IN.PACT AV Paclitaxel-coated Percutaneous Transluminal Angioplasty Balloon Catheter

P190008 · Medtronic Vascular, Inc. · PRC · Nov 21, 2019 · Cardiovascular

Device Facts

• Record ID: P190008
• Device Name: IN.PACT AV Paclitaxel-coated Percutaneous Transluminal Angioplasty Balloon Catheter
• Applicant: Medtronic Vascular, Inc.
• Product Code: PRC · Cardiovascular
• Decision Date: Nov 21, 2019
• Decision: APPR
• Device Class: Class 3
• Attributes: Therapeutic

Indications for Use

The IN.PACT™ AV Paclitaxel-coated PTA Balloon Catheter is indicated for percutaneous transluminal angioplasty, after appropriate vessel preparation, for the treatment of obstructive lesions up to 100 mm in length in the native arteriovenous dialysis fistulae with reference vessel diameters of 4 to 12 mm.

Device Story

The IN.PACT AV DCB is an over-the-wire balloon catheter used for percutaneous transluminal angioplasty (PTA) in native arteriovenous dialysis fistulae. The device features a balloon coated with a proprietary FreePac™ formulation containing paclitaxel (3.5 μg/mm²) and a hydrophilic urea excipient. During the procedure, the physician performs vessel preparation followed by inflation of the drug-coated balloon. The mechanical dilatation treats the obstructive lesion, while the paclitaxel is transferred to the vessel wall to inhibit neointimal hyperplasia and restenosis. The device is used in a clinical setting by physicians. By reducing restenosis, the device aims to maintain fistula patency, reduce the frequency of repeat interventions, and improve patient quality of life. The device is compatible with 0.035'' guidewires and various introducer sheaths.

Clinical Evidence

Pivotal prospective, multicenter, single-blinded, randomized (1:1) clinical study (IN.PACT AV Access, IDE #G160242) of 330 subjects. Primary safety endpoint: serious adverse event (SAE) rate involving AV access circuit through 30 days (4.2% DCB vs 4.4% PTA; non-inferiority p=0.002). Primary effectiveness endpoint: target lesion primary patency (TLPP) through 6 months (82.2% DCB vs 59.5% PTA; p<0.001). Secondary endpoints (TLR, interventions) also favored DCB. Increased rates of infections/infestations and pneumonia were observed in the DCB group through 360 days.

Technological Characteristics

Over-the-wire balloon catheter; balloon diameters 4.0-12.0 mm; lengths 40-120 mm. Coating: FreePac™ (paclitaxel 3.5 μg/mm² + urea excipient). Sterilization: Ethylene oxide (ISO 11135:2014). Compatible with 0.035'' guidewires. Materials and manufacturing processes leveraged from IN.PACT Admiral DCB (P140010).

Indications for Use

Indicated for patients ≥ 21 years old with native arteriovenous dialysis fistulae (AVF) requiring treatment of de novo or non-stented restenotic obstructive lesions (≤ 100 mm length, 4-12 mm vessel diameter). Contraindicated in coronary, renal, or supra-aortic/cerebrovascular arteries; patients unable to receive antiplatelet/anticoagulant therapy; patients with paclitaxel allergies; and pregnant, breastfeeding, or nursing women, or men intending to father children.

Regulatory Classification

Identification

Balloon dilatation of native and/or synthetic arteriovenous dialysis fistulae to establish or maintain patency

Predicate Devices

• IN.PACT Admiral DCB (P140010)

Submission Summary (Full Text)

{0}

SUMMARY OF SAFETY AND EFFECTIVENESS DATA (SSED)

I. GENERAL INFORMATION

Device Generic Name: Drug-Coated Balloon (DCB) Percutaneous Transluminal Angioplasty Catheter

Device Trade Name: IN.PACT™ AV Paclitaxel-coated Percutaneous Transluminal Angioplasty (PTA) Balloon Catheter

Device Product Code: PRC

Applicant’s Name and Address: Medtronic, Inc.
3576 Unocal Place
Santa Rosa, CA 95403

Date(s) of Panel Recommendation: None

Premarket Approval Application (PMA) Number: P190008

Date of FDA Notice of Approval: November 21, 2019

II. INDICATIONS FOR USE

The IN.PACT™ AV Paclitaxel-coated PTA Balloon Catheter is indicated for percutaneous transluminal angioplasty, after appropriate vessel preparation, for the treatment of obstructive lesions up to 100 mm in length in the native arteriovenous dialysis fistulae with reference vessel diameters of 4 to 12 mm.

III. CONTRAINDICATIONS

The IN.PACT AV Paclitaxel-coated PTA Balloon Catheter is contraindicated for use in the following anatomy and patient types:

- 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 adverse reaction in nursing infants from paclitaxel exposure

IV. WARNINGS AND PRECAUTIONS

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. Inadequate information is available to evaluate the potential mortality

PMA P190008: FDA Summary of Safety and Effectiveness Data

{1}

risk associated with the use of paclitaxel-coated devices for the treatment of other diseases/conditions, including this device indicated for use in arteriovenous dialysis fistulae. Physicians should discuss this late mortality signal and the benefits and risks of available treatment options for their specific disease/condition with their patients.

Additional warnings and precautions can be found in the IN.PACT AV Paclitaxel-coated PTA Balloon Catheter labeling.

# V. DEVICE DESCRIPTION

The IN.PACT AV Paclitaxel-coated PTA Balloon Catheter (hereinafter referred as IN.PACT AV DCB) is an over-the-wire balloon catheter with a drug-coated balloon at the distal end (see Figure 1).

Figure 1: IN.PACT AV 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. Drug-coated Balloon

# PTA Catheter Component

The IN.PACT AV DCB is available in balloon lengths ranging from 40 to $120\mathrm{mm}$ , balloon diameters ranging from 4.0 to $12.0\mathrm{mm}$ , and is offered in catheter effective lengths of 40, 80 and $130\mathrm{cm}$ . The IN.PACT AV DCB is compatible with $0.035''$ guidewires. The IN.PACT AV DCB product matrix is provided in Table 1 and the introducer sheath compatibility for the balloon diameters offered is provided in Table 2.

PMA P190008: FDA Summary of Safety and Effectiveness Data

{2}

Table 1: IN.PACT AV DCB Product Matrix

| Balloon Diameter (mm) | Balloon Length (mm) | | | | |
| --- | --- | --- | --- | --- | --- |
| | 40 | 60 | 80 | 120 | |
| 4.0 | x | x | x | x | 3 folds |
| 5.0 | x | x | x | x | 6 folds |
| 6.0 | x | x | x | x | |
| 7.0 | x | x | x | --- | |
| 8.0 | x | x | x | --- | |
| 9.0 | x | x | x | --- | |
| 10.0 | x | --- | --- | --- | |
| 12.0 | x | --- | --- | --- | |
| Notes: “---” indicates sizes not offered; “X” indicates All sizes offered will be available in 40, 80, and 130 cm catheter effective length. | | | | | |

Table 2: Nominal Pressure and Introducer Sheath Compatibility

| Balloon Diameter (mm) | Nominal Pressure | Introducer Sheath (F) |
| --- | --- | --- |
| 4.0 | 811 kPa / 8 atm | 5 |
| 5.0 | | 6 |
| 6.0 | | |
| 7.0 | | 7 |
| 8.0 | | |
| 9.0 | | |
| 10.0 | 608 kPa / 6 atm | |
| 12.0 | | 9 |

# Drug Components

The IN.PACT AV DCB is coated with the FreePac™ coating solution, which is a proprietary coating with a nominal drug dose density of $3.5\mu \mathrm{g}$ of paclitaxel per $\mathrm{mm}^2$ of the expanded balloon surface. The FreePac coating contains a hydrophilic excipient (urea) which facilitates the release and transfer of the active pharmaceutical ingredient (paclitaxel) into the arterial vessel wall. Additionally, the FreePac solution contains two solvents, tetrahydrofuran (THF) and pyrogen-free water, which are used during the FreePac formulation process and evaporate off the balloon surface after the FreePac coating is applied. Based on the nominal drug dose density of $3.5\mu \mathrm{g} / \mathrm{mm}^2$ , the total amount of paclitaxel for each balloon size is provided in Table 3.

PMA P190008: FDA Summary of Safety and Effectiveness Data

{3}

Table 3: Nominal Paclitaxel Content by Balloon Size

| Balloon Diameter (mm) | Balloon Length (mm) | Nominal Paclitaxel Content (μg) |
| --- | --- | --- |
| 4.0 | 40 | 1969 |
| 4.0 | 60 | 2848 |
| 4.0 | 80 | 3728 |
| 4.0 | 120 | 5487 |
| 5.0 | 40 | 2553 |
| 5.0 | 60 | 3653 |
| 5.0 | 80 | 4752 |
| 5.0 | 120 | 6951 |
| 6.0 | 40 | 3170 |
| 6.0 | 60 | 4489 |
| 6.0 | 80 | 5809 |
| 6.0 | 120 | 8448 |
| 7.0 | 40 | 3819 |
| 7.0 | 60 | 5358 |
| 7.0 | 80 | 6897 |
| 8.0 | 40 | 4494 |
| 8.0 | 60 | 6253 |
| 8.0 | 80 | 8012 |
| 9.0 | 40 | 5204 |
| 9.0 | 60 | 7183 |
| 9.0 | 80 | 9162 |
| 10.0 | 40 | 5943 |
| 12.0 | 40 | 7522 |

# Active Pharmaceutical Ingredient (API) - Paclitaxel

The API of the IN.PACT AV DCB is paclitaxel - an FDA-approved drug, indicated for the treatment of multiple cancers including breast and ovarian cancer. 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 is Benzenepropanoic acid, $\beta$ -(benzoylamino)- $\alpha$ -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-[2aa,4β,4aβ,6β,9α(αR, βS),11α,12α,12aα,12bα]] and the chemical formula is C $_{47}$ H $_{51}$ NO $_{14}$ . The chemical structure of paclitaxel is illustrated in Figure 2 below.

Figure 2: Chemical Structure of Paclitaxel

PMA P190008: FDA Summary of Safety and Effectiveness Data

{4}

PMA P190008: FDA Summary of Safety and Effectiveness Data
Page 5

# Excipient (Urea)

The FreePac coating contains urea, an excipient used to facilitate the release and transfer of the paclitaxel drug substance from the balloon to the vessel wall upon balloon inflation. The chemical structure of urea is shown in Figure 3 below.

Figure 3: Chemical Structure of Urea

# Mechanism of Action

The IN.PACT AV DCB's primary mode of action is mechanical dilatation of obstructive lesions by means of percutaneous transluminal angioplasty, with a secondary action of inhibition of restenosis (caused by the proliferative response to the PTA) through the application of paclitaxel to the vessel wall.

Additional details regarding the device can be found in the IN.PACT AV Paclitaxel-coated PTA Balloon Catheter labeling.

# VI. ALTERNATIVE PRACTICES AND PROCEDURES

There are other alternatives for the correction of obstructive lesions in the native arteriovenous fistula (AVF):

- percutaneous transluminal angioplasty (PTA),
- endovascular stent graft,
- surgical revision, or
- other drug-coated PTA balloon catheter approved for use in the AVF.

Each alternative has its own advantages and disadvantages. A patient should fully discuss these alternatives with his/her physician to select the method that best meets expectations and lifestyle.

# VII. MARKETING HISTORY

Outside of the United States, the IN.PACT™ AV Paclitaxel-coated PTA Balloon Catheter has been marketed for this indication in the European Union (EU) since January 2016. It is also currently marketed in the following countries:

Argentina
India
South Korea
Australia
Indonesia
Taiwan
Bosnia &amp; Herzegovina
Macedonia
Thailand
Colombia
Mexico
Turkey
Costa Rica
Peru
Ukraine
Ecuador
Saudi Arabia
Uruguay
Guatemala
Singapore

# VIII. POTENTIAL ADVERSE EFFECTS OF THE DEVICE ON HEALTH

Potential adverse effects which may be associated with balloon catheterization may include, but are not limited to, the following:

- Abrupt vessel closure
- Allergic reaction
- Arrhythmias
- Arterial or venous aneurysm

{5}

- Arterial or venous thrombosis
- Death
- Dissection
- Embolization
- Hematoma
- Hemorrhage
- Hypotension/hypertension
- Infection
- Ischemia or infarction of tissue/organ
- Loss of permanent access
- Pain
- Perforation or rupture of the artery or vein
- Pseudoaneurysm
- Restenosis of the dilated vessel
- Shock
- Stroke
- Vessel spasms or recoil

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

- 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, the following:

- 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

For the specific adverse events that occurred in the clinical study, please see Table 17 (Table of Serious Adverse Events) in the Clinical Study section (Section X) below.

## IX. SUMMARY OF NONCLINICAL STUDIES

A series of non-clinical laboratory studies related to the IN.PACT AV DCB were performed. These evaluations included biocompatibility studies, in vitro bench testing, animal studies, analytical testing, stability testing, shelf life testing, and sterilization.

The IN.PACT AV DCB product is based on the commercially approved IN.PACT Admiral DCB (P140010). In particular, the IN.PACT AV DCB 4.0 - 7.0 mm diameter balloon configurations are leveraged from the IN.PACT

PMA P190008: FDA Summary of Safety and Effectiveness Data
Page 6

{6}

Admiral DCB. The additional 8.0 - 12.0 mm diameter balloon configurations of the IN.PACT AV DCB have the same raw materials, components, component vendors, and manufacturing processes as the commercial IN.PACT Admiral DCB. Due to these similarities, a subset of the IN.PACT Admiral DCB non-clinical laboratory studies are directly applicable to IN.PACT AV DCB. However, since the proposed indication for IN.PACT AV DCB presents a new anatomical condition, performance attributes that are dependent on these anatomical use conditions were tested.

# A. Laboratory Studies

# Biocompatibility

A biocompatibility evaluation was completed to assess the commonalities between the IN.PACT AV DCB and the commercial IN.PACT Admiral DCB. Results of this evaluation confirmed that the biocompatibility testing performed on IN.PACT Admiral DCB is also applicable to the IN.PACT AV DCB and additional testing was not required. All biocompatibility testing below was leveraged from the IN.PACT Admiral DCB device. Biocompatibility testing performed on IN.PACT Admiral DCB was conducted separately on (1) the balloon with the drug coating, (2) the balloon with the excipient, and (3) the remainder of the balloon catheter. In addition, thrombogenicity and chemical characterization testing was conducted on the balloon catheter with the drug coating to support the overall biocompatibility of the drug-coated balloon. The drug coating was categorized as an implant device with permanent blood contact ( $&gt;30$ days), and the balloon catheter was categorized as an externally communicating device with limited contact duration ( $&lt;24$ hours) with circulating blood. A summary of the biocompatibility testing and results can be found in Table 4.

All biocompatibility testing was conducted in accordance with:

Class II Special Controls Guidance Document for Certain Percutaneous Transluminal Coronary Angioplasty (PTCA) Catheters (September 8, 2010)
- Guidance for Industry and FDA Staff: Non-Clinical Tests and Recommended Labeling for Intravascular Stents and Associated Delivery Systems (April 18, 2010)

Draft Guidance for Industry: Coronary Drug-Eluting Stents - Nonclinical and Clinical Studies Companion Document (March 2008)

Table 4: Summary of Biocompatibility Testing

| Test Name | Test Description | Balloon w/ Excipient (no Drug) | Balloon w/ Drug Coating | Balloon Catheter w/ Excipient (no drug) | Balloon Catheter w/ Drug Coating | Results |
| --- | --- | --- | --- | --- | --- | --- |
| Cytotoxicity | ISO MEM Elution Assay with L-929 Mouse Fibroblast Cells | X | X | X | - | Non-toxic |
| Sensitization | ISO Guinea Pig Maximization | X | X | X | - | Non-sensitizing |
| Irritation | ISO Intracutaneous Reactivity | X | X | X | - | Non-irritating |
| Acute Systemic Toxicity | ISO Systemic Toxicity | X | X | X | - | Non-toxic |
| Pyrogenicity | USP Material Mediated Pyrogenicity | X | X | X | - | Non-pyrogenic |

PMA P190008: FDA Summary of Safety and Effectiveness Data

{7}

| Test Name | Test Description | Balloon w/ Excipient (no Drug) | Balloon w/ Drug Coating | Balloon Catheter w/ Excipient (no drug) | Balloon Catheter w/ Drug Coating | Results |
| --- | --- | --- | --- | --- | --- | --- |
| Hemocompatibility | ASTM Hemolysis (Direct and Indirect Contact) | X | X | X | - | Non-hemolytic |
| | Complement Activation Assay (C3a and SC5b-9) | X | X | X | - | Not a complement activator |
| | In vivo Thrombogenicity | - | - | - | X | Non-thrombogenic |
| Chemical Characterization | Gas Chromatography - Mass Spectroscopy (GC/MS) for volatile and semi-volatile, organic compounds | X | X | - | - | Compounds consistent with manufacturing materials, and amounts do not raise toxicity concerns |
| | Inductively Coupled Plasma (ICP) Spectroscopy for metallic compounds | X | X | - | - | Compounds consistent with manufacturing materials, and amounts do not raise toxicity concerns |
| | Liquid Chromatography - Mass Spectroscopy (LC/MS) for semi-volatile and non-volatile organic compounds | X | X | - | - | Compounds consistent with manufacturing materials, and amounts do not raise toxicity concerns |

The following permanent implant biocompatibility studies were not conducted on the device: sub-chronic toxicity, chronic toxicity, and muscle implantation. The potential for sub-chronic toxicity, chronic toxicity and implantation were evaluated as part of other in vivo studies conducted to evaluate the safety and effectiveness of the device in porcine ilio-femoral artery model, as described in Section B, Animal Studies, below. These additional animal studies demonstrated a lack of inflammation and toxicity when the product was used in a clinically-relevant vascular location.

The omission of genotoxicity and carcinogenicity testing were supported by information regarding the starting materials and processing of the finished drug-coated balloon in conjunction with chemical characterization data and toxicity information from the literature.

The information provided demonstrates that the device is biocompatible for its intended use.

# In vitro Bench Testing

Table 5 provides an overview of the in vitro bench testing supporting the IN.PACT AV DCB. The table includes the tests performed, the objective of the tests, the acceptance criteria (as applicable), and the result of each test.

PMA P190008: FDA Summary of Safety and Effectiveness Data

{8}

Table 5: Summary of In vitro Bench Testing

| Test | Testing Summary/ Objective | Acceptance Criteria (Specification) | Results |
| --- | --- | --- | --- |
| Delivery System Profiles | To determine the maximum outer diameter (OD) of the catheter shaft and the balloon | | Balloon Diameter (mm) | Maximum Crossing Profile (mm) | | The device met the established acceptance criteria. |
| 4.0 | 1.88 |
| 5.0 | 2.00 |
| 6.0 | 2.10 |
| 7.0 | 2.33 |
| 8.0 |
| 9.0 |
| 10.0 |
| 12.0 | 3.00 |
| Catheter Effective Length (Catheter tip to strain relief) | To delineate the effective length of the catheter | 40 cm ± 2 cm
80 cm ± 2 cm
130 cm ± 2 cm | The device met the established acceptance criteria. |
| Balloon Working Length at Nominal Pressure | Determine the balloon length at nominal pressure | | Balloon Working Length (mm) | | The device met the established acceptance criteria. |
| Nominal | Minimum | Maximum |
| 40.0 | 36.0 | 44.0 |
| 60.0 | 56.0 | 64.0 |
| 80.0 | 75.0 | 85.0 |
| 120.0 | 114.0 | 126.0 |
| Balloon Preparation | Demonstrate that the catheter can be safely and reliably prepared, delivered, and retracted using the recommended techniques in the Instructions for Use without damage to the product | To demonstrate that the catheter can be safely and reliably prepared, delivered, and retracted using the recommended techniques in the Instructions for Use without damage to the product. | The device met the established acceptance criteria. |
| Balloon Rated Burst Pressure | Determine the minimum burst strength of the balloon and calculate the rated burst pressure (RBP) | Devices will not fail at or below the rated burst pressure: | The device met the established acceptance criteria. |
| Balloon Diameter (mm) | Rated Burst Pressure (atm) | |
| 4.0 | 14 |
| 5.0 |
| 6.0 |
| 7.0 |
| 8.0 | 10 |
| 9.0 |
| 10.0 | 9 |
| 12.0 |

PMA P190008: FDA Summary of Safety and Effectiveness Data

{9}

| Test | Testing Summary/ Objective | Acceptance Criteria (Specification) | | | Results |
| --- | --- | --- | --- | --- | --- |
| Marker Band Spacing | Determine the marker band spacing at nominal pressure | The inside edge of the marker band cannot be outside the balloon working length by more than 1.0 mm. The outside edge of the marker band cannot be inside the balloon working length by more than: | | | The device met the established acceptance criteria. |
| | | Balloon Length (mm) | Spacing (mm) | | |
| | | 40 | 2.0 | | |
| | | 60 | 2.5 | | |
| | | 80 | 3.0 | | |
| | | 120 | 4.0 | | |
| Balloon Fatigue | Determine that balloons will sustain 10 inflations to RBP in an unconstrained environment | Samples will withstand 10 cycles at rated burst pressure. | | | The device met the established acceptance criteria. |
| Balloon Compliance (Diameter vs. Pressure) | Evaluate the change in balloon diameter as a function of the inflation pressure | At nominal pressure balloon diameter must be within: • ± 0.4 mm for 4.0 mm diameter balloons • ± 0.5 mm for 5.0-7.0 mm diameter balloons • ± 0.6 mm for 8.0 and 9.0 mm diameter balloons • ± 0.7 mm for 10.0 and 12.0 mm diameter balloons | | | The device met the established acceptance criteria. |
| Balloon Inflation / Deflation Time | Demonstrate that inflation and deflation of the balloon can be accomplished within clinically acceptable time limits | Inflation Time: For characterization only. Deflation Time: Deflation time from RBP must be ≤ 60sec | | | The device met the established acceptance criteria. |
| Tensile Strength | Determine the tensile strength of the catheter bonds after preconditioning | Minimum Tensile Strength | | | The device met the established acceptance criteria. |
| | | Luer / Bilumen Tube | | ≥ 10 N | |
| | | Bilumen Tube/ Marker Tube | | | |
| | | Marker Tube / Tip Tube | | ≥ 5 N | |
| | | Proximal Balloon Weld | | ≥ 10 N | |
| | | Distal Balloon Weld | | ≥ 5 N | |
| Catheter Flexibility and Kink Resistance | Demonstrate that the catheter will not kink when subjected to flexural forces | Catheter shaft will not kink at radius of 9.0 mm | | | The device met the established acceptance criteria. |
| Torque Strength | Demonstrate that the catheter has adequate torque strength after pre-conditioning | The balloon catheter must withstand a minimum of 10 x 360-degree rotations inside the representative anatomical models with the distal end fixed and the guide wire in place | | | The device met the established acceptance criteria. |

# Analytical Testing

Analytical testing was performed to determine the identity, safety, purity and quality of the drug substance (paclitaxel) of the IN.PACT AV DCB, as seen in Table 6.

PMA P190008: FDA Summary of Safety and Effectiveness Data

{10}

Table 6: Summary of Analytical Testing

| Test | Testing Summary/Objective | Acceptance Criteria | Results |
| --- | --- | --- | --- |
| Drug (paclitaxel) Identification | Test the drug substance for identity and to ensure conformity to incoming specifications. | Identity must be confirmed via two different tests | The drug substance met the established acceptance criteria. |
| Coating Appearance | Visual inspection was conducted to verify that the IN.PACT AV DCB drug coating meets the appearance specification. | Must meet visual standard | The device met the established acceptance criteria. |
| Drug Content | Quantitative determination of the total amount of paclitaxel on the IN.PACT AV DCB. | USP <905> | The device met the established acceptance criteria. |
| Content Uniformity | Verification of the content uniformity of the paclitaxel coating from balloon to balloon. | USP <905> | The device met the established acceptance criteria. |
| Degradants/ Impurities | Quantitative determination of the type and amount of impurities and degradation products of the IN.PACT AV DCB. | ICH Guidance | The device met the established acceptance criteria. |
| Drug Release | Determination of the in vitro release rate of paclitaxel from the IN.PACT AV DCB. | USP <711> | The device met the established acceptance criteria. |
| Drug Content Circumferential Uniformity | Measure the relative uniformity of the drug content around the balloon circumference of the finished IN.PACT AV DCB. | This testing was performed for characterization only | N/A (For Information Only) |
| Drug Content Length Uniformity | Measure the relative uniformity of the drug content along the balloon length of the finished IN.PACT AV DCB. | This testing was performed for characterization only | N/A (For Information Only) |
| Particulate | Particulate levels measured for the IN.PACT AV DCB. | Particulate counts were performed at ≥10 μm, ≥25 μm, ≥50 μm and ≥100 μm using the principles of USP<788>. | N/A (For Information Only) |

PMA P190008: FDA Summary of Safety and Effectiveness Data

{11}

| Test | Testing Summary/Objective | Acceptance Criteria | Results |
| --- | --- | --- | --- |
| Particulate Identification | Identification of the particulate for the IN.PACT AV DCB. | This testing was performed for characterization only | N/A (For Information Only) |

# B. Animal Studies

Previously performed in vivo preclinical (animal) testing in porcine ilio-femoral arterial to support IN.PACT Admiral DCB is also applicable to the arteriovenous fistula model. This is due to the similarities in blood flow rate and the corresponding pharmacokinetic response between the porcine ilio-femoral arterial and arteriovenous fistula model. Previously performed studies are provided in the SSED of IN.PACT Admiral DCB (P140010). In addition, Medtronic has conducted in vivo preclinical testing in the arteriovenous porcine model to evaluate safety, 3X safety margin and pharmacokinetic profile in the intended clinically relevant vasculature. A summary of these studies is provided in Table 7 below. In addition to the major endpoints noted for each study, animals were carefully evaluated for general health (i.e. vital signs, behavior, nutritional condition, gait, etc.) and clinical responses to treatment.

Table 7: Summary of Animal Studies

| Study | Animal Model | Duration | Test and Control Article | Major Endpoints |
| --- | --- | --- | --- | --- |
| FS238 - 60 Day Pharmacokinetic and Downstream Tissue Safety Study* | 66 Domestic Farm Swine | PK: 0, 7, 28, 48 and 60 Days; Downstream Tissue Safety: 60 Days | Test: DCB Safety Margin (10.5 μg/mm2) and Therapeutic (3.5 μg/mm2) Control: Native AVF tissue | Acute Performance, Angiographic Performance, Histopathology (non-target tissue), Pharmacokinetics |
| FS241 - 90 Day Safety Evaluation of Treated and Downstream Tissue* | 21 Domestic Farm Swine | 90 Days | Test: DCB Safety Margin (10.5 μg/mm2) and Therapeutic (3.5 μg/mm2) Control: non drug-coated PTA Balloon Catheter | Acute Performance, Angiographic Performance, Histopathology (local and non-target tissue) |
| PS739 - 28 day Pharmacokinetic and Histological Evaluation of Treated and Downstream Tissue | 11 Domestic Farm Swine | 28 Days | Test: DCB Safety Margin (10.5 μg/mm2) and Therapeutic (3.5 μg/mm2) Histological Control: Native AVF tissue PK Control: non-drug-coated PTA Balloon Catheter | Angiographic Performance, Morphometric Analysis, Histopathology, Pharmacokinetics |
| * Studies conducted in accordance with FDA 21 CFR Part 58 GLP Regulations. Clinical responses to treatment utilizing the Subjective Objective Assessment Plan (SOAP) methodology were utilized in these studies. | | | | |

The porcine arterial and AVF model environments demonstrated that the device performs as intended and did not cause any unexpected histological indications of toxicity resulting from the therapeutic or safety margin doses. The pharmacokinetic and histological indicators of the extended drug activity in arteriovenous tissue provide evidence of effective drug transfer and safety at the intended dose.

PMA P190008: FDA Summary of Safety and Effectiveness Data

{12}

AV fistulas are known to mature and arterialize over time, thus presenting clinical similarities to arterial tissue. The effect on local and downstream non-target organ tissue analysis was completed in the 28-, 60- and 90-day studies referenced in Table 7 which confirms no risk of clinical sequelae using the AVF model. This data combined with the body of safety data provided in the arterial model provided in P140010 to support IN.PACT Admiral DCB indications, presents a strong evaluation of healing out to 365 days.

In addition to the studies listed in Table. 7, Medtronic also conducted two GLP preclinical animal studies (FS236 and FS237) to evaluate the IN.PACT AV DCB in the native femoral veins of healthy swine with timepoints at 28 and 90 days. Histological evaluation from these studies revealed medial smooth muscle loss and fibrin deposition on the luminal surface owing to the absence of atherosclerotic disease in the normal treated veins as well as the lower blood flow velocities and reduced local drug clearance in the venous environment relative to arteries. The treated veins were not compromised as there was no extravasation of blood and the veins maintained patent lumens. No pathologies were recorded in the downstream organs. All treated veins remained patent and exhibited no signs of clinically relevant sequelae during the in-life phase. These findings are not relevant to use in arteriovenous fistulas.

Overall, the preclinical program successfully established the systemic and local tissue exposure including safety margin doses of paclitaxel.

## C. Additional Studies

### Stability and Shelf Life Studies

Finished product stability studies were developed according to USP and ICH guidelines to establish the shelf life for the IN.PACT AV DCB finished product. The testing includes an evaluation of drug content, impurities, drug release, particulate, sterility, drug content uniformity, residual solvents, urea, water and endotoxins. Appropriate functional tests were also planned and performed on products and packaging to ensure that the IN.PACT AV DCB performed acceptably up to the intended shelf life. The data generated from the stability studies, coupled with the data generated from the shelf life studies, supports a 36-month shelf life for the product.

### Sterilization

IN.PACT AV DCB is sterilized using ethylene oxide sterilization and has been validated per ISO 11135:2014 "Sterilization of health care products--Ethylene Oxide--Requirements for development, validation and routine control of a sterilization process for medical devices" and EN 556-1:2001 "Sterilization of Medical Devices - Requirements for medical devices to be designated STERILE - Part 1: Requirements for terminally sterilized medical devices". The testing for ethylene oxide residuals was completed and acceptable per ISO 10993-7:2008. In addition, pyrogenic (LAL) testing was completed per ST72:2011. Results obtained from the sterilization studies show that the product satisfies a minimum Sterility Assurance Level (SAL) of $10^{-6}$. The amounts of bacterial endotoxin were verified to be within the specification limit.

## X. SUMMARY OF PRIMARY CLINICAL STUDY

The applicant performed a clinical study to establish a reasonable assurance of safety and effectiveness of percutaneous transluminal angioplasty, after pre-dilatation, with IN.PACT AV DCB for the treatment of obstructive lesions up to $100\mathrm{mm}$ in length in the native arteriovenous dialysis fistulae with reference vessel diameters of 4 to $12\mathrm{mm}$ in patients from the US, Japan and New Zealand under IDE # G160242. Data from this IDE clinical study were the basis for the PMA approval decision. A summary of the clinical study is presented below.

### A. Study Design

PMA P190008: FDA Summary of Safety and Effectiveness Data
Page 13

{13}

Subjects were treated between April 25, 2017 and May 10, 2018. The database for this PMA reflected data collected through December 6, 2018 and included 330 subjects from 29 investigational sites.

The IN.PACT AV Access study is a prospective, global, multicenter, single-blinded, randomized (1:1) clinical study to evaluate safety and effectiveness of the IN.PACT AV DCB (study group) vs. standard PTA (control group) for the treatment of obstructive lesions up to 100 mm in length in the native arteriovenous dialysis fistulae.

The IN.PACT AV Access study recruited subjects with a de novo or non-stented restenotic obstructive lesion located in the native arteriovenous dialysis fistulae. After the informed consent process and screening, subjects were randomized to treatment with IN.PACT AV DCB (study group) or standard PTA balloon (control group) using a 1:1 randomization scheme. The randomization was stratified by lesion type (de novo vs restenotic) and study sites. Randomization occurred after successful crossing and pre-dilatation of the target lesion. Subjects who did not meet the protocol-defined criteria after pre-dilation were considered screen failures, treated per standard practice; no further follow-up was required per the protocol.

The data from the IN.PACT AV Access study, with greater than 50% of subjects coming from the U.S. population (204 US subjects, 112 Japan subjects, and 14 New Zealand subjects) comprise the pivotal study data set. This aggregate data provides adequate statistical power for the 30-day primary safety and 6-month primary effectiveness endpoints. The statistical analysis plan included planned primary analysis of the intent to treat (ITT) subjects, as well as a fixed sequential testing procedure for four secondary endpoints through 6 months for the intent to treat (ITT) subjects in the order of cumulative target lesion revascularizations (TLR), number of interventions required to maintain target lesion patency, number of interventions required to maintain access circuit patency, and access circuit primary patency. The ITT population consisted of all randomized subjects, irrespective of the treatment actually delivered.

There were two primary hypotheses for the study, evaluating the primary safety endpoint through 30 days and the primary effectiveness endpoint through 6 months, respectively. Each hypothesis was tested on the ITT subjects at a one-sided significance level of 2.5%, as pre-specified in the Statistical Analysis Plan. The control group is standard percutaneous transluminal angioplasty (PTA).

For the primary safety endpoint, the study and control groups were compared for non-inferiority using the following hypothesis.

H₀: π_T ≥ π_C + 0.075
H_A: π_T &lt; π_C + 0.075

where π_T and π_C are the serious adverse event (SAE) rates of the study and control groups, respectively.

For the primary effectiveness endpoint, the study (p_T) and control (p_C) groups were compared for superiority using the following hypothesis:

H₀: p_T ≤ p_C
H_A: p_T &gt; p_C

where p_T and p_C are the target lesion primary patency (TLPP) rates of the study and control groups, respectively.

To control the overall Type I error the study was deemed success only if both primary effectiveness and primary safety endpoints were met.

Once the two primary endpoints were met, the following key secondary endpoints were tested for superiority between treatment groups sequentially by using the ITT analysis set, each at a one-sided significance level of 0.025, in the following order. The testing procedure would stop at the first failure to reject null hypothesis.

PMA P190008: FDA Summary of Safety and Effectiveness Data
Page 14

{14}

1) Cumulative (any) target lesion revascularizations (TLR) measured through 6 months post-procedure;

$$
\mathrm{H}_0: \quad \mathrm{t}_{\mathrm{T}} \geq \mathrm{t}_{\mathrm{C}}
$$

$$
\mathrm{H}_A: \quad \mathrm{t}_{\mathrm{T}} &lt; \mathrm{t}_{\mathrm{C}}
$$

where $t_x$ refers to the expected cumulative TLR rate through 6 months ($x = T$ for DCB; $x = C$ for PTA). A one-sided Z-test was performed at a significance level of 0.025.

2) Number of interventions required to maintain target lesion patency through 6 months post-procedure;

$$
\mathrm{H}_0: \quad \mathrm{l}_{\mathrm{T}} \geq \mathrm{l}_{\mathrm{C}}
$$

$$
\mathrm{H}_A: \quad \mathrm{l}_{\mathrm{T}} &lt; \mathrm{l}_{\mathrm{C}}
$$

where $l_X$ refers to the expected number of interventions to maintain target lesion patency through 6 months ($x = T$ for DCB; $x = C$ for PTA). The comparison was performed at a one-sided significance level of 0.025 using Wilcoxon Rank Sum Test.

3) Number of interventions required to maintain access circuit patency through 6 months post-procedure

$$
\mathrm{H}_0: \quad \mathrm{c}_{\mathrm{T}} \geq \mathrm{c}_{\mathrm{C}}
$$

$$
\mathrm{H}_A: \quad \mathrm{c}_{\mathrm{T}} &lt; \mathrm{c}_{\mathrm{C}}
$$

where $c_x$ refers to the expected number of interventions to maintain access circuit patency through 6 months ($x = T$ for DCB; $x = C$ for PTA). The comparison was performed at a one-sided significance level of 0.025 using Wilcoxon Rank Sum Test.

4) Access circuit primary patency through 6 months post-procedure;

$$
\mathrm{H}_0: \quad \mathrm{a}_{\mathrm{T}} \leq \mathrm{a}_{\mathrm{C}}
$$

$$
\mathrm{H}_A: \quad \mathrm{a}_{\mathrm{T}} &gt; \mathrm{a}_{\mathrm{C}}
$$

where $a_x$ refers to the expected access circuit primary patency rate through 6 months ($x = T$ for DCB; $x = C$ for PTA). One-sided Z-test will be performed at a significance level of 0.025.

Overview of the study flowchart is provided in Figure 4 and an overview of the IN.PACT AV Access study design is provided in Table 8 below.

PMA P190008: FDA Summary of Safety and Effectiveness Data
Page 15

{15}

Figure 4: Study Flowchart

PMA P190008: FDA Summary of Safety and Effectiveness Data

{16}

Table 8: IN.PACT AV Access Study Design

| Item | Description |
| --- | --- |
| Study Design | Prospective, global, multicenter, single-blinded, randomized (1:1) clinical study to evaluate IN.PACT™ AV DCB safety and effectiveness. |
| Number of Subjects Enrolled | 330 |
| Treatment Lesion | Obstructive lesions up to 100 mm in length in native arteriovenous dialysis fistulae with reference vessel diameters of 4 to 12 mm |
| Treatment Device | Study Group: IN.PACT™ AV Paclitaxel-coated PTA Balloon CatheterControl Group: Non-coated standard percutaneous transluminal angioplasty balloon catheter (standard PTA catheter) |
| Balloon Sizes | Balloon Diameters: 4, 5, 6, 7, 8, 9, 10, and 12 mmBalloon Lengths: 40, 60, 80, and 120 mm in length |
| Concomitant Medication | Single antiplatelet therapy, at a minimum, (e.g. aspirin, clopidogrel, ticlopidine or Prasugrel) should be administered before the procedure and for a minimum of 4 weeks after the intervention. |
| Primary Endpoints | Safety: Serious adverse event rate (SAE) involving the AV access circuit through 30 days post-procedure.Effectiveness: Target Lesion Primary Patency (TLPP) through 6 months. |
| Randomized Subject Follow-up Schedule | Subjects randomized and enrolled in the study will be followed up to 5 years. Follow-up assessments are scheduled for 30-day, 3, 6, 9, 12, 18, 24, 36, 48 and 60-months post index procedure.*Angiography: Unscheduled Visits1Duplex Ultrasound: 30 days, 6 months, 12 months and unscheduled visits1 |
| *Subjects will be contacted via phone for the 3-month, 9-month and 18-month assessments1Perform only if clinically warranted or institutional standard | |

The IN.PACT AV Access study utilized the following core labs/CROs:

- Clinical Events Committee (CEC): Responsible for adjudicating adverse events and deaths.
- Angiography Core Laboratory: Responsible for reviewing all angiographies
- Duplex Ultrasound Core Laboratory: Responsible for reviewing all duplex exams
- Data Monitoring Committee (DMC): Monitor subject safety and efficacy and evaluate the progress of the study
- Randomization Vendor: Managed the randomization for the study

# 1. Clinical Inclusion and Exclusion Criteria

Enrollment in the IN.PACT AV Access study was limited to patients who met the following inclusion criteria:

PMA P190008: FDA Summary of Safety and Effectiveness Data

{17}

- Patient is ≥ 21 years of age
- Patient has a life expectancy of ≥ 12 months
- Patient has a native AV fistula created ≥ 60 days prior to the index procedure
- The target AV fistula has undergone successful dialysis for at least 8 of 12 sessions during a four-week period
- Patient has a de novo and/or non-stented restenotic lesion located between the arteriovenous anastomosis and axillosubclavian junction with ≥50% stenosis
- Note: If the lesion is located in the anastomosis, the treatment may be delivered up to 2 cm upstream on the arterial side
- Note: If the lesion is located in the cephalic arch, the treatment may be delivered up to 2 cm into the subclavian vein
- Patient has a target lesion or a tandem lesion that is ≤ 100 mm in length (by visual estimate)
- Note: Tandem lesions may be enrolled provided they meet all of the following criteria:
- Separated by a gap of ≤ 30 mm (3 cm)
- Total combined lesion length, including 30 mm gap, ≤ 100 mm
- Able to be treated as a single lesion
- Patient has a target vessel diameter of 4.0 – 12.0 mm (by visual estimate)
- Patient underwent successful crossing of the target lesion with the guide wire and pre-dilatation with a high-pressure PTA balloon defined as:
- Residual stenosis of ≤ 30% AND
- Absence of a flow limiting dissection (Grade ≥ C) or perforation
- Patient provides written informed consent prior to enrollment in the study
- Patient is willing to comply with all follow-up evaluations at specified times

Patients were not permitted to enroll in the IN.PACT AV Access study if they met any of the following exclusion criteria:
- Women who are breastfeeding, pregnant, or are intending to become pregnant, or men intending to father children
- Patient is receiving immunosuppressive therapy
- Patient is anticipating a kidney transplant within 6 months of enrollment into the study
- Patient with secondary non-target lesion requiring treatment within 30 days post index procedure
- Patient with hemodynamically significant central venous stenoses that cannot be successfully treated prior to treatment of the target lesion
- Patient has undergone prior intervention of access site within 30 days of index procedure
- Patient with anticipated conversion to peritoneal dialysis
- Patient has an infected AV access or systemic infection
- Patient has planned surgical revision of access site

PMA P190008: FDA Summary of Safety and Effectiveness Data
Page 18

{18}

- Patient with target AVF or access circuit which previously had or currently has a thrombosis
- Patients judged to have a lesion that prevents complete inflation of an angioplasty balloon or proper placement of the delivery system
- Patient with target lesion located central to the axillosubclavian junction
- Patient has significant arterial inflow lesion requiring treatment more than $2\mathrm{cm}$ upstream from the anastomosis in the AV access
- Patient has presence of pseudoaneurysm or aneurysm requiring treatment at the lesion site
- Patient has presence of a stent located in the target AV access circuit
- Patients with known allergies or sensitivities to paclitaxel
- Patient with known contraindication, including allergic reaction, or sensitivity to contrast material that cannot be adequately pre-treated
- Patient who cannot receive recommended antiplatelet and/or anticoagulant therapy
- Patient with clinically significant Steal Syndrome requiring treatment
- Patient is enrolled in another investigational drug, device, or biologic study and has not completed the primary endpoint, or was previously enrolled in this study
- Patient has a co-morbid condition that, in the judgment of the Investigator, may cause him/her to be noncompliant with the protocol or confound the data interpretation

# 2. Follow-up Schedule

All patients were scheduled to return for follow-up examinations at 30 days, 6, 12, 24, 36, 48 and 60 months with a telephone follow-up at 3, 9, and 18 months post index procedure. Please see Table 9 below for the complete procedure and follow-up schedule.

Table 9: Procedure and Follow-up Schedule†

| Assessments/Procedure | Baseline/Screening | Index Procedure | Discharge (within 7 days post-procedure) | 30 Days (± 7 days) | 3 Months* (90 days ± 15 days) | 24 Months (720 days ± 30 days) | Unscheduled Visit | Target AVF Abandonment |
| --- | --- | --- | --- | --- | --- | --- | --- | --- |
| | | | | 6 Months (180 days ± 30 days) | 9 Months* (270 days ± 30 days) | 36 Months (1,080 days ± 30 days) | | |
| | | | | 12 Months (360 days ± 30 days) | 18 Months* (540 days ± 30 days) | 48 Months (1,440 days ± 30 days) 60 Months†† (1,800 days ± 30 days) | | |
| Informed Consent | X1 | | | | | | | |
| Medical History | X2 | | | | | | | |
| Physical Exam | X2 | | | | | | X4 | |
| Medication Assessment | X2 | X | X | X | X | X | | |
| EQ-5D | X2 | | | X | | X | | |
| Duplex Ultrasound | | | | X | | | X6 | |
| Angiography¥ | | X3 | | | | | X4 | |
| Randomization | | X | | | | | | |
| Adverse Event | X | X | X | X5 | X5 | X5 | X5 | X5 |
| Abandonment | | | | | | | | X |

PMA P190008: FDA Summary of Safety and Effectiveness Data

{19}

| Assessments/Procedure | Baseline/Screening | Index Procedure | Discharge (within 7 days post-procedure) | 30 Days (± 7 days) | 3 Months* (90 days ± 15 days) | 24 Months (720 days ± 30 days) 36 Months (1,080 days ± 30 days) 48 Months (1,440 days ± 30 days) 60 Months†† (1,800 days ± 30 days) | Unscheduled Visit | Target AVF Abandonment |
| --- | --- | --- | --- | --- | --- | --- | --- | --- |
| | | | | 6 Months (180 days ± 30 days) | 9 Months* (270 days ± 30 days) | | | |
| | | | | 12 Months (360 days ± 30 days) | 18 Months* (540 days ± 30 days) | | | |
| eCRF | | | | | | | | |
| 1Follow-up dates are calculated based on 30-day months 7Subjects will be contacted by telephone 3 months, 9 months, and 18 months post index procedure to assess adverse events and medications ††After assessments for the 60 months visit are completed, the subject will be exited from the study 8Angiograms performed outside of the index procedure and unscheduled visits (e.g. standard of care angiograms at 6 months post index-procedure) should be submitted to the angiographic core laboratory. 1Consent process may occur within 14 days prior to enrollment. Signing on the same day as procedure is allowed if allowed by the IRB/EC and source records document that the consent process was conducted and consent was signed pre-procedure 2Within 14 days prior to enrollment 3Angiogram must include all pre- and post-procedure images. 4Repeat at unscheduled visit only if clinically warranted or institutional standard 5After the primary endpoints are met (6 months), only SAEs, TLRs, and/or device related events will be collected 6Duplex Ultrasounds conducted within 2 years of index procedure should be submitted to the Core Laboratory; after the 24 month assessment DUS exams should no longer be submitted for evaluation | | | | | | | | |

The key timepoints are shown below in Table 16 and Table 18 summarizing safety and effectiveness.

# 3. Clinical Endpoints

The primary safety endpoint was the serious adverse event rate involving AV access circuit through 30 days post-procedure. The study aimed to demonstrate non-inferiority of the IN.PACT AV DCB to Standard PTA (7.5% non-inferiority margin) for the safety endpoint.

The primary effectiveness endpoint was Target Lesion Primary Patency (TLPP) through 6 months, defined as freedom from clinically-driven target lesion revascularization (CD-TLR) or access circuit thrombosis measured through 6 months post-procedure.

The study aimed to demonstrate superiority of the IN.PACT AV DCB to Standard PTA for the effectiveness endpoint.

# Secondary endpoints included:

- Access Circuit Primary Patency through 3 Months, 6 Months, 9 Months, 12 Months, 18 Months, and 24 Months Post-procedure
- Target Lesion Primary Patency through 3 Months, 9 Months, 12 Months, 18 Months, and 24 Months Post-procedure
- Cumulative Target Lesion Revascularizations Measured through 3 Months, 6 Months, 9 Months, 12 Months, 18 Months, and 24 Months Post-procedure
- Number of Interventions Required to Maintain Target Lesion Patency through 3 Months, 6 Months, 9 Months, 12 Months, 18 Months, and 24 Months Post-procedure

PMA P190008: FDA Summary of Safety and Effectiveness Data

{20}

- Number of Interventions Required to Maintain Access Circuit Patency through 3 Months, 6 Months, 9 Months, 12 Months, 18 Months, and 24 Months Post-procedure
- Cumulative Access Circuit Thromboses Measured through 3 Months, 6 Months, 9 Months, 12 Months, 18 Months, and 24 Months Post-procedure
- Device, Procedure, and Clinical Success
- Rate of Device and Procedure Related Adverse Events Reported through 30 Days, 3 Months, 6 Months, 9 Months, 12 Months, 18 Months, and 24 Months Post-procedure.

The following endpoints will be assessed annually up to 60 months in addition to the assessment through 24 months where applicable:

- Target Lesion Revascularizations
- Clinically-Driven Target Lesion Revascularizations
- Re-interventions in the access circuit
- Abandonment of Target AVF
- Serious Adverse Events

With regard to success/failure criteria, both the primary safety and effectiveness endpoints had to be met in order for the study to be considered successful.

The long term device safety and effectiveness of the IN.PACT AV DCB for treatment of AVF will be evaluated beyond the pre-specified 30-day (primary safety) and 6-month (primary effectiveness) endpoints.

## B. Accountability of PMA Cohort

At the time of database lock (December 6, 2018), of 330 patients enrolled in the PMA study, 95.7% (286/299) of patients completed a 6-month visit.

After successful pre dilatation, subjects were randomized 1:1 to IN.PACT AV DCB (n = 170) and Standard PTA (n = 160). Subject disposition through 6-month follow-up by visit is listed in Figure 5 and Subject disposition is listed in Table 10 below.

PMA P190008: FDA Summary of Safety and Effectiveness Data
Page 21

{21}

Figure 5: Subject Disposition through 6-month Follow-up by Visit

Table 10: Subject Disposition

| Description | Randomized (ITT) | 30 Day | 3 Month | 6 Month | 9 Month | 12 Month |
| --- | --- | --- | --- | --- | --- | --- |
| Follow-Up at Time Points | 330 (100.0%) | 313/330 (94.8%) | 309/330 (93.6%) | 286/330 (86.7%) | 206/330 (62.4%) | 120/330 (36.4%) |
| Discontinued Early1 | 0 | 6 | 19 | 31 | 43 | 49 |
| Not Due for Visit2 | 0 | 0 | 0 | 0 | 79 | 147 |
| Follow-Up of Eligible3 Subjects | 330 (100.0%) | 313/324 (96.6%) | 309/311 (99.4%) | 286/299 (95.7%) | 206/208 (99.0%) | 120/134 (89.6%) |
| Note: The compliance included in- and out-of-window visit. 1 Study exits are cumulative count. At each follow-up, subjects exited the study for any reasons before the upper limit of the window and had no follow-up visit will be counted. 2 Not due for visit are cumulative. At each follow-up, a subject is counted as not due for visit if he did not exit the study, had no follow-up visit and did not reach the upper limit of the window (i.e., snapshot date – index procedure date < upper window). 3 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) | | | | | | |

Table 11: Evaluable Subjects for Primary Endpoints Analyses (ITT Analysis Set)

| Summary | IN.PACT DCB (N=170) | Standard PTA (N=160) |
| --- | --- | --- |
| Primary Safety Endpoint (Day 30) % (n) | | |
| Evaluable1 | 97.6% (166) | 98.8% (158) |
| Not Evaluable2 | 2.4% (4) | 1.3% (2) |
| Death before Day 233 | 0.6% (1) | 0.0% (0) |
| Withdrawal of Consent before Day 233 | 0.6% (1) | 0.6% (1) |
| Other Discontinued before Day 233 | 0.6% (1) | 0.0% (0) |
| 30-day Visit not done | 0.6% (1) | 0.6% (1) |
| | | |
| TLPP through 6 months (Day 210), %(n) | | |

PMA P190008: FDA Summary of Safety and Effectiveness Data

{22}

| Summary | IN.PACT DCB (N=170) | Standard PTA (N=160) |
| --- | --- | --- |
| Evaluable4 | 89.4% (152) | 92.5% (148) |
| Not Evaluable2 | 10.6% (18) | 7.5% (12) |
| Death before Day 1503 | 4.1% (7) | 1.3% (2) |
| Abandon AV Circuit before Day 1503 | 0.6% (1) | 1.9% (3) |
| Withdrawal Consent Before Day 1503 | 1.8% (3) | 3.1% (5) |
| Other Discontinued before Day 1503 | 1.8% (3) | 1.3% (2) |
| 6-month Visit not done | 2.4% (4) | 0.0% (0) |
| 1 Include subjects with at least 23 days of follow-up or with a safety event within 30 days; 2 The reasons for unevaluable are ordered in hierarchy as applicable: Death > Abandon AV Circuit > Withdrew > Other Discontinuation > Visit Not Done; 3 Day 23 represents the first day of 1-month (or 30-day visit) clinical window, Day 150 represents first day of 6-month visit window; 4 Subjects with a clinically driven target lesion revascularization (TLR) or access circuit thrombosis within 210 days or without TLPP failure but had at least 150 days of clinical follow-up were considered evaluable. Subjects had no failure events but had abandoned AV Access circuit within 150 days were considered not evaluable. | | |

# C. Study Population Demographics and Baseline Parameters

Site reported baseline demographic and clinical characteristics for all 330 enrolled subjects are provided in Table 12 to Table 14 below. Treatment groups were well balanced in baseline demographics and clinical characteristics between IN.PACT AV DCB and PTA subjects. IN.PACT AV DCB subjects had a mean age of 65.8 years, $65.9\%$ were male, $62.9\%$ had diabetes, and $91.2\%$ had hypertension. Similarly, PTA subjects had a mean age of 65.5 years, $63.1\%$ were male, $68.8\%$ had diabetes, and $94.4\%$ had hypertension. All subjects $(100\%)$ reported renal insufficiency, have been receiving hemodialysis for a mean of 4.3 years, and have had their target AVF for a mean of 3.3 years. The most common type of AVF was radiocephalic $(50.3\%$ (166/330)), followed by brachiocephalic $(36.4\%$ (120/330)), brachiobasilic $(9.7\%$ (32/330)), and other $(3.6\%$ (12/330)). All subjects $(100\%$ (330/330)) presented with clinical symptoms indicating AV access dysfunction at baseline.

PMA P190008: FDA Summary of Safety and Effectiveness Data

{23}

Table 12: Baseline Demographics and Clinical Characteristics-ITT Analysis Set

| Subject Characteristics | IN.PACT AV
DCB
(N=170 Subjects) | Standard PTA
(N=160 Subjects) | Total
(N=330 Subjects) | p-value^{1} |
| --- | --- | --- | --- | --- |
| Age (yrs) | | | | |
| N | 170 | 160 | 330 | |
| Mean ± SD | 65.8 ± 13.1 | 65.5 ± 13.4 | 65.6 ± 13.3 | 0.837 |
| Median (Q1, Q3) | 67.0 (58, 75) | 68.0 (57, 75) | 67.0 (57, 75) | |
| Min, Max | 29, 94 | 29, 90 | 29, 94 | |
| Male | 65.9% (112/170) | 63.1% (101/160) | 64.5% (213/330) | 0.646 |
| Ethnicity | | | | |
| Hispanic/Latino | 9.0% (15/167) | 8.9% (14/157) | 9.0% (29/324) | 1.000 |
| Race | | | | 0.920 |
| White | 24.7% (42/170) | 28.8% (46/160) | 26.7% (88/330) | |
| Black or African American | 31.8% (54/170) | 30.0% (48/160) | 30.9% (102/330) | |
| Asian | 37.1% (63/170) | 35.6% (57/160) | 36.4% (120/330) | |
| Native Hawaiian or Other Pacific Islander | 3.5% (6/170) | 2.5% (4/160) | 3.0% (10/330) | |
| American Indian or Alaska Native | 0.0% (0/170) | 0.0% (0/160) | 0.0% (0/330) | |
| Other | 2.9% (5/170) | 3.1% (5/160) | 3.0% (10/330) | |
| Hypertension | 91.2% (155/170) | 94.4% (151/160) | 92.7% (306/330) | 0.295 |
| Hyperlipidemia | 54.1% (92/170) | 52.5% (84/160) | 53.3% (176/330) | 0.825 |
| Diabetes Mellitus | 62.9% (107/170) | 68.8% (110/160) | 65.8% (217/330) | 0.297 |
| Type I | 2.4% (4/170) | 3.8% (6/160) | 3.0% (10/330) | 0.532 |
| Type II | 60.6% (103/170) | 65.0% (104/160) | 62.7% (207/330) | 0.427 |
| Renal Insufficiency | 100.0% (170/170) | 100.0% (160/160) | 100.0% (330/330) | > 0.999 |
| Carotid Artery Disease | 4.1% (7/170) | 8.8% (14/160) | 6.4% (21/330) | 0.114 |
| Congestive Heart Failure | 22.9% (39/170) | 24.4% (39/160) | 23.6% (78/330) | 0.796 |
| Coronary Heart Disease | 35.9% (61/170) | 38.8% (62/160) | 37.3% (123/330) | 0.649 |
| Peripheral Artery Disease | 19.4% (33/170) | 15.1% (24/159) | 17.3% (57/329) | 0.312 |
| Current Smoker | 11.2% (19/170) | 16.3% (26/160) | 13.6% (45/330) | 0.201 |
| Former Smoker | 37.6% (64/170) | 28.1% (45/160) | 33.0% (109/330) | 0.079 |
| AVF Type | | | | 0.918 |
| Radiocephalic | 50.6% (86/170) | 50.0% (80/160) | 50.3% (166/330) | |
| Brachiocephalic | 36.5% (62/170) | 36.3% (58/160) | 36.4% (120/330) | |
| Brachiobasilic | 10.0% (17/170) | 9.4% (15/160) | 9.7% (32/330) | |
| Other | 2.9% (5/170) | 4.4% (7/160) | 3.6% (12/330) | |
| Dominant Arm | 22.4% (38/170) | 24.4% (39/160) | 23.3% (77/330) | 0.697 |
| Previous peripheral revascularization | 74.1% (126/170) | 75.0% (120/160) | 74.5% (246/330) | 0.900 |
| Years since AVF creation^{2} | | | | |
| N | 170 | 160 | 330 | |
| Mean ± SD | 3.2 ± 3.0 | 3.5 ± 3.8 | 3.3 ± 3.4 | 0.436 |
| Median (Q1, Q3) | 2.2 (1, 4) | 2.2 (1, 5) | 2.2 (1, 5) | |
| Min, Max | 0, 17 | 0, 28 | 0, 28 | |
| Years of Hemodialysis History^{3} | | | | |
| N | 170 | 159 | 329 | |
| Mean ± SD | 4.3 ± 5.1 | 4.2 ± 5.2 | 4.3 ± 5.1 | 0.755 |
| Median (Q1, Q3) | 2.7 (1, 6) | 2.3 (1, 6) | 2.6 (1, 6) | |
| Min, Max | 0, 32 | 0, 41 | 0, 41 | |
| ^{1}p-values for continuous variables were based on independent t-test, for binary variables were based on Fisher’s Exact test, for nominal variables were based on Cochran-Mantel-Haenszel (CMH) general association test, for ordinal variables were based on CMH score test. The p-values should be interpreted with caution because the analyses were not adjusted for multiplicity and the hypothesis testing was not pre-specified. | | | | |
| ^{2}41 subjects had partial dates and their years since AVF creation was calculated based on the imputed dates using the middle of the month or middle of the year. | | | | |
| ^{3}51 subjects had partial dates and their years of hemodialysis history was calculated based on the imputed dates using the middle of the month or middle of the year. | | | | |

PMA P190008: FDA Summary of Safety and Effectiveness Data

{24}

Table 13: Site Reported Baseline Lesion Characteristics – ITT Analysis Set

| Lesion Characteristics | IN.PACT AV DCB
(N=170 Subjects) | Standard PTA
(N=160 Subjects) | Total
(N=330 Subjects) | p-value¹ |
| --- | --- | --- | --- | --- |
| Target Arm | | | | 0.449 |
| Right Arm | 23.5% (40/170) | 27.5% (44/160) | 25.5% (84/330) | |
| Left Arm | 76.5% (130/170) | 72.5% (116/160) | 74.5% (246/330) | |
| Target Lesion Access | | | | 0.765 |
| Venous | 97.1% (165/170) | 96.3% (154/160) | 96.7% (319/330) | |
| Arterial | 2.9% (5/170) | 3.8% (6/160) | 3.3% (11/330) | |
| Lesion Type | | | | 0.905 |
| De Novo | 30.0% (51/170) | 30.6% (49/160) | 30.3% (100/330) | |
| Restenotic | 70.0% (119/170) | 69.4% (111/160) | 69.7% (230/330) | |
| ¹p-values for continuous variables were based on independent t-test, for binary variables were based on Fisher’s Exact test, for nominal variables were based on CMH general association test, for ordinal variables were based on CMH score test.
Note: Site reported data. The p-values should be interpreted with caution because the analyses were not adjusted for multiplicity and the hypothesis testing was not pre-specified. | | | | |

Table 14: Baseline / Procedural Angiographic Core Lab Characteristics – ITT Analysis Set

| Procedural Characteristics | IN.PACT AV DCB
(N=170 Subjects) | Standard PTA
(N=160 Subjects) | Difference
[95% CI] | p-value¹ |
| --- | --- | --- | --- | --- |
| Treated Vessel | | | | |
| Anastomosis | 33.7% (57/169) | 31.6% (50/158) | 2.1% [-8.8%, 12.9%] | 0.724 |
| Arterial Inflow | 0.0% (0/169) | 0.0% (0/158) | NA | > 0.999 |
| Cephalic Arch | 16.6% (28/169) | 22.8% (36/158) | -6.2% [-17.0%, 4.6%] | 0.166 |
| In Cannulation Zone | 26.6% (45/169) | 20.9% (33/158) | 5.7% [-5.1%, 16.5%] | 0.244 |
| Swing Point | 19.5% (33/169) | 20.9% (33/158) | -1.4% [-12.2%, 9.5%] | 0.784 |
| Venous Outflow | 3.6% (6/169) | 3.8% (6/158) | -0.2% [-11.1%, 10.6%] | 1.000 |
| Subjects with Tandem Lesion | 12.4% (21/170) | 16.3% (26/160) | -3.9% [-14.7%, 6.9%] | 0.346 |
| Target Lesion Length (mm) | | | | |
| N | 170 | 159 | | |
| Mean ± SD | 46.3 ± 28.1 | 41.9 ± 25.2 | 4.4 [-1.4, 10.2] | 0.137 |
| Median (Q1, Q3) | 42.7 (25, 61) | 37.5 (23, 58) | | |
| Min, Max | 3, 160 | 3, 157 | | |
| Minimum Lumen Diameter (mm) | | | | |
| N | 170 | 159 | | |
| Mean ± SD | 2.7 ± 1.6 | 2.8 ± 1.7 | -0.1 [-0.4, 0.3] | 0.731 |
| Median (Q1, Q3) | 2.6 (2, 4) | 2.4 (1, 4) | | |
| Min, Max | 0, 9 | 0, 9 | | |
| Reference Vessel Diameter (mm) | | | | |
| N | 170 | 159 | | |
| Mean ± SD | 7.5 ± 2.3 | 7.7 ± 2.6 | -0.2 [-0.7, 0.3] | 0.442 |
| Median (Q1, Q3) | 7.2 (6, 9) | 7.3 (6, 9) | | |
| Min, Max | 2, 13 | 3, 15 | | |
| Pre-procedure % Diameter Stenosis | | | | |
| N | 170 | 159 | | |
| Mean ± SD | 64.8 ± 13.3 | 64.8 ± 14.5 | 0.0 [-3.0, 3.0] | 0.986 |
| Median (Q1, Q3) | 64.7 (56, 74) | 65.6 (55, 76) | | |
| Min, Max | 27, 100 | 2, 100 | | |
| Subjects with Occluded Lesions | 1.2% (2/169) | 0.6% (1/159) | 0.6% [-10.3%, 11.4%] | 1.000 |
| Length of Occlusion | | | | |
| N | 2 | 1 | | |
| Mean ± SD | 37.5 ± 40.5 | 26.3 ± NA | 11.2 [NA, NA] | NA |

PMA P190008: FDA Summary of Safety and Effectiveness Data

{25}

Table 15: Treatment Devices Used During Index Procedure – All ITT Subjects

| Subject Characteristics | IN.PACT AV DCB (N=170 Subjects) | Standard PTA (N=160 Subjects) | Difference [95% CI] | p-value^{1} |
| --- | --- | --- | --- | --- |
| Subjects with | | | | < 0.001 |
| No Balloon | 0.0% (0/170) | 1.9% (3/160) | | |
| One Balloon | 75.3% (128/170) | 95.0% (152/160) | | |
| Two Balloons | 24.7% (42/170) | 3.1% (5/160) | | |
| Three Balloons | 0.0% (0/170) | 0.0% (0/160) | | |
| More than Three Balloons | 0.0% (0/170) | 0.0% (0/160) | | |
| Total Balloon Length per Subject (mm) | | | | |
| N | 170 | 160 | | |
| Mean ± SD | 73.5 ± 30.6 | 48.0 ± 18.5 | < 0.001 | |
| Median (Q1, Q3) | 80.0 (40, 100) | 40.0 (40, 60) | | |
| Min, Max | 40, 160 | 0, 120 | | |
| Number of Treatment Balloons per Subject | | | | |
| N | 170 | 160 | | |
| Mean ± SD | 1.2 ± 0.4 | 1.0 ± 0.2 | < 0.001 | |
| Median (Q1, Q3) | 1.0 (1, 1) | 1.0 (1, 1) | | |
| Min, Max | 1, 2 | 0, 2 | | |
| Subjects received provisional stents^{2} | 0.6% (1/170) | 0.6% (1/160) | 1.000 | |
| Number of provisional stents per subject^{2} | | | | |
| N | 170 | 160 | | |
| Mean ± SD | 0.0 ± 0.1 | 0.0 ± 0.1 | 0.966 | |
| Median (Q1, Q3) | 0.0 (0, 0) | 0.0 (0, 0) | | |
| Min, Max | 0, 1 | 0, 1 | | |
| Reasons for Provisional Stenting^{2, 3} | | | | |
| Persistent residual stenosis | 0.0% (0/169) | 0.6% (1/160) | 0.486 | |
| Major flow-limiting dissection | 0.0% (0/169) | 0.0% (0/160) | > 0.999 | |
| ^{1}p-values for continuous variables were based on independent t-test, for binary variables were based on Fisher’s Exact test, for nominal variables were based on CMH general association test, for ordinal variables were based on CMH score test. The p-values should be interpreted with caution because the analyses were not adjusted for multiplicity and the hypothesis testing was not pre-specified. | | | | |
| ^{2}Provisional stents are not allowed in Japan patients. | | | | |
| ^{3}One IN.PACT AV DCB study group subject, received provisional stenting for a grade C dissection (not considered flow-limiting) for subject safety, and therefore does not appear in the reasons for provisional stenting. | | | | |

PMA P190008: FDA Summary of Safety and Effectiveness Data

{26}

# D. Safety and Effectiveness Results

Results for the primary safety and effectiveness endpoints of the IN.PACT AV Access study are described and summarized below.

# 1. Safety Results

The primary safety endpoint was the rate of Serious Adverse Events (SAE) involving the AV access circuit through 30-day post-procedure. The 30-day SAE rate involving the AV access circuit was $4.2\%$ in the IN.PACT AV DCB study group and $4.4\%$ in the PTA control group (non-inferiority $\mathrm{p} = 0.002$ ). The upper limit of $95\%$ confidence interval for the risk difference was $5.0\%$ , less than the non-inferiority margin $(7.5\%)$ , demonstrating that IN.PACT AV DCB was non-inferior to PTA in terms of the primary safety endpoint. The primary safety outcomes for this study are presented below in Table 16. A Kaplan-Meier analysis of the primary safety endpoint is shown below in Figure 6 for all ITT subjects. The Kaplan-Meier survival curve estimate of freedom from SAEs involving the access circuit through 30 days was $95.9\%$ in the IN.PACT AV DCB study group vs. $95.6\%$ in the PTA control group. Figure 6 provides freedom from SAEs involving the access circuit through 180 days which are also listed in Table 17.

Table 16: Primary Safety Endpoint - ITT Analysis Set

| | IN.PACT AV DCB (N=170 Subjects) | Standard PTA (N=160 Subjects) | Difference [95% CI] | p-value† |
| --- | --- | --- | --- | --- |
| Primary Safety Endpoint | | | Non-inferiority Test with 7.5% Margin | |
| SAE involving the AV access circuit within 30 days | 4.2% (7/166) | 4.4% (7/158) | -0.2% [-5.5%, 5.0%] | 0.002 |
| Arteriovenous Fistula Occlusion | 14.3% (1/7) | 0.0% (0/7) | | |
| Arteriovenous Fistula Site Complication | 71.4% (5/7) | 57.1% (4/7) | | |
| Arteriovenous Fistula Thrombosis | 14.3% (1/7) | 14.3% (1/7) | | |
| Haemodialysis Complication | 14.3% (1/7) | 0.0% (0/7) | | |
| Vasospasm | 0.0% (0/7) | 14.3% (1/7) | | |
| Vessel Puncture Site Haematoma | 0.0% (0/7) | 14.3% (1/7) | | |
| †Non-inferiority p-values for the primary safety endpoint was based on the Farrington-Manning non-inferiority test with a margin of 7.5%. | | | | |

PMA P190008: FDA Summary of Safety and Effectiveness Data

{27}

Figure 6: Kaplan-Meier Plot – Freedom from SAE involving Access Circuit through 30 Days – ITT Analysis Set

PMA P190008: FDA Summary of Safety and Effectiveness Data
Page 28

{28}

PMA P190008: FDA Summary of Safety and Effectiveness Data
Page 29

| From day X To day Y | 0
0 | 1
7 | 8
14 | 15
21 | 22
30 |
| --- | --- | --- | --- | --- | --- |
| **IN.PACT AV Access DCB (N=170 Subjects)** | | | | | |
| # Entered | 170 | 166 | 164 | 161 | 159 |
| # Censored | 1 | 0 | 1 | 2 | 1 |
| # Events | 3 | 2 | 2 | 0 | 0 |
| Survival rate [%] | 98.2% | 97.1% | 95.9% | 95.9% | 95.9% |
| **STANDARD PTA (N=160 Subjects)** | | | | | |
| # Entered | 160 | 154 | 153 | 152 | 152 |
| # Censored | 2 | 0 | 0 | 0 | 0 |
| # Events | 4 | 1 | 1 | 0 | 1 |
| Survival rate [%] | 97.5% | 96.9% | 96.2% | 96.2% | 95.6% |
| The arrow bars are confidence intervals at each time point. The arrow bars and the log-rank p-value should be interpreted with caution because the analyses were not adjusted for multiplicity and the hypothesis testing was not pre-specified | | | | | |

## Serious Adverse Events

A SAE is an adverse event that a) led to death, b) led to a serious deterioration in the health of the subject, resulting in a life-threatening illness or injury, or a permanent impairment of a body structure or a body function, or in-patient or prolonged hospitalization, or medical or surgical intervention to prevent life-threatening illness or injury or permanent impairment to a body structure or a body function, c) led to fetal distress, fetal death or a congenital abnormality or birth defect. SAEs are summarized in Table 17. In total, 62.9% of IN.PACT AV DCB study group subjects experienced one or more serious adverse events and 71.9% of standard PTA control arm subjects experienced one or more serious adverse events within 360 days. All SAEs which led to death were CEC adjudicated as not related to the study device, procedure, or therapy.

Additional analysis on SAEs is presented in Table 18.

Table 17: Number of Subjects with One or More SAEs by MedDRA (Medical Dictionary for Regulatory Activities) System- Within 360 Days – ITT Analysis Set

| Adverse Event | IN.PACT AV DCB
(N=170 Subjects) | Standard PTA
(N=160 Subjects) |
| --- | --- | --- |
| SUBJECTS WITH ONE OR MORE SERIOUS ADVERSE EVENTS | 62.9% (107/170) | 71.9% (115/160) |
| BLOOD AND LYMPHATIC SYSTEM DISORDERS | 1.8% (3/170) | 1.3% (2/160) |
| ANAEMIA | 1.2% (2/170) | 1.3% (2/160) |
| LEUKOCYTOSIS | 0.6% (1/170) | 0.0% (0/160) |
| THROMBOCYTOPENIA | 0.6% (1/170) | 0.0% (0/160) |
| CARDIAC DISORDERS | 15.9% (27/170) | 14.4% (23/160) |
| ACUTE CORONARY SYNDROME | 0.6% (1/170) | 0.0% (0/160) |
| ACUTE MYOCARDIAL INFARCTION | 0.0% (0/170) | 1.9% (3/160) |
| ANGINA PECTORIS | 1.8% (3/170) | 1.3% (2/160) |
| ANGINA UNSTABLE | 0.6% (1/170) | 0.0% (0/160) |

{29}

PMA P190008: FDA Summary of Safety and Effectiveness Data
Page 30

| Adverse Event | IN.PACT AV DCB
(N=170 Subjects) | Standard PTA
(N=160 Subjects) |
| --- | --- | --- |
| AORTIC VALVE STENOSIS | 0.0% (0/170) | 0.6% (1/160) |
| ATRIAL FIBRILLATION | 2.4% (4/170) | 2.5% (4/160) |
| ATRIAL FLUTTER | 0.6% (1/170) | 0.0% (0/160) |
| BRADYCARDIA | 1.2% (2/170) | 0.6% (1/160) |
| CARDIAC ARREST | 2.4% (4/170) | 1.9% (3/160) |
| CARDIAC FAILURE | 0.6% (1/170) | 0.0% (0/160) |
| CARDIAC FAILURE CHRONIC | 0.6% (1/170) | 0.6% (1/160) |
| CARDIAC FAILURE CONGESTIVE | 2.9% (5/170) | 3.1% (5/160) |
| CARDIO-RESPIRATORY ARREST | 0.0% (0/170) | 0.6% (1/160) |
| CARDIOMYOPATHY | 0.0% (0/170) | 0.6% (1/160) |
| CORONARY ARTERY DISEASE | 1.2% (2/170) | 1.3% (2/160) |
| CORONARY ARTERY OCCLUSION | 0.6% (1/170) | 0.0% (0/160) |
| CORONARY ARTERY STENOSIS | 1.8% (3/170) | 1.3% (2/160) |
| DIASTOLIC DYSFUNCTION | 0.6% (1/170) | 0.0% (0/160) |
| ISCHAEMIC CARDIOMYOPATHY | 1.2% (2/170) | 0.0% (0/160) |
| MITRAL VALVE INCOMPETENCE | 0.6% (1/170) | 0.0% (0/160) |
| MYOCARDIAL ISCHAEMIA | 0.0% (0/170) | 0.6% (1/160) |
| PERICARDIAL EFFUSION | 1.2% (2/170) | 0.6% (1/160) |
| EAR AND LABYRINTH DISORDERS | 0.6% (1/170) | 0.0% (0/160) |
| DEAFNESS NEUROSENSORY | 0.6% (1/170) | 0.0% (0/160) |
| EYE DISORDERS | 1.8% (3/170) | 0.0% (0/160) |
| CATARACT | 1.2% (2/170) | 0.0% (0/160) |
| VITREOUS HAEMORRHAGE | 0.6% (1/170) | 0.0% (0/160) |
| GASTROINTESTINAL DISORDERS | 4.7% (8/170) | 6.9% (11/160) |
| ASCITES | 0.6% (1/170) | 0.0% (0/160) |
| COLITIS ISCHAEMIC | 0.6% (1/170) | 0.0% (0/160) |
| DIARRHOEA | 0.6% (1/170) | 0.0% (0/160) |
| DIVERTICULUM | 0.6% (1/170) | 0.0% (0/160) |
| DYSPHAGIA | 0.0% (0/170) | 1.3% (2/160) |
| GASTRIC POLYPS | 0.0% (0/170) | 0.6% (1/160) |
| GASTROINTESTINAL HAEMORRHAGE | 1.2% (2/170) | 1.3% (2/160) |
| HAEMATEMESIS | 0.0% (0/170) | 0.6% (1/160) |
| HAEMORRHOIDS | 0.6% (1/170) | 0.0% (0/160) |
| INGUINAL HERNIA | 0.0% (0/170) | 0.6% (1/160) |
| LARGE INTESTINAL STENOSIS | 0.0% (0/170) | 0.6% (1/160) |
| LOWER GASTROINTESTINAL HAEMORRHAGE | 0.0% (0/170) | 0.6% (1/160) |
| MESENTERIC HAEMATOMA | 0.6% (1/170) | 0.0% (0/160) |
| NAUSEA | 0.6% (1/170) | 0.0% (0/160) |
| PANCREATITIS ACUTE | 0.0% (0/170) | 0.6% (1/160) |
| UPPER GASTROINTESTINAL HAEMORRHAGE | 0.0% (0/170) | 0.6% (1/160) |
| VOMITING | 0.6% (1/170) | 0.6% (1/160) |

{30}

PMA P190008: FDA Summary of Safety and Effectiveness Data
Page 31

| Adverse Event | IN.PACT AV DCB
(N=170 Subjects) | Standard PTA
(N=160 Subjects) |
| --- | --- | --- |
| GENERAL DISORDERS AND ADMINISTRATION
SITE CONDITIONS | 2.4% (4/170) | 3.8% (6/160) |
| CHEST PAIN | 1.8% (3/170) | 1.3% (2/160) |
| COMPLICATION ASSOCIATED WITH DEVICE | 0.0% (0/170) | 0.6% (1/160) |
| DEATH | 0.0% (0/170) | 0.6% (1/160) |
| MULTIPLE ORGAN DYSFUNCTION SYNDROME | 0.6% (1/170) | 0.0% (0/160) |
| PERIPHERAL SWELLING | 0.0% (0/170) | 0.6% (1/160) |
| VASCULAR STENT STENOSIS | 0.0% (0/170) | 0.6% (1/160) |
| HEPATOBILIARY DISORDERS | 4.1% (7/170) | 0.0% (0/160) |
| BILE DUCT STONE | 0.6% (1/170) | 0.0% (0/160) |
| CHOLANGITIS | 0.6% (1/170) | 0.0% (0/160) |
| CHOLECYSTITIS | 0.6% (1/170) | 0.0% (0/160) |
| CHOLECYSTITIS ACUTE | 0.6% (1/170) | 0.0% (0/160) |
| CHOLELITHIASIS | 0.6% (1/170) | 0.0% (0/160) |
| HEPATIC CIRRHOSIS | 0.6% (1/170) | 0.0% (0/160) |
| PORTAL VEIN THROMBOSIS | 0.6% (1/170) | 0.0% (0/160) |
| IMMUNE SYSTEM DISORDERS | 0.0% (0/170) | 0.6% (1/160) |
| KIDNEY TRANSPLANT REJECTION | 0.0% (0/170) | 0.6% (1/160) |
| INFECTIONS AND INFESTATIONS | 17.1% (29/170) | 11.3% (18/160) |
| ABDOMINAL ABSCESS | 0.6% (1/170) | 0.0% (0/160) |
| ABSCESS LIMB | 0.6% (1/170) | 0.0% (0/160) |
| APPENDICITIS | 0.6% (1/170) | 0.0% (0/160) |
| BACTERAEMIA | 0.6% (1/170) | 0.0% (0/160) |
| BRONCHITIS | 0.6% (1/170) | 0.0% (0/160) |
| CELLULITIS | 2.4% (4/170) | 0.6% (1/160) |
| CLOSTRIDIUM DIFFICILE COLITIS | 0.0% (0/170) | 0.6% (1/160) |
| CLOSTRIDIUM DIFFICILE INFECTION | 0.0% (0/170) | 0.6% (1/160) |
| ENDOCARDITIS | 0.6% (1/170) | 0.0% (0/160) |
| ENTEROCOCCAL INFECTION | 0.0% (0/170) | 0.6% (1/160) |
| ESCHERICHIA BACTERAEMIA | 0.6% (1/170) | 0.0% (0/160) |
| GANGRENE | 0.6% (1/170) | 0.6% (1/160) |
| GASTROENTERITIS | 0.6% (1/170) | 0.0% (0/160) |
| GASTROINTESTINAL INFECTION | 0.6% (1/170) | 0.0% (0/160) |
| INFECTED SKIN ULCER | 0.6% (1/170) | 0.0% (0/160) |
| INFECTION | 0.0% (0/170) | 0.6% (1/160) |
| INFLUENZA | 0.0% (0/170) | 1.9% (3/160) |
| LOCALISED INFECTION | 0.6% (1/170) | 0.0% (0/160) |
| NECROTISING FASCIITIS | 0.0% (0/170) | 0.6% (1/160) |
| OSTEOMYELITIS | 1.2% (2/170) | 0.0% (0/160) |
| PNEUMONIA | 7.1% (12/170) | 3.1% (5/160) |
| PNEUMONIA STAPHYLOCOCCAL | 0.0% (0/170) | 0.6% (1/160) |
| POSTOPERATIVE WOUND INFECTION | 0.0% (0/170) | 0.6% (1/160) |

{31}

PMA P190008: FDA Summary of Safety and Effectiveness Data
Page 32

| Adverse Event | IN.PACT AV DCB
(N=170 Subjects) | Standard PTA
(N=160 Subjects) |
| --- | --- | --- |
| PYELONEPHRITIS | 0.6% (1/170) | 0.6% (1/160) |
| SEPSIS | 2.4% (4/170) | 2.5% (4/160) |
| SEPTIC SHOCK | 0.6% (1/170) | 0.0% (0/160) |
| STAPHYLOCOCCAL BACTERAEMIA | 0.6% (1/170) | 0.6% (1/160) |
| SUBCUTANEOUS ABSCESS | 0.6% (1/170) | 0.0% (0/160) |
| UPPER RESPIRATORY TRACT INFECTION | 0.6% (1/170) | 0.6% (1/160) |
| URINARY TRACT INFECTION | 1.2% (2/170) | 2.5% (4/160) |
| URINARY TRACT INFECTION BACTERIAL | 0.0% (0/170) | 0.6% (1/160) |
| UROSEPSIS | 0.0% (0/170) | 0.6% (1/160) |
| INJURY, POISONING AND PROCEDURAL
COMPLICATIONS | 38.8% (66/170) | 57.5% (92/160) |
| ACETABULUM FRACTURE | 0.6% (1/170) | 0.0% (0/160) |
| ARTERIOVENOUS FISTULA ANEURYSM | 1.8% (3/170) | 3.1% (5/160) |
| ARTERIOVENOUS FISTULA OCCLUSION | 1.8% (3/170) | 3.8% (6/160) |
| ARTERIOVENOUS FISTULA SITE COMPLICATION | 31.8% (54/170) | 49.4% (79/160) |
| ARTERIOVENOUS FISTULA SITE HAEMATOMA | 0.6% (1/170) | 0.6% (1/160) |
| ARTERIOVENOUS FISTULA SITE HAEMORRHAGE | 0.6% (1/170) | 1.3% (2/160) |
| ARTERIOVENOUS FISTULA THROMBOSIS | 0.6% (1/170) | 2.5% (4/160) |
| CORONARY ARTERY RESTENOSIS | 0.6% (1/170) | 0.0% (0/160) |
| DIALYSIS RELATED COMPLICATION | 0.6% (1/170) | 0.0% (0/160) |
| FEMORAL NECK FRACTURE | 0.6% (1/170) | 0.0% (0/160) |
| FEMUR FRACTURE | 0.0% (0/170) | 0.6% (1/160) |
| HAEMODIALYSIS COMPLICATION | 1.8% (3/170) | 0.0% (0/160) |
| HEAD INJURY | 0.6% (1/170) | 0.0% (0/160) |
| HIP FRACTURE | 0.0% (0/170) | 0.6% (1/160) |
| INCARCERATED INCISIONAL HERNIA | 0.0% (0/170) | 0.6% (1/160) |
| LIMB INJURY | 0.0% (0/170) | 0.6% (1/160) |
| MULTIPLE FRACTURES | 0.0% (0/170) | 0.6% (1/160) |
| OVERDOSE | 0.6% (1/170) | 0.0% (0/160) |
| POST PROCEDURAL HAEMORRHAGE | 0.0% (0/170) | 0.6% (1/160) |
| RECTAL INJURY | 0.6% (1/170) | 0.0% (0/160) |
| SKULL FRACTURE | 0.6% (1/170) | 0.0% (0/160) |
| SPINAL COMPRESSION FRACTURE | 0.0% (0/170) | 1.3% (2/160) |
| SUBDURAL HAEMATOMA | 0.6% (1/170) | 0.0% (0/160) |
| TIBIA FRACTURE | 0.0% (0/170) | 0.6% (1/160) |
| TOXICITY TO VARIOUS AGENTS | 0.0% (0/170) | 0.6% (1/160) |
| UPPER LIMB FRACTURE | 0.0% (0/170) | 0.6% (1/160) |
| INVESTIGATIONS | 0.0% (0/170) | 0.6% (1/160) |
| TROPONIN INCREASED | 0.0% (0/170) | 0.6% (1/160) |
| METABOLISM AND NUTRITION DISORDERS | 5.9% (10/170) | 8.1% (13/160) |
| FLUID OVERLOAD | 2.4% (4/170) | 1.9% (3/160) |
| HYPERGLYCAEMIA | 0.6% (1/170) | 0.6% (1/160) |

{32}

PMA P190008: FDA Summary of Safety and Effectiveness Data
Page 33

| Adverse Event | IN.PACT AV DCB
(N=170 Subjects) | Standard PTA
(N=160 Subjects) |
| --- | --- | --- |
| HYPERKALAEMIA | 1.8% (3/170) | 3.1% (5/160) |
| HYPERNATRAEMIA | 0.0% (0/170) | 0.6% (1/160) |
| HYPERVOLAEMIA | 0.6% (1/170) | 0.6% (1/160) |
| HYPOGLYCAEMIA | 0.6% (1/170) | 0.0% (0/160) |
| HYPOVOLAEMIA | 0.0% (0/170) | 0.6% (1/160) |
| LACTIC ACIDOSIS | 0.6% (1/170) | 0.6% (1/160) |
| MALNUTRITION | 0.6% (1/170) | 0.0% (0/160) |
| MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS | 3.5% (6/170) | 1.9% (3/160) |
| ARTHRITIS REACTIVE | 0.6% (1/170) | 0.0% (0/160) |
| BACK PAIN | 0.6% (1/170) | 0.6% (1/160) |
| CHONDROCALCINOSIS PYROPHOSPHATE | 0.6% (1/170) | 0.0% (0/160) |
| COSTOCHONDRITIS | 0.6% (1/170) | 0.0% (0/160) |
| FLANK PAIN | 0.0% (0/170) | 0.6% (1/160) |
| LUMBAR SPINAL STENOSIS | 0.6% (1/170) | 0.0% (0/160) |
| MUSCULAR WEAKNESS | 0.0% (0/170) | 0.6% (1/160) |
| SPINAL COLUMN STENOSIS | 0.6% (1/170) | 0.0% (0/160) |
| NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) | 1.8% (3/170) | 2.5% (4/160) |
| ANGIOSARCOMA | 0.0% (0/170) | 0.6% (1/160) |
| BLADDER CANCER | 0.6% (1/170) | 0.0% (0/160) |
| BREAST ANGIOSARCOMA | 0.0% (0/170) | 0.6% (1/160) |
| HEPATIC CANCER | 0.6% (1/170) | 0.0% (0/160) |
| LUNG ADENOCARCINOMA | 0.0% (0/170) | 0.6% (1/160) |
| METASTASES TO PERITONEUM | 0.0% (0/170) | 0.6% (1/160) |
| PROSTATE CANCER METASTATIC | 0.6% (1/170) | 0.0% (0/160) |
| RENAL CANCER | 0.0% (0/170) | 0.6% (1/160) |
| NERVOUS SYSTEM DISORDERS | 3.5% (6/170) | 6.9% (11/160) |
| BRAIN STEM STROKE | 0.0% (0/170) | 0.6% (1/160) |
| CAROTID ARTERY STENOSIS | 0.0% (0/170) | 0.6% (1/160) |
| CEREBRAL HAEMORRHAGE | 0.6% (1/170) | 0.0% (0/160) |
| CEREBROVASCULAR ACCIDENT | 1.2% (2/170) | 0.0% (0/160) |
| CERVICAL RADICULOPATHY | 0.0% (0/170) | 0.6% (1/160) |
| ENCEPHALOPATHY | 0.6% (1/170) | 1.3% (2/160) |
| HEPATIC ENCEPHALOPATHY | 0.6% (1/170) | 0.0% (0/160) |
| HYPERTENSIVE ENCEPHALOPATHY | 0.0% (0/170) | 0.6% (1/160) |
| ISCHAEMIC STROKE | 0.6% (1/170) | 0.6% (1/160) |
| METABOLIC ENCEPHALOPATHY | 0.0% (0/170) | 1.3% (2/160) |
| NARCOLEPSY | 0.0% (0/170) | 0.6% (1/160) |
| NEUROPATHY PERIPHERAL | 0.6% (1/170) | 0.0% (0/160) |
| PRESYNCOPE | 0.0% (0/170) | 0.6% (1/160) |
| SYNCOPE | 0.0% (0/170) | 0.6% (1/160) |

{33}

PMA P190008: FDA Summary of Safety and Effectiveness Data
Page 34

| Adverse Event | IN.PACT AV DCB
(N=170 Subjects) | Standard PTA
(N=160 Subjects) |
| --- | --- | --- |
| TRANSIENT ISCHAEMIC ATTACK | 0.6% (1/170) | 0.0% (0/160) |
| PSYCHIATRIC DISORDERS | 0.6% (1/170) | 1.3% (2/160) |
| DELIRIUM TREMENS | 0.6% (1/170) | 0.0% (0/160) |
| MENTAL STATUS CHANGES | 0.0% (0/170) | 1.3% (2/160) |
| RENAL AND URINARY DISORDERS | 1.2% (2/170) | 1.9% (3/160) |
| END STAGE RENAL DISEASE | 0.0% (0/170) | 1.3% (2/160) |
| RENAL CYST | 0.6% (1/170) | 0.0% (0/160) |
| RENAL MASS | 0.6% (1/170) | 0.0% (0/160) |
| URINARY RETENTION | 0.0% (0/170) | 0.6% (1/160) |
| RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS | 8.2% (14/170) | 5.6% (9/160) |
| ACUTE PULMONARY OEDEMA | 0.0% (0/170) | 0.6% (1/160) |
| ACUTE RESPIRATORY FAILURE | 1.8% (3/170) | 0.6% (1/160) |
| CHRONIC OBSTRUCTIVE PULMONARY DISEASE | 0.6% (1/170) | 0.0% (0/160) |
| DYSPNOEA EXERTIONAL | 0.6% (1/170) | 0.0% (0/160) |
| HYPOXIA | 0.6% (1/170) | 0.0% (0/160) |
| PLEURAL EFFUSION | 2.9% (5/170) | 0.0% (0/160) |
| PNEUMOTHORAX | 0.0% (0/170) | 0.6% (1/160) |
| PULMONARY HYPERTENSION | 0.0% (0/170) | 0.6% (1/160) |
| PULMONARY OEDEMA | 0.6% (1/170) | 1.3% (2/160) |
| RESPIRATORY ARREST | 0.6% (1/170) | 0.0% (0/160) |
| RESPIRATORY FAILURE | 1.8% (3/170) | 3.8% (6/160) |
| SKIN AND SUBCUTANEOUS TISSUE DISORDERS | 1.2% (2/170) | 1.9% (3/160) |
| DECUBITUS ULCER | 0.0% (0/170) | 0.6% (1/160) |
| DIABETIC FOOT | 0.6% (1/170…