TherOx Downstream System

P170027 · Zoll Circulation, Inc. · MWG · Apr 2, 2019 · Cardiovascular

Device Facts

• Record ID: P170027
• Device Name: TherOx Downstream System
• Applicant: Zoll Circulation, Inc.
• Product Code: MWG · Cardiovascular
• Decision Date: Apr 2, 2019
• Decision: APPR
• Device Class: Class 3
• Attributes: Therapeutic

Indications for Use

The TherOx DownStream System, is indicated for the preparation and delivery of SuperSaturated Oxygen Therapy (SSO₂ Therapy) to targeted ischemic regions perfused by the patient's left anterior descending coronary artery immediately following revascularization by means of percutaneous coronary intervention (PCI) with stenting that has been completed within 6 hours after the onset of anterior acute myocardial infarction (AMI) symptoms caused by a left anterior descending artery infarct lesion.

Device Story

System delivers SuperSaturated Oxygen Therapy (SSO₂) to ischemic myocardium post-PCI. Inputs: hospital-supplied oxygen gas and sterile saline. Console (DS-1) controls mixing/metering in disposable cartridge (DSC-2) to create hyperoxemic solution (pO2 760-1240 mmHg). Solution mixed with autologous arterial blood in extracorporeal circuit; hyperoxemic blood (100 ml/min) infused via 5F catheter into left main coronary artery ostium for 60 minutes. Used in cath lab by interventional cardiologists. Output: hyperoxemic blood delivery to target vessel. Effect: reduces infarct size; improves myocardial health. Benefits: potential reduction in infarct size adjunct to PCI.

Clinical Evidence

Evidence from two clinical trials: AMIHOT II (prospective, randomized, multicenter, N=301) and IC-HOT (single-arm, N=100). AMIHOT II showed superiority in median infarct size (20.0% vs 26.5% control, p=95.1% Bayesian probability). IC-HOT confirmed safety with 7.1% 30-day NACE rate, meeting pre-specified threshold of 10.7%. Adverse events included bleeding, stent thrombosis, and myocardial rupture, with higher rates in SSO₂ arm in AMIHOT II; IC-HOT safety profile was consistent with benchmarks. Bench testing verified system performance, biocompatibility, and sterilization.

Technological Characteristics

System includes electromechanical console (DS-1), single-use disposable cartridge (DSC-2), and 5F SSO₂ delivery catheter. Cartridge constructed of polycarbonate and PVC. Principle: dissolution of oxygen in saline under high pressure to create hyperoxemic solution, mixed with autologous blood. Connectivity: AC-powered console with battery backup. Sterilization: Ethylene Oxide (cartridge). Software: embedded control/monitoring algorithms. Complies with IEC 60601-1 and IEC 60601-1-2.

Indications for Use

Indicated for patients ≥18 years with anterior acute myocardial infarction (AMI) caused by a left anterior descending (LAD) artery infarct lesion, treated with successful PCI and stenting within 6 hours of symptom onset. Contraindications include cardiogenic shock, pregnancy, nursing, hemoglobin <10 g/dL, recent major surgery/bleeding, and specific cardiac conditions (e.g., valvular stenosis, pericardial disease, pseudoaneurysm).

Reference Devices

• AMIHOT I (IDE G980257)
• INFUSE-AMI

Submission Summary (Full Text)

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SUMMARY OF SAFETY AND EFFECTIVENESS DATA (SSED)

I. GENERAL INFORMATION

Device Generic Name: SuperSaturated Oxygen Therapy

Device Trade Name: TherOx DownStream System

Device Procode: MWG

Applicant's Name and Address: TherOx, Inc.
17500 Cartwright Rd.
Suite 100
Irvine, CA 92614

Date(s) of Panel Recommendation: None

Premarket Approval Application (PMA) Number: P170027

Date of FDA Notice of Approval: April 2, 2019

II. INDICATIONS FOR USE

The TherOx DownStream System, is indicated for the preparation and delivery of SuperSaturated Oxygen Therapy (SSO₂ Therapy) to targeted ischemic regions perfused by the patient's left anterior descending coronary artery immediately following revascularization by means of percutaneous coronary intervention (PCI) with stenting that has been completed within 6 hours after the onset of anterior acute myocardial infarction (AMI) symptoms caused by a left anterior descending artery infarct lesion.

III. CONTRAINDICATIONS

- Ipsilateral insertion of a second sheath in a single femoral artery for SuperSaturated Oxygen Therapy is strictly contraindicated.
- Presence of an intra-aortic balloon pump.
- Proximal coronary stenosis that restricts flow with the SSO₂ delivery catheter in place.

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- Presence of a post-intervention non-stented coronary dissection or perforation.
- Cardiac valvular stenosis or insufficiency, pericardial disease or non-ischemic cardiomyopathy.
- Pregnant or nursing women.
- Cardiogenic shock.
- Patients contraindicated for anticoagulation therapy.
- Subjects with ventricular pseudoaneurysm, VSD, or severe mitral valve regurgitation (with or without papillary muscle rupture).
- Hemoglobin &lt; 10 g/dL.
- Gastrointestinal or genitourinary bleeding within the last two months, or any major surgery (including CABG) within six weeks of procedure.

## IV. WARNINGS AND PRECAUTIONS

The warnings and precautions can be found in the Therox DownStream System labeling.

## V. DEVICE DESCRIPTION

The Therox DownStream System includes three components: the re-usable electromechanical console DownStream System (Model DS-1), the single-use disposable DownStream Cartridge (Model DSC-2), and the 5F SSO₂ Catheter. These component devices are supplied by TherOx exclusively for use in delivering SSO₂ Therapy. These components work in unison to perform the processes of SSO₂ Therapy delivery and blood circulation to support hyperoxemic blood delivery. A detailed description of these components follows.

### The DownStream System

The DownStream System (Model Number DS-1) is the medical electrical device (console) that controls the DownStream Cartridge and monitors performance and safety during administration of SSO₂ Therapy (see Figure 1). The DownStream System has a touch-screen display interface to guide the health care professional through setup and clinical operation. The system is non-sterile and has no direct patient contact. The DownStream System is intended primarily to be mains operated (AC-powered) and stationary during use, but it has handles and wheels to facilitate movement and is internally powered by a battery for operation during transport (note: the patient is not to be transported/moved while therapy is being provided). The DownStream System has several integrated subsystems mounted upon a single system chassis. The major subsystems are the Cartridge Control Subsystem (CCS), Display Subsystem (Display), Power Supply Subsystem (Power Supply), and Oxygen Supply Subsystem (Oxygen

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Supply). The CCS includes a housing to control mixing and metering operations for the oxygenated saline within the DownStream Cartridge. The CCS incorporates a peristaltic blood pump to control extracorporeal circuit blood flow rate; circuit pressure and bubble detection are monitored by the CCS. The CCS also includes a safety interlock which continuously monitors parameters critical to safe system operation and can safely stop therapy if necessary. The Display is the user interface for the DownStream System. The Display includes an LCD screen for user messages, a speaker for audible feedback and a keypad for user operation. The Power Supply is the power source for all system electronics, while the Oxygen Supply provides regulated oxygen to the CCS for cartridge operation.

Figure 1. DownStream System

## The DownStream Cartridge

The DownStream Cartridge (Model Number DSC-2) is a sterile, single-use device that is inserted in the DownStream System to support $\mathrm{SSO}_2$ Therapy (see Figure 2). The DownStream Cartridge comprises the blood-contact fluid flow path together with the $\mathrm{SSO}_2$ delivery catheter. The DownStream Cartridge, when controlled by the DownStream System, creates $\mathrm{SSO}_2$ solution from inputs of hospital-supplied oxygen gas and sterile saline solution. The DownStream Cartridge delivers and mixes autologous arterial blood from the patient with $\mathrm{SSO}_2$ solution in a carefully designed extracorporeal circuit to create oxygen-enriched hyperoxemic blood with an elevated $\mathrm{pO}_2$ level of $760 - 1240\mathrm{mmHg}$ . Because the $\mathrm{SSO}_2$ solution has a high oxygen concentration, the flow rate

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of $\mathrm{SSO}_2$ solution is only $3.5\mathrm{ml / min}$ out of a total return flow rate of $100\mathrm{ml / min}$ ; the fluid loading to the patient is thus minimal.

The DownStream Cartridge weighs less than one pound and is constructed primarily from injection-molded polycarbonate. The tubing material is polyvinyl chloride (PVC). The draw and return tubing have approximately 8 feet of working length. The blood priming volume of the DownStream Cartridge is approximately $60~\mathrm{ml}$ . The DownStream Cartridge is individually packaged.

Figure 2. DownStream Cartridge

# $\mathbf{SSO}_2$ Delivery Catheter

The qualified $\mathrm{SSO_2}$ Catheter ("catheter") is a 5F (O.D.) over-the-wire TherOx-supplied catheter that is equipped with a standard luer fitting at the proximal end for attachment to the return line of the cartridge. The $\mathrm{SSO_2}$ Catheter has been qualified by TherOx for delivery of $\mathrm{SSO_2}$ Therapy. The catheter has a 5F outer diameter, a length of $100\mathrm{cm}$ , and a single endhole for fluid output. The catheter is provided in Judkins Left (JL) tip shapes to facilitate placement in the left main coronary ostium using a femoral or radial access site. The catheter produces a nominal circuit pressure between 1000 to $1400\mathrm{mmHg}$ at a return blood flow rate of $100\mathrm{ml/min}$ . The catheter is placed in the ostium of the left main coronary artery (LMCA) using a guidewire by the trained physician and is connected to the cartridge after blood priming. Figure 3 shows the $\mathrm{SSO_2}$ Catheter.

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Figure 3. $\mathrm{SSO}_2$ Catheter

# Patient Connections

The DownStream Cartridge draw tubing connects to a femoral arterial sheath. This sheath may be the same sheath used for the index PCI procedure and subsequent placement of the $\mathrm{SSO}_2$ Catheter – this is the single access site approach. For the single access site approach placement is coaxial (using one femoral arterial access site) with the catheter inserted through a 7F or larger sheath and the draw tubing hooked up to the sheath sidearm. Alternatively, a dual access site approach may be used, requiring a single 5F femoral sheath for blood withdrawal, and catheter placement through a second 5F or larger sheath placed in either the radial artery or the contralateral femoral artery. The $\mathrm{SSO}_2$ Catheter is placed at the ostium of the left main coronary artery using standard catheterization laboratory techniques. When extracorporeal blood flow is initiated, the delivery catheter and DownStream Cartridge return tubing are wet-connected to ensure that no gaseous emboli are introduced to the patient during priming. The cartridge return tubing luer fitting connects to the luer hub of the delivery catheter.

Figure 4 provides a schematic of the patient connections during $\mathrm{SSO}_2$ Therapy administration.
Figure 4. Patient Connections

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# Principle of Operation

- Hospital-supplied oxygen gas is dissolved in physiologic saline under high pressure; the resultant highly oxygenated solution is called $\mathrm{SSO}_2$ solution.
- $\mathrm{SSO}_2$ solution (3.5 ml/min) is combined with the autologous arterial blood (96.5 ml/min) in an extracorporeal circuit, providing hyperoxemic blood at a flow rate of 100 ml/min with an elevated $\mathrm{pO}_2$ level of 1000 mmHg. A sixty-minute procedure requires 210 ml of fluid loading.
- Hyperoxemic blood is infused into the target coronary artery through the $\mathrm{SSO}_2$ delivery catheter for sixty minutes. Existing patient connections, including the femoral introducer sheath, can be used for blood withdrawal and coronary access. It is also possible to place the delivery catheter using radial artery access, using femoral access for blood withdrawal.

## VI. ALTERNATIVE PRACTICES AND PROCEDURES

No available therapeutic alternatives are known for the reduction of infarct size adjunct to PCI following AMI.

## VII. MARKETING HISTORY

The TherOx® DownStream® System has not been marketed in the United States or any foreign country.

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

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

- Death
- Acute Myocardial Infarction (AMI)
- Stent Thrombosis
- Revascularization (CABG or PCI)
- Congestive Heart Failure
- Hemorrhage
- Abrupt vessel closure/spasm
- Allergic reactions
- Aneurysm
- Anxiety/Dizziness

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- Arrhythmias
- Arteriovenous Fistula/Pseudoaneurysm
- Blood loss/damage
- Cardiogenic Shock
- Chest pain/angina
- Coronary Artery Occlusion
- Embolism (including air emboli and thromboemboli)
- Hematoma
- Hemolysis
- Hypertension/Hypotension
- Infection
- Myocardial Rupture
- Nausea/Vomiting
- Neck/back/groin pain
- Pericardial effusion
- Pulmonary Edema
- Renal complications
- Respiratory complications
- Restenosis
- Stroke/TIA
- Tamponade
- Thrombosis
- Vascular damage (dissection, perforation, rupture, or other mechanical injury)

Specific adverse events that were reported in completed clinical studies of $\mathrm{SSO}_2$ Therapy are presented in Section X below.

## IX. SUMMARY OF NONCLINICAL STUDIES

A summary of pre-clinical studies and information for the DownStream System and DownStream Cartridge are presented in this section. Results of biocompatibility testing, relevant animal studies of $\mathrm{SSO}_2$ Therapy, engineering testing of the device and components, and software testing are included herein.

## A. Biocompatibility

The TherOx DownStream System is the permanent hardware device component to administer $\mathrm{SSO}_2$ Therapy. The system has no liquid or blood contacting surfaces. The

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system operates in conjunction with two single-use disposable devices, the TherOx DownStream Cartridge and the $\mathrm{SSO}_2$ Catheter.

The ISO 10993-1 standard, "Biological Evaluation of Medical Devices Part-1: Evaluation and Testing" and the FDA's Blue Book Memo G95-1 were used as guidance in selecting the appropriate tests.

Per the ISO 10993-1 standard, the DownStream Cartridge is categorized as an "External communicating device" contacting circulating blood. Duration of contact is categorized as "Limited exposure", or less than 24 hours.

Biocompatibility and toxicity testing were performed on sterile finished devices and included the following battery: Cytotoxicity, Sensitization, Intracutaneous Reactivity, Systemic Toxicity, Hemolysis, and Genotoxicity. Table 1 provides a summary of the performed tests and corresponding document numbers. Each of these tests was conducted in compliance with Good Laboratory Practices (GLP). Results demonstrated that the DownStream Cartridge passed all required tests.

Table 1. Summary of DownStream Cartridge Biocompatibility/Toxicity Testing

| Biocompatibility/Toxicity Test | Pass/Fail |
| --- | --- |
| Cytotoxicity | Pass |
| Sensitization | Pass |
| Intracutaneous Reactivity | Pass |
| Systemic Toxicity | Pass |
| Hemolysis | Pass |
| Genotoxicity | Pass |
| LAL Test | Pass |

In addition, as part of the product sterile release system, pyrogen testing utilizing the Kinetic-Chromogenic LAL assay method has been performed for all sterilization loads with acceptable results.

Based on the results of these tests, the DownStream Cartridge materials were determined to meet the biocompatibility/toxicity requirements for the device.

# B. Animal Testing

Controlled studies were performed in both porcine and canine AMI models to investigate the safety, effectiveness, and mechanism of action of $\mathrm{SSO}_2$ Therapy. Key studies are summarized in Table 2. The findings of these studies demonstrated improved LV function, infarct size reduction, a microvascular mechanism of action, and that supersaturated oxygen therapy is non-toxic.

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Table 2. Summary of Key Animal Studies

| Description | Sample size | Measures | Results |
| --- | --- | --- | --- |
| Canine AMI model
Post-induced AMI comparison: SSO2 Therapy vs. autoreperfusion vs. normoxemic (pump) reperfusion (3 groups) | N=26 | Myocardial blood flow (radiolabeled microspheres), left ventricular function (ECHO), ECG changes | LVEF and ECG improvement in SSO2 group with increased microvascular blood blow compared to controls |
| Porcine AMI model
Post-induced AMI comparison: SSO2 Therapy vs. autoreperfusion vs. normoxic (pump) vs. pump with membrane oxygenator (4 groups) | N=59 | Left ventricular function (ECHO), infarct size (histology), myeloperoxidase assays in at-risk myocardium | LVEF improvement with reduced infarct size and reduced myeloperoxidase levels in SSO2 group compared to controls |
| Porcine AMI model
Post-induced AMI with stenting safety comparison: SSO2 Therapy vs. sham infusion (2 groups) | N=40 | Left ventricular function, infarct size, full pathology of heart and other end organs at 7 and 28 days | LV functional improvement and smaller infarct size in SSO2 group compared to controls with no toxicity noted in coronary arteries, myocardium, or other organs |

The key summary points from animal studies are:

- SSO₂ Therapy administration post-AMI acutely improves left ventricular ejection fraction (LVEF) and regional wall motion as compared with non-treated controls.
- Control animals exhibited larger infarcts than SSO₂-treated animals as determined by post-sacrifice histological measurements of infarct size
- SSO₂ Therapy was non-toxic to the coronary arteries, myocardium, and end organs in randomized, controlled swine studies with or without induced acute myocardial infarction.
- SSO₂ Therapy administration post-AMI has exhibited regional myocardial blood flow improvement in treated animals as compared to controls.
- A significant reduction in myeloperoxidase (MPO) levels was observed in SSO₂ - treated animals versus controls; reduced MPO levels indicate improvement in underlying myocardial hypoxia.
- Transmission electron microscopy (TEM) photographs showed amelioration of endothelial cell edema and restoration of capillary patency in ischemic zone cross-sectional histological examination of SSO₂-treated animals; non-treated controls exhibit significant edema and vessel constriction at the microvascular level.

The pre-clinical animal studies conducted with the TherOx DownStream System in AMI models have demonstrated acute improvements in cardiac function and metabolic indicators of myocardial health, as well as infarct size reduction versus controls.

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## C. Engineering / Bench Testing

The DownStream System and DownStream Cartridge have undergone bench testing in support of the current SSO₂ Therapy. DownStream System bench testing includes verification of subsystems to specifications, software verification and validation testing, and validation of the integrated system to its requirements and recognized equipment standards. DownStream Cartridge bench testing includes functional testing, proof testing blood path integrity testing, performance validation in combination with the DownStream System, packaging and shelf life validation testing.

## DownStream System Testing

The DownStream System hardware console was tested in accordance with its product specifications including functional and subsystem testing, software validation, and integrated performance validation testing. A summary of testing is provided in Table 3. The DownStream System software was verified and validated to its established requirements and complies with guidance document titled “Guidance for Industry and FDA Staff- Guidance for the Content of Pre-market Submissions for Software Contained in Medical Devices” (issued on May 11, 2005). The software met all safety, function, and design requirements. All safety requirements identified in the Software Hazards Analysis were validated. The Display Software within the Display Subsystem and the Cartridge Control, Bubble Detector and Cartridge Interface software within the CCS successfully completed Verification and Validation (V&amp;V) testing and the software was released for use with the DownStream System.

Validation testing was performed to demonstrate that the DownStream System Model DS-1 met its design requirements and complied with recognized equipment standards. Validation testing was conducted in compliance with Good Laboratory Practices (GLP) as outlined in 21 CFR §58. Safety, electromechanical compatibility and environmental testing were conducted by independent laboratories to recognized standards, including to IEC 60601-1, 2nd and 3rd editions and in accordance with IEC 60601-1-2 Issued: 2007 (3rd edition). The function and performance key subsystems were tested and satisfied all product requirements. The DownStream System safety response to simulated error conditions was tested and for all simulated events, the system responded in accordance with its safety requirements. SSO₂ Therapy performance validation testing demonstrated simulated clinical delivery of therapy successfully.

Based on the results from verification and validation testing, the DownStream System met established requirements and was validated to perform SSO₂ Therapy in combination with the DownStream System and SSO₂ delivery catheter.

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Table 3. DownStream System Bench Test Results

| Test Description | Test Article | Acceptance Criteria | Result |
| --- | --- | --- | --- |
| DownStream System Verification Testing | Cartridge Control Subsystem, Display Subsystem, Power Supply Subsystem, and Oxygen Supply Subsystem | Verification of established specifications for subsystem interfaces, functions and performance | PASS |
| DownStream System Software V&V Testing | Cartridge Control, Display, Cartridge Interface, Bubble Detector Software | Compliance with established software specifications and software requirements documents | PASS |
| Cartridge Control Subsystem Validation | DownStream System (n=3) | Compliance with Cartridge Control functional and performance requirements | PASS |
| Bubble Detector Subsystem Validation | DownStream System (n=3) | Compliance with Bubble Detector functional and performance requirements | PASS |
| Display Subsystem Validation | DownStream System (n=3) | Compliance with Display Subsystem functional and performance requirements | PASS |
| Power Supply Subsystem Validation | DownStream System (n=3) | Compliance with Power Supply functional and performance requirements | PASS |
| Oxygen Supply Subsystem Validation | DownStream System (n=3) | Compliance with Oxygen Supply functional and performance requirements | PASS |
| Integrated System Safety Validation Testing | DownStream System (n=3) | Compliance with DownStream System safety requirements | PASS |
| Integrated SSO2Therapy Performance Validation Testing | DownStream System (n=3) | Compliance with SSO2Therapy delivery performance requirements | PASS |

# DownStream Cartridge Validation Testing

Validation testing was performed to demonstrate that the DownStream Cartridge Model DSC-2 met its design requirements and complied with recognized equipment standards, including to IEC 60601-1, 2nd and 3rd editions and in accordance with IEC 60601-1-2 Issued: 2007 (3rd edition). Validation testing was conducted in compliance with Good Laboratory Practices (GLP) as outlined in 21 CFR §58. Tests were performed to verify the cartridge physical configuration, performance testing, non-destructive design limit testing, and proof testing. The DownStream Cartridge met established requirements and was validated to perform $\mathrm{SSO}_2$ Therapy in combination with the DownStream System and $\mathrm{SSO}_2$ delivery catheter. Specific test results are found in Table 4.

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Table 4. DownStream Cartridge Bench Test Results

| Test Description | Sample | Acceptance Criteria | Data | Result |
| --- | --- | --- | --- | --- |
| Blood hemolysis testing | N=6 | 3-hour blood test; blood hemolysis less than 20 mg/dL/hr | Hemolysis index 7.5 mg/dL/hr average | PASS |
| Packaging testing of 3-year real time aged product | N=30 | Peel test (1 lb min) per ASTM F88-09. Leak test per ASTM F2096-01. | All samples passed peel test and submersion leak test requirements | PASS |
| Blood path integrity | N=10 | No leakage or failures from proof testing or pull testing of cartridge blood path. Priming volume < 100 ml | All samples had no leakage at < 60 psig, no failures at 3.3 lb, Priming volume < 100 ml (62.5 ml average) | PASS |
| Cycle testing at design pressure | N=10 | Perform 100 flush cycles and 200 flow cycles at design pressure | All cartridges performed 100 flush cycles and 200 flow cycles at > 800 psig | PASS |
| Proof test at 1.5X design pressure | N=10 | Two minute proof test; no damage to cartridge | All cartridges completed proof testing at 1200 psig Oxygen Chamber and 1350 psig (Piston Chamber) | PASS |
| Performance simulation of 3-year real time aged product | N=9 | Cartridge prep in < 5 min Deliver pO2 > 760 mmHg Complete 90 minutes of circulation (1.5X duration) | Cartridge prepped in less than 5 min (90 sec average) Deliver pO2 > 760 mmHg Completed 90 minutes of therapy duration | PASS |

# $\mathbf{SSO}_2$ Catheter Qualification Testing

Qualification testing was performed to demonstrate that the $\mathrm{SSO_2}$ delivery catheter met specifications for use with $\mathrm{SSO_2}$ Therapy. Tests were performed to verify the catheter physical configuration, catheter integrity, and performance specifications. The $\mathrm{SSO_2}$ delivery catheter met established specifications to perform $\mathrm{SSO_2}$ Therapy in combination with the DownStream System and DownStream Cartridge. Specific test results are found in Table 5.

Table 5. ${\mathrm{{SSO}}}_{2}$ Catheter Bench Test Results

| Test Description | Sample | Acceptance Criteria | Data | Result |
| --- | --- | --- | --- | --- |
| Blood hemolysis testing of circuit including cartridge and catheter | N=6 | 3-hour blood test; blood hemolysis less than 20 mg/dL/hr | Hemolysis index 7.5 mg/dL/hr average | PASS |
| Catheter integrity testing | N=10 | No leakage from proof testing or failure from pull testing of catheter Priming volume < 3 ml | No leakage at 100 psig No vacuum leakage No tensile failures at 3.3 lb Priming volume < 3 ml (1.3 ml average) | PASS |
| Performance simulation of | N=9 | Deliver pO2 > 760 mmHg | Deliver pO2 > 760 mmHg | PASS |

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| Test Description | Sample | Acceptance Criteria | Data | Result |
| --- | --- | --- | --- | --- |
| circuit including cartridge and catheter | | Complete 90 minutes of circulation (1.5X duration) bubble free | Completed 90 minutes of therapy duration bubble free | |

## Sterilization

The DownStream Cartridge is ethylene oxide sterilized at a contracted sterilization facility. The sterilization cycle uses an Ethylene Oxide/ Carbon Dioxide gas mixture (8.5% and 91.5% respectively) with a minimum EO gas concentration of 230 mg/l. The nominal gas dwell time is 14.5 hours.

The sterilization cycle was validated using the "overkill" method outlined in ANSI/AAMI/ISO 11135. The validation consisted of three half-cycles, one fraction cycle, and three full cycles. The validation demonstrated that a sterility assurance level (SAL) of at least 10⁻⁶ is achieved. The sterilization cycle is requalified annually.

The SSO₂ Catheter is supplied to TherOx by the contract manufacturer pre-sterilized using Ethylene Oxide with SAL of 10⁻⁶ and this cycle has been qualified.

## Packaging

The DownStream Cartridge is placed in a custom thermoformed tray made of high impact styrene. A clear PETG lid snaps into the tray, keeping the Cartridge securely in place. The lid is well vented and does not interfere with the EO sterilization process. The tray is then placed in a Tyvek/poly pouch. The pouch is heat sealed, labeled, and placed in a unit box. The unit box is labeled and placed in an outer case. The cases are palletized and terminally sterilized with an ethylene oxide sterilant and carbon dioxide gas mixture. The packaged Cartridge has a three-year shelf life. The DownStream System is packaged separately, and has a three-year shelf life.

The SSO₂ Catheter is pre-packaged by the contract manufacturer with five catheters provided per box in the same JL tip shape configuration. Final labeling is applied by TherOx for use of the catheter in delivering SSO₂ Therapy. The SSO₂ Catheter has a two-year shelf life.

## X. SUMMARY OF CLINICAL STUDIES

## AMIHOT II Clinical Trial

The applicant performed a clinical study to establish a reasonable assurance of safety and effectiveness of SSO₂ Therapy with the TherOx DownStream System for reducing infarct size in anterior AMI patients treated within six hours of symptom onset in the US under IDE G980257. Data from this clinical study were part of the basis for the PMA approval decision. A summary of the clinical study is presented below.

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## A. Study Design

The study enrollment was conducted from September 13, 2005, the date of the first patient enrollment, to June 28, 2007, the date of completion for the last 30-day patient follow up at 20 investigational sites.

The study was a prospective, multicenter randomized clinical study of SSO₂ Therapy with the TherOx DownStream System compared to PCI/stenting alone to determine whether intracoronary perfusion of hyperoxemic blood SSO₂ Therapy group immediately after successful PCI/stenting for the treatment of acute myocardial infarction reduces the area of infarction (% left ventricle) at 14 days post-PCI, with no more than a 6% (absolute) increase in the incidence of Major Adverse Cardiac Events (MACE), death, re-infarction, target vessel revascularization, and stroke at the latter of either 30 days post-PCI or hospital discharge.

The AMIHOT II Clinical Events Committee (CEC) was responsible for comprehensive adverse event adjudication on an ongoing basis throughout the study. CEC membership was comprised of three (3) interventional cardiologists who did not participate in the study.

A Data Safety Monitoring Board (DSMB) was utilized for safety monitoring in this trial. No formal statistical rule for stopping the trial was defined, but comprehensive review of adjudicated adverse event reporting was performed during the study. DSMB membership consisted of three (3) interventional cardiologists, one (1) non-interventional cardiologist and one (1) biostatistician.

## 1. Clinical Inclusion and Exclusion Criteria

Enrollment in the AMIHOT II study was limited to patients who met the following inclusion criteria:

### Pre-PCI:

1. Patient must be ≥ 18 years of age
2. AMI must be anterior
3. Patient is experiencing clinical symptoms consistent with anterior AMI of &lt; 6 hour duration from time of symptom onset until admission to the emergency room
4. Complete medical history, history of AMI, previous coronary interventions, list of medications given within last 24 hours are available
5. 12-lead qualifying ECG criteria: Anterior infarction (ST-segment elevation ≥ 1 mm in two or more contiguous leads between V1 and V4 or new left bundle branch block (LBBB) with documentation of LAD system culprit lesion)
6. Patient provides written Informed Consent
7. Patient and his/her physician agree to all required follow-up procedures and visits

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8. Women of childbearing potential who have a negative pregnancy test (applies to female patients only)

Angiographic Inclusion Criteria: Evaluated after the subject provided signed Informed Consent but prior to randomization:

9. Based on coronary anatomy, PCI is indicated for culprit lesion with anticipated use of an Intra-Coronary Stent
10. TIMI 0, I, or II flow is present on the initial angiographic injection of the infarct-related artery
11. Successful angioplasty as documented by &lt; 50% diameter residual angiographic stenosis within and associated with the culprit lesion and ≥ TIMI II flow and no major complications such as perforation or shock
12. Documented time of reperfusion is ≤ 6 hours from the documented time of symptom onset

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

Pre PCI:

1. Patients with ventricular pseudoaneurysm, VSD, or papillary muscle rupture.
2. Absolute contraindications to anticoagulant therapy, including hemorrhagic diathesis or thrombocytopenia
3. Systemic Arterial pO₂ is &lt; 80 mmHg with supplemental oxygen
4. Placement of an intra-aortic balloon pump (IABP)
5. Patient has had coronary bypass surgery during the 30 day period preceding PCI
6. Severe known cardiac valvular stenosis or insufficiency, pericardial disease, or non-ischemic cardiomyopathy
7. Patients requiring cardiopulmonary resuscitation for &gt; 10 minutes
8. Cardiogenic shock (SBP &lt; 80 mm Hg for more than 30 minutes unresponsive to fluids or requiring intravenous pressors or placement of an IABP)
9. Expected survival of less than 6 months due to non-cardiac condition
10. Current participation in other investigational device or drug trials that have not finished the primary efficacy endpoint follow-up parameters
11. Patient has had a hemorrhagic stroke during the 6 month period preceding PCI
12. Physician discretion regarding unacceptability for enrollment

Angiographic Exclusion Criteria: Evaluated after the subject provided signed Informed Consent but prior to randomization:

13. Any proximal coronary diameter stenosis &gt; 40% that would restrict native flow with the infusion catheter in place

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14. Infarct-related vessels that are either saphenous vein grafts and/or small second order coronary vessels that do not supply significant areas of myocardium
15. Presence of a non-stented coronary dissection upon completion of the PCI procedure
16. Unprotected left main diameter stenosis &gt; 60%
17. Severe target vessel calcification or tortuosity
18. Multi - vessel disease that in the judgment of the investigator is best treated with emergent or urgent CABG or additional PCI within 30 days
19. In the investigator's opinion, the target vessel is unsuitable for either placing the infusion catheter or treatment with PCI.

# 2. Follow-up Schedule

Arterial blood gas (ABG) readings were taken before and during $\mathrm{SSO_2}$ Therapy administration in order to ensure adequate blood oxygenation for the procedure. Routine physiological parameters including blood pressure, ACT levels, and heart rate and rhythm measurements were taken immediately after completion of PCI for all patients and at 30, 60, and 90 minutes during $\mathrm{SSO_2}$ infusion for the $\mathrm{SSO_2}$ Therapy group. Cardiac enzyme levels and diagnostic information were collected from blood samples obtained at 8, 16 and 24 hours post-PCI. Table 6 summarizes the required schedule for AMIHOT II study assessments.

Table 6. AMIHOT II Study Assessments

| | H&P/Consent | 24-Hour ECG | Angiogram | Blood Labs | Blood Pressure | Arterial Blood Gas (ABG) | Heart rate/rhythm | ACT | Sestamibi Imaging | Follow-up Visit | Telephone Survey |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| Enrollment Screening/Baseline | ♥ | CONTINUOUS | | | | ♥ | | | | | |
| Pre-PCI/Stent | | | ♥ | ♥ | | | | ♥ | | | |
| Post PCI/Stent | | | ♥ | ♥ | ♥ | ♥ | ♥ | ♥ | | | |
| 30 min. SSO2Infusion | | | | | ♥ | ♥ | ♥ | ♥ | | | |
| 60 min. SSO2Infusion | | | | | ♥ | ♥ | ♥ | ♥ | | | |
| 90 min. SSO2Infusion | | | | | ♥ | ♥ | ♥ | ♥ | | | |
| 8 hours ± 2 hours | | | | ♥ | | | | | | | |
| 16 hours± 2 hours | | | | ♥ | | | | | | | |
| 24 hours± 2 hours | | | | ♥ | | | | | | | |
| 14 days± 7 days | | | | | | | | | ♥ | | |
| 30 days +15 days | | | | | | | | | ♥ | | |

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| | H&P/Consent | 24-Hour ECG | Angiogram | Blood Labs | Blood Pressure | Arterial Blood Gas (ABG) | Heart rate/rhythm | ACT | Sestamibi Imaging | Follow-up Visit | Telephone Survey |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| 6 months±30 days | | | | | | | | | | | ▼ |
| 12 months± 30 days | | | | | | | | | | | ▼ |

Shaded fields do not apply to Control subjects

## 3. Clinical Endpoints

The Primary Effectiveness Endpoint was infarct size as measured by percent of left ventricular mass, assessed by Tc-99m Sestamibi SPECT imaging at 14 days post PCI/stenting. The primary effectiveness endpoint was evaluated using a pre-specified superiority hypothesis.

The Primary Safety Endpoint was a composite safety endpoint based on the incidence of death, reinfarction, target vessel revascularization, and stroke occurring less than or equal to one month (30 days) after enrollment or until hospital discharge, whichever is later. The composite primary safety endpoint was evaluated using a pre-specified non-inferiority hypothesis. All Serious Adverse Events (regardless of device-relatedness) were reported.

Infarct size was measured by Tc-99 sestamibi SPECT imaging at 14(±7) days by the independent SPECT core laboratory at the Mayo Clinic (Rochester, MN). Primary safety endpoint adjudication was performed by the independent Clinical Events Committee (CEC).

The AMIHOT II trial had a Bayesian statistical design that allows for the informed borrowing of data from the previously completed AMIHOT I trial. The AMIHOT I trial examined both inferior and anterior AMI patients treated within 24 hours. The Bayesian statistical model was pre-specified; the model required that the posterior probability for success to be greater than 95.0% for both the primary effectiveness and safety endpoints. An unbalanced randomization ration of 2.8:1 (SSO₂ Therapy: Control) was utilized to satisfy the power requirements of the statistical model.

## B. Accountability of PMA Cohort

A total of 301 patients enrolled in the AMIHOT II study, 222 patients randomized to the SSO₂ Therapy group and 79 patients to the Control group.

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# C. Study Population Demographic and Baseline Characteristics

Tables 7 and 8, shown below, display median data for baseline patient characteristics and catheterization laboratory procedural results. Angiographic data were evaluated by an independent core laboratory, the Cardiology Research Foundation (CRF).

Table 7. AMIHOT II Baseline Patient Characteristics

| | Control Group (N=79) | SSO2 Therapy Group (N=222) |
| --- | --- | --- |
| Age (years) | 59 | 60 |
| Male | 87.3% | 77.9% |
| Diabetes | 13.9% | 16.2% |
| Hypertension | 45.6% | 46.9% |
| Hyperlipidemia | 43.0% | 45.1% |
| Current Smoking | 43.0% | 38.3% |
| Prior Myocardial Infarction | 8.9% | 9.0% |
| Prior PCI of target vessel | 10.1% | 5.9% |

The patient population treated in the AMIHOT clinical trials is comparable to a typical acute myocardial infarction clinical trial population, in terms of age and gender breakdowns.

Table 8. AMIHOT II Cardiac Catheterization Laboratory Procedural Results (pre-randomization)

| | Control Group (N=79) | SSO2 Therapy Group (N=222) |
| --- | --- | --- |
| Time intervals (min): | | |
| Symptom Onset to ER arrival | 90 | 110 |
| Door to Balloon | 75 | 77 |
| Symptom Onset to reperfusion | 171 | 195 |
| Infarct lesion location: | | |
| Proximal LAD** | 46.8% | 47.7% |
| Mid LAD | 51.9% | 49.1% |
| Distal LAD | 0% | 2.3% |
| Diagonal branch of LAD | 1.3% | 0.9% |
| LVEF % | 40 | 40 |
| Stent implanted | 97.5% | 99.1% |
| Glycoprotein IIb/IIIa inhibitor use | 64.6% | 68.0% |
| Rescue PCI (failed thrombolytics) | 8.9% | 5.0% |
| TIMI flow pre-PCI:*** | | |
| 0/1 | 69.9% | 75.5% |
| 2 | 13.7% | 17.1% |

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| | Control Group (N=79) | SSO2 Therapy Group (N=222) |
| --- | --- | --- |
| 3 | 16.4% | 7.4% |
| TIMI flow post-PCI:*** | | |
| 0/1 | 2.8% | 1.4% |
| 2 | 4.2% | 10.2% |
| 3 | 93.0% | 88.4% |

**LAD = left anterior descending coronary artery
***as determined by independent angiographic core laboratory

Table 8 shows that the study groups are well matched in terms of catheterization laboratory procedural characteristics as well. Time interval data for door-to-balloon, symptom onset to emergency room arrival, and symptom onset to reperfusion times are longer for the $\mathrm{SSO}_2$ Therapy group. Other procedural characteristics, including infarct lesion location, baseline left ventricular ejection fraction (LVEF), stent implantation, and incidence of rescue PCI cases showed similarity between the study groups. TIMI Grade 3 flow was more prevalent in the Control group pre-PCI, while Grade 0/1 flow was more prevalent in the $\mathrm{SSO}_2$ arm. TIMI Grade 3 flow was more prevalent in the Control arm after PCI.

# D. Safety and Effectiveness Results

# a. Effectiveness

The AMIHOT II study results demonstrated superiority of $\mathrm{SSO}_2$ Therapy compared to Control in median infarct size (26.5% of the left ventricular mass in the Control group; 20.0% in the $\mathrm{SSO}_2$ Therapy group). The Bayesian posterior probability of superiority is 95.1% for study success based on an analysis of available data; when the study results for missing data were imputed using pre-specified methods, the posterior probability of superiority is 96.9%. These results are shown below in Table 9.

Table 9. Infarct Size at 14 Days (% of Left Ventricle), Bayesian Evaluation of Primary Endpoint, Sensitivity of Imputation Methods†: Pre-specified Model (infarct size values presented on log-transformed scale with mean and standard error (SE))

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| | Control Group (mean ± SE) (n§) | AO Therapy Group (mean ± SE) (n§) | Difference# (± SE) | Posterior Probability of Superiority* |
| --- | --- | --- | --- | --- |
| ITT Analysis | | | | |
| No imputation (available data) | 3.42 ± 0.06 (n=52/68; 72) | 3.30 ± 0.04 (n=49/71; 209) | -0.12 ± 0.07 | 95.1% |
| 1stOrder Imputation | 3.42 ± 0.06 (n=53/79; 79) | 3.30 ± 0.04 (n=52/81; 222) | -0.12 ± 0.07 | 95.5% |
| 2ndOrder Imputation | 3.43 ± 0.06 (n=53/79; 79) | 3.30 ± 0.04 (n=52/81; 222) | -0.13 ± 0.07 | 96.9% |
| PP Analysis‡ | 3.40 ± 0.06 (n=52/68; 69) | 3.28 ± 0.04 (n=44/65; 175) | -0.12 ± 0.07 | 95.2% |

$^{\dagger}$ Analysis performed three ways: No imputation, $1^{\text{st}}$ order imputation, $2^{\text{nd}}$ order imputation methods
$^{\ddagger}$ No imputation (available data)
$^{\S}$ Sample size for Bayesian Evaluation given as $(\mathrm{x} / \mathrm{y};\mathrm{z})$ where $\mathbf{x} =$ number of Anterior $\leq 6$ hours in AMIHOT I, $\mathrm{y} =$ number of other subjects in AMIHOT I and $\mathrm{z} =$ number of subjects in AMIHOT II (all Anterior $\leq 6$ hours).
Posterior mean difference between AO and Control groups incorporating data from AMIHOT I study into the hierarchical model.
*Posterior probability that the average AO Therapy Group infarct size is smaller than the Control Group infarct size.

Table 10 shows the AMIHOT II infarct size results by group, and for key subgroups.

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Table 10. Infarct Size at 14 Days (% of Left Ventricle), Evaluation of Infarct Size for AMIHOT II ITT Analysis† (infarct size values presented as median data with interquartile range (IQR))

| | Control Group (n=79) (median ± IQR) (n) | SSO2 Therapy Group (n=222) (median ± IQR) (n) |
| --- | --- | --- |
| All Patients | 26.5 ± 35.5 (n=72) | 20 ± 31 (n=209) |
| Time strata (randomized) | | |
| 0 – 3 hrs to reperfusion | 31 ± 35 (n=37) | 15.5 ± 30.5 (n=96) |
| > 3 hrs to reperfusion | 24 ± 35 (n=35) | 24 ± 30 (n=113) |
| Time strata (actual) | | |
| 0 – 3 hrs to reperfusion | 32 ± 35 (n=41) | 14 ± 27 (n=88) |
| > 3 hrs to reperfusion | 21 ± 30 (n=31) | 26 ± 32 (n=121) |
| Infarct location (randomized) | | |
| Proximal LAD | 28 ± 37 (n=35) | 25 ± 32 (n=117) |
| Non-proximal LAD | 23 ± 35 (37) | 14 ± 28 (n=92) |
| Infarct location (actual) | | |
| Proximal LAD | 29.5 ± 36 (n=34) | 30 ± 33.5 (n=100) |
| Non-proximal LAD | 21.5 ± 30 (n=38) | 14 ± 26 (n=109) |
| Age | | |
| Age < 60 (median) | 20 ± 35 (n=42) | 21 ± 30 (n=101) |
| Age ≥ 60 (median) | 29.5 ± 36 (n=30) | 19 ± 32 (n=108) |
| Gender | | |
| Male | 24 ± 36 (n=65) | 20 ± 31 (n=167) |
| Female | 38 ± 27 (n=7) | 20.5 ± 23 (n=42) |
| Prior Myocardial Infarction | | |
| Prior MI | 37 ± 39 (n=6) | 32 ± 32 (n=19) |
| No Prior MI | 24 ± 36 (n=65) | 19 ± 29 (n=189) |
| Diabetes | | |
| Diabetic (Type I or II) | 20 ± 39 (n=10) | 21 ± 26.5 (n=32) |
| Non-diabetic | 28 ± 35 (n=61) | 19.5 ± 31 (n=172) |

†Available data for ITT patients analyzed as per Statistical Analysis Plan

## b. Safety

The primary safety endpoint evaluated for non-inferiority using a Bayesian hierarchical model that considered 30-day MACE data from the AMIHOT I and II studies. The primary safety analysis demonstrated statistical non-inferiority, with the Bayesian posterior probability of non-inferiority being 99.5%, successfully achieving the study endpoint. In the AMIHOT II trial, the 30-day MACE rates were 3.8% in the Control group and 5.4% in the SSO₂ group. The MACE component rate data are displayed in Table 11.

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Table 11. AMIHOT II 30-day MACE Rates

| Group | Death | Reinfarction | TVR | Stroke | Composite MACE
# Patients (%) |
| --- | --- | --- | --- | --- | --- |
| Control (n = 79) | 0 | 2 | 3 | 0 | 3 (3.8%) |
| SSO_{2} Therapy (n = 222) | 4 | 6 | 9 | 0 | 12 (5.4%) |

Overall 30-day adverse event data for the AMIHOT II trial are presented in Table 12.

During the 30-day follow-up period 118/222 (53.2%) patients in the SSO₂ Therapy group and 37/79 (46.8%) patients in the Control group experienced one or more adverse events. SSO₂ Therapy subjects received an additional 90 minutes of catheterization time, were administered increased anticoagulation therapy (heparin), and required either a larger single arterial access sheath or a second femoral arterial access site. These factors may have contributed to the higher adverse events rate observed in the SSO₂ arm (Table 12).

Table 12. AMIHOT II Overall Summary of Adjudicated Adverse Events within 30 days

| | Randomization Group | | | |
| --- | --- | --- | --- | --- |
| | Control (N=79) | | SSO_{2} Therapy (N=222) | |
| Adverse Event (AE) | # of Events | # (%) of Pts with Events | # of Events | # (%) of Pts with Events |
| Any Adverse Event | 58 | 37 (46.8%) | 255 | 118 (53.2%) |
| SSO_{2} device related AE | | | 0 | 0 (0%) |
| SSO_{2} procedure related AE | | | 45 | 39 (17.6%) |
| Index PCI procedure related AE | 16 | 14 (17.7%) | 43 | 34 (15.3%) |
| Coronary Artery Disease related AE | 23 | 17 (21.5%) | 94 | 64 (28.8%) |
| Study Medication related AE | 0 | 0 (0%) | 1 | 1 (0.5%) |
| Other relationship* | 18 | 15 (19.0%) | 63 | 47 (21.2%) |
| Unknown relationship | 1 | 1 (1.3%) | 9 | 9 (4.1%) |
| Serious Adverse Event (SAE) | 19 | 15 (19.0%) | 89 | 57 (25.7%) |
| SSO_{2} device related SAE | | | 0 | 0 (0%) |
| SSO_{2} procedure related SAE | | | 17 | 14 (6.3%) |
| Index PCI procedure related SAE | 4 | 4 (5.1%) | 17 | 14 (6.3%) |
| Coronary Artery Disease related SAE | 9 | 8 (10.1%) | 42 | 32 (14.4%) |
| Study Medication related SAE | 0 | 0 (0%) | 0 | 0 (0%) |
| Other relationship* | 6 | 5 (6.3%) | 10 | 10 (4.5%) |

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| | Randomization Group | | | |
| --- | --- | --- | --- | --- |
| | Control (N=79) | | SSO2 Therapy (N=222) | |
| Adverse Event (AE) | # of Events | # (%) of Pts with Events | # of Events | # (%) of Pts with Events |
| Unknown relationship | 0 | 0 (0%) | 3 | 3 (1.4%) |
| Adverse Event related to AMIHOT II Vessel | 8 | 5 (6.3%) | 26 | 20 (9.0%) |
| *Including pre-existing condition, concurrent condition, concurrent intervention and other relationships | | | | |

Table 13 summarizes bleeding events within 30 days by comparing the two study groups. These events were adjudicated by the Clinical Events Committee and categorized as follows:

Mild: Bleeding that does not require transfusion or result in hemodynamic compromise
Moderate: Bleeding requiring transfusion that is defined as any blood loss requiring transfusion of blood products
Severe: Intracranial bleeding or bleeding that results in substantial hemodynamic compromise requiring treatment

An increase in all bleeding events was observed in the $\mathrm{SSO}_2$ Therapy group as compared to the Control group (24.3% vs. 12.7%).

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Table 13. AMIHOT II 30-day Bleeding Events by Severity

| | | | Randomization Group | | | |
| --- | --- | --- | --- | --- | --- | --- |
| | | | Control (N=79) | | SSO2 Therapy (N=222) | |
| Location | Bleeding Category | Adverse Event | # of Events | n (%) of Pts with Events | # of Events | n (%) of Pts with Events |
| All Bleeding Events | | | 10 | 10 (12.7%) | 57 | 54 (24.3%) |
| All Severe/Life Threatening Bleeding Events | | | 1 | 1 (1.3%) | 3 | 3 (1.4%) |
| Access Site | | | 9 | 9 (11.4%) | 41 | 41 (18.5%) |
| | Mild | Catheter site hematoma | 8 | 8 (10.1%) | 34 | 34 (15.3%) |
| | Moderate | Catheter site hematoma | 0 | 0 (0%) | 5 | 5 (2.3%) |
| | | Catheter site hemorrhage | 0 | 0 (0%) | 1 | 1 (0.5%) |
| | Severe | Catheter site hemorrhage | 1 | 1 (1.3%) | 0 | 0 (0%) |
| | | Retroperitoneal hemorrhage | 0 | 0 (0%) | 1 | 1 (0.5%) |
| Non-Access Site | | | 1 | 1 (1.3%) | 16 | 15 (6.8%) |
| | Mild | Anemia | 0 | 0 (0%) | 5 | 5 (2.3%) |
| | | Hematuria | 0 | 0 (0%) | 1 | 1 (0.5%) |
| | | Implant site hematoma | 0 | 0 (0%) | 1 | 1 (0.5%) |
| | | Urogenital hemorrhage | 0 | 0 (0%) | 1 | 1 (0.5%) |
| | Moderate | Anemia | 1 | 1 (1.3%) | 1 | 1 (0.5%) |
| | | Hemorrhage | 0 | 0 (0%) | 4 | 4 (1.8%) |
| | | Traumatic hematoma | 0 | 0 (0%) | 1 | 1 (0.5%) |
| | Severe | Cardiac tamponade | 0 | 0 (0%) | 1 | 1 (0.5%) |
| | | Hematuria | 0 | 0 (0%) | 1 | 1 (0.5%) |
| Events Requiring Transfusion | | | 1 | 1 (1.3%) | 14 | 14 (6.3%) |

In addition to bleeding, the adverse events of death, myocardial rupture, and stent thrombosis Were also higher in the $\mathrm{SSO}_2$ arm of AMIHOT II (Table 14).

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Table 14. Safety Events of Interest (AMIHOT II)

| Event | Control Group (n=79) n (%) | SSO2 Therapy Group (n=222) n (%) |
| --- | --- | --- |
| Death | 0 (0.0%) | 4 (1.8%) |
| Myocardial Rupture | 0 (0.0%) | 2 (0.9%) |
| Stent thrombosis | 2 (2.5%) | 9 (4.1%) |
| Bleeding (any) | 10 (12.7%) | 54 (24.3%) |

After completing improvements to the hardware console and simplifying the catheter delivery system, additional data for $\mathrm{SSO}_2$ Therapy was obtained from follow-up clinical studies.

## IC-HOT Clinical Trial

The IC-HOT clinical trial was designed to confirm the safety and efficacy results of $\mathrm{SSO}_2$ Therapy in 100-patient IDE study in the target patient population.

## A. Study Design

Patients were treated between February 16, 2016 and May 2, 2017. The data were collected through May 17, 2018 and included 100 patients. There were 15 investigational sites.

IC-HOT was a non-randomized, single-arm study. Subjects with anterior STEMI requiring stent placement in the proximal and/or mid LAD who met all inclusion and exclusion criteria were treated with primary PCI with stenting; if successful and uncomplicated, PCI with stenting was immediately followed with post-procedure delivery of $\mathrm{SSO}_2$ Therapy for a duration of 60 minutes.

An independent Clinical Events Committee (CEC) reviewed and adjudicated all key, pre-specified adverse events.

An independent Data Safety Monitoring Board (DSMB) reviewed and assessed overall study safety both during and at the conclusion of the study.

The Cardiovascular Research Foundation’s Angiographic and MRI Core Laboratories evaluated patient angiographic and MRI scan data for the IC-HOT study.

### 1. Clinical Inclusion and Exclusion Criteria

Candidates in the IC-HOT study must have met ALL the following general inclusion criteria:

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# Pre-PCI:

1. The subject must be ≥18 and ≤80 years of age.
2. AMI must be anterior (ST-segment elevation ≥1 mm in two or more contiguous leads between V1 and V4 or new left bundle branch block).
3. Subject is experiencing clinical symptoms consistent with acute MI of ≤6 hour duration from time of symptom onset until admission to the emergency room.
4. The subject or legally authorized representative has been informed of the nature of the study, agrees to its provisions and has been provided and signed written informed consent, approved by the appropriate Institutional Review Board (IRB).
5. Subject and his/her physician agree to all required follow-up procedures and visits.

Angiographic Inclusion Criteria: Evaluated after the subject provided signed Informed Consent but prior to enrollment:

6. Based on coronary anatomy, PCI is indicated for revascularization of the culprit lesion(s) with use of a commercially available coronary stent (bare metal or drug-eluting, at operator discretion) in the LAD.
7. The primary stented infarct-related lesion(s) must be in the proximal and/or mid-LAD coronary artery (other lesions in the LAD target vessel, including diagonal branches, may be treated if clinically indicated).
8. Baseline (pre-PCI) TIMI flow grade 0, 1, 2, or 3 flow in the LAD.
9. Successful angioplasty is completed ≤6 hrs from symptom onset, as documented by &lt;50% diameter residual angiographic stenosis within all treated culprit lesions with TIMI 2 or 3 flow and no major complications such as perforation or shock.
10. Expected ability to place the SSO₂ delivery catheter in the coronary ostium of the left main coronary system to deliver SSO₂ Therapy with stable, coaxial alignment.

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

# Pre-PCI:

1. Prior CABG surgery.
2. Prior myocardial infarction, or known prior systolic dysfunction (known ejection fraction &lt;40% by any prior measure or regional wall motion abnormalities; this criterion does not include left ventricular dysfunction induced by the acute MI).
3. Thrombolytic therapy administered for this STEMI.
4. An elective surgical procedure is planned that would necessitate interruption of anti-platelet agents during the first 30 days post-enrollment.
5. Subjects who previously underwent coronary stent implantation and in whom coronary angiography demonstrates stent thrombosis to be the cause of the anterior AMI.

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6. Subjects who have previously undergone an angioplasty or stenting procedure in the left anterior descending coronary artery.
7. Subjects with ventricular pseudoaneurysm, VSD, or severe mitral valve regurgitation (with or without papillary muscle rupture).
8. Any contraindication to MRI imaging. This will include any of the following exclusions:

a. Cardiac pacemaker or implantable defibrillator;
b. Non-MRI compatible aneurysm clip;
c. Neural Stimulator (i.e., TENS unit);
d. Any implanted or magnetically activated device (insulin pump);
e. Any type of non-MRI compatible ear implant;
f. Metal shavings in the orbits;
g. Any metallic foreign body, shrapnel, or bullet in a location which the physician feels would present a risk to the subject;
h. Any history indicating contraindication to MRI, including claustrophobia or allergy to gadolinium;
i. Inability to follow breath hold instructions or to maintain a breath hold for &gt;15 seconds; and
j. Known hypersensitivity or contraindication to gadolinium contrast.

9. Known impaired renal function (creatinine clearance &lt;30 ml/min/1.73 m² by the MDRD formula) or on dialysis.
10. Known platelet count &lt;100,000 cells/mm³ or &gt;700,000 cells/mm³ or a known Hgb &lt;10 g/dL.
11. Subject has active bleeding or a history of bleeding diathesis or coagulopathy (including heparin induced thrombocytopenia), or refusal to receive blood transfusions if necessary.
12. History of intracerebral mass, aneurysm, arteriovenous malformation, or hemorrhagic stroke.
13. Stroke or transient ischemic attack within the past six (6) months, or any permanent neurological defect.
14. Gastrointestinal or genitourinary bleeding within the last two (2) months, or any major surgery (including CABG) within six weeks of enrollment.
15. Subject has received any organ transplant or is on a waiting list for any organ transplant.
16. Subject has other medical illness (e.g., cancer, dementia) or known history of substance abuse (alcohol, cocaine, heroin, etc.) that may cause non-compliance with the protocol, confound the data interpretation, or is associated with limited life expectancy of less than one year.
17. Subject has a known hypersensitivity or contraindication to unfractionated heparin, abciximab, aspirin, bivalirudin, cangrelor, clopidogrel, ticlopidine, prasugrel, eptifibatide, tirofiban or ticagrelor that cannot be adequately premeditated.

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18. Current use of warfarin, dabigatran, or factor Xa inhibitors, or known intent to administer these agents after the primary PCI.

19. Subjects presenting with or developing in the cath lab prior to completion of the primary PCI procedure any of the following conditions: cardiogenic shock (SBP &lt;80 mmHg for &gt;30 minutes), or requiring IV pressors or emergent placement of an intra-aortic balloon pump (IABP), Impella, or other hemodynamic support for hypotension treatment, or cardiopulmonary resuscitation for &gt;10 minutes, or ventricular fibrillation or tachycardia requiring cardioversion or defibrillation.

20. Severe known cardiac valvular stenosis or insufficiency, pericardial disease, or non-ischemic cardiomyopathy.

21. Any significant medical or social condition which in the investigator’s opinion may interfere with the subject’s participation in the study or ability to comply with follow-up procedures, including MRI (e.g. alcoholism, dementia, lives far from the research center, etc.).

22. Current participation in other investigational device or drug trials.

23. Previous enrollment in this study.

**Angiographic Exclusion Criteria:** Evaluated after the subject provided signed Informed Consent but prior to enrollment:

24. Anticipated inability to achieve a stable coaxial position in the left main coronary artery with the SSO₂ delivery catheter.

25. Treatment during the index procedure of any lesion in either the left main, LCX (including the ramus), and/or RCA.

26. Post-index procedure planned intervention within 30 days (i.e., PCI of non-target lesions in any vessel, or CABG). Note: Planned revascularization (PCI or bypass) of a non-target lesion &gt;30 days following the index procedure is allowed.

27. Anterior MI is due to thrombosis within or adjacent to a previously implanted stent.

28. Left ventriculography demonstrates severe mitral regurgitation, a ventricular septal defect, or a pseudoaneurysm.

29. Any left main coronary artery stenosis &gt;20%.

30. Any untreated LAD or diagonal branch lesion is present with diameter stenosis ≥ 50% in a vessel with reference vessel diameter &gt; 2.0 mm (visually estimated), or for which PCI will be required before the MRI study.

31. Presence of a non-stented coronary dissection with NHLBI grade ≥B upon completion of the PCI procedure.

2. **Follow-up Schedule**

Baseline, procedural, post-procedure, in-hospital, and 30-day clinical follow-up were performed. Cardiac MRI was performed at 4 (±1) days and at 30 days (±7 days) to collect device effectiveness data. Primary data collection including adverse event reporting was through 30 days; patient safety was tracked and reported through one year.

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The IC-HOT schedule of study assessments is presented in Table 15.

Table 15. Schedule of IC-HOT Assessments

| PROCEDURE / TEST | Pre-PCI - Stent | PCI / Stent Procedure | Post-PCI / Stent | Baseline SSO2 | 30 min SSO2 | 60 min SSO2 | 60 (±30) min post-SSO2 | 12 (±2) hrs | 24 (±2) hrs | Cardiac MRI (4 ± 1 days) | 30 (±7) days | 6 and 12 mos (±30 days) |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| Subject Medical / Clinical History / Physical Exam | ✓ | | | | | | | | | | | |
| Subject Informed Consent | ✓ | | | | | | | | | | | |
| General Inclusion / Exclusion Criteria | ✓ | | | | | | | | | | | |
| Angiographic Inclusion / Exclusion Criteria | | | ✓ | | | | | | | | | |
| Cardiac Enzymes: CK, CK-MB, and Troponin | ✓ | | | | | | | ✓ | ✓ | ✓1 | | |
| Arterial blood gas | | | | ✓ | | | | | | | | |
| WBC, hemoglobin, creatinine, platelet count | ✓8 | | | | | | | | ✓2 | | | |
| Cardiac MRI | | | | | | | | | | ✓3 | ✓4 | |
| HR, BP | ✓ | ✓ | ✓ | ✓ | ✓ | ✓ | | | | | | |
| ECG | ✓ | | | | | | ✓5 | | | ✓ | ✓ | |
| Anticoagulation (per protocol) | ✓ | | | | | | | | | | | |
| Antiplatelet loading dose | ✓ | | | | | | | | | | | |
| Cardiac cath lab procedures and information | | ✓ | | | | | | | | | | |
| Cine angiogram w/o contrast of angiographic delivery catheter | | | | ✓ | ✓ | ✓ | | | | | | |
| Coronary angiogram with TIMI flow grade assessment | ✓ | ✓6 | ✓ | | | ✓ | | | | | | |
| ACT (per protocol) | | ✓ | | ✓ | ✓9 | ✓ | | | | | | |
| SSO2 Therapy Procedure | | | ✓ | ✓ | ✓ | ✓ | | | | | | |
| Per Protocol Medications | ✓ | ✓ | ✓ | ✓ | ✓ | ✓ | | ✓ | | | ✓ | ✓ |
| Dual Antiplatelet Medication | ✓ | ✓ | ✓ | | | | | ✓7 | | | ✓7 | ✓ |
| Concomitant Cardiac Medications | ✓ | ✓ | ✓ | ✓ | ✓ | ✓ | | ✓ | | | ✓ | ✓ |
| Adverse Events | | | | ✓ | ✓ | ✓ | ✓ | ✓ | ✓ | ✓ | ✓ | ✓ |

# 3. Clinical Endpoints

The primary endpoint for the IC-HOT study evaluated safety, using the 30-day rate of the composite Net Adverse Clinical Events (NACE). NACE events were the following:

Death (all-cause)
Reinfarction
- Target Vessel Revascularization (clinically driven)
- TIMI major or minor bleeding
- New onset severe heart failure or rehospitalization for heart failure
- Stent thrombosis (ARC definite or probable)

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This composite endpoint includes safety categories that are of significance in contemporary AMI studies. The IC-HOT study used well-established clinical event definitions for the component NACE event categories.

The threshold for assessing success of the Primary Endpoint was that the observed 30-day NACE rate in IC-HOT be no greater than the 30-day NACE rate observed in the control arm of a contemporaneous study, INFUSE-AMI¹. The INFUSE-AMI study included a similar population of anterior wall STEMI patients with anticipated time to reperfusion less than five hours. INFUSE-AMI included a 2×2 treatment matrix with subjects receiving PCI w/stenting standard of care, with or without intracoronary abciximab and with or without intracoronary aspiration. The threshold rate of 10.7% was derived from a post hoc analysis of 112 INFUSE-AMI control subjects who had received neither aspiration nor intracoronary abciximab.

In addition, the specific 30-day NACE event categories of death, stent thrombosis, myocardial rupture, and bleeding were examined as individual events. Table 16 below shows FDA-recommended 30-day event rate benchmarks for these individual adverse events.

Table 16. FDA Guidelines for Acceptable Adverse Event Rates
| 30-Day NACE Event | IC-HOT Trial
FDA Guideline |
| --- | --- |
| Death | ≤3.0% |
| Stent Thrombosis | ≤3.0% |
| Myocardial Rupture | ≤1.0% |
| TIMI Major and Minor Bleeding | ≤3.0% |

## B. Accountability of the PMA Cohort

At the time of database lock, of the 100 patients enrolled in the IC-HOT study, 100% (n=100) of patients were available for analysis at the completion of the study, the 30-day post-procedural visit.

## C. Study Population Demographics and Baseline Characteristics

The patient baseline characteristics shown in Table 17 are consistent with an anterior STEMI population and the previously conducted AMIHOT II study.

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Table 17. IC-HOT Baseline Patient Characteristics

| | SSO2 Therapy Group (N=100) |
| --- | --- |
| Age (years) | 59.5 |
| Male | 83% |
| Diabetes | 26% |
| Hypertension | 55% |
| Hyperlipidemia | 51% |
| Current Smoking | 41% |

# D. Safety and Effectiveness Results

As shown in Table 18, IC-HOT had a median door-to-balloon time of $62\mathrm{min}$ and a median time from symptom onset to reperfusion of $138.5\mathrm{min}$ . Patients were evenly distributed between proximal or mid-LAD target lesion location. Angiographic core laboratory analysis of TIMI flow grade data showed that $16.2\%$ of subjects remained with TIMI Grade 2 flow after PCI and stenting.

Table 18. IC-HOT Cardiac Catheterization Laboratory Procedural Results (pre-enrollment)

| | SSO2 Therapy Group (N=100) |
| --- | --- |
| Time intervals (min): | |
| Symptom Onset to ER arrival | 67.5 |
| Door to Balloon | 62.0 |
| Symptom Onset to reperfusion | 138.5 |
| Infarct lesion location: | |
| Proximal LAD** | 44.6% |
| Mid LAD | 55.4% |
| Stent implanted | 100% |
| Glycoprotein IIb/IIIa inhibitor use | 46.0% |
| TIMI flow pre-PCI:*** | |
| 0/1 | 60.0% |
| 2 | 30.0% |
| 3 | 10.0% |
| TIMI flow post-PCI:*** | |
| 0/1 | 0.0% |
| 2 | 16.2% |
| 3 | 83.8% |

**LAD = left anterior descending coronary artery
***as determined by independent angiographic core laboratory

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# 1. Safety Results

The results for the primary composite safety endpoint (Table 19) show that $7.1\%$ (7/98) of subjects experienced a qualifying NACE event within 30 days of the index procedure (two subjects were lost to follow up). The point estimate of NACE rate was below the threshold limit of $10.7\%$ .

Table 19. IC-HOT 30-Day Net Adverse Clinical Events (NACE) - CEC Adjudicated

| Parameter | SSO2Therapy n/N (%) (N=100*) |
| --- | --- |
| NACE (death, reinfarction, clinically-driven target vessel revascularization, stent thrombosis (ARC definite or probable), new onset heart failure or readmission for heart failure, or TIMI major or minor bleeding) | 7/98 (7.1%) |
| | |
| Death | 0/98 (0.0%) |
| Cardiac | 0/98 (0.0%) |
| Vascular | 0/98 (0.0%) |
| Non-Cardiovascular | 0/98 (0.0%) |
| | |
| Reinfarction/Spontaneous | 1/98 (1.0%) |
| STEMI/NSTEMI | 1/98 (1.0%) |
| STEMI | 0/98 (0.0%) |
| NSTEMI | 1/98 (1.0%) |
| Undetermined | 0/98 (0.0%) |
| | |
| Q-wave/Non-Q-wave | 1/98 (1.0%) |
| Q-wave | 0/98 (0.0%) |
| Non-Q-wave | 1/98 (1.0%) |
| Undetermined | 0/98 (0.0%) |
| | |
| MI In the optimized SSO2therapy region (Target Vessel) | |
| In the optimized SSO2therapy region | 0/98 (0.0%) |
| Not in the optimized SSO2therapy region | 1/98 (1.0%) |
| Undetermined | 0/98 (0.0%) |
| | |
| Clinically Driven Target Vessel Revascularization (TVR) | 1/98 (1.0%) |
| PCI | 1/98 (1.0%) |
| CABG | 0/98 (0.0%) |
| | |

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| Parameter | SSO2 Therapy n/N (%) (N=100*) |
| --- | --- |
| Clinically Driven Target Lesion Revascularization (TLR) | 1/98 (1.0%) |
| PCI | 1/98 (1.0%) |
| CABG | 0/98 (0.0%) |
| | |
| Clinically Driven Target Vessel/Non-Target Lesion Revascularization (TVR/NTLR) | 1/98 (1.0%) |
| PCI | 1/98 (1.0%) |
| CABG | 0/98 (0.0%) |
| | |
| TIMI major or minor Bleeding | 4/98 (4.1%) |
| Minor | 4/98 (4.1%) |
| Major | 0/98 (0.0%) |
| | |
| New onset severe heart failure or re-hospitalization for heart failure | 1/98 (1.0%) |
| New onset heart failure | 1/98 (1.0%) |
| Required hospitalization | 1/98 (1.0%) |
| Re-hospitalization for previous heart failure | 0/98 (0.0%) |
| | |
| ARC Definite/Probable Stent Thrombosis | 1/98 (1.0%) |
| Acute | 1/98 (1.0%) |
| Definite | 1/98 (1.0%) |
| Probable | 0/98 (0.0%) |
| Subacute | 0/98 (0.0%) |
| Definite | 0/98 (0.0%) |
| Probable | 0/98 (0.0%) |

*2 subjects missed 30-day follow up visits and were unavailable for the 30-day NACE assessment.

A summary of 30-day adverse events (Table 20) shows that $48.0\%$ (48/100) of IC-HOT subjects experienced an adverse event within 30 days. $12.0\%$ (12/100) of subjects experienced a serious adverse event within 30 days. These adverse event and serious adverse event rates were lower than the rates observed in the AMIHOT II: $53.8\%$ and $25.7\%$ for the $\mathrm{SSO}_2$ Therapy arm and $46.8\%$ and $19.0\%$ for the Control arm.

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Table 20. IC-HOT 30-Day Summary of Adverse Events

| Parameter | SSO2 Therapy n/N(%) (N=100) |
| --- | --- |
| Any Adverse Event | 48/100 (48.0%) |
| Non-Serious Adverse Event | 43/100 (43.0%) |
| Serious Adverse Event | 12/100 (12.0%) |
| | |
| Adverse Event Relationship | |
| Related to Device (system/cartridge) | 0/100 (0.0%) |
| Related to SSO2 procedure | 2/100 (2.0%) |
| Related to Index PCI procedure | 7/100 (7.0%) |
| Related to Coronary Artery Disease | 21/100 (21.0%) |
| | |
| Was the adverse event related to the PCI target vessel | 5/100 (5.0%) |
| | |
| Serious Adverse Event Relationship | |
| Related to Device (system/cartridge) | 0/100 (0.0%) |
| Related to SSO2 procedure | 0/100 (0.0%) |
| Related to Index PCI procedure | 3/100 (3.0%) |
| Related to Coronary Artery Disease | 6/100 (6.0%) |
| | |
| Was the adverse event related to the PCI target vessel | 2/100 (2.0%) |

Table 21 provides detail of all 30-day events. Approximately $11.2\%$ of IC-HOT subjects experienced a bleeding event (as compared to $24.3\%$ of AMIHOT II $\mathrm{SSO}_2$ Therapy subjects and $12.7\%$ of AMIHOT II Control subjects). No patients with bleeding events required a transfusion.

Table 21. IC-HOT 30-Day Follow-up Clinical Outcomes

| Parameter | SSO2 Therapy n/N(%) (N=100) |
| --- | --- |
| Death | 0/98 (0.0%) |
| Cardiac | 0/98 (0.0%) |
| Non-Cardiac | 0/98 (0.0%) |
| Unknown | 0/98 (0.0%) |
| | |
| Myocardial Infarction | 1/98 (1.0%) |
| Spontaneous MI | 1/98 (1.0%) |
| Periprocedural MI - PCI | 0/98 (0.0%) |

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| Parameter | SSO2 Therapy n/N(%) (N=100) |
| --- | --- |
| Periprocedural MI - CABG | 0/98 (0.0%) |
| Reinfarction | 0/98 (0.0%) |
| | |
| STEMI | 0/98 (0.0%) |
| NSTEMI | 1/98 (1.0%) |
| Undetermined | 0/98 (0.0%) |
| | |
| Q-wave MI | 0/98 (0.0%) |
| Non-Q-wave MI | 1/98 (1.0%) |
| Undetermined | 0/98 (0.0%) |
| | |
| MI in the Optimized SSO2 Therapy Region | 0/98 (0.0%) |
| | |
| Recurrent ischemic pain >20 minutes unrelieved by NTG | 1/98 (1.0%) |
| ST segment elevation or depression | 1/98 (1.0%) |
| Cardiac enzyme elevations | 1/98 (1.0%) |
| | |
| Repeat Revascularization/Angiography | 5/98 (5.1%) |
| Repeat Angiography only | 4/98 (4.1%) |
| Repeat Revascularization | 1/98 (1.0%) |
| Clinically Driven Target Lesion Revascularization (TLR) | 1/98 (1.0%) |
| PCI | 1/98 (1.0%) |
| CABG | 0/98 (0.0%) |
| | |
| Clinically Driven Target Vessel/Non-Target Lesion Revascularization (TVR/NTLR) | 1/98 (1.0%) |
| PCI | 1/98 (1.0%) |
| CABG | 0/98 (0.0%) |
| | |
| Clinically Driven Non-Target Vessel Revascularization (NTVR) | 0/98 (0.0%) |
| PCI | 0/98 (0.0%) |
| CABG | 0/98 (0.0%) |
| | |
| Stent Thrombosis | 2/98 (2.0%) |
| Acute | 2/98 (2.0%) |
| Subacute | 0/98 (0.0%) |

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| Parameter | SSO2 Therapy n/N(%) (N=100) |
| --- | --- |
| | |
| Definite | 1/98 (1.0%) |
| Probable | 0/98 (0.0%) |
| Possible | 0/98 (0.0%) |
| Non-ARC | 1/98 (1.0%) |
| | |
| Hemorrhagic/Vascular event | 11/98 (11.2%) |
| Hemorrhage | 6/98 (6.1%) |
| Hematoma | 4/98 (4.1%) |
| Tamponade | 0/98 (0.0%) |
| Arteriovenous Fistula | 0/98 (0.0%) |
| Aneurysm/Pseudoaneurysm | 0/98 (0.0%) |
| Myocardial rupture | 0/98 (0.0%) |
| Vascular Damage | 0/98 (0.0%) |
| Peripheral Ischemia | 0/98 (0.0%) |
| Embolism | 0/98 (0.0%) |
| Thrombosis | 0/98 (0.0%) |
| | |
| TIMI Classification | |
| Minimal | 6/98 (6.1%) |
| Minor | 4/98 (4.1%) |
| Major | 0/98 (0.0%) |
| | |
| GUSTO Bleeding Classification | |
| Severe or life threatening | 0/98 (0.0%) |
| Moderate | 0/98 (0.0%) |
| Mild | 10/98 (10.2%) |
| | |
| Suspected Congestive Heart Failure | 10/98 (10.2%) |
| Symptoms (New or Worsening) | |
| Dyspnea | 4/98 (4.1%) |
| Decreased exercise tolerance | 2/98 (2.0%) |
| Fatigue | 3/98 (3.1%) |
| Other symptoms of worsened end-organ perfusion | 6/98 (6.1%) |
| | |
| Signs (New or Worsening) | |
| Peripheral edema | 0/98 (0.0%) |

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| Parameter | SSO2 Therapy n/N(%) (N=100) |
| --- | --- |
| Increasing abdominal distention or ascites | 0/98 (0.0%) |
| Pulmonary rales/crackles/crepitations | 2/98 (2.0%) |
| Increased jugular venous pressure and/or hepatojugular reflux | 2/98 (2.0%) |
| S3 cardiac gallop | 0/98 (0.0%) |
| Clinical significant or rapid weight gain thought to be related to fluid retention | 0/98 (0.0%) |
| | |
| NYHA classification at presentation | |
| I | 3/98 (3.1%) |
| II | 4/98 (4.1%) |
| III | 1/98 (1.0%) |
| IV | 1/98 (1.0%) |
| | |
| Neurologic event | 0/98 (0.0%) |
| Type of injury | |
| Ischemic | 0/98 (0.0%) |
| Hemorrhagic | 0/98 (0.0%) |
| Unknown | 0/98 (0.0%) |

Table 22 displays observed event rates for the pre-specified individual events of interest. The rates of 30-day mortality, stent occlusion, and myocardial rupture were lower than the respective FDA benchmarks. The rate of observed TIMI Major/Minor bleeding was higher than the benchmark; all bleeding events were classified as TIMI Minor.

Table 22. IC-HOT Events of Interest: 30-day Rates

| FDA Recommended Guidelines for Acceptable Adverse Event Rates 30-Day AE | FDA Threshold | IC-HOT 100 Pt. safety study |
| --- | --- | --- |
| Death | 3.0% | 0% (0/98) |
| Stent Occlusion | 3.0% | 1% (1/98) |
| Myocardial Rupture | 1.0% | 0% (0/98) |
| SAE bleeding | 3.0% | 4.1% (4/98) (TIMI Major/Minor Bleeding) |

# 2. Effectiveness Results

Cardiac MRI scans were required by protocol on day 4 (±1) and day 30 (±7).

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# Infarct Size Results

Cardiac MRI data are presented in Table 23 for the day 4 and day 30 scans including the 30-day infarct size results (% of Infarct Mass of Myocardial Mass). The median (Q1, Q3) infarct size (%) was 19.4 (8.8, 28.9). This result is consistent with the AMIHOT II result for median (Q1, Q3) infarct size (%) = 20.0 (6, 37) for the SSO₂ Therapy group.

Table 23. IC-HOT MRI Analysis at 4 and 30 Days (All Treated Subjects Population)

| Parameter | Statistics | Day 4 SSO₂ Therapy (N=88) | Day 30 SSO₂ Therapy (N=87) |
| --- | --- | --- | --- |
| Time from Index Procedure (day) | N | 88 | 87 |
| | Mean ± (StdDev) | 4.0 ± 1.3 | 33.6 ± 12.1 |
| | Median (Q1,Q3) | 4.0 (3.0, 5.0) | 30.0 (29.0, 34.0) |
| | Min,Max | 1.0, 7.0 | 23.0, 113.0 |
| | | | |
| Myocardial Mass (g) | N | 86 | 85 |
| | Mean ± (StdDev) | 129.6 ± 34.4 | 114.0 ± 29.0 |
| | Median (Q1,Q3) | 128.0 (104.0, 149.0) | 112.0 (93.6, 129.0) |
| | Min,Max | 57.0, 249.0 | 57.7, 206.0 |
| | | | |
| Area at Risk (g) | N | 80 | * |
| | Mean ± (StdDev) | 50.3 ± 19.6 | |
| | Median (Q1,Q3) | 51.1 (34.8, 62.0) | |
| | Min,Max | 0.0, 94.2 | |
| | | | |
| % of Area at Risk of Myocardial Mass | N | 80 | * |
| | Mean ± (StdDev) | 39.5 ± 11.8 | |
| | Median (Q1,Q3) | 38.2 (33.3, 47.4) | |
| | Min,Max | 0.0, 63.2 | |
| | | | |
| Salvage Mass (g) | N | 72 | * |
| | Mean ± (StdDev) | 19.9 ± 11.9 | |
| | Median (Q1,Q3) | 18.7 (11.3, 26.4) | |
| | Min,Max | 0.0, 71.0 | |
| | | | |
| Infarct Mass (g) | N | 78 | 85 |
| | Mean ± (StdDev) | 31.2 ± 19.2 | 21.9 ± 15.0 |
| | Median (Q1,Q3) | 29.5 (18.0, 46.9) | 20.6 (10.2, 31.2) |
| | Min,Max | 0.0, 74.8 | 0.0, 57.8 |
| Number with Infarct Mass=0g | n/N (%) | 4/78 (5.1%) | 7/85 (8.2%) |
| | | | |

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| Parameter | Statistics | Day 4 SSO2 Therapy (N=88) | Day 30 SSO2 Therapy (N=87) |
| --- | --- | --- | --- |
| MVO (g) | N | 78 | * |
| | Mean ± (StdDev) | 2.1 ± 2.9 | |
| | Median (Q1,Q3) | 0.5 (0.0, 3.5) | |
| | Min,Max | 0.0, 13.2 | |
| Number with MVO=0 | n/N (%) | 35/78 (44.9%) | |
| | | | |
| % of Infarct Mass of Myocardial Mass | N | 78 | 85 |
| | Mean ± (StdDev) | 23.8 ± 13.8 | 19.2 ± 12.5 |
| | Median (Q1,Q3) | 24.1 (14.4, 31.6) | 19.4 (8.8, 28.9) |
| | Min,Max | 0.0, 54.1 | 0.0, 46.4 |
| | | | |
| % of Infarct Mass of Area at Risk | N | 71 | * |
| | Mean ± (StdDev) | 57.2 ± 24.6 | |
| | Median (Q1,Q3) | 65.6 (42.9, 73.3) | |
| | Min,Max | 0.0, 99.1 | |
| | | | |
| % of Salvage Mass of Area at Risk | N | 71 | * |
| | Mean ± (StdDev) | 42.8 ± 24.6 | |
| | Median (Q1,Q3) | 34.4 (26.7, 57.1) | |
| | Min,Max | 0.9, 100.0 | |
| | | | |
| % of MVO of Myocardial Mass | N | 78 | * |
| | Mean ± (StdDev) | 1.5 ± 2.3 | |
| | Median (Q1,Q3) | 0.3 (0.0, 2.4) | |
| | Min,Max | 0.0, 11.1 | |
| | | | |
| % of MVO of Infarct Mass | N | 74 | * |
| | Mean ± (StdDev) | 4.6 ± 5.6 | |
| | Median (Q1,Q3) | 1.9 (0.0, 8.4) | |
| | Min,Max | 0.0, 21.1 | |
| | | | |
| % of MVO of Area at risk | N | 71 | * |
| | Mean ± (StdDev) | 3.3 ± 4.4 | |
| | Median (Q1,Q3) | 0.9 (0.0, 5.4) | |
| | Min,Max | 0.0, 19.4 | |
| | | | |
| Left Ventricular Ejection Fraction (%) | N | 86 | 85 |

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| Parameter | Statistics | Day 4 SSO2 Therapy (N=88) | Day 30 SSO2 Therapy (N=87) |
| --- | --- | --- | --- |
| | Mean ± (StdDev) | 41.7 ± 8.3 | 44.9 ± 8.4 |
| | Median (Q1,Q3) | 43.2 (35.9, 48.2) | 45.2 (39.3, 51.3) |
| | Min,Max | 18.7, 59.6 | 19.8, 60.7 |
| Q1=First quartile, Q3= Third quartile, MVO=microvascular obstruction. | | | |

*MVO and Area at Risk not collected at 30 day time point per protocol

# Propensity-Matched Comparison between IC-HOT and INFUSE-AMI

The IC-HOT study pre-specified that cardiac MRI-derived infarct size data be compared to results obtained in propensity-matched INFUSE-AMI control subjects. The analysis included 52 subjects with 4-day MRI scans and 78 subjects with 30-day cardiac MRI scans from INFUSE-AMI who were matched to IC-HOT subjects. Methodology for the propensity matching was not pre-specified, and covariate imbalances may exist within the analysis. In addition, lack of area at risk data for INFUSE-AMI is a limitation. Results for the comparison of infarct size are shown in Table 24. This pre-specified comparison failed to demonstrate, at either time point, a reduction in median or mean percent of infarct mass of myocardial mass when using adjunctive $\mathrm{SSO}_2$ .

Table 24. MRI Analysis at 4 and 30 Days: Propensity Score Matched Comparison between IC-HOT and INFUSE-AMI

| Parameter | Statistics | 4 day IC-HOT | 4 day INFUSE-AMI | 30 day IC-HOT | 30 day INFUSE-AMI |
| --- | --- | --- | --- | --- | --- |
| % of Infarct Mass of Myocardial Mass | N | 52 | 52 | 78 | 78 |
| | Mean ± (StdDev) | 23.6 ± 13.9 | 23.1 ± 12.0 | 19.0 ± 12.2 | 17.3 ± 11.3 |
| | Median (Q1,Q3) | 24.6 (13.9, 30.8) | 23.0 (17.3, 30.0) | 19.1 (8.8, 28.9) | 18.6 (8.1, 26.7) |
| | Min,Max | 0.0, 54.1 | 0.0, 49.2 | 0.0, 42.2 | 0.0, 42.8 |

# Changes in Left Ventricular Volumes, EF over 30 Days

The IC-HOT left ventricular changes over 30 days are displayed in Table 25 for patients with measurable scan data from both the day 4 and day 30 time points. Results are shown for all available data for day 4, day 30, and the per-patient changes from day 4 to day 30. Data were obtained for $n = 79$ subjects who had two readable scans. The median (Q1, Q3) changes over 30 days in EDV (ml) and ESV (ml) were -2.0 (-16.0, 9.0) and -7.6 (-16.9, 1.4), respectively, representing changes of -1.1% and -8.1%. Median results for IC-HOT subjects demonstrated a reduction in left ventricular volume over 30 days and no remodeling.

Ejection fraction results are also presented in Table 25, showing a median (Q1, Q3) EF recovery from day 4 to day 30 of $+3.4\%$ , with a 30-day median (Q1, Q3) EF (\%) of 45.2 (39.3, 51.3) (see Table 23).

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Table 25. IC-HOT MRI Changes from 4 Days to 30 Days

| Parameter |…