← Product Code MJO · P120024

# ACTIVL ARTIFICIAL DISC (P120024)

_Highridge Medical, LLC · MJO · Jun 11, 2015 · Orthopedic · APPR_

**Canonical URL:** https://fda.innolitics.com/device/P120024

## Device Facts

- **Applicant:** Highridge Medical, LLC
- **Product Code:** MJO
- **Decision Date:** Jun 11, 2015
- **Decision:** APPR
- **Device Class:** Class 3
- **Review Panel:** Orthopedic
- **Attributes:** Therapeutic

## Intended Use

The activL® Artificial Disc (activL) is indicated for reconstruction of the disc at one level (L4-L5 or L5-S1) following single-level discectomy in skeletally mature patients with symptomatic degenerative disc disease (DDD) with no more than Grade I spondylolisthesis at the involved level. DDD is defined as discogenic back pain with degeneration of the disc confirmed by patient history, physical examination, and radiographic studies. The activL® Artificial Disc is implanted using an anterior retroperitoneal approach. Patients receiving the activL® Artificial Disc should have failed at least six months of nonoperative treatment prior to implantation of the device.

## Device Story

The activL® Artificial Disc is a weight-bearing, modular lumbar total disc replacement device. It consists of two cobalt-chromium alloy endplates (spike or keel design) with a titanium/calcium phosphate coating and a UHMWPE inlay. The device is assembled intraoperatively by the surgeon and implanted via an anterior retroperitoneal approach. It is designed to restore disc height and allow motion at the treated level. The device is unconstrained in rotation. The surgeon uses implant-specific instrumentation for discectomy, endplate preparation, and insertion. The device provides a mobile bearing surface to mimic natural disc motion, potentially reducing stress on adjacent spinal levels compared to fusion. Clinical outcomes are monitored via patient-reported pain (VAS) and disability (ODI) scores, neurological assessments, and radiographic evaluation of range of motion and device stability.

## Clinical Evidence

Prospective, multi-center, randomized (2:1), single-masked, non-inferiority trial (IDE #G060262) comparing activL to Charité or ProDisc-L. 376 subjects treated (218 randomized activL, 106 randomized control). Primary endpoint: composite success at 24 months (ODI improvement ≥15, stable/improved neurological status, ROM maintenance/improvement, no device failure, no serious device-related adverse events). Results: activL non-inferior to control (10% delta). Overall success (missing imputed as failures): 42.2% (activL) vs 28.3% (control). Observed success: 49.7% (activL) vs 33.3% (control). Safety profile comparable to controls regarding adverse events and subsequent surgical interventions.

## Technological Characteristics

Modular implant: two cobalt-chromium alloy endplates (ASTM F75/ISO 5832-12) with Plasmapore μ-CaP coating (Titanium ISO 5832-2, Calcium Phosphate ASTM F1609) and UHMWPE inlay (ISO 5834-2/ASTM F648). Fixation via spikes or keels. Sizes: 4 endplate sizes, 4 inlay heights (8.5-14mm). Unconstrained rotation. Sterilization: Gamma radiation (endplates), E-beam (inlays).

## Reference Devices

- DePuy Spine Charité
- DePuy Synthes Spine ProDisc-L

## Submission Summary (Full Text)

> This content was OCRed from public FDA records by [Innolitics](https://innolitics.com). If you use, quote, summarize, crawl, or train on this content, cite Innolitics at https://innolitics.com.
>
> Innolitics is a medical-device software consultancy. We help companies design, build, and clear FDA-regulated software and AI/ML devices, including [a PMA](https://innolitics.com/services/regulatory/), [a 510(k)](https://innolitics.com/services/510ks/), [a SaMD](https://innolitics.com/services/end-to-end-samd/), [an AI/ML medical device](https://innolitics.com/services/medical-imaging-ai-development/), or [an FDA regulatory strategy](https://innolitics.com/services/regulatory/).

{0}

PMA P120024: FDA Summary of Safety and Effectiveness Data
Page 1 of 94

# SUMMARY OF SAFETY AND EFFECTIVENESS DATA (SSED)

## I GENERAL INFORMATION

Device Generic Name: Artificial Lumbar Disc

Device Trade Name: activL® Artificial Disc (activL)

Device Product Code: MJO

Applicant's Name and Address: Aesculap Implant Systems, Inc.
3773 Corporate Parkway
Center Valley, PA 18034

Date of Panel Recommendation: None

Premarket Approval Application (PMA) Number: P120024

Date of Notice of Approval to the Applicant: June 11, 2015

## II INDICATIONS FOR USE

The activL® Artificial Disc (activL) is indicated for reconstruction of the disc at one level (L4-L5 or L5-S1) following single-level discectomy in skeletally mature patients with symptomatic degenerative disc disease (DDD) with no more than Grade I spondylolisthesis at the involved level. DDD is defined as discogenic back pain with degeneration of the disc confirmed by patient history, physical examination, and radiographic studies. The activL® Artificial Disc is implanted using an anterior retroperitoneal approach. Patients receiving the activL® Artificial Disc should have failed at least six months of nonoperative treatment prior to implantation of the device.

## III CONTRAINDICATIONS

The activL® Artificial Disc should not be implanted in patients with the following conditions:

- Active systemic infection or localized infection near the surgical site
- Osteoporosis or osteopenia defined as DEXA bone mineral density T-score less than or equal to -1.0
- Allergy or sensitivity to the implant materials (cobalt, chromium, polyethylene, titanium, tantalum, or calcium phosphate)
- Isolated lumbar radiculopathy, especially due to herniated disc
- Chronic radiculopathy (unremitting pain with predominance of leg pain symptoms greater than back pain symptoms extending over a period of at least a year)
- Extruded disc material with sequestrum (i.e., free disc fragment)
- Myelopathy
- Spinal stenosis

{1}

- Spinal deformity such as scoliosis
- Spondylolysis/isthmic spondylolisthesis, degenerative spondylolisthesis > Grade I, or segmental instability
- Clinically compromised vertebral bodies at the affected level due to current or past trauma (e.g., current or prior vertebral fracture) or disease (e.g., ankylosing spondylitis)
- Facet ankylosis or facet joint degeneration
- Preoperative remaining disc height < 3mm
- Symptoms attributed to more than one vertebral level
- Abdominal pathology that would preclude an anterior retroperitoneal approach
- Involved vertebral endplate that is dimensionally smaller than 31mm in the medial-lateral and/or 26mm in the anterior-posterior directions

## IV WARNINGS AND PRECAUTIONS

The warnings and precautions can be found in the activL® Artificial Disc labeling.

## V DEVICE DESCRIPTION

The activL® Artificial Disc is a weight-bearing, modular implant which consists of two endplates and one polyethylene inlay.

### Endplates:

- Materials: The activL® Artificial Disc superior and inferior endplates are manufactured from a cobalt chromium alloy which conforms to ASTM F75 and ISO 5832-12. The surfaces of both endplates are coated with a Plasmapore μ-CaP surface coating, composed of Titanium conforming to ISO 5832-2 and a microscopic Calcium Phosphate over-coating which conforms to ASTM F1609.
- Fixation: There are two versions of the activL® Artificial Disc (spike version and keel version). Both have an identical articulation; the only difference is the method of initial stabilization. Longer-term fixation of the activL® Artificial Disc to the vertebral bodies is intended to be achieved through bone growth, with initial stabilization by either the spike or keel endplate design. The choice of the spike or keel endplate version is intended to allow selection of an optimal endplate to fit the individual patient's anatomy and to accommodate physician preference.
- Sizes: The endplates are provided in four sizes (each is available in either the spike or keel design). The superior endplates are provided in either 6° or 11° lordotic angle options, and the inferior endplates are provided in either 0° or 5° lordotic angle options. The 5° inferior endplate is designed for cases where the sacrum has a rounded posterior edge to allow placement of the endplate closer to the posterior border of the S1 vertebra, without the edges protruding.

### Inlay:

- Materials: The activL® Artificial Disc inlay is manufactured from ultra-high molecular weight polyethylene (UHMWPE) which conforms to ISO 5834-2 and ASTM F648. The inlay also includes an integrated tantalum radiographic marker.

PMA P120024: FDA Summary of Safety and Effectiveness Data
Page 2 of 94

{2}

- Sizes: The UHMWPE inlays are available in four heights (8.5, 10, 12, and  $14\mathrm{mm}$ ), and fit any of the endplates (both spike and keel designs) by seating into the grooves in the side wall of the inferior endplate.

# Assembly:

- The activL® Artificial Disc is assembled by the surgeon in the operating room prior to implantation. Two lateral wings on the inlay engage in grooves in the lateral walls of the inferior endplate. The superior endplate is then seated on the inferior endplate.
- Once assembled, the activL® Artificial Disc is mounted onto the inserter and implanted as a single unit via an anterior retroperitoneal approach.

![img-0.jpeg](img-0.jpeg)
Figure 1: Assembled Device
Keel Design

![img-1.jpeg](img-1.jpeg)
Spike Design

Table 1: Endplate Sizes

|  Endplate Size (Spike or Keel) | AP Dimension (mm) | Lateral Dimension (mm) | Lordotic Angle  |
| --- | --- | --- | --- |
|  Small - Inferior | 26 | 31 | 0° or 5°  |
|  Small - Superior | 26 | 31 | 6° or 11°  |
|  Medium - Inferior | 28 | 34.5 | 0° or 5°  |
|  Medium - Superior | 28 | 34.5 | 6° or 11°  |
|  Large - Inferior | 30 | 39 | 0° or 5°  |
|  Large - Superior | 30 | 39 | 6° or 11°  |
|  Xtra Large - Inferior | 33 | 40 | 0° or 5°  |
|  Xtra Large - Superior | 33 | 40 | 6° or 11°  |

PMA P120024: FDA Summary of Safety and Effectiveness Data

{3}

Table 2: Polyethylene Inlay Sizes

|  Polyethylene Inlay Size | AP Dimension (mm) | Lateral Dimension (mm) | Inlay Height / Total Device Height (mm)  |
| --- | --- | --- | --- |
|  Small | 21 | 21 | 5.3 / 8.5  |
|  Medium | 21 | 21 | 6.8 / 10  |
|  Large | 21 | 21 | 8.8 / 12  |
|  Xtra Large | 21 | 21 | 10.8 / 14  |

The maximum range of motion allowed by the activL® Artificial Disc (as measured through in vitro testing) is dependent on the endplate size and inlay height as outlined in the following table. Note that the device design limit for many configurations is not achievable in vivo due to anatomic constraints. The activL® Artificial Disc is unconstrained in rotation.

Table 3: Maximum Device Range of Motion as Measured Through in vitro Testing

|  Device Size Combination (endplate size / inlay height) | Flexion Design Limit (inlay anterior)* | Flexion Design Limit (inlay posterior)* | Extension Design Limit | Lateral Bending Design Limit | Translational Design Limit (mm)  |
| --- | --- | --- | --- | --- | --- |
|  Small / 8.5mm | 11.8° | 11.5° | 11.8° | ±10.6° | 1.5  |
|  Small / 10mm | 19.5° | 18.4° | 18.7° | ±15.6° | 1.5  |
|  Small / 12mm | 30.5° | 26.6° | 30.2° | ±25.8° | 1.5  |
|  Small / 14mm | 43.5° | 36.6° | 43.5° | ±34.1° | 1.5  |
|  Medium / 8.5mm | 11.7° | 9.8° | 11.7° | ±9.2° | 2  |
|  Medium / 10mm | 17.5° | 15.8° | 17.5° | ±14.3° | 2  |
|  Medium / 12mm | 27.3° | 22° | 27.3° | ±25.8° | 2  |
|  Medium / 14mm | 37.8° | 30.2° | 37.8° | ±32.9° | 2  |
|  Large / 8.5mm | 10.5° | 9.5° | 10.7° | ±8.3° | 2  |
|  Large / 10mm | 17.5° | 14.9° | 17.8° | ±12.9° | 2  |
|  Large / 12mm | 26.5° | 22.9° | 26.6° | ±19.6° | 2  |
|  Large / 14mm | 34.5° | 30.9° | 34.5° | ±26.1° | 2  |
|  Xtra Large / 8.5mm | 9° | 8.2° | 11° | ±8° | 2  |
|  Xtra Large / 10mm | 14.2° | 12.4° | 17.6° | ±12.6° | 2  |
|  Xtra Large / 12mm | 21.5° | 19° | 26.4° | ±18.8° | 2  |
|  Xtra Large / 14mm | 28.8° | 25.4° | 35° | ±25.4° | 2  |

* The Inlay is able to translate in the Anterior/Posterior direction 1.5 or 2.0mm based upon the endplate size. This affects the total flexion angle that can be obtained.

The activL® Artificial Disc is implanted using both implant-specific and general instrumentation.

Table 4: activL® Artificial Disc Instruments

|  Catalog Number | Description | Device Classification  |
| --- | --- | --- |
|  Preoperative Planning  |   |   |
|  FW921R | S1 X-ray trial plates | Class 3  |
|  FW959R | X-ray templates, various scales | Class 3  |
|  Midline Marking  |   |   |

PMA P120024: FDA Summary of Safety and Effectiveness Data

{4}

PMA P120024: FDA Summary of Safety and Effectiveness Data
Page 5 of 94

|  Catalog Number | Description | Device Classification  |
| --- | --- | --- |
|  FW938SU | Inferior midline marker tip | Class 1  |
|  FW955R | Anterior midline marker | Class 1  |
|  **Discectomy and Endplate preparation**  |   |   |
|  FW909R | Osteotome, angled | Class 1  |
|  FW912R | Rasp, straight | Class 1  |
|  FW913R | Rasp, angled | Class 1  |
|  FW914R | Curette, bilateral, round, angled 10mm | Class 1  |
|  **Distraction and Size Verification**  |   |   |
|  FW940R | Stem F/wedge | Class 1  |
|  FW941R | Wedge F/H 6mm | Class 1  |
|  FW942R | Wedge F/H 8.5mm | Class 1  |
|  FW943R | Wedge F/H 10mm | Class 1  |
|  FW944R | Wedge F/H 12mm | Class 1  |
|  FW951R | Spacer F/H 8.5mm | Class 1  |
|  FW952R | Spacer F/H 10mm | Class 1  |
|  FW953R | Spacer F/H 12mm | Class 1  |
|  FW954R | Spacer F/H 14mm | Class 1  |
|  FW960R | Distraction forceps, angled | Class 1  |
|  FW970R | Parallel distractor | Class 1  |
|  FW922R | S1 Inferior trial plate, small 5" | Class 3  |
|  FW923R | S1 Inferior trial plate, medium 5" | Class 3  |
|  FW924R | S1 Inferior trial plate, large 5" | Class 3  |
|  FW925R | S1 Inferior trial plate, x-large 5" | Class 3  |
|  FW926R | Inferior trial plate, x-large 0" | Class 3  |
|  FW927R | Superior trial plate, x-large 6" | Class 3  |
|  FW928R | Superior trial plate, x-large 11" | Class 3  |
|  FW971R | Inferior trial plate, small 0" | Class 3  |
|  FW972R | Inferior trial plate, medium 0" | Class 3  |
|  FW973R | Inferior trial plate, large 0" | Class 3  |
|  FW974R | Superior trial plate, small 6" | Class 3  |
|  FW975R | Superior trial plate, small 11" | Class 3  |
|  FW976R | Superior trial plate, medium 6" | Class 3  |
|  FW977R | Superior trial plate, medium 11" | Class 3  |
|  FW978R | Superior trial plate, large 6" | Class 3  |
|  FW979R | Superior trial plate, large 11" | Class 3  |
|  **Chiseling (For Keel Device only)**  |   |   |
|  FW980R | Handle, chisel guide | Class 3  |
|  FW981R | 8.5mm, 6" chisel guide | Class 3  |
|  FW982R | 10mm, 6" chisel guide | Class 3  |
|  FW983R | 12mm, 6" chisel guide | Class 3  |
|  FW984R | 14mm, 6" chisel guide | Class 3  |
|  FW985R | 8.5mm double chisel | Class 3  |
|  FW986R | 10mm double chisel | Class 3  |
|  FW987R | 12mm double chisel | Class 3  |
|  FW988R | 14mm double chisel | Class 3  |
|  FW989R | 8.5mm single chisel | Class 3  |
|  FW990R | 10mm single chisel | Class 3  |
|  FW991R | 12mm single chisel | Class 3  |
|  FW992R | 14mm single chisel | Class 3  |
|  FW993R | 8.5mm, 11" chisel guide | Class 3  |
|  FW994R | 10mm, 11" chisel guide | Class 3  |
|  FW995R | 12mm, 11" chisel guide | Class 3  |
|  FW996R | 14mm, 11" chisel guide | Class 3  |

{5}

|  Catalog Number | Description | Device Classification  |
| --- | --- | --- |
|  FW579R | Miaspas TL slotted hammer | Class 1  |
|  Implantation  |   |   |
|  FW961R | 8.5mm insertion instrument | Class 3  |
|  FW962R | 10mm insertion instrument | Class 3  |
|  FW963R | 12mm insertion instrument | Class 3  |
|  FW964R | 14mm insertion instrument | Class 3  |
|  FL045R | 30mm disc removal mallet | Class 1  |
|  FW945R | Key for insertion instrument | Class 3  |
|  FW999R | Impactor with Pins | Class 3  |
|  FW969R | Repositioner | Class 3  |
|  FW910R | activL® Impactor, straight | Class 3  |
|  FW911R | activL® Impactor, angled | Class 3  |
|  FW915R | activL® Implant Impactor | Class 3  |
|  FW916R | Adapter for FW915R – Height 8.5/10mm | Class 3  |
|  FW917R | Adapter for FW915R – Height 12/14mm | Class 3  |
|  Revision  |   |   |
|  FW965R | Revision instrument, distraction fork | Class 1  |
|  FW970R | Parallel distractor | Class 1  |
|  FW997R | Osteotome | Class 1  |
|  FW998R | activL revision handle | Class 1  |
|  FW966R | Revision instrument S/M | Class 3  |
|  FW967R | Revision instrument X/L | Class 3  |
|  FW968R | Revision instrument, PE Inlay | Class 3  |

# VI ALTERNATIVE PRACTICES AND PROCEDURES

There are several alternatives for the treatment of symptomatic degenerative disc disease at a single lumbar level (L4-L5 or L5-S1):

- Non-surgical alternatives include, but are not limited to, medications, physical therapy, spinal injections, chiropractic care, braces, exercise programs, or rest.
- Surgical alternatives include, but are not limited to, surgical decompression and/or fusion using various bone grafting techniques and devices (including but not limited to interbody fusion devices and posterior pedicle screw/rod systems). Symptomatic degenerative disc disease at a single lumbar level (L4-L5 or L5-S1) may also be treated surgically using another FDA approved lumbar total disc replacement device.

Each alternative has advantages and disadvantages which should be fully discussed with the patient's physician.

# VII MARKETING HISTORY

The activL® Artificial Disc has been in commercial distribution in markets outside of the United States since 2005. The device is available in the following countries: Argentina, Austria, Belgium, Brazil, Canada, the Czech Republic, Denmark, France, Germany, Hong Kong, Italy, Malaysia, Mexico, Norway, Poland, South Africa, South Korea, Spain, Switzerland, and the United Kingdom.

PMA P120024: FDA Summary of Safety and Effectiveness Data

{6}

The device has not been withdrawn from any market, for any reason.

## VIII POTENTIAL ADVERSE EFFECTS OF THE DEVICE ON HEALTH

The following is a list of the potential adverse effects (i.e., complications, risks) associated with the use of the activL® Artificial Disc identified from the activL® Artificial Disc clinical trial results, use of the activL® Artificial Disc outside of the United States, approved device labeling for other lumbar total disc replacement devices, and published scientific literature including: (1) those associated with any surgical procedure; (2) those associated with lumbar spinal surgery using an anterior approach; and (3) those associated with a lumbar total disc replacement device (including the activL® Artificial Disc). These risks may occur singly or in combination. In addition to the risks listed below, there is also the risk that the procedure may not be effective and may not relieve 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:
- 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;
- 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 specifically associated with lumbar spinal surgery using an anterior approach:
- Injury to surrounding organs and structures including the cauda equina, nerve roots, other neurologic structures adjacent to the spinal column, adjacent vertebrae, lymphatic vessels, blood vessels, soft tissue, dura, intestines, kidneys, or ureters;
- Neurological difficulties, including trouble with bowel and/or bladder function (including incontinence), sexual dysfunction (including retrograde ejaculation in males), muscle weakness or paralysis, changes in sensation (including numbness, dysesthesias, or paresthesias), chronic reflex sympathetic dystrophy, or pain;
- Back or leg pain;

PMA P120024: FDA Summary of Safety and Effectiveness Data
Page 7 of 94

{7}

- Epidural or retroperitoneal hematoma or fibrosis;
- Scarring, adhesions, or swelling including in the peritoneum;
- Hernia; and
- Meningitis.

3. Risks associated with a lumbar total disc replacement device (including the activL® Artificial Disc):
- 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 cauda equina, nerve roots, or other neurologic structures adjacent to the spinal column (which could cause pain, paralysis, numbness, or retrograde ejaculation in males) or blood vessel damage or erosion (which could cause catastrophic or fatal bleeding even in the late postoperative period);
- Deterioration in neurologic status;
- Development of new pain;
- Failure of the device to improve symptoms or function;
- Problems during placement of the device including trouble sizing the device, anatomical or technical difficulties implanting the device, 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 (cobalt, chromium, polyethylene, titanium, tantalum, calcium phosphate) or device wear debris which may lead to an adverse reaction of the local tissues or chronic inflammation that may lead to implant loosening or failure of the device, osteolysis, 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;
- Spinal stenosis;
- Fracture of the surrounding vertebrae;
- Unintended bone formation (i.e., heterotopic ossification, annular ossification) that may result in bridging trabecular bone and may reduce spinal motion or result in unintended fusion at either the treated level or adjacent levels; and
- Device failure which may require a subsequent surgical intervention (including removal of the activL, revision, re-operation or supplemental fixation).

Some of the adverse effects listed above were observed in the activL® Artificial Disc clinical trial. For more detailed information on the specific adverse effects that occurred during the clinical trial, please refer to Section X (Summary of Primary Clinical Study). Some of the most common adverse effects experienced by study patients were: lower extremity pain, lumbar pain alone, and both lumbar and lower extremity pain.

IX SUMMARY OF NONCLINICAL LABORATORY STUDIES

Several non-clinical studies were conducted to characterize the performance of the activL® Artificial Disc.

PMA P120024: FDA Summary of Safety and Effectiveness Data
Page 8 of 94

{8}

# A. Laboratory Studies

Static Endplate Expulsion
□Subsidence
□Static and Dynamic Compression Shear
□Creep Characterization
Subluxation
□Wear/Durability
□Impingement

# B. Animal Studies

□ Wear Debris Particulate

# C. Additional Studies

□ Retrieval Analysis
□ Sterilization Validation
□ Shelf Life and Packaging Validation
Biocompatibility
□ Instrument Testing

# A. Laboratory Studies

Table 5: Summary of Laboratory Studies

|  Test Name | Purpose | Method | Acceptance Criteria | Results  |
| --- | --- | --- | --- | --- |
|  Static Endplate Expulsion | To evaluate the loads required to expulse the activL® device. | Five (5) activL® spiked endplates and five (5) activL® keeled endplates were inserted onto custom grade 15 polycarbonate urethane foam blocks with a 1mm thickness of grade 80 foam on the surface to simulate the denser bone of the endplate.[1] A 450 N axial load was applied. Shear load was applied to the endplate at 5 mm/min. The force necessary to dislodge the endplates was measured. | The shear load endured by the activL® endplates and simulated bone should exceed the maximum shear forces in the lumbar spine of 400 N.[2] | The maximum shear force measured was 1258.82 ± 60.44 N in the activL® spiked endplates and 494.82 ± 13.88 N in the activL® keeled endplates.  |
|  Subsidence | To evaluate the activL® implant's resistance to subsidence into the vertebral endplate. | Five (5) activL® spiked endplates and five (5) activL® keeled endplates were compressed into custom grade 15 polycarbonate urethane foam blocks with a 1mm thickness of grade 80 | The fatigue loads endured by the activL® should exceed the maximum axial forces of 3400 N. [3] | The maximum subsidence load was 5760.57 ± 391.47 N for the spiked endplates and 5567.74 ± 458.01 N for the keeled endplates.  |

PMA P120024: FDA Summary of Safety and Effectiveness Data

{9}

|  Test Name | Purpose | Method | Acceptance Criteria | Results  |
| --- | --- | --- | --- | --- |
|   |  | foam on the surface to simulate the denser bone of the endplate4. Load was applied at 0.1mm/min. The maximum subsidence load was measured. |  |   |
|  Static Compression Shear | To evaluate the performance of the activL® under static compression-shear loading. | Five (5) activL® specimens with spiked endplates and five (5) activL® specimens with keeled endplates were tested under static compression-shear (10° angle) in saline at 37°C at a rate of 50N/sec until failure. | The loads endured by the activL® should exceed the fracture load of the L5 vertebral body (5500 N). [4] | The mean yield load of the specimens was 6625.53 ± 272.49 N for the spiked specimens and 6911.44 ± 231.13 N for the keeled design.  |
|  Dynamic Compression Shear | To evaluate the performance of the activL® under dynamic compression-shear loading. | Seven (7) activL® specimens were tested under compression shear loads (10° angle) in saline at 37°C using a sinusoidal wave form with R = 10 at 5 Hz until 10 million cycles or failure. | The fatigue loads endured by the activL® should exceed the maximum in vivo axial forces (3400 N).[3] | Four (4) activL® specimens ran out to 10 million cycles at 4000 N with no failure.  |
|  Creep Characterization | To evaluate the creep characteristics of the activL® device. | Six (6) specimens of each the 14 mm (tallest) and 8.5 mm (shortest) activL® UHMWPE inlay were loaded in compression shear (10° angle) in saline at 37°C as follows:1. Static: 300 N for 4 hours2. Dynamic: 300 N to 1000 N (1 Hz) for 16 hours3. Static: 300 N for 8 hours (relaxation phase)4. Dynamic: 300 N to 2000 N (1 Hz) for 16 hours5. Static: 300 N for 8 hours (relaxation phase)6. Dynamic: 300 N to 3000 N (1 Hz) for 16 hours7. Static: 300 N for 8 hours (relaxation phase) | The plastic deformations should be smaller than the diurnal changes of the intervertebral disc (1.5 mm).[5] | The maximum displacements of approximately 0.5 mm observed were in the 14 mm inlay after the 3000 N cyclic loading. Maximum plastic deformations of approximately 0.16 mm were observed in the same 14 mm specimens.  |
|  Subluxation | To characterize the shear force necessary to cause subluxation of the superior endplate relative to the polyethylene core. | Twenty (20) activL® specimens were tested in the following configurations: five (5) in neutral position loaded posterior-to-anterior, five (5) in neutral position loaded medial-lateral, five (5) in maximum flexion loaded posterior-to-anterior, and five | This test was performed for characterization only. | The mean subluxation force for the various scenarios described was as follows:0° A-P: 351.82 ± 4.65 N0° M-L: 324.14 ± 9.66 N29° A-P: 272.15 ± 4.11 N  |

PMA P120024: FDA Summary of Safety and Effectiveness Data

{10}

|  Test Name | Purpose | Method | Acceptance Criteria | Results  |
| --- | --- | --- | --- | --- |
|   |  | (5) in maximum lateral bending loaded medial-lateral. Specimens were loaded with a 500 N axial load. Testing was conducted in ambient air. The force necessary to sublux the superior endplate from the UHMWPE inlay was measured. |  | 25° M-L: 288.80 ± 12.65 N  |
|  Wear/Durability | To determine the wear and durability characteristics of the activL® device under physiologic conditions. | Six (6) activL® specimens were tested per ISO 18192-1 (2004-04-30) to 10 million cycles. A complex loading profile combining flexion/extension, lateral bending, axial rotation, and axial load was applied at a frequency of 1Hz. Specimens were tested in calf serum and deionized water solution with EDTA. Specimens were weighed prior to testing and at each 0.5 million cycle increment. | The amount of wear debris should be similar to that reported for other lumbar devices. | Average cumulative wear at 10 million cycles was 25.3mg and the mean wear rate was 2.7mg/million cycles.. The test setup was unable to create any backside wear of the polyethylene inlay.  |
|  Impingement | To determine the wear and durability characteristics of the activL® under conditions simulating device impingement. | Six (6) activL® specimens with the largest endplates (XL) and smallest height (8.5 mm) were tested under impingement conditions to 1 million cycles along with two soak controls. Specimens were cycled in flexion-extension 2° past the device range of motion limits in both flexion and extension. A cyclic axial load was applied such that the flexion and extension moments were 8 Nm. Testing was conducted in calf serum in deionized water (20 g/L) at 37°C. Weight measurements and photodocumentation was completed at 0, 0.125, 0.25, 0.5, and 1 million cycles. Particulate analysis was completed according to ASTM F1877. | This test was performed for characterization only. | Impingement behavior of the activL® included contact between the cobalt chromium endplates. Based on gravimetric measurements, the mean total material loss from both endplates was 1.5 ± 0.4 mm³. The UHMWPE inlays gained mass during testing.  |

PMA P120024: FDA Summary of Safety and Effectiveness Data

{11}

# B. Animal Studies

Table 6: Summary of Animal Studies

|  Test Name | Purpose | Method | Acceptance Criteria | Results  |
| --- | --- | --- | --- | --- |
|  Wear Debris Particulate Animal Study | To characterize the local or systemic reactions potentially caused by UHMWPE wear debris implanted into the epidural space of New Zealand white rabbits. | Animals were injected with a control solution, low dose (10 million) particles, or high dose (25 million) particles. Animals were sacrificed at three (3) months and six (6) months. There were six (6) animals per group, for a total of 36 animals. Assessments included clinical and neurological observations, and hematological, histological, and gross pathologic methods. | There should be no evidence of neurotoxicity, systemic toxicity, or local effects associated with the UHMWPE particulate debris. | The study showed no evidence of neurotoxicity, systemic toxicity, or local effects associated with treatment with the test article wear debris.  |

# C. Additional Studies

# Retrieval Analysis

A total of three (3) activL® devices were retrieved from revision surgeries during the IDE study. Unfortunately, these three activL® explants were lost and no retrieval analysis was performed. To address this situation, the sponsor provided: (i) additional patient information on the three (3) devices that were explanted, and (ii) supplementary retrieval analysis reports of four (4) explanted activL® devices (from the Netherlands) in conjunction with a NIH Study being conducted by Drexel University.

# (i) Summary of Additional Patient Information

The additional patient information provided on the three (3) explanted devices suggested no obvious device-related concerns, such as disassociation of components, osteolysis, gross subsidence or migration of the endplates. However, no photographs or analyses of these explants were provided.

# (ii) Summary of Supplementary Retrieval Analysis (from Drexel University)

The Drexel study included analysis from four (4) activL explants; however, only three (3) of these explants were accompanied by clinical information. These three (3) explants were removed after 1.3 – 7.5 years due to persistent pain. In addition to pain, two (2) of these explants showed evidence of subsidence, two (2) showed evidence of facet degeneration, and one (1) explant showed evidence of possible osteolysis. Overall, the UHMWPE inserts showed typical wear features for this device class, such as polishing, scratching, pitting, and embedded particles. There was no evidence of surface delamination or cracking. Of particular note, three (3) of the four (4) explanted UHMWPE inserts showed low to

PMA P120024: FDA Summary of Safety and Effectiveness Data

{12}

moderate oxidation levels, showing an average maximum oxidation index of  $1.0 \pm 0.8$  (range:  $0.4 - 2.2$ ). The Drexel study did reveal some whitening and white-banding of the UHMWPE slices, which corresponded to the higher oxidation indices measured. As for the Co-Cr endplates, all articular surfaces remained highly polished. A number of small impingement wear patterns were observed implying some endplate-to-endplate contact during use, which appeared to occur in a variety of locations (i.e., in both anterior-posterior and lateral aspects of the device).

# Sterilization Validation

Components of the activL® Artificial Disc are provided sterile. The activL® endplates are sterilized using gamma radiation and the UHMWPE inlays are sterilized using electron beam radiation. Sterilization validation according to ISO 11137-1 and -2 was conducted to confirm a sterility assurance level of  $10^{-6}$ .

# Shelf Life and Packaging Validation

Shelf life and packaging validation studies, including packaging seal and integrity, accelerated aging, and real-time aging testing, were conducted to demonstrate that the device packaging can maintain a sterile barrier, with a shelf life of 5 years.

# Biocompatibility

The materials used in the activL® Artificial Disc are standard materials commonly used in permanently implanted orthopedic devices, including cobalt-chromium-molybdenum alloy (CoCrMo per ISO 5832-12, ASTM F75), titanium plasma spray coating (per ISO 5832-2), calcium phosphate coating (per ASTM F1609) and ultra-high molecular weight polyethylene (UHMWPE per ISO 5834-2, ASTM F648). The inlays also incorporate a tantalum marker (per ASTM F560). These instruments are made of materials that have a long history of use in contact with human tissue and fluids, including surgical grade stainless steel per ISO 7153-1.

# Instrument Testing

The instruments used to implant the activL® device are provided non-sterile for sterilization by the user. Validation testing, including cleaning and steam sterilization, was appropriately conducted and met the acceptance criteria.

# X SUMMARY OF PRIMARY CLINICAL STUDY

The applicant performed a clinical trial within the United States to determine the safety and effectiveness of the activL® Artificial Disc (activL) for reconstruction of the disc at one level (L4-L5 or L5-S1) following single-level discectomy in skeletally mature subjects with symptomatic degenerative disc disease (DDD) and no more than Grade I spondylolisthesis at the involved level who had been unresponsive to at least six months of prior nonoperative treatment under IDE #G060262. Data from this clinical trial were the basis for the PMA approval decision. A summary of the clinical trial is presented below.

PMA P120024: FDA Summary of Safety and Effectiveness Data

{13}

PMA P120024: FDA Summary of Safety and Effectiveness Data
Page 14 of 94

# A. Trial Design

Subjects were treated between January 30, 2007 and December 3, 2009. The database for this PMA reflected data collected through April 11, 2013 and included a total of 376 subjects treated (including both randomized and non-randomized subjects) at 18 investigational sites in the United States.

The trial was a prospective, multi-center, randomized (2:1), single masked, concurrently controlled, non-inferiority clinical trial to compare the safety and effectiveness of the activL to one of two alternative lumbar total disc replacement control devices (DePuy Spine Charité (Charité) or DePuy Synthes Spine ProDisc-L (ProDisc-L)) in reconstruction of the disc at either L4-L5 or L5-S1 following single-level discectomy for symptomatic DDD in subjects who had failed to improve with nonoperative treatment for at least six months prior to enrollment. Subjects were randomized 2:1 to the activL or one of two controls (Charité or ProDisc-L). The choice of control device was at the discretion of the investigator (i.e., each investigator used one or the other for all of the subjects he or she treated), and subjects involved in the trial were specifically consented to one or the other control device prior to surgery. The first three subjects at each investigational site received the activL and were not randomized. In addition, investigators who had not performed at least three prior control device implantations were allowed to perform up to three non-randomized control procedures. The randomized subjects were masked to their treatment assignment, and every effort was made to maintain the masking through 24 months of follow-up. To assess the effectiveness of the masking, subjects were asked at each follow-up visit if they had learned which device they received. The investigator was not masked to the treatment.

Subjects were evaluated preoperatively, intraoperatively, immediately postoperatively, and at 6 weeks, 3 months, 6 months, 12 months, 24 months, and annually thereafter. Following completion of the procedure, subjects in both treatment groups received postoperative care customized to their postoperative needs and demonstrated progress. Typically, subjects were permitted to ambulate on the day of surgery, as tolerated, with an elastic bandage or lumbosacral orthosis (LSO) to provide support to the abdominal musculature. Lumbar stabilization therapy was initiated 2 to 4 weeks postoperatively as tolerated. Water therapy and/or swimming were encouraged and could start two weeks postoperatively. Aerobic walking was stressed for the first 6 postoperative weeks with more resistive exercise using fitness machines after that time. Subjects were also instructed not to engage in activities requiring lifting, bending or twisting for 6 months post-surgery. Subjects were not specifically treated with nonsteroidal anti-inflammatory drugs (NSAIDs) postoperatively in either treatment group.

All adverse events (device-related or not) were monitored over the course of the trial, and radiographic assessments were done by an independent core laboratory. Overall success was a composite endpoint which required success in the following five elements: Oswestry Disability Index (ODI), neurological status, radiographic range of motion status, device status, and no serious device related adverse events. Overall success was determined based on data collected during the initial 24 months of follow-up. For the PMA, all adverse events were independently adjudicated (for adverse event category, severity and relationship to the device and/or procedure) by a Clinical Events Committee (CEC) comprised of three practicing spine surgeons.

{14}

The trial was designed as a non-inferiority trial with a margin (delta) of 15%. Additional analyses using a delta of 10% as requested by FDA were also conducted. The protocol specified a sample size of 216 randomized activL subjects and 108 randomized control subjects, based on an assumed 65% success rate in both treatment groups, a 10% lost-to-follow-up rate, and 80% power for a one-sided 0.05 significance level. With the addition of up to 6 non-randomized subjects (3 activL and 3 control) per each of the planned 15-20 sites, the maximum total planned sample size was 414 (45 non-randomized activL, 216 randomized activL, 108 randomized control, and up to 45 non-randomized control).

## 1. Clinical Inclusion and Exclusion Criteria

Enrollment in the activL trial was limited to subjects who met the following inclusion criteria:

- Age 18-60 years and skeletally mature.
- Back pain at the operative level only (minimum Visual Analog Scale (VAS) back pain score of 40/100mm and greater than the higher of the two VAS leg pain scores).
- Symptomatic degenerative disc disease (DDD) with objective evidence of lumbar DDD, based on identification of any of the following characteristics by computed tomography (CT) or magnetic resonance imaging (MRI) scan:
- Instability as defined by ≥ 3mm translation or ≥ 5° angulation;
- Osteophyte formation of facet joints or vertebral endplates;
- Decreased disc height of > 2mm as compared to the adjacent level;
- Scarring/thickening of the ligamentum flavum, annulus fibrosus, or facet joint capsule;
- Herniated nucleus pulposus;
- Facet joint degeneration/changes; and/or
- Vacuum phenomenon.
- Single level symptomatic disease at L4/L5 or L5/S1.
- Minimum of 6 months of unsuccessful conservative treatment, including but not limited to physical therapy and/or medication.
- Minimum ODI score of 40/100.
- Surgical candidate for an anterior approach to the lumbar spine.
- Willing and able to return for follow-up visits regularly and sign an Informed Consent and HIPAA Authorization.

Subjects were not permitted to enroll in the activL trial if they met any of the following exclusion criteria:

- History of allergies to any of the device components including cobalt chromium alloy, titanium, UHMWPE, and calcium phosphate.
- Evidence of significant, symptomatic disc degeneration at another lumbar level.
- Previous surgery at any lumbar level, except intradiscal electro-thermal annuloplasty (IDET), percutaneous nucleoplasty, microdiscectomy, hemilaminectomy, or laminotomy.
- Chronic radiculopathy as defined by subject complaint of unremitting pain with a predominance of leg pain symptoms greater than back pain symptoms extending over a period of at least 1 year.
- Sequestered herniated nucleus pulposus with migration.

PMA P120024: FDA Summary of Safety and Effectiveness Data
Page 15 of 94

{15}

- Leg pain with migrated sequestrum fragment.
- Myelopathy.
- Previous compression or burst fracture at the affected level.
- Mid-sagittal stenosis of < 8mm (by MRI).
- Degenerative or lytic spondylolisthesis > 3mm.
- Spondylolysis or isthmic spondylolisthesis.
- Lumbar scoliosis (> 11° sagittal plane deformity).
- Preoperative remaining disc height < 3mm.
- Facet ankylosis or severe facet degeneration.
- Active systemic infection or infection at the site of surgery.
- Spinal tumor.
- Anatomic requirements incompatible with the available range of dimensions for the experimental or control devices, based on preoperative assessment using radiographic templates. Specifically endplate dimensions smaller than 34.5 mm in the medial-lateral and/or 27 mm in the anterior-posterior directions.
- Osteoporosis or osteopenia, indicated by a lumbar spine dual-energy X-ray absorptiometry (DEXA) T-score ≤ -1.
- Metabolic bone disease.
- Continuing steroid use or prior use for more than 2 months.
- Abdominal adhesions, endometriosis, inflammatory bowel disease, Crohn's disease, diverticulitis, ulcerative colitis or other abdominal pathology that would preclude the abdominal surgical approach.
- Prior nephrectomy.
- History of Pelvic Inflammatory Disease.
- Peritonitis.
- Morbid obesity (Body Mass Index > 35).
- History of rheumatoid arthritis, lupus, or other autoimmune disorder.
- Ankylosing spondylitis.
- History of human immunodeficiency virus/acquired immune deficiency syndrome (HIV/AIDS) or hepatitis that precludes surgery.
- History of deep vein thrombosis, symptoms of arterial insufficiency, or thromboembolytic disease.
- Insulin-dependent diabetes.
- Pregnant or planning to become pregnant within the next 2 years.
- Life expectancy less than 5 years.
- Undergone chemotherapy within 5 years, or had any cancer other than non-melanoma skin cancer treated with curative intent within 5 years.
- Current or recent history of illicit drug or alcohol abuse, or dependence as defined as the continued use of alcohol despite the development of social, legal, or health problems.
- Investigational drug or device use within 30 days.

PMA P120024: FDA Summary of Safety and Effectiveness Data
Page 16 of 94

{16}

- Any degenerative muscular or neurological condition that would interfere with evaluation of outcomes, including but not limited to Parkinson’s disease, amyotrophic lateral sclerosis (ALS), or multiple sclerosis.
- Currently in active spinal litigation as a result of medical negligence.
- A prisoner.
- Psychiatric or cognitive impairment that, in the opinion of the investigator, would interfere with the subject’s ability to comply with the study requirements, e.g., Alzheimer’s disease.

## 2. Follow-up Schedule

All subjects were scheduled to return for follow-up examinations at 6 weeks (±14 days), 3 months (±14 days), 6 months (±30 days), 12 months (±60 days), 24 months (±60 days), and annually thereafter (±60 days) through 7 years. The following parameters were measured according to the visit schedule below:

PMA P120024: FDA Summary of Safety and Effectiveness Data
Page 17 of 94

{17}

Table 7: Evaluation Schedule

|  Evaluation | Baseline | Intra-op | Discharge | 6 wks (±14 days) | 3 mo (±14 days) | 6 mo (±30 days) | 12 mo (±60 days) | 24 mo (±60 days) | 3-7 yrs (±60 days)  |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
|  Clinical Evaluations:  |   |   |   |   |   |   |   |   |   |
|  Inclusion/exclusion determination | X |  |  |  |  |  |  |  |   |
|  Osteoporosis/osteopenia screen | X |  |  |  |  |  |  |  |   |
|  Medical History/physical exam | X |  |  |  |  |  |  |  |   |
|  Work status | X |  |  | X | X | X | X | X | X  |
|  Pain medications | X |  | X |  |  |  | X | X | X  |
|  Antibiotics | X | X* | X |  |  |  |  |  |   |
|  VAS pain assessment | X |  |  | X | X | X | X | X | X  |
|  Neurological assessment | X |  | X | X | X | X | X | X | X  |
|  DVT prophylaxis |  |  | X |  |  |  |  |  |   |
|  Short Form 36 | X |  |  | X | X | X | X | X | X  |
|  ODI | X |  |  | X | X | X | X | X | X  |
|  Hospital stay |  |  | X |  |  |  |  |  |   |
|  Subject satisfaction |  |  |  |  |  |  | X | X | X  |
|  Adverse events** |  | X | X | X | X | X | X | X | X  |
|  Radiographic Evaluations:  |   |   |   |   |   |   |   |   |   |
|  MRI scan | X |  |  |  |  |  |  |  |   |
|  DEXA scan | X (if req) |  |  |  |  |  |  |  |   |
|  X-rays, A/P and lateral (standing neutral) | X | X (implant position) | X (implant position) | X | X | X | X | X | X  |
|  X-rays, A/P (R/L bending) | X |  |  | X | X | X | X | X | X  |
|  X-rays, lateral (flexion/extension) | X |  |  | X | X | X | X | X | X  |

*Prophylactic antibiotics
** Adverse events and complications were recorded at all visits (both scheduled and unscheduled).

## 3. Clinical Endpoints

The safety of the activL 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 interventions as well as maintenance or improvement in neurological status compared to the ProDisc-L/Charité control group.

The effectiveness of the activL was assessed by evaluating improvement in ODI score, back and leg pain measured at rest using a VAS, quality of life measured using the Short-Form 36 (SF-36) questionnaire,

PMA P120024: FDA Summary of Safety and Effectiveness Data

{18}

subject satisfaction, pain medication usage, and work status compared to the ProDisc-L/Charité control group.

In addition, several radiographic endpoints were considered in evaluating both safety and effectiveness, including range of motion, disc height, device migration, device subsidence, device condition, and heterotopic ossification.

Per the protocol, an individual subject was considered a success if the following criteria were met at 24 months postoperative:

- Improvement of at least 15 points in ODI score at 24 months compared to baseline;
- Maintenance or improvement in neurological status at 24 months compared to baseline as measured by motor and sensory evaluations with a decrease of one grade in either evaluation considered a failure;
- Maintenance or improvement in range of motion (ROM) at the index level, defined as: 24-month ROM – preoperative ROM ≥ 0 (with +2° measurement error applied) in a subject who did not meet the definition of fusion (evidence of continuous bridging bone and < 3° of angular motion from flexion to extension);
- No device failure requiring revision, re-operation, removal, or supplemental fixation at the index level; and
- Absence of serious device-related adverse events (SDAE) as adjudicated by the CEC.

In addition, because the ROM success component of the primary endpoint was such a notable driver of the difference in overall success rates in favor of activL when comparing the two randomized treatment groups, FDA requested an additional analysis of overall success without the ROM success component.

Overall study success criteria were based on a comparison of individual subject success rates, such that the subject success rate for the activL investigational group was required to be non-inferior to that of the ProDisc-L/Charité control group. The IDE was approved using a non-inferiority margin (delta) of 15% with an advisory that a non-inferiority margin of 10% would be required to demonstrate a reasonable assurance of the device's effectiveness. The non-inferiority hypothesis was to be evaluated according to the method of Blackwelder [6]. As outlined in the statistical analysis plan, if non-inferiority was demonstrated, then superiority would be evaluated.

The following two secondary effectiveness endpoints were designated as "powered" in the protocol for the purposes of generating potential labeling claims:

- Improvement in 24 month back pain (measured at rest) ≥ 20/100mm on a VAS compared to baseline; and
- Improvement in 24 month leg pain (measured at rest) ≥ 20/100mm on a VAS compared to baseline for the leg with the maximum pain at baseline with no worsening in the other leg.

PMA P120024: FDA Summary of Safety and Effectiveness Data
Page 19 of 94

{19}

Additional secondary effectiveness evaluations and other outcomes specified in the protocol included comparisons of:

- ODI (mean score, mean improvement from baseline, incidence of 15% improvement, incidence of 15 point improvement);
- Quality of Life, measured using the SF-36 Questionnaire with improvement of 15% compared to baseline considered clinically significant;
- Subject satisfaction;
- Device condition;
- Device migration (≥ 3 mm);
- Device subsidence (≥ 3 mm);
- Disc height (incidence of ≥ 3 mm change);
- ROM (flexion/extension, lateral bending) including comparison of 24 month ROM to baseline and to "normal" ROM at the operative level (defined as: 6 ± 2° ≤ ROM ≤ 20 ± 2° (device design limit) for L4-L5 and 5 ± 2° ≤ ROM ≤ 20 ± 2° (device design limit) for L5-S1) [7];
- Heterotopic ossification at the index level compared to baseline;
- Pain medication usage at 12 and 24 months compared to post-injury and pre-implant usage;
- Work status/return to work (including level of activity) as compared to pre- and post- injury conditions;
- Mean operative time, duration of hospitalization, and blood loss;
- Neurological status; and
- Adverse event rates.

For the primary and powered secondary endpoints, the protocol specified that subjects with incomplete or missing data would be classified as failures, and sensitivity analyses would be done to assess the potential impact of missing data on the trial outcomes. The specified sensitivity analyses were based on the Intent-to-Treat (ITT) population and included the following imputation methods: multiple imputation, last-observation-carried-forward, all subjects with missing data as successes, all control subjects with missing data as successes and all activL subjects with missing data as failures (worst case scenario), all control subjects with missing data as failures and all activL subjects with missing data as successes (best case scenario) and break-even analyses (tipping-point) where all missing data was counted as failures and then changed to successes one at a time to find the break-even point.

The protocol specified that missing values would be ignored for the analysis of additional secondary endpoints, other outcomes, and summaries of baseline characteristics.

## B. Accountability of PMA Cohort

Nineteen investigational sites were initiated for the activL trial. Eighteen of the 19 sites enrolled subjects. A total of 396 subjects (277 activL, 119 control) were enrolled. Of these 396 subjects, 55 subjects were non-randomized subjects (48 activL, 7 control). Three of the non-randomized subjects (2 activL, 1 control) withdrew prior to surgery. Of the remaining 341 subjects who were randomized, 17 subjects (11 activL, 6 control) withdrew prior to surgery either because the consent was withdrawn or

PMA P120024: FDA Summary of Safety and Effectiveness Data
Page 20 of 94

{20}

the subject did not meet the inclusion/exclusion criteria. Therefore, a total of 376 subjects enrolled in the trial and proceeded to surgery. Of the 376 enrolled subjects, 52 were non-randomized subjects (46 activL, 6 control) and 324 were randomized subjects after application of the ITT principle (218 activL, 106 control).

At the time of database lock (April 11, 2013), of the 324 randomized subjects enrolled in the PMA trial, all had reached the 24 month post-operative visit and 230 of the 273 expected randomized subjects (84%) had any 24 month data available for analysis.

More specifically, complete 24 month primary endpoint data was available for:

- 192 activL subjects (47 treated at L4-L5, 145 treated at L5-S1)
- 156 randomized (80 treated with the spike version of activL, 76 treated with the keel version of activL)
- 36 non-randomized (16 treated with spike version of activL, 20 treated with keel version of activL)
- 72 control subjects (24 treated at L4-L5, 48 treated at L5-S1)
- 67 randomized (40 treated with the ProDisc-L, 26 treated with the Charité)
- 5 non-randomized (5 treated with the ProDisc-L, 0 treated with the Charité)

A total of 33 activL subjects (29 randomized and 4 non-randomized) and 22 control subjects (21 randomized and 1 non-randomized) were primary endpoint failures at or prior to the 24 month visit because they had a removal, revision, reoperation, or supplemental fixation surgery at the index level or experienced a SDAE. Of the 33 activL subjects who were primary endpoint failures for these reasons, 18 received the spike version of the activL and 15 received the keel version of the activL.

A summary of subject accountability data for the 12-month, 24-month, 3-year, and 4-year follow-up visits is provided in Table 8 and a summary of data available at 24 months for specific evaluations is provided in Table 9. Limited 5-year data was also provided in the PMA, but is not included in this summary. In addition, the non-randomized control data is generally not included in the tables within this summary due to the limited sample size.

PMA P120024: FDA Summary of Safety and Effectiveness Data
Page 21 of 94

{21}

Note that one subject was randomized to the activL group but a control device was erroneously implanted instead. This was recorded as a protocol deviation, and the subject is included as an investigational subject in the ITT analysis set throughout this summary. Note that because this subject did not receive either the spike or keel device, he/she is not counted in any of the tables stratified by device design in this summary. Another subject was randomized to the control group (ProDisc-L) but was not implanted due to a posterior inferior rim fracture which occurred intra-operatively. The subject was subsequently fused and is included as a control subject in the ITT analysis set throughout this summary. Note that because this subject did not receive either control device, he/she is not counted in any of the tables stratified by control device in this summary. This explains why there are a total of 66 control subjects when stratified by device, rather than the 67 defined by the ITT population.

Table 8: Subject Accounting

|   | 12 Months |   |   | 24 Months |   |   | 3 Years |   |   | 4 Years  |   |   |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
|   | NR activL | R activL | R Contr | NR activL | R activL | R Contr | NR activL | R activL | R Contr | NR activL | R activL | R Contr  |
|  Treated | 46 | 218 | 106 | 46 | 218 | 106 | 46 | 218 | 106 | 46 | 218 | 106  |
|  Deaths (cumulative) | 0 | 1 | 0 | 0 | 1 | 0 | 0 | 1 | 0 | 0 | 1 | 0  |
|  Failures (cumulative)1 | 4 | 25 | 18 | 4 | 29 | 21 | 4 | 30 | 22 | 4 | 30 | 22  |
|  Not Yet Overdue | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 12 | 53 | 22  |
|  \(Expected^2\) | 42 | 192 | 88 | 42 | 188 | 85 | 42 | 187 | 84 | 30 | 134 | 62  |
|  Withdrawn (cumulative) | 1 | 0 | 0 | 1 | 0 | 1 | 1 | 1 | 1 | 2 | 1 | 1  |
|  Missed Visit | 4 | 4 | 2 | 2 | 7 | 6 | 5 | 29 | 10 | 6 | 53 | 26  |
|  Lost to Follow-Up (LTFU)/Presumed LTFU | 0 | 9 | 8 | 2 | 19 | 10 | 2 | 36 | 13 | 5 | 44 | 16  |
|  Actual, primary endpoint data (% follow-up)3 | 37(88%) | 174(91%) | 78(89%) | 36(86%) | 156(83%) | 67(79%) | 34(81%) | 115(61%) | 59(70%) | 17(57%) | 34(25%) | 17(27%)  |
|  Actual, primary endpoint data in window (% follow-up)4 | 36(86%) | 157(82%) | 73(83%) | 34(81%) | 144(77%) | 61(72%) | 31(74%) | 106(57%) | 53(63%) | 17(57%) | 33(25%) | 17(27%)  |
|  Actual, any data (% follow-up)5 | 37(88%) | 179(93%) | 78(89%) | 37(88%) | 162(86%) | 68(80%) | 34(81%) | 121(65%) | 60(71%) | 17(57%) | 36(27%) | 19(30%)  |

NR=Non-randomized; R=Randomized; Contr=Control
Subjects who had a removal, revision, reoperation or supplemental fixation surgery at the index level or experienced a SDAE.
Treated subjects - (Deaths + Not yet overdue + Failures).
${}^{3}$  Subjects with complete data for the primary endpoint, regardless of in-window status, and not a failure.
4 Subjects with complete data for the primary endpoint, evaluated per protocol, and in-window and not a failure.
5 Subjects with any follow-up data reviewed or evaluated and not a failure.

Table 9: 24 Month Data Accounting

|  Parameter | NR activL | R activL | R Contr  |
| --- | --- | --- | --- |
|  Treated | 46 | 218 | 106  |
|  \(Expected^1\) | 46 | 217 | 106  |

PMA P120024: FDA Summary of Safety and Effectiveness Data

{22}

|  Parameter | NR activL | R activL | R Contr  |
| --- | --- | --- | --- |
|  Primary endpoint: |  |  |   |
|  ODI (% of Expected) | 41 (89.1%) | 187 (86.2%) | 87 (82.1%)  |
|  Neurological assessment (% of Expected) | 41 (89.1%) | 188 (86.6%) | 87 (82.1%)  |
|  ROM (% of Expected) | 40 (87.0%) | 187 (86.2%) | 85 (80.2%)  |
|  Device failure (% of Expected) | 41 (89.1%) | 189 (87.1%) | 87 (82.1%)  |
|  SDAE (% of Expected) | 41 (89.1%) | 191 (88.0%) | 89 (84.0%)  |
|  All primary endpoint components (% of Expected) | 40 (87.0%) | 185 (85.3%) | 88 (83.0%)  |
|  Powered secondary endpoints: |  |  |   |
|  VAS back pain (% of Expected) | 41 (89.1%) | 185 (85.3%) | 87 (82.1%)  |
|  VAS leg pain (% of Expected) | 41 (89.1%) | 183 (84.3%) | 87 (82.1%)  |
|  Other secondary endpoints: |  |  |   |
|  SF-36 Mental Component Summary (% of Expected) | 41 (89.1%) | 185 (85.3%) | 86 (81.1%)  |
|  SF-36 Physical Component Summary (% of Expected) | 41 (89.1%) | 185 (85.3%) | 86 (81.1%)  |
|  Disc height (% of Expected) | 41 (89.1%) | 186 (85.7%) | 87 (82.1%)  |
|  Device subsidence (% of Expected) | 41 (89.1%) | 187 (86.2%) | 87 (82.1%)  |
|  Adverse events (% of Expected) | 41 (89.1%) | 189 (87.1%) | 87 (82.1%)  |
|  Subject Satisfaction | 41 (89.1%) | 187 (86.2%) | 87 (82.1%)  |
|  Device Migration | 40 (87.0%) | 187 (86.2%) | 87 (82.1%)  |
|  Device condition | 40 (87.0%) | 187 (86.2%) | 87 (82.1%)  |
|  Heterotopic Ossification Evaluation | 40 (87.0%) | 187 (86.2%) | 87 (82.1%)  |

Data was still collected on subjects who were already failures therefore the failures are added to the expected number from the subject accounting table to determine the number of subjects expected for data accounting.

In the tables that follow throughout this summary, primary and all secondary endpoint hypothesis testing results, safety results and all other summary data are presented for the following analysis datasets:

- Modified ITT data set (primary dataset): all randomized, implanted subjects analyzed according to their randomization assignment (218 randomized activL, 106 randomized control, 46 non-randomized activL, 6 non-randomized control)
- Complete case data set: randomized, implanted subjects with complete primary endpoint data including subjects who were already primary endpoint failures (185 randomized activL, 88 randomized control, 40 non-randomized activL, 6 non-randomized control)
- Per protocol data set: randomized, implanted subjects with complete primary endpoint data and no other major protocol deviations (153 randomized activL, 73 randomized control). The PP population definition specifies randomized subjects; therefore there are no non-randomized activL subjects or non-randomized control subjects included in the per protocol data set

For the primary endpoint analysis and analysis of the powered secondary endpoints, subjects with incomplete or missing data were imputed as failures. In addition, an observed analysis of the primary endpoint was performed for "as-treated" subjects based on all evaluable data with no imputation for missing data.

PMA P120024: FDA Summary of Safety and Effectiveness Data

{23}

# C. Study Population Demographics and Baseline Parameters

The demographics of the study population are typical for a lumbar artificial disc study conducted in the United States. Demographic data and preoperative evaluations for the randomized subjects treated in the study as well as the non-randomized activL subjects are included in Table 10 and Table 11. Although p-values were obtained without any adjustment for multiplicity, there were no statistically significant differences in demographics, baseline characteristics, or preoperative evaluations when comparing the randomized treatment groups. The non-randomized control data is not included due to the limited sample size.

Table 10: Subject Demographics and Baseline Characteristics

|  Demographic Measure/Baseline Characteristic | NR activL (N=46) | R activL (N=218) | R Contr (N=106)  |
| --- | --- | --- | --- |
|  Age (years; mean ± standard deviation) | 39.5 ± 8.3 | 39.0 ± 8.7 | 40.3 ± 8.6  |
|   |  Range: 22 – 54 | Range: 19 - 60 | Range: 19 - 56  |
|  Gender (n (%)) |  |  |   |
|  Male | 24 (52.2%) | 116 (53.2%) | 53 (50.0%)  |
|  Female | 22 (47.8%) | 102 (46.8%) | 53 (50.0%)  |
|  Race (n (%)) |  |  |   |
|  White | 43 (93.5%) | 190 (87.2%) | 100 (94.3%)  |
|  Asian | 1 (2.2%) | 2 (0.9%) | 0  |
|  Black | 1 (2.2%) | 17 (7.8%) | 5 (4.7%)  |
|  American Indian or Alaska Native | 0 | 3 (1.4%) | 0  |
|  Native Hawaiian or Other Pacific Islander | 0 | 0 | 0  |
|  Other | 1 (2.2%) | 6 (2.8%) | 1 (0.9%)  |
|  BMI (kg/m2; mean ± standard deviation) | 26.7 ± 4.4 | 26.6 ± 4.1 | 27.1 ± 4.4  |
|   |  Range: 19 – 35 | Range: 16 – 37 | Range: 16 - 34  |
|  Smoking Status* (n (%)) |  |  |   |
|  Current | 13 (28.3%) | 46 (21.1%) | 22 (20.8%)  |
|  Previous | 9 (19.6%) | 38 (17.4%) | 21 (19.8%)  |
|  Never | 24 (52.2%) | 134 (61.5%) | 63 (59.4%)  |
|  Duration of Back Pain Symptoms (n (%)) |  |  |   |
|  < 6 mo | 2 (4.3%) | 1 (0.5%) | 2 (1.9%)  |
|  6 mo – 1 year | 6 (13.0%) | 30 (13.8%) | 13 (12.3%)  |
|  ≥1 year | 38 (82.6%) | 187 (85.8%) | 91 (85.8%)  |
|  Duration of Leg Pain Symptoms (n (%)) |  |  |   |
|  < 6 mo | 4 (9.8%) | 15 (7.8%) | 10 (10.4%)  |
|  6 mo – 1 year | 9 (22.0%) | 46 (24.0%) | 19 (19.8%)  |
|  ≥1 year | 28 (68.3%) | 131 (68.2%) | 67 (69.8%)  |
|  Current or Previous Non-operative Spinal Therapies (n (%)) |  |  |   |
|  Physical Therapy | 44 (95.7%) | 195 (89.4%) | 97 (91.5%)  |
|  Chiropractic or Osteopathic Treatment | 33 (71.7%) | 120 (55.0%) | 51 (48.1%)  |
|  Pain Medication | 46 (100%) | 212 (97.2%) | 103 (97.2%)  |
|  Epidural Injections | 38 (82.6%) | 174 (79.8%) | 87 (82.1%)  |
|  Previous Operative Spinal Therapies (n (%)) |  |  |   |
|  Lumbar Spinal Surgery | 9 (19.6%) | 52 (23.9%) | 30 (28.3%)  |
|  Non-Lumbar Spinal Surgery | 2 (4.3%) | 10 (4.6%) | 12 (11.3%)  |

PMA P120024: FDA Summary of Safety and Effectiveness Data

{24}

Table 11: Preoperative Evaluation of Endpoints

|  Variable | NR activL | R activL | R Contr  |
| --- | --- | --- | --- |
|  ODI | N=46 | N=218 | N=106  |
|  mean ± standard deviation | 60.0 ±13.5 | 57.1 ± 13.9 | 58.6 ± 14.1  |
|   | Range: 34 - 94 | Range: 18 - 98 | Range: 33.3 - 96  |
|  VAS Back Pain (mm) | N=45 | N=212 | N=106  |
|  mean ± standard deviation | 81.5 ± 13.3 | 79.0 ± 14.9 | 79.1 ± 14.8  |
|   | Range: 48 - 100 | Range: 46 - 100 | Range: 41 - 100  |
|  VAS Right Leg Pain (mm) | N=45 | N=215 | N=104  |
|  mean ± standard deviation | 34.9 ± 31.7 | 28.7 ± 29.8 | 32.9 ± 29.6  |
|   | Range: 0 - 99 | Range: 0 - 96.5 | Range: 0 - 89.5  |
|  VAS Left Leg Pain (mm) | N=46 | N=216 | N=105  |
|  mean ± standard deviation | 33.6 ± 31.2 | 29.6 ± 29.4 | 30.7 ± 29.5  |
|   | Range: 0 - 98.5 | Range: 0 - 100 | Range: 0 - 98  |
|  SF-36 Mental Component Summary (MCS) | N=45 | N=213 | N=105  |
|  mean ± standard deviation | 37.6 ± 14.7 | 39.1 ± 13.9 | 39.6 ± 14.9  |
|   | Range: 10.5 - 66.8 | Range: 9.4 - 67.2 | Range: 8.3 - 67.8  |
|  SF-36 Physical Component Summary (PCS) | N=45 | N=213 | N=105  |
|  mean ± standard deviation | 28.4 ± 7.2 | 29.9 ± 6.2 | 28.4 ± 6.2  |
|   | Range: 9.3 - 43.9 | Range: 14.1 - 51.4 | Range: 11.2 - 49.7  |
|  ROM Flexion/Extension Rotation (°) | N=46 | N=214 | N=105  |
|  mean ± standard deviation | 7.3 ± 5.1 | 6.6 ± 5.1 | 6.6 ± 4.6  |
|   | Range: -0.1 to 18.9 | Range: -1.4 to 26.9 | Range: -0.7 to 19.4  |
|  ROM Flexion/Extension Translation (mm) | N=46 | N=212 | N=104  |
|  mean ± standard deviation | 0.6 ± 0.7 | 0.5 ± 0.7 | 0.6 ± 0.6  |
|   | Range: -0.1 to 3.2 | Range: -0.4 to 3.8 | Range: -1.4 to 2.8  |

Data on amount and length of tobacco use was not captured.

PMA P120024: FDA Summary of Safety and Effectiveness Data

{25}

The following tables provide select demographic and preoperative evaluation data stratified by device design (spike or keel) in the randomized activL group and by specific control device (ProDisc-L or Charité) in the randomized control group as well as by treatment level (L4-L5 or L5-S1) in both randomized groups.

Table 12: Select Demographic and Baseline Characteristics - Stratified

|  Demographic Measure / Baseline Characteristic | R activL (N=218) |   |   | R Contr (N=106)  |   |   |
| --- | --- | --- | --- | --- | --- | --- |
|   |  Spike (N=115) | Keel (N=102) | L4-L5 (N=62) | L5-S1 (N=156) | ProDisc-L (N=65) | Charité (N=41)  |
|  Age (years) mean ± standard deviation | 37.9 ± 9.4 | 40.3 ± 7.7 | 38.9 ± 9.2 | 39.0 ± 8.5 | 40.7 ± 8.5 | 39.6 ± 8.8  |
|  Gender (% Male) | 46.1% | 60.8% | 53.2% | 53.2% | 50.0% | 48.8%  |
|  BMI (kg/m2) mean ± standard deviation | 26.6 ± 4.2 | 26.7 ± 4.1 | 26.2 ± 4.1 | 26.7 ± 4.1 | 27.0 ± 4.8 | 27.1 ± 3.7  |
|  Smoking Status (%) |  |  |  |  |  |   |
|  Current | 17% | 25% | 19% | 22% | 27% | 12%  |
|  Previous | 22% | 13% | 18% | 17% | 22% | 17%  |
|  Never | 61% | 63% | 63% | 61% | 52% | 71%  |

Table 13: Preoperative Endpoint Evaluation Data - Stratified

|  Endpoint | R activL (N=218) |   |   |   | R Contr (N=106)  |   |   |   |
| --- | --- | --- | --- | --- | --- | --- | --- | --- |
|   |  Spike (N=115) | Keel (N=102) | L4-L5 (N=62) | L5-S1 (N=156) | ProDisc-L (N=65) | Charité (N=41) | L4-L5 (N=34) | L5-S1 (N=72)  |
|  ODI mean | 55.1 | 59.1 | 58.3 | 56.6 | 57.0 | 60.9 | 15.2 | 13.5  |
|  VAS Back Pain mean (mm) | 77.6 | 80.4 | 81.4 | 78.1 | 77.5 | 81.2 | 77.6 | 79.8  |
|  VAS Right Leg Pain mean (mm) | 28.3 | 29.5 | 26.9 | 29.5 | 30.1 | 36.1 | 37.4 | 29.9  |
|  VAS Left Leg Pain mean (mm) | 26.4 | 32.5 | 24.9 | 31.4 | 26.1 | 36.7 | 24.5 | 33.0  |
|  SF-36 MCS mean | 40.0 | 38.3 | 39.5 | 38.9 | 41.2 | 36.9 | 38.4 | 40.2  |
|  SF-36 PCS mean | 30.0 | 29.8 | 29.3 | 30.1 | 28.4 | 28.8 | 27.9 | 28.7  |
|  ROM Flexion/Extension Rotation mean (°) | 7.1 | 5.9 | 6.8 | 6.5 | 5.8 | 7.9 | 6.4 | 6.7  |
|  ROM Flexion/Extension Translation mean (mm) | 0.6 | 0.4 | 1.0 | 0.3 | 0.5 | 0.7 | 0.9 | 0.5  |

PMA P120024: FDA Summary of Safety and Effectiveness Data

{26}

|  Endpoint | R activL (N=218) |   |   |   | R Contr (N=106)  |   |   |   |
| --- | --- | --- | --- | --- | --- | --- | --- | --- |
|   |  Spike (N=115) | Keel (N=102) | L4-L5 (N=62) | L5-S1 (N=156) | ProDisc-L (N=65) | Charité (N=41) | L4-L5 (N=34) | L5-S1 (N=72)  |
|  ROM Lateral Bending AP Rotation mean (°) | 1.2 | 0.9 | 2.4 | 0.5 | 0.8 | 1.4 | 1.9 | 0.7  |
|  Normal Neurological Status (%) |  |  |  |  |  |  |  |   |
|  Motor (Grade 5, active movement against full resistance) | 89.6% | 88.2% | 91.9% | 87.8% | 89.2% | 92.7% | 91.2% | 90.3%  |
|  Sensory (Grade 2, normal) | 68.7% | 76.5% | 77.4% | 70.5% | 73.8% | 70.7% | 73.5% | 72.2%  |
|  Reflexes (Grade 2, normal) | 80.0% | 83.3% | 90.3% | 78.2% | 89.2% | 78.0% | 94.1% | 80.6%  |

# D. Safety and Effectiveness Results

# 1. Safety Results

The analysis of safety was based on the modified ITT cohort of subjects which consisted of all randomized, implanted subjects analyzed according to their randomization assignment (218 randomized activL, 106 randomized control, 46 non-randomized activL, 6 non-randomized control) available through April 11, 2013.

# Surgery and Hospitalization Data:

Surgical data for the randomized subjects treated in the study as well as the non-randomized activL subjects are included in Table 14. Although p-values were obtained without any adjustment for multiplicity, there were no statistically significant differences in procedural characteristics when comparing the randomized treatment groups. The non-randomized control data is not included due to the limited sample size. The majority of surgery was performed at the L5-S1 level.

Table 14: Procedural Characteristics

|  Procedural Characteristic | NR activL (N=46) | R activL (N=218) | R Contr (N=106)  |
| --- | --- | --- | --- |
|  Treated Level (n (%)) |  |  |   |
|  L4-L5 | 11 (23.9%) | 62 (28.4%) | 34 (32.1%)  |
|  L5-S1 | 35 (76.1%) | 156 (71.6%) | 72 (67.9%)  |
|  Operative Time (min) | 129.5 ± 48.7 | 109.8 ± 43.3 | 119.0 ± 52.1  |
|  mean ± standard deviation | Range: 40 - 243 | Range: 30 – 233 | Range: 35 - 373  |
|  Access Surgeon Used (n (%)) | 46 (100%) | 218 (100%) | 106 (100%)  |
|  Surgical Approach (n (%)) |  |  |   |
|  Retroperitoneal | 44 (95.7%) | 215 (98.6%) | 104 (98.1%)  |
|  Transperitoneal | 2 (4.3%) | 3 (1.4%) | 2 (1.9%)  |
|  Blood loss (cc) | 194.6 ± 220.6 | 135.2 ± 126.1 | 161.2 ± 200.0  |
|  mean ± standard deviation | Range: 25 - 1050 | Range: 10 - 900 | Range: 5 - 1800  |
|  Length of stay (days) | 2.7 ± 1.1 | 2.3 ± 1.3 | 2.3 ± 1.3  |
|  mean ± standard deviation | Range: 1 - 6 | Range: 1 - 11 | Range: 1 - 8  |
|  Return to Work Time (days) | 260.6 ± 410.7 | 262.5 ± 411.9 | 349.7 ± 491.7  |
|  mean ± standard deviation | Range: 6 - 1772 | Range: 2 - 1815 | Range: 6 - 1886  |

PMA P120024: FDA Summary of Safety and Effectiveness Data

{27}

Table 15 provides select procedural characteristic data stratified by device design (spike or keel) in the randomized activL group and by specific control device (ProDisc-L or Charité) in the randomized control group as well as by treatment level (L4-L5 or L5-S1) in both randomized groups.

Table 15: Select Procedural Characteristics - Stratified

|  Procedural Characteristic | R activL (N=218) |   |   |   | R Contr (N=106)  |   |   |   |
| --- | --- | --- | --- | --- | --- | --- | --- | --- |
|   |  Spike (N=115) | Keel (N=102) | L4-L5 (N=62) | L5-S1 (N=156) | ProDisc-L (N=64) | Charité (N=41) | L4-L5 (N=34) | L5-S1 (N=72)  |
|  Treated Level (n (%)) |  |  |  |  |  |  |  |   |
|  L4-L5 | 35 (30.4%) | 26 (25.5%) | 62 (100%) | -- | 19 (29.7%) | 15 (36.6%) | 34 (100%) | --  |
|  L5-S1 | 80 (69.6%) | 76 (74.5%) | -- | 156 (100%) | 45 (70.3%) | 26 (63.4%) | -- | 72 (100%)  |
|  Device Design |  |  |  |  |  |  |  |   |
|  Spike | 115 (100%) | -- | 35 (57.4%) | 80 (51.3%) | N/A | N/A | N/A | N/A  |
|  Keel | -- | 102 (100%) | 26 (42.6%) | 76 (48.7%) |  |  |  |   |
|  Control Device |  |  |  |  |  |  |  |   |
|  ProDisc-L | N/A | N/A | N/A | N/A | 64 (100%) | -- | 19 (55.9%) | 45 (63.4%)  |
|  Charité |  |  |  |  | -- | 41 (100%) | 15 (44.1%) | 26 (36.6%)  |
|  Operative Time (min) | 115.7 ± 43.8 | 102.9 ± 42.1 | 123.9 ± 41.5 | 104.2 ± 42.9 | 119.8 ± 58.9 | 118.3 ± 40.4 | 125.9 ± 52.4 | 115.7 ± 52.0  |
|  mean ± standard deviation |  |  |  |  |  |  |  |   |
|  Approach (n (%)) |  |  |  |  |  |  |  |   |
|  Retroperitoneal | 112 (97.4%) | 102 (100%) | 62 (100%) | 153 (98.1%) | 62 (96.9%) | 41 (100%) | 33 (97.1%) | 71 (98.6%)  |
|  Transperitoneal | 3 (2.6%) | 0 | 0 | 3 (1.9%) | 2 (3.1%) | 0 | 1 (2.9%) | 1 (1.4%)  |
|  Blood loss (cc) | 138.5 ± 127.2 | 131.9 ± 125.9 | 154.1 ± 146.7 | 127.7 ± 116.5 | 135.9 ± 98.4 | 200.1 ± 292.3 | 153.5 ± 138.8 | 164.9 ± 224.7  |
|  mean ± standard deviation |  |  |  |  |  |  |  |   |
|  Length of stay (days) | 2.4 ± 1.0 | 2.3 ± 1.6 | 2.6 ± 1.4 | 2.2 ± 1.3 | 2.0 ± 1.1 | 2.9 ± 1.5 | 2.2 ± 1.1 | 2.4 ± 1.4  |
|  mean ± standard deviation |  |  |  |  |  |  |  |   |

Table 16 provides an overview of the characteristics of activL devices implanted during the clinical trial. No subjects received the following  $11^{\text{st}}$  superior endplates: small spike, extra-large spike, or small keel. No subjects received the  $14\mathrm{mm}$  height inlay.

PMA P120024: FDA Summary of Safety and Effectiveness Data

{28}

Table 16: activL Implants Used

|  Size/Option | NR activL (N=46) | R activL (N=217)  |
| --- | --- | --- |
|  Endplate Design (n (%)) |  |   |
|  Spike | 21 (45.7%) | 115 (53.0%)  |
|  Keel | 25 (54.3%) | 102 (47.0%)  |
|  Superior Endplate Angle (n (%)) |  |   |
|  6° | 44 (95.7%) | 203 (93.5%)  |
|  11° | 2 (4.3%) | 14 (6.5%)  |
|  Inferior Endplate (n (%)) |  |   |
|  Small | 11 (23.91%) | 37 (17.05%)  |
|  Medium | 9 (19.57%) | 50 (23.04%)  |
|  Large | 13 (28.26%) | 48 (22.12%)  |
|  Extra-large | 1 (2.17%) | 8 (3.69%)  |
|  S1 | 12 (26.09%) | 74 (34.10%)  |
|  Superior Endplate (n (%)) |  |   |
|  Small | 14 (30.43%) | 59 (27.19%)  |
|  Medium | 12 (26.09%) | 77 (35.48%)  |
|  Large | 19 (41.30%) | 72 (33.18%)  |
|  Extra-large | 1 (2.17%) | 9 (4.15%)  |
|  Inlay Height (n (%)) |  |   |
|  8.5 mm | 40 (87.0%) | 189 (87.1%)  |
|  10 mm | 6 (13.0%) | 25 (11.5%)  |
|  12 mm | 0 | 3 (1.4%)  |
|  14 mm | 0 | 0  |
|  Endplate/Inlay Combinations (n (%)) |  |   |
|  Spike 6° Superior Endplate / 8.5 mm Inlay | 18 (39.1%) | 94 (43.3%)  |
|  Spike 6° Superior Endplate / 10 mm Inlay | 2 (4.3%) | 12 (5.5%)  |
|  Spike 6° Superior Endplate / 12 mm Inlay | 0 | 2 (0.9%)  |
|  Spike 6° Superior Endplate / 14 mm Inlay | 0 | 0  |
|  Spike 11° Superior Endplate / 8.5 mm Inlay | 1 (2.2%) | 7 (3.2%)  |
|  Spike 11° Superior Endplate / 10 mm Inlay | 0 | 0  |
|  Spike 11° Superior Endplate / 12 mm Inlay | 0 | 0  |
|  Spike 11° Superior Endplate / 14 mm Inlay | 0 | 0  |
|  Keel 6° Superior Endplate / 8.5 mm Inlay | 20 (43.5%) | 83 (38.2%)  |
|  Keel 6° Superior Endplate / 10 mm Inlay | 4 (8.7%) | 12 (5.5%)  |
|  Keel 6° Superior Endplate / 12 mm Inlay | 0 | 0  |
|  Keel 6° Superior Endplate / 14 mm Inlay | 0 | 0  |
|  Keel 11° Superior Endplate / 8.5 mm Inlay | 1 (2.2%) | 5 (2.3%)  |
|  Keel 11° Superior Endplate / 10 mm Inlay | 0 | 1 (0.5%)  |
|  Keel 11° Superior Endplate / 12 mm Inlay | 0 | 1 (0.5%)  |
|  Keel 11° Superior Endplate / 14 mm Inlay | 0 | 0  |

PMA P120024: FDA Summary of Safety and Effectiveness Data
Page 29 of 94

{29}

Adverse Events That Occurred in the PMA Clinical Trial:

# Adverse Event Summary

The CEC defined serious adverse events as events that met any of the following criteria:

- Potentially life-threatening or resulted in death;
- Required in-subject hospitalization (hospital stay &gt; 24 hours) or prolongation of hospitalization;
- Resulted in permanent impairment of body structure or a body function;
- Gave rise to a malignant tumor; or
- Led to a congenital anomaly in the offspring, or caused fetal distress or death.

In addition, the CEC defined device-related events as those with an etiology, temporal association, or cause related to the device. Procedure-related events were defined as those with an etiology, temporal association, or cause related to the surgical index procedure.

A summary of the adverse event data is presented in Table 17. The total number of adverse events, subsequent surgical interventions at the index level, adverse events classified by the CEC as device-related, procedure-related, serious, and serious device-related, as well as adverse events occurring within 2 days of the index procedure are shown for randomized subjects treated in the study as well as for non-randomized activL subjects. Although p-values were obtained without any adjustment for multiplicity, there were no statistically significant differences in all adverse events, subsequent surgical interventions at the index level, device-related adverse events, serious device-related adverse events, or adverse events within two days of the procedure when comparing the randomized treatment groups. Again, although p-values were obtained without any adjustment for multiplicity, there were statistically significant differences noted in procedure-related adverse events and serious adverse events in favor of the activL group when comparing the randomized treatment groups. The non-randomized control data is not included due to the limited sample size.

Table 17: Summary of Adverse Events

|  Adverse Event Category | NR activL (N=46) |   | R activL (N=218) |   | R Contr (N=106)  |   |
| --- | --- | --- | --- | --- | --- | --- |
|   |  Subjects n (%) | Events N | Subjects n (%) | Events N | Subjects n (%) | Events N  |
|  All Adverse Events | 40 (87.0%) | 145 | 186 (85.3%) | 701 | 95 (89.6%) | 366  |
|  Subsequent Surgical Interventions at the Index Level | 0 (0.0%) | 0 | 12 (5.5%) | 15 | 6 (5.7%) | 6  |
|  Device-Related Adverse Events | 30 (65.2%) | 45 | 134 (61.5%) | 217 | 69 (65.1%) | 114  |
|  Procedure-Related Adverse Events | 29 (63.0%) | 46 | 116 (53.2%) | 195 | 70 (66.0%) | 118  |
|  Serious Adverse Events | 18 (39.1%) | 21 | 72 (33.0%) | 121 | 51 (48.1%) | 68  |
|  Serious Device-Related Adverse Events | 6 (13.0%) | 6 | 28 (12.8%) | 31 | 20 (18.9%) | 20  |
|  Adverse Events within 2 days of Procedure | 7 (15.2%) | 8 | 39 (17.9%) | 49 | 23 (21.7%) | 33  |

Note: This table includes data collected beyond 24 months.

PMA P120024: FDA Summary of Safety and Effectiveness Data

{30}

Table 18 provides data on the total number of adverse events in each randomized treatment group stratified by device design and level treated for the randomized activL and control device and level treated for the randomized control group.

Table 18: Summary of Adverse Events - Stratified

|  Adverse Event (AE) Category | R activL (N=218) |   |   |   | R Contr (N=106)  |   |   |   |
| --- | --- | --- | --- | --- | --- | --- | --- | --- |
|   |  Device Design |   | Treatment Level |   | Control Device |   | Treatment Level  |   |
|   |  Spike (N=115) | Keel (N=102) | L4-L5 (N=62) | L5-S1 (N=156) | ProDisc-L (N=65) | Charité (N=41) | L4-L5 (N=34) | L5-S1 (N=72)  |
|  All AEs | 96 (83.5%) | 89 (87.3%) | 51 (82.3%) | 135 (86.5%) | 58 (90.6) | 36 (87.8%) | 34 (100%) | 61 (84.7%)  |
|  Subsequent Surgical Interventions at the Index Level | 3 (2.6%) | 0 (0.0%) | 1 (1.6%) | 2 (1.3%) | 1 (1.5%) | 0 (0.0%) | 0 (0.0%) | 1 (1.4%)  |
|  Device-Related AEs | 68 (59.1%) | 65 (63.7%) | 33 (53.2%) | 101 (64.7%) | 40 (62.5) | 29 (70.7%) | 23 (67.6%) | 46 (63.9%)  |
|  Procedure-Related AEs | 54 (47.0%) | 61 (59.8%) | 31 (50.0%) | 85 (54.5%) | 42 (65.6) | 27 (65.9%) | 22 (64.7%) | 48 (66.7%)  |
|  Serious AEs | 34 (29.6%) | 37 (36.3%) | 19 (30.6%) | 53 (34.0%) | 31 (48.4) | 19 (46.3%) | 16 (47.1%) | 35 (48.6%)  |
|  Serious Device-Related AEs | 16 (13.9%) | 15 (14.7%) | 10 (16.1%) | 21 (13.5%) | 10 (15.4%) | 10 (24.4%) | 7 (20.6%) | 13 (18.1%)  |

# All Adverse Events

The time course of adverse events reported in the PMA clinical trial from all 264 activL subjects (randomized and non-randomized) and 112 control subjects (randomized and non-randomized) are shown in Table 19. This table includes adverse events from all subjects, randomized and non-randomized, to establish the safety profile of the device. All investigational subjects (randomized and non-randomized) are summarized together in one group, and all control subjects (randomized and non-randomized) are summarized together in one group. 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 20. Subject adverse event rates are 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. Note that subjects with the same event reported within a window are counted once but may appear in multiple timepoints for the same event.

The percentage of subjects experiencing at least one adverse event is comparable in the "all activL" group and the "all Control" group. In the activL group, the most common reported adverse events were lower extremity pain, lumbar pain, and lumbar and lower extremity pain.

PMA P120024: FDA Summary of Safety and Effectiveness Data

{31}

Table 19: Time Course of All Adverse Events*

|  Adverse Event | Intra-Op** |   | Peri-Op (up to 6wks) |   | Short Term (>6wks-12mo) |   | Long Term (>12mo-24mo) |   | Longer Term (>24mo) |   | All activL (N=264) |   | All Contr (N=112)  |   |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
|   |  All activL | All Contr | All activL | All Contr | All activL | All Contr | All activL | All Contr | All activL | All Contr | Subjects n (%) | Events N | Subjects n (%) | Events N  |
|  Total Adverse Events | 69 | 46 | 178 | 77 | 303 | 150 | 145 | 52 | 151 | 73 | 226 (85.6%) | 846 | 100 (89.3%) | 398  |
|  Cancer | 0 | 0 | 0 | 0 | 2 | 0 | 1 | 2 | 0 | 1 | 3 (1.1%) | 3 | 3 (2.7%) | 3  |
|  Cardiac and Vascular Total | 14 | 4 | 3 | 1 | 7 | 3 | 5 | 2 | 9 | 2 | 27 (9.8%) | 38 | 12 (10.7%) | 12  |
|  Ble…

---

**Source:** [https://fda.innolitics.com/device/P120024](https://fda.innolitics.com/device/P120024)

**Published by [Innolitics](https://innolitics.com)** — a medical-device software consultancy. We help companies design, build, and clear FDA-regulated software and AI/ML devices. If you're preparing [a PMA](https://innolitics.com/services/regulatory/), [a 510(k)](https://innolitics.com/services/510ks/), [a SaMD](https://innolitics.com/services/end-to-end-samd/), [an AI/ML medical device](https://innolitics.com/services/medical-imaging-ai-development/), or [an FDA regulatory strategy](https://innolitics.com/services/regulatory/), [get in touch](https://innolitics.com/contact).

**Cite:** Innolitics at https://innolitics.com