Valiant Navion Thoracic Stent Graft System

P100040S036 · Medtronic Vascular · MIH · Oct 19, 2018 · Cardiovascular

Device Facts

• Record ID: P100040S036
• Device Name: Valiant Navion Thoracic Stent Graft System
• Applicant: Medtronic Vascular
• Product Code: MIH · Cardiovascular
• Decision Date: Oct 19, 2018
• Decision: APPR
• Device Class: Class 3
• Attributes: Therapeutic

Indications for Use

The Valiant Navion™ Thoracic Stent Graft System is indicated for the endovascular repair of all lesions of the descending thoracic aorta (DTA) in patients having the appropriate anatomy including: iliac or femoral artery access vessel morphology that is compatible with vascular access techniques, devices, or accessories; nonaneurysmal aortic diameter in the range of: 16 mm to 42 mm for fusiform and saccular aneurysms/penetrating ulcers, 16 mm to 44 mm for blunt traumatic aortic injuries, 19 mm to 45 mm for dissections; proximal landing zone (nonaneurysmal aortic proximal neck length for fusiform and saccular aneurysms/penetrating ulcers or nondissected length of aorta proximal to the primary tear for blunt traumatic aortic injuries and dissections) of: ≥ 20mm for FreeFlo configuration, ≥ 25mm for CoveredSeal configuration; and nonaneurysmal aortic distal neck length ≥ 20mm for FreeFlo and CoveredSeal configurations for fusiform and saccular aneurysms/penetrating ulcers.

Device Story

Valiant Navion Thoracic Stent Graft System is a self-expanding, endoluminal prosthesis for DTA lesion repair. System includes a nitinol-scaffolded polyester stent graft and a disposable delivery catheter (18-22 Fr). Physician inserts device via femoral/iliac artery over 0.035" guidewire; stent graft self-expands to seal against aortic wall. Platinum-Iridium markers provide radiographic visualization. Used in OR/cath lab by vascular specialists. Output is a physical barrier excluding the lesion from blood flow; reduces aneurysm pressure/risk of rupture. Benefits include smaller delivery profile, broader size range, and controlled deployment compared to predecessor (Valiant Captivia).

Clinical Evidence

Prospective, multi-center, single-arm IDE study (n=87 evaluable). Primary endpoint: composite of access/deployment failures and Major Device Effects (MDE) at 30 days. Results: 2.3% event rate (2/87), meeting 16% performance goal (p<0.0001). Secondary endpoints included mortality, endoleaks, and secondary procedures through 365 days. No loss of stent graft patency reported. 9.5% endoleak rate at 12 months. Bench testing and animal studies (ovine model) support device integrity.

Technological Characteristics

Self-expanding tubular endoprosthesis; polyester fabric with nitinol stent scaffold. Platinum-Iridium radiopaque markers. Delivery system: 18-22 Fr, 93 cm length, hydrophilic coating. E-Beam sterilized. MR Conditional (1.5T/3T). Complies with BS EN ISO 25539-1:2017.

Indications for Use

Indicated for endovascular repair of descending thoracic aorta (DTA) lesions (aneurysms, Type B dissections, transections) in patients ≥18 years with appropriate iliac/femoral access and specific aortic diameter/neck length criteria. Contraindicated in patients with infection-prone conditions or material allergies.

Predicate Devices

• Valiant Thoracic Stent Graft with the Captivia Delivery System (P100040)

Submission Summary (Full Text)

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# SUMMARY OF SAFETY AND EFFECTIVENESS DATA (SSED)

## I. GENERAL INFORMATION

Device Generic Name: Endovascular Graft

Device Trade Name: Valiant Navion™ Thoracic Stent Graft System

Device Procode: MIH

Applicant's Name and Address: Medtronic Vascular
3676 Unocal Place
Santa Rosa, CA 95403
USA

Date of Panel Recommendation: None

Premarket Approval Application (PMA) Number: P100040/S036

Date of FDA Notice of Approval: October 19, 2018

The Valiant Navion™ Thoracic Stent Graft System is Medtronic Vascular’s next generation thoracic stent graft system, based on the Valiant® Thoracic Stent Graft with the Captivia® Delivery System.

The original PMA (P100040) for the Valiant® Thoracic Stent Graft with the Captivia® Delivery System was approved on April 1, 2011 for the endovascular repair of fusiform aneurysms and saccular aneurysms/penetrating ulcers of the descending thoracic aorta (DTA). The indications for use were expanded to include the treatment of isolated lesions (excluding dissections) of the DTA in patients who have appropriate anatomy via P100040/S008 on October 26, 2012, based on the submission of data for the treatment of traumatic transections. The indications for use were further expanded for the Valiant® Thoracic Stent Graft with the Captivia® Delivery System via P100040/S012 on January 22, 2014 to include the treatment of all lesions of the DTA, including Type B dissections. The Summaries of Safety and Effectiveness Data (SSED) to support the original approval and the expanded indications are available on the CDRH website and are incorporated by reference here.

Original PMA Approval:

https://www.accessdata.fda.gov/cdrh_docs/pdf10/P100040B.pdf

Indication Expansion (P100040/S008):

https://www.accessdata.fda.gov/cdrh_docs/pdf10/P100040S008B.pdf

Indication Expansion (P100040/S012):

https://www.accessdata.fda.gov/cdrh_docs/pdf10/P100040S012B.pdf

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This panel-track PMA Supplement was submitted to obtain approval of the Valiant Navion™ Thoracic Stent Graft System, a modified device design from the Valiant® Thoracic Stent Graft with the Captivia® Delivery System, for the treatment of all lesions of the DTA including, but not limited to, aneurysm, Type B dissections, and transections.

## II. INDICATIONS FOR USE

The Valiant Navion™ Thoracic Stent Graft System is indicated for the endovascular repair of all lesions of the descending thoracic aorta (DTA) in patients having the appropriate anatomy including:

- iliac or femoral artery access vessel morphology that is compatible with vascular access techniques, devices, or accessories;
- nonaneurysmal aortic diameter in the range of:
- 16 mm to 42 mm for fusiform and saccular aneurysms/penetrating ulcers
- 16 mm to 44 mm for blunt traumatic aortic injuries
- 19 mm to 45 mm for dissections;
- proximal landing zone (nonaneurysmal aortic proximal neck length for fusiform and saccular aneurysms/penetrating ulcers or nondissected length of aorta proximal to the primary tear for blunt traumatic aortic injuries and dissections) of:
- ≥ 20mm for FreeFlo configuration
- ≥ 25mm for CoveredSeal configuration; and
- nonaneurysmal aortic distal neck length ≥ 20mm for FreeFlo and CoveredSeal configurations for fusiform and saccular aneurysms/penetrating ulcers.

### III. CONTRAINDICATIONS

The Valiant Navion™ Thoracic Stent Graft System is contraindicated in the following patient populations:

- Patients who have a condition that threatens to infect the graft
- Patients who are sensitive to or have allergies to the device materials

### IV. WARNINGS AND PRECAUTIONS

The warnings and precautions can be found in the Valiant Navion™ Thoracic Stent Graft System Instructions for Use.

### V. DEVICE DESCRIPTION

The Valiant Navion™ Thoracic Stent Graft System (also referred to as Valiant Navion Thoracic Stent Graft System) is comprised of two components:

- Valiant Navion stent graft
- Valiant Navion delivery system

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The Valiant Navion stent graft is intended to be delivered endoluminally via access through the femoral or iliac artery to the site of the lesion using the Valiant Navion delivery system. The stent graft is inserted into and constrained by the delivery system outer sheath (graft cover). The pre-loaded stent graft is advanced to the lesion location over a guidewire. Upon deployment, the stent graft self-expands due to the superelastic properties of the nitinol stents. The proximal and distal ends of the stent graft are intended to conform to the shape and size of the proximal and distal seal zones due to the radial force of the stents.

## Valiant Navion Stent Graft

Valiant Navion stent graft is a self-expanding, tubular endoprosthesis composed of polyester graft fabric and a stent scaffold made from nitinol wire. The metal scaffolding is composed of a series of sinusoidal stents stacked in a tubular configuration. Non-resorbable sutures attach the stents to the polyester fabric.

Platinum-Iridium radiopaque (RO) markers are sewn to the fabric to allow radiographic visualization of the edges of the graft material, and to provide a guide to the minimum overlap distance required when multiple stent grafts are used. The three proximal spherical markers and the two distal spherical markers indicate the extremities of the covered stent graft. The mid graft marker indicates a potential overlap edge, in the event additional stent grafts are used. The RO markers are at the same location and have the same configuration in all the Valiant Navion stent graft configurations.

A single, primary Valiant Navion stent graft may be used by itself if its length is sufficient to provide the desired coverage. Alternatively, it may be used in combination with additional Valiant Navion stent graft configurations that increase the graft length distally or proximally to the primary section.

The Valiant Navion stent graft is available in four configuration options:

# - • FreeFlo Straight

The FreeFlo Straight configuration stent grafts are available in diameters ranging from 20 mm to 46 mm and covered lengths of approximately 60mm, 100 mm, 175 mm, and 225 mm.

# - • FreeFlo Tapered

The FreeFlo Tapered configurations are available in proximal diameters ranging from 25 mm to 46 mm and distal diameters ranging from 20 mm to 40 mm. The covered length is approximately 175 mm with a stent graft taper of 5 mm for the smallest diameter configuration and 6 mm for the remaining sizes.

# - • CoveredSeal Straight

The CoveredSeal Straight configuration stent grafts are available in diameters ranging from 20 mm to 46 mm and covered lengths of approximately 60mm, 100 mm, 175 mm, and 225 mm.

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• CoveredSeal Tapered

The CoveredSeal Tapered configurations are available in proximal diameters ranging from 25 mm to 46 mm and distal diameters ranging from 20 mm to 40 mm. The covered length is approximately 175 mm and 200 mm with a stent graft taper of 5 mm for the smallest diameter configuration and 6 mm for the remaining sizes.

See Figure 1 below for the drawing of the four stent graft configurations of the Valiant Navion Thoracic Stent Graft System.

Figure 1: Stent Graft Configuration Components


1. FreeFlo Straight
2. FreeFlo Tapered
3. CoveredSeal Straight
4. CoveredSeal Tapered
5. Proximal end
6. Distal end
7. FreeFlo stent
8. Internal stent
9. Support stent
10. RO marker
11. Covered length
12. Total length

# Valiant Navion Delivery System

The Valiant Navion delivery system consists of a single-use, disposable catheter with an integrated handle, intended to provide controlled deployment. It is available in an outer diameter of 18, 20, and 22 Fr and a working length of 93 cm. The catheter assembly is flexible and exclusively compatible with a 0.035 in (0.89 mm) guidewire. A flexible tapered tip is attached to the end of the inner member and provides a smooth transition from the guidewire to the outer graft cover. The external surfaces of the tapered tip and graft cover are coated with a lubricious hydrophilic coating. Once activated with a sterile gauze

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saturated in saline, this coating facilitates vessel access and tracking through the anatomy. A distal RO marker indicates the graft cover edge under fluoroscopy. The flush port includes a one-way valve that prevents backflow of flush fluid and maintains hemostasis during the procedure, while allowing the delivery system to be flushed during device preparation. The stent graft is deployed by rotating or retracting the integrated slider handle. The tip capture release handle at the rear of the delivery system is unlocked and retracted to release the proximal end of the stent graft.

Figure 2: Delivery System Components


1. Luer connector

2. Screw gear

3. Slider handle

4. Trigger

5. Front grip

6. Graft cover

7. Stent stop

8. Tip capture mechanism

9. RO marker band

10. Tapered tip

11. Back-end lock

12. Tip capture release handle

13. Clamping ring

14. Flush port

For additional details on the Valiant Navion Thoracic Stent Graft System, refer to the Valiant Navion Thoracic Stent Graft System Instructions for Use.

### VI. ALTERNATIVE PRACTICES AND PROCEDURES

There are several alternatives for the treatment of lesions of the descending thoracic aorta including medical management, open surgical repair, and endovascular repair using another endovascular grafting system. Each alternative has its own advantages and disadvantages. A patient should fully discuss these alternatives with his/her physician to select the method that best meets expectations and lifestyle.

### VII. MARKETING HISTORY

The Valiant Navion Thoracic Stent Graft System has not been marketed in the United States or any foreign country.

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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 device provided from the Valiant Navion Thoracic Stent Graft System Instructions for Use.

| Access failure | Embolism | Procedural bleeding |
| --- | --- | --- |
| Access site complications (for example, spasm, trauma, bleeding, rupture, dissection) | Endoleaks | Prosthesis dilatation |
| Adynamic ileus | Excessive or inappropriate radiation exposure | Prosthesis infection |
| Allergic reaction (to contrast, antiplatelet therapy, stent graft material) | Extrusion/erosion | Prosthesis rupture |
| Amputation | Failure to deliver the stent graft | Prosthesis thrombosis |
| Anaphylaxis | Femoral neuropathy | Pseudoaneurysm |
| Anesthetic complications | Fistula (including aortobronchia, aortoenteric, aortoesophageal, arteriovenous, and lymph) | Pulmonary edema |
| Aneurysm rupture | Gastrointestinal bleeding/complications | Pulmonary embolism |
| Angina | Genitourinary complications | Reaction to anaesthesia |
| Aortic expansion (for example: aneurysm, false lumen) | Hematoma | Renal failure |
| Aortic valve damage | Hemorrhage/bleeding | Renal insufficiency |
| Aortic vessel rupture | Hypotension/hypertension | Reoperation |
| Arrhythmia | Infection or fever | Respiratory depression or failure |
| Arterial stenosis | Insertion or removal difficulty | Retrograde type A dissection |
| Atelectasis | Intercostal pain | Sepsis |
| Balloon rupture | Intramural hematoma | Seroma |
| Blindness | Leg edema/foot edema | Sexual dysfunction |
| Bowel ischemia | Loss of patency | Shock |
| Bowel necrosis | Lymphocele | Spinal neurological deficit |
| Bowel obstruction | Myocardial infarction | Stenosis |
| Branch vessel occlusion | Neck enlargement | Stent graft migration |
| Breakage of the metal portion of the device | Nerve injury | Stent graft misplacement |
| Buttock claudication | Neuropathy | Stent graft occlusion |

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| Cardiac tamponade | Occlusion - Venous or Arterial | Stent graft rupture (for example: holes, tears) |
| --- | --- | --- |
| Catheter breakage | Pain/reaction at catheter insertion site | Stent graft twisting or kinking |
| Cerebrovascular accident (CVA)/Stroke | Paralysis | Transient ischemic attack (TIA) |
| Change in mental status | Paraparesis | Thrombosis |
| Coagulopathy | Paraplegia | Tissue necrosis |
| Congestive heart failure | Paresthesia | Vascular ischemia |
| Contrast toxicity | Perfusion of the false lumen | Vascular trauma |
| Conversion to surgical repair | Peripheral ischemia | Wound dehiscence |
| Damage to the vessel | Peripheral nerve injury | Wound healing complications |
| Death | Pneumonia | Wound infection |
| Deployment difficulties/failures | Postimplant syndrome | |
| Dissection, perforation, or rupture of the aortic vessel & surrounding vasculature | Post-procedural bleeding | |

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

## IX. SUMMARY OF NONCLINICAL STUDIES

The following nonclinical studies were performed on the Valiant Navion Thoracic Stent Graft System:

- A. Biocompatibility Testing
- B. In Vitro Bench Testing
- C. Sterilization, Packaging, and Shelf Life
- D. Animal Studies

### A. Biocompatibility Testing

Biocompatibility testing was conducted on materials in the Valiant Navion Thoracic Stent Graft System in accordance with Good Laboratory Practice for Non clinical Laboratory Studies (21 CFR 58). The test strategy and biological end point requirements were selected in consideration of the following standard/ guidances:

- International Standard ISO 10993-1, Biological Evaluation of Medical Devices
- YAKUSHOKUKIHATSU No. 0301-20: 2012, Requirements specified by the Japanese Ministry of Health, Labour, and Welfare (MHLW)

Table 1 and Table 2 summarize the biocompatibility test results for the Valiant Navion stent graft and Valiant Navion delivery system, respectively.

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Test methods were performed in accordance with the following, as referenced:

- ISO 10993-3: Tests for genotoxicity, carcinogenicity, and reproductive toxicity
- ISO 10993-4: Selection of tests for interactions with blood
- ISO 10993-5: Tests for *in vitro* cytotoxicity
- ISO 10993-6: Tests for local effects after implantation
- ISO 10993-10: Tests for irritation and skin sensitization
- ISO 10993-11: Tests for systemic toxicity
- YAKUSHOKUKIHATSU No. 0301-20: 2012, Requirements specified by the Japanese Ministry of Health, Labour, and Welfare (MHLW)
- United States Pharmacopeia (USP) 38, National Formulary (NF) 33, General Chapter <151>, Pyrogen Test
- American Society for Testing and Materials (ASTM) F756, Standard Practice for Assessment of Hemolytic Properties of Materials
- American Society for Testing and Materials (ASTM) F2382, Standard Test Method for Assessment of Intravascular Medical Device Materials on Partial Thromboplastin Time (PTT)

**Table 1: Biocompatibility Test Results for Valiant Navion Stent Graft**

| Test Method | Test Purpose | Acceptance Criteria | Results |
| --- | --- | --- | --- |
| Cytotoxicity Study Using the Colony Assay (Extraction Method) – ISO 10993- 5 and MHLW | To evaluate the potential for leaching substances from the test article to produce cytotoxicity by measuring the effect on colony formation of Chinese hamster lung cells (V79-4). | An IC_{50} of 100% or more indicates no/very weak cytotoxicity; IC_{50} weaker than Positive Control B indicates weak cytotoxicity; IC_{50} midway between Positive Control A and Positive Control B indicates moderate cytotoxicity; IC_{50} stronger than Positive Control A indicates severe cytotoxicity. A cytotoxic response was determined as a 30% or greater reduction in colonies as compared to the reagent control. | Pass |
| Cytotoxicity Study Using the ISO 10993- 5 Direct Contact Method | To evaluate the cytotoxicity of a test article using an *in vitro* mammalian cell culture test. | The test article must result in a grade 2 or less. | Pass |
| Cytotoxicity Study Using the ISO 10993- 5 Elution Method | To determine whether leachables extracted from the test article would cause cytotoxicity. | The test article must result in a grade 2 or less. | Pass |
| Guinea Pig Maximization Sensitization Test – ISO 10993-10 | To evaluate the potential of the test article to cause delayed dermal contact sensitization in the guinea pig maximization test. | A grade of ≥ 1 in the test group indicates sensitization provided the corresponding control group is graded < 1. | Pass |

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| Test Method | Test Purpose | Acceptance Criteria | Results |
| --- | --- | --- | --- |
| Intracutaneous Study in Rabbits – ISO 10993-10 | To evaluate the local dermal irritation of a test article extract following intracutaneous injection in rabbits. | The difference between the test extract mean score and the corresponding control mean score must be 1.0 or less. | Pass |
| Systemic Toxicity Study in Mice, MHLW and ISO10993-11 | To evaluate acute systemic toxicity of a test article extract following a single intravenous or intraperitoneal injection in mice. | If during the observation period none of the test animals show a significantly greater reaction than the corresponding control animals, the test article meets the test requirements. | Pass |
| Systemic Toxicity in Rats Following Subcutaneous Implantation, 4 Weeks – ISO 10993-11 and ISO 10993-6 | To evaluate the potential for systemic toxicity of the test article following subcutaneous implantation in the rat for up to 4 weeks. The local tissue response to the test article at the implantation sites was also evaluated. | Body weight, organ weight, organ/body and organ/brain weight ratios, hematology, and clinical chemistry data will be evaluated statistically. Male and female data will be analyzed separately. Calculations resulting in p-values < 0.05 will be considered statistically significant. In the event of statistical significance for any hematologic parameter, the results may be compared to a reference range to determine biological significance. A pathologist will conduct a subjective microscopic evaluation of changes in tissues using a scoring scheme from 1 (minimal) to 4 (marked). The tissues will be evaluated for evidence of toxicity. Microscopic evaluation of the implant sites will be graded based on ISO, with the scores of the test article sites compared to the control article sites. | Pass |
| Systemic Toxicity Study in Rats Following Subcutaneous Implantation, 13 Weeks – ISO 10993-11 and ISO 10993-6 | To evaluate the potential for systemic toxicity of the test article following subcutaneous implantation in the rat for up to 13 weeks. The local tissue response to the test article at the implantation sites was also evaluated. | Body weight, organ weight, organ/body and organ/brain weight ratios, hematology, and clinical chemistry data will be evaluated statistically. Male and female data will be analyzed separately. Calculations resulting in p-values < 0.05 will be considered statistically significant. In the event of statistical significance for any | Pass |

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| Test Method | Test Purpose | Acceptance Criteria | Results |
| --- | --- | --- | --- |
| | | hematologic parameter, the results may be compared to a reference range to determine biological significance. A pathologist will conduct a subjective microscopic evaluation of changes in tissues using a scoring scheme from 1 (minimal) to 4 (marked). The tissues will be evaluated for evidence of toxicity. Microscopic evaluation of the implant sites will be graded based on ISO, with the scores of the test article sites compared to the control article sites. | |
| Rabbit Pyrogen Study, Material Mediated - USP38-NF33<151> and ISO 10993-11 | To determine whether an extract of the test article induced a pyrogenic response following intravenous injection in rabbits. | If no animal shows an individual rise in temperature of 0.5°C or more above its baseline temperature, the test article meets the requirements for the absence of pyrogens. | Pass |
| Bacterial Reverse Mutation Study – ISO 10993-3 | To evaluate whether a test article extract would cause mutagenic changes in *Salmonella typhimurium* tester strains TA98, TA100, TA1535, and TA1537, and *Escherichia coli* tester strain WP2*uvrA* in the presence and absence of mammalian metabolic activation. | For the test article to be identified as a potential mutagen, there must be a 2-fold or greater increase in the number of mean revertants over the means obtained from the negative control for strains TA98, TA100, and WP2*uvrA*. For the test article to be identified as a potential mutagen there must be a 3-fold or greater increase in the number of mean revertants over the means obtained from the negative control for strains TA1535 and TA1537. | Pass |
| Mouse Lymphoma Assay – ISO 10993-3 | To evaluate whether the test article extract induced gene mutations and chromosomal damage in mammalian cells. | The test article will be evaluated as positive if there is a two-fold or greater increase in mean mutation frequency over the mean background mutation frequency of the negative (vehicle) control. The test article will be evaluated as negative if a two-fold increase is not observed. The test article will be evaluated as equivocal if there is no consistent evidence for either | Pass |

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| Test Method | Test Purpose | Acceptance Criteria | Results |
| --- | --- | --- | --- |
| | | a positive or negative evaluation. | |
| Mouse Peripheral Blood Micronucleus Study – ISO 10993-3 | To evaluate the potential for a test article extract to cause damage to chromosomes or the mitotic apparatus of murine erythroblasts by measuring the frequency of micronucleated reticulocytes (MN-RETs) in mice. | The test article will be evaluated as positive if there is a two-fold or greater increase in mean mutation frequency over the mean background mutation frequency of the negative (vehicle) control. The test article will be evaluated as negative if a two-fold increase is not observed. The test article will be evaluated as equivocal if there is no consistent evidence for either a positive or negative evaluation. | Pass |
| Hemolysis Study – ASTM F756 and ISO 10993-4 | To determine whether the test article would cause hemolysis *in vitro* by direct contact or extraction. | Resulting hemolytic index of ≤ 2% will be considered non-hemolytic, 2 to 5% will be considered slightly hemolytic, and > 5% will be considered hemolytic. A resulting hemolytic index of ≤ 5% will be considered acceptable. | Pass |
| Complement Activation, C3a – ISO 10993-4 | To determine the complement activation potential of the test article using an *in vitro* system. | If the C3a concentration in the test article is statistically similar to at least the negative control, activated normal human serum (NHS), or the sponsor-provided control, the test article is not considered an activator of the complement system. If the C3a concentration in the test article is not statistically similar to any of the aforementioned controls, an evaluation with regards to overall patient safety will be completed. | Pass |
| Complement Activation, SC5b-9 – ISO 10993-4 | To determine the potential of the test article to activate the complement system. | If the SC5b-9 concentration in the test article is statistically similar to at least the negative control, activated NHS, or the sponsor-provided control, the test article is not considered an activator of the complement system. If the SC5b-9 concentration in the test article is not statistically similar to any of the aforementioned controls, an evaluation with regards to overall patient safety will be completed. | Pass |
| Partial Thromboplastin | To determine the potential of | % of negative control > 50% | Pass |

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| Test Method | Test Purpose | Acceptance Criteria | Results |
| --- | --- | --- | --- |
| Time – ASTM F2382 and ISO 10993-4 | the test article to cause an effect on the coagulation cascade via the intrinsic coagulation pathway. | is considered acceptable per ASTM F2382. | |
| *In vivo* thromboresistance – ISO 10993-4 | To evaluate relative thromboresistance of the test article *in vivo*. | Thrombi formation will be scored 0 (No significant thrombosis) to 5 (Vessel completely occluded). The test article must score better or similarly when compared to the commercially approved sponsor-provided control article. | Pass |

**Table 2: Biocompatibility Test Results for Valiant Navion Delivery System**

| Test Method | Test Purpose | Acceptance Criteria | Results |
| --- | --- | --- | --- |
| Cytotoxicity Study Using the ISO 10993-5 Elution Method | To determine whether leachables extracted from the test article would cause cytotoxicity. | The test article must result in a grade 2 or less. | Pass |
| Guinea Pig Maximization Sensitization Test – ISO 10993-10 | To evaluate the potential of the test article to cause delayed dermal contact sensitization in the guinea pig maximization test. | A grade of ≥ 1 in the test group indicates sensitization provided the corresponding control group is graded < 1. | Pass |
| Intracutaneous Study in Rabbits – ISO 10993-11 | To evaluate the local dermal irritation of a test article extract following intracutaneous injection in rabbits. | The difference between the test extract mean score and the corresponding control mean score must be 1.0 or less. | Pass |
| Systemic Toxicity Study in Mice – ISO 10993-11 | To determine whether leachables extracted from the test article would cause acute systemic toxicity following injection into mice. | If during the observation period none of the test animals show a significantly greater reaction than the corresponding control animals, the test article meets the test requirements. | Pass |
| Rabbit Pyrogen Study, Material Mediated – USP38-NF33<151> and ISO 10993-11 | To determine whether an extract of the test article induced a pyrogenic response following intravenous injection in rabbits. | If no animal shows an individual rise in temperature of 0.5°C or more above its baseline temperature, the test article meets the requirements for the absence of pyrogens. | Pass |

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| Test Method | Test Purpose | Acceptance Criteria | Results |
| --- | --- | --- | --- |
| Bacterial Reverse Mutation Study – ISO 10993-3 | To evaluate whether a test article extract would cause mutagenic changes in *Salmonella typhimurium* tester strains TA98, TA100, TA1535, and TA1537, and *Escherichia coli* tester strain WP2*uvrA* in the presence and absence of mammalian metabolic activation. | For the test article to be identified as a potential mutagen there must be a 2-fold or greater increase in the number of mean revertants over the means obtained from the negative control for strains TA98, TA100, and WP2*uvrA*. For the test article to be identified as a potential mutagen there must be a 3-fold or greater increase in the number of mean revertants over the means obtained from the negative control for strains TA1535 and TA1537. | Pass |
| Mouse Lymphoma Assay – ISO 10993-3 | To evaluate whether the test article extract induced gene mutations and chromosomal damage in mammalian cells. | The test article will be evaluated as positive if there is a two-fold or greater increase in mean mutation frequency over the mean background mutation frequency of the negative (vehicle) control. The test article will be evaluated as negative if a two-fold increase is not observed. The test article will be evaluated as equivocal if there is no consistent evidence for either a positive or negative evaluation. | Pass |
| Hemolysis Study – ASTM F756 and ISO 10993-4 | To determine whether the test article would cause hemolysis *in vitro* by direct contact or extraction. | Resulting hemolytic index of ≤ 2% will be considered non-hemolytic, 2 to 5% will be considered slightly hemolytic, and > 5% will be considered hemolytic. A resulting hemolytic index of ≤ 5% will be considered acceptable. | Pass |
| C3a Complement Activation Assay – ISO 10993-4 | To determine the complement activation potential of the test article using an *in vitro* system. | If the C3a concentration in the test article is statistically similar to at least the negative control, activated NHS, or the sponsor-provided control, the test article is not considered an activator of the complement system. If the C3a concentration in the test article is not statistically similar to any of the aforementioned controls, an evaluation with regards to overall patient safety will be completed. | Pass |

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| Test Method | Test Purpose | Acceptance Criteria | Results |
| --- | --- | --- | --- |
| SC5b-9 Complement Activation Assay – ISO 10993-4 | To determine the potential of the test article to activate the complement system. | If the SC5b-9 concentration in the test article is statistically similar to at least the negative control, activated NHS, or the sponsor-provided control, the test article is not considered an activator of the complement system. If the SC5b-9 concentration in the test article is not statistically similar to any of the aforementioned controls, an evaluation with regards to overall patient safety will be completed. | Pass |
| Partial Thromboplastin Time – ASTM F2382 and ISO 10993-4 | To determine the potential of the test article to cause an effect on the coagulation cascade via the intrinsic coagulation pathway. | % of negative control > 50% is considered acceptable per ASTM F2382. | Pass |
| *In Vivo* Thromboresistance Study in Swine – ISO 10993-4 | To evaluate relative thromboresistance of the materials *in vivo*. | Thrombi formation will be scored 0 (No significant thrombosis) to 5 (Vessel completely occluded). The test article must score better or similarly when compared to the commercially approved sponsor-provided control article. | Pass |

## **B. *In Vitro* Bench Testing**

*In vitro* design verification and validation testing of the Valiant Navion Thoracic Stent Graft System was carried out to determine whether the design met all associated Product Performance Specifications and to confirm similar *in vitro* performance to the Valiant® Thoracic Stent Graft with the Captivia® Delivery System (also referred to as the Valiant Captivia Thoracic Stent Graft System). Testing was conducted on a subset of device configurations/sizes representative of the entire catalog or worst-case for each test, as appropriate to represent the entire device range available with the Valiant Navion Thoracic Stent Graft System. All *in vitro* bench tests produced acceptable results.

Bench testing was performed per Medtronic Vascular test protocols which incorporated the requirements of the international standard BS EN ISO 25539-1:2017 *Cardiovascular Implants – Endovascular Devices – Part 1: Endovascular Prostheses*. The testing details include results from T=0 (baseline) as well as results using samples accelerated aged to 2 years (T=2). An asterisk (*) indicates testing was performed at both T=0 and T=2. A summary of the *in vitro* testing is provided in **Table 3**. Results obtained from *in vitro* testing provided evidence supporting the safety and effectiveness of the Valiant Navion Thoracic Stent Graft System.

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Table 3: Summary of Tests Performed Related to Functionality of the Valiant Navion Thoracic Stent Graft System

| In Vitro Test | Test Purpose | Acceptance Criteria | | Results |
| --- | --- | --- | --- | --- |
| Crossing Profile* | To assess the maximum outside diameter of the delivery system. | Appropriate ring gauge must pass over the loaded delivery system per the table below: | | Pass |
| | | Catheter Size | Crossing Profile (OD, max) | |
| | | 18 Fr | 6.17 mm | |
| | | 20 Fr | 6.83 mm | |
| | | 22 Fr | 7.50 mm | |
| Delivery System Dimensional Verification* | To determine the working length and the hydrophilic length of the delivery system. | Working Length = 93 ± 2 cm Hydrophilic Coating Length > 80 cm | | Pass |
| Stent Graft Dimensional Verification Post Deployment (Outer Diameter)* | To measure the diameter of a Valiant Navion stent graft post deployment. | Diameter ≥ (Labeled Nominal Diameter – 1 mm) | | Pass |
| Stent Graft Dimensional Verification Post Deployment (Length)* | To measure the stent graft length post deployment. | Covered Stent Graft Length = | | Pass |
| | | Nominal (mm) | Tolerance (mm) | |
| | | 60 | +3 / -6 | |
| | | 100 | +5 / -10 | |
| | | 175 | +10 / -15 | |
| | | 200 | +10 / -15 | |
| | | 225 | +10 / -20 | |
| Delivery System Hemostasis* | To determine the hemostatic flow rate of the delivery system when pressurized to physiologic conditions. | Water flow rate < 6.5 mL/min | | Pass |
| Graft Cover to Radiopaque Marker Bond Strength* | To determine the maximum load required to break the bond between the graft cover and radiopaque (RO) marker of the delivery system. | Ultimate Tensile Strength Lower Tolerance Limit (LTL) > 0.5 * Net Deployment Force UTL | | Pass |
| Graft Cover T-tube Tensile Strength* | To determine the maximum load required to break the bond between the graft cover and graft cover T-tube overmold of the delivery system. | Ultimate Tensile Strength LTL > Net Deployment Force UTL | | Pass |
| Graft Cover Yield Strength* | To determine the midpoint yield strength of the graft cover of the delivery system. | Midpoint Yield Strength LTL > Net Deployment Force UTL | | Pass |

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| In Vitro Test | Test Purpose | Acceptance Criteria | Results |
| --- | --- | --- | --- |
| Graft Cover Bond Strength* | To determine the maximum load required to break the bond between the two sections of the delivery system graft cover. | Yield Strength LTL > Net Deployment Force UTL | Pass |
| Graft Cover T-Tube Torque Strength* | To determine the maximum torque required to break the bond between the graft cover and graft cover T-tube overmold of the delivery system. | Ultimate Torque Strength LTL > 0.183 N·m | Pass |
| Front Grip Tensile Strength* | To measure the maximum load required to separate the front grip from the delivery system handle. | Ultimate Tensile Strength LTL > Deployment Force UTL | Pass |
| Tip Assembly to Guidewire Lumen Bond Tensile* | To determine the maximum load required to break the bond between the tapered tip and guidewire tube of the delivery system. | Ultimate Tensile Strength LTL > 44N | Pass |
| Spindle to Tapered Tip Tensile Strength* | To determine the maximum load required to break the bonds between the spindle, tapered tip insert, and the tapered tip of the delivery system. | Ultimate Tensile Strength LTL > 44N | Pass |
| Capture Fitting Tensile* | To determine the maximum load required to break the bond between the capture fitting and guidewire tube of the delivery system. | Ultimate Tensile Strength LTL > Net Tip Release Force UTL | Pass |
| Flush Port to Hypotube Tensile Strength* | To determine the maximum load required to break the bond between the flush port and hypotube of the delivery system. | Ultimate Tensile Strength LTL > 22 N | Pass |
| Middle Member to Flush Port Seal Compression* | To determine the maximum load required to compress the middle member by a set distance into the flush port seal of the delivery system. | Ultimate Compression LTL > UTL Net Deployment Force * 0.75 | Pass |
| Middle Member to Flush Port Seal Tensile* | To determine the maximum load required to separate the middle member from the flush port seal in the delivery system. | Ultimate Tensile Strength LTL > 22N | Pass |
| Middle Member to Flexible Stent Stop Bond Strength* | To determine the maximum load required to break the bond between the middle member and flexible stent stop of the delivery system. | Ultimate Tensile Strength LTL > 22N | Pass |

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| In Vitro Test | Test Purpose | Acceptance Criteria | Results |
| --- | --- | --- | --- |
| Middle Member to Extension Tube Bond Strength* | To determine the maximum load required to break the bond between the middle member and extension tube of the delivery system. | Ultimate Tensile Strength LTL > 15N | Pass |
| Middle Member to Sleeve Bond Strength* | To determine the maximum load required to break the bond between the middle member and sleeve of the delivery system. | Ultimate Tensile Strength LTL > 22 N | Pass |
| Backend Fitting Assembly Tensile* | To determine the maximum load required to break the bond between the backend fitting and guidewire tube of the delivery system. | Ultimate Tensile Strength LTL > 40N | Pass |
| Tip Release Fitting Assembly Tensile Strength* | To determine the maximum load required to break the bond between the tip release fitting and capture tube of the delivery system. | Ultimate Tensile Strength LTL > Tip release force UTL | Pass |
| T-Tube Seal Retainer Tensile Strength* | To determine the maximum load required to separate the T-tube seal retainer from the graft cover T-tube of the delivery system. | Ultimate Tensile Strength LTL > 22N | Pass |
| Screw Gear Disengagement Force* | To measure the force required to make the delivery system graft cover retractor skip over threads on a screw gear assembly. | Disengagement Force LTL > Deployment Force UTL | Pass |
| Spring Attachment Strength* | To test the attachment strength of the springs to the stent graft. | Spring Attachment Strength LTL > 133 N | Pass |
| Stent Graft Permeability | To determine the rate of water leakage through the stent graft. | Integral Water Permeability < 575 mL/min/cm² | Pass |
| Stent Graft Burst* | To determine the pressure required to burst the stent graft. | Stent Graft Burst Pressure LTL > 120 kPA | Pass |

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| In Vitro Test | Test Purpose | Acceptance Criteria | Results |
| --- | --- | --- | --- |
| Deployment Force* | To evaluate the forces required to release the stent graft from the delivery system in a simulated use model. | Deployment Force UTL < Lowest LTL of the following: Screw Gear Disengagement Force Front Grip Tensile Strength and Net Deployment Force UTL* < Lowest LTL of the following: Graft Cover Yield Strength Graft Cover Bond Strength Graft Cover T-Tube Tensile Strength 0.5 * Net Deployment Force UTL < Graft Cover to Radiopaque Marker Bond Strength LTL 0.75 * Net Deployment Force UTL < Middle Member to Flush Port Seal Compression LTL | Pass |
| Tip Release Force* | To evaluate the forces required to release the proximal end of the stent graft from the delivery system in a simulated use model. | Tip Release Force UTL < Tip Release Fitting Assembly Tensile Strength LTL Net Tip Release Force UTL < Capture Fitting Tensile Strength LTL | Pass |
| Stent Graft Body Conformability | To assess flexibility by measuring diameter reduction in the stent graft when placed at an angle of 90°. | Cross-sectional area of stent graft in 90° bend > 50% of cross-sectional area of stent graft at 0° | Pass |
| Stent Graft Radial Pressure | To determine the radial force exerted by the stent graft in the seal zones during radial compression consistent with anticipated clinical operating conditions. | Seal zone radial pressure > 8.0 mm Hg | Aneurysm: Pass |
| | | | Transection: Pass |

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| *In Vitro* Test | Test Purpose | Acceptance Criteria | Results |
| --- | --- | --- | --- |
| Stent Graft Joint Strength | To evaluate the joint strength between stent graft components. | Joint strength greater than or equal to previous generation device results, at a 95% level of confidence: - Ho: Valiant Navion stent graft results are >= Valiant Captivia stent graft results, - Ha: Valiant Navion stent graft results are < Valiant Captivia stent graft results. | Pass |
| Stent Graft Proximal Seal | This test evaluates the amount of water leakage at the stent graft seal zones. | Leak Rate results must be less than or equal to previous generation device results, at a 95% level of confidence: - Ho: Valiant Navion stent graft results are >= Valiant Captivia stent graft results, - Ha: Valiant Evo stent graft results are < Valiant Captivia stent graft results. | Pass |
| Stent Graft Migration | To measure the maximum pressure that a stent graft can withstand before migrating through a mock vessel over an intended landing zone length. | Migration Pressure results must be greater than or equal to previous generation device results, at a 95% level of confidence: - Ho: Valiant Navion stent graft results are ≥ Valiant Captivia stent graft results - Ha: Valiant Navion stent graft results are < Valiant Captivia stent graft results. | Pass |
| Stent Graft Proximal Conformability | To evaluate the extent of bird beaking (i.e. lack of wall apposition against the inner curve of the aortic arch) exhibited by the proximal end of the stent graft. | Bird beak covered length must be less than or equal to previous generation device results, at a 95% level of confidence: - Ho: Valiant Navion stent graft results are ≥ Valiant Captivia stent graft results - Ha: Valiant Navion stent graft results are < Valiant Captivia stent graft results. | Pass |

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| In Vitro Test | Test Purpose | Acceptance Criteria | Results |
| --- | --- | --- | --- |
| Stent Graft Visual Expansion Integrity* | To assess the visual expansion integrity of the stent graft. | 1. No broken or bent stent struts including crimp sleeve. 2. No graft hole(s) with area > 0.2 mm². 3. No stitch breaks permitted on Internal or Bare stent struts. Stitch breaks are acceptable at other stent locations provided that the minimum number of stitches are met. Stitch breaks on seam are acceptable provided that the minimum stitch density of 12 stitches/cm is maintained 1 cm on each side of the break. 4. Loose or frayed sutures are acceptable if the stent and/or RO marker remains attached to the graft material. 5. RO markers must remain attached to the stent graft. | Pass |
| Guidewire Acceptance* | To confirm that the delivery system accepts a 0.035" guidewire. | A 0.035" (0.89 mm) guidewire must be able to pass/track through the delivery system. | Pass |
| Finite Element Analysis | To calculate fatigue safety factors by quantifying the strain on the stent when subject to in vivo conditions. | The safety factors based on the endurance limit shall be > 1. | Pass |

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| In Vitro Test | Test Purpose | Acceptance Criteria | Results |
| --- | --- | --- | --- |
| MRI | To evaluate MRI compatibility with the stent graft. | 1. The device must be MR Conditional with respect to implant radiofrequency (RF) heating in a 1.5T and 3T system. 2. The magnetically induced deflection force is less than the force on the stent due to gravity (its weight). 3. The stent graft with the greatest clinically relevant metallic mass must exhibit insufficient magnetic torque in a 3.0-Tesla MRI system to align with the magnetic field when resting on a hard-smooth surface at the magnetic isocenter. 4. Characterize image artifact | Pass |
| Cyclic Potentiodynamic Polarization (Corrosion) | To evaluate the susceptibility of the stent rings to corrosion in a simulated physiological environment. | $$E_b - E_r > 200\text{mV}$$ | Pass |

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| *In Vitro* Test | Test Purpose | Acceptance Criteria | Results |
| --- | --- | --- | --- |
| Supported Single Layer Radial Dilatation Fatigue | To evaluate the device durability of a single layer of the stent graft following 10 years simulated (400 million cycles) accelerated *in vitro* testing under clinically-relevant loading conditions. | Each test sample must meet performance requirements of stent, graft material, and suture components after completing 400 million cycles of radial dilation fatigue testing. Stent: No CoveredSeal support stent fractures that result in the complete detachment of stent fragments from the stent graft. No stent fractures of all other stents. Graft material: Graft hole effective area must be less than or equal to 5.7 mm^{2}. Graft material for Transection Indication evaluated based on performance requirement of 40 million cycles (1 -Year equivalent) Suture: No suture breaks that result in the complete detachment of a stent or radiopaque marker. | Pass |
| Supported Overlap Radial Dilatation Fatigue | To evaluate the device durability of overlapped stent grafts within a supported, simulated vessel region following 10 years simulated (400 million cycles) accelerated *in vitro* testing under clinically-relevant loading conditions. | Each test sample must meet performance requirements of stent, graft material, and suture components after completing 400 million cycles of overlap radial dilation fatigue testing Stent: No CoveredSeal support stent fractures that result in the complete detachment of stent fragments from the stent graft. No stent fractures of all other stents. Graft material: Graft hole effective area must be less than or equal to 5.7 mm^{2}. Suture: No suture breaks that result in the complete detachment of a stent or radiopaque marker | Pass |

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| In Vitro Test | Test Purpose | Acceptance Criteria | Results |
| --- | --- | --- | --- |
| Unsupported Pulsatile Fatigue | To evaluate the device durability in an unsupported environment (simulating an aneurysm sac) following 10 years simulated (400 million cycles) accelerated in vitro testing under clinically-relevant loading conditions. | Each test sample must meet performance requirements of stent, graft material, and suture components after completing 400 million cycles of unsupported pulsatile fatigue testing **Stent:** No CoveredSeal support stent fractures that result in the complete detachment of stent fragments from the stent graft. No stent fractures of all other stents. **Graft material:** Graft hole effective area must be less than or equal to 1.7 mm². **Suture:** No suture breaks that result in the complete detachment of a stent or radiopaque marker | Pass |
| Simulated Use | For experienced physicians to evaluate the stent graft system's ability to perform in a simulated clinical environment. | Successfully meet performance requirements as the steps of the IFU are executed in a simulated clinical environment. The following attributes were evaluated to determine whether "clinically acceptable": • Guidewire compatibility • Ability to flush • Ancillary compatibility • Hydrocoating is activated • Ability to access • Visibility • Ability to accurately deploy and re-position • Fixation effectiveness • Iliac access • Ease of Use • Ability to withdraw • Troubleshooting techniques | Pass |
| LTL denotes Lower Tolerance Limit; UTL denotes the Upper Tolerance Limit. | | | |

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### C. Sterilization/Packaging/Shelf Life

The Valiant Navion Thoracic Stent Graft System is a single-use device that is provided sterile to the end user. The device is sterilized using E-Beam sterilization and is validated to demonstrate a Sterility Assurance Level (SAL) of 10$^{-6}$.

Packaging performance and stability testing demonstrate that the packaging designs for the Valiant Navion Thoracic Stent Graft System are sufficient to adequately protect the device and maintain the sterile integrity of the Valiant Navion Thoracic Stent Graft System package throughout its 2-year shelf-life claim.

Product shelf-life testing conducted on the Valiant Navion Thoracic Stent Graft System supports a 2-year shelf life claim. Shelf-life testing results are presented within the *in vitro* bench test results as part of **Table 3** above.

### D. Animal Studies

Preclinical *in vivo* animal testing of the Valiant Navion Thoracic Stent Graft System was conducted to evaluate acute technical performance, stent graft integrity, and histopathological response of the Valiant Navion Thoracic Stent Graft System in an ovine model for up to 6 months. The results demonstrated an adequate ability to access the target anatomical location, adequate handling and visualization of the delivery system and implant, and adequate deployment accuracy. Stent graft integrity and histopathological response were acceptable. The 28-day, 60-day and 180-day results of the animal study support the safety of the Valiant Navion stent graft.

**Table 4: Summary of the Animal Studies**

| Study Name/ Description and Sample Size | Evaluations | Outcome |
| --- | --- | --- |
| 28 and 60 Day Safety Evaluation in the Ovine Model One Valiant Navion Thoracic Stent Graft was placed in the thoracic aorta and one Endurant II Abdominal Stent Graft was placed in the abdominal aorta of each of 6 sheep for a total of 2 grafts per animal. | Acute Assessment: • Acute stent graft deployment, stent graft placement, and any device related effects at the time of implant. • Acute performance including: trackability, flexibility, pushability, kink resistance, atraumatic interface, and withdrawal of the Valiant Navion delivery system. • Compatibility of the delivery system with standard accessory products including guidewires, introducer sheaths, luer adapters and balloons. • Ability to inject contrast. • Visibility of the Valiant Navion Thoracic Stent Graft System under fluoroscopy for both stent graft and delivery system. • Functional hemostasis of delivery | • Acute delivery performance and compatibility with accessory devices was scored as 'clinically acceptable' by the interventionalist, based on the interventionalist's clinical experience. • All stent grafts were successfully delivered to the intended location. • There was one substantiated migration of the test devices. The cause was inconclusive and attributed to limitations in the animal model. • All vessels remained patent throughout the course of the studies. • There was no evidence of stent fractures. • Comparable histological indicators of vessel wall healing, including evaluation of strut induced vessel wall injury, inflammation, thrombus, |

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| Study Name/Description and Sample Size | Evaluations | Outcome |
| --- | --- | --- |
| | system. • Structural integrity of delivery system. • Evaluation of patency. • Ease of use, including ergonomics. Chronic Assessment: • Evaluation of the position of the implant at the time of implant and the time of explant (migration resistance). • Evaluation of patency. • Evaluation of the structural integrity of the Valiant Navion Stent Graft at the time of explant. • Evaluation of histology and pathology of explanted test and control articles and surrounding tissue. | endothelialization, and neointimal formation, was noted at 28 days and 60 days for each study respectively between the test and control articles. • Overall quantitative morphometric analysis of tissue sections from the native (non-stented) proximal and distal stented vessels and proximal bare spring of both test and control article, proximal support spring, middle, and distal portions of the stents showed that the response to the test device was comparable to the control article. |
| The 180 Day Safety Evaluation in the Ovine Model One Valiant Navion Thoracic Stent Graft was placed in the thoracic aorta and one Endurant II Abdominal Stent Graft was placed in the abdominal aorta of each of 8 sheep for a total of 2 grafts per animal. | Acute Assement: • Access and withdrawal of the delivery system. • Compatibility of the delivery system with standard accessory products including guidewires, introducer sheaths, luer adapters and balloons. • Acute stent graft deployment, stent graft placement, and any device related effects at the time of implants. • Ability to flush (guidewire lumen and graft cover) with saline (via syringe). • Visibility under fluoroscopy for both stent graft and the delivery system. • Functional hemostasis of delivery system (lack of bleed). • Structural integrity of the delivery system. • Evaluation of patency. • System ease of use. Chronic Assement: • Evaluation of the position of the implant at the time of implant, 28 ± 2 days and the time of explant (migration resistance). • Evaluation of patency at 28 ± 2 days and 180 days. • Evaluation of the structural integrity | • Acute delivery performance was scored as “clinically acceptable” by the interventionalist, based on the interventionalist’s clinical experience. • All stent grafts were successfully delivered to the intended location. • All vessels remained patent throughout the course of the study. • There was no evidence of stent fractures. • There were two cases of test article migration reported. The cause of both migrations was inconclusive and attributed to limitations of the animal model and the anatomical landmarks; these are not considered representative of the device performance in humans. • Comparable histological indicators of vessel wall healing, including strut induced vessel wall injury, inflammation, thrombus, endothelialization, and neointimal formation, was noted between the test and control articles. • Overall quantitative morphometric analysis of tissue sections from the native (non-stented) proximal and distal stented vessels and proximal bare spring of both test and control article, proximal support spring. |

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| Study Name/ Description and Sample Size | Evaluations | Outcome |
| --- | --- | --- |
| | of the Valiant Navion Thoracic Stent Graft System at the time of explant. • Evaluation of histology and pathology of explanted test and control articles and surrounding tissue. | middle, and distal portions of the stents showed that the response to test article was comparable to the control article. |

## **X. SUMMARY OF PRIMARY CLINICAL STUDY**

The applicant performed a clinical study to establish a reasonable assurance of safety and effectiveness of endovascular aneurysm repair with the Valiant Navion Thoracic Stent Graft System in the US, Canada, Denmark, Italy, France, Netherlands, and UK under IDE # G150251. Data from this clinical study were the basis for the panel-track PMA-S approval decision.

The Valiant Navion Thoracic Stent Graft System is Medtronic’s next generation thoracic stent graft system, based on the previously approved Valiant Captivia Thoracic Stent Graft System. The changes were intended to increase the range of stent graft sizes offered (shorter and longer lengths, smaller diameter, and increased stent graft taper offered), reduce the delivery system profile (18 Fr, 20 Fr, and 22 Fr instead of 22 Fr, 24 Fr, and 25 Fr), allow for the use of the CoveredSeal configuration as either the proximal or the distal device (previous Closed Web configuration was limited to use as the distal device), and allow for controlled delivery of all configurations.

Because the Valiant Navion Thoracic Stent Graft System is expected to perform similarly to Valiant Captivia Thoracic Stent Graft System, the clinical study (Valiant Evo IDE study) was designed to confirm that the device design modifications did not negatively impact clinical performance. The study was limited to the use of the device for the treatment of descending thoracic aortic aneurysms (DTAA) and penetrating aortic ulcers (PAU). The results from this study, with consideration of the clinical data from the evaluation of the Valiant Captivia Thoracic Stent Graft System, in combination with the nonclinical testing, supports the broad indication of all lesions of the descending thoracic aorta (DTA). The aortic anatomy associated with descending thoracic aortic aneurysms is technically most challenging, making them suitable patients to evaluate acute outcomes per the objectives of the Valiant Evo IDE study. Patients with aneurysm have been shown to be a worst-case population for endovascular repair of the thoracic aorta through prior clinical experience from Valiant Captivia Thoracic Stent Graft System. The aneurysm disease state is worst case when compared to transection and dissection disease states because the aneurysm poses additional challenge for the delivery system in traversing the aneurysm to reach the deployment target and deploying accurately within the short landing zone proximal to the aneurysm.

**Note: Information regarding the clinical evaluation of the Valiant Captivia Thoracic Stent Graft System to treat traumatic transections, acute complicated**

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dissections and DTAA can be found in the IFU for this device; Medtronic's VALOR II study (Section 6.3 of the Valiant Captivia Thoracic Stent Graft System IFU), Medtronic Dissection Trial (Section 6.1 of the Valiant Captivia Thoracic Stent Graft System IFU) and RESCUE study (Section 6.2 of the Valiant Captivia Thoracic Stent Graft System IFU).

**Note:** The Valiant Navion Thoracic Stent Graft System was called the Valiant Evo Thoracic Stent Graft System during the clinical study. Therefore, the device is referred to as the Valiant Evo Thoracic Stent Graft System in this clinical study summary.

### A. Study Design

Patients were treated between March 2016 and October 2017. The database for this Panel Track Supplement reflected data collected through December 11, 2017 and included 87 patients. There were 31 investigational sites.

A total of 100 subjects were consecutively enrolled as part of the Valiant Evo IDE study. Data on the first 87 of these subjects are presented in this clinical study summary [52 US, 35 OUS (6 Canada, 1 Denmark, 11 Italy, 8 France, 4 Netherlands, 5 UK)]. These 87 subjects were recruited from 31 medical centers worldwide, with 18 of the clinical sites coming from the United States and 13 from Outside the United States (OUS) (2 Canada, 1 Denmark, 4 Italy, 3 France, 2 Netherlands, and 1 UK).

The study was a prospective, multi-center, single-arm cohort, open-label clinical study with a dichotomous study outcome based on the binomial distribution for hypothesis testing. The primary study endpoint, the proportion of subjects with access failures, deployment failures, and/or Major Device Effects (MDE) within 30 days post index procedure, is a dichotomous study outcome, and was tested against a performance goal of 16%:

$$H_0: p \geq 16\% \text{ vs. } H_a: p < 16\%$$

where $p$ denotes the true event rate of the primary study endpoint in the target population. Thus, if the null hypothesis, $H_0$, was rejected at the one-sided 0.025 statistical significance level, the performance goal for the primary endpoint was reached. All other endpoints were analyzed descriptively, and the time to event was analyzed by the Kaplan-Meier method.

The total of 100 subjects ensured that 87 evaluable subjects were available at the 30-day primary endpoint for analysis. The sample size of 87 evaluable subjects provided 85% statistical power for the study hypothesis. The type I error was controlled with a one-sided 0.025 statistical significance level.

The Valiant Evo IDE study was monitored by an internal Medtronic Contract Research Organization. An Imaging Core Lab, Data Monitoring Committee (DMC)

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and Clinical Events Committee (CEC), all managed by the independent Contract Research Organization, were established to independently evaluate subject health status, device performance, and identify any safety concerns regarding subjects' well-being. The Clinical Events Committee (CEC) met to adjudicate MDEs, unanticipated adverse device effects (UADEs), unanticipated serious adverse device effects (USADEs), deaths, and all aneurysm ruptures for the global cohort. The Data Monitoring Committee (DMC) met to evaluate safety data during the course of the clinical study. The central imaging core lab was used to provide independent evaluation of imaging findings.

# 1. Clinical Inclusion and Exclusion Criteria

Enrollment in the Valiant Evo IDE study was limited to subjects who met the following inclusion criteria:

- ≥18 years old.
- Signed and dated the Informed Consent Form.
- Presented with a DTAA that was localized below the ostium of LSA and above the ostium of celiac trunk.
- Had a DTAA that was one of the following:
- A fusiform aneurysm with a maximum diameter that:
- was ≥ 50 mm and/or:
- was > 2 times the diameter of the non-aneurysmal thoracic aorta and/or:
- was < 50 mm and had grown ≥ 5 mm within previous 12 months
- A saccular aneurysm or a penetrating atherosclerotic ulcer
- Anatomy met all the following anatomical criteria as demonstrated on contrast-enhanced CT and/or on contrast-enhanced MRA obtained within four months prior to implant procedure:
- Proximal and distal non-aneurysmal aortic neck diameter measurements were ≥ 16 mm and ≤ 42 mm;
- Proximal non-aneurysmal aortic neck length was ≥ 20 mm (for FreeFlo configuration) and ≥ 25 mm (for Closed Web¹ configuration) distal to the left common carotid artery (LCCA). Note: Proximal aortic neck length may include covering the LSA (with or without discretionary revascularization) when necessary to optimize device fixation and maximize aortic neck length. If occlusion of the LSA ostium was required to obtain adequate neck length for fixation and sealing, transposition or bypass to the LSA may have been warranted.
- Distal non-aneurysmal aortic neck length was ≥ 20 mm

¹ Closed Web refers to CoveredSeal configurations used in the clinical trial.

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○ Adequate arterial access site or could tolerate a conduit that allowed endovascular access to the aneurysmal site with the delivery system of the appropriate sized device chosen for the treatment.

Subjects were not permitted to enroll in the Valiant Evo IDE study if they met any of the following exclusion criteria:

- Life expectancy of <1 year.
- Participating in another investigational drug or device study that would interfere with the endpoints and follow-ups of this study.
- Currently pregnant.
- Required planned placement of the covered proximal end of the stent graft to occur in zones 0 or 1.
- Had a thoracic aneurysm with a contained rupture or localized at the anastomosis of a previous graft (pseudo-/false aneurysm).
- Had mycotic aneurysm.
- Had a dissection (type A or B) or an intramural hematoma or an aortic rupture in addition to the thoracic aneurysm.
- Required emergent aneurysm treatment, e.g., trauma or rupture.
- Received a previous stent or stent graft or previous surgical repair in the ascending and/or descending thoracic aorta, and/or in the aortic arch.
- Required surgical or endovascular treatment of an infra-renal aneurysm at the time of implant.
- Previous surgical or endovascular treatment of an infra-renal aortic aneurysm.
- Treatment with the Valiant Evo Thoracic Stent Graft System would require intentional revascularization of the brachio-cephalic artery or the left common carotid artery or the celiac trunk.
- Had planned to have a major surgical or interventional procedure within 30 days before or 30 days after the planned implantation of the Valiant Evo Thoracic Stent Graft System, exclusive of planned procedures that are needed for the safe and effective placement of the stent graft.
- Had a significant and/or circumferential aortic mural thrombus at either the proximal or distal attachment sites that could compromise fixation and seal of the implanted stent graft.
- Had a connective tissue disease.
- Had a bleeding diathesis or coagulopathy, or refused blood transfusion.
- Had a MI within 3 months of the procedure.
- Had a CVA within 3 months of the procedure.
- Had a known allergy or intolerance to the device materials
- Had a known allergy to anesthetic drugs

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- Had a known hypersensitivity or contraindication to anticoagulants, or contrast media, which is not amenable to pretreatment.
- Had an active or systemic infection at the time of the index procedure.

# 2. Follow-up Schedule

All subjects in the study were scheduled to return for follow-up examinations at 1 month and 12 months postoperatively, and all subjects in the US sites were scheduled for an additional follow-up examination within 6 months postoperatively. Further follow-up evaluations are scheduled for all subjects who signed an updated Informed Consent Form for follow-up at 24 months, 36 months, 48 months, and 60 months, postoperatively. Forty one (41) of 100 subjects (37 of the 87 enrolled at the database lock for this PMA-S) signed the updated Informed Consent Form for 5 year follow-up, and reconsent is pending for 21 of 100 subjects (15 of the 87 at the database lock for this PMA-S). Thirty eight (38) of 100 subjects (35 of the 87 enrolled at the database lock for this PMA-S) are not participating in the 5 year follow-up and will participate in the study until the completion of their 2 year follow-up, as originally required.

Preoperatively, subjects underwent a comprehensive medical evaluation, American Society of Anesthesiologists (ASA) classification, appropriate imaging, and an assessment of the indication for Thoracic Endovascular Aortic Repair (TEVAR), as shown in Table 5. Postoperatively, the objective parameters measured during the study included the number of devices implanted, the configuration of each type of Valiant Evo Thoracic Stent Graft System implanted at the index procedure, implant zone of the most proximal component, adjunctive procedure, left subclavian artery (LSA) coverage information as the Valiant Evo stent graft can be landed in zone 2 thereby covering the ostium of the LSA either fully or partially, acute procedure observations and clinical utility measures and the effectiveness measures shown in the tables below. Adverse events and complications will be recorded at all visits.

Table 5: Data Collection Schedule

| DATA | Screening /Baseline | Index Procedure | Hospital Discharge | 1-Mo. F/U (±15 days) | 6-Mo. F/U^{d} (±30 days) | 12-Mo. F/U (±60 days) |
| --- | --- | --- | --- | --- | --- | --- |
| **GENERAL** | | | | | | |
| Informed Consent | ✓ | | | | | |
| Inclusion Criteria/ Exclusion Criteria | ✓ | | | | | |
| Physical Examination | ✓ | | | ✓ | ✓ | ✓ |
| Medical History | ✓ | | | | | |
| Current Health Status and Risk Factors | ✓ | | | | | |

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| DATA | Screening /Baseline | Index Procedure | Hospital Discharge | 1-Mo. F/U (±15 days) | 6-Mo. F/U^{d} (±30 days) | 12-Mo. F/U (±60 days) |
| --- | --- | --- | --- | --- | --- | --- |
| Device and Procedure Information | | ✓ | | | | |
| Pre-implant Adjunctive Procedures | | ✓ | | | | |
| Hospital Discharge Information | | | ✓ | | | |
| Adverse event assessment | ✓^{a} | ✓ | ✓ | ✓ | ✓ | ✓ |
| EQ-5D questionnaire | ✓ | | | ✓ | ✓ | ✓ |
| **IMAGING** | | | | | | |
| CT/MRI with contrast^{b} | ✓^{g} | | | ✓^{c,e,g} | ✓^{e,g} | ✓^{e,h} |
| Angiography | | ✓^{f} | | | | |
| ^{a} In case of screen failures, investigators will be requested to enter safety information in the electronic case report form (eCRF) from time point of enrollment until time point of screen failure ^{b} CT evaluation may include '3-phase technique', volume studies, 3-D reconstruction, or computer-aided measurements ^{c} A CT/MRI with contrast acquired at discharge (or before Day 15) due to medical necessity may be used to meet the 1-month follow-up visit CT/MRI requirement if a CT/MRI with contrast cannot be obtained within the 1-month follow-up window due to the subject's health status based upon physician discretion. ^{d} For subjects enrolled in the Valiant Evo International Clinical Trial in European countries, a six month follow up visit is not required per protocol. ^{e} MRI with contrast may be used for those patients experiencing renal failure or who are otherwise unable to undergo contrast-enhanced CT scan, with Transesophageal echocardiography (TEE) being an additional option in the event of suboptimal MR imaging. ^{f} Required to complete Procedure eCRF but not expected to be submitted to Medtronic or Core Lab unless further analysis is needed. ^{g} Imaging assessed by core lab. ^{h} Upon sponsor request, core lab analysis of imaging may be required. | | | | | | |

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

### 3. Clinical Endpoints

With regards to safety and effectiveness, the primary endpoint for the global cohort is a composite endpoint of both. It is defined as the proportion of subjects with access failures, deployment failures, and/or Major Device Effects (MDE) within 30 days post index procedure. For this study, access failure is defined as the inability to insert the device due to mechanical failure or anatomic exclusions of the femoral or iliac arteries. Deployment failure is defined as failure of deployment due to subject anatomy or mechanical failure. MDEs are defined as the occurrence of any of the following: device-related secondary procedures, device-related mortality,

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conversion to open surgery, and thoracic aortic aneurysm rupture.

This primary endpoint was selected based on Medtronic’s review of the design characteristics/components that were leveraged from Valiant Captivia Thoracic Stent Graft System to Valiant Evo Thoracic Stent Graft System. This review suggested that the design changes should only potentially impact device delivery and acute clinical outcomes, not long-term device performance. Access and deployment failures with the components of MDE comprise a clinically relevant measure of the effects of the design modifications because this composite endpoint addresses the potential failures relevant to the modifications. In addition, as MDEs are influenced little by aortic pathology, these measures are representative of device performance and are relatively independent of lesion type. Finally, results of the VALOR II (IDE study for Valiant Captivia Thoracic Stent Graft System in aneurysm conditions) clinical data showed that predominance of the MDEs occur within 30-days. As a result, the Valiant Evo IDE endpoint includes access failures, deployment failures, and MDEs at 30 days that were defined to include the potential clinical impacts that are related to the acute safety and effectiveness of stent graft placement.

Notably, the definition of deployment failure used for this study does not include deployment accuracy, deployment without the need for the use of bailout techniques, or the need for placing unintended additional devices. As such, FDA requested an ad hoc analysis of the primary endpoint to include these events which would generally count as delivery and deployment failures in endovascular graft studies.

Secondary objectives of the study included descriptive analyses of secondary endpoints, acute procedural observations and clinical utility measures. Secondary endpoints included adverse events (major adverse events (MAEs) and serious adverse events (SAEs)), MDEs, secondary procedures, all-cause mortality (ACM), aneurysm-related mortality (ARM), loss of stent graft patency, endoleaks, stent graft migration and aneurysm expansion.

With regards to study success/failure criteria, the study would be considered successful if the performance goal for the composite safety/effectiveness primary endpoint was met.

### **B. Accountability of PMA-S Cohort**

A total of 49 subjects failed screening after consent. The reasons for exclusion included subject anatomy did not meet criteria (n=22), investigator withdrew consent prior to procedure (n=8), previous aortic repair (n=4), DTAA not between LSA and celiac trunk (n=3), significant or circumferential aortic mural thrombus (n=3), previous repair of an infra-renal aortic aneurysm (n=3), inadequate arterial access site (n=2), life expectancy of less than 1 year (n=2), dissection, intramural

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hematoma, or aortic rupture (n=2), subject withdrew consent (n=2), major surgical intervention planned within 30 days (n=1), subject died prior to implant (n=1). Subject may have more than 1 reason for screen failure, thus, the total number rejected may be greater than the number of subjects that were screen failures.

At the time of database lock, 87 of the 100 subjects had been enrolled in the PMA study. The analysis for the study was based on these first 87 subjects evaluable for the 30-day endpoint. As shown in **Table 6** below, all 87 subjects were implanted with the Valiant Evo Thoracic Stent Graft System, and one subject died between implant and the 1-month visit window. Thus, a total of 86 subjects were available for the 1-month follow-up visit, with 84 (98%) of these having imaging follow-up. A total of 36 subjects completed the 6-month clinical and imaging follow-up, although this was not required of the OUS subjects. A total of 24 subjects were eligible for the 12-month clinical follow-up, with 21 of these (88%) having imaging follow-up.

**Table 6: Subject and Core Lab Imaging Accountability – All Subjects$^{1}$**

| Follow-up (Interval) | Subject Follow-up | | | Subjects with Imaging (Core Lab) | | Subjects with Adequate Imaging to Assess the Parameter (Core Lab) | | | | Subject Events Occurring before Next Visit | | | | | |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| | Eligible | Clinical Follow-up | Imaging Follow-up | CT/MR Imaging | Other Imaging^{2} | Loss of Patency | Endoleak | Migration | Aneurysm Expansion | No Implant | Conversion to Surgery | Death | Withdrawal/Early Termination | Lost to Follow-up | Not Due for Next Visit |
| Enrollment | 87 | | | | | | | | | 0 | | | | | |
| Events after Implant but before 1-Month Visit | | | | | | | | | | | 0 | 1 | 0 | 0 | 0 |
| 1-Month Visit (Day 1-90) | 86 | 85 (99%) | 84 (98%) | 84 (98%) | 0 (0.0%) | 81 (94%) | 81 (94%) | | | | | | | | |
| Events after 1-Month but before 6-Month Visit | | | | | | | | | | | 0 | 4 | 2 | 0 | 29 |
| 6-Month Visit (Day 91-304)^{3} | 51 | 36 (71%) | 36 (71%) | 36 (71%) | 0 (0.0%) | 31 (61%) | 31 (61%) | 35 (69%) | 36 (71%) | | | | | | |
| Events after 6-Month but before 12-Month Visit | | | | | | | | | | | 0 | 1 | 0 | 0 | 26 |

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| Follow-up (Interval) | Subject Follow-up | | | Subjects with Imaging (Core Lab) | | Subjects with Adequate Imaging to Assess the Parameter (Core Lab) | | | | Subject Events Occurring before Next Visit | | | | | |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| | Eligible | Clinical Follow-up | Imaging Follow-up | CT/MR Imaging | Other Imaging^{2} | Loss of Patency | Endoleak | Migration | Aneurysm Expansion | No Implant | Conversion to Surgery | Death | Withdrawal/Early Termination | Lost to Follow-up | Not Due for Next Visit |
| 12-Month Visit (Day 305-548) | 24 | 22 (92%) | 21 (88%) | 21 (88%) | 0 (0.0%) | 21 (88%) | 21 (88%) | 21 (88%) | 21 (88%) | | | | | | |
| ^{1} Data analysis sample size varies for each of the timepoints above. This variability is due to subject availability for follow-up, as well as, quantity and quality of images available from specific timepoints for evaluation. For example, the number of quality images available for evaluation of endoleak at 1 months is different than the number and quality of images available at 6 months due to variation in the number of images performed, the number of images provided from the clinical site to the Core Lab, and/or the number of images with acceptable evaluation quality. ^{2} Other imaging includes chest X-ray, angiogram, ultrasound, and other imaging of the stent graft region. ^{3} 6-month data is not required per OUS protocol; therefore, the follow-up rate is lower when US and OUS results are combined at this timepoint. | | | | | | | | | | | | | | | |

### C. Study Population Demographics and Baseline Parameters

#### Demographics

The demographics of the global study population are typical for a descending thoracic aortic aneurysm study performed in the US and are summarized in **Table 7** below. The median age of the global cohort was 72.0 years (ranging from 51 to 89 years) and was similar between the US and OUS cohorts and between genders. Of the 87 subjects enrolled in the global cohort, a total of 37.9% (33/87) were female; the gender distribution in the US cohort was 50.0% female (26/52), with the OUS cohort having a lower proportion of females (20.0%, 7/35 subjects). Racial data was only collected among the US cohort, with 78.8% (41/52) of the US subjects reported as white. Other baseline characteristics are covered in the preoperative **Table 8** through **Table 11**.

**Table 7: Subject Demographics**

| Subject Characteristics | Statistics/Category | Global Cohort |
| --- | --- | --- |
| **Gender** | | |
| | Female | 37.9% (33/87) |
| | Male | 62.1% (54/87) |
| **Age (years)** | | |
| **Total Population** | n | 87 |
| | Mean ± SD | 70.8 ± 8.7 |
| | Median | 72.0 |

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| Subject Characteristics | Statistics/Category | Global Cohort |
| --- | --- | --- |
| | Min, max | 51, 89 |
| **Female** | n | 33 |
| | Mean ± SD | 71.0 ± 8.7 |
| | Median | 73.0 |
| | Min, max | 51, 83 |
| **Male** | n | 54 |
| | Mean ± SD | 70.7 ± 8.7 |
| | Median | 72.0 |
| | Min, max | 54, 89 |
| **Race^{1}** | | |
| | White | 78.8% (41/52) |
| | Non-white | 21.2% (11/52) |

$^{1}$Race data were not collected in OUS per regulation.

### Medical History

Baseline medical history characteristics from the global cohort are summarized in **Table 8**. The most prevalent cardiovascular medical history diagnoses at baseline included:

- ■ Hypertension in 89.7% (78/87) of subjects
- ■ Hyperlipidemia in…