Medtronic ADM06002008P Instructions for Use

IN.PACT™ Admiral™

Paclitaxel-coated PTA Balloon Catheter

Instructions for Use

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

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Symbols

Sterilized using ethylene oxide

Catalogue number

Lot number

Manufacturer

Manufactured in

Use by

Quantity

Consult instructions for use at this website: www.medtronic.com/manuals

Consult instructions for use

Do not reuse

Do not resterilize

Keep away from sunlight

Keep dry

Do not use if package is damaged

Outer diameter

Temperature limit

Nonpyrogenic

Do not exceed rated burst pressure

Over the wire

Nominal pressure

Rated burst pressure

Pressure

Balloon diameter

Minimum sheath inner diameter

Maximum guidewire diameter

Balloon length

Usable catheter length

Table of contents

1. Product Name .................................................................................................................................................................. 2

2. Product Description ........................................................................................................................................................ 3

2.1. Device Component Description .............................................................................................................................. 3

2.2. Drug Component Description ................................................................................................................................. 4

3. Indications for Use .......................................................................................................................................................... 5

4. Contraindications ............................................................................................................................................................ 5

5. Warnings .......................................................................................................................................................................... 5

6. Precautions ...................................................................................................................................................................... 6

6.1. General Precautions ............................................................................................................................................... 6

6.2. Pre-procedure and Post-procedure Medication Regimen ...................................................................................... 6

6.3. Use of Multiple Balloons ......................................................................................................................................... 7

6.4. Use in Conjunction with Other Procedures ............................................................................................................. 7

6.5. Drug Interaction ...................................................................................................................................................... 7

6.6. Balloon Handling and Preparation Precautions ...................................................................................................... 7

6.7. Balloon Placement Precautions .............................................................................................................................. 7

6.8. Balloon Catheter Removal Precautions .................................................................................................................. 7

6.9. Post-procedure Precautions ................................................................................................................................... 8

7. Use in Special Populations ............................................................................................................................................. 8

7.1. Pregnancy and Lactation ........................................................................................................................................ 8

7.2. Gender .................................................................................................................................................................... 8

7.3. Ethnicity .................................................................................................................................................................. 8

7.4. Pediatric Use ........................................................................................................................................................... 8

7.5. Geriatric Use ........................................................................................................................................................... 8

8. Drug Information .............................................................................................................................................................. 8

8.1. Mechanism of Action .............................................................................................................................................. 8

8.2. Pharmacokinetics ................................................................................................................................................... 8

8.3. Metabolism .............................................................................................................................................................. 8

8.4. Carcinogenicity, Genotoxicity, and Reproductive Toxicity ....................................................................................... 8

9. Potential Adverse Effects ............................................................................................................................................... 9

10. Patient Counseling Information ................................................................................................................................... 10

11. Summary of Clinical Studies ........................................................................................................................................ 10

11.1. Late Mortality Signal for Paclitaxel-Coated Devices ............................................................................................. 10

11.2. IN.PACT SFA Trial ................................................................................................................................................ 10

11.3. IN.PACT SFA Trial Post-Approval Study .............................................................................................................. 21

11.4. Pharmacokinetic Sub-study .................................................................................................................................. 37

11.5. IN.PACT Global Study .......................................................................................................................................... 38

11.6. Summary of Rare Adverse Events ....................................................................................................................... 38

11.7. IN.PACT Admiral DCB ISR Clinical Evaluation ..................................................................................................... 38

11.8. IN.PACT Global DCB Long Lesion Sub-Cohort .................................................................................................... 46

12. How Supplied ................................................................................................................................................................. 63

13. Instructions for Use ....................................................................................................................................................... 64

13.1. Equipment ............................................................................................................................................................. 64

13.2. Balloon Catheter Size Selection ........................................................................................................................... 64

13.3. Recommendations for Optimal Treatment ............................................................................................................ 64

13.4. PTA Preparation .................................................................................................................................................... 65

13.5. IN.PACT Admiral DCB Preparation ....................................................................................................................... 65

13.6. Inflation Device Connection to the IN.PACT Admiral DCB ................................................................................... 65

13.7. Delivery and Dilatation Procedure ........................................................................................................................ 66

13.8. Removal Procedure .............................................................................................................................................. 66

13.9. Using Multiple IN.PACT Admiral DCBs ................................................................................................................. 66

14. DISCLAIMER OF WARRANTY ....................................................................................................................................... 68

1. Product Name

IN.PACT™ Admiral™ paclitaxel-coated percutaneous transluminal angioplasty (PTA) balloon catheter

2 Instructions for Use English

2. Product Description

Guidewire Port

Inflation Port Usable Catheter Length

Radiopaque Marker Bands

0.035 in Guidewire

Drug Coating

The IN.PACT Admiral paclitaxel-coated PTA balloon catheter is an over-the-wire (OTW) balloon catheter with a drug-coated balloon at the distal tip. The drug component, referred to as the FreePac™ drug coating, consists of the drug paclitaxel and the excipient urea. The device component physically dilates the vessel lumen by PTA, and the drug is intended to reduce the proliferative response that is associated with restenosis. Product Component Description (Table 1) summarizes the characteristics of the device, hereafter referred to as IN.PACT Admiral DCB.

Table 1. Product Component Description

Balloon

Available Balloon Diameters (mm) and Lengths (mm)

Diameter

(mm)

4.0 x x x x x x x x

5.0 x x x x x x x x

6.0 x x x x x x x x

20 40 60 80 120 150 200 250

7.0 x x x x --- --- --- ---

Note: “---” indicates size not offered; “x” indicates sizes offered

Balloon Coating

Paclitaxel (Active Pharmaceutical Ingredient) and Urea (excipient) (Drug Component)

Catheter Design Over-the-Wire (OTW) Usable Catheter

80 cm and 130 cm Lengths

Balloon Inflation Pressure

Nominal Pressure (except 200 and 250 mm

lengths): 8 atm (811 kPa)

Rated Burst Pressure (except 200 and 250 mm

lengths): 14 atm (1419 kPa)

Balloon

Diameter

4.0 mm 5.6 Fr (1.88 mm) 5 Fr

5.0 mm 6.0 Fr (2.00 mm)

Minimum Introducer Sheath Compatibility

6.0 mm (except

120 mm)

6.0 mm

6.3 Fr (2.10 mm) or 7.0 Fr

(120 mm

length)

7.0 mm 7.0 Fr (2.33 mm) 7 Fr

Guidewire Com-

The catheter is compatible with a guidewire diameter of 0.035 in (0.89 mm). patibility

Balloon Length (mm)

Nominal Pressure (200 and 250 mm lengths): 5 atm (507 kPa)

Rated Burst Pressure (200 and 250 mm lengths): 11 atm (1115 kPa)

Max Crossing Profile Introducer Sheath

6.3 Fr (2.10 mm)

(2.33 mm)

Consult device label

6 Fr

6 Fr or 7 Fr

2.1. Device Component Description

The OTW balloon catheter consists of a proximal hub, dual-lumen shaft, and a distal dilatation balloon. The central lumen extends to the distal tip and is used to pass the catheter over a guidewire with a diameter of 0.035 in (0.89 mm). The ballooninflation lumen is used to inflate and deflate the balloon with a mixture of contrast medium and saline solution. Two radiopaque platinum-iridium markers indicate the working length of the balloon to position the balloon across the target lesion during fluoroscopy. See IN.PACT Admiral Paclitaxel-coated PTA Balloon Catheter (Figure 1).

Note: The 2 center marker bands shown in the diagram of the balloon are only available in the 200 and 250 mm balloon configurations.

Figure 1. IN.PACT Admiral Paclitaxel-coated PTA Balloon Catheter

Instructions for Use English 3

2.2. Drug Component Description

3’

2’

1’

The FreePac™ drug coating on the balloon of the IN.PACT Admiral DCB consists of the drug paclitaxel and the excipient urea. The balloon surface has a nominal paclitaxel dose density of 3.5 μg/mm2.

2.2.1. Paclitaxel

The active pharmaceutical ingredient in the IN.PACT Admiral DCB is paclitaxel. The principal mechanism by which paclitaxel inhibits neointimal growth is through the stabilization of microtubules by preventing their depolymerization during the final G2/M phase of cell division.

The CAS Registry number of paclitaxel is 33069-62-4. The chemical name of paclitaxel is: Benzenepropanoic acid, ß-(benzoylamino)-α-hydroxy-,6,12b-bis(acetyloxy)-12-(benzoyloxy) -2a,3,4,4a,5,6,9,10,11,12,12a,12b-

dodecahydro-4,11-dhydroxy-4a,8,13,13-tetramethyl-5-oxo-7,11-methano-1H-cyclodeca[3,4]benz[1,2-b]-oxet-9-ylester,[2aR[2aα,4β,4aβ,6β,9α(αR, βS),11α,12α,12aα,12bα]]

See Chemical Structure of Paclitaxel (Figure 2) below.

Figure 2. Chemical Structure of Paclitaxel

Paclitaxel is a diterpenoid with a characteristic taxane skeleton of 20 carbon atoms, a molecular weight of 853.91 g/mol, and a molecular formula of C47H51NO14. It is a white powder, has extremely low water solubility, is highly lipophilic, and is freely soluble in methanol, ethanol, chloroform, ethyl acetate, and dimethyl sulfoxide.

2.2.2. Urea

The coating utilizes the inactive ingredient urea as an excipient to facilitate the release and transfer of paclitaxel into the arterial wall. See Chemical Structure of Urea (Figure 3) below.

Figure 3. Chemical Structure of Urea

2.2.3. Product Matrix and Paclitaxel Content

Table 2. Product Matrix and Paclitaxel Content

Product Code (80 cm

Usable Catheter

Length)

Product Code (130 cm

Usable Catheter

Length)

Nominal Balloon

Diameter (mm)

Nominal Balloon

Length (mm)

Nominal Paclitaxel

Content (μg)

ADM 040 020 08P ADM 040 020 13P 4.0 20 1089 ADM 040 040 08P ADM 040 040 13P 4.0 40 1969 ADM 040 060 08P ADM 040 060 13P 4.0 60 2848 ADM 040 080 08P ADM 040 080 13P 4.0 80 3728 ADM 040 120 08P ADM 040 120 13P 4.0 120 5487 ADM 040 150 08P ADM 040 150 13P 4.0 150 6807 ADM 040 200 08P ADM 040 200 13P 4.0 200 9006 ADM 040 250 08P ADM 040 250 13P 4.0 250 11205

4 Instructions for Use English

Product Code (80 cm

Usable Catheter

Length)

ADM 050 020 08P ADM 050 020 13P 5.0 20 1454 ADM 050 040 08P ADM 050 040 13P 5.0 40 2553 ADM 050 060 08P ADM 050 060 13P 5.0 60 3653 ADM 050 080 08P ADM 050 080 13P 5.0 80 4752 ADM 050 120 08P ADM 050 120 13P 5.0 120 6951 ADM 050 150 08P ADM 050 150 13P 5.0 150 8601 ADM 050 200 08P ADM 050 200 13P 5.0 200 11350 ADM 050 250 08P ADM 050 250 13P 5.0 250 14098 ADM 060 020 08P ADM 060 020 13P 6.0 20 1850 ADM 060 040 08P ADM 060 040 13P 6.0 40 3170 ADM 060 060 08P ADM 060 060 13P 6.0 60 4489 ADM 060 080 08P ADM 060 080 13P 6.0 80 5809 ADM 060 120 08P ADM 060 120 13P 6.0 120 8448 ADM 060 150 08P ADM 060 150 13P 6.0 150 10427 ADM 060 200 08P ADM 060 200 13P 6.0 200 13726 ADM 060 250 08P ADM 060 250 13P 6.0 250 17024 ADM 070 020 08P ADM 070 020 13P 7.0 20 2279 ADM 070 040 08P ADM 070 040 13P 7.0 40 3819 ADM 070 060 08P ADM 070 060 13P 7.0 60 5358 ADM 070 080 08P ADM 070 080 13P 7.0 80 6897

Product Code (130 cm

Usable Catheter

Length)

Nominal Balloon

Diameter (mm)

Nominal Balloon

Length (mm)

Nominal Paclitaxel

Content (μg)

3. Indications for Use

The IN.PACT Admiral paclitaxel-coated PTA balloon catheter is indicated for percutaneous transluminal angioplasty, after appropriate vessel preparation, of de novo, restenotic, or in-stent restenotic lesions with lengths up to 360 mm in superficial femoral or popliteal arteries with reference vessel diameters of 4-7 mm.

4. Contraindications

The IN.PACT Admiral DCB is contraindicated for use in:

■

coronary arteries, renal arteries, and supra-aortic/cerebrovascular arteries

■

patients who cannot receive recommended antiplatelet and/or anticoagulant therapy

■

patients judged to have a lesion that prevents complete inflation of an angioplasty balloon or proper placement of the delivery system

■

patients with known allergies or sensitivities to paclitaxel

■

women who are breastfeeding, pregnant, or are intending to become pregnant, or men intending to father children. It is unknown whether paclitaxel will be excreted in human milk and whether there is a potential for adverse reaction in nursing infants from paclitaxel exposure.

5. Warnings

■

A signal for increased risk of late mortality has been identified following the use of paclitaxel-coated balloons and paclitaxel-eluting stents for femoropopliteal arterial disease beginning approximately 2-3 years post-treatment compared with the use of non-drug coated devices. There is uncertainty regarding the magnitude and mechanism for the increased late mortality risk, including the impact of repeat paclitaxel-coated device exposure. Physicians should discuss this late mortality signal and the benefits and risks of available treatment options with their patients. See Section 11 for further information.

■

Use the product prior to the Use-by Date specified on the package.

■

Contents are supplied sterile. Do not use the product if the inner packaging is damaged or opened.

■

Do not use air or any gaseous medium to inflate the balloon. Use only the recommended inflation medium (equal parts contrast medium and saline solution).

■

Do not move the guidewire during inflation of the IN.PACT Admiral DCB.

■

Do not exceed the rated burst pressure (RBP). The RBP is 14 atm (1419 kPa) for all balloons except the 200 and 250 mm balloons. For the 200 and 250 mm balloons the RBP is 11 atm (1115 kPa). The RBP is based on the results of in vitro testing. Use of pressures higher than RBP may result in a ruptured balloon with possible intimal damage and dissection.

Instructions for Use English 5

■

The safety and effectiveness of using multiple IN.PACT Admiral DCBs with a total drug dosage exceeding 34,854 μg of paclitaxel in a patient has not been clinically evaluated.

6. Precautions

6.1. General Precautions

■

This product should only be used by physicians trained in percutaneous transluminal angioplasty (PTA).

■

Assess risks and benefits before treating patients with a history of severe reaction to contrast agents.

■

Administer appropriate drug therapy to the patient according to standard protocols for PTA before insertion of the dilatation catheter.

■

Take precautions to prevent or reduce clotting when any catheter is used. Flush and rinse all products entering the vascular system with heparinized normal saline or a similar solution. For the IN.PACT Admiral DCB catheter, flush the guidewire lumen through the guidewire port with heparinized normal saline until the fluid exits the distal tip. Do not rinse or wipe the

IN.PACT Admiral DCB catheter.

■

Identify allergic reactions to contrast media and antiplatelet therapy before treatment and consider alternatives for appropriate management prior to the procedure.

■

Prior to the procedure, inspect the product to verify that the product is intact.

■

Handle the product with caution to avoid any damage to the balloon coating or folded balloon.

■

This product is not intended for the expansion or delivery of a stent.

■

Do not use the IN.PACT Admiral DCB for pre-dilatation or for post-dilatation.

■

This product is designed for single patient use only. Do not reuse, reprocess, or resterilize this product. Reuse, reprocessing, or resterilization may compromise the structural integrity of the device and/or create a risk of contamination of the device, which could result in patient injury, illness, or death.

■

Do not expose the product to organic solvents such as alcohol.

■

To reduce the potential for vessel damage, the inflated diameter of the balloon should approximately match the diameter of the vessel just distal to the lesion.

■

The use of this product carries the risks associated with percutaneous transluminal angioplasty, including thrombosis, vascular complications, and/or bleeding events.

6.2. Pre-procedure and Post-procedure Medication Regimen

It is recommended that dual antiplatelet therapy (aspirin with clopidogrel; use ticlopidine as an alternate to clopidogrel in case of allergy) is administered before the procedure and for a minimum of one month after the intervention, and that aspirin is continued for a minimum of six months after the procedure. Prolonged antiplatelet therapy can be given at the discretion of the physician. See Recommended Pre-procedure and Post-procedure Medication Regimen (Table 3).

Table 3. Recommended Pre-procedure and Post-procedure Medication Regimen

Medication Pre-procedure During Procedure Post-procedure

Antiplatelet Aspirin (ASA) 300-325 mg loading

dose within 24 hours

prior to procedure

Antiplateletc,

Clopidogrel 75-300 mg within

24 hours prior to proce-

dure or 2 hours post-

Ticlopidine

procedure

500 mg/day for at least

3 consecutive days prior

81-325 mg/day

(6 months minimum)

75 mg/day

(1 month minimum)

NA 500 mg/day

(1 month minimum)

to procedure (last dose

within 24 hours of pro-

cedure)

Anticoagulation IV Heparin (or other

Dosing as per institutional standard

thrombin inhibitor)

For cases of provisional stenting, refer to the published patient management guidelines for dosing instruction.

ASA loading dose not required for subjects already on a chronic regimen, defined as at least 81 mg daily for at least 5 consecutive days pre-procedure, with the last dose given/taken within 24 hours prior to procedure.

The safety and efficacy of this dose has not been prospectively studied. Please refer to current package inserts.

Subjects on a prasugrel or ticagrelor regimen for acute coronary syndrome (ACS) may continue that regimen as antiplatelet therapy. Please refer to the current package insert for information about risks and benefits of these medications, as well as for information on concomitant use of ASA and other medications.

Clopidogrel loading dose not required for subjects who have been taking 75 mg/day for at least 3 consecutive days before the intervention, with the last dose being taken within 24 hours prior to procedure.

Recommended in subjects with allergies to clopidogrel.

It is recommended that a bolus of 3000 to 5000 units of heparin be given prior to the angioplasty procedure, and that anticoagulation is given as needed to maintain an activated clotting time (ACT) of ≥250 seconds, or ≥200 seconds where GP IIb/IIIa inhibitors are concomitantly administered.

6 Instructions for Use English

6.3. Use of Multiple Balloons

The extent of the patient’s exposure to the drug coating is directly related to the number of balloons used. Refer to Using Multiple IN.PACT Admiral DCBs (Section 13.9) and Product Matrix and Paclitaxel Content (Table 2) for details regarding the use of multiple balloons and a product matrix containing the nominal paclitaxel content for each device size, respectively.

6.4. Use in Conjunction with Other Procedures

The safety and effectiveness of the IN.PACT Admiral DCB used in conjunction with other drug-eluting stents or drug-coated balloons in the same procedure or following treatment failure has not been evaluated.

6.5. Drug Interaction

Formal drug interaction studies have not been conducted with the IN.PACT Admiral DCB. In the clinical pharmacokinetic (PK) sub-study, systemic levels of paclitaxel following treatment with IN.PACT Admiral DCB(s) were low and cleared rapidly, reducing possible impact of drug-drug interactions due to concomitant medications. Consideration for both systemic and local drug interactions should be given when deciding to use IN.PACT Admiral DCB(s) in a patient who is taking a drug with known interactions to paclitaxel or when deciding to initiate therapy with such a drug in a patient who has recently been treated with IN.PACT Admiral DCB(s). Please refer to Drug Information (Section 8).

6.6. Balloon Handling and Preparation Precautions

■

Do not remove the device from the pouch until it is needed for immediate use.

■

Handle the device with caution to avoid any damage to the balloon coating or folded balloon.

■

Keep the protective sheath in place when purging the balloon catheter of air bubbles.

■

Carefully remove and discard the balloon’s protective sheath. If present, remove and discard the stylet.

■

Do not use the protective sheath or stylet (if present) as an introduction aid or a rewrapping tool.

■

Do not apply positive pressure to the balloon during preparation.

6.7. Balloon Placement Precautions

■

Manipulate the catheter under fluoroscopic observation when it is exposed to the vascular system. Do not advance or retract the catheter unless the balloon is fully deflated under vacuum.

■

Do not move the guidewire during inflation of the balloon.

■

Do not manipulate the IN.PACT Admiral DCB while inflated.

■

Catheter applications vary. Select the technique on the basis of the patient’s condition and the experience of the interventionalist.

■

Introducer sheaths used must have lumen sizes that are suitable to accommodate the IN.PACT Admiral DCB. See Product Component Description (Table 1) for the introducer sheath compatibility and crossing profile of each device size.

■

If resistance occurs during manipulation, ascertain the cause via fluoroscopy, road mapping, or digital subtraction angiography (DSA) before moving the IN.PACT Admiral DCB backward or forward.

■

Do not manipulate the IN.PACT Admiral DCB without sufficient fluoroscopy.

■

Use a pressure-monitoring device to prevent overpressurization. Refer to Product Component Description (Table 1).

■

To ensure full coverage of the entire lesion, the balloon diameter must match the reference vessel diameter distal to the lesion and the balloon length must exceed the lesion length by approximately 1 cm on both ends. When using multiple balloons, do so only as described in Using Multiple IN.PACT Admiral DCBs (Section 13.9).

■

Never advance the IN.PACT Admiral DCB without the guidewire extending from the tip.

■

Maintaining balloon inflation is strongly recommended for 180 seconds. Adequate drug transfer occurs in the first 60 seconds of inflation.

■

Appropriate vessel preparation is required prior to use of the IN.PACT Admiral DCB.

Note: Vessel preparation using only pre-dilatation was studied in the clinical study. Other methods of vessel preparation, such as atherectomy, have not been studied clinically with IN.PACT Admiral DCB.

6.8. Balloon Catheter Removal Precautions

■

Prior to withdrawing the balloon catheter from the lesion, completely deflate the balloon under vacuum.

■

Center the IN.PACT Admiral DCB relative to the introducer sheath when withdrawing, and use caution when removing the IN.PACT Admiral DCB.

■

Should unusual resistance be felt at any time when withdrawing the balloon catheter back into the introducer sheath, remove the balloon catheter and the introducer sheath as a single unit to reduce the risk of vascular damage. This must be done under direct visualization with fluoroscopy.

■

If removal of the IN.PACT Admiral DCB is required prior to deployment and a repeat attempt is desired, use a new IN.PACT Admiral DCB.

Instructions for Use English 7

6.9. Post-procedure Precautions

■

Administer post-procedure antiplatelet therapy as described in Pre-procedure and Post-procedure Medication Regimen (Section 6.2).

7. Use in Special Populations

7.1. Pregnancy and Lactation

The IN.PACT Admiral DCB is contraindicated in women who are pregnant or breast-feeding. It is unknown whether paclitaxel will be excreted in human milk or whether there is a potential for adverse reaction from paclitaxel exposure in nursing infants. Pregnancy Category C: See Carcinogenicity, Genotoxicity, and Reproductive Toxicity (Section 8.4).

7.2. Gender

Gender was a predefined subgroup that was analyzed in the pivotal clinical study. The outcomes are shown in Primary Safety Composite and Primary Effectiveness by Gender (Table 9). The results of an interaction analysis indicate that the treatment differences between IN.PACT Admiral DCB and PTA groups are consistent between male and female subjects.

7.3. Ethnicity

Clinical studies of the IN.PACT Admiral DCB did not include a sufficient number of patients to assess for differences in safety or effectiveness due to ethnicity, regardless of assessment by individual ethnicity categories or assessment by Caucasian or nonCaucasian categories.

7.4. Pediatric Use

The safety and effectiveness of the IN.PACT Admiral DCB in pediatric patients has not been established.

7.5. Geriatric Use

The pivotal clinical study for the IN.PACT Admiral DCB had an upper age limit of 85 years, and had a predefined study subgroup of subjects 75 years or older (85 subjects). Within this subgroup, the IN.PACT Admiral DCB group showed improvement on the primary safety and effectiveness endpoints.

8. Drug Information

8.1. Mechanism of Action

The mechanism(s) by which the IN.PACT Admiral DCB affects neointimal production has not been fully established. The principal mechanism by which paclitaxel inhibits neointimal growth is through the stabilization of microtubules by preventing their depolymerization during the final G2/M phase of cell division. Consequently, the microtubule network may not maintain the dynamic rearrangement required for a normal mitotic process.

8.2. Pharmacokinetics

The pharmacokinetic profile of paclitaxel following treatment with the IN.PACT Admiral DCB was evaluated in 25 patients receiving 2,850 μg to 16,900 μg of paclitaxel. This evaluation was conducted as a sub-study of the randomized clinical trial and is described in Summary of Clinical Studies (Section 11). Paclitaxel systemic exposure in the treated subjects was low and cleared rapidly with a bi-phasic decline. The C

11.4 to 128.8 hr*ng/mL. These data indicate that treatment with the IN.PACT Admiral DCB provides low systemic exposure of paclitaxel.

8.3. Metabolism

Metabolic transformation of paclitaxel occurs predominantly in the liver through cytochromes P450 2C8 (CYP2C8) and 3A4 (CYP3A4). Agents which could compete with or inhibit the activity of the CYP2C8 and CYP3A4 isoenzymes may increase paclitaxel plasma levels. For more information on potential drug interactions, see Drug Interaction (Section 6.5).

8.4. Carcinogenicity, Genotoxicity, and Reproductive Toxicity

No long-term studies in animals have been published in peer-reviewed literature to evaluate the carcinogenic potential of paclitaxel. Paclitaxel was not mutagenic in the Ames test or the CHO/HGPRT gene mutation assay. However, the mechanism by which paclitaxel interferes with cellular proliferation may give rise to loss of chromosomes during cell division as a result of microtubule stabilization during cell division. Paclitaxel is an established aneugenic drug in vitro on human normal cells and will also produce a positive response in the mouse bone marrow micronucleus assay. It has not been established that paclitaxel exerts any direct action on DNA to induce strand fragmentation.

Reproductive toxicity has been previously evaluated in vivo in both rabbits and rats. When administered during rabbit fetal organogenesis, paclitaxel doses of 3.0 mg/kg/day caused embryo- and fetotoxicity; maternal toxicity was also observed. No teratogenic effects were observed at 1.0 mg/kg/day; effects at higher doses could not be assessed due to fetal mortality. In rats, fertility impairment was observed at doses ≥ 1 mg/kg/day. For comparison, the average dose of paclitaxel in the IN.PACT SFA PK Sub-study was 7454 μg, with an average subject weight of 91 kg, for a theoretical normalized dose of 0.082 mg/kg (assuming all the paclitaxel from the coating enters the systemic circulation).

ranged from 1.0 to 35.9 ng/mL and the AUC

max

ranged from

0-∞

8 Instructions for Use English

9. Potential Adverse Effects

Below is a list of the potential adverse effects (eg., complications) associated with the use of the device:

■

abrupt vessel closure

■

access site pain

■

allergic reaction to contrast medium, antiplatelet therapy, or catheter system components (materials, drugs, and excipients)

■

amputation/loss of limb

■

arrhythmias

■

arterial aneurysm

■

arterial thrombosis

■

arteriovenous (AV) fistula

■

death

■

dissection

■

embolization

■

fever

■

hematoma

■

hemorrhage

■

hypotension/hypertension

■

inflammation

■

ischemia or infarction of tissue/organ

■

local infection at access site

■

local or distal embolic events

■

perforation or rupture of the artery

■

pseudoaneurysm

■

renal insufficiency or failure

■

restenosis of the dilated artery

■

sepsis or systemic infection

■

shock

■

stroke

■

systemic embolization

■

vessel spasms or recoil

■

vessel trauma which requires surgical repair

Potential complications of peripheral balloon catheterization include, but are not limited to:

■

balloon rupture

■

detachment of a component of the balloon and/or catheter system

■

failure of the balloon to perform as intended

■

failure to cross the lesion These complications may result in adverse effects. Although systemic effects are not anticipated, potential adverse effects not captured above that may be unique to the paclitaxel

drug coating include, but are not limited to:

■

allergic/immunologic reaction

■

alopecia

■

anemia

■

gastrointestinal symptoms

■

hematologic dyscrasia (including leucopenia, neutropenia, thrombocytopenia)

■

hepatic enzyme changes

■

histologic changes in vessel wall, including inflammation, cellular damage, or necrosis

■

myalgia/arthralgia

■

myelosuppression

■

peripheral neuropathy Refer to the Physician’s Desk Reference for more information on the potential adverse effects observed with paclitaxel. There

may be other potential adverse effects that are unforeseen at this time.

Instructions for Use English 9

10. Patient Counseling Information

Physicians should consider the following when counseling patients about this product:

■

Discuss the risks associated with percutaneous transluminal angioplasty procedures.

■

Discuss the risks associated with the IN.PACT Admiral DCB.

■

Discuss the risks and benefits of the treatment specific to the patient.

■

Discuss short- and long-term post-procedure changes to the patient's lifestyle.

■

Discuss the risks of early discontinuation of the antiplatelet therapy.

11. Summary of Clinical Studies

11.1. Late Mortality Signal for Paclitaxel-Coated Devices

A meta-analysis of randomized controlled trials published in December 2018 by Katsanos et. al. identified an increased risk of late mortality at 2 years and beyond for paclitaxel-coated balloons and paclitaxel-eluting stents used to treat femoropopliteal arterial disease. In response to these data, FDA performed a patient-level meta-analysis of long-term follow-up data from the pivotal premarket randomized trials of paclitaxel-coated devices used to treat femoropopliteal disease using available clinical data through May 2019. The meta-analysis also showed a late mortality signal in study subjects treated with paclitaxel-coated devices compared to patients treated with uncoated devices. Specifically, in the 3 randomized trials with a total of 1090 patients and available 5-year data, the crude mortality rate was 19.8% (range 15.9% - 23.4%) in patients treated with paclitaxel-coated devices compared to 12.7% (range 11.2% - 14.0%) in subjects treated with uncoated devices. The relative risk for increased mortality at 5 years was 1.57 (95% confidence interval 1.16 - 2.13), which corresponds to a 57% relative increase in mortality in patients treated with paclitaxel-coated devices. As presented at the June 2019 FDA Advisory Committee Meeting, an independent meta-analysis of similar patient-level data provided by VIVA Physicians, a vascular medicine organization, reported similar findings with a hazard ratio of 1.38 (95% confidence interval 1.06 - 1.80). Additional analyses have been conducted and are underway that are specifically designed to assess the relationship of mortality to paclitaxel-coated devices.

The presence and magnitude of the late mortality risk should be interpreted with caution because of multiple limitations in the available data, including wide confidence intervals due to a small sample size, pooling of studies of different paclitaxel-coated devices that were not intended to be combined, substantial amounts of missing study data, no clear evidence of a paclitaxel dose effect on mortality, and no identified pathophysiologic mechanism for the late deaths.

Paclitaxel-coated balloons and stents improve blood flow to the legs and decrease the likelihood of repeat procedures to reopen blocked blood vessels compared to uncoated devices. The benefits of paclitaxel-coated devices (e.g., reduced reinterventions) should be considered in individual patients along with potential risks (e.g., late mortality).

In the IN.PACT SFA IDE Trial, based on the analysis completed for the June 2019 FDA Advisory Committee Meeting using AsTreated cohort and vital status update, the Kaplan Meier cumulative mortality estimates at 2, 3 and 5 years are 7.3% [3.8%,

10.8%], 10.5% [6.4%, 14.6%], 15.7% [10.8%, 20.6%], respectively, for the IN.PACT Admiral DCB treatment device and 0.9% [0%, 2.7%], 2.8% [0%, 5.9%], 11.2% [5.3%, 17.1%], respectively, for the PTA control device. Additional information regarding long-term outcomes can be found in Section 11.

11.2. IN.PACT SFA Trial

11.2.1. Primary Objective

The objective of the IN.PACT SFA Trial was to evaluate the safety and effectiveness of the IN.PACT Admiral DCB as compared with PTA when used to treat atherosclerotic lesions of the superficial femoral artery (SFA) and/or proximal popliteal artery (PPA).

11.2.2. Study Design

The IN.PACT SFA Trial was designed as a two-phase, multicenter, single-blind, randomized trial. Subjects in the IN.PACT SFA I phase were enrolled in Austria, Belgium, Germany, Italy, and Switzerland under ISO 14155:2003, Declaration of Helsinki, and ICH GCP. The second phase, IN.PACT SFA II, was conducted in the United States under an investigational device exemption (IDE). Subjects were randomized 2:1 to treatment with the IN.PACT Admiral DCB as compared to PTA. Provisional stenting was used in cases of PTA failure. Follow-up was completed at 30 days, 6 months, 12 months, 24 months, 36 months, 48 months, and 60 months post-index procedure.

The data from the IN.PACT SFA Trial, with greater than 50% subjects coming from the U.S. population (150 subjects Europe and 181 subjects U.S.), have been pooled and comprise the pivotal trial data. This aggregate data provides statistical power for the 12-month primary safety and effectiveness endpoints.

The primary endpoints for the IN.PACT SFA Trial are listed below.

■

Primary Safety Composite Endpoint:

■

Freedom from device- and procedure-related death through 30 days post-index procedure and freedom from target limb major amputation and clinically-driven target vessel revascularization (TVR)1 within 12 months post-index procedure

10 Instructions for Use English

For the primary safety endpoint, the treatment (πT) and control (πC) groups were compared in a non-inferiority format under the following hypothesis.

H0: πT ≤ πC - 0.1

HA: πT > πC - 0.1

■

Primary Effectiveness Endpoint:

■

Primary patency within 12 months post-index procedure, defined as freedom from clinically-driven target lesion revascularization (TLR)2 and freedom from restenosis as determined by duplex ultrasound (DUS)3 peak systolic velocity ratio (PSVR) ≤ 2.4

For the primary effectiveness endpoint, the treatment (pT) and control (pC) groups were compared in a superiority format under the following hypothesis.

H0: pT = p

HA: pT > p

The sample size was estimated using the two-group chi-square test for the primary effectiveness endpoint, and it was driven by the assumptions of a one-sided 0.024995 alpha and at least 80% desired power to show superiority of IN.PACT Admiral DCB to PTA.

The secondary endpoints for the IN.PACT SFA Trial are listed below.

■

Major Adverse Events (MAE) through 60 months. MAE are defined as all-cause death, clinically-driven TVR, major target

limb amputation, and thrombosis at the target lesion site

■

Death of any cause within 30 days, 6, 12, 24, 36, 48 and 60 months

■

TVR within 6, 12, 24, 36, 48 and 60 months

■

TLR within 6, 12, 24, 36, 48 and 60 months

■

Time to first clinically-driven target lesion revascularization (TLR) through 60 months post-index procedure

■

Major target limb amputation within 6, 12, 24, 36, 48 and 60 months

■

Thrombosis at the target lesion site within 6, 12, 24, 36, 48 and 60 months

■

Primary sustained clinical improvement at 6, 12, 24, 36 months post-procedure

■

Secondary sustained clinical improvement at 6, 12, 24, 36 months post-procedure

■

Duplex-defined binary restenosis (PSVR > 2.4) of the target lesion at 6, 12, 24 and 36 months or at the time of the re-

intervention prior to any pre-specified timepoint

■

Duplex-defined binary restenosis (PSVR > 3.4) of the target lesion at 6, 12, 24 and 36 months or at the time of the re-

intervention prior to any pre-specified timepoint

■

Quality of life assessment by EQ-5D questionnaire at 6, 12, 24, and 36 months as change from baseline

■

Walking distance as assessed by 6 Minute Walk Test at 30 days and at 6, 12, 24, and 36 months as change from baseline

(IN.PACT SFA II phase only)

■

Walking capacity assessment by walking impairment questionnaire (WIQ) at 30 days and at 6, 12, 24, and 36 months

■

Device success defined as successful delivery, balloon inflation and deflation and retrieval of the intact study device without

burst below the rated burst pressure (RBP)

■

Procedural success defined as residual stenosis of ≤ 50% (non-stented subjects) or ≤ 30% (stented subjects) by core

laboratory (if core laboratory was not available then the site-reported estimate was used)

■

Clinical success defined as procedural success without procedural complications (death, major target limb amputation,

thrombosis of the target lesion, or TVR) prior to discharge

■

Days of hospitalization due to the index lesion from procedure through 6, 12, 24, and 36 months As the four primary endpoint tests passed (and in a superiority manner), each at a critical level of 0.024995, several pre-defined

secondary endpoints were compared on all ITT non-stented subjects between treatment groups sequentially. These secondary endpoints were analyzed in the following order: (1) CD-TLR at 12 months, (2) primary sustained clinical improvement at 12 months, (3) walking distance at 12 months as assessed by the 6-minute walk test, and (4) duplex-defined binary restenosis (PSVR >2.4) at 24 months or at the time of reintervention. This sequential approach keeps the family-wise error rate at the

0.024995 level across the set of four secondary endpoints. The statistical analysis plan included planned primary analysis of all non-stented patients, as well as a secondary analysis of

the intent to treat (ITT) population. The demographics and results provided are for the ITT population, which demonstrated similar results as the all non-stented patient population.

Clinically-driven TVR is defined as any re-intervention within the target vessel due to symptoms or drop of ABI/TBI of ≥ 20% or > 0.15 when compared to post-procedure baseline ABI/TBI

Clinically-driven TLR is defined as any re-intervention at the target lesion due to symptoms or drop of ABI/TBI of ≥ 20% or > 0.15 when compared to post-procedure baseline ABI/TBI

Post-index procedure DUS (intended to establish a post-treatment baseline) does not contribute to the primary endpoint determination

Restenosis determined by either PSVR > 2.4 as assessed by an independent DUS core laboratory or > 50% stenosis as assessed by an independent angiographic core laboratory

Instructions for Use English 11

11.2.3. Patient Population

Subject demographics, medical history, and risk factors of the 331 subjects are summarized in Baseline Demographics and Medical History (Table 4), which shows similarity between subjects enrolled in both the IN.PACT Admiral DCB and PTA groups.

Table 4. Baseline Demographics and Medical History

IN.PACT DCB PTA p-value

(N=220 Subjects) (N=111 Subjects)

Age (yr) 67.5 ± 9.5 68.0 ± 9.2 0.612 Male 65.0% (143/220) 67.6% (75/111) 0.713

Race

White 78.3% (94/120) 83.3% (50/60) Black 14.2%(17/120) 11.7% (7/60) Asian 5.8% (7/120) 3.3% (2/60) Native Hawaiian or Other Pacific Islander 1.7% (2/120) 0.0% (0/60)

0.435

American Indian or Alaska Native 0.0% (0/120) 0.0% (0/60) Other 0.0% (0/120) 1.7% (1/60)

Obesity (BMI ≥ 30 kg/m2)

27.7% (61/220) 25.2% (28/111) 0.694 Diabetes Mellitus 40.5% (89/220) 48.6% (54/111) 0.161 Hypertension 91.4% (201/220) 88.3% (98/111) 0.431 Hyperlipidemia 84.5% (186/220) 82.0% (91/111) 0.637 Current Smoker 38.6% (85/220) 36.0% (40/111) 0.719 Coronary Heart Disease 57.0% (122/214) 55.0% (60/109) 0.813 Carotid Artery Disease 34.9% (73/209) 31.7% (32/101) 0.610 Renal Insufficiency (baseline serum creatinine

8.3% (18/217) 6.4% (7/109) 0.662

≥ 1.5 mg/dL) Below-the-knee Vascular Disease of Target Leg (Stenotic/

40.9% (90/220) 53.2% (59/111) 0.036 Occluded)

ABI / TBIb (mmHg ratio) 0.769 ± 0.228 (209) 0.744 ± 0.189 (106) 0.308 Rutherford Category

2 37.7% (83/220) 37.8% (42/111) 3 57.3% (126/220) 55.9% (62/111) 4 5.0% (11/220) 5.4% (6/111)

0.898

5 0.0% (0/220) 0.9% (1/111)

Numbers are % (counts/sample size) unless otherwise stated. Site reported data.

Race and ethnicity data was not collected in IN.PACT SFA I phase (Europe).

TBI was not measured in IN.PACT SFA I phase.

The baseline lesion characteristics, as reported by the sites and angiographic core laboratories, have been provided in Lesion Characteristics (Table 5). The total target lesion length treated was similar between treatment groups (IN.PACT Admiral DCB

8.94 cm, PTA 8.81 cm; p=0.815). Occluded lesions comprised 25.8% of IN.PACT Admiral DCB subject lesions and 19.5% of PTA subject lesions (p=0.222). Pre-dilatation using a PTA catheter was performed as part of the clinical study to prepare the vessel and occurred in 96.4% (212/220) of IN.PACT Admiral DCB subjects.

Table 5. Lesion Characteristics

IN.PACT DCB PTA p-value

Baseline Lesion Characteristics

(N=220 Subjects) (N=111 Subjects)

Lesion Type

De novo 95.0% (209/220) 94.6% (105/111) Restenotic (non-stented) 5.0% (11/220) 5.4% (6/111)

Lesion Location b,

(N=221 Lesions) (N=113 Lesions)

0.875

Superficial Femoral Artery 97.7% (216/221) 94.7% (107/113) 0.193 Proximal Popliteal Artery 6.8% (15/221) 7.1% (8/113) 1.000 Angiographic Lesion Characteristics

(N=221 Lesions) (N=113 Lesions)

Lesion Length (cm) 8.94 ± 4.89 8.81 ± 5.12 0.815 Reference Vessel Diameter (RVD) (mm) 4.647 ± 0.841 4.681 ± 0.828 0.728

12 Instructions for Use English

IN.PACT DCB PTA p-value

Minimum Lumen Diameter (MLD) (Pre-procedure) (mm) 0.900 ± 0.776 0.933 ± 0.771 0.711 Diameter Stenosis (Pre-procedure) 81.1% ± 15.5% 81.3% ± 13.7% 0.946 Occluded Lesions (100% Stenosis) 25.8% (57/221) 19.5% (22/113) 0.222 TASC Lesion Type

A 56.6% (125/221) 62.8% (71/113) B 30.8% (68/221) 26.5% (30/113) C 12.2% (27/221) 10.6% (12/113)

0.275

D 0.5% (1/221) 0.0% (0/113)

Calcification 59.3% (131/221) 58.4% (66/113) 0.907

Severe Calcification 8.1% (18/221) 6.2% (7/113) 0.662

# Run-off Vessels Occluded

0 41.5% (88/212) 35.7% (40/112) 1 41.5% (88/212) 33.0% (37/112) 2 13.7% (29/212) 26.8% (30/112)

0.042

3 3.3% (7/212) 4.5% (5/112)

Dissections (Post-procedure)

0 (No Dissection) 36.2% (80/221) 38.9% (44/113)

0.360A–C 63.8% (141/221) 60.2% (68/113)

D–F 0.0% (0/221) 0.9% (1/113) Minimum Lumen Diameter (Post-procedure) (mm) 3.903 ± 0.750 3.862 ± 0.732 0.632 Diameter Stenosis (Post-procedure) 19.9% ± 10.4% 19.1% ± 10.3% 0.535 Procedural Characteristics

(N=220 Subjects) (N=111 Subjects)

Pre-dilatation 96.4% (212/220) 85.6% (95/111) <0.001 Post-dilatation 26.8% (59/220) 18.9% (21/111) 0.135 Provisional Stenting 7.3% (16/220) 12.6% (14/111) 0.110 Numbers are % (counts/sample size) or mean ± standard deviation.

Note that four subjects in the trial were assessed by site as having tandem lesions treated during the index procedure and were assessed by the angiographic core laboratory as having two target lesions treated during the index procedure.

Site reported data.

Core laboratory reported data. All lesions within artery segment are counted.

All lesions within artery segment are counted

Required for IN.PACT SFA II phase; not required for IN.PACT SFA I phase.

11.2.4. Primary Safety and Effectiveness Endpoints

The primary safety endpoint of the study, a composite of freedom from device- and procedure-related death through 30 days, freedom from target limb major amputation within 12 months and freedom from clinically-driven target vessel revascularization within 12 months, was 95.7% in the IN.PACT Admiral DCB group and 76.6% in the PTA group (p<0.001). The IN.PACT Admiral DCB group met the predefined 10% non-inferiority margin and showed superiority in safety against the PTA group using a sequential analysis approach. The primary effectiveness endpoint, primary patency at 12 months, was 82.2% in the IN.PACT Admiral DCB group and 52.4% for the PTA group (p<0.001). The IN.PACT Admiral DCB group showed statistical superiority against the PTA group.

See Primary Safety and Effectiveness Endpoints (Table 6). Also see Kaplan-Meier Plot - Event-Free from Primary Safety Endpoint through 360 Days (Figure 4) and Kaplan-Meier Plot - Primary Patency through 390 Days (Figure 5).

Instructions for Use English 13

Table 6. Primary Safety and Effectiveness Endpoints

Outcome IN.PACT DCB

PTA (N=111) Difference [95% CI] p-value

(N=220)

Primary Safety Endpoint 95.7% (198/207) 76.6% (82/107) 19.0% [10.5%,

<0.001

27.5%]

Primary Effectiveness Endpoint – Primary Patency at 12 Months

■

Primary safety endpoint is defined as freedom from device- and procedure-related death through 30 days, target limb

82.2% (157/191) 52.4% (54/103) 26.2% [15.1%,

37.3%]

<0.001

major amputation within 360 days, and clinically-driven TVR within 360 days.

■

Primary patency is defined as freedom from clinically-driven TLR1 and freedom from restenosis as determined by duplex ultrasound2 (DUS) peak systolic velocity ratio (PSVR) ≤2.43 within 12 months. Key primary patency endpoint definition components:

1. Clinically-driven TLR is defined as any reintervention at the target lesion due to symptoms or drop of ABI/TBI of ≥20% or >0.15 when compared to postprocedure baseline ABI/TBI

2. Post-index procedure DUS is intended to establish a post-treatment baseline and does not contribute to the primary endpoint determination

3. Restenosis determined by either PSVR >2.4 as assessed by an independent DUS core laboratory or >50% stenosis as assessed by an independent angiographic core laboratory.

■

Post-index procedure DUS did not contribute to the primary effectiveness endpoint determination. Therefore, effectiveness results do not reflect four DCB patients who had post-procedure binary restenosis which was later not observed at 12 months.

Statistical references:

■

Numbers are % (counts/sample size). CI - Confidence Interval

■

Analysis sets: Effectiveness - all randomized subjects with multiple imputation performed on missing data for primary patency are provided in the Difference [95% CI] and p-value columns; Safety - all randomized subjects experiencing at least one component for the safety endpoint or with follow-up of at least 330 days post-procedure (i.e. the denominator was adjusted for missing data).

■

Non-inferiority on the primary safety endpoint was tested using the Farrington-Manning approach. The non-inferiority margin of 10% was met, however, the results shown above are for superiority testing.

Data sources:

All events were adjudicated by the independent Clinical Events Committee and all duplex ultrasound and angiographic measures were made by the independent core laboratories.

all alpha are one-sided with significance of 0.024995 required.

14 Instructions for Use English

100%

90%

80%

70%

60%

50%

40%

30%

20%

10%

IN.PACT DCB

PTA

Log-rank p < 0.001

0 30 60 90 120 150 180 210 240 270 300 330

Days after Index Procedure

360

Freedom from Primary Safety Endpoint

76.6%

95.6%

From day X To day Y

IN.PACT DCB (N=220 Subjects)

# Entered

# Censored

# Events

Event-free [%]

Greenwood SE [%]

PTA (N=111 Subjects)

0 0

31 60

61 90

120

121 150

151 180

181 210

211 240

241 270

271 300

301 330

331 360

220 220 215 214 214 212 210 208 206 205 203 197 195

0 0 0

0 0 0 0

2 2 21 1

1 1

100.0%

0.0%

99.1% 99.1% 99.1% 98.6% 98.6% 98.6% 98.1% 98.1% 98.1% 96.7% 96.2% 95.6%

0.6% 0.6% 0.6% 0.8% 0.8% 0.8% 0.9% 0.9% 0.9% 1.2% 1.3% 1.4%

# Entered

# Censored

# Events

Event-free [%]

Greenwood SE [%]

111

109 108 108 105 104 101 91 89 89 88 84

0 1 0 1 3 2 0 1

1 3 8

100.0%

0.0%

99.1% 98.2% 98.2% 95.5% 94.6% 91.8% 84.4% 82.6% 82.6% 81.7% 78.9% 76.6%

0.9% 1.3% 1.3% 2.0% 2.2% 2.6% 3.5% 3.6% 3.6% 3.7% 3.9% 4.1%

0 01 0 0 00 0 2 0

Survival Curves Comparison

Analysis Method Test Chi Square Degr. Freedom p-value

Kaplan-Meier Analysis Log-Rank 27.3314 1 <0.001

All events were adjudicated by the independent Clinical Events Committee.

Figure 4. Kaplan-Meier Plot - Event-Free from Primary Safety Endpoint through 360 Days

Instructions for Use English 15

100%

90%

80%

70%

60%

50%

40%

30%

20%

10%

IN.PACT DCB

PTA

Log-rank p < 0.001

0 30 60 90 120 150 180 210 240 270 300 330

Days after Index Procedure

360 390

Primary Patency through 390 Days

78.4%

89.8%

66.8%

49.5%

From day X To day Y

IN.PACT DCB (N=220 Subjects)

# Entered

# Censored

# Events

Event-free [%]

Greenwood SE [%]

PTA (N=111 Subjects)

0 0

31 60

61 9091120

121 150

151 180

181 210

211 240

241 270

271 300

301 330

331 360

220 220 215 214 214 212 210 208 207 206 204 200 198

0 0 0

0 0 0 0

2 2 21 1

1 1

1 14

100.0%

0.0%

99.1% 99.1% 99.1% 98.6% 98.6% 98.6% 98.6% 98.6% 98.6% 98.1% 97.6% 89.8%

0.6% 0.6% 0.6% 0.8% 0.8% 0.8% 0.8% 0.8% 0.8% 0.9% 1.0% 2.2%

# Entered

# Censored

# Events

Event-free [%]

Greenwood SE [%]

111

109 108 108 106 106 103 93 92 92 91 86

0 1 0 0 3 1 0 1

1 2 8

100.0%

0.0%

99.1% 98.2% 98.2% 96.4% 96.4% 93.6% 86.3% 85.3% 85.3% 84.4% 80.7% 66.8%

0.9% 1.3% 1.3% 1.8% 1.8% 2.3% 3.3% 3.4% 3.4% 3.5% 3.8% 4.7%

0 01 0 0 00 0 2 0

Survival Curves Comparison

Analysis Method Test Chi Square Degr. Freedom p-value

Kaplan-Meier Analysis Log-Rank 33.2068 1 <0.001

All TLR events were adjudicated by the independent Clinical Events Committee. All DUSs were analyzed by an independent core laboratory.

361 390

141

78.4%

3.4%

49.5%

5.4%

The primary safety and effectiveness outcomes of all non-stented patients and intent to treat (ITT) population are shown in Outcomes of All ITT and All Non-stented Populations (Table 7).

Figure 5. Kaplan-Meier Plot - Primary Patency through 390 Days

16 Instructions for Use English

Table 7. Outcomes of All ITT and All Non-stented Populations

All ITT All Non-Stented

IN.PACT DCB PTA IN.PACT DCB PTA

Primary Safety Endpoint 95.7% (198/207) 76.6% (82/107) 95.8% (183/191) 77.7% (73/94) Primary Effectiveness Endpoint –

82.2% (157/191) 52.4% (54/103) 82.9% (145/175) 52.2% (47/90)

Primary Patency at 12 Months

■

Primary safety endpoint is defined as freedom from device- and procedure-related death through 30 days, target limb major amputation within 360 days, and clinically-driven TVR within 360 days.

■

1. Clinically-driven TLR is defined as any reintervention at the target lesion due to symptoms or drop of ABI/TBI of ≥20% or >0.15 when compared to postprocedure baseline ABI/TBI

2. Post-index procedure DUS is intended to establish a post-treatment baseline and does not contribute to the primary endpoint determination

3. Restenosis determined by either PSVR >2.4 as assessed by an independent DUS core laboratory or >50% stenosis as assessed by an independent angiographic core laboratory.

■

Statistical references:

■

Numbers are % (counts/sample size).

■

Analysis sets: Effectiveness - all randomized subjects with as-observed results for primary patency; Safety - all randomized subjects experiencing at least one component for the safety endpoint or with follow-up of at least 330 days post-procedure (ie, the denominator was adjusted for missing data).

Data sources:

All events were adjudicated by the independent Clinical Events Committee and all duplex ultrasound and angiographic measures were made by the independent core laboratories.

11.2.5. Principal Safety and Effectiveness Results

A summary of the principal safety and effectiveness results through 12 months, including major secondary endpoints, have been shown below in Principal Safety and Effectiveness Results (Table 8). Secondary safety endpoints were more favorable in the IN.PACT Admiral DCB group. The 12-month major adverse event rate was 6.3% in the IN.PACT Admiral DCB group versus

24.3% in the PTA group (p<0.001). This statistical significance was primarily driven by a dramatic reduction in clinically-driven target vessel revascularization (CD-TVR) rate. The IN.PACT Admiral DCB group also showed highly statistically significant results of secondary effectiveness, such as clinically-driven TLR (CD-TLR) and primary sustained clinical improvement both of which passed hierarchical testing.

Table 8. Principal Safety and Effectiveness Results

IN.PACT DCB PTA Difference p-value

(N=220 Sub-

jects)

(N=111 Sub-

jects)

[95% CI]

Safety Parameters

Primary Safety Composite Endpoint – Freedom from:

Device- and Procedure-related Death

95.7% (198/207) 76.6% (82/107) 19.0% [10.5%,

<0.001

27.5%]

0.0% (0/218) 0.0% (0/111) NA >0.999

through 30 Days Target Limb Major Amputation within

0.0% (0/207) 0.0% (0/107) NA >0.999

360 Days Clinically-driven TVR within 360 Days 4.3% (9/207) 23.4% (25/107) -19.0% [-27.5%,

<0.001

-10.5%]

Death (all-cause) within 30 days 0.0% (0/218) 0.0% (0/111) NA >0.999

Effectiveness Parameters

Primary Effectiveness Endpoint – Primary Patency at 12 Months

82.2% (157/191) 52.4% (54/103) 26.2% [15.1%,

37.3%]

<0.001

Instructions for Use English 17

IN.PACT DCB PTA Difference p-value

(N=220 Sub-

jects)

Primary Sustained Clinical Improvement at

85.2% (167/196) 68.9% (73/106) 16.3% [6.2%,

12 Months Device Success 99.0% (308/311) 98.5% (128/130) 0.6% [-1.8%,

(N=111 Sub-

jects)

[95% CI]

<0.001

26.5%]

0.302

3.0%]

Procedural Success 99.5% (219/220) 98.2% (109/111) 1.3% [-1.3%,

0.111

4.0%]

Clinical Success 99.1% (218/220) 97.3% (108/111) 1.8% [-1.5%,

0.103

5.1%]

Binary Restenosis (PSVR >2.4) at 12 Months 16.5% (31/188) 33.7% (29/86) -17.2% [-28.5%,

0.001

-5.9%]

Binary Restenosis (PSVR >3.4) at 12 Months 7.3% (13/178) 21.4% (18/84) -14.1% [-23.7%,

<0.001

-4.6%]

Cumulative complications within 360 days

MAE Composite (Death, Major Target Limb Amputation, Clinically-driven TVR, Thrombosis)

Death (all-cause) 1.9% (4/207) 0.0% (0/107) 1.9% [0.1%,

6.3% (13/207) 24.3% (26/107) -18.0% [-26.8%,

-9.2%]

<0.001

0.926

3.8%]

Clinically-driven TVR 4.3% (9/207) 23.4% (25/107) -19.0% [-27.5%,

<0.001

-10.5%] Major Target Limb Amputation 0.0% (0/207) 0.0% (0/107) NA >0.999 Thrombosis 1.4% (3/207) 3.7% (4/107) -2.3% [-6.2%,

0.096

1.7%]

Clinically-driven TLR 2.4% (5/207) 20.6% (22/107) -18.1% [-26.1%,

<0.001

-10.2%]

Any TVR 4.8% (10/207) 23.4% (25/107) -18.5% [-27.1%,

<0.001

-10.0%]

Any TLR 2.9% (6/207) 20.6% (22/107) -17.7% [-25.7%,

<0.001

-9.7%]

■

Primary sustained clinical improvement was defined as freedom from target limb amputation, TVR, and increase in Rutherford class at 12 months post-procedure.

■

Device success defined as successful delivery, inflation, deflation and retrieval of the intact study balloon device without burst below the RBP.

■

Procedure success defined as residual stenosis of ≤50% (non-stented subjects) or ≤30% (stented subjects) by visual estimate.

■

Clinical success defined as procedural success without procedural complications (death, major target limb amputation, thrombosis of the target lesion, or TVR) prior to discharge.

■

Clinically-driven TLR/TVR is defined as any reintervention within the target vessel due to symptoms or drop of ABI/TBI of ≥20% or >0.15 when compared to post-procedure baseline ABI/TBI.

■

Major Adverse Events (MAE) defined as all-cause death, clinically-driven TLR/TVR, major target limb amputation, thrombosis at the target lesion site at 360 days.

■

Binary restenosis is defined as duplex restenosis (PSVR >2.4/3.4) or angiographic restenosis of the target lesion at 12 months postprocedure, or at the time of reintervention prior to any prespecified timepoint.

Statistical references:

■

Numbers are % (counts/sample size). CI - Confidence Interval

■

Data sources:

All events were adjudicated by the independent Clinical Events Committee, all duplex ultrasound and angiographic measures were made by the independent core laboratories.

all alpha are one-sided with significance of 0.024995 required. All tests were for superiority using the chi-square test for binary variables and t-test for continuous variables.

18 Instructions for Use English

11.2.6. Subgroup Analysis

Relative Risk [95% CI]

Subgroup

IN.PACT DCB %

Control PTA %

Overall ITT 95.7% 76.6%

Rutherford Category 2 96.2% 82.9%

Rutherford Category 3 95.8% 74.6%

Rutherford Category 4 90.9% 50.0%

Diabetes Mellitus 92.7% 73.1%

Age ≥75 98.0% 82.1%

Lesion Length <5 cm 97.9% 91.7%

Lesion Length ≥5 cm and <10 cm 98.6% 79.5%

Lesion Length ≥10 cm and <18 cm 92.1% 61.8%

Total Occlusion 96.3% 61.9%

Female Gender 94.6% 68.6%

Male Gender 96.2% 80.6%

Favors Control PTA

Favors IN.PACT DCB

0 1 2 3 4 5

Relative Risk [95% CI]

Subgroup

IN.PACT DCB %

Control PTA %

Overall ITT 82.2% 52.4%

Rutherford Category 2 82.2% 43.6%

Rutherford Category 3 82.4% 59.6%

Rutherford Category 4 80.0% 33.3%

Diabetes Mellitus 77.3% 49.0%

Age ≥75 84.4% 42.3%

Lesion Length <5 cm 93.3% 73.9%

Lesion Length ≥5 cm and <10 cm 83.3% 57.1%

Lesion Length ≥10 cm and <18 cm 74.6% 39.4%

Total Occlusion 83.3% 40.9%

Female Gender 75.7% 43.8%

Male Gender 86.0% 56.3%

Favors Control PTA

Favors IN.PACT DCB

0 5 10

Medtronic has analyzed trial results by different pre-defined subgroups to investigate the consistency of results through 12 months. Primary Safety Endpoint Event at 12 Months (Figure 6), Primary Patency at 12 Months (Figure 7), and Clinicallydriven Target Lesion Revascularization at 12 Months (Figure 8) have been illustrated for each subgroup in the forest plots below. All data for the subgroup analyses trended in favor of IN.PACT Admiral DCB over PTA.

Figure 6. Primary Safety Endpoint Event at 12 Months

Note: There were no significant treatment-by-subgroup interactions (p>0.15). The 95% confidence intervals were unadjusted for multiplicity.

Figure 7. Primary Patency at 12 Months

Instructions for Use English 19

Relative Risk [95% CI]

Subgroup

IN.PACT DCB %

Control PTA %

Overall ITT 2.4% 20.6%

Rutherford Category 2 2.6% 17.1%

Rutherford Category 3 1.7% 20.3%

Rutherford Category 4 9.1% 50.0%

Diabetes Mellitus 3.7% 23.1%

Age ≥75 0.0% 17.9%

Lesion Length <5 cm 0.0% 4.2%

Lesion Length ≥5 cm and <10 cm 1.4% 20.5%

Lesion Length ≥10 cm and <18 cm 5.3% 32.4%

Total Occlusion 1.9% 38.1%

Female Gender 4.1% 25.7%

Male Gender 1.5% 18.1%

Favors Control PTA

Favors IN.PACT DCB

0 1 2 3 4 5

Figure 8. Clinically-driven Target Lesion Revascularization at 12 Months

Note: There were no significant treatment by subgroup interactions (p>0.15) except in diabetes mellitus (p=0.027). The 95% confidence intervals were unadjusted for multiplicity.

11.2.7. Gender Analysis

There were 218 males and 113 females enrolled in the pivotal study. Based on gender subgroup analyses, both female and male subgroups showed improvement on the primary safety and effectiveness endpoints through 12 months. The results of an interaction analysis indicate that the treatment differences between IN.PACT Admiral DCB and PTA groups are consistent between male and female subjects.

Table 9. Primary Safety Composite and Primary Effectiveness by Gender

Females

Outcome IN.PACT DCB Standard PTA Difference

(N=77 Subjects) (N=36 Subjects)

Primary Safety Endpoint 94.6% (70/74) 68.6% (24/35) 26.0% Primary Effectiveness Endpoint –

75.7% (53/70) 43.8% (14/32) 29.3%

Primary Patency at 12 Months

Males

Outcome IN.PACT DCB Standard PTA Difference

Primary Safety Endpoint

(N=143 Subjects) (N=75 Subjects)

96.2% (128/133) 80.6% (58/72)

15.7%

20 Instructions for Use English

Primary Effectiveness Endpoint –

86.0% (104/121) 56.3% (40/71) 25.0%

Primary Patency at 12 Months

■

Primary safety endpoint is defined as freedom from device- and procedure-related death through 30 days, target limb major amputation within 360 days, and clinically-driven TVR within 360 days.

■

1. Clinically-driven TLR is defined as any reintervention at the target lesion due to symptoms or drop of ABI/TBI of ≥20% or >0.15 when compared to postprocedure baseline ABI/TBI

2. Post-index procedure DUS is intended to establish a post-treatment baseline and does not contribute to the primary endpoint determination

3. Restenosis determined by either PSVR >2.4 as assessed by an independent DUS core laboratory or >50% stenosis as assessed by an independent angiographic core laboratory.

■

Statistical references:

■

Numbers are % (counts/sample size).

■

Analysis sets: Effectiveness - all randomized subjects with multiple imputation performed on missing data for primary patency are provided in the Difference column; Safety - all randomized subjects experiencing at least one component for the safety endpoint or with follow-up of at least 330 days post-procedure (ie, the denominator was adjusted for missing data).

Data sources:

All events were adjudicated by the independent Clinical Events Committee and all duplex ultrasound and angiographic measures were made by the independent core laboratories.

11.2.8. Serious Adverse Events

For additional details on serious adverse events, see Summary of Adverse Events (Section 11.3.7).

11.3. IN.PACT SFA Trial Post-Approval Study

11.3.1. Primary Objective

The IN.PACT SFA Trial Post-Approval Study was designed to evaluate the long-term safety and effectiveness of the IN.PACT Admiral DCB via a two-year primary patency endpoint and a composite two-year safety endpoint for the treatment of lesions in the SFA and/or PPA.

11.3.2. Study Design

As a condition of premarket approval, the IN.PACT SFA Trial subjects were followed through 60 months post-index procedure and assessed for the primary and secondary endpoints listed below. Additional de novo subjects were not enrolled. For additional details regarding study design, refer to Section 11.2.2, Study Design.

The primary endpoints for the IN.PACT SFA Trial Post-Approval Study are listed below:

■

Primary Safety Endpoint:

■

Freedom from device- and procedure-related death at 30 days and freedom from target limb major amputation and clinically-driven target vessel revascularization (CD-TVR) at 24 months.

■

Primary Effectiveness Endpoint

■

Primary patency at 24 months, defined as freedom from clinically-driven TLR (CD-TLR) and freedom from restenosis as

determined by duplex ultrasound (DUS) peak systolic velocity ratio (PSVR) ≤ 2.4. The secondary endpoints for the IN.PACT SFA Trial Post-Approval Study are listed below: Assessed through 60 months:

■

Major adverse event (MAE) composite and its individual components (all-cause mortality, CD-TVR, major target limb amputation, and thrombosis at the target lesion site)

■

CD-TLR

■

All TVR

■

All TLR

■

Serious adverse events (SAEs)

Assessed at 24 and 36 months:

Instructions for Use English 21

■

Primary sustained clinical improvement

■

Secondary sustained clinical improvement

■

Duplex-defined binary restenosis (PSVR > 2.4) of the target lesion

■

Duplex-defined binary restenosis (PSVR > 3.4) of the target lesion

■

Quality of Life (QoL) assessment by EQ-5D Questionnaire

■

Walking capacity assessment by Walking Impairment Questionnaire (WIQ)

11.3.3. Patient Population

The 331 subjects assessed for the IN.PACT SFA Trial Post-Approval Study were the same subjects as originally enrolled in the IN.PACT SFA Trial. For additional details on the study population, refer to Section 11.2.3, Patient Population.

Follow-up compliance through the 60-month follow-up visit is presented in Subject Follow-up Compliance through 60 Months (Table 10). The overall follow-up compliance rates in the IN.PACT Admiral DCB group and the PTA group were greater than 90% from 12 months through 60 months.

Table 10. Subject Follow-up Compliance through 60 Months

Subject Compliance Characteristics IN.PACT DCB (N=220 Subjects) Standard PTA (N=111 Subjects)

12-Month Follow-up

Eligible Subjects

Death Withdrawal

202 108

5 0

13 3 Follow-up Not Done 5 4 Follow-up Visit Within Window Follow-up Visit Out of Window Within Window Follow-up Compliance (%) Overall Follow-up Compliance (%)

188 98

9 6

93.1% 90.7%

97.5% 96.3%

24-Month Follow-up

Eligible Subjects

Death Withdrawal

187 104

16 1

17 6 Follow-up Not Done 17 10 Follow-up Visit Within Window Follow-up Visit Out of Window

Within Window Follow-up Compliance (%) Overall Follow-up Compliance (%)

154 83

16 11

82.4% 79.8%

90.9% 90.4%

36-Month Follow-up

Eligible Subjects

Death Withdrawal

173 99

22 2

25 10 Follow-up Not Done 12 7 Follow-up Visit Within Window Follow-up Visit Out of Window

Within Window Follow-up Compliance (%) Overall Follow-up Compliance (%)

133 82

28 10

76.9% 82.8%

93.1% 92.9%

48-Month Follow-up

Eligible Subjects

Death Withdrawal

163 91

24 7

33 13 Follow-up Not Done 14 5 Follow-up Visit Within Window Follow-up Visit Out of Window

Within Window Follow-up Compliance (%) Overall Follow-up Compliance (%)

146 85

3 1

89.6% 93.4%

91.4% 94.5%

60-Month Follow-up

Eligible Subjects

155 88

22 Instructions for Use English

Subject Compliance Characteristics IN.PACT DCB (N=220 Subjects) Standard PTA (N=111 Subjects)

Death Withdrawal

29 10

36 13 Follow-up Not Done 8 3 Follow-up Visit Within Window Follow-up Visit Out of Window

Within Window Follow-up Compliance (%) Overall Follow-up Compliance (%)

142 83

5 2

91.6% 94.3%

94.8% 96.6%

Site reported data

Eligible subjects are all subjects who either have a follow-up visit form or are past due for their follow-up (beyond upper limit of window on study and did not exit the study before the upper limit of the window)

Death and withdrawal are cumulative

Within window visits are defined as: 30-days ± 7 days, 6-months ± 30 days, 12-months ± 30 days, 2-years ± 30 days, 3-years ± 30 days, 4-years ± 60 days, 5-years ± 60 days

Percentage based on number of subjects who had follow-up visit within window divided by total number of eligible subjects

Percentage based on number of subjects who had a follow-up visit within or out of window divided by total number of eligible subjects.

11.3.4. Primary Safety and Effectiveness Endpoints

The primary safety composite endpoint is defined as freedom from device- and procedure-related death through 30 days postprocedure and freedom from target limb major amputation and CD-TVR within 24 months post-index procedure. The primary safety composite endpoint at 24 months in the IN.PACT Admiral DCB group was 87.4% (173/198) versus 69.8% (74/106) in the PTA group (p<0.001). The primary effectiveness endpoint is defined as primary patency within 24 months post-index procedure. Primary patency is defined as freedom from CD-TLR and freedom from restenosis as determined by DUS PSVR ≤

2.4. Primary patency at 24 months in the IN.PACT Admiral DCB group was 69.2% (108/156) versus 50.5% (48/95) in the PTA group (p=0.005).

See Primary Safety and Effectiveness Endpoints at 24 Months (Table 11). Also see Kaplan-Meier Plot - Event-free from Primary Safety Endpoint through 720 Days (Figure 9) and Kaplan-Meier Plot - Cumulative Primary Patency through 750 Days (Figure 10).

Table 11. Primary Safety and Primary Effectiveness Endpoints at 24 Months

Primary Endpoints IN.PACT DCB

Primary Effectiveness Endpoint – Primary Patency at 24 Months

(N=220 Subjects)

69.2% (108/156) 50.5% (48/95) 18.7% [6.3%,

Standard PTA

(N=111 Subjects)

Difference

[95% CI]

31.1%]

p-value

0.005

Primary Safety Endpoint at 24 Months 87.4% (173/198) 69.8% (74/106) 17.6% [8.5%, ∞] <0.001* Endpoint definitions:

■

Primary patency is defined as freedom from clinically-driven TLRa and freedom from restenosis as determined by duplex ultrasoundb (DUS) Peak Systolic Velocity Ratio (PSVR) ≤ 2.4

■

Primary safety endpoint consists of freedom from device- and procedure-related death through 30 days; freedom from

target limb amputation within 24 months; and freedom from clinically-driven TVRd within 24 months.

Statistical references:

■

Numbers are % (counts/sample size) unless otherwise stated.

■

CI – Confidence Interval

■

Analysis sets: Effectiveness – all randomized subjects with multiple imputation performed on missing data for Primary Patency; Safety – all randomized subjects experiencing at least one component for the safety endpoint or with follow-up of at least 690 days post-procedure, i.e. the denominator was adjusted for missing data.

■

For the primary effectiveness endpoint the Z test of two proportions was used to compare treatment groups for all randomized subjects.

■

∞ means Not Applicable for this one-sided test.

■

*non-inferiority p-value.

■

Non-inferiority on the primary safety endpoint was tested using the Farrington-Manning risk difference between treatments (calculated as treatment minus control) and its one-sided lower 97.5005% confidence interval. The non-inferiority margin was 10%.

Data sources:

All events were adjudicated by the independent Clinical Events Committee, all duplex ultrasound and angiographic measures were made by the independent core laboratories

Key endpoint definition components:

Clinically-driven TLR is defined as any re-intervention at the target lesion due to symptoms or drop of ABI/TBI of ≥20% or >0.15 when compared to post-procedure baseline ABI/TBI

Post-index procedure DUS is intended to establish a post-treatment baseline and does not contribute to the Primary Endpoint determination

Restenosis determined by either PSVR >2.4 (determined by Target Lesion Category of ’50-99%’ or ‘Occluded’) as assessed by an independent DUS core lab or >50% stenosis as assessed by an independent angiographic core lab

Clinically-driven TVR is defined as any re-intervention within the target vessel due to symptoms or drop of ABI/TBI of ≥20% or >0.15 when compared to post-procedure baseline ABI/TBI

Instructions for Use English 23

100%

90%

80%

70%

60%

50%

40%

30%

20%

10%

0 60

120 180

210 300 360 420 480 540 600 660 720

Freedom from Primary Safety Endpoint

Days After Index Procedure

IN.PACT DCB

Log-Rank p < 0.001

PTA

From day X To day Y

IN.PACT DCB (N=220 Subjects)

# Entered

# Censored

# Events

Event-free [%]

Greenwood SE [%]

Standard PTA (N=111 Subjects)

0 0

120

121 180

181 240

241 300

301 360

361 420

421 480

481 540

541 600

601 660

661 720

220 220 215 213 209 206 199 193 175 173 171 166 162

0 1 0

3 2 1 1

4 4 11 2

1 4

0 0

100.0%

0.0%

99.1% 98.6% 98.6% 98.2% 96.7% 95.7% 89.6% 89.1% 88.6% 87.5% 87.5% 87.5%

0.6% 0.8% 0.8% 0.9% 1.2% 1.4% 2.2% 2.2% 2.2% 2.3% 2.3% 2.3%

# Entered

# Censored

# Events

Event-free [%]

Greenwood SE [%]

111

108 105 101 89 88 83 75 75 75 75 74

0 3 4 1 5 0 0 0

2 10 6

100.0%

0.0%

98.2% 95.5% 91.8% 82.6% 81.7% 77.0% 71.4% 71.4% 71.4% 71.4% 71.4% 70.4%

1.3% 2.0% 2.6% 3.6% 3.7% 4.0% 4.3% 4.3% 4.3% 4.3% 4.3% 4.4%

0 01 0 0 00 2 2 0

70.4%

87.5%

All events were adjudicated by the independent Clinical Events Committee.

Analysis Method Test Chi Square Degr. Freedom P-Value

Kaplan-Meier Analysis Log-Rank 16.7894 1 <0.001

Figure 9. Kaplan-Meier Plot – Event-free from Primary Safety Endpoint through 720 Days

Survival Curves Comparison

24 Instructions for Use English

100%

90%

80%

70%

60%

50%

40%

30%

20%

10%

0 60

120 180

210 300 360 420 480 540 600 660 720 750

Primary Patency

Days After Index Procedure

From day X To day Y

IN.PACT DCB (N=220 Subjects)

# Entered

# Censored

# Events

Event-free [%]

Greenwood SE [%]

Standard PTA (N=111 Subjects)

0 0

120

121 180

181 240

241 300

301 360

361 420

421 480

481 540

541 600

601 660

661 720

721 750

220 220 215 212 204 194 188 174 154 153 152 147 144

0 2 4

1 11 0 0

5 3 11 4

1 3

0 3

100.0%

0.0%

99.1% 98.2% 96.3% 93.4% 92.9% 87.5% 81.8% 81.8% 81.8% 80.7% 80.7% 79.0%

0.6% 0.9% 1.3% 1.7% 1.8% 2.3% 2.7% 2.7% 2.7% 2.8% 2.8% 2.9%

# Entered

# Censored

# Events

Event-free [%]

Greenwood SE [%]

111

108 105 90 69 68 60 53 51 51 51 50

0 3 14 1 8 1 0 0

2 20 5

100.0%

0.0%

98.2% 95.5% 82.6% 64.2% 63.2% 55.8% 51.1% 50.1% 50.1% 50.1% 50.1% 50.1%

1.3% 2.0% 3.6% 4.6% 4.6% 4.8% 4.8% 4.8% 4.8% 4.8% 4.8% 4.8%

0 11 0 0 00 1 2 1

127

73.8%

3.2%

47.7%

4.9%

50.1%

79.0%

IN.PACT DCB

Log-Rank p < 0.001

PTA

All TLR events were adjudicated by the independent Clinical Events Committee. All DUSs were analyzed by an independent core laboratory.

11.3.5. Secondary Safety and Effectiveness

A summary of the secondary safety and effectiveness endpoints through 60 months is shown in Secondary Safety and Effectiveness Endpoints through 60 Months (Table 12).

Within 720 days, the composite MAE rate was 18.6% (38/204) in the IN.PACT Admiral DCB group versus 30.6% (33/108) in the PTA group. CD-TVR rates were lower in the IN.PACT Admiral DCB group at 12.3% (25/204) versus 29.6% (32/108) in the PTA group. CD-TLR rates were lower in the IN.PACT Admiral DCB group at 8.8% (18/204) versus 27.8% (30/108) in the PTA group.

Analysis Method Test Chi Square Degr. Freedom P-Value

Kaplan-Meier Analysis Log-Rank 32.0231 1 <0.001

Figure 10. Kaplan-Meier Plot – Cumulative Primary Patency through 750 Days

Survival Curves Comparison

Instructions for Use English 25

Within 1080 days, the composite MAE rate was 27.5% (55/200) in the IN.PACT Admiral DCB group versus 36.8% (39/106) in the PTA group. CD-TVR rates were lower in the IN.PACT Admiral DCB group at 18.5% (37/200) versus 34.9% (37/106) in the PTA group. CD-TLR rates were lower in the IN.PACT Admiral DCB group at 15.0% (30/200) versus 30.2% (32/106) in the PTA group.

Within 1440 days, the composite MAE rate was 37.4% (71/190) in the IN.PACT Admiral DCB group versus 40.4% (42/104) in the PTA group. CD-TVR rates were lower in the IN.PACT Admiral DCB group 26.3% (50/190) versus 35.6% (37/104) in the PTA group. CD-TLR rates were lower in the IN.PACT Admiral DCB group 23.2% (44/190) versus 30.8% (32/104) in the PTA group.

Within 1800 days, the composite MAE rate was 42.9% (79/184) in the IN.PACT Admiral DCB group versus 48.1% (50/104) in the PTA group. CD-TVR rates were lower in the IN.PACT Admiral DCB group 29.3% (54/184) versus 40.4% (42/104) in the PTA group. CD-TLR rates were lower in the IN.PACT Admiral DCB group 25.5% (47/184) versus 35.6% (37/104) in the PTA group.

All deaths were adjudicated by the blinded, Clinical Events Committee and none were found to be device- or procedure-related. The causes of death were varied and found to occur relatively late in the study. One major amputation in the IN.PACT DCB group occurred 1653 days post-index procedure.

Table 12. Secondary Safety and Effectiveness Endpoints through 60 Months

Description of Event IN.PACT DCB (N=220 Subjects) Standard PTA (N=111 Subjects)

Cumulative Complications Within 720 Days

MAE (Death, Major Target Limb Amputation, Clinically-driven TVR, Thrombosis)

Death (all-cause) 7.8% (16/204) 0.9% (1/108) Clinically-driven TVR 12.3% (25/204) 29.6% (32/108) Major Target Limb Amputation 0.0% (0/204) 0.0% (0/108)

Thrombosis 1.5% (3/204) 3.7% (4/108) Clinically-driven TLR 8.8% (18/204) 27.8% (30/108) Any TVR 12.7% (26/204) 30.6% (33/108) Any TLR 9.8% (20/204) 28.7% (31/108)

Cumulative Complications Within 1080 Days

MAE (Death, Major Target Limb Amputation, Clinically-driven TVR, Thrombosis)

Death (all-cause) 10.5% (21/200) 1.9% (2/106)

Clinically-driven TVR 18.5% (37/200) 34.9% (37/106)

Major Target Limb Amputation 0.0% (0/200) 0.0% (0/106)

Thrombosis 2.0% (4/200) 4.7% (5/106) Clinically-driven TLR 15.0% (30/200) 30.2% (32/106) Any TVR 19.0% (38/200) 35.8% (38/106) Any TLR 16.0% (32/200) 33.0% (35/106)

Cumulative Complications Within 1440 Days

MAE (Death, Major Target Limb Amputation, Clinically-driven TVR, Thrombosis)

Death (all-cause) 12.6% (24/190) 6.7% (7/104)

Clinically-driven TVR 26.3% (50/190) 35.6% (37/104)

Major Target Limb Amputation 0.0% (0/190) 0.0% (0/104)

Thrombosis 2.1% (4/190) 4.8% (5/104) Clinically-driven TLR 23.2% (44/190) 30.8% (32/104) Any TVR 26.8% (51/190) 36.5% (38/104) Any TLR 24.2% (46/190) 33.7% (35/104)

Cumulative Complications Within 1800 Days

MAE (Death, Major Target Limb Amputation, Clinically-driven TVR, Thrombosis)

Death (all-cause) 15.8% (29/184) 9.6% (10/104)

Clinically-driven TVR 29.3% (54/184) 40.4% (42/104)

Major Target Limb Amputation 0.5% (1/184) 0.0% (0/104)

Thrombosis 2.2% (4/184) 4.8% (5/104)

18.6% (38/204) 30.6% (33/108)

27.5% (55/200) 36.8% (39/106)

37.4% (71/190) 40.4% (42/104)

42.9% (79/184) 48.1% (50/104)

26 Instructions for Use English

Description of Event IN.PACT DCB (N=220 Subjects) Standard PTA (N=111 Subjects)

Clinically-driven TLR 25.5% (47/184) 35.6% (37/104) Any TVR 29.9% (55/184) 40.4% (42/104) Any TLR 26.6% (49/184) 37.5% (39/104) Percentages are based on number of evaluable subjects at each time point, and all events are adjudicated by the CEC.

Cumulative complications within 720 days, 1080 days, 1440 days and 1800 days include both IN.PACT SFA I and SFA II phase subjects.

All randomized subjects experiencing at least one component for the safety endpoint or with follow-up of at least 690 days for 24-month, 1050 days for 36-month, 1380 days for 48-month, and 1740 days for 60-month post-procedure, were considered as evaluable subjects for the event rate calculation for each corresponding time point, i.e. the denominator was adjusted for missing data.

Major Adverse Events (MAE) defined as all-cause death, clinically-driven TVR, major target limb amputation, thrombosis at the target lesion site.

Clinically-driven TLR/TVR is defined as any re-intervention within the target vessel due to symptoms or drop of ABI/TBI of ≥ 20% or >0.15 when compared to post-procedure baseline ABI/TBI.

Numbers are % (counts/sample size) unless otherwise stated.

11.3.6. Functional Endpoints

A summary of functional outcomes through 24 months and 36 months are presented in Table 13. These functional tests are only assessed through the 36-month follow-up.

Primary sustained clinical improvement is defined as freedom from target limb amputation, TVR, and an increase in Rutherford classification. Outcomes for this endpoint at 24 months in the IN.PACT Admiral DCB subjects were 76.9% (133/173) versus

59.2% (61/103) in the PTA group. Secondary sustained clinical improvement is defined as freedom from target limb amputation and an increase in Rutherford classification. Outcomes for this endpoint at 24 months in the IN.PACT Admiral DCB subjects were 86.9% (146/168) versus 86.2% (81/94) in the PTA group.

The QoL assessment uses the EQ-5D Index four-digit scoring algorithm to calculate an overall score, that was generated by the five individual dimensions (mobility, self-care, activity, pain, and anxiety), where 0.109 represents the worst possible outcome and 1.000 represents the best possible outcome. At 24 months, the mean change from baseline in the IN.PACT Admiral DCB subjects was 0.0957 ± 0.2159 versus 0.0545 ± 0.2286 in the PTA group. The WIQ scoring (%) is expressed on a scale of 0% to 100%, with 0% meaning the patient was unable to perform the assessment due to claudication, and 100% meaning no impairment. The mean walking impairment score in the IN.PACT Admiral DCB group was 72.5% ± 34.1% versus

67.2% ± 33.6% in the PTA group. At 36 months, primary sustained clinical improvement in the IN.PACT Admiral DCB subjects was 68.7% (114/166) versus

52.6% (51/97) in the PTA group and secondary sustained clinical improvement in the IN.PACT Admiral DCB subjects was

85.3% (133/156) versus 87.8% (79/90) in the PTA group. At 36 months, the QoL mean change from baseline in the IN.PACT Admiral DCB subjects was 0.0832 ± 0.2293 versus

0.0662 ± 0.1977 in the PTA group. In the WIQ (%), the mean in the IN.PACT Admiral DCB group was 71.8% ± 34.2% versus

74.7% ± 29.2% in the PTA group.

Table 13. Secondary Safety and Effectiveness Endpoints through 36 Months

IN.PACT DCB (N=220 Subjects) Standard PTA (N=111 Subjects)

Outcomes At 24 Months

Primary Sustained Clinical Improvement 76.9% (133/173) 59.2% (61/103) Secondary Sustained Clinical Improvement 86.9% (146/168) 86.2% (81/94) Change in Quality of Life from Baseline by EQ-5D

Index

N 167 92

Mean ± SD 0.0957 ± 0.2159 0.0545 ± 0.2286

Median 0.1040 0.0370

Min, Max -0.786, 0.672 -0.696, 0.554 Walking Impairment by WIQ (%)

N 170 93

Mean ± SD 72.5 ± 34.1 67.2 ± 33.6

Median 100.0 75.0

Min, Max 0, 100 0, 100

Instructions for Use English 27

IN.PACT DCB (N=220 Subjects) Standard PTA (N=111 Subjects)

Outcomes At 36 Months

Primary Sustained Clinical Improvement 68.7% (114/166) 52.6% (51/97) Secondary Sustained Clinical Improvement 85.3% (133/156) 87.8% (79/90) Change in Quality of Life from Baseline by EQ-5D

Index

N 156 90

Mean ± SD 0.0832 ± 0.2293 0.0662 ± 0.1977

Median 0.0905 0.0620

Min, Max -0.759, 0.693 -0.689, 0.554 Walking Impairment by WIQ (%)

N 158 91

Mean ± SD 71.8 ± 34.2 74.7 ± 29.2

Median 100.0 75.0

Min, Max 0, 100 0, 100 Endpoint definitions:

■

Primary Sustained Clinical Improvement is defined as freedom from target limb amputation, TVR, and increase in Rutherford class of at least one class from baseline at 24 (36) months post-procedure.

■

Secondary Sustained Clinical Improvement is defined freedom from target limb amputation and increase in Rutherford class of at least one class at 24 (36) months post-procedure.

■

Quality of Life assessment by EQ-5D questionnaire index at 24 (36) months

■

Walking impairment assessed by Walking Impairment Questionnaire (WIQ) at 24 (36) months.

Statistical references:

■

Numbers are % (counts/sample size) unless otherwise stated. Data Source: All events were adjudicated by the independent Clinical Events Committee, all duplex ultrasound and angiographic measures

were made by the independent core laboratories, and all other data were site reported.

11.3.7. Summary of Adverse Events

Serious Adverse Event Rates by SOC and Preferred Term through 1-year and through 5-year snapshot (Table 14) shows serious adverse event rates by subject and stratified by system-organ class (SOC) and preferred term. Serious adverse events were site-reported, and SOC was assigned via MedDRA version 13.0 coding.

A serious adverse event (SAE) was defined as an adverse event that led to a death or to a serious deterioration in the health of the subject. A serious deterioration in the health of the subject is defined as one or more of the following:

■

a life-threatening illness or injury

■

a permanent impairment of a body structure or a body function

■

in-patient hospitalization or prolongation of an existing hospitalization

■

a medical or surgical intervention to prevent life-threatening illness or injury or permanent impairment to a body structure or body function

■

fetal distress, fetal death, or a congenital abnormality or birth defect.

Table 14. Serious Adverse Event Rates by SOC and Preferred Term through 1-year and through 5-year snapshot

Through 1-Year Through 5-Year

Serious Adverse Events IN.PACT DCB

(N=220 Subjects)

SUBJECTS WITH ONE OR MORE

46.4% (102/220) 55.9% (62/111) 79.1% (174/220) 84.7% (94/111)

Standard PTA

(N=111 Subjects)

IN.PACT DCB

(N=220 Subjects)

Standard PTA

(N=111 Subjects)

SERIOUS ADVERSE EVENTS BLOOD AND LYMPHATIC SYS-

TEM DISORDERS

2.3% (5/220) 1.8% (2/111) 8.2% (18/220) 2.7% (3/111)

ANAEMIA 1.8% (4/220) 0.9% (1/111) 5.9% (13/220) 2.7% (3/111) ANAEMIA OF MALIGNANT DIS-

0.0% (0/220) 0.0% (0/111) 0.5% (1/220) 0.0% (0/111)

EASE HAEMORRHAGIC ANAEMIA 0.5% (1/220) 0.0% (0/111) 0.9% (2/220) 0.0% (0/111) LEUKOCYTOSIS 0.0% (0/220) 0.0% (0/111) 0.5% (1/220) 0.0% (0/111) PANCYTOPENIA 0.0% (0/220) 0.9% (1/111) 0.5% (1/220) 0.9% (1/111)

28 Instructions for Use English

Through 1-Year Through 5-Year

Serious Adverse Events IN.PACT DCB

(N=220 Subjects)

CARDIAC DISORDERS

ACUTE CORONARY SYN-

9.5% (21/220) 6.3% (7/111) 30.5% (67/220) 21.6% (24/111)

0.5% (1/220) 0.0% (0/111) 0.5% (1/220) 0.0% (0/111)

Standard PTA

(N=111 Subjects)

IN.PACT DCB

(N=220 Subjects)

Standard PTA

(N=111 Subjects)

DROME ACUTE MYOCARDIAL INFARC-

1.4% (3/220) 0.0% (0/111) 5.9% (13/220) 1.8% (2/111)

TION ANGINA PECTORIS 0.9% (2/220) 0.9% (1/111) 2.7% (6/220)) 0.9% (1/111) ANGINA UNSTABLE 0.0% (0/220) 0.9% (1/111) 1.8% (4/220) 1.8% (2/111) ARRHYTHMIA 0.5% (1/220) 0.0% (0/111) 0.5% (1/220) 0.0% (0/111) ATRIAL FIBRILLATION 0.9% (2/220) 1.8% (2/111) 4.1% (9/220) 4.5% (5/111) ATRIAL FLUTTER 0.0% (0/220) 0.0% (0/111) 0.9% (2/220) 0.0% (0/111) ATRIOVENTRICULAR BLOCK

0.0% (0/220) 0.0% (0/111) 0.5% (1/220) 0.0% (0/111)

COMPLETE ATRIOVENTRICULAR BLOCK

0.0% (0/220) 0.0% (0/111) 0.9% (2/220) 0.0% (0/111)

SECOND DEGREE BRADYCARDIA 0.0% (0/220) 0.0% (0/111) 1.8% (4/220) 0.0% (0/111) CARDIAC ARREST 0.5% (1/220) 0.0% (0/111) 2.3% (5/220) 0.9% (1/111) CARDIAC FAILURE 0.0% (0/220) 0.0% (0/111) 3.2% (7/220) 0.9% (1/111) CARDIAC FAILURE ACUTE 0.0% (0/220) 0.0% (0/111) 1.4% (3/220) 0.0% (0/111) CARDIAC FAILURE CONGES-

2.7% (6/220) 0.9% (1/111) 8.2% (18/220) 2.7% (3/111)

TIVE CARDIOMYOPATHY 0.0% (0/220) 0.0% (0/111) 0.5% (1/220) 0.0% (0/111) CORONARY ARTERY DIS-

3.2% (7/220) 0.9% (1/111) 9.1% (20/220) 7.2% (8/111)

EASE CORONARY ARTERY DISSEC-

0.0% (0/220) 0.0% (0/111) 0.0% (0/220) 0.9% (1/111)

TION CORONARY ARTERY OCCLU-

0.0% (0/220) 0.0% (0/111) 0.5% (1/220) 0.9% (1/111)

SION CORONARY ARTERY STENO-

0.0% (0/220) 0.0% (0/111) 2.3% (5/220) 0.0% (0/111)

SIS CORONARY ARTERY THROM-

0.0% (0/220) 0.9% (1/111) 0.0% (0/220) 0.9% (1/111)

BOSIS HEART VALVE STENOSIS 0.0% (0/220) 0.0% (0/111) 0.5% (1/220) 0.0% (0/111) ISCHAEMIC CARDIOMYOP-

0.0% (0/220) 0.0% (0/111) 0.9% (2/220) 0.9% (1/111)

ATHY MITRAL VALVE DISEASE 0.0% (0/220) 0.0% (0/111) 0.5% (1/220) 0.0% (0/111) MITRAL VALVE INCOMPE-

0.0% (0/220) 0.0% (0/111) 0.5% (1/220) 0.0% (0/111)

TENCE MYOCARDIAL INFARCTION 0.9% (2/220) 0.9% (1/111) 3.2% (7/220) 2.7% (3/111) MYOCARDIAL ISCHAEMIA 0.5% (1/220) 0.0% (0/111) 0.5% (1/220) 0.0% (0/111) PERICARDITIS 0.0% (0/220) 0.0% (0/111) 0.0% (0/220) 0.9% (1/111) SINUS BRADYCARDIA 0.0% (0/220) 0.0% (0/111) 0.0% (0/220) 0.9% (1/111) SINUS TACHYCARDIA 0.5% (1/220) 0.0% (0/111) 0.5% (1/220) 0.0% (0/111) SUPRAVENTRICULAR TACHY-

0.0% (0/220) 0.9% (1/111) 0.0% (0/220) 0.9% (1/111)

CARDIA TRICUSPID VALVE DISEASE 0.0% (0/220) 0.0% (0/111) 0.5% (1/220) 0.0% (0/111) VENTRICULAR TACHYCARDIA 0.5% (1/220) 0.0% (0/111) 0.5% (1/220) 0.0% (0/111)

CONGENITAL, FAMILIAL AND GENETIC DISORDERS

0.0% (0/220) 0.0% (0/111) 0.5% (1/220) 0.9% (1/111)

ATRIAL SEPTAL DEFECT 0.0% (0/220) 0.0% (0/111) 0.5% (1/220) 0.0% (0/111) HYDROCELE 0.0% (0/220) 0.0% (0/111) 0.0% (0/220) 0.9% (1/111)

EAR AND LABYRINTH DISOR-

DERS

0.5% (1/220) 0.0% (0/111) 0.9% (2/220) 0.0% (0/111)

VERTIGO 0.5% (1/220) 0.0% (0/111) 0.5% (1/220) 0.0% (0/111)

Instructions for Use English 29

Through 1-Year Through 5-Year

Serious Adverse Events IN.PACT DCB

(N=220 Subjects)

Standard PTA

(N=111 Subjects)

IN.PACT DCB

(N=220 Subjects)

Standard PTA

(N=111 Subjects)

VERTIGO POSITIONAL 0.0% (0/220) 0.0% (0/111) 0.5% (1/220) 0.0% (0/111)

EYE DISORDERS

0.5% (1/220) 0.0% (0/111) 2.3% (5/220) 1.8% (2/111) CATARACT 0.0% (0/220) 0.0% (0/111) 1.8% (4/220) 0.0% (0/111) DIABETIC RETINOPATHY 0.5% (1/220) 0.0% (0/111) 0.5% (1/220) 0.0% (0/111) RETINAL DETACHMENT 0.0% (0/220) 0.0% (0/111) 0.0% (0/220) 0.9% (1/111) VISUAL IMPAIRMENT 0.0% (0/220) 0.0% (0/111) 0.0% (0/220) 0.9% (1/111)

GASTROINTESTINAL DISOR-

DERS

4.1% (9/220) 0.9% (1/111) 10.9% (24/220) 5.4% (6/111)

ABDOMINAL PAIN 0.5% (1/220) 0.0% (0/111) 0.5% (1/220) 0.9% (1/111) ANAL FISTULA 0.5% (1/220) 0.0% (0/111) 0.5% (1/220) 0.0% (0/111) ASCITES 0.0% (0/220) 0.0% (0/111) 0.5% (1/220) 0.0% (0/111) COLONIC POLYP 0.0% (0/220) 0.0% (0/111) 0.5% (1/220) 0.0% (0/111) DIABETIC GASTROPARESIS 0.0% (0/220) 0.0% (0/111) 0.5% (1/220) 0.0% (0/111) DIARRHOEA 0.0% (0/220) 0.0% (0/111) 0.0% (0/220) 0.9% (1/111) DYSPHAGIA 0.0% (0/220) 0.0% (0/111) 0.5% (1/220) 0.0% (0/111) GASTRIC PERFORATION 0.0% (0/220) 0.0% (0/111) 0.5% (1/220) 0.0% (0/111) GASTRIC ULCER 0.0% (0/220) 0.0% (0/111) 0.0% (0/220) 0.9% (1/111) GASTRITIS EROSIVE 0.0% (0/220) 0.0% (0/111) 0.5% (1/220) 0.0% (0/111) GASTROINTESTINAL HAE-

0.9% (2/220) 0.9% (1/111) 3.2% (7/220) 1.8% (2/111) MORRHAGE

GASTROINTESTINAL ULCER

0.0% (0/220) 0.0% (0/111) 0.5% (1/220) 0.0% (0/111) HAEMORRHAGE

GASTROOESOPHAGEAL

0.5% (1/220) 0.0% (0/111) 0.5% (1/220) 0.0% (0/111) REFLUX DISEASE

HAEMATOCHEZIA 0.0% (0/220) 0.0% (0/111) 0.5% (1/220) 0.0% (0/111) ILEUS 0.0% (0/220) 0.0% (0/111) 0.9% (2/220) 0.0% (0/111) IMPAIRED GASTRIC EMPTY-

0.5% (1/220) 0.0% (0/111) 0.5% (1/220) 0.0% (0/111) ING

INTESTINAL INFARCTION 0.0% (0/220) 0.0% (0/111) 0.0% (0/220) 0.9% (1/111) INTESTINAL ISCHAEMIA 0.0% (0/220) 0.0% (0/111) 0.9% (2/220) 0.0% (0/111) INTESTINAL OBSTRUCTION 0.5% (1/220) 0.0% (0/111) 0.5% (1/220) 0.0% (0/111) LARGE INTESTINE PERFORA-

0.5% (1/220) 0.0% (0/111) 0.9% (2/220) 0.0% (0/111) TION

MELAENA 0.0% (0/220) 0.9% (1/111) 0.0% (0/220) 0.9% (1/111) PANCREATITIS 0.5% (1/220) 0.0% (0/111) 0.5% (1/220) 0.0% (0/111) PERITONITIS 0.5% (1/220) 0.0% (0/111) 0.9% (2/220) 0.0% (0/111) PROCTITIS 0.0% (0/220) 0.0% (0/111) 0.5% (1/220) 0.9% (1/111) RECTAL HAEMORRHAGE 0.0% (0/220) 0.0% (0/111) 0.5% (1/220) 0.0% (0/111) SALIVARY GLAND FISTULA 0.0% (0/220) 0.0% (0/111) 0.5% (1/220) 0.0% (0/111) SALIVARY GLAND MASS 0.0% (0/220) 0.0% (0/111) 0.0% (0/220) 0.9% (1/111) SMALL INTESTINAL

0.5% (1/220) 0.0% (0/111) 0.5% (1/220) 0.9% (1/111) OBSTRUCTION

UMBILICAL HERNIA 0.0% (0/220) 0.0% (0/111) 0.5% (1/220) 0.0% (0/111) UPPER GASTROINTESTINAL

0.0% (0/220) 0.0% (0/111) 0.5% (1/220) 0.0% (0/111) HAEMORRHAGE

VARICES OESOPHAGEAL 0.0% (0/220) 0.0% (0/111) 0.5% (1/220) 0.0% (0/111)

GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS

5.5% (12/220) 4.5% (5/111) 11.4% (25/220) 9.9% (11/111)

ADVERSE DRUG REACTION 0.5% (1/220) 0.0% (0/111) 0.5% (1/220) 0.0% (0/111) CHEST PAIN 0.9% (2/220) 0.9% (1/111) 5.0% (11/220) 4.5% (5/111) DEATH 0.0% (0/220) 0.0% (0/111) 0.9% (2/220) 0.9% (1/111)

30 Instructions for Use English

Through 1-Year Through 5-Year

Serious Adverse Events IN.PACT DCB

(N=220 Subjects)

Standard PTA

(N=111 Subjects)

IN.PACT DCB

(N=220 Subjects)

Standard PTA

(N=111 Subjects)

DEVICE DISLOCATION 0.0% (0/220) 0.0% (0/111) 0.5% (1/220) 0.0% (0/111) DEVICE OCCLUSION 0.5% (1/220) 0.9% (1/111) 0.5% (1/220) 0.9% (1/111) GENERALISED OEDEMA 0.0% (0/220) 0.0% (0/111) 0.5% (1/220) 0.0% (0/111) IMPAIRED HEALING 0.5% (1/220) 0.9% (1/111) 1.4% (3/220) 0.9% (1/111) IMPLANT SITE THROMBOSIS 0.5% (1/220) 0.0% (0/111) 0.0% (0/220) 0.0% (0/111) MASS 0.0% (0/220) 0.9% (1/111) 0.0% (0/220) 0.0% (0/111) MULTI-ORGAN FAILURE 0.5% (1/220) 0.0% (0/111) 0.5% (1/220) 0.0% (0/111) NECROSIS 0.0% (0/220) 0.9% (1/111) 0.0% (0/220) 0.9% (1/111) EDEMA PERIPHERAL 0.5% (1/220) 0.0% (0/111) 0.5% (1/220) 0.9% (1/111) POLYP 0.5% (1/220) 0.0% (0/111) 0.5% (1/220) 0.0% (0/111) PYREXIA 0.0% (0/220) 0.0% (0/111) 0.5% (1/220) 0.0% (0/111) SUDDEN DEATH 0.5% (1/220) 0.0% (0/111) 0.5% (1/220) 0.0% (0/111) THROMBOSIS IN DEVICE 0.0% (0/220) 0.0% (0/111) 0.5% (1/220) 0.9% (1/111) VESSEL PUNCTURE SITE

0.9% (2/220) 0.0% (0/111) 0.5% (1/220) 0.0% (0/111) HAEMATOMA

HEPATOBILIARY DISORDERS

0.9% (2/220) 0.9% (1/111) 1.8% (4/220) 0.9% (1/111) BILE DUCT OBSTRUCTION 0.5% (1/220) 0.0% (0/111) 0.5% (1/220) 0.0% (0/111) CHOLECYSTITIS 0.5% (1/220) 0.0% (0/111) 0.5% (1/220) 0.0% (0/111) CHOLECYSTITIS ACUTE 0.0% (0/220) 0.0% (0/111) 0.5% (1/220) 0.0% (0/111) HEPATIC CIRRHOSIS 0.0% (0/220) 0.9% (1/111) 0.0% (0/220) 0.9% (1/111) HEPATIC MASS 0.0% (0/220) 0.0% (0/111) 0.5% (1/220) 0.0% (0/111) LIVER DISORDER 0.5% (1/220) 0.0% (0/111) 0.5% (1/220) 0.0% (0/111) PERFORATION BILE DUCT 0.0% (0/220) 0.0% (0/111) 0.5% (1/220) 0.0% (0/111) PORCELAIN GALLBLADDER 0.0% (0/220) 0.0% (0/111) 0.5% (1/220) 0.0% (0/111)

IMMUNE SYSTEM DISORDERS

KIDNEY TRANSPLANT REJEC-

0.0% (0/220) 0.0% (0/111) 0.5% (1/220) 0.0% (0/111)

0.0% (0/220) 0.0% (0/111) 0.5% (1/220) 0.0% (0/111) TION

INFECTIONS AND INFESTATIONS

3.6% (8/220) 1.8% (2/111) 16.4% (36/220) 13.5% (15/111)

ABSCESS 0.0% (0/220) 0.0% (0/111) 0.5% (1/220) 0.0% (0/111) APPENDICEAL ABSCESS 0.0% (0/220) 0.0% (0/111) 0.5% (1/220) 0.0% (0/111) APPENDICITIS 0.0% (0/220) 0.0% (0/111) 0.5% (1/220) 0.0% (0/111) ARTHRITIS BACTERIAL 0.5% (1/220) 0.0% (0/111) 0.5% (1/220) 0.0% (0/111) ARTHRITIS INFECTIVE 0.0% (0/220) 0.0% (0/111) 0.5% (1/220) 0.0% (0/111) BILIARY SEPSIS 0.5% (1/220) 0.0% (0/111) 0.5% (1/220) 0.0% (0/111) BRONCHIECTASIS 0.0% (0/220) 0.9% (1/111) 0.0% (0/220) 0.9% (1/111) BRONCHITIS 0.0% (0/220) 0.0% (0/111) 0.5% (1/220) 0.0% (0/111) BRONCHOPNEUMONIA 0.0% (0/220) 0.0% (0/111) 0.5% (1/220) 0.9% (1/111) CELLULITIS 0.0% (0/220) 0.0% (0/111) 0.9% (2/220) 2.7% (3/111) CLOSTRIDIAL INFECTION 0.0% (0/220) 0.0% (0/111) 0.0% (0/220) 0.9% (1/111) CLOSTRIDIUM DIFFICILE COL-

0.0% (0/220) 0.0% (0/111) 0.5% (1/220) 0.0% (0/111) ITIS

CYSTITIS 0.0% (0/220) 0.0% (0/111) 0.0% (0/220) 0.9% (1/111) DEVICE RELATED INFECTION 0.0% (0/220) 0.0% (0/111) 0.5% (1/220) 0.0% (0/111) DIVERTICULITIS 0.0% (0/220) 0.0% (0/111) 0.9% (2/220) 0.0% (0/111) EAR INFECTION 0.0% (0/220) 0.0% (0/111) 0.5% (1/220) 0.0% (0/111) GANGRENE 0.9% (2/220) 0.0% (0/111) 0.9% (2/220) 0.9% (1/111) GASTROENTERITIS 0.5% (1/220) 0.0% (0/111) 0.9% (2/220) 0.0% (0/111) HERPES ZOSTER 0.0% (0/220) 0.0% (0/111) 0.5% (1/220) 0.0% (0/111) INFECTED LYMPHOCELE 0.5% (1/220) 0.0% (0/111) 0.5% (1/220) 0.0% (0/111) INFECTION 0.0% (0/220) 0.0% (0/111) 0.5% (1/220) 0.0% (0/111) LOBAR PNEUMONIA 0.0% (0/220) 0.0% (0/111) 0.5% (1/220) 0.0% (0/111)

Instructions for Use English 31

Through 1-Year Through 5-Year

Serious Adverse Events IN.PACT DCB

(N=220 Subjects)

Standard PTA

(N=111 Subjects)

IN.PACT DCB

(N=220 Subjects)

Standard PTA

(N=111 Subjects)

LOCALISED INFECTION 0.5% (1/220) 0.0% (0/111) 0.5% (1/220) 0.0% (0/111) MEDIASTINITIS 0.0% (0/220) 0.0% (0/111) 0.5% (1/220) 0.0% (0/111) ORCHITIS 0.0% (0/220) 0.0% (0/111) 0.0% (0/220) 0.9% (1/111) OSTEOMYELITIS 0.0% (0/220) 0.9% (1/111) 0.9% (2/220) 3.6% (4/111) PNEUMONIA 0.5% (1/220) 0.0% (0/111) 5.5% (12/220) 2.7% (3/111) PNEUMONIA PRIMARY ATYPI-

0.0% (0/220) 0.0% (0/111) 0.5% (1/220) 0.0% (0/111) CAL

POST PROCEDURAL INFEC-

0.0% (0/220) 0.0% (0/111) 0.5% (1/220) 0.0% (0/111) TION

SEPSIS 0.5% (1/220) 0.0% (0/111) 2.3% (5/220) 3.6% (4/111) SEPTIC SHOCK 0.0% (0/220) 0.0% (0/111) 0.9% (2/220) 0.0% (0/111) STAPHYLOCOCCAL OSTEO-

0.0% (0/220) 0.0% (0/111) 0.0% (0/220) 0.9% (1/111) MYELITIS

SUBCUTANEOUS ABSCESS 0.0% (0/220) 0.0% (0/111) 0.0% (0/220) 0.9% (1/111) UPPER RESPIRATORY TRACT

0.0% (0/220) 0.0% (0/111) 0.0% (0/220) 0.9% (1/111) INFECTION

URINARY TRACT INFECTION 0.5% (1/220) 0.0% (0/111) 0.9% (2/220) 1.8% (2/111) UROSEPSIS 0.0% (0/220) 0.0% (0/111) 0.9% (2/220) 1.8% (2/111) WEST NILE VIRAL INFECTION 0.5% (1/220) 0.0% (0/111) 0.5% (1/220) 0.0% (0/111)

INJURY, POISONING AND PROCEDURAL COMPLICATIONS

5.9% (13/220) 12.6% (14/111) 21.8% (48/220) 24.3% (27/111)

ANAEMIA POSTOPERATIVE 0.0% (0/220) 0.0% (0/111) 0.5% (1/220) 0.0% (0/111) ARTERIAL RESTENOSIS 0.5% (1/220) 3.6% (4/111) 5.5% (12/220) 13.5% (15/111) BRAIN CONTUSION 0.0% (0/220) 0.0% (0/111) 0.0% (0/220) 0.9% (1/111) BURNS SECOND DEGREE 0.0% (0/220) 0.0% (0/111) 0.0% (0/220) 0.9% (1/111) CLAVICLE FRACTURE 0.0% (0/220) 0.0% (0/111) 0.0% (0/220) 0.9% (1/111) CONTUSION 0.0% (0/220) 0.0% (0/111) 0.0% (0/220) 0.9% (1/111) DELAYED RECOVERY FROM

0.0% (0/220) 0.0% (0/111) 0.5% (1/220) 0.0% (0/111) ANAESTHESIA

FACIAL BONES FRACTURE 0.5% (1/220) 0.0% (0/111) 0.5% (1/220) 0.0% (0/111) FALL 0.0% (0/220) 0.9% (1/111) 0.0% (0/220) 0.9% (1/111) FEMORAL NECK FRACTURE 0.5% (1/220) 0.9% (1/111) 1.4% (3/220) 0.9% (1/111) FIBULA FRACTURE 0.5% (1/220) 0.0% (0/111) 0.5% (1/220) 0.0% (0/111) FRACTURED COCCYX 0.5% (1/220) 0.0% (0/111) 0.5% (1/220) 0.0% (0/111) HIP FRACTURE 0.0% (0/220) 0.0% (0/111) 0.9% (2/220) 0.9% (1/111) IN-STENT ARTERIAL RESTE-

1.4% (3/220) 0.9% (1/111) 7.3% (16/220) 0.9% (1/111) NOSIS

IN-STENT CORONARY

0.5% (1/220) 0.0% (0/111) 0.5% (1/220) 0.0% (0/111) ARTERY RESTENOSIS

INCISIONAL HERNIA 0.0% (0/220) 0.0% (0/111) 0.5% (1/220) 0.0% (0/111) LUMBAR VERTEBRAL FRAC-

0.5% (1/220) 0.0% (0/111) 0.9% (2/220) 0.0% (0/111) TURE

OVERDOSE 0.0% (0/220) 0.0% (0/111) 0.5% (1/220) 0.0% (0/111) PATELLA FRACTURE 0.0% (0/220) 0.0% (0/111) 0.5% (1/220) 0.0% (0/111) PERIPHERAL ARTERIAL

0.0% (0/220) 3.6% (4/111) 0.9% (2/220) 1.8% (2/111) REOCCLUSION

POST PROCEDURAL HAE-

0.0% (0/220) 0.0% (0/111) 0.5% (1/220) 0.0% (0/111) MORRHAGE

RENAL INJURY 0.0% (0/220) 0.0% (0/111) 0.0% (0/220) 0.9% (1/111) RIB FRACTURE 0.0% (0/220) 0.0% (0/111) 0.0% (0/220) 2.7% (3/111) SHUNT MALFUNCTION 0.0% (0/220) 0.0% (0/111) 0.5% (1/220) 0.0% (0/111) SHUNT STENOSIS 0.0% (0/220) 0.0% (0/111) 0.5% (1/220) 0.0% (0/111)

32 Instructions for Use English

Through 1-Year Through 5-Year

Serious Adverse Events IN.PACT DCB

(N=220 Subjects)

SPINAL COMPRESSION

0.0% (0/220) 0.0% (0/111) 0.5% (1/220) 0.9% (1/111)

Standard PTA

(N=111 Subjects)

IN.PACT DCB

(N=220 Subjects)

Standard PTA

(N=111 Subjects)

FRACTURE SUBDURAL HAEMATOMA 0.0% (0/220) 0.0% (0/111) 0.0% (0/220) 0.9% (1/111) TRACHEAL INJURY 0.0% (0/220) 0.0% (0/111) 0.5% (1/220) 0.0% (0/111) UPPER LIMB FRACTURE 0.0% (0/220) 0.0% (0/111) 0.5% (1/220) 0.0% (0/111) URETHRAL INJURY 0.0% (0/220) 0.0% (0/111) 0.5% (1/220) 0.0% (0/111) VASCULAR GRAFT OCCLU-

0.5% (1/220) 0.0% (0/111) 0.9% (2/220) 0.9% (1/111) SION

VASCULAR PSEUDOANEUR-

1.4% (3/220) 2.7% (3/111) 2.7% (6/220) 2.7% (3/111) YSM

INVESTIGATIONS

GENERAL PHYSICAL CONDI-

0.0% (0/220) 0.9% (1/111) 0.9% (2/220) 1.8% (2/111)

0.0% (0/220) 0.0% (0/111) 0.5% (1/220) 0.0% (0/111) TION ABNORMAL

INTERNATIONAL NORMAL-

0.0% (0/220) 0.0% (0/111) 0.5% (1/220) 0.0% (0/111) ISED RATIO INCREASED

OXYGEN SATURATION

0.0% (0/220) 0.0% (0/111) 0.0% (0/220) 0.9% (1/111) DECREASED

PROSTATIC SPECIFIC ANTI-

0.0% (0/220) 0.9% (1/111) 0.0% (0/220) 0.9% (1/111) GEN INCREASED

METABOLISM AND NUTRITION DISORDERS

1.4% (3/220) 0.0% (0/111) 1.4% (3/220) 0.0% (0/111)

DEHYDRATION 0.0% (0/220) 0.0% (0/111) 0.0% (0/220) 0.9% (1/111) DIABETIC FOOT 0.0% (0/220) 0.0% (0/111) 0.0% (0/220) 0.9% (1/111) FLUID RETENTION 0.0% (0/220) 0.0% (0/111) 0.5% (1/220) 0.0% (0/111) HYPERCALCAEMIA 0.0% (0/220) 0.0% (0/111) 0.5% (1/220) 0.0% (0/111) HYPERGLYCAEMIA 0.5% (1/220) 0.0% (0/111) 0.9% (2/220) 0.0% (0/111) HYPERKALAEMIA 0.5% (1/220) 0.0% (0/111) 0.5% (1/220) 0.0% (0/111) HYPONATRAEMIA 0.0% (0/220) 0.0% (0/111) 0.5% (1/220) 0.0% (0/111) OBESITY 0.5% (1/220) 0.0% (0/111) 0.5% (1/220) 0.0% (0/111) URAEMIC ACIDOSIS 0.0% (0/220) 0.0% (0/111) 0.5% (1/220) 0.0% (0/111)

MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS

4.5% (10/220) 4.5% (5/111) 8.2% (18/220) 9.9% (11/111)

ARTHRALGIA 0.0% (0/220) 0.0% (0/111) 0.9% (2/220) 0.0% (0/111) BACK PAIN 0.5% (1/220) 0.9% (1/111) 0.5% (1/220) 2.7% (3/111) BURSITIS 0.0% (0/220) 0.0% (0/111) 0.5% (1/220) 0.0% (0/111) EXOSTOSIS 0.5% (1/220) 0.0% (0/111) 0.5% (1/220) 0.0% (0/111) FISTULA 0.0% (0/220) 0.0% (0/111) 0.0% (0/220) 0.9% (1/111) INTERVERTEBRAL DISC PRO-

0.0% (0/220) 0.9% (1/111) 0.0% (0/220) 0.9% (1/111) TRUSION

LUMBAR SPINAL STENOSIS 0.9% (2/220) 0.9% (1/111) 0.9% (2/220) 1.8% (2/111) MUSCULOSKELETAL PAIN 0.5% (1/220) 0.0% (0/111) 0.5% (1/220) 0.9% (1/111) OSTEOARTHRITIS 0.9% (2/220) 0.0% (0/111) 1.4% (3/220) 0.9% (1/111) PAIN IN EXTREMITY 0.9% (2/220) 0.9% (1/111) 3.2% (7/220) 0.9% (1/111) PATELLOFEMORAL PAIN SYN-

0.0% (0/220) 0.0% (0/111) 0.0% (0/220) 0.9% (1/111) DROME

RHABDOMYOLYSIS 0.0% (0/220) 0.0% (0/111) 0.5% (1/220) 0.0% (0/111) SPINAL COLUMN STENOSIS 0.0% (0/220) 0.9% (1/111) 0.0% (0/220) 1.8% (2/111) SPINAL OSTEOARTHRITIS 0.5% (1/220) 0.0% (0/111) 0.5% (1/220) 0.0% (0/111) SPONDYLOLISTHESIS 0.5% (1/220) 0.0% (0/111) 0.5% (1/220) 0.0% (0/111) SYNOVIAL CYST 0.5% (1/220) 0.0% (0/111) 0.5% (1/220) 0.0% (0/111) TENOSYNOVITIS 0.0% (0/220) 0.0% (0/111) 0.5% (1/220) 0.0% (0/111)

Instructions for Use English 33

Through 1-Year Through 5-Year

Serious Adverse Events IN.PACT DCB

(N=220 Subjects)

NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS)

0.9% (2/220) 4.5% (5/111) 8.6% (19/220) 13.5% (15/111)

Standard PTA

(N=111 Subjects)

IN.PACT DCB

(N=220 Subjects)

Standard PTA

(N=111 Subjects)

ADENOCARCINOMA 0.0% (0/220) 0.0% (0/111) 0.5% (1/220) 0.0% (0/111) ADENOCARCINOMA PAN-

0.0% (0/220) 0.0% (0/111) 0.5% (1/220) 0.0% (0/111) CREAS

B-CELL LYMPHOMA 0.0% (0/220) 0.0% (0/111) 0.5% (1/220) 0.0% (0/111) BASAL CELL CARCINOMA 0.0% (0/220) 0.9% (1/111) 0.0% (0/220) 0.9% (1/111) BLADDER CANCER 0.0% (0/220) 0.9% (1/111) 0.5% (1/220) 0.9% (1/111) BLADDER NEOPLASM 0.0% (0/220) 0.0% (0/111) 0.5% (1/220) 0.0% (0/111) BLADDER TRANSITIONAL

0.0% (0/220) 0.0% (0/111) 0.5% (1/220) 0.0% (0/111) CELL CARCINOMA

BREAST CANCER 0.0% (0/220) 0.0% (0/111) 0.0% (0/220) 0.9% (1/111) BRONCHIAL CARCINOMA 0.0% (0/220) 0.0% (0/111) 0.9% (2/220) 0.9% (1/111) COLON CANCER 0.0% (0/220) 0.0% (0/111) 0.9% (2/220) 0.9% (1/111) COLON CANCER METASTATIC 0.0% (0/220) 0.9% (1/111) 0.0% (0/220) 0.9% (1/111) GASTROINTESTINAL CARCI-

0.0% (0/220) 0.0% (0/111) 0.5% (1/220) 0.0% (0/111) NOMA

KERATOACANTHOMA 0.0% (0/220) 0.0% (0/111) 0.5% (1/220) 0.0% (0/111) LEUKAEMIA 0.0% (0/220) 0.0% (0/111) 0.5% (1/220) 0.0% (0/111) LIPOMA 0.0% (0/220) 0.9% (1/111) 0.0% (0/220) 0.9% (1/111) LUNG NEOPLASM 0.0% (0/220) 0.0% (0/111) 0.0% (0/220) 0.9% (1/111) LUNG NEOPLASM MALIG-

0.0% (0/220) 0.0% (0/111) 0.9% (2/220) 1.8% (2/111) NANT

LUNG SQUAMOUS CELL CAR-

0.0% (0/220) 0.0% (0/111) 0.5% (1/220) 1.8% (2/111) CINOMA STAGE UNSPECIFIED

MYELOID LEUKAEMIA 0.0% (0/220) 0.0% (0/111) 0.5% (1/220) 0.0% (0/111) NEOPLASM MALIGNANT 0.0% (0/220) 0.0% (0/111) 0.0% (0/220) 0.9% (1/111) NON-SMALL CELL LUNG CAN-

0.0% (0/220) 0.0% (0/111) 0.0% (0/220) 0.9% (1/111) CER

PROSTATE CANCER 0.5% (1/220) 0.0% (0/111) 0.5% (1/220) 0.0% (0/111) RECTAL ADENOMA 0.0% (0/220) 0.0% (0/111) 0.5% (1/220) 0.0% (0/111) RENAL CANCER 0.0% (0/220) 0.9% (1/111) 0.0% (0/220) 0.9% (1/111) RENAL CELL CARCINOMA 0.0% (0/220) 0.0% (0/111) 0.9% (2/220) 0.0% (0/111) SALIVARY GLAND NEOPLASM 0.0% (0/220) 0.0% (0/111) 0.5% (1/220) 0.0% (0/111) SMALL CELL LUNG CANCER

0.0% (0/220) 0.0% (0/111) 0.0% (0/220) 0.9% (1/111) STAGE UNSPECIFIED

TONSIL CANCER 0.5% (1/220) 0.0% (0/111) 0.5% (1/220) 0.0% (0/111)

NERVOUS SYSTEM DISORDERS

5.0% (11/220) 6.3% (7/111) 19.1% (42/220) 14.4% (16/111) AMNESIA 0.5% (1/220) 0.0% (0/111) 0.5% (1/220) 0.0% (0/111) BALANCE DISORDER 0.0% (0/220) 0.0% (0/111) 0.5% (1/220) 0.0% (0/111) BRAIN STEM STROKE 0.0% (0/220) 0.0% (0/111) 0.5% (1/220) 0.0% (0/111) CAROTID ARTERY DISEASE 0.0% (0/220) 0.9% (1/111) 0.0% (0/220) 1.8% (2/111) CAROTID ARTERY STENOSIS 0.5% (1/220) 1.8% (2/111) 3.6% (8/220) 4.5% (5/111) CARPAL TUNNEL SYNDROME 0.0% (0/220) 0.0% (0/111) 0.0% (0/220) 0.9% (1/111) CEREBRAL INFARCTION 0.5% (1/220) 0.9% (1/111) 0.5% (1/220) 0.9% (1/111) CEREBROVASCULAR ACCI-

0.5% (1/220) 0.0% (0/111) 1.8% (4/220) 1.8% (2/111)

DENT DEMENTIA 0.0% (0/220) 0.0% (0/111) 0.9% (2/220) 0.0% (0/111) DIZZINESS 0.0% (0/220) 0.0% (0/111) 0.5% (1/220) 0.0% (0/111) EMBOLIC CEREBRAL INFARC-

0.5% (1/220) 0.0% (0/111) 0.5% (1/220) 0.0% (0/111)

TION

34 Instructions for Use English

Through 1-Year Through 5-Year

Serious Adverse Events IN.PACT DCB

(N=220 Subjects)

Standard PTA

(N=111 Subjects)

IN.PACT DCB

(N=220 Subjects)

Standard PTA

(N=111 Subjects)

ENCEPHALOPATHY 0.0% (0/220) 0.0% (0/111) 0.9% (2/220) 0.9% (1/111) HAEMORRHAGE INTRACRA-

0.5% (1/220) 0.0% (0/111) 0.5% (1/220) 0.0% (0/111)

NIAL HAEMORRHAGIC STROKE 0.0% (0/220) 0.0% (0/111) 0.5% (1/220) 0.0% (0/111) HEPATIC ENCEPHALOPATHY 0.0% (0/220) 0.0% (0/111) 0.5% (1/220) 0.9% (1/111) HYPOAESTHESIA 0.5% (1/220) 0.0% (0/111) 0.9% (2/220) 0.0% (0/111) INTRACRANIAL HAEMATOMA 0.0% (0/220) 0.0% (0/111) 0.5% (1/220) 0.0% (0/111) LOSS OF CONSCIOUSNESS 0.0% (0/220) 0.0% (0/111) 0.5% (1/220) 0.0% (0/111) LUMBAR RADICULOPATHY 0.5% (1/220) 0.0% (0/111) 0.9% (2/220) 0.0% (0/111) ORTHOSTATIC INTOLERANCE 0.0% (0/220) 0.0% (0/111) 0.5% (1/220) 0.0% (0/111) PARAESTHESIA 0.0% (0/220) 0.9% (1/111) 0.0% (0/220) 0.9% (1/111) PARKINSON'S DISEASE 0.0% (0/220) 0.0% (0/111) 0.0% (0/220) 0.9% (1/111) PARTIAL SEIZURES 0.0% (0/220) 0.0% (0/111) 0.5% (1/220) 0.0% (0/111) PERIODIC LIMB MOVEMENT

0.0% (0/220) 0.0% (0/111) 0.5% (1/220) 0.0% (0/111)

DISORDER PRESYNCOPE 0.0% (0/220) 0.0% (0/111) 0.5% (1/220) 0.0% (0/111) REVERSIBLE POSTERIOR

0.0% (0/220) 0.0% (0/111) 0.5% (1/220) 0.0% (0/111) LEUKOENCEPHALOPATHY SYNDROME

SYNCOPE 0.5% (1/220) 1.8% (2/111) 2.7% (6/220) 2.7% (3/111) TRANSIENT ISCHAEMIC

1.4% (3/220) 0.0% (0/111) 1.8% (4/220) 0.0% (0/111) ATTACK

TREMOR 0.0% (0/220) 0.0% (0/111) 0.5% (1/220) 0.0% (0/111) VISUAL PATHWAY DISORDER 0.0% (0/220) 0.0% (0/111) 0.0% (0/220) 0.9% (1/111)

PSYCHIATRIC DISORDERS

0.0% (0/220) 0.0% (0/111) 0.0% (0/220) 2.7% (3/111) COMPLETED SUICIDE 0.0% (0/220) 0.0% (0/111) 0.0% (0/220) 0.9% (1/111) DELIRIUM TREMENS 0.0% (0/220) 0.0% (0/111) 0.0% (0/220) 0.9% (1/111) MENTAL STATUS CHANGES 0.0% (0/220) 0.0% (0/111) 0.0% (0/220) 0.9% (1/111)

RENAL AND URINARY DISOR-

DERS

0.5% (1/220) 2.7% (3/111) 8.2% (18/220) 6.3% (7/111)

CALCULUS URETERIC 0.0% (0/220) 0.0% (0/111) 0.0% (0/220) 0.9% (1/111) CALCULUS URINARY 0.0% (0/220) 0.0% (0/111) 0.5% (1/220) 0.0% (0/111) CYSTITIS HAEMORRHAGIC 0.0% (0/220) 0.0% (0/111) 0.5% (1/220) 0.0% (0/111) HAEMATURIA 0.0% (0/220) 0.9% (1/111) 0.9% (2/220) 1.8% (2/111) HAEMORRHAGE URINARY

0.0% (0/220) 0.0% (0/111) 0.5% (1/220) 0.0% (0/111) TRACT

HYDRONEPHROSIS 0.0% (0/220) 0.0% (0/111) 0.0% (0/220) 0.9% (1/111) NEPHROLITHIASIS 0.0% (0/220) 0.0% (0/111) 0.0% (0/220) 0.9% (1/111) RENAL ARTERY STENOSIS 0.0% (0/220) 0.0% (0/111) 0.9% (2/220) 0.9% (1/111) RENAL COLIC 0.0% (0/220) 0.9% (1/111) 0.0% (0/220) 0.0% (0/111) RENAL CYST 0.0% (0/220) 0.0% (0/111) 0.0% (0/220) 0.9% (1/111) RENAL FAILURE 0.0% (0/220) 0.9% (1/111) 1.8% (4/220) 2.7% (3/111) RENAL FAILURE ACUTE 0.5% (1/220) 0.0% (0/111) 3.6% (8/220) 0.9% (1/111) RENAL FAILURE CHRONIC 0.0% (0/220) 0.0% (0/111) 0.5% (1/220) 0.0% (0/111)

REPRODUCTIVE SYSTEM AND BREAST DISORDERS

BENIGN PROSTATIC HYPER-

0.5% (1/220) 0.0% (0/111) 0.5% (1/220) 0.9% (1/111)

0.0% (0/220) 0.0% (0/111) 0.0% (0/220) 0.9% (1/111) PLASIA

POSTMENOPAUSAL HAE-

0.5% (1/220) 0.0% (0/111) 0.5% (1/220) 0.0% (0/111) MORRHAGE

RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS

1.4% (3/220) 0.9% (1/111) 12.7% (28/220) 9.0% (10/111)

Instructions for Use English 35

Through 1-Year Through 5-Year

Serious Adverse Events IN.PACT DCB

(N=220 Subjects)

Standard PTA

(N=111 Subjects)

IN.PACT DCB

(N=220 Subjects)

Standard PTA

(N=111 Subjects)

ACUTE PULMONARY EDEMA 0.5% (1/220) 0.0% (0/111) 0.5% (1/220) 0.0% (0/111) ACUTE RESPIRATORY FAIL-

0.0% (0/220) 0.0% (0/111) 3.2% (7/220) 0.9% (1/111) URE

CHRONIC OBSTRUCTIVE

0.5% (1/220) 0.0% (0/111) 2.3% (5/220) 2.7% (3/111) PULMONARY DISEASE

DYSPNOEA 0.0% (0/220) 0.0% (0/111) 1.4% (3/220) 2.7% (3/111) DYSPNOEA EXERTIONAL 0.5% (1/220) 0.0% (0/111) 1.4% (3/220) 0.0% (0/111) HAEMOPTYSIS 0.0% (0/220) 0.0% (0/111) 0.0% (0/220) 0.9% (1/111) HAEMOTHORAX 0.0% (0/220) 0.0% (0/111) 0.0% (0/220) 0.9% (1/111) PLEURAL EFFUSION 0.0% (0/220) 0.0% (0/111) 1.4% (3/220) 0.0% (0/111) PNEUMONIA ASPIRATION 0.0% (0/220) 0.0% (0/111) 0.9% (2/220) 0.0% (0/111) PNEUMONITIS 0.0% (0/220) 0.0% (0/111) 0.9% (2/220) 0.0% (0/111) PNEUMOTHORAX 0.0% (0/220) 0.0% (0/111) 0.5% (1/220) 0.0% (0/111) PULMONARY CONGESTION 0.0% (0/220) 0.0% (0/111) 0.5% (1/220) 0.0% (0/111) PULMONARY EMBOLISM 0.0% (0/220) 0.0% (0/111) 0.5% (1/220) 0.0% (0/111) PULMONARY FIBROSIS 0.0% (0/220) 0.0% (0/111) 0.5% (1/220) 0.0% (0/111) PULMONARY HYPERTENSION 0.0% (0/220) 0.0% (0/111) 0.5% (1/220) 0.0% (0/111) PULMONARY OEDEMA 0.0% (0/220) 0.0% (0/111) 0.5% (1/220) 0.0% (0/111) RESPIRATORY FAILURE 0.5% (1/220) 0.9% (1/111) 1.8% (4/220) 0.9% (1/111) SLEEP APNOEA SYNDROME 0.0% (0/220) 0.0% (0/111) 0.9% (2/220) 0.0% (0/111)

SKIN AND SUBCUTANEOUS TISSUE DISORDERS

0.0% (0/220) 1.8% (2/111) 1.4% (3/220) 3.6% (4/111)

DECUBITUS ULCER 0.0% (0/220) 0.0% (0/111) 0.0% (0/220) 0.9% (1/111) DRY GANGRENE 0.0% (0/220) 0.9% (1/111) 0.0% (0/220) 0.9% (1/111) INGROWING NAIL 0.0% (0/220) 0.0% (0/111) 0.5% (1/220) 0.0% (0/111) LICHENIFICATION 0.0% (0/220) 0.0% (0/111) 0.0% (0/220) 0.9% (1/111) NEUROPATHIC ULCER 0.0% (0/220) 0.9% (1/111) 0.0% (0/220) 0.9% (1/111) SKIN NECROSIS 0.0% (0/220) 0.0% (0/111) 0.5% (1/220) 0.0% (0/111) SKIN ULCER 0.0% (0/220) 0.0% (0/111) 0.5% (1/220) 0.9% (1/111) SUBCUTANEOUS EMPHY-

0.0% (0/220) 0.0% (0/111) 0.5% (1/220) 0.0% (0/111) SEMA

SURGICAL AND MEDICAL PROCEDURES

0.9% (2/220) 0.9% (1/111) 1.4% (3/220 5.4% (6/111)

ANGIOPLASTY 0.0% (0/220) 0.0% (0/111) 0.0% (0/220) 0.9% (1/111) CAROTID ENDARTERECTOMY 0.0% (0/220) 0.0% (0/111) 0.0% (0/220) 0.9% (1/111) CORONARY REVASCULARI-

0.0% (0/220) 0.0% (0/111) 0.5% (1/220) 0.0% (0/111) SATION

DEBRIDEMENT 0.0% (0/220) 0.0% (0/111) 0.0% (0/220) 0.9% (1/111) IMPLANTABLE DEFIBRILLA-

0.0% (0/220) 0.0% (0/111) 0.0% (0/220) 0.9% (1/111) TOR REPLACEMENT

JOINT SURGERY 0.5% (1/220) 0.0% (0/111) 0.0% (0/220) 0.0% (0/111) PERIPHERAL ARTERY ANGIO-

0.0% (0/220) 0.0% (0/111) 0.5% (1/220) 0.0% (0/111) PLASTY

PERIPHERAL REVASCULARI-

0.0% (0/220) 0.9% (1/111) 0.0% (0/220) 0.9% (1/111) SATION

REMOVAL OF FOREIGN BODY

0.0% (0/220) 0.0% (0/111) 0.0% (0/220) 0.9% (1/111) FROM EYE

THERAPEUTIC EMBOLISA-

0.5% (1/220) 0.0% (0/111) 0.5% (1/220) 0.0% (0/111) TION

VASCULAR DISORDERS

22.7% (50/220) 35.1% (39/111) 46.8% (103/220) 57.7% (64/111) AORTIC ANEURYSM 0.0% (0/220) 0.0% (0/111) 0.5% (1/220) 0.9% (1/111) AORTIC DILATATION 0.0% (0/220) 0.0% (0/111) 0.5% (1/220) 0.0% (0/111) AORTIC STENOSIS 0.0% (0/220) 0.0% (0/111) 0.9% (2/220) 2.7% (3/111)

36 Instructions for Use English

Through 1-Year Through 5-Year

Serious Adverse Events IN.PACT DCB

(N=220 Subjects)

ARTERIAL OCCLUSIVE DIS-

0.5% (1/220) 0.0% (0/111) 0.9% (2/220) 0.0% (0/111)

Standard PTA

(N=111 Subjects)

IN.PACT DCB

(N=220 Subjects)

Standard PTA

(N=111 Subjects)

EASE ARTERIAL STENOSIS LIMB 0.5% (1/220) 2.7% (3/111) 3.2% (7/220) 5.4% (6/111) ARTERIAL THROMBOSIS LIMB 0.0% (0/220) 0.0% (0/111) 0.5% (1/220) 1.8% (2/111) ARTERIOVENOUS FISTULA 0.0% (0/220) 1.8% (2/111) 0.0% (0/220) 2.7% (3/111) ARTERY DISSECTION 3.2% (7/220) 1.8% (2/111) 5.5% (12/220) 6.3% (7/111) DEEP VEIN THROMBOSIS 0.0% (0/220) 0.0% (0/111) 0.0% (0/220) 0.9% (1/111) EMBOLISM 0.0% (0/220) 0.0% (0/111) 0.5% (1/220) 0.0% (0/111) FEMORAL ARTERIAL STENO-

6.8% (15/220) 9.0% (10/111) 18.6% (41/220) 20.7% (23/111)

SIS FEMORAL ARTERY DISSEC-

1.8% (4/220) 4.5% (5/111) 1.4% (3/220) 1.8% (2/111)

TION FEMORAL ARTERY OCCLU-

1.4% (3/220) 4.5% (5/111) 5.9% (13/220) 9.0% (10/111)

SION HAEMATOMA 0.0% (0/220) 0.9% (1/111) 0.9% (2/220) 0.9% (1/111) HAEMORRHAGE 0.5% (1/220) 0.0% (0/111) 0.5% (1/220) 0.0% (0/111) HYPERTENSION 0.0% (0/220) 0.0% (0/111) 1.4% (3/220) 0.0% (0/111) HYPERTENSIVE CRISIS 0.0% (0/220) 0.0% (0/111) 2.3% (5/220) 2.7% (3/111) HYPOTENSION 0.5% (1/220) 0.0% (0/111) 0.9% (2/220) 0.9% (1/111) ILIAC ARTERY OCCLUSION 0.0% (0/220) 0.0% (0/111) 0.5% (1/220) 0.0% (0/111) ILIAC ARTERY STENOSIS 0.9% (2/220) 0.9% (1/111) 5.0% (11/220) 3.6% (4/111) INTERMITTENT CLAUDICA-

3.2% (7/220) 9.9% (11/111) 9.1% (20/220) 13.5% (15/111)

TION LABILE HYPERTENSION 0.0% (0/220) 0.0% (0/111) 0.5% (1/220) 0.0% (0/111) LYMPHOCELE 0.0% (0/220) 0.0% (0/111) 0.0% (0/220) 0.9% (1/111) ORTHOSTATIC HYPOTENSION 0.5% (1/220) 0.9% (1/111) 0.5% (1/220) 0.9% (1/111) PERIPHERAL ARTERIAL

3.6% (8/220) 4.5% (5/111) 9.5% (21/220) 8.1% (9/111)

OCCLUSIVE DISEASE PERIPHERAL ARTERY DIS-

1.4% (3/220) 3.6% (4/111) 1.8% (4/220) 1.8% (2/111)

SECTION PERIPHERAL EMBOLISM 0.5% (1/220) 0.9% (1/111) 0.5% (1/220) 0.9% (1/111) PERIPHERAL ISCHAEMIA 0.9% (2/220) 1.8% (2/111) 1.8% (4/220) 3.6% (4/111) PERIPHERAL VASCULAR DIS-

0.9% (2/220) 0.0% (0/111) 3.6% (8/220) 3.6% (4/111)

ORDER SHOCK HAEMORRHAGIC 0.5% (1/220) 0.0% (0/111) 0.5% (1/220) 0.0% (0/111) SUBCLAVIAN ARTERY

0.0% (0/220) 0.9% (1/111) 0.0% (0/220) 0.9% (1/111)

STENOSIS VENOUS INSUFFICIENCY 0.0% (0/220) 0.0% (0/111) 0.5% (1/220) 0.0% (0/111) VESSEL PERFORATION 0.0% (0/220) 0.0% (0/111) 0.5% (1/220) 0.0% (0/111)

TOTAL SERIOUS ADVERSE

195 118 770 363

EVENTS

Numbers are % (counts/sample size).

Event verbatim terms are reported by sites. The events listed in this table are then coded using MedDRA version 13.0 and then stratified by System-Organ Class (SOC) and Preferred Term. Patients may be counted in this table more than once by Preferred Term, but are only counted once in the SOC summary line.

11.4. Pharmacokinetic Sub-study

Human pharmacokinetics was investigated as a sub-study of the IN.PACT SFA Trial. This sub-study was a prospective, multicenter, non-randomized study arm (IN.PACT Admiral DCB) conducted at multiple prespecified investigational sites, designed to evaluate the levels of paclitaxel in the systemic circulation of subjects at multiple time points. Pharmacokinetic parameters were determined for a total of 24 subjects (16 male and 8 female). A summary of the pharmacokinetic parameters is presented in Summary of Pharmacokinetic Parameters (Table 15). The pharmacokinetic sub-study demonstrated low systemic exposure with rapid clearance of paclitaxel.

Instructions for Use English 37

Table 15. Summary of Pharmacokinetic Parameters

Parameter Mean (N=24) Standard Deviation %CV Range

(hr) 0.17 0.067 38.8 0.07 – 0.32

max

(ng/mL) 7.9 7.70 97.9 1.0 - 35.9

max

AUC AUC T

(hr*ng/mL) 29.4 22.06 75.0 3.2 – 91.6

0-last

(hr*ng/mL) 47.8 28.98 60.6 11.4 – 128.8

0-inf

(hr) 72.5 39.70 54.7 8.2 – 153.5

1/2

CL/F (L/hr) 192.2 103.44 53.8 54.7 – 472.7 T

(hr) The timepoint where Cmax is reached

max

(ng/mL) Maximum plasma concentration

max

AUC AUC T

(hr*ng/mL) Area under plasma concentration-time curve from time zero to time of last measurable concentration

0-last

(hr*ng/mL) Area under the plasma concentration-time curve from time zero extrapolated to infinity

0-inf

(hr) Terminal half-life

1/2

CL/F (L/hr) Apparent clearance

11.5. IN.PACT Global Study

11.5.1. Study Overview

The IN.PACT Global Study is a prospective, multi-center, single-arm study designed to collect and assess global safety and effectiveness data on the IN.PACT Admiral DCB in treatment of atherosclerotic disease of the superficial femoral and/or popliteal arteries in a “real-world” population. The study is estimated to continue follow-up through 2019. The study will enroll approximately 1500 subjects at more than 60 sites in Europe, Australia, Asia, Northern Africa, Canada, the Middle East, and South America. Follow-up will be completed at 30 days, 6 months, and 12 months and 2, 3, 4, and 5 years. The interim data from the IN.PACT Global Study that were available at the time were provided to FDA for consideration as part of the PMA submission.

11.6. Summary of Rare Adverse Events

Medtronic has provided an evaluation of rare adverse events (RAE) in more than 800 subjects from the IN.PACT SFA Trial, the IN.PACT SFA PK Sub-study, and the IN.PACT Global Study.

The following RAEs were adjudicated by the independent Clinical Events Committees (CEC): paclitaxel-related vessel thrombosis within 30 days, paclitaxel-related distal embolic events within 360 days, paclitaxel-related neutropenia within 360 days, and paclitaxel-related drug hypersensitivity/reaction within 360 days. The rate of paclitaxel-related thrombosis within 30 days was 0.2% (2/890). There were no paclitaxel-related distal embolic events within 360 days (0/806), paclitaxel-related neutropenia within 360 days (0/806), or paclitaxel-related drug hypersensitivity/reaction within 360 days (0/806).

The current RAE outcomes demonstrate no increased risk of adverse events due to the paclitaxel coating.

11.7. IN.PACT Admiral DCB ISR Clinical Evaluation

11.7.1. Primary Objective

The objective of this clinical evaluation was to assess the safety and effectiveness of the IN.PACT Admiral DCB as compared with PTA when used to treat in-stent restenotic (ISR) lesions of the superficial femoral artery (SFA) or popliteal artery.

11.7.2. Design

This clinical evaluation was designed as an observational, propensity score-adjusted, comparative analysis of IN.PACT Admiral DCB subjects selected from the real-world IN.PACT Global Study (“DCB ISR Cohort”) and PTA subjects provided from the Society of Vascular Surgery (SVS) Vascular Quality Initiative (VQI) Registry database (“PTA ISR Comparator”).

A total of 164 DCB subjects from the IN.PACT Global Study comprised the DCB ISR Cohort, and a total of 153 PTA subjects from the SVS VQI Registry comprised the PTA ISR Comparator. Patients in the DCB ISR Cohort were treated at 31 sites in Austria, Belgium, Canada, Egypt, Germany, Hungary, Italy, The Netherlands, Poland, Singapore, Slovakia, South Korea, and Switzerland between June 6, 2012 and December 16, 2013, and patients in the PTA ISR Comparator were treated at 23 sites in the United States between 2011 and 2014.

The objective of this analysis was to demonstrate that the primary endpoint of 12-month target lesion revascularization (TLR) was significantly lower in the DCB ISR Cohort when compared to the PTA ISR Comparator group for the treatment of ISR.

For the primary effectiveness endpoint of 12-month TLR, the treatment (DCB ISR Cohort) and control (PTA ISR Comparator) groups were compared in a superiority format. Formally, the hypothesis tested was:

38 Instructions for Use English

H0: 12-month TLR rate in subjects in DCB ISR Cohort (pT) is equal to or higher than that for subjects in PTA ISR Comparator (pC).

H0: pT ≥ p

HA: 12-month TLR rate in subjects in DCB ISR Cohort (pT) is lower than that for subjects in PTA ISR Comparator (pC).

HA: pT < p

Due to the nature of this non-randomized retrospective comparison, it was necessary to adjust for expected baseline differences between the subjects in the two groups to ensure objectivity of the clinical evaluation design and the validity of the results. As pre-specified in the statistical analysis plan, propensity score analysis was performed using clinically relevant baseline characteristics. The propensity score calculation was carried out by an independent statistician without access to the outcomes of either group. The calculation results were submitted to the FDA for review and approval prior to performing the primary endpoint analyses.

The primary endpoint of the powered statistical analysis comparing ISR outcomes in the DCB ISR Cohort and the PTA ISR Comparator was the incidence of TLR through 12 months.

The clinically relevant secondary endpoints assessed included:

1. All-cause mortality at 30 days, 6 months, and 12 months.

2. Any TVR at 30 days, 6 months, and 12 months.

3. Major target limb amputation at 30 days, 6 months, and 12 months.

4. Time to first TLR through 12 months post-index procedure.

5. Time to all-cause mortality through 12 months post-index procedure. With regard to success criteria, the study was deemed successful if it demonstrated superiority of the DCB ISR Cohort on the

12-month primary endpoint of target lesion revascularization compared to the PTA ISR Comparator.

11.7.3. Patient Population

Table 16 below presents the baseline demographics and clinical characteristics for the 164 DCB ISR Cohort subjects and the 153 PTA ISR Comparator subjects. These 20 baseline variables were pre-specified as the covariates in the propensity score analysis, and all of the variables were included in the propensity score calculation except for the TASC lesion type due to a missing data rate in the DCB ISR Cohort that exceeded the pre-specified cutoff of 20%.

Table 16. Baseline Demographics and Clinical Characteristics

Baseline Characteristics DCB ISR Cohort

(N=164)

PTA ISR Comparator

(N=153)

Propensity Score Adjusted p-value

Baseline Demographics

Age (yrs)

Mean±SD (N) 66.95±9.84 (163) 66.79±11.23 (153) 0.795 Median (Q1, Q3) 67.00 (60.00,74.00) 66.00 (58.00,75.00)

Range (Min, Max) (39.00,86.00) (44.00,89.00) Male 72.6% (119/164) 51.6% (79/153) 0.536 BMI (kg/m2)

Mean±SD (N) 26.34±4.39 (164) 28.21±6.06 (153) 0.835

Median (Q1, Q3) 25.94 (23.63,28.57) 28.00 (24.00,30.00)

Range (Min, Max) (16.46,43.26) (13.00,50.00) Ankle-Brachial Index (ABI) (mmHg ratio)

Mean±SD (N) 0.64±0.22 (147) 0.70±0.41 (140) 0.786

Median (Q1, Q3) 0.65 (0.51,0.77) 0.64 (0.48,0.81)

Range (Min, Max) (0.00,1.43) (0.00,2.00)

Baseline Clinical Characteristics

Hypertension 83.4% (136/163) 87.6% (134/153) 0.972 Diabetes 36.6% (60/164) 49.0% (75/153) 0.920 Insulin-dependent Diabetes 16.5% (27/164) 22.9% (35/153) 0.946 On Dialysis 3.0% (5/164) 1.3% (2/153) 0.579 Coronary artery disease 20.5% (30/146) 24.2% (37/153) 0.964 Current smoker 36.0% (59/164) 32.7% (50/153) 0.915 Previous limb amputation (major or

5.5% (9/164) 4.6% (7/153) 0.980

minor)

Instructions for Use English 39

Baseline Characteristics DCB ISR Cohort

(N=164)

Renal insufficiency (per serum creatinine

9.5% (14/147) 9.9% (15/151) 0.931

PTA ISR Comparator

(N=153)

Propensity Score Adjusted p-value

≥1.5 mg/dl)

Baseline Lesion and Procedural Characteristics

TASC lesion type 0.906

A 20.2% (21/104) 30.7% (47/153)

B 30.8% (32/104) 27.5% (42/153)

C 36.5% (38/104) 30.1% (46/153)

D 12.5% (13/104) 11.8% (18/153) Lesion length (cm)

Mean±SD (N) 17.59±10.49 (164) 13.16±9.61 (151) 0.735

Median (Q1, Q3) 16.00 (10.00,27.00) 10.00 (6.00,20.00)

Range (Min, Max) (1.00,47.00) (2.00,47.00) Total occlusion 40.9% (67/164) 68.7% (103/150) 0.990 Occluded lesion length (cm)

Mean±SD (N) 7.47±11.65 (164) 7.87±9.40 (150) 0.709

Median (Q1, Q3) 0.00 (0.00,10.50) 4.00 (0.00,14.00)

Range (Min, Max) (0.00,42.00) (0.00,45.00) Pre-op aspirin 95.7% (157/164) 83.0% (127/153) 0.422

Indication of Claudication - Rutherford Clas-

87.8% (144/164) 74.5% (114/153) 0.633

sification or equivalent

Lesion Location: SFA 71.3% (117/164) 86.9% (133/153) 0.706 Provisional stent 15.9% (26/164) 33.3% (51/153) 0.814

Numbers are % (counts/sample size) unless otherwise stated. Categorical variables between groups were compared using the chi-squared test or Fisher's exact test as appropriate, and

continuous variables were compared using Student's t-test. Site reported data. All of the variables in this table were included in the propensity score calculation except TASC lesion type due to a missing

data rate that exceeded the pre-specified cutoff of 20%. p-values are not adjusted for multiplicity

The propensity score adjusted p-value was based on all subjects for each baseline variable. For each variable with missing values (<20%), a gender-specific imputation was performed by replacing the missing values of the variable with the gender-specific median observed value within each group.

Follow-up compliance for the 12-month follow-up visits is presented in Table 17 for the DCB ISR Cohort subjects. The rate of inwindow follow-up visit completion at 12 months was 92.3%.

Table 17. Subject Follow-up Compliance – IN.PACT Global DCB ISR Cohort Subjects

Subject Compliance Characteristics

DCB ISR Cohort

(N=164 Subjects)

12-Month Follow-up

Eligible Subjects

Death Withdrawal

155

8 Follow-up Not Done 7 Follow-up Visit Within Window Follow-up Visit Out of Window Follow-up Compliance (%)

Site reported data

Death and withdrawal are cumulative

Within window visits are defined as: 12-month ± 60 days.

Percentage based on number of subjects who had follow-up visit within window divided by total number of eligible subjects

143

92.3%

40 Instructions for Use English

11.7.4. Safety and Effectiveness Results

Primary Endpoint Analysis

The results of the powered statistical analysis comparing the 12-month primary endpoint between the DCB ISR Cohort and the PTA ISR Comparator are shown in Table 18.

The primary endpoint of the clinical evaluation was met, demonstrating superiority of the DCB ISR Cohort over the PTA ISR Comparator on the primary effectiveness endpoint of target lesion revascularization (TLR) at 12 months (10.13% vs. 35.92%, p<0.001).

Table 18. Primary Effectiveness Endpoint Results

DCB ISR Cohort

(N=164)

PTA ISR Comparator

(N=153)

Hazard Ratio [95% CI]

p-value

Effectiveness Parameters

Target Lesion Revascularization at

10.13% (16) 35.92% (51) 0.258 [0.128, 0.517] <0.001

12 Months Statistical references:

■

Numbers are cumulative incidence % (number of failures) based on Kaplan-Meier method. CI – Confidence Interval

■

Analysis sets: The primary analysis set was based on the intent-to-treat (ITT) principle. All subjects enrolled through the selection process specified in SAP Section 3.1 were included as ITT subjects.

■

To analyze the treatment differences between the DCB ISR Cohort and PTA ISR Comparator groups in the clinical/safety endpoints such as TLR, a propensity-quintile-stratified Cox proportional hazards model was employed, with time to event as the dependent variable and treatment group as the independent variable.

The Kaplan-Meier analysis of this primary effectiveness endpoint, presented as freedom from target lesion revascularization, is shown in Figure 11.

Instructions for Use English 41

Target Lesion Revascularization

DCB

# Entered

# Censored

# Events

Survived [%]

PTA

0 1-60 61-120 121-180 181-240 241-300 301-360 361-425

164 163 154 152 148 143 141 126

1 3

0 121 3

99.39%

96.27% 95.65% 93.75% 92.47% 91.82% 89.87% 84.53%

# Entered

# Censored

# Events

Survived [%]

153

151

144 138 125 113 90 56

2 6 13 10 64 10 3

98.69% 96.07% 92.06% 83.39% 76.66% 69.40% 64.08% 59.94%

0 03 13 280 2 17

0 60 120 180 240 300 360 425

100%

90%

80%

70%

60%

50%

40%

30%

20%

10%

Time after Initial Procedure (Days)

Freedom from Target

Lesion Revascularization

PTADCB

64.1%

59.9%

89.9%

84.5%

Figure 11. Kaplan-Meier Plot - Event-free from Target Lesion Revascularization through 360 and 425 Days

Secondary Safety and Effectiveness Endpoints

The results of the secondary endpoints for the IN.PACT Admiral DCB ISR Clinical Evaluation are shown in Table 19. In both the DCB ISR Cohort and the PTA ISR Comparator, there were high rates of acute success. Since the acute success

definitions differed, these were not able to be directly compared, but the DCB ISR Cohort had high rates of device success (99.5%), procedural success (99.4%), and clinical success (98.8%), while the PTA ISR Comparator had a high rate of technical success (97.4%). The definitions of each of these endpoints are provided in the footnotes of Table 19.

Clinical safety and effectiveness outcomes were reported at 30 days, 6 months, and 12 months. All event rates were low in both groups at 30 days, but lower event rates were observed at 6 months and at 12 months for both the TLR and the target vessel revascularization (TVR) endpoints in the DCB ISR Cohort. The 12-month TVR rate was 11.41% in the DCB ISR Cohort compared to 38.07% in the PTA ISR Comparator.

There were no major target limb amputations in the DCB ISR Cohort and three major target limb amputations in the PTA ISR Comparator within 12 months. Lastly, there was one death in the DCB ISR Cohort and no deaths in the PTA ISR Comparator within 12 months. One subject in the DCB ISR Cohort experienced a non-cardiac death at day 276 post-index procedure. The independent clinical events committee determined that the event was not device-related and not procedure-related.

42 Instructions for Use English

Table 19. Secondary Safety and Effectiveness Endpoint Results

DCB ISR Cohort

PTA ISR Comparator

(N=164)

Effectiveness Parameters

Device Success

Procedural Success Clinical Success

Technical Success

99.5% (364/366) NA

99.4% (163/164) NA

98.8% (162/164) NA NA 97.4% (149/153)

Safety Parameters

Cumulative complications within 30 days

Death (all-cause) 0.00% (0) 0.00% (0) Target Vessel Revascularization 0.61% (1) 2.61% (4) Major Target Limb Amputation 0.00% (0) 0.00% (0) Target Lesion Revascularization 0.61% (1) 2.61% (4)

Cumulative complications within 180 days

Death (all-cause) 0.00% (0) 0.00% (0) Target Vessel Revascularization 6.88% (11) 17.28% (26) Major Target Limb Amputation 0.00% (0) 1.33% (2) Target Lesion Revascularization 6.25% (10) 16.61% (25)

Cumulative complications within 360 days

Death (all-cause) 0.65% (1) 0.00% (0) Target Vessel Revascularization 11.41% (18) 38.07% (54) Major Target Limb Amputation 0.00% (0) 2.08% (3)

(N=153)

Other Major Secondary Endpoints at 12 Months DCB ISR Cohort

(N=164)

PTA ISR Comparator

(N=153)

Time to all-cause mortality (days)

Mean±SD (N) 276.00 (1) -Median 276.00 -(Min, Max) (276.00,276.00) --

Time to first TLR (days)

Mean±SD (N) 148.44±115.25 (16) 182.33±93.53 (51) Median 146.50 187.00 (Min, Max) (0.00,328.00) (0.00,335.00)

Endpoint definitions:

■

Device success (assessed for DCB ISR Cohort only) defined as successful delivery, balloon inflation and deflation and retrieval of the intact study device without burst below the rated burst pressure (RBP).

■

Procedure success (assessed for DCB ISR Cohort only) defined as residual stenosis of ≤ 50% (non-stented subjects) or ≤ 30% (stented subjects) by visual estimate.

■

Clinical success (assessed for DCB ISR Cohort only) defined as procedural success without procedural complications (mortality, major target limb amputation, thrombosis of the target lesion, or TVR) prior to discharge.

■

Technical success (assessed for PTA ISR Comparator only) defined as the ability to cross the lesion without resulting in occlusion and having residual stenosis ≤ 30% and resting systolic pressure gradient < 10 mmHg (if measured).

Statistical references:

■

Numbers are cumulative incidence % (number of failures) based on Kaplan-Meier method unless otherwise stated. CI – Confidence Interval

■

Numbers are % (counts/sample size)

■

Subgroup Analyses

Medtronic has analyzed the clinical evaluation results by the male and female gender subgroups. Both the male and female gender subgroups showed favorable trends on the primary effectiveness endpoint of 12-month TLR (male subgroup: 8.72% DCB vs. 32.94% PTA, and female subgroup: 14.08% DCB vs. 39.11% PTA). Favorable clinical trends were also noted for the

Instructions for Use English 43

secondary endpoint of 12-month TVR (male subgroup: 10.48% DCB vs. 34.67% PTA, and female subgroup: 14.08% DCB vs.

41.76% PTA).

Summary of Adverse Events

A serious adverse event was defined in the IN.PACT Global Study protocol as an adverse event that led to death; led to serious deterioration in the health of the subject that resulted in a life-threatening illness or injury, a permanent impairment of a body structure or a body function, in-patient or prolonged hospitalization, or medical or surgical intervention to prevent lifethreatening illness or injury or permanent impairment to a body structure of a body function; or led to fetal distress, fetal death or a congenital abnormality or birth defect.

Table 20 provides a summary of serious adverse event rates by system-organ class (SOC) through 360 days occurring in the DCB ISR Cohort.

Table 20. Serious Adverse Event Rates by SOC and Preferred Term through 360 Days – IN.PACT Global DCB ISR Cohort

Subjects

Serious Adverse Event DCB ISR Cohort

(N=164 Subjects) Subjects with One or More Serious Adverse Events 41.5% (68/164) CARDIAC DISORDERS

2.4% (4/164)

ACUTE MYOCARDIAL INFARCTION 0.6% (1/164) ATRIAL FIBRILLATION 0.6% (1/164) CONGESTIVE CARDIOMYOPATHY 0.6% (1/164) CORONARY ARTERY DISEASE 0.6% (1/164) MYOCARDIAL INFARCTION 0.6% (1/164)

CONGENITAL, FAMILIAL AND GENETIC DISORDERS

0.6% (1/164)

CONGENITAL CYSTIC KIDNEY DISEASE 0.6% (1/164)

EYE DISORDERS

1.2% (2/164)

CATARACT 0.6% (1/164) RETINAL ARTERY OCCLUSION 0.6% (1/164)

GASTROINTESTINAL DISORDERS

1.2% (2/164)

GASTRITIS 0.6% (1/164) OESOPHAGEAL HAEMORRHAGE 0.6% (1/164)

GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS

1.2% (2/164)

DEATH 0.6% (1/164) DEVICE BREAKAGE 0.6% (1/164)

HEPATOBILIARY DISORDERS

1.2% (2/164)

ACUTE HEPATIC FAILURE 0.6% (1/164) CHOLECYSTITIS 0.6% (1/164) CHOLELITHIASIS 0.6% (1/164)

INFECTIONS AND INFESTATIONS

3.0% (5/164)

CLOSTRIDIUM DIFFICILE COLITIS 0.6% (1/164) GANGRENE 0.6% (1/164) GROIN INFECTION 0.6% (1/164) PILONIDAL CYST 0.6% (1/164) PNEUMONIA 0.6% (1/164) PSEUDOMEMBRANOUS COLITIS 0.6% (1/164) URINARY TRACT INFECTION 0.6% (1/164)

INJURY, POISONING AND PROCEDURAL COMPLICATIONS

7.3% (12/164)

ARTERIAL RESTENOSIS 2.4% (4/164) IN-STENT ARTERIAL RESTENOSIS 4.3% (7/164) IN-STENT CORONARY ARTERY RESTENOSIS 0.6% (1/164) PERIPHERAL ARTERIAL REOCCLUSION 0.6% (1/164) VASCULAR PSEUDOANEURYSM 1.2% (2/164)

INVESTIGATIONS

0.6% (1/164)

INTERNATIONAL NORMALISED RATIO INCREASED 0.6% (1/164)

METABOLISM AND NUTRITION DISORDERS

1.2% (2/164)

DIABETES MELLITUS 0.6% (1/164)

44 Instructions for Use English

Serious Adverse Event DCB ISR Cohort

(N=164 Subjects)

DIABETIC FOOT 0.6% (1/164)

MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS

BACK PAIN 0.6% (1/164) INTERVERTEBRAL DISC PROTRUSION 0.6% (1/164) MUSCULOSKELETAL DISORDER 0.6% (1/164) MYOFASCIAL PAIN SYNDROME 0.6% (1/164) PAIN IN EXTREMITY 0.6% (1/164) SPINAL COLUMN STENOSIS 0.6% (1/164)

NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS)

LUNG NEOPLASM 0.6% (1/164) LUNG NEOPLASM MALIGNANT 0.6% (1/164) MALIGNANT NEOPLASM PROGRESSION 0.6% (1/164) NEOPLASM SKIN 0.6% (1/164) OESOPHAGEAL CARCINOMA 0.6% (1/164) PROSTATE CANCER RECURRENT 0.6% (1/164)

NERVOUS SYSTEM DISORDERS

CAROTID ARTERY STENOSIS 0.6% (1/164) CEREBROVASCULAR ACCIDENT 0.6% (1/164) FACIAL PALSY 0.6% (1/164) PARAESTHESIA 0.6% (1/164)

RENAL AND URINARY DISORDERS

BLADDER TAMPONADE 0.6% (1/164) NEPHROLITHIASIS 0.6% (1/164) RENAL COLIC 0.6% (1/164)

REPRODUCTIVE SYSTEM AND BREAST DISORDERS

UTERINE POLYP 0.6% (1/164)

RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS

DYSPNOEA 1.2% (2/164)

SURGICAL AND MEDICAL PROCEDURES

LEG AMPUTATION 0.6% (1/164)

VASCULAR DISORDERS

25.0% (41/164)

ARTERIAL OCCLUSIVE DISEASE 0.6% (1/164) ARTERIAL STENOSIS LIMB 0.6% (1/164) ARTERIAL THROMBOSIS 0.6% (1/164) ARTERIAL THROMBOSIS LIMB 3.0% (5/164) ARTERIOSCLEROSIS OBLITERANS 0.6% (1/164) EMBOLISM 0.6% (1/164) FEMORAL ARTERIAL STENOSIS 6.7% (11/164) FEMORAL ARTERY OCCLUSION 4.3% (7/164) HAEMORRHAGE 0.6% (1/164) HYPERTENSION 0.6% (1/164) HYPERTENSIVE CRISIS 0.6% (1/164) INTERMITTENT CLAUDICATION 3.7% (6/164) PERIPHERAL ARTERIAL OCCLUSIVE DISEASE 4.3% (7/164) PERIPHERAL EMBOLISM 0.6% (1/164) PERIPHERAL ISCHAEMIA 3.0% (5/164) VESSEL PERFORATION 0.6% (1/164)

3.7% (6/164)

2.4% (4/164)

1.2% (2/164)

0.6% (1/164)

1.2% (2/164)

0.6% (1/164)

Instructions for Use English 45

Serious Adverse Event DCB ISR Cohort

(N=164 Subjects) Total Serious Adverse Events 123

Numbers are % (counts/sample size) unless otherwise stated.

Site reported data.

11.8. IN.PACT Global DCB Long Lesion Sub-Cohort

11.8.1. Primary Objective

The objective of this clinical evaluation was to assess the safety and effectiveness of the IN.PACT Admiral DCB in the treatment of long restenotic lesions (lesion length >180 mm) in the superficial femoral and popliteal arteries.

11.8.2. Design

This clinical evaluation was designed as an observational, non-randomized, multi-center, single-arm evaluation that is intended to assess the safety and effectiveness performance of the IN.PACT Admiral DCB for the treatment of de novo, restenotic, or instent restenotic long lesions (lesion length > 180 mm) in the superficial femoral and/or popliteal artery vessels.

A total of 227 DCB subjects from the IN.PACT Global Study Imaging Cohorts (Long Lesion, In-Stent Restenosis and Chronic Total Occlusions), and meeting specific post-hoc inclusion criteria (including lesion lengths > 180 mm, Rutherford clinical category 2-4, and single unilateral treated lesions), comprised the DCB Long Lesion Sub-Cohort. Patients in the DCB Long Lesion Sub-Cohort were treated at 28 sites from 13 countries, including Austria, Belgium, Canada, Colombia, Germany, Hungary, Italy, The Netherlands, Singapore, Slovakia, South Korea, Switzerland and the United Kingdom. The 227 DCB subjects were enrolled at these IN.PACT Global Study sites between 6 June 2012 and 16 December 2013.

The primary effectiveness endpoint is Primary Patency within 12 months post-index procedure, which is defined as:

■

Freedom from clinically-driven TLR, and

■

Freedom from restenosis as determined by DUS Peak Systolic Velocity Ratio (PSVR) ≤ 2.4.

The Primary Safety Endpoint is a composite endpoint through 12 months. Composite Safety Endpoint is defined as freedom from device- and procedure-related death through 30 days post procedure and freedom from target limb major amputation and clinically-driven TVR within 12 months post index procedure.

The secondary endpoints include:

■

Major Adverse Events (MAE) through 12 months. MAE is defined as all-cause death, clinically-driven TVR, major target limb amputation, thrombosis at the target lesion site

■

All-cause mortality at 30 days, 6 months, and 12 months.

■

CD-TLR5 at 30 days, 6 months, and 12 months.

■

Any TVR at 30 days, 6 months and 12 months.

■

CD-TVR at 30 days, 6 months and 12 months.

■

Thrombosis at the target lesion site at 30 days, 6 months and 12 months.

■

Major target limb amputation at 30 days, 6 months and 12 months.

■

Time to first TLR through 12 months post-index procedure.

■

Time to all-cause mortality through 12 months post-index procedure.

■

Primary sustained clinical improvement6 at 6 and 12 months.

■

Secondary sustained clinical improvement7 at 6 and 12 months.

■

Walking impairment evaluation by Walking Impairment Questionnaire (WIQ) at 6 and 12 months.

■

Walking distance as measured by 6 Minute Walk Test at 6 and 12 months.

■

Device success

■

Procedural success

■

Clinical success

■

Binary restenosis within 12 months post-index procedure, which is determined by DUS PSVR > 2.4.

Clinically-driven TLR is defined as any re-intervention within the target lesion due to symptoms or drop of ABI of ≥ 20% or > 0.15 when compared to post-index procedure baseline ABI.

Primary sustained clinical improvement is defined as sustained upward shift of at least 1 category on Rutherford classification as compared to baseline without the need for repeated TLR or surgical revascularization in amputation-free surviving subjects.

Secondary sustained clinical improvement is defined as sustained upward shift of at least 1 category on Rutherford classification as compared to baseline including the need for repeated TLR or surgical revascularization in amputation-free surviving subjects.

Device success is defined as successful delivery, balloon inflation and deflation and retrieval of the intact study device without burst below the rated burst pressure (RBP).

Procedural success is defined as residual stenosis of ≤ 50% (non-stented subjects) or ≤ 30% (stented subjects) by visual estimate.

Clinical success is defined as procedural success without procedural complications (mortality, major target limb amputation, thrombosis of the target lesion, or TVR) prior to discharge.

46 Instructions for Use English

11.8.3. Patient Population

Subject demographics, medical history, and risk factors of the 227 IN.PACT Global DCB Long Lesion Sub-Cohort subjects are summarized in Baseline Demographics and Clinical Characteristics (Table 21).

Table 21. Baseline Demographics and Clinical Characteristics- IN.PACT Global DCB Long Lesion Sub-Cohort Subjects

Subject Characteristics

IN.PACT Admiral DCB

(N=227 Subjects)

Age (yrs)

N 226 Mean ± SD 68.8 ± 9.7 Median 69.0 Min, Max 37, 90

BMI (kg/m²)

N 222 Mean ± SD 26.7 ± 4.6 Median 26.4

Min, Max 16, 47 Obesity (BMI ≥ 30 kg/m²) 20.7% (46/222) Male 67.4% (153/227) Hypertension 86.7% (195/225) Hyperlipidemia 71.7% (157/219) Diabetes Mellitus 38.7% (87/225) Insulin Dependent Diabetes Mellitus 18.2% (41/225) Carotid Artery Disease 24.0% (49/204) Coronary Heart Disease 40.6% (89/219) Current Smoker 42.7% (97/227) Renal Insufficiency (baseline serum creatinine ≥ 1.5 mg/dl) 12.3% (25/203) On Dialysis 1.8% (4/226) Below-the-knee Vascular Disease of Target Leg (Stenotic/Occluded) 48.6% (101/208) Previous Peripheral Revascularization 58.1% (132/227)

Iliac 21.1% (48/227)

Common Femoral 7.0% (16/227)

Femoral Profunda 1.3% (3/227)

Superficial Femoral 48.9% (111/227)

Popliteal 14.1% (32/227)

Below-the-knee 8.4% (19/227)

Other Location 1.3% (3/227) Previous Limb Amputation 1.3% (3/227)

Toe 0.4% (1/227)

Transmetatarsal 0.0% (0/227)

Below-the-knee 0.0% (0/227)

Above-the-knee 0.9% (2/227) Rutherford Category

0 0.0% (0/227)

1 0.0% (0/227)

2 22.5% (51/227)

3 65.2% (148/227)

4 12.3% (28/227)

5 0.0% (0/227)

6 0.0% (0/227) ABIb (mmHg ratio)

N 198

Mean ± SD 0.625 ± 0.214

Median 0.630

Min, Max 0.00, 1.67

Instructions for Use English 47

Subject Characteristics

IN.PACT Admiral DCB

(N=227 Subjects)

Numbers are % (counts/sample size) unless otherwise stated. Rutherford clinical grades and categories: Grade Category Clinical Description 0 0 Asymptomatic, no hemodynamically significant occlusive dis-

ease I 1 Mild claudication I 2 Moderate claudication I 3 Severe claudication II 4 Ischemic rest pain III 5 Minor tissue loss; non-healing ulcer; focal gangrene with dif-

fuse pedal ischemia III 6 Major tissue loss extending above transmetatarsal level; func-

tional foot no longer salvageable

Site reported data

ABI for all target limbs treated during the 1st index procedure are included (can be bilateral)

The baseline lesion characteristics, as reported by the sites and angiographic core laboratories, have been provided in Procedural Lesion Characteristics (Table 22). The mean total target lesion length treated was 28.74 ± 7.11 cm.

Table 22. Procedural Lesion Characteristics – IN.PACT Global DCB Long Lesion Sub-Cohort Subjects

Procedural Lesion Characteristics (per lesion) IN.PACT Admiral DCB (N=227 Subjects) (N=227 Lesions)

Pre-procedure

RVD (mm)

N 133 Mean ± SD 4.611 ± 0.896 Median 4.500 Min, Max 2.25, 6.85

MLD (mm)

N 134 Mean ± SD 0.332 ± 0.568 Median 0.000

Min, Max 0.00, 2.65 Occluded Lesion (100% stenosis) 70.1% (157/224) Diameter Stenosis (%)

N 224

Mean ± SD 94.1 ± 10.7

Median 100.0

Min, Max 54, 100 Lesion Length (cm)

N 227

Mean ± SD 28.74 ± 7.11

Median 27.50

Min, Max 18.5, 53.0

Occluded Lesion Length (cm)

N 207

Mean ± SD 11.67 ± 11.32

Median 10.00

Min, Max 0.0, 45.0 Post-Procedure

Diameter Stenosis (%)

N 226

Mean ± SD 11.2 ± 12.3

Median 10.0

Min, Max 0, 60 Total Target Lesion Length Treated with Study Device (cm)

48 Instructions for Use English

Procedural Lesion Characteristics (per lesion) IN.PACT Admiral DCB (N=227 Subjects) (N=227 Lesions)

N 226

Mean ± SD 27.46 ± 6.68

Median 26.00

Min, Max 14.5, 47.0 Numbers are % (counts/sample size) unless otherwise stated.

Key Core Laboratory definitions: Reference Vessel Diameter (RVD) – angiographic measurement

of the normal artery proximal and/or distal to the lesion intended for treatment.

Minimum Lumen Diameter (MLD) – angiographic measurement of the tightest area of obstruction or stenosis located within the segment of interest or the intended area of treatment.

Lesion length – angiographic measurement from the proximal healthy vessel segment to the distal healthy vessel segment (e.g. length of obstruction).

Angio core lab reported data.

Site reported data.

As shown in Table 23 below, a total of 96 IN.PACT Global DCB Long Lesion Sub-Cohort subjects (42.5%) received provisional stenting. The mean total stent length per subject was 173.7 ± 104.7 mm.

Table 23. Provisional Stenting – IN.PACT Global DCB Long Lesion Sub-Cohort

Subject Characteristics IN.PACT Admiral DCB (N=227 Subjects)

Provisional Stent Rate per Subject 42.5% (96/226) Total Provisional Stent Length per Subject (mm)

N 96 Mean ± SD 173.7 ± 104.7 Median 150.0 Min, Max 10, 450

Numbers are % (counts/sample size). Site reported data.

Follow-up compliance through the 12-month follow-up visits is presented in Table 24 for the IN.PACT Global DCB Long Lesion Sub-Cohort subjects. The rate of in-window follow-up visit completion at 12 months was 84.5%.

Table 24. Subject Follow-up Compliance – IN.PACT Global DCB Long Lesion Sub-Cohort

Subject Compliance Characteristics

IN.PACT Admiral DCB (N=227)

30-Day Follow-up

Eligible Subjects

Death

Withdrawal Follow-up Not Done Follow-up Visit Within Window Follow-up Visit Out of Window Within Window Follow-up Compliance (%) Overall Follow-up Compliance (%)

225

197

87.6%

94.2%

6-Month Follow-up

Eligible Subjects

Death

Withdrawal Follow-up Not Done Follow-up Visit Within Window Follow-up Visit Out of Window

Within Window Follow-up Compliance (%) Overall Follow-up Compliance (%)

218

1 8

171

78.4%

87.6%

12-Month Follow-up

Instructions for Use English 49

Subject Compliance Characteristics

Eligible Subjects

Death

Withdrawal Follow-up Not Done Follow-up Visit Within Window Follow-up Visit Out of Window

Within Window Follow-up Compliance (%) Overall Follow-up Compliance (%)

Site reported data

Death, withdrawal and follow-up not done are cumulative

Within window visits are defined as: 30-day ± 7 days, 6-month ± 30 days, 12-month ± 30 days.

Percentage based on number of subjects who had follow-up visit within window divided by total number of eligible subjects

Percentage based on number of subjects who had a follow-up visit within or out of window divided by total number of eligible subjects

11.8.4.

Primary Effectiveness and Safety Results

IN.PACT Admiral DCB (N=227)

207

5 15 20

175

84.5%

90.3%

The primary effectiveness and safety results are shown in Table 25 and Figure 12 below. The primary effectiveness endpoint is defined as primary patency within 12 months post-index procedure. Primary patency is

defined as freedom from CD-TLR and freedom from restenosis as determined by DUS PSVR ≤ 2.4. Primary patency at 12 months was 64.9% for all subjects.

Table 25. Primary Effectiveness and Safety Results through 12 Months – IN.PACT Global DCB Long Lesion Sub-Cohort

Subjects

Parameters IN.PACT Admiral DCB

(N=227 Subjects)

Effectiveness Parameters

Primary Effectiveness Endpoint – Primary Patency at 12 Months 64.9% (98/151)

Safety Parameters

Primary Safety Composite Endpoint – Freedom from: 92.9% (195/210)

Device- and Procedure-related Death through 30 Days 0.0% (0/225) Target Limb Major Amputation within 360 Days 0.0% (0/210) Clinically-driven TVR within 360 Days 7.1% (15/210)

Death (all-cause) within 360 days 2.4% (5/210)

The Kaplan-Meier analysis of this primary effectiveness endpoint, presented as primary patency through 420 days, is shown in Figure 12.

50 Instructions for Use English

From day X To day Y

IN.PACT DCB

(N=227 Subjects)

# Censored

# Events

Event-free [%]

# Entered

303160619091120

121

150

151

180

181

210

211

240

241

270

271

300

301

330

331

360

361

390

391

420

227 227 224 215 214 214 213 210 205 203 200 195 190 181 157

100.0%

99.6%

97.7%

97.3%

96.8%

96.4%

95.9%

94.5%

94.0%

93.0%

89.1%

79.1%

77.1%

Primary Patency

Time after Index Procedure (days)

100%

90%

80%

70%

60%

50%

40%

30%

20%

10%

0 30 60 90 120 150 180 210 240 270 300 330 360 390 420

89.1%

77.1%

Figure 12. Kaplan-Meier Plot - Primary Patency through 420 Days

11.8.5. Secondary Safety and Effectiveness Endpoints

The results of the secondary endpoints for the IN.PACT Global DCB Long Lesion Sub-Cohort Clinical Evaluation are shown in Table 26.

The primary sustained clinical improvement was 80.9% (152/188) at 12-months post-procedure. The device, procedural and clinical success was over 99% for the entire subject population in this sub-cohort (99.2%, 99.1% and 99.1% respectively).

The MAE composite for the long lesion sub-cohort at 360-days was 10.5% (22/210). Reported MAEs within 360-days included

2.4% death (5/210), 3.3% thrombosis (7/210) and no cases of major target limb amputation. Reintervention rates were reported as 7.1% (15/210) clinically-driven TVR and 7.1% (15/210) clinically-driven TLR. The average time to first clinically-driven TLR was 177.8 days. Other major secondary endpoints included binary restenosis (PSVR>2.4) in 34.2% (51/149) of subjects.

Table 26. Secondary Endpoints through 12 Months – IN.PACT Global DCB Long Lesion Sub-Cohort

Parameters IN.PACT Admiral DCB

(N=227 Subjects)

Effectiveness Parameters

Primary Sustained Clinical Improvement at 12 Months 80.9% (152/188) Secondary Sustained Clinical Improvement at 12 Months 86.5% (160/185) Device Success 99.2% (653/658) Procedural Success 99.1% (224/226) Clinical Success 99.1% (224/226)

Cumulative complications within 360 days

MAE Composite (Death, Major Target Limb Amputation, Clinically-driven TVR, Thrombosis)

Death (all-cause) 2.4% (5/210) Clinically-driven TVR 7.1% (15/210)

10.5% (22/210)

Major Target Limb Amputation 0.0% (0/210)

Instructions for Use English 51

Parameters IN.PACT Admiral DCB

(N=227 Subjects)

Thrombosis 3.3% (7/210) Clinically-driven TLR 7.1% (15/210) Any TVR 7.1% (15/210) Any TLR 7.1% (15/210)

Other Major Secondary Endpoints at 12 Months

Binary Restenosis (PSVR >2.4) 34.2% (51/149) Time to First Clinically-driven TLR (days)

N 15

Mean ± SD 177.8 ± 115.9

Median 204.0

Min, Max 21, 356 Walking Impairment by WIQ (%)

N 178

Mean ± SD 73.7 ± 32.5

Median 100.0

Min, Max 0, 100

Endpoint definitions:

■

Clinically-driven TLR is defined as any reintervention at the target lesion due to symptoms or drop of ABI/TBI of ≥20% or >0.15 when compared to post-procedure baseline ABI/TBI

■

Device success defined as successful delivery, inflation, deflation and retrieval of the intact study balloon device without burst below the RBP. Results reported as device based summary.

■

Procedure success defined as residual stenosis of ≤ 50% (non-stented subjects) or ≤ 30% (stented subjects) by corelab (if corelab was not available then the site-reported estimate was used).

■

Clinical success defined as procedural success without procedural complications (death, major target limb amputation, thrombosis of the target lesion, or TVR) prior to discharge.

■

Safety composite endpoint consists of: freedom from device- and procedure-related death within 30 days, freedom from major target limb amputation, and freedom from clinically-driven TVR within 360 days post-index procedure.

■

Clinically-driven TLR/TVR is defined as any re-intervention within the target vessel due to symptoms or drop of ABI/TBI of ≥20% or >0.15 when compared to post-procedure baseline ABI/TBI.

■

Major Adverse Events (MAE) defined as all-cause death, clinically-driven TLR/TVR, major target limb amputation, thrombosis at the target lesion site at 360 days

■

Walking impairment assessed by Walking Impairment Questionnaire (WIQ) at 12 months.

Data sources:

All events were adjudicated by the independent Clinical Events Committee, all duplex ultrasound and angiographic measures were made by the independent core laboratories, and all other data were site reported.

11.8.6. Subgroup Analysis

Medtronic has analyzed the clinical evaluation results by lesion length grouping, gender, and assigned imaging cohorts.

11.8.7. Lesion Length Grouping Analysis

The outcomes for subjects by respective lesion length grouping are presented below in Table 27. The primary patency by lesion length group were 75.5% (40/53) for lesions >180-240 mm, 65.1% (28/43) for lesions >240-300 mm, 63.3% (19/30) for lesions >300-360 mm, and 44.0% (11/25) for lesions > 360 mm.

The primary safety composite by lesion length group were 95.8% (68/71) for lesions >180-240 mm, 93.7% (59/63) for lesions >240-300 mm, 92.3% (36/39) for lesions >300-360 mm, and 86.5% (32/37) for lesions > 360 mm. There were no device- or procedure-related deaths through 30 days or major target limb amputations through 12 months.

52 Instructions for Use English

Table 27. Principal Effectiveness and Safety Results through 12-months by Lesion Length Groups – IN.PACT Global DCB

Long Lesion Sub- Cohort

Parameters 18-24cm 24-30cm 30-36cm >36cm

(N=77 Subjects) (N=66 Subjects) (N=43 Subjects) (N=41 Subjects)

Lesion Length (cm)

N 77 66 43 41 Mean ± SD 21.65 ± 1.71 27.17 ± 1.88 32.74 ± 1.73 40.37 ± 3.83 Q1 20.0 25.5 31.0 37.5 Median 22.00 26.75 32.50 39.00 Q3 23.0 29.0 34.0 42.0 Min, Max 18.5, 24.0 24.5, 30.0 30.5, 36.0 36.5, 53.0

Effectiveness Parameters

Primary Patency at 12 Months

Primary Sustained Clinical Improvement at 12 Months

Secondary Sustained Clinical Improvement at 12 Months

Device Success 100.0% (178/178) 99.5% (186/187) 99.3% (136/137) 98.1% (153/156) Procedural Success 100.0% (76/76) 98.5% (65/66) 97.7% (42/43) 100.0% (41/41) Clinical Success 100.0% (76/76) 98.5% (65/66) 97.7% (42/43) 100.0% (41/41)

Safety Parameters

Primary Safety Composite Endpoint – Freedom from:

Device- and Procedurerelated Death through 30 Days

Target Limb Major Amputation within 360 Days

Clinically-driven TLR within 360 Days

Death (all-cause) within 30 days

Cumulative complications within 360 days

MAE Composite (Death, Major Target Limb Amputation, Clinically-driven TVR, Thrombosis)

Death (all-cause) 0.0% (0/71) 3.2% (2/63) 2.6% (1/39) 5.4% (2/37) Clinically-driven TVR 4.2% (3/71) 6.3% (4/63) 7.7% (3/39) 13.5% (5/37) Major Target Limb

Amputation Thrombosis at Target

Lesion Clinically-driven TLR 4.2% (3/71) 6.3% (4/63) 7.7% (3/39) 13.5% (5/37) Any TVR 4.2% (3/71) 6.3% (4/63) 7.7% (3/39) 13.5% (5/37) Any TLR 4.2% (3/71) 6.3% (4/63) 7.7% (3/39) 13.5% (5/37)

Other Major Secondary Endpoints at 12 Months

75.5% (40/53) 65.1% (28/43) 63.3% (19/30) 44.0% (11/25)

83.3% (55/66) 83.6% (46/55) 82.9% (29/35) 68.8% (22/32)

86.4% (57/66) 89.1% (49/55) 91.2% (31/34) 76.7% (23/30)

95.8% (68/71) 93.7% (59/63) 92.3% (36/39) 86.5% (32/37)

0.0% (0/76) 0.0% (0/66) 0.0% (0/42) 0.0% (0/41)

0.0% (0/71) 0.0% (0/63) 0.0% (0/39) 0.0% (0/37)

4.2% (3/71) 6.3% (4/63) 7.7% (3/39) 13.5% (5/37)

0.0% (0/76) 0.0% (0/66) 0.0% (0/42) 0.0% (0/41)

5.6% (4/71) 12.7% (8/63) 7.7% (3/39) 18.9% (7/37)

0.0% (0/71) 0.0% (0/63) 0.0% (0/39) 0.0% (0/37)

1.4% (1/71) 3.2% (2/63) 5.1% (2/39) 5.4% (2/37)

Instructions for Use English 53

Parameters 18-24cm 24-30cm 30-36cm >36cm

(N=77 Subjects) (N=66 Subjects) (N=43 Subjects) (N=41 Subjects)

Binary Restenosis

24.5% (13/53) 34.9% (15/43) 34.5% (10/29) 54.2% (13/24)

(PSVR >2.4) Time to First Clinically-

driven TLR (days)

N 3 4 3 5

Mean ± SD 221.0 ± 71.8 150.3 ± 149.2 91.7 ± 98.4 225.6 ± 110.9

Median 242.0 104.5 50.0 241.0

Min, Max 141, 280 37, 355 21, 204 50, 356 Walking Impairment by

WIQ (%)

N 63 54 32 29

Mean ± SD 73.0 ± 34.9 79.2 ± 28.2 75.0 ± 33.6 63.8 ± 32.4

Median 100.0 100.0 100.0 50.0

Min, Max 0, 100 0, 100 0, 100 0, 100

Endpoint definitions:

■

Primary patency is defined as freedom from clinically-driven TLR1 and freedom from restenosis as determined by duplex ultrasound2 (DUS) Peak Systolic Velocity Ratio (PSVR) ≤ 2.43 within 12 months. Key Primary Patency endpoint definition components:

Clinically-driven TLR is defined as any reintervention at the target lesion due to symptoms or drop of ABI/TBI of ≥20% or

>0.15 when compared to post-procedure baseline ABI/TBI

Post-index procedure DUS is intended to establish a post-treatment baseline and does not contribute to the Primary End-

point determination

Restenosis determined by either PSVR >2.4 (determined by Target Lesion Category of ’50-99%’ or ‘Occluded’) as

assessed by an independent DUS core lab or >50% stenosis as assessed by an independent angiographic core lab

■

Device success defined as successful delivery, inflation, deflation and retrieval of the intact study balloon device without burst below the RBP.

■

Results reported as a device-based summary.

■

Procedure success defined as residual stenosis of ≤ 50% (non-stented subjects) or ≤ 30% (stented subjects) by corelab (if corelab was not available then the site-reported estimate was used).

■

Clinical success defined as procedural success without procedural complications (death, major target limb amputation, thrombosis of the target lesion, or TVR) prior to discharge.

■

Safety composite endpoint consists of: freedom from device- and procedure-related death within 30 days; freedom from major target limb amputation; and freedom from clinically-driven TVR within 360 days post-index procedure.

■

Clinically-driven TVR/TLR is defined as any re-intervention within the target vessel due to symptoms or drop of ABI/TBI of ≥20% or >0.15 when compared to post-procedure baseline ABI/TBI.

■

Major Adverse Events (MAE) defined as all-cause death, clinically-driven TLR/TVR, major target limb amputation, thrombosis at the target lesion site at 360 days.

■

Binary restenosis is defined as duplex restenosis (PSVR > 2.4) of the target lesion at 12 months post-procedure, or at the time of reintervention prior to any pre-specified timepoint.

■

Walking impairment assessed by Walking Impairment Questionnaire (WIQ) at 12 months.

Data sources:

11.8.8. Gender Analysis

The results of sub-group analysis on gender are summarized in Table 28 below. The IN.PACT Global DCB Long Lesion SubCohort included 153 males and 74 females at the time of the procedure. The comparison between genders showed the primary patency at 12 months to be 66.7% (70/105) in males and 60.9% (28/46) in females. The primary safety composite endpoint at

54 Instructions for Use English

12 months was reported as 91.5% (129/141) and 95.7% (66/69) in males compared to females respectively. The MAE composite at 360 days were 10.6% (15/141) in males and 10.1% (7/69) in females.

Table 28. Principal Effectiveness and Safety Results through 12 Months by Gender – IN.PACT Global DCB Long Lesion Sub-

Cohort

Parameters Male Subjects (N=153 Subjects) Female Subjects (N=74 Subjects) Effectiveness Parameters

Primary Effectiveness Endpoint – Primary Patency at 12 Months

Primary Sustained Clinical Improvement at 12 Months

Secondary Sustained Clinical Improvement at 12 Months

Device Success 98.9% (455/460) 100.0% (198/198) Procedural Success 100.0% (153/153) 97.3% (71/73) Clinical Success 100.0% (153/153) 97.3% (71/73)

Safety Parameters

Primary Safety Composite Endpoint – Freedom from:

Device- and Procedure-related Death through 30 Days

Target Limb Major Amputation within 360 Days

Clinically-driven TVR within 360 Days 8.5% (12/141) 4.3% (3/69) Death (all-cause) within 30 days 0.0% (0/151) 0.0% (0/74)

Cumulative complications within 360 days

MAE Composite (Death, Major Target Limb Amputation, Clinically-driven TVR, Thrombosis)

Death (all-cause) 2.8% (4/141) 1.4% (1/69) Clinically-driven TVR 8.5% (12/141) 4.3% (3/69) Major Target Limb Amputation 0.0% (0/141) 0.0% (0/69) Thrombosis 2.8% (4/141) 4.3% (3/69) Clinically-driven TLR 8.5% (12/141) 4.3% (3/69) Any TVR 8.5% (12/141) 4.3% (3/69) Any TLR 8.5% (12/141) 4.3% (3/69)

Other Major Secondary Endpoints at 12 Months

Binary Restenosis (PSVR >2.4) 32.0% (33/103) 39.1% (18/46) Time to First Clinically-driven TLR (days) N 12 3 Mean ± SD 195.5 ± 113.5 107.0 ± 116.9 Median 213.0 42.0 Min, Max 21, 356 37, 242 Walking Impairment by WIQ (%) N 122 56 Mean ± SD 73.0 ± 32.1 75.4 ± 33.5 Median 100.0 100.0 Min, Max 0, 100 0, 100

66.7% (70/105) 60.9% (28/46)

79.7% (102/128) 83.3% (50/60)

86.4% (108/125) 86.7% (52/60)

91.5% (129/141) 95.7% (66/69)

0.0% (0/151) 0.0% (0/74)

0.0% (0/141) 0.0% (0/69)

10.6% (15/141) 10.1% (7/69)

11.8.9. Assigned Imaging Cohorts Analyses

The IN.PACT Global DCB Long Lesion Sub-Cohort was composed of subjects meeting the inclusion criteria specific to this analysis from the three imaging cohorts (Long Lesion, CTO, and ISR) in the IN.PACT Global study. As such, a breakdown of the subject outcomes for each of the imaging cohorts was conducted and the results of that analysis are presented in Table 29 below. Slight variability was seen in for the primary effectiveness outcome as the Long Lesion, CTO and ISR imaging groups reported patency at 12 months of 66.2% (47/71), 68.8% (33/48), and 56.3% (18/32) respectively. The primary safety composite

Instructions for Use English 55

endpoint amongst the three imaging cohorts was 94.2% (98/104) for Long Lesion, 92.2% (59/64) for CTO, and 90.5% (38/42) for ISR. The cumulative MAE rate at 360 days was 10.6% (11/104), 10.9% (7/64), 9.5% (4/42) for the Long Lesion, CTO and ISR imaging cohorts respectively. It is noted that the reintervention rates (TVR or TLR) were highest in the ISR group compared to Long Lesions or CTO. Conversely, the ISR group had no reported cases of death or thrombosis compared to the Long Lesion (2.9% and 4.8% respectively) and the CTO (3.1% and 3.1% respectively) imaging cohorts. Overall, binary restenosis in the imaging cohorts was 33.8% (24/71) for Long Lesion, 28.3% (13/46) for CTO, and 43.8% (14/32) for ISR.

Table 29. Principal Effectiveness and Safety Results through 12 Months by Assigned Imaging Sub-Cohort – IN.PACT Global

DCB Long Lesion Sub-Cohort

Parameters Long Lesion CTO De novo ISR

(N=114 Subjects) (N=67 Subjects) (N=46 Subjects)

Effectiveness Parameters

Primary Effectiveness Endpoint – Primary Patency at 12 Months

Primary Sustained Clinical Improvement at 12 Months

Secondary Sustained Clinical Improvement at 12 Months

Device Success 99.4% (324/326) 99.0% (191/193) 99.3% (138/139) Procedural Success 99.1% (112/113) 100.0% (67/67) 97.8% (45/46) Clinical Success 99.1% (112/113) 100.0% (67/67) 97.8% (45/46)

Safety Parameters

Primary Safety Composite Endpoint – Freedom from:

Device- and Procedure-related Death through 30 Days

Target Limb Major Amputation within 360 Days

Clinically-driven TVR within 360 Days

Death (all-cause) within 30 days

Cumulative complications within 360 days

MAE Composite (Death, Major Target Limb Amputation, Clinically-driven TVR, Thrombosis)

Death (all-cause) 2.9% (3/104) 3.1% (2/64) 0.0% (0/42) Clinically-driven TVR 5.8% (6/104) 7.8% (5/64) 9.5% (4/42) Major Target Limb Amputation 0.0% (0/104) 0.0% (0/64) 0.0% (0/42) Thrombosis 4.8% (5/104) 3.1% (2/64) 0.0% (0/42) Clinically-driven TLR 5.8% (6/104) 7.8% (5/64) 9.5% (4/42) Any TVR 5.8% (6/104) 7.8% (5/64) 9.5% (4/42) Any TLR 5.8% (6/104) 7.8% (5/64) 9.5% (4/42)

Other Major Secondary Endpoints at 12 Months

Binary Restenosis (PSVR >2.4) 33.8% (24/71) 28.3% (13/46) 43.8% (14/32) Time to First Clinically-driven

TLR (days) N 6 5 4 Mean ± SD 182.8 ± 123.3 224.0 ± 124.6 112.5 ± 85.7 Median 191.5 241.0 104.5 Min, Max 50, 355 21, 356 37, 204 Walking Impairment by WIQ

(%) N 86 53 39

66.2% (47/71) 68.8% (33/48) 56.3% (18/32)

82.6% (76/92) 83.9% (47/56) 72.5% (29/40)

85.7% (78/91) 90.7% (49/54) 82.5% (33/40)

94.2% (98/104) 92.2% (59/64) 90.5% (38/42)

0.0% (0/114) 0.0% (0/66) 0.0% (0/45)

0.0% (0/104) 0.0% (0/64) 0.0% (0/42)

5.8% (6/104) 7.8% (5/64) 9.5% (4/42)

0.0% (0/114) 0.0% (0/66) 0.0% (0/45)

10.6% (11/104) 10.9% (7/64) 9.5% (4/42)

56 Instructions for Use English

Parameters Long Lesion CTO De novo ISR

(N=114 Subjects) (N=67 Subjects) (N=46 Subjects)

Mean ± SD 70.3 ± 34.8 79.7 ± 28.2 73.1 ± 32.1 Median 75.0 100.0 100.0 Min, Max 0, 100 0, 100 0, 100

11.8.10. Summary of Serious Adverse Events

As shown in Table 30, there were a total of 246 serious adverse events reported in the IN.PACT Global DCB Long Lesion SubCohort within 360 days. In total, 52.0% of subjects experienced one or more serious adverse events.

Table 30. Number of Subjects with One or More Serious Adverse Events through 360 days by MedDRA System-Organ Class

and Preferred Term – IN.PACT Global DCB Long Lesion Sub-Cohort

Serious Adverse Event

IN.PACT Admiral DCB (N=227 Subjects)

Subjects with One or More Serious Adverse Events 52.0% (118/227) BLOOD AND LYMPHATIC SYSTEM DISORDERS

0.4% (1/227)

LEUKOCYTOSIS 0.4% (1/227)

CARDIAC DISORDERS

7.9% (18/227)

ACUTE MYOCARDIAL INFARCTION 0.9% (2/227) ANGINA PECTORIS 0.4% (1/227) ANGINA UNSTABLE 0.9% (2/227) ARTERIOSCLEROSIS CORONARY ARTERY 0.4% (1/227) ATRIAL FIBRILLATION 0.4% (1/227) ATRIAL FLUTTER 0.4% (1/227) ATRIAL THROMBOSIS 0.4% (1/227) CARDIAC FAILURE 1.3% (3/227) CARDIAC FAILURE ACUTE 0.4% (1/227) CARDIAC FAILURE CONGESTIVE 0.4% (1/227) CONGESTIVE CARDIOMYOPATHY 0.4% (1/227) CORONARY ARTERY DISEASE 2.6% (6/227) CORONARY ARTERY OCCLUSION 0.4% (1/227) CORONARY ARTERY STENOSIS 1.3% (3/227) HYPERTENSIVE HEART DISEASE 0.4% (1/227) ISCHAEMIC CARDIOMYOPATHY 0.9% (2/227)

EAR AND LABYRINTH DISORDERS

0.4% (1/227)

VERTIGO 0.4% (1/227)

ENDOCRINE DISORDERS

0.4% (1/227)

GOITRE 0.4% (1/227)

EYE DISORDERS

0.9% (2/227)

CATARACT 0.4% (1/227) RETINAL ARTERY OCCLUSION 0.4% (1/227)

GASTROINTESTINAL DISORDERS

3.1% (7/227)

COLITIS 0.4% (1/227) GASTRITIS 0.4% (1/227) GASTROINTESTINAL HAEMORRHAGE 1.3% (3/227) OESOPHAGEAL HAEMORRHAGE 0.4% (1/227) REFLUX OESOPHAGITIS 0.4% (1/227)

GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS

3.5% (8/227)

CHEST PAIN 0.9% (2/227) DEATH 0.4% (1/227)

DEVICE OCCLUSION 1.3% (3/227)

Instructions for Use English 57

Serious Adverse Event

IN.PACT Admiral DCB (N=227 Subjects)

IMPAIRED HEALING 0.4% (1/227) PUNCTURE SITE HAEMORRHAGE 0.4% (1/227)

HEPATOBILIARY DISORDERS

0.4% (1/227)

CHOLECYSTITIS 0.4% (1/227) CHOLELITHIASIS 0.4% (1/227)

INFECTIONS AND INFESTATIONS

5.3% (12/227)

BRONCHITIS 0.4% (1/227) ERYSIPELAS 0.4% (1/227) GANGRENE 0.4% (1/227) GASTROENTERITIS VIRAL 0.4% (1/227) GRAFT INFECTION 0.4% (1/227) GROIN INFECTION 0.4% (1/227) INFECTION 0.4% (1/227) NECROTISING FASCIITIS 0.4% (1/227) PNEUMONIA 1.8% (4/227)

INJURY, POISONING AND PROCEDURAL COMPLICATIONS

11.9% (27/227)

ARTERIAL RESTENOSIS 5.3% (12/227) IN-STENT ARTERIAL RESTENOSIS 3.1% (7/227) IN-STENT CORONARY ARTERY RESTENOSIS 0.4% (1/227) PERIPHERAL ARTERIAL REOCCLUSION 0.9% (2/227) POSTOPERATIVE THROMBOSIS 0.4% (1/227) THERMAL BURN 0.4% (1/227) VASCULAR GRAFT OCCLUSION 0.4% (1/227) VASCULAR PSEUDOANEURYSM 2.2% (5/227)

INVESTIGATIONS

1.3% (3/227)

BLOOD CREATININE INCREASED 0.4% (1/227) HAEMOGLOBIN DECREASED 0.4% (1/227) INTERNATIONAL NORMALISED RATIO INCREASED 0.4% (1/227)

METABOLISM AND NUTRITION DISORDERS

2.6% (6/227)

DIABETES MELLITUS 0.9% (2/227) GOUT 0.9% (2/227) HYPOKALAEMIA 0.4% (1/227) HYPONATRAEMIA 0.4% (1/227)

MUSCULOSKELETAL AND CONNECTIVE TISSUE DISOR-

DERS

4.4% (10/227)

ARTHRITIS 0.4% (1/227) BACK PAIN 0.9% (2/227) BURSITIS 0.4% (1/227) INTERVERTEBRAL DISC PROTRUSION 0.4% (1/227) NECK PAIN 0.4% (1/227) OSTEOARTHRITIS 0.4% (1/227) PAIN IN EXTREMITY 0.9% (2/227) ROTATOR CUFF SYNDROME 0.9% (2/227)

NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS)

4.0% (9/227)

BLADDER PAPILLOMA 0.4% (1/227) COLON ADENOMA 0.4% (1/227) LARYNGEAL CANCER 0.4% (1/227) LUNG NEOPLASM MALIGNANT 0.4% (1/227) OESOPHAGEAL CARCINOMA 0.4% (1/227) PROSTATE CANCER RECURRENT 0.4% (1/227) SMALL CELL LUNG CANCER STAGE UNSPECIFIED 0.4% (1/227) SQUAMOUS CELL CARCINOMA 0.4% (1/227) UNDIFFERENTIATED SARCOMA 0.4% (1/227)

58 Instructions for Use English

Serious Adverse Event

NERVOUS SYSTEM DISORDERS

IN.PACT Admiral DCB (N=227 Subjects)

3.5% (8/227)

BASAL GANGLIA INFARCTION 0.4% (1/227) BRAIN EDEMA 0.4% (1/227) CAROTID ARTERY STENOSIS 1.3% (3/227) CEREBRAL INFARCTION 0.4% (1/227) HEMIPARESIS 0.4% (1/227) METABOLIC ENCEPHALOPATHY 0.4% (1/227) SCIATICA 0.4% (1/227) SUBARACHNOID HAEMORRHAGE 0.4% (1/227)

PSYCHIATRIC DISORDERS

0.4% (1/227)

ALCOHOL WITHDRAWAL SYNDROME 0.4% (1/227)

RENAL AND URINARY DISORDERS

0.9% (2/227)

BLADDER TAMPONADE 0.4% (1/227) HAEMATURIA 0.4% (1/227)

REPRODUCTIVE SYSTEM AND BREAST DISORDERS

0.4% (1/227)

POSTMENOPAUSAL HAEMORRHAGE 0.4% (1/227)

RESPIRATORY, THORACIC AND MEDIASTINAL DISOR-

DERS

1.3% (3/227)

DYSPNOEA EXERTIONAL 0.4% (1/227) HYPERVENTILATION 0.4% (1/227) PLEURAL EFFUSION 0.4% (1/227)

SURGICAL AND MEDICAL PROCEDURES

1.3% (3/227)

ILEOSTOMY CLOSURE 0.4% (1/227) PERIPHERAL ARTERY ANGIOPLASTY 0.4% (1/227) PERIPHERAL REVASCULARISATION 0.4% (1/227)

VASCULAR DISORDERS

31.3% (71/227)

AORTIC ANEURYSM 0.4% (1/227) ARTERIAL STENOSIS LIMB 3.5% (8/227) ARTERIAL THROMBOSIS LIMB 2.6% (6/227) EMBOLISM 0.4% (1/227) FEMORAL ARTERIAL STENOSIS 11.9% (27/227) FEMORAL ARTERY DISSECTION 0.4% (1/227) FEMORAL ARTERY OCCLUSION 5.3% (12/227) HAEMATOMA 1.3% (3/227) HYPERTENSION 0.4% (1/227) HYPERTENSIVE CRISIS 0.4% (1/227) ILIAC ARTERY STENOSIS 1.3% (3/227) INTERMITTENT CLAUDICATION 1.3% (3/227) PERIPHERAL ARTERIAL OCCLUSIVE DISEASE 6.6% (15/227) PERIPHERAL EMBOLISM 1.8% (4/227) PERIPHERAL ISCHAEMIA 1.3% (3/227) PERIPHERAL VASCULAR DISORDER 0.4% (1/227) VESSEL PERFORATION 1.3% (3/227)

Total Serious Adverse Events 246

Numbers are % (counts/sample size) unless otherwise stated.

Site reported data

Event verbatim terms are reported by sites. The events listed in this table are then coded using MedDRA version 16.1 and then stratified by System-Organ Class (SOC) and Preferred Term. Patients may be counted in this table more than once by Preferred Term, but are only counted once in the SOC summary line.

11.8.11. Rare Adverse Events

The Clinical Events Committee (CEC) was responsible for adjudicating rare adverse events, including potential distal embolic events in the target limb, thrombosis, paclitaxel-related neutropenia, and paclitaxel-related drug hypersensitivity reaction through 12 months. As reported in Table 31 below, there were no rare adverse events reported for the IN.PACT Global DCB Long Lesion Sub-Cohort.

Instructions for Use English 59

Table 31. Rare Adverse Events - IN.PACT Global DCB Long Lesion Sub-Cohort

Description of Event IN.PACT Admiral DCB/

(N=227 Subjects)

Rare Adverse Events to 180 Days

Paclitaxel-related Thrombosis within 30 Days

Paclitaxel-related Distal Embolic Events within 180 Days Paclitaxel-related Neutropenia within 180 Days Paclitaxel-related Drug Hypersensitivity/Reaction within

180 Days

0.0% (0/225)

0.0% (0/219)

Rare Adverse Events to 360 Days

Paclitaxel-related Thrombosis within 30 Days

Paclitaxel-related Distal Embolic Events within 360 Days Paclitaxel-related Neutropenia within 360 Days Paclitaxel-related Drug Hypersensitivity/Reaction within

360 Days

0.0% (0/225)

0.0% (0/210)

Numbers are % (counts/sample size).

Thrombosis is defined as an occlusion due to thrombus formation which is rapidly evolving as confirmed by sudden onset of symptoms and documented by DUS and/or angiography at the index vessel within 14 days of symptom onset. Occlusions occurring within 30 days of the index procedure are assumed to be thrombotic, irrespective of symptoms, providing the sheath or guiding catheter has been removed and the patient has left the catheterization laboratory or angiography suite, and that they are documented by imaging with DUS and/or angiography of the index vessel. Thrombosis may be categorized as acute (occurring <1 day post- index), sub-acute (1-30 days) and late (>30 days). For rare adverse events reporting, CEC adjudication will occur through 30-days. Vessel thrombosis reported >30 days will be reported as MAE and CEC adjudicated through 60-months.

Distal Embolic Events are defined as embolism with concomitant suggestive clinical signs and symptoms, located separate from and distal to the target lesion. Classified by probability:

■

Definite Angiographic evidence of distal embolization with a new intraluminal filling defect and/or abrupt occlusion of a runoff vessel distal to a lesion that is clearly not attributable to wire trauma or dissection, irrespective of the time from the index procedure.

■

Probable: Suggestive clinical signs and symptoms of distal embolization occurring <= 30 days after the index procedure, in the absence of Angiographic evidence.

■

Possible: Suggestive clinical signs and symptoms of distal embolization occurring >30 days after the index procedure in the absence of Angiographic evidence.

Neutropenia is defined as ANC <1500/mm

■

If no ANC is available, the white blood cell count will be used.

■

If any WBC count is <3,000 cells/mm^super 3 and is a decrease of >50% of the baseline, the event will be adjudicated as

neutropenia.

■

If no baseline WBC count is available and site-reported concurrent fever and infection, then any WBC count <3,000 cells/mm^super 3 will be adjudicated as neutropenia.

Drug Hypersensitivity/Reactions is defined as events reported with signs and symptoms which include, but are not limited to the following: GI upset, Hair loss, Rash, Urticaria (Hives), Erythyroderma, Itchy skin, Pruritus, Vasculitis, Edema, Anaphylaxis / shock, Asthma / Asthmatic Attack / Bronchospasm, Dyspnea, Chest tightness, Tachycardia, and Eosinophilia. All events were adjudicated by the independent Clinical Events Committee.

11.8.12. Long Term data (24 month)

The results of the secondary endpoints of the IN.PACT Global DCB Long Lesion Sub-Cohort Clinical Evaluation through 24 months are shown in Table 32 below. The primary sustained clinical improvement was 71.0% (125/176) at 24-months postprocedure. Freedom from CD-TLR by Kaplan Meier estimate was 80.3% through 24-months and can be found below in Figure 13.

The MAE composite for the long lesion sub-cohort at 720-days was 24.7% (49/198). Reported MAEs within 720-days included

4.5% death (9/198), 5.1% thrombosis (10/198) and one subject had a major target limb amputation (0.5%, 1/198). Reintervention rates were reported as 20.2% (40/198) clinically-driven TVR and 20.2% (40/198) clinically-driven TLR. The average time to first clinically-driven TLR was 377.4 days.

60 Instructions for Use English

Table 32. Secondary Endpoints through 24 months – IN.PACT Global DCB Long Lesion Sub-Cohort

Parameters IN.PACT Admiral DCB

(N=227 Subjects)

Effectiveness Parameters

Primary Sustained Clinical Improvement at 24 Months 71.0% (125/176) Secondary Sustained Clinical Improvement at 24 Months 89.2% (149/167) Device Success 99.2% (653/658) Procedural Success 99.1% (224/226) Clinical Success 99.1% (224/226)

Safety Parameters

Primary Safety Composite Endpoint – Freedom from: 79.3% (157/198) Device- and Procedure-related Death through 30 Days 0.0% (0/225) Target Limb Major Amputation within 720 Days 0.5% (1/198) Clinically-driven TVR within 720 Days 20.2% (40/198) Death (all-cause) within 30 days 0.0% (0/225)

Cumulative complications within 720 days

MAE Composite (Death, Major Target Limb Amputation, Clinically-driven TVR, Thrombosis)

Death (all-cause) 4.5% (9/198) Clinically-driven TVR 20.2% (40/198) Major Target Limb Amputation 0.5% (1/198)

Thrombosis 5.1% (10/198) Clinically-driven TLR 20.2% (40/198) Any TVR 20.2% (40/198) Any TLR 20.2% (40/198)

Other Major Secondary Endpoints at 24 Months

Time to First Clinically-driven TLR (days)

N 40 Mean ± SD 377.4 ± 190.2 Median 394.5 Min, Max 21, 712

Walking Impairment by WIQ (%)

N 157 Mean ± SD 77.7 ± 29.6 Median 100.0

24.7% (49/198)

Instructions for Use English 61

Parameters IN.PACT Admiral DCB

(N=227 Subjects)

Min, Max 0, 100

Endpoint definitions: Clinically-driven TLR is defined as any reintervention at the target lesion due to symptoms or drop of ABI/TBI of ≥ 20% or

>0.15 when compared to post-procedure baseline ABI/TBI

■

Device success defined as successful delivery, inflation, deflation and retrieval of the intact study balloon device without burst below the RBP.

■

Procedure success defined as residual stenosis of ≤ 50% (non-stented subjects) or ≤ 30% (stented subjects) by corelab (if corelab was not available then the site-reported estimate was used).

■

Clinical success defined as procedural success without procedural complications (death, major target limb amputation, thrombosis of the target lesion, or TVR) prior to discharge.

■

Clinically-driven TLR/TVR is defined as any re-intervention within the target vessel due to symptoms or drop of ABI/TBI of ≥ 20% or >0.15 when compared to post-procedure baseline ABI/TBI.

■

Major Adverse Events (MAE) defined as all-cause death, clinically-driven TLR/TVR, major target limb amputation, thrombosis at the target lesion site at 720 days.

■

Walking impairment assessed by Walking Impairment Questionnaire (WIQ) at 24 months. Data sources: All events were adjudicated by the independent Clinical Events Committee, all duplex ultrasound and angiographic measures

were made by the independent core laboratories, and all other data were site reported.

62 Instructions for Use English

100%

90%

80%

70%

60%

50%

40%

30%

20%

10%

0 6 12 18 24

Freedom from Clinically driven TLR

Time after Index Procedure (months)

93.0%

80.3%

From day X To day Y

IN.PACT DCB

(N=227 Subjects)

# Entered

227 227 215 214 210 203 195 189 176 171 166 160 156

# Censored

0 7 1 2 5 4 4 5 1 1 2 1 5

# Events 0 5 0 2 2 4 2 8 4 4 4 3 2

Event-free [%]

Number of subjects at risk at the beginning of each interval.

Subjects are censored because their last follow-up has not reached the end of the time interval or because they are lost to follow-up.

Estimate made at the end of the time interval.

All events were adjudicated by the independent Clinical Events Committee.

100.0% 97.7% 97.7% 96.8% 95.9% 94.0% 93.0% 89.0% 87.0% 84.9% 82.9% 81.3% 80.3%

0 0

120

121 180

181 240 8M

241 300 10M

301 360

12M

361 420

14M

421 480

16M

481 540

18M

541 600

20M

601 660

22M

661 720

24M

Figure 13. Kaplan-Meier Plot – Event-free from Clinically-driven TLR through 24 months

12. How Supplied

STERILE: The IN.PACT Admiral DCB is sterilized by ethylene oxide (EtO) and is nonpyrogenic. It is intended for single use

only. Do not resterilize. Do not use if package is opened or damaged.

CONTENTS: The package contains 1 IN.PACT Admiral DCB. STORAGE: Store the device in the original container. Store between 15°C and 30°C (59°F and 86°F). Use product by the Use-

by Date noted on the package. Do not store near radiation or ultraviolet light sources. DISPOSAL INSTRUCTIONS: After use, this product may be a biohazard. Handle and dispose of all such devices in

accordance with accepted medical practice and applicable hospital, administrative, and government regulations. DEVICE RETURN INSTRUCTIONS: In the case of a product failure or malfunction related to the product, contact a Medtronic

Vascular representative for return or replacement. Any ancillary devices involved in the incident should also be returned to Medtronic, if possible.

Instructions for Use English 63

13. Instructions for Use

77 9

Figure 14. Schematic of the IN.PACT Admiral Paclitaxel-coated PTA Balloon Catheter

1. Guidewire Port

2. Hub

3. Inflation Port

4. Strain Relief

5. Shaft

6. Usable Catheter Length

7. Radiopaque Marker

8. Balloon

9. Central Balloon Markers (200 and 250 mm balloons only)

13.1. Equipment

■

0.035 in Guidewire

■

Introducer sheath

■

Vessel preparation device

■

Contrast medium

■

Sterile saline

■

Inflation device with manometer

■

Luer lock syringe for purging

13.2. Balloon Catheter Size Selection

■

The nominal balloon diameter must match the diameter of the vessel distal to the lesion. The balloon length must exceed the lesion length by about 1 cm on the proximal and distal ends.

■

If the lesion is longer than the longest available IN.PACT Admiral DCB, use multiple IN.PACT Admiral DCBs to treat the lesion, using the recommended overlap, as described in Using Multiple IN.PACT Admiral DCBs (Section 13.9), Recommended Overlap When Using Multiple IN.PACT Admiral DCBs (Figure 16), and Treatment of a Tandem Lesion with Multiple IN.PACT Admiral DCBs (Figure 18).

13.3. Recommendations for Optimal Treatment

■

Appropriate vessel preparation is required prior to the use of the IN.PACT Admiral DCB. Note: Vessel preparation using only pre-dilatation was studied in the clinical study. Other methods of vessel preparation,

such as atherectomy, have not been studied clinically with IN.PACT Admiral DCB.

■

When using a PTA balloon for vessel preparation, use a PTA balloon with a diameter 1 mm smaller than the reference vessel diameter to facilitate the passage of the appropriately sized IN.PACT Admiral DCB.

Note: Following vessel preparation, if the lesion cannot be crossed with the first inserted IN.PACT Admiral DCB, the second attempt must be made with a new IN.PACT Admiral DCB in order to ensure effective drug delivery.

■

When using a device other than a PTA balloon for vessel preparation, use the device per its Instructions for Use.

■

As noted in Delivery and Dilatation Procedure (Section 13.7), for optimal mechanical dilatation of the vessel, an inflation time of 180 seconds is strongly recommended for the IN.PACT Admiral DCB. Adequate drug transfer occurs in the first 60 seconds of inflation.

■

Post-dilatation should be completed according to the physician’s discretion. If adequate PTA results are not obtained after the IN.PACT Admiral DCB(s) balloon inflation, post-dilatation using a non–drug-coated PTA balloon of shorter length than the previously used IN.PACT Admiral DCB is recommended.

Note: In the randomized trial, provisional stenting with bare-metal stents was completed in cases where adequate results could not be obtained after using post-dilatation balloons, such as in the case of remaining residual stenosis [≥ 50%] or major [≥ Grade D] flow-limiting dissection after post-dilatation.

■

It is important to provide drug delivery to the entire length of the treated artery prior to post-dilatation or provisional stenting.

64 Instructions for Use English

13.4. PTA Preparation

1. Prepare the inflation device, introducer sheath, and guidewire according to the manufacturer's instructions. See Minimum Introducer Sheath Compatibility (Table 33) for help selecting the appropriately sized introducer sheath.

Table 33. Minimum Introducer Sheath Compatibility

Balloon Diameter Max Crossing Profile Introducer Sheath

4.0 mm 5.6 Fr (1.82 mm) 5 Fr

5.0 mm 6.0 Fr (2.00 mm)

6.0 mm (except 120 mm) 6.3 Fr (2.10 mm)

6.0 mm (120 mm length) 6.3 Fr (2.10 mm) or 7.0 Fr (2.33 mm) Consult device label

7.0 mm 7.0 Fr (2.33 mm) 7 Fr

Note: Use of a long introducer sheath extending beyond the iliac bifurcation is recommended if a contralateral approach is used.

2. Administer the appropriate medication to the patient prior to treatment as described in Pre-procedure and Post-procedure Medication Regimen (Section 6.2).

3. Prepare the vascular access site according to standard practice.

4. Insert a guidewire through the hemostatic valve following the manufacturer's instructions or standard practice. Advance the guidewire carefully into the introducer sheath.

5. Attach a torque device to the wire, if desired. Under fluoroscopy, advance the guidewire to the desired vessel, then across the stenosis. Remove the torque device once the guidewire is positioned.

Note: If treating an in-stent restenosis, ensure the guidewire has traversed the lesion intraluminally.

13.5. IN.PACT Admiral DCB Preparation

1. The catheter is packaged in a protective blister. Verify that the catheter and sterile packaging have not been damaged in shipment. After all preparation has been completed, carefully remove the catheter from the package. Do not remove the IN.PACT Admiral DCB from the packaging until it is ready for insertion.

Note: Avoid exposing the balloon drug coating to excessive handling or contact with liquids prior to preparation and delivery as the coating may be susceptible to damage or premature drug release.

2. The folded balloon catheter may contain air that should be purged prior to use. Connect a stopcock to the balloon port of the catheter hub. Connect a luer-lock syringe partially filled with saline solution to the stopcock. Open the stopcock. Keeping the syringe in a downward vertical position, draw back the plunger of the syringe and create a vacuum for 30 seconds in the balloon inflation line until air is completely evacuated.

Caution: If the air bubbles cannot be completely evacuated, there may be a leak in the catheter. Discard the device and select a new IN.PACT Admiral DCB.

Note: It is important to maintain the vacuum seal in order to keep the balloon profile tight before insertion into the introducer sheath.

Note: Keep the protective sheath in place during the purging procedure.

3. After air is completely evacuated, close the stopcock and remove the syringe.

4. Remove the stylet (if present) and the protective sheath from the balloon and discard. Do not use the protective sheath as an introduction aid or rewrapping tool.

5. Connect the filled syringe to the guidewire port. Flush the guidewire lumen through the guidewire port with heparinized normal saline until the fluid exits the distal tip.

Note: Drops of saline must emerge from the device tip. Note: To minimize the introduction of air, aspirate and flush the system and keep a tight catheter connection throughout the

procedure.

Consult device label

6 Fr

6 Fr or 7 Fr

13.6. Inflation Device Connection to the IN.PACT Admiral DCB

1. Fill the inflation device with 15 mL of saline-contrast mixture. Do not use air or any gaseous medium to inflate the balloon. Use only the recommended inflation medium (equal parts contrast medium and saline solution). Do not apply positive pressure to the balloon during preparation.

2. Evacuate all air present in the inflation device. Note: The inflation device should have no air bubbles present, either in the tube or in the cylinder; to remove any air

lodged, keeping the tip upward, purge approximately 1cc of saline-contrast mixture.

Instructions for Use English 65

3. With the stopcock connected to the balloon port in the closed position, securely couple the inflation device to the stopcock. Verify that no air is evident in both the stopcock and the inflation device's connection.

13.7. Delivery and Dilatation Procedure

1. Load the distal tip of the balloon catheter over the prepositioned guidewire, which has been placed through the lesion.

2. Advance the catheter under direct fluoroscopic visualization. To avoid kinking, advance the catheter through the hemostatic valve slowly and in small increments while the stopcock is closed. Open the hemostatic valve to allow for easy passage of the balloon and to prevent damage to the balloon coating. Once the balloon has passed through, the hemostatic valve should be closed as much as is needed to prevent blood return while still permitting easy movements of the catheter.

Note: If significant resistance is encountered, do not advance the catheter through the introducer sheath.

3. Under fluoroscopy, use the balloon radiopaque markers to position the balloon within the lesion to be dilated. If the inflation device has not already been connected, connect the inflation device according to instructions in Inflation Device Connection to the IN.PACT Admiral DCB (Section 13.6).

4. Open the stopcock and inflate the balloon to the appropriate pressure as described in the Compliance Chart included in the device packaging, then close the stopcock to maintain pressure. For optimal mechanical dilatation of the vessel, balloon inflation time of 180 seconds is strongly recommended. Adequate drug transfer occurs in the first 60 seconds of inflation. If the IN.PACT Admiral DCB was inflated for at least 60 seconds but the vessel requires additional dilatation due to suboptimal PTA results, a plain PTA balloon of the operator's choice can be used (PTA balloon should be of shorter length compared to the IN.PACT Admiral DCB).

Warning: Do not exceed rated burst pressure as indicated on the device label. Use of pressures higher than those specified on the device label may result in a ruptured balloon with possible intimal damage and dissection.

Note: The IN.PACT Admiral DCB is intended for single inflation only.

13.8. Removal Procedure

1. Open the stopcock and deflate the balloon by applying negative pressure to the inflation device. For all balloon lengths except for 200 and 250 mm, allow approximately 60 seconds for full balloon deflation. For the 200 and 250 mm balloon lengths, allow approximately 120 seconds for full balloon deflation. Larger balloons may require more time for deflation. Deflation of the balloon should be confirmed by absence of contrast medium within the balloon.

Note: The balloon must be completely deflated before removal.

2. Upon confirmation of full deflation, disconnect the inflation device, then open the hemostatic valve and withdraw the deflated balloon catheter from the introducer sheath, through the hemostatic valve. Tighten the knurled knob on the hemostatic valve.

3. If necessary, the balloon catheter can be exchanged for different balloon types or sizes using the guidewire/ introducer that remains in the vessel.

Note: If further dilatation is required, post-dilatation should be performed with a non–drug-coated PTA balloon of shorter length than the IN.PACT Admiral DCB.

4. When complete, withdraw the guidewire/introducer, and close the hemostatic valve. Note: After use, this device may be a biohazard. Handle and dispose of all such devices in accordance with accepted

medical practice and applicable hospital, administrative, and government regulations.

13.9. Using Multiple IN.PACT Admiral DCBs

Warning: The safety and effectiveness of using multiple IN.PACT Admiral DCBs with a total drug dosage exceeding 34,854 μg

paclitaxel in a patient has not been clinically evaluated. Additional IN.PACT Admiral DCBs should be used to treat a lesion only under either of the following circumstances:

■

The first IN.PACT Admiral DCB bursts prior to 60 seconds of inflation time.

■

The lesion length requires more than 1 IN.PACT Admiral DCB to fully cover the lesion and extend about 1 cm at both the proximal and distal edges.

If multiple IN.PACT Admiral DCBs are required due to a lesion length greater than the longest available DCB, the balloons must overlap by at least 1 cm. The size of additional DCBs should not be longer than required to allow for this overlap and complete the lesion coverage with about 1 cm extended beyond the lesion both proximally and distally. Proper size selection is important to avoid excessive overlap. Refer to Figure 15 through Figure 18 for further guidance.

Note: In order to reduce procedure-related complications, use only the minimum number of devices needed to cover the lesion(s).

66 Instructions for Use English

1 cm

1. approximately 1 cm

1 cm

Figure 15. Treatment of a Single Lesion

Figure 16. Recommended Overlap When Using Multiple IN.PACT Admiral DCBs

1. approximately 1 cm

2. at least 1 cm balloon overlap

Instructions for Use English 67

1 cm

≤ 3 cm

Figure 17. Treatment of a Tandem Lesion with a Single IN.PACT Admiral DCB

1 cm

≤ 3 cm

1. approximately 1 cm

2. lesion gap ≤ 3 cm

Figure 18. Treatment of a Tandem Lesion with Multiple IN.PACT Admiral DCBs

1. approximately 1 cm

2. lesion gap ≤ 3 cm

3. at least 1 cm balloon overlap

14. DISCLAIMER OF WARRANTY

ALTHOUGH THE IN.PACT ADMIRAL DRUG-COATED BALLOON CATHETER, HEREAFTER REFERRED TO AS “PRODUCT”, HAS BEEN MANUFACTURED UNDER CAREFULLY CONTROLLED CONDITIONS, MEDTRONIC, INC., AND AFFILIATES (COLLECTIVELY, “MEDTRONIC”) HAVE NO CONTROL OVER CONDITIONS UNDER WHICH THIS PRODUCT IS USED. THE WARNINGS CONTAINED IN THE PRODUCT LABELING PROVIDE MORE DETAILED INFORMATION AND ARE CONSIDERED AN INTEGRAL PART OF THIS DISCLAIMER OF WARRANTY. MEDTRONIC THEREFORE DISCLAIMS ALL WARRANTIES, BOTH EXPRESSED AND IMPLIED, WITH RESPECT TO THE PRODUCT, INCLUDING, BUT NOT LIMITED TO, ANY IMPLIED WARRANTY OF MERCHANTABILITY OR FITNESS FOR A PARTICULAR PURPOSE. MEDTRONIC SHALL NOT BE LIABLE TO ANY PERSON OR ENTITY FOR ANY MEDICAL EXPENSES OR ANY DIRECT, INCIDENTAL, OR CONSEQUENTIAL DAMAGES CAUSED BY ANY USE, DEFECT, FAILURE, OR MALFUNCTION OF THE

68 Instructions for Use English

PRODUCT, WHETHER A CLAIM FOR SUCH DAMAGES IS BASED UPON WARRANTY, CONTRACT, TORT, OR OTHERWISE. NO PERSON HAS ANY AUTHORITY TO BIND MEDTRONIC TO ANY REPRESENTATION OR WARRANTY WITH RESPECT TO THE PRODUCT.

The exclusions and limitations set out above are not intended to and should not be construed so as to contravene mandatory provisions of applicable law. If any part or term of this Disclaimer of Warranty is held to be illegal, unenforceable, or in conflict with applicable law by a court of competent jurisdiction, the validity of the remaining portions of this Disclaimer of Warranty shall not be affected.

Instructions for Use English 69

Medtronic, Inc.

*M052624T001*

710 Medtronic Parkway Minneapolis, MN 55432 USA www.medtronic.com

Medtronic Ireland Parkmore Business Park West Galway, Ireland

US CUSTOMER SERVICE/PRODUCT INQUIRIES:

Tel. (+1-888) 283-7868 Fax (+1-800) 838-3103

Medtronic ADM06002008P Instructions for Use

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User Manual