ETHIZIA Hemostatic Patch

P240035S002 · ETHICON, Inc. · SGV · Jun 25, 2026 · General, Plastic Surgery

Device Facts

Record IDP240035S002
Device NameETHIZIA Hemostatic Patch
ApplicantETHICON, Inc.
Product CodeSGV · General, Plastic Surgery
Decision DateJun 25, 2026
DecisionAPPR
Regulation21 CFR 878.4490
Device ClassClass 3
AttributesTherapeutic

Indications for Use

ETHIZIA Hemostatic Patch is indicated for use in adult patients with a body weight of ≥ 25kg as an adjunct to hemostasis in open and minimally invasive surgical procedures on the liver for minimal, mild, or moderate bleeding sites when control of bleeding by standard surgical techniques (such as suture, ligature or cautery) is ineffective or impractical.

Device Story

ETHIZIA is a sterile, resorbable hemostatic patch; porcine gelatin fiber-based carrier impregnated with NHS-POx/NU-POx granulate; blue colorant aids visualization. Applied by surgeons in OR during open or minimally invasive (laparoscopic/robotic) liver procedures; introduced through 12mm trocars. Patch adheres to bleeding site; provides mechanical seal; resorbs in 4-6 weeks. Used when standard techniques (suture, cautery) fail. Output is physical hemostasis; reduces blood loss; facilitates surgical workflow. Benefits include rapid hemostasis; persistent sealing; no need for removal.

Clinical Evidence

Pivotal prospective, randomized (1:1), multicenter IDE study (G230105) of 53 subjects (25 ETHIZIA, 28 SURGICEL Original) undergoing minimally invasive liver/gallbladder resection. Primary endpoint: delivery/adherence and hemostasis within 7 minutes without rebleeding at 10 minutes. Success rate: 100% (25/25) for ETHIZIA vs 82% (23/28) for control. Median time to hemostasis from pressure initiation: 30s for both. Safety profile comparable; no deaths or reoperations. Adverse events (e.g., application site hemorrhage) were low and manageable.

Technological Characteristics

Resorbable patch; 10x5cm; 1.6-2.5g. Composition: Porcine gelatin (1g), NHS-POx/NU-POx granulate (1g), FD&C Blue No. 1. Sterilization: SAL 10^-6. Flexible, cuttable for irregular surfaces. Standalone application; no energy source. Mechanical hemostatic principle.

Indications for Use

Indicated for adult patients ≥ 25kg undergoing open or minimally invasive liver surgery for minimal, mild, or moderate bleeding when standard techniques are ineffective. Contraindicated for severe (pulsatile) bleeding, intravascular use, infected wounds, or known hypersensitivity to porcine proteins or FD&C Blue #1.

Regulatory Classification

Identification

An absorbable hemostatic agent or dressing is a device intended to produce hemostasis by accelerating the clotting process of blood. It is absorbable.

Reference Devices

Submission Summary (Full Text)

{0} # SUMMARY OF SAFETY AND EFFECTIVENESS DATA (SSED) ## I. GENERAL INFORMATION Device Generic Name: Absorbable Hemostatic Agent Device Trade Name: ETHIZIA Hemostatic Patch Device Procode: SGV Applicant's Name and Address: ETHICON, Inc. 1000 US Highway 202 South Raritan, NJ 08869 Date(s) of Panel Recommendation: None Premarket Approval Application (PMA) Number: P240035/S002 Date of FDA Notice of Approval: June 25, 2026 The original PMA, P240035, was approved on December 15, 2025, and is indicated for: ETHIZIA Hemostatic Patch is indicated for use in adult patients with a body weight of $\geq 25\text{kg}$ as an adjunct to hemostasis in open liver surgery for minimal, mild, or moderate bleeding sites when control of bleeding by standard surgical techniques (such as suture, ligature or cautery) is ineffective or impractical. The SSED to support the indication of ETHIZIA Hemostatic Patch (ETHIZIA) is available on the CDRH website and is incorporated by reference here. The current supplement was submitted to expand the indication for the device. ## II. INDICATIONS FOR USE ETHIZIA Hemostatic Patch is indicated for use in adult patients with a body weight of $\geq 25\text{kg}$ as an adjunct to hemostasis in open and minimally invasive surgical procedures on the liver for minimal, mild, or moderate bleeding sites when control of bleeding by standard surgical techniques (such as suture, ligature or cautery) is ineffective or impractical. PMA P240035/S002: FDA Summary of Safety and Effectiveness Data 1 {1} ### III. CONTRAINDICATIONS - ETHIZIA is not indicated for use on severe (i.e., pulsatile) bleedings (defined by Surface Bleeding Severity Scale 4-5). - ETHIZIA is not intended for intravascular use. Do not attempt to force ETHIZIA into blood vessels, and only apply ETHIZIA after standard surgical techniques have been used to close the vessel. - ETHIZIA should not be used in infected wounds. - ETHIZIA should not be used in patients with a known hypersensitivity to the component materials, including porcine proteins and FD&C Blue #1. ### IV. WARNINGS AND PRECAUTIONS The warnings and precautions can be found in the ETHIZIA Hemostatic Patch labeling. ### V. DEVICE DESCRIPTION ETHIZIA is a sterile, resorbable hemostatic patch that should be applied on a visible bleeding site. It is presented as a blue, soft, flexible, porcine gelatin (1 ± 0.2 grams per ETHIZIA) fiber-based gelatin carrier impregnated with NHS-POx / NU-POx granulate (1 ± 0.2 grams per ETHIZIA). Blue color (202 – 686 μg per ETHIZIA) is an aid to visualize ETHIZIA when applied onto a bleeding location. ETHIZIA measures 10 by 5 cm and can be applied on both sides. As ETHIZIA is a homogenously impregnated fibrous material, it is also suited to being torn into smaller pieces for application on irregularly shaped structures and areas that are difficult to access. Figure 1 shows a representative image of ETHIZIA. ETHIZIA product specifications are listed in Table 1. The product is not removed at the end of surgery but is resorbed in 4-6 weeks. Degradation of ETHIZIA depends upon several factors including the amount used, the anatomical location, and degree of saturation with blood or other fluids. ![img-0.jpeg](img-0.jpeg) Figure 1. ETHIZIA PMA P240035/S002: FDA Summary of Safety and Effectiveness Data 2 {2} | **Table 1 – ETHIZIA Specifications** | | | --- | --- | | **Parameter** | **Specification** | | Appearance | Fibrous, coherent patch, homogeneously colored (blue) | | Shape | Rectangular | | Dimensions | Length: 100 ± 5 mm | | | Width: 50 ± 5 mm | | | Thickness: 5 ± 3 mm | | Weight | 1.6 – 2.5 g | | Composition | Porcine gelatin (1 ± 0.2 grams per ETHIZIA) | | | NHS POx/NU-POx granulate (1 ± 0.2 grams per ETHIZIA) | | | FD&C Blue No. 1 (202 – 686 µg per ETHIZIA) | | Ratio Blue NHS-POx/NU-POx | Blue NHS-POx/NU-POx (75:25 (w/w) to 85:15 (w/w)) | | Loading (% of granulates in final finished device) | 36-61% | | Sterility assurance level (SAL) | 10^{-6} | ## **VI. ALTERNATIVE PRACTICES AND PROCEDURES** There are several other alternatives for the correction of uncontrolled bleeding. Hemostasis involves the interaction of blood vessels, platelets, and the coagulation cascade to form a localized mechanical seal. A variety of adjunctive methods exist to achieve hemostasis. During a major hemorrhage, direct pressure or clamps may result in hemostasis. Minor bleeding can be controlled and stopped by ligation, pharmacological agents (topical thrombin and tissue sealants), laser cautery (heat, electric current, or a caustic substance) or topical agents such as oxidized cellulose, collagen, and gelatin sponges. 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** ETHIZIA is CE Marked and was introduced into commercial distribution in Europe, the Middle East and Africa, and Asia in 2024, and the product is currently marketed in the countries listed in Table 2 below. | **Table 2. CE-Marked Version of ETHIZIA Marketed Countries** | | | --- | --- | | **Europe** | Austria, Belgium, Czech Republic, Denmark, Finland, France, Germany, Greece, Italy, Latvia, Luxembourg, Netherlands, Norway, Poland, Spain, Sweden, Switzerland, United Kingdom | | **Middle East and Africa** | Bahrain, Israel, Jordan, Kuwait, Qatar, Saudi Arabia, United Arab Emirates | | **Asia** | Hong Kong | In December 2024, Ethicon filed PMA P240035 and received FDA approval for ETHIZIA in December 2025. PMA P240035/S002: FDA Summary of Safety and Effectiveness Data 3 {3} The ETHIZIA Hemostatic Patch has not been withdrawn from marketing for any reason relating to the safety and effectiveness of the device. ### **VIII. POTENTIAL ADVERSE EFFECTS OF THE DEVICE ON HEALTH** Below is a list of adverse effects (e.g., complications) reported during clinical trials with ETHIZIA: - Abdominal pain - Abscess / Infection - Application site hemorrhage (intra-operative bleeding / re-bleeding) - Bile leak / biloma (post-operative) - Hematoma - Intra-abdominal fluid collection - Pyrexia Below is a list of potential adverse effects that may occur with the use of a product such as ETHIZIA: - Allergic reaction - Anemia - Blockage of artery or vein/ischemia of organs - Closing of intestinal tract - Damage of organs and vessels - External compression of tubular structures such as arteries, bile ducts, veins, bowel - Gastrointestinal hemorrhage - Haemobilia - Hemostat migration, folding or fragmentation resulting in bowel erosion or obstruction - Imaging artifact (resulting in unnecessary invasive diagnostic procedures or reoperation) - Masking residual cancer at margin of resection resulting in higher local recurrence rates and decreased disease-free survival - New surgery - Pain - Pseudo abscess - Pseudo mass formation - Pulsatile hematoma - Rash - Toxic response - Thromboembolic event PMA P240035/S002: FDA Summary of Safety and Effectiveness Data 4 {4} # IX. SUMMARY OF NON-CLINICAL STUDIES Multiple non-clinical studies to support the safety and effectiveness of ETHIZIA, including design verification and validation, pre-clinical animal studies, biocompatibility, shelf life, packaging testing and sterilization, and endotoxin validation and testing were conducted. Please refer to the P240035 SSED available on the FDA website for a description of previously conducted studies. Additional animal and usability studies were conducted to support the safety and effectiveness of ETHIZIA for its intended use in laparoscopic and robotic procedures and reported in Table 3 below. | Table 3. Summary of Non-Clinical Animal Studies | | | | --- | --- | --- | | Study | Treatments Applied | Results | | *GLP hemostatic effectiveness trials* | | | | Evaluation of the ETHIZIA laparoscopic application on bleeding sites in a swine model -Organ: liver -Lesion type: biopsy punch -Procedure type: laparoscopic | 4 pigs 32 applications • 24 ETHIZIA • 8 Surgifoam + Thrombin (Topical RECOTHROM Thrombin (Baxter) was used in combination with every application of Surgifoam) | ETHIZIA achieved 96% hemostasis in 30 seconds, 100% in 5 minutes. Surgifoam + Thrombin 100% in 30 seconds. In 17% of the cases ETHIZIA needed a second patch and 0% a third patch. For Surgifoam + Thrombin 25% needed a second patch, and 13% a third patch. | | *Non-GLP studies* | | | | Usability and performance of ETHIZIA on liver biopsy punch bleeding model in laparoscopic procedure -Organ: liver -Lesion type: biopsy punch -Procedure type: laparoscopic | 2 pigs 16 bleeding sites 17 ETHIZIA pieces applied | Hemostasis was 81% (13/16) after initial 30 seconds of pressure, 94% (15/16) after 1 minute, and 100% at the primary endpoint of 3 minutes. No sites showed rebleeding within 30 minutes. | PMA P240035/S002: FDA Summary of Safety and Effectiveness Data 5 {5} | Table 3. Summary of Non-Clinical Animal Studies | | | | --- | --- | --- | | Study | Treatments Applied | Results | | Usability and performance of ETHIZIA on large liver lesions in laparoscopic procedure^{2} -Organ: liver, spleen -Lesion type: resection, metastasectomy, simulated traumatic lesion -Procedure type: laparoscopic | 2 pigs 12 bleeding sites 25 ETHIZIA pieces applied TachoSil applied to 3 bleeding sites with 2 follow-up ETHIZIA rescue treatment | For ETHIZIA, hemostasis after 30 seconds was 78% (7/9) in the liver and 33% (1/3) in the spleen. All (100%) ETHIZIA sites were hemostatic at primary endpoint of 3 minutes. TachoSil (applied to sites with SBSS 3 or 4) failed to reach hemostasis in 3 minutes in all 3 sites, and ETHIZIA was applied as rescue treatment to 2 sites. | | Usability performance of ETHIZIA on large liver lesions in robotic procedure^{2} -Organ: liver, blood vessel -Lesion type: resection, metastasectomy -Procedure type: robotic | 2 pigs 9 bleeding sites 17 ETHIZIA pieces applied TachoSil applied to 1 bleeding site with 1 follow-up ETHIZIA rescue treatment | For ETHIZIA, hemostasis of the liver was 86% (6/7) after the initial 30 seconds of pressure; the remaining liver site was hemostatic at 8 minutes. One blood vessel site with ETHIZIA was hemostatic after 30 seconds of pressure, the other at 3 min. The one TachoSil site was unsuccessful after 2 attempts in 10 minutes; ETHIZIA was applied for rescue treatment, with hemostasis after 30 seconds of pressure. | | Comparison of ETHIZIA versus TachoSil on large liver lesions in robotic procedure -Organ: liver -Lesion type: superficial, resection, metastasectomy -Procedure type: robotic | 4 pigs 18 bleeding sites 25 ETHIZIA pieces applied TachoSil applied to 18 bleeding sites with 1 follow-up ETHIZIA rescue treatment | For ETHIZIA, hemostasis was achieved in 83% (15/18) after 30 seconds of pressure and 100% after 5 minutes. Mean time to hemostasis was 64 ± 83 seconds. For TachoSil, hemostasis was 50% (9/18) at 5 minutes. Mean time to hemostasis was 220 ± 60 seconds (for those achieving hemostasis). | PMA P240035/S002: FDA Summary of Safety and Effectiveness Data 6 {6} | **Study** | **Treatments Applied** | **Results** | | --- | --- | --- | | Comparison of ETHIZIA versus standard suturing during partial nephrectomy in robotic procedure^{2} -Organ: kidney -Lesion type: resection -Procedure type: robotic | 4 pigs 16 bleeding sites 37 ETHIZIA pieces Standard suturing applied to 16 bleeding sites | Compared to standard suturing, sites treated with ETHIZIA had significantly shorter procedure times, including warm ischemia (arterial clamping) time. Active bleeding during treatment application was found in 19% of ETHIZIA sites compared to 94% of suturing sites. For ETHIZIA, hemostasis was 81% (13/16) after 30 seconds of pressure, 88% (14/16) at 3 minutes, and 100% by 8 minutes. A relook at ~4 hours after initial hemostasis was achieved showed rebleeding in 0% of ETHIZIA sites compared to 12.5% of suturing sites. | | ETHIZIA vs renorrhaphy in a robotic porcine partial nephrectomy survival model^{2} -Organ: kidney -Lesion type: metastasectomy -Procedure type: robotic | 12 pigs 18 ETHIZIA applications 18 standard suturing | ETHIZIA achieved hemostasis in 72% in 30 seconds, 78% in 2 minutes, 83% in 3 minutes, 88% in 6 minutes, 94% in 8 minutes and 100% in 9 minutes. ETHIZIA provided persistent hemostasis without signs of rebleeding over the course of a 6-week survival period. The primary use of ETHIZIA on a defect in the calyx was sufficient to provide adequate sealing over the course of tissue healing without the risk of urine leakage over a course of 6 weeks. No signs of migration of ETHIZIA, and degradation within 6 weeks. | | ^{1}The performance of ETHIZIA™ in anticoagulated patients has not been studied. ^{2}The safety and effectiveness of ETHIZIA™ has not been established for use in anatomic locations other than the liver. | | | PMA P240035/S002: FDA Summary of Safety and Effectiveness Data 7 {7} ## **X. SUMMARY OF PRIMARY CLINICAL STUDY** The applicant performed a clinical study to establish a reasonable assurance of safety and effectiveness of ETHIZIA as an adjunct to hemostasis in minimally invasive surgical procedures on the liver for minimal, mild or moderate bleeding sites when control of bleeding by standard surgical techniques (such as suture, ligature or cautery) is ineffective or impractical under IDE G230105 (NCT05900037). Data from this clinical study were the basis for the PMA approval decision. G230105 is a prospective, randomized (1:1), multicenter, pivotal IDE clinical investigation for subjects undergoing elective minimally invasive liver or gallbladder resection surgery. With a total of 53 eligible subjects randomized to ETHIZIA (n=25) or SURGICEL Original (n=28) at 6 clinical sites in the US. A summary of the descriptive clinical study is presented below. ### **A. Study Design** Patients were treated between October 6, 2023 and April 25, 2025. The database for this Panel Track Supplement reflected data collected through August 2025 (database lock) and included 53 patients. There were 6 investigational sites. This study was a pre-market, prospective, randomized, multicenter, pivotal clinical investigation evaluating the safety and effectiveness of ETHIZIA versus SURGICEL Original (Control) for hemostasis during minimally invasive liver and gallbladder surgery. The primary objective of this investigation was to evaluate minimally invasive use of ETHIZIA in robotic and laparoscopic liver and gallbladder surgery. In this investigation, hemostasis was defined as a grade of 0 (None/Dry) on the Surface Bleeding Severity Scale (SBSS). The study was conducted in compliance with United States Food and Drug Administration (FDA) regulations 21 CFR Parts 50, 54, 56, and 812, and International Council for Harmonization (ICH) E6 Good Clinical Practices (GCP). Sponsor collaborated with a Contract Research Organization (CRO) for study management, data management, site activation, site monitoring and data verification, medical writing, Independent Data Monitoring Committee (IDMC) and Independent Adjudication Committee (IAC) facilitation. An IDMC, comprised of independent medical experts and an expert biostatistician, oversaw the study throughout its duration to minimize bias through periodic review of blinded data pertaining to trial conduct, patient selection, and safety and effectiveness endpoints. An IAC of independent physicians reviewed all serious adverse events (SAEs) and adverse events of special interest (AESI; i.e., bleeding-related events, thromboembolic events, biloma, and allergic reaction) occurring during the 3-month PMA P240035/S002: FDA Summary of Safety and Effectiveness Data 8 {8} follow-up after surgery for relatedness to the device and expectedness of the event based on the clinical scenario comprising of patient and procedural characteristics. SURGICEL Original, an absorbable hemostat (oxidized regenerated cellulose), was used as the control. The clinical trial choice of comparator control product was based on the following considerations: - The control is a legally marketed alternative with similar indications for use. - A standard-of-care hemostatic patch to obtain the highest standards of clinical evidence when compared to the investigational device. - Both products being ready-to-use, which limits blood loss during surgery and increases the comparability in safety and performance. - Both products have similar risk-benefit ratio for patches because of position and structure of the patch on the target bleeding site in relation to the patient anatomy. - SURGICEL Original has been used as a comparator in hepatobiliary procedures in over 400 trial subjects. Subjects were randomized intraoperatively in a 1:1 ratio to ETHIZIA or SURGICEL Original. The pivotal minimally invasive surgery (MIS) study treated 53 subjects: 25 patients randomized to ETHIZIA and 28 patients randomized to SURGICEL Original. Subjects were treated between October 2023 and April 2025. There were 6 investigational sites enrolling patients. Subjects were blinded to their randomized treatment group. Due to the physical differences in the investigational and control devices, surgeons could not be blinded. To minimize investigator bias during this clinical investigation, a validated bleeding scale was used to assess the severity of bleeding before randomization and to evaluate hemostasis after patch use. Because the baseline bleeding severity was assessed prior to randomization the investigator was not aware of the treatment assignment when scoring the baseline bleeding site. # 1. Clinical Inclusion and Exclusion Criteria Enrollment in the Study was limited to patients who met the following inclusion criteria: - Subject is scheduled to undergo elective minimally invasive (robotic or laparoscopic) surgery on the liver, including cholecystectomy; - Subject is willing and able to give written informed consent for the clinical investigation participation; - Subject is 22 years of age or older at the time of enrollment; and - Subject has been informed of the nature of the clinical investigation. In addition, subjects must have met the following intraoperative inclusion criteria: - Subject undergoes a fully minimally invasive surgical approach without the use of a hand port at the time of randomization and application of the patch; PMA P240035/S002: FDA Summary of Safety and Effectiveness Data 9 {9} - Subject in whom the Investigator can identify a target bleeding site at the liver resection plane or cholecystectomy liver bed for which any applicable conventional means for hemostasis (e.g. suture, ligature or cautery) are ineffective or impractical and the choice is made to use a hemostat agent to stop the bleeding; and - Pressure on the surface of the hemostatic agent can be applied with the minimally invasive instruments to achieve hemostasis; and - Subject has a target bleeding site with a Surface Bleeding Severity Score (SBSS) of 1, 2, or 3. (e.g., reflecting minimal, mild, or moderate bleeding severities). Patients were not permitted to enroll in the study if they met any of the following exclusion criteria: - The target bleeding site is from a large defect in an artery or vein that requires vascular reconstruction with maintenance of vessel patency; - Subject is scheduled to undergo surgery on organs other than the liver and its associated biliary and vascular system, except for combined colorectal surgery; - Subject is scheduled to undergo a staged liver surgery procedure (e.g., Associating Liver Partition and Portal vein ligation for Staged hepatectomy [ALPPS]) - Subject is taking multiple antithrombotic therapies in therapeutic dosage up to the time of surgery, but allowing exclusive use of acetylsalicylic acid; - Subject has platelet count <100 x 109/L, an activated partial thrombin time of >100s, or international normalized ratio >2.5; - Subject has a total bilirubin level of ≥2.5 mg/dl; - Subject is pregnant, planning on becoming pregnant or actively breastfeeding during the 3-month follow-up period; - Subject has a known hypersensitivity to brilliant blue (FD&C Blue #1), or porcine gelatin; - Subject who has religious objections to receiving products containing porcine; - Subject has an active or suspected infection at the bleeding site; - Subject in whom the investigational device will be used at the site of a synthetic graft or patch implant; - Subject has a life expectancy of less than 3 months; - Subject has a documented severe congenital or acquired immunodeficiency; - Subject has had or has planned to receive any organ transplantation; - Subject is currently participating or has participated in another clinical investigation within the past 30 days that may affect the endpoints of the study, such as trials related to the surgical procedure and anti-coagulation; - Subject is not appropriate for inclusion in the clinical investigation, per the medical opinion of the Investigator; and PMA P240035/S002: FDA Summary of Safety and Effectiveness Data 10 {10} - Subject has any incidental (pre- and peri-operative) findings deemed by the Investigator to potentially jeopardize the safety or welfare of the subject. ## 2. Follow-up Schedule All subjects were scheduled to return for a follow-up visit at week 6 (± 2 weeks), which included a laboratory and ultrasound imaging assessment. An onsite or telephone assessment took place at week 12 (± 2 weeks). Adverse events and complications were recorded at all visits as well as relevant concomitant medications. Study procedures are summarized in Table 4, and the patient laboratory test schedule is summarized in Table 5 below. Preoperatively, information was collected on baseline demographics (age, sex, race and ethnicity), medical history (allergies, smoking status, cardiac disorders, systemic hypertension, renal dysfunction, diabetes, hereditary blood disorders, blood transfusions in the last 3 months, previous abdominal surgery, liver disease, portal hypertension, malignancies and prior therapies, indication for surgery, other critical medical condition or previous surgery, and American Society of Anesthesiologists classification), physical examination, relevant concomitant medications, and laboratory test data. Inclusion/exclusion criteria were confirmed preoperatively as well as intra-operatively. Postoperatively, the objective parameters measured during the study included hemostatic performance data (including primary and secondary study endpoints), surgical procedural data (type of MIS, device handling, surgery date, procedure length, number of devices used, blood loss in ml, SBSS of target bleeding site, use of adjunct hemostatic agents/techniques, pneumoperitoneum, amount of material needed, user satisfaction (ETHIZIA only, per investigator, per procedure), hospitalization information (duration of stay in intensive care unit, total hospitalization period, blood transfusions), intra- and post-operative adverse events, device deficiencies, and laboratory test data. At the week 6 visit the study procedure included imaging of the resection, laboratory tests, collection of adverse events and relevant (new) concomitant medications. The week 12 visit could either be conducted onsite or via phone call and included collection of adverse events and relevant (new) concomitant medications. PMA P240035/S002: FDA Summary of Safety and Effectiveness Data 11 {11} | **Assessments** | **Screening/ Baseline (< 6 Weeks Before Surgery)** | **Treatment** | **Post- Surgery to Hospital Discharge** | **Week 6 (±2 Weeks)** | **Week 12 (±2 Weeks)** | | --- | --- | --- | --- | --- | --- | | Informed consent | X | | | | | | Inclusion and exclusion criteria | X | X | | | | | Baseline demographics and medical history (including allergies) | X | | | | | | Medication (including those impacting coagulation) | X | | X | X | X | | Physical examination | X | | X | X | | | Laboratory tests | X | | X | X | | | Procedural data (including primary efficacy endpoint and Device Deficiency) | | X | | | | | User satisfaction questionnaire | | X | | | | | Adverse Event assessments (with specific attention to bleeding and thrombotic events) | | X | X | X | X | PMA P240035/S002: FDA Summary of Safety and Effectiveness Data 12 {12} | **Laboratory Tests** | **Screening/ Baseline^{a}** | **Through Admission^{b}** | **Week 6 (±2 Weeks)** | | --- | --- | --- | --- | | **Hematology** | | | | | Complete blood count | X | X | X | | **Coagulation** | | | | | Prothrombin time | X | X | b | | Activated partial thromboplastin time | X | X | b | | INR | X | X | b | | **Chemistry** | | | | | Bilirubin | X | X^{c} | X | | Calcium | X | b | b | | Potassium | X | b | b | | Sodium | X | b | b | | Chloride | X | b | b | | Albumin | X | X | X | | Creatinine | X | X | b | | AST | X | X | X | | ALT | X | X | X | | Gamma glutamyl transferase | X | X | X | | **Other** | | | | | Pregnancy test (if applicable) | X | N/A | N/A | | Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; INR, international normalized ratio; N/A, not applicable. | | | | | a. Laboratory tests had to be performed at least once before surgery during the screening/baseline visit, with the latest data being the final presurgical data used in analyses. | | | | | b. Only collected as per standard of care hospital routine. | | | | | c. Including drainage fluid of the surgical drain, if applicable. | | | | The key timepoints and assessments are shown below in the tables summarizing safety and effectiveness. ### 3. Clinical Endpoints With regards to efficacy, the primary performance endpoint is defined as delivery and adherence of the agent to the target bleeding site and achievement of hemostasis (defined by a grade of 0 on the SBSS, within 7 minutes from introduction of the first (piece of) patch through the trocar without rebleeding at the 10-minute timepoint from initiating pressure on the entire surface of the hemostatic agent and without the need to convert the surgical approach or use a hand port due to issues with hemostasis at the target bleeding site or device use. Hemostasis was defined as grade of 0 PMA P240035/S002: FDA Summary of Safety and Effectiveness Data 13 {13} (None/Dry) on the SBSS, of the direct surface onto which ETHIZIA or Control was applied. The combination of the first target bleeding site and any other bleeding sites treated with the hemostatic device were referred to as all target bleeding sites. Results for hemostasis across all treated target bleeding sites are summarized in Tables 15 and 16. No formal hypotheses are specified for this study. All study endpoints were summarized descriptively. The estimated sample size was 50 subjects, with 25 subjects undergoing treatment with ETHIZIA as assigned by 1:1 randomization. The primary analysis for the primary endpoint was performed using modified intent-to-treat (mITT), and supportive analysis was performed using the per-protocol (PP) population. The key secondary endpoint analysis was performed using the mITT population. Secondary efficacy endpoints of this clinical investigation consisted of: - Median time from introducing the first (piece of) hemostatic agent through the trocar and achieving hemostasis (seconds); - Median time from introducing the first (piece of) hemostatic agent through the trocar to initiating pressure on the entire surface of the agent (seconds); - Median time to hemostasis from initiating pressure on the entire surface of the agent (seconds); - Percentage of hemostasis from initiating pressure on the entire surface of the agent at 30, 60, 120, 180, 240, 300, 360, 420, 480, 540 and 600 seconds; - Kaplan-Meier estimated distribution of time to hemostasis from initiating pressure on the entire surface of the agent; - Treatment failure, defined as no hemostasis with the agent at 10 minutes from initiating pressure on the entire surface of the agent; - Rebleeding after the 10-minute time point from initiating pressure on the entire surface of the agent but before subject wound closure; and - Number of times an additional (piece of) hemostatic agent needs to be used to achieve hemostasis. With regards to safety, the incidence, severity and relation to hemostatic device of all AEs were assessed. The AEs for the ETHIZIA group were compared to those for the Control group. All AEs were collected, with AEs of special interest being: - Bleeding-related events, including rebleeding of the bleeding site(s) treated with hemostatic patch at any point in time (within 10 minutes of application, prior to subject closure, and postoperative), and including hematoma; - Thromboembolic events; - Biloma; and - Allergic reaction. PMA P240035/S002: FDA Summary of Safety and Effectiveness Data 14 {14} The following exploratory endpoints were collected: - Conversion from minimally invasive to open surgery, and reasons for conversion; - Procedure duration (minutes); - Duration of hepatic blood inflow reduction (minutes); - Estimated blood loss (mL) during surgery; - Number and type of blood transfusions during hospitalization; - Duration of Intensive Care Unit (ICU) stay; - Total hospitalization time; - Postoperative drainage volume, characteristics, and duration; - Need for and cause of reoperation; - Imaging of the liver resection at 6 weeks post-surgery to detect (1) fluid collection and its size (in mL) and aspect, (2) pseudo-aneurysm, (3) encapsulation of the agent, and (4) rolling up of the agent on the resection plane; - Amount of hemostatic material needed; and - User satisfaction (questionnaire) for ETHIZIA. #### 4. Statistical Analysis Plan No formal hypotheses were specified for this trial. All trial endpoints were summarized descriptively. For descriptive purposes, the 95% CI was provided for the primary efficacy endpoint and the key secondary efficacy endpoint (i.e., median time from introducing the first [piece of] hemostatic agent through the trocar and achieving hemostasis [seconds]). Continuous variables were summarized using the number of observations (n), mean, standard deviation (SD), median, minimum, and maximum. Categorical variables were summarized using frequencies and percentages of subjects in each category. #### 5. Sample Size The planned sample size was 50 subjects, with 25 subjects undergoing treatment with ETHIZIA as assigned by 1:1 randomization. A minimum of 50% of the subjects were planned to be enrolled in the US to help ensure that the subjects were representative of the US population for which this device was to be indicated. This sample size was chosen to reflect a focus on the usability of ETHIZIA during a MIS, where the aim was to provide descriptive data on the specific features of minimally invasive use, while a powered safety and efficacy assessment of ETHIZIA was being evaluated in a pivotal IDE trial (G210325). #### 6. Analysis Set Definitions PMA P240035/S002: FDA Summary of Safety and Effectiveness Data 15 {15} The All-Enrolled Population included all subjects who signed the informed consent form (ICF). The All-Enrolled Population was used for subject disposition and screen failure summaries. The Safety Population included all randomized subjects who received treatment with ETHIZIA or SURGICEL Original. The treatment group assignment in the Safety Population was defined by the treatment actually received. The Safety Population was used for the analysis of safety endpoints. The mITT Population included all randomized subjects who did not have i) a change in SBSS to ineligible (SBSS of 0, 4, or 5) between randomization and treatment; and ii) death of a subject between randomization and treatment. The treatment group assignment was designated according to initial randomization. The mITT Population served as the basis for the analysis of all efficacy endpoints. The Per-Protocol (PP) population included all subjects in mITT Population who received treatment with ETHIZIA or SURGICEL Original as randomized, had an assessment of the primary efficacy endpoint, and had no major CIP deviations impacting the primary efficacy endpoint. # 7. Interim Analysis A descriptive interim analysis of primary efficacy endpoint and AE data was performed to support the regulatory review of the open IDE clinical trial when approximately 50% of the subjects were randomized. The data required for the interim analysis were source data verified. The database did not undergo a formal database lock. No changes were made to the trial conduct based on this interim analysis. # B. Accountability of PMA Cohort At the time of the database lock, a total of 94 subjects signed informed consent and were enrolled in the PMA study. 40 subjects were screen-failed, and 54 patients were randomized to receive either ETHIZIA (N=26) or SURGICEL Original (N=28). One subject in the ETHIZIA treatment arm met the withdrawal criteria (change in SBSS to 0) after randomization and was therefore not treated with the product or followed up for the trial. Of the 25 ETHIZIA patients who received treatment, 21 completed the trial and 4 withdrew or were lost to follow-up. In the SURGICEL Original treatment arm 28 patients received the treatment and completed the trial; there were no withdrawals or lost to follow-up subjects. There were no deaths in either treatment arms. Subject disposition after randomization is highlighted in Table 6. PMA P240035/S002: FDA Summary of Safety and Effectiveness Data 16 {16} **Table 6. Subject Disposition of randomized subjects** | Category | ETHIZIA (N=26) n (%) | SURGICEL Original (N=28) n (%) | Overall (N=54) n (%) | | --- | --- | --- | --- | | Subjects randomized | 26 (100) | 28 (100) | 54 (100) | | Subjects treated | 25 (96.2)^{a} | 28 (100) | 53 (98.1) | | Subjects completed the trial (up to 12-week follow-up visit) | 21 (80.8) | 28 (100) | 49 (90.7) | | Subjects who withdrew from the trial prematurely | 5 (19.2) | 0 | 5 (9.3) | | Withdrawal of consent | 0 | 0 | 0 | | Investigator's and sponsor's decision | 0 | 0 | 0 | | Procedural eligibility criteria were not met | 1 (3.8)^{a} | 0 | 0 | | Non-compliance to protocol | 0 | 0 | 0 | | Lost to follow-up | 2 (7.7) | 0 | 2 (3.7) | | Adverse event | 0 | 0 | 0 | | Death | 0 | 0 | 0 | | Other | 2 (7.7)^{b} | 0 | 2 (3.7) | Abbreviations: N, number of subjects in the population; n, number of subjects with the specified outcome; - a. One subject in the ETHIZIA treatment group was withdrawn from the trial due to an exclusionary SBSS result between randomization and the planned application of the ETHIZIA Patch (SBSS changed to 0). - b. Two subjects in the ETHIZIA treatment group were not seen on site by the trial team at the 12-week follow-up visit, but the subjects' electronic health records were observationally followed by the site through 12 week study period to evaluate for AEs. Note: Percentages were based on the number of randomized subjects in each group. ### **C. Study Population Demographics and Baseline Parameters** The demographics of the study population were typical for liver surgery performed in the US. Subject demographics and operative characteristics are summarized below in Table 7. The mean age of subjects treated with ETHIZIA was 59.6 ± 14.4 years and the mean age of subjects treated with SURGICEL Original was 54.7 ± 14.2 years. The indications for surgery for subjects treated with ETHIZIA were hepatic cyst(s) (20.0%), cholangiocarcinoma (12.0%), cholecystitis or gall stones (12.0%), colorectal metastases (12.0%), hepatocellular carcinoma (12.0%), non-colorectal metastases (12.0%) and other (16.0%; metastatic leiomyosarcoma of the liver (4.0%), pneumobolia and contracted gallbladder (4.0%), adenocarcinoma (4.0%) and metastatic (to liver) cutaneous malignant melanoma (4.0%). The indications for surgery for subjects treated with SURGICEL PMA P240035/S002: FDA Summary of Safety and Effectiveness Data 17 {17} Original were benign tumor (17.9%), cholecystitis or gall stones (17.9%), hepatocellular carcinoma (17.9%), cholangiocarcinoma (14.3%), colorectal metastases (14.3%), hepatic cyst(s) (7.1%), and other (7.1%; Hurthle cell carcinoma (3.6%) and hepatic mass concerning hepatocellular carcinoma (3.6%)). Type of resections were similar between both groups for anatomic and non-anatomic resections – 68.0% of ETHIZIA surgeries were non-anatomic, and 67.9% of SURGICEL Original subjects underwent non-anatomic resections. Majority of minimally invasive surgeries across both groups were robotic (ETHIZIA: 68.0% and SURGICEL Original: 71.4%). | | **ETHIZIA (n=25)** | **SURGICEL Original (n=28)** | | --- | --- | --- | | Age (years) | | | | Mean (SD) | 59.6 (14.39) | 54.7 (14.24) | | Median | 60.0 | 52.5 | | Min, Max | 32, 80 | 24, 79 | | Sex, n (%) | | | | Male | 13 (52.0) | 14 (50.0) | | Female | 12 (48.0) | 14 (50.0) | | Race, n (%) | | | | White | 18 (72.0) | 20 (71.4) | | Asian | 1 (4.0) | 3 (10.7) | | Black or African American | 1 (4.0) | 2 (7.1) | | Other | 5 (20.0) | 3 (10.7) | | Ethnicity, n (%) | | | | Hispanic or Latino | 5 (20.0) | 5 (17.9) | | Not Hispanic or Latino | 19 (76.0) | 23 (82.1) | | Other | 1 (4.0) | 0 | | Child Pugh classification, n (%) | | | | A | 13 (52.0) | 14 (50.0) | | B | 0 | 0 | | C | 0 | 0 | | N/A | 12 (48.0) | 14 (50.0) | | ASA classification, n (%) | | | | 1 | 0 | 1 (3.6) | | 2 | 4 (16.0) | 6 (21.4) | | 3 | 20 (80.0) | 21 (75.0) | | 4 | 1 (4.0) | 0 | | 5 | 0 | 0 | | Indication for surgery, n (%) | | | | Benign tumor | 1 (4.0) | 5 (17.9) | | Cholangiocarcinoma | 3 (12.0) | 4 (14.3) | | Cholecystitis or gall stones | 3 (12.0) | 5 (17.9) | | Colorectal metastases | 3 (12.0) | 4 (14.3) | | Hepatocellular carcinoma | 3 (12.0) | 5 (17.9) | PMA P240035/S002: FDA Summary of Safety and Effectiveness Data 18 {18} | | **ETHIZIA (n=25)** | **SURGICEL Original (n=28)** | | --- | --- | --- | | Non colorectal metastases | 3 (12.0) | 0 | | Hepatic cyst(s) | 5 (20.0) | 3 (10.7) | | Other^{a} | 4 (16.0) | 2 (7.1) | | Minimally Invasive Surgery, n (%) | | | | Robotic | 17 (68.0) | 20 (71.4) | | Laparoscopic | 8 (32.0) | 8 (28.6) | | Procedure Duration (minutes) | | | | Mean (SD) | 164.7 (80.80) | 170.9 (106.01) | | Median (range) | 169.0 (52, 352) | 137.0 (54, 452) | | Type of resection, n (%) | | | | Anatomic | 7 (28.0) | 6 (21.4) | | Non-anatomic | 17 (68.0) | 19 (67.9) | | N/A | 1 (4.0) | 3 (10.7) | | Extent of resection, n (%) | | | | Cholecystectomy | 4 (16.0) | 5 (17.9) | | Left hemihepatectomy | 2 (8.0) | 2 (7.1) | | Right hemihepatectomy | 1 (4.0) | 2 (7.1) | | Extended left hemihepatectomy | 0 | 0 | | Extended right hemihepatectomy | 0 | 0 | | Segmentectomy | 8 (32.0) | 7 (25.0) | | Bisegmentectomy | 7 (28.0) | 4 (14.3) | | Trisegmentectomy | 0 | 0 | | Non-anatomical wedge resection | 3 (12.0) | 7 (25.0) | | Missing | 0 | 1 (3.6) | | Vascular reconstruction performed, n (%) | 0 | 1 (3.6) | | Biliary tree reconstruction performed, n (%) | 0 | 0 | | Visible bile leakage surgically treated during surgery, n (%) | 0 | 1 (3.6) | | Estimated total size of resection (cm^{2}), Mean ± SD | 85.8 ± 82.6 | 82.1 ± 83.3 | | Estimated mean (SD) blood loss (mL) | 270.8 (433.20) | 226.4 (502.27) | | Median (range) blood loss (mL) | 100 (5 – 2000) | 50 (2 – 2600) | | Blood transfusion during surgery (any), n (%) | | | | Red blood cells | 2 (8.0) | 1 (3.6) | | Plasma | 0 | 0 | | Other | 0 | 0 | | Blood transfusion post-surgery (any), n (%) | 2 (8.0) | 1 (3.6) | PMA P240035/S002: FDA Summary of Safety and Effectiveness Data 19 {19} | **Table 7. Subject Demographic and Operative Characteristics (Safety Population)** | | | | --- | --- | --- | | | **ETHIZIA (n=25)** | **SURGICEL Original (n=28)** | | Abbreviations: BMI, body mass index; Max, maximum; Min, minimum; mL, milliliter; N, number of subjects in the Safety Population; n, number of subjects with available data in each category; SD, standard deviation. Notes: Percentages were based on the total of each categorical variable. Age is in years and is the age of the subject at the time of randomization; height was measured at the screening/baseline visit; weight was measured at admission before surgery. ^{a} The other indications of surgery were metastatic hurthle cell carcinoma, metastatic leiomyosarcoma of the liver, pneumobolia and contracted gallbladder, adenocarcinoma, metastatic (to liver) cutaneous malignant melanoma^{1}, and hepatic mass concerning for HCC-cancer. | | | Target bleeding site information is summarized Table 8 below. The majority of the first target bleeding sites bleeding surface type were either flat surface (ETHIZIA: N=13, 52.0%; SURGICEL Original: N=12, 42.9%) or irregular surface (ETHIZIA: N=11, 44.0%; SURGICEL Original: N=13, 46.4%). Only a few first target bleeding sites had a bleeding surface type being dimple or pit (ETHIZIA: N=1, 4.0%, SURGICEL Original N=3, 10.7%). The mean target bleeding site size for the first target bleeding site in the ETHIZIA treatment group was 6.2 cm² and for SURGICEL Original treatment group 5.4 cm². Both the ETHIZIA treatment group and SURGICEL Original treatment group first target bleeding sites had more venous bleeding (ETHIZIA: N=17, 68.0%; SURGICEL Original: N=17, 60.7%), followed by mixed (ETHIZIA: N=7, 28.0%, SURGICEL Original: N=9, 32.1%) and arterial (ETHIZIA: N=1, 4.0%, SURGICEL Original: N=2, 7.1%). The ETHIZIA treatment group had more first target bleeding sites with an SBSS 3 (N=9, 36.0%) compared to the SURGICEL Original Treatment group (N=6, 21.4%), while the SURGICEL Original Treatment group had more SBSS 1 (N=12, 42.9%) compared to the ETHIZIA treatment group (N=8, 32.0%). Use of primary hemostatic techniques prior to applying patch and assessing SBSS were done in 48.0% of the first target bleeding sites in the ETHIZIA treatment group and in 57.1% of the SURGICEL Original treatment group. As the Clinical Investigation Plan (CIP) allowed for multiple bleeding sites to be treated with the randomized product; an additional 10 bleeding sites were treated with ETHIZIA (N=35), and 1 additional bleeding site was treated with SURGICEL Original (N=29). For all treated target bleeding sites, bleeding site parameters for all target bleeding sites were generally similar to the first target bleeding site. PMA P240035/S002: FDA Summary of Safety and Effectiveness Data 20 {20} | **First Target Bleeding site** | | | | | --- | --- | --- | --- | | | **Description** | **ETHIZIA (N=25)** | **SURGICEL Original (N=28)** | | Estimated total transected parenchyma area of current bleeding surface, maximum width (cm) | n | 25 | 27 | | | Mean (SD) | 8.876 (6.7257) | 8.529 (5.5023) | | | Median | 8.00 | 7.00 | | | Min, Max | 1.00, 35.00 | 1.00, 19.50 | | Estimated total transected parenchyma area of current bleeding surface, maximum length (cm) | n | 25 | 27 | | | Mean (SD) | 7.18 (3.689) | 7.55 (5.294) | | | Median | 7.00 | 6.00 | | | Min, Max | 1.0, 14.2 | 0.6, 21.0 | | Estimated size of total transected parenchyma area of current bleeding site, width × length (cm^{2}) | n | 25 | 27 | | | Mean (SD) | 63.576 (44.6792) | 80.370 (84.4169) | | | Median | 50.00 | 48.00 | | | Min, Max | 1.00, 151.94 | 1.00, 285.00 | | Target Bleeding site, n (%) | Flat Surface | 13 (52.0) | 12 (42.9) | | | Irregular surface | 11 (44.0) | 13 (46.4) | | | Dimple or pit | 1 (4.0) | 3 (10.7) | | Estimated size of target bleeding site, width × length (cm^{2}) | Mean (SD) | 6.20 (7.7889) | 5.437 (4.5879) | | | Median | 4.0 | 4.0 | | | Min, Max | 1.00, 30.00 | 0.24, 18.00 | | Bleeding type, n (%) | Arterial | 1 (4.0) | 2 (7.1) | | | Venous | 17 (68.0) | 17 (60.7) | | | Mixed | 7 (28.0) | 9 (32.1) | | SBSS, n (%) | 1 | 8 (32.0) | 12 (42.9) | | | 2 | 8 (32.0) | 10 (35.7) | | | 3 | 9 (36.0) | 6 (21.4) | | Use of primary hemostatic techniques | Yes | 12 (48.0) | 16 (57.1) | | | Cautery | 8 (32.0) | 12 (42.9) | | | Clips | 1 (4.0) | 0 | | | Staples | 0 | 0 | | | Sutures/Ligatures | 2 (8.0) | 1 (3.6) | | | Other | 1 (4.0) | 3 (10.7) | | | No | 13 (52.0) | 12 (42.9) | | Pneumoperitoneum level (mmHg), n (%) | ≤ 9 | 0 | 0 | | | 10 | 3 (12.0) | 1 (3.6) | | | 11 | 1 (4.0) | 2 (7.1) | | | 12 | 4 (16.0) | 9 (32.1) | | | 13 | 1 (4.0) | 3 (10.7) | | | 14 | 9 (36.0) | 8 (28.6) | | | 15 | 7 (28.0) | 5 (17.9) | PMA P240035/S002: FDA Summary of Safety and Effectiveness Data 21 {21} # **Table 8. Bleeding Site Information (Safety Population)** Abbreviations: cm, centimeter; Max, maximum; Min, minimum; mmHg, millimeters of mercury; N, number of subjects in the Safety Population; n, number of subjects with available data in each category; SBSS, Surface Bleeding Severity Scale; SD, standard deviation. Note: The presented frequencies and the denominator used to calculate percentages were based on subjects in each group in the Safety Population. # Surgical Procedure The type of MIS was more frequently robotic (ETHIZIA treatment group: 68.0%; SURGICEL Original treatment group: 71.4%) compared to laparoscopic (ETHIZIA treatment group: 32.0%; SURGICEL Original treatment group: 28.6%). Three subjects in the SURGICEL Original treatment group (10.7%) and no subjects in the ETHIZIA treatment group required conversion to open surgery or the addition of a hand port. Of the conversions, none were related to the use of the product. The most common trocar size used for patch introduction was 12 mm (ETHIZIA treatment group: 96.0%; SURGICEL Original treatment group: 92.9%). Washout periods were observed prior to surgery for acetylsalicylic acid, antiplatelet therapy, anticoagulation medications, and IV heparin, as no subjects in either treatment group were using these antithrombotic medications at the time of surgery. Similarly, no subjects were receiving oral Coumadin within 2 days before surgery. Only 1 subject from the SURGICEL Original treatment group was receiving antiplatelet medication within 5 days prior to surgery. The extent of liver resection was balanced across the treatment groups, with the majority of subjects undergoing minor liver resection (segmentectomy, bisegmentectomy, non-anatomical wedge resection, and cholecystectomy); however, there was a notable difference ($\geq 10\%$) between the treatment groups in the frequency of bisegmentectomies (ETHIZIA treatment group: 28.0%; SURGICEL Original treatment group: 14.3%) and non-anatomical wedge resections (ETHIZIA treatment group: 12.0%; SURGICEL Original treatment group: 25.0%). Non-anatomic resection was more common across both treatment groups (ETHIZIA treatment group: 68.0%; SURGICEL Original treatment group: 67.9%) compared to anatomic resection. The mean estimated total size of all resected areas was similar across the treatment groups (ETHIZIA treatment group: 85.8 cm2; SURGICEL Original treatment group: 82.1 cm2). One subject in the SURGICEL Original treatment group required vascular reconstruction. No subjects had biliary tree reconstruction. Visible bile leakage that was surgically treated was also infrequent in both treatment groups; only 1 subject in the SURGICEL Original treatment group required surgical treatment of a bile leak. The most common type of resection method was vessel sealing system (ETHIZIA treatment group: 40.0%; SURGICEL Original treatment group: 32.1%), followed by the 'other' resection category (ETHIZIA treatment group: 40.0%; SURGICEL Original treatment group: 25.0%), which represents a combination of the methods PMA P240035/S002: FDA Summary of Safety and Effectiveness Data 22 {22} listed in Table 9; this table also includes the data of other possible resection methods used. Most subjects were not treated with a hepatic blood inflow reduction method (ETHIZIA treatment group: 72.0%; SURGICEL Original treatment group: 75.0%); for the remainder, the Pringle maneuver was the hepatic blood inflow reduction method used (ETHIZIA treatment group: 28.0%; SURGICEL Original treatment group: 25.0%), with a mean duration of which was shorter in the SURGICEL Original treatment group (ETHIZIA treatment group: 38.1 minutes; SURGICEL Original treatment group: 27.9 minutes). The most frequent type of hepatic parenchyma was normal (ETHIZIA treatment group: 76.0%; SURGICEL Original treatment group: 67.9%), followed by steatotic hepatic parenchyma, which was more frequent in the SURGICEL Original treatment group (17.9%) compared to the ETHIZIA treatment group (12.0%). The mean estimated blood loss during the procedures was similar across the treatment groups (ETHIZIA treatment group: 270.8 mL; SURGICEL Original treatment group: 226.4 mL). The numbers of subjects requiring intraoperative blood transfusions were similar across the treatment groups (2 subjects in the ETHIZIA treatment group versus 1 subject in the SURGICEL Original treatment group). All subjects had pneumoperitoneum reduced to 0 mm Hg for a period of at least 5 minutes, before the finalization of surgery. Surgical drains were used in 39.6% of all subjects without a meaningful difference between the treatment groups (ETHIZIA treatment group: 36%; SURGICEL Original treatment group 42.9%). | **Table 9. Surgical Procedure Data (Safety Population** | | | | | | --- | --- | --- | --- | --- | | **Category** | **Response/Description** | **ETHIZIA (N = 25)** | **SURGICEL Original (N = 28)** | **Overall (N = 53)** | | Type of MIS, n (%) | Total | 25 | 28 | 53 | | | Laparoscopic | 8 (32.0) | 8 (28.6) | 16 (30.2) | | | Robotic | 17 (68.0) | 20 (71.4) | 37 (69.8) | | Need to convert to open surgery or add hand port, n (%) | Total | 25 | 28 | 53 | | | Yes | 0 | 3 (10.7) | 3 (5.7) | | | No | 24 (96.0) | 25 (89.3) | 49 (92.5) | | | Missing | 1 (4.0) | 0 | 1 (1.9) | | Trocar size used for patch introduction, n (%) | Total | 25 | 28 | 53 | | | 12 mm | 24 (96.0) | 26 (92.9) | 50 (94.3) | | | 15 mm | 1 (4.0) | 2 (7.1) | 3 (5.7) | | | Other | 0 | 0 | 0 | | Subject was receiving acetylsalicylic acid up to time of surgery, n (%) | Total | 25 | 28 | 53 | | | Yes | 0 | 0 | 0 | | | No | 25 (100) | 28 (100) | 53 (100) | | Subject was receiving any other antiplatelet therapy up to time of surgery, n (%) | Total | 25 | 28 | 53 | | | Yes | 0 | 0 | 0 | | | No | 25 (100) | 28 (100) | 53 (100) | | | Total | 25 | 28 | 53 | PMA P240035/S002: FDA Summary of Safety and Effectiveness Data 23 {23} | Category | Response/Description | ETHIZIA (N = 25) | SURGICEL Original (N = 28) | Overall (N = 53) | | --- | --- | --- | --- | --- | | Subject was receiving anticoagulation up to time of surgery, n (%) | Yes | 0 | 0 | 0 | | | No | 25 (100) | 28 (100) | 53 (100) | | IV heparin within 12 hours before surgery, n (%) | Total | 25 | 28 | 53 | | | Yes | 0 | 0 | 0 | | | No | 25 (100) | 28 (100) | 53 (100) | | Oral Coumadin within 2 days before surgery, n (%) | Total | 25 | 28 | 53 | | | Yes | 0 | 0 | 0 | | | No | 25 (100) | 28 (100) | 53 (100) | | Antiplatelet medications within 5 days prior to surgery, n (%) | Total | 25 | 28 | 53 | | | Yes | 0 | 1 (3.6) | 1 (1.9) | | | No | 25 (100) | 27 (96.4) | 52 (98.1) | | Extent of resection, n (%) | Total | 25 | 28 | 53 | | | Cholecystectomy | 4 (16.0) | 5 (17.9) | 9 (17.0) | | | Left hemihepatectomy | 2 (8.0) | 2 (7.1) | 4 (7.5) | | | Right hemihepatectomy | 1 (4.0) | 2 (7.1) | 3 (5.7) | | | Extended left hemihepatectomy | 0 | 0 | 0 | | | Extended right hemihepatectomy | 0 | 0 | 0 | | | Segmentectomy | 8 (32.0) | 7 (25.0) | 15 (28.3) | | | Bisegmentectomy | 7 (28.0) | 4 (14.3) | 11 (20.8) | | | Trisegmentectomy | 0 | 0 | 0 | | | Non-anatomical wedge resection | 3 (12.0) | 7 (25.0) | 10 (18.9) | | | Missing | 0 | 1 (3.6) | 1 (1.9) | | Anatomic and non-anatomic resection, n (%) | Total | 25 | 28 | 53 | | | Anatomic | 7 (28.0) | 6 (21.4) | 13 (24.5) | | | Non-anatomic | 17 (68.0) | 19 (67.9) | 36 (67.9) | | | N/A | 1 (4.0) | 3 (10.7) | 4 (7.5) | | Estimated total size of all resection areas (cm^{2}) | n | 25 | 27 | 52 | | | Mean (SD) | 85.8 (82.64) | 82.1 (83.31) | 83.9 (82.20) | | | Median | 70.0 | 50.0 | 57.0 | | | Min, Max | 1, 325 | 1, 285 | 1, 325 | | Vascular reconstruction performed, n (%) | Total | 25 | 28 | 53 | | | Yes | 0 | 1 (3.6) | 1 (1.9) | | | No | 25 (100) | 27 (96.4) | 52 (98.1) | | Biliary tree reconstruction performed, n (%) | Total | 25 | 28 | 53 | | | Yes | 0 | 0 | 0 | | | No | 25 (100) | 28 (100) | 53 (100) | PMA P240035/S002: FDA Summary of Safety and Effectiveness Data 24 {24} | Category | Response/Description | ETHIZIA (N = 25) | SURGICEL Original (N = 28) | Overall (N = 53) | | --- | --- | --- | --- | --- | | Visible bile leakage that was surgically treated, n (%) | Total | 25 | 28 | 53 | | | Yes | 0 | 1 (3.6) | 1 (1.9) | | | No | 25 (100) | 27 (96.4) | 52 (98.1) | | Resection method, n (%) | Total | 25 | 28 | 53 | | | CUSA | 1 (4.0) | 1 (3.6) | 2 (3.8) | | | Harmonic scalpel | 2 (8.0) | 4 (14.3) | 6 (11.3) | | | Vessel sealing system | 10 (40.0) | 9 (32.1) | 19 (35.8) | | | Bipolar cauterizing scissors | 2 (8.0) | 5 (17.9) | 7 (13.2) | | | Non-cauterizing scissors | 0 | 2 (7.1) | 2 (3.8) | | | Other | 10 (40.0) | 7 (25.0) | 17 (32.1) | | Blood inflow reduction method, n (%) | Total | 25 | 28 | 53 | | | None | 18 (72.0) | 21 (75.0) | 39 (73.6) | | | Pringle maneuver | 7 (28.0) | 7 (25.0) | 14 (26.4) | | | Total vascular exclusion | 0 | 0 | 0 | | | Other | 0 | 0 | 0 | | Duration of blood inflow reduction (min) | n | 7 | 7 | 14 | | | Mean (SD) | 38.1 (20.89) | 27.9 (14.36) | 33.0 (18.03) | | | Median | 30.0 | 25.0 | 29.5 | | | Min, Max | 25, 84 | 15, 55 | 15, 84 | | Type of hepatic parenchyma, n (%) | Total | 25 | 28 | 53 | | | Normal | 19 (76.0) | 19 (67.9) | 38 (71.7) | | | Cirrhotic | 2 (8.0) | 3 (10.7) | 5 (9.4) | | | Steatotic | 3 (12.0) | 5 (17.9) | 8 (15.1) | | | Other | 1 (4.0) | 0 | 1 (1.9) | | | Missing | 0 | 1 (3.6) | 1 (1.9) | | Estimated blood loss during procedure (mL) | n | 25 | 28 | 53 | | | Mean (SD) | 270.8 (433.20) | 226.4 (502.27) | 247.4 (467.01) | | | Median | 100.0 | 50.0 | 100.0 | | | Min, Max | 5, 2000 | 5, 2600 | 5, 2600 | | Intraoperative blood transfusion, n (%) | Total | 25 | 28 | 53 | | | Yes | 2 (8.0) | 1 (3.6) | 3 (5.7) | | | No | 23 (92.0) | 27 (96.4) | 50 (94.3) | | Type of transfusion, n (%) | Total | 2 | 1 | 3 | | | Red blood cells | 2 (100) | 1 (100) | 3 (100) | | | Platelets | 0 | 0 | 0 | | | Plasma | 0 | 0 | 0 | | | N/A | 0 | 0 | 0 | PMA P240035/S002: FDA Summary of Safety and Effectiveness Data 25 {25} | Category | Response/Description | ETHIZIA (N = 25) | SURGICEL Original (N = 28) | Overall (N = 53) | | --- | --- | --- | --- | --- | | Units of red blood cell transfusion | n | 2 | 1 | 3 | | | Mean (SD) | 1.5 (0.71) | 2.0 (N/A) | 1.7 (0.58) | | | Median | 1.5 | 2.0 | 2.0 | | | Min, Max | 1, 2 | 2, 2 | 1, 2 | | Reason for transfusion, n (%) | Total | 2 | 1 | 3 | | | Preoperative low Hb | 0 | 0 | 0 | | | Intraoperative blood loss | 2 (100) | 1 (100) | 3 (100) | | | Combination of reasons | 0 | 0 | 0 | | | Other | 0 | 0 | 0 | | | N/A | 0 | 0 | 0 | | Any additional transfusion, n (%) | Total | 2 | 1 | 3 | | | Yes | 0 | 0 | 0 | | | No | 2 (100) | 1 (100) | 3 (100) | | Patch applied, n (%) | Total | 25 | 28 | 53 | | | Yes | 25 (100) | 28 (100) | 53 (100) | | Segments of the resection surface the patch was applied, n (%) | Total | 25 | 28 | 53 | | | 2 | 3 (12.0) | 2 (7.1) | 5 (9.4) | | | 2, 3 | 1 (4.0) | 1 (3.6) | 2 (3.8) | | | 2, 4 | 0 | 1 (3.6) | 1 (1.9) | | | 3 | 0 | 2 (7.1) | 2 (3.8) | | | 4 | 0 | 2 (7.1) | 2 (3.8) | | | 4B | 0 | 1 (3.6) | 1 (1.9) | | | 4B, 7 | 1 (4.0) | 0 | 1 (1.9) | | | 4a | 0 | 1 (3.6) | 1 (1.9) | | | 4b | 2 (8.0) | 4 (14.3) | 6 (11.3) | | | 5 | 1 (4.0) | 1 (3.6) | 2 (3.8) | | | 6 | 2 (8.0) | 0 | 2 (3.8) | | | 7 | 4 (16.0) | 0 | 4 (7.5) | | | 8 | 0 | 1 (3.6) | 1 (1.9) | | | Bed of the gallbladder in lap cholecystectomy | 1 (4.0) | 0 | 1 (1.9) | | | Cut Surface of segment 5/6 | 1 (4.0) | 0 | 1 (1.9) | | | Cut surface of Segments 5 and 7 | 1 (4.0) | 0 | 1 (1.9) | | | Cut surface of liver remnant | 0 | 2 (7.1) | 2 (3.8) | | | Cut surface of segment 3 | 1 (4.0) | 0 | 1 (1.9) | | | Cut surface of segment 7 | 0 | 1 (3.6) | 1 (1.9) | | | Cut surface of segments 5 & 8 | 0 | 1 (3.6) | 1 (1.9) | PMA P240035/S002: FDA Summary of Safety and Effectiveness Data 26 {26} **Table 9. Surgical Procedure Data (Safety Population)** | Category | Response/ Description | ETHIZIA (N = 25) | SURGICEL Original (N = 28) | Overall (N = 53) | | --- | --- | --- | --- | --- | | | Deep resection margin | 1 (4.0) | 0 | 1 (1.9) | | | Gallbladder bed | 0 | 1 (3.6) | 1 (1.9) | | | Gallbladder fossa | 2 (8.0) | 0 | 2 (3.8) | | | IV and V | 0 | 1 (3.6) | 1 (1.9) | | | Left Lateral Segment 2 | 1 (4.0) | 0 | 1 (1.9) | | | Segment 4B | 1 (4.0) | 1 (3.6) | 2 (3.8) | | | Segment 5 | 1 (4.0) | 1 (3.6) | 2 (3.8) | | | Segment 6 | 1 (4.0) | 1 (3.6) | 2 (3.8) | | | Segment 8 | 0 | 1 (3.6) | 1 (1.9) | | | V | 0 | 1 (3.6) | 1 (1.9) | | | VI | 0 | 1 (3.6) | 1 (1.9) | | Segments of the resection surface the additional patches were applied, n (%) | Total | 8 | 0 | 8 | | | 4B, 7 | 1 (12.5) | 0 | 1 (12.5) | | | 4b | 1 (12.5) | 0 | 1 (12.5) | | | 7 | 2 (25.0) | 0 | 2 (25.0) | | | All placed on segment 5 | 1 (12.5) | 0 | 1 (12.5) | | | Cut segments of 5 and 7 | 1 (12.5) | 0 | 1 (12.5) | | | Cut surface of segment 5/6 | 1 (12.5) | 0 | 1 (12.5) | | | Deep resection margin | 1 (12.5) | 0 | 1 (12.5) | | Was pneumoperitoneum reduced to 0 mmHg for a period of at least 5 minutes, before finalization of surgery, n (%) | Total | 25 | 28 | 53 | | | Yes | 25 (100) | 28 (100) | 53 (100) | | | No | 0 | 0 | 0 | | Use of surgical drains, n (%) | Total | 25 | 28 | 53 | | | Yes | 9 (36.0) | 12 (42.9) | 21 (39.6) | | | No | 16 (64.0) | 16 (57.1) | 32 (60.4) | | Occurrence of any surgical complications impacting postoperative outcomes, or AEs, during surgery, n (%) | Total | 25 | 28 | 53 | | | Yes | 0 | 2 (7.1) | 2 (3.8) | | | No | 25 (100) | 26 (92.9) | 51 (96.2) | | Abbreviations: AE, adverse event; CUSA, Cavitron Ultrasonic Surgical Aspirator; Hb, hemoglobin; IV, intravenous; Max, maximum; Min, minimum; MIS, minimally invasive surgery; mL milliliter; mmHG, millimeters of mercury; N, number of subjects in the Safety Population; n, number of subjects with available data in each category; N/A, not applicable; SD, standard deviation. | | | | | | Note: Percentages were based on the total of each categorical variable. | | | | | PMA P240035/S002: FDA Summary of Safety and Effectiveness Data 27 {27} ## Device Handling Device handling is summarized in Table 10 for the Safety Population. Across both treatment groups, most subjects had 1 piece of patch introduced through the trocar for the first target bleeding site (ETHIZIA treatment group 76%; SURGICEL Original 92.9%). Two pieces of patch were introduced through the trocar for the remainder of first target bleeding sites for each subject; no subjects had $\geq 3$ pieces of patch introduced through the trocar to treat the subjects' first target bleeding sites. In the ETHIZIA treatment group, the majority of patches introduced through the trocar for the first target bleeding site across all subjects were cut into half sized pieces, followed by patches that were full sized and patches that were cut into one-third- or one-fourth-sized pieces; in the SURGICEL Original treatment group, the majority of patches introduced through the trocar for the first target bleeding site across all subjects in this treatment group were patches that were full sized, followed by patches that were cut into half sized pieces and patches that were cut into one-third- or one-fourth-sized pieces. Across both treatment groups, all of these (pieces of) patches were successfully introduced through the trocar to the subjects' first target bleeding sites (ETHIZIA treatment group: 31 pieces of patch across all 25 subjects' first target bleeding sites; SURGICEL Original treatment group: 30 pieces of patch across all 28 subjects' first target bleeding sites). In the ETHIZIA treatment group, after successful trocar introduction, 1 piece of patch was not successfully maneuvered to a subject's first target bleeding site and thus could not successfully be positioned on the bleeding site where sufficient pressure could be applied to control the bleed; however, the remaining 30 pieces of patch were successfully maneuvered and successfully positioned, and sufficient pressure was applied. In the SURGICEL Original treatment group, all 30 pieces of patch were successfully maneuvered and successfully positioned, and sufficient pressure was applied to the subjects' first target bleeding sites. Device handling data for all target bleeding sites was generally similar to the first target bleeding site. PMA P240035/S002: FDA Summary of Safety and Effectiveness Data 28 {28} **Table 10. Device Handling (Safety Population)** | | | ETHIZIA (N = 25) n (%) | SURGICEL Original (N = 28) n (%) | | --- | --- | --- | --- | | **Number of First Target Bleeding Sites** | **n** | **25** | **28** | | Number of pieces of patch that were introduced through the trocar for the first target bleeding site for each subject^{a} | 1 | 19 (76.0) | 26 (92.9) | | | 2 | 6 (24.0) | 2 (7.1) | | | ≥ 3 | 0 | 0 | | Total number of pieces of patch introduced through the trocar for the first target bleeding site across all subjects^{b} | n | 31 | 30 | | Proportion of patch introduced through the trocar^{c} | 1/4 | 2 (6.5) | 3 (10.0) | | | 1/3 | 2 (6.5) | 4 (13.3) | | | 1/2 | 15 (48.4) | 6 (20.0) | | | 1 | 12 (38.7) | 17 (56.7) | | | Other | 0 | 0 | | Piece of patch was successfully introduced^{c} | Yes | 31 (100) | 30 (100) | | | No | 0 | 0 | | Piece of patch was successfully maneuvered to the target bleeding site^{c} | Yes | 30 (96.8) | 30 (100) | | | No | 1 (3.2) | 0 | | Piece of patch was successfully positioned on the bleeding site^{c} | Yes | 30 (96.8) | 30 (100) | | | No | 1 (3.2) | 0 | | Sufficient pressure was provided on the entire surface of the piece of patch with minimally invasive tools^{c} | Yes | 30 (96.8) | 30 (100) | | | No | 1 (3.2) | 0 | | | | | | | **Number of All Target Bleeding Sites** | **n** | **35** | **29** | | Number of pieces of patch that were introduced through the trocar for all target bleeding sites for each subject^{d} | 1 | 27 (77.1) | 27 (93.1) | | | 2 | 8 (22.9) | 2 (6.9) | | | ≥ 3 | 0 | 0 | | Total number of pieces of patch introduced through the trocar for all target bleeding sites across all subjects^{b} | n | 43 | 31 | | Proportion of patch introduced through the trocar^{c} | 1/4 | 6 (14.0) | 3 (9.7) | | | 1/3 | 4 (9.3) | 5 (16.1) | | | 1/2 | 20 (46.5) | 6 (19.4) | | | 1 | 12 (27.9) | 17 (54.8) | | | Other (3×5 cm) | 1 (2.3) | 0 | PMA P240035/S002: FDA Summary of Safety and Effectiveness Data 29 {29} **Table 10. Device Handling (Safety Population)** | | | ETHIZIA (N = 25) n (%) | SURGICEL Original (N = 28) n (%) | | --- | --- | --- | --- | | Piece of patch was successfully introduced^{a} | Yes | 43 (100) | 31 (100) | | | No | 0 | 0 | | Piece of patch was successfully maneuvered to the target bleeding site^{c} | Yes | 40 (93.0) | 31 (100) | | | No | 3 (7.0) | 0 | | Piece of patch was successfully positioned on the bleeding site^{c} | Yes | 39 (90.7) | 31 (100) | | | No | 4 (9.3) | 0 | | Sufficient pressure was provided on the entire surface of the piece of patch with minimally invasive tools^{c} | Yes | 39 (90.7) | 31 (100) | | | No | 4 (9.3) | 0 | Abbreviations: N, number of subjects in the Safety Population; n, number of subjects/bleeding sites with available data in each category. - a. Percentages were based on the number of first target bleeding sites. - b. The total number of pieces of patch introduced was the sum of all pieces of patch across all subjects. - c. Percentages were based on the total number of pieces of patch introduced through the trocar. - d. Percentages were based on the number of all target bleeding sites. Notes: Subjects may have had multiple patches used within the same group. ## **D. Safety and Effectiveness Results** ### **1. Safety** The analysis of safety was based on all randomized subjects who received treatment with ETHIZIA (25) and SURGICEL Original (28). The key safety outcomes for this study are presented below in Tables 11 to 12. Adverse effects are reported in Table 13. Overall, 30 (56.6%) subjects experienced at least 1 AE (73 events) as reported in Table 11 below. The percentage of subjects with at least 1 AE was 60.0% in the ETHIZIA treatment group (34 events in 15 subjects) and 53.6% in the SURGICEL Original treatment group (39 events in 15 subjects). Overall, 5 (9.4%) subjects experienced at least 1 device-related AE per investigator assessment (i.e., ADE) (5 events). The percentage of subjects with device-related AEs per investigator assessment was 4.0% in the ETHIZIA treatment group (1 event in 1 subject) and 14.3% in the SURGICEL Original treatment group (4 events in 4 subjects). Adverse Events related to device application were defined as AEs associated with the application of the device (but not the device itself or other procedures of the surgery). Overall, 2 (3.8%) subjects experienced at least 1 device application-related AE per PMA P240035/S002: FDA Summary of Safety and Effectiveness Data 30 {30} investigator assessment (2 events). The percentage of subjects with device application-related AEs per investigator assessment was 4.0% in the ETHIZIA treatment group (1 event in 1 subject) and 3.6% in the SURGICEL Original treatment group (1 event in 1 subject). Overall, 6 (11.3%) subjects experienced at least 1 SAE (10 events). The percentage of subjects with SAEs was 16.0% in the ETHIZIA treatment group (5 events in 4 subjects) and 7.1% in the SURGICEL Original treatment group (5 events in 2 subjects). No subjects experienced SAEs that were considered device-related per investigator assessment (i.e., SADEs). The percentage of subjects with AEs leading to device removal was 4.0% in the ETHIZIA treatment group where (1 event in 1 subject) and 14.3% in the SURGICEL Original treatment group (4 events in 4 subjects). All AEs leading to device removal had a preferred term (PT) of application site haemorrhage. Device deficiencies were uncommon, affecting 1 (4.0%) subject in the ETHIZIA treatment group where it was reported that the patches (2 pieces of patch from 1 patch in total) became too soiled with blood prior to placement at the second target bleeding site (for usability of the patch). There was no device deficiencies reported for the SURGICEL Original treatment group. **Table 11. Overall Summary of Adverse Events (Safety Population)** | Category | ETHIZIA (N = 25) n (%) e | SURGICEL Original (N = 28) n (%) e | Overall (N = 53) n (%) e | | --- | --- | --- | --- | | At least 1 AE | 15 (60.0) 34 | 15 (53.6) 39 | 30 (56.6) 73 | | At least 1 SAE | 4 (16.0) 5 | 2 (7.1) 5 | 6 (11.3) 10 | | At least 1 device-related AE per investigator assessment | 1 (4.0) 1 | 4 (14.3) 4 | 5 (9.4) 5 | | At least 1 device application-related AE per investigator assessment | 1 (4.0) 1 | 1 (3.6) 1 | 2 (3.8) 2 | | At least 1 AE leading to device removal | 1 (4.0) 1 | 4 (14.3) 4 | 5 (9.4) 5 | | At least 1 AE leading to death | 0 | 0 | 0 | | At least 1 AESI | 5 (20.0) 7 | 5 (17.9) 7 | 10 (18.9) 14 | Abbreviations: AE, adverse event; AESI, adverse event of special interest; e, number of events; N, number of subjects in the Safety Population; n, number of subjects with data available in each category; SAE, serious adverse event. Notes: Percentages were based on the number of subjects in each group in the Safety Population. AEs were considered to be related to procedure/device, unless the relationship was “not related.” AEs with missing relationship were considered to be related. PMA P240035/S002: FDA Summary of Safety and Effectiveness Data 31 {31} All device-related AEs per investigator assessment (i.e., ADEs) are summarized by SOC and PT in Table 12. Overall, 5 (9.4%) subjects experienced at least 1 device-related AE per investigator assessment (5 events). The percentage of subjects with device-related AEs per investigator assessment was 4.0% in the ETHIZIA treatment group (1 event in 1 subject) and 14.3% in the SURGICEL Original treatment group (4 events in 4 subjects). All device-related AEs per investigator assessment were from the PT of application site haemorrhage. All device-related AEs per investigator assessment were considered AESIs. | Table 12. Device-related Adverse Events Per Investigator Assessment by System Organ Class and Preferred Term (Safety Population) | | | | | --- | --- | --- | --- | | System Organ Class Preferred Term | ETHIZIA (N = 25) n (%) e | SURGICEL Original (N = 28) n (%) e | Overall (N = 53) n (%) e | | At least 1 device-related AE per investigator assessment | 1 (4.0) 1 | 4 (14.3) 4 | 5 (9.4) 5 | | General disorders and administration site conditions | 1 (4.0) 1 | 4 (14.3) 4 | 5 (9.4) 5 | | Application site haemorrhage | 1 (4.0) 1 | 4 (14.3) 4 | 5 (9.4) 5 | | Abbreviations: AE, adverse event; e, event count; MedDRA, Medical Dictionary for Regulatory Activities; N, number of subjects in the Safety Population; n, number of subjects with available data in each category. | | | | | Notes: Percentages were based on the number of subjects in each group in the Safety Population. | | | | | AEs were coded using MedDRA v28.0. | | | | ### Serious Adverse Events All Serious Adverse Events (SAEs) are summarized by system organ class (SOC) and PT in Table 13 below. Overall, 6 (11.3%) subjects experienced at least 1 SAE (10 events). The percentage of subjects with SAEs was 16.0% in the ETHIZIA treatment group (5 events in 4 subjects) and 7.1% in the SURGICEL Original treatment group (5 events in 2 subjects). The most commonly recorded SAE SOC in the ETHIZIA treatment group was vascular disorders (8.0% of subjects; 2 subjects with 1 event each); all other SAE SOCs occurred in ≤ 1 subject. In the SURGICEL Original treatment group, all SAE SOCs occurred in ≤ 1 subject. There were no AEs leading to death in either treatment group Across both treatment groups, all SAE PTs occurred as single events. PMA P240035/S002: FDA Summary of Safety and Effectiveness Data 32 {32} Table 13. All Serious Adverse Events by System Organ Class and Preferred Term (Safety Population) | System Organ Class Preferred Term | ETHIZIA (N = 25) n (%) e | SURGICEL Original (N = 28) n (%) e | Overall (N = 53) n (%) e | | --- | --- | --- | --- | | At least 1 SAE | 4 (16.0) 5 | 2 (7.1) 5 | 6 (11.3) 10 | | Vascular disorders | 2 (8.0) 2 | 1 (3.6) 1 | 3 (5.7) 3 | | Hypotension | 1 (4.0) 1 | 1 (3.6) 1 | 2 (3.8) 2 | | Deep vein thrombosis | 1 (4.0) 1 | 0 | 1 (1.9) 1 | | Gastrointestinal disorders | 1 (4.0) 1 | 1 (3.6) 1 | 2 (3.8) 2 | | Vomiting | 1 (4.0) 1 | 1 (3.6) 1 | 2 (3.8) 2 | | Respiratory, thoracic and mediastinal disorders | 1 (4.0) 1 | 1 (3.6) 1 | 2 (3.8) 2 | | Acute respiratory failure | 0 | 1 (3.6) 1 | 1 (1.9) 1 | | Pulmonary embolism | 1 (4.0) 1 | 0 | 1 (1.9) 1 | | Blood and lymphatic system disorders | 0 | 1 (3.6) 1 | 1 (1.9) 1 | | Blood loss anaemia | 0 | 1 (3.6) 1 | 1 (1.9) 1 | | General disorders and administration site conditions | 1 (4.0) 1 | 0 | 1 (1.9) 1 | | Non-cardiac chest pain | 1 (4.0) 1 | 0 | 1 (1.9) 1 | | Injury, poisoning and procedural complications | 0 | 1 (3.6) 1 | 1 (1.9) 1 | | Procedural pain | 0 | 1 (3.6) 1 | 1 (1.9) 1 | Abbreviations: AE, adverse event; e, event count; MedDRA, Medical Dictionary for Regulatory Activities; N, number of subjects in the Safety Population; n, number of subjects with data available in each category; SAE, serious adverse event. Notes: Percentages were based on the number of subjects in each group in the Safety Population. AEs were coded using MedDRA v28.0. ### Adverse Events of Special Interest The following AESI categories were defined for this trial: bleeding-related events (4 events in ETHIZIA treatment group, 7 in SURGICEL Original treatment group), thromboembolic events (1 event in ETHIZIA treatment group, 0 in SURGICEL Original treatment group), biloma (1 event in ETHIZIA treatment group, 0 in SURGICEL Original), and allergic reaction (0 events). Of the AESIs, only bleeding-related AESIs were considered to have a (possible) relationship with the device: - Application site hemorrhage: PMA P240035/S002: FDA Summary of Safety and Effectiveness Data 33 {33} Three (12.0%) subjects from the ETHIZIA treatment group experienced a bleeding-related AESI under the PT of application site hemorrhage (3 events). The AESIs of application sites were non-serious. Two of the AESIs were considered not related to the device per investigator assessment and 1 event was considered to be causally related to the investigator assessment. Four (14.3%) subjects from the SURGICEL Original treatment group experienced a bleeding-related AESI under the PT of application site hemorrhage (4 events). The AESIs of application site hemorrhages were non-serious. The AESIs was considered probably related to the device per investigator assessment (2 events) or causally related per investigator assessment (2 events). - Abnormal uterine bleeding: Not applicable for ETHIZIA. One (3.6%) subject from the SURGICEL Original treatment group experienced a bleeding-related AESI under the PT of abnormal uterine bleeding. The AESI of abnormal uterine bleeding was non-serious. Causality to the device was excluded by the investigator (i.e., identified as not related). - Blood loss anemia: Not applicable for ETHIZIA. One (3.6%) subject from the SURGICEL Original treatment group experienced a bleeding-related AESI under the PT of blood loss anaemia, which occurred during surgery and was described as acute blood loss anemia from multiple venous branches within the liver parenchyma despite inflow control to the right liver. The AESI of blood loss anaemia was serious. Causality to the device was excluded by the investigator (i.e., identified as not related). - Incision site discharge: Not applicable for ETHIZIA. One (3.6%) subject from the SURGICEL Original treatment group experienced a bleeding-related AESI under the PT of incision site discharge. The AESI of incision site discharge was non-serious. Causality to the device was excluded by the investigator (i.e., identified as not related). - Intra-abdominal hematoma: One (4.0%) subject from the ETHIZIA treatment group experienced a bleeding-related AESI under the PT of intra-abdominal haematoma. The AESI of intra-abdominal haematoma was non-serious. Causality to the device was excluded by the investigator (i.e., identified as not related). Not applicable for SURGICEL Original. PMA P240035/S002: FDA Summary of Safety and Effectiveness Data 34 {34} # Exploratory Endpoint results: No subjects in the ETHIZIA treatment group had a conversion from minimally invasive to open surgery. One (3.6%) subject in the SURGICEL Original treatment group had a conversion from minimally invasive (laparoscopic surgery) to open surgery. The conversion was not due to issues with hemostasis at the target bleeding site or the hemostatic patch. No subjects in the ETHIZIA treatment group required the addition of a hand port. Two subjects in the SURGICEL Original treatment group required the addition of a hand port. These additions were not due to issues with hemostasis at the target bleeding site or the hemostatic patch. The mean duration of the procedure was similar across the treatment groups (ETHIZIA treatment group: 164.7 minutes; SURGICEL Original treatment group: 170.9 minutes). Most subjects were not treated with a hepatic blood inflow reduction method (ETHIZIA treatment group: 72.0%; SURGICEL Original treatment group: 75.0%); for the remainder, the Pringle maneuver was the hepatic blood inflow reduction method used (ETHIZIA treatment group: 28.0%; SURGICEL Original treatment group: 25.0%), with a mean duration of which was shorter in the SURGICEL Original treatment group (ETHIZIA treatment group: 38.1 minutes; SURGICEL Original treatment group: 27.9 minutes). The mean estimated total blood loss during surgery was similar across the treatment groups (ETHIZIA treatment group: 270.8 mL; SURGICEL Original treatment group: 226.4 mL). The means in both treatment groups were impacted by 2 subjects (1 in each treatment group) with high total intraoperative blood losses (≥ 2000 mL), unrelated to the randomized treatment. There were 3 subjects that required transfusions during hospitalization after surgery. In the ETHIZIA treatment group, 2 (8.0%) subjects were administered red blood cell transfusions. In the SURGICEL Original treatment group, 1 (3.6%) subject was administered red blood cell and plasma transfusions. In the ETHIZIA treatment group, no (0%) subjects were admitted to the ICU following surgery, compared to 2 (7.1%) subjects in the SURGICEL Original treatment group, with the admitted subjects staying between 1 to 4 days in the ICU. The number of subjects requiring hospitalization following surgery was similar across the treatment groups (21 [84.0%] subjects in the ETHIZIA treatment group and 24 [85.7%] subjects in the SURGICEL Original treatment group). For subjects hospitalized following surgery, the total median hospitalization time was the same for subjects in the ETHIZIA treatment group (3.8 days) and the SURGICEL Original treatment group (3.9 days). A lower proportion of subjects in the ETHIZIA treatment group (36.0%) required a drain to be placed during surgery compared to the SURGICEL Original treatment group (46.4%). The median (minimum, maximum) postoperative drainage duration was similar for the ETHIZIA treatment group (43.5 [4, 172] hours) and the PMA P240035/S002: FDA Summary of Safety and Effectiveness Data 35 {35} SURGICEL Original treatment group (48.0 [1, 240] hours). The median (minimum, maximum) volume of drainage was higher for the ETHIZIA treatment group (226.0 [99, 780] mL), compared to the SURGICEL Original treatment group (160.0 [10, 669] mL). Characteristics of postoperative drained fluid were similar for both treatment groups, with serosanguinous being the most common characteristic across both treatment groups. The median (minimum, maximum) bilirubin measured in drainage fluid was similar for the ETHIZIA treatment group (0.90 [0.4, 1.0] mg/dL), compared to the SURGICEL Original treatment group (0.90 [0.50, 1.6] mg/dL). No subjects underwent reoperation as a result of an SAE. At Week 6 imaging, there were no instances of device encapsulation, devic…
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