SELUTION SLR™ 014 PTCA Drug-Eluting Balloon

P250041 · MedAlliance, LLC · OOB · Sep 18, 2026

Device Facts

• Record ID: P250041
• Device Name: SELUTION SLR™ 014 PTCA Drug-Eluting Balloon
• Applicant: MedAlliance, LLC
• Product Code: OOB
• Decision Date: Sep 18, 2026
• Decision: APPR
• Device Class: Class 3
• Attributes: Therapeutic, Real-World Evidence

Real-World Evidence

Submission	Device	Sponsor	RWD Sources	RWE Use Summary	Key Tags
P250041 · Sep 18, 2026	SELUTION SLR™ 014 PTCA Drug-Eluting Balloon	MedAlliance, LLC	SELUTION4ALL Global Registry	Post-approval surveillance study to assess real-world safety and effectiveness, specifically focusing on patient populations underrepresented in the pivotal trial (women and racial/ethnic groups).	Post-approval surveillance; Registry; Real-world safety; Underrepresented populations

Clinical Evidence

Study Design	Population	Comparator	Key Endpoints
SELUTION SLR PTCA DEB Post-Approval Surveillance Analysis; Prospective observational registry; Follow-up/Duration: 2 years; Study Period: First 2 years following device approval	All consecutive patients treated with the device at US sites within the first 2 years following approval; Sample Size: Approximately 3,500 patients; Number of Sites: Multiple US sites	Not applicable for this study	In-hospital major adverse cardiac events, all-cause death, myocardial infarction, and revascularization

Indications for Use

The SELUTION SLR™ 014 PTCA Drug-Eluting Balloon Catheter is intended to be used after appropriate vessel preparation in adult patients undergoing percutaneous coronary intervention (PCI) in coronary arteries 2.25 mm to 4.50 mm in diameter and lesions ≤ 26 mm in length for the purpose of improving myocardial perfusion when treating in-stent restenosis (ISR).

Device Story

SELUTION SLR is a rapid exchange (RX) semi-compliant PTCA catheter; balloon coated with sirolimus encapsulated in PLGA microspheres within a lipid-based excipient (PEG-lipid, phosphatidylcholine, cholesterol derivative). Used in cath labs by interventional cardiologists for coronary ISR. Device mechanically dilates stenotic lesions; sirolimus inhibits restenosis via anti-proliferative/anti-inflammatory action. Radiopaque markers aid positioning. Hydrophilic coating on distal shaft enhances trackability. Physician uses fluoroscopy to guide catheter to lesion; inflates balloon to deliver drug to vessel wall. Benefits include improved myocardial perfusion and potential avoidance of additional stent layers in previously stented vessels.

Clinical Evidence

PMA based on SELUTION4ISR prospective, multicenter, randomized, single-blind, non-inferiority trial (n=418). Primary endpoint: 12-month target lesion failure (TLF). SELUTION DEB (16.2%) vs. SOC (14.5%) met non-inferiority (posterior probability 98.8%). Secondary endpoint (SELUTION vs. DES in 1-layer ISR) not met (posterior probability 76.1%). Safety profile comparable to SOC; no unanticipated adverse device effects.

Technological Characteristics

Rapid exchange (RX) semi-compliant PTCA catheter; 0.014" guidewire compatible. Coating: Sirolimus (CAS 53123-88-9) in PLGA (75:25 DL-lactide:glycolide) microspheres (4 μm) and lipid blend. Stainless steel hypotube; hydrophilic coating. E-beam sterilized (22.5-30.0 kGy). 18-month shelf life. Diameters 2.25-4.50 mm; lengths 15-30 mm. Nominal dose 1.0 μg/mm².

Indications for Use

Indicated for adult patients with coronary in-stent restenosis (ISR) in native coronary arteries 2.25-4.50 mm diameter and lesions ≤ 26 mm length. Contraindicated in patients with sirolimus hypersensitivity, inability to receive antiplatelet/anticoagulant therapy, unprotected left main disease, coronary spasm without stenosis, or neurovasculature.

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.

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: | SELUTION SLR™ 014 PTCA Drug-Eluting Balloon Catheter |
| Device Procode: | OOB |
| Applicant's Name and Address: | MedAlliance LLC 4 Jenner, Suite 190 Irvine, CA 92618 |
| Date(s) of Panel Recommendation: | None |
| Premarket Approval Application (PMA) Number: | P250041 |
| Date of FDA Notice of Approval: | September 18, 2026 |
| Breakthrough Device: | Granted breakthrough device status on February 21, 2019 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 SELUTION SLR™ 014 PTCA Drug-Eluting Balloon Catheter is intended to be used after appropriate vessel preparation in adult patients undergoing percutaneous coronary intervention (PCI) in coronary arteries 2.25 mm to 4.50 mm in diameter and lesions ≤ 26 mm in length for the purpose of improving myocardial perfusion when treating in-stent restenosis (ISR).

## III. CONTRAINDICATIONS

The SELUTION SLR™ PTCA Drug Eluting Balloon Catheter is contraindicated for use in:

- Patients with known allergies or hypersensitivities to sirolimus (or analogs).
- Patients who cannot receive recommended antiplatelet and/or anticoagulant therapy.
- Patients with unprotected native left main coronary artery disease
- Patients with coronary artery spasm in the absence of a significant stenosis
- Neurovasculature

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# IV. WARNINGS AND PRECAUTIONS

The warnings and precautions can be found in the SELUTION™ SLR PTCA Drug Eluting Balloon Catheter labeling.

# V. DEVICE DESCRIPTION

The SELUTION SLR™ 014 PTCA Drug Eluting Balloon Catheter (hereafter referred to as SELUTION DEB or SELUTION) is a device-drug combination product consisting of a standard rapid exchange (RX) semi-compliant percutaneous coronary intervention (PCI) catheter compatible with 0.014 inch guidewires; the balloon portion is coated with a micro-encapsulated drug formulation (sirolimus as the active pharmaceutical ingredient, and a three-lipid system comprising a PEG-lipid, a structural phosphatidylcholine, and a cholesterol derivative, combined in a proprietary molar ratio as the excipient). It is designed to improve myocardial perfusion and decrease the incidence of restenosis in previously stented coronary arteries by (1) physically opening the artery through the mechanical inflation of the balloon and (2) inhibiting restenosis through the anti-proliferative and anti-stenotic actions of sirolimus.

The distal end of the catheter has a coaxial dual lumen design. The outer lumen is used for inflation of the balloon to conform to the vessel wall, and the inner lumen permits the use of a guidewire to facilitate advancement of the catheter. The proximal remainder of the catheter continues with one lumen that is used for balloon inflation. The semi-compliant balloon is designed to provide an inflatable segment of known diameter and length at recommended pressures. The balloon has two radiopaque markers that indicate the balloon working length and aid in the positioning of the balloon relative to the stenosis. The catheter tip is tapered to facilitate advancement of the catheter to the treatment area and through the stenosis. The proximal shaft consists of a stainless steel hypotube and is marked with exit markers. The distal shaft is partially coated with a hydrophilic coating for lubricity. Figure 1 shows a schematic drawing of the SELUTION DEB.


Figure 1: Schematic Drawing of the SELUTION DEB

The SELUTION DEB is available in balloon diameters between 2.25 - 4.50 mm and in balloon lengths between 15 and 30 mm. The effective or usable length of the catheter is 140 cm.

# Mechanism of Action

SELUTION DEB's primary mode of action is mechanical dilation of the stenotic lesion with a secondary inhibition of restenosis through the application of sirolimus to the coronary vessel wall.

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# Drug Coating Description

The drug coating for the SELUTION DEB consists of sirolimus (the active pharmaceutical ingredient) encapsulated in poly(lactic-co-glycolic acid) (PLGA) polymer microspheres within a lipid-based excipient (the inactive ingredients).

## Drug Substance – Sirolimus

The active pharmaceutical ingredient in the proprietary SELUTION DEB coating is sirolimus (CAS no. 53123-88-9). Sirolimus is a drug that acts both as an anti-proliferative agent and as an anti-inflammatory immunosuppressant. Sirolimus inhibits T and B-lymphocyte activation and smooth muscle and endothelial cell proliferation in response to cytokine and growth factor stimulation. Sirolimus is used as a cell growth inhibiting compound in both medicinal products (drug products) and combination products (device/drug products).

The chemical name for sirolimus is :
(3S,6R,7E,9R,10R,12R,14S,15E,17E,19E,21S,23S,26R,27R,34AS)-9,10,12,13,14,21,22,23,24,25,26,27,32,33,34,34A-hexadecahydro-9,27-dihydroxy-3-((1R)-2-((1S,3R,4R)-4-hydroxy-3-methoxycyclohexyl)-1-methylethyl)-10,21-dimethoxy-6,8,12,14,20,26-hexamethyl-23,27-epoxy-3H-pyrido(2,1-C)-(1,4)oxaazacyclohentriacontine-1,5,11,28,29-(4H,6H,31H)-pentone.

Sirolimus has a molecular weight of 914.17 g/mol and chemical formula C51H79NO13. The stereochemical structure of sirolimus molecules are shown in Figure 2 below:


Figure 2: Sirolimus Chemical Structure

## Excipients

The inactive ingredients in the SELUTION DEB coating are PLGA and a three-lipid system comprising a PEG-lipid, a structural phosphatidylcholine, and a cholesterol derivative, combined in a proprietary molar ratio in which the PLGA microspheres are suspended.

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# PLGA

The PLGA used in the SELUTION DEB coating is a co-polymer made of DL-lactide and glycolide in a 75:25 molar ratio. PLGA is a biodegradable polymer that is used widely for medical devices and drug delivery. The PLGA microspheres are 4 μm in diameter and help to regulate the release of sirolimus, which is loaded into the polymers at 41% by weight, as the polymer breaks down over time. The chemical structure of PLGA is shown in Figure 3. An illustration of the drug-loaded microspheres is shown in Figure 4.


Poly(DL-lactide-co-glycolide)

Figure 3: Chemical Structure of PLGA


Figure 4: Drug loaded microspheres

# Lipid Blend

The lipid blend is made of a three-lipid system comprising a PEG-lipid, a structural phosphatidylcholine, and a cholesterol derivative, combined in a proprietary molar ratio. This blend aids in reducing drug coating wash-off in the bloodstream during insertion, tracking and lesion crossing. The blend also improves drug transfer to the tissue during the short-term balloon dilatation and helps the microspheres adhere to the surrounding tissue after SELUTION DEB treatment.

# Drug Dose

The nominal drug dose density on the SELUTION DEB is 1.0 μg/mm² of cylindrical balloon surface. The drug content for each size is defined by the product of the balloon surface area and the nominal drug dose density. The total amount of sirolimus for each balloon size is provided in Table Table 1Error! Reference source not found..

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Table 1: Nominal Sirolimus Content (μg) Per Balloon Size

| Nominal Balloon Diameter (mm) | Nominal Balloon Length (mm) | | | |
| --- | --- | --- | --- | --- |
| | 15 | 20 | 25 | 30 |
| 2.25 | 106 | 141 | 177 | 212 |
| 2.50 | 118 | 157 | 196 | 236 |
| 2.75 | 130 | 173 | 216 | 259 |
| 3.00 | 141 | 188 | 236 | 283 |
| 3.25 | 153 | 204 | 255 | 306 |
| 3.50 | 165 | 220 | 275 | 330 |
| 4.00 | 188 | 251 | 314 | 377 |
| 4.50 | 212 | 283 | 353 | 424 |

## VI. ALTERNATIVE PRACTICES AND PROCEDURES

There are several other alternatives for the 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; angioplasty with a balloon with no drug coating)
• Additional drug-eluting stent
• Drug-coated or drug-eluting balloon catheters

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

A version of the SELUTION DEB (using the identical drug coating but a different base catheter) has been commercially available for distribution in the European Union (EU) since receiving CE Mark in May 2020. Since that time, the SELUTION DEB 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

| Armenia | Egypt | Indonesia | Kuwait | Philippines | Slovenia |
| --- | --- | --- | --- | --- | --- |
| Austria | Finland | Iran | Lebanon | Poland | South Africa |
| Bangladesh | France | Iraq | Luxembourg | Portugal | Spain |
| Belarus | Georgia | Ireland | Malaysia | Qatar | Switzerland |
| Belgium | Germany | Israel | Morocco | Russia | Taiwan |
| Brunei | Greece | Italy | Netherlands | Saudi Arabia | Uzbekistan |
| Canary Islands | Hong Kong | Jordan | New Zealand | Serbia | Vietnam |
| Croatia | Hungary | Kazakhstan | Northern Ireland | Singapore | |
| Czech Republic | India | Kenya | Oman | Slovakia | |

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### 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 SELUTION DEB or the angioplasty procedure.

- Additional interventions, including surgical intervention
- Allergic reaction (e.g., to contrast medium, medications, device components, drug coating and its components)
- Arrhythmias
- Bleeding (including hemorrhage or hematoma possibly requiring transfusion or additional intervention)
- Chest pain (angina)
- Death
- Embolism (of tissue, plaque, thrombus, device, drug coating)
- Fever
- Hypertension
- Hypotension
- Infection/sepsis
- Inflammation
- Myocardial infarction/ischemia
- Pain or tenderness at the vascular access site
- Pericardial effusion/cardiac tamponade
- Kidney injury/failure
- Radiation injury
- Shock
- Stroke or transient ischemic attack (TIA)
- Vessel injury (dissection, perforation, rupture, arteriovenous fistula, aneurysm or pseudoaneurysm)
- Vessel occlusion (spasm, abrupt closure/recoil, slow flow/no reflow, thrombosis, restenosis)

Potential adverse events not captured above that have been associated with oral administration of sirolimus (the drug in the SELUTION DEB coating) at systemic doses include the following:

- Abnormal liver enzymes
- Anemia
- Arthralgia (joint pain)
- Diarrhea
- Hypercholesterolemia (high cholesterol)
- Hypersensitivity, including anaphylactic/anaphylactoid type reactions
- Hypertriglyceridemia (high triglycerides)
- Hypokalemia (low blood potassium)
- Infection
- Interstitial lung disease
- Leukopenia (low white blood cell count)

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- Lymphoma and other cancers
- Thrombocytopenia (low platelet count)

For the specific adverse events that occurred in the clinical study, see Section X below.

## IX. SUMMARY OF NON-CLINICAL 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 testing, shelf-life testing, and Good Laboratory Practice (GLP) animal studies.

#### i. Biocompatibility

Biocompatibility testing of the SELUTION DEB 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 as summarized in Table 3.

To ensure any potential effects of the drug coating component on biocompatibility could be differentiated from any potential effects of the device component, testing was conducted on three separate test articles:

1) the final, drug-coated SELUTION DEB catheter
2) the excipient-coated balloon catheter (no drug)
3) the uncoated PTCA balloon catheter

Table 3: Summary of Biocompatibility Testing

| Test | Applicable Standard | Test Article | | | Results |
| --- | --- | --- | --- | --- | --- |
| | | 1 | 2 | 3 | |
| Cytotoxicity - ISO MEM Elution Method | ISO 10993-5 | X | X | X | Not concerning* |
| Sensitization | ISO 10993-10 | X | - | X | Non-sensitizing |
| Intracutaneous Reactivity | ISO 10993-10 | X | X | X | Not concerning* |
| Hemolysis (Direct and Extract) | ISO 10993-4 | X | X | X | Not concerning* |
| SC5b9 Complement Activation | ISO 10993-4:2017 (E) | X | - | X | Not a complement activator** |
| Partial Thromboplastin Time (PTT) | ISO 10993-4 | X | - | - | Met requirements |
| Acute Systemic | ISO 10993-11:2017(E) | X | - | X | Non-toxic |

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| Test | Applicable Standard | Test Article | | | Results |
| --- | --- | --- | --- | --- | --- |
| | | 1 | 2 | 3 | |
| Toxicity | | | | | |
| Material-Mediated Pyrogenicity | ISO 10993-11:2017 (E) | X | - | X | Non-pyrogenic |
| Genotoxicity Bacterial Mutagenicity Test - AMES Assay | ISO 10993-3:2014 (E) | X | - | - | Not concerning* |
| Genotoxicity In-Vitro Mouse Lymphoma Assay | ISO 10993-3:2014 | X | X | - | Not concerning* |
| Chemical Characterization/ Toxicological Risk Assessment | ISO 10993-18:2020 | X | X | X | Extractables do not pose toxicity concerns for the endpoints of carcinogenicity, genotoxicity, and subchronic/chronic systemic toxicity. |
| *Although cytotoxic, genotoxic, irritation, and hemolytic response was noted for the neat extract of the finished SELUTION DEB and excipient coated balloons, the results are considered acceptable following extract dilutions and based on acceptable implantation response from the GLP animal studies as described in section B. **SELUTION DEB did not meet the acceptance criteria for SC5b-9 Complement Activation. However, the GLP animal safety study (section B) found no pathological evidence to suggest that uncontrolled complement activation occurred in-vivo and thus, the results were considered acceptable. | | | | | |

This biocompatibility assessment concluded that the SELUTION DEB demonstrated acceptable biological risk under its intended use.

Thrombogenicity, Implantation, Sub-chronic/Chronic Toxicity and Carcinogenicity endpoints, per ISO 10993-4, -6, -11 and -3, respectively, were leveraged from the GLP animal safety study using the SELUTION drug coated balloon catheter. The outcomes related to these endpoints were found to be acceptable.

## ii. Bench Testing

A summary of the bench testing studies to support the SELUTION DEB is provided in Table 4. All testing was completed in accordance with relevant standards and FDA guidance documents, as applicable, to support the approved indication.

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Table 4: Summary of Bench Testing

| Test | Objective | Acceptance Criteria | Results |
| --- | --- | --- | --- |
| Dimensional and Functional Attributes | Demonstrate accurate dimensions, including crossing profile, effective length, and balloon length. Demonstrate guidewire and accessory device compatibility consistent with the product label. | Compatible with labeled dimensions. | Pass |
| Rated Burst Pressure (constrained and unconstrained) | Ensure burst pressures are above the labeled range, including when inflated inside of a previously deployed stent. | The burst pressure must be ≥ 14 atm. | Pass |
| Balloon Compliance | Establish an accurate compliance chart by measuring the balloon diameter at multiple pressures. | Characterization | Acceptable |
| Balloon Inflation and Deflation Time | Ensure the balloon can inflate and deflate sufficiently quickly to avoid prolonged obstruction of blood flow. | The balloon must inflate in less than 10 seconds and deflate in less than 30 seconds. | Pass |
| Balloon Fatigue (constrained and unconstrained) | Ensure freedom from leakage or damage after multiple inflations, including when inflated inside of a previously deployed stent. | Must be able to withstand 10 inflation/deflation cycles. | Pass |
| Catheter Bond Strength | Ensure all bonds can withstand clinically relevant tensile forces. | 0.44-126.9N, depending on the bond | Pass |
| Flexibility and Kink | Ensure catheter can withstand flexural forces typical of clinical use in tortuous vasculature. | The catheter demonstrates a kink radius ≤ 15mm. | Pass |
| Torque Strength | Ensure catheter can withstand torsional forces typical of clinical use without fractures. | The catheter withstands a minimum of three (3) 180° rotations of the proximal hub. | Pass |
| Balloon Preparation, Delivery, and Retraction (Simulated Use) | Demonstrate that the balloon catheter can be safely and reliably prepared, tracked, and deployed in a stented mock vessel, then retracted out of the model without damage to the product as per the instructions for use. | The device can be prepared, tracked, deployed, and retracted with no damage. | Pass |
| Radiopacity | Ensure marker bands are visible under fluoroscopy to aid in placement of the balloon. | Marker bands must be radiopaque. | Pass (determined during in vivo animal studies) |

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| Test | Objective | Acceptance Criteria | Results |
| --- | --- | --- | --- |
| Hydrophilic Coating Integrity | Demonstrate the hydrophilic coating remains largely intact after simulated use. | Characterize | Acceptable |

### iii. Coating Characterization Testing

Coating characterization testing performed to evaluate characteristics of the SELUTION DEB drug coating are summarized in Table 5.

Table 5: Summary of Coating Characterization

| Test | Description | Results |
| --- | --- | --- |
| Acute Coating Integrity | High magnification imaging was used to inspect drug coated balloons and surface appearance. | Acceptable Outcomes |
| Coating Adhesion | A tape test was conducted to evaluate coating adhesion. | Acceptable Outcomes |
| Coating Thickness | The coating thickness was measured at the distal, middle, and proximal locations of each balloon. | Acceptable Outcomes |
| Drug Coating Circumferential Uniformity | The drug present in each circumferential segment was analyzed to demonstrate uniformity across the balloon. | Acceptable Outcomes |
| Drug Coating Length Uniformity | The drug present in each longitudinal segment was analyzed to demonstrate uniformity across the balloon. | Acceptable Outcomes |
| Particulate Quantification (Track & Deploy) | Track and deploy particulate testing quantified the particulate released from the coated balloon. | Acceptable Outcomes |

### iv. Chemistry, Manufacturing, and Controls (CMC)

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

Table 6: SELUTION DEB CMC Testing Requirements

| Test | Objective | Acceptance Criteria |
| --- | --- | --- |
| Appearance | Packaging inspected for damage and visual inspection of the drug coating conducted to verify that it meets the appearance specification. | Must meet visual standard |
| Drug Identity | The identity of the drug substance, sirolimus, is confirmed by high performance liquid chromatography (HPLC) analysis and its UV spectrum. | Identity must be confirmed |

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| Test | Objective | Acceptance Criteria |
| --- | --- | --- |
| Drug Content | Sirolimus content is quantified by HPLC to ensure product contains the labeled dose. | Drug content mean value should be 90.0 – 110.0% of label claim |
| Drug Content Uniformity | Sirolimus content is quantified by HPLC to ensure individual devices contain the labeled dose. | USP <905> |
| Impurities | The levels of drug degradants and impurities are quantified by HPLC to ensure they remain within acceptable levels. | ICH Q3B(R2) |
| Residual Solvent | The amount of residual solvents (cyclohexane, ethanol, heptane, and methylene chloride) is verified to be within the established specification limits using gas chromatography. | The device met the established specification limits for residual solvents (<5-24 ug depending on balloon size). |
| Dissolution/Drug Release | The released sirolimus is quantified by HPLC to ensure it is within limits. | The drug release at multiple timepoints must be within limits |
| Endotoxin | Endotoxin levels are evaluated per AAMI ST72 to ensure they are within established safety guidelines. | AAMI ST72 |
| Particulates | Particulate sizes and counts measured for the SELUTION SLR PTCA DEB using light obscuration on particulates released during simulated use testing. | Particulate sizes and counts must be within limits per USP 788 |
| Polymer Molecular Weight (MW) | Determine PLGA MW by gel permeability chromatography (GPC). | Molecular weight must meet specification |

### v. In Vitro Polymer Degradation Studies

GPC was used to determine the change in MW and mass of PLGA used in the SELUTION DEB. Under clinically relevant conditions (37°C), PLGA underwent expected hydrolytic degradation, where 88% of its MW and 97% of its mass was lost over 210 days.

### vi. Sterilization

The SELUTION DEB is sterilized using electron beam (E-beam) sterilization with a radiation dose range of 22.5-30.0 kGy. This cycle is validated using the VDmax$^{SD}$ method and controlled in accordance with ISO TIR13004 and ISO 11137-1:2006 (Sterilization of Health Care Products - Radiation - Requirements for Development, Validation and Routine Control of Sterilization Process for Medical Devices) to provide a Sterility Assurance Level (SAL) of at least 10$^{-6}$.

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# vii. Packaging

Packaging verification testing was performed to demonstrate that the SELUTION DEB 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, seal width, bubble leak testing, and seal strength testing. Testing was conducted at baseline and aged conditions after preconditioning, including thermal cycling per ASTM D4332 and transportation testing per ASTM D4169.

# viii. 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 SELUTION DEB product. The data generated supports an 18-month shelf life for the SELUTION DEB device and the product is labeled accordingly.

# B. Animal Studies

The following animal studies were conducted to evaluate the safety and pharmacokinetics (PK) of the SELUTION DEB. Four GLP animal studies were conducted in compliance with 21 CFR 58 (Good Laboratory Practices) and one animal study was not conducted in accordance with 21 CFR 58.

Animal studies are summarized in Table 7.

Table 7: Summary of Animal Studies

| Study ID | Number & Animal Type | Local Drug Dose | Balloon Size (mm x mm) | Time Points | Major Endpoints | Endpoints Met |
| --- | --- | --- | --- | --- | --- | --- |
| Safety Study (CR 2648-205G) | n=75 Yucatan Swine | 1X, 3X, excipient only, 2X overlap, POBA (control) | 3.00 x 15 3.50 x 15 3.00 x 40 (overlap) | ISR: 3d, 30d, 90d, 180d de novo: 3d, 30d, 90d, 180d, 270d | Device Performance, Quantitative Angiography, Animal Health, Histopathology and Pathology | Yes |
| Safety Study Confirmatory (APS SEB008-IS07) | n=19 Yorkshire Cross Domestic Swine | 1X, POBA (control) | 3.00 x 20 | de novo: 30d, 90d | Animal Health, Quantitative Angiography, Histopathology and Pathology | Yes |

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| Study ID | Number & Animal Type | Local Drug Dose | Balloon Size (mm x mm) | Time Points | Major Endpoints | Endpoints Met |
| --- | --- | --- | --- | --- | --- | --- |
| Embolic Safety APS (SEB009-IS07) | n=6 Yorkshire Cross Domestic Swine | 3X, POBA (control) | 3.00 x 20 | 30d | Animal Health, Quantitative Angiography, Histopathology and Pathology | Yes |
| Embolic Safety (100664590) | n=12 Yorkshire Cross Domestic Swine | 5X, POBA (control) | 3.00 x 40 3.50 x 40 | 28d | Animal Health, Quantitative Angiography, Histopathology and Pathology | Yes |
| PK Study (CR 2649-205G) | n=51 Yucatan Mini Swine | 1X | 3.00 x 15 | de novo: 1h, 6h, 1d, 3d, 7d, 14d, 30d, 60d, 90d, 105d ISR: 1h, 1d, 30d, 60d | Plasma and Tissue Analysis | Yes |

The primary animal safety study, CR 2648-205, demonstrated 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.
- All but one treated animals survived until scheduled euthanasia; one animal died on Day 0 due to complications during the balloon treatment. Cause of death was attributed to the balloon procedure and not a direct result of the SELUTION DEB device.
- No thrombosis was observed after treatment on any of the devices evaluated.
- All treated arteries were evaluated with no observations of aneurysm, dissection, lumen narrowing in the non-treated region, or thrombosis.
- The primary safety study identified deep granulomatous inflammation observed inconsistently across all test and control groups, including animals treated with PTCA balloon angioplasty

o A second safety study, SEB008-IS07, was performed to address this and no granulomas or deep inflammation were observed for any group at any time point.

- The downstream embolic studies showed no abnormalities suggestive of drug, embolic, and/or particulates activity in the arterioles in any of heart/myocardium sections examined.

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The preclinical PK study (CR-2649-205G) demonstrated effective drug delivery and uptake into arterial tissues at the therapeutic dose of 1.0 µg/mm² with no evidence of drug toxicity demonstrated as follows:

- Sirolimus was detectable in blood as early as 3 minutes after deployment. The maximum median concentration was reached after 6 hours. After 2 weeks, no sirolimus was quantifiable in blood.
- In the treated arteries, the maximum median sirolimus concentration was reached 1 hour after balloon deployment with a medium Cmax of 1.10 ng/mL. Sirolimus was undetectable in the treated artery tissue at 90 days.
- Sirolimus distributed into some non-target, peripheral tissues, with the highest median concentration in the left caudal lobe of the lung. With the exception of the lung, no sirolimus was quantifiable in the non-target peripheral tissues after 60 days. Sirolimus was no longer detectable in the lungs at 105 days. Animals were monitored up to 270 days and there was no evidence of systemic or local tissue toxicity.
- The PK profiles of SELUTION DEB 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 sirolimus 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 1.0 µg/mm² and range of allowable balloon sizes.

# X. SUMMARY OF PRIMARY CLINICAL STUDY

The applicant performed a clinical study, SELUTION4ISR, to establish a reasonable assurance of safety and effectiveness of the SELUTION DEB in patients with coronary in-stent restenosis (ISR). The study was conducted in the United States (US), Canada, Brazil, Belgium, France, Italy, and the Netherlands under IDE # G220237. 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 July 6, 2020 and July 16, 2024. The database for this PMA reflected data collected through August 15, 2025 and included 418 patients. There were 48 enrolling investigational sites: 34 sites in the United States, 1 site in Belgium, 2 sites in Brazil, 1 site in Canada, 4 sites in France, 3 sites in Italy, and 3 sites in the Netherlands.

The SELUTION4ISR Study was a prospective, multicenter, randomized, single-blind, noninferiority clinical study to assess the safety and effectiveness of the SELUTION DEB as compared to the standard of care (described below) in patients with ISR.

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The study was designed to enroll 418 randomized patients (including 60 subjects in an angiographic and optical coherence tomography [OCT] sub-study), stratified by study center, drug-eluting stent (DES) or bare metal stent (BMS) ISR, and whether there were currently one (first stent restenosis) or two (second stent restenosis) implanted stent layers at the target lesion. Randomization occurred in a 1:1 ratio to receive the SELUTION DEB or standard of care (SOC). Patients randomized to the standard of care were treated with either an FDA-approved zotoarolimus- or everolimus-eluting stent or with plain balloon angioplasty (POBA) without stenting.

The intent of including POBA as an option in the SOC arm was to ensure patients with lesions with clinical justification for avoiding implantation of another stent could be enrolled in the study, particularly those with two existing implanted stent layers. The protocol stated that POBA was an acceptable alternative to stenting if clinically justified, but investigator justifications were not required to be recorded. Investigators were required to declare which SOC option they would use prior to randomization. A maximum of 20% of patients randomized to SOC were allowed to be treated with POBA. At the time of the protocol approval, in the US, no DCBs were approved for use in coronary applications.

The trial was designed to assess the non-inferiority of the SELUTION DEB compared to the current SOC with respect to the primary endpoint of 12-month target lesion failure (TLF), defined as cardiac death, target vessel myocardial infarction (MI), or clinically-driven target lesion revascularization (TLR).

Statistical assessment for the primary hypothesis was conducted using a statistical test for non-inferiority of proportions based on posterior probability. The criterion for success was based on the posterior probability of the alternative hypothesis (i.e., of noninferiority being met).

The sample size was determined using the following assumptions:

- A true 12-month TLF rate of 12% for both study arms
- A true 12-month TLF rate of 9% in patients with one layer of previous stent in both DES and SELUTION DEB treatment groups
- 80% DES use and 20% POBA use in the SOC
- An absolute non-inferiority margin of 10%
- Posterior probability of 97.5% to meet the primary endpoint alternative hypothesis
- Posterior probability of 95% to meet the hypothesis-driven secondary endpoint.

A total of 396 patients had 84% power to reject the primary endpoint null hypothesis at the final analysis. To account for loss to follow-up (expected to be approximately 5%), a total of 418 patients were required to be randomized.

The non-inferiority margin of 10% was selected to maintain at least 50% of the absolute risk difference between DES and POBA based on a meta-analysis of TLF rates from historical trials of subjects with ISR treated with DES or POBA.

An angiographic core laboratory and optical coherence tomography (OCT) core laboratory were used for independent analysis of data. A Data Safety Monitoring Board

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(DSMB) had the responsibility to monitor safety aspects of the study. A Clinical Events Committee (CEC) developed specific criteria for categorization of clinical events and clinical endpoints in the trial and adjudicated events according to these criteria.

# 1. Clinical Inclusion and Exclusion Criteria

Enrollment in the SELUTION4ISR study was limited to patients who were ≥ 18 years with no chance of being pregnant who presented with a chronic coronary syndrome such as documented stable or unstable angina or stabilized non-ST elevated myocardial infarction (STEMI) whose clinical history indicated treatment with PCI and for whom an intervention was planned. Subjects also needed to be eligible for dual antiplatelet therapy (DAPT) with aspirin plus clopidogrel, prasugrel, or ticagrelor. Patients should have had a life expectancy > 1 year in opinion of investigator and needed to e willing and able to provide informed consent and comply with study procedures and required follow-up evaluations.

To be enrolled in the study, these patients also needed to meet the following imaging criteria. The target lesion must be within a native coronary artery or major branch <26mm in length with a reference vessel diameter (RVD) ≥ 2.00 mm and ≤ 4.50 mm. The lesion must be within a previously placed BMS or DES which is 50-99% restenosed, and the lesion must not extend further than 5 mm beyond either the proximal or distal edge of the stent. Up to two non-target lesions in non-target vessels could be treated, but successful PCI of the non-target lesions must be completed before treatment of the target lesion. Successful PCI was defined as no greater than 30% residual stenosis based on the operator's visual estimate, no dissection greater than National Heart, Lung, Blood Institute (NHLBI) type C, and Thrombolysis in Myocardial Infarction (TIMI) grade flow in the non-target lesion > 2. The target lesion must be successfully pre-dilated/pre-treated, defined as dilation or pre-treatment that achieves stent expansion of approximately 80% of the distal RVD (at the discretion of the investigator) based on intravascular ultrasound (IVUS)/optical coherence tomography (OCT) and no greater than 30% residual stenosis by visual estimate and no dissection greater than NHLBI type C. TIMI grade flow in the target lesion must be >2.

Patients were not permitted to enroll in the SELUTION4ISR study if they met any of the following clinical or imaging exclusion criteria:

# Clinical Exclusion Criteria

1. Known hypersensitivity or allergy to sirolimus or other pharmacologic agents required for the procedure.
2. STEMI within 30 days.
3. Planned treatment of additional lesions in the target vessel, or more than two non-target lesions within non-target vessels, during the index procedure.
4. Target lesion located within a bifurcation with planned treatment of side branch vessel.
5. More than two layers of stent present at any segment of the target lesion.
6. Any previous vascular brachytherapy treatment of target vessel, or planned to undergo brachytherapy at index procedure.
7. Previous PCI of the target vessel within 30 days.

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8. Planned PCI of a non-target vessel, or a non-target lesion in the target vessel, within 30 days of randomization.
9. Chronic renal insufficiency (dialysis dependent, or glomerular filtration rate [GFR] ≤30 ml/min/1.73 m² within 30 days of index procedure) or undergone renal transplantation.
10. Acute renal insufficiency confirmed by 50% increase of serum creatinine within 48 hours before procedure and/or decrease in urine output.
11. History of active peptic ulcer or gastrointestinal bleeding within prior 6 months or other inability to comply with the recommended duration of DAPT.
12. Pregnant, breast-feeding, or not using appropriate contraceptives to avoid becoming pregnant.
13. Documented left ventricular ejection fraction (LVEF) <25%.
14. Currently participating in another investigational drug or device study that has not completed primary endpoint follow-up.

# Imaging Exclusion Criteria

1. Target lesion is a total occlusion or has evidence of thrombus.
2. Target lesion involves an unprotected left main coronary artery.
3. Target lesion has >30% residual stenosis by visual estimate or dissection greater than NHLBI type C after pre-dilation/pre-treatment.

# 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.

Pre-procedure, patients were assessed for medical history, physical exam, angina status, complete blood count, kidney function (using serum creatinine), cardiac enzymes, COVID-19 status, cardiac rhythm (using electrocardiogram (ECG)), and use of cardiovascular and diabetic medications. Post-procedure, the objective parameters measured during the study included angina status, cardiac rhythm, cardiac enzymes (pre-discharge only), and use of cardiovascular and diabetic medications. Patients participating in the imaging sub-study were assessed using angiography and IVUS/OCT one year post-procedure. Adverse events and clinical endpoints were monitored and recorded at all visits. The schedule of pre-procedure and post-procedure evaluations is included in Table 8 below.

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Table 8: Evaluation and Data Collection Time Points

| Assessment | Screening / Baseline | | Index Procedure | Post-Procedure / Discharge | 1 Month ± 10 Days | 6 Months ± 14 Days | 12 Months ± 30 Days | 2, 3, 4, 5 Years ± 60 Days | Un-scheduled Visit |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| | Within 7 days Prior to Procedure | Within 24 hours Prior to Procedure | | | Clinic Visit | Clinic or Telephone Visit | Clinic Visit | Clinic or Telephone Visit | |
| Informed consent form | X | | | | | | | | |
| Demographic, medical, and cardiac history | X | | | | | | | | |
| Physical examination | X | | | | | | | | |
| Angina status | X | | | X | X | X | X | X | X |
| CBC | X | | | | | | | | |
| Creatinine | X | | | | | | | | |
| CKMB or troponin \( T^1 \) | | X | | X | | | | | \( X^3 \) |
| Pregnancy test | X | | | | | | | | |
| COVID-19 status (if available) | | X | | X | X | X | X | X | X |
| ECG | | X | | X | | | X | | \( X^3 \) |
| Coronary angiography | | | X | | | | \( X^2 \) | | \( X^3 \) |
| IVUS/OCT | | | X | | | | | | R |
| OCT (imaging sub-group only) | | | \( X^2 \) | | | | \( X^2 \) | | |
| AE/SAE monitoring | | | X | X | X | X | X | X | X |
| Device Deficiency | | | X | | | | | | |
| Concomitant Medication4 | | X | | X | X | X | X | X | X |

AE: adverse event; CBC: complete blood count; CKMB: creatine kinase-muscle/brain; ECG: electrocardiogram; IVUS: intravascular ultrasound; OCT: Optical coherence tomography; R: recommended; SAE: serious adverse event.

\( ^{1} \) CKMB or Troponin T preferred (Troponin I was not accepted after CIP Rev 7, adopted August 3, 2021). Obtained at baseline and 4-24 hours post-procedure; if the biomarker was elevated, then repeat levels at 4-6 hours were obtained to assess the peak value.

\( ^{2} \) Imaging subset only. Required after 12-month clinical follow-up completed. May be performed up to 30 days after clinical follow-up was completed, but not before clinical follow-up. However,

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patients who underwent clinically indicated angiography after 6 months (180 days) were considered compliant and did not require repeat 12-month angiography.

³ Obtained for repeat visits where ischemic event was suspected.
⁴ All cardiovascular and diabetic medications administered were recorded from 24 hours pre-procedure through the 12-month follow-up assessment. Use of antiplatelet/anticoagulant therapy was recorded throughout the 5-year follow-up period.

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 12-month rate of target lesion failure (TLF) defined as a composite of:

- Cardiac death
- Target vessel myocardial infarction (MI)
- Clinically-driven target lesion revascularization (TLR)

MI included spontaneous (Type 1) MI using the 4th Universal Definition of Myocardial Infarction (UDMI) and peri-procedural MI using the Society for Cardiac Angiography and Intervention (SCAI) definition. CK-MB and troponin T were the preferred cardiac biomarkers.

An additional safety and effectiveness composite hypothesis-driven secondary endpoint, which was to be evaluated if the primary endpoint was met, was the incidence of TLF at 12 months comparing the SELUTION DEB arm to the DES cohort of the SOC arm among patients with one previous layer of stent.

With regards to safety, additional endpoints included all-cause death, cardiovascular death, MI, stent thrombosis per Academic Research Consortium (ARC) definitions, and bleeding (to 12 months).

With regards to effectiveness, additional endpoints included device, lesion, and procedural success, TLR, and target vessel revascularization (TVR).

With regard to success/failure criteria, the study was considered a success if the SELUTION DEB was shown to be non-inferior to the SOC control for the primary endpoint of TLF at one year.

A statistical test for noninferiority of proportions based on posterior probability was to be used to test the following hypotheses:

$$\mathrm{H}_{0}: \mathrm{TLF}_{\mathrm{DEB}} - \mathrm{TLF}_{\mathrm{SOC}} \geq \delta$$

$$\mathrm{H}_{1}: \mathrm{TLF}_{\mathrm{DEB}} - \mathrm{TLF}_{\mathrm{SOC}} < \delta$$

where TLB$_{\text{DEB}}$ and TLF$_{\text{SOC}}$ are the 12-month TLF rates in the SELUTION DEB group and comparator SOC group, respectively, and δ = 10% is the noninferiority margin. A

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uniform prior was assumed for each group. The SELUTION DEB was to be declared noninferior to the SOC group if the posterior probability of the alternative hypothesis \( H_{1} \) was greater than 97.5%.

The primary analysis set for the primary endpoint was the per-protocol (PP) analysis population. Results are presented for this population unless otherwise specified.

### B. Accountability of PMA Cohort

At the time of database lock, of 418 patients enrolled in the PMA study, 94.7% (396/418) of patients were eligible for analysis at the completion of the primary endpoint, the 12-month post-procedure visit. Table 9 and Figure 5 show patient disposition from randomization through 12 months for the intent-to-treat (ITT) population (all enrolled patients).

Table 9: Patient Disposition Through 12 Months

| | SELUTION SLR PTCA DEB (N=210) | SOC (N=208) | Total (N=418) |
| --- | --- | --- | --- |
| All Randomized | 210 | 208 | 418 |
| \( Active^1 \) | 197 | 199 | 396 |
| \( Discontinued^2 \) | 13 | 9 | 22 |
| Withdrew consent | 1 | 1 | 2 |
| Death | 9 | 5 | 14 |
| Lost to follow-up | 1 | 0 | 1 |
| \( Other^3 \) | 2 | 3 | 5 |
| 1. A patient is active if they have had their procedure, have not discontinued the study, and are alive.2. Within one year of procedure date.3. “Other” includes “site closing and voluntarily withdrawing subject(s)” and “withdrawal with consent for continued electronic medical record and public records review.” | | | |

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Figure 5: Patient Disposition Flow Diagram


*Two non-randomized subjects were treated with the investigational device. These subjects were not enrolled in the study and followed for safety only.

Figure 6: Subject Enrollment Flow Diagram

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### C. Study Population Demographics and Baseline Parameters

The known demographics of the study population are typical for an interventional cardiovascular study performed in the US; information on patient race was not collected. Table 10 presents demographics for the PP analysis set. The treatment arms were well-balanced with no significant differences in any parameters, except for the prevalence of peripheral vascular disease, which was significantly higher in the SELUTION SLR PTCA DEB group compared with the SOC group (19.80% vs. 11.40%; p=0.026). The mean patient age was 69 years and 22% of patients were female.

Given the lower enrollment of female patients and the unknown race of the study participants, a post approval surveillance study will be initiated for an all-comers patient population with specific focus and analyses for these groups. See Section XIV below for details on the post-approval surveillance study.

Table 10: Patient Demographics (PP)

| Patient Characteristic | SELUTION (N=197) | SOC (N=193) | P-value^{1} |
| --- | --- | --- | --- |
| Age (years) Mean ± SD (N) | 68.2 ± 9.0 (197) | 69.6 ± 9.0 (193) | 0.13 |
| >75 | 21.3% (42/197) | 27.5% (53/193) | 0.19 |
| Sex | | | |
| Female | 18.3% (36/197) | 26.0% (50/193) | 0.09 |
| Ethnicity | | | 0.06 |
| Hispanic or Latino | 4.6% (9/197) | 7.8% (15/193) | |
| Non-Hispanic or non-Latino | 70.0% (137/197) | 75.1% (145/193) | |
| Not disclosed | 25.9% (51/197) | 17.1% (33/193) | |
| 1. P-value calculated using ANOVA for continuous variables and Fisher's exact test for categorical variables. | | | |

Table 11 shows the baseline clinical characteristics and cardiac history of the patient population. Approximately 43% of patients had diabetes, 48% had a history of MI, and 33% presented with acute coronary syndrome (ACS). In general, baseline clinical characteristics were comparable between the SELUTION DEB and SOC control groups.

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Table 11: Baseline Clinical Characteristics and Cardiac History (PP)

| Baseline Characteristic | SELUTION (N=197) | SOC (N=193) | P-value |
| --- | --- | --- | --- |
| Body Mass Index (kg/m^{2}) (Mean ± SD (N)) | 28.8 ± 5.5 (196) | 29.4 ± 5.5 (193) | 0.27 |
| **Clinical Characteristics** | | | |
| Smoking History | | | 0.896 |
| Current Smoker | 15.2% (30/197) | 14.0% (27/193) | |
| Ex-Smoker | 42.1% (83/197) | 41.4% (80/193) | |
| Diabetes | 43.1% (85/197) | 42.5% (82/193) | 0.92 |
| Renal Insufficiency | 16.8% (33/197) | 11.4% (22/193) | 0.15 |
| Undergoing Dialysis | 0.5% (1/197) | 1.0% (2/193) | 0.62 |
| Hyperlipidemia | 90.9% (179/197) | 88.6% (171/193) | 0.51 |
| Hypertension | 92.9% (183/197) | 93.3% (180/193) | 1.00 |
| Peripheral Vascular Disease | 19.8% (39/197) | 11.4% (22/193) | 0.03 |
| History of Stroke or TIA | 9.6% (19/197) | 6.2% (12/193) | 0.26 |
| **Cardiac History** | | | |
| Prior MI | 47.7% (94/197) | 48.2% (93/193) | 1.00 |
| Prior STEMI | 21.8% (43/197) | 19.2% (37/193) | 0.46 |
| Prior PCI | 100% (197/197) | 100.0% (193/193) | 1.00 |
| Treated with DES | 90.4% (178/197) | 95.8% (185/193) | 0.07 |
| Treated with Bare Metal Stent (BMS) | 19.3% (38/197) | 13.0% (25/193) | 0.10 |
| Prior CABG | 22.3% (44/197) | 20.7% (40/193) | 0.71 |
| **Baseline Cardiac Status** | | | |
| Angina Status | | | 0.98 |
| Stable Angina | 62.4% (123/197) | 61.7% (119/193) | |
| Unstable Angina | 30.5% (60/197) | 30.0% (58/193) | |
| No Angina (Silent Ischemia) | 7.1% (14/197) | 8.3% (16/193) | |
| CCS classification | | | 0.24 |
| I | 15.2% (30/197) | 18.6% (36/193) | |
| II | 35.0% (69/197) | 26.4% (51/193) | |
| III | 34.0% (67/197) | 39.4% (76/193) | |
| IV | 8.6% (17/197) | 6.7% (13/193) | |
| ACS^{2} | 34.5% (68/197) | 32.1% (62/193) | 0.67 |
| 2. Defined as: Patients with unstable angina or any elevated cardiac enzymes at baseline (any pre-procedure CK, CKMB, or troponin out of normal range). | | | |

Baseline lesion characteristics as assessed by the angiographic core laboratory are summarized in Table 12. Most characteristics were similar between arms, including the presence of two-layer in-stent restenosis (22% in both arms). Severe calcification was observed in 2.59% (5/193) of lesions treated with SOC; no lesions randomized to the SELUTION DEB arm had severe calcification. The number of severely calcified lesions in this study was too small to draw meaningful conclusions about the impact of calcification on the study results.

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Table 12: Baseline Target ISR Lesion Characteristics as Determined by the Angiographic Core Laboratory (PP)

| Measure | SOLUTION (N=197) | SOC (N=193) | P-value^{1} |
| --- | --- | --- | --- |
| **Number of Existing Stent Layers** | | | 0.90 |
| One | 77.7% (153/197) | 78.2% (151/193) | |
| Two | 22.3% (44/197) | 21.8% (42/193) | |
| **Target Lesion Vessel** | | | 0.30 |
| RCA | 34.5% (68/197) | 33.7% (65/193) | |
| LAD | 39.6% (78/197) | 39.4% (76/193) | |
| LCX | 25.4% (50/197) | 23.3% (45/193) | |
| Left Main | 0.5% (1/197) | 3.1% (6/193) | |
| **Minimal Lumen Diameter (mm)** (Mean ± SD (N)) | 0.9 ± 0.35 (108) | 0.9 ± 0.37 (102) | 0.73 |
| **RVD (mm)** (Mean ± SD (N)) | 2.5 ± 0.48 (106) | 2.6 ± 0.50 (101) | 0.06 |
| **RVD** | | | 0.831 |
| RVD ≤ 2.75 mm | 67.0% (132/197) | 65.8% (127/193) | |
| RVD > 2.75 mm | 33.0% (65/197) | 34.2% (66/193) | |
| **% Diameter Stenosis** (Mean ± SD (N)) | 64.6 ± 12.0 (106) | 65.1 ± 11.7 (101) | 0.76 |
| **Pre-Procedure TIMI Flow** | | | 0.21 |
| 0 | 0.0% (0/197) | 1.0% (2/193) | |
| 1 | 0.0% (0/197) | 0.5% (1/193) | |
| 2 | 4.1% (8/197) | 2.1% (4/193) | |
| 3 | 94.9% (187/197) | 94.8% (183/193) | |
| **Severe Calcification** | 0.0% (0/197) | 2.6% (5/193) | 0.02 |
| **Vessel Angulation** | | | 0.19 |
| None or Mild (<45 degrees) | 84.8% (167/197) | 88.6% (171/193) | |
| Moderate (≥45 - <90 degrees) | 14.2% (28/197) | 9.8% (19/193) | |
| Severe (≥90 degrees) | 0.5% (1/197) | 0.0% (0/193) | |
| **Vessel Tortuosity** | | | 1.00 |
| None or Mild | 98.5% (194/197) | 99.5% (192/193) | |
| Moderate | 0.5% (1/197) | 0.0% (0/193) | |
| **Bifurcation Lesion** | 37.6% (74/197) | 35.8% (69/193) | 0.75 |
| **Eccentric** | 55.3% (109/197) | 60.1% (116/193) | 0.35 |
| **Length, mm** | | | |
| Mean ± SD (N) | 12.4 ± 6.0 (196) | 11.9 ± 5.6 (190) | 0.42 |
| **Length** | | | 0.72 |
| Length ≤ 26 mm | 97.0% (191/197) | 96.9% (187/193) | |
| Length > 26 mm | 2.5% (5/197) | 1.6% (3/193) | |
| 1. P-values calculated using ANOVA for continuous variables and Fisher's exact test for categorical variables. | | | |

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Table 13 presents the procedural characteristics for the PP analysis set. Differences between study groups were seen in procedure time, study device length, study device inflation pressure, study device inflation time, prevalence of post-dilatation, post-procedure reference vessel diameter, post-procedure minimal lumen diameter, and post-procedure residual stenosis. Most differences can be attributed to the fundamental procedural differences between stenting and balloon angioplasty.

Procedures in the SELUTION DEB group were shorter on average (54 minutes) compared with the SOC group (60 minutes). Lesion lengths were similar across groups and the average SELUTION DEB device length (21.6 ± 6.0 mm) was similar to the average DES device length (20.4 ± 7.8 mm). The average SELUTION DEB device length was longer than the plain balloon angioplasty device length (15.2 ± 3.6 mm). This is not unexpected, as BA is primarily used for mechanical dilatation of the focal restenotic areas of a lesion while a drug-eluting balloon is designed to apply drug up to 5 mm beyond the lesion. The average inflation pressure was 10.2 ± 3.7 atm in the SELUTION DEB group compared to 16.1 ± 5.6 atm in the SOC group. This is also not unexpected as the rated burst pressure (RBP) of the SELUTION DEB is 12 atm while the RBPs of most control devices was greater. The mean inflation time was 69.2 ± 28.1 seconds for the SELUTION DEB group and 22.9 ± 19.8 seconds for the SOC group. A longer inflation time for the SELUTION DEB group was recommended in the clinical investigation protocol (minimum inflation time of 30 seconds, recommended inflation time of 60 seconds).

Post-dilatation was performed for 1.5% of SELUTION SLR PTCA DEB patients and 48.2% of SOC patients; post-dilation in patients treated with SELUTION occurred only when bailout stenting was needed. All bailout stents were placed due to persistent dissection ≥ NHLBI grade C.

Table 13: Procedural Characteristics (PP)

| Characteristic | SELUTION (N=197) | SOC (N=193) | P-value^{1} |
| --- | --- | --- | --- |
| Non-target lesion(s) treated | 10.7% (21/197) | 11.4% (22/193) | 0.87 |
| Procedure Time (min) (Mean ± SD (N)) | 54.0 ± 23.8 (197) | 60.2 ± 31.4 (193) | 0.03 |
| Pre-dilatation device^{2} | | | 0.43 |
| PTCA | 87.3% (172/197) | 83.9% (162/193) | |
| Cutting Balloon | 28.4% (56/197) | 35.8% (69/193) | |
| Scoring Balloon | 15.7% (31/197) | 17.1% (33/193) | |
| Number of SELUTION devices used | | | |
| 1 | 90.4% (178/197) | N/A | |
| 2 | 8.1% (16/197) | N/A | |
| 3 | 1.0% (2/197) | N/A | |
| Number of control DES used | | | |
| 1 | N/A | 90.9% (140/154) | |
| 2 | N/A | 8.4% (13/154) | |
| 3 | N/A | 0.6% (1/154) | |
| Number of control POBA devices used | | | |

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| Characteristic | SELUTION (N=197) | SOC (N=193) | P-value^{1} |
| --- | --- | --- | --- |
| 1 | N/A | 84.6% (33/39) | |
| 2 | N/A | 10.3% (4/39) | |
| 3 | N/A | 2.6% (1/39) | |
| 4 | N/A | 2.6% (1/39) | |
| Treatment device diameter (mm)^{3} (Mean ± SD (N)) | 3.3 ± 0.4 (197) | 3.3 ± 0.6 (193) | 1.00 |
| Treatment device length (mm)^{3} (Mean ± SD (N)) | 21.6 ± 6.0 (197) | 19.3 ± 7.5 (193) | <0.001 |
| Inflation pressure (atm)^{4} (Mean ± SD (N)) | 10.2 ± 3.7 (197) | 16.1 ± 5.6 (191) | <0.001 |
| Inflation time (s)^{5} (Mean ± SD (N)) | 69.2 ± 28.1 (197) | 22.9 ± 19.8 (190) | <0.001 |
| Post-dilatation performed after stenting | 1.5% (3/197) | 48.2% (93/193) | <0.001 |
| Bailout stenting occurred | 1.5% (3/197) | 0.5% (1/193) | 0.62 |
| 1. P-value calculated using ANOVA for continuous variables and Fisher's exact test for categorical variables. 2. A patient may have had more than one type of pre-treatment device used, so subgroups may sum to more than total. 3. If multiple treatment devices were present in the dataset, the final entry was used to summarize device diameter and length. 4. If multiple treatment devices were present in the dataset, the maximum inflation pressure (atm) was used. 5. If multiple treatment devices were present in the dataset, the inflation times were summed to present total inflation time. | | | |

Use of dual antiplatelet therapy (DAPT; aspirin plus a P2Y$_{12}$ inhibitor) at baseline (pre-procedure), one month, six months, and one year post-procedure is shown in Table 11. Although most patients in the SOC group received a stent, the percentage of patients treated with DAPT was similar between the two groups at each time point.

Table 14: Dual Antiplatelet Medication Usage Through 1 Year, ITT (N=390) Procedural Characteristics (PP)

| Medication | SELUTION (N=197) | SOC (N=193) |
| --- | --- | --- |
| DAPT (Aspirin and one of Clopidogrel, Prasugrel, Ticagrelor, Ticlopidine) | | |
| Baseline | 56.4% (111/197) | 57.0% (110/193) |
| 1 month follow-up | 75.3% (149/197) | 82.9% (160/193) |
| 6 month follow-up | 71.1% (140/197) | 76.7% (148/193) |
| 1 year follow-up | 60.4% (119/197) | 62.7% (121/193) |

### D. Safety and Effectiveness Results

The primary analysis of safety and effectiveness was based on the PP cohort of the 390 patients available for the 12-month evaluation of target lesion failure.

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The study primary endpoint was met. SELUTION DEB was noninferior to SOC as the posterior probability of noninferiority was above the defined success threshold of 97.5% in the PP population. As shown in Table 14, 16.2% (32/197) of patients treated with SELUTION DEB and 14.5% (28/193) of the SOC treated subjects experienced TLF by 1 year. The difference between the two groups was 1.7% with a corresponding 95% Bayesian credible interval of (-5.5%, 8.9%). The upper bound of the credible interval (8.9%) was therefore below the predefined noninferiority margin of 10%.

Table 14: Primary Endpoint Results

| 12-Month TLF | SELUTION (N=197) | SOC (N=193) | Difference [95% Credible Interval] | Posterior Probability of Non-inferiority |
| --- | --- | --- | --- | --- |
| PP | 16.2% (32/197) | 14.5% (28/193) | 1.1% [-5.5%,8.9%] | 98.80% |

Figure 7 depicts Kaplan Meier curves illustrating the percentage of patients free from TLF over time in each treatment group.


Figure 7: Kaplan-Meier Analysis (PP)

Intention-to-treat (ITT) analysis was also performed, and the result again demonstrated noninferiority. Sensitivity analysis of the primary endpoint, and multiple analyses for missing data, were conducted and confirmed the robustness of the primary analysis set findings. Some data was missing at 12 months follow-up for 5.7% (12/210) of patients in the SELUTION DEB group and 6.7% (14/208) of patients in the SOC group.

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Sensitivity analyses were conducted for the primary endpoint using a Bayesian analysis on the mPP cohort and on the ITT cohort after using a logistic regression model to account for the missing data. All analyses found that the SELUTION DEB was non-inferior to the SOC with a posterior probability of non-inferiority of >97%.

The hypothesis-driven secondary endpoint, incidence of TLF at 12 months comparing the SELUTION DEB arm to the DES cohort of the SOC arm among the cohort of patients with one previous layer of stent, was not met. As shown in Table 15, in the SELUTION DEB group, 14.2% (22/155) of patients with one previous stent layer experienced TLF within 12 months, compared to 6.5% (9/138) of DES patients with one previous stent layer in the SOC control group. The difference between the two groups was 7.5% with a corresponding 95% Bayesian credible interval of (0.6%, 14.6%). The posterior probability of non-inferiority was 76.1%, which was below the predefined success threshold of 95%. Similar results were seen in the ITT analysis population.

Table 15: Hypothesis-Driven Secondary Endpoint

| 12-Month TLF | SELUTION (1 Previous Stent Layer) (N=155) | DES (1 Previous Stent Layer) (N=138) | Difference [95% Credible Interval] | Posterior Probability of Non-inferiority |
| --- | --- | --- | --- | --- |
| PP | 14.2% (22/155) | 6.5% (9/138) | 7.5% [0.6%, 14.6%] | 76.1% |

The intent of this analysis was to directly compare outcomes of the SELUTION DEB to those of implanting an additional DES in patients with ISR. However, as investigators chose whether patients in the SOC arm were treated with DES or POBA, the two groups in this analysis were not randomized against each other. While it was anticipated that POBA would primarily be used to treat patients with more than one previous stent layer, 20 of the 39 patients chosen to be treated with POBA in the SOC group before the POBA enrollment cap was reached had only one previous stent layer.

# 1. Safety Results

The analysis of safety was based on the PP cohort of 390 patients available for the 12-month evaluation. The key safety outcomes for this study for all currently available timepoints are presented below in Table 16. Serious adverse events (SAEs) that were present at a rate of ≥0.95% are reported in Table 17.

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Table 16: Summary of Secondary Safety Endpoints by Timepoint (PP)

| Secondary Endpoints | SELUTION (N=197) | SOC (N=193) |
| --- | --- | --- |
| **In-Hospital** | | |
| Death | 0.0% (0/197) | 0.0% (0/193) |
| MI | 1.5% (3/197) | 1.0% (2/193) |
| Bleeding^{1} | 2.0% (4/197) | 2.6% (5/193) |
| **1-Month Follow-up** | | |
| Death | 0.0% (0/197) | 0.0% (0/193) |
| MI | 2.5% (5/197) | 2.6% (5/193) |
| Bleeding^{1} | 2.0% (4/197) | 3.6% (7/193) |
| **6-Month Follow-up** | | |
| Death | 0.5% (1/197) | 0.0% (0/193) |
| Cardiovascular death | 0.5% (1/197) | 0.0% (0/193) |
| Non-cardiovascular death | 0.0% (0/197) | 0.0% (0/193) |
| MI | 6.1% (12/197) | 4.7% (9/193) |
| Bleeding^{1} | 5.1% (10/197) | 5.7% (11/193) |
| **1-Year Follow-up** | | |
| Death | 2.5% (5/197) | 1.6% (3/193) |
| Cardiovascular death | 2.0% (4/197) | 1.6% (3/193) |
| Non-cardiovascular death | 0.5% (1/197) | 0.0% (0/193) |
| MI | 8.1% (16/197) | 6.7% (13/193) |
| Bleeding^{1} | 7.6% (15/197) | 9.3% (18/193) |
| Stent thrombosis | 2.0% (4/197) | 2.1% (4/193) |
| 1. Bleeding according to Bleeding Academic Research Consortium (BARC) classification 2-5. | | |

### Adverse effects that occurred in the PMA clinical study:

There were 432 adverse events reported in 143 patients in the SELUTION DEB group, compared to 395 adverse events reported in 134 patients in the SOC control group through 12 months of follow up. The frequency and nature of adverse events observed in the SELUTION DEB group were similar to those observed for the SOC control group.

Serious adverse events (SAEs) that occurred in the SELUTION4ISR study impacting ≥1.0% of patients in either group are presented in Table 17. Serious adverse events are defined as events that resulted in death, were life-threatening, required inpatient hospitalization or caused prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, or required intervention to prevent life-threatening illness or injury or permanent impairment. Adverse events were coded using MedDRA preferred terms. Only categories of serious adverse events occurring at a rate of ≥1.0% in either treatment group are reported; thus, the listed events may not add up to the total amount in each group or overall.

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Table 17: Patients with Serious Adverse Events Through 1 Year with Event Rate ≥1.0% (ITT)

| SAEs to 365 Days | MedDRA High-Level Group Term | MedDRA Preferred Term | SOLUTION (N=210) | SOC (N=208) |
| --- | --- | --- | --- | --- |
| Any SAE | Total | Total | 37.1% (78/210) | 43.8% (91/208) |
| Cardiac disorders | Total | Total | 21.9% (46/210) | 24.0% (50/208) |
| | Coronary artery disorders | Total | 18.1% (38/210) | 17.8% (37/208) |
| | | Angina pectoris | 5.7% (12/210) | 8.2% (17/208) |
| | | Acute myocardial infarction | 7.1% (15/210) | 5.3% (11/208) |
| | | Angina unstable | 3.8% (8/210) | 1.9% (4/208) |
| | | Arteriosclerosis coronary artery | 1.0% (2/210) | 2.4% (5/208) |
| | | Coronary artery disease | 1.0% (2/210) | 1.9% (4/208) |
| | | Myocardial infarction | 1.0% (2/210) | 1.0% (2/208) |
| | | Coronary artery dissection | 1.0% (2/210) | 0.5% (1/208) |
| | | Coronary artery stenosis | 1.0% (2/210) | 0.5% (1/208) |
| | | Myocardial ischaemia | 1.0% (2/210) | 0.0% (0/208) |
| | Heart failures | Total | 4.8% (10/210) | 2.4% (5/208) |
| | | Cardiac failure congestive | 1.9% (4/210) | 1.4% (3/208) |
| | | Cardiac failure | 1.9% (4/210) | 0.5% (1/208) |
| | | Cardiac failure acute | 1.0% (2/210) | 0.5% (1/208) |
| | | Cardiac failure chronic | 1.0% (2/210) | 0.0% (0/208) |
| | Cardiac arrhythmias | Total | 4.8% (10/210) | 6.7% (14/208) |
| | | Atrial fibrillation | 3.8% (8/210) | 1.4% (3/208) |
| | | Ventricular tachycardia | 0.0% (0/210) | 2.4% (5/208) |
| | | Cardiac arrest | 0.5% (1/210) | 1.0% (2/208) |
| | | Atrial flutter | 0.0% (0/210) | 1.0% (2/208) |
| | | Atrioventricular block complete | 0.0% (0/210) | 1.0% (2/208) |
| | | Bradycardia | 1.0% (2/210) | 0.0% (0/208) |
| | Cardiac valve disorders | Total | 0.0% (0/210) | 1.0% (2/208) |
| | | Aortic valve stenosis | 0.0% (0/210) | 1.0% (2/208) |

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| SAEs to 365 Days | MedDRA High-Level Group Term | MedDRA Preferred Term | SOLUTION (N=210) | SOC (N=208) |
| --- | --- | --- | --- | --- |
| Respiratory, thoracic and mediastinal disorders | Total | Total | 6.2% (13/210) | 4.3% (9/208) |
| | Respiratory disorders NEC | Total | 5.2% (11/210) | 2.4% (5/208) |
| | | Respiratory failure | 2.4% (5/210) | 0.5% (1/208) |
| | | Dyspnoea | 1.9% (4/210) | 0.0% (0/208) |
| | | Acute respiratory failure | 0.0% (0/210) | 1.4% (3/208) |
| | Bronchial disorders (excl neoplasms) | Total | 1.0% (2/210) | 0.5% (1/208) |
| | | Chronic obstructive pulmonary disease | 1.0% (2/210) | 0.5% (1/208) |
| Infections and infestations | Total | Total | 4.3% (9/210) | 4.8% (10/208) |
| | Infections – pathogen unspecified | Total | 2.9% (6/210) | 3.4% (7/208) |
| | | Urinary tract infection | 1.0% (2/210) | 1.4% (3/208) |
| | | Pneumonia | 1.0% (2/210) | 0.5% (1/208) |
| | | Septic shock | 0.5% (1/210) | 1.0% (2/208) |
| | Bacterial infectious disorders | Total | 1.9% (4/210) | 1.0% (2/208) |
| | Viral infectious disorders | Total | 0.0% (0/210) | 1.0% (2/208) |
| Injury, poisoning and procedural complications | Total | Total | 5.2% (11/210) | 7.2% (15/208) |
| | Procedural related injuries and complications NEC | Total | 4.8% (10/210) | 4.3% (9/208) |
| | | Coronary artery restenosis | 0.5% (1/210) | 1.4% (3/208) |
| | | Vascular access site haematoma | 1.0% (2/210) | 0.5% (1/208) |
| | | Vascular access site haemorrhage | 0.5% (1/210) | 1.0% (2/208) |
| | Injuries NEC | Total | 0.5% (1/210) | 1.4% (3/208) |
| | Bone and joint injuries | Total | 0.0% (0/210) | 1.4% (3/208) |
| | | Femur fracture | 0.0% (0/210) | 1.0% (2/208) |
| General disorders and administration site conditions | Total | Total | 6.2% (13/210) | 5.3% (11/208) |
| | General system disorders NEC | Total | 2.4% (5/210) | 3.8% (8/208) |
| | | Chest pain | 1.4% (3/210) | 3.4% (7/208) |
| | | Non-cardiac chest pain | 1.0% (2/210) | 0.0% (0/208) |
| | Complications associated with device | Total | 2.9% (6/210) | 1.4% (3/208) |
| | | Vascular stent stenosis | 2.4% (5/210) | 1.4% (3/208) |

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| SAEs to 365 Days | MedDRA High-Level Group Term | MedDRA Preferred Term | SOLUTION (N=210) | SOC (N=208) |
| --- | --- | --- | --- | --- |
| Nervous system disorders | Total | Total | 4.3% (9/210) | 5.3% (11/208) |
| | Neurological disorders NEC | Total | 1.0% (2/210) | 3.4% (7/208) |
| | | Syncope | 0.5% (1/210) | 1.9% (4/208) |
| | Central nervous system vascular disorders | Total | 2.9% (6/210) | 1.4% (3/208) |
| | | Cerebrovascular accident | 1.9% (4/210) | 0.0% (0/208) |
| | Neuromuscular disorders | Total | 1.0% (2/210) | 0.0% (0/208) |
| Gastrointestinal disorders | Total | Total | 3.3% (7/210) | 4.8% (10/208) |
| | Gastrointestinal haemorrhages NEC | Total | 1.4% (3/210) | 1.9% (4/208) |
| | | Rectal haemorrhage | 1.0% (2/210) | 1.0% (2/208) |
| | | Gastrointestinal haemorrhage | 0.0% (0/210) | 1.0% (2/208) |
| | Gastrointestinal stenosis and obstruction | Total | 0.5% (1/210) | 1.9% (4/208) |
| | | Small intestinal obstruction | 0.5% (1/210) | 1.9% (4/208) |
| | Gastrointestinal signs and symptoms | Total | 1.0% (2/210) | 0.5% (1/208) |
| Renal and urinary disorders | Total | Total | 3.3% (7/210) | 3.8% (8/208) |
| | Renal disorders (excl nephropathies) | Total | 2.9% (6/210) | 2.4% (5/208) |
| | | Acute kidney injury | 1.4% (3/210) | 1.9% (4/208) |
| | Urolithiases | Total | 0.5% (1/210) | 1.0% (2/208) |
| | | Nephrolithiasis | 0.5% (1/210) | 1.0% (2/208) |
| Vascular disorders | Total | Total | 4.8% (10/210) | 3.4% (7/208) |
| | Decreased and nonspecific blood pressure disorders and shock | Total | 2.4% (5/210) | 0.5% (1/208) |
| | | Hypotension | 1.4% (3/210) | 0.5% (1/208) |
| | | Orthostatic hypotension | 1.0% (2/210) | 0.0% (0/208) |
| | Arteriosclerosis, stenosis, vascular insufficiency and necrosis | Total | 1.9% (4/210) | 1.0% (2/208) |
| | | Aortic stenosis | 1.0% (2/210) | 0.0% (0/208) |
| | Vascular hypertensive disorders | Total | 0.5% (1/210) | 1.0% (2/208) |
| Investigations | Total | Total | 2.4% (5/210) | 1.0% (2/208) |
| | Enzyme investigations NEC | Total | 1.4% (3/210) | 0.5% (1/208) |
| | | Troponin increased | 1.0% (2/210) | 0.5% (1/208) |

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| SAEs to 365 Days | MedDRA High-Level Group Term | MedDRA Preferred Term | SOLUTION (N=210) | SOC (N=208) |
| --- | --- | --- | --- | --- |
| Metabolism and nutrition disorders | Total | Total | 2.4% (5/210) | 1.0% (2/208) |
| | Glucose metabolism disorders (incl diabetes mellitus) | Total | 1.0% (2/210) | 0.5% (1/208) |
| | Diabetic complications | Total | 1.0% (2/210) | 0.0% (0/208) |
| | | Diabetic ketoacidosis | 1.0% (2/210) | 0.0% (0/208) |
| Neoplasms benign, malignant and unspecified (incl cysts and polyps) | Total | Total | 1.4% (3/210) | 1.9% (4/208) |
| | Gastrointestinal neoplasms malignant and unspecified | Total | 1.0% (2/210) | 0.0% (0/208) |
| Blood and lymphatic system disorders | Total | Total | 1.4% (3/210) | 0.5% (1/208) |
| | Anaemias nonhaemolytic and marrow depression | Total | 1.4% (3/210) | 0.5% (1/208) |
| | | Anaemia | 1.4% (3/210) | 0.0% (0/208) |
| Surgical and medical procedures | Total | Total | 2.4% (5/210) | 0.5% (1/208) |
| | Arterial therapeutic procedures (excl aortic) | Total | 1.0% (2/210) | 0.0% (0/208) |
| | | Arterial revascularisation | 1.0% (2/210) | 0.0% (0/208) |
| Musculoskeletal and connective tissue disorders | Total | Total | 1.4% (3/210) | 1.0% (2/208) |
| | Musculoskeletal and connective tissue disorders NEC | Total | 1.4% (3/210) | 0.5% (1/208) |
| Skin and subcutaneous tissue disorders | Total | Total | 1.0% (2/210) | 0.5% (1/208) |
| | Skin and subcutaneous tissue disorders NEC | Total | 1.0% (2/210) | 0.0% (0/208) |
| Eye disorders | Total | Total | 0.5% (1/210) | 1.0% (2/208) |
| | Anterior eye structural change, deposit and degeneration | Total | 0.0% (0/210) | 1.0% (2/208) |
| | | Cataract | 0.0% (0/210) | 1.0% (2/208) |
| Psychiatric disorders | Total | Total | 1.0% (2/210) | 0.0% (0/208) |

## 2. Effectiveness Results

The primary analysis of effectiveness, which was a component of the primary endpoint, was based on the PP cohort of 390 evaluable patients at the 12-month time point as described above. Additional effectiveness outcomes, including components of the primary endpoints as well as procedural endpoints, are presented in Table 18.

Patients with available angiographic core lab data were analyzed for device, lesion, and/or procedure success. Device success was defined as attainment of <30% residual stenosis of the target lesion using the assigned study device only. Lesion

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success was defined as attainment of <30% residual stenosis of the target lesion using any percutaneous method. Procedure success was defined as the attainment of <30% residual stenosis of the target lesion using the assigned study device only without the occurrence of in-hospital major adverse cardiac events (all-cause death, MI, or clinically driven TLR). Acute success rates were comparable in both groups and as expected in this in-stent restenosis population.

The rate of clinically driven target lesion revascularization (TLR) at 12 months was similar between groups (12.7% versus 12.4% in the SELUTION DEB and SOC arms, respectively.)

Table 18: Summary of Effectiveness Outcomes

| | **SELUTION SLR PTCA DEB (N=197)** | **SOC (N=193)** |
| --- | --- | --- |
| **Acute Success** | | |
| Device Success | 89.9% (152/169) | 90.4% (122/135) |
| Lesion Success | 91.1% (154/169) | 90.4% (122/135) |
| Procedure Success | 88.8% (150/169) | 88.2% (119/135) |
| **Revascularization Events to 1 Month** | | |
| TVR | 1.0% (2/197) | 1.6% (3/193) |
| TLR | 0.5% (1/197) | 1.0% (2/193) |
| **Revascularization Events to 6 Months** | | |
| TVR | 7.1% (14/197) | 5.7% (11/193) |
| TLR | 5.1% (10/197) | 5.2% (10/193) |
| **Revascularization Events to 1 Year** | | |
| TVR | 15.8% (31/197) | 13.5% (26/193) |
| TLR | 12.7% (25/197) | 12.4% (24/193) |

### Imaging (Angiographic and OCT) Sub-study Results

The trial enrolled 60 of the randomized subjects in an angiographic and optical coherence tomography (OCT) sub-study. Subjects in the imaging sub-study had to meet the same inclusion and exclusion criteria as the main study subjects. The baseline and lesion characteristics of this sub-study were similar to the full study population. At the 12-month follow-up visit, several secondary endpoints were assessed by angiography, including binary angiographic restenosis, in-stent and in-segment percent diameter stenosis, in-stent and in-segment late lumen loss (LLL), and in-stent and in-segment MLD. OCT was used to evaluate neointimal hyperplasia, neo-atherosclerosis, and stent underexpansion (Table 19). Binary angiographic restenosis was identified in more patients treated with the SELUTION DEB (31.2%, 10/32) than the SOC control (18.8%, 3/16) although these differences were not statistically significant. Similarly, neoatherosclerosis was detected by OCT in more patients treated with the SELUTION DEB (26.9%, 7/26) than the SOC control (7.7%, 1/13) although these results were likewise not statistically significant.

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Table 19: Secondary Imaging Endpoints at 12 Months

| Secondary Endpoint | SELUTION SLR PTCA DEB (N=36) | SOC (N=24) |
| --- | --- | --- |
| Treated segment percent diameter stenosis Mean +/- SD (N) | 37.1 +/- 23.5 (32) | 27.7 +/- 18.3 (16) |
| Binary angiographic restenosis % (n/N) | 31.2% (10/32) | 18.8% (3/16) |
| Treated segment late lumen loss (LLL) Mean +/- SD (N) | 0.6 +/- 0.6 (32) | 0.5 +/- 0.5 (16) |
| Treated segment minimum lumen diameter (MLD) Mean +/- SD (N) | 1.6 +/- 0.6 (32) | 1.7 +/- 0.9 (18) |
| OCT study assessments | | |
| Neointimal hyperplasia | 57.7% (15/26) | 61.5% (8/13) |
| Neoatherosclerosis | 26.9% (7/26) | 7.7% (1/13) |
| Underexpansion | 15.4% (4/26) | 23.1% (3/13) |

### 3. Subgroup Analyses

The following baseline characteristics were pre-specified and evaluated for potential association with safety and effectiveness outcomes:

- 2 stent layers ISR vs 1 stent ISR (present in lesion prior to procedure)
- BMS ISR vs. no BMS ISR
- DES ISR vs. no DES ISR
- Diabetes vs. No Diabetes
- RVD ≤ 2.75 mm vs. >2.75 mm
- Lesion length ≤ 26 mm vs. > 26 mm
- Focal vs diffuse lesions
- ISR (< 1 year after stent implant vs > 1 year after stent implant)
- COVID-19 positive vs negative

The following additional baseline characteristics were not pre-specified but were also evaluated for potential association with safety and effectiveness outcomes:

- Age
- Sex
- Ethnicity

Information on patient race was not collected during the study and therefore no presentation of outcomes by race is possible.

The SELUTION4ISR Study was not designed or powered to study safety or effectiveness of the SELUTION SLR PTCA DEB versus SOC in these subgroups, so these analyses are considered hypothesis-generating. The primary endpoint results for

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these subgroups are included in Table 20 below.

Subgroup analyses of the primary endpoint demonstrated no significant interactions with treatment effect.

Table 20: Primary Endpoint Subgroup Analyses (PP)

| Subgroup | SOLUTION DEB (N=197) | SOC (N=193) | P-value for Interaction^{1} |
| --- | --- | --- | --- |
| **Stent Layers** | | | 0.167 |
| 1 | 14.2% (22/155) | 10.2% (16/157) | |
| 2 | 23.8% (10/42) | 33.3% (12/36) | |
| **BMS ISR** | | | 0.878 |
| Yes | 10.5% (4/38) | 8.0% (2/25) | |
| No | 17.7% (28/158) | 15.6% (26/167) | |
| **DES ISR** | | | 0.359 |
| Yes | 16.8% (30/178) | 15.1% (28/185) | |
| No | 11.1% (2/18) | 0.0% (0/8) | |
| **Diabetes** | | | 0.492 |
| Yes | 25.9% (22/85) | 20.7% (17/82) | |
| No | 8.9% (10/112) | 9.9% (11/111) | |
| **RVD** | | | 0.341 |
| > 2.75mm | 16.9% (11/65) | 10.6% (7/66) | |
| ≤ 2.75mm | 15.9% (21/132) | 16.5% (21/127) | |
| **Lesion Length** | | | 0.433 |
| > 26mm | 20.0% (1/5) | 0.0% (0/3) | |
| ≤ 26mm | 16.2% (31/192) | 14.7% (28/190) | |
| **Lesion Type** | | | 0.528 |
| Focal | 16.4% (12/73) | 17.1% (13/76) | |
| Diffuse | 8.8% (5/57) | 14.0% (7/50) | |
| **ISR** | | | 0.668 |
| < 1 year | 21.7% (13/60) | 20.6% (13/63) | |
| ≥ 1 year | 14.0% (17/121) | 10.7% (13/122) | |
| **Covid-19** | | | N/A |
| Yes | N/A | 0.0% (0/1) | |
| No | 20.6% (7/34) | 11.5% (3/26) | |
| **Age** | | | 0.513 |
| ≤ 75 years | 16.1% (25/155) | 12.9% (18/140) | |
| > 75 years | 16.7% (7/42) | 18.9% (10/53) | |
| **Sex** | | | 0.891 |
| Male | 16.2% (26/161) | 14.7% (21/143) | |
| Female | 16.7% (6/36) | 14.0% (7/50) | |
| **Ethnicity** | | | 0.441 |
| Hispanic or Latino | 0.0% (0/9) | 13.3% (2/15) | |
| Not Hispanic or Latino | 19.7% (27/137) | 15.9% (23/145) | |
| 1. Interaction was assessed using the Breslow-Day test. | | | |

PMA P250041: FDA Summary of Safety and Effectiveness Data

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# SOC Subgroup (POBA or DES)

Primary endpoint results broken down by SOC subgroup (DES and POBA) in patients with 1 or 2 existing stent layers are shown in Table 21. Investigators were permitted to choose DES or POBA for patients randomized to the control group until the 20% POBA enrollment cap was reached.

Table 21: 12-Month TLF in the SELUTION DEB, POBA, and DES

| Endpoint | SELUTION DEB | SOC | SOC: POBA | SOC: DES |
| --- | --- | --- | --- | --- |
| **One-Layer ISR** |…