0 0

2

0 2 0 0

0

0 0 0 0

1

0 (0.0%) 4 (1.9%) 5 (2.4%) 1 (0.5%)

8 (3.8%)

0 5 5 1

9

2 (1.1%) 1 (0.5%) 0 (0.0%) 1 (0.5%)

8 (4.3%)

3 1 0 1

11

0 (0.0%) 4 (1.9%) 6 (2.9%) 1 (0.5%)

9 (4.3%)

0 5 6 1

10

2 (1.1%) 1 (0.5%) 1 (0.5%) 1 (0.5%)

9 (4.8%)

3 1 1 1

12 INV=2-level PRESTIGE LP™ (N=209); CTR = 2-level ACDF control (N=188) * All other wound infections (non-surgical/non-study site), urinary tract infections, or other infection. ** 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.

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Table 34: Adverse Event Categories

Adverse Event Definition Cancer A malignancy or malignant tumor/ neoplasm Cardiac Disorders Any condition of the heart Death Termination of life due to any cause Dysphagia/ Dysphonia • Dysphagia • Dysphonia

• Difficulty in swallowing • Difficulty in speaking

Gastrointestinal Any condition pertaining to the stomach and intestines Heterotopic Ossification • Heterotopic Ossification – Cervical • Heterotopic Ossification - Non-

Cervical

• Event involving heterotopic ossification at any region of the cervical spine • Event involving heterotopic ossification at any region of the spine that is not cervical

or any other region of the body Implant Events • Implant Events – Breakage • Implant Events - Displacement • Implant Events – Displacement –

Subsidence • Implant Events - Loosening • Implant Events - Malpositioning • Implant Events - Other

• Breakage of any implant or implant component • Incomplete or partial dislocation of the implant • Event associated w ith implant subsidence into the vertebral body when the

reported term includes “ subsidence” • Wear around the implant and/ or loosening of the implant surface • Poor or inappropriate placement of the implant • Event that is implant-related, but does not meet the definition of malpositioned

implant, implant displacement, implant loosening, or implant breaking Infection Any wound infection that is non-surgical or is not of the surgical site, an infection of any

part of the urinary system, or any infection occurring in other surgical would not involving the study

Cervical Arm and/ or Neck Pain • Cervical Neck Pain • Cervical Arm Pain

• Pain involving the neck region, which does not include neurological systems.

These symptoms are such that cervical spine etiology cannot be ruled out. • Pain involving the arm, which does not include neurological symptoms. These

symptoms are such that a cervical spine etiology cannot be ruled out. Non-Cervical Arm and/ or Neck Pain Pain involving the arm and/ or neck which does not include neck neurological

symptoms. Information is available at the reported event time to reasonably rule out a cervical spine etiology.

Cervical Neurological • Spinal Cord Disturbance • Upper Extremity – Motor

• Upper Extremity - Sensory

• Condition in which there is a disruption or disturbance to the spinal cord • Event that involves stimulation of the motor neurons that induce movements, as

nerves or muscles. Such events would affect any part of the upper extremity including the shoulder, brachium, elbow, forearm, hand, and fingers and may be muscular in nature.

• Event that involves a feeling or awareness of condition w ithin the body resulting from stimulation of sensory receptors. Such sensation would affect any part of the upper extremity including the shoulder, brachium, elbow, forearm, hand and fingers and may be radiating, continuing, extending, or spreading to an adjacent anatomy.

Non-Cervical Neurological Neurological event not associated with the cervical spine Non-Union Failure of the vertebral bodies to fuse at the treated level Other

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

Other Pain Pain (including stiffness, strain, tightness) in an area that is not of the cervical spine region, occurring in the back (e.g., low back pain, thoracic back pain, back pain), occurring in the head (e.g. headache, migraine headache, head pain), occurring in the lower extremity and using the term “pain” (e.g., leg pain, knee pain, calf pain, foot pain), and/ or occurring in parts of the body that are not classified as a headache, back pain, or lower extremity pain (e.g. earache, fibromyalgia, non-cardiac chest pain, sore throat, arthritis)

Respiratory Ailments or symptoms associated with respiration or the respiratory system

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Adverse Event Definition Spinal Event • Spinal Event – Cervical Study

Surgery • Spinal Event – Cervical Non-Study

Surgery • Spinal Event - Non-Cervical

• Event involving cervical spine diagnoses at the study treatment level; usually

confirmed via radiologic findings • Event involving cervical spine diagnoses at one or more cervical spine level(s), with

the exception of the treated level; usually confirmed via radiologic findings • Event involving diagnoses at one or more spine levels other than cervical spine; usually

confirmed via radiologic findings

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 of excretion and reproduction

Vascular • Vascular – injury (intra-operative) • Vascular – Other

• Injury to a vascular structure that is sustained during the course of the operative

procedure; initial study surgery only • Disorder or condition in which the vascular system is affected

Wound (Non-Infectious) • Wound (Non-Infectious) - CSF Leak • Wound (Non-Infectious) –Dehiscence • Wound (Non-Infectious) – Hematoma • Wound (Non-Infectious) - Cervical

superficial surgical site • Wound (Non-Infectious) -Other

• Compromise or tear of the dura mater resulting in leakage of cerebral spinal

fluid, excluding infection. Fluid is clear and free of microorganisms • A bursting open or separation of a wound without the presence of

microorganisms • Swelling or mass of blood (usually clotted) confined to an organ, tissue, or space

and caused by a break in a blood vessel. Wound is not limited to a specific anatomic region and there is an absence of microorganisms

• An infection near the surface of the surgical incision • Wound condition in which there is an absence of infection or other feature (e.g.,

wound oozing, scar tissue, incisional edemas, scratches to skin surface) Bayesian analyses were conducted to compare adverse events in main categories and subcategories using non-informative priors. The results are presented in Table 35 with 95% Bayesian Credible Intervals (BCI) for the difference in adverse event rates (2-level PRESTIGE LP™ – 2-level ACDF). Although there was no adjustment for multiplicity, BCIs that exclude zero indicate statistical differences in the adverse event rates when comparing the 2-level PRESTIGE LP™ group and the 2-level ACDF control group.

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Table 35: Bayesian Comparison of Posterior Probabilities of Adverse Events in Main Categories Through 24-Month Interval (≤30 Months)

Adverse Event

Subjects Experiencing Adverse Events (%)

Posterior Mean and 95% HPD of Adverse Event Rate

Posterior Mean and 95% BCI* of the Difference of

Adverse Event Rate between INV and CTR

INV (N=209)

CTR (N=188) INV CTR INV - CTR

Total Subjects Experiencing Adverse Events

195 (93.3%) 173 (92.0%) 92.9 (89.4%, 96.2%) 91.6% (87.5%, 95.3%) 1.3% (-3.9%, 6.6%)

Cancer 0 (0.0%) 3 (1.6%) 0.5% (0.0%, 1.4%) 2.1% (0.4%, 4.2%) -1.6% (-4.0%, 0.4%) Cardiac Disorders 18 (8.6%) 16 (8.5%) 9.0% (5.3%, 12.9%) 8.9% (5.1%, 13.1%) 0.1% (-5.5%, 5.7%) Death 0 (0.0%) 1 (0.5%) 0.5% (0.0%, 1.4%) 1.1% (0.0%, 2.5%) -0.6% (-2.5%, 1.1%) Dysphagia / Dysphonia 14 (6.7%) 21 (11.2%) 7.1% (3.8%, 10.6%) 11.6% (7.2%, 16.2%) -4.5% (-10.2%, 1.2%)

Gastrointestinal 43 (20.6%) 38 (20.2%) 20.9% (15.5%, 26.4%) 20.5% (14.9%, 26.3%) 0.3 % (-7.6%, 8.2%) Heterotopic Ossification 22 (10.5%) 21 (11.2%) 10.9% (6.8%, 15.1%) 11.6% (7.2%, 16.2%) -0.7% (-6.9%, 5.5%)

Implant Events 13 (6.2%) 10 (5.3%) 6.6% (3.5%, 10.1%) 5.8% (2.7%, 9.2%) 0.8% (-3.9%, 5.6%) Infection 36 (17.2%) 32 (17.0%) 17.5% (12.6%, 22.8%) 17.4% (12.1%, 22.8%) 0.2% (-7.3%, 7.6%) Neck and / or Arm Pain 127 (60.8%) 114 (60.6%) 60.7% (54.0%, 67.2%) 60.5% (53.6%, 67.5%) 0.1% (-9.3%, 9.8%)

Neurological 89 (42.6%) 85 (45.2%) 42.7% (36.0%, 49.3%) 45.3% (38.3%, 52.4%) -2.6% (-12.3%, 7.1%) Non-Union 0 (0.0%) 18 (9.6%) 0.5% (0.0%, 1.4%) 10.0% (5.9%, 14.3%) -9.5% (-14.0%, -5.4%)** Other 97 (46.4%) 87 (46.3%) 46.4% (39.8%, 53.2%) 46.3% (39.2%, 53.4%) 0.1% (-9.6%, 9.9%) Other Pain 125 (59.8%) 113 (60.1%) 59.7% (53.1%, 66.2%) 60.0% (53.1%, 67.0%) -0.3% (-9.9%, 9.3%) Respiratory 29 (13.9%) 34 (18.1%) 14.2% (9.7%, 19.0%) 18.4% (13.0%, 24.0%) -4.2% (-11.5%, 3.0%) Spinal Event 74 (35.4%) 80 (42.6%) 35.5% (29.2%, 42.0%) 42.6% (35.7%, 49.7%) -7.1% (-16.5%, 2.5%) Trauma 37 (17.7%) 39 (20.7%) 18.0% (13.0%, 23.3%) 21.1% (15.4%, 26.9%) -3.0% (-10.8%, 4.7%) Urogenital 25 (12.0%) 19 (10.1%) 12.3% (8.1%, 16.8%) 10.5% (6.4%, 15.0%) 1.8% (-4.4%, 8.0%) Vascular 5 (2.4%) 8 (4.3%) 2.8% (0.9%, 5.1%) 4.7% (2.0%, 7.8%) -1.9% (-5.7%, 1.9%) Wound (Non-Infectious) 15 (7.2%) 11 (5.9%) 7.6% (4.2%, 11.2%) 6.3% (3.1%, 9.8%) 1.3% (-3.8%, 6.2%)

INV=2-level PRESTIGE LP™ (N=209); CTR = 2-level ACDF control (N=188) * BCI = Bayesian HPD Credible Interval **BCI excluding 0

Deaths: Through all available follow-up, there was one reported death in the 2-level PRESTIGE LP™ group (due to a motor vehicle accident in the 48 month window), and there were two reported deaths in the ACDF control group (one due to cardiac arrest possibly due to overdose in the 12 month and the other due to a motor vehicle accident in the 72 month windows). The deaths were evaluated by the CAC, and based upon available information were determined to be unrelated to the study treatments. Subsequent Surgical Interventions at the Index Level: Some adverse events resulted in surgical intervention at one or both of the index levels, subsequent to the initial surgery. Subsequent surgical interventions at the index level(s) were classified as revisions, supplemental fixations, non-elective removals, elective removals, reoperations or other surgical procedures. Per the study protocol, revisions, supplemental fixations, and non-elective removals were considered subsequent surgery failures, whereas

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reoperations, elective removals, and other surgical procedures were not considered subsequent surgery failures. Overall, there were 10 subsequent surgical interventions at the index level(s) in 8 (3.8%) 2-level PRESTIGE LP™ subjects and 26 subsequent surgical interventions at the index level(s) in 22 (11.7%) 2-level ACDF control subjects. The timecourse of the subsequent surgical interventions through all available follow-up is summarized in Table 36. Table 36 also presents the Bayesian statistical comparison of subsequent surgeries at the index level(s) through 24 months between the 2-level PRESTIGE LP™ and 2-level ACDF control treatment groups. Through 24 months, there were a greater number of subjects who underwent subsequent surgical procedures at the index level(s) in the 2-level ACDF control group [15 (8.0%)] compared to the 2-level PRESTIGE LP™ group [5 (2.4%)], and the rates were nominally statistically different without adjusting for multiplicity.

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Table 36: Subsequent Surgical Interventions at the Index Level(s) Through All Available Follow-up

INV=2-level PRESTIGE LP™ (N=209); CTR = 2-level ACDF control (N=188)

* BCI = Bayesian HPD Credible Interval 1 A procedure that adjusts or in any way modifies either one or both of the original implant configurations (e.g., adjusting position of the original configuration, removal with

replacement with the same type of study implant). 2 A procedure at the involved level(s) in which additional spinal devices not approved as part of the protocol are placed. This categorization of Supplemental Fixations does not

include supplemental therapies (i.e. external bone growth stimulators). 3 Any procedure that removes the device as the result of an adverse event.. 4 A procedure that removes the device at the discretion of the investigator and/or the patient and is not the result of an adverse event.. 5 A procedure that involves any surgical procedure at the involved level(s) that does not remove, modify, or add any components and that is not considered a Removal. Revision, or

Supplemental Fixation 6 There were a total of 6 external bone growth stimulators used in the 2-level ACDF control group. While the use of external bone growth stimulators were not considered a secondary

surgery, these subjects were considered failures in the original primary endpoint analysis. However, a sensitivity analysis was provided to FDA in which they were not considered failures.

Surgery Peri-Op

(1 day - <4 Weeks)

Short Term Long Term

Longer Term 6 Weeks

(≥4 Wks - < 9 Weeks)




24 Months (≥19 Mo- <30 Mo)

Posterior Mean and 95% HPD of Subsequent

Surgery Rate

Posterior Mean and 95% BCI* of Difference of

Subsequent Surgery Rate between

INV and CTR

# of Patients Reporting & Total Events

(≤ 24 Months)

# of Patients Reporting & Total Events (≤ 84 Months)

Type INV

CTR

INV

CTR

INV

CTR

INV

CTR

INV

CTR

INV

CTR

INV

CTR INV CTR

INV Subj. (% of 209)

INV Events

(N)

CTR Subj. (% of 188)

CTR Events

(N)

INV Subj. (% of 209)

INV Events

(N)

CTR Subj. (% of 188)

CTR Events

(N)

Revision1 0 0 0 0 0 1 0 0 0 0 0 0 0 0 0.5%

(0.0%, 1.4%) 1.1%

(0.0%, 2.5%) -0.6%

(-2.5%, 1.1%) 0

(0.0%) 0 1 (0.5%) 1 0

(0.0%) 0 1 (0.5%) 1

Supplemental fixation2 0 0 0 0 0 0 0 0 0 1 1 2 0 0 0.9%

(0.0%, 2.3%) 2.1%

(0.4%, 4.2%) -1.2%

(-3.7%, 1.2%) 1

(0.5%) 1 3 (1.6%) 3 1

(0.5%) 1 7 (3.7%) 7

Non-elective removal3 0 0 0 0 1 0 0 1 0 2 1 2 1 1 1.9%

(0.3%, 3.7%) 3.7%

(1.3%, 6.4%) -1.8%

(-5.1%, 1.4%) 3

(1.4%) 3 6 (3.2%) 6 6

(2.9%) 6 6 (3.2%) 6

Elective removal4 0 0 0 0 0 0 0 1 0 0 0 0 0 1 0.5%

(0.0%, 1.4%) 1.6%

(0.2%, 3.3%) -1.1%

(-3.3%, 0.8%) 0

(0.0%) 0 2 (1.1%) 2 0

(0.0%) 0 6 (3.2%) 6

Reoperation 0 0 0 0 0 0 0 2 1 0 1 2 0 1 1.4% (0.1%, 3.0%)

2.6% (0.7%, 4.9%)

-1.2% (-4.1%, 1.5%)

2 (1.0%) 2 4

(2.1%) 5 3 (1.4%) 3 5

(2.7%) 6

TOTAL 0 0 0 0 1 1 0 4 1 3 3 6 1 3 2.8% (0.8%, 5.1%)

8.4% (4.7%, 12.5%)

-5.6% (-10.2%, -1.1%)

5 (2.4%) 6 15

(8.0%) 17 8 (3.8%) 10 22

(11.7%) 26

External bone growth stimulator6 0 0 0 0 0 0 0 0 0 4 0 1 0 0

0.5% (0.0%, 1.4%)

3.2% (1.0%, 5.7%)

-2.7% (-5.5%, -0.2%)

0 (0.0%) 0 5

(2.7%) 5 0 (0.0%) 0 5

(2.7%) 5

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Table 37 provides detailed information on each 2-level PRESTIGE LP™ subsequent surgical intervention at the index level(s). Similarly, Table 38 provides detailed information on each 2-level ACDF control group subsequent surgical intervention at the index level(s).

Table 37: Detailed Information on 2-level PRESTIGE LP™ Subsequent Surgical Interventions at the Index Levels – Procedure Details

Surgical

Intervention Type

Procedure Type

Procedure Level(s)

Adverse Event Type Days From Index

Procedure

Device(s) Removed?


C4, C5, C6 laminectomy and C7 partial laminectomy; C3-C4, C4-C5, C5-C6, and C6-C7 arthrodesis; posterior cervical spinal instrumentation

C4-C5 & C5-C6

Cervical spondylotic myelopathy; cervical radiculopathy

553 No

Non-Elective Removal

Explant both PRESTIGE LP™ (C5-C6 & C6-C7); C5-C6 and C6-C7 partial corpectomy and fusion with allograft bone; C5-C6 and C6-C7 revision of foraminotomy and scar tissue debridement

C5-C6 & C6-C7

Right arm radicular pain; positive foraminal compression test

40 Yes, both levels


Explant both PRESTIGE LP™ (C5-C6 & C6-C7); C4-C5, C5-C6, and C6-C7 anterior decompression and discectomy; C4-C7 anterior cervical fusion

C5-C6 & C6-C7

Post-surgical cervical kyphosis; sagittal imbalance

486 Yes, both levels


Explant both PRESTIGE LP™ (C5-C6 and C6-C7); C5-C6 and C6-C7 anterior cervical discectomy and fusion; C4-C5 artificial disc (PRESTIGE ST)

C5-C6 & C6-C7

C4-C5 disc bulge/protrusion; C4-C5 left paracentral foraminal narrowing; C5-C6 and C6-C7 mid-foraminal encroachment; C6-C7 right foraminal narrowing; C5-C6 and C6-C7 posterior osteophytes



Explant one level PRESTIGE LP™ (C6-C7); iliac crest allograft arthrodesis and stabilization by plate

C5-C6 & C6-C7

Failed cervical disc arthroplasty with cervical stenosis and C6-C7 cord compression

929 Yes, one level


Explant both PRESTIGE LP™ (C5-C6 and C6-C7); redo anterior cervical microdiscectomy, bilateral anterior foraminotomies and central canal decompression at C5-C6 and C6-C7; anterior fusion using PEEK spacer and demineralized bone matrix plus anterior cervical titanium plate

C5-C6 & C6-C7

Foraminal stenosis secondary to loosening of hardware; Exacerbation of residual symptoms secondary to motor vehicle accident


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Explant both PRESTIGE LP™(C4-C5 and C5-C6 ); C5 corpectomy; C4 to C6 anterior fusion; revision bilateral C4-C5 and C5-C6 decompressive foraminotomy; C6-C7 anterior cervical discectomy and fusion using PEEK interbody cage and local autograft bone; combined C4 to C7 instrumented posterolateral fusion

C4-C5 & C5-C6

Progressive subsidence of C4-C5 and C5-C6 artificial discs, recurrent C4-C5 and C5-C6 bilateral foraminal stenosis, advanced C6-C7 cervical spondylitic degenerative change with bilateral C6-C7 foraminal stenosis, intractable neck pain and bilateral upper extremity radiculopathy, intractable cervicogenic headache


Reoperation C5-C6 and C6-C7 Microforaminotomy and C5, C6, and C7 partial right hemilaminectomy

C5-C6 & C6-C7

C5-C6 and C6-C7 foraminal stenosis on the right

222 No

Reoperation Rhizotomy C2-C3, C6-C7, and C7-T1 left/right

C5-C6 & C6-C7

Increased neck pain 529 No

Reoperation C4-C5 explant of PRESTIGE® ST artificial disc followed by removal of anterior cervical plate from C5 through C7, exploration of cervical spinal fusion mass C5 through C7 (solid), anterior partial vertebral corpectomy inferior C5 and superior C4, decompression of nerve roots and resection of spurs posteriorly with resection of scar tissue at C4-C5, anterior fusion, bone morphogenetic protein at C4-C5, anterior instrumentation with cervical plate at C4-5-6-7 with rescue screws and conventional screws

C5-C6 & C6-C7

C4-C5 central canal narrowing due to spurring behind the artificial disc replacement; cord compression

2061 No

Table 38: Detailed Information on 2-Level ACDF Control Group Subsequent Surgical Interventions at the Index Level(s)*

Surgical Intervention

Type

Procedure Type

Procedure Level(s)

Adverse Event Type Days From Index

Procedure

Device(s) Removed?

Revision C5-C6 and C6-C7 removal of plate and screws; C6-C7 allograft removal; C6-C7 replacement of C6-C7 allograft; new plate and screws

C5-C6 & C6-C7

C6-C7 recurrent disc herniation after traumatic injury

37 Yes, both levels


C5 to C7 posterior fusion and posterior lateral mass instrumentation; left iliac crest bone graft

C5-C6 & C6-C7

C5-C6 and C6-C7 pseudarthrosis; intractable neck pain

257 No

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C5-C6 and C6-C7 left laminotomy and foraminotomy; C5 to C7 posterior fusion; BMP and local graft

C5-C6 & C6-C7

C5-C6 and C6-C7 failed fusion; left cervical radiculopathy

319 No


C5-C6 bilateral foraminotomies and C5-C7 posterior fusion with autograft and instrumentation

C5-C6 & C6-C7

C5-C6 nonunion; cervical spondylosis

429 No


C6-C7 and C7-T1 posterior cervical laminotomy and foraminotomy; C6-C7 cervical wiring; posterior fusion using collagen sponge and iliac crest graft aspirate

C5-C6 & C6-C7

C6-C7 nonunion with cervical radiculopathy

1176 No


C5-C6 posterior fusion and posterior lateral mass screws and rods; BMP

C5-C6 & C6-C7

C5-C6 pseudarthrosis; neck pain 1351 No


C3, C4, C5, C6, and C7 laminoplasty and C3, C4, C5, C6, and C7 posterior fusion with allograft bone

C5-C6 & C6-C7

Cervical spinal cord compression 1861 No


C3 to C7 decompression and posterior spinal fusion

C5-C6 & C6-C7

C3-C4 osteophyte with central disc protrusion; cervical pain

2497 No


C5-C6 and C6-C7 anterior cervical removal of interbody grafts; C5, C6, and C7 partial vertebral corpectomies; anterior interbody arthrodesis with PEEK graft with Hydrosorb and BMP, anterior instrumentation

C5-C6 & C6-C7

C5-C6 and C6-C7 nonunion; biomechanical cervical pain; upper extremity radiculopathy



C5-C6 and C6-C7 removal of anterior instrumentation and interbody grafts; C5-C6 and C6-C7 decompression of spinal cord nerve root bilaterally; C5-C6 and C6-C7 anterior interbody arthrodesis with PEEK and BMP

C5-C6 & C6-C7

C6-C7 nonunion 162 Yes, both levels


C5-C6 and C6-C7 removal anterior cervical instrumentation and removal of interbody grafts; C5, C6, and C7 partial vertebral corpectomies; C5-C6 and C6-C7 anterior interbody fusion with PEEK and BMP; anterior instrumentation

C5-C6 & C6-C7

C5-C6 and C6-C7 nonunion with loosened hardware



C5-C6 hardware removal; C5-C6 corpectomy; C5-C6 fusion with PEEK cage and autograft; C5-C7 instrumentation

C4-C5 & C5-C6

Cervical spondylosis; C5-C6 cord compression; C6-C7 neural foraminal stenosis from osteophyte

550 Yes, one level

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C5-C6 and C6-C7 removal of anterior instrumentation; C5-C6 removal of interbody graft; C4-C5 anterior discectomy; C5-C6 arthrodesis with Hydrosorb and BMP; C5, C6 and C7 anterior cervical plate; C4-C5 PRESTIGE ST disc

C5-C6 & C6-C7

C5-C6 nonunion; fall; C4-C5 degenerative herniated disc



C4-C5 and C5-C6 anterior hardware removal; C4-C5 and C5-C6 exploration of fusion (C4-C5 with solid fusion); C5-C6 partial corpectomy; C5-C6 fusion; BMP; C5-C6 plate

C4-C5 & C5-C6

C5-C6 nonunion; headaches 624 Yes, both levels

Elective Removal

C5, C6, and C7 removal of anterior plate; C4-C5 discectomy; C4-C5 anterior decompression foraminotomy; C4-C5 interbody arthrodesis with structural allograft; C4, C5, C6, and C7 anterior plating

C5-C6 & C6-C7

Cervical spondylosis status post C5-C6 and C6-C7 anterior cervical discectomy and interbody arthrodesis; cervical radiculopathy

84 Yes, both levels

Elective Removal

C4-C5 and C5-C6 removal of anterior cervical plate; C4-C5 and C5-C6 exploration (solid bony union at these levels); C6 and C7 partial corpectomy; C6-C7 anterior cervical disc arthroplasty

C4-C5 & C5-C6

Cervical spondylosis; C6-C7 foraminal stenosis; intractable neck, shoulder, and arm pain


Elective Removal

C5-C6 and C6-C7 hardware removed; C4-C5 anterior cervical discectomy and fusion

C5-C6 & C6-C7

C4-C5 disc protrusion and spinal cord compression


Elective Removal

C5, C6, and C7 removal of anterior cervical instrumentation; C4-C5 microdiscectomy

C5-C6 & C6-C7

C4-C5 extruded herniated disc fragment with myelopathy and radiculopathy; head struck dashboard during a motor vehicle accident


Elective Removal

C4 to C6 removal of anterior cervical hardware; C3-C4 anterior cervical discectomy and disc arthroplasty; C3 and C4 partial corpectomy; PRESTIGE ST disc

C4-C5 & C5-C6

C3-C4 broad protrusion indenting the cervical cord


Elective Removal

C4 to C6 removal of plate and screws (fusion noted); C6-C7 anterior cervical discectomy and fusion with bone graft; osteophytectomy; microforaminotomy

C4-C5 & C5-C6

C6-C7 herniated nucleus pulposus; C6-C7 osteophyte


Reoperation C5-C6 posterior laminoforaminotomy with nerve root decompression and C7-T1 laminoforaminotomy with nerve root decompression

C5-C6 & C6-C7

C5-C6 foraminal narrowing; C5-C6 interbody graft subsidence; C7-T1 foraminal narrowing and bone spur extending into the foramen on the left side; cervical radiculopathy

82 No

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Reoperation C5-C6 and C7-T1 posterior cervical wound exploration; repair of dural tear and cerebrospinal fluid leak

C5-C6 & C6-C7

Postoperative cerebrospinal fluid leak

108 No

Reoperation C5, C6, C7 right median branch nerve therapeutic blocks with subsequent radiofrequency ablation

C5-C6 & C6-C7

C5-C6 graft subsidence; neck pain; C5-C6 and C6-C7 possible pseudarthrosis; C2-C3 and C3-C4 facet joints with severe degenerative arthropathy

419 No

Reoperation C5-C7 exploration of fusion mass posteriorly

C5-C6 & C6-C7

C5-C6 halo around the screw; neck pain/burning (rule out C5-C6 pseudarthrosis)

453 No

Reoperation C4-C5, C6-C7, and C7-T1 left posterior decompression

C4-C5 & C5-C6

Left upper extremity radiculopathy and arm weakness; motor vehicle accident

641 No

Reoperation C5-C7 removal of anterior cervical hardware; C4-C5 anterior cervical discectomy and bilateral foraminotomies; C4-C5 anterior interbody arthrodesis with allograft and PEEK intervertebral body device; C4, C5, C6, and C7 anterior cervical instrumentation

C5-C6 & C6-C7

C4-C5 spondylosis 1494 Yes, both levels


C5-C6 bone growth stimulator

C4-C5 & C5-C6

C5-C6 nonunion; headaches 187 No



C4-C5 & C5-C6

C5-C6 pseudarthrosis 188 No


Bone growth stimulator C5-C6 & C6-C7

Fell postoperative day 9; headaches; difficulty lifting right arm over head

188 No



C5-C6 & C6-C7

C6-C7 nonunion 206 No



C5-C6 & C6-C7

C5-C6 nonunion; fall; C4-C5 degenerative herniated disc

507 No

* As of September 29, 2014. Device-Related Adverse Events: The relationship between adverse events and the implant and/or surgical procedure was assessed separately by the Investigators and an independent Clinical Adjudication Committee (CAC) according to the following classifications: implant associated, surgical procedure associated, implant and surgical procedure associated, undetermined, and not related as outlined above. The timecourse and total number and percentage of subjects who experienced an adverse event classified by the CAC as either implant associated or implant and surgical procedure associated is provided in Table 39 by adverse event category.

Considering events classified by the CAC as either implant associated or implant and surgical procedure associated as device-related, through all available follow-up, 125 device-related events occurred in 48 (23.0%) 2-level PRESTIGE LP™ subjects and 126 device-related events occurred in 45 (23.9%) 2-level ACDF control subjects. Some of the more commonly reported device-related adverse events through all available follow-up were cervical neck and/or arm pain (in 7.2% of 2-level PRESTIGE LP™ subjects and 10.6% of 2-level ACDF control subjects), cervical

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neurological adverse events (in 6.7% of 2-level PRESTIGE LP™ subjects and 6.4% of 2-level ACDF control subjects), cervical study surgery spinal events (in 9.1% of 2-level PRESTIGE LP™ subjects and 3.7% of 2-level ACDF control subjects), cervical Heterotopic Ossification (in 7.7% of 2-level PRESTIGE LP™ subjects and 2.1% of 2-level ACDF control subjects), implant adverse events (in 6.2% of 2-level PRESTIGE LP™ subjects and 5.3% of 2-level ACDF control subjects), and non-union in the 2-level ACDF control group only (9.0%). Any numerical differences were most likely due to chance based on examining a great number of categories for these events.

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Table 39: Adverse Events Classified as Device-Related (Implant Associated or Implant and Surgical Procedure Associated) by the Clinical Adjudication Committee through All Available Follow-up

Surgery Peri-Op (1 day - < 4 Weeks)

Short Term Long Term # of Patients Reporting & Total adverse events (≤ 24 Months)

Longer Term # of Patients Reporting & Total adverse events

(≤ 84 Months) 6 Weeks





24 Months (≥19 Mo- <30 Mo)

36 Months (≥30 Mo- <42 Mo)

48 Months (≥42 Mo- <54 Mo)

60 Months (≥54 Mo- <66 Mo)

72 Months (≥66 Mo- <78 Mo)

84 Months (≥78 Mo- <90 Mo)

Adverse Event

Inve

st

Cont

rol

Inve

st

Cont

rol

Inve

st

Cont

rol

Inve

st

Cont

rol

Inve

st

Cont

rol

Inve

st

Cont

rol

Inve

st

Cont

rol INV

Subj. (% of 209)

INV Events

(N)

CTR Subj.

(% of 188)

CTR Events

(N) Inve

st

Cont

rol

Inve

st

Cont

rol

Inve

st

Cont

rol

Inve

st

Cont

rol

Inve

st

Cont

rol INV

Subj. (% of 209)

INV Events

(N)

CTR Subj.

(% of 188)

CTR Events

(N)

Total Adverse Events 18 5 26 40 8 24 1 28 3 12 19 6 20 0 33 (15.8%) 95 39 (20.7%) 115 9 4 6 0 9 4 0 0 6 3 48 (23.0%) 125 45 (23.9%) 126

Dysphagia / Dysphonia • Dysphagia

0

0

0

0

0 0

0

0

0

0

0

0

0

0

0 0

0

0

0

0

0

0

0

0

0

0

0

0

0 0 (0.0%)

0 (0.0%)

0 0

0 (0.0%)

• 0 (0.0%)

0 0

0 0

0 0

0 0

0 0

0 0

0 0

0 0

0 0

1 1

1 1

1 (0.5%)

1 (0.5%)

1 1

1 (0.5%)

1 (0.5%)

1 1

Heterotopic Ossification • Cervical

0 0

0 0

0 0

1 1

0 0

1 1

0 0

2 2

0 0

1 1

3 3

0 0

7 7

0 0

9 (4.3%)

9 (4.3%)

10

10

4 (2.1%)

4 (2.1%)

5 5

1 1

0 0

1 1

0 0

3 3

0 0

0 0

0 0

3 3

0 0

16 (7.7%)

16 (7.7%)

18 18

4 (2.1%)

4 (2.1%)

5 5

Implant Events • Breakage • Displacement • Displacement -

Subsidence • Loosening • Malpositioning • Other

4 1 1 0 0 2 0

0 0 0 0 0 0 0

2 0 0 0 0 1 1

2 1 0 0 1 0 0

1 0 1 0 0 0 0

1 0 0 1 0 0 0

0 0 0 0 0 0 0

2 1 0 0 1 0 0

1 0 0 1 0 0 0

0 0 0 0 0 0 0

0 0 0 0 0 0 0

3 0 1 1 1 0 0

4 0 2 1 0 0 1

0 0 0 0 0 0 0

11 (5.3%) 1 (0.5%) 4 (1.9%)

2 (1.0%)

0 (0.0%) 3 (1.4%) 2 (1.0%)

12 1 4 2 0 3 2

6 (3.2%) 2 (1.1%) 1 (0.5%)

2 (1.1%)

3 (1.6%) 0(0.0%) 0(0.0%)

8 2 1 2 3 0 0

2 1 1 0 0 0 0

0 0 0 0 0 0 0

0 0 0 0 0 0 0

0 0 0 0 0 0 0

1 0 0 1 0 0 0

3 0 0 0 3 0 0

0 0 0 0 0 0 0

0 0 0 0 0 0 0

0 0 0 0 0 0 0

1 0 1 0 0 0 0

13 (6.2%) 2 (1.0%) 5 (2.4%)

3 (1.4%)

0 (0.0%) 3 (1.4%) 2 (1.0%)

15 2 5 3 0 3 2

10 (5.3%) 2 (1.1%) 2 (1.1%)

2 (1.1%)

6 (3.2%) 0 (0.0%) 0 (0.0%)

12 2 2 2 6 0 0

Cervical Neck and / or Arm Pain • Cervical Neck Pain • Cervical Arm Pain

7 4 3

2 1 1

12 7 5

16 6 10

2 0 2

9 4 5

0 0 0

1 1 0

0 0 0

1 1 0

7 4 3

0 0 0

2 1 1

0 0 0

12 (5.7)

11 (5.3) 10 (4.8)

30

16 14

18 (9.6)

11 (5.9) 13 (6.9)

29

13 16

3 2 1

1 1 0

1 1 0

0 0 0

1 1 0

1 1 0

0 0 0

0 0 0

0 0 0

0 0 0

15 (7.2%)

14 (6.7%) 11 (5.3%)

35 20 15

20 (10.6%)

13 (6.9%) 13 (6.9%)

31 15 16

Non-Cervical Arm and/ or Neck Pain

0 0 0 0 0 0 0 2 0 0 0 0 0 0 0 (0.0) 0 1 (0.5) 2 0 0 0 0 0 0 0 0 0 0 0 (0.0%) 0 1 (0.5%) 2

Cervical Neurological • Spinal Cord

Disturbance • Upper

Extremity-Motor

4

0 0

1 0 1

8 0 1

6 0

0

4 0 2

7 1 0

1 0 0

5 0 2

1 0 0

0 0

0

1 0 1

0 0 0

0 0 0

0 0

0

13 (6.2%)

0 (0.0%)

4 (1.9%)

19 0

4

12 (6.4%)

1 (0.5%)

3 (1.6%)

19 1

3

0 0

0

0 0

0

3 0

1

0 0

0

0 0

0

0 0

0

0 0

0

0 0

0

0 0

0

0 0

0

14 (6.7%)

0 (0.0%)

5 (2.4%)

22 0

5

12 (6.4%)

1 (0.5%)

3 (1.6%)

19 1 3

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Surgery Peri-Op (1 day - < 4 Weeks)

Short Term Long Term # of Patients Reporting & Total adverse events (≤ 24 Months)

Longer Term # of Patients Reporting & Total adverse events

(≤ 84 Months) 6 Weeks





24 Months (≥19 Mo- <30 Mo)

36 Months (≥30 Mo- <42 Mo)

48 Months (≥42 Mo- <54 Mo)

60 Months (≥54 Mo- <66 Mo)

72 Months (≥66 Mo- <78 Mo)

84 Months (≥78 Mo- <90 Mo)

Adverse Event In

vest

Cont

rol

Inve

st

Cont

rol

Inve

st

Cont

rol

Inve

st

Cont

rol

Inve

st

Cont

rol

Inve

st

Cont

rol

Inve

st

Cont

rol INV

Subj. (% of 209)

INV Events

(N)

CTR Subj.

(% of 188)

CTR Events

(N) Inve

st

Cont

rol

Inve

st

Cont

rol

Inve

st

Cont

rol

Inve

st

Cont

rol

Inve

st

Cont

rol INV

Subj. (% of 209)

INV Events

(N)

CTR Subj.

(% of 188)

CTR Events

(N)

• Upper Extremity-

Sensory

4 0

7 6

2 6

1 3

1 0

0 0

0 0

10 (4.8%) 15 10 (5.3%)

15

0

0

2

0

0

0

0

0

0

0

11 (5.3%)

17

10 (5.3%)

15

Non-Cervical Neurological

0 0 1 0 0 2 0 0 0 0 0 0 0 0 1(0.5%) 1 1 (0.5%) 2 0 0 0 0 0 0 0 0 0 0 1 (0.5%) 1 1 (0.5%) 2

Non-Union 0 0 0 1 0 1 0 6 0 4 0 2 0 0 0 (0.0%) 0 14 (7.4%) 14 0 3 0 0 0 0 0 0 0 0 0 (0.0%) 0 17 (9.0%) 17 Other 1 0 0 0 0 0 0 1 0 0 1 0 0 0 2 (1.0%) 2 1 (0.5%) 1 0 0 0 0 0 0 0 0 0 0 2 (1.0%) 2 1 (0.5%) 1 Other Pain 1 1 3 2 1 2 0 0 0 0 2 0 0 0 5 (2.4%) 7 5 (2.7%) 5 0 0 0 0 0 0 0 0 0 1 5 (2.4%) 7 6 (3.2%) 6

Spinal Event • Cervical (Study

Surgery) • Cervical (Non-

Study Surgery)

1 1

0

0 0

0

0 0

0

12 9

3

0 0

0

1 0

1

0 0

0

9 4

5

1 1

0

5 2

3

4 4

0

1 1

0

7 5

2

0 0

0

12 (5.7%)

10 (4.8%)

2 (1.0%)

13

11

2

13 (6.9%)

7 (3.7%)

8 (4.3%)

28 16

12

3 3

0

0 0

0

1 1

0

0 0

0

4 4

0

0 0

0

0 0

0

0 0

0

2 1

1

0 0

0

21 (10.0%)

19 (9.1%)

3 (1.4%)

23 20

3

13 (6.9%)

7 (3.7%)

8 (4.3%)

28 16

12

Trauma 0 0 0 0 0 0 0 0 0 1 0 0 0 0 0 (0.0%) 0 1 (0.5%) 1 0 0 0 0 0 0 0 0 0 0 0 (0.0%) 0 1 (0.5%) 1

Vascular • Injury Intra-op

0 0

0 0

0 0

0 0

0 0

0 0

0 0

0 0

0 0

0 0

1 1

0 0

0 0

0 0

1 (0.5%)

1 (0.5%)

1 1

0 (0.0%)

0 (0.0%)

0 0

0 0

0 0

0 0

0 0

0 0

0 0

0 0

0 0

0 0

0 0

1 (0.5%)

1 (0.5%)

1 1

0 (0.0%)

0 (0.0%)

0 0

Wound (Non-Infectious) • CSF Leak

0 0

1 1

0 0

0 0

0 0

0 0

0 0

0 0

0 0

0 0

0 0

0 0

0 0

0 0

0 (0.0%)

0 (0.0%)

0 0

1 (0.5%)

1 (0.5%)

1 1

0 0

0 0

0 0

0 0

0 0

0 0

0 0

0 0

0 0

0 0

0 (0.0%)

0 (0.0%)

0 0

1 (0.5%)

1 (0.5%)

1 1

INV=2-level PRESTIGE LP™ (N=209); CTR = 2-level ACDF control (N=188) * Back and/or lower extremity (LE) pain adverse events (AE’s) and Headache AE’s were classified as “Other Pain” AE’s for the PRESTIGE LP™ IDE study.

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Severe Device-Related Adverse Events: Severity of adverse events was assessed according to the 4-tier World Health Organization (WHO) Recommendations for Grading of Acute and Subacute Toxic Effects. Of the events classified by the CAC as device-related, those classified as grade 3 or 4 according to the World Health Organization Recommendations for Grading of Acute and Subacute Toxic Effects were considered severe device-related adverse events. Through all available follow-up, 9 severe device-related events occurred in 5 (2.4%) 2-level PRESTIGE LP™ subjects and 30 severe device-related events occurred in 12 (6.4%) 2-level ACDF control subjects.

Some of the more commonly reported severe device-related adverse events through all available follow-up were cervical neck and/or arm pain in zero 2-level PRESTIGE LP™ subjects and 3 (1.6%) 2-level ACDF control subjects, cervical study surgery spinal events in 3 (1.4%) 2-level PRESTIGE LP™ subjects and 2 (1.1%) 2-level ACDF control subjects, cervical non-study surgery spinal events in zero 2-level PRESTIGE LP™ subjects and 4 (2.1%) 2-level ACDF control subjects, cervical Heterotopic Ossification in zero 2-level PRESTIGE LP™ subjects and 3 (1.6%) 2-level ACDF control subjects, implant adverse events in 2 (1.0%) 2-level PRESTIGE LP™ subjects and 3 (1.6%) 2-level ACDF control subjects, and non-union in zero 2-level PRESTIGE LP™ subjects and 9 (4.8%) 2-level ACDF control group subjects.

The total number and percentage of subjects who experienced an adverse event classified by the CAC as severe (grade 3 or 4) and either implant associated or implant and surgical procedure associated by adverse event category is provided in Table 40. Table 40: Adverse Events Classified as Severe (Grade 3 or 4) and Device-Related (Implant Associated or Implant and Surgical Procedure Associated) by the Clinical Adjudication Committee through All Available Follow-up

Adverse Event

INV (N=209)

CTR (N=188)

Subjects n (%)

Events N

Subjects n (%)

Events N

Total Severe Device-Related Adverse Events

5 (2.4%) 9 12 (6.4%) 30

Dysphagia/ Dysphonia • Dysphagia

1 (0.5%) 1 (0.5%)

1 1

0 (0.0%) 0 (0.0%)

0 0

Heterotopic Ossification • Cervical

0 (0.0%) 0 (0.0%)

0 0

3 (1.6%) 3 (1.6%)

3 3

Implant Events • Breakage • Displacement • Displacement - Subsidence • Loosening

2 (1.0%) 0 (0.0%) 1 (0.5%) 1 (0.5%) 0 (0.0%)

2 0 1 1 0

3 (1.6%) 1 (0.5%) 0 (0.0%) 1 (0.5%) 2 (1.1%)

4 1 0 1 2

Neck and/ or Arm Pain • Cervical Neck Pain

0 (0.0%) 0 (0.0%)

0 0

3 (1.6%) 3 (1.6%)

3 3

Cervical Neurological • Upper Extremity – Sensory

0 (0.0%) 0 (0.0%)

0 0

1 (0.5%) 1 (0.5%)

1 1

Non-Union 0 (0.0%) 0 9 (4.8%) 9 Other 1 (0.5%) 1 0 (0.0%) 0

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Adverse Event

INV (N=209)

CTR (N=188)

Subjects n (%)

Events N

Subjects n (%)

Events N

Spinal Event • Cervical (Study Surgery) • Cervical (Non-Study Surgery)

3 (1.4%) 3 (1.4%) 0 (0.0%)

4 4 0

5 (2.7%) 2 (1.1%) 4 (2.1%)

8 4 4

Trauma 0 (0.0%) 0 1 (0.5%) 1 Vascular • Injury Intra-op

1 (0.5%) 1 (0.5%)

1 1

0 (0.0%) 0 (0.0%)

0 0

Wound (Non-Infectious) • CSF Leak

0 (0.0%) 0 (0.0%)

0 0

1 (0.5%) 1 (0.5%)

1 1


Neurological Status: Neurological status was evaluated by assessment of motor function, sensory function, and reflexes. Available neurological status data at 6 weeks, 3 months, 6 months, 12 months, 24 months, 36 months, 60 months, and 84 months is provided for the 2-level PRESTIGE LP™ and 2-level ACDF control group subjects in Table 41 below. Neurologic success was defined as maintenance or improvement in all elements of neurologic status compared to baseline. The success rates at 24 months post-operative were 91.5% for the 2-level PRESTIGE LP™ group and 86.2% for the 2-level ACDF control group. At 24 months post-operative, there were numerically fewer subjects who exhibited neurologic deterioration in the 2-level PRESTIGE LP™ group (8.5%) as compared to the 2-level ACDF control group (13.8%).

Table 41: Timecourse of Overall Neurological Status

Timepoint Neurological Status INV (N=209)

CTR (N=188)

6 weeks Improved Stable Deteriorated

141/206 (68.4%) 36/206 (17.5%) 29/206 (14.1%)

126/182 (69.2%) 25/182 (13.7%) 31/182 (17.0%)

3 months Improved Stable Deteriorated

147/205 (71.7%) 37/205 (18.0%) 21/205 (10.2%)

119/178 (66.9%) 30/178 (16.9%) 29/178 (16.3%)


143/204 (70.1%) 42/204 (20.6%) 19/204 (9.3%)

121/174 (69.5%) 29/174 (16.7%) 24/174 (13.8%)


142/203 (70.0%) 40/203 (19.7%) 21/203 (10.3%)

109/165 (66.1%) 27/165 (16.4%) 29/165 (17.6%)


146/199 (73.4%) 36/199 (18.1%) 17/199 (8.5%)

108/159 (67.9%) 29/159 (18.2%) 22/159 (13.8%)


134/185 (72.4%) 33/185 (17.8%) 18/185 (9.7%)

97/148 (65.5%) 27/148 (18.2%) 24/148 (16.2%)


116/166 (69.9%) 34/166 (20.5%) 16/166 (9.6%)

95/136 (69.9%) 24/136 (17.6%) 17/136 (12.5%)


92/126 (73.0%) 24/126 (19.0%) 10/126 (7.9%)

63/96 (65.6%) 17/96 (17.7%) 16/96 (16.7%)


Effectiveness Results

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Primary Effectiveness Analysis: The analysis of effectiveness was based on the as-treated cohort of 397 total subjects which included all subjects who completed the surgical procedure and received a study device in either treatment group according to the treatment received (209 2-level PRESTIGE LP™ subjects and 188 2-level ACDF control subjects). The primary endpoint was a composite endpoint (Overall Success Protocol Definition) that defined a subject as a success if the following criteria were met at 24 months post-operative: • Improvement (reduction) of at least 15 points in NDI score at 24 months compared to pre-

operative baseline; • Maintenance or improvement in neurological status at 24 months compared to pre-operative

baseline as measured based on motor function, sensory function, and reflexes; • No serious adverse event classified as implant associated, or implant/surgical procedure

associated; and • No additional surgical procedure classified as a “failure.” As described above, because the additional surgical procedure component of the primary endpoint did not consider all subsequent surgeries at the index level as failures, FDA requested an additional analysis of overall success in which all subsequent surgeries at the index level and all intra-operative treatment conversions were considered failures (referred to as Overall Success Alternate Analysis in Table 42 below). Overall study success criteria were based on a comparison of individual subject success rates, such that the subject success rate for the 2-level PRESTIGE LP™ group was required to be non-inferior to that of the 2-level ACDF control group. The study was designed as a non-inferiority study with a margin (delta) of 10%. Non-inferiority was to be claimed if the posterior probability that the success rate in the 2-level PRESTIGE LP™ group was not lower than the success rate in the 2-level ACDF control group by more than 10% was greater than 95%. The observed success rates at 24 months post-operative for each of the overall success components and composite overall success as well as the Bayesian analyses are provided in Table 42. The posterior means for each treatment group can be interpreted as the average chance of component or overall success at 24 months, and the posterior mean of the difference between the two treatment groups can be interpreted as the average difference in the chance of component or overall success at 24 months. For example, given the results of the study, when a subject receives the 2-level PRESTIGE LP™ device, the average chance of overall (composite) success as defined in the clinical study at 24 months is 80.3%, and there is a 95% probability that the chance of success ranges from 75.0% to 85.8%. Similarly, given the results of the study, when a subject receives the 2-level ACDF control treatment, the average chance of overall (composite) success at 24 months is 69.0, and there is a 95% probability that the chance of overall success ranges from 61.8% to 75.7%. Then the average difference in the chance of overall success between the 2-level PRESTIGE LP™ group and the 2-level ACDF control group at 24 months is 11.3% with 95% probability that this difference falls in the range of 2.2% to 20.1%. For overall success, the posterior probability of non-inferiority of the 2-level PRESTIGE LP™ group to the 2-level ACDF control group at 24 months post-operative is essentially 100%, demonstrating non-inferiority. In addition, the posterior probability of superiority of the 2-level PRESTIGE LP™

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group to the 2-level ACDF control group at 24 months post-operative is above the 95% threshold, demonstrating statistical superiority. For the component endpoints of NDI and neurological status, multiple comparisons were carried out without adjustment for multiplicity. Table 42: Observed Component and Overall Success Rates and Posterior Probabilities of

Success at 24 Months

Primary Outcome

Component

24 Month Observed Success Rate

24 Month Posterior Mean (95% HPD Credible Interval)

24-Month Posterior Probabilities

(INV vs CTR) INV CTR INV CTR INV - CTR Non-

Inferiority Superiority

NDI Success (≥15 point improvement)*

175/199 (87.9%)

126/159 (79.2%)

87.1% (82.6%, 91.7%)

78.3% (71.9%, 84.1%)

8.8% (1.2%, 16.7%) ~100.0% 99.0%

Neurological Success (maintenance/ improvement)*

182/199 (91.5%)

137/159 (86.2%)

90.2% (86.2%, 94.2%)

85.2% (80.0%, 90.6%)

5.0% (-1.4%, 11.9%) ~100.0% 93.1%

Serious implant or implant/surgical procedure associated AE**

2 11 Not Available

Additional surgical procedure classified as “failure”*

4 12 Not Available

Overall success (Protocol Definition)

162/199 (81.4%)

111/160 (69.4%)

80.3% (75.0%, 85.8%)

69.0% (61.8%, 75.7%)

11.3% (2.2%, 20.1%) ~100.0% 99.3%

Overall Success (Alternate Analysis***)

162/201 (80.6%)

110/160 (68.8%)

79.5% (73.7%, 84.8%)

68,5% (61.5%, 75.3%)

11.0% (2.0%, 19.8%) ~100.0% 99.3%

INV=2-level PRESTIGE LP™ (N=209); CTR = 2-level ACDF control (N=188) * Analyses were conducted without adjustment for multiplicity. ** For the “Serious implant or implant/surgical procedure associated AE” and “Additional surgical procedure classified as failure”

rows, only the number of subjects experiencing these events were presented. ***All subsequent surgeries at index level and all intra-operative anatomical/technical difficulties considered failures.

Table 43 provides data on the timecourse of overall success rates for both treatment groups for Overall Success (Protocol Defined) and Overall Success (Alternate Analysis).

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Table 43: Time Course of Observed Success Rates

Primary Outcome Component 6 Months 12 Months 24 Months

INV CTR INV CTR INV CTR

NDI Success (≥15 point improvement)

185/203 (91.1%)

141/172 (82.0%)

183/202 (90.6%)

136/165 (82.4%)

175/199 (87.9%)

126/159 (79.2%)

Neurological Success (maintenance/ improvement)

185/204 (90.7%)

150/174 (86.2%)

182/203 (89.7%)

136/165 (82.4%)

182/199 (91.5%)

137/159 (86.2%)

Serious implant or implant/surgical procedure associated AE* 0 6 1 8 2 11

Additional surgical procedure classified as “failure”* 1 4 2 9 4 12


169/203 (83.3%)

126/174 (72.4%)

167/202 (82.7%)

117/166 (70.5%)

162/199 (81.4%)

111/160 (69.4%)

Overall Success (Alternate Analysis**) Not Available 167/204

(81.9%) 117/166 (70.5%)

162/201 (80.6%)

110/160 (68.8%)

Primary Outcome Component 36 Months 60 Months 84 Months INV CTR INV CTR INV CTR


166/185 (89.7%)

121/147 (82.3%)

148/166 (89.2%)

105/135 (77.8%)

110/126 (87.3%)

72/96 (75.0%)


167/185 (90.3%)

124/148 (83.8%)

150/166 (90.4%)

119/136 (87.5%)

116/126 (92.1%)

80/96 (83.3%)

Serious implant or implant/surgical procedure associated AE* 3 11 4 12 5 11

Additional surgical procedure classified as “failure”* 6 12 7 15 7 15


151/185 (81.6%)

105/149 (70.5%)

132/166 (79.5%)

91/138 (65.9%)

99/126 (78.6%)

62/99 (62.6%)

Overall Success (Alternate Analysis**) Not Available

INV=2-level PRESTIGE LP™ (N=209); CTR = 2-level ACDF control (N=188) * For the “Serious implant or implant/surgical procedure associated AE” and “Additional surgical procedure classified as failure” rows, only the number of subjects experiencing these events were presented. ** All subsequent surgeries at index level and all intra-operative anatomical/technical difficulties considered failures. Note: To be consistent with how NDI and neurological status success are determined, the subsequent surgery determination for the overall success timecourse table is based on the subject follow-up visit. For example, if a subsequent surgery occurred before the 6 month-visit, then it was counted as a failure at 6 months. If the subsequent surgery occurred after the 6-month visit, even if it was still within the 6-month visit window, it was counted as a failure at 12 months.

Table 44 provides overall success data for each treatment group stratified by the treated levels including post-hoc statistical analysis and comparisons between the 2-level PRESTIGE LP™ group and the 2-level ACDF control group through the 24 month timepoint using Frequentist methods. Overall success rates at 24 months were not significantly different between the 2-level PRESTIGE LP™ group and the 2-level ACDF control group at any treatment levels except for at

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the C5-C6 (superior) and C6-C7 (inferior) adjacent levels in which the 2-level PRESTIGE LP™ group had a higher success rate compared to the 2-level ACDF control group.

Table 44: Timecourse of Observed Overall Success (Protocol Definition) Rates by Level Treated

Timepoint Superior C3-C4 Inferior C4-C5



INV CTR INV CTR INV CTR 6 Months

Statistics*

3/3 (100%)

2/3 (66.7%)

33/42 (78.6%)

29/41 (70.7%)

133/158 (84.2%)

95/130 (73.1%)

33.3% (-26.3%, 93.0%) 7.8% (-10.9%, 26.5%) 11.1% (1.7%, 20.5%) 12 Months

Statistics*

2/2 (100%)

1/2 (50%)

32/41 (78.0%)

28/40 (70%)

133/159 (83.6%)

88/124 (71.0%)

50.0% (-34.9%, 100%) 8.0% (-11.0%, 27.1%) 12.7% (3.0%, 22.4%) 24 Months

Statistics*

1/2 (50.0%)

1/2 (50.0%)

31/39 (79.5%)

28/39 (71.8%)

130/158 (82.3%)

82/119 (68.9%)

0.0% (-98.0%, 98.0%) 7.7% (-11.4%, 26.7%) 13.4% (3.3%, 23.5%) 36 Months

Statistics*

3/3 (100%)

1/2 (50.0%)

33/40 (82.5%)

24/37 (64.9%)

115/142 (81.0%)

80/110 (72.7%)

50.0% (-21.6%, 100%) 17.6% (-2.0%, 37.2%) 8.3% (-2.2%, 18.7%) 60 Months

Statistics*

0/1 (0%)

0/1 (0%)

26/35 (74.3%)

23/31 (74.2%)

106/130 (81.5%)

68/106 (64.2%)

Not Available 0.1% (-21.0%, 21.2%) 17.4% (6.1%, 28.7%) 84 Months

Statistics*

0/1 (0%)

0/0 22/27 (81.5%)

18/24 (75.0%)

77/98 (78.6%)

44/75 (58.7%)

Not Available 6.5% (-16.1%, 29.1%) 19.9% (6.1%, 33.7%) INV=2-level PRESTIGE LP™ (N=209); CTR = 2-level ACDF control (N=188) * Point Estimate and 95% Confidence Interval of Difference of Success Rate between 2-level PRESTIGE LP™ and 2-level ACDF control. The 95% CI was provided using Frequentist Farrington and Manning methods.

Post-hoc subgroup analyses examining the primary endpoint (Overall Success Protocol Definition) stratified by subject gender and race at the 24 month timepoint were conducted, and the results for race are provided in Table 45. Due to the relatively small numbers of non-Caucasians treated in the IDE study, statistical conclusion regarding overall success outcomes based on race cannot be reliably made; however, qualitative differences were not observed. The rates for the primary outcome components were similar between males and females within each study group. The 2-level PRESTIGE LP overall success rates were qualitatively higher than the 2-level ACDF control group success rates in all subgroups.

Table 45: Overall Success (Protocol Definition) by Subject Race at 24

months

Primary Outcome Component

INV CTR

Caucasian (N = 195)


Caucasian (N = 172)



162/185 (87.6%)

13/14 (92.9%)

115/146 (78.8%)

11/13 (84.6%)


169/185 (91.4%)

13/14 (92.9%)

126/146 (86.3%)

11/13 (84.6%)

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Primary Outcome Component

INV CTR

Caucasian (N = 195)


Caucasian (N = 172)


No serious implant- or implant/surgical procedure-associated AE

2 0 9 2

No additional surgical procedure classified as “failure” 4 0 10 2

Overall Success (Protocol Definition)

150/185 (81.1%)

12/14 (85.7%)

102/147 (69.4%)

9/13 (69.2%)


Secondary Effectiveness Analysis Clinical Endpoints: In addition to the components of the primary endpoint presented above, secondary effectiveness variables were also assessed. Table 46 describes the results of the secondary effectiveness endpoints at 24 months. The results were comparable between the 2-level PRESTIGE LP™ group and the 2-level ACDF control group.

Table 46: Summary of Secondary Effectiveness Endpoints at 24 Months

Outcome Measure 24-Month Observed

Success Rate 24-Month Posterior Mean

(95% HPD Credible Interval) INV CTR INV CTR INV - CTR

Neck pain (any improvement)

195/199 (98.0%)

152/159 (95.6%)

96.9% (94.4%, 99.0%)

94.8% (91.4%, 97.7%)

2.1% (-1.9%, 6.2%)

Neck pain (≥2/10 point decrease in neck pain intensity from baseline)

185/199 (93.0%)

136/159 (85.5%)

91.7% (87.9%, 95.4%)

84.9% (79.3%, 90.0%)

6.9% (0.2%, 13.4%)

Arm pain (any improvement)

177/199 (88.9%)

143/159 (89.9%)

88.0% (83.6%, 92.4%)

88.9% (84.0%, 93.3%)

-0.8% (-7.3%, 5.6%)

Arm pain (≥2/10 point decrease in arm pain intensity from baseline)

169/199 (84.9%)

130/159 (81.8%)

83.8% (78.7%, 88.7%)

81.2%, (75.1%, 86.9%)

2.6% (-5.1%, 10.5%)

SF-36 PCS (any improvement)

178/197 (90.4%)

137/156 (87.8%)

89.6% (85.5%, 93.6%)

87.2% (82.1%, 92.1%)

2.4% (-4.2%, 8.8%)

SF-36 PCS (≥15% improvement)

158/197 (80.2%)

118/156 (75.6%)

79.6% (74.1%, 84.9%)

74.9% (68.2%, 81.3%)

4.7% (-4.2%, 12.8%)

SF-36 MCS (any improvement)

136/197 (69.0%)

113/156 (72.4%)

68.8% (62.5%, 75.3%)

71.2% (64.0%, 77.8%)

-2.4% (-12.0%, 6.7%)

SF-36 MCS (≥15% improvement)

100/197 (50.8%)

69/156 (44.2%)

50.9% (43.8%, 57.5%)

43.9% (36.5%, 51.4%)

7.0% (-3.6%, 17.0%)

Gait assessment (maintenance or improvement of pre-operative status)

199/199 (100%)

157/159 (98.7%)

99.0% (97.7%, 100%)

97.7% (95.5%, 99.5%)

1.3% (-1.3%, 4.0%)


Radiographic Endpoints: Radiographic Success:

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The protocol-specified radiographic success criteria for 2-level PRESTIGE LP™ subjects required angular motion on lateral flexion/extension radiographs >4° but <20° with no radiographic evidence of bridging trabecular bone that forms a continuous bony connection with the vertebral bodies (i.e., no bridging bone) at both treated levels. In the 2-level ACDF control group, radiographic success was defined as radiographic evidence of bone spanning the two vertebral bodies (i.e., bridging bone), angular motion on lateral flexion/extension radiographs ≤4°, and evidence of radiolucency covering more than 50% of either the superior or inferior surface of either graft. For this study, both treated levels were required to have evidence of fusion in order to claim overall radiographic fusion success. Based on those definitions, at 24 months post-operative, 51.0% (100/196) of 2-level PRESTIGE™ LP subjects achieved radiographic success at both treated levels while 82.1% (119/145) of 2-level ACDF control group subjects achieved radiographic success at both treated levels. Table 47 presents data on radiographic success at 24 months by treatment group.

Table 47: Radiographic Success at 24 Months

Treatment Level Angular Motion

>4° and ≤20°

No Bridging Bone Radiolucency

Overall Radiographic

Success

INV

Superior Level Only 141/198 (71.2%)

184/198 (92.9%) Not Applicable 137/197 (69.5%)

Inferior Level Only 136/196 (69.4%)

177/198 (89.4%) Not Applicable 126/195 (64.6%)

Both Treated Levels 106/197 (53.8%)

176/198 (88.9%) Not Applicable 100/196 (51.0%)

Treatment Level Angular Motion ≤4° Bridging Bone No Radiolucency

Overall Radiographic

Success

CTR

Superior Level Only 146/153 (95.4%)

154/154 (100%) 158/158 (100%) 144/151 (95.4%)

Inferior Level Only 127/148 (85.8%)

149/151 (98.7%) 158/158 (100.0%) 125/146 (85.6%)

Both Treated Levels 121/147 (82.3%)

149/151 (98.7%) 158/158 (100.0%) 119/145 (82.1%)


Range of Motion: Radiographic evaluations of mean range of motion, including angulation and translation (during flexion and extension), for the treated levels at the pre-operative, 12 month, and 24 month timepoints are provided in Table 48.

Table 48: Timecourse of Radiographic Mean Range of Motion Timepoint Treatment

Level Evaluation INV CTR

Pre-operative Superior

Flexion/extension angulation (º)

6.75° ± 4.16° Range: 0.08° - 18.15°

7.12° ± 4.14° Range: 0.45° - 19.72°

Flexion/extension translation (mm)

1.48mm ± 1.08mm Range: 0.13mm – 9.17mm

1.57mm ± 1.14mm Range: 0.03mm – 8.96mm

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Timepoint Treatment Level

Evaluation INV CTR

Inferior


5.56° ± 3.89° Range: 0.37° - 18.20°

5.37° ± 3.26° Range: 0.37° - 18.51°


1.04mm ± 0.74mm Range: 0.06mm – 3.42mm

1.14mm ± 0.93mm Range: 0.00mm – 6.60mm

12 Months

Superior


6.89° ± 4.04° Range: 0.11° - 20.56°

1.51° ± 1.21° Range: 0.07° - 8.53°


1.06mm ± 0.67mm Range: 0.00mm – 3.22mm

0.65mm ± 0.42mm Range: 0.01mm – 1.85mm

Inferior


6.70° ± 4.49° Range: 0.20° - 19.39°

1.70° ± 1.67° Range: 0.06° - 10.90°


1.02mm ± 0.63mm Range: 0.00mm – 3.31mm

0.72mm ± 0.53mm Range: 0.05mm – 3.78mm

24 Months

Superior


6.92° ± 3.96° Range: 0.21° - 18.89°

1.79° ± 1.33° Range: 0.09° - 7.51°


1.33mm ± 0.78mm Range: 0.00mm – 4.05mm

0.81mm ± 0.54mm Range: 0.03mm – 2.91mm

Inferior


6.85° ± 4.25° Range: 0.23° - 21.88°

2.31° ± 2.36° Range: 0.08° - 18.35°


1.16mm ± 0.71mm Range: 0.05mm – 4.04mm

0.98mm ± 0.67mm Range: 0.00mm – 3.49mm

36 Months

Superior


6.64° ± 4.37° Range: 0.22° - 19.83°

2.35° ± 1.78° Range: 0.05° - 10.56°


1.42mm ± 0.76mm Range: 0.00mm – 3.71mm

0.84mm ± 0.56mm Range: 0.12mm – 3.26mm

Inferior


7.08° ± 4.76° Range: 0.35° - 24.98°

2.04° ± 1.71° Range: 0.10° - 8.47°


1.27mm ± 0.79mm Range: 0.11mm – 4.34mm

1.01mm ± 0.72mm Range: 0.07mm – 3.46mm

60 Months

Superior


6.32° ± 4.12° Range: 0.13° - 18.97°

0.77° ± 1.37° Range: 0.06° - 7.22°


1.09mm ± 0.74mm Range: 0.00mm – 3.85mm

0.40mm ± 0.36mm Range: 0.03mm – 1.89mm

Inferior


6.47° ± 4.66° Range: 0.10° - 22.37°

0.56° ± 1.15° Range: 0.02° - 8.47°


0.92mm ± 0.58mm Range: 0.09mm – 3.19mm

0.47mm ± 0.46mm Range: 0.00mm – 2.48mm

84 Months

Superior


6.81° ± 4.07° Range: 0.08° - 17.26°

0.82° ± 1.18° Range: 0.04° - 4.74°


1.20mm ± 0.83mm Range: 0.00mm – 3.57mm

0.43mm ± 0.54mm Range: 0.01mm – 3.00mm

Inferior


6.75° ± 4.80° Range: 0.11° - 18.70°

0.73° ± 1.64° Range: 0.06° - 8.47°


0.89mm ± 0.58mm Range: 0.10mm – 2.34mm

0.38mm ± 0.35mm Range: 0.03mm – 1.75mm


The average angular range of motion (flexion/extension) and range of results for all 2-level PRESTIGE LP™ subjects at the pre-operative, 6 month, 12 month, 24 month, 36 month, 60 month, and 84 month timepoints are shown in Figures 3 and 4. The points represent the means, while the bars represent the range between the maximum and minimum at each timepoint.

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Figure 3: Time Course of PRESTIGE LP™ Cervical Disc Mean Flexion/Extension Range of Motion at Superior Index Level

Figure 4: Time Course of PRESTIGE LP™ Cervical Disc Mean Flexion/Extension Range of Motion at Inferior Index Level

The range of motion values measured from flexion/extension radiographs at 24 months for the 2-level PRESTIGE LP™ Cervical Disc subjects are presented in the histograms below (superior treated level only, inferior treated level only, and combined superior and inferior treated levels).

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These histograms use values obtained by rounding the recorded range of motion for each subject to the nearest integer.

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Figure 5: Histogram of PRESTIGE LP™ Cervical Disc Flexion/Extension Angular Range of Motion at 24 months (Superior Treated Level Only)

Figure 6: Histogram of PRESTIGE LP™ Cervical Disc Flexion/Extension Angular

Range of Motion at 24 months (Inferior Treated Level Only)

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Figure 7: Histogram of PRESTIGE LP™ Cervical Disc Flexion/Extension Angular Range of Motion at 24 months (Combined Superior and Inferior Treated Levels)

Table 49 presents data on change in range of motion from the pre-operative baseline for each timepoint by treatment group.

Table 49: Timecourse of Radiographic Change in Range of Motion

Timepoint Treatment Level Change in Angular

Range of Motion INV CTR

12 Months

Superior Level Only

Increased (≥ 2º) 71/193 (36.8%) 2/155 (1.3%) No Change (-2º to 2º) 58/193 (30.1%) 34/155 (21.9%) Decreased ≤ -2º) 64/193 (33.2%) 119/155 (76.8%)

Inferior Level Only


Both Treated Levels


24 Months

Superior Increased (≥ 2º) 72/190 (37.9%) 1/148 (0.7%) No Change (-2º to 2º) 56/190 (29.5%) 40/148 (27.0%) Decreased ≤ -2º) 62/190 (32.6%) 107/148 (72.3%)

Inferior Increased (≥ 2º) 77/180 (42.8%) 9/137 (6.6%) No Change (-2º to 2º) 52/180 (28.9%) 38/137 (27.7%) Decreased ≤ -2º) 51/180 (28.3%) 90/137 (65.7%)

Both Treated Levels


36 Months Superior Increased (≥ 2º) 61/175 (34.9%) 4/135 (3.0%)

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No Change (-2º to 2º) 44/175 (25.1%) 38/135 (28.1%) Decreased ≤ -2º) 70/175 (40.0%) 93/135 (68.9%)

Inferior


Both Treated Levels


60 Months


Inferior


Both Treated Levels


84 Months


Inferior


Both Treated Levels


Functional Spinal Unit (FSU) Height: Post-operative measurement of FSU height was considered a surrogate measure of subsidence due to loss of disc space height. A subject was considered a FSU height success if either the anterior or posterior post-operative FSU height was no more than 2 mm less than the 6 week post-operative FSU height at both treated levels. Table 50 presents timecourse data on observed FSU height success rates by treatment group. FSU height success was similar between the two treatment groups at all timepoints, and FSU height success rates at 24 months following surgery were 93.5% in the 2-level PRESTIGE LP™ group and 95.7% in the 2-level ACDF control group.

Table 50: Time Course of Radiographic Disc Height Success

Timepoint INV CTR

3 Months 155/173 (89.6%) 141/149 (94.6%)

6 Months 158/167 (94.6%) 143/149 (96.0%)

12 Months 163/171 (95.3%) 129/137 (94.2%)

24 Months 159/170 (93.5%) 132/138 (95.7%)

36 Months 146/159 (91.8%) 121/127 (95.3%)

60 Months 130/140 (92.9%) 109/117 (93.2%)

84 Months 53/58 (91.4%) 50/55 (90.9%)


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Implant Condition: In all of the post-operative radiographic reviews, implant condition was assessed for both treatment groups by independent radiologists. If a plate/screw/graft (control group) or PRESTIGE LP™ (investigational group) was found to be fractured, bent, broken or had migrated, the findings were recorded on the study Case Report Forms.

Through 84 months following surgery, one implant in the 2-level ACDF control group was found to have migrated (at the 12 month visit) and another was found to have broken (at the 60 month visit). In addition, there were 3 instances where at least one of the independent radiologists commented on a radiolucency near a PRESTIGE LP™ device (all at the 24 month visit). Note that these assessments were not pre-specified and therefore only limited data are available. Heterotopic Ossification: Available radiographs for the 2-level PRESTIGE LP™ study subjects were assessed by an independent radiographic evaluator to determine Heterotopic Ossification (HO) grade (grade 0 to grade IV) at both the superior and inferior treated levels according to the following grade definitions established by Mehren: • Grade 0: No HO present. • Grade I: HO detectable in front of the vertebral body but not in the anatomic interdiscal

space. • Grade II: HO growing into the disc space. Possible affection of the function of the prosthesis. • Grade III: Bridging ossifications which still allow movement of the prosthesis. • Grade IV: Complete fusion of the treated segment without movement in flexion/extension. In addition, the independent radiographic evaluator determined the number of subjects with stable or “worsening” (progressing by at least one grade) HO from visit to visit. The results are shown in Table 51. The majority of 2-level PRESTIGE LP™ subjects were assessed as having non-severe HO (grades 0, I, or II). At 24 months post-operative, 14.1% and 16.7% of 2-level PRESTIGE LP™ subjects were assessed as having grade III HO at the superior and inferior treated levels, respectively. Grade IV HO was present in 2.0% of 2-level PRESTIGE LP™ subjects at the superior treated level and 3.0% of 2-level PRESTIGE LP™ subjects at the inferior treated level at 24 months post-operative.

Table 51: Timecourse of Heterotopic Ossification (HO) Grade Superior Level Inferior Level

6 Months

Grade 0 185/202 (91.6%) 173/202 (85.6%) Grade I 5/202 (2.5%) 14/202 (6.9%) Grade II 10/202 (5.0%) 9/202 (4.5%) Grade III 2/202 (1.0%) 6/202 (3.0%) Grade IV 0/202 (0.0%) 0/202 (0.0%) Stable vs. Previous visit 188/201 (93.5%) 176/201 (87.6%) Worsening vs. Previous visit 13/201 (6.5%)

25/201 (12.4%)

12 Months

Grade 0 164/202 (81.2%) 151/202 (74.8%) Grade I 9/202 (4.5%) 11/202 (5.4%) Grade II 15/202 (7.4%) 18/202 (8.9%) Grade III 14/202 (6.9%) 21/202 (10.4%)

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Grade Superior Level Inferior Level Grade IV 0/202 (0.0%) 1/202 (0.5%) Stable vs. Previous visit 174/200 (87.0%) 162/199 (81.4%) Worsening vs. Previous visit 26/200 (13.0%)

37/199 (18.6%)

24 Months


44/197 (22.3%)

36 Months


24/182 (13.2%)

60 Months


38/161 (23.6%)

84 Months


11/71 (15.5%)

Available radiographs for the 2-level PRESTIGE LP™ study subjects were also assessed for bridging bone (Criteria was comparable to grade IV assessment on the McAfee and Mehren classification system for Heterotopic Ossification) between the vertebral bodies of the implanted motion segment. Bridging was defined as evidence of a continuous bony connection from the superior vertebral body to the inferior vertebral body laterally, anteriorly, and/or posteriorly. At 24 months post-operatively, 88.9% (176/198) of the subjects treated with the 2-level PRESTIGE LP™ exhibited no bridging bone at either treatment level, whereas 11.1% (22/198) exhibited bridging bone at one or both treatment levels [7.1% (14/198) at the superior treated level and 10.6% (21/198) at the inferior treated level]. Even though grade IV HO and bridging bone assessments are interrelated, the results are similar but not identical because the assessment methods were different and independent.

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Demographic and baseline characteristics were evaluated for potential correlation with HO grade, and no correlation was found. In addition, to assess the effect of HO on clinical outcomes, the applicant evaluated overall success (and component) outcomes as well as NDI outcomes and arm and neck pain outcomes in subjects with non-severe HO (defined as grades 0, I, and II) and in subjects with severe HO (defined as grades III and IV). No clinically meaningful correlation was found. Adjacent Level Treatments: Some subjects went on to receive post-operative treatment at adjacent level(s). The incidence and progression of adjacent level disease was not collected prospectively, but was assessed in terms of symptoms, treatment, and surgery performed at adjacent level(s) by a thorough review of adverse event source documentation for adverse events coded as pain (neck and/or upper extremity), dysesthesia (neck and/or upper extremity), neurological, weakness, muscle spasms, surgery, pseudoarthrosis, or headache to isolate possible adjacent level symptoms, diagnoses, treatments, and surgeries. Based on this review, the percentage of subjects who underwent surgery at adjacent level(s) (including those who had combined subsequent surgery at the index and adjacent level(s)) was 2.4% (5 subjects, 5 events) for the 2-level PRESTIGE LP™ group and 3.2% (6 subjects, 8 events) for the 2-level ACDF control group. The types of adjacent level procedures that were performed are summarized in Table 52.

Table 52: Types of Adjacent Level Treatments Adjacent Level Treatment INV CTR Adjacent level fusion-1 level 7 (3%) 7 (4%) Adjacent level fusion- 2 level 1 (0.5%) 2 (1%) Adjacent level decompression- 1 Level

6 (3%) 10 (5%)

Adjacent level decompression- 2 Level

0 (0%) 4 (2%)

Bone Growth Stimulator 0 (0%) 1 (0.5%) Cervical Total Disc Replacement- 1 Level

1 (0.5%) 4 (2%)

Cervical Total Disc Replacement- 2 Level

1 (0.5%) 0 (0%)

Cervical wound exploration and repair of dural tear and CSF leak

0 (0%) 1 (0.5%)

Rhizotomy 1 (0.5%) 0 (0%) Total 17 (8%) 29 (15%)

INV=2-level PRESTIGE LP™ (N=209); CTR = 2-level ACDF control (N=188) Decompression includes foraminotomy, laminotomy, laminoplasty, corpectomy, osteophytectomy, micorforaminotomy, laminoforaminotomy, hemilaminectomy, and laminectomy Most surgical interventions required more than one treatment type.

Pain Management: Table 53 presents data on pain and muscle relaxant medication use at baseline pre-operative and at 24 months post-operative by treatment group. Use of pain medication was similar in both

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treatment groups. For subjects on medication, the frequency of medication use ranged from once a week to three or more times a day.

Table 53: Pain and Muscle Relaxant Medication Usage Pre-operative and at 24 Months Post-operative

INV CTR Pre-operative Non-Narcotic Medications 138/208 (66.3%) 133/185 (71.9%) Weak Narcotic Medications* 83/208 (39.9%) 78/186 (41.9%) Strong Narcotic Medications** 52/207 (25.1%) 44/188 (23.4%) Muscle Relaxant Medications 75/208 (36.1%) 73/188 (38.8%) 24 Months Non-Narcotic Medications 85/199 (42.7%) 63/157 (40.1%) Weak Narcotic Medications* 25/197 (12.7%) 30/157 (19.1%) Strong Narcotic Medications** 15/196 (7.7%) 16/158 (10.1%) Muscle Relaxant Medications 35/197 (17.8%) 36/157 (22.9%)

INV=2-level PRESTIGE LP™ (N=209); CTR = 2-level ACDF control (N=188) *Weak narcotic medications include such examples as Tylenol #3, Darvocet N-100, Darvon, and Vicodin. ** Strong narcotic medications include such examples as Percodan, Percocet, Morphine, and Demerol.

Some subjects required additional non-surgical procedures at one or both of the index levels, subsequent to the initial surgery. Through all available follow-up, there were 101 additional procedures at the index level(s) in 52 (24.9%) 2-level PRESTIGE LP™ subjects and 116 additional procedures at the index level(s) in 42 (22.3%) 2-level ACDF control subjects. The timecourse of the additional procedures through all available follow-up is summarized in Table 54.

Table 54: Additional Procedures at the Index Level(s) Through All Available Follow-up Classified by Procedure Type

Procedure INV CTR Facet Injection 4 /209 (1.9%) 7/188 (3.7%) Medial Branch Block 0/209 (0.0%) 3/188 (1.6%) Selective Nerve Root Block 3/209 (1.4%) 3/188 (1.6%) Series of Epidural Steroid Injections 8/209 (3.8%) 7/188 (3.7%) Single Epidural Steroid Injection 18/209 (8.6%) 14/188 (7.4%) Steroid Injection 16/209 (7.7%) 20/188 (10.6%) Sympathetic Block (Including Ganglion) 0/209 (0.0%) 1/188 (0.5%) Trial Spinal Cord Stimulator 1/209 (0.5%) 2/188 (1.1%) Trigger Point Injection 3/209 (1.4%) 8/188 (4.3%) Other 21/209 (10.0%) 16/188 (8.5%) Total 52/209 (24.9%) 42/188 (22.3%)

INV=2-level PRESTIGE LP™ (N=209); CTR = 2-level ACDF control (N=188) Conclusions Drawn from the Study Data The clinical data support the reasonable assurance of safety and effectiveness of the PRESTIGE LP™ Cervical Disc when used in accordance with the indications for use. Based on the clinical study results, it is reasonable to conclude that a significant portion of the indicated patient population will achieve clinically significant results and that the clinical benefits of the use of the PRESTIGE LP™ Cervical Disc at two contiguous levels in terms of improvement in pain and function, and the potential for motion preservation, appear to outweigh the risks associated with

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the device and surgical procedure through 24 months follow-up when used in the indicated population in accordance with the directions for use. PACKAGING PRESTIGE LP™ Cervical Disc implants are supplied pre-packaged and sterile, using gamma irradiation. Packages for each of the components should be intact upon receipt. Once the seal on the sterile package has been broken, the product should not be re-sterilized. Do not use after the use-before date. All instrument sets should be carefully checked for completeness and all components should be carefully checked to ensure there is no damage prior to use. Damaged packages or products should not be used, and should be returned to Medtronic. HANDLING All instruments and implants should be treated with care. Improper use or handling may lead to damage and/or possible malfunction. Instruments should be checked to ensure that they are in working order prior to surgery. All instruments should be inspected prior to use to ensure that there is no unacceptable deterioration such as corrosion, discoloration, pitting, cracked seals, etc. Non-working or damaged instruments should not be used, and should be returned to Medtronic. CLEANING AND DECONTAMINATION The PRESTIGE LP™ reusable instruments are supplied non-sterile and must be cleaned and sterilized prior to use. Disassembly instructions, as well as detailed reprocessing instructions for the PRESTIGE LP™ reusable instruments, can be found at http://manuals.medtronic.com/. Refer to the PRESTIGE LP™ Reusable Instruments instructions for use - M708348B183 which include instructions for disassembly, cleaning, and sterilization for the PRESTIGE LP™ reusable instruments. STERILIZATION The PRESTIGE LP™ Cervical Disc implants are supplied packaged and sterile (gamma irradiation). Never sterilize or in any other way attempt to re-sterilize or re-use the PRESTIGE LP™ implants. The PRESTIGE LP™ instruments are supplied in non-sterile form unless otherwise indicated on the package label. Cleaning and sterilization instructions for the PRESTIGE LP™ reusable instruments can be found at http://manuals.medtronic.com/. Refer to the PRESTIGE LP™ Reusable Instruments instructions for use - M708348B183, which include instructions for disassembly, cleaning, and sterilization for the PRESTIGE LP™ reusable instruments.

Only sterile products should be placed in the operative field.

Implant package contents (superior and inferior disc components) are provided sterile. Instrument set contents are provided non-sterile. PRODUCT COMPLAINTS Any health care professional (e.g., customer or user of this system of products) who has any complaints or who has experienced any dissatisfaction in the product quality, identity, durability, reliability, safety, effectiveness, and/or performance, should notify the distributor or Medtronic.

http://manuals.medtronic.com/

http://manuals.medtronic.com/

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Further, if any of the implanted spinal system component(s) ever “malfunctions” (i.e., does not meet any of its performance specifications or otherwise does not perform as intended), or is suspected of doing so, the distributor or Medtronic should be notified immediately. If any Medtronic product ever malfunctions and may have caused or contributed to the death or serious injury of a patient, the distributor or Medtronic should be notified immediately by telephone, fax, or written correspondence. When filing a complaint, provide the component(s) name and number, lot number(s), your name and address, the nature of the complaint, and notification of whether or not a written report from the distributor is requested. Complaints may also be reported directly to Medwatch at http://www.fda.gov/medwatch. You will also be asked by Medtronic to provide data for a Postapproval Device Failure Study including information regarding the number of PRESTIGE LP™ Cervical Discs you have implanted, removed, and returned to Medtronic for explant analysis as well as detailed clinical information on any patient who has undergone a subsequent surgical procedure at one or both of the index levels including device removal. DEVICE RETRIEVALS Should it be necessary to remove a PRESTIGE LP™ Cervical Disc device, call Medtronic prior to the scheduled surgery to receive instructions regarding the required data collection (including clinical data on the patient and any adverse events, histopathological data, and mechanical data). Refer to the PRESTIGE LP™ Cervical Disc Surgical Technique for step-by-step instructions on the required technique for device retrieval to maximize the information that can be gleaned from the explant analysis as well as detailed instructions regarding the clinical data and device-specific data that needs to be collected. All explanted devices must be returned to Medtronic for analysis. FURTHER INFORMATION Recommended directions for use of this system (surgical operative techniques) are available at no charge upon request. If further information is needed or required, contact Medtronic. ©2016 Medtronic Sofamor Danek USA, Inc. All rights reserved.

DESCRIPTION OF DEVICE MARKINGS

Batch code

Catalogue number

CAUTION: Federal law (U.S.A.) restricts this device to sale by or on the order of a physician.

Consult instructions for use

Do not re-use

For U.S. audiences only.

http://www.fda.gov/medwatch

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Manufacturer

MR conditional

Sterilized using irradiation

Use-by date

Instructions for Use PRESTIGE LP™ CERVICAL DISC … LP™ CERVICAL DISC . Medtronic Sofamor Danek...

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