OrganOx metra System

P200035 · Organox Limited · QQK · Dec 9, 2021 · Gastroenterology, Urology

Device Facts

Record IDP200035
Device NameOrganOx metra System
ApplicantOrganox Limited
Product CodeQQK · Gastroenterology, Urology
Decision DateDec 9, 2021
DecisionAPPR
Device ClassClass 3
AttributesTherapeutic

Indications for Use

The OrganOx metra® is a transportable device intended to be used to sustain donor livers destined for transplantation in a functioning state for a total preservation time of up to 12 hours. The OrganOx metra® device is suitable for liver grafts from donors after brain death (DBD), or liver grafts from donors after circulatory death (DCD) ≤40 years old, with ≤20 mins of functional warm ischemic time (time from donor systolic blood pressure <50 mmHg), and macrosteatosis ≤15%, in a near-physiologic, normothermic and functioning state intended for a potential transplant recipient.

Device Story

The OrganOx metra® is a transportable, normothermic machine perfusion system that sustains donor livers ex-vivo for up to 12 hours. It consists of a reusable Retained Unit (centrifugal pump, oxygen concentrator, heat exchanger, blood gas analyzer) and a sterile, single-use Disposable Set (tubing, reservoir, organ bowl, cannulas). The device maintains the liver in a near-physiologic state by circulating oxygenated, nutrient-enriched blood-based perfusate. It automatically controls arterial and IVC pressures, monitors flow rates, and adjusts gas influx and temperature to maintain pO2, pCO2, and 37°C. Insulin, nutrition, and bile salts are infused to support metabolism. Operated by trained personnel, the system provides real-time quantitative data (pressures, flows, blood gases, bile production) via a GUI. This allows clinicians to assess graft viability before transplantation, potentially reducing preservation injury and post-reperfusion syndrome compared to static cold storage.

Clinical Evidence

Evidence from two randomized controlled trials (US IDE WP01, n=266; COPE WP02, n=222). Primary endpoint (EAD) in US study did not meet superiority (ITT: 20.6% NMP vs 23.7% SCS, p=0.275). COPE study showed 49.4% reduction in peak AST (p<0.001) and 74% lower odds of EAD in NMP arm. Both studies showed comparable 12-month graft/patient survival. NMP arm showed reduced post-reperfusion syndrome and lower peak transaminases. Safety profile was comparable to SCS.

Technological Characteristics

Electromechanical system; reusable Retained Unit and single-use Disposable Set. Materials: biocompatible plastics/tubing. Sensing: flow sensors, pressure sensors, blood gas analyzer (pO2, pCO2, pH). Actuation: centrifugal pump, proportional pinch valves, syringe pumps. Energy: mains/battery. Connectivity: wireless monitoring. Sterilization: Ethylene Oxide (disposables). Software: rule-based control algorithm for hemodynamic and thermal regulation.

Indications for Use

Indicated for donor livers (DBD or DCD ≤40 years old, ≤20 mins functional warm ischemia, ≤15% macrosteatosis) destined for transplantation. Contraindicated for living donor livers, split transplants, or recipients requiring ventilator support, inotropic support, renal replacement therapy, or those with acute/fulminant liver failure (UNOS 1A) or simultaneous organ transplantation.

Regulatory Classification

Identification

The device is intended for machine preservation of donor livers prior to transplantation.

Predicate Devices

Related Devices

Submission Summary (Full Text)

{0} SUMMARY OF SAFETY AND EFFECTIVENESS DATA (SSED) I. GENERAL INFORMATION Device Generic Name: Organ Preservation System Device Trade Name: OrganOx metra® System Device Procode: QQK Applicant’s Name and Address: OrganOx, Limited Oxford Science Park Magdalen Centre Robert Robinson Avenue Oxford OX4 4GA, UK Date(s) of Panel Recommendation: None Premarket Approval Application (PMA) Number: P200035 Date of FDA Notice of Approval: 12/9/2021 II. INDICATIONS FOR USE The OrganOx metra® is a transportable device intended to be used to sustain donor livers destined for transplantation in a functioning state for a total preservation time of up to 12 hours. The OrganOx metra® device is suitable for liver grafts from donors after brain death (DBD), or liver grafts from donors after circulatory death (DCD) ≤40 years old, with ≤20 mins of functional warm ischemic time (time from donor systolic blood pressure &lt;50 mmHg), and macrosteatosis ≤15%, in a near-physiologic, normothermic and functioning state intended for a potential transplant recipient. III. CONTRAINDICATIONS The OrganOx metra® should not be used for: A. Living donor liver B. Liver intended for split transplant PMA P200035: FDA Summary of Safety and Effectiveness Data Page 1 of 96 {1} C. Recipients requiring all of the following at the time of transplantation: - Oxygen therapy via a ventilator/respirator - Inotropic support - Renal replacement therapy - Acute/fulminant liver failure (UNOS status 1A) - Simultaneous organ transplantation ## IV. WARNINGS AND PRECAUTIONS A device malfunction or user error could lead to loss of a donor organ. Only trained and certified users should use the OrganOx metra® with the continuous support from OrganOx. The complete list of warnings and precautions can be found in the Organ Ox metra® System labeling. ## V. DEVICE DESCRIPTION ### A. Overview of the Device System The OrganOx metra® is a transportable device for sustaining donor livers outside the body in a near-physiologic, normothermic, and perfused state. It is intended to be used to transport donor livers destined for transplantation and can sustain them for periods up to 12 hours. The device is comprised of three main components as described below: **OrganOx metra® Retained Unit**: This is an electromechanical device that incorporates a centrigufal pump, oxygen concentrator, heat exchanger, and blood gas analyzer. These subassemblies are largely independent, but cooperate with each other under software control and are contained in the base unit. **OrganOx metra® Liver Perfusion Circuit (Disposable Set)**: The disposable set is a sterile, single-use perfusion circuit that maintains livers in a physiologic environment and has embedded sensors to control and monitor the perfusion parameters and bile production. **OrganOx metra® Sodium Taurocholate**: Sodium Taurocholate is infused into the circulating perfusate to replenish bile salt levels during ex-vivo perfusion on the OrganOx metra®. The OrganOx metra® is shown in Figure 1. PMA P200035: FDA Summary of Safety and Effectiveness Data Page 2 of 96 {2} ![img-0.jpeg](img-0.jpeg) Figure 1: Components of the OrganOx metra® System. The figure shows the Liver Perfusion Circuit (Disposable Set) mounted on the Retained Unit The OrganOx metra® Liver Perfusion Circuit Pack is used with the Retained Unit of the OrganOx metra® and contains all the disposables required for one liver perfusion. The OrganOx metra® Liver Perfusion Circuit Pack is supplied as a single-use device that has been sterilized by Ethylene Oxide by a subcontractor to OrganOx Ltd. and is connected to the device prior to the retrieval team accepting the organ. Venous blood exits the liver through the inferior vena cava (IVC) cannula and enters it through the arterial and portal cannulas. Excess blood is stored in the reservoir. Arterial and IVC pressures are directly measured and controlled; the rotation speed of the centrifugal pump and the degree of construction of the proportional pinch valve are adjusted in tandem until the IVC pressure falls within the range of -1 to $2\mathrm{mmHg}$ and the arterial pressure is in the range of $60 - 75\mathrm{mmHg}$ . Portal pressure is not controlled, and blood flows into the portal cannula from the reservoir under the effect of gravity. Both IVC and portal flows are directly measured, but not controlled; the portal flow sensor simultaneously functions as both a bubble detector and triggers an immediate shutdown of the portal pinch valve if air is detected to prevent air entrainment into the liver. During liver perfusion, blood passes through a combined oxygenator and heat exchanger. Based on inline measurements of partial pressure of oxygen, carbon dioxide, and temperature obtained by means of an integrated blood gas analyzer, the ratio of oxygen to air gas influx and inlet water temperature to the oxygenator are adjusted to maintain pO2 in the range of 12-18 kPa, pCO2 in the range of 4-7 kPa, and temperature at $37^{\circ}\mathrm{C}$ . During perfusion, the liver will normally "sweat" ascites and produce bile via the biliary duct. PMA P200035: FDA Summary of Safety and Effectiveness Data {3} Ascites can drain into the liver bowl through a perforated liver sling; the level of ascites in the bowl is automatically sensed via a level switch. When ascites within the collection bowl exceeds a predetermined level, a roller pump is activated, which returns ascites to the reservoir to maintain a constant perfusate volume. The throughput of bile excreted via the bile cannula is discarded and stored in a separate bile sump compartment within the liver bowl. To maintain cellular metabolism, the liver receives nutrition via a roller pump and insulin through the syringe pump. Insulin is infused at a constant rate whilst the nutrition pump is started once when the glucose falls below a threshold in accordance with the last glucose value entered by the user. Heparin, prostacyclin and bile salts are infused at a constant rate via the syringe driver pump in order to prevent clotting, provide vasodilation, and assist with bile production. The principle of the design of the OrganOx metra® is detailed in Figure 2. ![img-1.jpeg](img-1.jpeg) Figure 2: OrganOx metra® principles of operation ## B. Retained Unit (Product Code D0003) The reusable base unit implements a software-control algorithm that controls the perfusion function and allows for monitoring and adjustment of perfusion parameters. The device provides users with quantitative data acquired during perfusion, including: - Arterial and IVC pressures - Portal, arterial, and IVC flow rates - pO2, pCO2, and pH - Blood temperature - Glucose reading (latest manual input and time of manual input) - Bile production - Organ perfusion time PMA P200035: FDA Summary of Safety and Effectiveness Data Page 4 of 96 {4} - System status information, warning messages, and alarms ## C. Disposable Set (Product Code D0146) The Disposable Set used with the Retained Unit of the OrganOx metra® contains all the disposables required for organ perfusion. This includes: - A sterile tubing set containing a blood reservoir, perfusion lines, a blood oxygenator, centrifugal pump head, flow sensors, and pressure sensors - A sterile organ storage bowl (also called Liver Bowl), which is preconnected to the tubing set described above to retain the organ while on the device - Sterile cannulas for the hepatic artery, portal vein, and inferior vena cava with easy connection attachment to the perfusion circuit - Blood gas sensors for monitoring pO2, pCO2, and pH by means of online blood gas analysis - Sodium Taurocholate, provided as a sterile, lyophilized powder (see section below) ## D. Perfusion Solutions Note: All solutions required for the operation of the metra® (apart from the Sodium Taurocholate) are routinely available and are not supplied as part of the metra® device. Sodium Taurocholate (Product Code C0364) is manufactured from cholic acid and is provided as component of the Disposable Set. It is a nature-equivalent compound, chemically identical to the natural compound produced in the liver of many animal species. The perfusion solutions include bolus injections (given at the start of perfusion) and the maintenance infusions (given throughout perfusion). Before connection of the liver, the blood based perfusate is supplemented with: - Antibiotic to minimize risk of infection - Anticoagulant to prevent thrombosis in the circuit - Sodium bicarbonate (buffer) for adjusting the pH of the perfusate before the liver is placed on the device PMA P200035: FDA Summary of Safety and Effectiveness Data Page 5 of 96 {5} - Calcium gluconate to correct the binding of citrate to calcium During the perfusion the following are infused at a constant rate: - Parenteral nutrition solution (a source of amino acids and glucose for liver maintenance) - Insulin to control the perfusate glucose level - Anticoagulant to prevent coagulation - Epoprostenol (prostacyclin) to optimize microperfusion - Sodium taurocholate (bile salts) to maintain appropriate bile production VI. ALTERNATIVE PRACTICES AND PROCEDURES Liver transplantation is a treatment for end stage liver disease. There are multiple options for preservation of liver grafts prior to transplantation, including static cold storage (SCS) and normothermic machine perfusion (NMP). Static Cold Storage The current standard of donor liver preservation is based on static cold storage. During SCS, organs are flushed and cooled with specific chilled preservation solutions. After retrieval, the organ is placed in sterile plastic bags filled with preservation solution for transportation and stored in a cooler until transplantation. Hypothermia reduces the liver’s metabolic activity, and the preservation solution minimizes the cellular swelling that otherwise occurs. Normothermic Machine Perfusion NMP is another donor liver preservation technique allowing for the ex-vivo maintenance of organs at body temperature. During NMP, oxygen and nutrients are provided to the liver and a blood-based perfusate is pumped through the organ under physiological rates of pressure and flow. There is currently one US-marketed device indicated for the normothermic machine perfusion of donor liver grafts. The Food and Drug Administration approved the Organ Care System (OCS™) Liver device by TransMedics, Inc. on September 28, 2021, via P200031. The TransMedics® Organ Care System (OCS™) Liver is a portable extracorporeal liver perfusion and monitoring system indicated for preservation and monitoring of hemodynamics and metabolic function, which allows for ex-vivo assessment of liver allografts from donors after brain death (DBD) or liver allografts from donors after circulatory death (DCD) ≤ 40 years old and with ≤ 20 mins functional warm ischemic time, PMA P200035: FDA Summary of Safety and Effectiveness Data Page 6 of 96 {6} macrosteatosis ≤ 15%, in a near-physiologic, normothermic and functioning state intended for a potential transplant recipient. Each alternative has its own advantages and disadvantages. A patient should fully discuss these alternatives with his/her physician to select the method that best meets expectations and lifestyle. ## VII. MARKETING HISTORY The OrganOx metra® System received full CE marketing approval from the European Union (including the UK) in December 2018. The OrganOx metra® System is not marketed in the United States or any other foreign country. ## VIII. POTENTIAL ADVERSE EFFECTS OF THE DEVICE ON HEALTH There is no direct patient contact when this device is used as labeled; however, the device has direct contact with the liver that is subsequently transplanted into a recipient. The donor liver quality and optimization after preservation have direct effects on allograft function and survival. As such, device misuse or malfunction may result in conversion to SCS with extra organ manipulation, potential for contamination, and prolonged warm and cold ischemic time, leading to graft injury or graft loss. Below is a list of the potential adverse effects (e.g., complications) associated with liver transplants: - Abdominal wound dehiscence - Acute rejection - Anastomotic site complications; narrowing, bleeding or occlusion - Anemia - Ascites - Aspiration - Atrial fibrillation - Biliary strictures and bile leaks - Bleeding - Bowel obstruction - Bowel thromboembolic complications and gangrene - Cerebrovascular accident - Cholangitis - Coagulopathy - Convulsion - Death - Delirium, confusion and neurological complications - Diaphragmatic injury - Drug Toxicity - Early liver allograft dysfunction (EAD) - Fever - Gastritis - Gastro esophageal reflux disease (GERD) - GI Bleeding (upper or lower) - Hemodynamic instability - Hepatic artery thrombosis PMA P200035: FDA Summary of Safety and Effectiveness Data Page 7 of 96 {7} - Hepatic coma - Hepatic psychosis - Hyperacute rejection - Hyperammonemia - Ileus - Liver abscess - Liver primary non-function - Malignancy - Multiple organ failure - Pancreatitis - Peptic ulceration - Phrenic nerve injury - Pleural effusion - Portal vein thrombosis - Protamine and other anti-heparin medication reaction - Renal dysfunction and/or failure - Respiratory failure - Sepsis - Stroke - Transfusion reaction - Venous thromboembolism (deep venous thrombosis [DVT]) - Wound Infection For the specific adverse events that occurred in the US clinical study, please see Section X below. PMA P200035: FDA Summary of Safety and Effectiveness Data Page 8 of 96 {8} IX. SUMMARY OF NONCLINICAL STUDIES OrganOx conducted the following nonclinical studies to evaluate the OrganOx metra®: engineering bench testing, biocompatibility and biological safety, software verification and validation, cybersecurity, electrical and medical device safety, electromagnetic compatibility, sterilization, shelf-life, and animal functional testing. A. Sodium Taurocholate Testing A summary of the non-clinical laboratory testing performed on the sodium taurocholate solution is provided in Table 1 below: Table 1: Sodium Taurocholate Testing Summary | Test Performed | Device Description/ Sample Size | Test Method/Applicable Standard | Acceptance Criteria | Unexpected Results/Significant Deviations | Results | | --- | --- | --- | --- | --- | --- | | Dose Verification | 10 products | ISO 11137-2 | 8.2 kDy±10% ≤ 1 positive sterility test | None | Pass | | Bacteriostasis/ Fungistasis | 5 products | Direct inoculation | Positive growth at 5 days | None | Pass | | Dose Mapping | 1 packed shipper | ISO 11137-2 | 25 kGy minimum | None | Pass | | Dose Audit August 2017 | 10 products | ISO 11137-2 | 8.2 kDy±10% ≤ 1 positive sterility test | None | Pass | | Dose Audit June 2018 | 10 products | ISO 11137-2 | 8.2 kDy±10% ≤ 1 positive sterility test | None | Pass | | Impact of Irradiation FTIR | 1 batch irradiated; 1 batch non irradiated | FTIR internal method | Comparable FTIR spectra | None | Pass | | Impact of Irradiation HPLC | 1 sample irradiated; 1 sample non irradiated | HPLC internal method | Comparable HPLC trace and concentration | Slight increase in concentration but samples not weighed | Pass (FTIR) | PMA P200035: FDA Summary of Safety and Effectiveness Data Page 9 of 96 {9} PMA P200035: FDA Summary of Safety and Effectiveness Data Page 10 of 96 | Test Performed | Device Description/ Sample Size | Test Method/Applicable Standard | Acceptance Criteria | Unexpected Results/Significant Deviations | Results | | --- | --- | --- | --- | --- | --- | | Impact of Irradiation HPLC Additional Study | 3 samples irradiated; 1 sample non irradiated | HPLC internal method | Comparable HPLC trace and concentration | None | Pass | | Chemical Characterization | 3 samples; glass vial (50 mL) and rubber stopper | ISO 10993-18 | No significant leachable substances | None | Pass | | Heavy Metals Perfusate Solution at 24 hours | 2 samples of perfusate solution | AAS ISO 15747 | ≤maximum permissible concentration | Aluminum at maximum limit of 0.05 | Pass | | Bacterial Endotoxin | 3 batches | Turbidimetric kinetic method | <0.5EU/ml | None | Pass | | Sodium and Calcium Concentration Perfusate Solution at 24 Hours | 5 samples perfusate solution T=0 to T=4 | Ion Chromatography (IC) | No clinically significant changes over 24 hours | 51% decrease in calcium ion concentration | Pass | | Stability Perfusate Solution at 48 Hours | 6 samples perfusate solution T=0 to T=5 | HPLC internal method | No significant new peaks | None | Pass | | Shelf Life of Sodium Taurocholate (Accelerated) | 1 batch stored at 40°C 90% RH | Concentration HPLC Moisture content (mass loss/gain) | For information only ≤10% change | 12.5% in concentration Storage range is: 15°C to 25°C | Pass | | Shelf Life of Sodium Taurocholate (Real Time) | 1 batch stored at 25°C | Concentration HPLC Moisture content (mass loss/gain) | For information only ≤10% change | None | Pass | {10} | Test Performed | Device Description/ Sample Size | Test Method/Applicable Standard | Acceptance Criteria | Unexpected Results/Significant Deviations | Results | | --- | --- | --- | --- | --- | --- | | Packaging Seal Integrity Dye Penetration | 36 pouches | ASTM F3039-15 | No Leaks | None | Pass | | Packaging Seal Integrity Burst Strength | 34 pouches | ASTM F1140-07 | Minimum 139 mbar | None | Pass | | Viral Safety Report | Validation of scale down: 3 batches Inactivation studies: 1 sample per model virus and timepoint | ISO 22442-3 | Overall reduction of 6 log | Additional testing done to confirm antiviral activity of bile starting material | Pass | ## B. Disposable Set Testing A summary of the non-clinical laboratory testing performed on the Disposable Set is provided in Table 2 below: Table 2: Disposable Set Testing Summary | Test Performed | Device Description/ Sample Size | Test Method/Applicable Standard | Acceptance Criteria | Unexpected Results/Significant Deviations | Results | | --- | --- | --- | --- | --- | --- | | Equivalence of Sterilization Chambers | Full load per chamber half cycle | ISO 11135 | PPQ: cycle parameters meet specification; MPQ: no positives | None | Pass | | Sterilization MPQ | Reference loads 3 half cycles | ISO 11135 AnnexB.1.2a | No positive BI or PCDs | None | Pass | | Sterilization PPQ | 1 Full cycle | ISO 11135 AnnexB.1.2a | Cycle parameters meet specification | None | Pass | | Sublethal Comparison | 3 samples of Cold Liver | ISO 11135 | CFU count: product < PCD | None | Pass | PMA P200035: FDA Summary of Safety and Effectiveness Data Page 11 of 96 {11} PMA P200035: FDA Summary of Safety and Effectiveness Data Page 12 of 96 | Test Performed | Device Description/ Sample Size | Test Method/Applicable Standard | Acceptance Criteria | Unexpected Results/Significant Deviations | Results | | --- | --- | --- | --- | --- | --- | | | Perfusion Pack 3 PCDs | | | | | | Resistance Comparison | 3 samples Cold liver perfusion pack 3 PCDs | ISO 11135 | Resistance PCD ≥ product | None | Pass | | EO Residuals | 1 sample each pack per time point | ISO 10993-7 | ≤ 4 mg/device: Surgeons Pack Liver Perfusion Set ≤ 21mg/device: Perfusionist Pack | None | Pass | | Ethylene Chlorohydrin (ECH) Residuals | 1 sample each pack per time point | ISO 10993-7 | ≤ 9 mg/device: | None | Pass | | Bacterial Endotoxin | 1 sample per pack/part of pack tested in duplicate | Turbidimetric kinetic method | 20 EU/sample | None | Pass | | Bacterial Endotoxin | 1 disposable set and full perfusion of perfusion solution | Turbidimetric kinetic method | <20 EU/sample | None | Pass | | Shelf Life Visual | 18 units each time point and condition | Internal method | Seals intact No significant damage to set | Minor damage and discoloration | Pass | | Shelf Life Seal Integrity (Peel Strength) | 18 units each time point and condition | ASTM F88-15 | Maximum peel force at N15mm | None | Pass | {12} PMA P200035: FDA Summary of Safety and Effectiveness Data Page 13 of 96 | Test Performed | Device Description/ Sample Size | Test Method/Applicable Standard | Acceptance Criteria | Unexpected Results/Significant Deviations | Results | | --- | --- | --- | --- | --- | --- | | Shelf Life Dye Penetration | 18 units each time point and condition | ASTM F1929-15 ASTM F3039-15 | No leaks | None | Pass | | Shelf Life Functional | 18 units each time point and condition | Internal method | No persistent leakage | None | Pass | | Cytotoxicity | 1 disposable set | ISO 10993-5: L929 MEM Elution | < grade 2 | None | Pass | | Sensitization | 1 disposable set | ISO 10993-10: Guinea Pig maximization | No evidence of sensitization | None | Pass | | Irritation | 1 disposable set | ISO 10993-10: Intracutaneous Reactivity | No erythema or edema | None | Pass | | Acute Systemic Toxicity | 1 disposable set | ISO 10993-11 | No evidence of significant systemic toxicity or mortality | None | Pass | | Pyrogenicity | 1 disposable set | ISO 10993-11: Rabbit | Non-pyrogenic | None | Pass | | Leachables (at 24 Hours) | 3 Disposables Sets | HPLC internal method | No significant leachable substances | None | Pass | | Heavy Metals Perfusate Solution (at 24 Hours) | 2 samples perfusate solution | AAS ISO 15747 | ≤maximum permissible concentration | Aluminum at maximum limit of 0.05 | Pass | | Sodium and Calcium Concentration Perfusate Solution at 24 Hours | 5 samples perfusate solution T=0 to T=4 | IC | No clinically significant changes over 24 hours | 51% decrease in calcium ion concentration | Pass | {13} | Test Performed | Device Description/ Sample Size | Test Method/Applicable Standard | Acceptance Criteria | Unexpected Results/Significant Deviations | Results | | --- | --- | --- | --- | --- | --- | | Cytotoxicity (With perfusion solutions) | 1 disposable set and full perfusion of perfusion solution | ISO 10993-5 L929 MEM Elution | < grade 2 | None | Pass | | Sensitization (With perfusion solutions) | 1 disposable set and full perfusion of perfusion solution | ISO 10993-10 Guinea Pig maximization | No evidence of sensitization | None | Pass | | Irritation (With perfusion solutions) | 1 disposable set and full perfusion of perfusion solution | ISO 10993-10 Intracutaneous Reactivity | No erythema or edema | None | Pass | | Acute Systemic Toxicity (With perfusion solutions) | 1 disposable set and full perfusion of perfusion solution | ISO 10993-11 | No evidence of significant systemic toxicity or mortality | None | Pass | | Pyrogenicity (With perfusion solutions) | 1 disposable set and full perfusion of perfusion solution | ISO 10993-11 Rabbit | Non-pyrogenic | None | Pass | | Seal Integrity | 179 Disposable sets | ASTM F1929-15 Method A | No signs of leak | None | Pass | | Post-Aging functional testing | 179 Disposable sets | ISTA 3E, ASTM F1929-15, ASTM F3030/ASTM F88-15) | No signs of leak | None | Pass | | Sealing Validation | 60 Header bags | ISO 11607 | Lower limit of tolerance >14 N/15 mm | None | Pass | C. OrganOx metra® System Testing The OrganOx metra® was tested to demonstrate that it meets requirements for medical device safety, including electrical safety. The system was tested by an outside laboratory according to the IEC 60601-1 (Edition 3.1) and 60601-1-2:2014 (EMC; Edition 4) standards, as well as the ANSI/AAMI and CSA version of the standard. PMA P200035: FDA Summary of Safety and Effectiveness Data Page 14 of 96 {14} A summary of the non-clinical testing performed on the Retained Unit is provided in Table 3 and metra® system in Table 4 below: Table 3: Retained Unit Testing Summary | Test Performed | Device Description/ Sample Size | Test Method/Applicable Standard | Acceptance Criteria | Unexpected Results/ Significant Deviations | Results | | --- | --- | --- | --- | --- | --- | | Emissions Test | 1 Device | EN61000-3-2:2006 + A2:2009 | Class A | None | Class A | | Radiated Emissions | 1 Device | EN55011:2009 + A1:2010 | Class A | None | Class A | | Conducted Emissions | 1 Device | EN55011:2009 + A1:2010 | Class A | None | Class A | | Conducted Emissions – Line Impedance Stabilization Network | 1 Device | EN55022:2010 using CISPR 25 EN 301489 | Class A | None | Class A | | Mains Harmonic Emissions | 1 Device | EN61000-3-2:2006 + A2:2009 | Class A | None | Class A | | Mains Voltage Fluctuations and Flicker | 1 Device | EN61000-3-3:2013 | Complies | None | Complies | | Emissions Test | 1 Device | CFR 47 Part 15.107 and 15.109 | Class A | None | Class A | | Electrostatic Discharge (ESD) | 1 Device | EN61000-4-2:2009 | ±8 kV – contact discharge ± 15 kV – air discharge | None | Complies | | Radiated Immunity | 1 Device | EN61000-4-3:2006+A2:2010 | 3 V/m 80 MHz–2.7 GHz –Frequency range 10 V/m –voltage | None | Complies | | Electrical Fast Transient/Burst | 1 Device | EN61000-4-4:2012 | +2kV for input/output lines | None | Complies | | Surge | 1 Device | IEC61000-4-5:2006 | ±2kV for Common mode | None | Complies | PMA P200035: FDA Summary of Safety and Effectiveness Data Page 15 of 96 {15} PMA P200035: FDA Summary of Safety and Effectiveness Data Page 16 of 96 | Test Performed | Device Description/ Sample Size | Test Method/Applicable Standard | Acceptance Criteria | Unexpected Results/ Significant Deviations | Results | | --- | --- | --- | --- | --- | --- | | | | | ±1kV for Differential mode | | | | Immunity to Electromagnetic Disturbances Caused by Radio Frequency Disturbances Testing | 1 Device | EN61000-4-6:2009 | 3 Vrms 150 kHz – 80 MHz | None | Complies | | Power Frequency (50/60 Hz) Magnetic Field | 1 Device | EN61000-4-8:2010 | 30 A/m | None | Complies | | Voltage Dips, Short Interruptions and Voltage Variations on Power Supply Input Lines | 1 Device | EN61000-4-11:2004 | 100% reduction for 10 ms/half cycle 30% reduction for 500 ms/25 cycles 100% reduction for 20 ms/1 cycle 100% interruption for 5 s | None | Complies | | Conducted Transient Immunity | 1 Device | ISO 7637-2:2011 | Pulse severity level I/II | None | Complies | | Conducted Transient Emissions | 1 Device | ISO 7637-2:2011 | LISN 5 μH/50 Ω | None | Complies | | Basic Electrical Safety | 1 Device | IEC 60601-1:2005 + CORR. 1 2006 + CORR. 2:2007 + AM1:2012 | Compliant to Relevant clauses | None | Complies | | Device Alarms | 1 Device | IEC 60601-1-8:2006 + Am. 1:2012 | Equipment includes alarm systems complying with collateral standard | None | Complies | {16} PMA P200035: FDA Summary of Safety and Effectiveness Data Page 17 of 96 | Test Performed | Device Description/ Sample Size | Test Method/Applicable Standard | Acceptance Criteria | Unexpected Results/ Significant Deviations | Results | | --- | --- | --- | --- | --- | --- | | | | | as means of risk control to have equipment notify the operator of a hazardous situation. In line with clauses 4, 5.1, 5.2.1, 6.1.1, 6.1.2, 6.2, 6.3.1, 6.3.2, 6.3.3, 6.4, 6.4.1, 6.4.2, 6.5.1, 6.5.2, 6.5.3.1, 6.5.3.2, 6.5.4.1, 6.5.4.2, 6.5.5, 6.6.1, 6.7, 6.8.1, 6.8.2, 6.8.3, 6.8.4, 6.8.5, 6.9, 6.10, 6.11.1, 6.12 | | | | Usability Engineering | 1 Device | IEC 60601-1-6:2010 ISO 62366:2007 | Usability engineering process complies with IEC 62366 | None | Complies | | Environmental | 1 Device | EN 60068-2-1:2007 Cold EN 60068-2-2:2007 Dry Heat EN 60068-2-6:2008 Vibration (sine) EN 60068-2-14:2009 Temperature Change EN 60068-2-78:2002 Damp Heat EN 60601-1:2006/A1:2013 non UKAS | 30°C for 4 hours 28°C 93% RH for 7 days -5°C for 16 hours +55°C for 16 hours 0°C for 2 hours +40°C for 2 hours -5°C for 20 minutes | None | Pass with respect to all acceptance criteria | {17} PMA P200035: FDA Summary of Safety and Effectiveness Data Page 18 of 96 | Test Performed | Device Description/ Sample Size | Test Method/Applicable Standard | Acceptance Criteria | Unexpected Results/ Significant Deviations | Results | | --- | --- | --- | --- | --- | --- | | Environmental | 1 Device | EN 60068-2-64:2008 Vibration Random | 10-57 Hz at 0.15mm 57-150 Hz at 2g | None | Failed, but complies with device operational specification | | Environmental | 1 Device | EN 1789:2007 + A1:2010 non UKAS | 10-20 Hz at 0.05 g2/Hz 20-150 Hz at -3 db/octave | None | Failed but complies with device operational specification | | Secondary cells and batteries containing alkaline or other non-acid electrolytes – safety requirements for portable sealed secondary cells | 36 battery cells | ISO 62133:2002 | Compliant with clauses: 1, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 3.0, 4.0, 4.1, 4.2.2, 4.2.3, 4.2.4, 4.3, 4.3.2, 4.3.3, 4.3.4, 4.3.8, 6.2, 6.3, 7.0 | None | Complies | | Electromagnetic Compatibility – Emissions and Immunity | 1 Device | IEC 60601-1-2:2014 | Continuous phenomena – radiated RF immunity, conducted RF immunity, power frequency magnetic field immunity | None | Pass | | ElectroMagnetic Compatibility (EMC) standard for radio equipment and services; Part 17: Specific conditions for Broadband Data Transmission Systems; Harmonised Standard covering the essential requirements of article 3.1(b) of Directive 2014/53/EU | 1 Device | ESTI EN 301 489-17 | Liver On Board Mode Transient phenomena – ESD, electrical fast burst transient immunity, surge immunity, power line voltage dips and interrupts | None | Complies | {18} PMA P200035: FDA Summary of Safety and Effectiveness Data Page 19 of 96 | Test Performed | Device Description/ Sample Size | Test Method/Applicable Standard | Acceptance Criteria | Unexpected Results/ Significant Deviations | Results | | --- | --- | --- | --- | --- | --- | | | | | Liver On Board Mode and Preparation Mode | | | | Electromagnetic compatibility and Radio spectrum Matters (ERM); ElectroMagnetic Compatibility (EMC) standard for radio equipment and services; Part 1: Common technical requirements | 1 Device | ESTI EN 301 489-1 | | None | Complies | | Electromagnetic compatibility (EMC) - Product family standard for aftermarket electronic equipment in vehicles | 1 Device | EN 50498:2011 | | None | Complies | | Ingress Protection | 1 Device | IEC 60529:1992 + A2:2013 | IP44 Cover removed | None | Pass | | Powerbase Requirements | 1 Device | Internal Method | Current path switching hierarchy: 1. Mains PSU 2. External DC input 3. Internal Batteries Current path switching time: <5ms with no loss of machine performance Battery charging voltage: 36VDC max 2 channels | None | | {19} PMA P200035: FDA Summary of Safety and Effectiveness Data Page 20 of 96 | Test Performed | Device Description/ Sample Size | Test Method/Applicable Standard | Acceptance Criteria | Unexpected Results/ Significant Deviations | Results | | --- | --- | --- | --- | --- | --- | | | | | Battery charging current: 3Amps max, constant current, 2 channels M12 isolated voltage output: 12VDC +/-10% M12 current: 0.8Amps max M12 isolation >4kV RMS Digital I/O To interface board: Power status Keypad inputs From interface board: Keypad LEDs Cooling fan enabled | | | | Backplane requirements | 1 Device | Internal Method | Passive printed circuit board for interconnection and routing of signal and power for the following: DC board Interface board Master control board Trinamics carrier board Ancillary component (cooling fans, pumps, stepper motors, blood gas analyzer, thermal control unit, | None | | {20} PMA P200035: FDA Summary of Safety and Effectiveness Data Page 21 of 96 | Test Performed | Device Description/ Sample Size | Test Method/Applicable Standard | Acceptance Criteria | Unexpected Results/ Significant Deviations | Results | | --- | --- | --- | --- | --- | --- | | | | | oxygen concentrator control module) | | | | Interface board requirements | 1 Device | Internal Method | Integrate flow sensor electronics: EMTEK flow sensor daughter boards, 2 channels Serial communication protocols: RS485 to/from master control board RS232 to/from battery modules SPI to/from trinamics carrier and flow sensors I2C for digital I/O expander Processor: AT91SAM7 Power Rails: Digital Rail1 voltage: 3.3VDC +/-5% Digital Rail1 current: 1Amp max Digital Rail2 voltage: 5VDC +/-5% Digital Rail2 current: 0.12Amps max 12VPeripheral voltage: 12VDC +/-10% | None | | {21} PMA P200035: FDA Summary of Safety and Effectiveness Data Page 22 of 96 | Test Performed | Device Description/ Sample Size | Test Method/Applicable Standard | Acceptance Criteria | Unexpected Results/ Significant Deviations | Results | | --- | --- | --- | --- | --- | --- | | | | | 12V Peripheral current: 3.2Amps minimum 24V Peripheral voltage: 24VDC +/- 10% 24V Peripheral current: 1.2Amps minimum Digital I/O: Button press and status LEDs | | | | Master control board requirements | 1 Device | Internal Method | Integrate the following processor board: UCB+ V1.2 - Surface Measurement Systems Processor: AT91SAM7 Rail voltages: Input supply voltage: 12 VDC +/- 8% Input supply current: 0.6 Amps max Digital 5V voltage: 5 VDC +/-5% Digital 5V current: 1 A max Analogue 5V voltage: 5 VDC +/- 5% Analogue 5V current: 0.15 Amps max | None | | {22} PMA P200035: FDA Summary of Safety and Effectiveness Data Page 23 of 96 | Test Performed | Device Description/ Sample Size | Test Method/Applicable Standard | Acceptance Criteria | Unexpected Results/ Significant Deviations | Results | | --- | --- | --- | --- | --- | --- | | | | | Serial Communication Protocols: RS485 connection to Interface board RS232 connection to blood gas analyzer Digital I/O: Peltier control Reset Analogue interfaces: Pressure sensor amplifiers x 2 Thermistor amplifiers x 3 Glucose dial x 1 | | | | DC – DC Board requirements | 1 Device | Internal Method | Input supply voltage 24 VDC +/-20% Peltier output voltage when not current limited 24 VDC max Peltier maximum output current 15 Amps Blood gas analyzer supply voltage 12 VDC +/- 5% Blood gas analyzer supply current 3 Amps max | None | | {23} PMA P200035: FDA Summary of Safety and Effectiveness Data Page 24 of 96 | Test Performed | Device Description/ Sample Size | Test Method/Applicable Standard | Acceptance Criteria | Unexpected Results/ Significant Deviations | Results | | --- | --- | --- | --- | --- | --- | | | | | 12 Volt ancillary power supply voltage 12 VDC +/- 5% 12 Volt ancillary power supply current 8.25 Amps max 24 Volt ancillary power supply voltage 24 VDC +/- 5% 24 Volt ancillary power supply current 6 Amps max 5V Logic supply voltage 5V +/-5% 5V Logic supply current 0.2 Amps max | | | | Trinamics board requirements | 1 Device | Internal Method | Integrate the following 24-Volt motor controllers: TMCM 163 BLDC Controller x 2: Blood pump; and nutrient pump TMCM 113 Stepper motor controller x 3: Portal Pinch Valve; Arterial Pinch Valve; and Bile Pinch Valve Power rails: | None | | {24} PMA P200035: FDA Summary of Safety and Effectiveness Data Page 25 of 96 | Test Performed | Device Description/ Sample Size | Test Method/Applicable Standard | Acceptance Criteria | Unexpected Results/ Significant Deviations | Results | | --- | --- | --- | --- | --- | --- | | | | | 24RAW voltage: 24 VDC +/-10% 24RAW current: 10 Amps max 24VRegulated voltage: 24VDC +/- 10% 24VRegulated current: 4 Amps max 3V3SPI voltage: 3.3 VDC +/-5% 3V3SPI current: 0.5amps max Serial communication: SPI to UART(RS232) x 6 | | | | Oxygen concentrator control module requirements | 1 Device | Internal Method | Input supply voltage: 24 VDC +/-10% Input supply current: 3 Amps max Concentrator supply voltage: 19VDC +/-10% Serial communication protocols: USB to concentrator (unidirectional) Digital I/O from Interface board: Concentrator enable Oxygen demand PWM Concentrator Alarm | None | | {25} PMA P200035: FDA Summary of Safety and Effectiveness Data Page 26 of 96 | Test Performed | Device Description/ Sample Size | Test Method/Applicable Standard | Acceptance Criteria | Unexpected Results/ Significant Deviations | Results | | --- | --- | --- | --- | --- | --- | | | | | Diverter solenoid power: 24 VDC (pwm driven) | | | | Product Requirements | 81 Devices | Internal Protocol | All requirements are located within internal protocol | None | Pass | | Road Transit Testing | 1 Device | Internal Protocol | Product requirement specification 1.3, 1.5, 1.6, 1.12, 1.13, 1.20, 1.40, 1.43, 1.44, 1.47, 2.1, 27.1, 27.3 | None | Pass | | Human Factors | 1 Device | ISO 62366:2007 AAMI/ANSI HE75:2009 | Establishing a baseline of user performance, establishing and validating user performance measures, and identifying potential design concerns | None | Complies | | Durability | 1 Device | TRA-043105-27-TP-01B | Environmental Test Procedure in accordance with test plan TRA-043105-27-TP-01B Functional checks of the device under test: For operational testing: The device was operated without an organ and the performance of the hemodynamic controller, | Two errors were noted on the control panel screen during the Test 002 – Z-Axis – Broadband Random Road Transport Vibration Test, however, these were reset and cleared after | Pass | {26} PMA P200035: FDA Summary of Safety and Effectiveness Data Page 27 of 96 | Test Performed | Device Description/ Sample Size | Test Method/Applicable Standard | Acceptance Criteria | Unexpected Results/ Significant Deviations | Results | | --- | --- | --- | --- | --- | --- | | | | | thermal controller was monitored via the GUI and by noting any flow or temperature alarms present on the GUI. In addition, the integrity of the system was monitored for mechanical failure or wear-out and by monitoring system alarms (i.e., battery status alarms, blood pump failure alarm, or pinch valve failure alarms etc.). For non-operational stress testing (environmental conditioning) the device was switched on after each test in accordance with the test plan and placed in perfusion mode, without an organ. Alarms were monitored as above and any worn or damaged components noted. In all cases unexpected | the test and no further issues were reported throughout the remainder of the vibration and shock tests. | | {27} PMA P200035: FDA Summary of Safety and Effectiveness Data Page 28 of 96 | Test Performed | Device Description/ Sample Size | Test Method/Applicable Standard | Acceptance Criteria | Unexpected Results/ Significant Deviations | Results | | --- | --- | --- | --- | --- | --- | | | | | alarms, or alarms that would not self-resolve, component failure, or wear-out would constitute a premature failure of the device during the accelerated life testing. | | | | Biocompatibility | Component review | ISO 10993-1:2009 | All surfaces that are in contact with patients and operators are biocompatible | None | Complies | | Cleaning Validation | 1 Device | Internal Protocol | To establish a validated cleaning regime | None | Pass | | Device reliability | 9 Liver Perfusion Circuits/3 Retained Unit | Internal Method | To evaluate the performance of the *metra®* Liver Perfusion Circuit following all expected per-use environmental conditioning and use under stressed conditions, for a period of twice the intended device usage life. Testing to be conducted over 48-hours. | None | Complies | | Flow sensor accuracy | 2 flow sensors | Internal Method | Flows ≤1.0 L/min ±0.07 L/min Flows >1.0 L/min ±7% of reading | None | Pass | {28} Table 4: OrganOx metra® System Testing Summary | Test Performed | Device Description/ Sample Size | Test Method/Applicable Standard | Acceptance Criteria | Unexpected Results/Significant Deviations | Results | | --- | --- | --- | --- | --- | --- | | Usability Engineering | 1 Device | IEC 60601-1-6:2010 ISO 62366:2007 | Compliance with IEC 60601-1-6:2010 and ISO 62304 | none | Pass | | Software Static Analysis | 1 Device | ISO 62304:2006 + A1:2015 | Compliance with ISO 62304 | none | Pass | | GUI Software Verification | 1 Device | ISO 62304:2006 + A1:2015 | Compliance with ISO 62304 | none | Pass | | Software Integration Testing | 1 Device | ISO 62304:2006 + A1:2015 | Compliance with ISO 62304 | none | Pass | | Software system Testing | 1 Device | ISO 62304:2006 + A1:2015 | Compliance with ISO 62304 | none | Pass | | Wireless monitoring Verification | 1 Device | ISO 62304:2006 + A1:2015 | Compliance with ISO 62304 | none | Pass | | Durability Testing | 1 Device | TRA-043105-27-TP-01B | Environmental Test Procedure in accordance with test plan TRA-043105-27-TP-01B Functional checks of the device under test: For operational testing: The device was operated without an organ and the performance of the hemodynamic | Two errors were noted on the control panel screen during the Test 002 – Z-Axis – Broadband Random Road Transport Vibration Test, however these were reset and cleared after the test and no further issues were reported throughout the remainder of the vibration and shock tests. | Pass | PMA P200035: FDA Summary of Safety and Effectiveness Data Page 29 of 96 {29} | | | | controller, thermal controller was monitored via the GUI and by noting any flow or temperature alarms present on the GUI. In addition, the integrity of the system was monitored for mechanical failure or wear-out and by monitoring system alarms (i.e., battery status alarms, blood pump failure alarm, or pinch valve failure alarms etc.). | | --- | --- | --- | --- | | | | | For non-operational stress testing (environmental conditioning) the device was switched on after each test in accordance with the test plan and placed in perfusion mode, without an organ. Alarms were monitored as above and any worn or damaged components noted. | | | | | In all cases unexpected alarms, or alarms that | PMA P200035: FDA Summary of Safety and Effectiveness Data Page 30 of 96 {30} PMA P200035: FDA Summary of Safety and Effectiveness Data Page 31 of 96 | | | | would not self-resolve, component failure, or wear-out would constitute a premature failure of the device during the accelerated life testing. | | | | --- | --- | --- | --- | --- | --- | ## D. Animal Studies Early animal studies were conducted at the Nuffield Department of Medical Sciences, Oxford University. Due to the nature of this early scientific work, there are no final protocols and reports signed by the study director for each of the animal studies. These early animal studies were used as safety data to identify risk associated with the design of the clinical trials device, to influence future designs, to design pivotal trials and to be used in the feasibility stage of device development. Although the animal studies informed the non-clinical and clinical studies presented in support of this PMA, the Agency did not directly consider this information in its decision on this PMA. ## X. SUMMARY OF PRIMARY CLINICAL STUDIES The applicant performed a US clinical study to establish a reasonable assurance of safety and effectiveness of the OrganOx metra® System for use in donor livers destined for transplantation in a functioning state for periods of up to 12 hours under IDE G140243. This data was supported with additional data from a European clinical study, COPE WP02. Data from these clinical studies (Table 5) were the bases for the PMA approval decision. A summary of the clinical studies is presented below. Table 5: Supporting Clinical Studies | Study | OrganOx metra® (NMP) liver recipients | Static Cold Storage (SCS) liver recipients | | --- | --- | --- | | US IDE Study (WP01; G140243) | n = 136 | n = 130 | | European Consortium for Organ Preservation in Europe (COPE) WP02 Study | n = 121 | n = 101 | A summary of the US WP01 clinical study is presented below. A summary of the COPE WP02 study is presented in Section XI (“Summary of Supplemental Clinical Information”) of this SSED document. {31} US Study WP01 (IDE G140243) ## A. Study Design Patients were enrolled between October 9, 2016, and February 3, 2020. The data for this PMA was collected through the final database lock on July 1, 2021, and included 267 enrolled subjects, 266 transplanted livers (136 in the NMP arm and 130 in the SCS arm), and 383 randomized livers. There were 15 investigational sites, 14 of which enrolled patients. Data from the pivotal WP01 Study (via IDE G140243) was used to support the safety and effectiveness of the OrganOx metra®. The WP01 study was a multicenter, open label, randomized (1:1), controlled, non-blinded clinical trial comparing the efficacy of ex-vivo normothermic machine perfusion (NMP) using the OrganOx metra® device with static cold storage (SCS) in human liver transplantation. Subjects enrolled in the study were followed for 12 months (Days 1-7, Day 10, Day 30, Month 3, Month 6, and Month 12) post-transplant procedure. Donor livers were randomly assigned to the NMP or SCS arm with a 1:1 allocation as per a computer-generated randomization schedule using variable block randomization and the following stratification factors: participating (recipient) center and donor type (donation after brain death; DBD or donation after circulatory death; DCD). The randomization schedule was created by the study statistician and the size of the randomization blocks were known only to the study statistician and the Data Safety Monitoring Board (DSMB) statistician. A core laboratory was utilized to perform pathology evaluations of the study liver biopsies. The core lab histopathologists were blinded to randomization assignment, primary endpoints, and primary and secondary outcome results by randomization group. OrganOx representatives were blinded to primary endpoints and secondary outcome results by randomization group. Local investigators were blinded to primary and secondary outcome results by randomization group. All adverse events collected through follow-up were reviewed by an independent Medical Monitor. A Clinical Events Committee (CEC) adjudicated the most critical adverse events, and a DSMB reviewed aggregate safety data. ## 1. Clinical Inclusion and Exclusion Criteria Randomization in the WP01 clinical study was limited to donor livers that met the following inclusion criteria: ### Donor Inclusion Criteria 1. Donation after brain death (DBD) donor aged 40 years or greater 2. Donation after circulatory death (DCD) donor aged 16 years or greater 3. Liver allograft from DBD or DCD donors PMA P200035: FDA Summary of Safety and Effectiveness Data {32} Randomization of livers was not permitted in the WP01 clinical study if they met any of the following exclusion criteria: ## Donor Exclusion Criteria 1. Living donor liver 2. Liver intended for split transplant 3. Liver which Investigator is unwilling to randomize to either arm Enrollment in the WP01 clinical study was limited to subjects (recipients) that met the following inclusion criteria: ## Recipient Inclusion Criteria 1. Subject is 18 years of age or greater 2. Subject is registered as an active recipient on the UNOS waiting list for liver transplantation 3. Subject, or legally authorized representative, is able and willing to give informed consent and HIPAA authorization 4. Subject is able and willing to comply with all study requirements (in the opinion of the Investigator) Subjects were not permitted to enroll in the WP01 clinical study if they met any of the following exclusion criteria: ## Recipient Exclusion Criteria 1. Subject requiring all the following at the time of transplantation: a. Oxygen therapy via a ventilator/respirator b. Inotropic support c. Renal replacement therapy 2. Subject has acute/fulminant liver failure (UNOS status 1A) 3. Subject undergoing simultaneous transplantation of more than one organ (e.g., liver and kidney) 4. Subject is pregnant (as confirmed by urine or serum pregnancy test) or nursing 5. Concurrent enrollment in another clinical trial. Subjects enrolled in clinical trials or registries where only measurements and/or samples are taken (no test device or test drug used) are allowed to participate. ## 2. Follow-up Schedule PMA P200035: FDA Summary of Safety and Effectiveness Data Page 33 of 96 {33} All transplanted subjects were assessed daily (Days 1-7) and on Day 10 by their clinical team and managed according to standard local protocols during their post-transplant inpatient stay. Subjects were scheduled to return for follow-up examinations at the following post-transplant timepoints: - Day 30 (± 7 days) - Month 3 (± 14 days) - Month 6 (± 14 days) - Month 12 (± 30 days) Preoperative information on donor and recipient demographics was collected along with the EQ-5D quality of life questionnaire. Postoperatively, the objective parameters measured during the study included biochemical assessments in addition to assessments for primary non-function (PNF), graft survival, subject survival, resource use, safety outcomes, readmissions, and renal replacement therapy requirement. The EQ-5D quality of life questionnaire was also completed at the Month 6 follow-up. Adverse events and complications were recorded at all visits. 3. Clinical Endpoints Primary Endpoint The pre-specified primary endpoint was to compare the effect of NMP to SCS in preventing preservation-related graft injury as measured by early allograft dysfunction (EAD) during Days 1-7. EAD was defined as the presence of one of the following three outcomes: 1. Serum bilirubin ≥ 10 mg/dL at Day 7 post-transplant 2. International normalized ratio ≥ 1.6 at Day 7 post-transplant 3. Alanine aminotransferase ALT or aspartate aminotransferase AST &gt; 2000 IU/L within the first 7 days post-transplant The primary endpoint analysis was performed on all transplanted subjects. The hypothesis was written as follows: H₀: EADₙₐₚ ≥ EADₛ꜀ₛ Hₐ: EADₙₐₚ &lt; EADₛ꜀ₛ A one-sided significance level of α = 0.025 was used to test the primary endpoint; therefore, if the hypothesis test results in a one-sided p-value that is less than 0.025, the study would be considered a success. Secondary Endpoints PMA P200035: FDA Summary of Safety and Effectiveness Data Page 34 of 96 {34} The pre-specified secondary endpoints are listed below and compared between NMP and SCS arms: - To compare graft and subject survival between NMP and SCS livers based on PNF rates during the first 10 days after liver transplant; graft survival rates at 30 days, 3 months, and 6 months after liver transplant; and subject survival rates at 30 days, 3 months, and 6 months after liver transplant - To compare evidence of post-reperfusion syndrome between NMP and SCS livers on transplantation based on mean arterial pressure pre- and post-reperfusion in the context of vasopressor use - To compare biochemical liver function between NMP and SCS livers based on bilirubin, gamma glutamyl transferase (GGT), alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), and international normalized ratio (INR) at Days 1-7, Day 30, Month 3, and Month 6 post-transplant. Additionally, lactate measurements were taken at Days 1-7 while the subject was in the ICU - To compare evidence of ischemia-reperfusion injury between NMP and SCS livers based on post-reperfusion biopsies compared to baseline pre-reperfusion biopsies and graded according to standard histological criteria - To compare evidence of biliary complications between NMP and SCS livers based on incidence of biliary investigations and/or interventions between 7 days and 6 months post-transplant. Biliary investigations include magnetic resonance cholangiopancreatography, endoscopic retrograde cholangiopancreatography, and percutaneous transhepatic cholangiography. Biliary interventions include those that are surgical, radiological, or endoscopic in nature - To assess the feasibility and safety of NMP as a method of organ storage and transportation based on incidences of one or more of the following per randomized liver: (i) EAD; (ii) discard (non-transplant) of a retrieved liver; (iii) primary non-function - To compare organ utilization between NMP and SCS livers based on incidence of livers randomized but not transplanted and reasons for not transplanting - To assess the health economic implications of normothermic liver perfusion based on logistical and healthcare costs and quality of life measures No formal hypothesis testing was performed on the secondary endpoints PMA P200035: FDA Summary of Safety and Effectiveness Data Page 35 of 96 {35} B. Accountability of PMA Cohort Fifteen investigative sites were initiated during the study, fourteen of which enrolled study subjects. One site screened subjects throughout the study but did not enroll any subjects. As detailed in Figure 3, a total of 383 livers were randomized into either the NMP group (n=192) or SCS group (n=191). There were 267 enrolled subjects with 266 transplanted livers (136 in the NMP arm and 130 in the SCS arm). One liver was allocated to a study subject who was found to be inoperable at the start of surgery; the donor liver was reallocated to a second consented subject. At the time of the database lock, of the 267 subjects enrolled in the IDE study, 91.0% (243/267) of the subjects were available for analysis at the completion of the Month 12 post-transplant visit. The dataset included data for all eligible subjects through the Month 12 follow-up visit. 99.6% of subjects that were not exited from the study before Month 12 completed their Month 12 follow-up visit. Of enrolled subjects, 89.7% (122/136) of the NMP subjects and 92.4% (121/131) of the SCS subjects completed the Month 12 follow-up visit. The remaining Month 12 visits in each arm were not completed, as the subjects were exited from the study prior to the Month 12 follow-up visit. One enrolling site elected to discontinue participation during the study after enrolling two subjects and was closed following completion of subject follow-up at Month 12. Table 6 provides the detailed breakdown of subject disposition by randomization group and donor type along with the reason for study exit of livers that did not proceed to transplant. The flowchart in Figure 3 contains the data analysis for the final ITT population. PMA P200035: FDA Summary of Safety and Effectiveness Data Page 36 of 96 {36} ![img-2.jpeg](img-2.jpeg) Figure 3 - Study Accountability Flowchart PMA P200035: FDA Summary of Safety and Effectiveness Data {37} A total of 116 randomized livers were excluded from the study (56 NMP, 60 SCS). Of these livers, 90 livers were deemed unsuitable for retrieval for transplant by the study investigators (40 NMP, 50 SCS). Of these 90 livers, 86 livers were not procured (38 NMP, 48 SCS). Further information about the 90 livers deemed unsuitable are provided below: - Forty-six livers where the donor did not proceed (DCD donor did not proceed to donation or prolonged warm ischemic time, outside of local criteria for liver transplantation) (20 NMP, 26 SCS) - Twenty-one livers due to donor liver quality (cirrhosis/fibrosis/steatosis) (9 NMP, 12 SCS) - Fourteen livers due to other reasons (5 NMP, 9 SCS) - Two livers due to injury to the hepatic artery (1 NMP, 1 SCS) - One liver due to injury to the IVC/parenchymal damage (1 NMP, 0 SCS) - One liver due to abnormal lesion within the liver (1 NMP, 0 SCS) - One liver due to donor problem (1 NMP, 0 SCS) - Two livers were procured for research purposes (1 NMP, 1 SCS) - Two livers were procured and transplanted outside of the study (1 NMP, 1 SCS) Of the remaining twenty-six livers that were excluded from the study: - Eight livers were excluded because the subject was not medically suitable (eligible) on the day to proceed with the transplant (5 NMP, 3 SCS) - Five livers were discarded following retrieval, prior to transport (2 NMP, 3 SCS) - Three livers were discarded following transport (3 NMP, 0 SCS) - Two livers were excluded because the subject was withdrawn by the investigator (2 NMP, 0 SCS) due to cardiac issues (1 NMP) and heart arrhythmia (1 NMP) - Two livers were excluded because the subject withdrew consent (1 NMP, 1 SCS) - Six livers were excluded for other reasons (3 NMP, 3 SCS) PMA P200035: FDA Summary of Safety and Effectiveness Data Page 38 of 96 {38} Table 6: Subject Disposition by Randomized Group and Donor Type | | Overall | | DBD | | DCD | | | --- | --- | --- | --- | --- | --- | --- | | | NMP | SCS | NMP | SCS | NMP | SCS | | Randomized | 192 | 191 | 143 | 144 | 49 | 47 | | Enrolled (knife-to-skin contact) | 136 | 131 | 114 | 115 | 22 | 16 | | If enrolled, donor type | | | | | | | | DBD | 114 | 115 | 114 | 115 | 0 | 0 | | DCD | 22 | 16 | 0 | 0 | 22 | 16 | | Not Enrolled (no knife-to-skin contact) | 56 | 60 | 29 | 29 | 27 | 31 | | Reason for study exit | | | | | | | | Liver not Suitable for Retrieval | 40 | 50 | 15 | 22 | 25 | 28 | | Liver Discarded Before Transport | 2 | 3 | 1 | 2 | 1 | 1 | | Liver Discarded Following Transport | 3 | 0 | 3 | 0 | 0 | 0 | | Subject was not Eligible to Proceed with Transplant | 5 | 3 | 4 | 3 | 1 | 0 | | Subject Withdrew Consent | 1 | 1 | 1 | 0 | 0 | 1 | | Subject Withdrawn by Investigator | 2 | 0 | 2 | 0 | 0 | 0 | | Other | 3 | 3 | 3 | 2 | 0 | 1 | | Transplanted | 136 | 130 | 114 | 114 | 22 | 16 | PMA P200035: FDA Summary of Safety and Effectiveness Data Page 39 of 96 {39} | If transplanted, Per-Protocol analysis group | | | | | | | | --- | --- | --- | --- | --- | --- | --- | | NMP* | 133 | 0 | 113 | 0 | 20 | 0 | | SCS | 0 | 130 | 0 | 114 | 0 | 16 | | If transplanted, As-Treated analysis group | | | | | | | | NMP* | 133 | 2 | 113 | 1 | 20 | 1 | | SCS | 0 | 130 | 0 | 114 | 0 | 16 | | Re-allocated | 0 | 1 | 0 | 1 | 0 | 0 | | *One subject (AGBX122) was excluded from the analysis due to exclusion criteria being met. Two additional subjects (AEJX212, AELD404) were excluded due to being transported using Static Cold Storage. | | | | | | | The primary analysis was performed on all subjects in the intent-to-treat (ITT) population. Per the protocol and statistical analysis plan, additional sensitivity analyses included: - Analysis of donor type crossovers per the corrected donor type - Analysis of preservation type where any livers randomized to the NMP arm, but unable to be preserved on the machine and therefore preserved using SCS, were analyzed in the SCS arm - Multiple imputation for EAD status that is unable to be confirmed by complete labs or at least 1 lab value meeting criteria for EAD - Per Protocol analysis: For item 1 in the list above, there were no transplanted livers where the donor type was corrected and considered a crossover, therefore no results are presented The following is a summary of the populations analyzed: - The ITT population includes all transplanted subjects (a subject with reperfusion of a donor liver) and analyzes them in the groups to which the liver was randomly assigned, irrespective of whether the assigned method of preservation was actually used - The Per-Protocol population includes all transplanted subjects who were followed according to the protocol procedures with no major deviations: PMA P200035: FDA Summary of Safety and Effectiveness Data Page 40 of 96 {40} One subject (Subject 08-021/Liver AGBX122) was excluded from the Per-Protocol analysis due to exclusion criteria being met Two subjects (Subject 13-003/Liver AEJX212 and Subject 06-019/Liver AELD404) were excluded from the Per-Protocol analysis as they were randomized to NMP but were unable to be placed on the device and instead were transported using SCS - The As-Treated population includes all transplanted subjects and analyzes them in the treatment groups corresponding to the method of preservation that was actually used. One subject (Subject 08-021/Liver AGBX122) was excluded from the As-Treated analysis due to exclusion criteria being met Two subjects (Subject 13-003/Liver AEJX212 and Subject 06-019/Liver AELD404) were included in the SCS arm in the As-Treated analysis because they received livers that were randomized to NMP but were unable to be placed on the device and instead were transported using SCS There were three subjects (Subject 08-017/Liver AFJX183, Subject 03-049/Liver AGJY324, and Subject 09-002/Liver AECG396) identified as having elevated Day 7 INR values due to therapeutic anticoagulation. Day 7 INR values for these three subjects were therefore considered missing for all analyses and imputed to determine EAD status. # C. Study Population Demographics and Baseline Parameters Table 7 summarizes the baseline demographics of the donors in the intent-to-treat (ITT) cohort. The demographics of the study population are typical for a liver transplant study. Table 7: Donor Demographics with Attempted Transplant | | Overall | | DBD | | DCD | | | --- | --- | --- | --- | --- | --- | --- | | Characteristic | NMP | SCS | NMP | SCS | NMP | SCS | | Age (years) | | | | | | | | N | 136 | 130 | 114 | 114 | 22 | 16 | | Mean ± SD | 53.1 ± 12.9 | 52.5 ± 11.5 | 56.5 ± 9.3 | 54.4 ± 9.7 | 35.6 ± 15.2 | 38.7 ± 14.4 | | Median | 54.0 | 52.0 | 56.0 | 53.0 | 30.5 | 37.0 | | Range (Min, Max) | (18.0, 80.0) | (20.0, 79.0) | (40.0, 80.0) | (40.0, 79.0) | (18.0, 66.0) | (20.0, 61.0) | | IQR | 47.0, 60.0 | 45.0, 60.0 | 49.0, 62.0 | 47.0, 61.0 | 22.0, 47.0 | 27.0, 50.0 | | Sex | | | | | | | | Male | 45.6% (62/136) | 52.3% (68/130) | 43.0% (49/114) | 50.9% (58/114) | 59.1% (13/22) | 62.5% (10/16) | | Female | 45.6% (62/136) | 52.3% (68/130) | 43.0% (49/114) | 50.9% (58/114) | 59.1% (13/22) | 62.5% (10/16) | PMA P200035: FDA Summary of Safety and Effectiveness Data {41} | | Overall | | DBD | | DCD | | | --- | --- | --- | --- | --- | --- | --- | | Characteristic | NMP | SCS | NMP | SCS | NMP | SCS | | Female | 54.4% (74/136) | 47.7% (62/130) | 57.0% (65/114) | 49.1% (56/114) | 40.9% (9/22) | 37.5% (6/16) | | Race | | | | | | | | American Indian or Alaskan Native | 0.7% (1/136) | 0.8% (1/130) | 0.0% (0/114) | 0.9% (1/114) | 4.5% (1/22) | 0.0% (0/16) | | Asian | 0.0% (0/136) | 0.8% (1/130) | 0.0% (0/114) | 0.9% (1/114) | 0.0% (0/22) | 0.0% (0/16) | | Black or African American | 18.4% (25/136) | 20.8% (27/130) | 21.1% (24/114) | 23.7% (27/114) | 4.5% (1/22) | 0.0% (0/16) | | Native Hawaiian or other Pacific Islander | 0.0% (0/136) | 0.0% (0/130) | 0.0% (0/114) | 0.0% (0/114) | 0.0% (0/22) | 0.0% (0/16) | | White | 77.9% (106/136) | 75.4% (98/130) | 76.3% (87/114) | 73.7% (84/114) | 86.4% (19/22) | 87.5% (14/16) | | Other | 2.9% (4/136) | 2.3% (3/130) | 2.6% (3/114) | 0.9% (1/114) | 4.5% (1/22) | 12.5% (2/16) | | Ethnicity | | | | | | | | Hispanic or Latino | 23.1% (9/39) | 25.0% (10/40) | 24.2% (8/33) | 21.6% (8/37) | 16.7% (1/6) | 66.7% (2/3) | | Not Hispanic or Latino | 76.9% (30/39) | 75.0% (30/40) | 75.8% (25/33) | 78.4% (29/37) | 83.3% (5/6) | 33.3% (1/3) | | Selected Medical History | | | | | | | | Diabetes | 18.0% (24/133) | 11.8% (15/127) | 20.7% (23/111) | 13.5% (15/111) | 4.5% (1/22) | 0.0% (0/16) | | Smoker | 52.7% (69/131) | 47.2% (60/127) | 53.2% (58/109) | 45.9% (51/111) | 50.0% (11/22) | 56.3% (9/16) | | History of Heavy Alcohol Use | 19.5% (26/133) | 22.8% (29/127) | 21.4% (24/112) | 23.4% (26/111) | 9.5% (2/21) | 18.8% (3/16) | | History of Illicit Drug Use | 35.1% (47/134) | 41.3% (52/126) | 33.0% (37/112) | 40.5% (45/111) | 45.5% (10/22) | 46.7% (7/15) | | Diagnosis of Hepatitis C Virus (HCV) | 8.1% (11/136) | 3.8% (5/130) | 8.8% (10/114) | 3.5% (4/114) | 4.5% (1/22) | 6.3% (1/16) | | Diagnosis of Hepatocellular Carcinoma (HCC) | 0.0% (0/136) | 0.0% (0/130) | 0.0% (0/114) | 0.0% (0/114) | 0.0% (0/22) | 0.0% (0/16) | | Body Mass Index (BMI) (kg/m2) | | | | | | | | BMI (kg/m2) | 18.0% (25/133) | 17.0% (21/127) | 18.0% (22/111) | 17.0% (21/111) | 18.0% (2/21) | 18.0% (2/16) | | BMI (kg/m2) < 18.0 | 18.0% (25/133) | 17.0% (21/127) | 18.0% (22/111) | 17.0% (21/111) | 18.0% (2/21) | 18.0% (2/16) | | BMI (kg/m2) 18.0-24.9 | 18.0% (25/133) | 17.0% (21/127) | 18.0% (22/111) | 17.0% (21/111) | 18.0% (2/21) | 18.0% (2/16) | | BMI (kg/m2) 25.0-34.9 | 18.0% (25/133) | 17.0% (21/127) | 18.0% (22/111) | 17.0% (21/111) | 18.0% (2/21) | 18.0% (2/16) | | BMI (kg/m2) 35.0-49.9 | 18.0% (25/133) | 17.0% (21/127) | 18.0% (22/111) | 17.0% (21/111) | 18.0% (2/21) | 18.0% (2/16) | PMA P200035: FDA Summary of Safety and Effectiveness Data {42} Table 8 summarizes baseline characteristics of the donors with attempted transplants. There were no major differences in cause of death or mean donor risk index (DRI) between the randomization arms. Table 8: Donor Baseline Characteristics with Attempted Transplant | | Overall | | DBD | | DCD | | | --- | --- | --- | --- | --- | --- | --- | | Characteristic | NMP | SCS | NMP | SCS | NMP | SCS | | Cause of Death | | | | | | | | Cerebrovascular Accident (CVA) | 37.5% (51/136) | 44.6% (58/130) | 40.4% (46/114) | 47.4% (54/114) | 22.7% (5/22) | 25.0% (4/16) | | Hypoxia | 2.2% (3/136) | 1.5% (2/130) | 0.9% (1/114) | 1.8% (2/114) | 9.1% (2/22) | 0.0% (0/16) | | Trauma | 15.4% (21/136) | 15.4% (20/130) | 14.0% (16/114) | 13.2% (15/114) | 22.7% (5/22) | 31.3% (5/16) | | Anoxia | 40.4% (55/136) | 34.6% (45/130) | 41.2% (47/114) | 35.1% (40/114) | 36.4% (8/22) | 31.3% (5/16) | | Other | 4.4% (6/136) | 3.8% (5/130) | 3.5% (4/114) | 2.6% (3/114) | 9.1% (2/22) | 12.5% (2/16) | | Donor Risk Index (DRI) | | | | | | | | N | 136 | 130 | 114 | 114 | 22 | 16 | | Mean ± SD | 1.6 ± 0.3 | 1.6 ± 0.3 | 1.6 ± 0.3 | 1.6 ± 0.3 | 1.9 ± 0.4 | 1.9 ± 0.5 | | Median | 1.6 | 1.6 | 1.5 | 1.6 | 1.9 | 1.7 | | Range (Min, Max) | (1.1, 2.8) | (1.0, 3.1) | (1.1, 2.4) | (1.0, 2.3) | (1.4, 2.8) | (1.4, 3.1) | | IQR | 1.4, 1.8 | 1.4, 1.8 | 1.3, 1.8 | 1.4, 1.8 | 1.5, 2.1 | 1.6, 2.0 | PMA P200035: FDA Summary of Safety and Effectiveness Data {43} Donor livers randomized into the NMP and SCS arms were generally comparable with respect to donor baseline characteristics and demographics. Additionally, the proportion of male and female donors was comparable across arms. DBD donors were middle aged (44 to 67 years old) and had a low donor risk index (DRI; 1.6). DCD donors were younger (20 to 45 years old) and had a high DRI (1.9). All the above characteristics were comparable across arms. Table 9 summarizes the baseline demographics of the 267 enrolled subjects (136 NMP, 131 SCS). Table 9: Recipient Demographics by Donor Type and Randomization Arm | | Overall | | DBD | | DCD | | | --- | --- | --- | --- | --- | --- | --- | | Characteristic | NMP | SCS | NMP | SCS | NMP | SCS | | Age (years) | | | | | | | | N | 136 | 131 | 114 | 115 | 22 | 16 | | Mean ± SD | 57.4 ± 10.5 | 57.2 ± 10.6 | 57.7 ± 10.4 | 57.8 ± 10.5 | 55.8 ± 11.3 | 52.6 ± 10.3 | | Median | 59.0 | 60.0 | 59.5 | 60.0 | 58.0 | 55.0 | | Range (Min, Max) | (20.0, 76.0) | (21.0, 77.0) | (21.0, 76.0) | (21.0, 77.0) | (20.0, 73.0) | (37.0, 67.0) | | IQR | 54.0, 64.0 | 52.0, 65.0 | 54.0, 64.0 | 53.0, 65.0 | 53.0, 62.0 | 42.0, 59.0 | | Sex | | | | | | | | Male | 68.4% (93/136) | 63.4% (83/131) | 69.3% (79/114) | 66.1% (76/115) | 63.6% (14/22) | 43.8% (7/16) | | Female | 31.6% (43/136) | 36.6% (48/131) | 30.7% (35/114) | 33.9% (39/115) | 36.4% (8/22) | 56.3% (9/16) | | Race | | | | | | | | American Indian or Alaskan Native | 0.0% (0/136) | 0.0% (0/131) | 0.0% (0/114) | 0.0% (0/115) | 0.0% (0/22) | 0.0% (0/16) | | Asian | 0.0% (0/136) | 0.8% (1/131) | 0.0% (0/114) | 0.9% (1/115) | 0.0% (0/22) | 0.0% (0/16) | | Black or African American | 3.7% (5/136) | 6.9% (9/131) | 3.5% (4/114) | 7.0% (8/115) | 4.5% (1/22) | 6.3% (1/16) | | Native Hawaiian or other Pacific Islander | 0.0% (0/136) | 0.0% (0/131) | 0.0% (0/114) | 0.0% (0/115) | 0.0% (0/22) | 0.0% (0/16) | | White | 93.4% (127/136) | 90.8% (119/131) | 93.0% (106/114) | 90.4% (104/115) | 95.5% (21/22) | 93.8% (15/16) | | Other | 2.9% (4/136) | 0.8% (1/131) | 3.5% (4/114) | 0.9% (1/115) | 0.0% (0/22) | 0.0% (0/16) | | Ethnicity | | | | | | | | Hispanic or Latino | 11.0% (15/136) | 9.9% (13/131) | 11.4% (13/114) | 9.6% (11/115) | 9.1% (2/22) | 12.5% (2/16) | | Other | 0.0% (0/136) | 0.0% (0/131) | 0.0% (0/114) | 0.0% (0/115) | 0.0% (0/22) | 0.0% (0/16) | PMA P200035: FDA Summary of Safety and Effectiveness Data 44 of 96 {44} | | Overall | | DBD | | DCD | | | --- | --- | --- | --- | --- | --- | --- | | Characteristic | NMP | SCS | NMP | SCS | NMP | SCS | | Not Hispanic or Latino | 89.0% (121/136) | 90.1% (118/131) | 88.6% (101/114) | 90.4% (104/115) | 90.9% (20/22) | 87.5% (14/16) | | Etiology of Liver Disease/ Indication for Liver Transplant* | | | | | | | | Hepatocellular Disease | 81.6% (111/136) | 85.5% (112/131) | 83.3% (95/114) | 87.8% (101/115) | 72.7% (16/22) | 68.8% (11/16) | | Cholestatic Liver Disease | 8.1% (11/136) | 6.9% (9/131) | 6.1% (7/114) | 7.0% (8/115) | 18.2% (4/22) | 6.3% (1/16) | | Vascular Disease | 0.7% (1/136) | 0.0% (0/131) | 0.9% (1/114) | 0.0% (0/115) | 0.0% (0/22) | 0.0% (0/16) | | Metabolic disorder and metabolic liver disease | 5.1% (7/136) | 6.1% (8/131) | 5.3% (6/114) | 5.2% (6/115) | 4.5% (1/22) | 12.5% (2/16) | | Primary Hepatocellular carcinoma | 31.6% (43/136) | 29.8% (39/131) | 35.1% (40/114) | 29.6% (34/115) | 13.6% (3/22) | 31.3% (5/16) | | Toxic reactions | 0.0% (0/136) | 1.5% (2/131) | 0.0% (0/114) | 0.9% (1/115) | 0.0% (0/22) | 6.3% (1/16) | | Trauma | 0.0% (0/136) | 0.0% (0/131) | 0.0% (0/114) | 0.0% (0/115) | 0.0% (0/22) | 0.0% (0/16) | | Other | 11.0% (15/136) | 12.2% (16/131) | 8.8% (10/114) | 10.4% (12/115) | 22.7% (5/22) | 25.0% (4/16) | | Body Mass Index (BMI) (kg/m2) | | | | | | | | N | 136 | 131 | 114 | 115 | 22 | 16 | | Mean ± SD | 29.2 ± 5.7 | 29.5 ± 6.0 | 29.4 ± 5.8 | 29.8 ± 5.8 | 27.8 ± 4.9 | 27.7 ± 7.5 | | Median | 28.3 | 28.9 | 28.7 | 29.1 | 26.6 | 26.4 | | Range (Min, Max) | (18.5, 49.3) | (16.8, 49.5) | (18.5, 49.3) | (16.8, 49.5) | (21.8, 41.4) | (18.7, 47.4) | | IQR | 25.4, 32.0 | 25.4, 33.0 | 25.6, 32.1 | 25.6, 33.2 | 24.9, 30.3 | 22.1, 31.5 | | Selected Medical History | | | | | | | | Smoker | 31.9% (43/135) | 26.2% (34/130) | 32.7% (37/113) | 25.4% (29/114) | 27.3% (6/22) | 31.3% (5/16) | | History of Heavy Alcohol Use | 37.1% (49/132) | 33.1% (43/130) | 38.7% (43/111) | 31.6% (36/114) | 28.6% (6/21) | 43.8% (7/16) | | Re-transplant | 0.7% (1/136) | 1.5% (2/131) | 0.9% (1/114) | 1.7% (2/115) | 0.0% (0/22) | 0.0% (0/16) | | If re-transplant, cause of failure of previous liver transplant* | | | | | | | | Primary graft non-function | 0.0% (0/136) | 0.0% (0/131) | 0.0% (0/114) | 0.0% (0/115) | 0.0% (0/22) | 0.0% (0/16) | | Hepatic artery thrombosis | 0.0% (0/136) | 0.0% (0/131) | 0.0% (0/114) | 0.0% (0/115) | 0.0% (0/22) | 0.0% (0/16) | | Chronic rejection | 0.0% (0/136) | 1.5% (2/131) | 0.0% (0/114) | 1.7% (2/115) | 0.0% (0/22) | 0.0% (0/16) | PMA P200035: FDA Summary of Safety and Effectiveness Data {45} | | Overall | | DBD | | DCD | | | --- | --- | --- | --- | --- | --- | --- | | Characteristic | NMP | SCS | NMP | SCS | NMP | SCS | | Ischemic type biliary lesions after donation after cardiac death | 0.0% (0/136) | 0.0% (0/131) | 0.0% (0/114) | 0.0% (0/115) | 0.0% (0/22) | 0.0% (0/16) | | Recurrent non-neoplastic disease causing late graft failure | 0.0% (0/136) | 0.0% (0/131) | 0.0% (0/114) | 0.0% (0/115) | 0.0% (0/22) | 0.0% (0/16) | | Recurrence of original liver disease | 0.7% (1/136) | 0.0% (0/131) | 0.9% (1/114) | 0.0% (0/115) | 0.0% (0/22) | 0.0% (0/16) | | Other | 0.0% (0/136) | 0.8% (1/131) | 0.0% (0/114) | 0.9% (1/115) | 0.0% (0/22) | 0.0% (0/16) | | *Multiple responses are possible for 1 subject† Denominator includes all subjects that have a demographics assessment dateData reported as 'unknown' are considered as missing | | | | | | | In the US WP01 study, the 136 NMP recipients comprised of 93 males (68.4%) and 43 females (31.6%) with a mean age of $57.4 \pm 10.5$ years. The 131 recipients in the SCS group comprised of 83 males (63.4%) and 48 females (36.6%) with a mean age of $57.1 \pm 10.6$ years. There were no notable differences in the age of recipients and percentage of males between the NMP and SCS groups. A high proportion of recipients overall were white males. The mean calculated MELD score for the NMP arm $(N = 134)$ was $19.2 \pm 9.5$ and $19.4 \pm 8.8$ for the SCS arm $(N = 130)$ . MELD scores in the NMP-DBD $(N = 112)$ subgroup were $19.6 \pm 9.9$ and $19.3 \pm 9.3$ in the SCS-DBD subgroup $(N = 114)$ . MELD scores in the NMP-DCD subgroup $(N = 22)$ were $17.3 \pm 7.0$ and $20.3 \pm 4.7$ in the SCS-DCD subgroup $(N = 16)$ . There were no notable differences in the mean calculated MELD scores across arms. The site-reported MELD score for the NMP arm was $26.5 \pm 6.5$ and $26.6 \pm 6.2$ for the SCS arm. Site-reported MELD scores in the NMP-DBD subgroup were $27.0 \pm 6.5$ and $27.0 \pm 6.2$ in the SCS-DBD subgroup. Site-reported MELD scores in the NMP-DCD subgroup were $23.9 \pm 6.2$ and $24.4 \pm 5.4$ in the SCS-DCD subgroup. Sample sizes for each arm and subgroup are the same as those mentioned in the paragraph above. There were no notable differences in the mean site-reported MELD scores across arms. The highest proportion of MELD scores were in the 15-30 category for both randomization arms in the calculated and site-reproted scores. The expected survival benefit is greatest for subjects with high MELD scores and minimal for subjects with low MELD scores $(&lt; 15)$ . PMA P200035: FDA Summary of Safety and Effectiveness Data {46} Table 10 summarizes preservation times for NMP and SCS livers. The mean total preservation time using the As-Treated population was $75\%$ longer in the NMP arm of the study compared to the SCS arm (NMP $553.8 \pm 115.9$ minutes; SCS $316.9 \pm 94.1$ minutes). Table 10: NMP and SCS Preservation Times (As-Treated Analysis) | | Overall | | DBD | | DCD | | | --- | --- | --- | --- | --- | --- | --- | | Measure | NMP | SCS | NMP | SCS | NMP | SCS | | Cold Ischemia Time (minutes)1 | | | | | | | | N | 134 | 132 | 113 | 115 | 21 | 17 | | Mean ± SD | 134.9 ± 35.7 | 316.9 ± 94.1 | 130.3 ± 35.2 | 315.3 ± 95.8 | 159.9 ± 27.8 | 328.0 ± 82.8 | | Median | 133.5 | 303.0 | 126.0 | 303.0 | 156.0 | 315.0 | | Range (Min, Max) | (24.0, 229.0) | (143.0, 623.0) | (24.0, 229.0) | (143.0, 623.0) | (122.0, 228.0) | (211.0, 505.0) | | IQR | 111.0, 157.0 | 246.0, 370.5 | 108.0, 153.0 | 243.0, 368.0 | 141.0, 172.0 | 269.0, 395.0 | | Time on Pump (minutes) - NMP2 | | | | | | | | N | 133 | - | 112 | - | 21 | - | | Mean ± SD | 356.2 ± 105.9 | | 349.9 ± 103.7 | | 389.8 ± 113.6 | | | Median | 323.0 | | 322.0 | | 363.0 | | | Range (Min, Max) | (196.0, 701.0) | | (196.0, 701.0) | | (256.0, 616.0) | | | IQR | 269.0, 421.0 | | 262.5, 403.0 | | 297.0, 482.0 | | | Total Preservation Time (minutes)3 | | | | | | | | N | 134 | 132 | 113 | 115 | 21 | 17 | | Mean ± SD | 553.8 ± 115.9 | 316.9 ± 94.1 | 543.0 ± 110.0 | 315.3 ± 95.8 | 611.5 ± 132.2 | 328.0 ± 82.8 | | Median | 523.0 | 303.0 | 517.0 | 303.0 | 577.0 | 315.0 | | Range (Min, Max) | (365.0, 890.0) | (143.0, 623.0) | (365.0, 890.0) | (143.0, 623.0) | (439.0, 872.0) | (211.0, 505.0) | | IQR | 466.0, 617.0 | 246.0, 370.5 | 463.0, 594.0 | 243.0, 368.0 | 522.0, 676.0 | 269.0, 395.0 | PMA P200035: FDA Summary of Safety and Effectiveness Data {47} | | Overall | | DBD | | DCD | | | --- | --- | --- | --- | --- | --- | --- | | Measure | NMP | SCS | NMP | SCS | NMP | SCS | | Functional Warm Ischemia Time (minutes)4 | | | | | | | | N | 20 | 17 | - | - | 20 | 17 | | Mean ± SD | 12.3 ± 4.9 | 11.4 ± 3.6 | | | 12.3 ± 4.9 | 11.4 ± 3.6 | | Median | 12.5 | 11.0 | | | 12.5 | 11.0 | | Range (Min, Max) | (3.0, 22.0) | (7.0, 19.0) | | | (3.0, 22.0) | (7.0, 19.0) | | IQR | 9.5, 14.5 | 9.0, 14.0 | | | 9.5, 14.5 | 9.0, 14.0 | | 1Cold ischemia time (NMP) is calculated as time from aortic cold perfusion to initiation of NMP for the DCD arm and time of cross clamp to initiation of NMP for the DBD arm. 1Cold ischemia time (SCS) is calculated as time from aortic cold perfusion to portal reperfusion for the DCD arm and time from cross clamp to portal reperfusion for the DBD arm. 2Time on pump (NMP) is calculated as time from initiation of NMP to cessation of NMP. 3Total preservation time is calculated as time from cross clamp to portal reperfusion in the DBD arm and time from aortic cold perfusion to portal reperfusion in the DCD arm. 4Functional warm ischemia time (minutes) is calculated for DCD donors only as onset time of systolic blood pressure falling below 50mmHg (SBP < 50 mmHg) to earlier of time of start of aortic cold perfusion or time of start of portal cold perfusion. | | | | | | | Mean total preservation time (TPT) was longer in the NMP group (9.2 hours) compared to SCS (5.2 hours). The max TPT was 15 hours in the NMP, as compared to 10 hours in the SCS. The mean cold ischemia time (CIT) in the NMP group was $135.25 \pm 35.84$ minutes, with no difference in CIT between patients with EAD and those without EAD. The mean time on NMP was $358.71 \pm 107.62$ minutes; no significant difference was observed between patients with EAD and those without EAD. The mean CIT in the SCS group was $319.31 \pm 93.76$ minutes in recipients who displayed EAD. This is considered an acceptable CIT in SCS livers. Total operative time was prolonged in the DCD donors (6.3 hours) compared to NMP (5.4 hours). On the contrary, anastomosis time (defined as the time between removal of organ from ice (SCS) or perfusion device (NMP) to organ reperfusion) was prolonged in the NMP (50 to 55 minutes) compared to the SCS group (33 minutes). Table 11 shows procedural details for the NMP and SCS groups. The mean total operative time was similar between the groups (NMP 350.2 minutes; SCS 345.5 minutes). The increased mean anastomotic time reported for NMP livers (NMP $60.2 \pm 22.3$ versus SCS $38.5 \pm 19.2$ ) was not due to an increase in operative time. The increased PMA P200035: FDA Summary of Safety and Effectiveness Data {48} time was due to inclusion of the cold flush time following cessation of NMP in the calculation of anastomotic time, which is not required for SCS livers. Of note is the reduction in the occurrence of post-reperfusion syndrome in the NMP arm of the study (NMP 5.9%; SCS 14.6%). Table 11: Summary of Liver Procedures | | Overall | | DBD | | DCD | | | --- | --- | --- | --- | --- | --- | --- | | Characteristic | NMP | SCS | NMP | SCS | NMP | SCS | | Total Operative Time (mins.) | | | | | | | | N | 136 | 131 | 114 | 115 | 22 | 16 | | Mean ± SD | 350.2 ± 110.1 | 345.5 ± 112.5 | 345.1 ± 107.9 | 342.8 ± 107.4 | 376.6 ± 119.8 | 365.3 ± 146.6 | | Median | 332.5 | 326.0 | 328.0 | 324.0 | 381.5 | 381.0 | | Range (Min, Max) | (133.0, 670.0) | (104.0, 788.0) | (133.0, 670.0) | (104.0, 651.0) | (175.0, 588.0) | (160.0, 788.0) | | IQR | 277.0, 405.5 | 267.0, 409.0 | 277.0, 401.0 | 267.0, 408.0 | 281.0, 481.0 | 262.0, 429.0 | | Anastomotic time (secondary warm ischemia)1 (mins.) | | | | | | | | N | 132 | 129 | 110 | 113 | 22 | 16 | | Mean ± SD | 60.2 ± 22.3 | 38.5 ± 19.2 | 60.1 ± 22.7 | 38.7 ± 19.5 | 60.2 ± 20.5 | 37.4 ± 17.2 | | Median | 57.0 | 33.0 | 57.0 | 33.0 | 55.5 | 33.5 | | Range (Min, Max) | (22.0, 138.0) | (5.0, 129.0) | (22.0, 138.0) | (5.0, 129.0) | (28…
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