Medtronic PED-275-10 Instructions for Use

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INSTRUCTIONS FOR USE

Pipeline™ Flex Embolization Device

TABLE OF CONTENTS

Pipeline™ Flex Embolization Device

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English en Instructions for Use

Pipeline™ Flex Embolization Device

INDICATIONS FOR USE

The Pipeline™ Flex embolization device 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 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 widenecked (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.

WARNINGS

• Resheathing of the Pipeline™ Flex embolization device more than 2 full cycles may cause damage to the distal or proximal ends of the braid.

• 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 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 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 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 devices 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 and can lead to damage to the Pipeline™ Flex Embolization Device and microcatheter. Advancement or retraction of the Pipeline™ Flex embolization device against resistance may result in 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. 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.

WARNINGS

• 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. Observed 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.

PRECAUTIONS

• The Pipeline™ Flex embolization device 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 in patients.

• The Pipeline™ Flex embolization device is provided sterile 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 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 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.

POTENTIAL COMPLICATIONS

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

• 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

• Decreased therapeutic response including need for target aneurysm retreatement

• Risks associated with visual symptoms include Amaurosisfugax/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

DESCRIPTION

The Pipeline™ Flex embolization device consists of a permanent implant combined with a guidewire based delivery system. The Pipeline™ Flex embolization device implant is a braided, multi-alloy, mesh cylinder woven from platinum/tungsten and cobalt-chromium-nickel alloy wires. A photograph of the Pipeline™ Flex embolization device is shown in Figure 1a and the design of the distal delivery system is shown in Figure 1b. 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.

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 is advanced through the micro catheter. The proximal bumper and resheathing pad allows the user to push the Pipeline™ Flex embolization device out of the micro catheter when the delivery system is advanced. The resheathing pad allows the user to resheath the Pipeline™ Flex embolization device back into the micro catheter. The resheathing marker provides the user uoroscopic visualization for the limit of resheathing the Pipeline™ Flex embolization device.

The Pipeline™ Flex embolization device 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 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.

Figure 1a. The Pipeline™ Flex embolization device

≈200cm (Total Length)

15 mm

1 2

≈125cm (Tip Coil to Fluorosafe)

3 mm (Covered by Braid)

Figure 1b. The Pipeline™ Flex embolization device

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

Table 1. Size Ranges: Pipeline™ Flex embolization device.

Labeled Diameter

(mm)

Self Expanded

Diameter (mm)

Labeled Lengths (mm)

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

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

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

Labeled Diameter

(mm)

Self Expanded

Diameter (mm)

Labeled Lengths (mm)

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

MAGNETIC RESONANCE IMAGING

Non-clinical testing has demonstrated that the Pipeline™ Flex embolization device is MR Conditional. It can be scanned safely under the following conditions:

• Static magnetic eld of 3 Tesla or less.

• Spatial gradient eld of 720 Gauss/cm or less.

• Maximum whole-body-averaged specic absorption rate (SAR) of 4.0 W/kg for 15 minutes of scanning.

In non-clinical testing, the Pipeline™ Flex embolization device produced a temperature rise of less than

0.6°C at a maximum whole body averaged specic absorption rate (SAR) of 4.0 W/kg for 15 minutes of MR

scanning in a 3 Tesla MR 750 GE Signa 20.0 system MR Scanner.

The Pipeline™ Flex embolization device may create local eld inhomogeneity and susceptibility artifacts which may degrade the diagnostic quality of the MRI images. Based on the non-clinical testing of the 5.0 mm device using standard views, the worst case maximum artifact was <4 mm when subjected to 3.0 Tesla. Local eld artifact from the Pipeline™ Flex embolization device 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. Therefore, it may be necessary to optimize MR imaging parameters for the presence of this metallic implant.

PACKAGING AND STORAGE

Store in a cool dry place.

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.

NOTE: It is recommended to use a heparinized saline drip to continuously ush micro catheter during Pipeline™ Flex embolization device use.

2. Choose a Pipeline™ Flex embolization device with labeled diameter that approximates the target vessel diameter.

• Select an appropriate sized Pipeline™ Flex embolization device such that its fully expanded diameter is equivalent to that of the largest target vessel. An incorrectly sized Pipeline™ Flex embolization device may result in inadequate device placement, incomplete opening or migration.

• The Pipeline™ Flex embolization device foreshortens substantially (50-60%) during deployment. Take device foreshortening into account when deploying the Pipeline™ Flex embolization device.

3. Choose a Pipeline™ Flex embolization device 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 250mmHg 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 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 into the micro catheter by 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, 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 against resistance may result in

damage, including unintended device or component separation, fracture, or breakage of the delivery

4 5

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.

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

13. Begin to deliver the Pipeline™ Flex embolization device using a combination of unsheathing the Pipeline™ Flex embolization device and pushing the delivery wire simultaneously.

WARNING

• 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 and can lead to damage to the Pipeline™ Flex Embolization Device 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 has successfully expanded, deploy the remainder of Pipeline™ Flex embolization device by pushing the delivery wire and/or unsheathing the Pipeline™ Flex embolization device. 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.

CAUTION: Under uoroscopy, carefully monitor the tip coil during Pipeline™ Flex embolization device deployment.

15. Resheathing Instructions: During deployment of the Pipeline™ Flex embolization device resheathing can be performed by advancing the micro catheter while pulling the delivery wire.

• The Pipeline™ Flex embolization device can be resheathed until the resheathing marker has reached

the distal marker of the micro catheter (see Figure 2 below).

• The Pipeline™ Flex embolization device 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.

WARNING

• Resheathing the Pipeline™ Flex embolization device more than 2 full cycles may cause damage to the distal or proximal ends of the braid.

4. Resheathing Marker 8. Device Detached

16. After the entire Pipeline™ Flex embolization device 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, retract the delivery wire into the micro catheter tip.

CAUTION: If the catheter cannot be advanced through the Pipeline™ Flex embolization device, carefully remove the delivery wire through the Pipeline™ Flex embolization device 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 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.

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 patents 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: The Pipeline™ Flex embolization device utilizes the same implant as the Pipeline™ embolization device in the PUFS-PAS trial.

Figure 2. Pipeline™ Flex embolization device

(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

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

MedDRA®* Term 180 days 1 year 3 year 5 year

Total 18

(13.4%)

(17.9%)

(20.1%)

Cerebral haemorrhage 6 (4.5%) 6 (4.5%) 6 (4.5%) 6 (4.5%)

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

Cerebral ischaemia 3 (2.2%) 3 (2.2%) 3 (2.2%) 3 (2.2%)

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

Iiird nerve disorder 2 (1.5%) 2 (1.5%) 2 (1.5%) 2 (1.5%)

Ischaemic stroke 2 (1.5%) 2 (1.5%) 2 (1.5%) 2 (1.5%)

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

Carotid artery aneurysm 1 (0.7%) 1 (0.7%) 1 (0.7%) 1 (0.7%)

Carotid artery occlusion 1 (0.7%) 1 (0.7%) 1 (0.7%) 1 (0.7%)

Carpal tunnel syndrome 0 (0.0%) 0 (0.0%) 1 (0.7%) 1 (0.7%)

Cerebral artery embolism 0 (0.0%) 0 (0.0%) 1 (0.7%) 1 (0.7%)

Cerebral artery stenosis 0 (0.0%) 0 (0.0%) 1 (0.7%) 1 (0.7%)

Cerebrovascular accident 1 (0.7%) 1 (0.7%) 1 (0.7%) 1 (0.7%)

Dementia alzheimer's type 0 (0.0%) 0 (0.0%) 1 (0.7%) 1 (0.7%)

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

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

Nervous system disorder 0 (0.0%) 0 (0.0%) 0 (0.0%) 1 (0.7%)

Transient ischaemic attack 0 (0.0%) 0 (0.0%) 1 (0.7%) 1 (0.7%)

Vith nerve disorder 1 (0.7%) 1 (0.7%) 1 (0.7%) 1 (0.7%)

Gastrointestinal disorders

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

Gastrointestinal

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

haemorrhage

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

Diverticulitis intestinal

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

haemorrhagic

Intra-abdominal

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

haemorrhage

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

Oesophageal spasm 0 (0.0%) 0 (0.0%) 0 (0.0%) 1 (0.7%)

Peptic ulcer 1 (0.7%) 1 (0.7%) 1 (0.7%) 1 (0.7%)

Rectal haemorrhage 1 (0.7%) 1 (0.7%) 1 (0.7%) 1 (0.7%)

Retroperitoneal haematoma 1 (0.7%) 1 (0.7%) 1 (0.7%) 1 (0.7%)

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

MedDRA®*

Category

Injury, poisoning and procedural complications

MedDRA®* Term 180 days 1 year 3 year 5 year

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

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

Joint injury 1 (0.7%) 1 (0.7%) 2 (1.5%) 2 (1.5%)

Ankle fracture 0 (0.0%) 0 (0.0%) 0 (0.0%) 1 (0.7%)

Arterial injury 1 (0.7%) 1 (0.7%) 1 (0.7%) 1 (0.7%)

Corneal abrasion 1 (0.7%) 1 (0.7%) 1 (0.7%) 1 (0.7%)

Procedural haemorrhage 1 (0.7%) 1 (0.7%) 1 (0.7%) 1 (0.7%)

Road trac accident 0 (0.0%) 0 (0.0%) 0 (0.0%) 1 (0.7%)

Vascular pseudoaneurysm 1 (0.7%) 1 (0.7%) 1 (0.7%) 1 (0.7%)

Surgical and medical procedures

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

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

Arterial aneurysm repair 0 (0.0%) 0 (0.0%) 1 (0.7%) 1 (0.7%)

Atrial septal defect repair 0 (0.0%) 0 (0.0%) 1 (0.7%) 1 (0.7%)

Intra-cerebral aneurysm

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

operation

Knee arthroplasty 0 (0.0%) 0 (0.0%) 0 (0.0%) 1 (0.7%)

Eye disorders Total 5 (3.7%) 6 (4.5%) 9 (6.7%) 9 (6.7%)

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

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

Eye pain 1 (0.7%) 1 (0.7%) 1 (0.7%) 1 (0.7%)

Retinal artery embolism 1 (0.7%) 1 (0.7%) 1 (0.7%) 1 (0.7%)

Vision blurred 1 (0.7%) 1 (0.7%) 1 (0.7%) 1 (0.7%)

Visual impairment 0 (0.0%) 0 (0.0%) 1 (0.7%) 1 (0.7%)

Cardiac disorders

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

Atrial brillation 1 (0.7%) 1 (0.7%) 1 (0.7%) 2 (1.5%)

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

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

Myocardial infarction 0 (0.0%) 0 (0.0%) 1 (0.7%) 1 (0.7%)

Ventricular brillation 1 (0.7%) 1 (0.7%) 1 (0.7%) 1 (0.7%)

Wol-parkinson-white

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

syndrome

Vascular disorders

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

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

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

Deep vein thrombosis 1 (0.7%) 1 (0.7%) 1 (0.7%) 1 (0.7%)

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

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

Intermittent claudication 0 (0.0%) 0 (0.0%) 0 (0.0%) 1 (0.7%)

Peripheral vascular disorder 0 (0.0%) 0 (0.0%) 0 (0.0%) 1 (0.7%)

*MedDRA® Medical Dictionary for Regulatory Activities

MedDRA®*

Category

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

MedDRA®* Term 180 days 1 year 3 year 5 year

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

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

Breast cancer 0 (0.0%) 0 (0.0%) 1 (0.7%) 1 (0.7%)

Breast cancer recurrent 0 (0.0%) 1 (0.7%) 1 (0.7%) 1 (0.7%)

Colon cancer 0 (0.0%) 0 (0.0%) 0 (0.0%) 1 (0.7%)

Lung neoplasm malignant 0 (0.0%) 1 (0.7%) 1 (0.7%) 1 (0.7%)

Metastatic neoplasm 0 (0.0%) 0 (0.0%) 1 (0.7%) 1 (0.7%)

Non-small cell lung cancer

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

stage iiib

Prostate cancer 0 (0.0%) 0 (0.0%) 0 (0.0%) 1 (0.7%)

Infections and infestations

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

Cholecystitis infective 1 (0.7%) 2 (1.5%) 2 (1.5%) 2 (1.5%)

Abdominal abscess 0 (0.0%) 0 (0.0%) 1 (0.7%) 1 (0.7%)

Herpes zoster 0 (0.0%) 1 (0.7%) 1 (0.7%) 1 (0.7%)

Meningitis viral 0 (0.0%) 0 (0.0%) 1 (0.7%) 1 (0.7%)

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

Upper respiratory tract

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

infection

Respiratory, thoracic and mediastinal disorders

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

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

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

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

Pulmonary embolism 0 (0.0%) 0 (0.0%) 1 (0.7%) 1 (0.7%)

General disorders and administration site conditions

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

Catheter site discharge 1 (0.7%) 1 (0.7%) 1 (0.7%) 1 (0.7%)

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

Multi-organ failure 0 (0.0%) 0 (0.0%) 1 (0.7%) 1 (0.7%)

Oedema peripheral 0 (0.0%) 1 (0.7%) 1 (0.7%) 1 (0.7%)

Endocrine disorders

Musculoskeletal and connective tissue disorders

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

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

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

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

Intervertebral disc

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

degeneration

Blood and lymphatic system disorders

Ear and labyrinth disorders

Psychiatric disorders

Renal and urinary disorders

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

Bone marrow failure 1 (0.7%) 1 (0.7%) 1 (0.7%) 1 (0.7%)

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

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

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

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

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

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

Total 37

(27.6%)

*MedDRA® Medical Dictionary for Regulatory Activities

(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

MedDRA®* Term

Total 47

disorders

Headache 39

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

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

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

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

Visual eld defect 1 (0.7%) 2 (1.5%) 2 (1.5%) 2 (1.5%)

Carotid artery occlusion 1 (0.7%) 1 (0.7%) 1 (0.7%) 1 (0.7%)

Cerebral artery stenosis 0 (0.0%) 0 (0.0%) 1 (0.7%) 1 (0.7%)

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

Coordination abnormal 0 (0.0%) 0 (0.0%) 1 (0.7%) 1 (0.7%)

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

Facial paresis 0 (0.0%) 0 (0.0%) 1 (0.7%) 1 (0.7%)

Facial spasm 1 (0.7%) 1 (0.7%) 1 (0.7%) 1 (0.7%)

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

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

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

Iiird nerve disorder 1 (0.7%) 1 (0.7%) 1 (0.7%) 1 (0.7%)

Iiird nerve paralysis 1 (0.7%) 1 (0.7%) 1 (0.7%) 1 (0.7%)

Intracranial aneurysm 0 (0.0%) 0 (0.0%) 0 (0.0%) 1 (0.7%)

Ivth nerve paralysis 1 (0.7%) 1 (0.7%) 1 (0.7%) 1 (0.7%)

Migraine with aura 0 (0.0%) 0 (0.0%) 0 (0.0%) 1 (0.7%)

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

Transient ischaemic attack 0 (0.0%) 0 (0.0%) 1 (0.7%) 1 (0.7%)

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

Upper motor neurone lesion 1 (0.7%) 1 (0.7%) 1 (0.7%) 1 (0.7%)

Vith nerve paralysis 1 (0.7%) 1 (0.7%) 1 (0.7%) 1 (0.7%)

Vith nerve paresis 1 (0.7%) 1 (0.7%) 1 (0.7%) 1 (0.7%)

MedDRA®: Medical Dictionary for Regulatory Activities *NEC; Not Elsewhere Classied

180

days

(35.1%)

(29.1%)

1 year 3 year 5 year

(35.8%)

(29.1%)

(41.8%)

(32.8%)

(46.3%)

(34.3%)

MedDRA®*

Category

MedDRA®* Term

180

days

Eye disorders Total 28

(20.9%)

Visual impairment 14

(10.4%)

Eyelid ptosis 4 (3.0%) 4 (3.0%) 4 (3.0%) 4 (3.0%)

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

Eye pain 1 (0.7%) 1 (0.7%) 2 (1.5%) 2 (1.5%)

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

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

Vision blurred 1 (0.7%) 1 (0.7%) 2 (1.5%) 2 (1.5%)

Visual acuity reduced 1 (0.7%) 1 (0.7%) 1 (0.7%) 2 (1.5%)

Abnormal sensation in eye 0 (0.0%) 0 (0.0%) 0 (0.0%) 1 (0.7%)

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

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

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

Eye haemorrhage 1 (0.7%) 1 (0.7%) 1 (0.7%) 1 (0.7%)

Eye pruritus 1 (0.7%) 1 (0.7%) 1 (0.7%) 1 (0.7%)

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

Optic nerve disorder 1 (0.7%) 1 (0.7%) 1 (0.7%) 1 (0.7%)

Vitreous oaters 1 (0.7%) 1 (0.7%) 1 (0.7%) 1 (0.7%)

Vascular disorders Total 11

(8.2%)

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

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

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

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

Aortic aneurysm 0 (0.0%) 0 (0.0%) 0 (0.0%) 1 (0.7%)

Arterial occlusive disease 0 (0.0%) 1 (0.7%) 1 (0.7%) 1 (0.7%)

Arterial stenosis 0 (0.0%) 0 (0.0%) 0 (0.0%) 1 (0.7%)

Blood pressure inadequately

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

controlled

Orthostatic hypotension 0 (0.0%) 0 (0.0%) 1 (0.7%) 1 (0.7%)

Thrombophlebitis supercial 1 (0.7%) 1 (0.7%) 1 (0.7%) 1 (0.7%)

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

Gastrointestinal disorders

Total 14

(10.4%)

Nausea 11

(8.2%)

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

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

Abdominal distension 1 (0.7%) 1 (0.7%) 1 (0.7%) 1 (0.7%)

Abdominal pain upper 0 (0.0%) 0 (0.0%) 1 (0.7%) 1 (0.7%)

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

Paraesthesia oral 0 (0.0%) 0 (0.0%) 0 (0.0%) 1 (0.7%)

Rectal haemorrhage 1 (0.7%) 1 (0.7%) 1 (0.7%) 1 (0.7%)

1 year 3 year 5 year

(20.9%)

(10.4%)

(9.0%)

(10.4%)

(8.2%)

(23.9%)

(10.4%)

(9.7%)

(11.2%)

(8.2%)

(26.1%)

(10.4%)

(14.9%)

(12.7%)

(9.0%)

MedDRA®*

Category

Injury, poisoning

MedDRA®* Term

Total 10 and procedural complications

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

Head injury 2 (1.5%) 2 (1.5%) 3 (2.2%) 3 (2.2%)

Ankle fracture 0 (0.0%) 0 (0.0%) 0 (0.0%) 1 (0.7%)

Contrast media reaction 0 (0.0%) 1 (0.7%) 1 (0.7%) 1 (0.7%)

Corneal abrasion 1 (0.7%) 1 (0.7%) 1 (0.7%) 1 (0.7%)

Foot fracture 0 (0.0%) 0 (0.0%) 1 (0.7%) 1 (0.7%)

Muscle strain 1 (0.7%) 1 (0.7%) 1 (0.7%) 1 (0.7%)

Radiation exposure 1 (0.7%) 1 (0.7%) 1 (0.7%) 1 (0.7%)

Radiation injury 1 (0.7%) 1 (0.7%) 1 (0.7%) 1 (0.7%)

Spinal compression fracture 0 (0.0%) 1 (0.7%) 1 (0.7%) 1 (0.7%)

General disorders

Total 9 (6.7%) 10 and administration site conditions

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

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

Adverse drug reaction 0 (0.0%) 0 (0.0%) 0 (0.0%) 1 (0.7%)

Catheter site discharge 1 (0.7%) 1 (0.7%) 1 (0.7%) 1 (0.7%)

Catheter site swelling 1 (0.7%) 1 (0.7%) 1 (0.7%) 1 (0.7%)

Chest pain 0 (0.0%) 1 (0.7%) 1 (0.7%) 1 (0.7%)

Facial pain 1 (0.7%) 1 (0.7%) 1 (0.7%) 1 (0.7%)

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

Feeling cold 1 (0.7%) 1 (0.7%) 1 (0.7%) 1 (0.7%)

Oedema peripheral 1 (0.7%) 1 (0.7%) 1 (0.7%) 1 (0.7%)

Vessel puncture site

haemorrhage

Musculoskeletal

Total 4 (3.0%) 5 (3.7%) 8 (6.0%) 11 and connective tissue disorders

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

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

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

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

Back pain 1 (0.7%) 1 (0.7%) 1 (0.7%) 1 (0.7%)

Groin pain 1 (0.7%) 1 (0.7%) 1 (0.7%) 1 (0.7%)

Pain in extremity 1 (0.7%) 1 (0.7%) 1 (0.7%) 1 (0.7%)

Infections and infestations

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

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

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

Chronic sinusitis 0 (0.0%) 0 (0.0%) 1 (0.7%) 1 (0.7%)

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

Tooth abscess 0 (0.0%) 0 (0.0%) 0 (0.0%) 1 (0.7%)

Urinary tract infection 0 (0.0%) 0 (0.0%) 0 (0.0%) 1 (0.7%)

MedDRA®: Medical Dictionary for Regulatory Activities *NEC; Not Elsewhere Classied

180

days

(7.5%)

1 year 3 year 5 year

(7.5%)

(9.7%)

(7.5%)

(10.4%)

(8.2%)

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

(8.2%)

MedDRA®*

Category

Psychiatric disorders

MedDRA®* Term

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

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

180

days

1 year 3 year 5 year

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

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

Behavioural and psychiatric

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

symptoms of dementia

Mental status changes 0 (0.0%) 1 (0.7%) 1 (0.7%) 1 (0.7%)

Panic attack 0 (0.0%) 0 (0.0%) 0 (0.0%) 1 (0.7%)

Respiratory, thoracic and mediastinal disorders

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

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

Oropharyngeal pain 2 (1.5%) 2 (1.5%) 2 (1.5%) 2 (1.5%)

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

Blood and lymphatic system disorders

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

Haemorrhagic disorder 3 (2.2%) 3 (2.2%) 3 (2.2%) 3 (2.2%)

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

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

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

Corneal reex decreased 1 (0.7%) 1 (0.7%) 1 (0.7%) 1 (0.7%)

Electrocardiogram qt

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

prolonged

Ophthalmological examina-

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

tion abnormal

Weber tuning fork test

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

abnormal

Metabolism and nutrition disorders

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

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

Diabetes mellitus 0 (0.0%) 0 (0.0%) 0 (0.0%) 1 (0.7%)

Iron deciency 0 (0.0%) 0 (0.0%) 1 (0.7%) 1 (0.7%)

Renal and urinary disorders

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

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

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

Reproductive system and breast disorders

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

Breast cyst 0 (0.0%) 0 (0.0%) 0 (0.0%) 1 (0.7%)

Female genital tract stula 1 (0.7%) 1 (0.7%) 1 (0.7%) 1 (0.7%)

Ovarian cyst 1 (0.7%) 1 (0.7%) 1 (0.7%) 1 (0.7%)

Vaginal haemorrhage 1 (0.7%) 1 (0.7%) 1 (0.7%) 1 (0.7%)

Ear and labyrinth disorders

Neoplasms benign, malignant and unspecied (incl cysts and polyps) Congenital, familial and genetic disorders

Immune system disorders

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

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

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

Cervix carcinoma recurrent 0 (0.0%) 0 (0.0%) 0 (0.0%) 1 (0.7%)

Neoplasm malignant 0 (0.0%) 0 (0.0%) 1 (0.7%) 1 (0.7%)

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

Arnold-chiari malformation 0 (0.0%) 0 (0.0%) 1 (0.7%) 1 (0.7%)

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

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

MedDRA®*

Category

Skin and subcutaneous tissue disorders

Surgical and medical procedures

MedDRA®* Term

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

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

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

Rotator cu repair 0 (0.0%) 0 (0.0%) 0 (0.0%) 1 (0.7%)

Total 84

MedDRA®: Medical Dictionary for Regulatory Activities

*NEC; Not Elsewhere Classied

180

days

(62.7%)

1 year 3 year 5 year

(62.7%)

(67.9%)

(73.1%)

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 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.

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

All AEs

Incidence of AE

(n/N) (%)

[# of events]

Total Total 116/141(82.3%)

[313]

Blood and lymphatic system disorders

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

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

Haemorrhagic

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

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]

diathesis

Lymphoid tissue

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

hyperplasia

Cardiac disorders Total 3/141(2.1%) [3] 3/141(2.1%) [3] 0

Atrial utter 1/141(0.7%) [1] 1/141(0.7%) [1] 0

Cardiac failure

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

congestive

Ventricular

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

tachycardia

Ear and labyrinth disorders

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

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

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

MedDRA®*

System Organ

Class

Eye disorders Total 33/141(23.4%)

Gastrointestinal disorders

General disorders and administration site conditions

Hepatobiliary disorders

Immune system disorders

MedDRA®*

Preferred Term

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

Conjunctival haemorrhage

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

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

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

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

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

Visual impairment

Vitreous detachment

Vitreous oaters 5/141(3.5%) [5] 0 5/141(3.5%) [5]

Total

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

Gastrointestinal haemorrhage

Gastrointestinal inammation

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

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

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

Peritoneal haemorrhage

Total

Adverse drug reaction

Catheter site haematoma

Catheter site haemorrhage

Catheter site pain 6/141(4.3%) [6] 0 6/141(4.3%) [6]

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

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

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

Thrombosis in device

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

Portal vein thrombosis

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

Anaphylactic reaction

All AEs

Incidence of AE

(n/N) (%)

[# of events]

[40]

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

15/141(10.6%)

[15]

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

10/141(7.1%) [14]

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

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

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

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]

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

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]

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

4/141(2.8%) [4]

All Non SAEs

Incidence of AE

(n/N) (%)

[# of events]

32/141(22.7%)

[39]

15/141(10.6%)

[15]

30/141(21.3%)

[31]

13/141(9.2%)

[13]

MedDRA®*

System Organ

Class

Infections and infestations

Injury, poisoning and procedural complications

Metabolism and nutrition disorders

Musculoskeletal and connective tissue disorders

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

MedDRA®*

Preferred Term

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

Catheter site infection

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

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

Inuenza 1/141(0.7%) [1] 1/141(0.7%) [1] 0

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

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

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

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

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

Periorbital haemorrhage

Procedural hypertension

Vascular pseudoaneurysm

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

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

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

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

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

Compartment syndrome

Muscular weakness

Musculoskeletal pain

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

Pain in extremity 1/141(0.7%) [1] 0 1/141(0.7%) [1]

Spinal osteoarthritis

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

Adenocarcinoma of colon

Basal cell carcinoma

Total

All AEs

Incidence of AE

(n/N) (%)

[# of events]

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]

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

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

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

Carotid artery dissection

Carotid artery stenosis

Cerebral haemorrhage

Cerebral infarction

Cerebral vasoconstriction

Disturbance in attention

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

Haemorrhage intracranial

Headache

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

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

Intracranial artery dissection

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

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

Multiple sclerosis relapse

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

Neuropathy peripheral

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

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

Sensory disturbance

Subarachnoid haemorrhage

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

Transient ischaemic attack

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

Visual eld defect 1/141(0.7%) [1] 0 1/141(0.7%) [1]

All AEs

Incidence of AE

(n/N) (%)

[# of events]

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]

36/141(25.5%)

[40]

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] 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]

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

Respiratory, thoracic and mediastinal disorders

Skin and subcutaneous tissue disorders

Surgical and medical procedures

Vascular disorders

MedDRA®*

Preferred Term

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

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

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

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

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

Mental status changes

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

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

Renal failure chronic

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

Benign prostatic hyperplasia

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

Ovarian cyst ruptured

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

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

Total

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

Ecchymosis

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]

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

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

Arteriovenous stula

Deep vein thrombosis

All AEs

Incidence of AE

(n/N) (%)

[# of events]

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

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

30/141(21.3%)

[32]

28/141(19.9%)

[28]

38/141(27.0%)

[42]

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

All SAEs

Incidence of AE

(n/N) (%)

[# of events]

3/141(2.1%) [3]

All Non SAEs

Incidence of AE

(n/N) (%)

[# of events]

30/141(21.3%)

[32]

28/141(19.9%)

[28]

35/141(24.8%)

[39]

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]

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]

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

Vasospasm

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.

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

28/141(19.9%)

[29]

28/141(19.9%)

[29]

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 wide-necked intracranial aneurysms (Table 4). 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 5) were predominantly in the cavernous and paraophthalmic portions of the internal carotid artery.

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

Characteristic Value

Age, mean (SD, range) 56.2 (12.0, 23.7-75.5)

Female gender, n (%) 115 (85.2%)

Race

White 124 (91.9%)

Black 8 (5.9%)

Not reported 3 (2.2%)

Ethnicity, % Hispanic or Latino 7 (5.2%)

Medical history

Subarachnoid hemorrhage 11 (8.1%)

Stroke 9 (6.7%)

Coronary artery disease 70 (51.9%)

Smoking

Never smoker 56 (41.5%)

Current smoker 38 (28.1%)

Previous smoker 41 (30.4%)

Prior treatments for target IA 14 (10.4%)

Coil embolization 11 (8.1%)

Surgery 2 (1.5%)

Other 1 (0.7%)

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

Characteristic N (%) or Mean (Range)

Side

Left 68 (50.4%)

Right 67 (49.6%)

Location

Petrous 6 (4.4%)

Cavernous 54 (40.0%)

Carotid cave 2 (1.5%)

Ophthalmic 5 (3.7%)

Paraclinoid 8 (5.9%)

Superior hypohyseal 11 (8.1%)

Lateral clinoidal 2 (1.5%)

Paraophthalmic 37 (27.4%)

Supraclinoid 9 (6.7%)

Posterior communicating 1 (0.7%)

Maximum fundus diameter (mm), mean (SD, range) 18.0 (6.3, 6.2-36.1)

“Small” (<10 mm), N (%) 3 (2.2%)

“Large” (>10 mm), N (%) 106 (78.5%)

“Giant” (>25 mm), N (%) 26 (19.3%)

Neck (mm), mean (SD, range) 9.5 (7.1, 4.0-60.0)

Target IA partially thrombosed, N (%) 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%)

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 D iameter, 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 180 day Posterior

Probability***

Intracranial aneurysms

treated (N=106)

Subjects treated

(N=104)

Intracranial aneurysms

attempted (N=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%

78/106

73.6% (64.4, 81.0)*

76/104

73.1% (63.8, 80.7)*

80/110

72.7% (63.7, 80.2)*

>0.9999 75/106

>0.9999 73/104

>0.9999 77/110

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

1 year

70.8% (61.1, 79.2)**

70.2% (60.4, 78.7)**

70.7% (58.6, 76.7)**

Occlusion Ranking 180 days

(N=99 IAs)

1 year

(N=91 IAs)

Total 99 (100%) 91 (100%)

*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 135 135 135 135 135 135 135

Deaths 3 3 3 4 5 6 7

Discontinued 1 3 6 7 13 13 19

Not yet due for

Follow-up

Expected Due1132 132 132 131 130 129 128

Actually Included 130 124 114 122 107 106 100

Missed Visit 1 5 12 2 10 10 9

Follow-up rate298.5% 93.9% 86.4% 93.1% 82.3% 82.2% 78.1%

Expected Due is all subjects minus any deaths

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

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

Occlusion Ranking 180 days

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

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

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

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

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

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

Primary Endpoint Safety Success

PUFS-PAS <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.

0 0 0 0 0 0 0

angiographic data.

(N=124 IAs)

1 year

(N=117 IAs)

3 years

(N=100 IAs)

5 years

(N=80 IAs)

Result 5-Year Kaplan-Meier

Threshold

Estimate

Occlusion Ranking 180 days

(N=99 IAs)

1 year

(N=91 IAs)

Complete occlusion 81 (81.8%) 78 (85.7%)

Residual neck 8 (8.1%) 5 (5.5%)

Residual aneurysm 6 (6.1%) 5 (5.5%)

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

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 11. 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 11).

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 12).

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 ≥ 4mm 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 81mg 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 75mg daily for a minimum of 7 days prior to PED and 75mg daily for a minimum of 3 months after PED). The primary eectiveness endpoint of the study was complete aneurysm occlusion of the target aneurysm without major stenosis (≤ 50%) of the parent artery or retreatment of the target aneurysm at one-year post-procedure. The primary eectiveness endpoint was judged by a core radiologic laboratory and was graded using the Raymond-Roy occlusion scale. 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.

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 common. 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 Overall

(N=141 Subjects)

Age 54.6±11.3 (141) [53.0] (30 - 77)

≥ 22 to <50 34.8% (49)

50 to <60 31.2% (44)

60 to <70 22.7% (32)

70 to 80 11.3% (16)

Gender

Male 12.1% (17)

Female 87.9% (124)

Race

American Indian or Alaska Native 0.7% (1)

Asian 2.8% (4)

Black or African American 11.3% (16)

Native Hawaiian or Other Pacic Islander 0.0% (0)

White 80.9% (114)

Unknown 0.0% (0)

Not reported 4.3% (6)

Ethnicity

Hispanic or Latino 8.5% (12)

Not Hispanic or Latino 81.6% (115)

Not Reported 5.0% (7)

Unknown 5.0% (7)

Medical History

Hypertension 72(51.1%)

Variable Overall

History of SAH 14(9.9%)

Current cigarette smoking 41(29.1%)

Former smoker within past 10 years 21(14.9%)

Drug use 1(0.7%)

Alcohol abuse 3(2.1%)

Epilepsy 13(9.2%)

Psychiatric disorder 71(50.4%)

Atrial brillation 7(5.0%)

Cardiac arrhythmias 20(14.2%)

Congestive heart failure 2(1.4%)

Myocardial infarction 2(1.4%)

Smoking

Never smoked or has not smoked within the last 10 years

Current or Past Smoker (within the past 10 years) 44.0% (62/141)

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

Current smoker, less than one pack per day 19.1% (27/141)

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

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

Aneurysm Characteristics Target aneurysm

Imaging Type

CT 0

CTA 0

MR 0

MRA 0

Angiogram 100.0%(141/141)

Other 0

Aneurysm Side Aneurysm Side

Right 48.9%(69/141)

Left 51.1%(72/141)

Parent Artery Location

Internal Carotid Artery 95.0%(134/141)

C1 (Cervical Segment) 0

C2 (Petrous Segment) 0.7%(1/134)

C3 (Lacerum Segment) 0

C4 (Cavernous Segment) 2.2%(3/134)

C5 (Clinoid Segment) 8.2%(11/134)

C6 (Ophthalmic Segment) 74.6%(100/134)

C7 (Communicating Segment) 14.2%(19/134)

Vertebral Artery 5.0%(7/141)

V1 (Pre-Foraminal)

V2 (Foraminal) 0

V3 (C2 to Dura)

(N=141 Subjects)

56.0% (79/141)

14.9% (21/141)

9.9% (14/141)

%(n/N)

(N=141 Aneurysms)

Aneurysm Characteristics Target aneurysm

V4 (Intradural)

Aneurysm Morphology

Saccular

Sidewall

Terminus -

Involved Side Branch -

Bifurcation Branch -

No Side Branch 65.4%(89/136)

Side Branch 34.6%(47/136)

Branch arising from neck of aneurysm 17.6%(24/136)

Branch arising from dome of aneurysm 8.8%(12/136)

Branch adjacent to aneurysm neck 8.1%(11/136)

Fusiform 3.5%(5/141)

Pseudoaneurysm -

Partially Thrombosed Partially Thrombosed

Yes 3.5%(5/141)

Aneurysm Measurement

Aneurysm Maximal Diameter (mm) 5.0±1.92(141)[4.6](1.7 - 11.1)

Dome Width (mm) 4.5±1.83(141)[4.2](1.3 - 11)

Dome Height (mm) 4.0±1.60(141)[3.8](1 - 9.2)

Aneurysm Neck Length (mm) 4.0±1.42(141)[3.7](1.3 - 9.5)

Dome/Neck Ratio 1.1±0.28(141)[1.1](0.6 - 1.9)

Parent Artery Diameter Proximal to Target Aneurysm(mm) 3.9±0.60(141)[3.9](2.1 - 5)

Parent Artery Diameter Distal to Target Aneurysm (mm) 3.5±0.59(141)[3.5](2.2 - 5.1)

Aneurysm Size 5.0±1.92(141)[4.6](1.7 - 11.1)

Small (<7 mm) 84.4%(119/141)

Aneurysm Size (<3mm) 9.9%(14/141)

Aneurysm Size (3-<7mm) 74.5%(105/141)

Medium (7-<13mm) 15.6%(22/141)

Large (13-<25 mm) 0

Giant (>= 25 mm) 0

Aneurysm Measurement

1Aneurysm Size Ratio >3 4.3%(6/141)

2Aneurysm Size Ratio>3 2.1%(3/141)

3Aneurysm Aspect Ratio>1.6 6.4%(9/141)

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

%(n/N)

(N=141 Aneurysms)

100.0%(7/7)

96.5%(136/141)

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 ≥ 4mm 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

Study Device

Diameter (mm)

Patient Follow-Up: Of the 141 treated subjects, the rate of one-year follow-up was high with clinical

follow-up obtained in 98.6% (139/141) of subjects and imaging follow-up obtained in 97.9% (138/141) of

Procedure by Dimension -mITT Population with Observed Data

Study Device Length(mm)

10 12 14 16 18 20 25 30 Total

2.50 0 0 1 0 0 0 0 0 1

3.00 0 1 1 1 0 1 0 0 4

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

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 (%)

1-sided 97.5% Exact Lower

Binomial Condence Interval

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

78.98% 72.05%

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)

69.34%

with missing data (n=2) considered failures*

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 Rate % (n/N)

(N = 134 Subjects)*

Rate % (n/N)

(N = 129 Subjects)**

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

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

Stenosis greater than 50% 3.0% (4/132) 3.1% (4/129)

Target aneurysm retreatment 3.0% (4/132) 3.1% (4/129)

Total 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.

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% Ex-

act Upper Binomial

Condence Interval

Threshold 1-Sided p-value

from Binomial

Distribution

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

Primary Safety

Endpoint

ICA population (N=134) 2.20%

Rate (%) 1-Sided 97.5% Ex-

act Upper Binomial Condence Interval

6.40% 15% <0.0001

Threshold 1-Sided p-value

from Binomial

Distribution

(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.

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

Procedure Related SAEs

*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.

1.1% (1/93), [0.0%,5.9%]

2.2% (2/93), [0.3%,7.6%]

1.1% (1/93), [0.0%,5.9%]

4.3% (4/93),

[1.2%,10.7%]

6.5% (6/93),

[2.4%,13.5%]

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%]

6.3% (3/48),

[1.3%,17.2%]

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%]

6.4% (9/141), [3.0%,11.8%]

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

Procedure – mITT Population

Variable

Rate

(N=141)

1-sided 97.5% exact upper

binomial condence interval

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

1.4% (2/141) 5.0%

post procedure)

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

0.7% (1/141) 3.9%

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

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

Procedure – ICA Population

Variable

Rate

(N=134)

1-sided 97.5% exact upper

binomial condence interval

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%

Table 24. Change in mRS (same, worse, or better) compared to pre-procedure in the mITT and

mRS Change

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

Decrease in mRS

Table 23. Additional Safety Analysis; Cerebrovascular Events (Ischemic and Hemorrhagic) in the

mITT and ICA Population up to 1-Year Post-Procedure

Variable

Analysis of Cerebrovascular Events

(Ischemic and Hemorrhagic) *

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

mITT Population

% (n/N)[E]

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

ICA Population

% (n/N)[E]

No change

Increase in mRS

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

ª 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

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.

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.

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

1mm<2mm (N=1)

2mm-

<3mm

(N=13)

3mm-

<4mm

(N=36)

4mm<5mm (N=29)

5mm-

<6mm

(N=26)

6mm-

<7mm

(N=14)

Primary Eectiveness Endpoint:

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

0.0% (0/1)

76.9%

(10/13)

86.1%

(31/36)

75.9%

(22/29)

73.1%

(19/26)

78.6%

(11/14)

the target aneurysm

Primary Safety Endpoint: No major stroke or neurological death.

*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).

0.0% (0/1)

7.7%

(1/13)

0.0%

(0/36)

3.4%

(1/29)

0.0%

(0/26)

0.0%

(0/14)

ICA population at 1-Year Post-Procedure

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%]

7mm-

<8mm

(N=10)

40.0% (4/10)

0.0%

(0/10)

8mm<9mm (N=5)

80.0% (4/5)

20.0% (1/5)

9mm-

<10mm

(N=4)

75.0% (3/4)

0.0% (0/4)

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%]

10mm-

<11mm

(N=1)

100.0% (1/1)

0.0% (0/1)

11mm-

<12mm

(N=2)

50.0% (1/2)

0.0% (0/2)

Final Conclusions

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

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, 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 if the distal end of the Pipeline™ Flex embolization device has expanded at an undesirable location?

A Yes. A partially deployed Pipeline™ Flex embolization device can be resheathed per resheathing instructions, step 15 in the Directions for Use.

Q Can I retrieve a fully deployed Pipeline™ Flex embolization device?

A Once fully deployed, the Pipeline™ Flex embolization device cannot be removed. A second Pipeline™ Flex embolization device can be deployed if needed.

Q Can I place a second Pipeline™ Flex embolization device inside another Pipeline™ Flex embolization device?

A Yes. A second Pipeline™ Flex embolization device can be placed inside another Pipeline™ Flex embolization device. After placing the rst Pipeline™ Flex embolization device, advance the micro catheter over the delivery

wire while keeping the delivery core wire across the Pipeline™ Flex embolization device. Position the micro catheter at the desired location and retrieve the delivery wire. Select a new appropriate Pipeline™ Flex embolization device and deploy it as normal.

Caution: Placement of multiple Pipeline™ Flex embolization devices 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 diameter do I choose?

A Choose a Pipeline™ Flex embolization device that matches larger (typically proximal) vessel diameter to ensure proper anchoring.

This page is intentionally left blank.

STERILIZE

REF

Symbol Glossary

Sterilized using ethylene oxide

Do not re-use

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

Do not resterilize

www.medtronic.com/manuals

Consult instructions for use at this website

Caution

Do not use if package is damaged

MR Conditional

Non-pyrogenic

Keep away from sunlight

Keep dry

Catalogue number

CONTENTS

Manufacturer

Use-by date

Batch code

Contents of Package

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

Tel: +1.949.837.3700

M009457CDOC2 Rev. A (08/2020)

Medtronic PED-275-10 Instructions for Use

Specifications and Main Features

Frequently Asked Questions

User Manual