← Product Code OPR · P170032

# Woven EndoBridge (WEB) Aneurysm Embolization System (P170032)

_MicroVention, Inc. · OPR · Dec 31, 2018 · Neurology · APPR_

**Canonical URL:** https://fda.innolitics.com/device/P170032

## Device Facts

- **Applicant:** MicroVention, Inc.
- **Product Code:** OPR
- **Decision Date:** Dec 31, 2018
- **Decision:** APPR
- **Device Class:** Class 3
- **Review Panel:** Neurology
- **Attributes:** Therapeutic

## Intended Use

The WEB Aneurysm Embolization System is indicated for use at the middle cerebral artery (MCA) bifurcation, internal carotid artery (ICA) terminus, anterior communicating artery (AComm) complex, or basilar artery apex for the endovascular treatment of adult patients with saccular, wide neck, bifurcation intracranial aneurysms with dome diameter from 3 mm to 10 mm and either neck size 4 mm or greater or the dome-to-neck ratio is greater than 1 and less than 2.

## Device Story

Intrasaccular flow disruption device; consists of braided, self-expanding nitinol mesh implant and delivery system. Implanted into intracranial aneurysm sac via microcatheter; electro-thermally detached using hand-held, battery-powered controller. Used in clinic/OR by neurovascular specialists. Device disrupts blood flow within aneurysm sac; promotes occlusion. Physician selects size/shape (barrel or sphere) based on aneurysm morphology. Output is physical occlusion of aneurysm; visualized via fluoroscopy using platinum radiopaque markers. Benefits include potential for aneurysm occlusion without parent artery stenting; reduced thromboembolic risk; lower antiplatelet requirements.

## Clinical Evidence

Prospective, multi-center, single-arm, open-label pivotal study (WEB-IT) (N=150). Primary safety endpoint: composite of death or major stroke within 30 days or major ipsilateral stroke/neurological death 31-365 days. Primary effectiveness endpoint: complete aneurysm occlusion (WOS A/B) without retreatment, recurrent SAH, or >50% parent artery stenosis at 1 year. Primary safety event rate: 0.67% (1/150). Primary effectiveness success rate: 54.77% (lower 90% CI 47.97%). 12.6% recurrence rate (recanalization/regrowth). Bench and animal studies supported mechanical/biocompatibility performance.

## Technological Characteristics

Implant: braided, self-expanding mesh of nitinol wires and nitinol wires with platinum core. Barrel or sphere shapes. Platinum-iridium coupler. Platinum radiopaque markers. Delivery system: navigated via microcatheter. Detachment: electro-thermal via battery-powered controller. MRI Conditional (3T). Sterilization: Gamma (implant), Ethylene Oxide (controller).

## Regulatory Identification

An intrasaccular flow disruption device is intended for use to treat wide-neck intracranial aneurysms in the neurovasculature through an endovascular approach.

## Reference Devices

- Low-Profile Visualized Intraluminal Support (LVIS) and LVIS Jr. ([P170013](/device/P170013.md))
- Stryker Neurovascular Neuroform EZ, 3, Atlas Stent Systems (H020002)
- Codman & Shurtleff, Inc. Enterprise Vascular Reconstruction Device and Delivery System (H060001)
- Pulsar Vascular, Inc. PulseRider Aneurysm Neck Reconstruction Device (H160002)
- Micro Therapeutics, Inc., Pipeline Embolization Device (PED) ([P100018](/device/P100018.md))
- Pipeline Flex Embolization Device ([P100018](/device/P100018.md))
- Stryker Neurovascular's Surpass Streamline Flow Diverter ([P170024](/device/P170024.md))

## Submission Summary (Full Text)

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SUMMARY OF SAFETY AND EFFECTIVENESS DATA (SSED)

I. GENERAL INFORMATION

Device Generic Name: Intrasaccular Flow Disruption Device

Device Trade Name: Woven EndoBridge (WEB) Aneurysm Embolization System

Device Procode: OPR

Applicant's Name and Address: Sequent Medical, Inc. 11A Columbia Street Aliso Viejo, CA 92656

Date(s) of Panel Recommendation: September 27, 2018

Premarket Approval Application (PMA) Number: P170032

Date of FDA Notice of Approval: 12/31/2018

II. INDICATIONS FOR USE

The WEB Aneurysm Embolization System is indicated for use at the middle cerebral artery (MCA) bifurcation, internal carotid artery (ICA) terminus, anterior communicating artery (AComm) complex, or basilar artery apex for the endovascular treatment of adult patients with saccular, wide neck, bifurcation intracranial aneurysms with dome diameter from 3 mm to 10 mm and either neck size 4 mm or greater or the dome-to-neck ratio is greater than 1 and less than 2.

III. CONTRAINDICATIONS

The WEB Aneurysm Embolization System is contraindicated in the following patients:

- Patients with known active bacterial infection that may interfere with or negatively affect the implantation procedure.
- Patients with known hypersensitivity to nickel.

IV. WARNINGS AND PRECAUTIONS

The warnings and precautions can be found in the WEB Aneurysm Embolization System labeling.

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# V. DEVICE DESCRIPTION

The WEB Aneurysm Embolization System ("WEB") consists of an implantable device attached to a delivery system. The delivery system is navigated through compatible microcatheters with a specified minimum inner diameter (see Table 1) to the intracranial aneurysm (IA). An introducer sheath can be used to assist in the placement of the delivery system into the microcatheter. The WEB implant is electro-thermally detached by the physician with a hand-held, battery-powered detachment controller device designed specifically for the WEB Aneurysm Embolization System. The WEB Detachment Controller (WDC) is provided separately and is for single use only.

![img-0.jpeg](img-0.jpeg)
Figure 1. WEB Aneurysm Embolization System

The WEB implant is manufactured from nitinol wires and nitinol wires with a platinum core in a braided, self-expanding mesh configuration. The WEB implant is provided in a range of sizes (diameters and lengths) and two different shapes (barrel and sphere) (see Figure 2 and Table 1). During treatment, the physician selects the appropriate device size and shape based on the size, shape, and location of the IA.

![img-1.jpeg](img-1.jpeg)
Figure 2. WEB Single Layer - Enhanced Visualization (SL EV) (left) and WEB Single Layer Sphere - Enhanced Visualization (SLS EV) (right) Implant Shapes

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Table 1. WEB Sizes and Recommended Microcatheters

| WEB SL/SLS EV Diameter (mm) | SL Heights Offered (mm) | SLS Height Offered (mm) | Minimum Microcatheter Inner Diameter (inches) | Recommended Microcatheter |
| --- | --- | --- | --- | --- |
| 4 | 3 | 2.6 | 0.021 | VIA 21 |
| 4 |
| 5 | 3 | 3.6 | 0.021 |
| 4 |
| 5 |
| 6 | 3 | 4.6 | 0.021 |
| 4 |
| 5 |
| 7 | 3 | 5.6 | 0.021 |
| 4 |
| 5 |
| 6 |
| 8 | 3 | 6.6 | 0.027 | VIA 27 |
| 4 |
| 5 |
| 6 |
| 7 |
| 9 | 4 | 7.6 | 0.027 |
| 5 |
| 6 |
| 7 |
| 8 |
| 10 | 5 | 8.6 | 0.032 | VIA 33 |
| 6 |
| 7 |
| 8 |
| 11 | 6 | 9.6 | 0.032 |
| 7 |
| 8 |
| 9 |

As shown in Figure 3 below, proximal and distal platinum radiopaque markers in all WEB device models allow WEB implant delivery under fluoroscopic visualization. The proximal end of all WEB implants incorporates a platinum-iridium coupler for attachment to the delivery system. There is zero (0) interwire distance at the proximal marker band adjacent to the coupler where all the wires converge (100% metal coverage and zero porosity).

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![img-2.jpeg](img-2.jpeg)
Figure 3. WEB Implant Design Characteristics

# VI. ALTERNATIVE PRACTICES AND PROCEDURES

There are several other alternatives for the treatment of wide-neck intracranial aneurysms that are directed at the aneurysm itself. These alternatives include open surgical clipping and endovascular treatment using neurovascular embolic coil assist stents to support embolization coils in the intracranial aneurysm sac and balloon catheter assisted coiling of the intracranial aneurysm. The neurovascular embolic coil assist stents available in the United States (US) for stent-assisted coiling of wide-neck intracranial aneurysms were approved through the premarket approval (PMA) and Humanitarian Device Exemption (HDE) regulatory pathways. Specifically, these are the MicroVention, Inc. Low-Profile Visualized Intraluminal Support (LVIS) and LVIS Jr. (P170013), the Stryker Neurovascular Neuroform EZ, 3, Atlas Stent Systems (H020002), and the Codman & Shurtleff, Inc. Enterprise Vascular Reconstruction Device and Delivery System (H060001). A similar HDE approved device that is indicated to support neurovascular embolization coils specifically for the treatment of unruptured wide-necked intracranial aneurysms originating on or near a vessel bifurcation of the basilar tip or carotid terminus is the Pulsar Vascular, Inc. PulseRider Aneurysm Neck Reconstruction Device (H160002).

Neurovascular flow-diverting stents are implanted in the parent artery adjacent to an aneurysm. They are intended to be used by themselves as a stand-alone device. Flow diverters are implanted in the parent artery across the neck of the intracranial aneurysm to divert the blood flow away from the intracranial aneurysm sac. Eventually, endothelial growth around the stent may promote intracranial aneurysm occlusion. The Micro Therapeutics, Inc., Pipeline Embolization Device (PED) and Pipeline Flex Embolization Device (P100018) and Stryker Neurovascular's Surpass Streamline Flow Diverter (P170024) are approved neurovascular flow diverting stents in the US. The PED is approved with the indications for use of endovascular treatment of adults (22 years of age or older) with large or giant wide-necked intracranial aneurysms in the internal carotid artery (ICA) from the petrous to the superior hypophyseal segments. The Pipeline Flex Embolization Device has the same indications for use as the PED and also the expanded indications for use in the ICA up to the terminus for the endovascular treatment of adults (22 years of age or older) with small and medium wide-necked (neck width  $\geq 4$  mm or dome-to-neck ratio  $< 2$ ) saccular or fusiform IAs arising from a parent vessel with a diameter  $\geq 2.0$  mm and  $\leq 5.0$  mm. The Surpass Streamline Flow Diverter is approved

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with the indications for use in the endovascular treatment of patients (18 years of age and older) with unruptured large or giant saccular wide-neck (neck width ≥ 4 mm or dome-to-neck ratio < 2) or fusiform IAs in the ICA from the petrous segment to the terminus arising from a parent vessel with a diameter ≥ 2.5 mm and ≤ 5.3 mm.

Instead of interventional treatments, some may choose conservative medical management or observation with brain imaging to detect any significant morphological changes in the intracranial aneurysm.

Each alternative has its own advantages and disadvantages. Also, each of these alternatives has long and short-term risks and benefits that should be understood by the patients. A patient should fully discuss these alternatives with his/her physician to select the method that best meets expectations and lifestyle.

## VII. MARKETING HISTORY

The WEB Aneurysm Embolization System is approved for marketing in the following countries:

Argentina, Austria, Australia, Belgium, Bulgaria, Chile, Colombia, Czech Republic, Denmark, Finland, France, Germany, Hungary, Ireland, Italy, Lebanon, Netherlands, New Zealand, Norway, Slovenia, Spain, Sweden, Switzerland, Turkey, United Arab Emirates, and United Kingdom.

The WEB Aneurysm Embolization System has not been withdrawn from marketing for any reason related to its safety or effectiveness.

## VIII. PROBABLE ADVERSE EFFECTS OF THE DEVICE ON HEALTH

Below is a list of the probable adverse effects and complications associated with the use of the device.

- Allergic reaction, including but not limited to: contrast dye, nitinol metal, and any other medications used during the procedure
- Anesthesia related complications including airway injury, dental injury, adverse effects of anesthetics, hypoxia, corneal abrasions, and malignant hyperthermia
- Local field inhomogeneity and susceptibility artifacts during magnetic resonance angiography (MRA)
- Aphasia
- Blindness
- Cardiac arrhythmia
- Complications of arterial puncture including pain, local bleeding, local infection, pseudoaneurysm, arteriovenous fistula, injury to the artery, vein, or adjacent nerves, limb ischemia, and retroperitoneal hematoma
- Cranial neuropathy
- Death

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- Device fracture, migration or misplacement including device prolapse or migration into normal vessel adjacent to intracranial aneurysm
- Embolic shower: thrombus, cholesterol, or air emboli
- Dissection or perforation of the aneurysm or vessels in the vasculature
- Headache
- Hemorrhage including intracranial hemorrhage (ICH), subarachnoid hemorrhage (SAH), retroperitoneal (or in other locations), and gastrointestinal
- Hemiplegia
- Hydrocephalus
- Infection
- Injury to normal vessel or tissue
- Ischemia
- Mass effect
- Myocardial infarction
- Neurological deficits
- Patient positioning related injuries including pressure ulcers, limb ischemia, and neuropathy
- Pseudoaneurysm formation
- Reactions to anti-platelet and anti-coagulant agents
- Reactions due to radiation exposure including alopecia, burns ranging in severity from skin reddening to ulcers, cataracts, and delayed neoplasia
- Renal failure
- Rupture of intracranial aneurysm
- Seizure
- Stroke or transient ischemic attack
- Thromboembolic event
- Urinary tract injury secondary to bladder catheterization
- Vasospasm
- Visual impairment

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

## IX. SUMMARY OF NONCLINICAL STUDIES

The WEB Aneurysm Embolization System and the WDC underwent non-clinical mechanical, functional, biocompatibility, sterilization validation, bacterial endotoxin, and animal testing to support the proposed intended use.

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# A. Laboratory Studies

Performance (Bench) Testing

The following table (Table 2) shows laboratory design verification bench testing performed on the WEB Aneurysm Embolization System. The device met all established acceptance criteria.

Table 2. WEB Aneurysm Embolization System Bench Testing

|  Test Name | Test Method Description | Results  |
| --- | --- | --- |
|  Visual and Dimensional (WEB Implant and Delivery System) | Inspect for visual WEB Implant and Delivery System criteria. Measures dimensional attributes of the WEB Implant and Delivery System. Measures the device's initial electrical resistance. | PASS  |
|  Dome Deployment Force | Measures peak force exerted on the dome of an aneurysm model as WEB Implant is deployed. | PASS  |
|  Flat Plate Crush (Radial Force) | Measures the force required to compress the WEB Implant between two plates until it reaches a defined percent of its original outer diameter. | PASS  |
|  WEB Tensile Distal End Weld | Measures ultimate tensile strength (peak force) of WEB Implant (distal to proximal marker band). | PASS  |
|  Detachment Zone Tensile | Measures ultimate tensile strength (peak force) of distal detachment zone junction (tether to WEB Implant) and ultimate tensile strength of tether anchor junction (tether to WEB Delivery System). | PASS  |
|  Hypotube to Core Wire Tensile | Measures ultimate tensile strength of proximal WEB Delivery System junctions. | PASS  |
|  Proximal Connector to Core Wire Tensile | Measures ultimate tensile strength of proximal WEB Delivery System junctions. | PASS  |
|  Overcoil Tensile: Hypotube to Segment II | Measures ultimate tensile strength of overcoil junctions. Tests that the overcoil will not kink when subjected to a worst-case diameter. | PASS  |
|  Overcoil Tensile: Segment II to Segment III | Measures ultimate tensile strength of overcoil junctions. Tests that the overcoil will not kink when subjected to a worst-case diameter. | PASS  |
|  Overcoil Kink | Measures ultimate tensile strength of overcoil junctions. Tests that the overcoil will not kink when subjected to a worst-case diameter. | PASS  |
|  Tracking Force | Measures the peak force required to track a WEB device through the smallest recommended microcatheter in a clinically relevant tortuous model. | PASS  |

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|  Test Name | Test Method Description | Results  |
| --- | --- | --- |
|  WEB Retraction in Microcatheter | Measures the distance that the microcatheter tip pulls back when a worst-case WEB size is recaptured inside of a clinically relevant tortuous model. | PASS  |
|  Particulate Evaluation after Simulated Use with Microcatheter | Counts the particulates generated after a worst-case WEB size is cycled through a microcatheter inside a clinically relevant tortuous model. | PASS  |
|  Cycling and Detachment | Test that the device's electrical resistance remains intact during worst case cycling through a microcatheter in a clinically relevant tortuous model. Test that the tether does not break during worst case cycling through a microcatheter in a clinically relevant tortuous model. Test that the WEB Implant successfully detaches after worst case cycling through a microcatheter in a clinically relevant tortuous model. | PASS  |
|  Magnetic Resonance Imaging (MRI) Compatibility | Magnetic field interaction heating and image artifacts at 3 Tesla (T). Detailed methods described in test report. | PASS  |
|  Corrosion Resistance | Measures the pitting/crevice corrosion of WEB Implants pre-fatigue, as well as after 3-month and 10-year simulated fatigue. Measures rate of galvanic corrosion for WEB Implant wires/marker band couples. | PASS  |
|  WEB Wire Integrity after 10-Year Equivalent Fatigue | Measures number of broken WEB Implant wires after simulated fatigue. Implants are deployed in mock vessels and are subjected to clinically relevant flow conditions for a defined number of cycles equivalent to 10-years before inspection for broken wires. | PASS  |
|  WEB Percent Metal Analysis | Characterization Only – Characterizes the relationship between number of wires, wire size, braid angle, and percent metal coverage compared to flow diverter. Mathematical calculations to establish porosity and % metal coverage of WEB Implants. | N/A – Characterization Only. Average WEB Implant % metal coverage at aneurysm neck is ≥ 58%. The % metal coverage of WEB Implant is greater than comparison flow diverter device.  |
|  WEB Fluid Penetration Characteristics (Wash-Out from an | Characterization Only – Devices deployed in in-vitro aneurysm model. Dye penetration and wash out characteristics were captured with digital imaging/video. | N/A – Characterization Only. Dye penetration and washout characteristics  |
|  Wash-Out from an | Data collection and analysis of WEB Implants. | N/A – Characterization Only. WASHOUT characteristics were captured with digital imaging/video.  |

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Table 3 shows laboratory design verification bench testing performed on the WDC. The device met all established acceptance criteria.

Table 3. WEB Detachment Controller Bench Testing

|  Test Name | Test Method Description | Results  |
| --- | --- | --- |
|  Power Off When Not in Use | Test there is no current through device when device is not in use, tested at both the +8 volt (V) and +5 V terminals. | PASS
All units had a current ≤ 1 mA at both terminals when device was powered off.  |
|  Timeout | Device shuts off automatically if detachment button is not pressed within specified length of time. Measures the time until shut off after a WEB Delivery System is inserted. | PASS  |
|  Detachment Voltage Output and Duration (Detachment Time) | Measures the voltage output and firing duration during detachment. | PASS  |
|  Pre-detachment Resistance Check - Load In Range (LIR) & Load Out of Range (LOR) | Verifies that the WDC produces the correct indicators when both in-range and out-of-range probes are inserted. | PASS
All units displayed correct light emitting diode (LED), buzzer, and firing signals for LIR and LOR probes.  |
|  Shut-off Current | The WDC shuts off automatically if current limit is reached. Measures current at which WDC automatically shuts off. | PASS  |
|  Electrical Safety Testing | Ensures the WDC passes all electrical safety testing in accordance with ISO 60601-1:2006+A12:2014. | PASS  |
|  Electromagnetic Compatibility (EMC) Testing | Ensures the WDC passes all EMC testing in accordance with ISO 60601-1-2:2015. | PASS  |

## Biocompatibility

Biocompatibility testing of sterile finished WEB Aneurysm Embolization Systems were performed in accordance with ISO 10993-1, Biological Evaluation of Medical Devices – Part 1: Evaluation and Testing within a Risk Management Process (see Table 4 and Table 5

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for biocompatibility testing for the WEB implant and delivery system, respectively). The device passed all established acceptance criteria.

Table 4. WEB Implant Biocompatibility

|  Biological Effect | Test | Applicable Standard | Result  |
| --- | --- | --- | --- |
|  Cytotoxicity | International Standard Organization (ISO) Minimum Essential Media (MEM) Elution Assay with L-929 Mouse Fibroblast | ISO 10993-5:2009 | Non-cytotoxic  |
|  Sensitization | ISO Guinea Pig Maximization Sensitization | ASTM F720-81 (2002) | No sensitization response  |
|  Irritation/Intracutaneous Reactivity | ISO Intracutaneous Reactivity Test | ISO 10993-10:2010 | Non-irritant  |
|  Systemic Toxicity (Acute) | ISO Acute Systemic Injection Test | ISO 10993-11:2006 | Non-toxic  |
|  Pyrogenicity | Materials Mediated Rabbit Pyrogen Test | ISO 10993-11:2006 | Non-pyrogenic  |
|  Implantation | 2 Week Subcutaneous Implant Study in Rabbits | ISO 10993-6:2007 | Non-toxic, non-irritant compared to control.  |
|  Subchronic Toxicity/Implantation | 13 Week Subcutaneous Implant Toxicity Study in Rabbits | ISO 10993-6:2007 ISO 10993-11:2006 | Non-toxic, non-irritant compared to control.  |
|  Genotoxicity | In Vitro Mouse Lymphoma Assay | ISO 10993-3:2003 | Non-mutagenic  |
|  Genotoxicity | Bacterial Mutagenicity Test – Ames Assay | ISO 10993-3:2003 | Non-mutagenic  |
|  Genotoxicity | In Vivo Mouse Micronucleus Assay | ISO 10993-3:2003 | Non-mutagenic  |
|  Hemocompatibility | Complement Activation with Comparison Article | ISO 10993-4:2002 (2006) | Results of test group comparable to control group.  |
|  Hemocompatibility | ASTM Hemolysis Assay Direct Contact and Extract | ISO 10993-4:2002 (2006) ASTM F619-03 ASTM F756-08 | Non-hemolytic under direct and extract test conditions.  |
|  Extractables and Leachables Testing  |   |   |   |
|  Metal Leachables Testing | 14-Day and 60-Day Metal Leachables in Saline at 37 °C | N/A | All metal leachables below tolerable intake levels.  |
|  Extractables Testing (Metals | Metal and Organic Chemical Extractables Testing in Worst Case | N/A | All extractables below tolerable intake levels.  |

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Table 5. WEB Delivery System Biocompatibility

|  Biological Effect | Test | Applicable Standard | Result  |
| --- | --- | --- | --- |
|  Cytotoxicity | ISO MEM Elution Assay with L-929 Mouse Fibroblast | ISO 10993-5:2009 | Non-cytotoxic  |
|  Sensitization | ISO Guinea Pig Maximization Sensitization | ASTM F720-81 (2002) | No sensitization response  |
|  Irritation/Intracutaneous Reactivity | ISO Intracutaneous Reactivity Test | ISO 10993-10:2010 | Non-irritant  |
|  Systemic Toxicity (Acute) | ISO Acute Systemic Injection Test | ISO 10993-11:2006 | Non-toxic  |
|  Pyrogenicity | Materials Mediated Rabbit Pyrogen Test | ISO 10993-11:2006 | Non-pyrogenic  |
|  Genotoxicity | In Vitro Mouse Lymphoma Assay | ISO 10993-3:2003 | Non-mutagenic  |
|  Genotoxicity | Bacterial Mutagenicity Test – Ames Assay | ISO 10993-3:2003 | Non-mutagenic  |
|  Genotoxicity | In Vivo Mouse Micronucleus Assay | ISO 10993-3:2003 | Non-mutagenic  |
|  Hemocompatibility | Complement Activation with Comparison Article | ISO 10993-4:2002 (2006) | Results of test group comparable to control group.  |
|  Hemocompatibility | 4 Hour Thromboresistance Evaluation in Dogs | ISO 10993-4:2002 (2006) | Thromboresistance characteristics of test group similar to control.  |
|  Hemocompatibility | ASTM Hemolysis Assay Direct Contact and Extract | ISO 10993-4:2002 (2006) ASTM F619-03 ASTM F756-08 | Non-hemolytic under direct and extract test conditions.  |
|  Extractables Testing  |   |   |   |
|  Extractables Testing (Metals and Organic Chemicals) | Metal and Organic Chemical Extractables Testing in Worst Case Solvents (IPA, Hexane, Acidified Water) at 50 °C | N/A | All extractables below tolerable intake levels.  |

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## B. Animal Studies

Animal studies in elastase induced aneurysms in New Zealand White rabbits were performed to evaluate the acute, subchronic, and chronic performance of the WEB Aneurysm Embolization System regarding immediacy, degree, and durability of aneurysm occlusion (see Table 6). Histopathology findings were also examined and reported in some studies. Test results show that the 45-day, 90-day and 365-day specimens demonstrated high rates of progressive aneurysm occlusion. Histologic evaluation demonstrated an absent or mild inflammatory response.

Table 6. Preclinical Animal Studies

|  Study | Animal Model | Total # of Animals | Follow-up Time Points | Major Endpoints  |
| --- | --- | --- | --- | --- |
|  Feasibility of WEB SL and SLS | Rabbit vein-pouch arterial aneurysm model | 8 | Time of deployment, 2-months, and 3-months. | Immediacy, degree, and durability of aneurysm occlusion.  |
|  Feasibility of WEB SLS | Rabbit elastase aneurysm model | 6 | Time of deployment and 1.5 months. | Immediacy, degree, and durability of aneurysm occlusion. Histopathology.  |
|  Acute, Subchronic, and Chronic Evaluation of WEB | Rabbit elastase aneurysm model | 36 | Time of deployment, 3-months, and 12-months. | Immediacy, degree, and durability of aneurysm occlusion. Histopathology.  |

## C. Additional Studies

### MRI Compatibility

Non-clinical testing demonstrated that the WEB implant is magnetic resonance (MR) Conditional. It can be scanned safely under the following conditions:

- Static magnetic field of 3-Tesla or less.
- Maximum spatial gradient field of 4,000-Gauss/cm (40-T/m).
- Maximum MR system reported, whole body averaged specific absorption rate (SAR) of 2.0-W/kg for 15 minutes of scanning (i.e., per pulse sequence) in the Normal Operating Mode.

Under the scan conditions defined above, the WEB implant is expected to produce a maximum temperature rise of +1.4 °C after 15 minutes of continuous scanning (i.e., per pulse sequence).

In non-clinical testing, the image artifact caused by the WEB implant extends approximately 5 mm from the implant when imaged with a gradient echo pulse sequence and a 3-Tesla MRI system.

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The WEB device may create local field inhomogeneity and susceptibility artifacts during magnetic resonance angiography (MRA), which may degrade the diagnostic quality to assess effective intracranial aneurysm treatment. Users should only use digital subtraction angiography (DSA) or computed tomography angiography (CTA) to assess intracranial aneurysm occlusion for patient follow-up.

## Sterilization Validation

The WEB Aneurysm Embolization System is sterilized using gamma irradiation with a sterility assurance level (SAL) of $10^{-6}$ validated per BS EN ISO 11137-1 (2013) and BS EN ISO 11137-2 (2015). The WEB Detachment Controller is sterilized using ethylene oxide sterilization to a SAL of $10^{-6}$ and validated per BS EN ISO 11135-1 (2014) and ISO 10993-7 (2009).

Routine Limulus Amebocyte Lysate (LAL) batch release testing is performed for every sterile load of WEB devices using the kinetic chromogenic method. Devices are held to the specification of $< 0.06$ endotoxin units (EU)/mL and $< 2.15$ EU/device in accordance with ANSI/AAMI ST72 (2011).

## Shelf-Life

Real time shelf-life testing was conducted on the WEB device and packaging to support a labeled shelf-life of 36 months. Real time shelf-life testing was conducted on the WEB Detachment Controller and packaging to support a labeled shelf-life of 12 months.

## X. SUMMARY OF PRIMARY CLINICAL STUDY (WEB-IT)

The applicant performed a clinical study to establish a reasonable assurance of safety and effectiveness of endovascular treatment with the WEB Aneurysm Embolization System for obtaining occlusion of wide-neck aneurysms at the MCA bifurcation, ICA terminus, AComm complex, and basilar apex. The study was limited to adult patients with saccular, wide neck, bifurcation intracranial aneurysms ranging in size from $3\mathrm{mm}$ to $10\mathrm{mm}$ in dome diameter, where the neck size is $4\mathrm{mm}$ or greater or the dome-to-neck ratio is greater than 1 and less than $2\mathrm{mm}$. The study was performed in the US, Canada, Denmark, Hungary, Turkey, and Germany under IDE #G130286. Data from this clinical study are the basis for the PMA approval decision. A summary of the clinical study is presented below.

## A. Study Design

Patients were treated between August 19, 2014 and March 7, 2016. The database for this PMA reflected data collected through April 21, 2017 and included 179 patients. There were 27 investigational sites.

The study, titled "The WEB Intrasaccular Therapy Study (WEB-IT)," was a prospective, multi-center, single arm, open label clinical study. The pivotal study included follow-up

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at discharge, 30-days, 6-months and 12-months. The pre-specified safety and effectiveness primary endpoints in the clinical study protocol were:

- Safety: The proportion of subjects with death of any non-accidental cause or any major stroke (defined as an ischemic or hemorrhagic stroke resulting in an increase of 4 points or more on the National Institutes of Health Stroke Scale (NIHSS) as of day 7 post onset) within the first 30-days after treatment or major ipsilateral stroke or death due to neurologic cause from day 31 to 365 days after treatment.
- Effectiveness: Successful aneurysm treatment with WEB as defined by complete aneurysm occlusion using the WEB Occlusion Scale (WOS) without retreatment, recurrent subarachnoid hemorrhage, or significant parent artery stenosis (> 50% stenosis) at one year after treatment as assessed by the Core Lab.

The control group was based on performance goals (PGs) developed using prior published data from endovascular intracranial aneurysm treatment and open surgical clipping. The PGs for the primary safety and effectiveness endpoints are 20% and 35%, respectively. Study analyses were conducted using a standard frequentist approach to statistical analysis. The clinical study report provides descriptive statistics such as mean, standard deviation, and frequency charts for baseline participant characteristics, subject disposition, and other relevant study parameters. The primary analysis population was the 150-patient modified intent-to-treat (mITT) population of all study subjects in whom there is an attempt to place the WEB device. All planned statistical analyses were performed using a one-sided nominal significance level of 0.05.

This study included an independent Clinical Events Committee (CEC), Data Safety and Monitoring Board (DSMB), angiographic imaging Core Laboratory (“Core Lab”), and study monitors who confirmed neurological assessments, adverse events, imaging data, and study data with source documentation.

1. Clinical Inclusion and Exclusion Criteria

Enrollment in the WEB-IT study was limited to patients who met the following inclusion criteria.

- Patient must be 18-75 years of age at the time of screening.
- Patient must have a single ruptured or unruptured IA requiring treatment. If the patient had an additional IA requiring treatment, the additional IA must not require treatment within 60-days of the index procedure.

Definition: For the purposes of this study, a ruptured IA patient was defined as a patient with computed tomography (CT), magnetic resonance imaging (MRI), or lumbar puncture (LP) evidence of subarachnoid hemorrhage attributed to the index aneurysm within the last 60-days.

- The IA treated must have had the following characteristics:
- Saccular in shape;

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○ Located in basilar apex (BA), MCA bifurcation, ICA terminus, anterior communicating artery complex (AComm);
○ Dome-to-Neck (DN) ratio ≥ 1;
○ Diameter of the IA appropriate for treatment with the WEB Aneurysm Embolization System per device Instructions for Use; and
○ Wide-neck IA with neck size ≥ 4 mm or DN < 2.

- Patient had an IA that was appropriate for treatment with WEB without the use of additional implanted devices.
- If the IA previously ruptured, patient must be neurologically stable with Hunt & Hess Score of I or II.
- Patient was able to comply with all aspects of the screening, evaluation, treatment, and the post-procedure follow-up schedule.
- Patient signed and dated an institutional review board (IRB)/Ethics Committee (EC)-approved written informed consent prior to initiation of any study procedures.

Patients were not permitted to enroll in the WEB-IT study if they met any of the following exclusion criteria.

- Patient had an IA with characteristics unsuitable for endovascular treatment.
- Microcatheter did not reach patient’s index aneurysm to allow necessary access to treat with study device.
- Patient had vessel characteristics, tortuosity or morphology which precluded safe access and support during treatment with study device.
- Patient had vascular disease or other vascular anomaly that precluded the necessary access to the aneurysm for use of the study device.
- Patient had clinical, angiographic or CT evidence of vasospasm, vasculitis, an intracranial tumor (except small meningioma) or any other intracranial vascular malformations on presentation.
- Patient had conditions placing them at high risk for ischemic stroke or had exhibited ischemic symptoms such as transient ischemic attacks, minor strokes, or stroke-in-evolution within the prior 60-days.
- Patient had any circulatory, neurovascular, cardiovascular, or neurologic conditions that resulted in unstable neurological symptoms.
- Patient had modified Rankin Scale (mRS) score ≥ 2 prior to presentation or rupture (as applicable).
- Patient had an SAH from a non-index aneurysm or any other intracranial hemorrhage within 90-days.
- Patient had physical, neurologic or psychiatric conditions which precluded his/her ability to comply with all aspects of the screening, evaluation, treatment, and the post-procedure follow-up schedule.
- Patient’s index IA was previously treated.
- Patient was taking anticoagulants or had a known blood dyscrasia, coagulopathy, or hemoglobinopathy.
- Patient was pregnant.

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- Patient had known hypersensitivity, which could not be medically treated, to any component of the study device, procedural materials, or medications commonly used during the procedure.
- Patient was concurrently involved in another investigational study or a post-market study that could affect the safety and effectiveness of IA treatment with the study device or with the study's follow-up schedule.
- Patient had an acute life-threatening illness other than the neurological disease to be treated in this trial.
- Patient had a life expectancy of less than 5 years due to other illness or condition (in addition to an intracranial aneurysm).

## 2. Follow-up Schedule

All patients were scheduled to return for follow-up examinations at discharge, 30 days (± 7 days), 6 months (± 30 days), and 12 months (± 7 weeks) postoperatively. Table 7 shows the parameters measured during the study visits, which included a review of the concomitant medications, physical, clinical, neurological, and angiographic evaluations. Adverse events and complications were recorded at all visits. The key assessment timepoints are shown below in the tables summarizing safety and effectiveness.

Table 7. Schedule of Assessments.

|  Parameter | Screening | Procedure | Discharge | 30-Day Follow-Up | 6-Month Follow-Up | 1-Year Follow-Up | 2- and 4-Year Follow-Up | 3- and 5-Year Follow-Up  |
| --- | --- | --- | --- | --- | --- | --- | --- | --- |
|  Health history | X |  |  |  |  |  |  |   |
|  Physical examination | X | X | X |  | X | X |  | X  |
|  Neurological examination | X |  |  |  | X | X |  | X  |
|  Site and subject information | X |  |  |  |  |  |  |   |
|  Aneurysm information (size, location, etc.) | X | X |  |  |  |  |  |   |
|  Rupture status | X |  |  |  |  |  |  |   |
|  Hunt and Hess Grade (ruptured aneurysms only) | X |  |  |  |  |  |  |   |
|  Microcatheter(s) used |  | X |  |  |  |  |  |   |
|  Ancillary devices used (e.g., stent, balloon used) |  | X |  |  |  |  |  |   |
|  Medications used | X | X | X |  | X | X |  | X  |
|  Size and lot number of WEB device(s) used |  | X |  |  |  |  |  |   |
|  WEB procedure fluoroscopy time |  | X |  |  |  |  |  |   |
|  Total procedure fluoroscopy time |  | X |  |  |  |  |  |   |
|  3D angiographic imaging | X | X |  |  | X | X | Optional | X*  |
|  Additional imaging per standard of care |  |  |  |  |  |  | X | X  |
|  Occlusion assessments (Core Lab) |  | X |  |  | X | X | Optional | X*  |
|  Modified Rankin Scale (mRS) score | X |  | X | X | X | X |  |   |
|  NIHSS score | X | As required  |   |   |   |   |   |   |
|  Quality of Life (QOL) Assessment (EQ-5D) |  |  |  |  | X |  |  |   |

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|  Parameter | Screening | Procedure | Discharge | 30-Day Follow-Up | 6-Month Follow-Up | 1-Year Follow-Up | 3- and 4-Year Follow-Up | 5- and 5-Year Follow-Up  |
| --- | --- | --- | --- | --- | --- | --- | --- | --- |
|  Additional scales as appropriate |  | X |  |  | X | X | Optional | Optional  |
|  Technical events |  | X |  |  |  |  |  |   |
|  Adverse events |  | X | X | X | X | X | X | X  |
|  Retreatments/Additional Procedures |  |  |  | X | X | X | X | X  |
|  Re-bleed (if ruptured)/New bleed |  |  | X | X | X | X | X | X  |
|  Comments | X | X | X | X | X | X | X | X  |

* Per local site standard of care.

## 3. Clinical Endpoints

With regards to safety, the percentage of patients who had a disabling stroke (defined as mRS score ≥ 3 assessed at a minimum of 90-days post-stroke event), major stroke (increase of 4 or more points on the NIHSS at 24 hours after symptom onset), or neurological death within 12-months post-procedure was used to analyze the clinical study results.

With regards to effectiveness, the percentage of subjects who had complete occlusion of the target intracranial aneurysm assessed using the WOS A or B without re-treatment, recurrent subarachnoid hemorrhage (SAH), or significant parent artery stenosis (> 50% stenosis) within 12-months post-procedure was used to analyze the clinical study results.

Criteria for success and failure compared the primary outcomes to pre-specified PGs developed from the published literature based on a patient population similar to those treated in the WEB-IT trial using alternative treatment modalities (endovascular treatment or open surgery). The primary endpoints were analyzed using the mITT population and Fisher's Exact Binomial test. The mITT population (N=150) was defined in the clinical protocol as all enrolled subjects for whom the investigational device entered the body, regardless of whether the device was successfully implanted. For safety, a one-sided p-value < 0.05 results in rejecting the null hypothesis that the primary safety endpoint is 20% or higher with the WEB Aneurysm Embolization System. For effectiveness, a one-sided p-value < 0.05 results in rejecting the null hypothesis that the likelihood of effective treatment with the subject device based on the primary effectiveness endpoint definition is ≤ 35%. As part of the decision-making process for the subject PMA, the FDA did not consider the effectiveness or safety PGs of 35% and 20%, respectively, to be acceptable and evaluated the safety and effectiveness profile of the WEB Aneurysm Embolization System based on the results of the WEB-IT trial.

## B. Accountability of PMA Cohort

At the time of database lock, of 179 patients enrolled in the PMA study, 83.8% (150) of patients are available for analysis at the completion of the study, the 12-month post-

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operative visit. See Figure 4 below for a modified CONSORT diagram of the disposition of subjects enrolled in the study.

Figure 4. Subject Accountability in WEB-IT Study
![img-3.jpeg](img-3.jpeg)
[1] All subjects with attempted implant followed through 30 days

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# C. Study Population Demographics and Baseline Parameters

The demographics of the study population are typical for an intracranial aneurysm treatment study performed in the US. This disease predominantly affects more women than men and most patients are Caucasian. The WEB-IT trial population baseline characteristics aligned with these expectations. Baseline characteristics are described in Table 8 and Table 9. Table 8 presents baseline age, weight, and height and digital subtraction angiogram (DSA) measurements of the target intracranial aneurysm.

Table 8. IA Continuous Baseline Measurements (N=150)

|  Characteristic | Mean (Standard Deviation (SD)) Median (Min, Max)  |
| --- | --- |
|  Age | 58.98 (10.16) 59 (29, 79)  |
|  Weight (kg) | 77.25 (19.47) 75.8 (40.8, 142.9)  |
|  Height (cm) | 165.33 (9.70) 163.5 (149.9, 193.0)  |
|  Index Aneurysm - Maximum Sac Width (mm) | 6.35 (1.55) 6.25 (3.58, 11.40)  |
|  Index Aneurysm - Maximum Neck Width (mm) | 4.75 (1.13) 4.67 (2.0, 8.2)  |
|  Index Aneurysm - Max Dome-to-Neck Ratio | 1.3365 (0.2474) 1.2898 (1.0000, 1.9968)  |

Table 9. Categorical Baseline Characteristics

|  Characteristic | Number (%) Unadjusted (Lower Confidence Limit, Upper Confidence Limit)  |
| --- | --- |
|  Gender (Male) | 40/150 (26.67) (19.78, 34.49)  |
|  Racea |   |
|  Asian | 4/116 (3.45) (0.95, 8.59)  |
|  Black or African American | 14/116 (12.07) (6.76, 19.42)  |
|  White | 98/116 (84.48) (76.59, 90.54)  |
|  Ethnicitya |   |
|  Hispanic or Latino | 2/116 (1.72) (0.20, 6.09)  |
|  Not Hispanic or Latino | 114/116 (98.28) (93.91, 99.79)  |
|  Prior Rupture | 9/150 (6.00) (2.78, 11.08)  |
|  Hunt and Hess (Ruptured Only) |   |
|  I | 6/9 (66.67) (29.93, 92.51)  |
|  II | 3/9 (33.33) (7.49, 70.07)  |
|  Unruptured |   |
|  Symptomatic | 33/141 (23.40) (16.69, 31.27)  |

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|  Characteristic | Number (%) Unadjusted (Lower Confidence Limit, Upper Confidence Limit)  |
| --- | --- |
|  Incidental | 108/141 (76.60) (68.73, 83.31)  |
|  History of Cardiovascular/Circulatory Disease | 106/150 (70.67) (62.69, 77.81)  |
|  Angina | 2/150 (1.33) (0.16, 4.73)  |
|  Arrhythmia | 7/150 (4.67) (1.90, 9.38)  |
|  Cardiomyopathy | 1/150 (0.67) (0.02, 3.66)  |
|  Coronary Artery Disease | 21/150 (14.00) (8.88, 20.60)  |
|  Heart Failure | 3/150 (2.00) (0.41, 5.73)  |
|  Heart Block | 1/150 (0.67) (0.02, 3.66)  |
|  Hypertension | 98/150 (65.33) (57.14, 72.91)  |
|  Hypotension | 5/150 (3.33) (1.09, 7.61)  |
|  Myocardial Infarction | 6/150 (4.00) (1.48, 8.50)  |
|  Peripheral Vascular Disease | 5/150 (3.33) (1.09, 7.61)  |
|  Valve Disease/Dysfunction | 5/150 (3.33) (1.09, 7.61)  |
|  History of Dermatological Disease | 5/150 (3.33) (1.09, 7.61)  |
|  Acne | 1/150 (0.67) (0.02, 3.66)  |
|  Eczema | 2/150 (1.33) (0.16, 4.73)  |
|  Psoriasis | 2/150 (1.33) (0.16, 4.73)  |
|  History of Endocrine Disease | 30/150 (20.00) (13.92, 27.30)  |
|  Diabetes | 14/150 (9.33) (5.20, 15.16)  |
|  Hyperthyroidism | 4/150 (2.67) (0.73, 6.69)  |
|  Hypothyroidism | 13/150 (8.67) (4.70, 14.36)  |
|  History of Eye, Ear, Nose, Throat, Head or Neck Disease | 29/150 (19.33) (13.35, 26.57)  |
|  Cataracts | 16/150 (10.67) (6.22, 16.74)  |
|  Chronic Ear Infection | 2/150 (1.33) (0.16, 4.73)  |
|  Glaucoma | 4/150 (2.67) (0.73, 6.69)  |
|  Macular Degeneration | 3/150 (2.00) (0.41, 5.73)  |
|  Tinnitus | 11/150 (7.33) (3.72, 12.74)  |
|  History of Gastrointestinal Disease | 56/150 (37.33) (29.58, 45.60)  |
|  Colitis | 3/150 (2.00) (0.41, 5.73)  |
|  Crohn’s Disease | 1/150 (0.67) (0.02, 3.66)  |
|  Diverticulitis | 7/150 (4.67) (1.90, 9.38)  |
|  Gallstones | 2/150 (1.33) (0.16, 4.73)  |
|  Gastroesophageal Reflux Disease (GERD) | 49/150 (32.67) (25.24, 40.79)  |
|  Hepatitis B | 1/150 (0.67) (0.02, 3.66)  |
|  Hepatitis C | 3/150 (2.00) (0.41, 5.73)  |
|  Pancreatitis | 3/150 (2.00) (0.41, 5.73)  |
|  Ulcers | 3/150 (2.00) (0.41, 5.73)  |
|  History of Genitourinary Disease | 36/150 (24.00) (17.41, 31.65)  |
|  Endometriosis | 4/110 (3.64) (1.00, 9.05)  |
|  Menopause | 18/110 (16.36) (10.00, 24.62)  |
|  Polycystic Ovaries | 1/110 (0.91) (0.02, 4.96)  |
|  Prostate Problems | 9/40 (22.50) (10.84, 38.45)  |

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|  Characteristic | Number (%) Unadjusted (Lower Confidence Limit, Upper Confidence Limit)  |
| --- | --- |
|  Sexual Dysfunction | 1/150 (0.67) (0.02, 3.66)  |
|  Sexually Transmitted Diseases | 1/150 (0.67) (0.02, 3.66)  |
|  Testicular Disorders | 1/40 (2.50) (0.06, 12.16)  |
|  Urinary Incontinence | 5/150 (3.33) (1.09, 7.61)  |
|  Uterine Fibroids | 2/110 (1.82) (0.22, 6.41)  |
|  History of Hematological or Lymphatic Disease | 12/150 (8.00) (4.20, 13.56)  |
|  Anemia | 7/150 (4.67) (1.90, 9.38)  |
|  Bleeding Disorder | 1/150 (0.67) (0.02, 3.66)  |
|  Blood Clots/Deep Vein Thrombosis (DVT) | 1/150 (0.67) (0.02, 3.66)  |
|  HIV/AIDS | 1/150 (0.67) (0.02, 3.66)  |
|  Leukemia | 1/150 (0.67) (0.02, 3.66)  |
|  Lupus | 1/150 (0.67) (0.02, 3.66)  |
|  Rheumatoid Disease/Arthritis | 3/150 (2.00) (0.41, 5.73)  |
|  History of Metabolic Disorders | 64/150 (42.67) (3464, 50.99)  |
|  Cancer | 6/150 (4.00) (1.48, 8.50)  |
|  Diabetes Mellitus | 7/150 (4.67) (1.90, 9.38)  |
|  Hypercholesterolemia | 21/150 (14.00) (8.88, 20.60)  |
|  Hyperlipidemia | 42/150 (28.00) (20.98, 35.91)  |
|  History of Musculoskeletal Disorders | 45/150 (30.00) (22.80, 38.01)  |
|  Arthritis | 33/150 (22.00) (15.65, 29.49)  |
|  Fractures | 8/150 (5.33) (2.33, 10.24)  |
|  Gout | 1/150 (0.67) (0.02, 3.66)  |
|  Osteoporosis | 8/150 (5.33) (2.33, 10.24)  |
|  Scoliosis | 2/150 (1.33) (0.16, 4.73)  |
|  History of Neurological Disorders | 73/150 (48.67) (40.43, 56.95)  |
|  Headaches/Migraines | 61/150 (40.67) (32.73, 48.98)  |
|  Intracranial Bleeding | 8/150 (5.33) (2.33, 10.24)  |
|  Meningitis | 1/150 (0.67) (0.02, 3.66)  |
|  Multiple Sclerosis | 2/150 (1.33) (0.16, 4.73)  |
|  Neuropathy | 12/150 (8.00) (4.20, 13.56)  |
|  Seizures | 7/150 (4.67) (1.90, 9.38)  |
|  History of Psychological/Psychiatric Disorders | 64/150 (42.67) (34.64, 50.99)  |
|  Anxiety | 43/150 (28.67) (21.59, 36.61)  |
|  Depression | 44/150 (29.33) (22.19, 37.31)  |
|  Schizophrenia | 3/150 (2.00) (0.41, 5.73)  |
|  Addiction | 3/150 (2.00) (0.41, 5.73)  |
|  History of Respiratory Disorders | 35/150 (23.33) (16.82, 30.93)  |
|  Asthma | 13/150 (8.67) (4.70, 14.36)  |
|  Chronic Bronchitis | 2/150 (1.33) (0.16, 4.73)  |
|  Chronic Obstructive Pulmonary Disease | 15/150 (10.00) (5.71, 15.96)  |
|  Emphysema | 5/150 (3.33) (1.09, 7.61)  |
|  Pneumonia | 5/150 (3.33) (1.09, 7.61)  |
|  Sleep Apnea | 10/150 (6.67) (3.24, 11.92)  |

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|  Characteristic | Number (%) Unadjusted (Lower Confidence Limit, Upper Confidence Limit)  |
| --- | --- |
|  Tuberculosis | 1/150 (0.67) (0.02, 3.66)  |
|  History of Renal Diseases | 6/150 (4.00) (1.48, 8.50)  |
|  Kidney Failure/History of Dialysis | 1/150 (0.67) (0.02, 3.66)  |
|  Renal Insufficiency | 1/150 (0.67) (0.02, 3.66)  |
|  Kidney Stones | 2/150 (1.33) (0.16, 4.73)  |
|  Urinary tract Infection | 2/150 (1.33) (0.16, 4.73)  |
|  Current or Former Smoker |   |
|  Current | 66/150 (44.00) (35.91, 52.33)  |
|  Former | 32/150 (21.33) (15.07, 28.76)  |
|  Non-Smoker | 52/150 (34.67) (27.09, 42.86)  |
|  Visual Disturbance | 26/150 (17.33) (11.65, 24.36)  |
|  Motor Disturbance | 13/150 (8.67) (4.70, 14.36)  |
|  Aneurysm Location |   |
|  AComm Complex | 40/150 (26.67) (19.78, 34.49)  |
|  Basilar Apex | 59/150 (39.33) (31.47, 47.63)  |
|  ICA Terminus | 6/150 (4.00) (1.48, 8.50)  |
|  MCA Bifurcation | 45/150 (30.00) (22.80, 38.01)  |
|  Previous Ischemic Stroke | 18/150 (12.00) (7.27, 18.30)  |
|  Previous Hemorrhagic Stroke | 10/150 (6.67) (3.24, 11.92)  |
|  NIHSS Score at Baseline |   |
|  0 | 135/150 (90.00) (84.04, 94.29)  |
|  1 | 11/150 (7.33) (3.72, 12.74)  |
|  2 | 2/150 (1.33) (0.16, 4.73)  |
|  5 | 1/150 (0.67) (0.02, 3.66)  |
|  6 | 1/150 (0.67) (0.02, 3.66)  |
|  mRS (Unruptured) |   |
|  0 | 114/141 (80.85) (73.38, 86.99)  |
|  1 | 27/141 (19.15) (13.01, 26.62)  |

a Race and ethnicity were not obtained for subjects from the European and Canadian sites (N=34) due to Ethics Committee regulations in these countries.

## D. Safety and Effectiveness Results

### 1. Safety Results

The analysis of safety was based on the mITT cohort of 150 patients available for the 12-month evaluation. The key safety outcomes for this study are presented below in Tables 10 to 14. Adverse effects are reported in Table 15 and Table 16. The major stroke and death rate, the primary safety outcome, at one year in WEB-IT study is less than 1%. The rate for all strokes and neurological deaths at one year is 8%.

The primary safety endpoint is the proportion of subjects with death of any non-accidental cause or any major stroke (an ischemic or hemorrhagic stroke resulting in

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an increase of 4 points or more on the NIHSS as of day 7 post onset) within the first 30-days after treatment or major ipsilateral stroke or death due to neurologic cause from day 31 to 365 after treatment. A major stroke is “a stroke, which increased the NIHSS by  $\geq 4$  at the time of assessment and which remained present after 7 days.” A stroke is any “rapidly developing clinical signs of focal (or global) disturbance of cerebral function lasting more than 24 hours with no apparent cause other than of vascular origin, including ischemic stroke and/or hemorrhagic stroke (i.e., intraparenchymal hemorrhage (IPH), subarachnoid hemorrhage (SAH), subdural hemorrhage (SDH), epidural hemorrhage (EDH)) accompanied with radiological evidence.”

The primary safety endpoint analysis based on subjects with clinical information at 12-months post-procedure  $(N = 147)$  is presented in Table 10. There were 3 missing subjects in the mITT cohort at 12-months postoperative in which 2 subjects did not have a WEB device implanted and 1 subject withdrew prior to the 12-month follow-up visit.

There was a single primary safety endpoint event. A major stroke caused by SAH occurred on post-procedure day 22. Adjudicators determined the SAH was likely related to antiplatelet medication and underlying cerebrovascular disease and was not related to the treated IA. The location was ipsilateral but remote from the target IA. The subject's intracranial aneurysm was unruptured, in the AComm complex, and with an IA sac width of  $7.4\mathrm{mm}$ . The subject had a baseline NIHSS and mRS of 0 (zero). The subject's NIHSS was 13 on day 7 post-stroke. At 12-months, the subject had an mRS of 4 due to residual left hemiplegia. The IA was completely occluded with no stenosis of the parent artery. This subject was therefore considered a primary effectiveness endpoint success and a primary safety endpoint failure.

Table 10. Primary Safety Composite Endpoint Analysis in Completed Cases (N=147)

|  Endpoint | n/N (%) | 90% Upper Confidence Limita  |
| --- | --- | --- |
|  Composite | 1/147 (0.68) | 3.19  |
|  Death within 30-Days | 0/147 (0.68) | 2.02b  |
|  Major Stroke within 30-Days | 1/147(0.68) | 3.19b  |
|  Major Ipsilateral Stroke Days 31 to 365 | 0/147 (0.00) | 2.02b  |
|  Neurological Death Days 31 to 365 | 0/147 (0.00) | 2.02b  |

a To be compared to a PG of  $20\%$ . The upper  $90\%$  confidence limit needs to be less than the PG rate of 0.20.
b Unadjusted  $90\%$  upper confidence limit.

A sensitivity tipping point analysis was performed to account for the 3 missing subjects with 12-month data as primary safety endpoint failures (Table 11) using the mITT cohort  $(N = 150)$ .

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Table 11. Sensitivity Analysis for Primary Safety Imputation = Tipping Point Analysis

|  Tipping Point Analysis Steps | Subject Successes n/N (%) | Upper 90% Confidence Limita  |
| --- | --- | --- |
|  1-Worst Case | 4/150 (2.67) | 6.00  |
|  2 | 3/150 (2.00) | 5.09  |
|  3 | 2/150 (1.33) | 4.14  |
|  4-Best Case | 1/150 (0.67) | 3.12  |

a When stated as a percent, this value must be smaller than  $20\%$  to reject the null primary endpoint hypothesis. Tested sequentially.

A modified primary safety endpoint analysis that included any subject with neurological death or stroke within 12-months follow-up as a primary safety endpoint failure was also performed (see Table 12). For this modified primary safety endpoint analysis, there were an additional 11 subjects in the mITT population who had ischemic or hemorrhagic stroke events in the WEB-IT study within 12-months postprocedure that were not counted as failures based on the pre-specified primary safety endpoint definition.

Table 12. FDA-Requested All Stroke Primary Safety Endpoint

|  Endpoint | n/N (%) | Unadjusted 95% Exact Confidence Interval (CI)*  |
| --- | --- | --- |
|  Composite FDA Requested All Stroke Primary Safety Endpoint | 12a/150(8.00%) | (4.20, 13.56)  |
|  Death within 30-Days | 0/150 (0.00%) | (0.00, 2.43)  |
|  Any Stroke within 30-Days | 10/150 (6.67%) | (3.24, 11.92)  |
|  Any Ipsilateral Stroke Days 31 to 365 | 2/147 (1.36%) | (0.17, 4.83)  |
|  Neurological Death Days 31 to 365 | 0/147 (0.00) | (0.00, 2.48)  |

a One subject experienced two events: SAH and ischemic stroke.
*The CI was calculated without multiplicity adjustment. As such, the CI is provided to show the variability only and should not be used to draw any statistical conclusions.

Modified Rankin Scale (mRS) scores were evaluated for the subset of subjects with unruptured target intracranial aneurysms at 12-months post-procedure compared to their baseline pre-procedure mRS as displayed in Table 13  $(N = 141)$ . There were 6 subjects with unruptured IAs that did not have 12-month mRS scores resulting in  $N = 135$  subjects. Of these 135 subjects with available mRS data at 12-months postoperative, the large majority of unruptured IA subjects had an mRS of 0 (111 subjects) or mRS of 1 (22 subjects) at 12-months. Eleven (11) out of the 135 subjects with available mRS scores at the 12-month follow-up visit had increased mRS scores  $(8.1\%)$  compared with their baseline mRS, signifying a worsening in disability after device treatment. If the 6 subjects with missing mRS data at 12-months postoperative were assumed to have a worsening of their mRS scores compared to their baseline scores in a worst-case analysis, then the rate of subjects with worsening mRS after device treatment would be  $12\%$  (17/141).

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Table 13. Modified Rankin Score Change from Baseline to 12-Months in Unruptured Aneurysms (N=135)

|  mRS Score at Baseline | mRS Score at 12-Months |   |   |   | Total  |
| --- | --- | --- | --- | --- | --- |
|   |  0 x/n (%)a LCL, UCL | 1 x/n (%)a LCL, UCL | 3 x/n (%)a LCL, UCL | 4 x/n (%)a LCL, UCL  |   |
|  0 | 99 (90.83) 83.77, 95.51 | 9 (8.26) 3.84, 15.10 | 0 (0.00) 0.00, 3.33 | 1 (0.92) 0.02, 5.01 | 109  |
|  1 | 12 (46.15) 26.59, 66.63 | 13 (50.00) 29.93, 70.07 | 1 (3.85) 0.10, 19.64 | 0 (0.00) 0.00, 13.23 | 26  |
|  Total | 111 (82.22) 74.71, 88.26 | 22 (16.30) 10.50, 23.63 | 1 (0.74) 0.02, 4.06 | 1 (0.74) 0.02, 4.06 | 135b  |

a Percent of the row total.
b Six unruptured subjects did not have an mRS score at 12-months.
Note: All 95% CIs are unadjusted. As such, the CI is provided to show the variability only and should not be used to draw any statistical conclusions.

Eight of the 9 subjects with ruptured target intracranial aneurysms at baseline had 12-month mRS scores (see Table 14). One subject had missing mRS scores at 6-months and 12-months. This subject was evaluated as mRS 1 at baseline, discharge and 30-day follow-up; therefore, the mRS at follow-up was carried forward for this subject using the worst-case approximation technique.

After treatment with the WEB device, 7 out of these 9 ruptured IA subjects (77.78%) demonstrated an unchanged mRS score at 12-months. Two subjects with baseline ruptured aneurysms had an mRS improvement of one (1) point from mRS of 1 at baseline to mRS 0 at 12-months. More than half of the treated ruptured intracranial aneurysms were located in the basilar artery apex (5/9 (56%)).

Table 14. Modified Rankin Scale Score Change from Baseline to 12-Months in Ruptured Intracranial Aneurysms

|  mRS Score at Baseline | mRS Score at 12-Months |   | Total  |
| --- | --- | --- | --- |
|   |  0 x/n (%) | 1 x/n (%)  |   |
|  0 | 5/5 (100.00) | 0/5 (0.00) | 5  |
|  1 | 2/4 (50.00) | 2/4 (50.00) | 4  |
|  Total | 7/9 (77.78) | 2/9 (22.22) | 9  |

# Adverse effects that occurred in the PMA clinical study:

Within the first peri-procedural 30 days, 135 non-serious adverse events (AEs) occurred in 68 subjects  $(45.3\%)$ . Of the 135 non-serious AEs, the most common peri-procedural non-serious AEs were headache (20 events in 20 subjects, 20/150  $(13.3\%)$ ), nausea (10 events/9 subjects, 9/150  $(6.0\%)$ ), and vessel puncture site related events (13 events including puncture site reaction, bruise, hematoma, hemorrhage, and pain, 13/150  $(8.7\%)$ ). No other non-serious peri-procedural adverse events occurred in greater than  $5\%$  of the treated population. Adverse drug reactions within the first 30-days occurred in  $4.7\%$  of subjects  $(7/150)$  and were attributed to

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antiplatelet therapy in 3 cases (bruising, general malaise) and to procedure or postprocedure medications (anesthesia, pain medications, Ativan, anti-hypertensives) in the other 4 cases.

Between day 31 and day 365, 151 non-serious AEs occurred in 65 subjects (65/150,  $43.3\%$ ). The most common AE occurring between day 31 and day 365 was headache (24 events in 20 subjects, 20/150  $(13.3\%)$ ). No other non-serious AE occurred in more than  $5\%$  of subjects. All the non-serious AEs observed within 12-months postprocedure coded by the Medical Dictionary for Regulatory Activities (MedDRA, Version 18.0) are presented in Table 15.

Table 15. Non-Serious Adverse Events in 1-Year

|  System Organ Class | Preferred Term | AE Ratea n/N (%) (Unadjusted LCL, UCL) Events  |
| --- | --- | --- |
|  Non-serious Adverse Events within 30-days  |   |   |
|  All | All | 68/150 (45.33) (37.20, 53.66) 135  |
|  Blood and Lymphatic System Disorders | Anemia | 1/150 (0.67) (0.02, 3.66) 1  |
|  Cardiac Disorders | Angina Pectoris | 1/150 (0.67) (0.02, 3.66) 1  |
|   |  Arrhythmia | 2/150 (1.33) (0.16, 4.73) 2  |
|  Ear and Labyrinth Disorders | Tinnitus | 1/150 (0.67) (0.02, 3.66) 1  |
|  Eye Disorders | Diplopia | 1/150 (0.67) (0.02, 3.66) 1  |
|   |  Visual Impairment | 4/150 (2.67) (0.73, 6.69) 4  |
|   |  Vitreous Detachment | 1/150 (0.67) (0.02, 3.66) 1  |
|  Gastrointestinal Disorders | Abdominal Pain | 3/150 (2.00) (0.41, 5.73) 3  |
|   |  Constipation | 1/150 (0.67) (0.02, 3.66) 1  |
|   |  Gastroesophageal Reflux Disease | 1/150 (0.67) (0.02, 3.66) 1  |
|   |  Nausea | 9/150 (6.00) (2.78, 11.08) 10  |
|   |  Vomiting | 2/150 (1.33) (0.16, 4.73) 2  |
|  General Disorders and Administration Site Conditions | Adverse Drug Reaction | 7/150 (4.67) (1.90, 9.38) 8  |
|   |  Chest Discomfort | 2/150 (1.33) (0.16, 4.73) 2  |
|   |  Chest Pain | 1/150 (0.67) (0.02, 3.66) 1  |
|   |  Fatigue | 1/150 (0.67) (0.02, 3.66)  |

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|  System Organ Class | Preferred Term | AE Ratea n/N (%) (Unadjusted LCL, UCL) Events  |
| --- | --- | --- |
|   |  | 1  |
|   |  Influenza Like Illness | 1/150 (0.67) (0.02, 3.66) 1  |
|   |  Puncture Site Reaction | 1/150 (0.67) (0.02, 3.66) 1  |
|   |  Vessel Puncture Site Bruise | 2/150 (1.33) (0.16, 4.73) 2  |
|   |  Vessel Puncture Site Hematoma | 4/150 (2.67) (0.73, 6.69) 4  |
|   |  Vessel Puncture Site Hemorrhage | 1/150 (0.67) (0.02, 3.66) 1  |
|   |  Vessel Puncture Site Pain | 5/150 (3.33) (1.09, 7.61) 5  |
|  Infections and Infestations | Laryngitis | 1/150 (0.67) (0.02, 3.66) 1  |
|   |  Respiratory Tract Infection | 1/150 (0.67) (0.02, 3.66) 1  |
|   |  Urinary Tract Infection | 1/150 (0.67) (0.02, 3.66) 1  |
|  Injury, Poisoning and Procedural Complications | Arterial Injury | 1/150 (0.67) (0.02, 3.66) 1  |
|   |  Contusion | 1/150 (0.67) (0.02, 3.66) 1  |
|   |  Traumatic Hematoma | 1/150 (0.67) (0.02, 3.66) 1  |
|   |  Vascular Pseudoaneurysm | 1/150 (0.67) (0.02, 3.66) 1  |
|  Investigations | Blood Pressure Increased | 2/150 (1.33) (0.16, 4.73) 2  |
|  Metabolism and Nutrition Disorders | Electrolyte Imbalance | 2/150 (1.33) (0.16, 4.73) 3  |
|  Musculoskeletal and Connective Tissue Disorders | Arthralgia | 2/150 (1.33) (0.16, 4.73) 2  |
|   |  Back Pain | 3/150 (2.00) (0.41, 5.73) 3  |
|   |  Muscular Weakness | 1/150 (0.67) (0.02, 3.66) 1  |
|   |  Neck Pain | 2/150 (1.33) (0.16, 4.73) 2  |
|   |  Pain in Extremity | 4/150 (2.67) (0.73, 6.69) 4  |
|  Nervous System Disorders | Ataxia | 1/150 (0.67) (0.02, 3.66) 1  |
|   |  Carotid Artery Dissection | 1/150 (0.67) (0.02, 3.66) 1  |
|   |  Dizziness | 1/150 (0.67) (0.02, 3.66) 1  |
|   | Dizziness | 1/150 (0.67) (0.02, 3.66) 1  |
|  Osteoporosis | Osteoporosis | 1/150 (0.67) (0.02, 3.66) 1  |
|   |  Osteoporosis | 1/150 (0.67) (0.02, 3.66) 1  |
|  Nephritis and Other Diseases | Nephritis | 1/150 (0.67) (0.02, 3.66) 1  |
|   |  Nephritis | 1/150 (0.67) (0.02, 3.66) 1  |
|  Other Diseases | Other | 1/150 (0.67) (0.02, 3.66) 1  |
|   |  Other | 1/150 (0.67) (0.02, 3.66) 1  |
|  Other Diseases | Other | 1/150 (0.67) (0.02, 3.66) 1  |
|   |  Other | 1/150 (0.67) (0.02, 3.66)  |

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| System Organ Class | Preferred Term | AE Ratea n/N (%) (Unadjusted LCL, UCL) Events |
| --- | --- | --- |
|  | Dizziness Postural | 1/150 (0.67) (0.02, 3.66) 1 |
| Headache | 20/150 (13.33) (8.34, 19.84) 20 |
| Hypoesthesia | 1/150 (0.67) (0.02, 3.66) 1 |
| Ischemic Stroke | 1/150 (0.67) (0.02, 3.66) 1 |
| Migraine | 2/150 (1.33) (0.16, 4.73) 2 |
| Nystagmus | 1/150 (0.67) (0.02, 3.66) 1 |
| Paresthesia | 1/150 (0.67) (0.02, 3.66) 1 |
| Subarachnoid Hemorrhage | 1/150 (0.67) (0.02, 3.66) 1 |
| Transient Ischemic Attack | 3/150 (2.00) (0.41, 5.73) 3 |
| Psychiatric Disorders | Alcohol Abuse | 1/150 (0.67) (0.02, 3.66) 1 |
| Renal and Urinary Disorders | Urinary Incontinence | 1/150 (0.67) (0.02, 3.66) 1 |
| Urinary Retention | 2/150 (1.33) (0.16, 4.73) 2 |
| Reproductive System and Breast Disorders | Postmenopausal Hemorrhage | 1/150 (0.67) (0.02, 3.66) 1 |
| Respiratory, Thoracic and Mediastinal Disorders | Cough | 1/150 (0.67) (0.02, 3.66) 1 |
| Dyspnea | 1/150 (0.67) (0.02, 3.66) 1 |
| Skin and Subcutaneous Tissue Disorders | Alopecia | 1/150 (0.67) (0.02, 3.66) 1 |
| Dermatosis | 1/150 (0.67) (0.02, 3.66) 1 |
| Vascular Disorders | Arterial Spasm | 1/150 (0.67) (0.02, 3.66) 1 |
| Arterial Thrombosis | 2/150 (1.33) (0.16, 4.73) 2 |
| Femoral Artery Dissection | 1/150 (0.67) (0.02, 3.66) 1 |
| Hypertension | 2/150 (1.33) (0.16, 4.73) 2 |
| Hypotension | 1/150 (0.67) (0.02, 3.66) 1 |
| Labile Blood Pressure | 1/150 (0.67) (0.02, 3.66) 1 |
| Thrombophlebitis | 1/150 (0.67) (0.02, 3.66) |
|  | Hypotension | 1/150 (0.67) (0.02, 3.66) |
| Diabetes | 1/150 (0.67) (0.02, 3.66) |
| Vascular Disorders | Arterial Infarct | 1/150 (0.67) (0.02, 3.66) |
| Arterial Infarct | 2/150 (1.33) (0.16, 4.73) |
| Vascular Disorders | Arterial Infarct | 2/150 (1.33) (0.16, 4.73) |
| Arterial Infarct | 3/150 (2.00) (0.41, 5.73) |

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Page 29

|  System Organ Class | Preferred Term | AE Rate^{a}
n/N (%) (Unadjusted LCL, UCL) Events  |
| --- | --- | --- |
|   |  | 1  |
|   |  Vasospasm | 5/150 (3.33) (1.09, 7.61)
5  |
|  Non-serious Adverse Events within 31-365 Days  |   |   |
|  All | All | 65/150 (43.33) (35.27, 51.66)
151  |
|  Blood and Lymphatic System Disorders | Anemia | 1/150 (0.67) (0.02, 3.66)
1  |
|  Cardiac Disorders | Angina Pectoris | 1/150 (0.67) (0.02, 3.66)
2  |
|   |  Arrhythmia | 1/150 (0.67) (0.02, 3.66)
1  |
|   |  Cardiac Valve Disease | 1/150 (0.67) (0.02, 3.66)
1  |
|  Ear and Labyrinth Disorders | Ear Pain | 1/150 (0.67) (0.02, 3.66)
1  |
|   |  Vertigo | 1/150 (0.67) (0.02, 3.66)
2  |
|  Eye Disorders | Visual Impairment | 4/150 (2.67) (0.73, 6.69)
4  |
|  Gastrointestinal Disorders | Abdominal Pain | 1/150 (0.67) (0.02, 3.66)
2  |
|   |  Constipation | 1/150 (0.67) (0.02, 3.66)
1  |
|   |  Diarrhea | 1/150 (0.67) (0.02, 3.66)
2  |
|   |  Gastric Ulcer | 1/150 (0.67) (0.02, 3.66)
1  |
|   |  Nausea | 1/150 (0.67) (0.02, 3.66)
1  |
|   |  Esophageal Spasm | 1/150 (0.67) (0.02, 3.66)
1  |
|   |  Pancreatitis | 1/150 (0.67) (0.02, 3.66)
1  |
|  General Disorders and Administration Site Conditions | Adverse Drug Reaction | 7/150 (4.67) (1.90, 9.38)
7  |
|   |  Application Site Hemorrhage | 1/150 (0.67) (0.02, 3.66)
1  |
|   |  Fatigue | 1/150 (0.67) (0.02, 3.66)
1  |
|   |  Edema | 1/150 (0.67) (0.02, 3.66)
1  |
|   |  Edema Peripheral | 1/150 (0.67) (0.02, 3.66)
1  |
|   |  Pyrexia | 1/150 (0.67) (0.02, 3.66)
1  |

{29}

| System Organ Class | Preferred Term | AE Ratea n/N (%) (Unadjusted LCL, UCL) Events |
| --- | --- | --- |
|  | Vessel Puncture Site Hematoma | 4/150 (2.67) (0.73, 6.69) 4 |
| Vessel Puncture Site Pain | 1/150 (0.67) (0.02, 3.66) 1 |
| Infections and Infestations | Cellulitis | 1/150 (0.67) (0.02, 3.66) 1 |
| Laryngitis | 1/150 (0.67) (0.02, 3.66) 1 |
| Oral Herpes | 1/150 (0.67) (0.02, 3.66) 1 |
| Otitis Media | 1/150 (0.67) (0.02, 3.66) 1 |
| Pneumonia | 1/150 (0.67) (0.02, 3.66) 1 |
| Respiratory Tract Infection | 1/150 (0.67) (0.02, 3.66) 1 |
| Sinusitis | 1/150 (0.67) (0.02, 3.66) 1 |
| Staphylococcal Skin Infection | 1/150 (0.67) (0.02, 3.66) 1 |
| Tooth Infection | 2/150 (1.33) (0.16, 4.73) 2 |
| Urinary Tract Infection | 3/150 (2.00) (0.41, 5.73) 4 |
| Viral Infection | 2/150 (1.33) (0.16, 4.73) 2 |
| Injury, Poisoning and Procedural Complications | Animal Bite | 1/150 (0.67) (0.02, 3.66) 1 |
| Contusion | 1/150 (0.67) (0.02, 3.66) 1 |
| Head Injury | 1/150 (0.67) (0.02, 3.66) 1 |
| Laceration | 1/150 (0.67) (0.02, 3.66) 1 |
| Lower Limb Fracture | 1/150 (0.67) (0.02, 3.66) 1 |
| Investigations | Blood Creatinine Increased | 1/150 (0.67) (0.02, 3.66) 1 |
| Blood Pressure Decreased | 1/150 (0.67) (0.02, 3.66) 1 |
| Blood Pressure Increased | 2/150 (1.33) (0.16, 4.73) 2 |
| Metabolism and nutrition disorders | Diabetes Mellitus | 1/150 (0.67) (0.02, 3.66) 1 |
| Electrolyte Imbalance | 3/150 (2.00) (0.41, 5.73) 3 |
| Hyperlipidemia | 1/150 (0.67) (0.02, 3.66) |
|  | Hypertension | 1/150 (0.67) (0.02, 3.66) |
| Other | Cancer | 1/150 (0.67) (0.02, 3.66) 1 |
| Other | 1/150 (0.67) (0.02, 3.66) |

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Page 31

|  System Organ Class | Preferred Term | AE Rate^{a}
n/N (%) (Unadjusted LCL, UCL) Events  |
| --- | --- | --- |
|   |  | 1  |
|   |  Hypocalcemia | 1/150 (0.67) (0.02, 3.66)
1  |
|  Musculoskeletal and Connective Tissue Disorders | Arthralgia | 1/150 (0.67) (0.02, 3.66)
1  |
|   |  Arthritis | 3/150 (2.00) (0.41, 5.73)
3  |
|   |  Back Pain | 4/150 (2.67) (0.73, 6.69)
4  |
|   |  Muscle Spasms | 1/150 (0.67) (0.02, 3.66)
1  |
|   |  Neck Pain | 3/150 (2.00) (0.41, 5.73)
3  |
|   |  Palmar Fasciitis | 1/150 (0.67) (0.02, 3.66)
1  |
|  Neoplasms Benign, Malignant and Unspecified (Including Cysts and Polyps) | Paranasal Sinus Neoplasm | 1/150 (0.67) (0.02, 3.66)
1  |
|   |  Uterine Leiomyoma | 1/150 (0.67) (0.02, 3.66)
1  |
|  Nervous System Disorders | Aphasia | 1/150 (0.67) (0.02, 3.66)
1  |
|   |  Carpal Tunnel Syndrome | 1/150 (0.67) (0.02, 3.66)
1  |
|   |  Cerebrovascular Disorder | 1/150 (0.67) (0.02, 3.66)
1  |
|   |  Dementia | 1/150 (0.67) (0.02, 3.66)
1  |
|   |  Dizziness | 1/150 (0.67) (0.02, 3.66)
1  |
|   |  Gait Disturbance | 1/150 (0.67) (0.02, 3.66)
1  |
|   |  Headache | 20/150 (13.33) (8.34, 19.84)
24  |
|   |  Ischemic Stroke | 2/150 (1.33) (0.16, 4.73)
2  |
|   |  Memory Impairment | 1/150 (0.67) (0.02, 3.66)
1  |
|   |  Migraine | 2/150 (1.33) (0.16, 4.73)
2  |
|   |  Restless Leg Syndrome | 1/150 (0.67) (0.02, 3.66)
1  |
|   |  Sciatica | 1/150 (0.67) (0.02, 3.66)
1  |
|   |  Sensory loss | 2/150 (1.33) (0.16, 4.73)
2  |
|   |  Transient Ischemic Attack | 2/150 (1.33) (0.16, 4.73)
2  |

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|  System Organ Class | Preferred Term | AE Ratea n/N (%) (Unadjusted LCL, UCL) Events  |
| --- | --- | --- |
|  Psychiatric Disorders | Anxiety | 3/150 (2.00) (0.41, 5.73) 3  |
|   |  Depression | 4/150 (2.67) (0.73, 6.69) 4  |
|   |  Insomnia | 2/150 (1.33) (0.16, 4.73) 2  |
|  Renal and Urinary Disorders | Calculus Ureteric | 1/150 (0.67) (0.02, 3.66) 1  |
|   |  Nephrolithiasis | 1/150 (0.67) (0.02, 3.66) 1  |
|  Reproductive System and Breast Disorders | Benign Prostatic Hyperplasia | 1/150 (0.67) (0.02, 3.66) 1  |
|  Respiratory, Thoracic and Mediastinal Disorders | Dyspnea | 1/150 (0.67) (0.02, 3.66) 1  |
|   |  Rhinitis Allergic | 1/150 (0.67) (0.02, 3.66) 1  |
|  Skin and Subcutaneous Tissue Disorders | Dermatitis | 1/150 (0.67) (0.02, 3.66) 1  |
|  Surgical and Medical Procedures | Aneurysm Repair | 1/150 (0.67) (0.02, 3.66) 1  |
|   |  Eye Operation | 1/150 (0.67) (0.02, 3.66) 1  |
|   |  Intra-cerebral Aneurysm Operation | 1/150 (0.67) (0.02, 3.66) 1  |
|  Vascular Disorders | Aortic Aneurysm | 1/150 (0.67) (0.02, 3.66) 1  |
|   |  Hypertension | 3/150 (2.00) (0.41, 5.73) 5  |
|   |  Hypotension | 1/150 (0.67) (0.02, 3.66) 1  |
|   |  Phlebitis | 1/150 (0.67) (0.02, 3.66) 1  |

a Summing across preferred terms or system organ classes will not result in the same sum overall because of multiple events per subject even in the same preferred term or organ class.
Note: The CI was calculated without multiplicity adjustment. As such, the CI is provided to show the variability only and should not be used to draw any statistical conclusions.

There were no deaths in the WEB-IT study through the primary endpoint time point of 1 year. Late deaths (> 1-year) occurred in 4 subjects (4/150, 2.7%). The cause of death in these 4 subjects included intracranial hemorrhage (ICH) on day 753 related to a traumatic head injury, SAH on day 625 resulting from procedural rupture of the AComm IA after a second retreatment procedure of the index aneurysm with a different device, respiratory failure on day 589, and bladder cancer on day 826.

A total of 62 serious adverse events (SAEs) occurred in 33 subjects (33/150,  $22\%$ ) through day 365. Twenty-one (21) subjects (21/150,  $14.0\%$ ) experienced 27 SAEs within the first 30-days (peri-procedural). Most of these events are related to nervous

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system disorders and included events of seizure, headache, stroke, SAH, transient ischemic attack (TIA), aphasia, and syncope. In only 4 cases were peri-procedural device-related SAEs identified (ischemic stroke, SAH, TIA, and arterial thrombosis).

Between day 31 and 365, 21 subjects (21/150,  $14.0\%$ ) experienced 35 SAEs. Nervous system disorders accounted for 8 of the 35 SAEs and included intracranial hemorrhage, ischemic stroke, headache, TIA, seizure, and benign intracranial hypertension. The CEC determined that no SAEs after day 30 were device-related. All the SAEs observed in the WEB-IT study within 1-year post-procedure are presented in Table 16 as coded by MedDRA.

Table 16. Serious Adverse Events within 1-Year

|  System Organ Class | Preferred Term | SAE Ratea n/N (%) (Unadjusted LCL, UCL) Events  |
| --- | --- | --- |
|  Serious Adverse Events within 30-days  |   |   |
|  All | Any | 21/150 (14.00) (8.88, 20.60) 27  |
|  Cardiac Disorders | Angina Pectoris | 1/150 (0.67) (0.02, 3.66) 1  |
|   |  Coronary Artery Disease | 1/150 (0.67) (0.02, 3.66) 1  |
|  Gastrointestinal Disorders | Vomiting | 1/150 (0.67) (0.02, 3.66) 1  |
|  General Disorders and Administration Site Conditions | Vessel Puncture Site Hematoma | 3/150 (2.00) (0.41, 5.73) 3  |
|  Investigations | Blood Pressure Increased | 1/150 (0.67) (0.02, 3.66) 1  |
|  Musculoskeletal and Connective Tissue Disorders | Lumbar Spinal Stenosis | 1/150 (0.67) (0.02, 3.66) 1  |
|  Neoplasms Benign, Malignant and Unspecified (Including Cysts and Polyps) | Uterine Leiomyoma | 1/150 (0.67) (0.02, 3.66) 1  |
|  Nervous System Disorders | Aphasia | 1/150 (0.67) (0.02, 3.66) 1  |
|   |  Headache | 1/150 (0.67) (0.02, 3.66) 1  |
|   |  Ischemic Stroke | 6/150 (4.00) (1.48, 8.50) 6  |
|   |  Seizure | 1/150 (0.67) (0.02, 3.66) 1  |
|   |  Subarachnoid Hemorrhage | 2/150 (1.33) (0.16, 4.73) 2  |
|   |  Syncope | 1/150 (0.67) (0.02, 3.66) 1  |
|   |  Transient Ischemic Attack | 2/150 (1.33) (0.16, 4.73) 2  |
|  Psychiatric Disorders | Confusional State | 1/150 (0.67) (0.02, 3.66) 1  |

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|  System Organ Class | Preferred Term | SAE Ratea n/N (%) (Unadjusted LCL, UCL) Events  |
| --- | --- | --- |
|  Respiratory, Thoracic and Mediastinal Disorders | Pulmonary Embolism | 1/150 (0.67) (0.02, 3.66) 1  |
|  Vascular Disorders | Arterial Thrombosis | 1/150 (0.67) (0.02, 3.66) 1  |
|   |  Hypertension | 1/150 (0.67) (0.02, 3.66) 1  |
|  Serious Adverse Events from 31 to 365 Days  |   |   |
|  All | All | 21/150 (14.00) (8.88, 20.60) 35  |
|  Cardiac Disorders | Angina Pectoris | 1/150 (0.67) (0.02, 3.66) 3  |
|   |  Cardiac Arrest | 1/150 (0.67) (0.02, 3.66) 1  |
|   |  Coronary Artery Disease | 1/150 (0.67) (0.02, 3.66) 1  |
|  Endocrine Disorders | Cushing's Syndrome | 1/150 (0.67) (0.02, 3.66) 2  |
|  Gastrointestinal Disorders | Crohn's Disease | 1/150 (0.67) (0.02, 3.66) 1  |
|   |  Enteritis | 1/150 (0.67) (0.02, 3.66) 1  |
|   |  Gastrointestinal Hemorrhage | 2/150 (1.33) (0.16, 4.73) 2  |
|   |  Impaired Gastric Emptying | 1/150 (0.67) (0.02, 3.66) 1  |
|  General Disorders and Administration Site Conditions | Chest Pain | 1/150 (0.67) (0.02, 3.66) 1  |
|   |  Vessel Puncture Site Hematoma | 1/150 (0.67) (0.02, 3.66) 1  |
|  Hepatobiliary Disorders | Cholelithiasis | 1/150 (0.67) (0.02, 3.66) 1  |
|  Infections and Infestations | Cytomegalovirus Infection | 1/150 (0.67) (0.02, 3.66) 1  |
|   |  Diverticulitis | 1/150 (0.67) (0.02, 3.66) 1  |
|   |  Pneumonia | 1/150 (0.67) (0.02, 3.66) 1  |
|  Injury, Poisoning and Procedural Complications | Fracture | 1/150 (0.67) (0.02, 3.66) 1  |
|  Neoplasms Benign, Malignant and Unspecified (Including Cysts and Polyps) | Meningioma | 1/150 (0.67) (0.02, 3.66) 1  |
|  Nervous System Disorders | Benign Intracranial Hypertension | 1/150 (0.67) (0.02, 3.66) 1  |
|   |  Hemorrhage Intracranial | 1/150 (0.67) (0.02, 3.66) 1  |
|   |  Headache | 1/150 (0.67) (0.02, 3.66)  |
|  Surgical and Surgical Procedures  |   |   |
|  All | All | 21/150 (14.00) (8.88, 20.60) 35  |
|  Cardiac Diseases | Arterial Thrombosis | 1/150 (0.67) (0.02, 3.66) 1  |
|   |  Cardiac Arrest | 1/150 (0.67) (0.02, 3.66) 1  |
|   |  Coronary Artery Disease | 1/150 (0.67) (0.02, 3.66) 1  |
|  Endocrine Disorders | Cushing's Syndrome | 1/150 (0.67) (0.02, 3.66) 2  |
|  Gastrointestinal Disorders | Crohn's Disease | 1/150 (0.67) (0.02, 3.66) 1  |
|   |  Enteritis | 1/150 (0.67) (0.02, 3.66) 1  |
|   |  Gastrointestinal Hemorrhage | 2/150 (1.33) (0.16, 4.73) 2  |
|  Impaired Gastric Emptying | 1/150 (0.67) (0.02, 3.66) 1  |   |
|  General Disorders and Administration Site Conditions | Chest Pain | 1/150 (0.67) (0.02, 3.66) 1  |
|   |  Vessel Puncture Site Hematoma | 1/150 (0.67) (0.02, 3.66) 1  |
|  Hepatobiliary Disorders | Cholelithiasis | 1/150 (0.67) (0.02, 3.66) 1  |
|  Infections and Infestations | Cytomegalovirus Infection | 1/150 (0.67) (0.02, 3.66) 1  |
|   |  Diverticulitis | 1/150 (0.67) (0.02, 3.66) 1  |
|   |  Pneumonia | 1/150 (0.67) (0.02, 3.66) 1  |
|  Injury, Poisoning and Procedural Complications | Fracture | 1/150 (0.67) (0.02, 3.66) 1  |
|  Neoplasms Benign, Malignant and Unspecified (Including Cysts and Polyps) | Meningioma | 1/150 (0.67) (0.02, 3.66) 1  |
|  Nervous System Disorders | Benign Intracranial Hypertension | 1/150 (0.67) (0.02, 3.66) 1  |
|   |  Hemorrhage Intracranial | 1/150 (0.67) (0.02, 3.66) 1  |
|   |  Headache | 1/150 (0.67) (0.02, 3.66)  |

PMA P170032: FDA Summary of Safety and Effectiveness Data

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|  System Organ Class | Preferred Term | SAE Rate^{a} n/N (%) (Unadjusted LCL, UCL) Events  |
| --- | --- | --- |
|   |  | 1  |
|   |  Ischemic Stroke | 1/150 (0.67) (0.02, 3.66)
1  |
|   |  Seizure | 1/150 (0.67) (0.02, 3.66)
1  |
|   |  Transient Ischemic Attack | 2/150 (1.33) (0.16, 4.73)
3  |
|  Respiratory, Thoracic and Mediastinal Disorders | Hypoxia | 1/150 (0.67) (0.02, 3.66)
1  |
|   |  Pulmonary Embolism | 1/150 (0.67) (0.02, 3.66)
1  |
|   |  Respiratory Failure | 1/150 (0.67) (0.02, 3.66)
1  |
|   |  Tracheal Stenosis | 1/150 (0.67) (0.02, 3.66)
1  |
|  Vascular Disorders | Hypertension | 1/150 (0.67) (0.02, 3.66)
2  |
|   |  Vascular Occlusion | 1/150 (0.67) (0.02, 3.66)
1  |

a Summing across preferred terms or system organ classes may not result in the same sum overall because of multiple events per subject even in the same preferred term or organ class.
Note: The CI was calculated without multiplicity adjustment. As such, the CI is provided to show the variability only and should not be used to draw any statistical conclusions.

## 2. Effectiveness Results

Using imputation for 14 patients with missing outcome data, approximately 55% of the 150 patients had complete occlusion of the aneurysm with less than 50% stenosis of the parent artery after 1 year without retreatment and recurrent SAH. There were 18 subjects (12%) who showed recanalization or regrowth of the aneurysm at 1 year. For the 150 subjects, 211 device placement attempts resulted in 148 device placements (148/211 = 70%).

The analysis of effectiveness was based on the 150 evaluable patients at the 12-month time point. Key effectiveness outcomes are presented in Table 17 to Table 20. As specified in the WEB-IT study protocol, the primary effectiveness endpoint was defined as the proportion of subjects with complete target intracranial aneurysm occlusion using the WEB Occlusion Scale (WOS) (Lubicz et al. 2014) without retreatment, recurrent SAH, or significant parent artery stenosis (>50% stenosis) at one year after treatment as assessed by the Core Lab.

For the analysis of the primary effectiveness endpoint, subjects with missing outcomes were categorized as missing at random or not missing at random. Subjects whose data are not missing at random, such as those who exit the study due to a device-related primary safety event were considered a failure. Subjects in whom the placement of the device fails (no implant placed) or in whom adjunctive devices were

PMA P170032: FDA Summary of Safety and Effectiveness Data

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medically necessary were considered failures for the primary effectiveness endpoint. Subjects who were absent at 12-months and can be assumed to be missing at random had their success or failure imputed for the primary effectiveness endpoint. If a subject withdrew for reasons other than a device-related primary safety event or died due to an unrelated cause, that subject was not imputed as a failure for the effectiveness endpoint but was imputed by the methods discussed further below. An accounting of the available and missing data is described in Table 17 below. Subjects were determined to be complete cases with valid 12-month DSA imaging assessment without the use of adjunctive devices in 136 of the 150 subjects.

Table 17. Primary Effectiveness Endpoint Imputation Patient Groups

|  Group | Number of Subjects  |
| --- | --- |
|  Completed case subjects with valid 12-month assessment | 136^{a}  |
|  Subjects without 12-month assessment assumed to be missing at random (MAR) | 7  |
|  Completed case subjects not missing at random imputed as a failure | 7  |

aOne subject was not included in the top row because the subject had imaging that demonstrated full occlusion but did not allow assessment of parent artery stenosis.

Seven subjects did not have adequate imaging to assess aneurysm occlusion or parent artery stenosis. These seven subjects without 12-month assessment were considered missing at random and had their primary effectiveness endpoint outcome imputed based on outcomes of similar subjects in the study. Of note, 1 subject assumed to be missing at random at 12-months refused a 12-month imaging angiogram. Computed tomography angiography (CTA) was conducted for this subject and per assessment of the Core Lab, this CTA did not allow for a complete assessment of parent artery stenosis. The subject had successful IA occlusion per the Core Lab. As no subject with complete occlusion had parent artery stenosis > 50%, subjects with adequate IA occlusion assessed via imaging without sufficient imaging of the parent artery were imputed as a success for purposes of the primary effectiveness endpoint (1 subject). An additional 7 subjects that were categorized as not missing at random were imputed as failures due to failed device placement (2), use of adjunctive device at time of procedure (2), or index IA retreatment or planned retreatment prior to 12-months (3).

Subjects with missing data who were assumed to be missing at random were grouped by IA location and rupture status. For each imputation, the subject was assigned the occlusion status and parent vessel score (assessment of stenosis) of a subject with the same IA location and rupture status. Imputation was performed 20 times each with a randomly chosen 5-digit seed used for generation of random numbers. The results of the imputations, the summary into a single inference that includes within and between imputation variability, and the completed cases and per protocol cohort results are provided in Ta…

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**Source:** [https://fda.innolitics.com/device/P170032](https://fda.innolitics.com/device/P170032)

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