SUPERION INTERSPINOUS SPACER

P140004 · Boston Scientific Neuromodulation · NQO · May 20, 2015 · Orthopedic

Device Facts

• Record ID: P140004
• Device Name: SUPERION INTERSPINOUS SPACER
• Applicant: Boston Scientific Neuromodulation
• Product Code: NQO · Orthopedic
• Decision Date: May 20, 2015
• Decision: APPR
• Device Class: Class 3
• Attributes: Therapeutic

Indications for Use

The Superion® InterSpinous Spacer (ISS) is indicated to treat skeletally mature patients suffering from pain, numbness, and/or cramping in the legs (neurogenic intermittent claudication) secondary to a diagnosis of moderate degenerative lumbar spinal stenosis, with or without Grade 1 spondylolisthesis, confirmed by X-ray, MRI and/or CT evidence of thickened ligamentum flavum, narrowed lateral recess, and/or central canal or foraminal narrowing. The Superion® ISS is indicated for those patients with impaired physical function who experience relief in flexion from symptoms of leg/buttock/groin pain, numbness, and/or cramping, with or without back pain, and who have undergone at least 6 months of non-operative treatment. The Superion® ISS may be implanted at one or two adjacent lumbar levels in patients in whom treatment is indicated at no more than two levels, from L1 to L5.

Device Story

Superion® ISS is a one-piece titanium alloy (Ti6Al-4V ELI) interspinous spacer implanted via minimally-invasive surgery to treat moderate lumbar spinal stenosis. The device features an internal actuation mechanism that deploys two cam lobes (wings) to encompass the lateral aspects of adjacent spinous processes, providing distraction and extension blockage. It is available in five sizes (8-16mm). The device is implanted by a surgeon; it functions by increasing canal and foraminal dimensions in extension and reducing ligamentum flavum thickness. The spacer remains in situ to provide segmental stability and relieve neurogenic claudication symptoms. Patients benefit from reduced leg/buttock/groin pain and improved physical function. The device is MR Conditional.

Clinical Evidence

Prospective, randomized, single-blinded, multi-center trial (IDE #G070118) with 391 subjects (190 Superion®, 201 X-STOP®). Primary endpoint: Composite Clinical Success (CCS) at 24 months. Superion® success rate 52.7% vs. 50.2% for control (mITT). Non-inferiority established (posterior probability 0.9927). Secondary endpoints (ODI, VAS, SF-12) showed comparable improvements in pain and function. Spinous process fractures were more frequent in the Superion® group (16.3% vs 8.5%), but were largely asymptomatic and did not impact clinical success at 24 months.

Technological Characteristics

One-piece implant composed of titanium alloy (Ti6Al-4V ELI, ASTM F136). Features internal actuation mechanism with two deployable cam lobes. Available in 8-16mm sizes. MR Conditional (1.5T/3.0T). Sterilized via gamma irradiation (25 kGy). Mechanical performance validated per ASTM F1717 (static/dynamic axial compression and torsion).

Indications for Use

Indicated for skeletally mature patients (≥45 years) with moderate degenerative lumbar spinal stenosis (L1-L5, 1-2 levels) and Grade 1 or no spondylolisthesis. Patients must have neurogenic intermittent claudication, impaired physical function (ZCQ score ≥2.0), and symptoms relieved by flexion. Must have failed ≥6 months of non-operative treatment. Contraindicated in patients with severe osteoporosis, spinal instability, scoliosis >10°, active infection, or allergy to titanium.

Regulatory Classification

Identification

This device is an interspinous spacer or spinous process plate that is implanted between the spinous processes or attached to the spinous process.

Predicate Devices

• X-STOP® IPD®

Submission Summary (Full Text)

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SUMMARY OF SAFETY & EFFECTIVENESS DATA (SSED)

I. GENERAL INFORMATION

Device Generic Name: Prosthesis, Spinous Process Spacer/Plate

Device Trade Name: Superion® InterSpinous Spacer (ISS)

Device Product Code: NQO

Applicant's Name and Address: VertiFlex®, Incorporated
1351 Calle Avanzado, Suite 100
San Clemente, CA 92673

Date(s) of Panel Recommendation: February 20, 2015

Premarket Approval Application (PMA) Number: P140004

Date of FDA Notice of Approval: May 20, 2015

II. INDICATIONS FOR USE

The Superion® InterSpinous Spacer (ISS) is indicated to treat skeletally mature patients suffering from pain, numbness, and/or cramping in the legs (neurogenic intermittent claudication) secondary to a diagnosis of moderate degenerative lumbar spinal stenosis, with or without Grade 1 spondylolisthesis, confirmed by X-ray, MRI and/or CT evidence of thickened ligamentum flavum, narrowed lateral recess, and/or central canal or foraminal narrowing. The Superion® ISS is indicated for those patients with impaired physical function who experience relief in flexion from symptoms of leg/buttock/groin pain, numbness, and/or cramping, with or without back pain, and who have undergone at least 6 months of non-operative treatment. The Superion® ISS may be implanted at one or two adjacent lumbar levels in patients in whom treatment is indicated at no more than two levels, from L1 to L5.

For this intended use, moderate degenerative lumbar spinal stenosis was defined as follows:

- 25% to 50% reduction in the central canal and/or nerve root canal (subarticular, neuroforaminal) compared to the adjacent levels on radiographic studies, with radiographic confirmation of any one of the following:

- Evidence of thecal sac and/or cauda equina compression
- Evidence of nerve root impingement (displacement or compression) by either osseous or non-osseous elements
- Evidence of hypertrophic facets with canal encroachment

- AND associated with the following clinical signs:

- Presents with moderately impaired Physical Function (PF) defined as a score of ≥ 2.0 of the Zurich Claudication Questionnaire (ZCQ)
- Ability to sit for 50 minutes without pain and to walk 50 feet or more.

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III. CONTRAINDICATIONS

The Superion® ISS is contraindicated in patients with:

- an allergy to titanium or titanium alloy;
- spinal anatomy or disease that would prevent implantation of the device or cause the device to be unstable in situ, such as:
- instability of the lumbar spine, e.g., isthmic spondylolisthesis or degenerative spondylolisthesis greater than grade 1 (on a scale of 1 to 4);
- an ankylosed segment at the affected level(s);
- fracture of the spinous process, pars interarticularis, or laminae (unilateral or bilateral);
- scoliosis (Cobb angle >10 degrees);
- Cauda equina syndrome defined as neural compression causing neurogenic bladder or bowel dysfunction;
- diagnosis of severe osteoporosis, defined as bone mineral density (from DEXA scan or equivalent method) in the spine or hip that is more than 2.5 S.D. below the mean of adult normals;
- active systemic infection, or infection localized to the site of implantation;
- prior fusion or decompression procedure at the index level;
- morbid obesity defined as a body mass index (BMI) greater than 40.

IV. WARNINGS AND PRECAUTIONS

The warnings and precautions can be found in the Superion® ISS labeling.

V. DEVICE DESCRIPTION

The Superion® ISS is a one-piece implant that requires no assembly in situ. It consists of an implant body, within which resides the actuation mechanism, and two Cam Lobes, or "wings" which – when deployed – rotate away from the axis of the implant body to encompass the lateral aspects of the superior and inferior spinous processes (see Figure 1).

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Figure 1: Superion® device in spine model

The Superion® ISS is composed entirely of titanium alloy (Ti6Al-4V ELI conforming to ASTM F136). The Superion® ISS is intended to be implanted via minimally-invasive surgical methods using a set of proprietary accessory instruments provided by VertiFlex® expressly for use with the Superion® ISS device. Together, the implants and manual instruments form a complete system for implantation of the Superion® ISS.

To accommodate variations in patient anatomy, Superion® ISS implants are available in five (5) sizes, ranging from 8mm to 16mm in 2mm increments, each of which is color-coded and laser-etched to indicate implant size. The size selection determines the amount of "spacing" between the two adjacent spinous processes. Implant size is determined by the distance between the bottom of the "saddle" of each of the Cam Lobes, which represents the point at which the adjacent spinous processes would rest within a deployed implant.

# VI. ALTERNATIVE PRACTICES AND PROCEDURES

Non-surgical alternatives include non-steroidal anti-inflammatory drugs (NSAIDs), analgesics, oral and epidural steroids, rest, exercise, physical therapy, and bracing. Surgical alternatives to the Superion® ISS vary, depending upon the severity of the stenosis, the contribution of back pain, and the presence of instability, among other factors, and can include various direct decompressive procedures (e.g. laminectomy, laminotomy, hemilaminotomy, foraminotomy, etc.), other FDA-approved interspinous distraction devices, direct decompression with non-fusion posterior stabilization devices, and decompression with posterolateral fusion with pedicle screw instrumentation. Each alternative has its own advantages and disadvantages. A patient should discuss these alternatives with his or her physician to select the option that best meets their clinical condition, lifestyle and expectations.

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# VII. MARKETING HISTORY

The Superion® ISS has been marketed outside of the United States since 2007, and has not been withdrawn from marketing for any reason. The Superion® ISS is marketed in: Germany, Israel, Italy, Mexico, Netherlands, South Africa, Spain and the United Kingdom.

# VIII. POTENTIAL ADVERSE EFFECTS OF THE DEVICE ON HEALTH

Below is a list of potential adverse effects (e.g., complications) associated with use of the Superion® ISS. This listing was derived from results of the Superion® ISS clinical trial conducted under Investigational Device Exemption (IDE) #G070118, approved device labeling for other interspinous devices, and published clinical literature. It includes (1) those adverse effects potentially associated with any surgical procedure; (2) those potentially associated with lumbar spine surgery; (3) those potentially associated with lumbar spinal implants, and in particular with interspinous process implants; and (4) those potentially associated with the Superion® ISS in particular. In some instances, additional surgery may be required to correct adverse effects.

1. Risks associated with any surgical procedure include: anesthetic medication reactions; blood loss, blood vessel damage, phlebitis or hematoma; blood transfusion which may cause circulatory collapse, blood incompatibility, kidney damage, hepatitis or infection with HIV; myocardial infarction or circulatory problems; deep vein thrombosis, pulmonary embolism or thrombus formation in other vessels; stroke; fever or infection; pneumonia; injury to muscle, soft tissue or nerves; wound swelling, drainage or delayed healing; discomfort and rehabilitation associated with recovery from surgery; inability to perform certain tasks, such as lifting or exercise; and death.

2. Risks associated with lumbar spine surgery include: damage to nerve roots or the spinal cord causing partial or complete sensory or motor loss (paralysis); loss of bladder and/or bowel functions; dural leaks (tears in the tissue surrounding and protecting the spinal cord); instruments used during surgery may break or malfunction which may cause damage to the operative site or adjacent structures; fracture, damage or remodeling of adjacent anatomy, including bony structures or soft tissues during or after surgery; new or worsened back or leg pain; and surgery at the incorrect location or level.

3. Risks associated with lumbar spine implants and associated instruments include: sensitivity or allergy to the implant material; failure of the device/procedure to improve symptoms and/or function; pain and discomfort associated with the operative site or presence of implants; implant malposition or incorrect orientation; spinous process fracture; production of wear debris which may damage surrounding soft tissues including muscle or nerve; formation of scar tissue at implant site; migration or dislodgement of the implant from the original position so that it becomes ineffective or causes damage to adjacent bone or soft tissues including nerves; loosening, fatigue, deformation, breakage or disassembly of the implant, which may require another operation to remove the implant and may require another method treatment.

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4. Risks specifically associated with the Superion® ISS include deformation, breakage or disassembly of the implant, and spinous process fracture.

For the specific adverse events that occurred in the clinical study of the Superion® ISS, please see Section X below.

## IX. SUMMARY OF PRECLINICAL STUDIES

A variety of non-clinical tests were conducted to characterize the performance of the Superion® ISS. These tests as are listed below and summarized in Table 1 and Table 2:

### A. Laboratory Studies

- Static Axial Compression
- Static Torsion
- Dynamic Axial Compression
- Dynamic Torsion
- Implant Deployment Under Load
- Static Torsion After Repeated Deployment Under Load
- Quantification and Characterization of Wear Debris
- Kinematic and Kinetic Behavior in Human Cadaver Spines
- Role of Supraspinous Ligament in Biomechanical Stability
- Effects of Implant on Canal and Foraminal Dimensions

### B. Additional Studies

- Sterilization, Shelf-Life and Packaging
- Biocompatibility
- MRI Compatibility

### A. Laboratory Studies

Table 1: Laboratory Studies on Superion® ISS

| Test | Purpose | Method | Acceptance Criteria | Results |
| --- | --- | --- | --- | --- |
| Static Axial Compression | To evaluate the performance of the Superion® ISS under static axial compressive loading, under worst-case conditions. | Six (6) samples of the largest (16mm) and smallest (8mm) implant were tested in accordance with methods specified by ASTM F1717 | Maximum compressive strength must exceed maximum expected in vivo spinous process failure load (320N).^{1} | Mean yield load was >8,900 N (8mm) and >8,100 N (16mm). These results suggest that the device can resist compressive loads that exceed the anticipated physiologic failure load (320N) in the lumbar spine. |

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Table 1: Laboratory Studies on Superion ${}^{ \oplus }$ ISS

| Test | Purpose | Method | Acceptance Criteria | Results |
| --- | --- | --- | --- | --- |
| Static Torsion Testing | To evaluate the performance of the Superion® ISS under static torsional loading, under worst-case conditions. | Six (6) samples of the largest (16mm) and smallest (8mm) implant were tested in accordance with methods specified by ASTM F1717 | Maximum torsional strength must exceed maximum expected in vivo spinous process failure load (320N).1 | Mean yield torque was >30.6 N-m (8mm) and >15 N-m (16mm). These results suggest that the device can resist torsional loads that exceed the anticipated physiologic failure load (320N) in the lumbar spine. |
| Dynamic Axial Compression | To evaluate the performance of the Superion® ISS under dynamic axial compressive loading, under worst-case conditions. | Six (6) samples of the largest (16mm) and smallest (8mm) implant were tested in accordance with methods specified by ASTM F1717 | Maximum dynamic runout load to 10 million cycles must exceed maximum expected in vivo spinous process failure load (320N).1 | Dynamic runout load to 10 million cycles for both 8mm and 16mm implant sizes was 1,750 N. These results suggest that the device can resist dynamic compressive loads that exceed the anticipated physiologic failure load (320N) in the lumbar spine. |
| Dynamic Torsion | To evaluate the performance of the Superion® ISS under dynamic torsional loading, under worst-case conditions. | Six (6) samples of the largest (16mm) and smallest (8mm) implant were tested in accordance with methods specified by ASTM F1717 | Maximum dynamic runout torsion to 10 million cycles must exceed maximum expected in vivo spinous process failure load (320N).1 | Dynamic runout load to 10 million cycles was ±2.5 N-m (8mm) and ±3 N-m (16mm). These results suggest that the device can resist dynamic torsional loads that exceed the anticipated physiologic failure load (320N) in the lumbar spine. |
| Implant Deployment Under Load | To evaluate the ability of the Superion® ISS to be deployed under axial load | Five (5) implants were deployed under constant resisting axial loads of 250, 300, and 350 N. | Implants must deploy without damage or functional failure under axial load exceeding failure strength of the spinous processes (320N).1 | All implants deployed without failure under axial loads of 250, 300, and 350 N. These results suggest that the device can adequately deploy in the presence of loads that exceed the strength of the spinous processes and anticipated physiologic loads in the lumbar spine. |

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Table 1: Laboratory Studies on Superion ${}^{ \oplus }$ ISS

| Test | Purpose | Method | Acceptance Criteria | Results |
| --- | --- | --- | --- | --- |
| Static Torsion Testing After Repeated Deployment Under Load | To evaluate the torsional strength of the Superion® ISS after repeated deployment under resisting axial load. | Five (5) 16mm implants were deployed five (5) times each under constant resisting axial load of 300 N, and tested in accordance with methods specified by ASTM F1717 | Maximum torsional strength must not be adversely affected by loaded deployment. Test is for characterization only; no acceptance criteria were identified. | Mean yield torque was 18 N-m. These results suggest that the device is not adversely affected after repeated deployment. |
| Quantification and Characterization of Wear Debris | To quantify and characterize any wear debris generated from the Superion® ISS during dynamic axial compression testing. | Wear debris generated from 10 million cycle runout samples of size 8mm and size 16mm implants was quantified and characterized in accordance with ASTM F1714. | Types and total volumetric amounts of wear debris must be of a type and amount similar to other legally marketed spinal devices (10 - 12mg). | Total titanium debris amounted to 0.022 mg (8mm) and 0.017 mg (16mm), well below 10-12mg deemed acceptable in scientific literature, and also lower than wear debris volumes seen in previously cleared/approved spinal devices. |
| Kinematic and Kinetic Behavior in Human Cadaver Spines | Kinematic and kinetic behavior of the Superion® ISS, including range of motion and intradiscal pressures, were characterized in human lumbar spine specimens. | Six (6) lumbar spine specimens (L1 to S1) were tested. The S1 segment was fixed, and a follower load was used to apply compressive preloads up to 400N at the L1 segment. Spine specimens were preconditioned by cycling in each plane (flexion, extension, lateral bending, and rotation) to a maximum bending moment of 7.5N. Implants (undersized, nominal, and oversized) were placed at 1 and 2 levels. Motion of the L1, L2, L3, L4, and L5 vertebrae were then measured, relative to the sacrum, using an optoelectronic motion measurement system, and intradiscal pressures were measured by transducers placed at the implanted and adjacent levels. | Demonstration of normal flexion, rotational, and lateral bending ranges of motion, and restriction of extension. This test was used to generate benchmark physiologic data and there was no acceptance criteria identified. | Angular displacement was reduced in extension in all configurations, with little or no impact upon rotation or lateral bending. These results suggest that the device has no detrimental impact to the kinematics of the functional spinal unit(s). |

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Table 1: Laboratory Studies on Superion ${}^{ \circ }$ ISS

| Test | Purpose | Method | Acceptance Criteria | Results |
| --- | --- | --- | --- | --- |
| Role of Supraspinous Ligament in Biomechanical Stability | To determine if unintended disruption of the supraspinous ligament (SSL) impacts segmental stability after placement of the Superion® ISS. | Three (3) lumbar spine specimens (L1 to S1) were dissected into three (3) L2-L3 motion segments and three (3) L4-L5 segments. The caudal vertebral body of each was fixed in a kinematic profile apparatus, and the cephalad body was left free to move. A 400N preload was applied, and segments were tested intact, with the SSL dilated and a spacer placed, with the SSL 50% transected and a spacer placed, with the SSL 100% transected but with no spacer placed. Segments were tested to a maximum bending moment of 10N-m in flexion, extension, rotation, and lateral bending. In each test case, motion of the segment was measured, relative to the fixed body, using an optoelectronic motion measurement system. | The Superion® implant must provide segmental stability to a segment having a disrupted SSL equal to or greater than that of an intact segment. This test was used to generate benchmark bending moment data and there was no acceptance criteria identified. | Bending moments of all implanted specimens were 100% to 135% greater in extension than for an intact specimen, and 60% to 75% greater in flexion. There was no difference in bending moments between the 50% or 100% transected SSL segments, and the intact SSL segments. |
| Effects of Implant on Canal and Foraminal Dimensions | To quantify the effects of spacer implantation upon canal and foraminal dimensions. | Seven (7) human cadaveric lumbar spine segments were dissected into individual motion segments, seven (7) each of L2-L3 and L4-L5 segments. Each was placed in a frame, with the caudal end fixed, and the cephalad end free to move, to a maximum of 10° flexion and 5° extension. Using CT imaging, key dimensions were measured in neutral, flexion and extension, including canal area, subarticular diameter, ligamentum flavum thickness, and foraminal height, width, and area. Measurements were acquired on the intact specimens, on the same specimens after implantation of a spacer, and on the implanted specimens after 60,000 cycles of coupled 15° flexion-extension under 400N axial preload. | To establish that placement of a Superion® spacer increases canal and foraminal dimensions in extension, and reduces ligamentum flavum thickness. This test was used to generate benchmark characterization data and there was no acceptance criteria identified. | These results confirmed that central canal area and foraminal dimensions increased in extension, with little change in neutral or flexion. Ligamentum flavum thickness decreased in extension, neutral and flexion. |

1White A., Panjabi, M., Clinical Biomechanics of the Spine, J.B. Lippincott, Philadelphia. $2^{\mathrm{nd}}$ Edition.

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# B. Additional Studies

Table 2: Additional Studies on Superion® ISS

| Test | Method and Results |
| --- | --- |
| Sterilization, Shelf-Life and Packaging | The Superion® ISS is provided in a sterile package ready for use. The Superion® ISS is sterilized using a gamma irradiation dose of 25 kGy to substantiate a sterility assurance level (SAL) of 10-6. Sterilization validation according to ISO 11137, Sterilization of Health Care Products, Parts 1 and 2 was conducted to confirm that the sterility of the implant is achieved, and is maintained by a sterile barrier package. Sterilization validation according to ISO 11137, Sterilization of Health Care Products, Part 1 was conducted to confirm that the recommended sterilization cycle provides sterility of the manual instruments. 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 Superion® ISS is manufactured from titanium alloy (Ti-6Al-4V ELI) conforming to ASTM F136. This material has a long history of use in medical implants with no significant biocompatibility issues, as shown in the literature. |
| MRI Compatibility | Non-clinical testing has demonstrated that the Superion® ISS is MR Conditional. The preclinical tests included assessments of magnetic field interaction (translational attraction, migration, and torque), radiofrequency heating, and artifact measurements. All tests conducted were for characterization and labeling purposes and acceptance criteria were not established. The Superion® ISS can be scanned safely at 1.5T or 3.0T under conditions which are identified in the device labeling. |

# X. SUMMARY OF CLINICAL STUDY

The applicant performed a clinical study to determine a reasonable assurance of safety and effectiveness of the Superion® ISS for the treatment of moderate degenerative lumbar spinal stenosis in the US under IDE #G070118. Data from this clinical study were the basis of the PMA approval decision. A summary of the clinical study is presented below.

# A. Study Design

Patients were treated between June 2008 and December 2011. The database for this PMA reflected data collected through July 7, 2014 and included 470 patients. There were 31 investigational sites.

The study was a prospective, multi-center, single-blinded, randomized controlled clinical trial comparing the Superion® ISS to a control group consisting of the X-STOP® IPD®, a legally marketed alternative with similar indications for use. The study evaluated use of the Superion® ISS in the treatment of subjects aged 45 or older suffering from moderate symptoms of neurogenic intermittent claudication, secondary to a confirmed diagnosis of moderate degenerative lumbar spinal stenosis (LSS) at one or two contiguous levels from L1 to L5, i.e., from the L1-L2 level to the L4-L5 level. A maximum of 35 investigative sites in the U.S. and up to 10 sites outside the U.S. were approved to enroll subjects into the trial using a 1:1 randomization assignment and an adaptively selected sample size ranging from 250 to 350 subjects (125-175 enrolled into each group) using a Bayesian adaptive

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design. Up to an additional 50 subjects (25 per group) could be enrolled to allow for loss to follow-up. In addition, prior to initiating the randomized trial, clinical sites were permitted to enroll up to 2 non-randomized subjects to receive the Superior® ISS. A maximum of 70 such additional Superior® ISS "training" cases were built into the protocol. Thus, a maximum of 470 subjects were approved to be enrolled into the study. If the study requirements outlined in the Statistical Analysis Plan were met prior to enrolling 470 subjects, the study enrollment could be stopped and the PMA application could subsequently be submitted early. An investigative site was defined as a facility or facilities in the same general geographic location if they are under the control of a local Institutional Review Board (IRB).

All adverse events (device-related or not) were monitored over the course of the study and radiographic assessments were reviewed by an independent core laboratory. Overall success was determined by data collected during the initial 24 months of follow-up. All device-related adverse events, major procedure-related, and adjacent-level-related adverse events and therapeutic failures reported by the clinical investigators were independently adjudicated (for adverse event code, severity and relationship to the device and/or procedure) by a Clinical Events Committee (CEC) composed of three independent spine surgeons. In addition, adverse events reported as having unknown or undetermined relationships to the device by the clinical investigators were to be adjudicated by the CEC.

After implantation of the Superior® ISS or the X-STOP® IPD® device, each investigator provided a postoperative care regimen individualized to the specific needs of each subject. The regimen included but was not limited to: medications, a corset or brace, acupuncture, traction, physical therapy, chiropractic treatment, use of a TENS unit, and massage therapy.

Subjects were required to complete a VAS questionnaire to evaluate pain status at discharge following the index procedure. At each follow-up visit, subjects were interviewed to determine if they had experienced adverse events (AEs) since the previous follow-up visit. A neurological assessment was performed for all subjects at baseline and at all follow-up visits. All subjects were required to complete the Zurich Claudication Questionnaire (ZCQ), Oswestry Disability Index (ODI), Visual Analog Scale (VAS), SF-12 and the VertiFlex Superior® Patient Satisfaction questionnaires to evaluate disability, function, pain, quality of life, and satisfaction at each follow-up visit.

This clinical study was designed as a Bayesian adaptive trial with a minimum of 250 evaluable subjects and a maximum of 350 evaluable subjects, with an additional adjustment for loss-to-follow-up of 15%. The final sample size in the randomized mITT population consisted of 190 Superior® ISS and 201 X-STOP® IPD® control subjects (391 total subjects). The primary hypothesis of this randomized controlled trial was that the clinical performance of the Superior® ISS is non-inferior to the clinical performance achieved with the active control. The study endpoint was the rate of overall subject success at 24 months. A subject was considered a success if they were a success on each of the four individual primary outcome criteria. The hypotheses tested for this primary study endpoint are as follows: H₀: Superior® ISS overall success rate is inferior (Superion® ISS rate – Control rate < -Δ); Hₐ: Superior® ISS overall success rate is non-inferior (Superion® ISS rate – Control rate ≥ -Δ).

A Bayesian approach was used to test for non-inferiority. If the posterior probability of the alternative hypothesis was at least 95.8%, using non-informative uniform (Beta[1,1]) priors for each success rate then the claim of non-inferiority would be made. The choice of non-inferiority margin, Δ (i.e., delta)

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was 10% for the overall subject success rate. The value of 0.958 was selected to control the type I error of this design (type 1 error less than 0.05).

An adaptive sample size approach was used to allow for modifications based on interim results, with a maximum of 350 evaluable subjects and a minimum of 250 subjects. The operating characteristics of the adaptive design demonstrate 86.3% power when the Superior® ISS group was superior to the X-STOP® IPD® control group by 5% and 73.6% power when the advantage is 2.5%. In these calculations, the X-STOP® IPD® was assumed to have a 65% success rate.

## 1. Clinical Inclusion and Exclusion Criteria

Enrollment in the Superior® ISS study was limited to subjects who met the following inclusion criteria:

1. Male or female subjects ≥ 45 years of age.
2. Persistent leg/buttock/groin pain, with or without back pain, that is relieved by flexion activities (example: sitting or bending over a shopping cart)
3. Subjects who have been symptomatic and undergoing conservative care treatment for at least 6 months.
4. Diagnosis of degenerative spinal stenosis of the lumbar spine, defined as the narrowing of the midline sagittal spinal canal (central) and/or narrowing between the facet superior articulating process (SAP), the posterior vertebral margin (lateral recess), and the nerve root canal (foraminal).
5. Radiographic confirmation of at least moderate spinal stenosis which narrows the central, lateral, or foraminal spinal canal at one or two contiguous levels from L1-L5. Moderate spinal stenosis is defined as 25% to 50% reduction in lateral/central foramen compared to the adjacent levels, with radiographic confirmation of any one of the following:
a. Evidence of thecal sac and/or cauda equina compression
b. Evidence of nerve root impingement (displacement or compression) by either osseous or non-osseous elements
c. Evidence of hypertrophic facets with canal encroachment

Note: All imaging studies used to confirm LSS were completed within 3 months prior to enrollment. Radiographic (imaging) confirmation of LSS included MRI and/or CT. In the case of a transitional L5/L6 segment with a sufficiently prominent L6 spinous process, these subjects were included by a deviation request from the applicant.

6. Must present with moderately impaired Physical Function (PF) defined as a score of ≥ 2.0 of the Zurich Claudication Questionnaire (ZCQ)
7. Must be able to sit for 50 minutes without pain and to walk 50 feet or more
8. Subjects who are able to give voluntary, written informed consent to participate in this clinical investigation and from whom consent has been obtained
9. Subjects, who, in the opinion of the Clinical Investigator, are able to understand this clinical investigation, cooperate with the investigational procedures and are willing to return for all the required post-treatment follow-ups.

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Subjects were not permitted to enroll in the Superior® ISS study if they met any of the following exclusion criteria:

1. Axial back pain only
2. Fixed motor deficit
3. Diagnosis of lumbar spinal stenosis which requires any direct neural decompression or surgical intervention other than those required to implant the control or investigational device
4. Unremitting pain in any spinal position
5. Significant peripheral neuropathy or acute denervation secondary to radiculopathy
6. Lumbar spinal stenosis at more than two levels determined pre-operatively to require surgical intervention
7. Significant instability of the lumbar spine as defined by ≥ 3 mm translation or ≥ 5° angulation
8. Sustained pathologic fractures of the vertebrae or multiple fractures of the vertebrae and/or hips
9. Spondylolisthesis or degenerative spondylolisthesis greater than grade 1 (on a scale of 1-4)
10. Spondylolysis (pars fracture)
11. Degenerative lumbar scoliosis with a Cobb angle of > 10° at treatment level
12. Osteopenia or osteoporosis. To confirm eligibility, at the Clinical Investigator’s discretion, the following subjects may have a DEXA scan performed:
- Women 65 or older
- Postmenopausal women < age 65
- Subjects with major risk factors for or diagnosed with osteoporosis or osteopenia
i. If DEXA is required, exclusion is defined as a DEXA bone density measurement T score ≤ -2.5
13. Morbid obesity, defined as Body Mass Index (BMI) greater than 40 kg/m²
14. Insulin-dependent diabetes mellitus
15. Significant peripheral vascular disease (diminished dorsalis pedis or tibial pulses)
16. Prior surgery of the lumbar spine
17. Cauda equina syndrome (defined as neural compression causing neurogenic bowel or bladder dysfunction)
18. Infection in the disc or spine, past or present
19. Evidence of active (systemic or local) infection at time of surgery
20. Active systemic disease such as AIDS, HIV, hepatitis, etc.
21. Paget’s disease at involved segment or metastasis to the vertebra, osteomalacia, or other metabolic bone disease
22. Currently undergoing immunosuppressive therapy or long-term steroid use
23. Known allergy to titanium or titanium alloys
24. Tumor in the spine or a malignant tumor except for basal cell carcinoma
25. Known or suspected history of alcohol and/or drug abuse
26. Prisoner or transient
27. Life expectancy less than two years
28. Angina, active rheumatoid arthritis, or any other systemic disease that would affect the subject’s welfare or outcome of the clinical investigation
29. Any significant mental illness (e.g., major depression, schizophrenia, bipolar disorder, etc.) that could impair the consent process or ability to complete subject self-report questionnaires
30. Involved in pending litigation of the spine or worker’s compensation related to the back

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31. Enrolled in the treatment phase of another drug or device clinical investigation (currently or within past 30 days)
32. Congenital defect of the spine
33. Pregnant or lactating

## 2. Follow-Up Schedule

All subjects were scheduled to return for follow-up examinations at 6 weeks (± 2 weeks), 3 months (± 2 weeks), 6 months (± 1 month), 12 months (± 2 months), 18 months (± 2 months), 24 months (± 2 months) post-treatment and annually thereafter to collect data for the primary evaluation of safety and effectiveness.

The evaluations performed in relation to the index procedure pre-operatively, as well as the assessments performed which were used to assess the endpoints post-operatively, are shown in Table 3. Adverse events were recorded at all visits.

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Table 3: Follow-Up Visit Schedule

| | Screening-Baseline | Surgical Treatment | Discharge (±0-7 days) | 6-week (±2 weeks) | 3-month (±2 weeks) | 6-month (±1 month) | 12-month (±2 months) | 18-month (±2 months) | 24-month^{c} (±2 months) |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| Study Visit Window | | Day 0 | 0-7 days | 4-8 weeks | 10-14 weeks | 5-7 months | 10-14 months | 16-20 months | 22-26 months |
| Signed Informed Consent | X | | | | | | | | |
| Demographic Information | X | | | | | | | | |
| Complete History & Physical | X | | | | | | | | |
| Randomization | X | | | | | | | | |
| Standing AP & Lateral Lumbar Spine X-rays | X^{a} | | X | X | X | X | X | X | X |
| Flexion / Extension Lateral Lumbar Spine X-rays | X^{a} | | | X | X | X | X | X | X |
| Lumbar Spine MRI/CT Scan | X^{a} | | | | | | | | |
| DEXA Scan^{b} | As needed | | | | | | | | |
| SF-12 –Health Survey (v2) | X | | | X | X | X | X | X | X |
| Zurich Claudication Questionnaire (ZCQ) | X | | | X | X | X | X | X | X |
| Oswestry Disability Index (v2) | X | | | X | X | X | X | X | X |
| Neurological Status | X | | X | X | X | X | X | X | X |
| Visual Analogue Scale | X | | X | X | X | X | X | X | X |
| VertiFlex® Patient Satisfaction Questionnaire | | | | X | X | X | X | X | X |
| Assess Adverse Events | | X | X | X | X | X | X | X | X |

aLumbar spine x-rays and MRI/CT taken within 3 months of enrollment can be used to confirm eligibility.
bIn order to confirm eligibility, at the Investigator’s discretion, subjects previously diagnosed with osteoporosis, osteopenia, osteomalacia, female subjects over the age of 65, and post-menopausal female subjects under the age of 65 with any of the risk factors for osteoporosis, will have DEXA scans performed prior to study entry.
cSubjects may be required to return for additional follow-up visits annually (±2 months) for up to ten (10) years, or until Applicant notifies Investigator of study conclusion at an earlier time.

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# 3. Clinical Endpoints

The effectiveness of the Superion® ISS was assessed using a composite definition of study success as compared to the X-STOP® IPD® control group.

The safety of the Superion® ISS was assessed by comparison to the X-STOP® IPD® control group with respect to the nature and frequency of adverse events (overall and in terms of seriousness and relationship to the implant), secondary surgical procedures as well as maintenance or improvement in neurological status.

The primary endpoint of the investigation was individual patient success, which required the patient to meet all of the following criteria at 24 months:

- Clinically significant improvement in outcomes compared to baseline, as determined by meeting the criterion for at least two of three domains of ZCQ
- ≥ 0.5 point improvement in physical function
- ≥ 0.5 point improvement in symptom severity
- score of ≤ 2.5 points on patient satisfaction domain

- No reoperations, removals, revisions, or supplemental fixation at the index level(s)

- No major implant or procedure-related complications
- no dislodgement, migration, or deformation
- no new or persistent worsened neurological deficit at the index level
- no spinous process fractures
- no deep infection, death, or other permanent device attributed disability

- No clinically significant confounding treatments:
- no epidural injections, nerve block procedures at index level, spinal cord stimulators or rhizotomies

# B. Accountability of PMA Cohort

At the time of database lock (July 7, 2014), of 391 per protocol patients (190 Superion® ISS and 201 X-STOP® IPD®) enrolled in the PMA study. Overall, 94.6% (183 Superion® ISS and 187 X-STOP® IPD®) of patients enrolled in the study were available for analysis at the study completion (24-month post-operative visit). The Superion® ISS cohort had a follow-up rate of 97.3% and the X-STOP® IPD® cohort had a follow-up rate of 94.9% through 24 months.

The primary analysis cohort for this study was the Modified Intent-to-Treat Cohort, defined as:

Modified Intent-to-treat patient population (mITT): The mITT patient population will include all patients randomized and having an anesthesia start time, where patients will be classified by the group in which they are randomized. Subjects with an anesthesia start time, but that do not receive a device, or receive the wrong device, will be failures.

Confirmatory analysis was performed in the Per Protocol Cohort, defined as:

Per protocol (PP) Population: The PP patient population will include all subjects with 24-month follow-up data and no major protocol deviations and subjects that failed before 24 months.

Patient accounting and follow-up (Table 4), a patient accounting tree (Figure 2), and a summary of patient and data accounting at 24 months (Table 5) are provided below.

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Table 4: Patient Accounting and Follow-up Compliance Table for Superion® ISS and X-STOP® IPD® mITT Analysis Sets

| Date of data transfer 07/07/2014 | Pre-op | | Week 6 | | Month 3 | | Month 6 | | Month 12 | | Month 18 | | Month 24 | |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| | I¹ | C² | I | C | I | C | I | C | I | C | I | C | I | C |
| (1) Theoretical follow-up | 190 | 201 | 190 | 201 | 190 | 201 | 190 | 201 | 190 | 201 | 190 | 201 | 190 | 201 |
| (2) Cumulative deaths | 0 | 0 | 0 | 0 | 1 | 0 | 1 | 0 | 2 | 2 | 2 | 3 | 2 | 5 |
| (3) Cumulative Revisions, Reoperations, and Injections | 0 | 0 | 3 | 3 | 8 | 11 | 20 | 19 | 40 | 32 | 46 | 48 | 51 | 53 |
| (4) Not Yet Overdue | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| (5) Deaths + term failures among theoretical due | 0 | 0 | 3 | 3 | 9 | 11 | 21 | 19 | 42 | 34 | 48 | 51 | 53 | 57 |
| (6) Expected due for clinical visit | 190 | 201 | 187 | 198 | 181 | 190 | 169 | 182 | 148 | 167 | 142 | 150 | 137 | 144 |
| (7) Failures among theoretical due | 0 | 0 | 3 | 3 | 8 | 11 | 20 | 19 | 40 | 32 | 46 | 48 | 51 | 53 |
| (8) Expected due + failures among theoretical due | 190 | 201 | 190 | 201 | 189 | 201 | 189 | 201 | 188 | 199 | 188 | 198 | 188 | 197 |
| All Evaluated Accounting (Actual) Among Expected Due Procedures | | | | | | | | | | | | | | |
| (9) # of procedures with any clinical data in interval | 190 | 201 | 182 | 193 | 171 | 182 | 164 | 177 | 145 | 162 | 132 | 137 | 131 | 133 |
| (10) All Evaluated Visit Compliance (%) | 100% | 100% | 97.3% | 97.0% | 94.5% | 95.8% | 97.0% | 97.3% | 98.0% | 97.0% | 93.0% | 91.3% | 95.6% | 92.4% |
| (11) XCQ Responder status determined | 190 | 201 | 181 | 183 | 171 | 182 | 164 | 177 | 145 | 162 | 132 | 137 | 131 | 133 |
| (12) Radiographic evaluation | 184 | 194 | 175 | 178 | 165 | 187 | 170 | 182 | 162 | 175 | 147 | 161 | 145 | 150 |
| (13) Composite clinical success | 190 | 201 | 184 | 196 | 179 | 193 | 184 | 197 | 185 | 195 | 179 | 187 | 183 | 187 |
| (14) Actual % Follow-up for CCS | 100% | 100% | 96.8% | 97.5% | 94.5% | 95.8% | 97.0% | 97.3% | 98.0% | 97.0% | 93.0% | 91.3% | 97.3% | 94.9% |
| Within Window Accounting (Actual) Among Expected Due | | | | | | | | | | | | | | |
| | I | C | I | C | I | C | I | C | I | C | I | C | I | C |
| (15) ZCQ Responder status determined | 190 | 201 | 168 | 179 | 169 | 180 | 152 | 167 | 111 | 122 | 129 | 131 | 115 | 113 |
| (16) Radiographic evaluation | 184 | 194 | 162 | 162 | 162 | 186 | 154 | 169 | 123 | 131 | 138 | 152 | 127 | 128 |
| (17) Composite clinical success | 190 | 201 | 171 | 182 | 177 | 191 | 172 | 186 | 151 | 154 | 175 | 179 | 166 | 166 |
| (18) Actual % Follow-up for CCS | 100% | 100% | 89.8% | 90.4% | 93.4% | 94.7% | 89.9% | 91.8% | 75.0% | 73.1% | 90.8% | 87.3% | 88.3% | 84.3% |

I¹ = Superior® ISS, C² = X-STOP® IPD®

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The patient accounting tree for the Superion® ISS IDE is depicted below in Figure 2.

Figure 2: Patient Accounting Tree
*There were no subjects with misallocations of randomization, meaning all subjects received the device to which they were randomized. As such, the mITT cohort is identical to the "As-Treated" patient cohort.

Of the 51 post-consent screen failures, there were 2 subjects in the training group and 49 that were randomized for the pivotal cohort that did not proceed to treatment. The 49 post-consent screen failures included 28 in the Superion® ISS arm and 21 in the X-STOP® IPD® arm. The subjects that were post-consent screen failures were blinded to treatment group to mitigate bias.

Subjects were expected due at 24 months if they had not terminally failed due to death or clinical failure defined as reoperation, revision or additional treatment. Data were missing for 7 Superion® ISS and 14 X-STOP® IPD® subjects at 24 months.

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Table 5: 24 Month Data Accounting for Superion® ISS IDE

| Parameter | Superion® ISS | X-STOP® IPD® |
| --- | --- | --- |
| Randomized or Assigned to Training | 248 | 222 |
| Withdrawn Prior to Treatment | 30 | 21 |
| Training Patients | 28 | 0 |
| Subjects Treated (mITT) | 190 | 201 |
| Composite Clinical Success Responders | 183 | 187 |
| Deaths + Clinical Failures Among Implanted¹ | 53 | 57 |
| Expected (mITT) | 137 | 144 |
| ZCQ | 131 | 133 |
| VAS Leg and Back Pain | 131 | 133 |
| ODI | 131 | 133 |
| SF-12 | 128 | 133 |
| Neurological Evaluation | 150 | 157 |
| Radiographic Evaluation | 145 | 150 |
| Patient Satisfaction Evaluation | 152 | 157 |

¹Patients with reoperations, revisions, and epidural steroid injection

# C. Study Population Demographics and Baseline Parameters

The demographics of the study population are typical for a lumbar interspinous spacer study performed in the US. Baseline demographic information and operative variables are presented in Table 6, Table 7, and Table 8.

Table 2: Summary of Baseline and Demographic Categorical Variables Superion® ISS and X-STOP® IPD® Control mITT Analysis Sets

| | Superion® ISS | | X-STOP® IPD® | |
| --- | --- | --- | --- | --- |
| | N | % | N | % |
| Number of subjects | 190 | - | 201 | - |
| Males | 110 | 57.9 | 129 | 64.2 |
| Females | 80 | 42.1 | 72 | 35.8 |
| Race | N | % | N | % |
| White | 177 | 93.2 | 196 | 97.5 |
| Asian | 0 | 0.0 | 1 | 0.5 |
| African American | 8 | 4.2 | 1 | 0.5 |
| American Indian or Alaska Native | 0 | 0.0 | 0 | 0.0 |
| Native Hawaiian or Other Pacific Islander | 0 | 0.0 | 1 | 0.5 |
| Other | 5 | 2.6 | 2 | 1.0 |
| Ethnicity | N | % | N | % |
| Hispanic or Latino | 5 | 2.6 | 11 | 5.5 |
| Not Hispanic or Latino | 185 | 97.4 | 190 | 94.5 |
| Use of nicotine products | N | % | N | % |
| No | 89 | 46.8 | 101 | 50.2 |
| Current Use | 24 | 12.6 | 24 | 11.9 |
| Previous Use | 77 | 40.5 | 76 | 37.8 |

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Statistical analysis of baseline demographics did not show any significant differences between subjects randomized into the Superior® ISS group compared to those randomized into the X-STOP® IPD® control group.

Table 3: Summary of Baseline and Demographic Continuous Variables Superion® ISS and X-STOP® IPD® mITT Analysis Set

| | Superion® ISS | | | X-STOP® IPD® | | |
| --- | --- | --- | --- | --- | --- | --- |
| Demographics – All | N | Mean | SD | N | Mean | SD |
| Age at surgery (yrs) | 190 | 66.9 | 9.4 | 201 | 66.2 | 10.2 |
| Height (inches) | 190 | 67.2 | 4.2 | 201 | 67.9 | 3.8 |
| Weight (lbs) | 190 | 189.7 | 36.5 | 201 | 195.8 | 36.9 |
| BMI (k/m2) | 190 | 29.5 | 4.6 | 201 | 29.7 | 4.6 |
| Demographics – Male | N | Mean | SD | N | Mean | SD |
| Age at surgery (yrs) | 110 | 68.0 | 9.0 | 129 | 66.4 | 10.2 |
| Height (inches) | 110 | 69.9 | 2.6 | 129 | 70.0 | 2.8 |
| Weight (lbs) | 110 | 204.9 | 32.6 | 129 | 207.2 | 32.0 |
| BMI (k/m2) | 110 | 29.5 | 4.3 | 129 | 29.7 | 4.0 |
| Demographic – Female | N | Mean | SD | N | Mean | SD |
| Age at surgery (yrs) | 80 | 65.3 | 9.7 | 72 | 65.8 | 10.3 |
| Height (inches) | 80 | 63.4 | 2.8 | 72 | 64.2 | 2.5 |
| Weight (lbs) | 80 | 168.8 | 31.0 | 72 | 175.4 | 36.3 |
| BMI (k/m2) | 80 | 29.5 | 5.0 | 72 | 29.8 | 5.4 |
| Baseline Functional Status | N | Mean | SD | N | Mean | SD |
| Oswestry (ODI) | 190 | 39.1 | 13.4 | 201 | 39.9 | 11.6 |
| Zurich Claudication Qx Severity | 190 | 3.33 | 0.64 | 201 | 3.37 | 0.61 |
| Zurich Claudication Qx Physical | 190 | 2.63 | 0.43 | 201 | 2.72 | 0.43 |
| SF-12 PCS (Physical) | 189 | 29.4 | 8.1 | 201 | 28.5 | 6.9 |
| SF-12 MCS (Mental Health) | 189 | 50.0 | 12.7 | 201 | 48.9 | 12.2 |
| VAS Back pain | 190 | 55.4 | 27.9 | 201 | 55.1 | 27.4 |
| VAS Leg pain (right leg) | 190 | 55.0 | 31.3 | 201 | 52.9 | 32.5 |
| VAS Leg pain (left leg) | 190 | 49.6 | 31.8 | 201 | 50.8 | 31.7 |

Descriptive comparisons of device group mean differences at baseline, device group differences over time, and change from baseline over time were facilitated using Cohen's standardized effect size. While there were small statistical differences in Race and ZCQ - Physical Function baseline parameters, it was determined that these differences were not clinically important for the investigational and control groups.

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Table 4: Operative Variables and Types of Stenosis Superion® ISS and X-STOP® IPD® mITT Analysis Set

| | Superion® ISS | | X-STOP® IPD® | |
| --- | --- | --- | --- | --- |
| | n | % | n | % |
| Number of Subjects Treated | 189 | 99.5 | 199 | 99.0 |
| Subjects Attempted / Not Implanted | 1 | 8.4 | 2 | 3.7 |
| Number of Levels Treated | n | % | n | % |
| 1 | 99 | 52.4 | 99 | 49.7 |
| 2 | 90 | 47.6 | 100 | 50.3 |
| Stenosis Type | n | % | n | % |
| Central Only | 66 | 34.7 | 60 | 29.9 |
| Lateral Only | 16 | 8.4 | 15 | 7.5 |
| Central and Lateral Stenosis | 100 | 52.6 | 118 | 58.7 |
| Foraminal Stenosis | 8 | 4.2 | 8 | 4.0 |

Baseline differences in operative covariates such as treated levels or stenosis type did not have an overall impact on the clinical success of subjects receiving either Superior® ISS or X-STOP® IPD®.

## D. Safety and Effectiveness Results

### 1. Safety Results

The analysis of safety was based on the mITT cohort of 391 subjects (190 Superion® ISS subjects and 201 X-STOP® IPD® subjects) available for the 24 month evaluation. When making an assessment of safety, an Adverse Event (AE) was considered as: any undesired clinical response or complication experienced by a subject. All operative and postoperative AEs, whether device-related or not, were recorded on the AE Case Report Forms. Safety outcomes were determined by evaluating the type, frequency, seriousness, and relationship to device of AEs through the 24-month time point for all subjects. AEs were categorized as device-related, procedure-related, adjacent-level-related, or systemic.

### AE Device/Procedure-Relatedness

The clinical investigator, on the basis of his or her clinical judgment and the following definitions, determined the severity and relationship of the AE to the device and/or procedure:

- Not related: The AE is clearly not related
- Unknown/Undetermined: The AE is unknown or undetermined to be related
- Related: The AE is clearly related
- Device-related: The AE is related to the Study device or the control device
- Procedure-related: The AE is related to the procedure to implant the investigational or control device.

### AE Severity

The severity of an AE was categorized as mild, moderate or severe. Severity was determined by the clinical investigator, using the following definitions:

- Mild: The AE is transient or causes mild discomfort. There usually is no intervention/therapy required and the AE does not interfere with the subject's normal activities.

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- Moderate: The AE causes some limitation in activity and some assistance may be needed. There is no or minimal medical intervention/therapy required.
- Severe: The AE causes marked limitation in activity. The subject’s usual daily activity is interrupted. The subject may require medical intervention/therapy, hospitalization is possible.

## Serious AEs

The AE was regarded as a Serious Adverse Event (SAE) if the injury or illness:

- Results in death
- Is life-threatening,
- Results in or prolongs hospitalization
- Results in permanent impairment of a body function or permanent damage to a body structure, or
- Necessitates medical or surgical intervention to preclude permanent impairment of a body function or permanent damage to a body structure.

## Serious Adverse Device Effect

A Serious Adverse Device Effect (SADE) is a device-related adverse event that has resulted in any of the consequences characteristic of a serious AE or that might have led to any of these consequences if suitable action had not been taken or intervention had not been made.

## Unanticipated Adverse Device Effect

An Unanticipated Adverse Device Effect (UADE) is any serious adverse effect on health or safety, any life-threatening problem or death caused by, or associated with a device, if that effect, problem, or death was not previously identified in nature, severity, or degree of incidence in the risks identified for the investigational or control device; or any other unanticipated serious problem associated with a device that relates to the rights, safety, or welfare of subjects.

## Role of the CEC

Adverse events were evaluated by the Medical Monitor. Data were evaluated for safety endpoints by an independent CEC. The CEC had predetermined stopping rules, one of which was greater than 10% postoperative observation of *in situ* study device unlocking with full or partial collapse of the cam lobes at annual review. The first stopping review occurred after a minimum of 30 subjects in the study group had been accrued. This observation was monitored annually throughout the study. Additionally, all device-related events, major procedure-related, and adjacent level-related events and therapeutic failures reported by the clinical investigators were adjudicated by the independent CEC. In addition, events reported as having unknown or undetermined relationships to the device by the clinical investigators were to be adjudicated by the CEC.

The key safety outcomes for this study are presented below in Table 9 through Table 30.

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# Adverse Effects that Occurred in the PMA Clinical Study

# Overall Adverse Events

A summary of the total number of adverse events, adverse events related to the device or procedure, serious adverse events, and serious adverse events that were related to the device or procedure is shown below in Table 9.

The safety profile of the Superion® ISS device is similar to the X-STOP® IPD® device when considering adverse event incidence. The overall incidence of any adverse event (Superion® ISS: 94.7% vs. X-STOP® IPD®: 91.5%), device-related adverse events (Superion® ISS: 11.6% vs. X-STOP® IPD®: 7.5%), procedure-related adverse events (Superion® ISS: 14.2% vs. X-STOP® IPD®: 15.9%), serious adverse events (Superion® ISS: 46.3% vs. X-STOP® IPD®: 45.8%), and device- or procedure-related serious adverse events (Superion® ISS: 21.1% vs. X-STOP® IPD®: 23.4%) were similar between both groups. No device-related or procedure-related deaths were reported during follow-up in either the Superion® ISS or X-STOP® IPD® control groups.

Table 5: Comparisons of Summary Adverse Event Rates between Superion® ISS and X-STOP® IPD® mITT Analysis Sets at 24 Months

| | Superion® ISS (N=190) | | X-STOP® IPD® (N=201) | | I vs. C1 | | |
| --- | --- | --- | --- | --- | --- | --- | --- |
| | n | % | n | % | Diff | LB | UB |
| Any adverse event (per patient) | 180 | 94.7 | 184 | 91.5 | -3.2 | -13.1 | 6.8 |
| Any device- related AE | 22 | 11.6 | 15 | 7.5 | -4.1 | -14.0 | 5.8 |
| Any procedure- related AE | 27 | 14.2 | 32 | 15.9 | 1.7 | -8.2 | 11.6 |
| Any serious AE | 88 | 46.3 | 92 | 45.8 | -0.5 | -10.5 | 9.4 |
| Serious AE that is either device- or procedure-related | 16 | 8.4 | 19 | 9.5 | 1.0 | -8.9 | 10.9 |
| Deaths | 6 | 3.2 | 5 | 2.5 | -0.7 | -10.6 | 9.3 |
| Notes: 1 Exact 95% confidence interval for the group difference. Diff signifies difference between percentages of groups. LB signifies lower bound of 95% confidence interval. UB signifies upper bound of 95% confidence interval. | | | | | | | |

As described above, during the clinical study, adverse events were classified as device-related or procedure-related, not device-related or procedure-related, or as having an "unknown/undetermined" relationship. At FDA's request, an additional analysis was performed that grouped adverse events with an "unknown/undetermined" assessment for device and procedure relation with those events deemed to have a definite device or procedure relation as a "worst case" assessment. These results are presented below in Table 10.

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Table 6: Worst Case Comparisons of Summary Adverse Event Rates between Superion® ISS and X-STOP® IPD® mITT Analysis Sets with Unknown/Undetermined Events Grouped with Related Events at 24 Months

| | Superion® ISS (N=190) | | X-STOP® IPD® (N=201) | | I vs. C¹ | | |
| --- | --- | --- | --- | --- | --- | --- | --- |
| | n | % | n | % | Diff | LB | UB |
| Any adverse event (per patient) | 180 | 94.7 | 184 | 91.5 | -3.2 | -13.1 | 6.8 |
| Any device -related AE² | 73 | 38.4 | 79 | 39.3 | 0.9 | -9.0 | 10.8 |
| Any procedure-related AE² | 72 | 37.9 | 99 | 49.3 | 11.4 | 1.4 | 21.1 |
| Any serious AE | 88 | 46.3 | 92 | 45.8 | -0.5 | -10.5 | 9.4 |
| Serious AE that is either device-or procedure-related | 40 | 21.1 | 47 | 23.4 | 2.3 | -7.6 | 12.2 |
| Deaths | 6 | 3.2 | 5 | 2.5 | -0.7 | -10.6 | 9.3 |
| Notes: ¹ Exact 95% confidence interval for the group difference. ² Includes “Yes” and “Unknown/Undetermined” relationships | | | | | | | |

Specific adverse events are listed in alphabetical order according to adverse event categories in Table 11. Adverse event rates are based on the number of subjects having at least one occurrence of an adverse event, and divided by the number of subjects in that treatment group. Events per subject are based on the number of adverse events, divided by the total number of subjects in each cohort. Subjects experiencing adverse events in more than one category are represented in each category in which they experienced an adverse event. Regarding specific adverse events, the most common adverse events observed in the Superion® ISS group and X-STOP® IPD® group were Pain - Back, Pain - Leg, Pain - Buttock & Groin, Spinal stenosis symptoms at index level, and Spinous process fracture.

As shown in the detailed overall adverse event table (Table 11), pain-related adverse events were distributed differently between the Superion® ISS and X-STOP® IPD® groups. X-STOP® IPD® patients were more likely to have Pain - Back or Pain - Leg adverse events, while Superion® ISS patients were more likely to have Pain - Buttock & Groin adverse events. Overall, X-STOP® IPD® patients were more likely to have a back, leg, buttock, or groin adverse event compared with Superion® ISS patients. In addition, X-STOP® IPD® patients were more likely to have events related to soft tissue damage or fever. In contrast, Superion® ISS patients were more likely to have an adverse event related to spinous process fracture. In general, there were no clinically important differences in either treatment group, aside from spinous process fracture and device migration/dislodgement, which will be discussed later.

Table 7: Specific Adverse Events in Superion® ISS IDE up to 24 months (mITT cohort)

| | Superion® ISS (I) (N=190) | | | X-STOP® IPD® (C) (N=201) | | | I vs C¹ | | |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| Adverse Event Type | No. of Events | No. of Pts. | % of Pts. | No. of Events | No. of Pts. | % of Pts. | Diff | LB | UB |
| Abdominal pain | 1 | 1 | 0.5 | 0 | 0 | 0 | -0.5 | -10.4 | 9.4 |
| Accidental injury | 20 | 15 | 7.9 | 22 | 19 | 9.5 | 1.6 | -8.4 | 11.4 |

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Table 7: Specific Adverse Events in Superion® ISS IDE up to 24 months (mITT cohort)

| | Superion® ISS (I) (N=190) | | | X-STOP® IPD® (C) (N=201) | | | I vs C¹ | | |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| Adverse Event Type | No. of Events | No. of Pts. | % of Pts. | No. of Events | No. of Pts. | % of Pts. | Diff | LB | UB |
| Adjacent level DDD | 1 | 1 | 0.5 | 1 | 1 | 0.5 | 0 | -9.9 | 9.9 |
| Adjacent level stenosis | 1 | 1 | 0.5 | 4 | 2 | 1 | 0.5 | -9.4 | 10.4 |
| Allergic reaction | 4 | 4 | 2.1 | 6 | 6 | 3 | 0.9 | -9 | 10.8 |
| Anemia | 4 | 3 | 1.6 | 1 | 1 | 0.5 | -1.1 | -11 | 8.8 |
| Angina | 3 | 3 | 1.6 | 0 | 0 | 0 | -1.6 | -11.5 | 8.3 |
| Bronchitis | 2 | 2 | 1.1 | 6 | 5 | 2.5 | 1.4 | -8.5 | 11.3 |
| Cancer/Neoplasm | 13 | 11 | 5.8 | 14 | 13 | 6.5 | 0.7 | -9.3 | 10.6 |
| Cardiovascular | 25 | 20 | 10.5 | 20 | 16 | 8 | -2.6 | -12.5 | 7.4 |
| Cerebrovascular accident (CVA) | 2 | 2 | 1.1 | 1 | 1 | 0.5 | -0.6 | -10.5 | 9.4 |
| Chronic obstructive pulmonary disease (COPD) | 0 | 0 | 0 | 0 | 0 | 0 | . | . | . |
| Coronary episode, ischemic | 3 | 2 | 1.1 | 5 | 2 | 1 | -0.1 | -10 | 9.9 |
| Deep infection at the operative site | 0 | 0 | 0 | 3 | 2 | 1 | 1 | -8.9 | 10.9 |
| Deep vein thrombosis | 2 | 2 | 1.1 | 1 | 1 | 0.5 | -0.6 | -10.5 | 9.4 |
| Dental | 0 | 0 | 0 | 2 | 2 | 1 | 1 | -8.9 | 10.9 |
| Device breakage | 0 | 0 | 0 | 1 | 1 | 0.5 | 0.5 | -9.4 | 10.4 |
| Device breakage preventing device placement | 0 | 0 | 0 | 0 | 0 | 0 | . | . | . |
| Device deformation preventing device placement | 1 | 1 | 0.5 | 0 | 0 | 0 | -0.5 | -10.4 | 9.4 |
| Device dislodgement | 1 | 1 | 0.5 | 2 | 2 | 1 | 0.5 | -9.4 | 10.4 |
| Device migration | 1 | 1 | 0.5 | 8 | 7 | 3.5 | 3 | -7 | 12.9 |
| Device subsidence | 4 | 4 | 2.1 | 0 | 0 | 0 | -2.1 | -12 | 7.8 |
| Diabetes mellitus | 0 | 0 | 0 | 2 | 2 | 1 | 1 | -8.9 | 10.9 |
| Diabetes mellitus inadequate control | 0 | 0 | 0 | 1 | 1 | 0.5 | 0.5 | -9.4 | 10.4 |
| Dizziness | 5 | 5 | 2.6 | 0 | 0 | 0 | -2.6 | -12.5 | 7.3 |
| Dural leaks | 6 | 6 | 3.2 | 3 | 3 | 1.5 | -1.7 | -11.6 | 8.3 |
| Dyspnea | 0 | 0 | 0 | 1 | 1 | 0.5 | 0.5 | -9.4 | 10.4 |
| Edema | 2 | 2 | 1.1 | 4 | 4 | 2 | 0.9 | -9 | 10.8 |
| EENT | 2 | 2 | 1.1 | 0 | 0 | 0 | -1.1 | -11 | 8.9 |
| Endocrine/Metabolic | 11 | 11 | 5.8 | 13 | 11 | 5.5 | -0.3 | -10.2 | 9.6 |
| Facet cyst | 4 | 3 | 1.6 | 0 | 0 | 0 | -1.6 | -11.5 | 8.3 |
| Fever | 0 | 0 | 0 | 4 | 4 | 2 | 2 | -7.9 | 11.9 |
| Gallstones | 0 | 0 | 0 | 1 | 1 | 0.5 | 0.5 | -9.4 | 10.4 |
| Gastroesophageal reflux disease (GERD) | 1 | 1 | 0.5 | 0 | 0 | 0 | -0.5 | -10.4 | 9.4 |
| Gastrointestinal | 9 | 7 | 3.7 | 10 | 9 | 4.5 | 0.8 | -9.1 | 10.7 |
| Gastrointestinal (GI) bleed | 2 | 2 | 1.1 | 1 | 1 | 0.5 | -0.6 | -10.5 | 9.4 |
| Genitourinary | 25 | 22 | 11.6 | 17 | 17 | 8.5 | -3.1 | -13 | 6.8 |
| Headache | 1 | 1 | 0.5 | 5 | 5 | 2.5 | 2 | -7.9 | 11.9 |
| Hematologic | 0 | 0 | 0 | 2 | 2 | 1 | 1 | -8.9 | 10.9 |
| Hematoma | 0 | 0 | 0 | 1 | 1 | 0.5 | 0.5 | -9.4 | 10.4 |
| Immune | 0 | 0 | 0 | 1 | 1 | 0.5 | 0.5 | -9.4 | 10.4 |
| Infection* | 15 | 14 | 7.4 | 17 | 16 | 8 | 0.6 | -9.3 | 10.5 |
| Instruments breakage or malfunction preventing device placement | 0 | 0 | 0 | 0 | 0 | 0 | . | . | . |
| Loss of bladder control | 0 | 0 | 0 | 2 | 2 | 1 | 1 | -8.9 | 10.9 |

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Table 7: Specific Adverse Events in Superior® ISS IDE up to 24 months (mITT cohort)

| | Superion® ISS (I) (N=190) | | | X-STOP® IPD® (C) (N=201) | | | I vs C¹ | | |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| Adverse Event Type | No. of Events | No. of Pts. | % of Pts. | No. of Events | No. of Pts. | % of Pts. | Diff | LB | UB |
| Loss of bowel control | 0 | 0 | 0 | 0 | 0 | 0 | . | . | . |
| Multi-level DDD | 1 | 1 | 0.5 | 0 | 0 | 0 | -0.5 | -10.4 | 9.4 |
| Muscle damage | 1 | 1 | 0.5 | 1 | 1 | 0.5 | 0 | -9.9 | 9.9 |
| Musculoskeletal** | 108 | 78 | 41.1 | 100 | 70 | 34.8 | -6.2 | -16.1 | 3.7 |
| Myocardial infarction | 5 | 5 | 2.6 | 3 | 3 | 1.5 | -1.1 | -11 | 8.8 |
| Nausea | 0 | 0 | 0 | 4 | 4 | 2 | 2 | -7.9 | 11.9 |
| Nerve root damage | 0 | 0 | 0 | 0 | 0 | 0 | . | . | . |
| Neurological disorder | 27 | 22 | 11.6 | 13 | 13 | 6.5 | -5.1 | -15 | 4.8 |
| Ophthalmic | 10 | 8 | 4.2 | 6 | 6 | 3 | -1.2 | -11.1 | 8.7 |
| Osteolysis | 0 | 0 | 0 | 1 | 1 | 0.5 | 0.5 | -9.4 | 10.4 |
| Other, specify*** | 15 | 14 | 7.4 | 10 | 5 | 2.5 | -4.9 | -14.8 | 5.1 |
| Pain – Back | 56 | 50 | 26.3 | 71 | 66 | 32.8 | 6.5 | -3.4 | 16.4 |
| Pain – Back & Buttock | 1 | 1 | 0.5 | 0 | 0 | 0 | -0.5 | -10.4 | 9.4 |
| Pain – Back & Hip | 1 | 1 | 0.5 | 0 | 0 | 0 | -0.5 | -10.4 | 9.4 |
| Pain – Buttock | 1 | 1 | 0.5 | 2 | 2 | 1 | 0.5 | -9.4 | 10.4 |
| Pain – Buttock & Groin | 23 | 21 | 11.1 | 13 | 13 | 6.5 | -4.6 | -14.5 | 5.3 |
| Pain – Hip | 2 | 2 | 1.1 | 3 | 3 | 1.5 | 0.4 | -9.5 | 10.4 |
| Pain – Leg | 41 | 37 | 19.5 | 54 | 47 | 23.4 | 3.9 | -6 | 13.8 |
| Peripheral Vascular Disorder | 0 | 0 | 0 | 3 | 3 | 1.5 | 1.5 | -8.4 | 11.4 |
| Pneumonia | 5 | 4 | 2.1 | 5 | 5 | 2.5 | 0.4 | -9.5 | 10.3 |
| Presence of osteophyte formation associated with severe disc or facet degeneration | 1 | 1 | 0.5 | 1 | 1 | 0.5 | 0 | -9.9 | 9.9 |
| Progression of underlying disease | 0 | 0 | 0 | 1 | 1 | 0.5 | 0.5 | -9.4 | 10.4 |
| Psychiatric/Substance abuse | 1 | 1 | 0.5 | 4 | 4 | 2 | 1.5 | -8.4 | 11.4 |
| Pulmonary edema | 0 | 0 | 0 | 1 | 1 | 0.5 | 0.5 | -9.4 | 10.4 |
| Pulmonary embolism | 1 | 1 | 0.5 | 0 | 0 | 0 | -0.5 | -10.4 | 9.4 |
| Renal failure | 3 | 3 | 1.6 | 1 | 1 | 0.5 | -1.1 | -11 | 8.8 |
| Renal insufficiency | 2 | 2 | 1.1 | 2 | 2 | 1 | -0.1 | -10 | 9.9 |
| Respiratory disorder | 4 | 3 | 1.6 | 4 | 4 | 2 | 0.4 | -9.5 | 10.3 |
| Respiratory distress | 2 | 2 | 1.1 | 0 | 0 | 0 | -1.1 | -11 | 8.9 |
| Respiratory infection | 0 | 0 | 0 | 2 | 2 | 1 | 1 | -8.9 | 10.9 |
| Rheumatoid arthritis | 1 | 1 | 0.5 | 0 | 0 | 0 | -0.5 | -10.4 | 9.4 |
| Sensory loss | 3 | 2 | 1.1 | 4 | 4 | 2 | 0.9 | -9 | 10.8 |
| Shortness of breath | 0 | 0 | 0 | 1 | 1 | 0.5 | 0.5 | -9.4 | 10.4 |
| Skin and subcutaneous tissue | 2 | 2 | 1.1 | 10 | 8 | 4 | 2.9 | -7 | 12.8 |
| Soft tissue damage | 1 | 1 | 0.5 | 7 | 7 | 3.5 | 3 | -7 | 12.9 |
| Spinal stenosis symptoms at index level | 37 | 35 | 18.4 | 38 | 34 | 16.9 | -1.5 | -11.4 | 8.4 |
| Spinous process fracture | 24 | 22 | 11.6 | 14 | 13 | 6.5 | -5.1 | -15 | 4.8 |
| Stroke | 1 | 1 | 0.5 | 1 | 1 | 0.5 | 0 | -9.9 | 9.9 |
| Syncope | 0 | 0 | 0 | 2 | 2 | 1 | 1 | -8.9 | 10.9 |
| Transient ischemic attack (TIA) | 0 | 0 | 0 | 1 | 1 | 0.5 | 0.5 | -9.4 | 10.4 |
| Urinary tract infection | 8 | 7 | 3.7 | 6 | 6 | 3 | -0.7 | -10.6 | 9.2 |
| Vertebral compression fractures | 1 | 1 | 0.5 | 3 | 3 | 1.5 | 1 | -8.9 | 10.9 |
| Wound dehiscence or delayed healing | 0 | 0 | 0 | 1 | 1 | 0.5 | 0.5 | -9.4 | 10.4 |
| Wound drainage | 1 | 1 | 0.5 | 4 | 4 | 2 | 1.5 | -8.4 | 11.4 |

¹ Exact 95% confidence interval for the group difference.

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*Infection AEs are defined as: including superficial infections and seroma at the surgical site, as well as infections at remote sites (e.g., sinus or throat infection)
**Musculoskeletal AEs are defined as: including weakness, cramping, joint pain, joint surgery or replacement, and other disorders in non-lumbar spinal tissues
***Other adverse events includes events not fitting a specific existing adverse event category, including insomnia, psychological disorder, weight loss, general weakness, ganglion cyst, and drug withdrawal.

Table 12 provides the actual counts of specific events by time of onset. Most adverse events were evenly distributed throughout the course of the study up to 24 months. The exception is the occurrence of spinous process fracture. The majority of these fractures occurred within the first 6 months post-operatively in both cohorts. No other clinically important trends in adverse event occurrence were demonstrated by the data.

Table 12: Counts of Specific Adverse Events by Time of Occurrence up to 24 Months (mITT cohort)

| | Day of Surgery | | Immed. Post-Op to Month 3 (Day 1-90) | | >Mo. 3 to Mo. 6 (Day 91-180) | | >Mo. 6 to Mo. 12 (Day 181-365) | | >Mo. 12 to Mo. 24 (Day 365-730) | | Post Month 24 (Day >730) | | Totals | |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| | I1 | C1 | I | C | I | C | I | C | I | C | I | C | I | C |
| Abdominal pain | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 1 | 0 |
| Accidental Injury | 1 | 0 | 2 | 5 | 1 | 2 | 7 | 5 | 6 | 8 | 2 | 2 | 19 | 22 |
| Adjacent Level DDD | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 1 | 1 |
| Adjacent Level Stenosis | 0 | 0 | 0 | 3 | 0 | 0 | 0 | 1 | 0 | 0 | 1 | 0 | 1 | 4 |
| Allergic reaction | 0 | 1 | 1 | 1 | 0 | 1 | 1 | 2 | 2 | 1 | 0 | 0 | 4 | 6 |
| Anemia | 0 | 0 | 3 | 0 | 0 | 0 | 1 | 0 | 0 | 1 | 0 | 0 | 4 | 1 |
| Angina | 0 | 0 | 1 | 0 | 1 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 3 | 0 |
| Bronchitis | 0 | 0 | 0 | 2 | 0 | 1 | 0 | 2 | 2 | 1 | 0 | 0 | 2 | 6 |
| Cancer/Neoplasm | 0 | 0 | 2 | 2 | 2 | 2 | 3 | 5 | 4 | 4 | 2 | 1 | 13 | 14 |
| Cardiovascular | 1 | 0 | 2 | 2 | 5 | 3 | 3 | 0 | 12 | 10 | 2 | 5 | 25 | 20 |
| Cerebrovascular accident (CVA) | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 1 | 0 | 1 | 0 | 2 | 1 |
| Chronic obstructive pulmonary disease (COPD) | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Coronary episode, ischemic | 0 | 0 | 1 | 4 | 1 | 0 | 0 | 0 | 1 | 1 | 0 | 0 | 3 | 5 |
| Deep infection at the operative site | 0 | 0 | 0 | 2 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 3 |
| Deep vein thrombosis | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 2 | 0 | 2 | 1 |
| Dental | 0 | 0 | 0 | 2 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 2 |
| Device breakage | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 |
| Device breakage preventing device placement | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Device deformation preventing device placement | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 |
| Device dislodgement | 0 | 0 | 1 | 1 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 2 |
| Device erosion | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Device migration | 0 | 0 | 1 | 4 | 0 | 2 | 0 | 0 | 0 | 2 | 0 | 0 | 1 | 8 |
| Device subsidence | 0 | 0 | 0 | 0 | 3 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 4 | 0 |
| Dextroscoliosis | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Diabetes mellitus | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 1 | 0 | 0 | 0 | 2 |
| Diabetes mellitus inadequate | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 1 |

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Table 12: Counts of Specific Adverse Events by Time of Occurrence up to 24 Months (mITT cohort)

| | Day of Surgery | | Immed. Post-Op to Month 3 (Day 1-90) | | >Mo. 3 to Mo. 6 (Day 91-180) | | >Mo. 6 to Mo. 12 (Day 181-365) | | >Mo. 12 to Mo. 24 (Day 365-730) | | Post Month 24 (Day >730) | | Totals | |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| | I1 | C2 | I | C | I | C | I | C | I | C | I | C | I | C |
| control | | | | | | | | | | | | | | |
| Disc bulge | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Dizziness | 0 | 0 | 3 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 1 | 0 | 5 | 0 |
| Dural leaks | 2 | 0 | 0 | 0 | 0 | 1 | 2 | 0 | 2 | 1 | 0 | 1 | 6 | 3 |
| Dyspnea | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 1 |
| Edema | 0 | 0 | 2 | 0 | 0 | 0 | 0 | 2 | 0 | 2 | 0 | 0 | 2 | 4 |
| EENT | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 2 | 0 |
| Endocrine/Metabolic | 0 | 3 | 2 | 2 | 1 | 2 | 3 | 1 | 2 | 4 | 3 | 1 | 11 | 13 |
| Facet cyst | 0 | 0 | 1 | 0 | 0 | 0 | 1 | 0 | 2 | 0 | 0 | 0 | 4 | 0 |
| Fever | 0 | 0 | 0 | 2 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 2 | 0 | 4 |
| Gallstones | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 1 |
| Gastroesophageal reflux disease (GERD) | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 1 | 0 |
| Gastrointestinal | 0 | 0 | 1 | 2 | 1 | 2 | 2 | 2 | 1 | 2 | 4 | 2 | 9 | 10 |
| Gastrointestinal (GI) bleed | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 1 | 1 | 0 | 0 | 2 | 1 |
| Genitourinary | 6 | 1 | 9 | 7 | 2 | 2 | 4 | 2 | 3 | 3 | 1 | 2 | 25 | 17 |
| Headache | 0 | 0 | 1 | 3 | 0 | 0 | 0 | 0 | 0 | 2 | 0 | 0 | 1 | 5 |
| Hematologic | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 2 | 0 | 0 | 0 | 2 |
| Hematoma | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 |
| Immune | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 |
| Infection* | 0 | 0 | 4 | 4 | 3 | 2 | 5 | 3 | 3 | 6 | 0 | 2 | 15 | 17 |
| Instruments breakage or malfunction preventing device placement | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Loss of bladder control | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 2 | 0 | 0 | 0 | 2 |
| Loss of bowel control | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Multi-level DDD | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 1 | 0 |
| Muscle damage | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 1 | 1 |
| Musculoskeletal** | 1 | 0 | 29 | 24 | 12 | 13 | 20 | 12 | 32 | 38 | 14 | 13 | 108 | 100 |
| Myocardial Infarction | 0 | 0 | 1 | 0 | 0 | 0 | 2 | 2 | 1 | 1 | 1 | 0 | 5 | 3 |
| Nausea | 0 | 3 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 4 |
| Nerve root damage | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Neurological disorder | 0 | 2 | 6 | 3 | 2 | 1 | 6 | 2 | 10 | 4 | 3 | 1 | 27 | 13 |
| Ophthalmic | 2 | 0 | 3 | 0 | 0 | 0 | 3 | 2 | 1 | 4 | 1 | 0 | 10 | 6 |
| Osteolysis | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 1 |
| Other*** | 0 | 2 | 4 | 3 | 1 | 0 | 3 | 3 | 6 | 2 | 1 | 0 | 15 | 10 |
| Pain - Back | 0 | 1 | 14 | 23 | 12 | 7 | 8 | 19 | 14 | 15 | 8 | 6 | 56 | 71 |
| Pain - Back & Buttock | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 1 | 0 |
| Pain - Back & Hip | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 1 | 0 |
| Pain - Back & Leg | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Pain - Buttock | 0 | 0 | 0 | 1 | 0 | 0 | 1 | 1 | 0 | 0 | 0 | 0 | 1 | 2 |
| Pain - Buttock & Groin | 0 | 0 | 7 | 5 | 2 | 2 | 4 | 3 | 8 | 2 | 2 | 0 | 23 | 12 |
| Pain - Buttocks and Hip | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |

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Table 12: Counts of Specific Adverse Events by Time of Occurrence up to 24 Months (mITT cohort)

| | Day of Surgery | | Immed. Post-Op to Month 3 (Day 1-90) | | >Mo. 3 to Mo. 6 (Day 91-180) | | >Mo. 6 to Mo. 12 (Day 181-365) | | >Mo. 12 to Mo. 24 (Day 365-730) | | Post Month 24 (Day >730) | | Totals | |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| | I¹ | C² | I | C | I | C | I | C | I | C | I | C | I | C |
| Pain - Hip | 0 | 0 | 1 | 2 | 0 | 0 | 0 | 0 | 0 | 1 | 1 | 0 | 2 | 3 |
| Pain - Leg | 1 | 0 | 12 | 17 | 6 | 10 | 7 | 13 | 12 | 10 | 2 | 4 | 40 | 54 |
| Peripheral Vascular Disorder | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 1 | 0 | 1 | 0 | 0 | 0 | 3 |
| Pneumonia | 0 | 0 | 0 | 0 | 1 | 1 | 1 | 1 | 2 | 2 | 1 | 1 | 5 | 5 |
| Presence of osteophyte formation associated with severe disc or facet degeneration | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 1 | 1 | 1 |
| Progression of underlying disease | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 1 |
| Psychiatric/Substance abuse | 0 | 0 | 0 | 1 | 0 | 1 | 1 | 0 | 0 | 1 | 0 | 1 | 1 | 4 |
| Pulmonary edema | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 |
| Pulmonary embolism | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 |
| Renal failure | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 2 | 1 | 0 | 0 | 3 | 1 |
| Renal insufficiency | 0 | 0 | 0 | 1 | 0 | 0 | 1 | 0 | 0 | 1 | 1 | 0 | 2 | 2 |
| Respiratory disorder | 0 | 3 | 0 | 0 | 0 | 1 | 0 | 0 | 2 | 0 | 2 | 0 | 4 | 4 |
| Respiratory distress | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 1 | 0 | 0 | 0 | 2 | 0 |
| Respiratory infection | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 1 | 0 | 2 |
| Rheumatoid arthritis | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 |
| Sensory loss | 0 | 0 | 1 | 2 | 1 | 0 | 1 | 1 | 0 | 1 | 0 | 0 | 3 | 4 |
| Shortness of breath | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 1 |
| Skin and subcutaneous tissue | 0 | 0 | 1 | 4 | 0 | 2 | 0 | 0 | 0 | 4 | 1 | 0 | 2 | 10 |
| Soft tissue damage | 0 | 0 | 0 | 0 | 0 | 2 | 0 | 1 | 1 | 2 | 0 | 2 | 1 | 7 |
| Spinal stenosis symptoms associated with non-index condition | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Spinal stenosis symptoms at index level | 0 | 0 | 10 | 10 | 8 | 5 | 12 | 7 | 4 | 12 | 3 | 4 | 37 | 38 |
| Spinous process fracture | 4 | 2 | 13 | 9 | 3 | 1 | 2 | 1 | 1 | 1 | 1 | 0 | 24 | 14 |
| Stroke | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 1 | 0 | 0 | 0 | 1 | 1 |
| Syncope | 0 | 0 | 0 | 2 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 2 |
| Synovial cyst | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Transient ischemic attack (TIA) | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 |
| Urinary tract infection | 1 | 1 | 3 | 1 | 3 | 0 | 1 | 1 | 0 | 3 | 0 | 0 | 8 | 6 |
| Vertebral compression fractures | 0 | 0 | 0 | 1 | 0 | 0 | 1 | 0 | 0 | 1 | 0 | 1 | 1 | 3 |
| Wound dehiscence or delayed healing | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 |
| Wound drainage | 0 | 0 | 0 | 3 | 0 | 1 | 0 | 0 | 1 | 0 | 0 | 0 | 1 | 4 |

I¹ = Superior® ISS, C² = X-STOP® IPD®
*Infection AEs are defined as: including superficial infections and seroma at the surgical site, as well as infections at remote sites (e.g., sinus or throat infection)
**Musculoskeletal AEs are defined as: including weakness, cramping, joint pain, joint surgery or replacement, and other disorders in non-lumbar spinal tissues
***Other adverse events includes events not fitting a specific existing adverse event category, including insomnia, psychological disorder, weight loss, general weakness, ganglion cyst, and drug withdrawal.

PMA P140004: FDA Summary of Safety and Effectiveness Data

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# Device-Related Adverse Events

The most frequent device-related adverse events were spinous process fractures, as noted in Table 13 below, which occurred in $7.9\%$ of Superion® ISS patients and $2.5\%$ of X-STOP® IPD® patients. There were no large numerical differences in the number of device-related adverse events, with the exception of Deep infection at the operative site, Device dislodgement, Device migration, Device subsidence, Spinal stenosis symptoms at index level, and Spinous process fractures. However, given the low incidences of the aforementioned device-related adverse events, it is difficult to draw conclusions regarding the clinical importance of these differences.

Table 13: Specific Device-Related Adverse Events in Superion® ISS IDE up to 24 months (mITT cohort)

| | Superion® ISS (N=190) | | | X-STOP® IPD® (N=201) | | |
| --- | --- | --- | --- | --- | --- | --- |
| Adverse Event Type | No. of Events | No. of Pts. | % of Pts. | No. of Events | No. of Pts. | % of Pts. |
| Deep infection at the operative site | 0 | 0 | 0.0 | 2 | 1 | 0.5 |
| Device breakage | 0 | 0 | 0.0 | 1 | 1 | 0.5 |
| Device deformation preventing device placement | 1 | 1 | 0.5 | 0 | 0 | 0.0 |
| Device dislodgement | 1 | 1 | 0.5 | 2 | 2 | 1.0 |
| Device migration | 1 | 1 | 0.5 | 5 | 5 | 2.5 |
| Device subsidence | 4 | 4 | 2.1 | 0 | 0 | 0.0 |
| Dural leaks | 1 | 1 | 0.5 | 0 | 0 | 0.0 |
| Loss of bowel control | 0 | 0 | 0.0 | 1 | 1 | 0.5 |
| Pain - Back | 1 | 1 | 0.5 | 0 | 0 | 0.0 |
| Pain - Leg | 1 | 1 | 0.5 | 0 | 0 | 0.0 |
| Spinal stenosis symptoms at index level | 0 | 0 | 0.0 | 3 | 3 | 1.5 |
| Spinous process fracture | 16 | 15 | 7.9 | 5 | 5 | 2.5 |

# Procedure-Related Adverse Events

The most frequent procedure-related adverse events, as noted in Table 14 below, were spinous process fractures, which occurred in $7.9\%$ of Superion® ISS patients and $2.5\%$ of X-STOP® IPD® patients. There were no large numerical differences in the number of procedure-related adverse events, with the exception of Deep infection at the operative site, Device migration, Device subsidence, Dural leaks, Spinal stenosis symptoms at index level, Spinous process fracture and Wound drainage. However, given the low incidences of the aforementioned procedure-related adverse events, it is difficult to draw conclusions regarding the clinical importance of these differences.

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Table 14: Specific Procedure- Related Adverse Events in Superion® ISS IDE up to 24 months (mITT cohort)

| | Superion® ISS (N=190) | | | X-STOP® IPD® (N=201) | | |
| --- | --- | --- | --- | --- | --- | --- |
| Adverse Event Type | No. of Events | No. of Pts. | % of Pts. | No. of Events | No. of Pts. | % of Pts. |
| Coronary episode, ischemic | 0 | 0 | 0.0 | 4 | 1 | 0.5 |
| Deep infection at the operative site | 0 | 0 | 0.0 | 3 | 2 | 1.0 |
| Device deformation preventing device placement | 1 | 1 | 0.5 | 0 | 0 | 0.0 |
| Device dislodgement | 1 | 1 | 0.5 | 1 | 1 | 0.5 |
| Device migration | 1 | 1 | 0.5 |…