LUTONIX® 035 Drug Coated Balloon PTA Catheter, Model 9010

P170003 · Lutonix · PRC · Aug 25, 2017 · Cardiovascular

Device Facts

• Record ID: P170003
• Device Name: LUTONIX® 035 Drug Coated Balloon PTA Catheter, Model 9010
• Applicant: Lutonix
• Product Code: PRC · Cardiovascular
• Decision Date: Aug 25, 2017
• Decision: APPR
• Device Class: Class 3
• Attributes: Therapeutic

Indications for Use

The LUTONIX® 035 Drug Coated Balloon PTA Catheter is indicated for percutaneous transluminal angioplasty (PTA), after pre-dilatation, for the treatment of stenotic lesions in dysfunctional native arteriovenous dialysis fistulae that are 4mm to 12mm in diameter and up to 80mm in length.

Device Story

The LUTONIX® 035 DCB is an over-the-wire percutaneous transluminal angioplasty (PTA) catheter featuring a paclitaxel-based drug coating (2μg/mm²) on the balloon surface. It includes the GEOALIGN® marking system for visual positioning. Used in clinical settings by physicians, the device functions primarily through mechanical vessel dilation, with the paclitaxel coating providing an ancillary anti-proliferative effect to inhibit neointimal hyperplasia and restenosis in dysfunctional native arteriovenous fistulae. The device is delivered over a 0.035" guidewire. By reducing restenosis, the device aims to maintain fistula patency, potentially reducing the frequency of repeat re-interventions required for hemodialysis access maintenance. The healthcare provider uses fluoroscopic imaging to guide placement and monitor the procedure.

Clinical Evidence

Pivotal prospective, multicenter, randomized controlled trial (IDE #G150067) of 285 patients (141 DCB, 144 control). Primary safety endpoint (freedom from serious adverse events involving AV access circuit through 30 days) met (94.9% DCB vs 95.8% control, p=0.0019). Primary effectiveness endpoint (Target Lesion Primary Patency at 6 months) was 71.4% for DCB vs 63.0% for control (p=0.0562, superiority not met). Clinical benefit demonstrated by reduced number of re-interventions at 6, 9, and 12 months.

Technological Characteristics

Over-the-wire PTA catheter; balloon coated with paclitaxel (API), polysorbate, and sorbitol (excipients). Balloon diameters 4-12mm, lengths 20-100mm. Compatible with 0.035" guidewire. GEOALIGN® non-radiopaque marker bands. Sterilized via ethylene oxide (ISO 11135-1:2014). Biocompatibility per ISO 10993-1.

Indications for Use

Indicated for patients ≥21 years with dysfunctional native arteriovenous dialysis fistulae (4-12mm diameter, ≤80mm length) requiring percutaneous transluminal angioplasty. Contraindicated in pregnant/breastfeeding women, men intending to father children within 2 years, and patients with lesions preventing complete balloon inflation or delivery system placement.

Regulatory Classification

Identification

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

Submission Summary (Full Text)

SUMMARY OF SAFETY AND EFFECTIVENESS DATA (SSED)

I. GENERAL INFORMATION

Device Generic Name: Drug Coated Balloon Percutaneous Transluminal Angioplasty Catheter

Device Trade Name: LUTONIX® 035 Drug Coated Balloon PTA Catheter, Model 9010

Device Product Code: PRC

Applicant's Name and Address: Lutonix, Inc.
A Subsidiary of C.R. Bard
9409 Science Center Drive
New Hope, MN 55428

Date of Panel Recommendation: None

Premarket Approval Application (PMA) number: P170003

Date of FDA Notice of Approval: August 25, 2017

The device was originally approved for a Superficial Femoral Artery indication under P130024 on June 12, 2014 and subsequently modified under PMA supplements. The SSED to support this indication is available on the CDRH website and is incorporated by reference here (https://www.accessdata.fda.gov/cdrh_docs/pdf13/P130024b.pdf). The current submission was submitted to expand the indication for the Lutonix® 035 Drug Coated Balloon PTA Catheter for treatment of stenotic lesions in dysfunctional native arteriovenous dialysis fistulae. Select bench, biocompatibility, pre-clinical, coating characterization, sterilization, stability, and chemistry, manufacturing, and controls (CMC) data were leveraged from P130024 for the smaller device diameters (4-7 mm). See the SSED referenced above for further information regarding the leveraged testing.

II. INDICATIONS FOR USE

The LUTONIX® 035 Drug Coated Balloon PTA Catheter is indicated for percutaneous transluminal angioplasty (PTA), after pre-dilatation, for the treatment of stenotic lesions in dysfunctional native arteriovenous dialysis fistulae that are 4mm to 12mm in diameter and up to 80mm in length.

III. CONTRAINDICATIONS

The LUTONIX® 035 Drug Coated Balloon PTA Catheter is contraindicated for use in:

PMA P170003: FDA Summary of Safety and Effectiveness Data

- Women who are breastfeeding, pregnant or are intending to become pregnant or men intending to father children over the next 2 years. It is unknown whether paclitaxel will be excreted in human milk and there is a potential for adverse reaction in nursing infants from paclitaxel exposure.
- Patients judged to have a lesion that prevents complete inflation of an angioplasty balloon or proper placement of the delivery system.

## IV. WARNINGS AND PRECAUTIONS

The warnings and precautions can be found in the LUTONIX® 035 Drug Coated Balloon PTA Catheter labeling.

## V. DEVICE DESCRIPTION

The LUTONIX® 035 Drug Coated Balloon PTA Catheter (LUTONIX® 035 DCB) is an over-the-wire drug coated percutaneous angioplasty catheter with a paclitaxel-based drug coating on the balloon portion of the catheter (see Figure 1). The GEOALIGN® Marking system is placed at 1 cm increments with numerical value (distance from the distal tip) every 10 cm and a thicker marker band at the 5 cm marks (see Figure 2). The markers are non-radiopaque and are designed to be visualized outside of the introducer sheath.

Figure 1. Lutonix® 035 Drug Coated Balloon PTA Catheter, Model 9010

Figure 2. GeoAlign™ Marker Bands on the catheter shaft

## PTA Catheter Component

The LUTONIX® 035 DCB is compatible with a 0.035" guidewire and is available in 40 cm, 75 cm, and 100 cm catheter lengths. Balloon sizes range from 4.0 mm - 12.0 mm in diameter and from 20 mm - 100 mm in length (see Table 1). The design of the LUTONIX® 035 DCB catheter component is similar to standard PTA catheters.

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Table 1. Balloon Size Matrix

| Balloon Diameter (mm) | Balloon Length | | | | |
| --- | --- | --- | --- | --- | --- |
| | 20 mm | 40 mm | 60 mm | 80 mm | 100 mm |
| 4.0 | | ✓ | ✓ | ✓ | ✓ |
| 5.0 | | ✓ | ✓ | ✓ | ✓ |
| 6.0 | | ✓ | ✓ | ✓ | ✓ |
| 7.0 | | ✓ | ✓ | | |
| 8.0 | ✓ | ✓ | ✓ | | |
| 9.0 | ✓ | ✓ | ✓ | | |
| 10.0 | ✓ | ✓ | ✓ | | |
| 12.0 | ✓ | ✓ | | | |

# Drug Component

The Lutonix drug coating contains paclitaxel, a well-known anti-proliferative drug, as the active pharmaceutical ingredient (API), and the excipients polysorbate and sorbitol. The paclitaxel coating is distributed evenly across the working length of the balloon at a surface concentration of $2\mu \mathrm{g} / \mathrm{mm}^2$ . The total nominal dosage of paclitaxel per balloon size for each model is provided in Table 2.

Table 2. Balloon Size Matrix and Total Nominal Dosage - Paclitaxel (mg)

| Balloon Diameter (mm) | Total Dosage (mg) per Respective Balloon Length (mm) | | | | |
| --- | --- | --- | --- | --- | --- |
| | 20 | 40 | 60 | 80 | 100 |
| 4.0 | | 1.0 | 1.5 | 2.0 | 2.5 |
| 5.0 | | 1.3 | 1.9 | 2.5 | 3.1 |
| 6.0 | | 1.5 | 2.3 | 3.0 | 3.8 |
| 7.0 | | 1.8 | 2.6 | | |
| 8.0 | 1.0 | 2.0 | 3.0 | | |
| 9.0 | 1.1 | 2.3 | 3.4 | | |
| 10.0 | 1.3 | 2.5 | 3.8 | | |
| 12.0 | 1.5 | 3.0 | | | |

Paclitaxel is a cytotoxic anticancer drug used for oncological indications and manufactured using a semi-synthetic process (see Table 3).

The excipients polysorbate and sorbitol utilized in the Lutonix drug coating are as described in the USP National Formulary. The key functional characteristic of the excipients polysorbate and sorbitol in the formulation is to allow for adequate release of the paclitaxel drug substance to the tissue of the vascular wall during the balloon inflation.

PMA P170003: FDA Summary of Safety and Effectiveness Data

Table 3. Paclitaxel Drug Details

| Nomenclature | |
| --- | --- |
| United States Adopted Name (USAN) | Paclitaxel |
| Chemical Name | (2aR,4S,4aS,6R,7E,9S,11S,12S,12aR,12bS)-4,11-dihydroxy-4a,8,13,13-tetramethyl-5-oxo-2a,3,4,4a,5,6,9,10,11,12,12a,12b-dodecahydro-7,11-methano-1H-cyclodeca[[d]benzoxetine-6,9,12,12b-tetrayl 6, 12b-diacetate 12-benzoate 9 -[(2R,3S)-3-(benzoylamino)-2-hydroxy-3-phenylpropanoate] or 5β,20-epoxy-1,7β-dihydroxy-9-oxotax-11-ene-2α,4,10β,13α-tetrayl 4,10-diacetate 2-benzoate 13-[(2R,3S)-3-(benzoylamino)-2-hydroxy-3-phenylpropanoate] |
| CAS Registry Number | 33069-62-4 |
| Compendial Name (USP) | Paclitaxel |
| Structure | |
| Molecular Formula | C47H51NO14 |
| Relative Molecular Mass | Mr: 854 |
| Structural Formula | |

# Mechanism of Action

The primary mode of operation for the LUTONIX® 035 DCB is the mechanical dilation of the vessel, with the paclitaxel-based drug coating having an ancillary effect. The primary effect attributed to the device forms the basis for primary regulation by the FDA Center for Devices and Radiological Health (CDRH) with consultation from the FDA Center for Drug Evaluation and Research (CDER). The mechanism by which neointimal growth is inhibited by the addition of the drug coating has not been established. In general, paclitaxel is a lipophilic, anti-mitotic agent that prevents microtubule destruction, which has been reported in prior studies to prevent migration/proliferation of smooth muscle cells, inflammatory cells, and fibroblasts,

PMA P170003: FDA Summary of Safety and Effectiveness Data

and by preventing secretion of extracellular matrix proteins. Several studies in animal models have also shown that paclitaxel applied locally reduces restenosis by inhibiting smooth muscle cell proliferation and neointimal hyperplasia. $^{1,2}$

# VI. ALTERNATIVE PRACTICES AND PROCEDURES

There are other alternatives for the treatment of native dysfunctional arteriovenous fistula (AVF), including other minimally invasive treatment (plain old balloon angioplasty (POBA), endovascular stent graft) or surgical revision. 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

The LUTONIX® 035 Drug Coated Balloon PTA Catheter has been commercially available in the European Union (EU) since receiving CE Mark in September of 2013 for use in treatment of narrowed native dialysis fistulae or synthetic grafts (see Table 4).

Table 4. Commercial Availability, AV Indication

| Country | | | | |
| --- | --- | --- | --- | --- |
| Austria | Greece | South Africa | Iran | Mexico |
| Belgium | Holland | Spain | Israel | Colombia |
| Denmark | Italy | Sweden | Poland | Argentina |
| Finland | Ireland | Switzerland | Saudi Arabia | Taiwan |
| France | Norway | United Kingdom | Singapore | Thailand |
| Germany | Portugal | Czech Republic | Turkey | India |

# VIII. POTENTIAL ADVERSE EFFECTS OF THE DEVICE ON HEALTH

Potential adverse events which may be associated with a percutaneous peripheral balloon angioplasty procedure include, but are not limited to, the following:

Additional intervention
- Allergic reaction to drugs or contrast medium
Aneurysm or pseudoaneurysm
- Arrythmias
- Embolization
Hematoma
- Hemorrhage, including bleeding at the puncture site
Hypotension/hypertension
Inflammation
Loss of permanent access
- Occlusion

PMA P170003: FDA Summary of Safety and Effectiveness Data

- Pain or tenderness
- Sepsis/infection
- Shock
- Stroke
- Thrombosis
- Vessel dissection, perforation, rupture, or spasm

Although systemic effects are not anticipated, refer to Physician’s Desk Reference for more information on the potential adverse effects observed with paclitaxel. Potential adverse events not described in the above source, which may be unique to the paclitaxel drug coating include, but are not limited to, the following:

- Allergic/immunologic reaction to drug coating
- Alopecia
- Anemia
- Blood product transfusions
- Gastrointestinal symptoms
- Hematologic dyscrasia (including leukopenia, 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, reference Table 21 (Summary of Serious Adverse Events (SAE)).

## IX. SUMMARY OF NONCLINICAL STUDIES

A series of non-clinical laboratory studies were performed on the 8-12 mm diameter LUTONIX® 035 DCB Catheters. These evaluations included: in-vitro functional bench testing, coating characterization, analytical (CMC) testing, stability, and GLP in-vivo animal studies. The larger diameter devices (8-12 mm) were adopted into the current sterilization cycle for the 4-7 mm devices approved in P130024 and data from the 4-7 mm devices were leveraged to support the biocompatibility of the 8-12 mm diameter devices. A summary of each of the evaluations is provided below.

## A. Laboratory Studies

### Catheter Bench Testing

Table 5 provides an overview of the functional testing performed according to the FDA Guidance Document for PTCA catheters and Lutonix internal requirements. The table includes tests performed at baseline and aged conditions, objective of the test, acceptance criteria, and the result of the test.

PMA P170003: FDA Summary of Safety and Effectiveness Data

Table 5. Functional Testing Performed on the LUTONIX® 035 DCB

| Test | Description of Test | Acceptance Criteria | Test Results |
| --- | --- | --- | --- |
| Dimensional and Functional Attributes | The catheter is dimensionally measured and functionally tested with accessory devices to confirm their compatibility with the catheter. | FDA PTCA Guidance, Section B.1: 40, 75, and 100 cm in shaft length; 0.035” guidewire compatible and 5F sheath (4.0 - 7.0mm balloon size), 7F sheath (8.0 - 9.0mm balloon size), 8F sheath (10.0 mm balloon size) and 9F sheath (12.0 mm balloon size) compatible. | The device met the established acceptance criteria. |
| Minimum Balloon Burst Strength | Balloon is incrementally inflated until burst. | FDA PTCA Guidance, Section B.2: Rated burst pressure (RBP) of the balloon with 95% confidence and 99.9% reliability shall be ≥ 12 atm (4.0 - 8.0mm balloon size), ≥ 11 atm (9.0 - 10.0 mm) and 10 atm (12.0 mm balloon size). | The device met the established acceptance criteria. |
| Balloon Compliance | Balloon is incrementally inflated and measured to determine the balloon compliance curve. | FDA PTCA Guidance, Section B.3: Characterization only for development of the balloon compliance curve. | The device met the established acceptance criteria. |
| Balloon Inflation and Deflation Time | Time to inflate and deflate the balloon to and from RBP is measured. | FDA PTCA Guidance, Section B.4: Inflation time is ≤ 20 Seconds (4.0 - 7.0 mm balloon size) and ≤ 30 seconds (8.0 - 12.0 mm balloon size). Deflation time is ≤ 40 seconds. | The device met the established acceptance criteria. |
| Balloon Fatigue | Balloon is inflated to RBP and deflated for total of 20 cycles. | FDA PTCA Guidance, Section B.5: With 95% confidence and 90% reliability, balloon shall not rupture when inflated and deflated to RBP for up to 20 cycles. | The device met the established acceptance criteria. |
| Tensile Strength | Testing is performed to confirm the tensile strength of the catheter. | FDA PTCA Guidance, Section B.6: Catheter tensile strength ≥ 10N. | The device met the established acceptance criteria. |
| Flexibility and Shaft Kink | Testing is performed on the catheter shaft to determine its bend radius before kink may occur. | FDA PTCA Guidance, Section B.8: Characterization only. | The device met the established acceptance criteria. |
| Torque Strength | Testing is performed in a simulated use tracking model to determine the rotation of the catheter before damage may occur. | FDA PTCA Guidance, Section B.9: Characterization only. | The device met the established acceptance criteria. |
| Balloon Preparation, Delivery and Retrieval | Catheter is prepared per the IFU and tracked and retrieved through a simulated use track model. | FDA PTCA Guidance, Section B.10: Catheter shall not be damaged after preparation, track and retrieval through a simulated use track model. | The device met the established acceptance criteria. |
| Radiopacity | The radiopacity of the catheter markers are confirmed to be acceptably visible under fluoroscopic imaging. | FDA PTCA Guidance, Section B.11: Marker bands shall be visible under fluoroscopy imaging. | The device met the established acceptance criteria. |

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Results confirm the LUTONIX® 035 DCB catheter met all of the requirements of the catheter bench testing.

## Biocompatibility

Biocompatibility testing for the Lutonix DCB was conducted separately on (1) the balloon with drug coating, and (2) the Lutonix balloon catheter without the drug coating. In addition, chemical characterization testing was conducted on the LUTONIX® balloon catheter with drug coating to support the overall biocompatibility of the drug-coated balloon. The balloon with drug coating was categorized as an implant device with permanent blood contact (>30 days), and the Lutonix balloon catheter without the drug coating was categorized as an externally communicating device with limited contact duration (< 24 hours) with circulating blood. Tests were conducted on ethylene oxide sterilized products.

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 Document (April 18, 2010)
- Draft Guidance for Industry: Coronary Drug-Eluting Stents- Nonclinical and Clinical Studies Companion Document (March 2008)
- Draft Guidance for Industry: Coronary Drug-Eluting Stents- Nonclinical and Clinical Studies (March 2008)
- Good Laboratory Practices Regulations (21 CFR § 58)
- ISO 10993-1, Biological Evaluation of Medical Devices: Evaluation and testing within a risk management framework (2009)

A summary of the biocompatibility data provided in P130024 that was leveraged to support this PMA is shown in Table 6 below.

Table 6. Biocompatibility Data

| Test Name | Test Description | Balloon and Coating only | Balloon Catheter w/o Drug Coating | Lutonix DCB w/Drug Coating | Results |
| --- | --- | --- | --- | --- | --- |
| Cytotoxicity | ISO MEM Elution Assay with L-929 Mouse Fibroblast Cells | X | X | | Non-toxic |
| Sensitization | ISO Guinea Pig Maximization | X | X | | Non-sensitizing |
| Irritation | ISO Intracutaneous Reactivity | X | X | | Non-irritating |

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| Test Name | Test Description | Balloon and Coating only | Balloon Catheter w/o Drug Coating | Lutonix DCB w/Drug Coating | Results |
| --- | --- | --- | --- | --- | --- |
| Acute Systemic Toxicity | ISO Systemic Toxicity Study | X | X | | Non-toxic |
| Pyrogenicity | USP Material Mediated Pyrogenicity | X | X | | Non-pyrogenic |
| Hemocompatability | ASTM Hemolysis Study (Direct and Indirect Contact) | X | X | | Non-hemolytic |
| | Complement Activation Assay C3a and SC5b-9 | X | X | | Not a complement activator |
| **Supportive Analytical Chemistry Tests** | | | | | |
| 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 Couple 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. |

*FTIR and USP Physicochemical data were also provided but were not used to support the biocompatibility of this device.

The following traditional biocompatibility studies were not conducted on the Lutonix DCB: *in vivo* thrombogenicity, sub-chronic toxicity, chronic toxicity, and muscle implantation. The potential for thrombogenicity, 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 product in a vascular location, as described in Section B, below. These additional animal studies

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demonstrated a lack of significant thrombus formation, 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 results confirm the LUTONIX® 035 DCB catheter is biocompatible for its intended use.

# B. Animal Studies

Detailed histopathology information is not attainable through human clinical trials so a series of animal studies were conducted to evaluate the safety of the LUTONIX® 035 DCB and to supplement the animal studies previously performed with the LUTONIX® 035 DCB in femoral arteries provided in P130024 to support the SFA indication. Results from these previous studies demonstrated minimal endothelial loss, fibrin deposition, and inflammation with healing of the treated arteries being evident at 180 days. Additional Safety, Safety Margin, Safety Overlap, and Pharmacokinetics studies were conducted with the LUTONIX® 035 DCB in swine models in veins or AV anastomoses in order to demonstrate safety in the venous vasculature. These studies were conducted in accordance with FDA 21 CFR Part 58 GLP Regulations. The results of the animal studies are summarized in Table 7.

Table 7. Animal Study Overview Summary

| Study | Animal Model | Device | Study Design | Time Points | Endpoints |
| --- | --- | --- | --- | --- | --- |
| Safety (14-09G) | 18 Domestic Swine | Test devices – Nominal dose Lutonix DCB. Control – uncoated balloon. | Single balloon treatment: control and test balloon inflated in femoral veins distal to AV anastomosis. | 28, 60 Days | • Quantitative Angiography • Histopathology & SEM • Clinical Safety • Device Handling |
| Safety Margin (14-12G) | 10 Domestic Swine | Test devices – Lutonix DCB with 2X dosage. Control – NA. | Double dose balloons, 100% overlapping and single DCB inflated in femoral veins to reach minimal target systemic dose (24mg/pig). | 28, 60 Days | • Plasma Paclitaxel level (3minutes, 1hour, 24hours, 7days, 14days, 28days, 60days) • Downstream organ histopathology • Organ functions assessments • Clinical Safety |

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| Study | Animal Model | Device | Study Design | Time Points | Endpoints |
| --- | --- | --- | --- | --- | --- |
| Overlap Safety (14-11G) | 18 Domestic Swine | Test devices – Nominal dose Lutonix DCB. Control – uncoated balloon. | Two test balloons 100% overlapped, control and test in femoral veins distal to AV anastomosis. | 28, 60 Days | • Quantitative Angiography • Histopathology & SEM • Clinical Safety |
| PK Study (14-10G) | 25 Domestic Swine | Test devices – Nominal dose Lutonix DCB. Control – uncoated balloon. | Single balloon inflated in femoral veins distal to AV anastomosis. | 3mins*, 1hour,24hours, 7days, 14days, 28 days, and 60 days *Plasma PK only | • Vein Tissue Levels • Organ Levels • Plasma Levels |

# GLP Animal Study Overall Conclusion

Results from these studies support the conclusion that the LUTONIX® 035 DCB Catheter is generally safe to deploy in both single and overlapped configuration in the venous anatomy. Also, the pharmacokinetics of drug delivery and elimination are similar in the venous system as compared to the arterial system that has been previously evaluated. The elimination rate in tissue is also comparable between vein and artery. A 3X safety margin has also been established with respect to the systemic dose of paclitaxel, where an average systemic exposure of $27\mathrm{mg}$ resulted in no significant findings in downstream organs (lungs, liver, kidneys, and heart).

# C. Additional Studies

# Coating Testing

The drug coating tests for characterization and to confirm the specification requirement are summarized in Table 8.

Table 8. Drug Coating Tests

| Test | Test Description | Acceptance Criteria | Test Results |
| --- | --- | --- | --- |
| Circumferential and Longitudinal Coating Uniformity | Coated balloon is sectioned and the drug content of each section is measured. | Drug content along the length and circumference of the balloon surface shall be within ±15% of proportional content. | The device met the established acceptance criteria |
| Coating Thickness | Cross section of the drug coating is measured for characterization. | Characterization Only | Characterization of the coating thickness described in the test description was performed. |
| Particulate Matter | Testing was performed to evaluate the number of particles ≥10 μm, ≥25 μm and ≥50 μm in size associated with simulated use tracking and deploying. | Particulate sizes and counts must be within limits established based on safety information | Characterization of the amount of particulate matter generated under conditions described in the test description was performed. |

PMA P170003: FDA Summary of Safety and Effectiveness Data

| Test | Test Description | Acceptance Criteria | Test Results |
| --- | --- | --- | --- |
| Coating Integrity | SEM imaging of the drug coating surface to confirm uniform drug coating and for characterization. | Characterization Only | Drug coating was found to be uniform across the balloon surface. |

# Chemistry, Manufacturing and Controls (CMC) Testing

The following analytical testing was performed on the LUTONIX® 035 DCB as part of the CMC testing. Each batch of finished devices was tested according to the CMC release tests summarized in Table 9 below.

Table 9. CMC Release Tests

| Test | Description of Test | Result |
| --- | --- | --- |
| Appearance | Visual inspection was conducted to verify that the LUTONIX® 035 DCB drug coating meets the appearance specification. | The device met the established acceptance criteria. |
| Identification | Testing conducted using two (2) different methods to verify the identity of paclitaxel drug on the LUTONIX® 035 DCB. | The device met the established acceptance criteria. |
| Assay | Quantitative determination to verify that the total amount of drug on the LUTONIX® 035 DCB met specification, USP <905>. | The device met the established acceptance criteria. |
| Content Uniformity | Multiple catheters are tested for assay content to verify the uniformity of the drug content across the individual catheters, USP <905>. | The device met the established acceptance criteria. |
| Related Substances | Testing is conducted to verify the amount and type of degradation products on the LUTONIX® 035 DCB, ICH Guideline. | The device met the established acceptance criteria. |
| Residual Solvent | The amount of residual solvent is verified to be within the established specification limits, ICH Guideline. | The device met the established acceptance criteria. |
| Dissolution | Dissolution testing is performed to verify the drug release profile of the LUTONIX® 035 DCB, USP <711>. | The device met the established acceptance criteria. |
| Particulate Matter | Simulated use particulate release testing is performed to confirm particulate release characteristics of the LUTONIX® 035 DCB. | The device met the established acceptance criteria. |

# Sterilization

The LUTONIX® 035 DCB is sterilized using ethylene oxide (EO) sterilization. The cycle is validated per the ISO 11135-1:2014 (Medical Devices - Validation and Routine Control of Ethylene Oxide Sterilization). Results show that the product satisfies a minimum Sterility Assurance Level (SAL) of $10^{-6}$ . In addition, the amount of EtO residual and bacterial endotoxin was verified to be within the specification limits.

PMA P170003: FDA Summary of Safety and Effectiveness Data

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## Stability/Shelf-Life

Drug coating stability studies were conducted according to International Council for Harmonisation (ICH) Guidelines to establish an expiration date/shelf-life for the drug coating on the LUTONIX® 035 DCB. Stability testing includes assay, related substances, dissolution, and in-vitro particulate matter. Functional testing was performed on the aged LUTONIX® 035 DCB and compared to baseline to confirm established acceptance criteria are met through the shelf-life. Packaging tests were performed on packaging subjected to the worst case shipping simulation and then aged to ensure that the packaging would remain acceptable for the shelf life of the LUTONIX® 035 DCB. Data generated from stability testing currently supports a 36 month shelf life for the 4-7mm sizes and 24 months for the 8-12mm sizes of the product. The expiration date/shelf life of the finished product will be evaluated and extended as additional stability data becomes available.

## X. SUMMARY OF PRIMARY CLINICAL STUDIES

The applicant performed a clinical study to establish a reasonable assurance of safety and effectiveness of percutaneous balloon angioplasty, after predilation, of dysfunctional dialysis access fistulae with the LUTONIX® 035 DCB in the USA under IDE # G150067. Data from this pivotal IDE study were the basis for the PMA approval decision. A summary of the clinical study is presented below.

### A. Study Design

Patients were treated between June 30, 2015 and March 30, 2016. The database for this PMA reflected data collected through April 28, 2017 and included 285 patients. There were 23 US investigational sites.

The LUTONIX® AV trial was a prospective, multicenter, randomized, controlled study designed to evaluate the safety and effectiveness of the LUTONIX® 035 Drug Coated Balloon PTA Catheter compared to a standard PTA Catheter in treating subjects presenting with clinical and hemodynamic abnormalities in native arteriovenous (AV) fistulae located in the upper extremity.

The LUTONIX® AV trial recruited patients with de-novo or restenotic lesions in the arteriovenous fistulae. After baseline angiogram and protocol-defined pre-dilation, subjects who were likely to have successful revascularization using PTA balloon were randomized 1:1 to treatment with either the LUTONIX® 035 Drug Coated Balloon PTA Catheter (Test Arm) or standard PTA catheter (Control Arm). 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.

Overview of the study flowchart is provided in the Figure 3 and the overview of the LUTONIX® AV trial study design is provided in Table 10 below.

Figure 3: Study Flow Chart

Table 10. Lutonix AV Study Design

| Item | Description |
| --- | --- |
| Study Design | Prospective, Global, Multicenter, Randomized, Safety and Effectiveness |
| Number of Subjects Enrolled | 285 |
| Treatment Lesion | Native arteriovenous (AV) fistulae located in the upper extremity, lesion length of ≤ 10 cm in length and reference vessel of 4 mm – 12mm in diameter. |
| Treatment Device | Test Arm: LUTONIX® 035 Drug Coated Balloon PTA Catheter *Control Arm: Non-coated standard percutaneous transluminal angioplasty balloon catheter (standard PTA catheter) |

PMA P170003: FDA Summary of Safety and Effectiveness Data

| Item | Description |
| --- | --- |
| Balloon Sizes | Balloon Diameters: 4, 5, 6, 7, 8, 9, 10, and 12 mm,
Balloon Lengths: 40, 60, 80, and 100 mm in length. |
| Concomitant Medication | NA |
| Primary Endpoints | Safety: Freedom from any serious adverse event(s) involving the AV access circuit through 30 days.
Effectiveness: Target Lesion Primary Patency (TLPP) through 6 months. |
| Randomized Subject Follow-Up Schedule | Clinical: 6 Months
Angiography: Un-scheduled revascularization
Telephone: 1, 3, 9, 12, 18, 24 Months |

*Note: Only the 75 cm catheter shaft length was used in the clinical trial. However, the 40 cm and 100 cm catheter shaft lengths will also be available for marketing.

The Lutonix AV trial utilized an independent Clinical Events Committee (CEC) that was responsible for adjudicating adverse events as well as an angiographic core laboratory.

1. Clinical Inclusion and Exclusion Criteria

Enrollment in the LUTONIX® AV trial was limited to subjects who met the following inclusion criteria:

- Age ≥21 years;
- The subject is legally competent, has been informed of the nature, the scope and the relevance of the study, voluntarily agrees to participation and the study’s provisions, and has duly signed the informed consent form (ICF);
- Arteriovenous fistula located in the arm presenting with any clinical, physiological or hemodynamic abnormalities warranting angiographic imaging as defined in the K/DOQI guidelines;
- Native AV fistula was created ≥30 days prior to the index procedure and has undergone one or more hemodialysis sessions utilizing two (2) needles and the catheter has been removed for ≥30 days (immature fistulae are not allowed);
- Venous stenosis of an AV fistula meeting the following criteria:

- Target lesion is located from the anastomosis to the axillosubclavian junction, as defined by insertion of the cephalic vein
- Length ≤10 cm
- Reference vessel diameter 4-12 mm
- ≥50% stenosis by angiographic measurement
- At least one clinical, physiological, or hemodynamic abnormality attributable to the stenosis as defined in the K/DOQI guidelines;

- Successful pre-dilation of the target lesion with a percutaneous transluminal angioplasty (PTA) balloon defined as:

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- No clinically significant dissection
- No extravasation requiring treatment
- Residual stenosis ≤30% by angiographic measurement
- Ability to completely efface the waist using the pre-dilation balloon

- Intended target lesion or if a tandem lesion (≤2 cm apart) can be treated with ≤120 mm of DCBs in length;

Patients were not permitted to enroll in the Lutonix AV trial if they met any of the following exclusion criteria:

- Women who are pregnant, lactating, or planning on becoming pregnant during the study;
- Hemodialysis access is located in the leg;
- Subject has more than two (2) lesions in the access circuit (can only treat one target lesion and one secondary non-target lesion);
- Subject has a secondary non-target lesion that cannot be successfully treated (Successful treatment defined as ≤30% residual stenosis by angiographic measurement without procedural complications);
- Target lesion is located central to the axillosubclavian junction;
- The subject has a secondary lesion located in the central venous system (central to the axillosubclavian junction) which, in the opinion of the investigator, is clinically significant; (treatment of an asymptomatic lesion is not allowed)
- A thrombosed access or an access with a thrombosis treated ≤30 days prior to the index procedure;
- Surgical revision of the access site planned or expected ≤6 months after the index procedure;
- Prior surgical interventions of the access site ≤30 days before the index procedure;
- Planned concomitant procedure (e.g., coil embolization) during the index procedure;
- Known contraindication (including allergic reaction) or sensitivity to iodinated contrast media, that cannot be adequately managed with pre-and post-procedure medication;
- Known contraindication (including allergic reaction) or sensitivity to paclitaxel.
- Subjects who are taking immunosuppressive therapy or are routinely taking ≥10 mg of prednisone per day;

2. Follow-up Schedule

All patients were scheduled to return for a follow-up examination at 6 month post index procedure. Telephone follow-up occurred at 1, 9, 12, 18, and 24 months post index procedure. Table 11 shows the complete follow-up schedule.

Table 11. Procedure and Follow-Up Schedule

| Visits | Screening/Baseline | Index Procedure | Post-Procedure/Discharge | Month 1 (30 day) (Call^{5}) | Month 3 (90 days) (Call^{5}) | Month 6 (180 days) (Visit^{6}) | Month 9 (270 days) (Call^{5}) | Month 12 (365 days) (Call^{5}) | Month 18 (545 days) (Call^{5}) | Month 24 (730 days) (Call^{5}) | Un-scheduled Revascularization |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| Visit window (days) | | | | ± 7 | ± 30 | ± 30 | ± 30 | ± 30 | ± 60 | ± 60 | |
| Informed Consent | ✓ | | | | | | | | | | |
| Inclusion/Exclusion Criteria | ✓ | ✓ | | | | | | | | | |
| Demographics, Medical History | ✓ | | | | | | | | | | |
| AVF Assessment (physical exam)^{1} | ✓ | | ✓ | | | ✓ | | | | | ✓ |
| Pregnancy Test^{2} | ✓ | | | | | | | | | | |
| Angiography^{3} | | ✓ | | | | | | | | | ✓^{4} |
| AV Access Status | ✓ | | | ✓ | ✓ | ✓ | ✓ | ✓ | ✓ | ✓ | ✓ |
| Collection of Kt/V values^{7} | ✓ | | | ✓ | ✓ | ✓ | ✓ | ✓ | ✓ | ✓ | ✓ |
| Collection of flow rates^{8} | ✓ | | | ✓ | ✓ | ✓ | ✓ | ✓ | ✓ | ✓ | ✓ |
| Adverse Event Assessment | | ✓ | ✓ | ✓ | ✓ | ✓ | ✓ | ✓ | ✓ | ✓ | ✓ |

1. AVF assessment must be performed by a medical doctor at follow-up if completed as an office visit.
2. Pregnancy test for females of childbearing potential.
3. Submit angiogram to core lab if performed during a follow up visit.
4. Angiography is required when a revascularization of the access circuit is performed.
5. Phone call includes calls with both subject and dialysis center. Visit may be performed as an office visit, though not required.
6. The office visit must have a phone call to the dialysis unit to obtain required information.
7. Kt/V values will be collected on a monthly basis and reported according to the follow up time points.
8. Flow rates can be obtained via the dialysis machine or Transonic. The most recent dialysis session flow rate will be collected.

The key time points are shown below in the tables summarizing safety and effectiveness.

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# 3. Clinical Endpoints

With regard to safety, the primary safety endpoint is freedom from any serious adverse events directly involving AV access circuit through 30 days. The study aimed to demonstrate non-inferiority of the Lutonix DCB to Standard PTA (10% non-inferiority margin) for the safety endpoint.

Secondary endpoints for safety included the rate of device and procedure related adverse events assessed at 1, 3, 6, 9, 12, 18, and 24 months.

With regard to effectiveness, the primary effectiveness endpoint was defined as Target Lesion Primary Patency (TLPP) through 6 months. Target Lesion Primary Patency (TLPP) ends with the next clinically driven re-intervention of the target lesion or access thrombosis. The study aimed to demonstrate superiority of the Lutonix DCB to Standard PTA for the effectiveness endpoint.

Secondary endpoints for effectiveness included:

- Device, Procedural, and Clinical Success
- Access Circuit Primary Patency (ACPP) evaluated at 3, 6, 9, 12, 18, and 24 months
- TLPP evaluated at 3, 9, 12, 18, and 24 months
- TLPP evaluated at 6 months for subjects in whom a fiber pre-dilation balloon was used before the Lutonix DCB as compared to those in whom a non-fiber pre-dilation balloon
- Abandonment of permanent access in the index extremity at 3, 6, 9, 12, 18 and 24 months
- Number of re-interventions required to maintain target lesion patency at 3, 6, 9, 12, 18, and 24 months
- Number of re-interventions required to maintain access circuit patency at 3, 6, 9, 12, 18, and 24 months

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.

To assess the long term device safety and effectiveness of the Lutonix DCB for treatment of AVF, primary safety and effectiveness were reviewed beyond the pre-specified 30-day (primary safety) and 6-month (primary effectiveness) endpoint. Confidence intervals at time points beyond the pre-specified 30 days (primary safety) and 6 months (primary effectiveness) should be interpreted with caution because the analyses were not pre-specified and were not adjusted for multiplicity, and there may be various sources of confounding effects which cannot be separated from the treatment effect.

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# B. Accountability of PMA Cohort

There were a total of 285 subjects enrolled in the Lutonix AV trial across 23 investigational centers, all in the U.S. After successful predilatation, subjects were randomized 1:1 to Lutonix DCB (n=141) and Standard PTA (n=144). Subject disposition and follow-up compliance of the enrolled subjects are at the time of database lock on April 28, 2017. Overall, 90.5% of study subjects completed a 6-month evaluation (258/285). Subject disposition by visit is listed in Table 12 and the evaluable patients at the primary endpoint analyses are listed in Table 13. All 12-month follow-up phone calls had been performed as of April 28, 2017 with 85% of the subjects having completed a 12-month follow-up visit. Eighteen-month follow-up phone calls are ongoing.

Table 12. Subject Disposition

| Description | Randomized Treated (mITT) | Post-Procedure/Discharge | 30 Day | 6 Month | 9 Month | 12 Month | 18 Month |
| --- | --- | --- | --- | --- | --- | --- | --- |
| Follow-Up at Time Points | 285/285 (100.0%) | 285/285 (100.0%) | 268/285 (94.0%) | 258/285 (90.5%) | 249/285 (87.4%) | 242/285 (84.9%) | 72/285 (25.3%) |
| Discontinued Early | 0 | 0 | 4 | 23 | 31 | 39 | 44 |
| Follow-Up of Eligible Subjects | 285 (100.0%) | 285 (100.0%) | 268/281 (95.4%) | 258/262 (98.5%) | 249/254 (98.0%) | 242/246 (98.4%) | 72/241 (29.9%) |

Table 13. Evaluable Subjects for Primary Endpoint Analyses (ITT Population)

| Summary | LTX DCB (N=141) | Standard PTA (N=144) |
| --- | --- | --- |
| Primary Safety Analysis (Day 30), % (n)^{1}
Evaluable | 97.2% (137) | 100% (144) |
| Not Evaluable | 2.8% (4) | 0% (0) |
| Death before Day 30 | 1.4% (2) | |
| Withdrawal of Consent before Day 30 | 1.4% (2) | |
| TLPP Analysis at 6 months (Day 180), % (n)^{2}
Evaluable | 89.4% (126) | 97.2% (140) |
| Not Evaluable | 10.64% (15) | 2.8% (4) |
| Death before 6 Months (Day 150^{3}) | 6.4% (9) | 2.1% (3) |
| Lost to Follow-up before 6 Months (Day 150) | 0.7% (1) | 0 |
| Other discontinued before 6 months (Day 150) | 2.1% (3) | 0 |
| Abandon AV circuit (Before Day 150) | 1.4% (2) | 0.7% (1) |

1 Includes subjects with at least 30 days of follow-up or with a safety event within 30 days
2 Includes subjects completing 6 months or with a clinically driven target lesion revascularization (TLR) or access thrombosis before 6 months
3 Day 150 represents first day of 6 month window

# C. Study Population Demographics and Baseline Parameters

The demographics of the study population are typical for an arteriovenous fistulae study performed in the U.S. and the baseline patient characteristics were similar between the LUTONIX® 035 DCB and PTA control treatment groups.

Demographics (Table 14), medical history (Table 15), and clinical characteristics (Table 16) are similar for the two (2) treatment groups. There were similar frequencies of subjects with diabetes (58.2% vs. 65.3%), cardiovascular disease (58.9% vs. 66.7%) and prior stroke (12.8% vs. 9.0%) in both groups. Overall, comorbidities at baseline are well-matched and representative of the patient population.

Similarly, baseline angiographic data (Table 17) indicate that the LUTONIX® 035 DCB and control PTA subjects were well-balanced with respect to lesions treated, lesion length, diameter of stenosis, lesion class, classification, occlusion, location, and other lesion-specific measures. A summary of the study devices can be found in Table 18.

Table 14. Demographics

| Description | LTX DCB (N=141) | Standard PTA (N=144) | Total (N=285) | P-value1 |
| --- | --- | --- | --- | --- |
| Age (Years), Mean (SD) | 63.6 (14.46) | 61.0 (13.36) | 62.3 (13.95) | 0.1322 |
| Gender | | | | 0.7165 |
| Male | 87 (61.7%) | 85 (59.0%) | 172 (60.4%) | |
| Female | 54 (38.3%) | 59 (41.0%) | 113 (39.6%) | |
| Ethnicity | | | | 0.3479 |
| Hispanic Or Latino | 21 (14.9%) | 28 (19.4%) | 49 (17.2%) | |
| Not Hispanic Or Latino | 120 (85.1%) | 116 (80.6%) | 236 (82.8%) | |
| Race | | | | 0.7951 |
| American Indian Or Alaska Native | 5 (3.5%) | 4 (2.8%) | 9 (3.2%) | |
| Asian | 3 (2.1%) | 1 (0.7%) | 4 (1.4%) | |
| Black Or African American | 52 (36.9%) | 56 (38.9%) | 108 (37.9%) | |
| White | 79 (56.0%) | 78 (54.2%) | 157 (55.1%) | |
| Weight (kg), Mean (SD) | 84.11 (22.25) | 83.70 (24.03) | 83.90 (23.12) | 0.6295 |
| Height (cm), Mean (SD) | 169.69 (11.13) | 168.78 (10.68) | 169.23 (10.89) | 0.5465 |
| BMI (kg/m2), Mean (SD) | 29.20 (7.18) | 29.37 (8.02) | 29.29 (7.60) | 0.8016 |

$^{1}$ P-value associated with Wilcoxon Rank sum Test comparing LTX DCB and Standard PTA groups or Fisher Exact Test for categorical data.

Table 15. Medical History

| Description | LTX DCB (N=141) | Standard PTA (N=144) | Total (N=285) | P-value1 |
| --- | --- | --- | --- | --- |
| Risk Factors | 138 (97.9%) | 143 (99.3%) | 281 (98.6%) | 0.3671 |
| Diabetes | 82 (58.2%) | 94 (65.3%) | 176 (61.8%) | |
| Type 1 | 3 (2.1%) | 7 (4.9%) | 10 (3.5%) | |
| Type 2 | 79 (56.0%) | 87 (60.4%) | 166 (58.2%) | |
| Dyslipidemia | 85 (60.3%) | 84 (58.3%) | 169 (59.3%) | |
| Hypertension | 133 (94.3%) | 142 (98.6%) | 275 (96.5%) | |
| Cigarette Smoking | 64 (45.4%) | 66 (45.8%) | 130 (45.6%) | |
| Current | 19 (13.5%) | 21 (14.6%) | 40 (14.0%) | |
| Former | 45 (31.9%) | 45 (31.3%) | 90 (31.6%) | |
| Cardiovascular Disease | 83 (58.9%) | 96 (66.7%) | 179 (62.8%) | 0.1800 |

PMA P170003: FDA Summary of Safety and Effectiveness Data

| Description | LTX DCB (N=141) | Standard PTA (N=144) | Total (N=285) | P-value1 |
| --- | --- | --- | --- | --- |
| Congestive Heart Failure (CHF) | 33 (23.4%) | 33 (22.9%) | 66 (23.2%) | |
| Stroke | 18 (12.8%) | 13 (9.0%) | 31 (10.9%) | |
| Coronary Artery Disease (CAD) | 43 (30.5%) | 40 (27.8%) | 83 (29.1%) | |
| Myocardial Infarction (MI) | 16 (11.3%) | 23 (16.0%) | 39 (13.7%) | |
| Peripheral Arterial/Vascular Disease (PAD) (PVD) | 14 (9.9%) | 26 (18.1%) | 40 (14.0%) | |
| Other | 47 (33.3%) | 41 (28.5%) | 88 (30.9%) | |
| Other Disease | 123 (87.2%) | 133 (92.4%) | 256 (89.8%) | 0.1733 |
| Bleeding Disorder | 1 (0.7%) | 1 (0.7%) | 2 (0.7%) | |
| Cancer | 33 (23.4%) | 26 (18.1%) | 59 (20.7%) | |
| Glomerulonephritis | 7 (5.0%) | 1 (0.7%) | 8 (2.8%) | |
| Steal Syndrome | 4 (2.8%) | 2 (1.4%) | 6 (2.1%) | |
| Allergic Reaction or Contraindication to Iodinated Contrast Media or Paclitaxel | 1 (0.7%) | 4 (2.8%) | 5 (1.8%) | |
| Other | 119 (84.4%) | 129 (89.6%) | 248 (87.0%) | |

$^{1}$ P-value associated with Fisher Exact Test comparing LTX DCB and Standard PTA groups.

Table 16. Clinical Characteristics

| Description | LTX DCB (N=141) | Standard PTA (N=144) | Total (N=285) | P-value1 |
| --- | --- | --- | --- | --- |
| Access Age (days)2 | | | | 0.1321 |
| N | 141 | 144 | 285 | |
| Mean (SD) | 1164 (973) | 1056 (1122) | 1109 (1050) | |
| Median | 896 | 756 | 829 | |
| Min – Max | 123 - 6149 | 154 - 10795 | 123 - 10795 | |
| Target Limb | | | | 0.0875 |
| Left Arm | 94/141 (66.7%) | 110/144 (76.4%) | 204/285 (71.6%) | |
| Right Arm | 47/141 (33.3%) | 34/144 (23.6%) | 81/285 (28.4%) | |
| Access Site | | | | 0.0805 |
| Across Antecubital Fossa | 6/141 (4.3%) | 8/144 (5.6%) | 14/285 (4.9%) | |
| Transposed | 0 | 2/8 (25.0%) | 2/14 (14.3%) | |
| Non-Transposed | 6/6 (100.0%) | 6/8 (75.0%) | 12/14 (85.7%) | |
| Forearm | 47/141 (33.3%) | 31/144 (21.5%) | 78/285 (27.4%) | |
| Transposed | 5/47 (10.6%) | 4/31 (12.9%) | 9/78 (11.5%) | |
| Non-Transposed | 42/47 (89.4%) | 27/31 (87.1%) | 69/78 (88.5%) | |
| Upper Arm | 88/141 (62.4%) | 105/144 (72.9%) | 193/285 (67.7%) | |
| Transposed | 40/88 (45.5%) | 42/105 (40.0%) | 82/193 (42.5%) | |
| Non-Transposed | 48/88 (54.5%) | 63/105 (60.0%) | 111/193 (57.5%) | |

$^{1}$ P-value associated with Fisher Exact Test comparing LTX DCB and Standard PTA groups

PMA P170003: FDA Summary of Safety and Effectiveness Data

2Time in days since arteriovenous fistula creation

Table 17. Baseline Angiographic Data

| Description | LTX DCB (N=141) | Standard PTA (N=144) | Total (N=285) |
| --- | --- | --- | --- |
| Target Index Limb | | | |
| Right Arm | 47/141 (33.3%) | 34/143 (23.8%) | 81/284 (28.5%) |
| Left Arm | 94/141 (66.7%) | 109/143 (76.2%) | 203/284 (71.5%) |
| Access Site | | | |
| Across Antecubital Fossa | 7/141 (5.0%) | 7/143 (4.9%) | 14/284 (4.9%) |
| Forearm | 47/141 (33.3%) | 31/143 (21.7%) | 78/284 (27.5%) |
| Upper Arm | 87/141 (61.7%) | 105/143 (73.4%) | 192/284 (67.6%) |
| Target Lesion Location | | | |
| Anastomotic | 6/139 (4.3%) | 5/142 (3.5%) | 11/281 (3.9%) |
| Cephalic Arch | 26/139 (18.7%) | 32/142 (22.5%) | 58/281 (20.6%) |
| In Cannulation Zone | 6/139 (4.3%) | 14/142 (9.9%) | 20/281 (7.1%) |
| Inflow | 47/139 (33.8%) | 42/142 (29.6%) | 89/281 (31.7%) |
| Outflow | 34/139 (24.5%) | 32/142 (22.5%) | 66/281 (23.5%) |
| Swing Point | 20/139 (14.4%) | 17/142 (12.0%) | 37/281 (13.2%) |
| Tandem Lesion less than or equal to 2 cm apart | | | |
| Yes | 4/141 (2.8%) | 10/143 (7.0%) | 14/284 (4.9%) |
| No | 137/141 (97.2%) | 133/143 (93.0%) | 270/284 (95.1%) |
| Lesion Fully Effaced | | | |
| Yes | 121/141 (85.8%) | 126/143 (88.1%) | 247/284 (87.0%) |
| No | 10/141 (7.1%) | 8/143 (5.6%) | 18/284 (6.3%) |
| Unable To Assess | 10/141 (7.1%) | 9/143 (6.3%) | 19/284 (6.7%) |
| Lesion Length (mm) | | | |
| N | 141 | 143 | 284 |
| Mean (SD) | 28.4 (15.09) | 29.5 (18.69) | 28.9 (16.98) |
| Median | 26.9 | 25.6 | 26.1 |
| Min – Max | 6.1 - 83.1 | 4.6 - 93.2 | 4.6 - 93.2 |

Table 18. Summary of Study Device

| Description | LTX DCB (N=141) | Standard PTA (N=144) | Total (N=285) |
| --- | --- | --- | --- |
| Maximum Pressure of Pre-Dilatation Inflation (atm) | | | |
| N | 140 | 143 | 283 |
| Mean (SD) | 21.3 (7.98) | 21.7 (8.33) | 21.5 (8.15) |
| Median | 20.0 | 20.0 | 20.0 |
| Min – Max | 8-40 | 6-40 | 6-40 |
| Max Inflation Pressure ≥25atm Difference (95% CI) | - | - | 84/285 (29.5%) |
| Number of Study Devices | | | |

PMA P170003: FDA Summary of Safety and Effectiveness Data

| Description | LTX DCB (N=141) | Standard PTA (N=144) | Total (N=285) |
| --- | --- | --- | --- |
| 1 | 128/141 (90.8%) | 143/144 (99.3%) | 271/285 (95.1%) |
| 2 | 13/141 (9.2%) | 1/144 (0.7%) | 14/285 (4.9%) |
| Balloon Diameter (mm) | | | |
| N | 154 | 145 | 299 |
| Mean (SD) | 8.31 (1.79) | 8.12 (1.79) | 8.22 (1.79) |
| Median | 8.00 | 8.00 | 8.00 |
| Min - Max | 4.0 - 12.0 | 5.0 - 12.0 | 4.0 - 12.0 |
| Balloon Length (mm) | | | |
| N | 154 | 145 | 299 |
| Mean (SD) | 51.2 (12.10) | 45.7 (12.41) | 48.5 (12.53) |
| Median | 60.0 | 40.0 | 40.0 |
| Min - Max1 | 40 - 100 | 40 - 100 | 40 - 100 |
| Transit Time (sec) | | | |
| N | 152 | 142 | 294 |
| Mean (SD) | 18.1 (32.16) | 19.1 (38.57) | 18.6 (35.35) |
| Median | 11.0 | 10.0 | 10.0 |
| Min - Max | 0 - 320 | 1 - 420 | 0 - 420 |
| Device Inserted into Subject | | | |
| Yes | 151/154 (98.1%) | 145/145 (100.0%) | 296/299 (99.0%) |
| Device Used to Treat Target Lesion | | | |
| Yes | 150/154 (97.4%) | 145/145 (100.0%) | 295/299 (98.7%) |
| If No, Reason | | | |
| User Error | 4/4 (100.0%) | 0 | 4/4 (100.0%) |
| Number of Inflations per Device | | | |
| 1 | 151/151 (100.0%) | 122/145 (84.1%) | 273/296 (92.2%) |
| 2 | 0 | 20/145 (13.8%) | 20/296 (6.8%) |
| 3 | 0 | 3/145 (2.1%) | 3/296 (1.0%) |
| Type of Catheter use for Treatment2 | | | |
| Conventional (RBP < 15 atm), n/N (%) | 150/150 (100%) | 83/144 (57.6%) | 233/294 (79.4%) |
| High Pressure/Fiber (RBP ≥ 15 atm), n/N (%) | 0/150 (0%) | 61/144 (42.4%) | 61/144 (20.7%) |
| Maximum Pressure of Balloon Inflation (atm)3 | | | |
| N | 150 | 167 | 318 |
| Mean (SD) | 9.7 (2.13) | 12.1 (4.96) | 11.0 (4.11) |
| Median | 10.0 | 11.0 | 10.0 |
| Min - Max | 4 - 14 | 3 - 35 | 3 - 35 |
| Max Inflation Pressure ≤12atm, n/N(%) | 139/140 (99.3%) | 95/143 (66.4%) | 234/283 (82.7%) |
| Max Inflation Pressure >12atm, n/N(%) | 1/140 (0.7%) | 48/143 (33.6%) | 49/283 (17.3%) |
| Total Duration of Inflation (sec) | | | |
| N | 1501 | 170 | 321 |
| Mean (SD) | 115.1 (33.78) | 89.7 (40.88) | 101.4 (39.75) |
| Median | 10.0 | 11.0 | 10.0 |
| Min - Max | 0 - 110 | 0 - 110 | 0 - 110 |

PMA P170003: FDA Summary of Safety and Effectiveness Data

| Description | LTX DCB (N=141) | Standard PTA (N=144) | Total (N=285) |
| --- | --- | --- | --- |
| Median | 120.0 | 120.0 | 120.0 |
| Min – Max | 30 – 180 | 5 – 240 | 5 – 240 |
| Operator able to Deliver to the Intended Treatment Site, Inflate and Retrieve the Device | | | |
| Yes | 151/151 (100.0%) | 171/171 (100.0%) | 322/322 (100.0%) |
| Final %Diameter Stenosis [Core Lab]4 | | | |
| N | 141 | 143 | 284 |
| Mean (SD) | 16.6 (11.02) | 17.0 (10.27) | 16.8 (10.64) |
| Median | 16.6 | 16.5 | 16.6 |
| Min – Max | -27.5 – 47.4 | -16.0 – 44.2 | -27.5 – 47.4 |

1 The study did not enroll the 20 mm length device size though approval is being granted for this device size.
2 Maximum RBP rating for Lutonix DCB is 12 atm.
3 Occurrence of balloon burst are excluded from the analysis.
4 Final residual stenosis is the last value of stenosis post deployment, post dilation, or after other treatment modalities.

## D. Safety and Effectiveness Results

Results for the primary safety and effectiveness endpoints of the Lutonix AV trial are described and summarized below. The Modified Intent-To-Treat (mITT) population, which consists of enrolled, randomized, and treated subjects, was pre-specified as the primary analysis population. In the mITT population among completers, 94.9% of the patients in the Lutonix DCB group were free from the primary safety event, compared to 95.8% of the Standard PTA group. The lower bound of the 95% confidence interval of the rate difference was greater than -10% (10% non-inferiority margin); therefore, the objective of the primary safety endpoint was met. For the primary effectiveness endpoint, TLPP at Day 180 was 71.4% for the Lutonix DCB group compared to 63.0% for the Standard PTA group. The study did not meet the primary effectiveness endpoint for superiority (p=0.0562).

## 1. Safety Results

The primary safety endpoint is freedom from serious adverse events directly involving the AV access circuit through 30 days. Data from a total of 281 subjects were available for analysis of the primary safety endpoint (Table 8.4.1-1). The primary safety endpoint for non-inferiority for the Lutonix DCB vs. Standard PTA was met. The proportion of subjects that did not have a serious adverse event (SAE) involving the access circuit through Day 30 was 94.9% in the Lutonix DCB arm, and 95.8% in the Standard PTA arm (p = 0.004). See Table 19 below.

PMA P170003: FDA Summary of Safety and Effectiveness Data

Table 19. Primary Safety Endpoint

| Primary Safety Endpoint | Lutonix DCB (N=141) n/N (%) | Standard PTA (N=144) n/N (%) | P-value1 | DCB Non-inferiority2 (p < 0.025) |
| --- | --- | --- | --- | --- |
| Freedom from SAEs related to the AV Access Circuit for ≤ 30 days | 130/137 (94.9%) | 138/144 (95.8%) | 0.0019 | Yes |

${}^{1}95\%$ CI of the difference and the one sided p-value were calculated using non-inferiority Farrington and Manning Test, with $10\%$ as non-inferiority margin.
${}^{2}\mathrm{H}_{0}$ : $p_{I} \leq \mathrm{p}_{2} - \delta$ vs. $\mathrm{H}_{1}$ : $p_{I} &gt; \mathrm{p}_{2} - \delta$ where $\delta = 10\%$ non-inferiority margin for DCB safety rate, $\mathrm{p}_{I} = \mathrm{DCB}$ primary safety rate, $\mathrm{p}_{2} = \mathrm{Control}$ primary safety rate.

Survival analysis of the primary safety endpoint was also performed through 12 months. Freedom from primary safety events by Kaplan Meier estimates for 12 months was $39.5\%$ for Lutonix DCB and $31.0\%$ for the Control cohort. The survival curve for the primary safety endpoint is shown below in Figure 4 and Table 20.

Figure 4. Kaplan-Meier Analysis of Primary Safety through 12 Months

Table 20. Freedom from Primary Safety Endpoint by Kaplan-Meier (ITT)

| Description | LTX DCB (N=141) | Standard PTA (N=144) | Difference % (95% CI)1 |
| --- | --- | --- | --- |
| Number of Events, n (%) | 80 (56.7%) | 99 (68.8%) | |
| Number Censored, n (%) | 61 (43.3%) | 45 (31.3%) | |
| Discontinued Early | 20 (14.2%) | 8 (5.6%) | |

PMA P170003: FDA Summary of Safety and Effectiveness Data

| Description | LTX DCB (N=141) | Standard PTA (N=144) | Difference % (95% CI)1 |
| --- | --- | --- | --- |
| No Event | 41 (29.1%) | 37 (25.7%) | |
| Time to Event (days, Median) | 219.0 | 189.0 | 30.0 |
| 30 Day Event Free (Primary Safety) - % | 95.0% | 95.8% | -0.8% (-5.7%, 4.0%) |
| 3 Month Event Free | 83.9% | 81.8% | 2.1% (-6.7%, 10.9%) |
| 6 Month Event Free | 59.2% | 54.0% | 5.1% (-6.6%, 16.9%) |
| 9 Month Event Free | 44.5% | 40.0% | 4.5% (-7.4%, 16.4%) |
| 12 Month Event Free | 39.5% | 31.0% | 8.5% (-3.0%, 20.1%) |

$95\%$ CI of the rate and the rate difference at each time point were calculated based on normal approximation and were not adjusted for multiplicity.

## Serious Adverse Effects Listing

Serious adverse events are summarized in Table 21. Of the 773 adverse events reported by the sites as serious, 397 events were evaluated by the Clinical Events Committee (CEC) for adjudication. Over two thirds of DCB and PTA subjects experienced at least one SAE (66.7% in the DCB arm, 72.2% in the PTA arm). Overall, there was no evidence that treatment with the LUTONIX® 035 DCB led to increased risk of any SAE.

Table 21. Summary of Serious Adverse Events through 12 Months

| Body System/Preferred Term | LTX DCB (N=141) | Standard PTA (N=144) |
| --- | --- | --- |
| Any Serious Adverse Events | 196 | 201 |
| Any Subjects with at least One Serious Adverse Event | 94 (66.7%) | 104 (72.2%) |
| Cardiac disorders | 7 (5.0%) | 6 (4.2%) |
| Acute coronary syndrome | 1 (0.7%) | 0 |
| Cardiac arrest | 3 (2.1%) | 3 (2.1%) |
| Cardiogenic shock | 0 | 1 (0.7%) |
| Mitral valve incompetence | 1 (0.7%) | 0 |
| Myocardial infarction | 0 | 2 (1.4%) |
| Pulseless electrical activity | 1 (0.7%) | 0 |
| Ventricular tachycardia | 1 (0.7%) | 0 |
| Gastrointestinal disorders | 1 (0.7%) | 0 |
| Colitis ischaemic | 1 (0.7%) | 0 |
| General disorders and administration site conditions | 2 (1.4%) | 1 (0.7%) |
| Cardiac death | 1 (0.7%) | 0 |
| Death | 1 (0.7%) | 1 (0.7%) |

PMA P170003: FDA Summary of Safety and Effectiveness Data

| Body System/Preferred Term | LTX DCB (N=141) | Standard PTA (N=144) |
| --- | --- | --- |
| Infections and infestations | 2 (1.4%) | 1 (0.7%) |
| Pneumonia | 1 (0.7%) | 1 (0.7%) |
| Septic shock | 1 (0.7%) | 0 |
| Injury, poisoning and procedural complications | 79 (56.0%) | 96 (66.7%) |
| Arteriovenous fistula aneurysm | 3 (2.1%) | 3 (2.1%) |
| Arteriovenous fistula occlusion | 0 | 1 (0.7%) |
| Arteriovenous fistula site complication | 76 (53.9%) | 90 (62.5%) |
| Arteriovenous fistula site haemorrhage | 1 (0.7%) | 0 |
| Arteriovenous fistula thrombosis | 6 (4.3%) | 10 (6.9%) |
| Vascular graft thrombosis | 1 (0.7%) | 0 |
| Metabolism and nutrition disorders | 1 (0.7%) | 3 (2.1%) |
| Diabetic complication | 0 | 1 (0.7%) |
| Hyperkalaemia | 1 (0.7%) | 1 (0.7%) |
| Hypervolaemia | 0 | 1 (0.7%) |
| Nervous system disorders | 1 (0.7%) | 0 |
| Cerebrovascular accident | 1 (0.7%) | 0 |
| Renal and urinary disorders | 3 (2.1%) | 1 (0.7%) |
| Renal failure chronic | 3 (2.1%) | 1 (0.7%) |
| Respiratory, thoracic and mediastinal disorders | 1 (0.7%) | 1 (0.7%) |
| Acute respiratory failure | 0 | 1 (0.7%) |
| Respiratory failure | 1 (0.7%) | 0 |
| Skin and subcutaneous tissue disorders | 1 (0.7%) | 0 |
| Skin ulcer | 1 (0.7%) | 0 |
| Skin ulcer haemorrhage | 1 (0.7%) | 0 |
| Vascular disorders | 3 (2.1%) | 4 (2.8%) |
| Arteriosclerosis | 0 | 1 (0.7%) |
| Deep vein thrombosis | 0 | 1 (0.7%) |
| Hypertension | 0 | 1 (0.7%) |
| Steal syndrome | 2 (1.4%) | 0 |
| Thrombosis | 0 | 1 (0.7%) |
| Venous occlusion | 1 (0.7%) | 0 |

# Deaths

The total number of deaths that have been reported as of the data cut off is shown in Table 22. None of the deaths were related to the test device or the procedure. The death rate observed in the Lutonix AV trial for both study arms is consistent with reported rates for this patient population which is $22.5\%$ per year $^3$ .

PMA P170003: FDA Summary of Safety and Effectiveness Data

Table 22. Number of Deaths at 12 Months

| Description | LTX DCB (N=141) (n/N %) | Standard PTA (N=144) (n/N %) |
| --- | --- | --- |
| Total Number of Deaths through Day 365 | 18 (12.8%) | 14 (9.7%) |

# 2. Effectiveness Results

The primary effectiveness endpoint is Target Lesion Primary Patency (TLPP) by Kaplan Meier survival analysis was evaluated at Day 180. TLPP ends with the next clinically driven reintervention of the target lesion or access thrombosis.

A total of 285 subjects had data available for analysis. TLPP at Day 180 was $71.4\%$ for the DCB arm and $63.0\%$ for the Control (PTA) arm. This result for the DCB arm was numerically higher than the PTA arm but did not meet the primary effectiveness endpoint for superiority $(p = 0.0562$ ; single sided, $p &lt; 0.025$ criteria). See Figure 5 and Table 23, for Kaplan Meier survival curve and associated data.

Figure 5. Kaplan-Meier Analysis of TLPP Through 12 Months

Table 23. Primary Effectiveness Endpoint

| | LTX DCB (N=141) | Standard PTA (N=144) | Difference % (95% CI) | P-value |
| --- | --- | --- | --- | --- |
| Number of Events, n (%) | 37 (26.2%) | 52 (36.1%) | | |
| Number Censored, n (%) | 104 (73.8%) | 92 (63.9%) | | |
| Discontinued Early | 16 (11.3%) | 7 (4.9%) | | |
| No Event | 88 (62.4%) | 85 (59.0%) | | |

PMA P170003: FDA Summary of Safety and Effectiveness Data

| | LTX DCB (N=141) | Standard PTA (N=144) | Difference % (95% CI) | P-value |
| --- | --- | --- | --- | --- |
| Day 180 Event Free | 71.4% | 63.0% | 8.4% (-2.8%, 19.6%) | 0.0562 |

Secondary Endpoint: TLPP at 3, 6, 9 and 12 months

Kaplan-Meier survival analysis was used to estimate the survival rate of TLPP in the DCB and PTA groups through 12 months. Patency was sustained through 12 months in 42.9% of patients in the DCB arm and 32.7% in the PTA control arm. The KM curve and table are shown in Figure 5 and Table 24.

Table 24. Kaplan Meier Analysis of TLPP through 12 Months

| Description | LTX DCB (N=141) | Standard PTA (N=144) | Difference % (95% CI)¹ |
| --- | --- | --- | --- |
| Number of Events, n (%) | 70 (49.6%) | 91 (63.2%) | |
| Number Censored, n (%) | 71 (50.4%) | 53 (36.8%) | |
| Discontinued Early | 27 (19.1%) | 14 (9.7%) | |
| No Event | 44 (31.2%) | 39 (27.1%) | |
| Time to Event (days, Median) | 292.0 | 236.0 | 56.0 |
| 180 Day Event Free Rate | 71.4% | 63.0% | 8.4% (-2.8%, 19.6%) |
| 210 Day Event Free Rate | 64.1% | 52.5% | 11.6% (-0.2%, 23.4%) |
| 270 Day Event Free Rate | 58.2% | 46.4% | 11.8% (-0.3%, 23.9%) |
| 300 Day Event Free Rate | 48.6% | 42.5% | 6.1% (-6.0%, 18.3%) |
| 365 Day Event Free Rate | 43.8% | 36.0% | 7.8% (-4.3%, 19.9%) |
| 395 Day Event Free Rate | 42.9% | 32.7% | 10.2% (-1.9%, 22.2%) |

¹95% CI rate difference at each time point were calculated based on normal approximation using Greenwood formula variance estimators and were not adjusted for multiplicity.

Secondary Endpoint: Number of re-interventions required to maintain target lesion patency:

The number of re-interventions that had been performed at the 12-month time point for the PTA control subjects was 115, compared to 138 interventions reported in DCB subjects. On average, the number of interventions required to maintain primary patency of the target lesion was lower in the DCB arm compared to control at all time points: 3 months, 6 months, 9 months, and 12 months, see Table 25.

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Table 25. Number of Re-interventions Required to Maintain Target Lesion Patency Through 12 Months

| Number of interventions required | LTX DCB (N=141) | Standard PTA (N=144) | Percent Reduction |
| --- | --- | --- | --- |
| 3 Month – Interventions (Subjects) | 11 (n=10) | 19 (n=19) | 42.1% (8/19) |
| 6 Month – Interventions (Subjects) | 44 (n=37) | 64 (n=52) | 31.3% (20/64) |
| 9 Month – Interventions (Subjects) | 76 (n=53) | 103 (n=74) | 26.2% (27/103) |
| 12 Month – Interventions (Subjects) | 115 (n=69) | 138 (n=87) | 16.7% (23/138) |

3. Subgroup Analyses

The following preoperative characteristics were evaluated for potential association with outcomes:

Gender:

In the subgroup analysis by gender, clinical benefit of the Lutonix DCB at Day 180 was observed in both the males (TLPP: 76.0% DCB vs. 67.5% PTA) and females (TLPP: 62.7% DCB vs. 56.1% PTA). In addition, primary safety events at Day 30 were similar in both males (95.2% DCB vs. 96.5% PTA) and females (94.3% DCB vs. 94.9% PTA).

4. Pediatric Extrapolation

In this premarket application, existing clinical data was not leveraged to support approval of a pediatric patient population.

E. Financial Disclosure

The Financial Disclosure by Clinical Investigators regulation (21 CFR 54) requires applicants who submit a marketing application to include certain information concerning the compensation to, and financial interests and arrangement of, any clinical investigator conducting clinical studies covered by the regulation. The pivotal clinical study included 74 investigators of which none were full-time or part-time employees of the sponsor and two (2) had disclosable financial interests/arrangements as defined in 21 CFR 54.2(a), (b), (c) and (f) and described below:

- Compensation to the investigator for conducting the study where the value could be influenced by the outcome of the study: 0
- Significant payment of other sorts: 2
- Proprietary interest in the product tested held by the investigator: 0
- Significant equity interest held by investigator in sponsor of covered study: 0

Statistical analyses were conducted by FDA to determine whether the financial interests/arrangements had any impact on the clinical study outcome. FDA determined the information provided did raise questions about the reliability of the

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data. The following additional actions were taken and deemed necessary to ensure the reliability of the data (21 CFR 54.5(c)): Initiating agency audits of the data derived from the clinical investigator(s) in question.

## XI. PANEL MEETING RECOMMENDATION AND FDA'S POST PANEL ACTION

In accordance with the provisions of section 515(c)(3) of the act as amended by the Safe Medical Devices Act of 1990, this PMA was not referred to the Circulatory System Devices Panel, an FDA advisory committee, for review and recommendation because the information in the PMA substantially duplicates information previously reviewed by this panel.

## XII. CONCLUSIONS DRAWN FROM PRECLINICAL AND CLINICAL STUDIES

### A. Effectiveness Conclusions

The primary effectiveness data drawn from the LUTONIX® AV randomized clinical study demonstrated a reasonable assurance of effectiveness for the LUTONIX® 035 Drug Coated Balloon when used in accordance with the inclusion and exclusion criteria for the indicated patient population. Target Lesion Primary Patency at 180 days from the LUTONIX® AV randomized trial was 71.4% in the LUTONIX® 035 DCB group and 63.0% in the Standard PTA group (p=0.0562). Although the primary effectiveness hypothesis of the study was not met at 180 days, overall results demonstrated a numerically higher patency rate in the LUTONIX® 035 DCB group as compared to conventional angioplasty through 12 months, though statistical significance was not achieved. Clinical benefit is observed through reduction of number of target lesion reinterventions (31% reduction at 6 months, 26% reduction at 9 months, and 17% reduction at 12 months). These results support the effectiveness of the LUTONIX® 035 DCB for the treatment of dysfunctional arteriovenous fistulae in the upper extremities.

### B. Safety Conclusions

The risks of the device are based on non-clinical laboratory and animal studies as well as data collected in the clinical study conducted to support PMA approval as described above. The primary safety data drawn from the LUTONIX® AV randomized clinical study demonstrated a reasonable assurance of safety for the LUTONIX® 035 DCB when used in accordance to its indication for use. The event-free survival at 30 days from the LUTONIX® AV randomized trial was 94.9% in the LUTONIX® 035 DCB group and 95.8% in the Standard PTA group. In conclusion, the primary safety hypothesis of the study was met, indicating that treatment with the LUTONIX® 035 DCB is as safe as treatment with standard PTA (p &lt; 0.01). These results support the safety of the LUTONIX® 035 DCB for the treatment of dysfunctional arteriovenous fistulae in the upper extremities.

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## C. Benefit-Risk Determination

The probable benefits of the device are based on data collected in the clinical study conducted to support PMA approval as described above. Clinical results show a numerically higher rate of primary patency in the Lutonix DCB vs. PTA arm through 12 months (available time period to date): rate difference of 5.9% at Day 90, 8.4% at Day 180, 11.6% at Day 210, 11.8% at Day 270, 7.8% at Day 365, and 10.2% at Day 395. Additionally, a meaningful reduction in the number in reinterventions was noted: 31% (44 DCB vs. 64 PTA) at 6 months, 26% (76 DCB vs. 103 PTA) reduction at 9 months, and 17% (115 DCB vs. 138) at 12 months. As described above, the event-free survival at 30 days was non-inferior to PTA, indicating that the probable risks from the LUTONIX® 035 DCB are similar to standard PTA. Additional factors to be considered in determining probable risks and benefits for the LUTONIX® 035 Drug Coated Balloon included:

- Patient follow-up was satisfactory and with limited missing data. Follow-up times for the primary endpoints were 30 days for safety and 180 days for effectiveness, but follow-up will continue for 2 years to evaluate the longer term device performance, such as the duration of the benefit and long term adverse event rates.
- This treatment may be preferred by patients compared to the alternatives as their quality of life may improve due to lesser need for repeat procedures.

## 1. Patient Perspectives

This submission did not include specific information on patient perspectives for this device.

In conclusion, given the available information above, the clinical data support that the probable benefits outweigh the probable risks for using the device for the treatment of de novo or restenotic symptomatic lesions in native arteriovenous fistulae in the arm, having reference vessel diameter from 4 mm to 12 mm and total lesion lengths up to 80 mm.

## D. Overall Conclusions

The data in this application support the reasonable assurance of safety and effectiveness of this device when used in accordance with the indications for use. Though not statistically significant, the patency rate for the LUTONIX® 035 Drug Coated Balloon was trending higher than the patency rate for Standard PTA through the 12-month time point, demonstrating with reasonable assurance the effectiveness for percutaneous transluminal angioplasty with the LUTONIX® 035 Drug Coated Balloon. In addition, the event-free survival rate for the LUTONIX® 035 Drug Coated Balloon treatment group was non-inferior to the Standard PTA group at 30 days, indicating that percutaneous transluminal angioplasty with the LUTONIX® 035 Drug Coated Balloon is as safe as the current standard care of Standard PTA.

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# XIII. CDRH DECISION

CDRH issued an approval order on August 25, 2017. The final conditions of approval cited in the approval order are described below.

1. ODE Lead PMA Post-Approval Study – IDE Cohort Post Approval Study: The Office of Device Evaluation (ODE) will have the lead for this clinical study, which was initiated prior to device approval. This study will evaluate the long-term safety and effectiveness of the Lutonix 035AV Drug Coated Balloon Catheter (Lutonix 035 DCB) in the remaining 265 subjects from the premarket study. The premarket study was designed as a global, multicenter, single blind, randomized (1:1 Lutonix 035 DCB to PTA) trial. Subjects will be followed every 6 months through 24 months post-procedure.

The primary effectiveness endpoint is target lesion primary patency (TLPP) through 24 months. The primary safety endpoint is freedom from any serious adverse event(s) involving the AV access circuit through 24 months.

Additional endpoints to be assessed through 24 months post-procedure are: (1) access circuit primary patency (ACPP), (2) device, procedural, and clinical success, (3) abandonment of permanent access in the index extremity, (4) number of interventions required to maintain access circuit patency, (5) number of interventions required to maintain target lesion patency, and (6) rate of device and procedure related adverse events.

2. OSB Lead PMA Post-Approval Study – New Enrollment Post Approval Study Registry: The Office of Surveillance and Biometrics (OSB) will have the lead for studies initiated after device approval. This study will be conducted to assess the safety and effectiveness of the Lutonix DCB for treatment of dysfunctional native arteriovenous (AV) fistulae located in the arm in a heterogeneous patient population in real-world clinical practice.

This will be a prospective, single-arm, global multicenter, registry study of patients presenting with clinical and hemodynamic abnormalities in native AV fistulae located in the arm. Patients will be followed for 2 years and assessment will be performed at 6, 12, 18, and 24 months after the index procedure by either clinical visit or telephone. Follow-up requirements including tests (e.g. angiography, Duplex Ultrasound) and examinations (AV assessment) will be conducted per standard of care.

A sample size of 213 newly treated subjects will be enrolled from 15 to 30 US and international sites. Approximately 50% of subject enrollment and number of sites will be from the U.S.

The primary effectiveness endpoint is Target Lesion Primary Patency (TLPP) through 6 months compared to a performance goal (PG) of 61.4%. The primary

safety endpoint is freedom from any serious adverse event(s) involving the AV access circuit through 30 days compared to a PG of 89%.

The secondary effectiveness endpoints include device, procedural and clinical success; TLPP assessed at 12, 18, and 24 months, and number of reinterventions to maintain target lesion patency, Access Circuit Primary Patency (ACPP), number of reinterventions to maintain access circuit patency, and abandonment of permanent access in the index extremity assessed at 6, 12, 18 and 24 months. The secondary safety endpoints include freedom from any serious adverse event(s) involving the AV access circuit and rate of device and procedure related adverse events assessed at 6, 12, 18, and 24 months. The secondary endpoints will be summarized with descriptive statistics and confidence intervals.

The applicant’s manufacturing facilities have been inspected and found to be in compliance with the device Quality System (QS) regulation (21 CFR 820).

## XIV. APPROVAL SPECIFICATIONS

Directions for use: See device labeling.

Hazards to Health from Use of the Device: See Indications, Contraindications, Warnings, Precautions, and Adverse Events in the device labeling.

Post-approval Requirements and Restrictions: See approval order.

## XV. REFERENCES

1. Sollott SJ, Cheng L, Pauly RR, Jenkins GM, Monticone RE, Kuzuya M, et al. Taxol inhibits neointimal smooth muscle cell accumulation after angioplasty in the rat. J Clin Invest. 1995;95 (4):1869-76.
2. Axel DI, Kunert W, Göggelmann C et al. Paclitaxel inhibits arterial smooth muscle cell proliferation and migration in vitro and in vivo using local drug delivery. Circulation. 1997;96 (2):636-45.
3. United States Renal Data System. https://www.usrds.org/2016/view/v1_03.aspx

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