AGENT Paclitaxel-Coated Balloon Catheter

P230035 · Boston Scientific Corporation · OOB · Feb 29, 2024 · Cardiovascular

Device Facts

• Record ID: P230035
• Device Name: AGENT Paclitaxel-Coated Balloon Catheter
• Applicant: Boston Scientific Corporation
• Product Code: OOB · Cardiovascular
• Decision Date: Feb 29, 2024
• Decision: APPR
• Device Class: Class 3
• Attributes: Therapeutic

Indications for Use

The AGENT™ Paclitaxel-Coated Balloon Catheter is intended to be used after appropriate vessel preparation in adult patients undergoing percutaneous coronary intervention (PCI) in coronary arteries 2.0 mm to 4.0 mm in diameter and lesions up to 26 mm in length for the purpose of improving myocardial perfusion when treating in-stent restenosis (ISR).

Device Story

The AGENT Paclitaxel-Coated Balloon Catheter is a monorail, semi-compliant PTCA catheter used in coronary interventions. It features a balloon coated with TransPax™ (paclitaxel and acetyl tributyl citrate) to inhibit neointimal proliferation. The device is advanced over a guidewire (≤0.014 in) to the target lesion. Upon inflation, the balloon mechanically expands the vessel while transferring paclitaxel to the arterial wall. It is operated by physicians in a cardiac catheterization lab. The output is the mechanical dilation of the stenosis and localized drug delivery, which reduces the rate of target lesion failure and restenosis compared to plain old balloon angioplasty (POBA). The device benefits patients by improving myocardial perfusion and reducing the need for repeat revascularization.

Clinical Evidence

PMA approval based on the AGENT IDE Study, a prospective, multicenter, 2:1 randomized controlled superiority trial (N=600). Primary endpoint: 1-year target lesion failure (TLF). Results: AGENT DCB demonstrated superiority to POBA with 1-year TLF rates of 18.2% vs 29.0% (p=0.0051). Safety endpoints (death, MI, stent thrombosis) were comparable or favored AGENT. Supplemental data from the AGENT Japan SV Study (non-inferiority) and ISR Substudy supported these findings.

Technological Characteristics

Monorail, semi-compliant PTCA catheter; stainless steel hypotube; dual-lumen distal section. Balloon coated with paclitaxel (active) and acetyl tributyl citrate (excipient) at 2 µg/mm² density. Hydrophilic ZGlide™ shaft coating. Radiopaque marker bands for fluoroscopic positioning. Sterilized via 100% ethylene oxide (EO) cycle per ISO 11135:2014. Compatible with ≤0.014 in guidewires.

Indications for Use

Indicated for adult patients undergoing PCI for in-stent restenosis in native coronary arteries (2.0-4.0 mm diameter, lesions ≤26 mm). Contraindicated in supra-aortic/cerebrovascular arteries, unprotected left main disease, coronary spasm without stenosis, paclitaxel hypersensitivity, inability to receive antiplatelet/anticoagulant therapy, and pregnancy/breastfeeding.

Regulatory Classification

Identification

A drug-eluting percutaneous transluminal coronary angioplasty catheter is a combination product intended for balloon dilatation of a hemodynamically significant coronary artery or bypass graft stenosis in patients evidencing coronary ischemia for the purpose of improving myocardial perfusion. A drug-eluting ptca catheter may also be intended for the treatment of acute myocardial infarction; Treatment of in-stent restenosis (isr) and/or post-deployment stent expansion. A drug-eluting ptca catheter delivers a drug to the vessel as part of the angioplasty procedure, which is intended to inhibit restenosis.

Reference Devices

• Emerge™ PTCA Balloon Catheter System (K163174)
• Ranger™ DCB (P190019)
• SeQuent® Please Paclitaxel-Releasing Coronary Balloon Catheter

Submission Summary (Full Text)

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SUMMARY OF SAFETY AND EFFECTIVENESS DATA (SSED)

I. GENERAL INFORMATION

Device Generic Name: Drug-eluting percutaneous transluminal coronary angioplasty catheter

Device Trade Name: AGENT™ Paclitaxel-Coated Balloon Catheter

Device Procode: OOB

Applicant's Name and Address: Boston Scientific Corporation One Scimed Place Maple Grove, MN 55311

Date(s) of Panel Recommendation: None

Premarket Approval Application (PMA) Number: P230035

Date of FDA Notice of Approval: February 29, 2024

Breakthrough Device: Granted breakthrough device status on January 22, 2021 because the combination product and proposed indication for use met the criteria outlined in FDA Guidance Document "Breakthrough Devices Program."

II. INDICATIONS FOR USE

The AGENT™ Paclitaxel-Coated Balloon Catheter is intended to be used after appropriate vessel preparation in adult patients undergoing percutaneous coronary intervention (PCI) in coronary arteries 2.0 mm to 4.0 mm in diameter and lesions up to 26 mm in length for the purpose of improving myocardial perfusion when treating in-stent restenosis (ISR).

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III. CONTRAINDICATIONS

Use of the AGENT™ Drug-Coated Balloon Catheter is contraindicated in the following:

- Use in the supra-aortic/cerebrovascular arteries.
- Unprotected native left main coronary artery disease.
- Coronary artery spasm in the absence of a significant stenosis.
- Patients with known hypersensitivity to paclitaxel (or structurally-related compounds).
- Patients who cannot receive recommended antiplatelet and/or anticoagulant therapy.
- Pregnant or breast-feeding women or women who are intending to become pregnant, or men intending to father children.

IV. WARNINGS AND PRECAUTIONS

The warnings and precautions can be found in the AGENT™ Paclitaxel-Coated Balloon Catheter labeling.

V. DEVICE DESCRIPTION

The AGENT™ Paclitaxel-Coated Balloon Catheter (hereafter referred to as AGENT Drug-Coated Balloon (DCB), AGENT Balloon Catheter, or AGENT DCB) is a monorail, semi-compliant percutaneous coronary intervention (PCI) catheter; the balloon portion of the device is coated with a TransPax™ coating (paclitaxel as the active pharmaceutical ingredient and acetyl tributyl citrate (ATBC) as the excipient). The AGENT Drug-Coated Balloon, see Figure 1, is designed to inhibit restenosis by delivering drug to the diseased arterial tissue. The distal section of the catheter is dual lumen and coaxial.

The outer lumen is used for inflation of the balloon to conform to the vessel wall, and the inner lumen permits the use of guidewires ≤0.014 in (0.36 mm) to facilitate advancement of the catheter. The proximal section of the catheter is a single-lumen, stainless steel hypotube with a single luer port hub for inflation/deflation of the balloon during drug delivery. The semi-compliant balloon is designed to provide an inflatable segment of known diameter and length at recommended pressures. The balloon is available in diameters of 2.0-4.0 mm and in lengths of 12-30 mm. A balloon protector is placed over the drug-coated balloon to maintain a low profile and to protect the balloon and drug coating. A mandrel is placed into the inner lumen to protect the patency of the catheter during storage. The catheter tip is tapered to facilitate advancement of the catheter to the treatment area and through the stenosis. The shaft is coated with a hydrophilic coating (ZGlide™), which is present from the guidewire port to just proximal to the balloon. The

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effective length of the catheter is $144~\mathrm{cm}$ . Marks on the proximal portion of the catheter shaft indicate the exit of the balloon catheter tip out of the guide catheter (one mark at 90 cm and two marks at $100~\mathrm{cm}$ ). Two radiopaque marker bands, in conjunction with fluoroscopy, aid in positioning the AGENT Drug-Coated Balloon.

Figure 1: AGENT Paclitaxel-Coated Balloon Catheter

The AGENT DCB's catheter is identical to the cleared Emerge™ PTCA Balloon Catheter System (K163174). The coating used on the AGENT DCB's balloon, including its drug dose density, is the identical TransPax drug coating as used on the Ranger™ DCB (P190019).

# Mechanism of Action

AGENT DCB provides mechanical expansion of a diseased vessel (primary mode of action) while transferring a pharmacological agent (i.e., paclitaxel) to inhibit neointimal proliferation of the vessel wall.

# DRUG COATING DESCRIPTION

The drug coating for the AGENT balloon catheter consists of paclitaxel (the active pharmaceutical ingredient) and acetyl tributyl citrate (the inactive ingredient).

# Drug Substance - Paclitaxel (PTx)

The active pharmaceutical ingredient in the proprietary AGENT balloon coating is paclitaxel [CAS no. 33069-62-4]. Paclitaxel as an active substance is well described in scientific literature and is used in both medicinal products (drug products) and combination products (device/drug products). The principal mechanism by which paclitaxel inhibits neointimal growth is through the stabilization of microtubules by preventing depolymerization during the final G2/M phase of cell division.

The chemical name of paclitaxel 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-

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

Paclitaxel is a diterpenoid with a characteristic taxane skeleton of 20 carbon atoms, a molecular weight of $853.91\mathrm{g / mol}$ and a molecular formula of $\mathrm{C_{47}H_{51}NO_{14}}$ (Figure 2). It is highly lipophilic and insoluble in water, but freely soluble in polar solvents such as methanol, ethanol, chloroform, ethyl acetate and dimethyl sulfoxide.

Figure 2: Paclitaxel Chemical Structure

# Excipient - Acetyl Tributyl Citrate

The inactive ingredient in the AGENT DCB coating is acetyl tributyl citrate (ATBC), which constitutes $20\%$ of the coating formulation by weight. ATBC has no pharmacological effect and serves as an excipient in the DCB coating, designed to enhance coating integrity and facilitate drug coating transfer to the treated lesion vessel.

ATBC is a carboxylic acid ester with a molecular weight of $402.48\mathrm{g / mol}$ . It is a colorless, slightly viscous, liquid. ATBC is an excipient used for various commercially available products, including oral tablets (up to $18\mathrm{mg}$ per tablet / capsule) and in aqueous pharmaceutical coatings, controlled release systems, transdermal patches, and drug coated balloons for peripheral indications (e.g., BSC's Ranger™ device). The chemical structure of acetyl tributyl citrate is shown in Figure 3.

Figure 3: ATBC Chemical Structure

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# DRUG DOSE

The nominal drug dose density on the AGENT DCB is 2 µg/mm² of cylindrical balloon surface. The target drug content for every balloon size is defined by the product of the calculated cylindrical balloon surface area (A) and the nominal drug dose density, as shown in the following equation:

Target Drug Content 2 µg/mm² x A (mm²)

AGENT balloons have diameters ranging from 2.00 mm to 4.00 mm and lengths of 12 mm to 30 mm. An overview of the AGENT DCB product matrix, including their respective total drug amount, is provided in Table 1.

Table 1: Nominal Drug Content Per Balloon Size

| Diameter (mm) | Drug Dose by Balloon Length | | | |
| --- | --- | --- | --- | --- |
| | 12 mm | 15 mm | 20 mm | 30 mm |
| 2.00 | 165 µg | 204 µg | 272 µg | 406 µg |
| 2.25 | 177 µg | 219 µg | 291 µg | 435 µg |
| 2.50 | 196 µg | 243 µg | 322 µg | 482 µg |
| 2.75 | 216 µg | 266 µg | 354 µg | 529 µg |
| 3.00 | 235 µg | 290 µg | 386 µg | 577 µg |
| 3.50 | 274 µg | 338 µg | 449 µg | 672 µg |
| 4.00 | 312 µg | 386 µg | 513 µg | 767 µg |

# VI. ALTERNATIVE PRACTICES AND PROCEDURES

There are several other alternative therapeutic options for treatment of coronary in-stent restenosis, including:

- Medical therapy and risk factor modification (e.g., diet, exercise, smoking cessation)
- Coronary artery bypass graft (CABG) surgery
- Vascular brachytherapy
- Plain old balloon angioplasty (POBA; i.e., angioplasty with a balloon with no drug coating)
- Additional stent

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.

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# VII. MARKETING HISTORY

The AGENT Drug-Coated Balloon has been commercially available for distribution in the European Union (EU) since receiving CE Mark in July 2014. Since that time, the AGENT device has been commercially available in the countries identified in Table 2. During this time, the device has not been withdrawn from marketing for any reason related to its safety or effectiveness.

Table 2: List of Approved Countries

| Afghanistan | Algeria | Andorra | Antigua and Barbuda |
| --- | --- | --- | --- |
| Argentina | Armenia | Aruba | Australia |
| Austria | Azerbaijan | Bahamas | Bahrain |
| Barbados | Belgium | Belize | Bermuda |
| Bonaire Saba | Bosnia-Herzegovina | Brunei | Bulgaria |
| Cambodia | Cayman Islands | Chile | Colombia |
| Costa Rica | Croatia | Curacao | Cyprus |
| Czech Republic | Denmark | Dominican Republic | Dutch Antilles |
| Ecuador | Egypt | El Salvador | Estonia |
| Finland | France | Georgia | Germany |
| Great Britain | Greece | Guatemala | Guyana |
| Haiti | Honduras | Hong Kong | Hungary |
| Iceland | India | Indonesia | Iraq |
| Ireland | Israel | Italy | Jamacia |
| Japan | Jordan | Kenya | Kosovo |
| Kuwait | Kyrgyzstan | Latvia | Lebanon |
| Libya | Liechtenstein | Lithuania | Luxembourg |
| Macau | Macedonia | Malaysia | Malta |
| Martinique | Mauritius | Mexico | Moldova |
| Mongolia | Montenegro | Morocco | Myanmar |
| Namibia | Nepal | Netherlands | New Zealand |
| Norway | Oman | Panama | Pakistan |
| Paraguay | Peru | Philippines | Poland |
| Portugal | Qatar | Romania | Russia |
| Saudi Arabia | Singapore | Saint Maarten | Slovakia |
| Slovenia | South Africa | South Korea | Spain |
| Sudan | Suriname | Sweden | Switzerland |
| Taiwan | Tajikistan | Thailand | Trinidad and Tobago |

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| Tunisia | Turkey | Turkmenistan | United Arab Emirates |
| --- | --- | --- | --- |
| Uruguay | Uzbekistan | Vietnam | Palestine |
| Yemen | | | |

## VIII. POTENTIAL ADVERSE EFFECTS OF THE DEVICE ON HEALTH

Below is a list of the potential adverse effects (e.g., complications) associated with the use of the AGENT DCB or the angioplasty procedure.

- Additional, possibly surgical, intervention
- Allergy (drug coating and its components, device, medications, contrast)
- Arrhythmia including conduction system disorder
- Bleeding (including hemorrhage or hematoma possibly requiring transfusion or additional intervention)
- Cerebrovascular accident (stroke) / transient ischemic attack (TIA)
- Death
- Embolism (tissue, plaque, thrombus, device, drug coating)
- Fever/inflammation
- Hemodynamic instability
- Hypotension/hypertension (shock)
- Kidney injury/failure
- Myocardial ischemia/infarction
- Organ insufficiency/failure (heart, liver, lungs)
- Pain (anginal, non-anginal)
- Pericardial effusion/cardiac tamponade
- Radiation injury
- Sepsis/infection
- Slow flow/no reflow
- Vessel injury (spasm, dissection, perforation, rupture, arteriovenous fistula, aneurysm)
- Vessel occlusion (abrupt closure, slow flow / no reflow, thrombosis, restenosis)

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Potential adverse events not captured above, that have been associated with administration of paclitaxel at systemic doses, include the following:

- Abnormal liver enzymes
- Allergic / immunologic reaction to drug (paclitaxel or structurally-related compounds)
- Alopecia
- Anemia
- Blood product transfusion
- Gastrointestinal symptoms
- Hematologic dyscrasia (including leukopenia, neutropenia, thrombocytopenia)
- Hepatic enzyme changes
- Histologic changes in vessel wall, including inflammation, cellular damage or necrosis
- Myalgia/arthralgia
- Peripheral neuropathy

IX. SUMMARY OF NONCLINICAL STUDIES

A. LABORATORY STUDIES

A series of non-clinical laboratory studies related to the product were performed to evaluate the device, including: biocompatibility studies, bench testing, coating characterization testing, chemistry, manufacturing and controls (CMC) testing, sterilization testing, packaging/shelf life testing, and Good Laboratory Practice (GLP) animal studies. A summary for each of the evaluations is provided below.

i. Biocompatibility

Biocompatibility testing of the AGENT Paclitaxel-Coated Balloon Catheter (AGENT DCB) was conducted in accordance with ISO 10993-1 Biological Evaluation of Medical Devices – Part 1: Evaluation and Testing within a Risk Management Process, FDA Guidance – Use of International Standard ISO 10993-1 – Guidelines for Industry and Food and Drug Administration Staff. Testing was completed separately on three separate test articles:

1) the final, drug-coated AGENT balloon catheter,
2) the bare (no drug or excipient) AGENT balloon catheters, and

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3) on the isolated AGENT Drug-Coated Balloon only (with no catheter).

Multiple test articles were used in order to ensure that any potential effects of the drug coating component on biocompatibility could be differentiated from any potential effects of the device component.

The results of the biocompatibility studies conducted are summarized in Table 3.

Table 3: Summary of Biocompatibility Testing

| Test Name | Applicable ISO Standard(s) | Test Article | | | Result(s) |
| --- | --- | --- | --- | --- | --- |
| | | 1 | 2 | 3 | |
| Cytotoxicity Study Using the ISO Elution Method | ISO 10993-5 | ✓ | ✓ | ✓ | Non-cytotoxic |
| Cytotoxicity Study Using the Direct Contact Method | ISO 10993-5 | | | ✓ | Non-cytotoxic |
| ISO Guinea Pig Maximization Sensitization Test | ISO 10993-10 | ✓ | ✓ | ✓ | Non-sensitizer |
| ISO Intracutaneous Reactivity Study in Rabbits | ISO 10993-10 | ✓ | ✓ | ✓ | Non-irritant |
| ISO Acute Systemic Toxicity Study in Mice | ISO 10993-11 | ✓ | ✓ | ✓ | Non-toxic |
| USP Rabbit Pyrogen Study, Materials Mediated | ISO 10993-11 | ✓ | ✓ | ✓ | Non-pyrogenic |
| ASTM Hemolysis Study – Direct Method | ISO 10993-4 | ✓ | ✓ | ✓ | Non-hemolytic |
| ASTM Hemolysis Study – Extract | ISO 10993-4 | ✓ | ✓ | ✓ | Non-hemolytic |
| Partial Thromboplastin Time | ISO 10993-4 | ✓ | | | Met requirements |
| Platelet and Leukocyte Count | ISO 10993-4 | ✓ | | | Met requirements |
| Complement Activation (SC5b-9 Assay) | ISO 10993-4 | ✓ | ✓ | ✓ | Not a complement activator |

This biocompatibility assessment concluded the AGENT DCB demonstrated acceptable biological risk under its intended use.

The Thrombogenicity, Implantation, and Sub-chronic/Chronic Toxicity endpoints, per ISO 10993-4, -6, and -11, respectively, were leveraged from the GLP animal

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safety study using the final AGENT drug coated balloon catheter. The outcomes related to these endpoints were found to be acceptable.

Chemical characterization per ISO 10993-18 (Exhaustive Extraction and Analysis by GC/MS, LC/MS, ICP/MS) and associated toxicological risk assessments were performed. These studies supported the acceptable biological risk for the AGENT DCB for endpoints of Sub-chronic/Chronic Toxicity, Genotoxicity, and Carcinogenicity.

# ii. Bench Testing

A summary of the in vitro engineering studies to support the AGENT Paclitaxel-Coated Balloon Catheter is provided in Table 4. All testing was completed in accordance with national and international standards and FDA guidance documents, as applicable, to support the approved indication.

Table 4: Summary of Bench Testing

| Test | Testing Objective | Acceptance Criteria | Test Results |
| --- | --- | --- | --- |
| Dimensional and Functional Attributes | Demonstrate accurate dimensions, including crossing profile, effective length, balloon length, and guidewire compatibility, on the product label and compatible with accessory devices. | Compatible with labeled dimensions | Pass |
| Rated Burst Pressure | To ensure catheter/ balloon burst pressures are above the labeled pressure range. | >14 atm (2.0-3.0 mm) and >12 atm (3.5-4 mm) | Pass |
| Balloon Compliance | Measure the balloon to supply accurate compliance chart. | Characterize for development of the balloon compliance curve | Acceptable Outcomes |
| Balloon Inflation and Deflation Time | To ensure balloon can inflate and deflate to achieve labeled balloon diameter without delays to procedure. | Characterize inflation time; ≤60 s deflation | Acceptable outcomes; Pass |
| Balloon Fatigue | Repeat inflations to ensure freedom from leakage and damage on multiple inflations. | Must be able to withstand 10 repeat inflations | Pass |
| Tensile Strength | To ensure all bonds present on the balloon catheter withstands certain tensile forces without fractures. | ≥1.3-22.2N, depending on bond | Pass |
| Flexibility and Shaft Kink | Catheter is wrapped around challenging radii mandrels till kink and confirmed catheter can perform as intended wire movement or inflation/deflation. | Characterize | Acceptable Outcomes |
| Torque Strength | To ensure catheter withstands rotational | Characterize | Acceptable |
| | tensile strength | | |

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# iii. Coating Characterization Testing

Analytical and characterization testing was performed to evaluate characteristics of the AGENT DCB drug coating. A summary of the test and test description is located within Table 5.

Table 5: Summary of AGENT DCB Coating Characterization

| Test | Description | Test Results |
| --- | --- | --- |
| Particulate Quantitation (Simulated Use) | Characterize the total counts and sizes of particulates generated from AGENT DCB in simulated use conditions | Acceptable Outcomes |
| Particulate Identity and Crystallinity Characterization | Characterize chemical identification and crystallinity of particulates | Acceptable Outcomes |
| Drug Coating Thickness | Characterize coating thickness of the balloon at multiple locations along the length and circumference of the balloon | Acceptable Outcomes |
| Drug Coating Circumferential Uniformity | Measure the uniformity of drug content of multiple circumferential segments of finished AGENT DCB | Acceptable Outcomes |
| Drug Coating Longitudinal Uniformity | Measure the uniformity of drug content of multiple longitudinal segments, depending on balloon length, of finished AGENT DCB | Acceptable Outcomes |
| Drug Coating Durability | Durability and any performance impact to durability, is manifested in an assessment of drug content. Cohesion and adhesion of the coating is assessed in the measurement of drug content after the following steps: 1. Insertion through a guide catheter 2. Track through simulated anatomy | Acceptable Outcomes |
| Drug Coating Crystallinity Characterization | Characterize degree of crystallinity of the drug coating | Acceptable Outcomes |
| Drug Coating Integrity | Characterize drug coating Integrity including quantification of coated area after the | Acceptable Outcomes |
| | coating system | |
| Drug Coating Coating Coating Coating Coating Coating Coating Coating Coating Coating Coating Coating Coating Coating Coating Coating Coating Coating Coating Coating Coating Coating Coating Coating Coating Coating Coating Coating Coating Coating Coating Co | Assess the quality of the coating and its components, including the size, shape, and size of the coating, and the size of the coating, and the size of the coating, and the size of the coating, and the size of the coating, and the size of the coating, and the size of the coating, and the size of the coating, and the size of the coating, and the size of the coating, and the size of the coating, and the size of the coating, and the size of the coating, and the size of the coating, and the size of the coating, and | Acceptable Outcomes |

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iv. Chemistry, Manufacturing and Controls (CMC) Testing

The established requirements for ongoing AGENT DCB release batch and stability testing are summarized in Table 6.

Table 6: AGENT DCB CMC Testing Requirements

| Test | Description | Acceptance Criteria |
| --- | --- | --- |
| Appearance | Packaging securement and appearance of the balloon coating appearance is evaluated by visual inspection | Must meet visual standard |
| Drug Identity | The identity of the drug substance, paclitaxel, is confirmed by HPLC analysis and its UV spectrum | Identity must be confirmed |
| Drug Content Assay | Paclitaxel content is quantified by high performance liquid chromatography (HPLC) to ensure product contains the labeled dose | Drug content mean value should be 90.0 – 110.0% of label claim |
| Drug Content Uniformity | Paclitaxel content is quantified by HPLC to ensure individual devices contain the labeled dose | USP <905> |
| Drug Degradants and Impurities | The levels of drug degradants and impurities are quantified by HPLC to ensure they remain within acceptable levels | ICH Q3B(R2) |
| Residual Acetone Content | The residual acetone from the manufacturing process is quantified by gas chromatography – flame ionization detector (GC-FID) to ensure it remains within acceptable levels | Residual acetone levels must be within limits |
| Drug Release | The released paclitaxel is quantified by HPLC to ensure it is within limits | The drug release at multiple timepoints must be within limits. |
| Device Sterility | The sterility of the single-use device is evaluated per USP <71> | USP <71> |
| Endotoxins | Endotoxin levels are evaluated per AAMI ST72 to ensure they are within established safety guidelines | AAMI ST72 |
| Particulates | Device particulate matter is evaluated using light obscuration particle counting procedures documented in USP <788>. | Particulate sizes and counts must be within limits |

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v. Sterilization

The AGENT Paclitaxel-Coated Balloon Catheter device is sterilized using the BSC2000-2 100% ethylene oxide (EO) sterilization cycle. The BSC2000-2 cycle is an all-in-one process, a type of dynamic sterilization cycle in which conditioning and aeration as well as sterilization occur in the sterilizer chamber. This cycle is validated and controlled in accordance with ISO 11135:2014 (Sterilization of Health Care Products - Ethylene Oxide - Requirements for Development, Validation and Routine Control of Sterilization Process for Medical Devices) to provide a Sterility Assurance Level (SAL) of at least 10⁻⁶.

The amount of bacterial endotoxin was verified to be within the ANSI/AAMI ST72 specification limit.

vi. Packaging

Packaging verification testing was performed to demonstrate that the AGENT DCB packaging can withstand the hazards of distribution and the environment, and that the sterility of the device is maintained throughout the labeled shelf life. Package integrity testing included a visual assessment, bubble leak testing, and seal strength testing. Testing was conducted at baseline, aged, challenge sterilization, and distribution conditions.

vii. Shelf Life

Shelf-life studies evaluating the effects of aging on the mechanical properties of the catheter, packaging, and the stability of the drug were conducted to establish a shelf life/expiration date for the AGENT DCB product. The data generated support a 24-month shelf life for the AGENT DCB device and the product is labeled accordingly.

B. ANIMAL STUDIES

The following in vivo animal testing was conducted in a porcine coronary artery model to evaluate the safety of the AGENT DCB. Two animal studies were conducted in accordance with 21 CFR 58 (Good Laboratory Practices) and one animal study was not conducted in accordance with 21 CFR 58.

- One GLP pharmacokinetic (PK) study was completed evaluating drug content in blood (time points from 0.5 hours to 14 days), treated coronary arterial tissue, and downstream myocardium/organ specimens (time points from 1 hours to 144 days) in a naive, non-ISR coronary artery swine model.

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- One non-GLP PK study was completed evaluating drug content in blood (time points from 0.5 hours to 28 days), treated coronary arterial tissue, and downstream myocardium/organ specimens (time points from 1 to 28 days) in an in-stent restenosis coronary artery swine model.
- One GLP safety and safety margin study was completed (time points from 4 to 180 days) providing evidence of drug delivery, tissue response, and safety in a non-injured coronary artery swine model.

In addition to the principal endpoints noted for each study, all animals were carefully evaluated for general health (i.e., vital signs, behavior, nutritional condition, gait, etc.) and clinical responses to treatment.

A list and description of the animal studies conducted is presented in Table 7.

Table 7: Summary of Animal Safety, Safety Margin, and PK Studies

| Study ID | Number & Animal Type | Local Drug Dose | Balloon Size | Time Points | Major Endpoints | Endpoints Met |
| --- | --- | --- | --- | --- | --- | --- |
| GLP Pharmacokinetics (19-020G) | n=18 Domestic Swine | 1x | 3.0 & 3.5 x 15 mm | Tissue 1 hour, 1/7/14/28/60/90/144 days | Quantitative Angiography; Clinical Health; Arterial, Non-Target Tissue, and Blood Levels | Yes |
| | | | | Blood Baseline, 10/30 minutes, 1/8/12/16 hours, 1/3/7/14 days | | |
| Non-GLP Pharmacokinetics ISR Model (19-026N) | n=3 Domestic Swine | 1x | 3.0 & 3.5 x 15 mm | Tissue 1/7/28 days | Quantitative Angiography; Clinical Health; Arterial, Non-Target Tissue, and Blood Levels; Acute Performance | Yes |
| | | | | Blood Baseline, 10/30 minutes, 1/8/12/16 hours, 1/3/7/14/28 days | | |
| GLP Safety, Safety Margin, and Vascular Response (18-095G) | n=24 Domestic Swine | 1x, 3x | 3.0 & 3.5 x 20 mm | 4/30/90/180 days | Quantitative Angiography; Clinical Safety; Histology; Morphometric and Morphologic Analysis | Yes |

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The preclinical studies conducted demonstrate and confirm the safety of the AGENT DCB. The GLP safety evaluation study (18-095G) of the AGENT DCB demonstrated favorable safety parameters as defined by the following:

- Successful delivery of the device to the target treatment location without major procedural or device related complications, such as acute thrombosis, major bleeding, or flow-limiting dissection.
- No morbidity or mortality device-related complications during the treatment procedures and in-life phases of the experiments.
- No major angiographic differences observed between test and control treatment groups. No major vessel abnormalities were reported. Angiographic flow and stenosis were similar across treatment arms (1X, 3X, and Uncoated Balloon).
- The histological morphometric assessments of the treated iliofemoral arteries were generally comparable across treatment arms (1X, 3X, and Uncoated Balloon) including external elastic lamina, internal elastic lamina, lumen, medial, and neointimal areas, neointimal thickness and percent stenosis. There were no incidences of thrombotic occlusion or aneurysmal formation out to 180 days.
- Comparable histological indicators of vessel wall healing such as: injury, inflammation, and fibrosis with the test articles (1X, 3X) when compared to control tissue sections. The extent of endothelial coverage as determined by light microscopy in tissue sections were comparable between arms with endothelization nearly complete by 30 days and no abnormal findings on any endothelial surface.
- Downstream non-target tissues, including myocardium and organs, showed no clinically relevant evidence of adverse effects such as embolization-associated ischemia, thrombosis, or systemic organ toxicity.
- Acute performance data demonstrated acceptable clinical safety (including no thrombus formation) and device performance.

The preclinical pharmacokinetic studies (19-020G and 19-026N) demonstrated effective drug delivery and uptake into the arterial tissues at the therapeutic dose density (2.0 $\mu \mathrm{g} / \mathrm{mm}^2$ ) with no evidence of drug toxicity demonstrated as follows:

- Arterial paclitaxel concentrations were highest at the early time points, notably at day 1 post-procedure, and decreased to low but detectable levels through 144 days in the GLP de novo PK study. Pharmacokinetic parameters of arterial tissue demonstrated a $C_{\mathrm{max}}$ of $162.8~\mathrm{ng / mg}$ (19-020G model).
- Blood paclitaxel concentrations reached their maximum at the earliest time points, within hours post-device deployment, followed by a rapid elimination profile,

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reaching levels below quantification by 3 days post-procedure in the GLP de novo PK study.

- Paclitaxel was detected at low levels in distal tissues and organs, including the distal myocardium, sub-adjacent myocardium, and lungs, out to 90 days. Detectable levels out to 14 days were also present in the spleen and liver. The presence of paclitaxel in major organs or muscles was not associated with any clinically relevant adverse clinical reactions. Systemic concentrations in non-target tissues exhibited much lower paclitaxel concentrations relative to the treated arteries at the earlier time points and further decreased to non-detectable or almost non-detectable levels over 144 days. Results indicate limited systemic and non-target tissue drug exposure to paclitaxel with treatment using AGENT DCB.
- The PK profiles of AGENT DCB in treated vessel, blood, and downstream tissues and organs were similar between the de novo and in-stent restenosis animal models. Based on this data, the de novo model was found to be sufficient to represent and predict the paclitaxel PK profiles and arterial concentrations in an in-stent restenosis model.

Pharmacokinetic data demonstrated localization of paclitaxel with limited systemic and non-target tissue exposure. Histopathology data demonstrated an acceptable drug dose and embolic load safety margin for the intended therapeutic dose of 2.0 μg/mm² and range of allowable balloon sizes.

## X. SUMMARY OF PRIMARY CLINICAL STUDY

The applicant performed a clinical study, AGENT IDE Study, to establish a reasonable assurance of safety and effectiveness of the AGENT Paclitaxel-Coated Balloon Catheter in patients with in-stent restenosis (ISR) of a previously treated lesion of up to 26 mm in length (by visual estimate) in a native coronary artery 2.0 mm to 4.0 mm in diameter. The study was conducted in the US under IDE # G200100. Data from this clinical 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 May 2021 and August 2022. The database for this PMA reflected data collected through October 18, 2023 and included 600 patients. There were 40 investigational sites, all in the United States (US).

The AGENT IDE clinical study was a prospective, multicenter, 2:1 randomized (AGENT DCB to "plain old balloon angioplasty" (POBA)), controlled, single-blind,

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superiority trial to assess the safety and effectiveness of the AGENT DCB as compared to POBA in patients with ISR.

The AGENT IDE Study used an adaptive group-sequential design with an initial planned enrollment of 480 patients, and one formal interim analysis on the 1-year data after randomization of the first 90% of subjects, with the expectation that the first 40% of randomized patients would have 1-year follow up at that time. The interim analysis was prespecified to be performed by the Data Monitoring Committee (DMC) for potential sample size re-estimation of up to 600 patients. Due to rapid enrollment in the trial, no subjects had completed 1-year follow-up for the interim analysis at the time of the planned interim analysis; therefore, the DMC recommended to continue enrollment to the maximum of 600 patients. To determine final sample size for the primary endpoint analysis, the sponsor and FDA agreed the DMC would perform an interim analysis on the first 40% of patients (n=192) with 1-year data when those data were available using the prespecified adaptive design strategy. Based on this interim analysis, the DMC's recommendation was to evaluate the primary endpoint on the first 480 patients, which was consistent with the initial planned sample for the trial.

The primary endpoint of 1-year target lesion failure (TLF) was analyzed based on the primary endpoint cohort (N=480). The primary endpoint analysis was also performed on the total enrollment cohort (N=600). Results for both are presented within this SSED. All other data, including the additional clinical endpoints presented below, are based on the total enrollment cohort (N=600).

1. Clinical Inclusion and Exclusion Criteria

Enrollment in the AGENT IDE Study was limited to patients who met the following clinical and angiographic inclusion criteria (Table 8):

Table 8: Inclusion Criteria

| Clinical Inclusion Criteria | CI1. | Subject must be at least 18 years of age. |
| --- | --- | --- |
| | CI2. | Subject (or legal guardian) understands the trial requirements and the treatment procedures, and provides written informed consent before any trial-specific tests or procedures are performed. |
| | CI3. | Subject is eligible for percutaneous coronary intervention (PCI). |
| | CI4. | Subject is willing to comply with all protocol-required follow-up evaluation. |
| | CI5. | Women of child-bearing potential must agree to use a reliable method of contraception from the time of screening through 12 months after the index procedure. |
| Angiographic Inclusion Criteria (visual) | AI1. | In-stent restenosis in a lesion previously treated with either a drug-eluting stent or bare metal stent, located in a native coronary artery with a visually estimated reference vessel diameter (RVD > 2.0 mm and ≤ 4.0 mm. |

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Patients were not permitted to enroll in the AGENT IDE Study if they met any of the following exclusion criteria (Table 9):

Table 91: Exclusion Criteria

| Clinical Exclusion Criteria | CE1. | Subject has other serious medical illness (e.g., cancer, congestive heart failure) that may reduce life expectancy to less than 24 months. |
| --- | --- | --- |
| | CE2. | Subject has current problems with substance abuse (e.g., alcohol, cocaine, heroin, etc.). |
| | CE3. | Subject has planned procedure that may cause non-compliance with the protocol or confound data interpretation. |
| | CE4. | Subject is participating in another investigational drug or device clinical study that has not reached its primary endpoint. |
| | CE5. | Subject intends to participate in another investigational drug or device clinical study within 12 months after the index procedure. |
| | CE6. | Woman who is pregnant or nursing. (A pregnancy test must be performed within 7 days prior to the index procedure, except for women who definitely do not have child-bearing potential.) |
| | CE7. | Left ventricular ejection fraction known to be < 25%. |
| | CE8. | Patient had PCI or other coronary interventions within the last 30 days. |
| Clinical Exclusion Criteria | CE9. | Planned PCI or CABG after the index procedure. |
| | CE10. | STEMI or QWMI <72h prior to the index procedure. |
| | CE11. | Cardiogenic shock (SBP < 80 mmHg requiring inotropes, IABP or fluid support). |
| | CE12. | Known allergies against paclitaxel or other components of the used medical devices. |
| | CE13. | Known hypersensitivity or contraindication for contrast dye that in the opinion of the investigator cannot be adequately pre-medicated. |
| | CE14. | Intolerance to antiplatelet drugs, anticoagulants required for procedure. |
| | CE15. | Platelet count <100k/mm3 (risk of bleeding) or >700k/mm3. |
| | CE16. | Subject with renal insufficiency (creatinine ≥2.0 mg/dl) or failure (dialysis dependent). |
| | CE17. | Subject has suspected or proven COVID-19 at present or within the past 4 weeks with |
| | | or a known history of heart failure. |
| | CE18. | Patient has a history of heart failure, or is not currently on a medical treatment. |
| | CE19. | Patient has a history of heart failure, or is currently on a medical treatment. |
| | CE20. | Patient has a history of heart failure, or is currently on a medical treatment. |
| CE21. | Patient has a history of heart failure, or is currently on a medical treatment. | |

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# 2. Follow-up Schedule

All patients were scheduled to return for follow-up examinations at hospital discharge, 30 days, 6 months, 1 year, and then annually between 2 and 5 years post-procedure. Adverse events and complications were recorded at all visits. Patients who were enrolled but who did not receive treatment were to be followed through 12 months only.

Pre-procedure, patients were assessed for quality of life (using the EQ-5D questionnaire), medical history, angina, cardiac enzymes, cardiac rhythm (using ECG), kidney function (using serum creatinine), use of antiplatelet medications, and complete blood count including platelets. Post-procedure, the objective parameters measured during the study included quality of life, angina, cardiac enzymes (pre-discharge only), cardiac rhythm, and use of antiplatelet medications. Adverse events and clinical endpoints were recorded at all visits. The schedule of pre-procedure and post-procedure evaluations is included in Table 10 below.

Table 10: AGENT IDE Study Follow-up Schedule

| Procedure/Assessment | Baseline/Screening# | Procedure | Postprocedure/Discharge | Follow-up Visits | | | | |
| --- | --- | --- | --- | --- | --- | --- | --- | --- |
| | | | | 30 Days (± 7 Days)† Telephone Interview or Office Visit | 6 Months (± 30 Days)† Telephone Interview or Office Visit | 12 Months (± 30 Days)† Office Visit | 2 year, 3 year (± 30 Days)† Office Visit | 4 year, 5 Year (± 30 Days)† Telephone Interview or Office Visit |
| Informed consent process, including informed consent signature data# | X | | | | | | | |
| EQ-5D Questionnaire | X | | X | | | X | X | |
| Demographics, including age, gender, and race and ethnicity (unless restricted by local laws) | X | | | | | | | |
| Medical history, including diabetes mellitus status# | X | | | | | | | |
| Angina assessment | X | | X | X | X | X | X | X |
| Cardiac enzymes# | X | | X | | | | | |
| 12-lead ECG | X | | X | | | X | | |
| Serum creatinine/ CBC and platelets | X | | | | | | | |
| Antithrombotic medications | | X | | | | | | |
| Antiplatelet medications | X | X | X | X | X | X | X | X |
| PCI procedure information for target lesion | X | | | | | | | |
| Procedural, target lesion, non-target lesion (if applicable) predilation, postdilation (if applicable), and study device information | | X | | | | | | |
| Angiography | | X | | | | | | |
| AE and ADE assessment | | X | X | X | X | X | | |
| SAE, SADE, UADE, USADE, all CEC events and device deficiency assessment# | | X | X | X | X | X | X | X |

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a: Baseline/ Screening assessments must take place ≤ 14 Days before procedure unless otherwise noted.
b: If the study Informed Consent Form is modified during the course of the trial, study subjects will be re-consented, if necessary.
c: All follow-up dates will be calculated from the date of the index procedure. The protocol-required follow-ups may be performed via telephone interview and/or an office visit within the applicable follow-up window as noted in the protocol. Beyond the 12-month follow-up, follow-up will be limited to the Safety Population (e.g., those study subjects who received a study/control device). Subjects who are enrolled but who do not receive a study / control device will be followed for 12 months only.
d: Height and weight should be documented in the eCRF if available in the subject medical record.
e: Preprocedure cardiac enzymes can be drawn from the sheath at the time of sheath insertion. If cardiac enzymes are drawn preprocedure, the two results drawn closest to the procedure time should be recorded in the eCRF.
f: Two cardiac enzyme draws must be obtained at intervals per standard of care within 24 hours after the index procedure. The first draw should be performed 6-12 hours postprocedure and the second draw should be performed 18-24 hours postprocedure. If the subject is discharged prior to 18 hours postprocedure, the second draw should be obtained at the time of discharge (it is recommended that in these cases the second draw occur no earlier than 16 hours postprocedure).
g: SAEs, SADEs, UADEs, CEC events, and device deficiencies will be monitored and reported to BSC from the time of enrollment through the 12-month follow-up for all subjects enrolled (regardless of whether a study/ control device was received) and beyond the 12-month follow-up through the 3-year follow-up for the Safety Population (e.g., those study subjects who received a study/ control device). AEs and ADEs will only be collected through the 12-month follow up.

Abbreviations: AE = Adverse event, ADE=adverse device effect; BSC=Boston Scientific Corporation; PCI=percutaneous coronary intervention; SADE=serious adverse device effect; SAE=serious adverse events; UADE=unanticipated adverse device effect

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

## 3. Clinical Endpoints

The primary endpoint, which included components for both safety and effectiveness, is the 1-year rate of target lesion failure (TLF) defined as a composite of:

- Any ischemia-driven target lesion revascularization (TLR).
- Myocardial infarction (MI; Q-wave and non-Q-wave) related to the target vessel.
- Cardiac death.

Myocardial infarction included both peri-procedural MI and spontaneous MI. Peri-procedural MI (within 48 hours of the index procedure) was defined per the SCAI definition Error! Bookmark not defined. and spontaneous MI (more than 48 hours after the index procedure) per 4th Universal definition Error! Bookmark not defined.

As agreed upon with FDA prior to unblinding, in order to account for potential heterogeneity in outcomes related to the use of multiple enzymes and ULNs, a unified ULN for cTn-I (ULN = 0.045 ng/ml) and a unified ULN for cTn-T (ULN = 0.022 ng/ml) were used to identify potential PPMI events.

With regards to safety, additional endpoints were measured, including all cause death, cardiac death, MI, and stent thrombosis per Academic Research Consortium (ARC) definitions.

With regards to effectiveness, additional endpoints included clinical procedural success rate, technical success rate, target lesion revascularization (TLR), target vessel revascularization (TVR), and change in quality of life.

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With regard to success/failure criteria, the study was considered a success if the AGENT DCB was shown to be superior to the POBA control for the primary endpoint of TLF at one year.

A z-test with unpooled variance for the difference of two proportions was to be used to test the hypothesis of superiority of the AGENT DCB over POBA in the 12-month clinical endpoint:

$\mathrm{H_0}$ : $\mathrm{TLF_{DCB}}\geq \mathrm{TLF_{POBA}}$

$\mathrm{H}_{1}$ : $\mathrm{TLF_{DCB}} &lt; \mathrm{TLF_{POBA}}$

where $\mathrm{TLF_{DCB}}$ and $\mathrm{TLF_{POBA}}$ are the TLF rates through 12 months for the DCB and POBA arms, respectively.

The primary analysis set for the primary endpoint was the intent to treat (ITT) analysis set.

# B. ACCOUNTABILITY OF FULL COHORT

At the time of database lock, of 600 patients enrolled in the PMA study, $95.8\%$ (389/406) of AGENT DCB and $95.9\%$ (186/194) of POBA subjects were eligible for analysis at the completion of the primary endpoint, the 12 month post-procedure visit (Table 11). Figure 4 shows the AGENT IDE Study randomization and enrollment process and follow-up schedule.

Table 11: AGENT IDE Subject Disposition Table, ITT (N=600)

| Patient Disposition | POBA | AGENT | Total |
| --- | --- | --- | --- |
| Intent-to-Treat Analysis Set | 194 | 406 | 600 |
| Death ≤395 days with no 12-month clinical follow-up performed | 8 | 17 | 25 |
| Eligible for 12-month clinical follow-upa | 95.9% (186/194) | 95.8% (389/406) | 95.8% (575/600) |
| 12-month clinical follow-up performedb | 94.6% (176/186) | 95.9% (373/389) | 95.5% (549/575) |
| Office visit | 135 | 275 | 410 |
| Telephone contact | 41 | 98 | 139 |
| 12-month clinical follow-up not performed | 10 | 16 | 26 |
| Prematurely discontinued | 3 | 7 | 10 |

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| Patient Disposition | POBA | AGENT | Total |
| --- | --- | --- | --- |
| Patient withdrew consent | 2 | 7 | 9 |
| Lost to follow-up | 0 | 0 | 0 |
| Investigator discretion | 1 | 0 | 1 |
| Missed 12-month visit; no later follow-up visit performed | 7 | 9 | 16 |
| 12-month clinical follow-up or deathc | 94.8% (184/194) | 96.1% (390/406) | 95.7% (574/600) |
| Numbers are counts of subjects or % (Count/Sample Size).a. Subjects who died prior to completion of follow-up window and prior to completing a 12-month clinical follow-up visit are considered censored and are excluded from calculation of proportion of subjects who completed clinical follow-up visit.b. Based on subjects eligible for 12-month clinical follow-up (excludes subjects who died within 395 days with no 12-month follow-up).c. Includes subjects who have died in both the numerator and the denominator; based on Intent-to-Treat analysis set. | | | |

Figure 4: AGENT IDE Study Enrollment and Randomization Process and Follow-up Schedule

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# C. STUDY POPULATION DEMOGRAPHICS AND BASELINE PARAMETERS

The demographics of the study population are typical for an interventional cardiovascular study performed in the US. Table 12 presents demographics for the ITT analysis set. AGENT and POBA treatment arms were well-balanced with no significant differences in any demographic parameters. Combining both treatment arms, patient mean age was 68.3 years, $26.2\%$ of patients were female, and $75.3\%$ of patients were white.

Given lower enrollment of racial and ethnic minorities and female patients as compared to the general coronary artery disease population in the US, a post approval surveillance study will be initiated for an all-comers patient population with specific focus and analyses for these underrepresented groups. See Section XIV below for details on the post-approval surveillance study.

Table 12: Demographics, ITT (N=600)

| Demographics | POBA N=194 | AGENT N=406 | P-value |
| --- | --- | --- | --- |
| Age (years) | 67.90 ± 9.68 (194) | 68.42 ± 9.79 (406) | 0.54 |
| ≥75 | 28.4% (55/194) | 26.8% (109/406) | 0.70 |
| Sex | | | |
| Female | 27.3% (53/194) | 25.6% (104/406) | 0.66 |
| Male | 72.7% (141/194) | 74.4% (302/406) | 0.66 |
| Race† | | | |
| American Indian or Alaska Native | 0.5% (1/194) | 0.0% (0/406) | 0.32 |
| Asian | 3.1% (6/194) | 2.2% (9/406) | 0.58 |
| Black or African American | 5.2% (10/194) | 7.9% (32/406) | 0.22 |
| Native Hawaiian or Other Pacific Islander | 0.5% (1/194) | 0.2% (1/406) | 0.54 |
| White | 76.3% (148/194) | 74.9% (304/406) | 0.71 |
| Other | 1.5% (3/194) | 3.9% (16/406) | 0.12 |
| Not Disclosed | 9.3% (18/194) | 5.7% (23/406) | 0.10 |
| Ethnicity† | | | |
| Hispanic or Latino | 4.6% (9/194) | 6.4% (26/406) | 0.39 |
| Numbers are presented as % (count/sample size) or mean ± standard deviation (n).P-values are 2-sided and from Student's t Test for continuous variables and the Chi-square or Fisher's Exact (*)Test for discrete variables. The p values have not been adjusted for multiplicity. | | | |

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Table 13 and 14 show the baseline clinical characteristics and cardiac history of the patient population. Approximately $50\%$ of patients had diabetes, $50\%$ had a history of MI, and $37\%$ presented with unstable angina or recent MI. In general, baseline clinical characteristics were comparable between the Agent DCB and POBA control groups.

Table 132: Baseline Clinical Characteristics, ITT (N=600)

| Baseline Characteristic | POBA N=194 | AGENT N=406 | P-value |
| --- | --- | --- | --- |
| Physical Assessment | | | |
| Height (cm) | 171.98 ± 9.83 (191) | 172.12 ± 10.55 (396) | 0.88 |
| Weight (kg) | 89.65 ± 21.67 (193) | 89.07 ± 18.48 (404) | 0.74 |
| Body Mass Index‡ (kg/m2) | 30.10 ± 5.85 (191) | 30.01 ± 5.53 (396) | 0.86 |
| Medical History | | | |
| Smoking, Ever | 57.7% (112/194) | 57.6% (234/406) | 0.98 |
| Current | 9.8% (19/194) | 10.3% (42/406) | 0.83 |
| Previous | 47.9% (93/194) | 47.3% (192/406) | 0.88 |
| Smoking History Unknown | 0.0% (0/194) | 1.7% (7/406) | 0.10 |
| Diabetes Mellitus | 50.0% (97/194) | 51.0% (206/404) | 0.82 |
| Medically Treated | 46.4% (90/194) | 44.3% (179/404) | 0.63 |
| Insulin or Other Injectables | 25.3% (49/194) | 23.0% (93/404) | 0.55 |
| Hyperlipidemia | 94.8% (184/194) | 94.6% (382/404) | 0.88 |
| Hypertension | 95.9% (186/194) | 94.6% (383/405) | 0.49 |
| Bleeding Disorder | 2.6% (5/193) | 2.3% (9/399) | 0.78 |
| Peripheral Vascular Disease | 16.1% (31/192) | 19.5% (78/401) | 0.33 |
| Chronic Obstructive Pulmonary Disease | 10.3% (20/194) | 9.7% (39/403) | 0.81 |
| History of Stroke or TIA | 9.8% (19/194) | 14.2% (57/402) | 0.13 |
| History of Renal Disease | 16.6% (32/193) | 18.4% (74/402) | 0.59 |
| Prior COVID-19 Infection | 13.3% (23/173) | 13.0% (49/376) | 0.93 |
| COVID-19 Vaccination | 84.7% (138/163) | 87.2% (287/329) | 0.43 |
| Numbers are presented as % (count/sample size) or mean ± standard deviation (n). | | | |

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| Baseline Characteristic | POBA N=194 | AGENT N=406 | P-value |
| --- | --- | --- | --- |
| P-values are 2-sided and from Student's t Test for continuous variables and the Chi-square or Fisher's Exact (*) Test for discrete variables. The p values have not been adjusted for multiplicity. 2The body mass index is the weight in kilograms divided by the square of the height in meters. Abbreviation: ITT=intent-to-treat; TIA=transient ischemic attack | | | |

Table 143: Cardiac History and Baseline Status, ITT (N=600)

| Cardiac History | POBA N=194 | AGENT N=406 | P-value |
| --- | --- | --- | --- |
| Family History of CAD | 99.5% (193/194) | 99.8% (405/406) | 0.54 |
| Prior MI | 50.0% (95/190) | 49.7% (198/398) | 0.95 |
| Prior CABG | 28.6% (55/192) | 30.8% (124/403) | 0.60 |
| History of Heart Failure | 21.4% (41/192) | 22.9% (92/401) | 0.66 |
| NYHA Classification | | | 0.56 |
| I – No Symptoms | 3.6% (7/192) | 2.0% (8/401) | 0.27 |
| II – Mild Symptoms | 7.3% (14/192) | 8.0% (32/401) | 0.77 |
| III – Limited Activity | 5.2% (10/192) | 4.7% (19/401) | 0.80 |
| IV – Severe Limitations | 0.0% (0/192) | 0.0% (0/401) | Undef |
| Unknown | 5.2% (10/192) | 8.2% (33/401) | 0.18 |
| History of Arrhythmia | 18.2% (35/192) | 21.9% (88/401) | 0.30 |
| Indication for Procedure | | | |
| Recent MI | 6.2% (12/194) | 5.2% (21/406) | 0.61 |
| Unstable angina | 31.4% (61/194) | 31.5% (128/406) | 0.98 |
| Stable angina | 51.5% (100/194) | 55.4% (225/406) | 0.37 |
| Silent ischemia | 2.6% (5/194) | 1.7% (7/406) | 0.54 |
| Other indication | 8.2% (16/194) | 6.2% (25/406) | 0.34 |
| LVEF Measurement (%) | 54.23 ± 9.89 (189) | 54.05 ± 10.56 (393) | 0.84 |
| History of Multivessel Disease | 78.4% (149/190) | 79.3% (317/400) | 0.82 |
| History of Left Main Disease | 20.7% (39/188) | 22.6% (89/394) | 0.62 |
| Numbers are presented as % (count/sample size) or mean ± standard deviation (n). P-Values are 2-sided and from Student's t Test for continuous variables and the Chi-square or Fisher's Exact (*) Test for discrete variables. The p values have not been adjusted for multiplicity. The Mantel-Haenszel (MH) tests use non-missing data and exclude the 'Unknown' category. For NYHA classification, the MH test is performed on all subjects with congestive heart failure. Note: Recent MI is defined as MIs that occurred within 2 weeks prior to the index procedure. Patients with STEMI fewer than 72 hours prior were excluded. | | | |

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Table 15 presents baseline lesion characteristics as determined by core laboratory quantitative coronary angiography (QCA). Most characteristics were similar between arms, including the presence of multiple-layer in-stent restenosis (AGENT 43.3% versus POBA 42.3%), mean reference vessel diameter (2.7 ± 0.5 mm in both arms), and lesion length (AGENT 12.8 ± 6.3 mm vs. POBA 11.8 ± 6.6 mm). Some differences are noted for various lesion characteristics, including certain ISR patterns and ulceration, but the sample sizes are low and these differences were not likely to influence the outcome of the study.

Table 15: Baseline Target Lesion Characteristics as Determined by the Angiographic Core Laboratory, ITT (N=600)

| Target Lesion Characteristic | POBA N=194 Lesions, N=194 Subjects | AGENT N=407 Lesions, N=406 Subjects | P-value |
| --- | --- | --- | --- |
| Single Stent Layer† | 57.7% (112/194) | 56.7% (230/406) | 0.80 |
| Multiple Stent Layer† | 42.3% (82/194) | 43.3% (176/406) | 0.80 |
| Target Lesion Vessel | | | |
| LAD | 35.6% (69/194) | 34.7% (141/406) | 0.84 |
| LCx | 24.2% (47/194) | 24.1% (98/406) | 0.98 |
| RCA | 35.6% (69/194) | 38.4% (156/406) | 0.49 |
| LM | 4.6% (9/194) | 2.7% (11/406) | 0.22 |
| Lesion Location | | | |
| Proximal | 32.0% (62/194) | 31.5% (128/406) | 0.92 |
| Mid | 40.2% (78/194) | 44.1% (179/406) | 0.37 |
| Distal | 12.4% (24/194) | 11.1% (45/406) | 0.64 |
| Ostial | 15.5% (30/194) | 13.3% (54/406) | 0.48 |
| Minimal Lumen Diameter (mm) | 0.92 ± 0.40 (191) | 0.95 ± 0.36 (405) | 0.35 |
| Mean Lumen Diameter (mm) | 2.27 ± 0.58 (189) | 2.31 ± 0.50 (399) | 0.39 |
| % Diameter Stenosis (mm) | 66.41 ± 12.76 (191) | 64.98 ± 12.05 (405) | 0.19 |
| Mehran ISR Pattern | | | |
| 1A (articulation) | 0.0% (0/189) | 0.0% (0/403) | Undef |
| 1B (margin) | 1.1% (2/189) | 1.0% (4/403) | 1.00 |
| 2A (articulation) | 0.0% (0/189) | 0.0% (0/403) | Undef |
| 2B (margin) | 0.0% (0/189) | 0.0% (0/403) | Undef |

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| Target Lesion Characteristic | POBA N=194 Lesions, N=194 Subjects | AGENT N=407 Lesions, N=406 Subjects | P-value |
| --- | --- | --- | --- |
| 1C (focal) | 44.4% (84/189) | 36.7% (148/403) | 0.07 |
| 1D (multifocal) | 1.1% (2/189) | 0.7% (3/403) | 0.66 |
| 2 (intrastent) | 47.1% (89/189) | 57.1% (230/403) | 0.02 |
| 3 (proliferative) | 4.8% (9/189) | 4.0% (16/403) | 0.66 |
| 4 (total occlusion) | 1.6% (3/189) | 0.5% (2/403) | 0.33 |
| Tortuosity, Any | 0.0% (0/192) | 0.7% (3/405) | 0.55 |
| Moderate | 0.0% (0/192) | 0.7% (3/405) | 0.55 |
| Severe | 0.0% (0/192) | 0.0% (0/405) | Undef |
| Calcification, Any | 12.5% (13/104) | 12.6% (28/222) | 0.98 |
| Moderate | 2.9% (3/104) | 5.0% (11/222) | 0.56 |
| Severe | 9.6% (10/104) | 7.7% (17/222) | 0.55 |
| Ulceration | 1.5% (3/194) | 0.0% (0/406) | 0.03 |
| Aneurysm | 0.5% (1/194) | 0.0% (0/406) | 0.32 |
| Pre-Procedure TIMI Flow | | | |
| 0 | 3.1% (6/192) | 2.0% (8/405) | 0.39 |
| 1 | 1.6% (3/192) | 0.5% (2/405) | 0.33 |
| 2 | 4.2% (8/192) | 5.2% (21/405) | 0.59 |
| 3 | 91.1% (175/192) | 92.3% (374/405) | 0.61 |
| Lesion Preparation (Pretreatment)† | | | |
| Target lesion successfully dilated | 100% (194/194) | 99.5% (405/407) | 1.00 |
| Numbers are presented as % (count/sample size) or mean ± standard deviation (n). P-values are two-sided and from Student's t Test for continuous variables and Chi-square or Fisher's Exact (*) Test for discrete variables. The p values have not been adjusted for multiplicity. †Site-reported values. Abbreviations: ITT=intent-to-treat, MLD=minimum lumen diameter; TIMI= Thrombolysis In Myocardial Infarction; LAD=left anterior descending; LCx=left circumflex; LMCA=left main coronary artery; NA=not applicable; RCA=right coronary artery; Undef=undefined | | | |

Table 16 presents procedural characteristics. AGENT and POBA treatment groups were well-balanced with no significant differences in procedural characteristics. Mean procedure time was 55.2 minutes, $87.2\%$ of patients had only the target lesion treated and $12.8\%$ had both target plus one non-target lesion treated. Only one study device was allowed for the AGENT DCB arm, hence the slight difference in number of study devices used (3.6% of subjects in the POBA arm had 2 study devices used). Similarly, one target lesion was allowable in the study, though one patient had 2 target lesions treated, which was considered a protocol deviation. The use of cutting balloons was similar in lesions treated with AGENT DCB as compared to lesions treated

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with POBA (25.1% vs. 23.7%). Intravascular imaging was performed in approximately 74% of patients during the procedure.

Table 16: Procedural Characteristics, ITT (N=600)

| Measure | POBA N=194 Lesions, N=194 Subjects | AGENT N=407† Lesions, N=406 Subjects | P-value |
| --- | --- | --- | --- |
| Urgency of intervention | | | |
| Elective | 90.2% (175/194) | 89.7% (364/406) | 0.83 |
| Urgent / Emergent | 9.8% (19/194) | 10.3% (42/406) | 0.83 |
| Procedure Time (min) | 53.15 ± 27.06 (193) | 56.19 ± 29.81 (402) | 0.23 |
| Target Lesions Treated by Subject | 1.00 ± 0.00 (194) | 1.00 ± 0.05 (406) | 0.49 |
| 1 Target Lesion Treated | 100% (194/194) | 99.8% (405/406) | 1.00* |
| 2 Target Lesions Treated | 0.0% (0/194) | 0.2% (1/406)† | 1.00* |
| Study Device (POBA or AGENT) Usage by Subject in Target Lesion | | | |
| 0 Study Devices | 0.0% (0/194) | 0.2% (1/406)‡ | 1.00* |
| 1 Study Device | 95.4% (185/194) | 99.8% (405/406) | 0.0002* |
| 2 Study Devices | 3.6% (7/194) | 0.0% (0/406) | 0.0003* |
| 3 Study Devices | 1.0% (2/194) | 0.0% (0/406) | 0.10* |
| Subjects with Only Target Lesion Treated | 86.6% (168/194) | 87.4% (355/406) | 0.77 |
| Subjects with Both Target & Non-Target Lesions Treated | 13.4% (26/194) | 12.6% (51/406) | 0.77 |
| Cutting Balloon Use | 23.7% (46/194) | 25.1% (102/407) | 0.72 |
| Intravascular Imaging During Procedure | 76.8% (149/194) | 72.4% (294/406) | 0.25 |
| Post-Procedure | | | |
| Hospital Length of Stay (days) | 0.72 ± 1.75 (194) | 0.59 ± 0.93 (406) | 0.24 |
| Numbers are presented as % (count/sample size) or mean ± standard deviation (n). P-values are two-sided and from Student's t Test for continuous variables and the Chi-square or Fisher's Exact (*) Test for discrete variables. The p values have not been adjusted for multiplicity †One patient in the DCB arm had two target lesions treated with DCB that was counted as a protocol deviation. ‡Study balloon rupture in the DCB arm causing perforation. This was counted as a device deficiency | | | |

Use of dual antiplatelet therapy (DAPT; aspirin plus a $\mathrm{P2Y}_{12}$ inhibitor) pre-procedure, at hospital discharge, 30-day, 6-month, and 1-year follow-up time points is shown in Table 17. The percentage of subjects on DAPT was similar between the two treatment groups at each time point.

Table 17: Dual Antiplatelet Medication Usage Through 1 Year, ITT (N=600)

| Medication | POBA N=194 | AGENT N=406 | P-value |
| --- | --- | --- | --- |
| DAPT (Aspirin and one of Clopidogrel, Ticlopidine, Prasugrel or Ticagrelor) | | | |

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| Medication | POBA
N=194 | AGENT
N=406 | P-value |
| --- | --- | --- | --- |
| Prior Regimen or Loading Dose | 77.8% (151/194) | 73.4% (298/406) | 0.24 |
| Discharge | 95.4% (185/194) | 95.8% (389/406) | 0.80 |
| 30 Days | 90.5% (172/190) | 91.3% (365/400) | 0.77 |
| 6 Months | 83.2% (158/190) | 85.7% (335/391) | 0.43 |
| 12 Months | 77.8% (137/176) | 79.6% (297/373) | 0.63 |

Numbers are % (count/sample size). P-values are from two-sided from Chi-square test. The p values have not been adjusted for multiplicity

## D. SAFETY AND EFFECTIVENESS RESULTS

The primary analysis of safety and effectiveness was based on the ITT cohort of the initial 480 patients available for the 12-month evaluation of target lesion failure.

The study primary endpoint was met. AGENT DCB was superior to POBA as the one-sided upper 97.5% confidence bound for the difference in 1-year TLF was less than zero in the ITT population. Specifically, 18.2% subjects treated with AGENT and 29.3% of the POBA treated subjects in the ITT population experienced TLF by 1 year. Per-protocol analysis was also performed, and the result was identical. Table 18 shows the primary endpoint of 1-year TLF for the primary endpoint analysis cohort (N=480).

Table 18: Primary Endpoint Results, N=480

| 12-Month TLF | POBA
N=159 | AGENT
N=321 | Difference
(95% CI) | One-sided
97.5%
UCB | One-sided
P-value for
superiority |
| --- | --- | --- | --- | --- | --- |
| ITT | 29.3%
(44/150) | 18.2%
(55/302) | -11.1%
[-19.6%, -2.6%] | -2.6% | 0.0051 |

## Primary Endpoint Analysis: Full Cohort (N=600): 12-Month TLF

The primary endpoint analysis was also performed on the total enrollment cohort (N=600) after that data became available. As shown in Table 19, the rate of 1-year TLF was 18.2% in patients treated with AGENT and 29.0% of patients treated with POBA in the ITT population. These data demonstrate very similar outcomes to the initial 480-patient analysis presented above. Per-protocol analysis was also performed, and the result was again identical.

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Table 19: Primary Endpoint Results, Full Cohort (N=600)

| 12-Month TLF | POBA N=194 | AGENT N=406 | Difference [95% CI] | One-sided 97.5% UCB |
| --- | --- | --- | --- | --- |
| ITT | 29.0% (54/186) | 18.2% (71/390) | -10.8% [-18.4%, -3.3%] | -3.3% |

Time-to-event event curves (Kaplan-Meier analysis) to 1 year for target lesion failure are shown below in Figure 5 for the full 600 patient cohort. The estimated event rate was $17.9\%$ for AGENT and $28.6\%$ for POBA.

Figure 5: Kaplan-Meier Event Curve for TLF to 12 Months, N=600

Values are presented as cumulative event rate $\pm 1.5$ standard error

# 1. Safety Results

The analysis of safety was based on the ITT cohort of 582 patients available for the 12-month evaluation. The key safety outcomes for this study are presented below in Table 20. Adverse effects are reported in Table 21.

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Safety endpoints adjudicated by the CEC included death (all-cause and cardiac death), MI, and ISR stent thrombosis. Rates of death were comparable across treatment groups. Rates of MI at 12 months numerically favored the AGENT DCB over POBA (7.4% AGENT vs 12.2% POBA). None of the subjects in the AGENT arm experienced definite/probable ISR stent thrombosis compared to 6 subjects in the POBA arm (0.0% versus 3.2%). Table 20 below presents a summary of the safety-related endpoints adjudicated by the CEC at all currently available timepoints.

Table 20: Summary of CEC-Adjudicated Safety Endpoints (N=600)

| Event | POBA (N=194) | DCB (N=406) |
| --- | --- | --- |
| In-Hospital Safety Events | | |
| Death | 0.0% (0/194) | 0.0% (0/406) |
| MI | 2.6% (5/194) | 1.5% (6/406) |
| ARC ISR Stent Thrombosis Related to Target Lesion | 0% (0/194) | 0.0% (0/406) |
| Events to 30 Days | | |
| Death | 0.0% (0/194) | 0.5% (2/406) |
| Cardiac Death | 0.0% (0/194) | 0.2% (1/406) |
| Non-Cardiac Death | 0.0% (0/194) | 0.2% (1/406) |
| MI | 2.6% (5/194) | 2.0% (8/406) |
| ARC ISR Stent Thrombosis Related to Target Lesion | 0% (0/194) | 0.0% (0/406) |
| Events to 6 Months | | |
| Death | 0.5% (1/194) | 1.7% (7/404) |
| Cardiac Death | 0.5% (1/194) | 1.5% (6/404) |
| Non-Cardiac Death | 0.0% (0/194) | 0.2% (1/404) |
| MI | 8.2% (16/194) | 4.2% (17/404) |
| ARC ISR Stent Thrombosis Related to Target Lesion | 2.1% (4/194) | 0.0% (0/404) |
| Events to 12 Months | | |
| Death | 3.7% (7/189) | 4.1% (16/393) |
| Cardiac Death | 1.6% (3/189) | 2.8% (11/393) |
| Non-Cardiac Death | 2.1% (4/189) | 1.3% (5/393) |
| MI | 12.2% (23/189) | 7.4% (29/393) |
| ARC ISR Stent Thrombosis Related to Target Lesion | 3.7% (7/189) | 0.3% (1/393) |

*Rates presented include definite, probable, and possible stent thrombosis events

There were a total of 623 serious adverse events reported in 226 patients in the AGENT DCB group, compared to a total of 306 serious adverse events reported in 113 patients in the POBA control group through 12 months of follow up. The frequency and nature of adverse events observed in the AGENT DCB group were similar to those observed for the POBA control group.

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When evaluating all adverse events, including non-serious adverse events, a numerical increase was observed for Acute Kidney Injury in the DCB arm as compared to POBA (6.7% vs 3.1%). However, most observations were non-serious, the event rates in both arms were low compared to known rates of acute kidney injury after PCI procedures, and the observed difference was likely due to chance.

Serious adverse events that occurred in the AGENT IDE Study with an event rate $&gt;1\%$ are presented in Table 21. A serious adverse event either resulted in death, was life-threatening, required inpatient hospitalization or caused prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, or required intervention to prevent permanent impairment of damage. Adverse events were reported by sites and coded using MedDRA preferred terms. Only categories of adverse events occurring at a rate of $&gt;1\%$ in either treatment group are reported. Thus, the listed events may not add up to the total amount in each group or overall.

Table 21: Serious Adverse Events Through 1 Year with Event Rate $&gt;1\%$ (N=600)

| Serious Adverse Event | | | POBA (N=194 Subjects) | | DCB (N=406 Subjects) | |
| --- | --- | --- | --- | --- | --- | --- |
| MedDRA System Organ Class | MedDRA High-Level Group Term | MedDRA Preferred Term | Events (n) | Percent of Subjects with Event (n/N) | Event s (n) | Percent of Subjects with Event (n/N) |
| Total | Total | Total | 306 | 58.2% (113/194) | 623 | 55.7% (226/406) |
| Cardiac disorders | Total | Total | 132 | 38.7% (75/194) | 238 | 35.0% (142/406) |
| | Coronary artery disorders | Total | 98 | 33.0% (64/194) | 153 | 28.8% (117/406) |
| | | Angina unstable | 36 | 12.9% (25/194) | 43 | 8.6% (35/406) |
| | | Angina pectoris | 28 | 11.9% (23/194) | 43 | 9.9% (40/406) |
| | | Acute myocardial infarction | 16 | 7.2% (14/194) | 25 | 5.2% (21/406) |
| | | Coronary artery disease | 12 | 5.7% (11/194) | 21 | 5.2% (21/406) |
| | | Myocardial infarction | 2 | 1.0% (2/194) | 7 | 1.7% (7/406) |
| | | Acute coronary syndrome | 2 | 1.0% (2/194) | 5 | 1.2% (5/406) |
| | Heart failures | Total | 20 | 7.7% (15/194) | 35 | 5.9% (24/406) |
| | | Cardiac failure | 2 | 1.0% (2/194) | 17 | 2.5% (10/406) |
| | | Cardiac failure congestive | 10 | 4.1% (8/194) | 8 | 1.7% (7/406) |
| | | Cardiac failure acute | 4 | 2.1% (4/194) | 3 | 0.7% (3/406) |
| | | Left ventricular failure | 2 | 1.0% (2/194) | 3 | 0.7% (3/406) |
| | Cardiac arrhythmias | Total | 9 | 4.6% (9/194) | 39 | 6.4% (26/406) |
| | | Atrial fibrillation | 5 | 2.6% (5/194) | 16 | 3.4% (14/406) |
| | Cardiac valve disorders | Total | 2 | 1.0% (2/194) | 4 | 1.0% (4/406) |

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| Serious Adverse Event | | | POBA (N=194 Subjects) | | DCB (N=406 Subjects) | |
| --- | --- | --- | --- | --- | --- | --- |
| MedDRA System Organ Class | MedDRA High-Level Group Term | MedDRA Preferred Term | Events (n) | Percent of Subjects with Event (n/N) | Event s (n) | Percent of Subjects with Event (n/N) |
| | Myocardial disorders | Total | 2 | 1.0% (2/194) | 4 | 1.0% (4/406) |
| | | Cardiomyopathy | 2 | 1.0% (2/194) | 0 | 0.0% (0/406) |
| Infections and infestations | Total | Total | 20 | 7.7% (15/194) | 50 | 10.1% (41/406) |
| | Infections - pathogen unspecified | Total | 13 | 4.6% (9/194) | 36 | 7.4% (30/406) |
| | | Pneumonia | 5 | 2.6% (5/194) | 10 | 2.2% (9/406) |
| | | Urinary tract infection | 2 | 1.0% (2/194) | 3 | 0.7% (3/406) |
| | Viral infectious disorders | Total | 5 | 2.6% (5/194) | 6 | 1.5% (6/406) |
| | | COVID-19 | 2 | 1.0% (2/194) | 3 | 0.7% (3/406) |
| | | COVID-19 pneumonia | 2 | 1.0% (2/194) | 2 | 0.5% (2/406) |
| | Bacterial infectious disorders | Total | 2 | 1.0% (2/194) | 8 | 2.0% (8/406) |
| | | Cellulitis | 2 | 1.0% (2/194) | 3 | 0.7% (3/406) |
| General disorders and administration site conditions | Total | Total | 19 | 8.2% (16/194) | 38 | 8.1% (33/406) |
| | General system disorders NEC | Total | 11 | 4.1% (8/194) | 24 | 5.7% (23/406) |
| | | Non-cardiac chest pain | 5 | 2.6% (5/194) | 11 | 2.7% (11/406) |
| | | Chest pain | 4 | 1.5% (3/194) | 5 | 1.2% (5/406) |
| | Complications associated with device | Total | 5 | 2.6% (5/194) | 6 | 1.5% (6/406) |
| | | Vascular stent stenosis | 3 | 1.5% (3/194) | 5 | 1.2% (5/406) |
| | | Vascular stent thrombosis | 2 | 1.0% (2/194) | 0 | 0.0% (0/406) |
| | Administration site reactions | Total | 2 | 1.0% (2/194) | 5 | 1.2% (5/406) |
| Vascular disorders | Total | Total | 19 | 8.2% (16/194) | 28 | 6.2% (25/406) |
| | Decreased and nonspecific blood pressure disorders and shock | Total | 4 | 2.1% (4/194) | 12 | 3.0% (12/406) |
| | | Hypotension | 3 | 1.5% (3/194) | 8 | 2.0% (8/406) |
| | Arteriosclerosis, stenosis, vascular insufficiency and necrosis | Total | 5 | 2.6% (5/194) | 8 | 1.5% (6/406) |
| | | Aortic stenosis | 2 | 1.0% (2/194) | 2 | 0.5% (2/406) |
| | | Peripheral arterial occlusive disease | 2 | 1.0% (2/194) | 1 | 0.2% (1/406) |
| | Vascular hypertensive disorders | Total | 5 | 2.6% (5/194) | 4 | 1.0% (4/406) |
| | | Hypertension | 4 | 2.1% (4/194) | 3 | 0.7% (3/406) |
| | Vascular haemorrhagic disorders | Total | 3 | 1.5% (3/194) | 0 | 0.0% (0/406) |
| | | Haematoma | 3 | 1.5% (3/194) | 0 | 0.0% (0/406) |
| Respiratory, thoracic and mediastinal disorders | Total | Total | 23 | 8.2% (16/194) | 45 | 5.9% (24/406) |
| | Respiratory disorders NEC | Total | 9 | 4.1% (8/194) | 21 | 3.4% (14/406) |
| | | Acute respiratory failure | 3 | 1.5% (3/194) | 8 | 1.0% (4/406) |
| | | Dyspnoea | 3 | 1.5% (3/194) | 6 | 1.5% (6/406) |
| | Bronchial disorders (excl neoplasms) | Total | 6 | 3.1% (6/194) | 12 | 1.5% (6/406) |
| | | Chronic obstructive | 4 | 2.1% (4/194) | 10 | 1.2% (5/406) |

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| Serious Adverse Event | | | POBA
(N=194 Subjects) | | DCB
(N=406 Subjects) | |
| --- | --- | --- | --- | --- | --- | --- |
| MedDRA System Organ Class | MedDRA High-Level Group Term | MedDRA Preferred Term | Events (n) | Percent of Subjects with Event (n/N) | Events (n) | Percent of Subjects with Event (n/N) |
| | | pulmonary disease | | | | |
| | Lower respiratory tract disorders (excl obstruction and infection) | Total | 2 | 1.0% (2/194) | 6 | 1.5% (6/406) |
| | | Pulmonary oedema | 2 | 1.0% (2/194) | 2 | 0.5% (2/406) |
| | Pulmonary vascular disorders | Total | 3 | 1.5% (3/194) | 1 | 0.2% (1/406) |
| | | Pulmonary embolism | 2 | 1.0% (2/194) | 0 | 0.0% (0/406) |
| | Pleural disorders | Total | 2 | 1.0% (2/194) | 3 | 0.7% (3/406) |
| | | Pleural effusion | 2 | 1.0% (2/194) | 2 | 0.5% (2/406) |
| Nervous system disorders | Total | Total | 21 | 7.7% (15/194) | 29 | 6.4% (26/406) |
| | Neurological disorders NEC | Total | 7 | 3.6% (7/194) | 11 | 2.7% (11/406) |
| | | Syncope | 2 | 1.0% (2/194) | 3 | 0.7% (3/406) |
| | | Presyncope | 2 | 1.0% (2/194) | 1 | 0.2% (1/406) |
| | Central nervous system vascular disorders | Total | 8 | 3.6% (7/194) | 6 | 1.5% (6/406) |
| | | Cerebrovascular accident | 4 | 2.1% (4/194) | 2 | 0.5% (2/406) |
| Injury, poisoning and procedural complications | Total | Total | 15 | 6.7% (13/194) | 30 | 5.9% (24/406) |
| | Procedural related injuries and complications NEC | Total | 7 | 3.6% (7/194) | 11 | 2.2% (9/406) |
| | | Plaque shift | 2 | 1.0% (2/194) | 3 | 0.7% (3/406) |
| | | Vascular pseudoaneurysm | 2 | 1.0% (2/194) | 0 | 0.0% (0/406) |
| | Injuries NEC | Total | 4 | 2.1% (4/194) | 13 | 3.0% (12/406) |
| | | Fall | 2 | 1.0% (2/194) | 3 | 0.7% (3/406) |
| | Bone and joint injuries | Total | 4 | 2.1% (4/194) | 5 | 0.7% (3/406) |
| | | Humerus fracture | 2 | 1.0% (2/194) | 0 | 0.0% (0/406) |
| Gastrointestinal disorders | Total | Total | 12 | 5.2% (10/194) | 38 | 5.4% (22/406) |
| | Gastrointestinal haemorrhages NEC | Total | 0 | 0.0% (0/194) | 9 | 1.7% (7/406) |
| | Gastrointestinal signs and symptoms | Total | 2 | 0.5% (1/194) | 8 | 1.2% (5/406) |
| | Gastrointestinal stenosis and obstruction | Total | 2 | 1.0% (2/194) | 5 | 0.7% (3/406) |
| | Dental and gingival conditions | Total | 2 | 1.0% (2/194) | 3 | 0.7% (3/406) |
| | | Dental caries | 2 | 1.0% (2/194) | 2 | 0.5% (2/406) |
| | Abdominal hernias and other abdominal wall conditions | Total | 2 | 1.0% (2/194) | 2 | 0.5% (2/406) |
| | Diverticular disorders | Total | 2 | 1.0% (2/194) | 0 | 0.0% (0/406) |
| Renal and urinary disorders | Total | Total | 6 | 3.1% (6/194) | 27 | 5.4% (22/406) |
| | Renal disorders (excl nephropathies) | Total | 3 | 1.5% (3/194) | 15 | 3.0% (12/406) |
| | | Acute kidney injury | 3 | 1.5% (3/194) | 12 | 2.5% (10/406) |
| | | Total | 2 | 1.0% (2/194) | 6 | 1.5% (6/406) |

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| Serious Adverse Event | | | POBA (N=194 Subjects) | | DCB (N=406 Subjects) | |
| --- | --- | --- | --- | --- | --- | --- |
| MedDRA System Organ Class | MedDRA High-Level Group Term | MedDRA Preferred Term | Events (n) | Percent of Subjects with Event (n/N) | Events (n) | Percent of Subjects with Event (n/N) |
| | Urinary tract signs and symptoms | Urinary retention | 0 | 0.0% (0/194) | 5 | 1.2% (5/406) |
| Metabolism and nutrition disorders | Total | Total | 11 | 4.1% (8/194) | 23 | 3.7% (15/406) |
| | Glucose metabolism disorders (incl diabetes mellitus) | Total | 5 | 2.6% (5/194) | 6 | 1.5% (6/406) |
| | | Hyperglycaemia | 5 | 2.6% (5/194) | 3 | 0.7% (3/406) |
| | Electrolyte and fluid balance conditions | Total | 3 | 1.0% (2/194) | 6 | 1.2% (5/406) |
| | | Hypokalaemia | 2 | 1.0% (2/194) | 1 | 0.2% (1/406) |
| | Acid-base disorders | Total | 3 | 1.0% (2/194) | 3 | 0.7% (3/406) |
| Blood and lymphatic system disorders | Total | Total | 7 | 3.6% (7/194) | 16 | 3.7% (15/406) |
| | Anaemias nonhaemolytic and marrow depression | Total | 5 | 2.6% (5/194) | 11 | 2.7% (11/406) |
| | | Anaemia | 5 | 2.6% (5/194) | 7 | 1.7% (7/406) |
| | Platelet disorders | Total | 2 | 1.0% (2/194) | 1 | 0.2% (1/406) |
| | | Heparin-induced thrombocytopenia | 2 | 1.0% (2/194) | 0 | 0.0% (0/406) |
| Musculoskeletal and connective tissue disorders | Total | Total | 5 | 2.6% (5/194) | 13 | 3.0% (12/406) |
| | Joint disorders | Total | 2 | 1.0% (2/194) | 7 | 1.5% (6/406) |
| | Musculoskeletal and connective tissue deformities (incl intervertebral disc disorders) | Total | 2 | 1.0% (2/194) | 2 | 0.5% (2/406) |
| | | Cervical spinal stenosis | 2 | 1.0% (2/194) | 0 | 0.0% (0/406) |
| Neoplasms benign, malignant and unspecified (incl cysts and polyps) | Total | Total | 4 | 2.1% (4/194) | 11 | 2.5% (10/406) |
| | Gastrointestinal neoplasms malignant and unspecified | Total | 2 | 1.0% (2/194) | 1 | 0.2% (1/406) |
| Investigations | Total | Total | 3 | 1.5% (3/194) | 13 | 2.0% (8/406) |
| | Microbiology and serology investigations | Total | 2 | 1.0% (2/194) | 3 | 0.7% (3/406) |
| | | SARS-CoV-2 test positive | 2 | 1.0% (2/194) | 3 | 0.7% (3/406) |
| Eye disorders | Total | Total | 1 | 0.5% (1/194) | 7 | 1.5% (6/406) |
| Skin and subcutaneous tissue disorders | Total | Total | 2 | 1.0% (2/194) | 3 | 0.7% (3/406) |
| Immune system disorders | Total | Total | 2 | 1.0% (2/194) |…