← Product Code [ONU](/productcode/ONU) · P140010S037

# IN.PACT Admiral Paclitaxel-Coated Percutaneous-Transluminal Angioplasty Balloon Catheter (P140010S037)

_Medtronic, Inc. · ONU · Apr 19, 2018 · Cardiovascular · APPR_

**Canonical URL:** https://fda.innolitics.com/device/P140010S037

## Device Facts

- **Applicant:** Medtronic, Inc.
- **Product Code:** [ONU](/productcode/ONU.md)
- **Decision Date:** Apr 19, 2018
- **Decision:** APPR
- **Device Class:** Class 3
- **Review Panel:** Cardiovascular
- **Attributes:** Therapeutic, Real-World Evidence

## Real-World Evidence

| Submission | Device | Sponsor | RWD Sources | RWE Use Summary | Key Tags |
| --- | --- | --- | --- | --- | --- |
| P140010S037 · Apr 19, 2018 | IN.PACT Admiral Paclitaxel-Coated Percutaneous-Transluminal Angioplasty Balloon Catheter | Medtronic, Inc. | IN.PACT Global DCB Study database (observational, multicenter, non-randomized clinical study) | The sponsor used a retrospective sub-cohort analysis of 227 patients from the existing IN.PACT Global DCB study to support the expansion of the device indication to treat long lesions (180-360 mm). | Long Lesion; Post-hoc analysis; Observational study; Retrospective sub-cohort |

### Clinical Evidence

| Study Design | Population | Comparator | Key Endpoints |
| --- | --- | --- | --- |
| IN.PACT Global DCB Long Lesion Sub-Cohort Clinical Evaluation; Observational, non-randomized, multicenter, single-arm evaluation (post-hoc sub-cohort analysis); Follow-up/Duration: Up to 5 years; key data reported at 12 and 24 months; Study Period: June 6, 2012 to December 16, 2013 | Patients with de novo, restenotic, or in-stent restenotic long lesions (>180 mm) in the superficial femoral and/or popliteal artery; Sample Size: 227; Number of Sites: 28 non-US investigational sites | Not applicable for this study | Primary Safety: Freedom from device/procedure-related death (30 days), major target limb amputation, and CD-TVR (12 months). Primary Effectiveness: Primary Patency (12 months) defined as freedom from CD-TLR and restenosis (PSVR ≤2.4). |

## Indications for Use

The IN.PACT™ Admiral™ Paclitaxel-coated PTA Balloon Catheter is indicated for percutaneous transluminal angioplasty, after appropriate vessel preparation, of de novo, restenotic, or in-stent restenotic lesions with lengths up to 360 mm in superficial femoral or popliteal arteries with reference vessel diameters of 4-7 mm.

## Device Story

The IN.PACT Admiral DCB is an over-the-wire balloon catheter used for percutaneous transluminal angioplasty (PTA) in peripheral arteries. The device features a balloon coated with FreePac, a proprietary formulation of paclitaxel (3.5 µg/mm²) and a hydrophilic urea excipient. During the procedure, the physician performs vessel preparation followed by balloon inflation; the excipient facilitates the transfer of paclitaxel into the arterial wall. The drug acts by stabilizing microtubules to inhibit neointimal hyperplasia and restenosis. The device is used in a clinical setting by physicians to treat long lesions (up to 360 mm) in the superficial femoral or popliteal arteries. By combining mechanical dilatation with local drug delivery, the device aims to improve vessel patency, reduce the need for reintervention, and improve patient walking distance and clinical symptoms compared to standard PTA.

## Clinical Evidence

Evidence from the IN.PACT Global DCB Long Lesion Sub-Cohort (n=227), an observational, multicenter, single-arm study. Primary safety endpoint (freedom from device/procedure-related death at 30 days, major amputation, and CD-TVR at 12 months) was 92.9%. Primary effectiveness endpoint (primary patency at 12 months) was 64.9%. Secondary endpoints included 80.9% primary sustained clinical improvement at 12 months and 7.1% CD-TLR rate. Results were sustained at 24 months with 80.3% freedom from CD-TLR. No major target limb amputations were reported at 12 months.

## Technological Characteristics

Over-the-wire balloon catheter; 0.035" guidewire compatible; 5F-7F sheath compatibility. Balloon lengths 20-150 mm; diameters 4.0-7.0 mm. Coating: FreePac (paclitaxel 3.5 µg/mm² + urea excipient). Mechanical dilatation principle with secondary pharmacological inhibition of restenosis via paclitaxel microtubule stabilization. Sterilized device.

## Regulatory Identification

A drug-eluting peripheral transluminal angioplasty catheter is a combination product intended for balloon dilatation of peripheral vasculature to establish or maintain patency. A drug-eluting PTA catheter delivers a drug to the vessel as part of the angioplasty procedure and is intended to inhibit restenosis. Intended to provide percutaneous transluminal angioplasty of lesions in peripheral arteries including iliac, popliteal, femoral, and iliofemoral.

## Submission Summary (Full Text)

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>
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# SUMMARY OF SAFETY AND EFFECTIVENESS DATA (SSED)

## I. GENERAL INFORMATION

|  Device Generic Name: | Drug-Coated Balloon (DCB) Percutaneous Transluminal Angioplasty Catheter  |
| --- | --- |
|  Device Trade Name: | IN.PACT™ Admiral™ Paclitaxel-Coated Percutaneous Transluminal Angioplasty (PTA) Balloon Catheter  |
|  Device Procode: | ONU  |
|  Applicant's Name and Address: | Medtronic Vascular, Inc. 3576 Unocal Place Santa Rosas, CA 95403  |
|  Date(s) of Panel Recommendation: | None  |
|  Premarket Approval Application (PMA) Number: | P140010/S037  |
|  Date of FDA Notice of Approval: | April 19, 2018  |

The original PMA (P140010) was approved on December 30, 2014 and is indicated for percutaneous transluminal angioplasty, after pre-dilatation, of *de novo* or restenotic lesions up to 180 mm in length in native superficial femoral or popliteal arteries with reference vessel diameters of 4-7 mm. In addition, P140010/S015, a panel track supplement, was approved on September 7, 2016 to support an indication for in-stent restenotic lesions. The SSEDs to support both the indication in the Original P140010 and in P140010/S015 are available on the CDRH website (https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfPMA/pma.cfm) and are incorporated by reference here. The current supplement was submitted to expand the indication for the IN.PACT™ Admiral™ Paclitaxel-Coated Percutaneous Transluminal Angioplasty (PTA) Balloon Catheter to treat lesions up to 360 mm in length.

## II. INDICATIONS FOR USE

The IN.PACT™ Admiral™ Paclitaxel-coated PTA Balloon Catheter is indicated for percutaneous transluminal angioplasty, after appropriate vessel preparation, of *de novo*, restenotic, or in-stent restenotic lesions with lengths up to 360 mm in superficial femoral or popliteal arteries with reference vessel diameters of 4-7 mm.

## III. CONTRAINDICATIONS

The IN.PACT Admiral DCB is contraindicated for use in:

- coronary arteries, renal arteries, and supra-aortic/cerebrovascular arteries

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• patients who cannot receive recommended antiplatelet and/or anticoagulant therapy
• patients judged to have a lesion that prevents complete inflation of an angioplasty balloon or proper placement of the delivery system
• patients with known allergies or sensitivities to paclitaxel
• women who are breastfeeding, pregnant, or are intending to become pregnant, or men intending to father children. It is unknown whether paclitaxel will be excreted in human milk and whether there is a potential for adverse reaction in nursing infants from paclitaxel exposure.

# IV. WARNINGS AND PRECAUTIONS

The warnings and precautions can be found in the IN.PACT™ Admiral™ Paclitaxel-coated Percutaneous Transluminal Angioplasty Balloon Catheter labeling.

# V. DEVICE DESCRIPTION

The IN.PACT Admiral DCB is an over-the-wire balloon catheter with a drug coated balloon at the distal tip (see Figure 1).

Figure 1: Schematic of the IN.PACT Admiral DCB

![img-0.jpeg](img-0.jpeg)

# PTA Catheter Component

The IN.PACT Admiral DCB will be available in balloon lengths ranging from 20 mm to 150 mm, balloon diameters ranging from 4.0 mm to 7.0 mm, and will be offered in catheter effective lengths of 80 cm and 130 cm. The IN.PACT Admiral DCB is compatible with 0.035" guidewires. Devices are compatible with 5F (for the 4.0 mm balloon diameter), 6F (for the 5.0-6.0 mm balloon diameters), and 7F (for the 7 mm balloon diameter) introducer sheaths. The IN.PACT Admiral DCB product matrix is provided in Table 1.

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**Table 1: IN.PACT Admiral DCB Product Matrix**

|  Diameter (mm) | Balloon Length (mm) |   |   |   |   |   | Balloon Wrap  |
| --- | --- | --- | --- | --- | --- | --- | --- |
|   |  20 | 40 | 60 | 80 | 120 | 150  |   |
|  4.0 | ✓ | ✓ | ✓ | ✓ | ✓ | ✓ | 3 folds  |
|  5.0 | ✓ | ✓ | ✓ | ✓ | ✓ | ✓ | 6 folds  |
|  6.0 | ✓ | ✓ | ✓ | ✓ | ✓ | ✓  |   |
|  7.0 | ✓ | ✓ | ✓ | ✓ | --- | ---  |   |

### Drug Components

The IN.PACT Admiral DCB is coated with the FreePac® coating solution, which is a proprietary coating with a nominal drug dose density of 3.5 µg of paclitaxel per mm² of the expanded balloon surface. The FreePac coating contains a hydrophilic excipient (urea) which facilitates the release and transfer of the active pharmaceutical ingredient (paclitaxel) into the arterial vessel wall. Additionally, the FreePac solution contains two (2) solvents, tetrahydrofuran (THF) and pyrogen-free water, which are used during the FreePac formulation process but evaporate off the balloon surface after the FreePac coating is applied.

Based on the nominal drug dose density of 3.5 µg/mm², the total amount of paclitaxel for each balloon size is provided in Table 2.

**Table 2: Nominal Paclitaxel Content by Balloon Size**

|  IN.PACT Admiral DCB Balloon Size (mm) | Nominal Paclitaxel Content (µg)  |
| --- | --- |
|  4.0 x 20 | 1089  |
|  4.0 x 40 | 1969  |
|  4.0 x 60 | 2848  |
|  4.0 x 80 | 3728  |
|  4.0 x 120 | 5487  |
|  4.0 x 150 | 6807  |
|  5.0 x 20 | 1454  |
|  5.0 x 40 | 2553  |
|  5.0 x 60 | 3653  |
|  5.0 x 80 | 4752  |
|  5.0 x 120 | 6951  |
|  5.0 x 150 | 8601  |
|  6.0 x 20 | 1850  |
|  6.0 x 40 | 3170  |
|  6.0 x 60 | 4489  |
|  6.0 x 80 | 5809  |

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|  IN.PACT Admiral DCB Balloon Size (mm) | Nominal Paclitaxel Content (μg)  |
| --- | --- |
|  6.0 x 120 | 8448  |
|  6.0 x 150 | 10427  |
|  7.0 x 20 | 2279  |
|  7.0 x 40 | 3819  |
|  7.0 x 60 | 5358  |
|  7.0 x 80 | 6897  |

# Active Pharmaceutical Ingredient (API) - Paclitaxel

The API of the IN.PACT Admiral DCB is paclitaxel. Paclitaxel is a FDA-approved drug, indicated for the treatment of multiple cancers including breast and ovarian cancer. The principal mechanism by which paclitaxel inhibits neointimal growth is through the stabilization of microtubules by preventing their depolymerization during the final G2/M phase of cell division. The CAS Registry number of paclitaxel is 33069-62-4. The chemical name is (2aR-(2aa,4β,4aβ,6β,9α(α R*,βS*),11α,12α,12ba))-β-(Benzoylamino)-α-hydroxybenzenepropanoic acid 6,12b-bis(acetyloxy)-12-(benzoyloxy)-2a,3,4,4a,5,6,9,10,11,12,12a,12b-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 and the chemical formula is C47H51NO14. The chemical structure of paclitaxel is illustrated in Figure 2 below.

Figure 2: The Chemical Structure of Paclitaxel

![img-1.jpeg](img-1.jpeg)

# Excipient

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

Figure 3: The Chemical Structure of Urea

![img-2.jpeg](img-2.jpeg)

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# Mechanism of Action

The IN.PACT Admiral DCB's primary mode of action is mechanical dilatation of de novo, restenotic, or in-stent restenotic lesions by means of percutaneous transluminal angioplasty, with a secondary action of inhibition of restenosis (caused by the proliferative response to the PTA) through the application of paclitaxel to the vessel wall.

# VI. ALTERNATIVE PRACTICES AND PROCEDURES

There are several other alternatives for the treatment of de novo, restenotic, and in-stent restenotic lesions in the superficial femoral and proximal popliteal arteries:

- Non-invasive (conservative) treatment (risk factor modification, exercise, and/or drug therapy)
- Minimally invasive treatment (balloon angioplasty, bare metal or drug-eluting stent, cutting/scoring balloons, or atherectomy)
- Surgical treatment (surgical bypass)

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

# VII. MARKETING HISTORY

The IN.PACT Admiral DCB received CE Mark on March 12, 2009, and the original PMA (P140010) was approved on December 30, 2014. On September 7, 2016 P140010/S015 was approved by FDA to expand the indication for use including treatment of in-stent restenosis (ISR). The device has never been withdrawn from the market for any reason. The IN.PACT Admiral DCB is globally commercialized and includes the following countries: Albania, Algeria, Argentina, Australia, Austria, Bangladesh, Belgium, Brazil, Bulgaria, Canada, Colombia, Costa Rica, Croatia, Cyprus, Czech Republic, Denmark, Ecuador, Egypt, El Salvador, Estonia, Finland, France, Georgia, Germany, Ghana, Greece, Honduras, Hong Kong, Hungary, India, Indonesia, Iran, Ireland, Israel, Italy, Jordan, Kenya, Republic of Korea, Kuwait, Lebanon, Libya, Liechtenstein, Lithuania, Luxemburg, Macau, Macedonia, Malaysia, Malta, Mexico, Moldova, Nepal, Netherlands, New Caledonia, New Zealand, Norway, Oman, Pakistan, Peru, Philippines, Poland, Portugal, Puerto Rico, Qatar, Romania, Russia, Saudi Arabia, Serbia, Singapore, Slovakia, Slovenia, South Africa, Spain, Sudan, Syria, Sweden, Switzerland, Taiwan, Thailand, Trinidad and Tobago, Turkey, United Arab Emirates, United Kingdom, United States of America, Uruguay, Venezuela, and Vietnam.

# VIII. PROBABLE ADVERSE EFFECTS OF THE DEVICE ON HEALTH

Below is a list of the probable adverse effects (e.g., complications) associated with the use of the device:

- abrupt vessel closure
- access site pain

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- allergic reaction to contrast medium, antiplatelet therapy, or catheter system components (materials, drugs, and excipients)
- amputation/loss of limb
- arrhythmias
- arterial aneurysm
- arterial thrombosis
- arteriovenous (AV) fistula
- death
- dissection
- embolization
- fever
- hematoma
- hemorrhage
- hypotension/hypertension
- inflammation
- ischemia or infarction of tissue/organ
- local infection at access site
- local or distal embolic events
- perforation or rupture of the artery
- pseudoaneurysm
- renal insufficiency or failure
- restenosis of the dilated artery
- sepsis or systemic infection
- shock
- stroke
- systemic embolization
- vessel spasms or recoil
- vessel trauma which requires surgical repair

Probable complications of peripheral balloon catheterization include, but are not limited to:

- balloon rupture
- detachment of a component of the balloon and/or catheter system
- failure of the balloon to perform as intended
- failure to cross lesion

These complications may result in adverse events.

Although systemic effects are not anticipated, probable adverse events not captured above that may be unique to the paclitaxel drug coating include, but are not limited to:

- allergic/immunologic reaction
- alopecia
- anemia
- gastrointestinal symptoms

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- hematologic dyscrasia (including leucopenia, neutropenia, thrombocytopenia)
- hepatic enzyme changes
- histologic changes in vessel wall, including inflammation, cellular damage, or necrosis
- myalgia/arthralgia
- myelosuppression
- peripheral neuropathy

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

# IX. SUMMARY OF NONCLINICAL STUDIES

All the laboratory, animal, shelf life, and stability testing previously performed and provided in P140010 and subsequent supplements are applicable to and support the use of the IN.PACT Admiral DCB for the treatment of long lesions (180 - 360 mm) in the superficial femoral artery and popliteal arteries. Note: The SSED containing the pre-clinical studies to support the de novo, restenotic, and in-stent restenotic lesions up to 180 mm is available on the CDRH website. No changes have been made to the product design or specifications.

# A. Animal Studies

A confirmatory animal study was performed on the IN.PACT Admiral DCB to support the safety when treating long lesions (180-360 mm). An overview of the testing performed is provided in Table 3 below.

Table 3: Additional Animal Study to Support Modified Indication

|  Test | Testing Summary and/or Objective | Test Result  |
| --- | --- | --- |
|  28 Day Safety and PK Study of IN.PACT Admiral DCB in Domestic Swine Peripheral Arteries | Histological evaluation in downstream tissues and PK evaluation of paclitaxel in plasma after treatment with a 6x local therapeutic drug dose (per limb). | No safety concerns were noted based on overall animal health, organ function, target tissue and downstream histopathology, or plasma PK assessment  |

Success criteria for this study were met: test articles were successfully delivered to the target arteries of all animals with no procedural or device-related complications at the time of treatment or over the In-Life duration. There was no procedural or post-operative animal mortality related to device complications. Additionally, no complications occurred during the acute tracking evaluation.

For all vessels treated, no aneurysms or filling defects were present as noted at Day 28 pre-terminal angiography. Likewise, all vessels were patent with complete filling. There were no apparent device-related abnormalities noted at necropsy. The animals remained healthy through the duration of the In-Life period and variances in clinical pathology were minor and clinically insignificant.

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Histological examination of downstream tissues showed minute focal areas of vessel wall hypocellularity of small arterioles within the skeletal muscles and coronary bands with very low severity. Lesions of peracute muscle necrosis were also detected in two (2) isolated occurrences, with the exact cause not readily-apparent upon histological examination, but incompatible with the time course of drug toxicity. There were no clinical signs associated with any of the identified lesions and were therefore not considered adverse changes.

The safety of 6x local therapeutic drug dose treatments delivered to the proximal arterial flow was demonstrated by the absence of clinical lameness and the lack of clinically relevant histopathological lesions present in the coronary band and at non-target organs. This dose also provided sufficient safety margin to ensure no embolic safety concerns related to particulates in downstream tissues.

# X. SUMMARY OF PRIMARY CLINICAL STUDIES

The primary clinical evidence to support the expansion of indications to include treatment of lesions up to 360 mm using IN.PACT Admiral DCB comes from the IN.PACT Admiral DCB Long Lesion Sub-Cohort Clinical Evaluation, which consists of descriptive statistics from the IN.PACT Global DCB Study Imaging Cohorts (Long Lesion, ISR, and chronic total occlusions (CTO)) meeting the post-hoc inclusion criteria. A summary of this clinical evaluation is presented below.

# A. Study Design

Patients were treated between June 6, 2012 and December 16, 2013. The database for this Panel Track Supplement included 227 patients that met the retrospectively applied inclusion criteria and comprise the IN.PACT Global DCB Long Lesion Sub-Cohort. There were 28 non-US investigational sites.

This clinical evaluation was an observational, non-randomized, multicenter, single-arm evaluation intended to assess the safety and effectiveness of the IN.PACT Admiral DCB for the treatment of de novo, restenotic, or in-stent restenotic long lesions (lesion length >180 mm) in the superficial femoral and/or popliteal artery vessels. There was no control group.

# 1. Clinical Inclusion and Exclusion Criteria

Enrollment in the IN.PACT Admiral DCB Long Lesion Sub-Cohort Clinical Evaluation was limited to patients who met all inclusion criteria of the IN.PACT Global Study Clinical Investigation Plan as well as the following criteria:

- Lesion length >180 mm (based on angiographic core lab assessment)
- Rutherford Clinical Category 2-4
- Single unilateral treated lesion confirmed by angiographic core lab and site reported procedure information

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Patients were not permitted to enroll in the IN.PACT Admiral DCB Long Lesion Sub-Cohort Clinical Evaluation if they met any of the exclusion criteria in the IN.PACT Global Study Clinical Investigation Plan.

2. Follow-up Schedule

All patients were scheduled to return for follow-up examinations at 1 month, 6 months, 1 year, and then annually up to 5 years postoperatively. The key timepoints are shown below in the tables summarizing safety and effectiveness.

3. Clinical Endpoints

With regards to safety, the Primary Safety Endpoint was freedom from device- and procedure-related death through 30 days post-procedure and freedom from target limb major amputation and clinically-driven target vessel revascularization (CD-TVR) within 12 months post-index procedure.

With regards to effectiveness, the Primary Effectiveness Endpoint: Primary Patency within 12 months post-index procedure, defined as freedom from clinically-driven target lesion revascularization (CD-TLR), and freedom from restenosis as determined by Doppler Ultrasound (DUS) Peak Systolic Velocity Ratio (PSVR) ≤2.4.

The secondary endpoints include:

1. Major Adverse Events (MAE) through 12 months.
   *MAE defined as all-cause death, clinically-driven TVR, major target limb amputation, thrombosis at the target lesion site*
2. All-cause mortality at 30 days, 6 months, and 12 months.
3. CD-TLR at 30 days, 6 months, and 12 months.
4. Any TVR at 30 days, 6 months and 12 months.
5. CD-TVR at 30 days, 6 months and 12 months.
6. Thrombosis at the target lesion site at 30 days, 6 months and 12 months.
7. Major target limb amputation at 30 days, 6 months and 12 months.
8. Time to first TLR through 12 months post-index procedure.
9. Time to all-cause mortality through 12 months post-index procedure.
10. Primary sustained clinical improvement at 6 and 12 months.
11. Secondary sustained clinical improvement at 6 and 12 months.
12. Walking impairment evaluation by Walking Impairment Questionnaire (WIQ) at 6 and 12 months.
13. Walking distance as measured by 6 Minute Walk Test at 6 and 12 months.
14. Device success.
15. Procedural success.
16. Clinical success.

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17. Binary restenosis within 12 months post-index procedure, which is *determined by DUS PSVR >2.4*.

With regard to success/failure criteria, there were no criteria for this evaluation. The data were analyzed based on descriptive statistics.

# **B. Accountability of PMA Cohort**

At the time of database lock, of 227 patients enrolled in the clinical study, 90.3% (n=187) of eligible patients are available for analysis at the 12-month post-operative visit. Follow-up compliance through the 12-month follow-up visits is presented in Table 4 for the IN.PACT Global DCB Long Lesion Sub-Cohort subjects.

**Table 4: Subject Clinical Follow-up Compliance**

|  Subject Follow-up | IN.PACT Admiral DCB (N=227)  |
| --- | --- |
|  **30-Day Follow-up**  |   |
|  Eligible Subjects^{a} | 225  |
|  Death^{b} | 0  |
|  Withdrawal^{b} | 2  |
|  Follow-up Not Done^{b} | 13  |
|  Follow-up Visit Within Window^{c} | 197  |
|  Follow-up Visit Out of Window^{c} | 15  |
|  Within Window Follow-up Compliance (%)^{d} | 87.6%  |
|  Overall Follow-up Compliance (%)^{e} | 94.2%  |
|  **6-Month Follow-up**  |   |
|  Eligible Subjects^{a} | 218  |
|  Death^{b} | 1  |
|  Withdrawal^{b} | 8  |
|  Follow-up Not Done^{b} | 27  |
|  Follow-up Visit Within Window^{c} | 171  |
|  Follow-up Visit Out of Window^{c} | 20  |
|  Within Window Follow-up Compliance (%)^{d} | 78.4%  |
|  Overall Follow-up Compliance (%)^{e} | 87.6%  |
|  **12-Month Follow-up**  |   |
|  Eligible Subjects^{a} | 207  |
|  Death^{b} | 5  |
|  Withdrawal^{b} | 15  |

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|  Follow-up Not Done^{b} | 20  |
| --- | --- |
|  Follow-up Visit Within Window^{c} | 175  |
|  Follow-up Visit Out of Window^{c} | 12  |
|  Within Window Follow-up Compliance (%)^{d} | 84.5%  |
|  Overall Follow-up Compliance (%)^{e} | 90.3%  |
|  **24-Month Follow-up**  |   |
|  Eligible Subjects^{a} | 193  |
|  Death^{b} | 10  |
|  Withdrawal^{b} | 24  |
|  Follow-up Not Done^{b} | 26  |
|  Follow-up Visit Within Window^{c} | 160  |
|  Follow-up Visit Out of Window^{c} | 7  |
|  Within Window Follow-up Compliance (%)^{d} | 82.9%  |
|  Overall Follow-up Compliance (%)^{e} | 86.5%  |
|  ^{a}Eligible subjects are all subjects who either have a follow-up visit form or are past due for their follow-up (beyond upper limit of window on study and did not exit the study before the upper limit of the window)  |   |
|  ^{b}Death, withdrawal and follow-up not done are cumulative  |   |
|  ^{c}Within window visits are defined as: 30-day ± 7 days, 6-month ± 30 days, 12-month ± 60 days 24-month ± 60 days.  |   |
|  ^{d}Percentage based on number of subjects who had follow-up visit within window divided by total number of eligible subjects  |   |
|  ^{e}Percentage based on number of subjects who had a follow-up visit within or out of window divided by total number of eligible subjects  |   |
|  Site Reported Data  |   |

### C. Study Population Demographics and Baseline Parameters

The demographics of the study population are similar to those expected for the US population. Subject demographics, medical history, and risk factors of the 227 IN.PACT Global DCB Long Lesion Sub-Cohort subjects are summarized in Baseline Demographics and Clinical Characteristics (Table 5).

**Table 5: Baseline Demographic and Clinical Characteristics**

|  Subject Characteristics | IN.PACT Admiral DCB (N=227 Subjects)  |
| --- | --- |
|  Age (yrs) |   |
|  N | 226  |

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|  Subject Characteristics | IN.PACT Admiral DCB (N=227 Subjects)  |
| --- | --- |
|  Mean ± SD | 68.8 ± 9.7  |
|  Median | 69.0  |
|  Min, Max | 37, 90  |
|  BMI (kg/m²) |   |
|  N | 222  |
|  Mean ± SD | 26.7 ± 4.6  |
|  Median | 26.4  |
|  Min, Max | 16, 47  |
|  Obesity (BMI ≥30 kg/m²) | 20.7% (46/222)  |
|  Male | 67.4% (153/227)  |
|  Hypertension | 86.7% (195/225)  |
|  Hyperlipidemia | 71.7% (157/219)  |
|  Diabetes Mellitus | 38.7% (87/225)  |
|  Insulin Dependent Diabetes Mellitus | 18.2% (41/225)  |
|  Carotid Artery Disease | 24.0% (49/204)  |
|  Coronary Heart Disease | 40.6% (89/219)  |
|  Current Smoker | 42.7% (97/227)  |
|  Renal Insufficiency (baseline serum creatinine ≥ 1.5 mg/dl) | 12.3% (25/203)  |
|  On Dialysis | 1.8% (4/226)  |
|  Below-the-knee Vascular Disease of Target Leg (Stenotic/Occluded) | 48.6% (101/208)  |
|  Previous Peripheral Revascularization | 58.1% (132/227)  |
|  Iliac | 21.1% (48/227)  |
|  Common Femoral | 7.0% (16/227)  |
|  Femoral Profunda | 1.3% (3/227)  |
|  Superficial Femoral | 48.9% (111/227)  |
|  Popliteal | 14.1% (32/227)  |
|  Below-the-knee | 8.4% (19/227)  |
|  Other Location | 1.3% (3/227)  |
|  Previous Limb Amputation | 1.3% (3/227)  |

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|  Subject Characteristics |   | IN.PACT Admiral DCB (N=227 Subjects)  |
| --- | --- | --- |
|  Toe |   | 0.4% (1/227)  |
|  Transmetatarsal |   | 0.0% (0/227)  |
|  Below-the-knee |   | 0.0% (0/227)  |
|  Above-the-knee |   | 0.9% (2/227)  |
|  Rutherford Category |   |   |
|  0 |   | 0.0% (0/227)  |
|  1 |   | 0.0% (0/227)  |
|  2 |   | 22.5% (51/227)  |
|  3 |   | 65.2% (148/227)  |
|  4 |   | 12.3% (28/227)  |
|  5 |   | 0.0% (0/227)  |
|  6 |   | 0.0% (0/227)  |
|  ABI^{#} (mmHg ratio) |   |   |
|  N |   | 198  |
|  Mean ± SD |   | 0.625 ± 0.214  |
|  Median |   | 0.630  |
|  Min, Max |   | 0.00, 1.67  |
|  Numbers are % (counts/sample size) unless otherwise stated.  |   |   |
|  Rutherford clinical grades and categories:  |   |   |
|  Grade | Category | Clinical Description  |
|  0 | 0 | Asymptomatic, no hemodynamically significant occlusive disease  |
|  I | 1 | Mild claudication  |
|  I | 2 | Moderate claudication  |
|  I | 3 | Severe claudication  |
|  II | 4 | Ischemic rest pain  |
|  III | 5 | Minor tissue loss; non-healing ulcer; focal gangrene with diffuse pedal ischemia  |
|  III | 6 | Major tissue loss extending above transmetarsal level; functional foot no longer salvageable  |
|  ^{#}ABI for all target limbs treated during the 1^{st} index procedure are included (can be bilateral)  |   |   |
|  Site reported data  |   |   |

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The baseline lesion characteristics, as reported by the sites and angiographic core laboratories, have been provided in Procedural Lesion Characteristics (Table 6). The mean total target lesion length treated was 287.4 ± 71.1 mm.

Table 6: Procedural Lesion Characteristics

|  Procedural Lesion Characteristics (per lesion) | IN.PACT Admiral DCB (N=227 Subjects and Lesions)  |
| --- | --- |
|  Pre-procedure^{1} |   |
|  RVD (mm) |   |
|  N | 133  |
|  Mean ± SD | 4.611 ± 0.896  |
|  Median | 4.500  |
|  Min, Max | 2.25, 6.85  |
|  MLD (mm) |   |
|  N | 134  |
|  Mean ± SD | 0.332 ± 0.568  |
|  Median | 0.000  |
|  Min, Max | 0.00, 2.65  |
|  Occluded Lesion (100% stenosis) | 70.1% (157/224)  |
|  Diameter Stenosis (%) |   |
|  N | 224  |
|  Mean ± SD | 94.1 ± 10.7  |
|  Median | 100.0  |
|  Min, Max | 54, 100  |
|  Lesion Length (cm) |   |
|  N | 227  |
|  Mean ± SD | 28.74 ± 7.11  |
|  Median | 27.50  |
|  Min, Max | 18.5, 53.0  |
|  Occluded Lesion Length (cm) |   |
|  N | 207  |
|  Mean ± SD | 11.67 ± 11.32  |
|  Median | 10.00  |
|  Min, Max | 0.0, 45.0  |
|  Post-Procedure^{2} |   |

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|  Procedural Lesion Characteristics (per lesion) | IN.PACT Admiral DCB (N=227 Subjects and Lesions)  |
| --- | --- |
|  Diameter Stenosis (%) |   |
|  N | 226  |
|  Mean ± SD | 11.2 ± 12.3  |
|  Median | 10.0  |
|  Min, Max | 0, 60  |
|  Total Target Lesion Length Treated with Study Device (cm) |   |
|  N | 226  |
|  Mean ± SD | 27.46 ± 6.68  |
|  Median | 26.00  |
|  Min, Max | 14.5, 47.0  |
|  Numbers are % (counts/sample size) unless otherwise stated.  |   |
|  Key Core Laboratory definitions:  |   |
|  Reference Vessel Diameter (RVD) – angiographic measurement of the normal artery proximal and/or distal to the lesion intended for treatment.  |   |
|  Minimum Lumen Diameter (MLD) – angiographic measurement of the tightest area of obstruction or stenosis located within the segment of interest or the intended area of treatment.  |   |
|  Lesion length – angiographic measurement from the proximal healthy vessel segment to the distal healthy vessel segment (e.g. length of obstruction).  |   |
|  ^{1}Angio core lab reported data.  |   |
|  ^{2}Site reported data.  |   |

As shown in Table 7 below, a total of 96 (42.5%) IN.PACT Global DCB Long Lesion Sub-Cohort subjects received provisional stenting. The mean total stent length per subject was 173.7 ± 104.7 mm.

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**Table 7: Provisional Stenting**

|  Subject Characteristics | IN.PACT Admiral DCB (N=227 Subjects)  |
| --- | --- |
|  **Provisional Stent Rate per Subject** | 42.5% (96/226)  |
|  **Total Provisional Stent Length per Subject (mm)** |   |
|  N | 96  |
|  Mean ± SD | 173.7 ± 104.7  |
|  Median | 150.0  |
|  Min, Max | 10, 450  |
|  Numbers are % (counts/sample size).  |   |
|  Site reported data.  |   |

#### **D. Safety and Effectiveness Results**

##### **1. Safety Results**

The analysis of safety was based on the cohort of 210 subjects available for the 12-month evaluation. The key safety outcomes for this study are presented below in Table 8. Adverse effects are reported in Table 9.

**Table 8: Primary Safety Results through 12-months**

|  Parameters | IN.PACT Admiral DCB (N=227 Subjects)  |
| --- | --- |
|  **Safety Parameters** |   |
|  Primary Safety Composite Endpoint – Freedom from: | 92.9% (195/210)  |
|  Device- and Procedure-related Death through 30 Days | 0.0% (0/225)  |
|  Target Limb Major Amputation within 360 Days | 0.0% (0/210)  |
|  Clinically-driven TVR within 360 Days | 7.1% (15/210)  |
|  Death (all-cause) | 2.4% (5/210)  |

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**Table 9: Number of Subjects with One or More Serious Adverse Events through 360 days by MedDRA System-Organ Class and Preferred Term**

|  Serious Adverse Event | IN.PACT Admiral DCB (N=227 Subjects)  |
| --- | --- |
|  **Subjects with One or More Serious Adverse Events** | **52.0% (118/227)**  |
|  **Blood and Lymphatic System Disorders^{a}** | **0.4% (1/227)**  |
|  Leukocytosis | 0.4% (1/227)  |
|  **Cardiac Disorders^{a}** | **7.9% (18/227)**  |
|  Acute Myocardial Infarction | 0.9% (2/227)  |
|  Angina Pectoris | 0.4% (1/227)  |
|  Angina Unstable | 0.9% (2/227)  |
|  Arteriosclerosis Coronary Artery | 0.4% (1/227)  |
|  Atrial Fibrillation | 0.4% (1/227)  |
|  Atrial Flutter | 0.4% (1/227)  |
|  Atrial Thrombosis | 0.4% (1/227)  |
|  Cardiac Failure | 1.3% (3/227)  |
|  Cardiac Failure Acute | 0.4% (1/227)  |
|  Cardiac Failure Congestive | 0.4% (1/227)  |
|  Congestive Cardiomyopathy | 0.4% (1/227)  |
|  Coronary Artery Disease | 2.6% (6/227)  |
|  Coronary Artery Occlusion | 0.4% (1/227)  |
|  Coronary Artery Stenosis | 1.3% (3/227)  |
|  Hypertensive Heart Disease | 0.4% (1/227)  |
|  Ischaemic Cardiomyopathy | 0.9% (2/227)  |
|  **Ear and Labyrinth Disorders^{a}** | **0.4% (1/227)**  |
|  Vertigo | 0.4% (1/227)  |
|  **Endocrine Disorders^{a}** | **0.4% (1/227)**  |
|  Goitre | 0.4% (1/227)  |
|  **Eye Disorders^{a}** | **0.9% (2/227)**  |
|  Cataract | 0.4% (1/227)  |
|  Retinal Artery Occlusion | 0.4% (1/227)  |
|  **Gastrointestinal Disorders^{a}** | **3.1% (7/227)**  |
|  Colitis | 0.4% (1/227)  |
|  Gastritis | 0.4% (1/227)  |

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|  Serious Adverse Event | IN.PACT Admiral DCB (N=227 Subjects)  |
| --- | --- |
|  Gastrointestinal Haemorrhage | 1.3% (3/227)  |
|  Oesophageal Haemorrhage | 0.4% (1/227)  |
|  Reflux Oesophagitis | 0.4% (1/227)  |
|  **General Disorders and Administration Site Conditions^{a}** | **3.5% (8/227)**  |
|  Chest Pain | 0.9% (2/227)  |
|  Death | 0.4% (1/227)  |
|  Device Occlusion | 1.3% (3/227)  |
|  Impaired Healing | 0.4% (1/227)  |
|  Puncture Site Haemorrhage | 0.4% (1/227)  |
|  **Hepatobiliary Disorders^{a}** | **0.4% (1/227)**  |
|  Cholecystitis | 0.4% (1/227)  |
|  Cholelithiasis | 0.4% (1/227)  |
|  **Infections and Infestations^{a}** | **5.3% (12/227)**  |
|  Bronchitis | 0.4% (1/227)  |
|  Erysipelas | 0.4% (1/227)  |
|  Gangrene | 0.4% (1/227)  |
|  Gastroenteritis Viral | 0.4% (1/227)  |
|  Graft Infection | 0.4% (1/227)  |
|  Groin Infection | 0.4% (1/227)  |
|  Infection | 0.4% (1/227)  |
|  Necrotising Fasciitis | 0.4% (1/227)  |
|  Pneumonia | 1.8% (4/227)  |
|  **Injury, Poisoning and Procedural Complications^{a}** | **11.9% (27/227)**  |
|  Arterial Restenosis | 5.3% (12/227)  |
|  In-Stent Arterial Restenosis | 3.1% (7/227)  |
|  In-Stent Coronary Artery Restenosis | 0.4% (1/227)  |
|  Peripheral Arterial Reocclusion | 0.9% (2/227)  |
|  Postoperative Thrombosis | 0.4% (1/227)  |
|  Thermal Burn | 0.4% (1/227)  |
|  Vascular Graft Occlusion | 0.4% (1/227)  |
|  Vascular Pseudoaneurysm | 2.2% (5/227)  |

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|  Serious Adverse Event | IN.PACT Admiral DCB (N=227 Subjects)  |
| --- | --- |
|  **Investigations^{a}** | **1.3% (3/227)**  |
|  Blood Creatinine Increased | 0.4% (1/227)  |
|  Haemoglobin Decreased | 0.4% (1/227)  |
|  International Normalised Ratio Increased | 0.4% (1/227)  |
|  **Metabolism and Nutrition Disorders^{a}** | **2.6% (6/227)**  |
|  Diabetes Mellitus | 0.9% (2/227)  |
|  Gout | 0.9% (2/227)  |
|  Hypokalaemia | 0.4% (1/227)  |
|  Hyponatraemia | 0.4% (1/227)  |
|  **Musculoskeletal and Connective Tissue Disorders^{a}** | **4.4% (10/227)**  |
|  Arthritis | 0.4% (1/227)  |
|  Back Pain | 0.9% (2/227)  |
|  Bursitis | 0.4% (1/227)  |
|  Intervertebral Disc Protrusion | 0.4% (1/227)  |
|  Neck Pain | 0.4% (1/227)  |
|  Osteoarthritis | 0.4% (1/227)  |
|  Pain in Extremity | 0.9% (2/227)  |
|  Rotator Cuff Syndrome | 0.9% (2/227)  |
|  **Neoplasms Benign, Malignant and Unspecified (Incl Cysts and Polyps)^{a}** | **4.0% (9/227)**  |
|  Bladder Papilloma | 0.4% (1/227)  |
|  Colon Adenoma | 0.4% (1/227)  |
|  Laryngeal Cancer | 0.4% (1/227)  |
|  Lung Neoplasm Malignant | 0.4% (1/227)  |
|  Oesophageal Carcinoma | 0.4% (1/227)  |
|  Prostate Cancer Recurrent | 0.4% (1/227)  |
|  Small Cell Lung Cancer Stage Unspecified | 0.4% (1/227)  |
|  Squamous Cell Carcinoma | 0.4% (1/227)  |
|  Undifferentiated Sarcoma | 0.4% (1/227)  |
|  **Nervous System Disorders^{a}** | **3.5% (8/227)**  |
|  Basal Ganglia Infarction | 0.4% (1/227)  |

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|  Serious Adverse Event | IN.PACT Admiral DCB (N=227 Subjects)  |
| --- | --- |
|  Brain Oedema | 0.4% (1/227)  |
|  Carotid Artery Stenosis | 1.3% (3/227)  |
|  Cerebral Infarction | 0.4% (1/227)  |
|  Hemiparesis | 0.4% (1/227)  |
|  Metabolic Encephalopathy | 0.4% (1/227)  |
|  Sciatica | 0.4% (1/227)  |
|  Subarachnoid Haemorrhage | 0.4% (1/227)  |
|  **Psychiatric Disorders^{a}** | **0.4% (1/227)**  |
|  Alcohol Withdrawal Syndrome | 0.4% (1/227)  |
|  **Renal and Urinary Disorders^{a}** | **0.9% (2/227)**  |
|  Bladder Tamponade | 0.4% (1/227)  |
|  Haematuria | 0.4% (1/227)  |
|  **Reproductive System and Breast Disorders^{a}** | **0.4% (1/227)**  |
|  Postmenopausal Haemorrhage | 0.4% (1/227)  |
|  **Respiratory, Thoracic and Mediastinal Disorders^{a}** | **1.3% (3/227)**  |
|  Dyspnoea Exertional | 0.4% (1/227)  |
|  Hyperventilation | 0.4% (1/227)  |
|  Pleural Effusion | 0.4% (1/227)  |
|  **Surgical and Medical Procedures^{a}** | **1.3% (3/227)**  |
|  Ileostomy Closure | 0.4% (1/227)  |
|  Peripheral Artery Angioplasty | 0.4% (1/227)  |
|  Peripheral Revascularisation | 0.4% (1/227)  |
|  **Vascular Disorders^{a}** | **31.3% (71/227)**  |
|  Aortic Aneurysm | 0.4% (1/227)  |
|  Arterial Stenosis Limb | 3.5% (8/227)  |
|  Arterial Thrombosis Limb | 2.6% (6/227)  |
|  Embolism | 0.4% (1/227)  |
|  Femoral Arterial Stenosis | 11.9% (27/227)  |
|  Femoral Artery Dissection | 0.4% (1/227)  |
|  Femoral Artery Occlusion | 5.3% (12/227)  |
|  Haematoma | 1.3% (3/227)  |
|  Hypertension | 0.4% (1/227)  |

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|  Serious Adverse Event | IN.PACT Admiral DCB (N=227 Subjects)  |
| --- | --- |
|  Hypertensive Crisis | 0.4% (1/227)  |
|  Iliac Artery StenosisS | 1.3% (3/227)  |
|  Intermittent Claudication | 1.3% (3/227)  |
|  Peripheral Arterial Occlusive Disease | 6.6% (15/227)  |
|  Peripheral Embolism | 1.8% (4/227)  |
|  Peripheral Ischaemia | 1.3% (3/227)  |
|  Peripheral Vascular Disorder | 0.4% (1/227)  |
|  Vessel Perforation | 1.3% (3/227)  |
|  **Total Serious Adverse Events** | **246**  |

Numbers are % (counts/sample size) unless otherwise stated.

aEvent verbatim terms are reported by sites. The events listed in this table are then coded using MedDRA version 16.1 and then stratified by System-Organ Class (SOC) and Preferred Term. Patients may be counted in this table more than once by Preferred Term, but are only counted once in the SOC summary line.

Site reported data.

## 2. Effectiveness Results

The analysis of effectiveness for the entire Long Lesion cohort was based on the 151 evaluable patients at the 12-month time point. Key effectiveness outcomes are presented in Table 10 and Figure 4 below.

Table 10: Primary Effectiveness Results through 12-months

|  Parameters | IN.PACT Admiral DCB (N=227 Subjects)  |
| --- | --- |
|  **Effectiveness Parameters** |   |
|  Primary Effectiveness Endpoint – Primary Patency at 12 Months | 64.9% (98/151)  |

The Kaplan-Meier analysis of this primary effectiveness endpoint, presented as primary patency through 420 days, is shown in Figure 4.

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**Figure 4: Kaplan-Meier analysis of primary effectiveness endpoint, presented as primary patency through 420 days**

![img-3.jpeg](img-3.jpeg)

|  From day X To day Y IN.PACT DCB (N=227 Subjects) | 0 0 0M | 1 30 1M | 31 60 2M | 61 90 3M | 91 120 4M | 121 150 5M | 151 180 6M | 181 210 7M | 211 240 8M | 241 270 9M | 271 300 10M | 301 330 11M | 331 360 12M | 361 390 13M | 391 420 14M  |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
|  # Entered | 227 | 227 | 224 | 215 | 214 | 214 | 213 | 210 | 205 | 203 | 200 | 195 | 190 | 181 | 157  |
|  # Censored | 0 | 2 | 5 | 1 | 0 | 0 | 2 | 4 | 1 | 0 | 4 | 3 | 1 | 4 | 1  |
|  # Events | 0 | 1 | 4 | 0 | 0 | 1 | 1 | 1 | 1 | 3 | 1 | 2 | 8 | 20 | 4  |
|  Event-free [%] | 100.0% | 99.6% | 97.7% | 97.7% | 97.7% | 97.3% | 96.8% | 96.4% | 95.9% | 94.5% | 94.0% | 93.0% | 89.1% | 79.1% | 77.1%  |

### 3. Secondary Safety and Effectiveness Endpoints

The results of the secondary endpoints for the IN.PACT Global DCB Long Lesion Sub-Cohort Clinical Evaluation through 12-months are shown in Table 11 below.

The primary sustained clinical improvement was 80.9% (152/188) at 12-months post-procedure. The device, procedural and clinical success was over 99% for the entire subject population in this sub-cohort (99.2%, 99.1% and 99.1% respectively).

The MAE composite for the long lesion sub-cohort at 360-days was 10.5% (24/215). Reported MAEs within 360-days included 2.4% death (5/210), 3.3% thrombosis (7/210), and no cases of major target limb amputation. Reintervention

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rates were reported as 7.1% (15/210) clinically-driven TVR and 7.1% (15/210) clinically-driven TLR. The average time to first clinically-driven TLR was 177.8 days. Other major secondary endpoints included binary restenosis (PSVR>2.4) in 34.2% (51/149) of subjects.

**Table 11: Secondary Endpoints through 12-months**

|  Parameters | IN.PACT Admiral DCB (N=227 Subjects)  |
| --- | --- |
|  **Effectiveness Parameters**  |   |
|  Primary Sustained Clinical Improvement at 12 Months | 80.9% (152/188)  |
|  Secondary Sustained Clinical Improvement at 12 Months | 86.5% (160/185)  |
|  Device Success | 99.2% (653/658)  |
|  Procedural Success | 99.1% (224/226)  |
|  Clinical Success | 99.1% (224/226)  |
|  **Cumulative complications within 360 days**  |   |
|  MAE* Composite (Death, Major Target Limb Amputation, Clinically-driven TVR, Thrombosis) | 10.5% (22/210)  |
|  Death (all-cause) | 2.4% (5/210)  |
|  Clinically-driven TVR | 7.1% (15/210)  |
|  Major Target Limb Amputation | 0.0% (0/210)  |
|  Thrombosis | 3.3% (7/210)  |
|  Clinically-driven TLR | 7.1% (15/210)  |
|  Any TVR | 7.1% (15/210)  |
|  Any TLR | 7.1% (15/210)  |
|  **Other Major Secondary Endpoints at 12 Months**  |   |
|  Binary Restenosis (PSVR >2.4) | 34.2% (51/149)  |
|  Time to First Clinically-driven TLR (days) |   |
|  N | 15  |
|  Mean ± SD | 177.8 ± 115.9  |
|  Median | 204.0  |
|  Min, Max | 21, 356  |
|  Walking Impairment by WIQ** (%) |   |

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|  Parameters | IN.PACT Admiral DCB (N=227 Subjects)  |
| --- | --- |
|  N | 178  |
|  Mean ± SD | 73.7 ± 32.5  |
|  Median | 100.0  |
|  Min, Max | 0, 100  |
|  Endpoint definitions: Clinically-driven TLR is defined as any reintervention at the target lesion due to symptoms or drop of ABI/TBI of ≥20% or >0.15 when compared to post-procedure baseline ABI/TBI •Device success defined as successful delivery, inflation, deflation and retrieval of the intact study balloon device without burst below the RBP. Results reported as device based summary. •Procedure success defined as residual stenosis of ≤50% (non-stented subjects) or ≤30% (stented subjects) by corelab (if corelab was not available then the site-reported estimate was used). •Clinical success defined as procedural success without procedural complications (death, major target limb amputation, thrombosis of the target lesion, or TVR) prior to discharge. •Primary sustained clinical improvement is defined as sustained upward shift of at least 1 category on Rutherford classification as compared to baseline without the need for repeated TLR or surgical revascularization in amputation-free surviving subjects. •Secondary sustained clinical improvement is defined as sustained upward shift of at least 1 category on Rutherford classification as compared to baseline including the need for repeated TLR or surgical revascularization in amputation-free surviving subjects. •Safety composite endpoint consists of: freedom from device- and procedure-related death within 30 days, freedom from major target limb amputation, and freedom from clinically-driven TVR within 360 days post-index procedure. •Clinically-driven TLR/TVR is defined as any re-intervention within the target vessel due to symptoms or drop of ABI/TBI of ≥20% or >0.15 when compared to post-procedure baseline ABI/TBI. *Major Adverse Events (MAE) defined as all-cause death, clinically-driven TLR/TVR, major target limb amputation, thrombosis at the target lesion site at 360 days. **Walking impairment assessed by Walking Impairment Questionnaire (WIQ) at 12 months. Data sources: All events were adjudicated by the independent Clinical Events Committee, all duplex ultrasound and angiographic measures were made by the independent core laboratories, and all other data were site reported.  |   |

The results of the secondary endpoints for the IN.PACT Global DCB Long Lesion Sub-Cohort Clinical Evaluation through 24 months are shown in Table 12 below. The primary sustained clinical improvement was 71.0% (125/176) at 24-

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months post-procedure. Freedom from CD-TLR by Kaplan Meier estimate was 80.3% through 24-months and can be found below in Figure 5.

The MAE composite for the long lesion sub-cohort at 720-days was 24.7% (49/198). Reported MAEs within 720-days included 4.5% death (9/198), 5.1% thrombosis (10/198), and one subject had a major target limb amputation (0.5%, 1/198). Reintervention rates were reported as 20.2% (40/198) clinically-driven TVR and 20.2% (40/198) clinically-driven TLR. The average time to first clinically-driven TLR was 377.4 days.

**Table 12: Secondary Endpoints through 24 months**

|  Parameters | IN.PACT Admiral DCB (N=227 Subjects)  |
| --- | --- |
|  **Effectiveness Parameters**  |   |
|  Primary Sustained Clinical Improvement at 24 Months | 71.0% (125/176)  |
|  Secondary Sustained Clinical Improvement at 24 Months | 89.2% (149/167)  |
|  **Safety Parameters**  |   |
|  Primary Safety Composite Endpoint – Freedom from: | 79.3% (157/198)  |
|  Device- and Procedure-related Death through 30 Days | 0.0% (0/225)  |
|  Target Limb Major Amputation within 720 Days | 0.5% (1/198)  |
|  Clinically-driven TVR within 720 Days | 20.2% (40/198)  |
|  Death (all-cause) within 30 days | 0.0% (0/225)  |
|  **Cumulative complications within 720 days**  |   |
|  MAE Composite (Death, Major Target Limb Amputation, Clinically-driven TVR, Thrombosis) | 24.7% (49/198)  |
|  Death (all-cause) | 4.5% (9/198)  |
|  Clinically-driven TVR | 20.2% (40/198)  |
|  Major Target Limb Amputation | 0.5% (1/198)  |
|  Thrombosis | 5.1% (10/198)  |
|  Clinically-driven TLR | 20.2% (40/198)  |
|  Any TVR | 20.2% (40/198)  |
|  Any TLR | 20.2% (40/198)  |
|  **Other Major Secondary Endpoints at 24 Months**  |   |
|  Time to First Clinically-driven TLR (days)  |   |
|  N | 40  |
|  Mean ± SD | 377.4 ± 190.2  |
|  Median | 394.5  |
|  Min, Max | 21, 712  |
|  Walking Impairment by WIQ (%)  |   |
|  N | 157  |
|  Mean ± SD | 77.7 ± 29.6  |

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|  Parameters | IN.PACT Admiral DCB (N=227 Subjects)  |
| --- | --- |
|  Median | 100.0  |
|  Min, Max | 0, 100  |
|  Endpoint definitions: Clinically-driven TLR is defined as any reintervention at the target lesion due to symptoms or drop of ABI/TBI of ≥20% or >0.15 when compared to post-procedure baseline ABI/TBI •Device success defined as successful delivery, inflation, deflation and retrieval of the intact study balloon device without burst below the RBP. •Procedure success defined as residual stenosis of ≤50% (non-stented subjects) or ≤30% (stented subjects) by corelab (if corelab was not available then the site-reported estimate was used). •Clinical success defined as procedural success without procedural complications (death, major target limb amputation, thrombosis of the target lesion, or TVR) prior to discharge. •Primary sustained clinical improvement is defined as sustained upward shift of at least one (1) category on Rutherford classification as compared to baseline without the need for repeated TLR or surgical revascularization in amputation-free surviving subjects. •Secondary sustained clinical improvement is defined as sustained upward shift of at least one (1) category on Rutherford classification as compared to baseline including the need for repeated TLR or surgical revascularization in amputation-free surviving subjects. •Safety composite endpoint consists of: freedom from device- and procedure-related death within 30 days, freedom from major target limb amputation, and freedom from clinically-driven TVR within 720 days post-index procedure. •Clinically-driven TLR/TVR is defined as any re-intervention within the target vessel due to symptoms or drop of ABI/TBI of ≥20% or >0.15 when compared to post-procedure baseline ABI/TBI. •Major Adverse Events (MAE) defined as all-cause death, clinically-driven TLR/TVR, major target limb amputation, thrombosis at the target lesion site at 720 days. •Walking impairment assessed by Walking Impairment Questionnaire (WIQ) at 24 months. Data sources: All events were adjudicated by the independent Clinical Events Committee, all duplex ultrasound and angiographic measures were made by the independent core laboratories, and all other data were site reported.  |   |

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**Figure 5: Kaplan-Meier Plot – Event-free from Clinically-driven TLR through 24 months**

![img-4.jpeg](img-4.jpeg)

|  From day X To day Y IN.PACT DCB (N=227 Subjects) | 0 0 0M | 1 60 2M | 61 120 4M | 121 180 6M | 181 240 8M | 241 300 10M | 301 360 12M | 361 420 14M | 421 480 16M | 481 540 18M | 541 600 20M | 601 660 22M | 661 720 24M  |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
|  # Entered^{1} | 227 | 227 | 215 | 214 | 210 | 203 | 195 | 189 | 176 | 171 | 166 | 160 | 156  |
|  # Censored^{2} | 0 | 7 | 1 | 2 | 5 | 4 | 4 | 5 | 1 | 1 | 2 | 1 | 5  |
|  # Events | 0 | 5 | 0 | 2 | 2 | 4 | 2 | 8 | 4 | 4 | 4 | 3 | 2  |
|  Event-free [%]^{3} | 100.0% | 97.7% | 97.7% | 96.8% | 95.9% | 94.0% | 93.0% | 89.0% | 87.0% | 84.9% | 82.9% | 81.3% | 80.3%  |

$^{1}$Number of subjects at risk at the beginning of each interval.

$^{2}$Subjects are censored because their last follow-up has not reached the end of the time interval or because they are lost to follow-up.

$^{3}$Estimate made at the end of the time interval.

All events were adjudicated by the independent Clinical Events Committee.

#### 4. Subgroup Analyses

Medtronic has analyzed the clinical evaluation results by lesion length grouping, gender, diabetic status, and assigned imaging cohorts.

##### *Lesion Length Grouping Analysis*

The outcomes for subjects by respective lesion length grouping is presented below in Table 13.

The primary patency by lesion length group were 75.5% (40/53) for lesions >180-240 mm, 65.1% (28/43) for lesion >240-300 mm, 63.3% (19/30) for lesion >300-360 mm, and 44.0% (11/25) for lesions >360 mm.

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The primary safety composite by lesion length group were 95.8% (68/71) for lesions >180-240 mm, 93.7% (59/63) for lesion >240-300 mm, 92.3% (36/39) for lesion >300-360 mm, and 86.5% (32/37) for lesions >360 mm. There were no device- or procedure-related deaths through 30 days or major target limb amputations through 12 months.

**Table 13: Principal Effectiveness and Safety Results through 12-months by Lesion Length Groups**

|  Parameters | 18-24cm (N=77 Subjects) | 24-30cm (N=66 Subjects) | 30-36cm (N=43 Subjects) | >36cm (N=41 Subjects)  |
| --- | --- | --- | --- | --- |
|  Lesion Length (cm) |  |  |  |   |
|  N | 77 | 66 | 43 | 41  |
|  Mean ± SD | 21.65 ± 1.71 | 27.17 ± 1.88 | 32.74 ± 1.73 | 40.37 ± 3.83  |
|  Q1 | 20.0 | 25.5 | 31.0 | 37.5  |
|  Median | 22.00 | 26.75 | 32.50 | 39.00  |
|  Q3 | 23.0 | 29.0 | 34.0 | 42.0  |
|  Min, Max | 18.5, 24.0 | 24.5, 30.0 | 30.5, 36.0 | 36.5, 53.0  |
|  **Effectiveness** |  |  |  |   |
|  **Parameters** |  |  |  |   |
|  Primary Patency at 12 Months | 75.5% (40/53) | 65.1% (28/43) | 63.3% (19/30) | 44.0% (11/25)  |
|  Primary Sustained Clinical Improvement at 12 Months | 83.3% (55/66) | 83.6% (46/55) | 82.9% (29/35) | 68.8% (22/32)  |
|  Secondary Sustained Clinical Improvement at 12 Months | 86.4% (57/66) | 89.1% (49/55) | 91.2% (31/34) | 76.7% (23/30)  |
|  Device Success | 100.0% (178/178) | 99.5% (186/187) | 99.3% (136/137) | 98.1% (153/156)  |
|  Procedural Success | 100.0% (76/76) | 98.5% (65/66) | 97.7% (42/43) | 100.0% (41/41)  |
|  Clinical Success | 100.0% (76/76) | 98.5% (65/66) | 97.7% (42/43) | 100.0% (41/41)  |
|  **Safety Parameters** |  |  |  |   |
|  Primary Safety Composite Endpoint – Freedom from: | 95.8% (68/71) | 93.7% (59/63) | 92.3% (36/39) | 86.5% (32/37)  |
|  Device- and Procedure-related Death through 30 Days | 0.0% (0/76) | 0.0% (0/66) | 0.0% (0/42) | 0.0% (0/41)  |

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|  Parameters | 18-24cm (N=77 Subjects) | 24-30cm (N=66 Subjects) | 30-36cm (N=43 Subjects) | >36cm (N=41 Subjects)  |
| --- | --- | --- | --- | --- |
|  Target Limb Major Amputation within 360 Days | 0.0% (0/71) | 0.0% (0/63) | 0.0% (0/39) | 0.0% (0/37)  |
|  Clinically-driven TLR within 360 Days | 4.2% (3/71) | 6.3% (4/63) | 7.7% (3/39) | 13.5% (5/37)  |
|  Death (all-cause) within 30 days | 0.0% (0/76) | 0.0% (0/66) | 0.0% (0/42) | 0.0% (0/41)  |
|  **Cumulative complications within 360 days**  |   |   |   |   |
|  MAE Composite (Death, Major Target Limb Amputation, Clinically-driven TVR, Thrombosis) | 5.6% (4/71) | 12.7% (8/63) | 7.7% (3/39) | 18.9% (7/37)  |
|  Death (all-cause) | 0.0% (0/71) | 3.2% (2/63) | 2.6% (1/39) | 5.4% (2/37)  |
|  Clinically-driven TVR | 4.2% (3/71) | 6.3% (4/63) | 7.7% (3/39) | 13.5% (5/37)  |
|  Major Target Limb Amputation | 0.0% (0/71) | 0.0% (0/63) | 0.0% (0/39) | 0.0% (0/37)  |
|  Thrombosis at Target Lesion | 1.4% (1/71) | 3.2% (2/63) | 5.1% (2/39) | 5.4% (2/37)  |
|  Clinically-driven TLR | 4.2% (3/71) | 6.3% (4/63) | 7.7% (3/39) | 13.5% (5/37)  |
|  Any TVR | 4.2% (3/71) | 6.3% (4/63) | 7.7% (3/39) | 13.5% (5/37)  |
|  Any TLR | 4.2% (3/71) | 6.3% (4/63) | 7.7% (3/39) | 13.5% (5/37)  |
|  **Other Major Secondary Endpoints at 12 Months**  |   |   |   |   |
|  Binary Restenosis (PSVR >2.4) | 24.5% (13/53) | 34.9% (15/43) | 34.5% (10/29) | 54.2% (13/24)  |
|  Time to First Clinically-driven TLR (days) |  |  |  |   |
|  N | 3 | 4 | 3 | 5  |
|  Mean ± SD | 221.0 ± 71.8 | 150.3 ± 149.2 | 91.7 ± 98.4 | 225.6 ± 110.9  |
|  Median | 242.0 | 104.5 | 50.0 | 241.0  |
|  Min, Max | 141, 280 | 37, 355 | 21, 204 | 50, 356  |
|  Walking Impairment by WIQ (%) |  |  |  |   |

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|  Parameters | 18-24cm (N=77 Subjects) | 24-30cm (N=66 Subjects) | 30-36cm (N=43 Subjects) | >36cm (N=41 Subjects)  |
| --- | --- | --- | --- | --- |
|  N | 63 | 54 | 32 | 29  |
|  Mean ± SD | 73.0 ± 34.9 | 79.2 ± 28.2 | 75.0 ± 33.6 | 63.8 ± 32.4  |
|  Median | 100.0 | 100.0 | 100.0 | 50.0  |
|  Min, Max | 0, 100 | 0, 100 | 0, 100 | 0, 100  |

# **Endpoint definitions:**

- Primary patency is defined as freedom from clinically-driven TLR$^{1}$ and freedom from restenosis as determined by duplex ultrasound$^{2}$ (DUS) Peak Systolic Velocity Ratio (PSVR) ≤ 2.4$^{3}$ within 12 months.

- Key Primary Patency endpoint definition components:

$^{1}$ Clinically-driven TLR is defined as any reintervention at the target lesion due to symptoms or drop of ABI/TBI of ≥20% or >0.15 when compared to post-procedure baseline ABI/TBI

$^{2}$ Post-index procedure DUS is intended to establish a post-treatment baseline and does not contribute to the Primary Endpoint determination.

$^{3}$ Restenosis determined by either PSVR >2.4 (determined by Target Lesion Category of '50-99%' or 'Occluded') as assessed by an independent DUS core lab or >50% stenosis as assessed by an independent angiographic core lab.

- Device success defined as successful delivery, inflation, deflation and retrieval of the intact study balloon device without burst below the RBP. Results reported as device based summary.

- Procedure success defined as residual stenosis of ≤50% (non-stented subjects) or ≤30% (stented subjects) by corelab (if corelab was not available then the site-reported estimate was used).

- Clinical success defined as procedural success without procedural complications (death, major target limb amputation, thrombosis of the target lesion, or TVR) prior to discharge.

- Primary sustained clinical improvement is defined as sustained upward shift of at least 1 category on Rutherford classification as compared to baseline without the need for repeated TLR or surgical revascularization in amputation-free surviving subjects.

- Secondary sustained clinical improvement is defined as sustained upward shift of at least 1 category on Rutherford classification as compared to baseline including the need for repeated TLR or surgical revascularization in amputation-free surviving subjects.

- Safety composite endpoint consists of: freedom from device- and procedure-related death within 30 days, freedom from major target limb amputation, and freedom from clinically-driven TVR within 360 days post-index procedure.

- Clinically-driven TLR/TVR is defined as any re-intervention within the target vessel due to symptoms or drop of ABI/TBI of ≥20% or >0.15 when compared to post-procedure baseline ABI/TBI.

- Major Adverse Events (MAE) defined as all-cause death, clinically-driven TLR/TVR, major target limb amputation, thrombosis at the target lesion site at 360 days.

- Binary restenosis is defined as duplex restenosis (PSVR >2.4) of the target lesion at 12 months post-procedure, or at the time of reintervention prior to any pre-specified timepoint.

- Walking impairment assessed by Walking Impairment Questionnaire (WIQ) at 12 months.

# **Data sources:**

All events were adjudicated by the independent Clinical Events Committee, all duplex ultrasound and angiographic measures were made by the independent core laboratories, and all other data were site reported.

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### *Gender Analysis*

The results of sub-group analysis on gender are summarized in Table 14 below. The IN.PACT Global DCB Long Lesion Sub-Cohort included 153 males and 74 females at the time of the procedure. The comparison between genders showed the primary patency at 12 months to be 66.7% (70/105) in males and 60.9% (28/46) in females. The primary safety composite endpoint at 12 months was reported as 91.5% (129/141) and 95.7% (66/69) in males compared to females respectively. The MAE composite at 360 days were 10.6% (15/141) in males and 10.1% (7/69) in females.

**Table 14: Principal Effectiveness and Safety Results through 12-months by Gender**

|  Parameters | Male Subjects (N=153 Subjects) | Female Subjects (N=74 Subjects)  |
| --- | --- | --- |
|  **Effectiveness Parameters**  |   |   |
|  Primary Effectiveness Endpoint – Primary Patency at 12 Months | 66.7% (70/105) | 60.9% (28/46)  |
|  Primary Sustained Clinical Improvement at 12 Months | 79.7% (102/128) | 83.3% (50/60)  |
|  Secondary Sustained Clinical Improvement at 12 Months | 86.4% (108/125) | 86.7% (52/60)  |
|  Device Success | 98.9% (455/460) | 100.0% (198/198)  |
|  Procedural Success | 100.0% (153/153) | 97.3% (71/73)  |
|  Clinical Success | 100.0% (153/153) | 97.3% (71/73)  |
|  **Safety Parameters**  |   |   |
|  Primary Safety Composite Endpoint – Freedom from: | 91.5% (129/141) | 95.7% (66/69)  |
|  Device- and Procedure-related Death through 30 Days | 0.0% (0/151) | 0.0% (0/74)  |
|  Target Limb Major Amputation within 360 Days | 0.0% (0/141) | 0.0% (0/69)  |
|  Clinically-driven TVR within 360 Days | 8.5% (12/141) | 4.3% (3/69)  |
|  Death (all-cause) within 30 days | 0.0% (0/151) | 0.0% (0/74)  |
|  **Cumulative complications within 360 days**  |   |   |
|  MAE Composite (Death, Major Target Limb Amputation, Clinically-driven TVR, Thrombosis) | 10.6% (15/141) | 10.1% (7/69)  |
|  Death (all-cause) | 2.8% (4/141) | 1.4% (1/69)  |
|  Clinically-driven TVR | 8.5% (12/141) | 4.3% (3/69)  |
|  Major Target Limb Amputation | 0.0% (0/141) | 0.0% (0/69)  |
|  Thrombosis | 2.8% (4/141) | 4.3% (3/69)  |
|  Clinically-driven TLR | 8.5% (12/141) | 4.3% (3/69)  |
|  Any TVR | 8.5% (12/141) | 4.3% (3/69)  |
|  Any TLR | 8.5% (12/141) | 4.3% (3/69)  |
|  **Other Major Secondary Endpoints at 12 Months**  |   |   |

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|  Parameters | Male Subjects (N=153 Subjects) |   | Female Subjects (N=74 Subjects)  |   |
| --- | --- | --- | --- | --- |
|   |  Binary Restenosis (PSVR >2.4) | 32.0% (33/103) |   | 39.1% (18/46)  |
|  Time to First Clinically-driven TLR (days) |  |   |   |   |
|  N | 12 |   | 3  |   |
|  Mean ± SD | 195.5 ± 113.5 |   | 107.0 ± 116.9  |   |
|  Median | 213.0 |   | 42.0  |   |
|  Min, Max | 21, 356 |   | 37, 242  |   |
|  Walking Impairment by WIQ (%) |  |   |   |   |
|  N | 122 |   | 56  |   |
|  Mean ± SD | 73.0 ± 32.1 |   | 75.4 ± 33.5  |   |
|  Median | 100.0 |   | 100.0  |   |
|  Min, Max | 0, 100 |   | 0, 100  |   |

### *Assigned Imaging Cohorts Analyses*

The IN.PACT Global DCB Long Lesion Sub-Cohort was composed of subjects meeting the inclusion criteria specific to this analysis from the three (3) imaging cohorts (Long Lesion, CTO, and ISR) in the IN.PACT Global study. As such, a breakdown of the subject outcomes for each of the imaging cohorts was conducted and the results of that analysis are presented in Table 15 below. Slight variability was seen in for the primary effectiveness outcome as the Long Lesion, CTO and ISR imaging groups reported patency at 12 months of 66.2% (47/71), 68.8% (33/48) and 56.3% (18/32), respectively. The primary safety composite endpoint amongst the three (3) imaging cohorts was 94.2% (98/104) for Long Lesion, 92.2% (59/64) for CTO, and 90.5% (38/42) for ISR. The cumulative MAE rate at 360 days was 10.6% (11/104), 10.9% (7/64), 9.5% (4/42) for the Long Lesion, CTO, and ISR imaging cohorts, respectively. It is noted that the reintervention rates (TVR or TLR) were highest in the ISR group compared to Long Lesions or CTO. Conversely, the ISR group had no reported cases of death or thrombosis compared to the Long Lesion (2.9% and 4.8%, respectively) and the CTO (3.1% and 3.1%, respectively) imaging cohorts. Overall, binary restenosis in the imaging cohorts was 33.8% (24/71) for Long Lesion, 28.3% (13/46) for CTO, and 43.8% (14/32) for ISR.

**Table 15: Principal Effectiveness and Safety Results through 12-months by Assigned Imaging Sub-cohort**

|  Parameters | Long Lesion (N=114 Subjects) | CTO (N=67 Subjects) | De novo ISR (N=46 Subjects)  |
| --- | --- | --- | --- |
|  **Effectiveness Parameters** |  |  |   |
|  Primary Effectiveness Endpoint – Primary Patency at 12 Months | 66.2% (47/71) | 68.8% (33/48) | 56.3% (18/32)  |
|  Primary Sustained Clinical Improvement at 12 Months | 82.6% (76/92) | 83.9% (47/56) | 72.5% (29/40)  |

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|  Parameters | Long Lesion (N=114 Subjects) | CTO (N=67 Subjects) | De novo ISR (N=46 Subjects)  |
| --- | --- | --- | --- |
|  Secondary Sustained Clinical Improvement at 12 Months | 85.7% (78/91) | 90.7% (49/54) | 82.5% (33/40)  |
|  Device Success | 99.4% (324/326) | 99.0% (191/193) | 99.3% (138/139)  |
|  Procedural Success | 99.1% (112/113) | 100.0% (67/67) | 97.8% (45/46)  |
|  Clinical Success | 99.1% (112/113) | 100.0% (67/67) | 97.8% (45/46)  |
|  **Safety Parameters**  |   |   |   |
|  Primary Safety Composite Endpoint – Freedom from: | 94.2% (98/104) | 92.2% (59/64) | 90.5% (38/42)  |
|  Device- and Procedure-related Death through 30 Days | 0.0% (0/114) | 0.0% (0/66) | 0.0% (0/45)  |
|  Target Limb Major Amputation within 360 Days | 0.0% (0/104) | 0.0% (0/64) | 0.0% (0/42)  |
|  Clinically-driven TVR within 360 Days | 5.8% (6/104) | 7.8% (5/64) | 9.5% (4/42)  |
|  Death (all-cause) within 30 days | 0.0% (0/114) | 0.0% (0/66) | 0.0% (0/45)  |
|  **Cumulative complications within 360 days**  |   |   |   |
|  MAE Composite (Death, Major Target Limb Amputation, Clinically-driven TVR, Thrombosis) | 10.6% (11/104) | 10.9% (7/64) | 9.5% (4/42)  |
|  Death (all-cause) | 2.9% (3/104) | 3.1% (2/64) | 0.0% (0/42)  |
|  Clinically-driven TVR | 5.8% (6/104) | 7.8% (5/64) | 9.5% (4/42)  |
|  Major Target Limb Amputation | 0.0% (0/104) | 0.0% (0/64) | 0.0% (0/42)  |
|  Thrombosis | 4.8% (5/104) | 3.1% (2/64) | 0.0% (0/42)  |
|  Clinically-driven TLR | 5.8% (6/104) | 7.8% (5/64) | 9.5% (4/42)  |
|  Any TVR | 5.8% (6/104) | 7.8% (5/64) | 9.5% (4/42)  |
|  Any TLR | 5.8% (6/104) | 7.8% (5/64) | 9.5% (4/42)  |
|  **Other Major Secondary Endpoints at 12 Months**  |   |   |   |
|  Binary Restenosis (PSVR >2.4) | 33.8% (24/71) | 28.3% (13/46) | 43.8% (14/32)  |
|  Time to First Clinically-driven TLR (days)  |   |   |   |
|  N | 6 | 5 | 4  |
|  Mean ± SD | 182.8 ± 123.3 | 224.0 ± 124.6 | 112.5 ± 85.7  |
|  Median | 191.5 | 241.0 | 104.5  |
|  Min, Max | 50, 355 | 21, 356 | 37, 204  |
|  Walking Impairment by WIQ (%)  |   |   |   |
|  N | 86 | 53 | 39  |
|  Mean ± SD | 70.3 ± 34.8 | 79.7 ± 28.2 | 73.1 ± 32.1  |
|  Median | 75.0 | 100.0 | 100.0  |

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|  Parameters | Long Lesion (N=114 Subjects) | CTO (N=67 Subjects) | De novo ISR (N=46 Subjects)  |
| --- | --- | --- | --- |
|  Min, Max | 0, 100 | 0, 100 | 0, 100  |
|  Endpoint definitions:  |   |   |   |
|  •Primary patency is defined as freedom from clinically-driven TLR^{1} and freedom from restenosis as determined by duplex ultrasound^{2} (DUS) Peak Systolic Velocity Ratio (PSVR) ≤2.4^{3} within 12 months.  |   |   |   |
|  •Key Primary Patency endpoint definition components:  |   |   |   |
|  ^{1} Clinically-driven TLR is defined as any reintervention at the target lesion due to symptoms or drop of ABI/TBI of ≥20% or >0.15 when compared to post-procedure baseline ABI/TBI.  |   |   |   |
|  ^{2} Post-index procedure DUS is intended to establish a post-treatment baseline and does not contribute to the Primary Endpoint determination.  |   |   |   |
|  ^{3} Restenosis determined by either PSVR >2.4 (determined by Target Lesion Category of '50-99%' or 'Occluded') as assessed by an independent DUS core lab or >50% stenosis as assessed by an independent angiographic core lab.  |   |   |   |
|  •Device success defined as successful delivery, inflation, deflation and retrieval of the intact study balloon device without burst below the RBP. Results reported as device based summary.  |   |   |   |
|  •Procedure success defined as residual stenosis of ≤50% (non-stented subjects) or ≤30% (stented subjects) by corelab (if corelab was not available then the site-reported estimate was used).  |   |   |   |
|  •Clinical success defined as procedural success without procedural complications (death, major target limb amputation, thrombosis of the target lesion, or TVR) prior to discharge.  |   |   |   |
|  •Primary sustained clinical improvement is defined as sustained upward shift of at least 1 category on Rutherford classification as compared to baseline without the need for repeated TLR or surgical revascularization in amputation-free surviving subjects.  |   |   |   |
|  •Secondary sustained clinical improvement is defined as sustained upward shift of at least 1 category on Rutherford classification as compared to baseline including the need for repeated TLR or surgical revascularization in amputation-free surviving subjects.  |   |   |   |
|  •Safety composite endpoint consists of: freedom from device- and procedure-related death within 30 days, freedom from major target limb amputation, and freedom from clinically-driven TVR within 360 days post-index procedure  |   |   |   |
|  •Clinically-driven TLR/TVR is defined as any re-intervention within the target vessel due to symptoms or drop of ABI/TBI of ≥20% or >0.15 when compared to post-procedure baseline ABI/TBI.  |   |   |   |
|  •Major Adverse Events (MAE) defined as all-cause death, clinically-driven TLR/TVR, major target limb amputation, thrombosis at the target lesion site at 360 days.  |   |   |   |
|  •Binary restenosis is defined as duplex restenosis (PSVR >2.4 of the target lesion at 12 months post-procedure, or at the time of reintervention prior to any pre-specified timepoint.  |   |   |   |
|  •Walking impairment assessed by Walking Impairment Questionnaire (WIQ) at 12 months.  |   |   |   |
|  Data sources:  |   |   |   |
|  All events were adjudicated by the independent Clinical Events Committee, all duplex ultrasound and angiographic measures were made by the independent core laboratories, and all other data were site reported.  |   |   |   |

## 5. Pediatric Extrapolation

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

## E. Financial Disclosure

The Financial Disclosure by Clinical Investigators regulation (21 CFR 54) requires applicants who submit a marketing application to include certain information concerning the compensation to, and financial interests and arrangement of, any clinical investigator conducting clinical studies covered by the regulation. The

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pivotal clinical study included 130 investigators of which 0 were full-time or part-time employees of the sponsor and 3 had disclosable financial interests/arrangements as defined in 21 CFR 54.2(a), (b), (c) and (f) and described below:

- Compensation to the investigator for conducting the study where the value could be influenced by the outcome of the study: 0
- Significant payment of other sorts: 3
- Proprietary interest in the product tested held by the investigator: 0
- Significant equity interest held by investigator in sponsor of covered study: 0

The applicant has adequately disclosed the financial interest/arrangements with clinical investigators. Statistical analyses were conducted by FDA to determine whether the financial interests/arrangements had any impact on the clinical study outcome. The information provided does not raise any questions about the reliability of the data.

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

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

# XII. CONCLUSIONS DRAWN FROM PRECLINICAL AND CLINICAL STUDIES

# A. Effectiveness Conclusions

The primary effectiveness data are drawn from the IN.PACT Admiral Global DCB Long Lesion Sub-Cohort Clinical Evaluation. The results showed positive outcomes for treatment of long lesions (180-360 mm). Primary patency for all subjects in the sub-cohort was 64.9% at 12 months, with a mean total lesion length of 287.4 ± 71.1 mm. The results by lesion length trended as expected and showed favorable effectiveness results for lesion lengths up to 360 mm. The rate of CD-TLR was 7.1% at 12 months. The primary sustained clinical improvement was 80.9% at 12-months post-procedure. The device, procedural and clinical success was over 99% for the entire subject population in this sub-cohort. The effectiveness results were demonstrated to be sustained to 24 months, demonstrated by a CD-TLR rate of 20.2%.

# B. Safety Conclusions

The risks of the device are based on animal studies as well as data collected in a clinical study conducted to support PMA approval as described above. The IN.PACT Admiral Global DCB Long Lesion Sub-Cohort Clinical Evaluation showed positive outcomes for treatment of long lesions (180-360 mm). The primary safety composite endpoint for this this sub-cohort was 92.9%. Secondary endpoints also demonstrated the safety

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of the IN.PACT Admiral DCB in the treatment of long lesions (180-360 mm), with a total MAE composite rate at 12 months of 10.5%; which included 2.4% (5/210) deaths, 7.1% (15/210) CD-TVR, 3.3% (7/210) cases of thrombosis, and no reported major target limb amputations. The results by lesion length demonstrated favorable safety results for lesion lengths up to 360 mm.

### C. Benefit-Risk Determination

The probable benefits of the device are also based on data collected in a clinical study conducted to support PMA approval as described above. The probable benefits of the IN.PACT Admiral for improving patient symptoms outweigh the probable risks associated with use of the device for this indication. The IN.PACT Admiral DCB has favorable results for the 12-month primary endpoints.

Secondary endpoints also demonstrated the safety and effectiveness of the IN.PACT Admiral DCB in the treatment of long lesions up to 360 mm, with no major target limb amputations and five (5) non-device related deaths.

Additional outcomes, including CD-TLR, CD-TVR, adverse events, and serious adverse events, were reported for the DCB Long Lesion Cohort subjects to further support the safety and effectiveness of the IN.PACT Admiral DCB in the treatment of long lesions up to 360 mm in superficial femoral or popliteal arteries.

#### 1. Patient Perspectives

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

In conclusion, given the available information above, the data supports that the probable benefits outweighs the probable risks for percutaneous transluminal angioplasty, after appropriate vessel preparation, of *de novo*, restenotic, or in-stent restenotic lesions with lengths up to 360 mm in superficial femoral or popliteal arteries with reference vessel diameters of 4-7 mm.

### D. Overall Conclusions

The clinical and non-clinical data support with reasonable assurance of safety and effectiveness of this device when used in accordance with the indications for use. The results from the global clinical study support that the probable benefits outweigh the probable risks to support the use of the IN.PACT Admiral DCB for percutaneous transluminal angioplasty, after appropriate vessel preparation, of *de novo*, restenotic, or in-stent restenotic lesions with lengths up to 360 mm in superficial femoral or popliteal arteries with reference vessel diameters of 4-7 mm when used in accordance with the Instructions for Use. In consideration of the regulatory history and clinical information previously available for this device as well as the quality and robustness of the clinical data provided in this submission, the results provide valid scientific evidence supporting the proposed indication expansion.

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### XIII. CDRH DECISION

CDRH issued an approval order on April 19, 2018.

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

### XIV. APPROVAL SPECIFICATIONS

Directions for use: See device labeling.

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

Post-approval Requirements and Restrictions: See approval order.

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**Source:** [https://fda.innolitics.com/device/P140010S037](https://fda.innolitics.com/device/P140010S037)

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