AeroPace® System

P240012 · Lungpacer Medical USA, Inc. · SDL · Dec 4, 2024 · Anesthesiology

Device Facts

• Record ID: P240012
• Device Name: AeroPace® System
• Applicant: Lungpacer Medical USA, Inc.
• Product Code: SDL · Anesthesiology
• Decision Date: Dec 4, 2024
• Decision: APPR
• Device Class: Class 3
• Attributes: Therapeutic

Indications for Use

The AeroPace System (a Temporary Transvenous Diaphragm Activation System) is intended for temporary stimulation of the phrenic nerve(s) to increase diaphragmatic strength in mechanically ventilated patients. The AeroPace System utilizes a temporarily placed, central venous neurostimulation catheter and an external control unit, designed to operate in conjunction with mechanical ventilation in any mode, to transvenously stimulate the left and/or right phrenic nerves to strengthen the diaphragm and facilitate weaning.

Device Story

AeroPace System provides temporary transvenous phrenic nerve stimulation to strengthen the diaphragm in mechanically ventilated patients. The system consists of a central venous neurostimulation catheter, an external neurostimulation console, and an airway sensor. The catheter is inserted into the left jugular or subclavian vein; it also functions as a standard central venous catheter for fluid/medication delivery. The airway sensor connects to the ventilator circuit to provide pressure data to the console. The console uses this data to synchronize stimulation with the ventilator, delivering charge-balanced biphasic pulses to the phrenic nerves to induce diaphragm contraction. Therapy is typically delivered twice daily for up to 30 days. The system is operated by clinicians in an ICU setting. By strengthening the diaphragm, the device aims to facilitate weaning from mechanical ventilation, reduce ventilator days, and decrease reintubation rates, addressing diaphragm atrophy caused by prolonged mechanical ventilation.

Clinical Evidence

Evidence includes preclinical porcine studies and clinical trials (RESCUE 1, 2, and 3). RESCUE 3 (N=223) was a randomized, controlled, open-label, international multicenter trial comparing AeroPace + SoC vs. SoC alone. Primary endpoint: successful weaning by Day 30. Results showed numerical superiority for the Treatment group (72.4% mITT) vs. Control (62.0% mITT). Treatment group showed 1.9 fewer days on MV, 60% relative risk reduction for reintubation, and improved MIP (4.1 cmH2O difference). Safety profile was consistent with CVC use; device-related SAEs (9.6%) included infections and cardiac events (e.g., inadvertent stimulation).

Technological Characteristics

System includes an 8.5Fr, 23cm central venous catheter with 30 integrated electrodes, an external neurostimulation console, and a disposable airway sensor. Stimulation uses a charge-balanced biphasic asymmetrical waveform, constant current, 200-300 μs pulse duration, and 15-40 Hz frequency. Catheter is EO-sterilized, single-use, and compatible with 0.032in guidewires. Console features a touchscreen GUI and operates in Manual or Auto modes. Connectivity is standalone; no wireless/WiFi/RFID capabilities.

Indications for Use

Indicated for patients ages 18 years or older on mechanical ventilation ≥ 96 hours who have not weaned, to improve weaning success, increase weaning, reduce ventilator days, and reduce reintubation. Contraindicated in patients with active implanted cardiac pacemakers, defibrillators, or other implantable electronics within proximity to the AeroPace Catheter.

Regulatory Classification

Identification

The device is intended to be implanted transvenously to stimulate the phrenic nerves to improve weaning from a mechanical ventilator. The device is temporary (<30 days) and is for use only in patients 18 years of age or older.

Submission Summary (Full Text)

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SUMMARY OF SAFETY AND EFFECTIVENESS DATA (SSED)

# I. GENERAL INFORMATION

Device Generic Name: Transvenous temporary phrenic nerve stimulator

Trade Name: AeroPace® System

Device Procode: SDL

Applicant's Name and Address: Lungpacer Medical USA, Inc.
260 Sierra Drive, Suite 116
Exton, PA 19341

Date(s) of Panel Recommendation: None

Premarket Approval Application (PMA) Number: P240012

Date of FDA Notice of Approval: December 4, 2024

Breakthrough Device: Granted breakthrough device designation status on May 4, 2016 for patients 18 years or older, who are not hypovolemic and who have failed at least two spontaneous breathing trials, because the device is intended to treat or diagnose a life-threatening or irreversibly debilitating disease or condition. In addition, the device has met at least one criterion for addressing an unmet need: 1) The device may represent a breakthrough technology that provides a clinically meaningful advantage over existing legally marketed technology; 2) The availability of the device may be in the best interest of patients (e.g. addresses an unmet medical need).

# II. INDICATIONS FOR USE

The AeroPace System is indicated to improve weaning success – increase weaning, reduce ventilator days, and reduce reintubation - in patients ages 18 years or older on mechanical ventilation ≥ 96 hours and who have not weaned.

# III. CONTRAINDICATIONS

Do not use the AeroPace System with active implanted cardiac pacemakers, defibrillators, or other implantable electronics within proximity to the AeroPace Catheter. The AeroPace System has not been clinically evaluated for safety with implantable devices.

# IV. WARNINGS AND PRECAUTIONS

The warnings and precautions can be found in the labeling for the AeroPace System User Guide and the AeroPace Catheter Instructions for Use.

# V. DEVICE DESCRIPTION

The AeroPace System (a Temporary Transvenous Diaphragm Activation System) is intended for temporary stimulation of the phrenic nerve(s) to increase diaphragmatic strength in mechanically ventilated patients. The AeroPace System utilizes a temporarily placed, central venous neurostimulation catheter and an external control unit, designed to operate in conjunction with mechanical ventilation in any mode, to transvenously stimulate the left and/or right phrenic nerves to strengthen the diaphragm and facilitate weaning. After placement of the AeroPace Catheter, the

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AeroPace System is used to deliver 60 stimulations to contract the diaphragm twice a day, a total of 120 stimulations or diaphragm contractions daily, for up to 30 days. The sterile single-use AeroPace Catheter also functions as a standard central venous catheter for use for up to 30 days. A diagram of the AeroPace System shown relative to a patient and mechanical ventilator is shown in Figure 1.

Figure 1: Diagram of AeroPace System

Shown relative to patient and mechanical ventilator, with the Catheter placed in the left jugular vein and Airway Sensor placed in the inspiratory limb of the ventilator airway circuit.

# AeroPace Neurostimulation Console and Cart

The AeroPace Neurostimulation Console contains software-controlled electronics, housed in an enclosure, that generate stimulation output that is transmitted from the Console through the Catheter Cable to the electrodes on the AeroPace Catheter (Table 1). The Console is mounted on

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the Cart containing cable and Handheld Controller storage. The Console includes a touchscreen monitor with a graphical user interface (GUI), allowing the operator to interact with and control the System. The Console can operate in either Manual or Automatic (Auto) mode. Auto modes for Placement, Mapping and Therapy are facilitated by the interface to the Airway Sensor. The Console is plugged into hospital-grade wall power.

Table 1: AeroPace System Stimulation Characteristics

| Parameter | Specification |
| --- | --- |
| Waveform Type | Charge-balanced biphasic asymmetrical |
| Pulse Delivery Mode | Constant current stimulation pulses |
| Pulse Durations | 200 μs ± 5% to 300 μs ± 5% |
| Pulse Repetition Frequencies | 15 Hz (default), 20 Hz, 25 Hz, 30 Hz, and 40 Hz options in Therapy mode for each channel.
Typically, 4 Hz in Mapping & Placement modes. Tolerance: ± 5% |
| Maximum Voltage | Current
regulated 33V
maximum |
| Maximum Current | 27.0 mA ± 5% at 300
27.0 mA ± 5% at 500
27.0 mA ± 5% at 1000 (typical impedance)
13.0 mA ± 5% at 2000
6.0 mA ± 5% at 4500 |
| Net DC Current (nA) at maximum pulse rate | ≤ 100 nA |

Abbreviations: Hz=hertz; mA=milliampere; nA=nanoampere; V=volt

## Handheld Controller

Certain controls on the GUI are duplicated on the AeroPace Handheld Controller, allowing specific Auto and Manual mode tasks to be performed by the operator without needing to be in arm's reach of the Console. The Handheld Controller has visual indicators for each of four procedural commands and for connection to the Console.

## Airway Sensor and Cable

The Airway Sensor is a non-sterile, disposable, single-patient-use sensor that interfaces with the patient's ventilator airway circuit to measure the airway pressure and to communicate the data to the Console through the Airway Sensor Cable. The Airway Sensor is connected in the inspiration limb of the ventilator airway circuit. The Airway Sensor can also be connected to the patient's ventilator airway circuit and to the patient's tracheostomy/endotracheal tube. The Airway Sensor consists of an enclosure with integral patient airway connections and sensing electronics.

## AeroPace Catheter and Cable

The AeroPace Catheter is intended for use as part of the AeroPace System for temporary transvenous diaphragm activation, and for short-term (&lt; 30 days) central venous access for administering IV fluids, blood products, medications, and parenteral nutrition solutions, as well as blood withdrawal, central venous pressure monitoring, and power injection of contrast media.

The Catheter is provided sterile, for single-use, and can be inserted into either the left subclavian vein or the left jugular vein using an over-the-wire procedure and is marked with numerals to

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indicate the distance from the tip of the Catheter. The Catheter is connected to the Console by way of the Catheter Cable. An intravascular electrogram (ECG) signal, acquired through electrodes on the catheter, can be visualized on the Console and can be used to assist the placement of the AeroPace Catheter tip in the distal superior vena cava (SVC). The Catheter contains one distal lumen for the guidewire, for over-the-wire insertion. After guidewire removal, three lumens are available for fluid and/or medication delivery. The distal lumen is rated for high-pressure injection. The Catheter's 30 integrated electrodes are activated via the AeroPace Neurostimulation Console to stimulate the left and right phrenic nerves, causing the diaphragm to contract.

## AeroPace Catheter Kit

The AeroPace Catheter Kit contains one AeroPace Catheter and accessories that may be used for insertion of the Catheter (Table 2). The AeroPace Catheter Kit is sterilized by exposure to ethylene oxide (EO) gas. The AeroPace Catheter and accessories provided in the Catheter Kit are designed for single use only.

Table 2: AeroPace Catheter Kit Components

| Catheter Kit Component | Qty | Catheter Kit Component | Qty |
| --- | --- | --- | --- |
| AeroPace Catheter, 8.5Fr. (2.8mm) x 23cm | 1 | Primary Cable Clamp | 1 |
| Over-the-Needle Catheter, 18G x 2.5in (1.3mm x 64mm) | 1 | Guidewire Tip Protector | 1 |
| Needle, 18G x 2.75in (1.3mm x 70mm) | 1 | Dressing, Tegaderm, 4in x 4.75in (10cm x 12cm) | 1 |
| Scalpel, #11 | 1 | Gauze, 4in x 4in (10cm x 10cm) | 5 |
| Sharps Receptacle | 1 | Suture, 3-0 Silk, C7 Reverse Cutting Needle | 1 |
| Syringe, 3ml, Luer Lock with 25G x 1in (0.5mm x 25mm) Needle | 1 | Drape, 24in x 36in (60cm x 90cm), with 4in (10cm) Fenestration | 1 |
| Syringe, 5ml, Luer Slip | 2 | Catheter Clamp Fastener | 1 |
| Needle-Free Male Luer Lock Injection Site | 3 | Guidewire J-Tip, EHD 0.032in (0.81mm) x 70cm | 1 |
| Guidewire Dispenser | 1 | Dilator, 8Fr. x 4in (2.7mm x 10cm) | 1 |
| Guidewire J Straightener | 1 | Needle Holder, 5in (13cm) | 1 |
| Catheter Clamp | 1 | | |

Abbreviations: cm=centimeter; Fr=French; G=gauge; mm=millimeter; In=inch.

## VI. ALTERNATIVE PRACTICES AND PROCEDURES

There are several other alternatives for weaning patients from mechanical ventilation (MV). Daily Ventilator Liberation Trials (also known as Spontaneous Breathing Trials, or SBTs) are used to facilitate weaning in adults on MV for more than 24 hours and are regarded as the standard of care (SoC) for weaning patients from MV (Girard, 2017, American Thoracic Society/American College of Chest Physicians “Liberation from Mechanical Ventilation in Critically Ill Adults, Rehabilitation Protocols, Ventilator Liberation Protocols, and Cuff Leak Tests”).

Ventilator settings using assisted breathing modes and devices that facilitate these ventilator modes are used to facilitate weaning patients from MV. Respiratory maneuvers using volitional

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breathing against resistance are used to facilitate spontaneous breathing in MV patients. There are no alternatives that have a direct action on diaphragm strengthening to facilitate weaning from MV. 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 AeroPace System has not been previously marketed in the United States or any foreign country.

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

The potential complications associated with diaphragm or phrenic nerve stimulation are:

- Arrhythmia
- Bradycardia
- Diaphragm injury
- Discomfort
- Hypercapnia / hypocapnia
- Hypoxia
- Liberation of lung mucus plugs/secretions
- Muscle fatigue or discomfort
- Nerve injury
- Pain or discomfort during stimulation
- Inappropriate stimulation
- Phrenic nerve damage or injury
- Syncope

The potential complications associated with central venous catheters are:

- Adverse tissue response
- Allergic reaction
- Arrhythmia
- Bleeding / Hemorrhage
- Bradycardia
- Bruising, swelling or seroma at insertion site
- Cardiac structure damage
- Central line-associated blood stream infection
- Cerebrovascular event
- Discomfort
- Embolism
- Hematoma
- Hemothorax
- Hypertension / hypotension
- Inadvertent arterial or venous puncture
- Infection
- Lung injury

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- Lymphatic / thoracic duct injury
- Mediastinal injury
- Nerve injury
- Pain, tenderness, swelling, discomfort at access site
- Pneumohematoma
- Pneumomediastinum
- Pneumothorax
- Procedural complications
- Pseudo aneurysm or AV fistula at access site
- Sepsis
- Seroma
- Skin irritation
- Syncope
- Thrombosis / stenosis
- Tissue inflammation, fibrosis or damage
- Vessel occlusion
- Vessel wall damage / perforation
- Wound healing issues
- Wound infection / phlebitis

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

## IX. SUMMARY OF NONCLINICAL STUDIES

Two preclinical animal model studies provided proof of principle for the AeroPace System for its intended use, and two animal model studies verified device safety and performance. Evaluations of biocompatibility, physical and mechanical testing, electrical safety, electromagnetic compatibility (EMC), sterilization, packaging and shelf life, software, human usability, and international standards compliance confirmed that the AeroPace System is acceptable for human use.

## A. Laboratory Studies

### Biocompatibility Testing

Biocompatibility testing was conducted for the AeroPace Catheter which is the only component of the AeroPace System with patient contact, and it was conducted for the AeroPace Airway Sensor which is the one component that has airway (gas pathway) contact. Patient-contacting components of the AeroPace Catheter Kit were subject to biocompatibility testing at the time of their 510(k) clearance.

### AeroPace Catheter

Biocompatibility testing for the patient-contacting parts of the AeroPace Catheter was performed as required by ISO 10993-1, and FDA’s guidance document “Use of International Standard ISO 10993-1, Biological evaluation of medical devices - Part 1: Evaluation and testing within a risk management process” (issued September 4, 2020). All patient-contacting components of the Catheter were classified as contact duration Category B: prolonged contact, &gt;24 hours to 30 days, based on the intended use, per ISO 10993-1. Biocompatibility testing was completed according to Good Laboratory Practice (GLP) requirements 21 CFR 58.

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Table 3 summarizes the results of testing performed on the AeroPace Catheter and demonstrates the catheter is biocompatible per its intended use per ISO 10993-1.
Table 3: Biocompatibility Testing – AeroPace Catheter

| Biological Endpoint | Biocompatibility Test | Applied Standard | Results |
| --- | --- | --- | --- |
| Cytotoxicity | MEM Elution | ISO 10993-5: Biological evaluation of medical devices - Part 5: Tests for In Vitrocytotoxicity | Pass
Non-cytotoxic |
| Irritation | Rabbit Intracutaneous Reactivity Assay | ISO 10993-10: Biological evaluation of medical devices - Part 10: Tests for irritation and skin sensitization | Pass
Non-irritating |
| Sensitization | Guinea Pig Magnusson-Kligman Maximization Assay | ISO 10993-10: Biological evaluation of medical devices - Part 10: Tests for irritation and skin sensitization | Pass
Non-sensitizing |
| Pyrogenicity | Rabbit Pyrogen Test (Material Mediated) | United States Pharmacopeia (USP) Pyrogen Test Procedure, Section <151> | Pass
Non-pyrogenic |
| Hemocompatibility | Hemolysis (direct and indirect) | ISO 10993-4:2017: Biological evaluation of medical devices Part 4: Tests for blood | Pass
Non-hemolytic |
| | Complement Activation | | Pass
Not a complement activator |
| | Dog Thrombogenicity (NAVI) | | Pass
Thromboresistant |
| Extractables and Leachables Testing | Chemical Characterization and Toxicological Risk Analysis | ISO 10993-18, Biological evaluation of medical devices Part 18: Chemical characterization of materials within a risk management process | Pass
The AeroPace Catheter does not pose a significant systemic (acute, subacute/subchronic, or chronic), genotoxic, or carcinogenic toxicological safety risk to the patient when used as intended. |
| Acute, Subacute, Subchronic/Chronic Toxicity, Carcinogenicity, and Genotoxicity | | ISO 10993-17, Biological evaluation of medical devices Part 17: Toxicological risk assessment of medical device constituents | Pass
The AeroPace Catheter does not pose a significant systemic (acute, subacute/subchronic, or chronic), genotoxic, or carcinogenic toxicological safety risk to the patient when used as intended. |

Abbreviations: ISO=International organizations for standardization; MEM=minimum essential medium; NAVI=non-anticoagulated venous implant model

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AeroPace Airway Sensor

A Toxicological Risk Assessment examined potential toxicological hazards and demonstrated the overall biological safety of the AeroPace Airway Sensor per its intended use according to ISO 18562-1, "Biocompatibility evaluation of breathing gas pathways in healthcare applications - Part 1: Evaluation and testing within a risk management process" for the airway-contacting (i.e., gas pathway) parts of the Airway Sensor. Biological safety evaluation for the Airway Sensor was conducted in accordance with ISO 18562-2, "Biocompatibility evaluation of breathing gas pathways in healthcare applications - Part 2: Tests for emissions of particulate matter" and ISO 18562-3, "Biocompatibility evaluation of breathing gas pathways in healthcare applications - Part 3: Tests for emissions of volatile organic compounds (VOCs) standards".

The evaluation of the results of the chemical characterization study per ISO 10993-18, and the risk assessment, indicate that there is no expected risk of acute, subacute/subchronic, and chronic toxicity, genotoxicity, and carcinogenicity from exposure to the extractables detected from potential condensate in the AeroPace Airway Sensor.

# Physical and Mechanical Testing

Testing was conducted on the AeroPace System (Catheter, Neurostimulation Console, and accessories) according to test standards for active medical devices and to software verification/validation requirements following unique test protocols for the system. The AeroPace System, inclusive of the AeroPace Neurostimulation Console, AeroPace Catheter and all other system components passed all integrity and performance design verification testing. Table 4 summarizes the testing that was performed on the AeroPace System. The completed testing verified that applicable material, function, system compatibility, and durability product specifications were met.

Testing related to sterilization, package integrity, shelf life and transport durability is summarized below.

Table 4: Summary of Verification Testing - AeroPace System

| Test | Purpose | Acceptance Criteria | Results |
| --- | --- | --- | --- |
| Radio-detectability | To verify that the AeroPace Catheter can be visualized with x-ray imaging techniques | Detectable by x-ray or by other means per ISO 10555-1 | Pass |
| Surface Condition and Distal Tip | To ensure the AeroPace Catheter is free from surface defects and extraneous matter | The external surface of the effective length of the catheter shall appear free from extraneous matter and free from process and surface defects which could cause trauma to vessels during use | Pass |
| Corrosion Resistance | To verify that the metallic components intended for fluid path contact show no signs of corrosion when tested as described in ISO 10555-1 | Metallic components of the catheter intended for fluid path contact shall show no signs of corrosion per ISO 10555-1 | Pass |

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| Test | Purpose | Acceptance Criteria | Results |
| --- | --- | --- | --- |
| Peak Tensile Force | To verify that the AeroPace Catheter meets the requirements defined in ISO 10555-1 & ISO 10555-3 with respect to the peak tensile force for each tubular portion, and each junction between tubular portions | The AeroPace catheter tubular portions and joints shall withstand the pre-specified minimum tensile force requirements per ISO 10555-1 & ISO 10555-3 | Pass |
| Freedom from Leakage | To verify that the AeroPace Catheter does not leak liquid under pressure or allow air to enter lumen under aspiration | • Air shall not enter the catheter under aspiration per ISO 10555-1
• The catheter shall not leak liquid under pressure per ISO 10555-1 | Pass |
| Flow Rate | To verify that the AeroPace Catheter meets a minimum of 90% of its defined flow rate | For all lumens, the average flow rate is greater than 90% of recommended labeling flow rate as per ISO 10555-1 | Pass |
| Burst Pressure | To verify that the AeroPace Catheter meets the burst pressure requirements of ISO 10555-1 | The Catheter burst pressure shall exceed the peak pressure present in the catheter at maximum flow conditions per ISO 10555-1 | Pass |
| Nominal Size | To ensure that the nominal outside diameter (crossing profile) and the nominal effective length are as designated on the labeling, and to perform dimensional | • The AeroPace Catheter crossing profile 8.5 French
• The AeroPace Catheter’s effective length 230 ± 5 mm
• The AeroPace Catheter's inner diameter compatible with 0.032 in guidewires | Pass |
| Distance Markings | To verify that distance markings on the AeroPace Catheter meet the requirements defined in ISO 10555-3 | Distance (depth) markers shall indicate the distance from the distal tip of the catheter per ISO 10555-3 | Pass |
| Cleaning Agent Compatibility | To confirm that commonly used cleaning agents may be used to clean the AeroPace Catheter | At least one recommended cleaning agent is provided in labeling per ISO 10555-3 | Pass |
| DC Resistance Test | To measure the DC resistance of each electrical conductor within the AeroPace Catheter | The DC resistance of each conductor shall meet the predetermined specification | Pass |
| Dielectric Strength Test | To ensure that there will not be crosstalk between conductors during normal operating conditions | Insulating parts that incorporate electrical conductors and are subject to electrical potential differences withstand pre-determined dielectric strength | Pass |
| Test for biphasic charge balanced waveform | To verify that the AeroPace System is not delivering residual charge into the body | The AeroPace System shall deliver biphasic, charge balanced waveforms | Pass |

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| Test | Purpose | Acceptance Criteria | Results |
| --- | --- | --- | --- |
| Test for maximum pulse frequency | To verify the maximum pulse frequency delivered by AeroPace System | The maximum stimulation pulse rate delivered by the AeroPace System shall be less than 45 Hz (pulses per second) per side | Pass |
| Defibrillation protection | To verify the AeroPace System remains safe when subjected to energy applied during a patient defibrillation event | The System shall conform to applicable sections of 60601-1 | Pass |
| Functional testing | To verify that the AeroPace Airway Sensor meets requirements | The AeroPace Airway Sensor shall conform to applicable sections of ISO 5356-1 for conical connectors | Pass |
| Electrical Safety | To determine the electrical safety of the AeroPace System | The AeroPace System shall conform to applicable sections of IEC 60601-1 | Pass |
| AIM7351731 - Medical Electrical Equipment and System Electromagnetic Immunity Test for Exposure to Radio Frequency Identification Readers | To determine RFID compatibility of the AeroPace System | The AeroPace System shall conform to applicable sections of AIM7351731 | Pass |
| Electromagnetic Compatibility (EMC) | To determine the Electromagnetic Compatibility (EMC) of the AeroPace System | The AeroPace System shall conform to applicable sections of IEC 60601-1-2 | Pass |
| Human Factors (Usability) Testing | Formative and summative human factors testing to evaluate the usability of the AeroPace System | In accordance with applicable standards for medical device human factors engineering and risk management and in accordance with FDA's guidance, Applying Human Factors and Usability Engineering to Medical Devices (2016). | Pass |

Abbreviations: AIM=Association for Automatic Identification and Mobility; DC=direct current; IEC=International electrotechnical commission; ISO=International organizations for standardization; MEM=minimum essential medium

# Sterilization

The AeroPace Catheter Kit is the only subsystem of the AeroPace System that is supplied sterile. It is sterilized by ethylene oxide (EO). The EO sterilization process was successfully validated in accordance with ISO 11135. The test results from the sterilization testing confirmed that the product can be adequately sterilized to the desired level of sterility assurance of $10^{-6}$ .

Additionally, routine testing of biological indicators is performed to confirm that the sterilization process is effective in eradicating viable microorganisms.

# Packaging and Shelf Life

Packaging qualification testing (visual inspection, package integrity (bubble leak), and seal

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strength testing) demonstrated the ability of the packaging to protect the product and maintain a sterile barrier following environmental conditioning and simulated distribution. A shelf life of two years was established for the AeroPace Catheter Kit based on product and package shelf-life testing.

# B. Animal Studies

Two preclinical studies in a porcine model, verified proof of principle of the AeroPace System for activation of the diaphragm to retain diaphragmatic strength in mechanically ventilated subjects (Reynolds, 2017a; Rohrs, 2021). Two animal studies in the same porcine model validated safety and performance of the AeroPace System as summarized in Table 5.

Table 5: AeroPace System Pre-Clinical Animal Testing

| Study | Functional Validation of the Lungpacer AeroPace System in an Acute Swine Model |
| --- | --- |
| Purpose | Validate the safety and functionality of the AeroPace System in an acute preclinical study. |
| Methods | ·Anesthetized porcine subjects (3) on MV had an AeroPace Catheter placed into the left subclavian or left jugular vein ·Evaluate functionality of AeroPace System components in both Pressure Support Mode and Volume Control Mode, with each of 3 ICU ventilators. ○ Auto and Manual Placement ○ Auto Mapping and Therapy ○ Manual Mapping and Therapy ·The functionality of the AeroPace System was validated in an acute setting. |
| Results | All study objectives were met, and system functionality was validated in both Pressure Support Mode and Volume Control Mode, each with 3 different models of ventilators. Specifically, the following aspects of the AeroPace System functionality were validated: ·Successful Catheter was insertion into the left jugular vein or left subclavian vein. ·Intravascular electrogram assisted placement of the AeroPace Catheter. ·AeroPace Catheter lumens were successfully used as central line lumens. ·Placement of the left electrode array was successfully executed in Auto and Manual Modes. ·Mapping of the left and right electrodes and Thresholds were successfully executed using Auto and Manual Modes. ·Therapy was successfully executed using Auto and Manual Modes with the touchscreen or Handheld Controller. ·The AeroPace Catheter was successfully removed. Transvenous stimulation of the phrenic nerves was well tolerated and did not cause clinically relevant changes in clinical parameters evaluated. |
| Purpose | Evaluate the effect of maximum charge stimulation on the left subclavian/jugular vein and cranial vena cava and the effect of stimulation on the phrenic nerves. |
| Methods | ·Anesthetized porcine subjects (3) on MV with AeroPace Catheter placed into the left jugular vein. ·Continuous charge using maximum intensity was delivered in the treatment mode for approximately 6 hours. ·Post-study pathological and histological evaluations were conducted for the phrenic nerves and targeted vessels. |
| Results | ·No adverse events related to the use of the AeroPace System were observed. ·Maximum-charge transvenous stimulation was well tolerated and did not cause clinically relevant changes in clinical parameters evaluated. ·No pathological or histopathological changes were found that indicated clinically adverse nerve or vessel damage. |

Abbreviations: MV=mechanical ventilation

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C. Additional Studies

Additional testing of the AeroPace System included electrical safety testing per IEC 60601-1, electromagnetic compatibility (EMC) testing per IEC 60601-1-2, formative and summative human factors (usability) testing and software testing, per FDA guidance and relevant standards. See Table 4 above for information on electrical safety testing, EMC testing, usability testing.

Software documentation was provided in accordance with FDA’s “Guidance for the Content of Premarket Submissions for Software Contained in Medical Devices” and the FDA-recognized software standard IEC 62304, “Medical device software – Software life cycle processes”.

Lungpacer performed the following software verification and validation (V&amp;V) activities:

- Code Reviews
- Static tool analysis used a Static Analysis tool to analyze the code for any coding errors or areas with potential errors
- Software unit verification
- Software Heavy Unit Testing (HUT) - developer-based testing to evaluate implementation of the software and confirm correct functionality. Heavy Unit testing evaluated the software itself and used fault injection and software demonstration to thoroughly test the most safety critical functions.

There is negligible cybersecurity risk for the AeroPace System. The AeroPace System does not have any electronics allowing for direct external contactless/wireless communications. The AeroPace System does not include any capability to connect to WiFi. The AeroPace System does not include RFID technology.

X. SUMMARY OF PRIMARY CLINICAL STUDIES

A. Feasibility Studies

The clinical program for the AeroPace System included six single-arm studies (total N=61) that evaluated the safety and feasibility of an early version of the AeroPace System in patients undergoing a diagnostic procedure or surgery and receiving short-term MV. These studies showed that stimulation of the phrenic nerves via the electrodes in the Catheter placed in the left subclavian vein (Reynolds, 2017b) or the left jugular vein (Gani, 2020), elicited contractions, and that bilateral or unilateral pacing in synchrony with MV resulted in airway pressure reductions (Reynolds, 2017b). No adverse events occurred in any patient. A summary of the feasibility studies is provided in Table 6.

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Table 6. Feasibility Studies Applicable to the AeroPace System

| Protocol No. Study Type (access) Year(s) | Study Design | Study Objectives | Study Population | No. Subjects Locations |
| --- | --- | --- | --- | --- |
| First-in-Human (subclavian) 2015 | Prospective, single-center, single treatment group | Catheter placement, Mapping | Non-MV patients undergoing a diagnostic procedure or surgery | N=4 Paraguay (one site) |
| First-in-Human (subclavian) 2015 | | Catheter placement, Mapping, Diaphragm pacing | Short-term MV patients undergoing a diagnostic procedure or surgery | N=13 Paraguay (one site) |
| Next-in-Human (subclavian) 2016 (Reynolds, 2017b) | | Catheter placement, Mapping, Diaphragm pacing, heart rate data capture, multipolar stimulation | | N=11 Paraguay (one site) |
| Jugular Access Feasibility (jugular) 2018 (Gani, 2019) | Prospective, multi-center, single treatment group | Catheter placement from left jugular vein, mapping, diaphragm pacing; heart rate data capture, multipolar stimulation, tidal volume generation | Short-term MV patients undergoing a diagnostic procedure or surgery | N=13 Paraguay (one site) |
| Jugular Access Feasibility (jugular) 2019 (Gani, 2020) | | Catheter placement from left jugular vein, mapping, diaphragm packing; heart rate data capture, multipolar stimulation | | N=20 Paraguay (one site) |
| P-100 RESCUE 1 Feasibility Study (subclavian) 2017-2018 (Ataya, 2020) | Prospective, multi-center, single treatment group | Safety & feasibility for up to 30 days
• Catheter placement, phrenic nerve capture and activation, delivery of Lungpacer DPT up to 30 days.
• Observational outcomes for weaning, MIP, RSBI, diaphragm thickening fraction. | Patients who failed ≥2 weaning trials and received ≥7 days MV | N=11 U.S. (three sites) |

Abbreviations: FiH=first in human; MIP=maximal inspiratory pressure; MV=mechanical ventilation; N=number; NiH=next in human; RSBI=Rapid Shallow Breathing Index; US=United States.

RESCUE 1 was an open-label single-arm feasibility study conducted in 2018 at three (3) US sites in 11 patients who received MV for ≥7 days and who had failed ≥2 weaning attempts (IDE G170057). RESCUE 1 evaluated an early model of the AeroPace System using two to three sessions per day of 120 stimulations daily for up to 30 days. The study evaluated the safety and

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feasibility of catheter placement/removal, phrenic nerve capture and therapy delivery for up to 30 days. Nine of the 11 patients formed the modified Intent-to-Treat (mITT) population which included all patients for whom the Catheter entered a blood vessel. Patients received the Catheter in the left subclavian vein for a median duration of 10 days, and all patients (mITT) met the feasibility outcomes.

Observational outcomes were collected for the mITT population. Of the nine patients, seven patients (77.8%) successfully weaned. Rapid shallow breathing index (RSBI) improved by 44% with a mean change of -627± 60.4 (mITT, N=8) and -63.5 ± 64.4 (mITT, weaned, N=6). Maximal inspiratory pressure (MIP) improved 64% to 105% with a mean change of 13.9 cm H₂O ± 20.6 (mITT, N=9) and 19.7 cm H₂O ± 17.9 (mITT, weaned, N=7). Maximal inspiratory pressure (MIP) improvement had a significant dose-response relationship with the number of stimulations delivered (mITT). The median increase in B-Mode diaphragm thickening fraction (right hemidiaphragm) was 28%, while the mean increase was 36.8% ± 51.8% (N=7, mITT).

Adverse events collected for the ITT population were as expected for ICU patients on MV. A serious adverse event of bronchial mucus plug was associated with the procedure of Trendelenburg positioning used for left subclavian vein access (Ataya, 2020). There were no deaths in the study.

RESCUE 1 demonstrated the safety and feasibility of the AeroPace System (equivalent model) for use up to 30 days in patients on MV ≥7 days and who had failed to wean. Two independent indicators of diaphragm strengthening, MIP and diaphragm thickening fraction, improved. Both MIP and RSBI were significantly improved in the subjects who successfully weaned. The study results were published in Ataya (2020).

## B. Randomized Controlled Trials

The applicant performed a clinical study, RESCUE 3, to establish a reasonable assurance of safety and effectiveness of the AeroPace System to improve weaning success of patients who have been on MV ≥ 96 hours in the US and EU under IDE G180237. Data from this clinical study were the basis for the PMA decision. A summary of the clinical study is presented below.

Two randomized controlled trials (RCT) were conducted to evaluate the safety and effectiveness of the AeroPace System or equivalent device models (with SoC) compared with SoC alone to increase diaphragmatic strength and improve weaning success in patients on MV ≥ 96 hours and who failed ≥ 2 weaning trials. This population had a high likelihood of diaphragm atrophy after 96 hours on MV, as was verified by mean baseline MIP values. Two weaning trials were utilized; the first weaning trial excluded patients who were able to wean with SoC alone, while the second weaning trial was used to implement a protocol-specific ventilator-liberation trial (VLT) to standardize the declaration of weaning failure across all sites.

RESCUE 2 (N=112) was a pilot RCT that enrolled subjects at 20 sites in Germany and France (Dres, 2022). The primary endpoint was the proportion of subjects successfully weaned through 30 days. Additional endpoints were days on MV, MIP and RSBI changes from baseline to last available measurement, diaphragm thickening fraction, mortality, incidences of reintubation and tracheostomy, and ICU and hospital discharge.

RESCUE 3 (N=223) was the main RCT to support the PMA decision that enrolled a similar

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patient population, had a similar study design, and evaluated similar study endpoints as RESCUE 2. RESCUE 3 enrolled subjects at 48 sites in the US, France, Germany, and Spain. The study used a group sequential design. The designs and objectives of these studies are summarized in Table 7.

Table 7: Randomized Controlled Trials - AeroPace System

| Protocol No. Study Type (access) Year(s) | Study Design | Study Objectives | Study Population | No. Subjects Locations |
| --- | --- | --- | --- | --- |
| RESCUE 2 (P-200) Safety & effectiveness Pilot RCT (subclavian) 2019-2020 (Dres, 2022) | Pilot randomized (1:1), controlled, open-label, multicenter clinical trial of Lungpacer therapy with Standard of Care vs. Standard of Care alone. | Safety, effectiveness & performance of the AeroPace System (equivalent model) for up to 30 days. • Primary endpoint: successful weaning. • Secondary endpoints: days on MV, MIP, RSBI, mortality. • Observational endpoints: reintubation, tracheostomy, ventilator settings, ICU and hospital discharge. | Patients on MV ≥ 96 hours and who failed ≥2 weaning trials | N=112 randomized, N=12 roll-in Europe (France & Germany) (20 sites) |
| RESCUE 3 (P-300) Safety & effectiveness main RCT (subclavian & jugular) 2019-2022 | Randomized (1:1), controlled, open-label, multicenter group sequential design clinical trial of Lungpacer therapy with Standard of Care vs. Standard of Care alone | Safety & effectiveness of the AeroPace System and equivalent model for up to 30 days. • Primary endpoint: successful weaning Secondary endpoints: days on MV, MIP, RSBI, mortality Observational endpoints: reintubation, tracheostomy, ventilator settings, ICU and hospital discharge. | Patients on MV ≥ 96 hours and who failed ≥2 weaning trials | N=223 randomized N=33 roll-in US & Europe (France, Germany, Spain) (48 sites) |

Abbreviations: MIP=maximal inspiratory pressure; MV=mechanical ventilation; N=number; RSBI=Rapid Shallow Breathing Index; RCT=randomized controlled trial; US=United States.

# RESCUE 2

# 1. Study Design and Population

RESCUE 2 was a randomized, controlled, open-label, multicenter clinical trial to investigate the safe and effective performance of an equivalent model of the AeroPace System in subjects on MV $\geq 96$ hours and who had failed $\geq 2$ weaning trials. Subjects were randomized 1:1 to Treatment with the Lungpacer system (plus SoC) compared with Control (SoC alone). One to two Roll-In

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subjects were allowed per site. The duration of the study was 30 days with follow-up to Day 32 or study exit. The study enrolled subjects at 20 clinical centers in the EU and was completed in 2020.

One-hundred and twelve (112) randomized subjects (ITT population), 57 subjects in the Treatment group and 55 subjects in the Control group, and 12 non-randomized Roll-In subjects were enrolled. The overall study population was 57.1% (64/112) male, with a mean age of 64.6 years. The most common reason for MV was ARDS/ARF (37.5% (42/112)), followed by pneumonia, surgery, COPD and "other" that ranged from 18.8% to 12.8%. The mean duration of MV at enrollment was 28 days. More than half of the subjects (54.5% (61/112)) were tracheotomized at enrollment.

In the Treatment group, 43 subjects formed the mITT population for whom the Catheter could be placed (seven subjects excluded), stimulation delivered to at least one phrenic nerve (seven subjects excluded) and the diaphragm contracted. The Catheter placement was in the left subclavian vein with a median duration of 10 days. Catheters were used for infusion for 52% (35/67) of inserted catheters (some subjects had multiple catheters inserted and removed).

Lungpacer therapy was delivered in 4-6 sets of 10 stimulations, 2-3 times daily for a total of 120 stimulations/day, intensity maximized based on subject comfort, for up to 30 days or until study exit. A Treatment/Roll-In subject could receive a maximum of 3600 stimulations during the study. The maximum study duration for subjects was 32 days. Of all subjects, 62.8% (27/43) of required stimulations were delivered and 79% (34/43) of subjects received ≥50% of the protocol required stimulations (which defined the Per Protocol group (PP)).

## 2. Effectiveness Results

The primary effectiveness outcome was the difference in the proportion of subjects successfully weaned by Day 30 in the Treatment group compared with the Control group, which, in this pilot RCT, was not statistically powered. "Successfully weaned" was defined as passing a protocol-specific VLT, and not returned to MV within 48 hours. Weaning success was 81.5% and 74.1% in the Treatment and Control groups, respectively, for 7.4% greater weaning success for Treatment subjects (p=0.586, mITT).

There were fewer days on MV in the Treatment group compared with the Control group (1.4 days, mean, mITT). MIP mean change from baseline was 16.6 cm H2O and 4.8 cm H2O in the Treatment and Control groups, respectively, for a mean difference between groups of 11.8 cm H2O (mITT), representing a 245% MIP improvement with Treatment compared to Control. There was a dose-response relationship between MIP improvement and number of stimulations (mITT). Ultrasound was performed in 34 subjects at eight sites to assess diaphragm changes from baseline to last available measure. The change in right side diaphragm thickening fraction (DTf) with M-mode ultrasound was higher in the Treatment group (16.6%, mITT) compared with a decrease in DTf in the Control group (-13.6%, mITT). RSBI improved 127% in the Treatment group compared with the Control group for a difference between groups of 23 breaths/min/L (mITT).

## 3. Safety Results

Safety was assessed by documentation of AEs and SAEs during the study. AEs were reported in 57.9% of subjects in the Treatment group (96 AEs/33 subjects) and in 69.1% of the Control group (88 AE/38 subjects). SAEs were equally distributed between the randomized groups: 47.4% in the Treatment group (47 SAEs/27 subjects) and 49.1% in the Control group (39 SAEs/27 subjects).

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AEs and SAEs by System Organ Class (SOC) with an incidence $&gt;10\%$ in the Treatment group are shown in Table 8. The highest incidences were for respiratory / thoracic / mediastinal disorders and infections. The AEs and SAEs were typical for patients in an intensive care setting and using a central venous catheter (CVC). There were no unanticipated adverse device effects.

Table 8: Adverse and Serious Adverse Events by Randomized Group – System Organ Class (ITT)

| System Organ Class | Adverse Events | | | | Serious Adverse Events | | | |
| --- | --- | --- | --- | --- | --- | --- | --- | --- |
| | Treatment | | Control | | Treatment | | Control | |
| | # of events | # (%) of subjects | # of events | # (%) of subjects | # of events | # (%) of subjects | # of events | # (%) of subjects |
| Cardiac disorders | 9 | 8 (14.0%) | 6 | 6 (10.9%) | 4 | 4 (7.0%) | 4 | 4 (7.3%) |
| General disorders and administration site conditions | 10 | 7 (12.3%) | 5 | 5 (9.1%) | 3 | 3 (5.3%) | 3 | 3 (5.5%) |
| Infections and infestations | 16 | 13 (22.8%) | 22 | 18 (32.7%) | 8 | 8 (14.0%) | 7 | 7 (12.7%) |
| Investigations | 6 | 6 (10.5%) | 0 | 0 | 2 | 2 (3.5%) | 0 | 0 |
| Nervous system disorders | 7 | 7 (12.3%) | 4 | 4 (7.3%) | 0 | 0 | 3 | 3 (5.5%) |
| Respiratory, thoracic and mediastinal disorders | 17 | 13 (22.8%) | 14 | 11 (20.0%) | 15 | 13 (22.8%) | 8 | 8 (14.5%) |

Device- or procedure-related AEs, as determined by the investigator, by SOC for the Treatment group were most commonly for infections (14.5%), respiratory / thoracic / mediastinal disorders (14.0%), cardiac disorders (10.5%), and general disorders and administration site conditions (8.8%). Cardiac AEs included temporary arrhythmias related to transvenous electrical stimulation that were addressed by repositioning of the catheter without sequelae. All other AEs were related to the catheter or catheter placement.

There were no differences between Treatment and Control groups in the overall incidence of $28.1\%$ vs. $29.1\%$ , respectively, in device- or procedure-related SAEs. Device- or procedure-related SAEs were higher for the Treatment group compared with the Control group for respiratory / thoracic / mediastinal disorders (14%, Treatment; 5.5%, Control), mostly for pleural effusion and pneumothorax, and for infections (8.8%, Treatment; 5.5%, Control).

Pain was assessed in Treatment and Roll-In subjects using the 10-point Wong-Baker FACES® Pain Rating Scale (Wong-Baker FACES Foundation (2018)) at the beginning and end of each therapy session. Pain scores were collected in $84\%$ (36/43) of subjects during at least one therapy session resulting in a mean pain score of 0 (interquartile range = 0, 3). Pain was reported in $9\%$ of the sessions during which pain was assessed. For the subjects who reported pain in at least one session $(44\%, 16/36)$ , the highest pain score reported per subject was $3.8 \pm 3.5$ ("hurts a little more") on the 10-point rating scale.

Eleven deaths were reported in the study, 3 deaths $(7\%)$ in the mITT Treatment group and 8 deaths $(15\%)$ in the Control groups, which is within the expected 30-day mortality rates for patients on MV (Boles, 2007; Damuth, 2015; Beduneau, 2017).

# 4. Conclusions

The results of the RESCUE 2 study demonstrated that therapy using an early model of the

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AeroPace System was well tolerated and had a safety profile as expected for CVCs and for temporary transvenous electrical stimulation. SAEs of infection, and pleural effusion and pneumothorax following misplacement of a CVC, occurred in the study at incidences consistent with the medical literature (Rai, 2023; Smit, 2018). AeroPace therapy with SoC compared with SoC alone improved diaphragmatic strength in MV patients as evaluated by two independent indicators of diaphragm strength: MIP and diaphragm thickening fraction. MIP and diaphragm thickening fraction are associated with weaning success in MV patients (Supinski, 2016; Martin, 2014; Goligher, 2018; Ferrari, 2014; Jung, 2016). Consistent with literature expectations, improvements with the AeroPace System compared to SoC were observed for RSBI, weaning success, and days on MV (Dres, 2022).

## RESCUE 3

RESCUE 3 data were the main basis for the PMA approval decision.

### 1. Study Design and Population

The study was a randomized, controlled, open-label, international multi-center trial using a group sequential design to determine the safety and effectiveness of the AeroPace System or an equivalent model plus SoC (Treatment) compared to SoC (Control) to improve diaphragmatic strength and weaning success in patients on MV. Patients were ≥18 years of age and had received MV for ≥96 hours and had failed ≥2 weaning trials. The study duration was 30 days with follow-up to Day 32 or study exit.

The study enrolled 223 randomized subjects and 33 Roll-In subjects between June 14, 2019 and January 27, 2023. There were 48 investigational sites (27 US; 21 EU) that enrolled at least one subject.

Up to two Roll-In subjects could be enrolled at each site to obtain experience with the investigational device. All Roll-In subjects received Treatment and SoC. Data for Roll-In subjects were collected in the same manner as for randomized Treatment subjects but were analyzed separately from the randomized study population. Study results for Roll-In subjects and randomized Treatment group subjects were similar.

The AeroPace System was used to deliver six sets of 10 stimulations, twice daily for a total of 120 stimulations/day (stimulation intensity was maximized based on subject comfort) for up to 30 days or until study exit. A Treatment/Roll-In subject could receive a maximum of 3600 stimulations delivered over 30 days. Treatment and Control subjects received SoC for weaning, which included one daily protocol-specific weaning trial (maximum of two weaning trials daily). The maximum study duration for subjects was 32 days.

Standard of care included a daily protocol-specific physician-directed VLT, and no more than one additional weaning trial daily. Sedation for patients on MV &gt;24 hours was minimized, if possible, and institutional practices were followed for limb movement and exercise. Non-invasive ventilation or high flow oxygen was used, if needed, to prevent post-extubation respiratory failure for subjects who passed a VLT or who were removed from MV. Inspiratory muscle strength training (IMST) protocols were prohibited.

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## Statistical Design

The study was designed to randomize 200 to 400 subjects 1:1 blocked by investigational site to Treatment or Control and using a group sequential design borrowing data from the RESCUE 2 trial for subjects who met RESCUE 3 inclusion/exclusion criteria and furthermore were propensity matched.

Bayesian analyses and frequentist analyses were used for the primary endpoint of successful weaning and the related secondary endpoints of days on MV and mortality. All other endpoints were evaluated using frequentist analyses using RESCUE 3 data only.

Propensity score adjustment was used to account for potential residual differences between subjects in the two studies and were calculated based on various pre-specified demographic, clinical and medical history characteristics. The propensity score adjustment included rescaling weights (discounting) that resulted in an equivalent of 64 subjects from RESCUE 2 borrowed in a power prior approach. Sensitivity analyses were performed to demonstrate the robustness of the RESCUE 2 borrowing based on different possible weighting schemes.

The group sequential design allowed for interim analyses, limited to unblinded review only by the study DSMB, of aggregate data for the primary effectiveness and safety outcomes while study enrollment continued without interruption. Interim analyses with the potential for stopping occurred at 150 subjects and every 50 subjects thereafter, up to the maximal sample size of 400 subjects. This range of sample sizes provided 86% power in the anticipated scenario. The sample size included a 15% expected study attrition rate. No more than 25% of subjects were to be randomized at any given investigational site. At least 20% of subjects were to be randomized in the US.

## Safety Monitoring

An unblinded Clinical Events Committee (CEC) operated independently from the study Sponsor and study sites according to the study CEC Charter to adjudicate individual SAEs meeting certain criteria for relatedness to the device or procedure and was empowered to make judgements regarding the safety data and safety endpoints. All SAEs were adjudicated for verification as an SAE, and all deaths were adjudicated. SAEs and UADEs were adjudicated for Treatment and Roll-in subjects including determining the relationship to the device or procedure.

A Data Safety Monitoring Board (DSMB) conducted safety assessments and planned interim analyses according to the study DSMB Charter.

Study stopping rules were for the occurrence of two incidences of death or massive hemothorax / pneumohemothorax, defined as rapid blood loss of more than 30% of blood volume (1500-2000 mL), that were device-related or procedure-related.

## 2. Clinical Inclusion and Exclusion Criteria

Enrollment in the RESCUE 3 study were limited to patients who met the following inclusion criteria:

1) 18 years or older, and,
2) Mechanically ventilated for ≥96 hours (4 days) and,
3) Satisfied the Readiness-to-Wean criteria, and,

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4) Failed ≥2 weaning attempts*:
- That were conducted ≥48 hours after initiation of MV, and,
- That were conducted on different calendar days, and,
- ≥1 of which was the protocol-specific VLT.

*Self-extubation from MV with subsequent re-intubation within 48 hours was considered a failed weaning attempt. Institutional weaning attempt was in accordance with the institution’s defined standard of practice and weaning attempt was to be documented in the subject’s medical records.

Patients were not permitted to enroll in RESCUE 3 if they met any of the following exclusion criteria:

1) MIP (absolute value) &gt;50 cm H2O;
2) Invasive MV &gt;90 days;
3) Currently on ECMO;
4) Weaning failure due to hypervolemia;
5) Medical history (including imaging) or known anatomy that prevents percutaneous insertion of the Catheter into the intended thoracic vein on the left side;
6) Clinically overt congestive heart failure that is preventing weaning;
7) Currently being treated with neuromuscular blockade;
8) Pre-existing neurologic, neuromuscular, or muscular disorder that could affect the respiratory muscles;
9) Pre-existing severe chronic pulmonary fibrosis;
10) Pleural effusions occupying greater than one-third of the pleural space on either side;
11) BMI &gt;45 kg/m²;
12) Known or suspected phrenic nerve paralysis;
13) Any electrical device (implanted or external) that may be prone to interaction with or interference from the Lungpacer DPTS, including neurological pacing/stimulator devices, cardiac pacemakers, and defibrillators;
14) Current hemodynamic instability, sepsis, or septic shock;
15) Bacteremia within the last 48 hours;
16) Anticipating withdrawal of life support and/or shift to palliation as the goal of care;
17) Known or suspected to be pregnant or lactating;
18) Currently being treated in another clinical trial studying an experimental treatment that could affect the study primary outcome.

## 3. Follow-up Schedule and Assessments

The following study evaluations and follow-up were conducted:

- After consent and prior to randomization
- Qualifying protocol-specific Ventilator Liberation Trial
- RSBI/RASS/MIP
- SOFA
- Laboratory tests
- Daily up until the day of MV removal, transfer to a facility outside of the enrolling institution, or study completion, whichever comes first:

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- Ventilator Settings (PS, PEEP, RR, FiO2, Ventilation Mode, VT),
- Protocol-specific Ventilator Liberation Trial

- For Treatment subjects only:
- Wong-Baker 10-point Pain Visual Analogue Scale (at the beginning and end of each therapy session)
- Stimulation Discomfort and Sensation Tool (at the end of each therapy session)

- Baseline, Day 7 ± 1, 14 ± 1, 21 ± 1, 28 ± 1 or Day 30 while on MV, as well as the day of removal from MV (Day 1 is the anticipated placement date) until removal from MV associated with successful weaning, prior to transfer to a facility outside of the enrolling institution or study completion, whichever comes first:
- Rapid Shallow Breathing Index (RSBI)
- Richmond Agitation-Sedation Scale (RASS)
- Maximal Inspiratory Pressure (MIP)

- Following Catheter Removal (for Treatment subjects only):
- Treatment Subject Questionnaire (completed at study exit or before transfer, whichever comes first)

- Other data evaluations to Day 30 and follow-up:
- The time to first successful VLT after randomization;
- Cessation and re-instatement of mechanical ventilation;
- Date of tracheotomy, if applicable;
- ICU admissions and discharges;
- Hospital admission and discharges, and
- Mortality

The following safety evaluations and follow-up were conducted:

- Safety Evaluations (AE and SAE data collection during study before Safety Evaluation Follow-up):
- All Subjects: all AEs and SAEs until withdrawal or death, until completion of placement attempt, or until Catheter removal, transfer, successful weaning, or unsuccessful weaning by Day 30.

- Safety Follow-up Evaluations (SAE-only data collection after study Safety Evaluation completed):
- Treatment Subjects:
- Withdrawal or death – no follow-up;
- Unsuccessful placement of the Catheter – SAEs for 48 hours after placement attempt or Catheter removal;
- Successful wean/Unsuccessful wean/Transfer – SAEs to Day 30, or 48 hours after Catheter removal, or 48 hours after successful VLT or removal from MV, whichever is latest.
- Control Subjects:
- Withdrawal or death – no follow-up;

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- Successful wean/Unsuccessful wean/Transfer – SAEs to Day 30, or 48 hours after successful VLT, or removal from MV, whichever is latest.

## 4. Clinical Endpoints

### Primary Endpoint

With regards to effectiveness, the primary endpoint was the cumulative incidence (proportion) of subjects “successfully weaned” by Day 30. “Successfully weaned” was defined as passing the protocol-specific VLT, or removed from MV, and not returned to MV within 48 hours. A protocol-specific VLT was used to standardize weaning trials and all study sites were trained on its use. The primary effectiveness outcome was superiority for Treatment subjects compared with Control subjects for successful weaning within the 30-day study period.

The primary null and alternative hypotheses are:

**Ho**: The hazard ratio for successful weaning is the same in subjects randomized to Treatment as compared to those randomized to Control, HR=1.

**H1**: The hazard ratio for successful weaning is greater than 1, indicating subjects wean faster on the Lungpacer device, HR&gt;1.

The primary analysis was performed on the mITT population. As a sensitivity analysis, the model was repeated for the Per Protocol (PP) population.

A 10% improvement in weaning success for Treatment compared with Control was defined as a minimal clinically important difference (MCID) for RESCUE 3 based on a large RCT evaluation of 3 weaning strategies (VENISE Trial, Girault, 2011) using rate of extubation, i.e., successful weaning, as the primary outcome.

With regards to safety, the primary endpoint was assessment of AEs for subjects randomized to Treatment (Lungpacer DPTS plus SoC) compared with subjects randomized to Control (SoC) over the study period and follow-up. The study’s primary safety outcome was the expected safety profile for Treatments subjects compared with Control subjects.

### Secondary Endpoints

Secondary effectiveness endpoints in priority order were:

- Days on mechanical ventilation from Day 1 to removal from MV associated with successful weaning or Day 30, whichever comes first. Days on MV had a pre-specified MCID of 0.5 days.
- Change in MIP from randomization (baseline) to last available measure. MIP is an indirect measurement of diaphragmatic strength.
- Change in RSBI from randomization (baseline) to last available measure. RSBI measures the ratio of the Respiratory Rate to Tidal Volume (breaths/min/L) and is an index for weaning success.
- Day 30 mortality/survival.

## C. Accountability of PMA Cohort

There were 326 subjects consented, 70 screen fail subjects, 33 Roll-In subjects, and 223 randomized subjects (109 Treatment; 114 Control) in the RESCUE 3 study (Figure 2). For

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randomized Treatment subjects, 102 subjects had successful catheter placement, and comprised the mITT Treatment population.

At the time of database lock, of 223 patients enrolled in the PMA study, $83\%$ (184) patients are available for analysis at the completion of the study, 30 days after device placement.

Figure 2: RESCUE 3 Subject Disposition
Abbreviations: ITT=Intent to treat, mITT=modified intent to treat; N=number. Source: RESCUE 3 Frequentist Final Report_2023_06_26, Figure 1

The Keystone System/LIVE Catheter was used in $67.6\%$ (69/102) of randomized mITT Treatment subjects, and the AeroPace System/AeroPace Catheter was used in $32.4\%$ (33/102) of randomized mITT Treatment subjects. Catheters were used for infusion for $64\%$ of (65/102) subjects.

The analyses utilized the mITT and PP Treatment populations except for 30-day mortality which used the ITT population, as defined below:

- Intent-to-treat (ITT) population: all subjects who were randomized, with study group defined by the randomization. There were 109 Treatment subjects and 114 Control subjects in the ITT group.
- Modified Intent-to-Treat (mITT) population: a subset of the ITT population for the Treatment group consisting of 102 subjects that had successful placement of the Catheter defined as entering the vein, at least one phrenic nerve captured, and the diaphragm stimulated. The mITT and ITT groups were the same for Control subjects.
- Per Protocol (PP) population: a subset of the mITT population for Treatment subjects, consisting of 90 subjects defined by completion of $\geq 50\%$ of the protocol-required number of stimulations (Stims) in $\geq 1$ phrenic nerve, without a major protocol deviation that precluded effectiveness evaluation (no subjects met this criteria), and who had observed data for evaluation of the primary effectiveness endpoint. The PP, mITT and ITT groups

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were the same for Control subjects.

Subject completion in the randomized groups is summarized in Figure 3. For randomized Treatment subjects, 102 subjects had successful catheter placement, and comprised the mITT Treatment population. Eighty-four percent (84%, 86/102) of the mITT Treatment group and 86% (98/114) of the Control group completed the study to Day 30.

Figure 3: Randomized mITT, Primary Endpoint and Study Completion
Abbreviations: ITT=Intent to treat, mITT=modified intent to treat; N=number. Source: RESCUE 3 Frequentist Final Report_2023_06_26, Figure 2


# D. Study Population Demographics and Baseline Parameters

The demographics (age, sex, race/ethnicity) of the study population were typical for a population of mechanically ventilated patients in a randomized study performed in the US and EU.

Baseline demographics for randomized subjects are provided in Table 9. The average age of subjects was 64 years. Subjects were primarily male (65% (145/223)), with mean BMI of 28.5 $\mathrm{kg} / \mathrm{m}^2$ , and $65\%$ (145/223) were previous or current smokers. Subjects were randomized in the US (36.3% (81/223)) and EU (63.7% (142/223)). Subjects from the US had race collected and were Caucasian (34.5% (28/81)), Black (7.6% (6/81)) and Asian (2.7% (2/81)). There were no statistical differences in the baseline demographics between study groups.

Table 9: Baseline Demographics

| Parameter | % (n/N) or Mean ± SD (N) (Min, Median, Max) | | | | |
| --- | --- | --- | --- | --- | --- |
| | Randomized | | | ITT | mITT |
| | Treatment (ITT=109) | Treatment (mITT=102) | Control (ITT=mITT=114) | p-value1 | p-value1 |
| Age (years)* | 64.9 ± 12.0 (30.0, 66.0, 87.0) | 64.6 ± 12.1 (30.0, 66.0, 87.0) | 63.8 ± 11.5 (27.0, 65.0, 87.0) | 0.4943 | 0.6119 |

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| Male* | 65.1% (71) | 67.6% (69) | 66.7% (76) | 0.8878 | 0.8858 |
| --- | --- | --- | --- | --- | --- |
| BMI* (kg/m2) | 28.4 ± 6.2 (106) | 28.3 ± 6.1 (99) | 28.7 ± 6.7 (113) | 0.7987 | 0.7263 |
| Smoking | | | | | |
| Current | 17.4% (19/109) | 17.6% (18/102) | 17.5% (20/114) | 0.6287 | 0.7097 |
| Previous | 44.0% (48/109) | 45.1% (46/102) | 50.0% (57/114) | | |
| Never | 38.5% (42/109) | 37.3% (38/102) | 32.5% (37/114) | | |
| Race | | | | | |
| American Indian or Alaska Native | 1.8% (2) | 2.0% (2) | 0.9% (1) | 0.6852 | 0.6004 |
| Asian | 2.8% (3) | 2.0% (2) | 2.6% (3) | | |
| Black or African American | 9.2% (10) | 8.8% (9) | 6.1% (7) | | |
| Caucasian | 32.1% (35) | 30.4% (31) | 36.8% (42) | | |
| Not Reported | 47.7% (52) | 50.0% (51) | 50.0% (57) | | |
| Other | 0.0% (0) | 0.0% (0) | 0.9% (1) | | |
| Unknown | 6.4% (7) | 6.9% (7) | 2.6% (3) | | |
| Ethnicity | | | | | |
| Hispanic or Latino | 5.5% (6) | 4.9% (5) | 3.5% (4) | 0.8861 | 0.8868 |
| Not Hispanic or Latino | 37.6% (41) | 35.3% (36) | 38.6% (44) | | |
| Not Reported | 48.6% (53) | 51.0% (52) | 50.9% (58) | | |
| Unknown | 8.3% (9) | 8.8% (9) | 7.0% (8) | | |

Abbreviations: BMI=body mass index; ITT=Intent-to-Treat; mITT=Modified Intent-to-Treat; SD=standard deviation
Wilcoxon Rank Sum Test or Fisher's Exact Test.
* Pre-specified factors to compare between randomized groups at baseline.

Baseline clinical characteristics for randomized subjects are provided in Table 10. Subjects had received a mean 29.1 days of MV at enrollment. More than half of the subjects (65% (145/223)) were tracheostomized at enrollment consistent with their duration on MV. Mean baseline MIP was 28.8 cm H2O indicating the presence of diaphragm atrophy. Mean baseline RSBI was 112.5 breaths/min/L. The baseline values for MIP and RSBI were below the values known to be predictive for successful weaning.

One-half of subjects required MV due to acute respiratory stress disorder (ARDS) or acute respiratory failure (ARF), followed by surgical, pneumonia (independent of chronic obstructive pulmonary disease (COPD), ARDS/ARF or surgery), and COPD each in 12% to 16% of subjects. Fewer than 10% of subjects were on MV for trauma or "other" reasons. The heterogeneity of the underlying causes for respiratory failure and the higher incidence of ARDS/ARF was consistent with an ICU population requiring extended durations of MV. Baseline clinical characteristics were not statistically different between study groups.

Table 10: Baseline Clinical Characteristics

| Parameter | % (n/N) or Mean ± SD (N) (Min, Median, Max) | | | | |
| --- | --- | --- | --- | --- | --- |
| | Randomized | | | ITT | mITT |
| | Treatment (ITT=109) | Treatment (mITT=102) | Control (ITT=mITT=114) | p-value1 | p-value1 |
| Tracheostomy Prior to Enrollment* | 61.5% (67) | 61.8% (63) | 67.3% (76/113) | 0.4018 | 0.4752 |
| | 27.9 ± 19.0 | 27.8 ± 19.1 | 30.3 ± 19.5 (113) | 0.2656 | 0.2544 |

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| Days on MV at Randomization* | (5.0, 23.0, 85.0) | (5.0, 22.5, 85.0) | (5.0, 27.0, 86.0) | | |
| --- | --- | --- | --- | --- | --- |
| Absolute Value of Baseline MIP* | 29.0 ± 11.2 (109) | 29.9 ± 10.7 (102) | 28.7 ± 11.0 (114) | 0.6636 | 0.3506 |
| | (2.4, 29.8, 48.9) | (4.9, 30.3, 48.9) | (0.2, 27.8, 49.4) | | |
| Baseline RSBI* | 122.0 ± 116.0 (106) | 120.0 ± 113.4 (99) | 103.4 ± 79.8 (110) | 0.2914 | 0.3535 |
| | (14.8, 91.8, 891.3) | (14.8, 90.5,891.3) | (17.9, 83.1, 676.5) | | |
| Baseline SOFA Score* | 4.0 ± 2.2 (108) | 4.0 ± 2.3 (101) | 3.9 ± 2.5 (111) | 0.4534 | 0.6444 |
| | (0.0, 3.0, 10.0) | (0.0, 3.0, 10.0) | (0.0, 3.0, 12.0) | | |
| Reason for Mechanical Ventilation | | | | | |
| ARDS/ARF | 45.9% (50) | 46.1% (47) | 53.1% (60) | 0.6652 | 0.6028 |
| COPD | 11.9% (13) | 12.7% (13) | 11.5% (13) | | |
| Pneumonia** | 15.6% (17) | 14.7% (15) | 9.7% (11) | | |
| Surgical | 16.5% (18) | 16.7% (17) | 14.2% (16) | | |
| Trauma | 2.8% (3) | 2.0% (2) | 5.3% (6) | | |
| Other*** | 7.3% (8) | 7.8% (8) | 6.2% (7) | | |

Abbreviations: ARDS=acute respiratory distress syndrome; ARF=acute respiratory failure; COPD=Chronic Obstructive Pulmonary Disease; ITT=Intent-to-Treat; mITT=Modified Intent-to-Treat; MIP=maximal inspiratory pressure; MV=mechanical ventilation; RSBI=Rapid Shallow Breathing Index; SD=standard deviation; SOFA=Sequential Organ Failure Assessment
1Wilcoxon Rank Sum Test or Fisher's Exact Test.
* Pre-specified factors to compare between randomized groups at baseline.
** Pneumonia independent of COPD, ARDS/ARF or Surgery
*** Others were recategorized into existing categories by Lungpacer.

Baseline medical history was as expected for patients on MV and was not statistically different between randomized groups except for a prior history of ARF and Type II Diabetes. Subgroup analyses evaluating the presence or absence of ARF on successful weaning outcomes showed no statistical difference between groups. Similar analyses for Type II Diabetes found no difference in successful weaning between the Treatment and Control groups for the subgroup with Type II Diabetes but found a significantly higher rate of successful weaning in the subgroup without Type II Diabetes $(p = 0.0185)$ . A prior medical history of Type II Diabetes, associated with worse outcomes, was present in $39\%$ (43/109) of Treatment subjects compared with $26\%$ (29/112) of Control subjects, a difference unlikely to impact study outcomes.

Overall, the randomization was successful, resulting in balanced baseline characteristics between the Treatment and Control groups.

# E. Safety and Effectiveness Results

# Safety Results

The analysis of safety was based on the ITT cohort of 223 subjects (109 Treatment subjects and 114 Control subjects). The study's primary safety outcome, that the safety data would show the expected safety profile for Treatment subjects compared with Control subjects, was met.

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

Adverse events (AEs) and serious adverse events (SAEs) were collected through Day 30 unless the patient was withdrawn from the study or died. Patients in the Treatment group with an unsuccessful Catheter placement were followed for 48 hours for post-procedural complications and then exited from the study. Patients who did not wean by Day 30, had their Catheter removed on Day 30 and were then followed for 48 hours (Day 32) for safety events. AEs and SAEs were

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categorized by MedDRA System Organ Class (SOC) and lower-level term (LLT).

There were 189 AEs in 74 Treatment subjects (67.9%) and 152 AEs in 60 Control subjects (52.6%). Among all AEs, 70 events in 39 Treatment subjects (35.8%) and 46 events in 27 Control subjects (23.7%) were SAEs. The number and types of AEs reported were consistent with an expected safety profile of critically ill, mechanically ventilated patients. The higher incidence of catheter-related events in Treatment subjects reflect higher (100%) catheter usage compared with Control subjects (typically 50%-80%, Climo, 2003).

AE and SAEs, by SOC, that occurred in &gt;10% of Treatment group subjects are shown in Table 11. There were no AEs or SAEs of ventilator dyssynchrony with stimulation or reports of diaphragm injury. The Catheter was used for fluid delivery in 63.8% (65/102) of mITT Treatment subjects and there were no AEs reported related to use of the Catheter for fluid delivery.

Table 11: AEs and SAEs in Treatment Group (ITT) with &gt; 10% Incidence

| Body System Organ Class | Adverse Events | | | | Serious Adverse Events* | | | |
| --- | --- | --- | --- | --- | --- | --- | --- | --- |
| | Treatment N=109 | | Control N=114 | | Treatment N=109 | | Control N=114 | |
| | # of events | # (%) of Subjects | # of events | # (%) of Subjects | # of events | # (%) of subjects | # of events | # (%) of subjects |
| Infections | 44 | 34 (31.2%) | 37 | 27 (23.7%) | 22 | 19 (17.4%) | 16 | 12 (10.5%) |
| Respiratory, thoracic and mediastinal disorders | 33 | 27 (24.8%) | 32 | 24 (21.1%) | 15 | 14 (12.8%) | 16 | 13 (11.4%) |
| Cardiac disorders | 21 | 17 (15.6%) | 15 | 11 (9.6%) | 13 | 12 (11.0%) | 2 | 2 (1.8%) |
| Vascular disorders | 17 | 15 (13.8%) | 8 | 8 (7.0%) | 1 | 1 (0.9%) | 2 | 2 (1.8%) |
| Gastrointestinal disorders | 16 | 11 (10.1%) | 11 | 9 (7.9%) | 6 | 4 (3.7%) | 3 | 3 (2.6%) |

Abbreviations: ITT=Intent-to-Treat; N=Number
*SAE relationship and seriousness were adjudicated by the study Clinical Events Committee. AE relationship and seriousness were determined by the investigator.

AEs and SAEs determined to be possibly, probably, or definitely related to the study device and/or procedure are shown by SOC in Table 12. There were no unanticipated adverse device events.

The overall incidence of device- or procedure-related AEs in the Treatment group was 21.1% (36 events in 23 subjects). The most frequent device- or procedure-related AEs by SOC were infections (9.2%), cardiac disorders (6.4%), and vascular disorders (3.7%). Other less frequent related AEs were procedural or catheter placement complications.

AEs for infection were mostly related to the device rather than the procedure and were associated with catheter insertion and use. AEs for cardiac disorders were mainly due to inadvertent cardiac stimulation associated with the device for transvenous stimulation. Vascular AEs were mostly related to the device and were associated with catheter placement (hemothorax/pneumothorax).

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Table 12: Procedure/Device-Related AEs and SAEs in Treatment Subjects System (ITT)

| Body System Organ Class | Procedure or Device-Related Adverse Events | | Procedure or Device-Related Serious Adverse Events | |
| --- | --- | --- | --- | --- |
| | # of events | # (%) of subjects | # of events | # (%) of Subjects |
| Blood and lymphatic system disorders | 1 | 1 (0.9%) | 0 | 0 |
| Cardiac disorders | 10 | 7 (6.4%) | 4 | 3 (2.6%) |
| General disorders and administration site conditions | 3 | 3 (2.8%) | 0 | 0 |
| Infections and infestations | 11 | 10 (9.2%) | 7 | 7 (6.1%) |
| Injury, poisoning and procedural complications | 6 | 3 (2.8%) | 0 | 0 |
| Surgical and medical procedures | 1 | 1 (0.9%) | 0 | 0 |
| Vascular disorders | 4 | 4 (3.7%) | 1 | 1 (0.9%) |
| Total | 36 | 23 (21.1%) | 12 | 11 (9.6%) |

Abbreviations: ITT=Intent-to-Treat; N=Number
*SAE relationship and seriousness were adjudicated by the study Clinical Events Committee. AE relationship and seriousness were determined by the investigator.

The overall incidence of device- or procedure-related SAEs was 9.6% (12 events in 11 subjects). The most frequently reported related SAEs by SOC were infections (6.1%) and cardiac disorders (2.6%).

Infection and cardiac disorder device- or procedure-related SAEs were predominantly related to the device rather than the procedure. Cardiac SAEs were associated with inadvertent cardiac stimulation due to transvenous stimulation during electrode mapping (1.8%) or were related to catheter misplacement (0.9%). These AEs were temporary, were resolved by stopping stimulation with no further sequelae, and did not occur in subsequent sessions. Acute coronary syndrome in one (1) subject who died was possibly related to the procedure due to possible undetected tension pneumothorax. There was one vascular SAE of hypovolemic shock in one (1) subject who died that was possibly related to the device due to hemothorax / pneumohemothorax.

Deaths occurred in 9.2% (10/109) of ITT subjects in the Treatment group and 10.5% (12/114) of ITT subjects in the Control group due to cardiac/cardiopulmonary shock, organ failure, respiratory failure, or ARDS/pneumonia. Mortality was at the lower end of the expected range of 10% to 30% for this critically ill population.

Discomfort and pain assessment was conducted using a 10-point visual analogue pain rating scale before and after each therapy session. The mean pain scale rating before and after all therapy sessions for mITT Treatment subjects was negligible with an increase of 0.2 points (2% of the 10-point scale). The percentage of sessions in which subjects perceived any pain after therapy was approximately 8% (8/102) indicating therapy was well tolerated even with stimulation delivered at maximum intensity in 83% (85/102) of subjects.

In summary, safety events in the RESCUE 3 trial were as expected for a patient population on MV. Safety events related to the AeroPace System, or its procedures, were those expected for a CVC delivering transvenous electrical stimulation. Transvenous stimulation may cause inadvertent cardiac stimulation during electrode mapping or therapy. These expected cardiac events were temporary, occurred at a low incidence (2.6%), and were resolved without sequelae.

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# Effectiveness Results

The effectiveness of the AeroPace System was evaluated based on data from 223 subjects randomized in RESCUE 3 study.

The trial was prematurely terminated due to the difficulty in enrollment and the final population consists of 223 randomized subjects. Given the unplanned deviation from the study design, the study results are reported descriptively.

Successful weaning was numerically superior in the Treatment group compared with the Control group for RESCUE 3 subjects. There were $10.4\%$ (mITT) to $14.1\%$ (PP) more patients in the Treatment group who were successfully weaned compared with the Control group. These results exceeded a pre-specified minimal clinically important difference (MCID) of $\geq 10\%$ , with a relative risk reduction of remaining on MV by day 30 of up to $37\%$ ( $RR = 0.629$ ). RESCUE 3 patients in the Treatment group required 1.9 (mITT) to 2.432 (PP) fewer days on MV compared with the Control group, for up to a 5-fold greater reduction than the pre-specified MCID of 0.5 MV days. Mortality at day 30 was lower by $1.3\%$ for patients in the Treatment group (ITT) compared with the Control group.

Re-intubation rates were 2.4 to 2.6 times lower for patients in the Treatment group (5.6% mITT; 6.1% PP), compared with the Control group (14.5%), for a relative risk reduction for reintubation within 30 days of 60% (RR=0.386, mITT). MIP change from baseline to last available measurement for patients in the Treatment group compared with the Control group was greater by 4.1 cmH2O (mITT) to 5.1 cmH2O (PP), a 50% comparatively greater improvement. RSBI was numerically improved from baseline for patients in the Treatment group (mITT: -35.0 breaths/min/L; PP: -37.0 breaths/min/L) compared to the Control group (-19.9 breaths/ min/L).

Patients in the Treatment group had numerically fewer tracheostomies over 30 days (mITT: $12.8\%$ ; PP: $11.4\%$ ) compared with the Control group ( $18.8\%$ ). Patients in the Treatment group also required reduced ventilator requirements from Day 1 to last available measurement for pressure support (mITT: $-1.9 \pm 5.0$ cmH2O; PP: $-2.0 \pm 4.9$ cmH2O) compared with the Control group $(-0.1 \pm 4.5$ cmH2O) and for fraction of inspired oxygen (mITT:

-2.7% ±8.6; PP: -3.0% ±8.7), compared with the Control group (0.1% ±10.9). The effectiveness outcomes are summarized in Table 13.

Table 13: RESCUE 3 Effectiveness Outcomes

| Effectiveness Endpoint | Analysis Population | Treatment (95% CI1) [min, med, max] | Control (95% CI) [min, med, max] | Treatment Minus Control (95%CI) |
| --- | --- | --- | --- | --- |
| Successful Weaning (%) | mITT | 72.4% (62.1, 80.3) | 62.0% (52.2, 70.4) | 10.4% |
| | PP | 76.1% (65.4, 83.9) | 62.0% (52.2, 70.4) | 14.1% |
| Days on MV (Days) | mITT | 15.4 ± 10.2 [0,0, 13.0, 29.0] | 17.3 ± 10.9 [1.0, 18.0, 29.0] | -1.9 (-4.8, 1.0) |
| | PP | 14.9 ± 9.9 [0,0, 12.5, 29.0] | 17.3 ± 10.9 [1.0, 18.0, 29.0] | -2.43 (-5.3, 0.5) |
| Mortality (%) | ITT | 9.2% (3.8, 14.6) | 10.5% (4.9, 16.2) | -1.3% |
| Reintubation (%) | mITT | 5.6% (2.7, 11.0) | 14.5% (6.2, 22.8) | -8.9% (-18.7, 1.0) |
| | PP | 6.1% (3.0, 11.8) | 14.5% (6.2, 22.8) | -8.4% (-18.5, 1.7) |
| | mITT | 13.9 ± 19.3 [-32.7, 12.8, 81.9] | 9.8 ± 15.2 [-32.5, 7.7, 48.4] | 4.1 (-0.6, 8.8) |

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| MIP (cm H2O, absolute) | PP | 14.9 ± 19.9 [-32.7, 13.7, 81.9] | 9.8 ± 15.2 [-32.5, 7.7, 48.4] | 5.1 (0.1, 10.1) |
| --- | --- | --- | --- | --- |
| RSBI (breaths/min/L) | mITT | -35.0 ± 107.9 [-819.9, -12.2, 258.6] | -19.8 ± 78.2 [-611.7, -8.6, 225.0] | -15.1 (-41.1, 10.8) |
| | PP | -37.0 ± 106.4 [-819.9, -12.4, 71.4] | -19.8 ± 78.2 [-611.7, -8.…