Medtronic PED2-250-12 Instructions for Use

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INSTRUCTIONS FOR USE

Pipeline™ Flex Embolization Device

with Shield Technology™

TABLE OF CONTENTS

Pipeline™ Flex Embolization Device with Shield Technology™

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English en Instructions for Use

Pipeline™ Flex Embolization Device with Shield Technology™

DESCRIPTION

The Pipeline™ Flex Embolization Device with Shield Technology™ consists of a permanent implant combined with a guidewire based delivery system. The Pipeline™ Flex Embolization Device with Shield Technology™ implant is a braided, multi-alloy, mesh cylinder woven from platinum/tungsten and cobalt-chromium-nickel alloy wires. An image of the Pipeline™ Flex Embolization Device with Shield Technology™ is shown in Figure 1 and the design of the distal delivery system is shown in Figure 2. The woven wires of the device provide approximately 30% metal coverage of the arterial wall surface area. The implant is designed for placement in a parent vessel across the neck of an intracranial aneurysm (IA). The expanded or unconstrained diameter is 0.25 mm larger than the labeled diameter. Shield Technology™ is a synthetic polymer surface modication and is not derived from any animal or human sources.

The tip coil is made of platinum-tungsten alloy, the proximal bumper is a platinum-iridium alloy, and the tip, distal, and proximal solder joints are tin-silver. The protective sleeves are designed to protect the distal portion of the braid while the Pipeline™ Flex Embolization Device with Shield Technology™ is advanced through the micro catheter. The proximal bumper and resheathing pad allows the user to push the Pipeline™ Flex Embolization Device with Shield Technology™ out of the micro catheter when the delivery system is advanced. The resheathing pad allows the user to resheath the Pipeline™ Flex Embolization Device with Shield Technology™ back into the micro catheter. The resheathing marker provides the user uoroscopic visualization for the limit of resheathing the Pipeline™ Flex Embolization Device with Shield Technology™.

The Pipeline™ Flex Embolization Device with Shield Technology™ implant is mounted on a 304 stainless steel micro-guidewire approximately 200 cm long and compressed inside an introducer sheath. The Pipeline™ Flex Embolization Device with Shield Technology™ is designed to be delivered only through a compatible micro catheter of 0.027 inch (0.69 mm) inside diameter at least 135 cm in length.

Labeled Diameter (mm)

3.00 3.25 10, 12, 14, 16, 18, 20, 25, 30, 35

3.25 3.50 10, 12, 14, 16, 18, 20, 25, 30, 35

3.50 3.75 10, 12, 14, 16, 18, 20, 25, 30, 35

3.75 4.00 10, 12, 14, 16, 18, 20, 25, 30, 35

4.00 4.25 10, 12, 14, 16, 18, 20, 25, 30, 35

4.25 4.50 10, 12, 14, 16, 18, 20, 25, 30, 35

4.50 4.75 10, 12, 14, 16, 18, 20, 25, 30, 35

4.75 5.00 10, 12, 14, 16, 18, 20, 25, 30, 35

5.00 5.25 10, 12, 14, 16, 18, 20, 25, 30, 35

Self Expanded Diameter (mm)

Labeled Lengths (mm)

INDICATIONS FOR USE

The Pipeline™ Flex Embolization Device with Shield Technology™ is indicated for the endovascular treatment of adults (22 years of age or older) with large or giant wide-necked intracranial aneurysms (IAs) in the internal carotid artery from the petrous to the superior hypophyseal segments.

The Pipeline™ Flex Embolization Device with Shield Technology™ is also indicated for use in the internal carotid artery up to the terminus for the endovascular treatment of adults (22 years of age or older) with small and medium wide-necked (neck width ≥ 4 mm or dome-to-neck ratio < 2) saccular or fusiform intracranial aneurysm (IAs) arising from a parent vessel with a diameter ≥ 2.0 mm and ≤ 5.0 mm.

CONTRAINDICATIONS

• Patients with active bacterial infection.

• Patients in whom dual antiplatelet and/or anticoagulation therapy (aspirin and clopidogrel) is contraindicated.

• Patients who have not received dual antiplatelet agents prior to the procedure.

• Patients in whom a pre-existing stent is in place in the parent artery at the target aneurysm location.

• Patients in whom the parent vessel size does not fall within the indicated range.

Figure 1. The Pipeline™ Flex Embolization Device with Shield Technology™

≈200 cm (Total Length)

15mm

1 2

Figure 2. The Pipeline™ Flex Embolization Device with Shield Technology™

1. Tip Coil 5. Fluorosafe Marker 9. Resheathing Pad

2. Proximal Bumper 6. Delivery Wire 10. Resheathing Marker

3. Introducer Sheath 7. Distal Marker

4. Braid 8. PTFE Sleeves

≈125 cm (Tip Coil to Fluorosafe Marker)

3mm (Covered by Braid)

Table 1. Size Ranges: Pipeline™ Flex Embolization Device with Shield Technology™.

Labeled Diameter (mm)

2.50 2.75 10, 12, 14, 16, 18, 20

2.75 3.00 10, 12, 14, 16, 18, 20

Self Expanded Diameter (mm)

Labeled Lengths (mm)

DIRECTIONS FOR USE

1. Using standard interventional radiographic technique, place the micro catheter tip at least 20 mm past the distal edge of the aneurysm. Gently retract the micro catheter to reduce slack in the micro catheter prior to inserting Pipeline™ Flex Embolization Device with Shield Technology™.

NOTE: It is recommended to use a heparinized saline drip to continuously ush micro catheter during Pipeline™ Flex Embolization Device with Shield Technology™ use.

2. Choose a Pipeline™ Flex Embolization Device with Shield Technology™ with labeled diameter that approximates the target vessel diameter.

• Select an appropriate sized Pipeline™ Flex Embolization Device with Shield Technology™ such that

its fully expanded diameter is equivalent to that of the largest target vessel. An incorrectly sized Pipeline™ Flex Embolization Device with Shield Technology™ may result in inadequate device placement, incomplete opening or migration.

• The Pipeline™ Flex Embolization Device with Shield Technology™ foreshortens substantially (50-60%)

during deployment. Take device foreshortening into account when deploying the Pipeline™ Flex Embolization Device with Shield Technology™.

3. Choose a Pipeline™ Flex Embolization Device with Shield Technology™ with labeled length that is at least 6 mm longer than the aneurysm neck.

4. Remove packaging hoop from the pouch and pull the distal end of the introducer sheath from the blue clip on the packaging hoop.

5. Carefully remove system from packaging hoop until the delivery wire is exposed.

6. Partially insert introducer sheath into the rotating hemostatic valve (RHV) at the catheter hub and close the RHV. Using a ush pressure of 250 mmHg or greater, conrm back ush of the saline at the proximal end of the introducer sheath prior to advancing the Pipeline™ Flex Embolization Device with Shield Technology™ into the micro catheter.

7. Advance introducer sheath into the RHV; visually conrm the tip of the sheath is seated deeply in the hub of the micro catheter.

8. Secure introducer sheath to the hub by locking down the RHV tightly.

9. Advance the proximal end of the delivery wire until it aligns with the proximal end of the introducer sheath.

10. Remove the introducer sheath.

NOTE: The delivery wire has a uorosafe marker no further than 125 cm from the distal end.

CAUTION: The uorosafe marker is only compatible with micro catheters with a minimum length of

135 cm.

11. Advance the Pipeline™ Flex Embolization Device with Shield Technology™ into the micro catheter by

4 5

pushing the delivery wire until the tip of the delivery wire aligns with the tip of the micro catheter.

CAUTION: If high forces or excessive friction is encountered during delivery due to severe tortuosity, discontinue delivery of the device and identify the cause of the resistance, remove device and micro catheter simultaneously. Advancement or retraction of the Pipeline™ Flex Embolization Device with Shield Technology™ against resistance may result in device damage, including unintended device or component separation, fracture, or breakage of the delivery system due to inherent exibility limits of device design. Device damage may result in patient injury or death.

CAUTION: The presence of other indwelling endovascular stents may interfere with proper deployment and function of the Pipeline™ Flex Embolization Device with Shield Technology™.

12. Once the tip of delivery system and micro catheter are aligned, verify that the Pipeline™ Flex Embolization Device with Shield Technology™ is in the desired location. The distal end of Pipeline™ Flex Embolization Device with Shield Technology™ should be placed at least 3 mm past the distal edge of the aneurysm.

13. Begin to deliver the Pipeline™ Flex Embolization Device with Shield Technology™ using a combination of unsheathing the Pipeline™ Flex Embolization Device with Shield Technology™ and pushing the delivery wire simultaneously.

WARNINGS

• Pushing delivery wire without retracting the micro catheter at the same time will cause the open end braid to move distally in the vessel. This may cause damage to the braid or vessel.

• Use in tortuous anatomy may result in diculty or inability to deploy the Pipeline™ Flex Embolization Device with Shield Technology™ and can lead to damage to the Pipeline™ Flex Embolization Device with Shield Technology™ and microcatheter. To mitigate potential problems as a result of increased delivery forces, reduce the load in the system by:

• Unloading the microcatheter to the inner curves of vessel by pulling back on the system (i.e., the

microcatheter and delivery wire together).

• Continue unloading the system until advancement of the device (inside of microcatheter) is

observed, while minimizing the distal tip movement to prevent loss of position.

• Begin to re-advance the delivery wire while maintaining reduced load in the microcatheter. This

process should be repeated until the device passes through tortuous area and the delivery force is decreased.

14. After the distal end of Pipeline™ Flex Embolization Device with Shield Technology™ has successfully expanded, deploy the remainder of Pipeline™ Flex Embolization Device with Shield Technology™ by pushing the delivery wire and/or unsheathing the Pipeline™ Flex Embolization Device with Shield Technology™. Resheathing and/or manipulation of the micro catheter by locking down the delivery wire and moving both as a system may facilitate expansion of the Pipeline™ Flex Embolization Device with Shield Technology™.

CAUTION: Under uoroscopy, carefully monitor the tip coil during Pipeline™ Flex Embolization Device with Shield Technology™ deployment.

15. Resheathing Instructions: During deployment of the Pipeline™ Flex Embolization Device with Shield Technology™ resheathing can be performed by advancing the micro catheter while pulling the delivery wire.

The Pipeline™ Flex Embolization Device with Shield Technology™ can be resheathed until the resheathing marker has reached the distal marker of the micro catheter (see Figure 3 below).

The Pipeline™ Flex Embolization Device with Shield Technology™ is fully resheathed when the distal marker is retracted completely inside the micro catheter. The system is designed to allow for a 2 full cycles of resheathing of the Pipeline™ Flex Embolization Device with Shield Technology™.

WARNINGS

• Resheathing the Pipeline™ Flex Embolization Device with Shield Technology™ more than 2 full cycles may cause damage to the distal or proximal ends of the braid.

Figure 3. Pipeline™ Flex Embolization Device with Shield Technology™

(Resheathing schematic as seen under uoroscopy, image not to scale).

1. Proximal End of device 5. Proximal Bumper

2. Micro Catheter 6. Delivery Wire

3. Micro Catheter Distal Marker 7. Resheathing Limit

4. Resheathing Marker 8. Device Detached

16. After the entire Pipeline™ Flex Embolization Device with Shield Technology™ is deployed, advance the micro catheter through the device making sure not to dislodge the braid. When the micro catheter tip is distal to the Pipeline™ Flex Embolization Device with Shield Technology™, retract the delivery wire into the micro catheter tip.

CAUTION: If the catheter cannot be advanced through the Pipeline™ Flex Embolization Device with Shield Technology™, carefully remove the delivery wire through the Pipeline™ Flex Embolization Device with Shield Technology™ construct. CAUTION: If the delivery wire cannot be retracted into the micro catheter, carefully remove the delivery core wire and micro catheter simultaneously.

17. Carefully inspect the deployed Pipeline™ Flex Embolization Device with Shield Technology™ under uoroscopy to conrm that it is completely apposed to the vessel wall and not kinked. If the device is not fully apposed or is kinked, consider using a balloon catheter, micro catheter, or guidewire to fully open it. DISPOSAL: The implant and or delivery system should be disposed of or returned to the manufacturer per institutional guidelines.

POTENTIAL COMPLICATIONS

Potential complications of the device and the endovascular procedure include, but are not limited to, the following:

• Access site complications like hematoma, inammation, infection, necrosis, pain and tenderness, granuloma.

• Adverse reaction to antiplatelet/anticoagulation agents, anesthesia, reactions due to radiation exposure (such as alopecia, burns ranging in severity from skin reddening to ulcers, cataracts, and delayed neoplasia) or contrast media, including organ failure

• Vascular Complications like vasospasm, stenosis, dissection, perforation, rupture, stula formation, pseudo aneurysm, occlusion ,thromboembolic complications including ischemia (to unintended territory)

• Device complications like fracture, breakage (including unintended device or component separation), misplacement, migration / delayed foreshortening or reaction to device materials may occur.

• Systemic Complications like: Infection, Pain, fever, allergic reactions, organ failure, nerve damage

• Bleeding/ hemorrhagic complication including retroperitoneal hemorrhage

• Neurological Decits or dysfunctions including Stroke, Infarction, Loss of vision, Seizures, TIA, Headache, Cranial Nerve Palsies, Confusion, Coma, Hand Dysfunction

• Decreased therapeutic response including need for target aneurysm retreatment

• Risks associated with visual symptoms include Amaurosis Fugax/transient blindness, Blindness, Diplopia, Reduced visual acuity/eld, Retinal artery occlusion, Retinal ischemia, Retinal infarction, Vision impairment including scintillations, blurred vision, eye oaters

• Intra-Cranial Hemorrhage (including from Aneurysm Rupture) Brain Edema, Hydrocephalus, Mass Eect

• Death

WARNINGS

• Resheathing of the Pipeline™ Flex Embolization Device with Shield Technology™ more than 2 full cycles may cause damage to the distal or proximal ends of the braid.

WARNINGS

• Persons with known allergy to platinum or cobalt/chromium alloy (including the major elements platinum, cobalt, chromium, nickel, molybdenum or tungsten) may suer an allergic reaction to the Pipeline™ Flex Embolization Device with Shield Technology™ implant.

• Person with known allergy to tin, silver, stainless steel or silicone elastomer may suer an allergic reaction to the Pipeline™ Flex Embolization Device with Shield Technology™ delivery system.

• Do not reprocess or resterilize. Reprocessing and resterilization increase the risk of patient infection and compromised device performance.

• Post-procedural movement (migration and/or foreshortening) of the Pipeline™ Flex Embolization Device with Shield Technology™ implant may occur following implantation and can result in serious adverse events and/or death.

• Factors which may contribute to post procedural device movement include (but are not limited to) the following:

• Failure to adequately size the implant (i.e., under sizing)

• Failure to obtain adequate wall apposition during the implant deployment

• Implant stretching

• Vasospasm

• Severe vessel tapering

• Tortuous anatomy

• Delayed rupture may occur with large and giant aneurysms.

• Placement of multiple Pipeline™ Flex Embolization Device with Shield Technology™ may increase the risk of ischemic complications.

• Use in anatomy with severe tortuosity, stenosis or parent vessel narrowing may result in diculty or inability to deploy the Pipeline™ Flex Embolization Device with Shield Technology™ and can lead to damage to the Pipeline™ Flex Embolization Device with Shield Technology™ and microcatheter. Advancement or retraction of the Pipeline™ Flex Embolization Device with Shield Technology™ against resistance may result in damage, including unintended device or component separation, fracture, or breakage of the deliver system due to inherent exibility limits of device design. Device damage may result in patient injury or death. Refer to page 4 in the instructions for use for additional information.

• Do not attempt to reposition the device after full deployment.

• The benets may not outweigh the risks of treatment of small and medium asymptomatic extradural intracranial aneurysms, including those located in the cavernous internal carotid artery. The risk of rupture for small and medium asymptomatic extradural intracranial aneurysms is very low if not negligible.

• A decrease in the proportion of patients who achieve complete aneurysm occlusion without signicant parent artery stenosis has been observed with the use of the device in the communicating segment (C7) of the internal carotid artery (47.4% (9/19 subjects in the PREMIER study at 1 year)), including those IAs fed by the posterior circulation or have retrograde lling. Ensure appropriate patient selection and weigh the benets and risks of alternative treatments prior to use of this device for the treatment of intracranial aneurysms located in this region of the ICA. The following anatomical characteristics, associated with retrograde lling, should be carefully considered during procedural planning of C7 intracranial aneurysms:

1. PComm of fetal origin (A PCA of fetal origin is dened as a small, hypoplastic, or absent P1 segment of the PCA

with the PComm artery supplying a majority of blood ow to the ICA);

2. PComm overlapping with the aneurysm neck; and/or

3. PComm branch arising from the dome of the aneurysm.

• The safety and eectiveness of this device for radial neurovasculature access in direct comparison to a transfemoral approach has not been demonstrated. The risks and benets for radial access against a transfemoral approach should be carefully weighed and considered for each patient.

PRECAUTIONS

• The Pipeline™ Flex Embolization Device with Shield Technology™ should be used only by physicians trained in percutaneous, intravascular techniques and procedures at medical facilities with the appropriate uoroscopic equipment.

• Physicians should undergo appropriate training prior to using the Pipeline™ Flex Embolization Device with Shield Technology™ in patients.

• The Pipeline™ Flex Embolization Device with Shield Technology™ is intended for single use only.

• Store in a cool, dry place.

• Carefully inspect the sterile package and device components prior to use to verify that they have not been damaged during shipping.

• Do not use kinked or damaged components.

• Do not use product if the sterile package is damaged

• Use the Pipeline™ Flex Embolization Device with Shield Technology™ system prior to the “Use By” date printed on the package.

• The appropriate anti-platelet and anti-coagulation therapy should be administered in accordance with standard medical practice.

• A thrombosing aneurysm may aggravate pre-existing, or cause new, symptoms of mass eect and may require medical therapy.

• Use of implants with labeled diameter larger than the parent vessel diameter may result in decreased eectiveness and additional safety risk due to incomplete foreshortening resulting in an implant longer than anticipated.

• The Pipeline™ Flex Embolization Device with Shield Technology™ may create local eld inhomogeneity and susceptibility artifacts during magnetic resonance angiography (MRA), which may degrade the diagnostic quality to assess eective intracranial aneurysm treatment.

• Take all necessary precautions to limit X-radiation doses to patients and themselves by using sucient shielding, reducing uoroscopy times, and modifying X-ray technical factors where possible.

• Carefully weigh the benets of treatment vs. the risks associated with treatment using the device for each individual patient based on their medical health status and risks factors for intracranial aneurysm rupture during their expected life time such as age, medical comorbidities, history of smoking, intracranial aneurysm size, location, and morphology, family history, history of prior asymptomatic subarachnoid hemorrhage (aSAH), documented growth of intracranial aneurysm on serial imaging, presence of multiple intracranial aneurysms, and presence of concurrent pathology. The benets of device use may not outweigh the risks associated with the device in certain patients; therefore, judicious patient selection is recommended.

• The safety and eectiveness of the device has not been established for treatment of fusiform IAs.

• There may be a decrease in eectiveness and increase in safety events when the device is used in patients ≥ 60 years old.

• The safety and eectiveness of the device has not been evaluated or demonstrated for ruptured aneurysms.

• If using radial artery access, perform a screening examination of the radial artery per institutional practices to ensure that radial access is appropriate for the patient.

HOW SUPPLIED

This device is supplied STERILE using ethylene oxide. This device is Non-pyrogenic.

STORAGE AND DISPOSAL

• This device should be stored in a dry place, away from sunlight.

• Dispose of device in accordance with hospital, administrative, and/or local government policy.

MAGNETIC RESONANCE IMAGING (MRI) SAFETY INFORMATION

Non-clinical testing has demonstrated that the Pipeline™ Flex Embolization Device with Shield Technology™ is MR Conditional for single and overlapping stents up to 70 mm in length. A patient with this device can be scanned safely in an MR system immediately after placement under the following conditions:

• Static magnetic eld 1.5 Tesla and 3 Tesla, only.

• Maximum spatial gradient eld of 30 T/m (3000 Gauss/cm) or less.

• Maximum MR system reported, whole body averaged specic absorption rate (SAR) of 2-W/kg for 15 minutes of scanning in the Normal Operating Mode for the MR system

• Maximum head SAR of 3.2W/kg

• Quadrature driven RF birdcage coil only

Under the scan conditions dened, the Pipeline™ Flex Embolization Device with Shield Technology™ is expected to produce a maximum temperature rise of 3.1 ˚C after 15-minutes of continuous scanning.

In non-clinical testing, the image artifact caused by the Pipeline™ Flex Embolization Device with Shield Technology™ extends approximately 11.0 mm from this implant when imaged using a T1-weighted spin echo pulse sequence and a 3-Tesla MR system.

Local eld artifact from the Pipeline™ Flex Embolization Device with Shield Technology™ may decrease the accuracy of MR angiogram in assessing vessel luminal patency.

MR image quality may be compromised if the area is in the exact same area or relatively close to the position of the Pipeline™ Flex Embolization Device with Shield Technology™. Therefore, it may be necessary to optimize MR imaging parameters for the presence of this metallic implant.

OBSERVED ADVERSE EVENTS

There were two prospective investigational trials conducted on the Pipeline™ device, the PUFS and PREMIER studies.

PUFS was a prospective, multicenter international study of patients with large and giant wide-necked unruptured aneurysms of the internal carotid artery treated with the Pipeline™ Embolization device (PED). 108 subjects were enrolled and treated in the PUFS study. The PUFS-CA study was also a prospective, multicenter study of patients with large and giant unruptured aneurysms of the internal carotid artery treated with the Pipeline™ Embolization device (PED). 27 subjects were enrolled and treated in the PUFS-CA study. The PUFS-PAS study was a single arm-prospective, multicenter cohort study of patients implanted with PED, the study population consisted of patients with large and giant unruptured aneurysms that were enrolled in the PUFS-PUFS-CA studies. 135 subjects were enrolled and 134 subjects were treated in the PUFS-PAS study. Serious adverse events reported to ve year follow-up are shown in Table 2 and non-serious adverse events are shown in Table 3. In the PUFS-PAS study, cerebral haemorrhage was reported in 4.5% (6/134) subjects, cerebral ischaemia was reported in 2.2% (3/134) subjects, and ischaemic stroke was reported in 1.5% (2/134) subjects at 5 years (Table 2). Five occurred in the peri-procedural period (prior to discharge) and 6 in the post-procedural period. Two of the events were fatal, both intracerebral hemorrhages. One peri-procedural ischemic stroke and 2 post-procedural ischemic strokes were associated with parent artery occlusion. A history of hypertension is associated with increased risk of ipsilateral stroke or neurovascular death following PED treatment.

NOTE: With the exception of the surface modication, the Pipeline™ Flex Embolization device with Shield Technology™ implant is identical to the Pipeline ™ embolization device implant used in the PUFS-PAS trial.

Table 2. Serious adverse events in PUFS-PAS by MedDRA®* category and term –

cumulative incidence at 180 days, one year, three years and ve years

(N= 134 subjects).

MedDRA®* Category

Nervous system disorders

Gastrointestinal disorders

Injury, poisoning and procedural complications

MedDRA®* Term

Total

Cerebral haemorrhage

Headache

Cerebral ischaemia

Convulsion

IIIrd nerve disorder

Ischaemic stroke

Syncope

Carotid artery aneurysm

Carotid artery occlusion

Carpal tunnel syndrome

Cerebral artery embolism

Cerebral artery stenosis

Cerebrovascular accident

Dementia alzheimer's type

Dizziness

Hemiparesis

Nervous system disorder

Transient ischaemic attack

VIth nerve disorder

Total

Gastrointestinal haemorrhage

Colitis

Diverticulitis intestinal haemorrhagic

Intra-abdominal haemorrhage

Nausea

Oesophageal spasm

Peptic ulcer

Rectal haemorrhage

Retroperitoneal haematoma

Vomiting

Total

Hip fracture

Joint injury

Ankle fracture

Arterial injury

Corneal abrasion

Procedural haemorrhage

Road trac accident

Vascular pseudoaneurysm

180 days 1 year 3 year 5 year

(13.4%)

6 (4.5%) 6 (4.5%) 6 (4.5%) 6 (4.5%)

5 (3.7%) 6 (4.5%) 6 (4.5%) 6 (4.5%)

3 (2.2%) 3 (2.2%) 3 (2.2%) 3 (2.2%)

0 (0.0%) 0 (0.0%) 0 (0.0%) 2 (1.5%)

2 (1.5%) 2 (1.5%) 2 (1.5%) 2 (1.5%)

0 (0.0%) 1 (0.7%) 2 (1.5%) 2 (1.5%)

1 (0.7%) 1 (0.7%) 1 (0.7%) 1 (0.7%)

0 (0.0%) 0 (0.0%) 1 (0.7%) 1 (0.7%)

1 (0.7%) 1 (0.7%) 1 (0.7%) 1 (0.7%)

0 (0.0%) 0 (0.0%) 1 (0.7%) 1 (0.7%)

0 (0.0%) 1 (0.7%) 1 (0.7%) 1 (0.7%)

1 (0.7%) 1 (0.7%) 1 (0.7%) 1 (0.7%)

0 (0.0%) 0 (0.0%) 0 (0.0%) 1 (0.7%)

0 (0.0%) 0 (0.0%) 1 (0.7%) 1 (0.7%)

1 (0.7%) 1 (0.7%) 1 (0.7%) 1 (0.7%)

7 (5.2%) 8 (6.0%) 9 (6.7%) 10 (7.5%)

0 (0.0%) 1 (0.7%) 3 (2.2%) 3 (2.2%)

1 (0.7%) 1 (0.7%) 1 (0.7%) 1 (0.7%)

0 (0.0%) 0 (0.0%) 1 (0.7%) 1 (0.7%)

1 (0.7%) 1 (0.7%) 1 (0.7%) 1 (0.7%)

0 (0.0%) 0 (0.0%) 0 (0.0%) 1 (0.7%)

1 (0.7%) 1 (0.7%) 1 (0.7%) 1 (0.7%)

5 (3.7%) 5 (3.7%) 7 (5.2%) 10 (7.5%)

0 (0.0%) 0 (0.0%) 1 (0.7%) 2 (1.5%)

1 (0.7%) 1 (0.7%) 2 (1.5%) 2 (1.5%)

0 (0.0%) 0 (0.0%) 0 (0.0%) 1 (0.7%)

1 (0.7%) 1 (0.7%) 1 (0.7%) 1 (0.7%)

0 (0.0%) 0 (0.0%) 0 (0.0%) 1 (0.7%)

1 (0.7%) 1 (0.7%) 1 (0.7%) 1 (0.7%)

(13.4%)

(17.9%)

(20.1%)

MedDRA®* Category

Surgical and medical procedures

MedDRA®* Term

Total

Aneurysm repair

Arterial aneurysm repair

Atrial septal defect repair

Intra-cerebral aneurysm operation

Knee arthroplasty

Eye disorders Total

Amaurosis fugax

Ophthalmoplegia

Eye pain

Retinal artery embolism

Vision blurred

Visual impairment

Cardiac disorders Total

Atrial brillation

Bradycardia

Arrhythmia

Myocardial infarction

Ventricular brillation

Wol-parkinson-white syndrome

Vascular disorders

Total

Haematoma

Aneurysm

Deep vein thrombosis

Embolism

Hypotension

Intermittent claudication

Peripheral vascular disorder

Neoplasms benign, malignant and unspecied (incl. cysts and polyps)

Total

Adenocarcinoma

Breast cancer

Breast cancer recurrent

Colon cancer

Lung neoplasm malignant

Metastatic neoplasm

Non-small cell lung cancer stage IIIB

Prostate cancer

180 days 1 year 3 year 5 year

0 (0.0%) 2 (1.5%) 9 (6.7%) 10 (7.5%)

0 (0.0%) 2 (1.5%) 6 (4.5%) 6 (4.5%)

0 (0.0%) 0 (0.0%) 1 (0.7%) 1 (0.7%)

0 (0.0%) 0 (0.0%) 0 (0.0%) 1 (0.7%)

5 (3.7%) 6 (4.5%) 9 (6.7%) 9 (6.7%)

1 (0.7%) 2 (1.5%) 3 (2.2%) 3 (2.2%)

1 (0.7%) 1 (0.7%) 2 (1.5%) 2 (1.5%)

1 (0.7%) 1 (0.7%) 1 (0.7%) 1 (0.7%)

0 (0.0%) 0 (0.0%) 1 (0.7%) 1 (0.7%)

4 (3.0%) 4 (3.0%) 5 (3.7%) 8 (6.0%)

1 (0.7%) 1 (0.7%) 1 (0.7%) 2 (1.5%)

1 (0.7%) 1 (0.7%) 1 (0.7%) 1 (0.7%)

0 (0.0%) 0 (0.0%) 1 (0.7%) 1 (0.7%)

1 (0.7%) 1 (0.7%) 1 (0.7%) 1 (0.7%)

0 (0.0%) 0 (0.0%) 0 (0.0%) 1 (0.7%)

5 (3.7%) 5 (3.7%) 6 (4.5%) 8 (6.0%)

2 (1.5%) 2 (1.5%) 2 (1.5%) 2 (1.5%)

0 (0.0%) 0 (0.0%) 1 (0.7%) 1 (0.7%)

1 (0.7%) 1 (0.7%) 1 (0.7%) 1 (0.7%)

0 (0.0%) 0 (0.0%) 0 (0.0%) 1 (0.7%)

0 (0.0%) 2 (1.5%) 4 (3.0%) 7 (5.2%)

0 (0.0%) 0 (0.0%) 1 (0.7%) 1 (0.7%)

0 (0.0%) 1 (0.7%) 1 (0.7%) 1 (0.7%)

0 (0.0%) 0 (0.0%) 0 (0.0%) 1 (0.7%)

0 (0.0%) 1 (0.7%) 1 (0.7%) 1 (0.7%)

0 (0.0%) 0 (0.0%) 1 (0.7%) 1 (0.7%)

0 (0.0%) 0 (0.0%) 0 (0.0%) 1 (0.7%)

MedDRA®* Category

Infections and infestations

MedDRA®* Term

Total

Cholecystitis infective

Abdominal abscess

Herpes zoster

Meningitis viral

Pneumonia

Upper respiratory tract infection

Respiratory, thoracic and mediastinal disorders

Total

Epistaxis

Haemoptysis

Emphysema

Pulmonary embolism

General disorders and administration site conditions

Total

Catheter site discharge

Death

Multi-organ failure

Oedema peripheral

Endocrine disorders

Musculoskeletal and connective tissue disorders

Total

Hypothyroidism

Total

Arthritis

Intervertebral disc

degeneration

Blood and lymphatic system disorders

Ear and labyrinth disorders

Psychiatric disorders

Renal and urinary disorders

Total

Bone marrow failure

Total

Tinnitus

Total

Depression

Total

Haematuria

Total

*MedDRA® Medical Dictionary for Regulatory Activities

180 days 1 year 3 year 5 year

2 (1.5%) 3 (2.2%) 5 (3.7%) 6 (4.5%)

1 (0.7%) 2 (1.5%) 2 (1.5%) 2 (1.5%)

0 (0.0%) 0 (0.0%) 1 (0.7%) 1 (0.7%)

0 (0.0%) 1 (0.7%) 1 (0.7%) 1 (0.7%)

0 (0.0%) 0 (0.0%) 1 (0.7%) 1 (0.7%)

1 (0.7%) 1 (0.7%) 1 (0.7%) 1 (0.7%)

0 (0.0%) 0 (0.0%) 0 (0.0%) 1 (0.7%)

2 (1.5%) 2 (1.5%) 5 (3.7%) 6 (4.5%)

2 (1.5%) 2 (1.5%) 2 (1.5%) 2 (1.5%)

0 (0.0%) 0 (0.0%) 1 (0.7%) 2 (1.5%)

0 (0.0%) 0 (0.0%) 1 (0.7%) 1 (0.7%)

2 (1.5%) 3 (2.2%) 4 (3.0%) 4 (3.0%)

1 (0.7%) 1 (0.7%) 1 (0.7%) 1 (0.7%)

0 (0.0%) 0 (0.0%) 1 (0.7%) 1 (0.7%)

0 (0.0%) 1 (0.7%) 1 (0.7%) 1 (0.7%)

0 (0.0%) 0 (0.0%) 0 (0.0%) 3 (2.2%)

0 (0.0%) 1 (0.7%) 2 (1.5%) 2 (1.5%)

0 (0.0%) 1 (0.7%) 1 (0.7%) 1 (0.7%)

0 (0.0%) 0 (0.0%) 1 (0.7%) 1 (0.7%)

1 (0.7%) 1 (0.7%) 1 (0.7%) 1 (0.7%)

0 (0.0%) 0 (0.0%) 0 (0.0%) 1 (0.7%)

(27.6%)

(32.1%)

(46.3%)

(52.2%)

Table 3. Non-serious adverse events in PUFS-PAS by Five years – by decreasing

incidence (N= 134 subjects).

MedDRA®* Category

Nervous system disorders

MedDRA®* Term

Total

Headache

Dizziness

Hypoaesthesia

Paraesthesia

Migraine

Visual eld defect

Carotid artery occlusion

Cerebral artery stenosis

Convulsion

Coordination abnormal

Dementia

Facial paresis

Facial spasm

Formication

Hyperaesthesia

Hypotonia

IIIrd nerve disorder

IIIrd nerve paralysis

Intracranial aneurysm

IVth nerve paralysis

Migraine with aura

Sciatica

Transient ischaemic attack

Tremor

Upper motor neurone lesion

VIth nerve paralysis

VIth nerve paresis

180 days 1 year 3 year 5 year

(35.1%)

(29.1%)

2 (1.5%) 4 (3.0%) 5 (3.7%) 6 (4.5%)

3 (2.2%) 3 (2.2%) 4 (3.0%) 5 (3.7%)

1 (0.7%) 2 (1.5%) 3 (2.2%) 4 (3.0%)

1 (0.7%) 1 (0.7%) 1 (0.7%) 3 (2.2%)

1 (0.7%) 2 (1.5%) 2 (1.5%) 2 (1.5%)

1 (0.7%) 1 (0.7%) 1 (0.7%) 1 (0.7%)

0 (0.0%) 0 (0.0%) 1 (0.7%) 1 (0.7%)

0 (0.0%) 0 (0.0%) 0 (0.0%) 1 (0.7%)

0 (0.0%) 0 (0.0%) 1 (0.7%) 1 (0.7%)

0 (0.0%) 0 (0.0%) 0 (0.0%) 1 (0.7%)

0 (0.0%) 0 (0.0%) 1 (0.7%) 1 (0.7%)

1 (0.7%) 1 (0.7%) 1 (0.7%) 1 (0.7%)

0 (0.0%) 0 (0.0%) 1 (0.7%) 1 (0.7%)

1 (0.7%) 1 (0.7%) 1 (0.7%) 1 (0.7%)

0 (0.0%) 0 (0.0%) 0 (0.0%) 1 (0.7%)

1 (0.7%) 1 (0.7%) 1 (0.7%) 1 (0.7%)

0 (0.0%) 0 (0.0%) 0 (0.0%) 1 (0.7%)

0 (0.0%) 0 (0.0%) 1 (0.7%) 1 (0.7%)

1 (0.7%) 1 (0.7%) 1 (0.7%) 1 (0.7%)

(35.8%)

(29.1%)

(41.8%)

(32.8%)

(46.3%)

(34.3%)

MedDRA®* Category

MedDRA®* Term

Eye disorders Total

Visual impairment

Eyelid ptosis

Diplopia

Eye pain

Glaucoma

Photopsia

Vision blurred

Visual acuity reduced

Abnormal sensation in eye

Amaurosis

Amblyopia

Conjunctivitis

Eye haemorrhage

Eye pruritus

Ophthalmoplegia

Optic nerve disorder

Vitreous oaters

Vascular

Total

disorders

Vasospasm

Haematoma

Hypertension

Aneurysm

Aortic aneurysm

Arterial occlusive disease

Arterial stenosis

Blood pressure inadequately controlled

Orthostatic hypotension

Thrombophlebitis supercial

Thrombosis

Gastrointestinal

Total

disorders

Nausea

Constipation

Vomiting

Abdominal distension

Abdominal pain upper

Haematochezia

Paraesthesia oral

Rectal haemorrhage

180 days 1 year 3 year 5 year

(20.9%)

(10.4%)

4 (3.0%) 4 (3.0%) 4 (3.0%) 4 (3.0%)

3 (2.2%) 3 (2.2%) 3 (2.2%) 3 (2.2%)

1 (0.7%) 1 (0.7%) 2 (1.5%) 2 (1.5%)

2 (1.5%) 2 (1.5%) 2 (1.5%) 2 (1.5%)

0 (0.0%) 0 (0.0%) 1 (0.7%) 2 (1.5%)

1 (0.7%) 1 (0.7%) 2 (1.5%) 2 (1.5%)

1 (0.7%) 1 (0.7%) 1 (0.7%) 2 (1.5%)

0 (0.0%) 0 (0.0%) 0 (0.0%) 1 (0.7%)

0 (0.0%) 0 (0.0%) 1 (0.7%) 1 (0.7%)

0 (0.0%) 1 (0.7%) 1 (0.7%) 1 (0.7%)

0 (0.0%) 0 (0.0%) 1 (0.7%) 1 (0.7%)

1 (0.7%) 1 (0.7%) 1 (0.7%) 1 (0.7%)

0 (0.0%) 0 (0.0%) 1 (0.7%) 1 (0.7%)

1 (0.7%) 1 (0.7%) 1 (0.7%) 1 (0.7%)

11 (8.2%) 12 (9.0%) 13 (9.7%) 20

4 (3.0%) 4 (3.0%) 4 (3.0%) 5 (3.7%)

4 (3.0%) 4 (3.0%) 4 (3.0%) 4 (3.0%)

1 (0.7%) 1 (0.7%) 1 (0.7%) 3 (2.2%)

0 (0.0%) 0 (0.0%) 0 (0.0%) 2 (1.5%)

0 (0.0%) 0 (0.0%) 0 (0.0%) 1 (0.7%)

0 (0.0%) 1 (0.7%) 1 (0.7%) 1 (0.7%)

0 (0.0%) 0 (0.0%) 0 (0.0%) 1 (0.7%)

0 (0.0%) 0 (0.0%) 1 (0.7%) 1 (0.7%)

1 (0.7%) 1 (0.7%) 1 (0.7%) 1 (0.7%)

(10.4%)

11 (8.2%) 11 (8.2%) 11 (8.2%) 12 (9.0%)

2 (1.5%) 2 (1.5%) 2 (1.5%) 2 (1.5%)

1 (0.7%) 1 (0.7%) 1 (0.7%) 1 (0.7%)

0 (0.0%) 0 (0.0%) 1 (0.7%) 1 (0.7%)

1 (0.7%) 1 (0.7%) 1 (0.7%) 1 (0.7%)

0 (0.0%) 0 (0.0%) 0 (0.0%) 1 (0.7%)

1 (0.7%) 1 (0.7%) 1 (0.7%) 1 (0.7%)

(20.9%)

(10.4%)

(23.9%)

(10.4%)

(11.2%)

(26.1%)

(10.4%)

(14.9%)

(12.7%)

MedDRA®* Category

Injury, poisoning and procedural complications

General disorders and administration site conditions

Musculoskeletal and connective tissue disorders

Infections and infestations

MedDRA®* Term

Total

Contusion

Head injury

Ankle fracture

Contrast media reaction

Corneal abrasion

Foot fracture

Muscle strain

Radiation exposure

Radiation injury

Spinal compression fracture

Total

Pain

Pyrexia

Adverse drug reaction

Catheter site discharge

Catheter site swelling

Chest pain

Facial pain

Fatigue

Feeling cold

Oedema peripheral

Vessel puncture site

haemorrhage

Total

Neck pain

Arthralgia

Arthritis

Muscular weakness

Back pain

Groin pain

Pain in extremity

Total

Infection

Cellulitis

Chronic sinusitis

Sinusitis

Tooth abscess

Urinary tract infection

180 days 1 year 3 year 5 year

10 (7.5%) 10 (7.5%) 13 (9.7%) 14

(10.4%)

4 (3.0%) 4 (3.0%) 5 (3.7%) 5 (3.7%)

2 (1.5%) 2 (1.5%) 3 (2.2%) 3 (2.2%)

0 (0.0%) 0 (0.0%) 0 (0.0%) 1 (0.7%)

0 (0.0%) 1 (0.7%) 1 (0.7%) 1 (0.7%)

1 (0.7%) 1 (0.7%) 1 (0.7%) 1 (0.7%)

0 (0.0%) 0 (0.0%) 1 (0.7%) 1 (0.7%)

1 (0.7%) 1 (0.7%) 1 (0.7%) 1 (0.7%)

0 (0.0%) 1 (0.7%) 1 (0.7%) 1 (0.7%)

9 (6.7%) 10 (7.5%) 10 (7.5%) 11 (8.2%)

2 (1.5%) 2 (1.5%) 2 (1.5%) 2 (1.5%)

0 (0.0%) 0 (0.0%) 0 (0.0%) 1 (0.7%)

1 (0.7%) 1 (0.7%) 1 (0.7%) 1 (0.7%)

0 (0.0%) 1 (0.7%) 1 (0.7%) 1 (0.7%)

1 (0.7%) 1 (0.7%) 1 (0.7%) 1 (0.7%)

0 (0.0%) 0 (0.0%) 1 (0.7%) 1 (0.7%)

1 (0.7%) 1 (0.7%) 1 (0.7%) 1 (0.7%)

4 (3.0%) 5 (3.7%) 8 (6.0%) 11 (8.2%)

1 (0.7%) 1 (0.7%) 2 (1.5%) 3 (2.2%)

0 (0.0%) 0 (0.0%) 1 (0.7%) 2 (1.5%)

0 (0.0%) 1 (0.7%) 2 (1.5%) 2 (1.5%)

1 (0.7%) 1 (0.7%) 1 (0.7%) 1 (0.7%)

6 (4.5%) 6 (4.5%) 7 (5.2%) 9 (6.7%)

6 (4.5%) 6 (4.5%) 6 (4.5%) 6 (4.5%)

0 (0.0%) 0 (0.0%) 1 (0.7%) 1 (0.7%)

0 (0.0%) 0 (0.0%) 0 (0.0%) 1 (0.7%)

MedDRA®* Category

Psychiatric disorders

MedDRA®* Term

Total

Depression

Alcoholism

Anxiety

Behavioural and psychiatric symptoms of dementia

Mental status changes

Panic attack

Respiratory, thoracic and mediastinal disorders

Total

Epistaxis

Oropharyngeal pain

Cough

Blood and lymphatic system disorders

Total

Haemorrhagic disorder

Anaemia

Thrombocytopenia

Investigations Total

Corneal reex decreased

Electrocardiogram qt prolonged

Ophthalmological examination abnormal

Weber tuning fork test abnormal

Metabolism and nutrition disorders

Total

Hypercholesterolaemia

Diabetes mellitus

Iron deciency

Renal and

urinary disorders

Total

Haematuria

Pollakiuria

Reproductive system and breast disorders

Total

Breast cyst

Female genital tract stula

Ovarian cyst

Vaginal haemorrhage

Ear and labyrinth disorders

Total

Tinnitus

180 days 1 year 3 year 5 year

0 (0.0%) 1 (0.7%) 5 (3.7%) 7 (5.2%)

0 (0.0%) 0 (0.0%) 2 (1.5%) 2 (1.5%)

0 (0.0%) 0 (0.0%) 1 (0.7%) 1 (0.7%)

0 (0.0%) 0 (0.0%) 0 (0.0%) 1 (0.7%)

0 (0.0%) 0 (0.0%) 1 (0.7%) 1 (0.7%)

0 (0.0%) 1 (0.7%) 1 (0.7%) 1 (0.7%)

0 (0.0%) 0 (0.0%) 0 (0.0%) 1 (0.7%)

5 (3.7%) 5 (3.7%) 7 (5.2%) 7 (5.2%)

3 (2.2%) 3 (2.2%) 4 (3.0%) 4 (3.0%)

2 (1.5%) 2 (1.5%) 2 (1.5%) 2 (1.5%)

0 (0.0%) 0 (0.0%) 1 (0.7%) 1 (0.7%)

5 (3.7%) 5 (3.7%) 5 (3.7%) 5 (3.7%)

3 (2.2%) 3 (2.2%) 3 (2.2%) 3 (2.2%)

2 (1.5%) 2 (1.5%) 2 (1.5%) 2 (1.5%)

0 (0.0%) 0 (0.0%) 0 (0.0%) 1 (0.7%)

2 (1.5%) 3 (2.2%) 4 (3.0%) 4 (3.0%)

1 (0.7%) 1 (0.7%) 1 (0.7%) 1 (0.7%)

0 (0.0%) 0 (0.0%) 1 (0.7%) 1 (0.7%)

1 (0.7%) 1 (0.7%) 1 (0.7%) 1 (0.7%)

0 (0.0%) 1 (0.7%) 1 (0.7%) 1 (0.7%)

0 (0.0%) 0 (0.0%) 3 (2.2%) 4 (3.0%)

0 (0.0%) 0 (0.0%) 2 (1.5%) 2 (1.5%)

0 (0.0%) 0 (0.0%) 0 (0.0%) 1 (0.7%)

0 (0.0%) 0 (0.0%) 1 (0.7%) 1 (0.7%)

2 (1.5%) 2 (1.5%) 2 (1.5%) 3 (2.2%)

2 (1.5%) 2 (1.5%) 2 (1.5%) 2 (1.5%)

0 (0.0%) 0 (0.0%) 0 (0.0%) 1 (0.7%)

3 (2.2%) 3 (2.2%) 3 (2.2%) 3 (2.2%)

0 (0.0%) 0 (0.0%) 0 (0.0%) 1 (0.7%)

1 (0.7%) 1 (0.7%) 1 (0.7%) 1 (0.7%)

1 (0.7%) 2 (1.5%) 2 (1.5%) 2 (1.5%)

MedDRA®* Category

Neoplasms benign, malignant and unspecied (incl. cysts and polyps) Congenital, familial

MedDRA®* Term

Total

Cervix carcinoma recurrent

Neoplasm malignant

Total

Arnold-chiari malformation

180 days 1 year 3 year 5 year

0 (0.0%) 0 (0.0%) 1 (0.7%) 2 (1.5%)

0 (0.0%) 0 (0.0%) 0 (0.0%) 1 (0.7%)

0 (0.0%) 0 (0.0%) 1 (0.7%) 1 (0.7%)

and genetic disorders

Immune system disorders

Skin and subcutaneous tissue disorders

Surgical and medical

procedures

Total

Hypersensitivity

Total

Pruritus

Total

Rotator cu repair

Total 84

1 (0.7%) 1 (0.7%) 1 (0.7%) 1 (0.7%)

0 (0.0%) 0 (0.0%) 0 (0.0%) 1 (0.7%)

(62.7%)

84 (62.7%)

91 (67.9%)

98 (73.1%)

MedDRA®: Medical Dictionary for Regulatory Activities

*NEC; Not Elsewhere Classied

PREMIER was a prospective, multi-center, single-arm study of patients with small and medium unruptured wide-neck intracranial aneurysms of the internal carotid artery and vertebral artery segments treated with the Pipeline™ device. A total of 141 subjects were enrolled and treated with the Pipeline™ device. All CEC adjudicated adverse events through 1-years by system organ class and preferred term are presented in Table

4. Eight strokes occurred in 7 subjects (5.0%) at 1-year, of which 3 were major (a stroke, which is present for 24 hrs or more and increases the NIH Stroke Scale of the subject by ≥ 4) and 5 were minor (A stroke, which is present for 24 hrs or more and increases the NIH Stroke Scale of the subject by ≤ 3). All strokes were ischemic in nature, with 3 of the 8 strokes having a hemorrhagic transformation of the core ischemic infarct. No stroke events were observed peri-procedurally (Day 0), two of the 3 major stroke events occurred in the Acute period (Day 1-Day 30), and 1 event occurred in the delayed period (Day 31-Day 365). Of the 3 major stroke events that occurred through 1-year, one resulted in death, one was disabling (modied Rankin Scale (mRS) score of ≥ 3 at a minimum of 90‐days post‐stroke event) at 1-year and one was non-disabling at 1-year. Of the 5 minor strokes that occurred through 1-year, no events were observed peri-procedurally. Four of the 5 events occurred in the acute period and 1 event was delayed.

NOTE: The Pipeline™ embolization device and Pipeline™ Flex Embolization Device utilize the same implant and were both used in the PREMIER trial. With the exception of the surface modication, the Pipeline ™ Flex Embolization device with Shield Technology™ implant is identical to the Pipeline™/Pipeline™ Flex embolization device implant used in the PREMIER trial.

Table 4. Summary of CEC Adjudicated Adverse Events through 1-Year by System Organ

Class and Preferred Term -mITT Population with Observed Data

MedDRA®* System Organ Class

MedDRA®* Preferred Term

Total Total

Blood and lymphatic system disorders

Total

Anaemia

Haemorrhagic diathesis

Lymphoid tissue hyperplasia

All AEs

Incidence of AE

(n/N) (%)

[# of events]

116/141 (82.3%)

[313]

4/141 (2.8%) [4] 1/141 (0.7%) [1] 3/141 (2.1%) [3]

1/141 (0.7%) [1] 1/141 (0.7%) [1] 0

2/141 (1.4%) [2] 0 2/141 (1.4%) [2]

1/141 (0.7%) [1] 0 1/141 (0.7%) [1]

All SAEs

Incidence of AE

(n/N) (%)

[# of events]

39/141 (27.7%)

[64]

All Non SAEs

Incidence of AE

(n/N) (%)

[# of events]

104/141 (73.8%)

[249]

MedDRA®* System Organ Class

MedDRA®* Preferred Term

Cardiac disorders Total

Atrial utter

Cardiac failure congestive

Ventricular tachycardia

Ear and labyrinth disorders

Total

Vertigo

Vertigo positional

Eye disorders Total

Blepharospasm

Conjunctival haemorrhage

Diplopia

Eye pain

Photophobia

Photopsia

Vision blurred

Visual impairment

Vitreous detachment

Vitreous oaters

Gastrointestinal disorders

Total

Abdominal pain

Gastrointestinal haemorrhage

Gastrointestinal inammation

Hiatus hernia

Nausea

Pancreatitis

Peritoneal haemorrhage

All AEs

Incidence of AE

(n/N) (%)

[# of events]

3/141 (2.1%) [3] 3/141 (2.1%) [3] 0

1/141 (0.7%) [1] 1/141 (0.7%) [1] 0

3/141 (2.1%) [3] 0 3/141 (2.1%) [3]

2/141 (1.4%) [2] 0 2/141 (1.4%) [2]

1/141 (0.7%) [1] 0 1/141 (0.7%) [1]

33/141 (23.4%)

[40]

1/141 (0.7%) [1] 0 1/141 (0.7%) [1]

3/141 (2.1%) [3] 0 3/141 (2.1%) [3]

2/141 (1.4%) [2] 0 2/141 (1.4%) [2]

1/141 (0.7%) [2] 0 1/141 (0.7%) [2]

2/141 (1.4%) [2] 0 2/141 (1.4%) [2]

8/141 (5.7%) [8] 1/141 (0.7%) [1] 7/141 (5.0%) [7]

15/141 (10.6%)

[15]

1/141 (0.7%) [1] 0 1/141 (0.7%) [1]

5/141 (3.5%) [5] 0 5/141 (3.5%) [5]

10/141 (7.1%) [14] 6/141 (4.3%) [9] 5/141 (3.5%) [5]

1/141 (0.7%) [1] 1/141 (0.7%) [1] 0

3/141 (2.1%) [5] 3/141 (2.1%) [5] 0

1/141 (0.7%) [1] 0 1/141 (0.7%) [1]

4/141 (2.8%) [4] 1/141 (0.7%) [1] 3/141 (2.1%) [3]

1/141 (0.7%) [1] 1/141 (0.7%) [1] 0

All SAEs

Incidence of AE

(n/N) (%)

[# of events]

1/141 (0.7%) [1]

All Non SAEs

Incidence of AE

(n/N) (%)

[# of events]

32/141 (22.7%)

[39]

15/141 (10.6%)

[15]

MedDRA®* System Organ Class

General disorders and administration site conditions

Hepatobiliary disorders

Immune system disorders

Infections and infestations

Injury, poisoning and procedural complications

Metabolism and nutrition disorders

MedDRA®* Preferred Term

Total

Adverse drug reaction

Catheter site haematoma

Catheter site haemorrhage

Catheter site pain

Chest pain

Fatigue

Local swelling

Thrombosis in device

Total

Portal vein thrombosis

Total

Anaphylactic reaction

Total

Catheter site infection

Diverticulitis

Gastroenteritis

Inuenza

Wound infection

Total

Concussion

Fall

Head injury

Periorbital haemorrhage

Procedural hypertension

Vascular pseudoaneurysm

Total

Dehydration

Hypervolaemia

Hypovolaemia

All AEs

Incidence of AE

(n/N) (%)

[# of events]

34/141 (24.1%)

[35]

3/141 (2.1%) [3] 2/141 (1.4%) [2] 1/141 (0.7%) [1]

13/141 (9.2%) [13] 0 13/141 (9.2%) [13]

9/141 (6.4%) [9] 0 9/141 (6.4%) [9]

6/141 (4.3%) [6] 0 6/141 (4.3%) [6]

1/141 (0.7%) [1] 1/141 (0.7%) [1] 0

1/141 (0.7%) [1] 0 1/141 (0.7%) [1]

1/141 (0.7%) [1] 1/141 (0.7%) [1] 0

5/141 (3.5%) [5] 4/141 (2.8%) [4] 1/141 (0.7%) [1]

1/141 (0.7%) [1] 0 1/141 (0.7%) [1]

1/141 (0.7%) [1] 1/141 (0.7%) [1] 0

7/141 (5.0%) [7] 2/141 (1.4%) [2] 5/141 (3.5%) [5]

1/141 (0.7%) [1] 0 1/141 (0.7%) [1]

1/141 (0.7%) [1] 1/141 (0.7%) [1] 0

2/141 (1.4%) [2] 1/141 (0.7%) [1] 1/141 (0.7%) [1]

3/141 (2.1%) [4] 1/141 (0.7%) [2] 2/141 (1.4%) [2]

1/141 (0.7%) [2] 1/141 (0.7%) [2] 0

1/141 (0.7%) [1] 0 1/141 (0.7%) [1]

All SAEs

Incidence of AE

(n/N) (%)

[# of events]

4/141 (2.8%) [4]

All Non SAEs

Incidence of AE

(n/N) (%)

[# of events]

30/141 (21.3%)

[31]

MedDRA®* System Organ Class

Musculoskeletal and connective tissue disorders

Neoplasms benign, malignant and unspecied (incl. cysts and polyps)

MedDRA®* Preferred Term

Total

Compartment syndrome

Muscular weakness

Musculoskeletal pain

Neck pain

Pain in extremity

Spinal osteoarthritis

Total

Adenocarcinoma of colon

Basal cell carcinoma

Total

All AEs

Incidence of AE

(n/N) (%)

[# of events]

6/141 (4.3%) [6] 1/141 (0.7%) [1] 5/141 (3.5%) [5]

1/141 (0.7%) [1] 1/141 (0.7%) [1] 0

1/141 (0.7%) [1] 0 1/141 (0.7%) [1]

2/141 (1.4%) [2] 2/141 (1.4%) [2] 0

1/141 (0.7%) [1] 1/141 (0.7%) [1] 0

61/141 (43.3%)

[95]

All SAEs

Incidence of AE

(n/N) (%)

[# of events]

14/141 (9.9%) [19]

All Non SAEs

Incidence of AE

(n/N) (%)

[# of events]

52/141 (36.9%)

[76]

MedDRA®* System Organ Class

Nervous system disorders

MedDRA®* Preferred Term

Aphasia

Balance disorder

Carotid artery dissection

Carotid artery stenosis

Cerebral haemorrhage

Cerebral infarction

Cerebral vasoconstriction

Disturbance in attention

Dizziness

Haemorrhage intracranial

Headache

Hemiparesis

Hypoaesthesia

Intracranial artery dissection

Ischaemic stroke

Migraine

Multiple sclerosis relapse

Muscle spasticity

Neuropathy peripheral

Paraesthesia

Presyncope

Sensory disturbance

Subarachnoid haemorrhage

Syncope

Transient ischaemic attack

Tremor

Visual eld defect

All AEs

Incidence of AE

(n/N) (%)

[# of events]

3/141 (2.1%) [3] 0 3/141 (2.1%) [3]

1/141 (0.7%) [1] 1/141 (0.7%) [1] 0

3/141 (2.1%) [3] 3/141 (2.1%) [3] 0

3/141 (2.1%) [3] 1/141 (0.7%) [1] 2/141 (1.4%) [2]

1/141 (0.7%) [1] 0 1/141 (0.7%) [1]

5/141 (3.5%) [6] 0 5/141 (3.5%) [6]

1/141 (0.7%) [1] 0 1/141 (0.7%) [1]

36/141 (25.5%)

[40]

1/141 (0.7%) [1] 0 1/141 (0.7%) [1]

2/141 (1.4%) [2] 0 2/141 (1.4%) [2]

1/141 (0.7%) [1] 0 1/141 (0.7%) [1]

4/141 (2.8%) [5] 3/141 (2.1%) [4] 1/141 (0.7%) [1]

4/141 (2.8%) [4] 2/141 (1.4%) [2] 2/141 (1.4%) [2]

1/141 (0.7%) [1] 1/141 (0.7%) [1] 0

1/141 (0.7%) [1] 0 1/141 (0.7%) [1]

2/141 (1.4%) [2] 0 2/141 (1.4%) [2]

5/141 (3.5%) [5] 0 5/141 (3.5%) [5]

2/141 (1.4%) [2] 1/141 (0.7%) [1] 1/141 (0.7%) [1]

1/141 (0.7%) [1] 0 1/141 (0.7%) [1]

3/141 (2.1%) [3] 0 3/141 (2.1%) [3]

1/141 (0.7%) [1] 0 1/141 (0.7%) [1]

All SAEs

Incidence of AE

(n/N) (%)

[# of events]

4/141 (2.8%) [5]

All Non SAEs

Incidence of AE

(n/N) (%)

[# of events]

33/141 (23.4%)

[35]

MedDRA®* System Organ Class

Psychiatric disorders

Renal and urinary disorders

Reproductive system and breast disorders

All AEs

MedDRA®* Preferred Term

Total

Confusional state

Delirium

Dysphemia

Major depression

Mental status changes

Suicide attempt

Total

Renal failure chronic

Incidence of AE

(n/N) (%)

[# of events]

4/141 (2.8%) [6] 2/141 (1.4%) [3] 3/141 (2.1%) [3]

1/141 (0.7%) [1] 0 1/141 (0.7%) [1]

1/141 (0.7%) [1] 1/141 (0.7%) [1] 0

1/141 (0.7%) [1] 0 1/141 (0.7%) [1]

1/141 (0.7%) [1] 1/141 (0.7%) [1] 0

1/141 (0.7%) [1] 0 1/141 (0.7%) [1]

1/141 (0.7%) [1] 1/141 (0.7%) [1] 0

Total 3/141 (2.1%) [3] 2/141 (1.4%) [2] 1/141 (0.7%) [1]

Benign prostatic hyperplasia

1/141 (0.7%) [1] 1/141 (0.7%) [1] 0

All SAEs

Incidence of AE

(n/N) (%)

[# of events]

All Non SAEs

Incidence of AE

(n/N) (%)

[# of events]

Menorrhagia 1/141 (0.7%) [1] 0 1/141 (0.7%) [1]

Ovarian cyst ruptured 1/141 (0.7%) [1] 1/141 (0.7%) [1] 0

Respiratory,

Total 4/141 (2.8%) [4] 0 4/141 (2.8%) [4] thoracic and mediastinal disorders

Skin and subcutaneous tissue disorders

Epistaxis 4/141 (2.8%) [4] 0 4/141 (2.8%) [4]

Total

30/141 (21.3%) [32]

Alopecia 2/141 (1.4%) [2] 0 2/141 (1.4%) [2]

Ecchymosis

28/141 (19.9%) [28]

Petechiae 1/141 (0.7%) [1] 0 1/141 (0.7%) [1]

Swelling face 1/141 (0.7%) [1] 0 1/141 (0.7%) [1]

Surgical and medical procedures

Vascular disorders

Total 5/141 (3.5%) [5] 5/141 (3.5%) [5] 0

Aneurysm repair 5/141 (3.5%) [5] 5/141 (3.5%) [5] 0

Total

38/141 (27.0%) [42]

3/141 (2.1%) [3]

35/141 (24.8%) [39]

Arterial stenosis 4/141 (2.8%) [4] 0 4/141 (2.8%) [4]

Arteriovenous stula 1/141 (0.7%) [1] 0 1/141 (0.7%) [1]

Deep vein

thrombosis

1/141 (0.7%) [1] 0 1/141 (0.7%) [1]

Vascular disorders Flushing 1/141 (0.7%) [1] 0 1/141 (0.7%) [1]

Haematoma 2/141 (1.4%) [2]

2/141 (1.4%) [2] 1/141 (0.7%) [1]

1/141 (0.7%) [1]

Haemorrhage 1/141 (0.7%) [1] 0 1/141 (0.7%) [1]

Hypertensive crisis 1/141 (0.7%) [1] 1/141 (0.7%) [1] 0

Hypotension 1/141 (0.7%) [1] 0 1/141 (0.7%) [1]

Vascular occlusion 1/141 (0.7%) [1] 1/141 (0.7%) [1] 0

Vasospasm

28/141 (19.9%) [29]

MedDRA®* System Organ Class

MedDRA®* Preferred Term

All AEs

Incidence of AE

(n/N) (%)

[# of events]

All SAEs

Incidence of AE

(n/N) (%)

[# of events]

All Non SAEs

Incidence of AE

(n/N) (%)

[# of events]

Note1: Events numbers are total episodes of each type of event among all subjects.

Note2: In CEC form, if CEC adjudicated the site reported event is Not an Adverse Event, the event was

excluded in CEC adjudicated event analysis.

Rate of Subjects with Event numbers are percent of subjects who experienced one or more episodes of the event.

Events numbers for TOTAL are the sum of the individual event category totals.

Rate of Subjects with Event numbers for TOTAL is the percent of subjects who experienced an adverse event.

CLINICAL TRIAL RESULTS – PUFS, PUFS-CA, AND PUFS-PAS (PIPELINE FOR UNCOILABLE OR FAILED ANEURYSMS) STUDIES

Purpose

The purpose of the PUFS study was to evaluate the short-term safety and eectiveness of PED for the endovascular treatment of patients with unruptured large and giant intracranial aneurysms of the internal carotid artery from the petrous to superior hypophyseal segments. The purpose of the PUFS-CA study was to provide investigators with continued access to Pipeline™ (PED) during the PMA approval process. The purpose of the PUFS-PAS study was to combine the PUFS and PUFS-CA study cohorts to evaluate the longterm safety and eectiveness of PED for endovascular treatment of patients with unruptured large and giant intra-cranial aneurysms of the internal carotid artery from the petrous to superior hypophyseal segments.

Design

PUFS and PUFS-CA were prospective, multi-center, single-arm, open label clinical studies. PUFS was conducted at 8 sites in the US and 2 sites outside of the US. PUFS-CA was conducted at 2 sites in the US. PUFS-PAS combines PUFS and PUFS-CA cohorts; the PUFS-PAS study was conducted at 10 sites in the US and 2 sites outside of the US. PUFS-PAS subjects were adults with a single target aneurysm on the internal carotid artery with size ≥10 mm and neck ≥4 mm. Patients were excluded if they had recent surgery or subarachnoid hemorrhage, if they had a bleeding disorder and if a stent was already in place. All patients received perioperative aspirin (325 mg daily for 2 days prior to PED and 325 mg daily for 6 months after PED) and clopidogrel (75 mg daily for 7 days [or a 650 mg oral bolus the day prior to the procedure] and 75 mg daily for 3 months after PED).*

The primary eectiveness endpoint of the PUFS study was complete occlusion of the target aneurysm on 180-day cerebral angiography in the absence of use of other treatments and in the absence of major (>50%) stenosis of the parent artery. The primary eectiveness endpoint was judged by a core radiologic laboratory. The primary safety endpoint of the PUFS study was the occurrence of major ipsilateral stroke or neurologic death by 180 days. The primary safety endpoint of the PUFS-PAS study was occurrence of ipsilateral stroke or neurologic death at 5 years. The primary safety endpoints were judged by a clinical events committee. Based on a literature review, PUFS was designed to be considered a success if the primary eectiveness endpoint rate was statistically greater than 50% and the primary safety endpoint rate was statistically <20%. A Bayesian statistical approach with non-informative prior distributions was used for the primary endpoint analysis. The long-term primary safety endpoint for PUFS-PAS includes all ipsilateral stroke events while the short-term primary safety endpoint for PUFS only includes major ipsilateral stroke events. The PUFS-PAS study did not have a primary eectiveness endpoint. Therefore, all data analyses are combined and reported under PUFS-PAS except for the analyses of the short-term primary safety and eectiveness endpoints which are reported separately under the PUFS study.

Demographics

Demographic characteristics of the study population were typical for patients with large and giant widenecked intracranial aneurysms (Table 5). Subjects were predominantly female and hypertension was common. There was a history of subarachnoid hemorrhage in 11 subjects (11/135, 8.1%), one of which had occurred within 60 days of treatment. Target IAs (Table 6) were predominantly in the cavernous and paraophthalmic portions of the internal carotid artery.

Table 5. Baseline characteristics – PUFS-PAS (n=135).

Characteristic

Age, mean (SD, range)

Female gender, n (%)

Race

White

Black

Value

56.2 (12.0, 23.7-75.5)

115 (85.2%)

124 (91.9%)

8 (5.9%)

Characteristic

Not reported

Ethnicity, % Hispanic or Latino

Value

3 (2.2%)

7 (5.2%)

Medical history

Subarachnoid hemorrhage

Stroke

Coronary artery disease

11 (8.1%)

9 (6.7%)

70 (51.9%)

Smoking

Never smoker

Current smoker

Previous smoker

Prior treatments for target IA

Coil embolization

Surgery

Other

56 (41.5%)

38 (28.1%)

41 (30.4%)

14 (10.4%)

11 (8.1%)

2 (1.5%)

1 (0.7%)

Table 6. Target IA characteristics in PUFS-PAS (n=135 ).

Characteristic

Side

Left

Right

Location

Petrous

Cavernous

Carotid cave

Ophthalmic

Paraclinoid

Superior hypophyseal

Lateral clinoidal

Paraophthalmic

Supraclinoid

Posterior communicating

Maximum fundus diameter (mm), mean (SD, range)

“Small” (<10 mm), N (%)

“Large” (>10 mm), N (%)

“Giant” (>25 mm), N (%)

Neck (mm), mean (SD, range)

Target IA partially thrombosed, N (%)

N (%) or Mean (Range)

68 (50.4%)

67 (49.6%)

6 (4.4%)

54 (40.0%)

2 (1.5%)

5 (3.7%)

8 (5.9%)

11 (8.1%)

2 (1.5%)

37 (27.4%)

9 (6.7%)

1 (0.7%)

18.0 (6.3, 6.2-36.1)

3 (2.2%)

106 (78.5%)

26 (19.3%)

9.5 (7.1, 4.0-60.0)

22 (16.3%)

Technical Results

PED was placed successfully in 134 of 135 attempted subjects. In one subject, the parent artery distal to the IA could not be catheterized and the PED procedure was aborted. A mean of 3.1 PEDs was placed per subject (Table 7). PEDs of most diameters and lengths were used (Table 8).

* Mean procedure time was 124 minutes and mean uoroscopy time was 48.4 minutes.

Table 7. Number of PEDs placed per subject in PUFS-PAS (n = 134 subjects)

# of PEDs placed N (%)

1 9 (6.7%)

2 43 (32.1%)

# of PEDs placed N (%)

3 57 (42.5%)

4 13 (9.7%)

5 or more 12 (9.0%)

Mean (range) 3.1 (1-15)

Table 8. Length and diameter of PEDs used in PUFS -PAS (n=134 subjects)

Length, mm N Diameter, mm N

10 15 3.25 7

12 61 3.50 38

14 76 3.75 97

16 78 4.00 105

18 84 4.25 75

20 95 4.50 57

25 4 4.75 21

30 3 5.00 19

35 3

Total 419

PUFS Short-Term Patient Follow-Up

Of the 104 subjects with 106 IAs in the IAs treated population, 97 subjects with 99 treated IAs had angiography 180 days after treatment and 89 subjects with 91 treated IAs had angiography 1 year after treatment. Clinical and angiographic follow-up was obtained in 96% of available subjects at 180 days.

PUFS Short-Term Results

The analysis of eectiveness was evaluated in three populations (Table 9). The posterior probability that the study met its primary eectiveness endpoint was >0.9999 in all three analyses. Complete IA occlusion was seen in 81.8% (81/99) of treated IAs at 180 days and 85.7% (78/91) at 1 year for only those subjects that had available angiographic data at these follow-up visits (Table 10). *Lengths greater than 20 mm were not available during the study.

Table 9. Analyses of proportion of PUFS subjects who met the primary eectiveness

endpoint.

Population

Intracranial aneurysms treated (N=106)

Subjects treated

(N=104)

Intracranial aneurysms attempted (N=110)

180 day Posterior

78/106

73.6% (64.4, 81.0)*

76/104

73.1% (63.8, 80.7)*

80/110

72.7% (63.7, 80.2)*

Probability***

>0.9999 75/106

>0.9999 73/104

>0.9999 77/110

*95% posterior credible interval (Condence/credible intervals are calculated without multiplicity adjustment. As such, the condence/credible intervals are provided to show variability only and should not be used to draw any statistical conclusions)

**95% exact condence interval (Condence/credible intervals are calculated without multiplicity adjustment. As such, the condence/credible intervals are provided to show variability only and should not be used to draw any statistical conclusions)

***Probability that observed eectiveness rate was >50%

1 year

70.8% (61.1, 79.2)**

70.2% (60.4, 78.7)**

70.7% (58.6, 76.7)**

Table 10. IA occlusion status at 180 days and 1 year for PUFS subjects with

angiographic data.

Occlusion Ranking

Complete occlusion

Residual neck

Residual aneurysm

180 days

(N=99 IAs)

81 (81.8%) 78 (85.7%)

8 (8.1%) 5 (5.5%)

6 (6.1%) 5 (5.5%)

1 year

(N=91 IAs)

Occlusion Ranking

Other

Total

180 days

(N=99 IAs)

4* (4.0%) 3** (3.3%)

99 (100%) 91 (100%)

1 year

(N=91 IAs)

*1 subject with carotid-cavernous stula and 3 subjects with carotid occlusion in whom IA not visualized

**2 subjects with carotid occlusion, 1 transvenous coil embolization in whom IA not visualized

The analysis of the PUFS primary safety endpoint was based on the safety cohort of 107 subjects treated with PED. The study’s primary safety endpoint, ipsilateral major stroke or neurologic death by 180 days after treatment, occurred in 6 subjects (5.6%, 95% posterior credible interval CI 2.6 - 11.7%). The posterior probability that the major safety endpoint rate was less than 20%, the predetermined safety success threshold, was 0.999979.

Both the eectiveness and safety endpoint posterior probability values exceeded the pre-study probability threshold of 0.975, indicating that both results were statistically signicant.

Adverse events are listed in “Observed Adverse Events” Section.

PUFS-PAS Long-term Patient Follow-up

Of the 134 subjects treated in the PUFS-PAS study, clinical follow-up was obtained for (107/130) 82.3% of subjects at 3 years and (100/128) 78.1% of subjects at 5 years. Angiographic follow-up was obtained for 100 subjects at 3 years after treatment and 80 subjects at 5 years after treatment.

Table 11. Subject Disposition (Number of Patients) in the PUFS-PAS (PUFS + PUFS-CA)

Trial

30-Day 180-Day 1-Year 2-Year 3-Year 4-Year 5-Year

All Subjects

Deaths

Discontinued

Not yet due for

135 135 135 135 135 135 135

3 3 3 4 5 6 7

1 3 6 7 13 13 19

0 0 0 0 0 0 0

Follow-up

Expected Due

Actually Included

Missed Visit

Follow-up rate

Expected Due is all subjects minus any deaths

Based on the number of subjects ‘Actually Included’ and ‘Expected Due’’

132 132 132 131 130 129 128

130 124 114 122 107 106 100

1 5 12 2 10 10 9

98.5% 93.9% 86.4% 93.1% 82.3% 82.2% 78.1%

Table 12. Occlusion status at 180 days, 1 year, 3 years, and 5 years for PUFS-PAS

subjects with angiographic data.

Occlusion Ranking

Complete Occlusion

Residual Neck

Residual Aneurysm

Indeterminate

Total

180 days

(N=124 IAs)

95 (76.6%) 98 (83.8%) 90 (90.0%) 75 (93.8%)

12 (9.7%) 7 (6.0%) 4 (4.0%) 3 (3.8%)

14 (11.3%) 11 (9.4%) 2 (2.0%) 2 (2.5%)

3 (2.4%) 1 (0.9%) 4 (4.0%) 0 (0.0%)

124 (100%) 117 (100%) 100 (100%) 80 (100%)

1 year

(N=117 IAs)

3 years

(N=100 IAs)

5 years

(N=80 IAs)

Table 13. Ipsilateral stroke or neurological death at 5 years for PUFS-PAS.

Primary Endpoint

PUFS-PAS

Safety Success

Threshold

<25% 8.2% (11/134) 8.3% (4.7%, 14.4%)

NOTE: The condence intervals are calculated without multiplicity adjustment. As such, the condence intervals are provided to show the variability only and should not be used to draw any statistical conclusions.

NOTE: The intervals noted in the table for the 5 year Kaplan-Meier Estimate are the 95% posterior credible intervals CI.

Result 5-Year Kaplan-Meier

Estimate

PUFS-PAS Long-Term Results

Complete aneurysm occlusion was measured according to the total number of intracranial aneurysms with available imaging. Aneurysm occlusion status at 180 days, 1 year, 3 years, and 5 years are shown in Table 12. Complete IA occlusion was seen in 76.6% (95/124) of subjects at 180 days, 83.8% (98/117) of subjects at 1 year, 90% (90/100) of subjects at 3 years and 93.8% (75/80) of subjects at 5 years (Table 12).

The analysis of the PUFS-PAS primary safety endpoint was based on the safety cohort of 134 subjects treated with PED. The study’s primary safety endpoint, ipsilateral stroke or neurologic death at 5 years occurred in 11 subjects (8.3%, 95% posterior credible interval CI 4.7% - 14.4%) (Table 13).

Final Conclusions

The PUFS study met the pre-specied primary eectiveness and safety endpoints at 180 days which remained statistically signicant at one year. The primary safety endpoint was also met at 5 years in the combined PUFS-PAS study.

CLINICAL TRIAL RESULTS - PREMIER (PROSPECTIVE STUDY ON EMBOLIZATION OF INTRACRANIAL ANEURYSMS WITH THE PIPELINE DEVICE)

Purpose

The purpose of the PREMIER study was to evaluate the safety and eectiveness of the Pipeline™ device for the endovascular treatment of patients with unruptured wide-neck intracranial aneurysms, measuring ≤ 12 mm, located in the internal carotid artery (up to the terminus) or the vertebral artery segment up to and including the posterior inferior cerebellar artery.

Design

PREMIER was a prospective, multi-center, single-arm clinical study conducted at 22 sites in the US and 1 site outside of the US. PREMIER subjects were adults with a target aneurysm on the internal carotid artery or vertebral artery with size ≤ 12 mm, neck ≥ 4 mm or dome to neck ratio ≤ 1.5 mm. Patients were excluded if they had major surgery or subarachnoid hemorrhage within 30 days, if they had an irreversible bleeding disorder, signs of active bleeding, and if a stent was already in place at the target aneurysm. All patients were required to receive aspirin (minimum of 81 mg daily for a minimum of 7 days prior to PED and 81 mg daily for a minimum of 6 months after PED) and clopidogrel (minimum of 75 mg daily for a minimum of 7 days prior to PED and 75 mg daily for a minimum of 3 months after PED). The primary eectiveness endpoint of the study complete aneurysm occlusion (dened by the Scale of Roy1) without signicant parent artery stenosis (≤ 50%) or retreatment of the target aneurysm 1-year postprocedure. The primary eectiveness endpoint was judged by a core radiologic laboratory and was graded using the Raymond-Roy occlusion scale1. The primary safety endpoint was the occurrence of major stroke in the territory supplied by the treated artery or neurological death by 1-year post-procedure. The primary safety endpoint was judged by an independent clinical events committee. Based on a literature review, PREMIER was designed to be considered a success if the primary eectiveness endpoint rate was statistically greater than 50% and the primary safety endpoint rate was statistically less than 15%. Primary endpoints analyses were based on 1-sided 97.5% Clopper- Pearson exact binomial condence interval.

Roy D, Milot G, Raymond J.Endovascular treatment of unruptured aneurysms. Stroke. 2001;32 (9): 1998-2004

Demographics

Demographic characteristics of the study population were typical for patients with small and medium wide-necked IAs (Table 14); Subjects were predominately female and hypertension was co on. There was a history of subarachnoid hemorrhage in 13 (9.2%) subjects. Target IAs (Table 14) were predominately in the ophthalmic, communicating and clinoid segments of the ICA.

Table 14. Baseline characteristics – PREMIER (n=141).

Variable

Age

≥ 22 to <50

50 to <60

60 to <70

70 to 80

Gender

Male

Female

Race

American Indian or Alaska Native

Asian

Black or African American

Overall

(N=141 Subjects)

54.6±11.3 (141) [53.0] (30 - 77)

34.8% (49)

31.2% (44)

22.7% (32)

11.3% (16)

12.1% (17)

87.9% (124)

0.7% (1)

2.8% (4)

11.3% (16)

Variable

Native Hawaiian or Other Pacic Islander

White

Unknown

Not reported

Ethnicity

Hispanic or Latino

Not Hispanic or Latino

Not Reported

Unknown

Medical History

Hypertension

History of SAH

Current cigarette smoking

Former smoker within past 10 years

Drug use

Alcohol abuse

Epilepsy

Psychiatric disorder

Atrial brillation

Cardiac arrhythmias

Congestive heart failure

Myocardial infarction

Smoking

Never smoked or has not smoked within the last 10 years

Current or Past Smoker (within the past 10 years)

Not a current smoker, but has smoked within the past 10 years

Current smoker, less than one pack per day

Current smoker, greater than or equal to one pack per day

Table 15. Target IA characteristics in PREMIER (n=141).

Aneurysm Characteristics

Imaging Type

CTA

MRA

Angiogram

Other

Aneurysm Side

Right

Left

Parent Artery Location

Internal Carotid Artery

C1 (Cervical Segment)

Overall

(N=141 Subjects)

0.0% (0)

80.9% (114)

0.0% (0)

4.3% (6)

8.5% (12)

81.6% (115)

5.0% (7)

72 (51.1%)

14 (9.9%)

41 (29.1%)

21 (14.9%)

1 (0.7%)

3 (2.1%)

13 (9.2%)

71 (50.4%)

7 (5.0%)

20 (14.2%)

2 (1.4%)

56.0% (79/141)

44.0% (62/141)

14.9% (21/141)

19.1% (27/141)

9.9% (14/141)

Target aneurysm

% (n/N)

(N=141 Aneurysms)

100.0% (141/141)

Aneurysm Side

48.9% (69/141)

51.1% (72/141)

95.0% (134/141)

Aneurysm Characteristics

C2 (Petrous Segment)

C3 (Lacerum Segment)

C4 (Cavernous Segment)

C5 (Clinoid Segment)

C6 (Ophthalmic Segment)

C7 (Communicating Segment)

Vertebral Artery

V1 (Pre-Foraminal)

V2 (Foraminal)

V3 (C2 to Dura)

V4 (Intradural)

Aneurysm Morphology

Saccular

Sidewall

Terminus

Involved Side Branch

Bifurcation Branch

No Side Branch

Side Branch

Branch arising from neck of aneurysm

Branch arising from dome of aneurysm

Branch adjacent to aneurysm neck

Fusiform

Pseudoaneurysm

Partially Thrombosed

Yes

Aneurysm Measurement

Aneurysm Maximal Diameter (mm)

Dome Width (mm)

Dome Height (mm)

Aneurysm Neck Length (mm)

Dome/Neck Ratio

Parent Artery Diameter Proximal to Target Aneurysm (mm)

Parent Artery Diameter Distal to Target Aneurysm (mm)

Aneurysm Size

Small (<7 mm)

Aneurysm Size (<3 mm)

Aneurysm Size (3-<7 mm)

Medium (7-<13 mm)

Large (13-<25 mm)

Giant (>= 25 mm)

Aneurysm Measurement

1Aneurysm Size Ratio >3

2Aneurysm Size Ratio>3

3Aneurysm Aspect Ratio>1.6

Target aneurysm

% (n/N)

(N=141 Aneurysms)

0.7% (1/134)

2.2% (3/134)

8.2% (11/134)

74.6% (100/134)

14.2% (19/134)

5.0% (7/141)

100.0% (7/7)

96.5% (136/141)

65.4% (89/136)

34.6% (47/136)

17.6% (24/136)

8.8% (12/136)

8.1% (11/136)

3.5% (5/141)

Partially Thrombosed

3.5% (5/141)

5.0±1.92 (141)[4.6] (1.7 - 11.1)

4.5±1.83 (141)[4.2] (1.3 - 11)

4.0±1.60 (141)[3.8] (1 - 9.2)

4.0±1.42 (141)[3.7] (1.3 - 9.5)

1.1±0.28 (141)[1.1] (0.6 - 1.9)

3.9±0.60 (141)[3.9] (2.1 - 5)

3.5±0.59 (141)[3.5] (2.2 - 5.1)

5.0±1.92 (141)[4.6] (1.7 - 11.1)

84.4% (119/141)

9.9% (14/141)

74.5% (105/141)

15.6% (22/141)

4.3% (6/141)

2.1% (3/141)

6.4% (9/141)

Aneurysm Characteristics

Number of Subject with 1Aneurysm Size Ratio >3 and Aneurysm Aspect Ratio>1.6

Number of Subject with 2Aneurysm Size Ratio >3 and Aneurysm Aspect Ratio>1.6

Target aneurysm

% (n/N)

(N=141 Aneurysms)

Inclusion Criteria

Subjects met all the of the following general inclusion criteria:

1. Subject provided written informed consent using the IRB/EC-approved consent form and agreed to comply with protocol requirements

2. Age 22-80 years

3. Subject had a target intracranial aneurysm located in the: a. Internal carotid artery (up to the carotid terminus) OR b. Vertebral artery segment up to and including the posterior inferior cerebellar artery

4. Subject had a target intracranial aneurysm that was ≤ 12 mm

5. Subject had a target intracranial aneurysm that had a parent vessel with diameter 1.5–5.0 mm distal/ proximal to the target intracranial aneurysm

6. Subject had a target intracranial aneurysm with an aneurysm neck ≥ 4 mm or a dome to neck ratio ≤ 1.5

7. Subject had a pre-procedure PRU value between 60–200

Exclusion Criteria

Subjects did not meet any of the following general exclusion criteria:

1. Subject had received an intracranial implant (e.g., coils) in the area of the target intracranial aneurysm within the past 12 weeks

2. Subarachnoid hemorrhage in the past 30 days

3. Subject with anatomy not appropriate for endovascular treatment due to severe intracranial vessel tortuosity or stenosis determined from baseline or pre-procedure imaging, or a history of intracranial vasospasm not responsive to medical therapy

4. Major surgery in the last 30 days

5. History of irreversible bleeding disorder and/or subject presented with signs of active bleeding

6. Any known contraindication to treatment with the Pipeline™ device, including: a. Stent in place in the parent artery at the target intracranial aneurysm location b. Contraindication to dual antiplatelet therapy (DAPT) c. Relative contraindication to angiography (e.g., serum creatinine >2.5 mg/dL, allergy to contrast that cannot be medically controlled) d. Known severe allergy to platinum or cobalt/chromium alloys e. Evidence of active infection at the time of treatment (e.g., fever with temperature > 38°C and/or WBC > 1.5 109/L)

7. The Investigator determined that the health of the subject or the validity of the study outcomes (e.g., high risk of neurologic events, worsening of clinical condition in the last 30 days) may be compromised by the subject’s enrollment

8. Pregnant or breast-feeding women or women who wish to become pregnant during the length of study participation

9. Participated in another clinical trial during the follow-up period that could confound the treatment or outcomes of this investigation

Technical Results:

The Pipeline™ device was placed successfully in 140 of 141 attempted subjects (99.3%) at the Index procedure. A mean of 1.1 ± 0.3 Pipeline™ devices was placed per subject with the majority of subjects (92.9%) receiving a single Pipeline™ device. PEDs of most diameters and lengths were used (Table 14). Mean time from skin incision to skin closure was 78.4 ± 40.3 minutes, mean time from rst Pipeline™ device introduction to last Pipeline™ device delivery system removal was 14.3 ± 15.1 minutes and mean uoroscopy time was 27.9 ± 14.8 minutes.

Table 16. Summary of the Number of Pipeline™ Devices Attempted During the Study

Index Procedure by Dimension -mITT Population with Observed Data

Study Device Length (mm)

Study Device

Diameter (mm)

2.50 0 0 1 0 0 0 0 0 1

3.00 0 1 1 1 0 1 0 0 4

10 12 14 16 18 20 25 30 Total

Study Device Length (mm)

3.25 0 1 1 1 0 0 1 0 4

3.50 2 2 7 2 4 2 1 0 20

3.75 1 4 6 5 2 2 2 0 22

4.00 1 6 10 9 4 3 2 0 35

4.25 1 5 6 6 1 2 1 1 23

4.50 0 2 8 8 3 3 1 0 25

4.75 0 3 0 1 4 1 0 0 9

5.00 1 0 1 4 1 2 1 2 12

Total 6 24 41 37 19 16 9 3 155

Patient Follow-Up: Of the 141 treated subjects, the rate of one-year follow-up was high with clinical followup obtained in 98.6% (139/141) of subjects and imaging follow-up obtained in 97.9% (138/141) of subjects. One subject died prior to one-year follow-up, one subject missed the 1-year follow-up visit and one subject returned for the 1-year visit but did not have imaging performed.

Patient Analysis Population:

Modied Intention to Treat (mITT): dened as all enrolled subjects in whom deployment of the Pipeline™ device was attempted. The mITT population consisted of 141 subjects.

Internal Carotid Artery Population (ICA Population): dened as a subset of the mITT population that included subjects with small or medium wide-neck aneurysms of the internal carotid artery (up to the terminus); subjects with aneurysms of the posterior circulation (aneurysms of vertebral artery) were not included in the ICA population. The ICA population consisted of 134 subjects (excludes 7 subjects with aneurysm in the vertebral artery). An additional eectiveness endpoint analysis was performed excluding the 5 subjects from the ICA population as they underwent adjunctive coiling (N = 129).

Results: The primary eectiveness endpoint were higher than the a priori threshold of 50% for both the ICA Population (N=134) and for ICA Population excluding subjects with adjunctive coiling (N = 129); thus, the primary eectiveness endpoint was met (Table17).

Table 17. Summary of Incidence of Primary Eectiveness Endpoint 1-Year Post-

Procedure ICA Population

Primary Eectiveness Endpoint Parameter Rate (%)

Complete Aneurysm Occlusion without signicant parent artery stenosis (≤ 50%) or retreatment of the

78.98% 72.05%

target aneurysm (N=134) - Multiple Imputations

Complete Aneurysm Occlusion without signicant parent artery stenosis (≤ 50%) or retreatment of the target aneurysm (N=134); Subjects with missing data

77.61%

(104/134) 69.61%

(n=2) considered failures*

Complete Aneurysm Occlusion without signicant parent artery stenosis (≤ 50%) or retreatment of the target aneurysm (excluding 5 subjects with use of coils

78.91% 71.84%

as adjunctive devices at procedure) (N=129) - Multiple Imputations

Complete Aneurysm Occlusion without signicant parent artery stenosis (≤ 50%) or retreatment of the target aneurysm (excluding 5 subjects with use of coils as adjunctive devices at procedure) (N=129); Subjects

77.52%

(100/129)

with missing data (n=2) considered failures*

1-sided 97.5% Exact Lower

Binomial Condence Interval

69.34%

Note1: ICA population-Indication Population

Note2: The condence intervals are calculated without multiplicity adjustment. As such, the condence intervals are provided to show the variability only and should not be used to draw any statistical conclusions.

*1-year imaging follow-up for 2 subjects was missing and imputed as failure

Table 18. Reasons for Primary Eectiveness Endpoint Non-Success (ICA Population)

Reason

Residual neck

Residual aneurysm

Stenosis greater than 50%

Target aneurysm retreatment

Total

Rate % (n/N)

(N = 134 Subjects)*

1.5% (2/132) 1.6% (2/129)

14.4% (19/132) 14.0% (18/129)

3.0% (4/132) 3.1% (4/129)

21.2% (28/132) 20.9% (27/129)

*ICA Population; 1-year imaging follow-up for 2 subjects was missing from the ICA Population

** ICA Population excluding the 5 subjects with adjunctive coiling

The primary safety endpoint, occurrence of major stroke in the territory supplied by the treated artery or neurological death 1-year post-procedure occurred in 2.17% and 2.2% (3/134) of subjects in the mITT and ICA populations respectively. The 1-sided 97.5% exact upper binomial condence interval was 4.61% and

6.40% in the mITT and ICA populations respectively, which was below the threshold of 15%; therefore, the

primary safety endpoint of the study was met.

Rate % (n/N)

(N = 129 Subjects)**

Table 19. Primary Safety Endpoint (Major stroke in the territory supplied by the

treated artery or Neurological death)-mITT Population and ICA Population

Primary Safety Endpoint

Rate (%)

1-Sided 97.5% Exact

Upper Binomial

Condence Interval

Threshold

mITT Population (N=141)* 2.17% 6.51% 15% 0.0002

ICA population (N=134) 2.20%

6.40% 15% <0.0001

(3/134)

*Missing data for subjects who fail to complete the 1-year post-procedure evaluation without any evidence of a major stroke in the territory supplied by the treated artery or neurological death were imputed in the analysis using the multiple imputation procedure from SAS (Proc MI). Subjects who withdraw from the study prior to the 1-year evaluation visit and have experienced a major stroke in the territory supplied by the treated artery or neurological death at any time prior to the 1-year evaluation were counted as having experienced the event of interest.

Note: The condence intervals are calculated without multiplicity adjustment. As such, the condence intervals are provided to show the variability only and should not be used to draw any statistical conclusions.

Adverse events are listed in “Observed Adverse Events” Section

The safety endpoints and events by age ≥60 years and <60 years are presented in table 20.

1-Sided p-value

from Binomial

Distribution

Table 20. Subgroup Analysis of Safety Endpoints and Events by Age≥60 Yrs* vs. <60

Yrs (mITT Population)

Analysis Parameter Age < 60 yrs

(N=93)

Primary Safety Endpoint: (Neurological Death + Major Stroke)

All Stroke** (Subject level)

Major Strokes

Minor Strokes

Device Related SAEs

1.1% (1/93),

[0.0%,5.9%]

2.2% (2/93),

[0.3%,7.6%]

1.1% (1/93),

[0.0%,5.9%]

1.1% (1/93),

[0.0%,5.9%]

4.3% (4/93),

[1.2%,10.7%]

Age ≥ 60 yrs (N=48)

4.2% (2/48),

[0.5%,14.3%]

10.4% (5/48),

[3.5%,22.7%]

4.2% (2/48),

[0.5%,14.3%]

8.3% (4/48),

[2.3%,20.0%]

12.5% (6/48),

[4.7%,25.3%]

mITT (N=141)

2.1% (3/141),

[0.4%,6.1%]

5.0% (7/141),

[2.0%,10.0%]

2.1% (3/141),

[0.4%,6.1%]

3.5% (5/141),

[1.2%,8.1%]

7.1% (10/141),

[3.5%,12.7%]

Analysis Parameter Age < 60 yrs

(N=93)

Procedure Related SAEs

6.5% (6/93),

[2.4%,13.5%]

Age ≥ 60 yrs (N=48)

6.3% (3/48),

[1.3%,17.2%]

mITT (N=141)

6.4% (9/141),

[3.0%,11.8%]

*Use of PFED in patients >60 years of age may result in decreased eectiveness and additional safety risks.

** A total of 8 stroke events (major and minor) were reported in 7 subjects; 1 subject (≥60 years age) had a major and minor stroke.

Note1: mITT: modied Intent-to-Treat population

Note2: Numbers are % (Count/Sample Size) [Condence Interval]. Condence Interval is based on exact Binomial Distribution

Note3: The condence intervals are calculated without multiplicity adjustment. As such, the condence intervals are provided to show the variability only and should not be used to draw any statistical conclusions.

A post-hoc analysis showing the composite occurrence of neurological death and disabling stroke (dened as mRS ≥3 at a minimum of 90 days after stroke event)) for the mITT population is presented in Table 21 and ICA population is presented in Table 22.

Table 22. Post-hoc Safety Analysis of Neurological Death or Disabling Stroke at 1-Year

Post- Procedure – ICA Population

Variable

Rate

(N=134)

Primary Safety Composite Rate (disabling stroke with mRS score >= 3 or neurological

1.5% (2/134) 5.3%

death at 1-Year post procedure)

Disabling stroke with mRS score >= 3 at 1 Year post procedure

0.7% (1/134) 4.1%

Neurological death at 1-Year post procedure 0.7% (1/134) 4.1%

The incidence of all ischemic and hemorrhagic events (includes Major Stroke, Minor Stroke, Symptomatic Cerebral Infarction, Asymptomatic Cerebral Infarction, ICH, TIA, and Aneurysm Rupture) in the mITT and ICA population is presented in Table. 23.

1-sided 97.5% exact upper binomial condence interval

Table 23. Additional Safety Analysis; Cerebrovascular Events (Ischemic and

Hemorrhagic) in the mITT and ICA Population up to 1-Year Post-Procedure

Table 21. Post-hoc Safety Analysis of Neurological Death or Disabling Stroke at 1-Year

Post-Procedure – mITT Population

Variable

Composite Safety Rate (disabling stroke with mRS score ≥ 3 or neurological death at 1-year post procedure)

Disabling stroke with mRS score ≥ 3 at 1-year post procedure

Rate

(N=141)

1.4% (2/141) 5.0%

0.7% (1/141) 3.9%

1-sided 97.5% exact upper binomial condence interval

Variable

Analysis of Cerebrovascular Events

(Ischemic and Hemorrhagic) *

mITT Population

% (n/N)[E]

7.8% (11/141)[18] 8.2% (11/134)[18]

n = number of subjects with events, N = total number of subjects, E = total number of events

*Includes incidence of Stroke (Major or Minor, Ipsilateral or Contralateral), Cerebral Infarction (Symptomatic or Asymptomatic), Intracranial Hemorrhage, Transient Ischemic Attack, and Target Aneurysm Rupture

ICA Population

% (n/N)[E]

Neurological death at 1-year post procedure 0.7% (1/141) 3.9%

Disabling stroke dened as mRS of 3 or higher measured at least 90 days after stroke event

The change in mRS (same, worse, or better) compared to the pre-procedure mRS measurements in the mITT and ICA population is presented in Table 24.

Table 24. Change in mRS (same, worse, or better) compared to pre-procedure in the mITT and ICA population at 1-Year Post-Procedure

ICA Population

% (n/N)

[Condence Interval]

9.2% (12/131),

[4.82%,15.4

80.9% (106/131),

[73.13%,87.25%]

9.9% (13/131),

[5.39%,16.37%]

mRS Change

Decrease in mRS

No change

Increase in mRS

mITT Population

% (n/N)

[Condence Interval]

10.3% (14/136),

[5.74%,16.67%]

80.1% (109/136),

[72.45%,86.49%]

9.6% (13/136),

[5.19%,15.79%]

Note1: mITT: modied Intent-to-Treat population.

Note2: Numbers are % (Count/Sample Size) [Condence Interval]. Condence Interval is based on exact Binomial Distribution

The mITT Population had 5 subjects that did not have paired mRS readings and thus, not included in this analysis

The ICA Population had 3 subjects that did not have paired mRS readings and thus, not included in this analysis

The summary of Primary Eectiveness and Safety Endpoints at 1-Year Post-Procedure, by Aneurysm Size (mITT Population)*is presented in Table 25

Table 25. Summary of Primary Eectiveness and Safety Endpoints at 1-Year Post-Procedure, by Aneurysm Size (mITT Population)*

Primary Endpoint Analysis Parameter

1 mm-

<2 mm

(N=1)

2 mm-

<3 mm

(N=13)

3 mm-

<4 mm

(N=36)

4 mm-

<5 mm

(N=29)

5 mm-

<6 mm

(N=26)

6 mm-

<7 mm

(N=14)

7 mm-

<8 mm

(N=10)

8 mm-

<9 mm

(N=5)

9 mm-

<10 mm

(N=4)

10 mm-

<11 mm

(N=1)

11 mm-

<12 mm

(N=2)

Primary Eectiveness Endpoint: Complete

Aneurysm Occlusion without signicant parent artery stenosis (≤ 50%) or retreatment of the target

0.0% (0/1)

76.9%

(10/13)

86.1%

(31/36)

75.9%

(22/29)

73.1%

(19/26)

78.6%

(11/14)

40.0%

(4/10)

80.0% (4/5)

75.0% (3/4)

100.0% (1/1)

50.0% (1/2)

aneurysm

Primary Safety Endpoint: No major stroke or neurological death.

0.0% (0/1)

7.7%

(1/13)

0.0%

(0/36)

3.4%

(1/29)

0.0%

(0/26)

0.0%

(0/14)

0.0%

(0/10)

20.0% (1/5)

0.0% (0/4)

0.0% (0/1)

0.0% (0/2)

*Subjects who have failed to complete the 1-year evaluation visit are counted as not having met the primary eectiveness endpoint

Note1: mITT: modied Intent-to-Treat population.

Note2: Numbers are % (Count/Sample Size).

Final Conclusions

The PREMIER study met the primary eectiveness and safety endpoints at one year in the ICA population.

Table 26. Follow-up Compliance Visit - mITT and ICA Population with Observed Data

Variable

Underwent the study procedure

Evaluated at the 30-day follow-up visit

Evaluated at the 180-day follow-up visit

Imaging completed at the 180-day follow-up visit (not a mandatory follow-up visit)

Evaluated at the 1-year follow-up visit

Imaging completed at the 1-year follow-up visit

Evaluated at the 2-year follow-up visit

Imaging completed at the 2-year follow-up visit (mandatory only for those with incomplete occlusion at 1 year)

Mandatory Imaging at 2-year follow up visit

Evaluated at the 3-year follow-up visit

Imaging completed at the 3-year follow-up visit (mandatory only for those with incomplete occlusion at 1 and/or 2- year)

Mandatory Imaging at 3-year follow up visit

*Reasons for 6 subjects missing the 2-year imaging follow up visits: Subject refusal/unable to undergo follow-up DSA (3 subjects) and Imaging not expected as initial single reader core lab assessment was complete occlusion (later adjudicated as incomplete occlusion by multi-reader core lab) (3 subjects)

**Reasons for 9 mITT subjects missing the 3-year imaging: Subject refusal/unable to undergo follow-up DSA – (4 subjects), Imaging not expected as initial single reader core lab assessment was complete occlusion (later adjudicated as incomplete occlusion by multi-reader core lab) (3 subjects), and lost to follow-up (2 subjects)

Note1: mITT- Modied Intent to treat population.

Note2: Imaging completed denotes that a subject had core lab reviewed data for analysis.

Note3: Evaluated denotes that a subject had assessment per NIHS, mRS and Site Imaging form.

Note4: N=number of subjects with observed data

mITT Subjects (N=141) ICA Subjects (N=134)

100.0% (141) 100.0% (134)

99.3% (140) 99.3% (133)

95.0% (134) 94.8% (127)

76.6% (108) 76.9% (103)

98.6% (139) 99.3% (133)

97.9% (138) 98.5% (132)

95.0% (134) 96.3% (129)

39.7% (56) 39.6% (53)

76.0% (19/25)* 76.2% (16/21)

90.8% (128) 91.0% (122)

39.0% (55) 38.1% (51)

64.0% (16/25)** 66.7% (14/21)

Table 27. Summary Of Post-Procedure Target Aneurysm Occlusion Results at 1-, 2-, and 3-year Follow-up Visits Post-Procedure (mITT and ICA Population with Observed Data)

Population

mITT (N=141 Subjects)

ICA (N=134 Subjects)

(LOCF for 2- and 3-year Data)

Variable 1-Year 2-Year (LOCF)*¥ 3-Year (LOCF)* ¥

Complete Occlusion 81.9% (113/138) 81.9% (113/138) 83.3% (115/138)

Residual Neck 2.2% (3/138) 3.6% (5/138) 5.1% (7/138)

Residual Aneurysm 15.9% (22/138) 14.5% (20/138) 11.6% (16/138)

Complete Occlusion 84.1% (111/132) 84.1% (111/132) 85.6% (113/132)

Residual Neck 1.5% (2/132) 3.0% (4/132) 4.5% (6/132)

Residual Aneurysm 14.4% (19/132) 12.9% (17/132) 9.8% (13/132)

Population

*Using this LOCF approach, for subjects with 2-year/3-year evaluable imaging, the results from the 2-year/3-year core lab consensus reading were utilized, whereas, for the remaining subjects, the core lab consensus reading from 1-year/2-year follow-up images were used

¥Note: Imaging was only mandatory at 2- and 3 -year if the aneurysm was not completely occluded at the 1- and/or 2-year imaging; additionally, for subjects with complete aneurysm occlusion, imaging was collected and assessed by core lab only if performed per standard of care. At 2-year follow-up, of the 138 mITT subjects, 56 subjects completed imaging, 34 subjects had complete occlusion, 4 subjects had residual neck, 15 subjects had residual aneurysm and 3 images could not be read. For 3-year follow-up, 55 mITT subjects completed imaging, 40 subjects had complete occlusion, 6 subjects had residual neck, 8 subjects had residual aneurysm and 1 image could not be read.

For the ICA population at 2-year follow-up, of the 132 subjects, 53 subjects completed imaging, 34 subjects had complete occlusion, 4 subjects had residual neck, 12 subjects had residual aneurysm and 3 images could not be read. For 3-year follow-up, 51 ICA subjects completed imaging, 38 subjects had complete occlusion, 5 subjects had residual neck, 7 subjects had residual aneurysm and 1 image could not be read.

Note1: mITT- Modied Intent to treat population.

Note2: Numbers are % (Count/Sample Size).

Note3: N=number of subjects with observed data

Variable 1-Year 2-Year (LOCF)*¥ 3-Year (LOCF)* ¥

Table 28. Recurrence and Retreatment Rates Through 3-years Post-Procedure (mITT and ICA Population with Observed Data) (LOCF for 2- and 3-year Data)

1-Year 2-Year (LOCF)* 3-Year (LOCF)*

Population Variable Overall 2-sided 95% Exact

Binomial CI

Overall 2-sided 95% Exac t

Binomial CI

Overall 2-sided 95% Exact

Binomial CI

Target Aneurysm Recurrence * 0.0% (0/138) [0.00%,2.64%] 0.0% (0/138) [0.00%,2.64%] 0.7% (1/138) [0.02%,3.97%]

mITT (N=141)

Target Aneurysm Retreatment 2.8% (4/141) [0.78%,7.10%] 5.0% (7/141) [2.02%,9.96%] 5.0% (7/141) [2.02%,9.96%]

Target Aneurysm Recurrence * 0.0% (0/132) [0.00%,2.76%] 0.0% (0/132) [0.00%,2.76%] 0.8% (1/132) [0.02%,4.15%]

ICA (N=134)

*Imaging was only mandatory at 2- and 3 -year if the aneurysm was not completely occluded at the 1- and/or 2-year imaging; additionally, for subjects with complete aneurysm occlusion, imaging was collected and assessed by core lab only if performed per standard of care. For subjects with 2-year and 3-year imaging, the results from the core lab consensus reading were utilized for recurrence analysis, whereas, for the remaining subjects, the core lab consensus reading from 1-year/2-year follow-up images were used for recurrence analysis (LOCF method).

Note1: mITT: modied Intent-to-Treat population; ICA: ICA population.

Note2: Numbers are % (Count/Sample Size)

Note3: CI: Condence Interval.

Target Aneurysm Retreatment 3.0% (4/134) [0.82%,7.47%] 3.7% (5/134) [1.22%,8.49%] 3.7% (5/134) [1.22%,8.49%]

Table 29. Summary of CEC adjudicated Adverse Events through 3-year Follow-Up by Seriousness (mITT and ICA Population with Observed Data)

0-3-Year

Numbers of Subject with CEC adjudicated Adverse

Events [# events]

All AE’s

n (%) [# of Events]

All SAE’s

n (%) [# of Events]

All Non-Serious AE’s

n (%) [# of Events]

mITT Population

ICA Population

Note1: Event numbers are total episodes of each type of event among all subjects.

Rate of Subjects with Event numbers are percent of subjects who experienced one or more episodes of the event.

Event numbers for TOTAL are the sum of the individual event category totals.

Rate of Subjects with Event numbers for TOTAL is the percent of subjects who experienced an adverse event.

124/141 (87.9%) [429] 60/141 (42.6%) [134] 112/141 (79.4%) [295]

118/134 (88.1%) [409] 55/134 (41.0%) [128] 108/134 (80.6%) [281]

Table 30. Summary of Parent Artery Stenosis per Multiple Reader Core Laboratory Analysis for Primary Eectiveness Endpoint at 1-, 2-, and 3-year Follow Up

(mITT and ICA Population with Observed Data)

Parent Artery Stenosis

(Signicant stenosis (> 50%))

No 97.1% (134/138) 96.2% (51/53) 100.0% (54/54) mITT Population (N=141 Subjects)

Yes 2.9% (4/138) 3.8% (2/53) 0

Cannot Determine 0 3 1

No 97.0% (128/132) 96.0% (48/50) 100.0% (50/50) ICA Population (N=134 Subjects)

Yes 3.0% (4/132) 4.0% (2/50) 0

Cannot Determine 0 3 1

Note1: Numbers are % (Count/Sample Size) or Mean±SD (N) [Median] (Min, Max).

Note2: Data presented based on Core Lab.

Note3: Target Aneurysms only.

Note4: N=number of subjects with observed data

1-Year 2-Year 3-Year

Strengths:

The PREMIER Study was the rst prospective, multicenter trial to evaluate the use of the Pipeline™ device for the treatment of small and medium, unruptured aneurysms of the intracranial carotid and proximal vertebral artery. The PREMIER Study had predened hypotheses, study objectives/endpoints, study population selections, statistical analyses, subgroup analyses, and follow-up evaluations.

To avoid and minimize bias in the PREMIER Study, an independent Clinical Events Committee (CEC), Imaging Core Laboratory, and Data Monitoring Committee (DMC) were established to assess the primary safety and eectiveness endpoints, as well as to oversee the safety of the study. All study AEs were reviewed and adjudicated by CEC, which consisted of three independent physicians knowledgeable and Board Certied in the appropriate disciplines and medical specialties pertinent to the disease state. In addition, the CEC adjudicated specied event denitions (where available), event relatedness, event severity, and event outcome. Therefore, the CEC adjudication provided an unbiased assessment for safety outcomes in the PREMIER Study. The Imaging Core Laboratory provided an independent angiography examination to assess baseline aneurysm and procedural aneurysm characteristics, aneurysm occlusion status, parent artery stenosis, and occurrence of device migration.

The PREMIER Study included a long-term 3-year follow-up with high subject retention; 90.8% (128/141) of subjects completed 3-year clinical follow up visit. The 3-year follow-up results showed durability of aneurysm occlusion with modest rise of new primary safety events, and low new overall complications, supporting the longer-term safety and ecacy of the Pipeline™ Device in the populations in treating small and medium widenecked, intracranial aneurysms.

Weaknesses:

The PREMIER Study was a single-arm clinical study without the use of a control group. Note that a single-arm trial was necessary, as alternative, minimally invasive treatments that could form a reasonable concurrent control group were not approved at the onset of this study. The study only included a limited number of subjects with vertebral artery aneurysms (7/141). Of the subjects requiring mandatory imaging follow-ups at 2-year and 3-year visits, only 76% (19/25) and 64.0% (16/25), respectively completed the required imaging. The key reasons for missing imaging were changes in multi-reader core lab assessments (implemented post-hoc per FDA feedback), subject refusal/unable to undergo follow-up imaging, and lost-to-follow-up (details in Table 26).

QUESTIONS AND ANSWERS

Q If excessive friction is experienced during the insertion of delivery system at any time during the delivery of Pipeline™ Flex Embolization Device with Shield Technology™, what should I do? A Carefully remove the entire system simultaneously (micro catheter and delivery system).

Q Can I retrieve the Pipeline™ Flex Embolization Device with Shield Technology™ if the distal end of the Pipeline™ Flex Embolization Device with Shield Technology™ has expanded at an undesirable location? A Yes. A partially deployed Pipeline™ Flex Embolization Device with Shield Technology™ can be resheathed per resheathing instructions, step 15 in the Directions for Use.

Q Can I retrieve a fully deployed Pipeline™ Flex Embolization Device with Shield Technology™? A Once fully deployed, the Pipeline™ Flex Embolization Device with Shield Technology™ cannot be removed. A second Pipeline™ Flex Embolization Device with Shield Technology™ can be deployed if needed.

Q Can I place a second Pipeline™ Flex Embolization Device with Shield Technology™ inside another Pipeline™ Flex Embolization Device with Shield Technology™? A Yes. A second Pipeline™ Flex Embolization Device with Shield Technology™ can be placed inside another Pipeline™ Flex Embolization Device with Shield Technology™. After placing the rst Pipeline™ Flex Embolization

Device with Shield Technology™, advance the micro catheter over the delivery wire while keeping the delivery core wire across the Pipeline™ Flex Embolization Device with Shield Technology™. Position the micro catheter at the desired location and retrieve the delivery wire. Select a new appropriate Pipeline™ Flex Embolization Device with Shield Technology™ and deploy it as normal.

Caution: Placement of multiple Pipeline™ Flex Embolization Device with Shield Technology™ may increase the risk of ischemic complications.

Q If there is a dierence between the proximal and distal diameter, which Pipeline™ Flex Embolization Device with Shield Technology™ diameter do I choose? A Choose a Pipeline™ Flex Embolization Device with Shield Technology™ that matches larger (typically proximal) vessel diameter to ensure proper anchoring.

Symbol Glossary

Sterilized using ethylene oxide Non-pyrogenic

Do not re-use Keep away from sunlight

Caution: Federal (USA) law restricts this device to sale by or on the order of a physician

Do not resterilize Catalogue number

Consult instructions for use at this website Manufacturer

Caution Use-by date

Do not use if package is damaged Batch code

MR Conditional Contents of Package

Keep dry

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Micro Therapeutics, Inc. d/b/a ev3 Neurovascular 9775 Toledo Way Irvine, CA 92618 USA

Tel: +1.949.837.3700

M002318CDOC2 Rev. B (03/2021)

Medtronic PED2-250-12 Instructions for Use

Specifications and Main Features

Frequently Asked Questions

User Manual