BARRICAID ANULAR CLOSURE DEVICE (ACD)

P160050 · Intrinsic Therapeutics · QES · Feb 8, 2019 · Orthopedic

Device Facts

• Record ID: P160050
• Device Name: BARRICAID ANULAR CLOSURE DEVICE (ACD)
• Applicant: Intrinsic Therapeutics
• Product Code: QES · Orthopedic
• Decision Date: Feb 8, 2019
• Decision: APPR
• Device Class: Class 3
• Attributes: Therapeutic

Intended Use

The Barricaid® ACD is indicated for reducing the incidence of reherniation and reoperation in skeletally mature patients with radiculopathy (with or without back pain) attributed to a posterior or posterolateral herniation, and confirmed by history, physical examination and imaging studies which demonstrate neural compression using MRI to treat a large anular defect (between 4-6 mm tall and between 6-10 mm wide) following a primary discectomy procedure (excision of herniated intervertebral disc) at a single level between L4 and S1.

Device Story

Barricaid ACD is a permanent implant used as an adjunct to lumbar discectomy to block anular defects and reduce reherniation. It consists of a flexible woven PET polymer fabric component and a Ti-6Al-4V ELI titanium bone anchor. The device is provided preloaded on a single-use disposable delivery tool. During surgery, the surgeon taps the anchor into the vertebral body to secure the polymer fabric across the anular defect. The device includes a platinum-iridium radiopaque marker for radiographic visualization. It is used in a clinical setting by spine surgeons. The device acts as a physical barrier to retain nucleus pulposus material. By reducing reherniation, it aims to decrease the need for secondary surgical interventions and improve patient outcomes following primary discectomy.

Clinical Evidence

Prospective, multi-center, randomized controlled trial (RCT) comparing Barricaid to discectomy alone in 554 subjects. Primary endpoints at 24 months: reherniation rate and a composite of safety/effectiveness (ODI, VAS leg pain, disc height, neurological status, device integrity, no spontaneous fusion, no reherniation, no secondary surgery). Barricaid demonstrated superiority in both co-primary endpoints. Long-term data through 60 months showed significantly lower rates of symptomatic reherniation (14.2% vs 29.8%, p<0.0001) and secondary surgical interventions (16.15% vs 22.69%, p<0.05) for Barricaid. Endplate lesions (EPLs) were observed more frequently in the Barricaid group but were determined to be stable and not associated with negative clinical outcomes.

Technological Characteristics

Materials: PET (polyethylene terephthalate) woven fabric, PTFE-coated PET suture, Ti-6Al-4V ELI titanium alloy (ASTM F136-11), platinum-iridium radiopaque marker. Principle: Mechanical barrier to anular defect, anchored to vertebral body. Dimensions: 8mm or 10mm width, 15mm length. Connectivity: None. Sterilization: Gamma irradiation (ISO 11137). MR Conditional (1.5T and 3T).

Indications for Use

Indicated for skeletally mature patients with radiculopathy (with/without back pain) due to posterior/posterolateral disc herniation, confirmed by MRI, with large anular defects (4-6mm tall, 6-10mm wide) post-primary discectomy at a single level (L4-S1). Contraindicated in patients with systemic/site infection, prior surgery at index level (except specific procedures like microdiscectomy/laminotomy), allergies to device materials, osteoporosis/osteopenia (T-score ≤ -2.0), required spinal surgery other than discectomy, unknown etiology of pain, scoliosis >10°, spondylolisthesis >Grade 1, compromised vertebral bodies, insulin-dependent diabetes, peripheral neuropathy, arterial insufficiency, or BMI > 40.

Regulatory Classification

Identification

The device is intended to reduce the incidence of reherniation, and reoperation following primary limited lumbar discectomy procedures (excision of herniated intervertebral disc).

Reference Devices

• Solinas Medical SMI Cardiovascular Patch (K112683)
• Teleflex Cottony Silky II PET suture (K021019)
• Spineology Rampart D Lumbar Interbody Fusion Device (K160074)

Submission Summary (Full Text)

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SUMMARY OF SAFETY AND EFFECTIVENESS DATA (SSED)

I. GENERAL INFORMATION

Device Generic Name: Reherniation reduction device
Device Trade Name: Barricaid® Anular Closure Device (ACD)
Device Product Code: QES
Applicant's Name and Address: Intrinsic Therapeutics
30 Commerce Way
Woburn, MA 01801
Date(s) of Panel Recommendation: December 12, 2017
Premarket Approval Application: P160050 (PMA Number)
Date of FDA Notice of Approval: February 8, 2019

II. INDICATIONS FOR USE

The Barricaid® ACD is indicated for reducing the incidence of reherniation and reoperation in skeletally mature patients with radiculopathy (with or without back pain) attributed to a posterior or posterolateral herniation, and confirmed by history, physical examination and imaging studies which demonstrate neural compression using MRI to treat a large anular defect (between 4-6 mm tall and between 6-10 mm wide) following a primary discectomy procedure (excision of herniated intervertebral disc) at a single level between L4 and S1.

III. CONTRAINDICATIONS

The Barricaid® ACD should not be implanted in patients with active systemic infection or infection at the site of implantation.

The Barricaid® ACD should not be implanted in patients with prior surgery at the index level other than intradiscal electro-thermal annuloplasty (IDET), percutaneous nucleoplasty, microdiscectomy, hemilaminectomy, or laminotomy.

The Barricaid® ACD should not be implanted in patients with allergies/hypersensitivity to the device's components (polyethylene terephthalate [PET], polytetra-fluoroethylene, titanium, platinum, iridium).

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The Barricaid® ACD should not be implanted in patients with osteoporosis or osteopenia defined as DEXA bone mineral density T-score less than or equal to -2.0.

The Barricaid® ACD should not be implanted in patients who require spinal surgery other than a discectomy (with or without laminotomy) to treat leg/back pain (scar tissue and osteophyte removal is allowed).

The Barricaid® ACD should not be implanted in patients with back or non-radicular leg pain of unknown etiology, scoliosis &gt;10° (rotational or angular), spondylolisthesis &gt;Grade 1, or clinically compromised vertebral bodies in the lumbosacral region due to any traumatic, neoplastic, metabolic, or infectious pathology.

The Barricaid® ACD should not be implanted in patients with a preoperative posterior disc height &lt;5 mm or with anular defects outside of these size ranges: between 4-6 mm tall and between 6-10 mm wide.

The Barricaid® ACD should not be implanted in patients with insulin-dependent diabetes, peripheral neuropathy, arterial insufficiency, or a BMI &gt; 40.

## IV. WARNINGS AND PRECAUTIONS

Please refer to the Barricaid® ACD Instructions for Use for warnings and precautions.

## V. DEVICE DESCRIPTION

The Barricaid® ACD, also referred to as "Barricaid," is implanted at the time of a lumbar discectomy, after the discectomy is complete. The Barricaid is a permanent implant that has two major subcomponents: a flexible woven polymer fabric component is intended to close the anular defect, and a bone anchor to affix the flexible polymer component in place.


The Barricaid serves as an adjunct to the discectomy procedure and is intended to act as a barrier to block the anular defect that is identified as part of the discectomy. The Barricaid is provided to the user preloaded onto a single use disposable delivery tool.

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The flexible polymer component is formed from a flexible woven fabric comprising multiple layers of counter-angulated fibers made from a non-degrading polymer (PET, or polyethylene terephthalate) with a history of cleared use as a permanently implantable material. The individual layers are sequentially sewn together using PTFE (polytetrafluoroethylene)-coated PET suture. The flexible polymer component contains a platinum-iridium (Pt-Ir) radiopaque marker for observation of flexible polymer component position on intra- and/or post-operative radiographs. The Barricaid anchor component is made from a standard orthopedic titanium alloy (Ti-6Al-4V ELI). The titanium alloy is in compliance with ASTM F136-11 Standard Specification for Wrought Titanium-6 Aluminum-4 Vanadium ELI (Extra Low Interstitial) Alloy for Surgical Implant Applications.

The Barricaid is offered in two sizes to accommodate a range of anular defect sizes, each providing a barrier for closure of the anular defect. The device is available with 8mm and 10mm flexible polymer component widths, while the flexible polymer component length (15mm) and base anchor is identical for the two different flexible polymer component sizes.

The device is tapped into the vertebral body enabling the titanium bone anchor to secure one end of the flexible polymer component into the vertebral body. The anchor component is intended to help position the flexible polymer component within the anular defect.

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VI. ALTERNATIVE PRACTICES AND PROCEDURES

For the patients with radicular leg pain caused by herniated lumbar discs, non-surgical alternatives include non-steroidal anti-inflammatory drugs (NSAIDs), analgesics, oral and epidural steroids, rest, exercise, and physical therapy. Surgical alternatives vary, depending upon the severity of the disc herniation, the contribution of back pain, and the presence of instability, among other factors, and most commonly include discectomy procedures. Rarely performed index surgical interventions include fusion procedures (e.g., interbody cages, pedicle screw systems) and bone graft, or a lumbar disc arthroplasty.²,³ Literature also includes reports of reduction in reherniation rates after discectomy by completely removing the nucleus with an aggressive nucleotomy.⁴ 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 and lifestyle.

VII. MARKETING HISTORY

The Barricaid has been marketed outside of the United States since 2009. The Barricaid is marketed in the following countries: Germany, Austria, Greece, Netherlands, Italy, Switzerland, Belgium, Turkey, Israel, South Korea, Russia, South Africa, Chile, Costa Rica, Poland, Hungary, Slovenia, Bulgaria, Saudi Arabia and Australia. The device has not been withdrawn from marketing for any reason related to its safety or effectiveness.

VIII. POTENTIAL ADVERSE EFFECTS OF THE DEVICE ON HEALTH

A list of potential adverse effects (e.g., complications) associated with use of the Barricaid is presented below. This listing was derived from results of the Barricaid clinical trial and published clinical literature for clinical experiences within the same patient population. It includes (1) those adverse effects potentially associated with lumbar spine surgery; (2) those potentially associated with lumbar discectomies; (3) those potentially associated with implantation of the Barricaid device. In some instances, additional surgery may be required to correct adverse effects.

1. Risks associated with lumbar spine surgery 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; operative site infection; 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; formation of scar tissue; wound swelling, drainage, dehiscence, necrosis or delayed healing; discomfort and rehabilitation associated with recovery from surgery; inability to perform certain tasks, such as lifting or exercise; surgical site pain or discomfort; and death.

2. In addition to the risks listed above, risks associated with lumbar discectomies include: vertebral bone resorption (endplate lesions); problems from anesthesia;

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spinal fluid leaks; new or worsened back or leg pain; loss of bladder and/or bowel functions; reherniation of nucleus into the epidural space, which could cause impingement or damage to neural elements, and nerve complications; damage to nerve roots or the spinal cord causing partial or complete sensory or motor loss (paralysis); dural tears (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, unintended or spontaneous fusion; loss of disc height; foraminal stenosis; canal stenosis; facet hypertrophy; loss of appropriate spine curvature; osteomyelitis, epidural abscess, meningitis, spinal instability and surgery at the incorrect location or level.

3. In addition to the risks listed above, risks associated with implantation of the Barricaid device and associated instruments include: Expulsion of some or all of the device into the epidural space, which may cause impingement or damage to neural elements; subsidence of some or all of the device into the vertebral body; 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; separation of the flexible fabric component from the bone anchor component; loosening of the bone anchor component from the bone; decrease in bone density due to stress shielding; fracture of bony structures; fracture of the device; implant material sensitivity, or allergic reaction to a foreign body; discomfort, or abnormal sensations due to the presence of the device; nerve root irritation and/or damage from insertion and/or removal of device and associated instruments; excessive scar tissue formation; reoperation for removal of the device; increased vertebral bone resorption (increased frequency and size of endplate lesions); implant malposition or incorrect orientation; production of wear debris or other factors which may damage surrounding bone.

For the specific adverse events that occurred in the Barricaid clinical study, please see Section 10.5 below. For detailed information on endplate lesions, see Section X.E.9.

## IX. SUMMARY OF NONCLINICAL STUDIES

A number of non-clinical studies were conducted by the sponsor including:

- Monotonic Anchor Push-Out Testing
- Cyclic Anchor Push-Out Testing
- Cyclic Nucleus Pressure Testing
- Flexible polymer Component Migration Testing
- Flexible polymer Component Detachment Testing

There were limitations to the non-clinical studies conducted, therefore limited conclusions could be drawn based on the studies performed. Due to these limitations in the non-clinical testing above, clinical data were provided to address the risk of flexible

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polymer component and anchor migration, flexible polymer component detachment and ability to retain the disc nucleus that would typically be characterized by this testing.

A cadaveric usability study was performed to evaluate the implantation and removal of the device by independent surgeons.

## A. Animal Studies

### 1. Rabbit Particulate Study

This study was designed to assess the local and systemic effect of PET particulate, with particular focus on the presence of activated macrophages and other parameters as deemed appropriate by the project pathologist. The study also assessed systemic tissues for architecture, presence of PET particulate (test material), as well as signs of foreign body giant cell/granulomas, inflammatory reactions.

Study samples (study slides) from twenty (20) rabbits implanted with the test article, polyethylene terephthalate (PET) particles, along the membranous covering and neural structures of the spinal canal at L5-L6 or left untreated after epidural exposure alone (sham control) and sacrificed at 3 or 6 months were received for microscopic evaluation.

Findings related to treatment with PET were limited to localized foreign body inflammation, and while PET particles were still present at 6 months, the inflammatory and fibrous tissue response appeared to be appropriate and non-adverse, and there was no evidence of systemic toxicity or PET particulate (test material).

### 2. Baboon Study

This study was designed to evaluate radiological and histopathological response of Barricaid following long-term implantation in a worst-case animal (baboon) model. A worst-case animal model was used to evaluate device migration and expulsion, the device's ability to withstand physiologic loading, wear debris generation, and risks associated with device implantation.

Nine (9) mature male baboons were implanted with the test device, Barricaid, at two operative levels of the lower lumbar spine (L4-L5 and L5-L6) and received a nucleotomy (operative control) at the L3-L4 level. Three (3) animals were sacrificed at each of three timepoints - 3 months, 6 months and 12 months. Histopathology, microradiographs, MRI and CT imaging were performed. Study samples (images, tissue and study slides) were received for microscopic evaluation.

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Specimen #951 - L4-L6 Experimental Treatments.

Figure 9.1 Twelve Month Baboon Study Results

Example of undecalcified sagittal histologic (left) and corresponding microradiographic (right) images from the Baboon Implantation Study at 12 months. (Note that results from the animal study may not directly correlate with clinical outcomes.) The histologic tissue image is stained with Villanueva's Osteochrome Bone Stain. Note that the purple-stained tissue is the remnant intervertebral disc (nucleus pulposus) and cartilage lining the vertebral endplate following partial nucleotomy (discectomy). Please note that the device appears in white and is labeled as "anchor" and "head" on microradiograph in the image on the right, and appears black in the corresponding location in the histologic sample on the left. The upper device (L4-L5) shows superior endplate disruption (white arrow) with the mesh (opaque whitish-brown material) subsidence into a bone loss or resorption cavity (osteolysis) with green-stained fibrous connective tissue (replacement fibrosis = F). Osteophyte formation is shown with the white arrowhead. The lower device (L5-L6) shows both superior and inferior endplate disruption (white arrow), mesh subsidence inferiorly, and bone resorption cavities with fibrosis

The limitations to the baboon study were related to the sizing mismatch for the implant and instruments due to the differences between the baboon and the human disc. The potential of oversized implant may have contributed to the development or enlargement of the lesions seen in the baboon study. Furthermore, the loading environment was altered due to a different surgical approach. An anterolateral

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approach (as compared to the posterior approach used in humans), and the convex curvature of baboon endplates may promote focal loading on the flexible polymer component that is different than in humans. Lastly, imaging was performed only at post-sacrifice so it was not possible to determine longitudinal progression of bony changes. Altogether, with the over-sized device and different anatomy, there may be differences in the outcomes of the baboon study compared to clinical outcomes in humans despite the similar appearance of lesions within the vertebral body.

Osteolysis, fibrosis, endplate disruption and flexible polymer component subsidence were observed. Reactive changes in response to the flexible polymer component were observed in the form of reactive sclerosis on CT and bone marrow edema on MRI. Imaging was only performed after sacrifice. Endplate lesions at 12 months did not appear to stabilize or diminish when compared to 3 or 6-month images from other animals sacrificed at these earlier timepoints.

There was no evidence of device extrusion, fracture or separation nor was there wear debris locally or systemically. There was no evidence of systemic toxicity. However, the following risks were found to be associated with Barricaid device implantation in the baboon 1-year study:

- Vertebral endplate disruption
- Device (flexible polymer component) subsidence beyond the endplates
- Inflammation
- Fibrosis
- Osteolysis
- Osteophyte formation

Due to these results, detailed radiographic assessments as well as extensive analyses were performed on the clinical data collected and provided. The lesions were observed, measured and considered in the clinical study as potential safety risks and are discussed in further detail in Section X.E below.

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# B. Additional Studies

Table 9-1. Summary of Additional Studies on Barricaid

| Test | Method and Results |
| --- | --- |
| Sterilization, Packaging and Shelf Life | The Barricaid is sterilized under controlled conditions via gamma irradiation. The minimum dose has been validated, and routine applied doses are established by dose mapping, according to ISO 11137. A protocol for substantiation of 25 kGy was utilized to verify that a minimum sterilization dose of 25 kGy will provide a Sterility Assurance Level (SAL) of 10-6, or no more than one non-sterile unit for each one million units sterilized. Shelf life and packaging validation studies, including simulated distribution and subsequent package integrity, as well as real-time aging and subsequent seal strength testing, were conducted to validate package integrity and support shelf life claim of 3 years. |
| Biocompatibility | The Barricaid device, based on its intended use, is classified as a permanent implant (>30 days) in contact with tissue/bone. To thoroughly evaluate the safety of the device, the FDA Blue Book Memo G95-1 and the most recent FDA-recognized ISO 10993-1 standard were considered to determine the recommended testing. The sponsor provided testing or rationales to support all the required biocompatibility endpoints. Please see the above, Section IX.A for the animal studies conducted to satisfy the recommended implantation study. |
| MRI Compatibility | Non-clinical testing demonstrated that the Intrinsic Therapeutics Barricaid device is MR Conditional. A patient with this device can be scanned safely in an MR system immediately after placement under the following conditions: • Static magnetic field of 1.5-Tesla and 3-Tesla, only • Maximum spatial gradient magnetic field of 3000 Gauss/cm or less • Maximum MR system reported, whole body averaged specific absorption rate (SAR) of 2-W/kg for 15 minutes of scanning in the Normal Operating Mode of operation for the MR system Under the scan conditions defined, the Intrinsic Therapeutics Barricaid device is expected to produce a maximum temperature rise of 1.6°C after 15-minutes of continuous scanning. In non-clinical testing, the image artifact caused by the Intrinsic Therapeutics Barricaid device extends approximately 15 mm from this implant when imaged using a gradient echo pulse sequence and a 3-Tesla MR system. |

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# 1. Retrieval Analysis

An independent laboratory, Exponent Inc. (Philadelphia, PA), performed analysis of retrieved Barricaid devices and associated tissues. All analyses were conducted using ASTM F561 Standard Practice for Retrieval and Analysis of Medical Devices, and Associated Tissues and Fluids as a guide. This includes Stage I, II analyses for 22 of 26 explanted devices, and histological analysis for 12 of 26 explanted devices. Of the 4 missing devices, 3 were discarded at the site and one was returned to the patient per attorney request and in compliance with local regulation.

Attenuated Total Reflection-Fourier Transform Infrared Spectroscopy (ATR-FTIR) of the cleaned flexible polymer component found similar spectra between the exemplar (as-manufactured) and explanted flexible polymer component indicating a lack of material degradation.

Histological analyses of 12 explanted devices:

A chronic foreign-body type granulomatous inflammatory response was observed in 7 out of 12 explant patients, when the foreign material (PET flexible polymer component) exited the immunoprivileged disc space (i.e., subsidence or migration of the PET flexible polymer component). This inflammation was associated the polymer fibers or particles and fibrous encapsulation, which was not unexpected as a foreign body response. The chronic inflammation severity was highest in explants from patients implanted with the device for at least 3 years. There was no indication of infection and no large colonies of polymorphonuclear leukocytes (neutrophils) observed in any of the twelve patients. In explant analyses of tissues which contained bone from subjects with flexible polymer component subsidence or migration, osteolysis was noted in four (4) out of five (5) subjects. Bone loss (osteolysis) is an additional potential safety concern with flexible polymer component subsidence or migration.

Herniated or migrated nucleus pulposus tissue, as well as PET polymeric particles, were associated with the inflammatory response. Nucleus pulposus was present on some of the histopathologic slides in the 7 cases above in which histiocytic inflammation was observed; chronic granulomatous inflammation (with foreign-body multinucleated giant cell macrophages) was associated with PET polymeric particles.

The retrieval analysis further supported concerns seen within the baboon study regarding the formation of lesions and related osteolysis due to the device. While there are concerns resulting from the retrieval analyses, particularly with the continued inflammation at late timepoints, these data were captured from patients who had the device removed and were already considered failures of the study composite endpoint. Additional concern for low level inflammation or lesion progression will be addressed in the post-approval studies.

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# X. SUMMARY OF PRIMARY CLINICAL STUDY

The applicant performed a clinical study to determine whether there was a reasonable assurance of safety and effectiveness of the Barricaid to reduce the incidence of reherniation, and reoperation for patients who require a lumbar discectomy in response to radiculopathy (with or without back pain), a posterior or posterolateral herniation, characterized by radiographic confirmation of neural compression using MRI, and a large anular defect post discectomy for a primary surgery, at one level between L1 and S1. Data from this clinical study, which was conducted in Germany, Switzerland, Austria, the Netherlands, Belgium and France, were the basis of the PMA. A summary of the clinical study is presented below.

## A. Study Design

Subjects were treated between December 2010 and October 2014. The database for this PMA reflected data collected through June 4, 2018 and included 554 subjects who were randomized intra-operatively following discectomy.

The Barricaid study was a prospective, multi-center, randomized controlled clinical trial comparing the Barricaid procedure to discectomy alone. The trial was conducted under Good Clinical Practice (GCP), was ISO 14155 compliant and was conducted under all applicable local and federal regulations.

A prospective superiority analysis was performed to determine the safety and effectiveness of the Barricaid device. Subjects included in this trial were considered at higher risk for reherniation due to the presence of anular defects at least 6mm wide after limited discectomy. The overall success criteria defined prospectively was at 24 months, based on improvement documented in the Oswestry Disability Index (ODI), VAS Leg pain, disc height maintenance, lack of reherniations at the index level, no posterior device migration, no device fracture or disassembly, maintenance or improvement in the neurological score, no spontaneous fusion, and no reoperation of any kind at the index level including removal or revision of the Barricaid or supplemental fixation. Intrinsic Therapeutics performed this clinical study with an a priori statistical analysis plan that enabled the generation of valid scientific evidence to claim superiority per the Statistical Analysis Plan ("SAP").

All adverse events (device-related or not) were monitored over the course of the study and radiographic assessments were performed by an independent core laboratory. Overall success was initially determined with data collected during the initial 24 months of follow-up. All serious adverse events, other adverse events, and protocol deviations reported by the clinical investigators were independently adjudicated (for adverse event group, severity and relatedness to the device and/or procedure) by a Data Safety Monitoring Board ("DSMB") composed of three independent, US-Board certified spine surgeons and one independent US board-certified musculoskeletal radiologist.

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In order to address concerns expressed by the Agency and the FDA's Orthopedic and Rehabilitation Devices Panel regarding continued development and longer-term impact of bone lesions, additional longer-term data from the original RCT cohort was provided by the company. Each enrolled subject will be followed until he/she reaches 60 months. Data handling and analyses were performed by third-party statisticians.

## 1. Clinical Inclusion and Exclusion Criteria

The inclusion/exclusion criteria were:

| Enrollment in the study was limited to patients who met the following inclusion criteria:
- Age 21 to 75 years old and skeletally mature (male or female).
- Patients with posterior or posterolateral disc herniations at one level between L1 and S1 with radiographic confirmation of neural compression using MRI. [Note: Intraoperatively, only patients with an anular defect (post discectomy) between 4mm and 6mm tall and 6mm and 10mm wide qualified.]
- At least six (6) weeks of failed, conservative treatment prior to surgery, including physical therapy, use of anti-inflammatory medications at maximum specified dosage and/or administration of epidural/facet injections.
- Minimum posterior disc height of 5mm at the index level.
- Radiculopathy (with or without back pain) with a positive Straight Leg Raise (0 - 60 degrees)6 (L4-5, L5-S1) or Femoral Stretch Test (L1-2, L2-3, L3-4).
- Oswestry Questionnaire score of at least 40/100 at baseline.
- VAS leg pain (one or both legs) of at least 40/100 at baseline.
- Psychosocially, mentally and physically able to fully comply with the clinical protocol and willing to adhere to follow-up schedule and requirements. Intraoperative Inclusion Criteria
- Only patients with an anular defect (post discectomy) between 4mm and 6 mm tall and 6 mm and 10 mm wide qualified. | Patients were not permitted to enroll in the study if they met any of the following exclusion criteria:
- Spondylolisthesis Grade II or higher (25% slip or greater).
- Subject required spinal surgery other than a discectomy (with or without laminotomy) to treat leg/back pain (scar tissue and osteophyte removal is allowed).
- Subject had back or non-radicular leg pain of unknown etiology.
- Prior surgery at the index lumbar vertebral level.
- Subject requiring a spine Dual-Energy X-Ray Absorptiometry (“DEXA”) (i.e., subjects with SCORE of ≥ 6) with a T Score less than -2.0 at the index level. For patients with a herniation at L5-S1, the average T score of L1-L4 was used.
- Subject had clinically compromised vertebral bodies in the lumbosacral region due to any traumatic, neoplastic, metabolic, or infectious pathology.
- Subject had sustained pathologic fractures of the vertebra or multiple fractures of the vertebra or hip.
- Subject has scoliosis of greater than ten (10) degrees (both angular and rotational).
- Any metabolic bone disease.
- Subject had an active infection either systemic or local.
- Subject had cauda equina syndrome or neurogenic bowel/bladder dysfunction.
- Subject had severe arterial insufficiency of the legs or other peripheral vascular disease. (Screening on physical examination for subjects with diminution or absence of dorsalis pedis or posterior tibialis pulses. If diminished or absent by palpation, then an arterial ultrasound was required with vascular plethysmography. If the absolute arterial pressure was below 50mm of Hg at the index level, the arterial pressure was not below 50mm.) |
| --- | --- |

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| | calf or ankle level, then the subject was excluded.)
• Subject had significant peripheral neuropathy; subjects with Type I or Type II diabetes or similar systemic metabolic condition causing decreased sensation in a stocking-like or non-radicular and non-dermatomal distribution in the lower extremities.
• Subject had insulin-dependent diabetes mellitus.
• Subject was morbidly obese (defined as a body mass index >40 or weighed more than 100 lbs. over ideal body weight).
• Subject with active hepatitis, AIDS, or HIV.
• Subject with rheumatoid arthritis or other autoimmune disease.
• Subject with a known allergy to titanium, polyethylene or polyester materials.
• Any subject that could not have a baseline MRI taken.
• Subject was pregnant or interested in becoming pregnant in the next three (3) years.
• Subject had active tuberculosis or tuberculosis in the past three (3) years.
• Subject with a history of active malignancy: a subject with a history of any invasive malignancy (except non-melanoma skin cancer), unless he/she had been treated with curative intent and there were no signs or symptoms of the malignancy for at least two (2) years.
• Subject was immunologically suppressed and/or having received steroids >1 month over the past year.
• Subject was currently taking anticoagulants, other than aspirin, unless the subject could be taken off the anticoagulant for surgery.
• Subject with a current chemical/alcohol dependency or significant psychosocial disturbance.
• Subject with a life expectancy of less than three (3) years.
• Subject involved in active spinal litigation.
• Subject involved in another investigational study.
• Subject was incarcerated.
• Any contraindication for MRI or CT scan (e.g. claustrophobia, contrast allergy). |
| --- | --- |

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2. Follow-Up Schedule

All patients were scheduled to return for follow-up examinations in the schedule shown with the windows listed below in Table 10-1. The measurements taken preoperatively and postoperatively are also listed in this table. Adverse events and complications were recorded at all visits.

Table 10-1: Follow-Up Schedule
| Measurement | Baseline | Surgery | Discharge | 6 Weeks (± 2W) | 3 Months (± 2W) | 6 Months (± 1M) | 12 Months (± 2M) | 24 Months (± 2M) | 36 Months (± 2M) | Annually Thereafter* (± 2M) |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| ODI | X | | | X | X | X | X | X | X | X |
| VAS (Back and Leg) | X | | | X | X | X | X | X | X | X |
| SF-36v2™ | X | | | X | X | X | X | X | X | X |
| Neurological Assessment | X | | | X | X | X | X | X | X | X |
| Adverse Events | X | X | X | X | X | X | X | X | X | X |
| MRI with both T1 and T2 weighted axial and sagittal images | X | | | | | | X | X | X | X |
| Multiplanar Low dose CT at index level with 2D Coronal Reconstructions | X | | | | | | X | X | X | X |
| Neutral AP X-rays | X | | X | X | X | X | X | X | X | X |
| Neutral Lateral X-rays | X | | X | X | X | X | X | X | X | X |
| Flexion/Extension X-rays | X | | | | | | X | X | X | X |

*The current protocol states this will be continued out to 60 months.

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3. Clinical Endpoints

Per the original protocol, success of each individual subject and the study was determined at the 24-month evaluation time point. This study had two co-primary endpoints. Success of the study is based on the Barricaid population achieving statistical superiority over the concurrently randomized, non-implanted discectomy population for each of the two endpoints independently.

a. Reherniation: To be considered a success, a subject will have no evidence of recurrent herniation at the index level at any time up to and including the 24-month follow-up. Recurrent herniation may be confirmed surgically, or radiographically as determined by an independent review (unless surgically confirmed that the suspected herniation is not a herniation, e.g. scar tissue or residual nucleus material). This includes all reherniations, including both symptomatic and asymptomatic reherniations.

b. A composite of safety and effectiveness. To be considered a success, a subject will have achieved success in each of the following components at 24 months:

- 15-point (out of 100 points) improvement in Oswestry Disability Index (ODI) compared to pre-op
- 20-point (on a 100-point scale) improvement in VAS Leg (based on the primary leg complaint; if both legs have a minimum of 40/100 pre-operatively, the average leg score will be used)
- Maintenance of average disc height (75% or greater of preoperative disc height) compared to pre-op
- No deterioration of neurological status at the index level
- Device integrity: Maintenance of device condition and lack of implant migrations (radiographic, implanted subjects only)
- No spontaneous fusion
- No reherniation at the index level (on either side)
- No secondary surgical interventions (SSI) at the index level

While this original composite endpoint was complex, this was a novel device for which evaluation of other endpoints was considered necessary to provide surgeons and subjects a more complete understanding of how the Barricaid performed clinically. Intrinsic Therapeutics collected a number of other endpoints and evaluations. Safety concerns regarding the device also necessitated a longer-term follow-up and assessment compared to the 24-month primary success criteria originally planned by the sponsor. These outcomes are presented in the Safety and Effectiveness sections below.

Intrinsic Therapeutics also collected the following additional endpoints, the most notable to surgeons and patients is the recurrence of symptomatic herniation. Symptomatic reherniation was defined as radiographically or surgically confirmed herniation of the index level that were associated with any of the following criteria:

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- reoperation of the index level,
- an unscheduled visit,
- adverse event with treatment for index level herniation,
- adverse event for pain or neurological issue associated with the index level within a 2-month window, or
- VAS leg ≥40/100, ODI ≥40/100, and a positive straight leg raise (L4-5 or L5-S1) or femoral stretch test (L1-L4).

These criteria were designed after study initiation and approved by the DSMB, thereby creating a broad net which captured any index level reherniation that could be associated with concordant adverse symptoms, in an effort to avoid the bias created by under-reporting of events by sites.

In addition to the endpoints described above, other secondary endpoints and assessments included the following:

- Visual Analog Scale - Back Pain and Contralateral Leg Pain (mean score, mean improvement from baseline, incidence of 20 point improvement)
- Quality of Life - SF36 Mental and Physical Component Scores (mean scores, mean improvement from baseline)
- Adverse Event Rates
- Quantitative x-ray measures: Translational and Angular Range of Motion during Flexion-Extension, Sagittal Disc Angle, Spondylolisthesis (mean values, change from baseline)
- Endplate Lesion Number, Dimensions (mean size, change from prior timepoint)
- Endplate Lesion Features: Location, Proximity to Device
- Device Subsidence (prevalence)

## 4. DSMB Safety Oversight

The DSMB reviewed accumulating data from the ongoing clinical trial on a quarterly basis. This board consisted of experts in the field of neurological or orthopedic spine surgery and musculoskeletal radiology, with a statistician providing input as needed. The purpose of the DSMB was to advise Intrinsic Therapeutics regarding the continued safety of all study participants. The DSMB process included review, adjudication, and grouping of adverse events, serious adverse events, and protocol deviations, as well as monitoring study progress and compliance. The DSMB maintained the ability to stop the study due to pre-defined safety concerns.

## B. Accountability of PMA Cohort

Subject accounting and compliance is provided in Table 10-2. Both theoretical and actual follow-up are provided for each follow-up interval through 60 months, for both randomized arms of the trial. Note that there is an allowable "window" within which the various follow-up visits may occur. The determination of whether a subject is theoretically due was based upon the exact anniversary of the surgical procedure.

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Shown, for each scheduled follow-up visit, are the theoretical follow-up, defined as the number of subjects for whom data would be available at each time point if all subjects returned for follow-up on the exact anniversary of their Barricaid or Control procedure. “Not yet overdue” includes subjects whose surgical anniversary has occurred; however, clinical data has not yet been collected (i.e., ODI and/or VAS is currently unavailable) but the subject is still in the protocol specified follow-up window. Such subjects may yet be observed and so follow-up compliance estimates account for this by removing such subjects from the denominator as well as from the numerator when determining compliance ratios.

From “theoretical due” we subtract cumulative deaths and cumulative “secondary surgical intervention failures” (i.e., reoperations, revisions, removals, and supplemental fixation) – as well as those not yet overdue – to calculate the number of subjects expected for a follow-up visit. This would reflect the total number of subjects. Adding the expected follow-up to the number of secondary surgical interventions provides the total number of subjects serving as the denominator for composite clinical success (CCS) outcomes per the Clinical Protocol Definition (CPD).

There are two compliance estimates provided in this table. The first is follow-up compliance for clinical visit outcomes including ODI and VAS. This is determined by dividing the number of subjects with clinical visit data (among expected due) divided by total expected due as defined above. As can be seen in Table 10-2, these rates are 94% (228/243) and 91% (211/233) for Barricaid and Controls, respectively. Most importantly, Table 10-1 summarizes follow-up compliance for the primary CCS endpoint. Primary endpoint compliance rates were high at 91% (246/272) and 94% (260/278) for Barricaid and the Control group respectively. When interpreting these results in comparison to the sample sizes based on the analysis data sets presented in the analysis tables, it should be noted that all analysis tables utilized all available data so sample sizes were not restricted to subjects who were theoretically and not yet overdue. Consequently, the samples sizes with observed data are slightly higher.

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Table 10-2: Subject Accounting and Follow-up Compliance Table Efficacy Evaluable Modified Intent to Treat (mITT) Barricaid (I) and Control Subjects (C)

| | Mo. 24 | | Mo. 36 | | Mo. 48 | | Mo. 60 | |
| --- | --- | --- | --- | --- | --- | --- | --- | --- |
| | I | C | I | C | I | C | I | C |
| (1) Theoretical follow-up | 272 | 278 | 272 | 278 | 260 | 267 | 184 | 187 |
| (2) Cumulative deaths | 1 | 0 | 1 | 0 | 1 | 0 | 1 | 1 |
| (3a) Cumulative SSI + No implantation | 28 | 45 | 32 | 51 | 40 | 55 | 43 | 57 |
| (3b) Cumulative Reherniation | 118 | 179 | 135 | 194 | 144 | 203 | 150 | 204 |
| (4) Not Yet Overdue | 0 | 0 | 0 | 0 | 5 | 7 | 3 | 5 |
| (5) Deaths+SSI failures among theoretically due | 29 | 45 | 33 | 51 | 41 | 53 | 37 | 36 |
| (6) Expected due for clinic visit [(6) = (1) - (4) - (5)] | 243 | 233 | 239 | 227 | 214 | 207 | 144 | 146 |
| (7) SSI failures among theoretically due | 28 | 45 | 32 | 51 | 40 | 53 | 36 | 35 |
| (8) Expected due+SSI fails among theoretically Due [(8) = (6) + (7)] | 271 | 278 | 271 | 278 | 254 | 260 | 180 | 181 |
| All Evaluated Accounting (Actual B) Among Expected Due Procedures | | | | | | | | |
| | Mo. 24 | | Mo. 36 | | Mo. 48 | | Mo. 60 | |
| (9) Procedures with any clinical data in interval (Chg VAS or ODI) | 228 | 211 | 185 | 166 | 162 | 144 | 103 | 107 |
| (10) Visit Compliance (%) | 94% | 91% | 77% | 73% | 76% | 70% | 72% | 73% |
| (11) Change in ODI | 228 | 211 | 185 | 166 | 162 | 144 | 103 | 107 |
| (12) Change in VAS Leg | 227 | 211 | 184 | 166 | 161 | 144 | 103 | 107 |
| (13) Neuro evaluations | 252 | 251 | 203 | 207 | 187 | 177 | 131 | 123 |
| (14) Radiography (Avg Disc HT) | 213 | 197 | 156 | 143 | 129 | 104 | 73 | 78 |
| (15) CCS-CPD | 246 | 260 | 219 | 248 | 208 | 224 | 145 | 158 |
| (16) Actual B % Follow-up for CCS-CPD | 91% | 94% | 81% | 89% | 82% | 86% | 81% | 87% |
| Within Window Accounting (Actual A) Among Expected Due Procedures | | | | | | | | |
| | I | C | I | C | I | C | I | C |
| (17) Procedures with any clinical data in interval (Chg VAS or ODI) | 203 | 188 | 156 | 129 | 139 | 108 | 69 | 79 |
| (18) Visit Compliance (%) | 84% | 81% | 65% | 57% | 65% | 52% | 48% | 54% |
| (19) Change in ODI | 203 | 188 | 156 | 129 | 139 | 108 | 69 | 79 |
| (20) Change in VAS Leg | 202 | 188 | 155 | 129 | 138 | 108 | 69 | 79 |
| (21) Neuro evaluations | 222 | 223 | 173 | 165 | 160 | 138 | 88 | 92 |
| (22) Radiography (Avg Disc HT) | 192 | 178 | 130 | 114 | 108 | 84 | 50 | 59 |
| (23) CCS-CPD | 212 | 223 | 158 | 162 | 147 | 134 | 81 | 92 |
| (24) Actual A % Follow-up for CCS-CPD | 78% | 80% | 58% | 58% | 58% | 52% | 45% | 51% |

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Figure 10.1:Subject Accounting Tree Relating to Evaluable Subjects for CCS Calculation at 2 years

# C. Study Population Demographics and Baseline Parameters

Analyses in the PMA demonstrated the demographics of the OUS study population are similar to typical lumbar herniation US population published in literature. Demographic data and preoperative evaluations for the randomized subjects treated in the study are included in Table 10-3 and Table 10-4. There were no statistically significant differences in demographics, baseline characteristics, or preoperative evaluations when comparing the randomized treatment groups.

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Table 10-3: Summary of Baseline and Demographic Continuous Variables

| | Barricaid (n=272) | | | Control (n=278) | | | Nominal* t-test p-value |
| --- | --- | --- | --- | --- | --- | --- | --- |
| | Mean | SD | Med | Mean | SD | Med | |
| Baseline Demographics | | | | | | | |
| Age, years | 42.9 | 10.9 | 43.0 | 44.0 | 10.4 | 43.0 | 0.235 |
| Height, cm | 175.8 | 9.4 | 176.0 | 175.5 | 9.1 | 175.0 | 0.687 |
| Weight, kg | 81.4 | 15.3 | 81.3 | 81.3 | 14.9 | 80.0 | 0.939 |
| BMI, kg/m2 | 26.3 | 4.1 | 25.5 | 26.3 | 4.1 | 25.8 | 0.809 |
| Baseline Clinical Scores | | | | | | | |
| VAS Leg | 80.8 | 15.1 | 84.0 | 80.8 | 14.6 | 83.0 | 0.970 |
| VAS Back | 56.6 | 30.0 | 66.0 | 55.7 | 31.4 | 66.0 | 0.743 |
| ODI | 59.0 | 12.4 | 58.0 | 58.2 | 13.7 | 56.0 | 0.476 |

BMI=body mass index, Med=median, ODI=Oswestry disability index, SD=standard deviation, VAS=visual analog scale
* "Nominal" means the statistic was not adjusted for multiple comparisons

Table 10-4: Summary of Baseline and Demographic Categorical Variables

| | Barricaid | | | Control | | | Nominal Chi-squared p-value |
| --- | --- | --- | --- | --- | --- | --- | --- |
| | N | n | % | N | n | % | |
| Gender, % | | | | | | | |
| Female | 272 | 116 | 42.6% | 278 | 107 | 38.5% | 0.321 |
| Male | 272 | 156 | 57.4% | 278 | 171 | 61.5% | 0.321 |
| Smoker %* | | | | | | | |
| Current | 272 | 121 | 44.5% | 278 | 123 | 44.2% | 0.955 |
| History | 176 | 52 | 29.5% | 186 | 52 | 28.0% | 0.739 |
| Current or History | 272 | 173 | 63.6% | 278 | 175 | 62.9% | 0.874 |
| Race, % | | | | | | | |
| Caucasian | 272 | 270 | 99.3% | 278 | 273 | 98.2% | 0.266 |
| Non-Caucasian | 272 | 2 | 0.7% | 278 | 5 | 1.8% | 0.266 |

* With regards to smoking status, the question "Have you ever smoked?" is only asked of subjects who answered "no" to "Do you currently smoke?"

## D. Surgical Level and Approach Data

Surgical level, anular defect characteristics and surgical approach data are summarized below in Table 10-5. Barricaid devices were implanted into the inferior vertebral body of the disc in 61.4% of cases (164/267). Similarly, exploratory analyses concluded that device orientation had no significant impact on clinical outcomes.

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Table 10-5: Summary of surgical level and approach data

| | Overall | | | Barricaid | | | Control | | | Significance | |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| | N | n | % | N | n | % | N | n | % | Δ | Nominal Chi-squared p-value |
| Index Level, % | | | | | | | | | | | 0.077 |
| L2/3 | 550 | 3 | 0.5% | 272 | 2 | 0.7% | 278 | 1 | 0.4% | 0.3% | |
| L3/4 | 550 | 13 | 2.4% | 272 | 8 | 2.9% | 278 | 5 | 1.8% | 1.1% | |
| L4/5 | 550 | 225 | 40.9% | 272 | 124 | 45.6% | 278 | 101 | 36.3% | 9.3% | |
| L5/S1 | 550 | 309 | 56.2% | 272 | 138 | 50.7% | 278 | 171 | 61.5% | -10.8% | |
| Anulus Defect Type, % | | | | | | | | | | | 0.356 |
| Bulge/Weakness | 550 | 165 | 30.0% | 272 | 80 | 29.4% | 278 | 85 | 30.6% | -1.2% | |
| Fissure | 550 | 101 | 18.4% | 272 | 46 | 16.9% | 278 | 55 | 19.8% | -2.9% | |
| Full Thickness | 550 | 282 | 51.3% | 272 | 146 | 53.7% | 278 | 136 | 48.9% | 4.8% | |
| None | 550 | 2 | 0.4% | 272 | 0 | 0.0% | 278 | 2 | 0.7% | -0.7% | |
| Geometry, % | | | | | | | | | | | 0.056 |
| Box | 550 | 341 | 62.0% | 272 | 182 | 66.9% | 278 | 159 | 57.2% | 9.7% | |
| Cruciate | 550 | 29 | 5.3% | 272 | 11 | 4.0% | 278 | 18 | 6.5% | -2.5% | |
| Puncture/Slit | 550 | 155 | 28.2% | 272 | 65 | 23.9% | 278 | 90 | 32.4% | -8.5% | |
| None | 550 | 25 | 4.5% | 272 | 14 | 5.1% | 278 | 11 | 4.0% | 1.1% | |
| Surgical Approach, % | | | | | | | | | | | 0.343 |
| Created New | 550 | 205 | 37.3% | 272 | 96 | 35.3% | 278 | 109 | 39.2% | -3.9% | |
| Through Existing | 550 | 345 | 62.7% | 272 | 176 | 64.7% | 278 | 169 | 60.8% | 3.9% | |
| Defect Width | | | | | | | | | | | 0.288 |
| 6 mm | 550 | 93 | 16.9% | 272 | 49 | 18.0% | 278 | 44 | 15.8% | 2.2% | |
| 7 mm | 550 | 120 | 21.8% | 272 | 65 | 23.9% | 278 | 55 | 19.8% | 4.1% | |
| 8 mm | 550 | 173 | 31.5% | 272 | 88 | 32.4% | 278 | 85 | 30.6% | 1.8% | |
| 9 mm | 550 | 82 | 14.9% | 272 | 37 | 13.6% | 278 | 45 | 16.2% | -2.6% | |
| 10 mm | 550 | 82 | 14.9% | 272 | 33 | 12.1% | 278 | 49 | 17.6% | -5.5% | |
| Defect Height | | | | | | | | | | | 0.934 |
| 4 mm | 550 | 169 | 30.7% | 272 | 83 | 30.5% | 278 | 86 | 30.9% | -0.4% | |
| 5 mm | 550 | 271 | 49.3% | 272 | 136 | 50.0% | 278 | 135 | 48.6% | 1.4% | |
| 6 mm | 550 | 110 | 20.0% | 272 | 53 | 19.5% | 278 | 57 | 20.5% | -1.0% | |

Surgeons were trained in definitions of “Defect Type (bulge/weakness, Fissure, Full thickness defect (through hole), or None)” and “Defect Geometry (Puncture/Slit, Cruciate, Box, or None)” during the site initiation visit, prior to enrollment of the first subject at that site.

Surgeon investigators were trained to measure the size (height and width separately) of the anular defect per the instructions in the surgical technique manual. Specifically, surgeons

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were trained to insert incrementally larger Defect Measurement Tools (provided in 1-mm increments) into the anular defect until a size is reached that passes with light resistance while the next-larger tool does not pass. Surgeons were trained to measure the height and width separately and to not rotate the tool within the defect (e.g., from width to height, or vice-versa).

## E. Safety Results

### 1. Adverse Event Summary

The analysis of safety was based on the As-Treated (AT) cohort of 550 subjects (267 Barricaid subjects and 283 Control subjects) available for evaluation. All Adverse Event (AE) data presented includes all events observed at the time of data lock, which includes all patients having reached three years and additional subjects reaching four (4) and five (5) years as documented in the subject accounting table. Prior to analysis, the DSMB adjudicated all AEs for relatedness and severity. In addition, the DSMB grouped each site-reported AE into DSMB-defined categories intended to be as clinically meaningful as possible (Table 10).

When making an assessment of safety, an 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 for all subjects. AEs were categorized as device-related or procedure-related.

### AE Device/Procedure-Relatedness:

- Unknown: The relationship between the adverse event and the device (or procedure) cannot be determined based upon available data.
- Not-Related: A temporal relationship to investigational product implantation or its ongoing use, which makes a causal relationship clearly and incontrovertibly due to extraneous causes, such as other drugs, products, chemicals, underlying diseases, environment, etc. Not-related to the investigational product administration.
- Possibly-Related: Occurring within a reasonable period of time relative to investigational product administration or its ongoing use which makes causal relationship possible, but plausible explanations may also be provided by other causes, such as other drugs, products, chemicals, underlying disease, environment, etc. Possibly-related to investigational product administration.
- Probably-Related: Occurring within a reasonable period of time relative to investigational product administration or its ongoing use, which makes a causal relationship probable where the relationship cannot be attributed to other causes, such as other drugs, products, chemicals, underlying disease, environment, etc. Probably-related to the investigational product administration.

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- Definitely-Related: Occurring within a reasonable period of time relative to investigational product administration or can be directly related to the ongoing use of an investigational product, which makes a causal relationship definite where the relationship cannot be attributed to other causes, such as other drugs, products, chemicals, underlying disease, environment, etc. Definitely-related to the investigational product administration.

# Serious AEs:

- Serious: Per ISO 14155, an adverse event that:

Led to death,
- Led to serious deterioration in the health of the subject that either resulted in

A life-threatening illness or injury,
A permanent impairment of a body structure or body function, or
Requires inpatient hospitalization or prolongation of existing hospitalization,
Medical or surgical intervention to prevent a life threatening illness or injury or permanent impairment to a body structure or body function

- Led to fetal distress, fetal death, or a congenital anomaly or birth defect

Table 10-6: AE Definitions used by DSMB

| Adverse Event | Definition |
| --- | --- |
| Benign soft tissue masses/tumors | lipoma, subcutaneous nodules, liver lesion, benign mass/tumor - non-lumbar |
| Cancer | Includes cases of lung lymph node metastasis, brain tumor (non-malignant), CEA increase, and cholangiocarcinoma |
| Cardiac and Vascular • Bleeding - index procedure • Other | • Blood loss requiring intervention due to index study procedure, epidural hemorrhage, • The Cardiac and Vascular total also includes the following subcategories which are not listed in detail: transient ischemic attack (TIA)/stroke, pulmonary embolism, aneurysm of the aorta, hypertension, heart surgery, mesenteric ischemia, varicose veins, chest pain/angina, myocardial infarction, cardiac/heart failure, cardiac arrhythmia, circulation problems |
| Death | Includes case of death due to metatstatic cancer of unknown primary |
| Dermatologic | Includes any condition of the skin such as: fungal infection, herpes zoster, and skin rash. If condition is around surgical site, AE coded to wound issue. |

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| Adverse Event | Definition |
| --- | --- |
| **Device Deficiency**
• Anchor (whole device) migration
• Mesh Migration
• Mesh Subsidence
• Mesh Detachment
• Anchor Fracture
• Other | • Includes anchor (whole device) migration out of the vertebral body.
• Includes migration of the occlusion component into the epidural space (extradiscal), normal occlusion component movement within the disc space (intradiscal)
• Includes occlusion component subsidence into a vertebral body with or without occlusion component detachment
• Includes clear detachment of the occlusion component from the anchor into the epidural space (extradiscal) or within the disc space (intradiscal)
• Includes fracture of the titanium anchor component of the device
• Includes difficulty upon implantation |
| **Disc Herniation**
• Herniation - Index Level
• Residual herniation - Index Level
• Disc Herniation - Adjacent Level
• Disc Herniation - Non-Adjacent Level | • Includes post-operative herniation at the index level (both ipsi- and contralateral)
• Includes residual herniation at index level
• Includes disc herniations at a level adjacent to the index level
• Includes disc herniations at a level not adjacent to the index level including lumbar, thoracic and cervical levels |
| **Endocrine** | Includes thyroid disorders, diabetes |
| **Eyes/Ears/Nose/Throat (EENT)** | Any condition of the eyes, ears, nose, throat or mouth including: sinusitis, tinnitis, hearing loss, dental procedures/disorder, eye injury/disorder/surgery, tracheitis |
| **Gastrointestinal** | Includes nausea, vomiting, gastroenteritis, diarrhea, abdominal pain, esophageal reflux, gastric bypass/banding, gastric ulcer, appendicitis, fatty liver degeneration, hernia, diverticulitis, intestinal polyps, gastrointestinal bleeding, cholecystectomy, and ileus |
| **Genitourinary** | Includes erectile dysfunction, retrograde ejaculation, urinary retention/incontinence, urinary tract infection, sterilization/vasectomy, testicular infection, prostatic hypertrophy, nephrolithiasis, sexual dysfunction, epididymitis |
| **OB/GYN** | Pregnancy, elective abortion, temporary loss of menstruation, ovarian cysts, breast biopsy, hysterectomy |
| **Infectious Disease** | Includes systemic or local viral, bacterial or fungal infections not associated with the index or secondary lumbar procedures, sepsis |
| **Immunological** | Includes allergic reaction to medications, Grave's Disease and rheumatoid arthritis |
| **Metabolic/Hematologic/Electrolytes** | Includes hypothermia, anemia, edema, lipedema, and electrolyte disorders |

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| Adverse Event | Definition |
| --- | --- |
| Musculoskeletal - Lumbar
• Spinal Instability
• Scoliosis
• Radiographic Finding
• Facet Syndrome
• Other | • Abnormal movement between spinal segments
• Abnormal curvature of the lumbar spine
• Includes post-operative osteophyte formation. Does not include necrosis of bone or resorption.
• Includes post-operative symptomatic lumbar facet joint degeneration/disorder
• Includes pseudarthrosis (after secondary surgery), reoperation, and osteochondrosis |
| Musculoskeletal - Non-Lumbar | Includes non-radicular hip, knee, foot and ankle pain or injury; SI joint pain and discomfort; cervical, thoracic, sacral and coccygeal spinal pain, injury or disorders; upper extremity including, shoulder, elbow, wrist and hand pain or injury; arthritis, tendonitis, bursitis, and restless leg syndrome |
| Neurological - Lumbar and Lower Extremity
• Nerve or Spinal Root Injury: Index Surgery
• Nerve Root or Spinal cord Impingement
• Musculoskeletal Spasms of the Back or Legs
• Neurological Deterioration
• Other | • Includes nerve or spinal root injury during the index surgery
• Includes numbness or lumboischialgia due to nerve root or spinal cord impingement. Does not include trauma during index surgery
• Includes cramping or spasms in the back and/or legs
• Includes clinically significant neurological deterioration from baseline and prior visit such as: new paraesthesia, absent reflexes, weakness, decreased motor strength, and sensory deficits
• Includes post-lumbar puncture and polyneuropathy of unknown origins |
| Neurological - Non- Lumbar/Lower Extremity | Includes peripheral nerve entrapment such as: carpal tunnel syndrome, cubital syndrome; peripheral neuropathy, loss of bowel and bladder control, cervical radiculopathy, multiple sclerosis, Bell's Palsy, facial myoclonus, psychological paraplegia, and headache/migraine |
| Pain - Lumbar and Lower Extremity
• Lower Extremity Pain Only
• Lumbar Pain Only
• Lumbar and Lower Extremity Pain
• Lumbar and/or Lower Extremity Pain: non-specific | • Pain in the upper and/or lower leg
• Includes low back pain or non-specified back pain. Does not include thoracic pain (coded to Musculoskeletal - Non-Lumbar/Lower Extremity)
• Pain in the upper and/or lower leg(s) and back pain
• Non-specific pain as reported by the site in the back and/or legs. |
| Psychological | Includes depression, and anxiety and burnout |

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| Adverse Event | Definition |
| --- | --- |
| Respiratory/Pulmonary | Includes COPD, pneumothorax, sleep apnea, bronchitis, pneumonia, influenza, and upper respiratory tract infection |
| Trauma | Includes fall, vehicle accident, sporting accident, work injury, animal bite, and assault |
| Wound Issue- Index or Secondary Surgery at Index Level | |
| • Dural Injury/Tear or CSF Leak | • Any tear of the dura or cerebrospinal fluid leak caused by or occurring during the index procedure or secondary surgery at index procedure |
| • Wound Infection | • Any wound infection, with the wound being identified as the surgical site for any index procedure or secondary surgery at index procedure. All other infections get coded with specific body systems. This includes both deep and superficial infections. |
| • Hematoma | • Includes seroma, hematoma associated with the index procedure or secondary surgery at index procedure |
| • Delayed Wound Healing | • Any delayed wound healing not associated with infection |
| •Deep | •Includes wound seromas |
| • Dehiscence | • Rupture along the incision from any index procedure or secondary surgery at index procedure |
| Necrosis of Bone or Resorption | Includes endplate lesions at the index level as identified by the investigator as a radiographic finding on control and treated patients. |

Please note that "Necrosis of Bone or Resorption" was the category listed on the Case Report Forms (CRFs). This was the only category available for which the physician was able to report the presence of endplate lesions (EPLs) as an AE; however, it does not necessarily mean that the physician observed necrosis, or that treatment was prescribed.

The key safety outcomes are presented in Table 10-7 through Table 10-9.

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 10-7.

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Table 10-7: Comparisons of Summary Adverse Event Rates between Barricaid and Control Discectomy – AT Analysis Sets

| | Barricaid (N=267) | | | Control (N=283) | | | |
| --- | --- | --- | --- | --- | --- | --- | --- |
| | Events | Subjs | % | Events | Subjs | % | Nominal p-value† |
| All Adverse Events | | | | | | | |
| Any Adverse event (per patient) | 680 | 227 | 85.0% | 635 | 231 | 81.6% | 0.305 |
| Device Related Adverse Events | | | | | | | |
| Any device related* AE | 362 | 182 | 68.2% | 9 | 6 | | |
| Any device related (Definite / Probable) AE | 96 | 82 | 30.7% | 3 | 2 | | |
| Any device related (Possible / Unknown) AE | 266 | 149 | 55.8% | 6 | 4 | | |
| Procedure Related Adverse Events | | | | | | | |
| Any procedure related* AE | 394 | 189 | 70.8% | 356 | 183 | 64.7% | 0.145 |
| Any procedure related (Definite / Probable) AE | 160 | 115 | 43.1% | 145 | 103 | 36.4% | 0.117 |
| Any procedure related (Possible / Unknown) AE | 290 | 153 | 57.3% | 214 | 140 | 49.5% | 0.073 |
| Device or Procedure Related Adverse Events | | | | | | | |
| Any device or procedure related* AE | 395 | 189 | 70.8% | 356 | 183 | 64.7% | 0.145 |
| Any device or procedure (Definite/Probable) AE | 168 | 119 | 44.6% | 145 | 103 | 36.4% | 0.056 |
| Any device or procedure (Possible/Unknown) AE | 227 | 132 | 49.4% | 211 | 140 | 49.5% | 1.000 |
| All Serious Adverse Events (SAE) | | | | | | | |
| Any Serious AE | 209 | 113 | 42.3% | 219 | 126 | 44.5% | 0.607 |
| SAE - Device Related | | | | | | | |
| SAE - Dev. Related* | 77 | 49 | 18.4% | 3 | 2 | | |
| SAE - Dev. Related (Definite / Probable) | 18 | 16 | 6.0% | 2 | 1 | | |
| SAE - Dev. Related (Possible / Unknown) | 59 | 40 | 15.0% | 1 | 1 | | |
| SAE - Procedure Related | | | | | | | |
| SAE - Proc. Related* | 82 | 51 | 19.1% | 115 | 72 | 25.4% | 0.082 |
| SAE - Proc. Related (Definite / Probable) | 41 | 31 | 11.6% | 80 | 58 | 20.5% | 0.005 |
| SAE - Proc. Related (Possible / Unknown) | 41 | 28 | 10.5% | 35 | 26 | 9.2% | 0.668 |
| SAE - Device or Procedure Related | | | | | | | |
| SAE - Dev. or Proc. Related* | 83 | 51 | 19.1% | 115 | 72 | 25.4% | 0.082 |
| SAE - Dev. or Proc. Related (Definite / Probable) | 43 | 32 | 12.0% | 80 | 58 | 20.5% | 0.008 |
| SAE - Dev. or Proc. Related (Possible / Unknown) | 63 | 41 | 15.4% | 36 | 27 | 9.5% | 0.051 |
| Death | | | | | | | |
| Death | 1 | 1 | 0.4% | 1 | 1 | 0.4% | 0.999 |
| †Fisher's Exact
*Definite, Probable, Possible, Unknown | | | | | | | |

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Table 10-7 shows the comparison of complication rates between the Barricaid and Control AT discectomy cohorts. Device-related events could potentially be reported in the Control AT population because it includes subjects who were randomized to Barricaid but not successfully implanted (n=5) as well as Control subjects who were later treated with a Barricaid implant due to a reherniation failure (n=5). Overall, the impact of these events in interpreting the safety data is limited as evidenced by the rare occurrences of device-related Serious Adverse Events (SAEs) in the Control AT population (3 events in 2 subjects).

There was one statistically significant difference with regards to SAEs that were definitely or probably device-related or procedure-related (12% vs. 20.5%, nominal p=0.008). Please note that “nominal” means that the p-value was not adjusted for multiple comparisons. This statistical difference was in the direction of fewer events, primarily reherniations, in the Barricaid group. This outcome is important since it balances SAEs related to Barricaid (consisting mainly of device failures such as migration) with the procedure-related SAEs (consisting mainly of reherniation-related SAE’s). Despite the presence of a device, the combined device- or procedure-related SAE rate was still higher in the Control discectomy group, thereby suggesting discectomy plus Barricaid has a greater safety profile compared to discectomy alone.

Specific adverse events are listed in alphabetical order according to adverse event groups in Table 10-8. The data shows the comparison of percentages with adverse event groups and types between the Barricaid and Control cohorts for specific adverse event groups and types.

There was a statistically significant difference with disc herniation events which were significantly lower in the Barricaid group (21% vs. 32.5%, nominal p=0.003). It is important to note these were AEs documented by the clinical site, rather than the core radiographic lab, therefore less uniform in reporting.

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Table 10-8: Counts and Percentages of Subjects with Specific Adverse Events (Group and Type) in Barricaid and Control Discectomy – AT Population

| | Barricaid (N = 267) | | | Control (N = 283) | | | Significance | |
| --- | --- | --- | --- | --- | --- | --- | --- | --- |
| | Events Subjs | | % | Events Subjs | | % | Dif | p-value† |
| BENIGN SOFT TISSUE MASSES/TUMORS | 3 | 3 | 1.1% | 2 | 2 | 0.7% | 0.4% | 0.678 |
| CANCER | 8 | 7 | 2.6% | 5 | 4 | 1.4% | 1.2% | 0.371 |
| CARDIAC AND VASCULAR | 26 | 23 | 8.6% | 25 | 24 | 8.5% | 0.1% | 1.000 |
| bleeding | 2 | 2 | 0.7% | 0 | 0 | 0.0% | 0.7% | 0.235 |
| other | 24 | 21 | 7.9% | 25 | 24 | 8.5% | -0.6% | 0.877 |
| DEATH | 1 | 1 | 0.4% | 1 | 1 | 0.4% | 0.0% | 1.000 |
| DERMATOLOGIC | 3 | 3 | 1.1% | 4 | 4 | 1.4% | -0.3% | 1.000 |
| DEVICE DEFICIENCY | 35 | 34 | 12.7% | 1 | 1 | | | |
| anchor (whole device) migration | 5 | 5 | 1.9% | 0 | 0 | | | |
| occlusion component | 29 | 29 | 10.9% | 1 | 1 | | | |
| other | 1 | 1 | 0.4% | 0 | 0 | | | |
| DISC HERNIATION | 71 | 56 | 21.0% | 120 | 92 | 32.5% | -11.5% | 0.003 |
| herniation - index level | 40 | 36 | 13.5% | 101 | 83 | 29.3% | -15.8% | <.001 |
| residual herniation - index level | 2 | 2 | 0.7% | 0 | 0 | 0.0% | 0.7% | 0.235 |
| disc herniation - adjacent level | 19 | 17 | 6.4% | 15 | 14 | 4.9% | 1.4% | 0.580 |
| disc herniation - non-adjacent level | 10 | 9 | 3.4% | 4 | 4 | 1.4% | 2.0% | 0.164 |
| ENDOCRINE | 8 | 8 | 3.0% | 4 | 4 | 1.4% | 1.6% | 0.250 |
| EYES/EARS/NOSE/THROAT (EENT) | 11 | 11 | 4.1% | 22 | 22 | 7.8% | -3.7% | 0.075 |
| GASTROINTESTINAL | 28 | 21 | 7.9% | 36 | 31 | 11.0% | -3.1% | 0.245 |
| GENITOURINARY | 18 | 18 | 6.7% | 17 | 16 | 5.7% | 1.1% | 0.601 |
| OB/GYN | 11 | 10 | 3.7% | 8 | 8 | 2.8% | 0.9% | 0.635 |
| INFECTIOUS DISEASE | 7 | 5 | 1.9% | 4 | 4 | 1.4% | 0.5% | 0.746 |
| IMMUNOLOGICAL | 3 | 3 | 1.1% | 7 | 7 | 2.5% | -1.3% | 0.341 |
| METABOL./HEMATO./ELECTROLYTES | 4 | 4 | 1.5% | 8 | 8 | 2.8% | -1.3% | 0.385 |
| MUSCULOSKELETAL - LUMBAR | 19 | 17 | 6.4% | 14 | 11 | 3.9% | 2.5% | 0.244 |
| spinal instability | 2 | 2 | 0.7% | 0 | 0 | 0.0% | 0.7% | 0.235 |
| scoliosis | 0 | 0 | 0.0% | 3 | 3 | 1.1% | -1.1% | 0.249 |
| radiographic finding | 5 | 5 | 1.9% | 0 | 0 | 0.0% | 1.9% | 0.026 |
| facet syndrome | 10 | 9 | 3.4% | 8 | 6 | 2.1% | 1.3% | 0.438 |
| other | 2 | 2 | 0.7% | 3 | 3 | 1.1% | -0.3% | 1.000 |
| MUSCULOSKELETAL - NON-LUMBAR | 89 | 66 | 24.7% | 85 | 64 | 22.6% | 2.1% | 0.616 |
| NEURO - LUMBAR AND LOWER EXTREMITY | 44 | 37 | 13.9% | 33 | 30 | 10.6% | 3.3% | 0.297 |
| nerve or spinal root injury: index surgery | 2 | 2 | 0.7% | 4 | 4 | 1.4% | -0.7% | 0.687 |
| nerve root or spinal cord impingement | 4 | 4 | 1.5% | 2 | 1 | 0.4% | 1.1% | 0.204 |
| muskuloskeletal spasms of the back or legs | 9 | 9 | 3.4% | 1 | 1 | 0.4% | 3.0% | 0.009 |
| neurological deterioration | 28 | 23 | 8.6% | 26 | 24 | 8.5% | 0.1% | 1.000 |
| other | 1 | 1 | 0.4% | 0 | 0 | 0.0% | 0.4% | 0.485 |
| NEURO - NON-LUMBAR/LOWER EXTREMITY | 21 | 18 | 6.7% | 15 | 11 | 3.9% | 2.9% | 0.181 |
| PAIN - LUMBAR AND LOWER EXTREMITY | 146 | 100 | 37.5% | 142 | 109 | 38.5% | -1.1% | 0.861 |
| lower extremity only | 43 | 38 | 14.2% | 53 | 46 | 16.3% | -2.0% | 0.554 |
| lumbar | 72 | 62 | 23.2% | 72 | 64 | 22.6% | 0.6% | 0.919 |
| lumbar and lower extremity | 29 | 25 | 9.4% | 17 | 14 | 4.9% | 4.4% | 0.047 |
| non-specific | 2 | 2 | 0.7% | 0 | 0 | 0.0% | 0.7% | 0.235 |
| PSYCHOLOGICAL | 15 | 15 | 5.6% | 15 | 15 | 5.3% | 0.3% | 1.000 |
| RESPIRATORY/PULMONARY | 6 | 6 | 2.2% | 14 | 14 | 4.9% | -2.7% | 0.112 |
| TRAUMA | 23 | 22 | 8.2% | 24 | 22 | 7.8% | 0.5% | 0.876 |
| WOUND ISSUE- SSI AT INDEX LEVEL | 26 | 22 | 8.2% | 24 | 21 | 7.4% | 0.8% | 0.753 |
| dural injury/tear or csf leak | 19 | 18 | 6.7% | 14 | 14 | 4.9% | 1.8% | 0.467 |
| infection | 2 | 2 | 0.7% | 5 | 4 | 1.4% | -0.7% | 0.687 |
| hematoma | 3 | 3 | 1.1% | 2 | 2 | 0.7% | 0.4% | 0.678 |
| delayed wound healing | 1 | 1 | 0.4% | 0 | 0 | 0.0% | 0.4% | 0.485 |
| dehiscence | 0 | 0 | 0.0% | 1 | 1 | 0.4% | -0.4% | 1.000 |
| dysp | 1 | 1 | 0.4% | 2 | 2 | 0.7% | -0.3% | 1.000 |
| NECROSIS OF BONE OR RESORPTION | 54 | 52 | 19.5% | 5 | 5 | 1.8% | 17.7% | <.001 |

† Fisher's Exact.

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Table 10-9 provides the actual counts of specific events by time of onset. While most device deficiency adverse events were distributed throughout the 24-month timepoint (24/35), roughly a third of these device deficiencies occurred at 24 months (12), with fewer events (11/35) occurring after 24 months, though the subjects with complete five year follow-up remains incomplete. The proportion of subjects with other clinically relevant adverse event categories such as lumbar and lower extremity pain (nominal p=0.861), lumbar or lower extremity neurological events (nominal p=0.181), musculoskeletal lumbar events (nominal p=0.244), and wound issues (nominal p=0.753) were not statistically different between Barricaid and Control and do not suggest any increased safety risk associated with the implant. As an example, lumbar and lower extremity pain adverse events were similar in overall number (146 Barricaid vs. 142 Control) and tracked similarly at each annual timepoint (e.g. 67 Barricaid vs. 71 Control at year 1, 93 Barricaid vs. 97 Control at year 2).

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Table 10-9: Counts of Specific Adverse Events (Groups, Types) by Time of Occurrence – Barricaid and Control Discectomy AT Analysis Sets

| | Immed PostOp | | 1 mo | | 3 mo | | 6 mo | | 12 mo | | 24 mo | | 36 mo | | 48 mo | | 60 mo | | 60+ mo | | Total | |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| | I | C | I | C | I | C | I | C | I | C | I | C | I | C | I | C | I | C | I | C | I | C |
| BENIGN SOFT TISSUE MASSES/TUMORS | 0 | 0 | 0 | 1 | 2 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 3 | 2 |
| CANCER | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 2 | 0 | 2 | 0 | 1 | 0 | 2 | 2 | 0 | 3 | 1 | 0 | 8 | 5 |
| CARDIAC AND VASCULAR | 3 | 3 | 1 | 4 | 2 | 2 | 2 | 3 | 2 | 0 | 3 | 2 | 5 | 3 | 6 | 6 | 2 | 1 | 0 | 1 | 26 | 25 |
| bleeding | 2 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 2 | 0 |
| other | 1 | 3 | 1 | 4 | 2 | 2 | 2 | 3 | 2 | 0 | 3 | 2 | 5 | 3 | 6 | 6 | 2 | 1 | 0 | 1 | 24 | 25 |
| DEATH | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 1 | 1 |
| DERMATOLOGIC | 0 | 1 | 1 | 1 | 0 | 0 | 0 | 1 | 1 | 0 | 1 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 3 | 4 |
| DEVICE DEFICIENCY | 1 | 0 | 0 | 0 | 3 | 0 | 2 | 0 | 5 | 0 | 13 | 1 | 10 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 35 | 1 |
| anchor (whole device) migration | 0 | 0 | 0 | 0 | 2 | 0 | 1 | 0 | 1 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 5 | 0 |
| occlusion component | 0 | 0 | 0 | 0 | 1 | 0 | 1 | 0 | 4 | 0 | 12 | 1 | 10 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 29 | 1 |
| other | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 |
| DISC HERNIATION | 1 | 0 | 3 | 11 | 2 | 11 | 4 | 8 | 12 | 17 | 20 | 32 | 10 | 20 | 14 | 11 | 3 | 8 | 2 | 2 | 71 | 120 |
| herniation - index level | 0 | 0 | 2 | 11 | 1 | 11 | 3 | 8 | 5 | 13 | 13 | 28 | 7 | 17 | 6 | 10 | 1 | 3 | 2 | 0 | 40 | 101 |
| residual herniation - index level | 1 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 2 | 0 |
| disc herniation - adjacent level | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 4 | 3 | 6 | 3 | 2 | 2 | 5 | 1 | 2 | 4 | 0 | 2 | 19 | 15 |
| disc herniation - non-adjacent level | 0 | 0 | 0 | 0 | 1 | 0 | 1 | 0 | 3 | 1 | 1 | 1 | 1 | 1 | 3 | 0 | 0 | 1 | 0 | 0 | 10 | 4 |
| ENDOCRINE | 0 | 0 | 1 | 0 | 1 | 0 | 0 | 0 | 0 | 1 | 1 | 0 | 1 | 1 | 3 | 1 | 1 | 1 | 0 | 0 | 8 | 4 |
| EYES/EARS/NOSE/THROAT (EENT) | 0 | 0 | 0 | 3 | 2 | 2 | 0 | 2 | 4 | 3 | 3 | 7 | 1 | 0 | 0 | 3 | 1 | 2 | 0 | 0 | 11 | 22 |
| GASTROINTESTINAL | 3 | 3 | 2 | 4 | 2 | 2 | 1 | 2 | 4 | 5 | 5 | 4 | 6 | 7 | 2 | 3 | 2 | 6 | 1 | 0 | 28 | 36 |
| GENITOURINARY | 1 | 0 | 0 | 1 | 3 | 0 | 1 | 2 | 3 | 2 | 4 | 3 | 2 | 2 | 1 | 5 | 3 | 1 | 0 | 1 | 18 | 17 |
| OB/GYN | 0 | 1 | 0 | 0 | 1 | 1 | 2 | 0 | 1 | 2 | 1 | 0 | 2 | 1 | 1 | 3 | 3 | 0 | 0 | 0 | 11 | 8 |
| INFECTIOUS DISEASE | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 1 | 0 | 1 | 1 | 1 | 1 | 0 | 1 | 1 | 1 | 2 | 0 | 7 | 4 |
| IMMUNOLOGICAL | 1 | 1 | 0 | 0 | 0 | 1 | 0 | 0 | 1 | 1 | 0 | 0 | 0 | 3 | 1 | 1 | 0 | 0 | 0 | 0 | 3 | 7 |
| METABOL/Hemato/ ELECTROLYTES | 0 | 3 | 0 | 1 | 0 | 0 | 0 | 2 | 0 | 1 | 3 | 0 | 0 | 1 | 0 | 0 | 1 | 0 | 0 | 0 | 4 | 8 |
| MUSCULOSKELETAL - LUMBAR | 0 | 0 | 1 | 0 | 1 | 1 | 5 | 1 | 1 | 2 | 2 | 2 | 2 | 2 | 2 | 3 | 3 | 3 | 2 | 0 | 19 | 14 |
| spinal instability | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 2 | 0 |
| scoliosis | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 3 | 3 |
| radiographic finding | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 1 | 0 | 0 | 0 | 2 | 0 | 1 | 0 | 5 | 0 |
| facet syndrome | 0 | 0 | 1 | 0 | 1 | 1 | 5 | 0 | 0 | 1 | 1 | 2 | 0 | 1 | 1 | 0 | 1 | 3 | 0 | 0 | 10 | 8 |
| other | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 1 | 2 | 0 | 0 | 1 | 0 | 2 | 3 |
| MUSCULOSKELETAL - NON-LUMBAR | 1 | 1 | 3 | 2 | 6 | 8 | 14 | 14 | 8 | 14 | 14 | 9 | 22 | 14 | 9 | 12 | 10 | 9 | 2 | 2 | 89 | 85 |
| NEURO - LUMBAR AND LOWER EXTREMITY | 3 | 6 | 4 | 1 | 6 | 9 | 5 | 7 | 5 | 2 | 8 | 2 | 6 | 1 | 4 | 3 | 3 | 0 | 0 | 2 | 44 | 33 |
| nerve or spinal root injury: index surgery | 2 | 4 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 2 | 4 |
| nerve root or spinal cord impingement | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 3 | 0 | 0 | 2 | 1 | 0 | 0 | 0 | 4 | 2 |
| muskuloskeletal spasms of the back or legs | 0 | 0 | 2 | 0 | 2 | 1 | 1 | 0 | 1 | 0 | 1 | 0 | 1 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 9 | 1 |
| neurological deterioration | 1 | 2 | 2 | 1 | 4 | 8 | 4 | 7 | 4 | 2 | 6 | 2 | 2 | 1 | 3 | 1 | 2 | 0 | 0 | 1 | 28 | 26 |
| other | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 |
| NEURO - NON-LUMBAR/LOWER | 1 | 2 | 2 | 1 | 2 | 1 | 3 | 1 | 1 | 2 | 5 | 2 | 4 | 4 | 2 | 2 | 1 | 0 | 0 | 0 | 21 | 15 |
| PAIN - LUMBAR AND LOWER EXTREMITY | 1 | 0 | 7 | 12 | 29 | 14 | 17 | 22 | 13 | 23 | 26 | 26 | 18 | 23 | 14 | 11 | 14 | 10 | 7 | 1 | 146 | 142 |
| lower extremity only | 0 | 0 | 3 | 8 | 9 | 7 | 7 | 8 | 4 | 8 | 8 | 10 | 2 | 4 | 3 | 4 | 5 | 4 | 2 | 0 | 43 | 53 |
| lumbar | 1 | 0 | 2 | 3 | 14 | 6 | 8 | 12 | 8 | 11 | 12 | 14 | 12 | 18 | 7 | 5 | 4 | 3 | 4 | 0 | 72 | 72 |
| lumbar and lower extremity | 0 | 0 | 1 | 1 | 6 | 1 | 2 | 2 | 1 | 4 | 6 | 2 | 4 | 1 | 4 | 2 | 5 | 3 | 0 | 1 | 29 | 17 |
| non-specific | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 2 | 0 | |
| PSYCHOLOGICAL | 0 | 0 | 0 | 1 | 1 | 1 | 2 | 0 | 1 | 1 | 3 | 4 | 2 | 1 | 5 | 4 | 1 | 3 | 0 | 0 | 15 | 15 |
| RESPIRATORY/PULMONARY | 0 | 0 | 0 | 1 | 1 | 1 | 0 | 1 | 0 | 3 | 2 | 5 | 1 | 2 | 1 | 1 | 1 | 0 | 0 | 0 | 6 | 14 |
| TRAUMA | 0 | 2 | 0 | 0 | 1 | 2 | 2 | 1 | 0 | 7 | 12 | 5 | 4 | 2 | 3 | 2 | 1 | 3 | 0 | 0 | 23 | 24 |
| WOUND ISSUE- SSI AT INDEX LEVEL | 14 | 9 | 6 | 5 | 0 | 2 | 0 | 3 | 3 | 0 | 0 | 2 | 0 | 1 | 1 | 2 | 1 | 0 | 1 | 0 | 26 | 24 |
| dural injury/tear or csf leak | 12 | 7 | 1 | 0 | 0 | 1 | 0 | 2 | 3 | 0 | 0 | 1 | 0 | 1 | 1 | 2 | 1 | 0 | 1 | 0 | 19 | 14 |
| infection | 0 | 0 | 2 | 3 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 2 | 5 |
| hematoma | 2 | 2 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 3 | 2 |
| delayed wound healing | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 |
| dehiscence | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 1 |
| deep | 0 | 0 | 1 | 2 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 2 |
| NECROSIS OF BONE OR RESORPTION | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 9 | 0 | 27 | 3 | 10 | 1 | 3 | 0 | 4 | 0 | 1 | 1 | 54 | 5 | |

## 2. Device- and Procedure-Related Adverse Events

The device- and procedure-related adverse events by Group are presented in Table 10-10. There were two statistically significant differences. First, is the disc herniation AEs (14.2% vs. 29.3%, nominal p&lt;.001) related to the device or procedure. These outcomes mirror the Barricaid intended use, which is to reduce the incidence of reherniation. The

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subject table demonstrates Barricaid significantly decreases the incidence of disc herniations, as reported by physician AEs, considered to be related to the device or procedure. This complements the reherniation analyses presented in Section 10.6.4.1 that also demonstrate Barricaid reduces the occurrence of both symptomatic and asymptomatic reherniation. The significant difference in procedure or device related reherniation AEs outweighed the number of AEs related to the device deficiencies. Device deficiency adverse events were reported in 12.7% of Barricaid subjects, with the majority (29/34) exhibiting a deficiency related to the polymer component of the implant. As discussed in further detail in 10.5.7, approximately half of observed device deficiencies were asymptomatic.

The second significant difference was site-reported bone resorption or necrosis, which were lik…