Zephyr Endobronchial Valve System

P180002 · Pulmonx Corporation · NJK · Jun 29, 2018 · Anesthesiology

Device Facts

• Record ID: P180002
• Device Name: Zephyr Endobronchial Valve System
• Applicant: Pulmonx Corporation
• Product Code: NJK · Anesthesiology
• Decision Date: Jun 29, 2018
• Decision: APPR
• Device Class: Class 3
• Attributes: Therapeutic

Indications for Use

The Pulmonx Zephyr® Endobronchial Valves are implantable bronchial valves indicated for the bronchoscopic treatment of adult patients with hyperinflation associated with severe emphysema in regions of the lung that have little to no collateral ventilation.

Device Story

Zephyr Endobronchial Valve (EBV) system is a minimally invasive, bronchoscopic lung volume reduction treatment for severe emphysema. The system includes silicone duckbill valves in self-expanding nitinol retainers, a loader system, and a delivery catheter. During bronchoscopy, the physician deploys multiple valves into the target bronchial lumen to occlude hyperinflated lung lobes. The valves function as one-way check valves, allowing air and secretions to escape from the target lobe during exhalation while preventing air from entering during inhalation. This mechanism induces lobar collapse, reducing hyperinflation and improving lung function, exercise capacity, and quality of life. The procedure is performed by pulmonologists or thoracic surgeons. Clinical benefit is realized through improved FEV1, 6-minute walk distance, and reduced dyspnea. The device is intended for patients who have failed or are not candidates for surgical lung volume reduction or transplant.

Clinical Evidence

PMA approval based on the LIBERATE pivotal trial (IDE #G120008), a prospective, multi-center, randomized, controlled study (N=190). Primary endpoint: ≥15% improvement in post-bronchodilator FEV1 at 1 year (47.7% EBV vs 16.8% Control; p<0.001). Secondary endpoints (FEV1, 6MWD, SGRQ) were statistically significant (p<0.005). Safety data showed higher short-term (45-day) respiratory adverse events in the EBV group (e.g., pneumothorax 29.7% vs 0.0%), but comparable long-term safety. Supplemental data from IMPACT and TRANSFORM trials supported effectiveness.

Technological Characteristics

Implant: One-way silicone duckbill valve in self-expanding nitinol retainer. Sizes: 4.0, 4.0-LP, 5.5 mm. Delivery: Flexible delivery catheter via standard adult bronchoscope (2.8 mm working channel). Sterilization: 100% Ethylene Oxide (EO) gas. Biocompatibility: ISO 10993 compliant. Durability: Nitinol frame tested for 6 years of simulated cough cycles.

Indications for Use

Indicated for adult patients with hyperinflation associated with severe emphysema in lung regions with little to no collateral ventilation. Contraindicated in patients with active pulmonary infection, allergies to nitinol or silicone, large bullae (>30% of lung), or those who have not quit smoking.

Regulatory Classification

Identification

To improve lung function in patients with emphysema

Reference Devices

• Chartis® Catheter (K111522)
• Chartis® Console (K111764)
• Myrian CT software (K071000)

Submission Summary (Full Text)

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SUMMARY OF SAFETY AND EFFECTIVENESS DATA (SSED)

I. GENERAL INFORMATION

Device Generic Name: One-way valve system

Device Trade Name: Zephyr® Endobronchial Valve System

Device Procode: NJK (Valve, Pulmonary)

Applicant's Name and Address: Pulmonx Corporation
700 Chesapeake Drive
Redwood City, CA 94063

Date(s) of Panel Recommendation: N/A

Premarket Approval Application (PMA) Number: P180002

Date of FDA Notice of Approval: June 29, 2018

Breakthrough Device: Granted breakthrough device status (formerly known as the Expedited Access Pathway, or EAP) on May 4, 2017 because the device intends to treat patients with severe emphysema, an irreversible and life threatening progressive disease. This represents a breakthrough technology as the device offers bronchoscopic lung volume reduction without surgery and its associated risks. This device offers significant clinically meaningful advantage over the current standard of care and therefore its availability is also in the best interest of patients.

II. INDICATIONS FOR USE

The Pulmonx Zephyr® Endobronchial Valves are implantable bronchial valves indicated for the bronchoscopic treatment of adult patients with hyperinflation associated with severe emphysema in regions of the lung that have little to no collateral ventilation.

III. CONTRAINDICATIONS

- Patients for whom bronchoscopic procedures are contraindicated
- Patients with evidence of active pulmonary infection
- Patients with known allergies to Nitinol (nickel-titanium) or its constituent metals (nickel or titanium)
- Patients with known allergies to silicone
- Patient who have not quit smoking
- Patients with large bullae encompassing greater than 30% of either lung

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# IV. WARNINGS AND PRECAUTIONS

The warnings and precautions can be found in the Zephyr® Endobronchial Valve labeling.

# V. DEVICE DESCRIPTION

The Zephyr® Endobronchial Valve (Zephyr Valve) is an endobronchial implant designed to occlude a hyperinflated lobe of the lungs with multiple valves, allowing air to escape while blocking airflow into the treated lobe (Figure 1). This is intended to result in a reduction in lung volume and hyperinflation in the targeted area.

The Zephyr® Endobronchial Valve System consists of the following major components:

The Zephyr Endobronchial Valve (EBV) is a one-way, removable, silicone, duckbill valve mounted in a nitinol, self-expanding retainer that is covered with a thin silicone membrane. The valve is available in three (3) sizes (4.0 EBV, 4.0-LP EBV, and 5.5 EBV) and implanted during bronchoscopy in bronchial lumens ranging from 4.0 to 8.5 mm in diameter. More than one valve may be needed to achieve the desired clinical outcome. In the pivotal study, the median number of valves used per procedure was four (4). The maximum number of valves used during a procedure was eight (8).

Figure 1: Zephyr® Endobronchial Valve in Bronchial Lumen

The Endobronchial Loader System (ELS) (Figure 2) is designed to compress and load the EBV into the housing of the Endobronchial Delivery Catheter (EDC). The Zephyr Valve is secured in an uncompressed or expanded state inside the ELS during manufacturing and is shipped and stored in its expanded state. Immediately prior to use, the Zephyr Valve is compressed within the ELS and then transferred into the Zephyr EDC. The ELS is a non-patient contacting, single use, disposable device.

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Figure 2: Zephyr® Endobronchial Loader System

The flexible Zephyr® Endobronchial Delivery Catheter (EDC) (Figure 3) facilitates placement of the EBV into the targeted bronchus. The Zephyr EDC is guided to the treatment location through the working channel of a standard adult flexible bronchoscope with constant visual feedback. The Zephyr Valve is then deployed and released to expand inside the target airway. The Zephyr EDC is a single-patient use, disposable device.

Figure 3: Zephyr® Endobronchial Delivery Catheter

The Zephyr® Endobronchial Valve System is designated for professional use only.

## VI. ALTERNATIVE PRACTICES AND PROCEDURES

There are several alternatives for the treatment of severe emphysema. 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.

- Medications for relief of the symptoms of emphysema
- Smoking cessation
- Pulmonary rehabilitation
- Long-term administration of oxygen to patients
- Lung volume reduction surgery (LVRS)
- Lung transplantation

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# VII. MARKETING HISTORY

The Zephyr Valve received the CE mark in 2003 and is commercially available in Argentina, Australia, Austria, Belgium, Brazil, Chile, China, Colombia, Czech Republic, Denmark, France, Germany, Hong Kong, Ireland, Israel, Italy, Malaysia, Netherlands, Norway, Portugal, South Africa, South Korea, Spain, Sweden, Switzerland, Turkey, United Arab Emirates, United Kingdom, and Vietnam. The Zephyr Valve has not been withdrawn from marketing for any reason related to its safety or effectiveness.

# 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:

- Acute respiratory distress syndrome
- Airway erosion
- Airway stenosis
- Aphonia
- Bowel function impairment
- Bronchitis
- Bronchospasm
- Chest Pain
- Chronic obstructive pulmonary disease (COPD) exacerbation
- Cough
- Death
- Disorientation/anxiety
- Dyspnea
- Empyema
- Epistaxis
- Fever
- Granulation tissue/ulceration formation
- Headache
- Heart arrhythmia
- Heart Failure
- Hematoma
- Hemoptysis
- Hemothorax
- Hypotension

- Hypercapnia
- Hypoxemia
- Iatrogenic injuries
- Impaired lung function
- Increased mucus secretions
- Infection
- Insomnia
- Musculoskeletal event
- Myocardial infarction
- Nausea/vomiting
- Pain
- Pleural effusion
- Pneumonia
- Pneumothorax
- Pulmonary embolism
- Pulmonary shunting
- Residual volume increase
- Respiratory failure
- Sepsis
- Shortness of breath
- Sore throat
- Stroke/CVA/TIA
- Systemic inflammatory response syndrome (SIRS)
- Valve migration/expectoration
- Vocal cord injury
- Wheeze or whistling

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

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# IX. SUMMARY OF NONCLINICAL STUDIES

Pulmonx conducted the following nonclinical studies to evaluate the Zephyr® Endobronchial Valve System:

## A. Laboratory Studies

### Biocompatibility

Pulmonx has conducted biocompatibility evaluations of the Zephyr® Endobronchial Valve System in compliance with applicable requirements in the Good Laboratory Practice (GLP) regulations in 21 CFR 58, applicable ISO 10993 standard, Biological evaluation of medical devices – Part 1: Evaluation and testing within a risk management process and the FDA guidance, Use of International Standard ISO 10993-1, "Biological evaluation of medical devices - Part 1: Evaluation and testing within a risk management process," published June 16, 2016. For the Zephyr® Endobronchial Valve, as a device with permanent duration contact (&gt;30 days) with endobronchial tissue, the biocompatibility evaluation addressed the following: cytotoxicity, sensitization, intracutaneous reactivity, acute systemic toxicity, materials mediated pyrogen, genotoxicity, implantation, subacute/subchronic toxicity, chronic toxicity, and carcinogenicity. To address the subacute/subchronic toxicity, chronic toxicity, genotoxicity, and carcinogenicity endpoints for Zephyr Valves, a material characterization through chemical analysis testing and a toxicological risk assessment were performed.

For the Zephyr® Endobronchial Delivery Catheter, as a device with limited exposure contact (≤ 24 hours) with endobronchial tissue, the biocompatibility evaluation addressed the following: cytotoxicity, sensitization, and intracutaneous reactivity.

Table 1 and Table 2 summarize the biocompatibility testing performed for the Zephyr® Endobronchial Valve and Zephyr® Endobronchial Delivery Catheter, including information about the test, purpose, and results. The tests were conducted as per the performance Standards listed in the Table. The results of these evaluations support the conclusion that the Zephyr® Endobronchial Valve System is biocompatible for its intended use.

Table 1: Zephyr® Endobronchial Valve (EBV) Biocompatibility Summary

| Test | Purpose | Results |
| --- | --- | --- |
| Minimal Essential Media (MEM) Elution test per ISO 10993-5: 2009 for cytotoxicity | To evaluate the potential for cytotoxicity. | Pass.
No evidence of causing cell lysis; no evidence of reactivity. |
| ISO Guinea Pig Maximization Sensitization test per ISO 10993-10: 2010 | To evaluate the allergenic potential or sensitizing capacity. | Pass.
No sensitization response was observed. |
| Intracutaneous Reactivity per ISO 10993-10: 2010 | To evaluate intracutaneous reactivity or local irritation. | Pass.
No significant dermal reactions were observed. |

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Table 2: Zephyr® Endobronchial Delivery Catheter (EDC) Biocompatibility Summary

| Test | Purpose | Results |
| --- | --- | --- |
| Minimal Essential Media (MEM) Elution test per ISO 10993-5: 2009 for cytotoxicity | To evaluate the potential for cytotoxicity. | Pass. No evidence of causing cell lysis; no evidence of reactivity. |
| ISO Guinea Pig Maximization Sensitization test per ISO 10993-10: 2010 | To evaluate the allergenic potential or sensitizing capacity. | Pass. No sensitization response was observed. |
| Intracutaneous Reactivity per ISO 10993-10: 2010 | To evaluate intracutaneous reactivity or local irritation. | Pass. No significant dermal reactions were observed. |
| Intramuscular Implant Test per ISO 10993-10: 2010 | To evaluate the local effects of a test article in direct contact with living skeletal muscle tissue. | Pass. No significant dermal reactions were observed. |

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# In-Vitro Bench Testing

The integrity and performance of the Zephyr® Endobronchial Valve System was evaluated through in vitro bench testing. The completed testing demonstrates that applicable material, functional, system compatibility, and durability in the product specifications have been met. These specifications were found to be adequate to ensure the device will perform safely and effectively under expected clinical conditions. The Zephyr® Endobronchial Valve System has completed all in vitro bench testing demonstrating that it conforms to user needs and its indication for use. Table 3 summarizes the bench testing performed for the Zephyr® Endobronchial Valve, including information about the test, purpose, acceptance criteria, and results. Table 4 summarizes the bench testing performed for the Zephyr® Endobronchial Delivery Catheter, including information about the test, purpose, acceptance criteria, and results.

Table 3: Summary of Zephyr® Endobronchial Valve Bench Testing

| Test | Purpose | Acceptance Criteria | Results |
| --- | --- | --- | --- |
| Zephyr® Endobronchial Valve | | | |
| Valve Flow vs. Pressure Test | Quantify the pressure across the valve when subjected to a specific flow rate. | The pressure measured across the valve must be within specified limits. | Pass |
| Leak Test | Determine the inhalation pressure required to generate a leak in the Zephyr Endobronchial Valve in a bronchial model. | The valve device must not leak in the direction of inhalation when deployed at the minimum and maximum labeled diameters. | Pass |
| Valve Response Test | Evaluate the valve response time of the Zephyr Endobronchial Valve in terms of the time it takes for the valve to close and create a seal in the inhalation direction. | The valve must close within the time specified in the product specification. | Pass |
| Valve Inversion Test | Evaluate the valve resistance to inversion when subjected to pressure differentials common in bronchoscopic procedures. | The valve must not invert and must return to its original position within the valve protector when subject to pressure differentials common in bronchoscopic procedures (175 in H20). | Pass |
| Inspiratory Migration Test | Evaluate the migration resistance of the Zephyr Endobronchial Valve within a bronchial model during a simulated maximal inhalation. | The device must not migrate > 1mm distally. | Pass |
| Cough Migration Test | Evaluate the migration resistance of the Zephyr Endobronchial Valve within a bronchial model during a simulated cough. | The device must not migrate > 1mm proximally. | Pass |

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| Test | Purpose | Acceptance Criteria | Results |
| --- | --- | --- | --- |
| Wet Cracking Pressure Test | Quantify the pressure required for the valve component to open in exhalation during simulated physiological conditions. | The valve must vent at or below pressure differentials developed during early clinical research based on clinical outcomes. | Pass |
| Deployed Length Verification Test | Confirm that the deployed length of the sealing portion of the Zephyr Endobronchial Valve meets the specification. | The valve device must fit within the targeted bronchial segment. | Pass |
| Radial Expansion Test | Quantify the radial force exerted by the Zephyr Endobronchial Valve during radial expansion. | At the minimum labeled diameter, the radial force of the valve device retainer (implant frame) must be atraumatic relative to the bronchi. The radial force value correlates to no necrosis as per histopathological assessment. | Pass |
| | | At the maximum labeled diameter, the radial force of the valve device retainer (implant frame) must be sufficient to resist migration. The radial force value correlates to little to no migration as evaluated bronchoscopically. | |
| Valve Deployment Force Test | Evaluate the force required to deploy a Zephyr Endobronchial Valve out of the Zephyr Endobronchial Delivery Catheter. | The device must be compatible with the delivery catheter. The force required to deploy the valve must be less than the force generated by the catheter. | Pass |
| Valve Loading Tests | Evaluate the force required to load the valve device.Evaluate the tensile strength of the Loading Tool Assembly used to pull the valve device into the funnel. | The loading force of the valve device must be less than the tensile force of the cord bundle used to pull the device into the funnel. | Pass |
| | Evaluate the ability of the device to be loaded and deployed. | The valve device must be capable of being successfully loaded and deployed one time without compromising its ability to meet functional requirements. | |
| Retainer (Implant Frame) Strut Strength Test | Determine the tensile strength of the Zephyr Endobronchial Valve retainer (implant frame) struts. | The tensile strength of the retainer (implant frame) strut shall be at least 25% greater than the maximum force specified to load the valve device. | Pass |
| Removability Test | Confirm the Zephyr Endobronchial Valve (EBV) can be removed through an endotracheal tube. | Must be removable through a 7.5 mm endotracheal tube. | Pass |

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| Test | Purpose | Acceptance Criteria | Results |
| --- | --- | --- | --- |
| Retainer (Implant Frame) Cycle Fatigue Test | Assess the durability of the Valve Device Nitinol frame (retainer) following 6 years of simulated coughing at worst case cough frequency and cough pressure. | No membrane or strut fractures after 6 years of simulated worst case cough cycles. | Pass |
| Valve Cycle Fatigue Test | Assess the durability of the valve component following cyclic conditioning for the period of time necessary to simulate expected worst case use. | Following the cyclic conditioning, the valve device must pass the following tests: • Valve flow vs. pressure test • Leak test • Valve response test • Valve inversion test • Wet cracking pressure test | Pass |
| Corrosion Testing | To assess the resistance to corrosion of the device compared to a tracheobronchial stent of similar material that is implanted in the lung. Testing conducted as per ASTM F2129 Standard Test Method for Conducting Cyclic Potentiodynamic Polarization Measurements to Determine the Corrosion Susceptibility of Small Implant Devices. | All materials must perform (performance measured as breakdown potential or corrosion margin of safety) equal to or better than a tracheobronchial stent of similar material that is implanted in the lung. | Pass |
| Drug Compatibility | To assess the compatibility of the valve device to inhaled COPD medications. | The valve device must not change significantly when exposed to inhaled COPD medications. | Pass |

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Table 4: Summary of Zephyr® Endobronchial Delivery Catheter Bench Testing

| Test | Purpose | Acceptance Criteria | Results |
| --- | --- | --- | --- |
| Zephyr® Endobronchial Delivery Catheter | | | |
| Inner Shaft to Hardstop Tensile Test | Evaluate the tensile strength of the inner shaft to hardstop joint in the Zephyr Endobronchial Delivery Catheter. | All attachment joints must remain attached throughout the forces expected during clinical use and valve deployment(s). | Pass |
| Inner Shaft Tensile Strength Test | Evaluate the tensile strength of the inner shaft to inner shaft retention lock joint within the Zephyr Endobronchial Delivery Catheter handle. | | Pass |
| Housing to Outer Shaft Tensile Strength Test | Evaluate the tensile strength of the housing to outer shaft bond in the Zephyr Endobronchial Delivery Catheter. | | Pass |
| Outer Shaft to Handle Tensile Strength Test | Evaluate the tensile strength of the outer shaft to handle joint in the Zephyr Endobronchial Delivery Catheter. | | Pass |
| Outer Shaft Torque Test | Evaluate the torsional strength of the outer shaft of the Zephyr Endobronchial Delivery Catheter. | | Pass |

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| Test | Purpose | Acceptance Criteria | Results |
| --- | --- | --- | --- |
| Outer Shaft to Handle Torque Test | Evaluate the torsional strength of the outer shaft to handle joint of the Zephyr Endobronchial Delivery Catheter. | | Pass |
| Outer Sheath Tensile Strength Test | Evaluate the tensile strength of the bond joint between the outer sheath and handle in the Zephyr Endobronchial Delivery Catheter. | | Pass |
| Delivery Catheter Placement Test | Evaluate the Zephyr Endobronchial Delivery Catheter's ability to advance to the simulated target bronchus and place a Zephyr Endobronchial Valve in a simulated target bronchus. | The catheter must be able to deliver an EBV to the simulated bronchus through the 2.8 mm working channel of an adult bronchoscope. The delivery catheter must be capable of performing this at least six (6) times. | Pass |
| Delivery Catheter Sizing Gauge Endurance Test (Part 1-Performance) | Evaluate the functional endurance of the sizing gauges on the Zephyr Endobronchial Delivery Catheter by measuring the sizing gauges after six insertion/retraction cycles. | Must remain functional after six insertions and retractions through a bronchoscope. | Pass |
| Delivery Catheter Sizing Gauge Endurance Test (Part 2-Safety) | Evaluate the endurance of the sizing gauges on the Zephyr Endobronchial Delivery Catheter by inspecting the sizing gauges after 15 insertion/retraction cycles. | Sizing gauges must remain intact and attached after 15 insertions and retractions through an adult bronchoscope. | Pass |
| Depth Mark Verification Test | Verify the depth mark distance(s) on the Zephyr Endobronchial Delivery Catheter meet the dimensional requirements. | The delivery catheter housing must contain mark(s) accurately indicating the length of the retention portion of the valve device being placed. | Pass |
| Delivery Catheter Force Test | Verify that the distal output load and handle load of the Zephyr Endobronchial Delivery Catheter meet the product specification requirements. | When placed inside the 2.8 mm working channel of an adult bronchoscope at a bend of 180°, the force generated by the catheter must be greater than the force required to deliver the valve device.The force exerted by the user to deploy the valve shall be within the expected capability of the user. | Pass |
| Catheter Working Length Verification Test | Verify that the working length of the Zephyr Endobronchial Delivery Catheter meets the dimensional requirements. | The working length of the delivery catheter must exceed the length of the bronchoscope working channel of an adult bronchoscope. | Pass |

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| Test | Purpose | Acceptance Criteria | Results |
| --- | --- | --- | --- |
| Handle Safety Test | Evaluate the force required to overcome the safety lock feature of the actuator on the Zephyr Endobronchial Delivery Catheter handle. | The actuator lock must withstand a force greater than what is expected during insertion through the 2.8 mm working channel of an adult bronchoscope. | Pass |

# Sterilization Validation

The Zephyr® Endobronchial Valve System is sterilized with 100% Ethylene Oxide (EO) gas. The sterilization cycle was validated in accordance with ISO 11135-1:2007, Ethylene oxide - Part 1: Requirements for development, validation and routine control of a sterilization process for medical devices, and AAMI Technical Information Report 28:2009, Product adoption and process equivalence for ethylene oxide sterilization. The purpose of the testing is to demonstrate that the sterilization process is capable of sterilizing the Zephyr® Endobronchial Valve System to a minimum Sterility Assurance Level (SAL) of 10⁻⁶. A summary of the sterilization validation testing performed is provided in Table 5. The process validation study demonstrated that the Zephyr Valves and Zephyr EDC can be routinely processed to meet a Sterility Assurance Level (SAL) of 10⁻⁶. The results for ethylene oxide (EO) and ethylene chlorohydrin (ECH) met the requirements of ISO 10993-7:2008, "Biological evaluation of medical devices – Part 7: Ethylene oxide sterilization residuals." Product was at releasable levels after 48 hours of heated aeration for a one-time exposure and 48 hours heated aeration for a two-time exposure. These times are in addition to an 18 hour period of ambient aeration.

Table 5: Summary of Sterilization Validation Testing

| Acceptance Criteria | Results |
| --- | --- |
| **Microbiological Performance Qualification Test (per ISO 11135-1:2007)** | |
| All half cycle parameters must be met for the four (4) runs. | Pass. All half cycle parameters were met for each of the four (4) runs. |
| Positive controls must show growth. | Pass. All positive controls showed growth. |
| The minimum required lethality (SAL) is achieved. | Pass. The cycles performed in the execution of this study yielded the specified lethality to internal surrogate process challenge device (PCD) in the half cycle. Therefore, with a full cycle, the SAL of 10⁻⁶ biological indicator spore population placed in the load will be equal to or less than 10⁻⁶, providing a spore log reduction (SLR) of the biological indicator equal to or greater than 12. |
| The half cycles must demonstrate 100% Biological Indicator (BI) lethality of the internal and/or master PCD. | Pass. The half cycles demonstrated 100% BI lethality of the internal and/or master PCD. |

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| Acceptance Criteria | Results |
| --- | --- |
| The minimum required amount of internal temperature and relative humidity sensors must be functional at the completion of each half cycle. | Pass. The minimum required amount of internal temperature and relative humidity sensors was functional at the completion of each half cycle. |
| Physical Performance Qualification Test (per ISO 11135-1:2007, unless otherwise noted) | |
| All full cycle parameters must be met for the three (3) runs. | Pass. All full cycle parameters were met for each of the three (3) runs. |
| The full cycle must demonstrate 100% BI lethality of the external process challenge device (EPCD). | Pass. All full cycles demonstrated 100% BI lethality of the EPCD. |
| Positive controls must show growth. | Pass. All positive controls showed growth. |
| The results for EO and ECH residuals will meet the requirements of ISO 10993-7:2008, following aeration. | Pass. The results for EO and ECH met the requirements of ISO 10993-7:2008. |

# Packaging Validation

Packaging validation testing has been completed for the Zephyr® Endobronchial Valve System in accordance with applicable standards. The Zephyr Valves and EDC package systems were subjected to ethylene oxide sterilization, conditioning, and distribution testing outlined in the ASTM D4169, "Standard Practice for Performance Testing of Shipping Containers and Systems." Table 6 summarizes the packaging validation testing conducted, including information about the test, purpose, acceptance criteria, and results. The ability of the package systems to protect the Zephyr Valves and Zephyr EDC from hazards typically associated with the shipping and distribution environment has been validated and maintained through the shelf-life of the product.

To evaluate the physical condition of the device packaging post-distribution conditioning per ASTM D4332, "Standard Practice for Conditioning containers, Packages, or Packaging Components for Testing"

Table 6: Summary of Zephyr® Endobronchial System Packaging Validation Testing

| Test | Purpose | Acceptance Criteria | Results |
| --- | --- | --- | --- |
| Visual Inspection | To evaluate the physical condition of the device packaging post-conditioning per ASTM D4332, “Standard Practice for Conditioning Containers, Packages, or Packaging Components for Testing.” (packaging carton, overshipper box, pouch, labels) | No visual damage post-distribution as specified in protocol. | EBV: Pass EDC: Pass |
| Dye Penetration | To detect if there are any leaks in the pouch in accordance with ASTM | Each pouch must meet requirements per ASTM | EBV: Pass |

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| Test | Purpose | Acceptance Criteria | Results |
| --- | --- | --- | --- |
| | F1929-98, “Standard Test Method for Detecting Seal Leaks in Porous Medical Packaging by Dye Penetration.” | F1929-98 following worst case handling as specified in test protocol. | EDC: Pass |
| Pouch Peel Tensile Strength | To determine the pouch peel tensile strength of the pouch seal. | Peel strength of the pouch must be > 2.0 lbs. | EBV: Pass
EDC: Pass |

## Shelf Life Testing

A shelf-life of two (2) years has been established for the Zephyr® Endobronchial Valve System based on product and package shelf-life testing. The integrity and performance of the device after aging was evaluated through functional testing and visual inspections. The shelf-life testing performed after aging repeated the tests summarized in Table 3, Table 4, and Table 6, and all testing passed. The completed testing validates the proposed shelf-life duration of two (2) years and demonstrates that applicable requirements in the product specifications have been met. The device has completed the testing demonstrating that it conforms to user needs and its intended uses throughout its proposed shelf-life.

## B. Animal Studies

The Zephyr® Endobronchial Valve System has been extensively studied in the sheep model. Performance was demonstrated by the evaluation of implantation, removability, atelectasis, and migration. No long-term safety concerns have been identified based on histological examination of the implant sites. Table 7 summarizes the preclinical study conducted for the Zephyr 4.0-LP Endobronchial Valve, including information about the test, purpose, acceptance criteria, and results.

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Table 7: Summary of Zephyr 4.0-LP Endobronchial Valve 30 Day Implantation Study in Sheep Model

| Test | Purpose | Acceptance Criteria | Results |
| --- | --- | --- | --- |
| Implant Placement | Evaluate the ability of the device to be deployed in the target airway with correct placement and occlude the target airway. | Device must be able to deploy distal to the carina of the target airway per the IFU. Device must also occlude the target airway. | Devices were placed properly to occlude the target airway. |
| Acute Removability | Verify that the device can be removed after placement. | Device must be able to be removed after proper placement in an airway. | Devices were placed and successfully removed with minimal resistance and without any complications. |
| Sub-chronic Removability | Verify that the device can be removed after placement and 30±2 day implantation. | Device must be able to be removed after proper placement and 30±2 day implantation in an airway. | Devices were placed and successfully removed after 29 days of implantation. |
| Migration | Verify that the device maintains its original position in the airway. | Device must be seated distal to the carina and occlude the airway for each of the original placement locations. | 10 out of 12 of the devices maintained position. Two (2) devices migrated and were assumed to be expectorated. The root cause for these migrations was the growth of the animal over the 29 day implantation period. The body mass for both sheep increased by at least 8% during the implantation period. This root cause is not expected in the clinical setting and the results were determined to be acceptable. |
| Pathology | Evaluate the histopathological effects of the device at the implant sites after 30 day implantation. | Histological analysis of the implant site must yield an acceptable result for clinical use as determined by a pathologist. | Pathologist concluded that tissue specimens examined had “mild cellular reactions consistent with a Sub-chronic host response to a bio- compatible foreign body implantation”. Additionally, “laceration and/or tissue perforation were not noted.” Therefore, the pathology results are considered acceptable. |

C. Human Factors/Usability Testing

Human factors and usability validation testing was completed for the Zephyr® Endobronchial Valve System in accordance with the FDA Guidance, Applying Human Factors and Usability Engineering to Medical Devices, published February 3, 2016. The results from the human factors and usability validation testing demonstrated that all 20 test participants, currently licensed pulmonologists or thoracic surgeons residing in the

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U.S., were able to complete all four (4) critical tasks of the Zephyr® Endobronchial Valve System procedure. There were no occurrences of use errors during the testing, and the testing supports the conclusion that the use error rates with the Zephyr® Endobronchial Valve System have been reduced to the extent possible and are acceptable.

# X. SUMMARY OF PRIMARY CLINICAL STUDY

# Prior Clinical Study

The VENT trial $^{1}$ , conducted in 2004, was a randomized, controlled study with U.S. and European cohorts, comparing Zephyr EBV treatment to a Control group of subjects who received optimum medical care. Post-hoc subgroup analyses (Table 8) were performed to identify the population that was to be studied in the pivotal trial.

Table 8: Overview of VENT post-hoc sub-group

| No. of Sites | No. of Patients | Planned Follow-up | Outcomes |
| --- | --- | --- | --- |
| 31 (U.S.) | 122 (61 EBV with complete fissures and lobar occlusion & 61 Controls with complete fissures) | Primary endpoint at 6 months Follow-up out to 12-months | •Co-Primary Endpoints Mets: The mean group difference (EBV-SoC*) for the change in FEV1 and 6MWD from Baseline to 6-months was 24.8% (mean, p<0.001) and 18.0 m (median, P<0.0397), respectively •Significant improvements in residual volume (L), mMRC$, & SGRQ$ at 6-months. •Increase in respiratory adverse events during 30-Day Treatment Period (Hemoptysis & Non-cardiac chest pain) •Acceptable long-term safety profile, with a higher observed rate of Hemoptysis in the EBV group. |
| 23 (OUS) | | | |

*SoC (Standard of Care) (i.e., Control Group)
**Sponsored by Emphasys Medical (acquired by Pulmonx)
$Modified Medical Research Council (mMRC)
$\ddagger$ St. George's Respiratory Questionnaire (SGRQ)

# LIBERATE Pivotal Trial

The applicant performed a clinical study to establish a reasonable assurance of safety and effectiveness of the Zephyr® Endobronchial Valves (Zephyr Valves) for the treatment of patients with severe emphysema in the U.S., UK, Brazil, and the Netherlands under IDE #G120008. Data from this clinical study were the basis for the PMA approval decision. A summary of the clinical study is presented below.

# A. Study Design

Patients were treated between October 15, 2013 and September 30, 2017. The database for this PMA reflected data collected through November 16, 2017 at 24 investigational

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sites and included 190 patients (130 patients at 18 U.S. sites and 60 patients at 6 OUS sites).

The study was a prospective, multi-center, randomized, controlled, two-arm, one way crossover, unmasked, pivotal clinical study. Qualifying subjects with heterogeneous emphysema were randomized at a 2:1 ratio into either the Zephyr EBV treatment arm or Control (Standard of Care) arm. All subjects underwent bronchoscopy with Chartis assessment for collateral ventilation. To conduct the Chartis assessment for collateral ventilation, the Pulmonx Chartis System (composed of the Chartis® Catheter (K111522) and Chartis® Console (K111764)), was used and is designed to measure pressure and flow to calculate resistance to airflow and quantify collateral ventilation in isolated lung compartments. This procedure was performed to select the target lobe for EBV placement. The subjects in the EBV arm had Zephyr® Endobronchial Valves placed in the target lobe to achieve lobar occlusion and continued to receive optimal medical management according to current clinical practice guidelines based on GOLD 2013 recommendation. The Control group subjects only received optimal medical management according to current clinical practice guidelines based on GOLD 2013 recommendations for the duration of the study. However, following their 12-month evaluation, the Control group subjects could be crossed over to Zephyr EBV treatment.

Random assignment was performed using a stratified permuted block design, generated separately for each clinical site, with assignment stratified by anatomical site of the planned treatment (e.g., right lung or left lung). An interim analysis was performed when 74 subjects completed their 12-month follow-up, to evaluate effectiveness for continuing crossover of Control arm subjects at the 1-year follow-up to Zephyr EBV treatment.

The primary effectiveness endpoint in the Zephyr EBV treatment and Control arms were compared using the standard normal Z-statistic for both the interim and end of 12-month study analyses. To preserve an overall Type I error rate of 0.05 for the study, the Z-statistic had to exceed 2.571 at the interim analysis and 2.004 at the final analysis for the null hypothesis of no difference to be rejected.

Secondary effectiveness endpoints were analyzed using an Analysis of Covariance (ANCOVA) model with treatment as a fixed effect and the corresponding baseline as a covariate. To control the family-wise Type I error rate at 0.05, the Hochberg step-up procedure was utilized for multiplicity adjustment. The Intent-to-Treat (ITT) population consisting of all randomized subjects was used as the primary analysis population for all the effectiveness endpoints analyses.

A Data and Safety Monitoring Board (DSMB) comprising of three (3) voting members was established to oversee subject safety in the LIBERATE Study. A Clinical Events Committee (CEC) comprising of four (4) voting members was established to adjudicate select respiratory, all serious adverse events and all device-related adverse events in the LIBERATE Study.

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1. Clinical Inclusion and Exclusion Criteria

There were three (3) sets of enrollment criteria: screening, baseline, and procedure. Enrollment in the LIBERATE study was limited to patients who met the following inclusion criteria.

Screening Inclusion
- Signed Screening or Study Procedure Informed Consent using a form that was reviewed and approved by the IRB.
- Age 40 to 75 years.
- Body Mass Index (BMI) less than 35 kg/m².
- Stable with less than 20mg prednisone (or equivalent) daily.
- Nonsmoking for 4 months prior to screening interview.

Baseline Inclusion
- Completed a supervised pulmonary rehabilitation program less than equal to 6 months prior to the baseline exam or is regularly performing maintenance respiratory rehabilitation if initial supervised therapy occurred greater than 6 months prior.
- Baseline evaluation occurred ≤120 days after screening exam.
- Signed written informed consent to participate in study using a form that was reviewed and approved by the IRB.
- Continued nonsmoking between initial screening and baseline exams.
- Willing and able to complete protocol required study follow-up assessments and procedures.
- FEV₁ between 15% and 45% of predicted value at baseline exam.
- Post-rehabilitation 6-minute walk distance between 100 meters and 500 meters at baseline exam.
- Current Pneumococcus vaccination.
- Current Influenza vaccination.

Procedure Eligibility Inclusion
- Procedure occurs &lt; 60 days following baseline exam.
- Continues to meet all screening and baseline eligibility criteria.
- Little or no collateral ventilation (CV-) as determined using the Chartis System.

Patients were not permitted to enroll in the LIBERATE study if they met any of the following exclusion criteria:

Screening Exclusion
- Currently enrolled in another clinical trial studying an experimental treatment.
- Previously enrolled in this study for which protocol required follow up is not complete.

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- Clinically significant (greater than 4 tablespoons per day) sputum production.
- Two or more COPD exacerbation episodes requiring hospitalization in the last year at screening.
- Two or more instances of pneumonia episodes in the last year at screening.
- Unplanned weight loss &gt;10% usual weight &lt;90 days prior to enrollment.
- History of exercise-related syncope.
- Myocardial Infarction or congestive heart failure within 6 months of screening.
- Prior lung transplant, LVRS, bullectomy or lobectomy.
- Clinically significant bronchiectasis.
- Unable to safely discontinue anti-coagulants or platelet activity inhibitors for 7 days.
- Uncontrolled pulmonary hypertension (systolic pulmonary arterial pressure &gt;45 mm Hg) or evidence or history of CoPulmonale as determined by recent echocardiogram (completed within the last 3 months prior to screening visit).
- Pulmonary nodule requiring surgery as noted by chest X-ray or CT scan.
- High resolution computed tomography (HRCT) collected per CT scanning protocol within the last 3 months of screening date and evaluated by clinical site personnel using Myrian CT software (K071000) shows:
- Parenchymal destruction score of greater than 75% in all three right lobes or both left lobes.
- Emphysema heterogeneity score less than 15% (Not Applicable for Crossover subjects).
- Large bullae encompassing greater than 30% of either lung.
- Insufficient landmarks to evaluate the CT study using the software as it is intended.
- Left ventricular ejection fraction (LVEF) less than 45% as determined by recent echocardiogram (completed within the last 3 months prior to screening visit).
- Resting bradycardia (&lt;50 beats/min), frequent multifocal PVCs, complex ventricular arrhythmia, sustained SVT.
- Dysrhythmia that might pose a risk during exercise or training.
- Post-bronchodilator FEV₁ less than 15% or greater than 45% of predicted value at screening.
- Total lung capacity (TLC) less than 100% predicted (determined by body plethysmography) at screening.
- Residual volume (RV) less than 175% predicted (determined by body plethysmography) at screening.
- Diffusion capacity for carbon monoxide (DLCO) less than 20% predicted value at screening.
- 6-minute walk distance less than 100 meters or greater than 450 meters at screening.

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- PaCO2 greater than 50 mm Hg (Denver greater than 55 mm Hg) on room air at screening.
- PaO2 less than 45 mm Hg (Denver less than 30 mm Hg) on room air at screening.
- Elevated white cell count (&gt;10,000 cells/μL) at screening.
- Presence of alpha-1 anti-trypsin deficiency as determined by local laboratory ranges.
- Plasma cotinine level greater than 13.7 ng/ml (or arterial carboxyhemoglobin &gt;2.5% if using nicotine products) at screening.
- Any disease or condition that interferes with completion of initial or follow-up assessments.

## Baseline Exclusion
- Myocardial infarction or diagnosis of congestive heart failure between screening and baseline exams.
- Fever or other clinical evidence of active infection at baseline exam.
- Two (2) or more COPD exacerbation episodes between screening and baseline exams.
- Two (2) or more pneumonia episodes between screening and baseline exams.

## Procedure Eligibility Exclusion
- Evidence of collateral ventilation (CV+) as determined using the Chartis System.
- Collateral ventilation could not be determined using the Chartis System.
- Collateral ventilation assessment was not conducted using the Chartis System.

## 2. Follow-up Schedule
All patients were scheduled to return for follow-up examinations at 45-days, 3-months, 6 months, 9 months, and 1 year postoperatively. Subjects in the Zephyr EBV treatment arm had additional daily phone call follow-ups for the first 10 days, and office visits at 7 days and 30 days.

The Zephyr EBV treatment arm will have annual follow-up visit out to 5 years. Control group subjects who crossed over to the Zephyr EBV treatment arm after completing their 12 months follow-up will also undergo annual follow-up visits for an additional 5 years.

The key assessments performed at specific timepoints are shown in Table 9.

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Table 9: Key assessments performed at each visit

| TESTING | Screen Eligibility | Pre-Base line | Baseline Eligibility | Day 0 - Index Procedure | Day 1 | Day 2 | Day 3 | Day 4 | Day 5 (or day of Discharge) | Daily Phone Call (for 10 days after Discharge) | Day 7 After Discharge | 30 Days | 45 Days | 3 Months | 6 Months | 9 Months | 1 Year | 2 to 5 Year | ET/EWD |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| IMAGING | | | | | | | | | | | | | | | | | | | |
| Chest X-ray | | | | XEBV | XEBV | XEBV | XEBV | XEBV | XEBV | | XEBV | XEBV | X | | | | | | |
| Electrocardiography | X | | | | | | | | | | | | | | | | X | | |
| ECG | X | | | | | | | | | | | | | | | | | | |
| High Resolution CT Scan | X | | | | | | | | | | | | XEBV | | | | XEBV | | |
| LUNG FUNCTION TESTING | | | | | | | | | | | | | | | | | | | |
| Spirometry | X | | X | | | | | | | | | | X | | X | | X | X | X |
| Body Plethysmography | X | | | | | | | | | | | | X | | | | X | | |
| Diffusing Capacity | X | | | | | | | | | | | | X | | | | X | | |
| EXERCISE TOLERANCE Six-Minute Walk Test | | | | | | | | | | | | | | | | | | | |
| | X | | X | | | | | | | | | | | X | | X | | X | |
| BASIC MEDICAL | | | | | | | | | | | | | | | | | | | |
| Medical History | X | | | | | | | | | | | | | | | | | | |
| Pulse Oximetry (first 24 hours after procedure) | | | | XCONT. | XEBV | | | | | | | | | | | | | | |
| Vital Signs / Physical Exam | X | | X | X | | | | | XEBV | | XEBV | XEBV | X | X | X | | X | | X |
| Symptom Checklist | | | | | | | | | | XEBV | XEBV | | | | | | | | |
| Review of Medications | X | | | | | | | | | | | XEBV | X | X | X | X | X | | X |
| BLOOD WORK | | | | | | | | | | | | | | | | | | | |
| Arterial Blood Gases (ABGs) | X | | | XCONT. | XEBV | | | | | | | | | | | | X | | |

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| TESTING | Screen Eligibility | Pre-Base line | Baseline Eligibility | Day 0 - Index Procedure | Day 1 | Day 2 | Day 3 | Day 4 | Day 5 (or day of Discharge) | Daily Phone Call (for 10 days after Discharge) | Day 7 After Discharge | 30 Days | 45 Days | 3 Months | 6 Months | 9 Months | 1 Year | 2 to 5 Year | ET/EWD |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| Complete Blood Counts (CBCs) | X | | | | | | | | | | | | | | | | X | | |
| Alpha-1 Antitrypsin | X | | | | | | | | | | | | | | | | | | |
| Plasma Cotinine or Arterial Carboxyhemoglobin | X | | | | | | | | | | | | | | | | X | | |
| Serum Fibrinogen | X | | | XCONT. | XEBV | | | | | | | | | | | | X | | |
| MEDICAL MANAGEMENT | | | | | | | | | | | | | | | | | | | |
| Pulmonary Rehabilitation | | X | | | T | | | | | | XEBV | | | | | | | | |
| Pneumococcal Vaccine | | | X | | | | | | | | | | | | | | | | |
| Influenza Vaccine | | | X | | | | | | | | | | | | | | | | |
| HEALTH SURVEYS | | | | | | | | | | | | | | | | | | | |
| SGRQ | | | X | | | | | | | | | | | X | X | | X | | |
| mMRC | | | X | | | | | | | | | | X | | X | | X | | |
| BDI/TDI | | | X | | | | | | | | | | | X | X | X | X | | |
| CAT | | | X | | | | | | | | | | | X | X | X | X | | |
| SF-36 | | | X | | | | | | | | | | | | | | X | | |
| EQ-5D | | | X | | | | | | | | | | | | | | X | | |
| Health Care Utilization | | | X | | | | | | | | | | | X | X | X | X | | |
| DAILY DIARY*** | | | | | | | | | | | | | | | | | | | |
| PR Compliance | | | X | | | | | | | | | | X | X | X | X | X | | |
| Exact-PRO | | | X | | XEBV | XEBV | XEBV | XEBV | XEBV | XEBV | XEBV | XEBV | X | X | X | X | X | | |
| Health Status Change | | | X | | XEBV | XEBV | XEBV | XEBV | XEBV | XEBV | XEBV | XEBV | X | X | X | X | X | | |
| SAFETY | | | | | | | | | | | | | | | | | | | |

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| TESTING | Screen Eligibility | Pre-Base line | Baseline Eligibility | Day 0 - Index Procedure | Day 1 | Day 2 | Day 3 | Day 4 | Day 5 (or day of Discharge) | Daily Phone Call (for 10 days after Discharge) | Day 7 After Discharge | 30 Days | 45 Days | 3 Months | 6 Months | 9 Months | 1 Year | 2 to 5 Year | ET/EWD |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| Adverse Events | | | | X | XEBV | XEBV | XEBV | XEBV | XEBV | XEBV | XEBV | XEBV | X | X | X | X | X | X | X |
| CONT.: Assessments required for subjects randomized to the Control arm.
EBV: Assessments required for subjects randomized to the EBV arm. | | | | | | | | | | | | | | | | | | | |

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3. Clinical Endpoints

With regards to safety, adverse events up to 45 days (short term) and from day 46 to 1 year (long term) were evaluated.

With regards to effectiveness, the primary effectiveness endpoint was the percentage of study subjects in the Zephyr EBV treatment arm who met the threshold of ≥15% improvement in post-bronchodilator forced expiratory volume in one second (FEV₁) as compared to the Control arm at 1 year.

Secondary effectiveness endpoints included:

1. FEV₁: Difference between study arms in absolute change from baseline for FEV₁ at 1 year.
2. Six-minute Walk Distance (6MWD): Difference between study arms in absolute change from baseline for 6MWD at 1 year.
3. St. George’s Respiratory Questionnaire (SGRQ): Difference between study arms in absolute change from baseline for SGRQ score at 1 year.

Other additional endpoints included other measures of lung function, exercise capacity, breathlessness, and quality of life. Additionally, the 6MWD responder rate for the percent of subjects with improvement of ≥25 m and ≥54 meters was also collected.

With regards to success/failure criteria, the study would be considered a success if the difference between the Zephyr EBV treatment and Control arms for the percentage of subjects meeting the threshold of ≥15% improvement in post-bronchodilator FEV₁ was statistically significant (two-sided test at p ≤ 0.05) in favor of the Zephyr EBV treatment group at 1 year.

B. Accountability of PMA Cohort

At the time of database lock, of 190 patients enrolled in the PMA study, 91.6% (174) of enrolled patients were available for analysis at the completion of the study (data from four (4) additional patients from treatment arm was not available), the 12 month post-operative visit. Patient accountability is summarized in the Figure 4 and Table 10 below.

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Figure 4: Patient Accountability

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Table 10: Summary of Subject Enrollment and Evaluability (Randomized Subjects)

| | EBV | Control |
| --- | --- | --- |
| Number of Subjects Randomized | 128 | 62 |
| | | |
| Number of Subjects Included in the Intent-to-Treat Population | 128 (100.0%) | 62 (100.0%) |
| Number of Subjects Excluded from the Intent-to-Treat Population | 0 (0.0%) | 0 (0.0%) |
| | | |
| Number of Subjects Included in the Completed Cases Population | 115 (89.8%) | 59 (95.2%) |
| Number of Subjects Excluded from the Completed Cases Population | 13 (10.2%) | 3 (4.8%) |
| Reason for Exclusion from Completed Cases Population | | |
| Did Not Receive Treatment as Randomized | 0 (0.0%) | 0 (0.0%) |
| Did Not Attend 1 Year Follow-up Visit | 13 (10.2%) | 3 (4.8%) |
| | | |
| Number of Subjects Included in the Per-Protocol Population | 108 (84.4%) | 55 (88.7%) |
| Number of Subjects Excluded from the Per-Protocol Population | 20 (15.6%) | 7 (11.3%) |
| Reason for Exclusion from Per-Protocol Population | | |
| Did Not Receive Treatment as Randomized | 0 (0.0%) | 0 (0.0%) |
| Did Not Meet Study Eligibility | 11 (8.6%) | 5 (8.1%) |
| Did Not Have Follow-up within Window for Primary Endpoint | 16 (12.5%) | 5 (8.1%) |
| | | |
| Number of Subjects Included in the Safety Population | 128 (100.0%) | 62 (100.0%) |
| Number of Subjects Excluded from the Safety Population | 0 (0.0%) | 0 (0.0%) |

# C. Study Population Demographics and Baseline Parameters

The demographics of the study population are typical for a pivotal study performed in the U.S. Baseline demographics and clinical characteristics of the study population are presented in Table 11, Table 12, and Table 13 below.

Overall, the Control and treatment arm baseline characteristics were similar, except there were more males (53.2% in Control vs. 43.8% in treatment) and stage IV GOLD (74.2% in Control vs. 57.8% in treatment) subjects in the Control group. The majority of subjects enrolled in the study (91.4%) were caucasians. These differences are not expected to impact the clinical trial.

Table 11: Baseline Demographics

| Variable | EBV (N=128) | | Control (N=62) | | t-test p-value |
| --- | --- | --- | --- | --- | --- |
| | Mean | SD (Min, Max) | Mean | SD (Min, Max) | |
| Age (years) | 64.0 | 6.85 (46 to 75) | 62.5 | 7.12 (45 to 74) | 0.161a |
| Weight (lbs.) | 152.41 | 32.44 (88.0 to 251.33) | 153.34 | 35.09 (85.50 to 230.00) | 0.857a |

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Table 12: Baseline Clinical Characteristics – Lung Function Measures

| Variable | EBV (N=128) | | Control (N=62) | | t-test p-value |
| --- | --- | --- | --- | --- | --- |
| | Mean | SD (Min, Max) | Mean | SD (Min, Max) | |
| Pulmonary Function Tests and Lung Volumes | Mean (n) | SD (Min, Max) | Mean (n) | SD (Min, Max) | |
| Forced Expiratory Volume in 1 sec. (FEV1) – Post-bronchodilator (L) | 0.763 (128) | 0.252 (0.279 to 1.428) | 0.752 (62) | 0.217 (0.471 to 1.374) | 0.767a |
| Forced Expiratory Volume in 1 sec. (FEV1) – Post-bronchodilator (% predicted) | 28.0 (128) | 7.45 (15 to 45) | 26.2 (62) | 6.28 (16 to 44) | 0.101a |

a P-value from two-sided t-test assuming equal variance.
b P-value from two-sided Fisher's exact test.

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| Variable | EBV (N=128) | | Control (N=62) | | t-test p-value |
| --- | --- | --- | --- | --- | --- |
| Forced Vital Capacity (FVC) (L) | 2.596 (128) | 0.865 (0.940 to 4.493) | 2.631 (62) | 0.790 (0.978 to 5.041) | 0.792a |
| Forced Vital Capacity (FVC) (% predicted) | 71.2 (128) | 15.99 (38 to 111) | 68.5 (62) | 13.59 (37 to 108) | 0.248a |
| FEV1/FVC | 0.302 (128) | 0.063 (0.17 to 0.46) | 0.294 (62) | 0.063 (0.19 to 0.50) | 0.421a |
| Diffusing Capacity (mL CO/min/mm Hg) | 8.528 (126) | 3.475 (3.53 to 25.72) | 8.342 (61) | 2.708 (4.23 to 15.49) | 0.714a |
| Diffusing Capacity (% predicted) | 34.6 (126) | 11.34 (20 to 72) | 33.1 (61) | 9.84 (20 to 59) | 0.393a |
| Residual Volume (RV) (L) | 4.709 (126) | 1.046 (1.70 to 8.00) | 4.759 (61) | 0.901 (3.10 to 6.48) | 0.752a |
| Residual Volume (% predicted) | 224.5 (126) | 42.45 (175 to 349) | 224.6 (61) | 38.86 (175 to 359) | 0.987a |
| Total Lung Capacity (TLC) (L) | 7.537 (126) | 1.593 (5.00 to 13.00) | 7.634 (61) | 1.369 (5.25 to 10.40) | 0.683a |
| Total Lung Capacity (% predicted) | 133.5 (126) | 21.17 (105 to 307) | 130.2 (61) | 12.44 (106 to 161) | 0.256a |
| RV/TLC | 0.631 (126) | 0.086 (0.13 to 0.81) | 0.626 (61) | 0.073 (0.45 to 0.79) | 0.689a |
| Functional Residual Capacity (FRC) (L) | 5.807 (126) | 1.301 (3.73 to 12.18) | 5.903 (61) | 1.106 (3.80 to 8.10) | |
| GOLD Stage | 54 (42.2%) Stage III 74 (57.8%) Stage IV | | 16 (25.8%) Stage III 46 (74.2%) Stage IV | | 0.037b |
| HRCT Characteristics | | | | | |
| Emphysema Destruction score of the Target Lobe at -910 HU* | 70.9 (128) | 8.52 (50 to 88) | 70.9 (62) | 8.77 (51 to 86) | 0.998a |
| Ipsilateral Lobe Destruction Score (%) | 45.4 (128) | 11.12 (11 to 68) | 44.8 (62) | 12.36 (11 to 69) | 0.739a |
| Heterogeneity Index† | 25.5 (128) | 9.85 (15 to 70) | 26.1 (62) | 9.81 (15 to 61) | 0.694a |

a P-value from two-sided t-test assuming equal variance.
b P-value from Fisher's Exact test.
c Classification of airflow limitation severity in COPD (based post-bronchodilator $\mathrm{FEV}_1$ ): GLOBAL STRATEGY FOR THE DIAGNOSIS, MANAGEMENT, AND PREVENTION OF COPD (2017 REPORT)
Note: Baseline results are the latest results prior to EBV or Assessment procedure. To convert Diffusing Capacity from SI units (mmol / min / kPa) to standard units (mL CO /min /mmHg), values were multiplied by 2.987.
* Emphysema destruction score was assessed as the percentage of voxels of less than -910 Hounsfield units on CT.

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† Volume weighted Heterogeneity Index assessed as the difference in the Emphysema destruction score between the target and the ipsilateral lobe. A difference of ≥15% was required between target and ipsilateral lobes

Table 13: Baseline Clinical Characteristics – Exercise Tolerance and Quality of Life Measures

| Variable | EBV (N=128) | | Control (N=62) | | t-test p-value |
| --- | --- | --- | --- | --- | --- |
| Exercise Tolerance and Quality of Life Measures | Mean (n) | SD (Min, Max) | Mean (n) | SD (Min, Max) | |
| 6 Minute Walk Distance (m) | 311.33 (128) | 81.33 (142 to 482) | 301.91 (62) | 78.54 (102 to 474) | 0.450a |
| BORG before 6MWD | 1.16 (128) | 1.391 (0.0 to 7.0) | 1.07 (62) | 1.201 (0.0 to 4.0) | |
| BORG after 6MWD | 4.45 (128) | 2.174 (0.0 to 10.0) | 4.94 (62) | 2.282 (0.5 to 10.0) | |
| SGRQ Total score‡ | 55.15 (127) | 14.09 (30.1 to 88.1) | 53.10 (61) | 14.14 (25.9 to 91.8) | 0.352a |
| mMRC Dyspnea Grade score§ | 2.4 (126) | 0.97 (0 to 4) | 2.2 (62) | 0.83 (0 to 4) | 0.091b |
| BODE Index** | 5.34 (126) | 1.52 (2.0 to 10.0) | 5.32 (62) | 1.56 (2.0 to 9.0) | 0.819b |
| CAT Total score1 | 19.2 (128) | 6.32 (5 to 37) | 19.3 (62) | 6.35 (6 to 34) | 0.890a |
| EQ-5D Index | 0.7 (127) | 0.16 (0 to 1) | 0.7 (61) | 0.16 (0 to 1) | 0.647b |
| EQ-5D VAS score | 58.4 (121) | 20.46 (4 to 100) | 53.1 (59) | 20.76 (5 to 80) | 0.159b |

a P-value from two-sided t-test assuming equal variance.
b P-value from Wilcoxon Rank Sum Test.
‡ St. George’s Respiratory Questionnaire (SGRQ) scores range from 0 to 100, with higher scores indicating worse quality of life.
§ Modified Medical Research Council (mMRC) Dyspnea Scale ranges from 0 to 4, with higher scores indicating more severe dyspnea.
1 COPD Assessment Test (CAT) score ranges from 0-40 with higher scores indicating a more severe impact of COPD on a patient’s life.
**BODE Index (Body mass index, airflow Obstruction, Dyspnea and Exercise capacity) score ranges from 0 to 10 based on a multidimensional scoring system to include FEV₁, Body-Mass Index, 6 Minute Walk Distance, and the modified MRC Dyspnea score. Higher scores denote a greater risk of mortality.

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D. Safety and Effectiveness Results

1. Safety Results

The analysis of safety was based on the 190 patients available for the Treatment Period (Day of procedure/randomization to 45 days) and 184 patients available for the Longer-Term Period (46 days after the study procedure/randomization until the 1-year follow-up visit). The key safety outcomes for this study are presented below in Table 14 and Table 15. Adverse events are reported in Table 16, Table 17, and Table 18.

Table 14: Key Safety Outcomes within 45 Days of EBV/Assessment Procedure (Safety Subjects)

| | EBV
(N=128) | Control
(N=62) |
| --- | --- | --- |
| | | |
| Total Number of Adverse Events Reported | 352 | 35 |
| Subjects Reporting Any Adverse Event | 106 (82.8%) | 25 (40.3%) |
| | | |
| Total Number of Serious Adverse Events Reported | 63 | 5 |
| Subjects Reporting Any Serious Adverse Event | 48 (37.5%) | 5 (8.1%) |
| | | |
| Subjects Who Died | 4 | 0 |
| | | |
| Subjects Reporting Adverse Events by Maximum Severity | | |
| Severe | 30 (23.4%) | 4 (6.5%) |
| Moderate | 45 (35.2%) | 10 (16.1%) |
| Mild | 31 (24.2%) | 11 (17.7%) |
| | | |
| Subjects Reporting Adverse Events by Strongest Relationship to Study Device (Investigator Reported) | | |
| Definitely | 39 (30.5%) | NA |
| Probably | 24 (18.8%) | |
| Possibly | 18 (14.1%) | |
| Not Related | 25 (19.5%) | |
| Unknown | 0 (0.0%) | |
| Subjects Reporting Adverse Events by Strongest Relationship to Study Procedure (Investigator Reported) | | |
| Definitely | 29 (22.7%) | NA |
| Probably | 18 (14.1%) | |
| Possibly | 34 (26.6%) | |
| Not Related | 25 (19.5%) | |
| Unknown | 0 (0.0%) | |

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Table 15: Key Safety Outcomes between 46 Days Post EBV/Assessment Procedure and One Year Visit (Safety Subjects)

| | EBV
(N=122) | Control
(N=62) |
| --- | --- | --- |
| | | |
| Total Number of Adverse Events Reported | 326 | 144 |
| Subjects Reporting Any Adverse Event | 110 (90.2%) | 51 (82.3%) |
| | | |
| Total Number of Serious Adverse Events Reported | 86 | 47 |
| Subjects Reporting Any Serious Adverse Event | 48 (39.3%) | 21 (33.9%) |
| | | |
| Subjects Who Died | 1 | 1 |
| | | |
| Subjects Reporting Adverse Events by Maximum Severity | | |
| Severe | 28 (23.0%) | 15 (24.2%) |
| Moderate | 59 (48.4%) | 23 (37.1%) |
| Mild | 23 (18.9%) | 13 (21.0%) |
| | | |
| Subjects Reporting Adverse Events by Strongest Relationship to Study Device (Investigator Reported) | | |
| Definitely | 6 (4.9%) | NA |
| Probably | 14 (11.5%) | |
| Possibly | 30 (24.6%) | |
| Not Related | 59 (48.4%) | |
| Unknown | 1 (0.8%) | |
| | | |
| Subjects Reporting Adverse Events by Strongest Relationship to Study Procedure (Investigator Reported) | | |
| Definitely | 3 (2.5%) | NA |
| Probably | 7 (5.7%) | |
| Possibly | 17 (13.9%) | |
| Not Related | 83 (68.0%) | |
| Unknown | 0 (0.0%) | |

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

For the short term, periprocedural period up to 45 days, the overall number of subjects reporting any adverse event was higher in the EBV group at 106 (82.8%) vs. 25 (40.3%) in the Control group (Table 14). There were a higher number of respiratory adverse events in the Zephyr EBV group compared to the Control group during the Treatment Period (79.7% subjects vs. 30.6% subjects). All adverse events occurring at an incidence rate of $\geq 3.0\%$ in either the Zephyr EBV or Control groups during the Treatment Period (Day of procedure/ randomization to 45 days) and Longer-Term Period (46 days after the study procedure/ randomization until the 1-year follow-up visit is provided in (Table 16).

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The most common respiratory adverse events in the Zephyr EBV vs. Control subjects during the Treatment Period were pneumothorax in 29.7% vs. 0.0% subjects, respectively; chest pain in 25.8% vs. 1.6% subjects, respectively; COPD exacerbations in 19.5% vs. 11.3% subjects, respectively; cough in 18.0% vs. 4.8% subjects, respectively; and dyspnea in 16.4% vs. 3.2% subjects, respectively.

There were more respiratory-related serious adverse events (SAEs) (Table 17) in the Zephyr EBV group with 35.2% vs. 4.8% in the Control group. The most common serious adverse event during the short term period was pneumothorax, which occurred in 34 (26.6%) of the EBV treated subjects. There were also four (4) early deaths (3.1%) with three (3) related to pneumothoraces (Table 16). Other respiratory serious adverse events included increased COPD exacerbations (7.8% of EBV subjects (10 events) vs. 4.8% of Control subjects (3 events)), respiratory failure (1.6% of EBV subjects (2 events)), dyspnea (1.6% of EBV subjects (4 events)), and pneumonia (1 EBV subject). The non-respiratory adverse events were observed in both arms at rates expected for subjects with COPD.

In the Longer-Term Period (46 days after the study procedure/randomization until the 1-year follow-up visit), the frequency of respiratory SAEs (Table 18) was comparable between arms, with 33.6% of the Zephyr EBV group subjects and 30.6% of the Control group subjects experiencing one or more respiratory SAE. Some of the higher number of adverse events in the Zephyr EBV group during this period were associated with protocol-allowed bronchoscopy procedures for valve adjustment. There were eight (8) subjects (6.6%) that had a pneumothorax after 45 days in the EBV arm, five (5) of which had undergone a second bronchoscopy for valve adjustment. The Control group had a higher frequency of COPD exacerbations that were SAEs (29 events in 19 (30.6%) subjects compared to 40 events in 28 (23.0%) subjects in the Zephyr EBV group), a higher frequency of pneumonias (6 events in 5 (8.1%) subjects compared to 7 events in 7 (5.7%) subjects in the Zephyr EBV group), and respiratory failure (3 events in 2 (3.2%) subjects compared to 1 event in 1 (0.8%) subject in the Zephyr EBV group). During the Longer-Term Period from 46 days to the 12-month visit date, death occurred in 0.8% of subjects in the Zephyr EBV group (1 subject), and 1.6% of the Control group (1 subject), both due to disease progression.

Table 16: Adverse Events Occurring in at Least 3% of Subjects in Either Group

| | Treatment Period
(Day of Procedure/
Randomization to 45 Days) | | Longer-Term Period
(45 Days from the Study
Procedure/Randomization
until 12-Month Visit Date | |
| --- | --- | --- | --- | --- |
| | Zephyr EBV
(N=128) | Control
(N=62) | Zephyr
EBV
(N=122) | Control
(N=62) |
| Respiratory | | | | |
| Pneumothorax | 38 (29.7%) | 0 (0.0%) | 8 (6.6%) | 0 (0.0%) |
| Chest pain | 33 (25.8%) | 1 (1.6%) | 8 (6.6%) | 0 (0.0%) |
| COPD | 25 (19.5%) | 7 (11.3%) | 69 (56.6%) | 35 (56.5%) |

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| | Treatment Period (Day of Procedure/ Randomization to 45 Days) | | Longer-Term Period (45 Days from the Study Procedure/Randomization until 12-Month Visit Date | |
| --- | --- | --- | --- | --- |
| | Zephyr EBV (N=128) | Control (N=62) | Zephyr EBV (N=122) | Control (N=62) |
| Respiratory | | | | |
| Cough | 23 (18.0%) | 3 (4.8%) | 6 (4.9%) | 2 (3.2%) |
| Dyspnea | 21 (16.4%) | 2 (3.2%) | 16 (13.1%) | 1 (1.6%) |
| Haemoptysis | 11 (8.6%) | 1 (1.6%) | 12 (9.8%) | 0 (0.0%) |
| Oropharyngeal Pain | 10 (7.8%) | 3 (4.8%) | 0 (0.0%) | 0 (0.0%) |
| Pleural Effusion | 9 (7.0%) | 0 (0.0%) | 1 (0.8%) | 0 (0.0%) |
| Chest discomfort | 8 (6.3%) | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) |
| Hypoxia | 7 (5.5%) | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) |
| Pneumonia | 6 (4.7%) | 0 (0.0%) | 11 (9.0%) | 6 (9.7%) |
| Death | 4 (3.1%) | 0 (0.0%) | 1 (0.8%) | 1 (1.6%) |
| Sputum increased | 4 (3.1%) | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) |
| Pulmonary mass | 0 (0.0%) | 0 (0.0%) | 7 (5.7%) | 3 (4.8%) |
| Upper respiratory tract infection | 1 (0.8%) | 0 (0.0%) | 7 (5.7%) | 0 (0.0%) |
| Bronchitis | 1 (0.8%) | 0 (0.0%) | 6 (4.9%) | 3 (4.8%) |
| Lower respiratory tract congestion | 3 (2.6%) | 0 (0.0%) | 5 (4.1%) | 0 (0.0%) |
| Sinusitis | 0 (0.0%) | 0 (0.0%) | 3 (2.5%) | 3 (4.8%) |
| Respiratory failure | 2 (1.6%) | 0 (0.0%) | 1 (0.8%) | 2 (3.2%) |
| Pharyngitis | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | 2 (3.2%) |
| Non-Respiratory | | | | |
| Headache | 10 (7.8%) | 1 (1.6%) | 4 (3.3%) | 0 (0.0%) |
| Nausea | 10 (7.8%) | 0 (0.0%) | 1 (0.8%) | 0 (0.0%) |
| Constipation | 8 (6.3%) | 0 (0.0%) | 1 (0.8%) | 0 (0.0%) |
| Functional Gastrointestinal disorder | 6 (4.7%) | 0 (0.0%) | 1 (0.8%) | 0 (0.0%) |
| Arrhythmia | 5 (3.9%) | 0 (0.0%) | 2 (1.6%) | 2 (3.2%) |
| Dizziness | 4 (3.1%) | 0 (0.0%) | 1 (0.8%) | 0 (0.0%) |
| Pyrexia | 4 (3.1%) | 1 (1.6%) | 0 (0.0%) | 0 (0.0%) |
| Infection | 1 (0.8%) | 1 (1.6%) | 10 (8.2%) | 4 (6.5%) |
| Urinary Tract Infection | 1 (0.8%) | 1 (1.6%) | 2 (1.6%) | 4 (6.5%) |
| Diverticulitis | 0 (0.0%) | 0 (0.0%) | 1 (0.8%) | 2 (3.2%) |
| Nephrolithiasis | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | 2 (3.2%) |

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Table 17: Respiratory Serious Adverse Events Occurring within 45 Days Post EBV/Assessment Procedure and One Year Visit (Safety Subjects)

| Classa Preferred Term | EBV Subjectsb (N=128) | | Control Subjectsb (N=62) | |
| --- | --- | --- | --- | --- |
| | n (%) | Events: n | n (%) | Events: n |
| | | | | |
| Respiratory Adverse Events | 45 (35.2%) | 55 | 3 (4.8%) | 3 |
| Anesthetic complication pulmonary | 1 (0.8%) | 1 | 0 | |
| Chest pain | 1 (0.8%) | 1 | 0 | |
| Chronic obstructive pulmonary disease | 10 (7.8%) | 10 | 3 (4.8%) | 3 |
| Dyspnea | 2 (1.6%) | 4 | 0 | |
| Pleural effusion | 2 (1.6%) | 2 | 0 | |
| Pneumonia | 1 (0.8%) | 1 | 0 | |
| Pneumothorax | 34 (26.6%) | 34 | 0 | |
| Respiratory failure | 2 (1.6%) | 2 | 0 | |

aRespiratory Serious Adverse Events map to primary, secondary, or tertiary MedDRA System Organ Class of "Respiratory, thoracic and mediastinal disorders."
bSubjects are counted once at each level of summarization.

Table 18: Respiratory Serious Adverse Events Occurring between 46 Days Post EBV/Assessment Procedure and One Year Visit (Safety Subjects)

| Classa Preferred Term | EBV Subjectsb (N=122) | | Control Subjectsb (N=62) | |
| --- | --- | --- | --- | --- |
| | n (%) | Events: n | n (%) | Events: n |
| | | | | |
| Respiratory Adverse Events | 41 (33.6%) | 64 | 19 (30.6%) | 39 |
| Chronic obstructive pulmonary disease | 28 (23.0%) | 40 | 19 (30.6%) | 29 |
| Dyspnea | 3 (2.5%) | 3 | 0 | |
| Haemoptysis | 2 (1.6%) | 2 | 0 | |
| Pleural effusion | 1 (0.8%) | 1 | 0 | |
| Pneumonia | 7 (5.7%) | 7 | 5 (8.1%) | 6 |
| Pneumothorax | 8 (6.6%) | 8 | 0 | |
| Pulmonary embolism | 0 | | 1 (1.6%) | 1 |
| Pulmonary mass | 1 (0.8%) | 1 | 0 | |
| Respiratory failure | 1 (0.8%) | 1 | 2 (3.2%) | 3 |
| Respiratory tract infection | 1 (0.8%) | 1 | 0 | |

aRespiratory serious adverse events map to primary, secondary, or tertiary MedDRA System Organ Class of "Respiratory, thoracic and mediastinal disorders."
bSubjects are counted once at each level of summarization.

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# 2. Effectiveness Results

The analysis of effectiveness was based on the 190 evaluable patients at the 12-month time point. Key effectiveness outcomes are presented in Table 19 and Table 20.

The LIBERATE study met the primary effectiveness endpoint. After 12 months of follow-up, the proportion of subjects with $\geq 15\%$ improvement in post-bronchodilator $\mathrm{FEV}_1$ was statistically significantly greater in the Zephyr EBV treatment group than in the Control group (47.7% vs. 16.8%, treatment difference = 31.0%, 95% CI = (18.0%, 43.9%), p &lt; 0.001, see Table 19, Figure 5.

Table 19: Primary Analysis of the Primary Effectiveness Endpoint (Intent-to-Treat Population)

| | Zephyr EBV (N=128) | Control (N=62) | Delta (95% CI) | Z-statistic | P-value |
| --- | --- | --- | --- | --- | --- |
| Percent of Subjects with ≥15% Improved Post-Bronchodilator FEV1 at 1 Year | 47.7% | 16.8% | 31.0% (18.0% to 43.9%) | 4.130 | <0.001 |
| Note: To account for the interim analysis, Z>2.004 is the threshold for significance. Intermittent missing values imputed with linear interpolation. Truncated missing values imputed with multiple imputation (propensity score method). Death prior to 1-year endpoint imputed as failure. Values have been adjusted for multiple imputation. Averages across imputations are presented for Z and p-value. | | | | | |

Figure 5: Primary Effectiveness Endpoint (Percent of Subjects with $\mathrm{FEV}_1$ Improvement of $\geq 15\%$ at 12-months)

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The three (3) secondary effectiveness endpoints were also met for the study since the mean change from baseline in $\mathrm{FEV}_1$ , 6MWD, and SGRQ score after 12 months of follow-up were all clinically meaningful and statistically significantly better in the Zephyr EBV treatment group than in the Control group (all $p &lt; 0.005$ after Hochberg step-up procedure for multiplicity testing adjustment). Specifically, as Table 20 and Figure 6 show:

- the mean change from baseline to 12 months in post-bronchodilator $\mathrm{FEV}_1$ was $0.104\mathrm{L} \pm 0.200$ (mean $\pm$ SD) in the Zephyr EBV treatment group and $-0.003\mathrm{L} \pm 0.194$ in the Control group, with a treatment difference of 0.106 liters (95% CI = (0.047, 0.165));
- the mean change from baseline to 12 months in 6MWD was $12.98\mathrm{m} \pm 81.54$ in the Zephyr EBV treatment group and $-26.33\mathrm{m} \pm 81.50$ in the Control group, with a treatment difference of 39.31 meters (95% CI = (14.64, 63.98)); and
- the mean change from baseline to 12 months in SGRQ score was -7.55 points ± 15.71 in the Zephyr EBV treatment group and -0.50 points ± 15.50 in the Control group, with a treatment difference of -7.05 points (95% CI = (-11.84, -2.27)).

Table 20: Primary Analysis Results for the Secondary Effectiveness Endpoints (ITT Population)

| | EBV (N=128) | Control (N=62) | Delta | Treatment P-Valuea |
| --- | --- | --- | --- | --- |
| Post-Bronchodilator FEV1(L) | | | | |
| 1 Year – Absolute Change from Baseline | | | | |
| LS Meana | 0.1035 | -0.0026 | 0.1061 | <0.001* |
| LS SDa | 0.20029 | 0.19394 | | |
| 95% Confidence Intervala | (0.0688, 0.1382) | (-0.0509, 0.0457) | (0.0471, 0.1651) | |
| | | | | |
| Six Minute Walk Distance (m) | | | | |
| 1 Year – Absolute Change from Baseline | | | | |
| LS Meana | 12.98 | -26.33 | 39.31 | 0.002* |
| LS SDa | 81.537 | 81.500 | | |
| 95% Confidence Intervala | (-1.15, 27.11) | (-46.62, -6.04) | (14.64, 63.98) | |
| | | | | |
| St. George's Respiratory Questionnaire (points) | | | | |
| 1 Year – Absolute Change from Baseline | | | | |
| LS Meana | -7.55 | -0.50 | -7.05 | 0.004* |
| LS SDa | 15.708 | 15.504 | | |

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| | EBV (N=128) | Control (N=62) | Delta | Treatment P-Valuea |
| --- | --- | --- | --- | --- |
| 95% Confidence Intervala | (-10.28, -4.82) | (-4.39, 3.39) | (-11.84, -2.27) | |
| aP-values, least squares means, standard deviations and confidence intervals from an analysis of covariance (ANCOVA) with factor of treatment and the respective baseline value as a covariate. Values have been adjusted for multiple imputation. Note: To control the family-wise type I error rate at 5%, the Hochberg step-up procedure was utilized, and each p-value with an (*) is to be considered statistically significant. | | | | |

Figure 6: Secondary Effectiveness Endpoints

The durability of key and additional effectiveness outcomes is shown graphically in Figure 7.

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Figure 7: Durability of Key and Additional Effectiveness Outcomes




RV: Residual Value.


Data from the LIBERATE study demonstrated that Pulmonx Zephyr® Endobronchial Valve System was effective in improving lung function, exercise capacity, and quality of

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life at 1 year post-procedure in patients with severe heterogeneous emphysema who had little to no collateral ventilation as determined by Pulmonx Chartis System.

## Protocol Deviations

There was a total of 560 protocol deviations during the conduct of the LIBERATE study with 129 Major deviations and 431 Minor deviations. All deviations are summarized in Table 21. These deviations did not have a major impact on the tested endpoint and safety evaluations.

Table 21. Summary of Major and Minor Protocol Deviations

| Deviation Type | Number of Deviations |
| --- | --- |
| MAJOR | 129 |
| Informed Consent not properly obtained | 6 |
| Subject did not meet Inclusion/Exclusion criteria | 38 |
| Safety calls or follow-up missed | 48 |
| Protocol required evaluation test not done | 18 |
| Treatment period chest x-ray | 15 |
| 45 Day CT Scan | 2 |
| Screening ECG | 1 |
| Secondary Valve Procedure performed outside of protocol specified window | 4 |
| Other | 15 |
| Existing test results used for subject eligibility | 8 |
| Subject discharged 1 day early | 1 |
| Late reporting of serious adverse event | 2 |
| Protocol required visit performed remotely | 4 |
| MINOR | 431 |
| Follow-up visit missed | 25 |
| Follow-up visit outside protocol required window | 92 |
| Protocol required evaluation test not done | 155 |
| Test or procedure done outside of protocol required window | 45 |
| Other | 114 |
| Test or procedure performed by un-trained staff | 1 |
| Test or procedure not performed per protocol | 11 |
| Daily diary not completed or not downloaded per protocol | 57 |
| Past-procedure pulmonary rehab not completed per protocol | 37 |
| Pulmonary rehabilitation log missing | 8 |
| TOTAL DEVIATIONS | 560 |

## 3. Subgroup Analyses

The following preoperative characteristics were evaluated for potential association with outcomes: race, ethnicity, regional location, gender, and age. Treatment effects on proportion of subjects with $\geq 15\%$ improvement in post-bronchodilator $\mathrm{FEV}_1$ at 1 year between the Zephyr EBV treatment and Control groups were consistent across the

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subgroups defined by race, ethnicity, study site, and geography (U.S. vs. non-U.S.), as no significant treatment-by-subgroup interactions were observed (all p &gt; 0.15). While the treatment-by-age and treatment-by-gender interactions for the primary effectiveness outcome were found to be statistically significant (both p &lt; 0.15), the interactions were quantitative, meaning that the treatment differences observed in the subgroups of age and gender were all in the same direction favoring the Zephyr EBV treatment.

## 4. Pediatric Extrapolation

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

## E. Financial Disclosure

The Financial Disclosure by Clinical Investigators regulation (21 CFR 54) requires applicants who submit a marketing application to include certain information concerning the compensation to, and financial interests and arrangement of, any clinical investigator conducting clinical studies covered by the regulation. The pivotal clinical study included 33 principal investigators of which none were full-time or part-time employees of the sponsor and one 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: 1
- 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. SUMMARY OF SUPPLEMENTAL CLINICAL INFORMATION

In addition to the results of the pivotal trial, the use of Zephyr Valves for the treatment of severe emphysema was also supported by the results from 12 months of follow-up in the IMPACT and TRANSFORM trials that were conducted…