Medtronic IPU04004020P Instructions for Use

IN.PACT™ 018

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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Sterilized using ethylene oxide

Catalogue number

Lot number

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Manufactured in

Use-by date

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

Inflation 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 ...................................................................................................................................................................... 5

6.1. General Precautions ............................................................................................................................................... 5

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

6.3. Use of Multiple Balloons ......................................................................................................................................... 6

6.4. Use in Conjunction with Other Procedures ............................................................................................................. 6

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 ................................................................................................................................... 7

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

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 ............................................................................................................................................... 8

10. Patient Counseling Information ..................................................................................................................................... 9

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 ....................................................................................................................................................... 63

13.1. Equipment ............................................................................................................................................................. 63

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

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

13.4. PTA Preparation .................................................................................................................................................... 64

13.5. IN.PACT 018 DCB Preparation ............................................................................................................................. 64

13.6. Inflation Device Connection to the IN.PACT 018 DCB .......................................................................................... 65

13.7. Delivery and Dilatation Procedure ........................................................................................................................ 65

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

13.9. Using Multiple IN.PACT 018 DCBs ....................................................................................................................... 66

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

1. Product Name

IN.PACT™ 018 paclitaxel-coated percutaneous transluminal angioplasty (PTA) balloon catheter

2 Instructions for Use English

2. Product Description

The IN.PACT 018 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 018 DCB.

Table 1. Product Component Description

Balloon Diam-

eter (mm)

Available Balloon Diameters (mm) and Lengths (mm)

Balloon Coating (Drug Component)

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

Lengths Balloon Inflation

Pressure

Minimum Introducer Sheath Compatibility

Guidewire Compatibility

4.0 x x x x x x 3 folds

5.0 x x x x x x

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

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

Paclitaxel (Active Pharmaceutical Ingredient) and Urea (excipient)

80 cm, 130 cm, and 200 cm

Nominal Pressure: 8 atm (811 kPa) Rated Burst Pressure : 10 atm (1013 kPa)

Balloon Diam-

eter (mm)

4.0 mm

6.0 mm

7.0 mm 2.00 6

The catheter is compatible with a guidewire diameter of 0.018 in (0.46 mm).

Max Crossing Profile

Balloon Length (mm)

40 60 80 100 120 150 Balloon Wrap

Configuration

6 folds6.0 x x x x x x

Introducer Sheath (Fr)

(mm)

1.86 55.0 mm

2.1. Device Component Description

The OTW balloon catheter consists of a proximal hub, a coaxial 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 0.018 in (0.46 mm). The balloon-inflation 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 018 Paclitaxel-coated PTA Balloon Catheter (Figure 1).

Figure 1. IN.PACT 018 Paclitaxel-coated PTA Balloon Catheter

1. Guidewire Port

2. Hub

3. Inflation Port

4. Strain Relief

5. Shaft

6. Usable Catheter Length

Instructions for Use English 3

7. Radiopaque Marker

3’

2’

1’

8. Balloon

2.2. Drug Component Description

The FreePac™ drug coating on the balloon of the IN.PACT 018 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 018 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

Model number

(80 cm usable

catheter length)

IPU04004008P IPU04004013P IPU04004020P 4.0 40 1995 IPU04006008P IPU04006013P IPU04006020P 4.0 60 2875 IPU04008008P IPU04008013P IPU04008020P 4.0 80 3754 IPU04010008P IPU04010013P IPU04010020P 4.0 100 4634 IPU04012008P IPU04012013P IPU04012020P 4.0 120 5513 IPU04015008P IPU04015013P IPU04015020P 4.0 150 6833

Model number

(130 cm usable

catheter length)

Model number

(200 cm usable

Nominal balloon

diameter (mm)

Nominal balloon

Length (mm)

Nominal paclitaxel

content (μg)

catheter length)

4 Instructions for Use English

Model number

(80 cm usable

catheter length)

IPU05004008P IPU05004013P IPU05004020P 5.0 40 2575 IPU05006008P IPU05006013P IPU05006020P 5.0 60 3674 IPU05008008P IPU05008013P IPU05008020P 5.0 80 4774 IPU05010008P IPU05010013P IPU05010020P 5.0 100 5873 IPU05012008P IPU05012013P IPU05012020P 5.0 120 6973 IPU05015008P IPU05015013P IPU05015020P 5.0 150 8622 IPU06004008P IPU06004013P IPU06004020P 6.0 40 3188 IPU06006008P IPU06006013P IPU06006020P 6.0 60 4508 IPU06008008P IPU06008013P IPU06008020P 6.0 80 5827 IPU06010008P IPU06010013P IPU06010020P 6.0 100 7147 IPU06012008P IPU06012013P IPU06012020P 6.0 120 8466 IPU06015008P IPU06015013P IPU06015020P 6.0 150 10445 IPU07004008P IPU07004013P IPU07004020P 7.0 40 3837 IPU07006008P IPU07006013P IPU07006020P 7.0 60 5376 IPU07008008P IPU07008013P IPU07008020P 7.0 80 6916

Model number

(130 cm usable

catheter length)

Model number

(200 cm usable

catheter length)

Nominal balloon

diameter (mm)

Nominal balloon

Length (mm)

Nominal paclitaxel

content (μg)

3. Indications for Use

The IN.PACT 018 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 018 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 018 DCB.

■

Do not exceed the rated burst pressure (RBP). The RBP is 10 atm (1013 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.

■

The safety and effectiveness of using multiple IN.PACT 018 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.

Instructions for Use English 5

■

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 018 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 018 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 018 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.

6.3. 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 018 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 018 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 Instructions for Use English

6.5. Drug Interaction

Formal drug interaction studies have not been conducted with the IN.PACT 018 DCB. In the clinical pharmacokinetic (PK) substudy, systemic levels of paclitaxel following treatment with DCB(s) were low and cleared rapidly, reducing possible impact of drug-drug interactions due to concomitant medications (see Section 11.4). Consideration for both systemic and local drug interactions should be given when deciding to use IN.PACT 018 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 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 peel-away balloon protector in place when purging the balloon catheter of air bubbles.

■

Do not use the peel-away balloon protector 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 018 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 018 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 018 DCB backward or forward.

■

Do not manipulate the IN.PACT 018 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 018 DCBs (Section 13.9).

■

Never advance the IN.PACT 018 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 018 DCB.

Note: Vessel preparation using only pre-dilatation was studied in the clinical study (see Section 11). Other methods of vessel preparation, such as atherectomy, have not been studied clinically with IN.PACT 018 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 018 DCB relative to the introducer sheath when withdrawing, and use caution when removing the IN.PACT 018 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 018 DCB is required prior to deployment and a repeat attempt is desired, use a new IN.PACT 018 DCB.

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

IN.PACT 018 DCB has not been evaluated for use in special populations. The safety and effectiveness of drug-coated balloon treatment using paclitaxel has been established based on clinical studies discussed in Section 11.

Instructions for Use English 7

7.1. Pregnancy and Lactation

The IN.PACT 018 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 (Section 11.2.7, Table 9). The results of an interaction analysis indicate that the treatment differences between DCB and PTA groups in the pivotal clinical study are consistent between male and female subjects.

7.3. Ethnicity

Clinical studies (refer to Section 11) 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 018 DCB in pediatric patients has not been established.

7.5. Geriatric Use

The pivotal clinical study (refer to Section 11.2) 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 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 018 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 paclitaxel 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 018 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).

ranged from 1.0 to 35.9 ng/mL and the AUC

max

ranged from

0-∞

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 (Section 11.4) 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).

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

8 Instructions for Use English

■

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.

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 018 DCB.

Instructions for Use English 9

■

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

The safety and effectiveness of the IN.PACT Admiral DCB (.035 in guidewire compatible), as established in the clinical studies described below that were performed primarily via femoral access, can be considered supportive for the IN.PACT 018 DCB. The IN.PACT 018 DCB has not been evaluated in a clinical study.

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

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

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 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

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