The University of Alberta Negative Pressure Ventilation Ex-Vivo Lung Perfusion (NPV-EVLP) Trial

Study Overview
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Brief Summary
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This project is focused on helping one of the most vulnerable patient populations in medicine, patients with end-stage chronic lung disease. Lung transplantation is the only cure for end-stage lung disease, however, due to the persistent shortage of donor organs, either due to low organ donation rates or unacceptable organs, only a minority of patients receive desperately needed lung transplants. Currently less than 30% of potential donated thoracic organs are being used for transplantation. The major causes for under utilization of donor thoracic organs are injury sustained by the lungs in trauma or emergency resuscitation or lungs that come from donors who are pronounced dead due to cardiac arrest (known as DCD donors). It has been hypothesized that these injuries may be reversible or repairable if there was an opportunity to evaluate and repair these organs outside of the body (ex-vivo), prior to transplantation. In fact, studies have shown that the use of normothermic Ex-Vivo Lung Perfusion (EVLP) has increased the rate of donor organ utilization at centers that have adopted the technology. Current methodology for all clinically available EVLP devices uses Positive Pressure Ventilation (PPV). Researchers at the University of Alberta (UofA), however, have developed an EVLP device that will apply Negative Pressure Ventilation (NPV) to the lungs, as opposed to PPV, which is the most ideal mimicry of native lung physiology. The objective of this early feasibility safety trial is to show that the UofA developed NPV-EVLP device is acceptable in evaluating and improving the quality of marginal donor lungs compared to currently used EVLP devices, ultimately allowing for these types of donor lungs to be safely transplanted into patients on the lung transplant recipient waitlist.

Official Title
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The University of Alberta Negative Pressure Ventilation Ex-Vivo Lung Perfusion (NPV-EVLP) Trial

Conditions
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Ex-Vivo Lung Transplantation

Intervention / Treatment
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* Device: NPV-EVLP


Participation Criteria
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Eligibility Criteria
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5.2 PRE-NPV-EVLP Donor Eligibility Criteria 5.2.1 Donor MUST meet ANY ONE of the following Inclusion Criteria to proceed with NPV-EVLP: Best ratio of the PaO2 to FiO2 of < 300mmHg; Pulmonary edema, defined as bilateral interstitial infiltrates without evidence of infection, detected on the last chest radiograph by the lung-transplantation physician assessing the donor; Poor lung deflation or inflation during direct intraoperative visual examination at the donor site; Donor age is ≥ 55 years; Expected cold ischemic time > 6 hours; Blood transfusions ≥ 10 units; or Donation after cardiac death (DCD), as defined by Maastricht category III (donor without a heartbeat and with cardiocirculatory death imminent after withdrawal of treatment) or category IV (cardiocirculatory death in a brain-dead donor). 5.2.2 Donor Exclusion Criteria to NOT proceed with NPV-EVLP: Donor lungs with established pneumonia; Severe mechanical lung injury (i.e., contusions in more than one lobe) or trauma determined by chest x-ray, bronchoscopy, CT scan or visual inspection; or Gross gastric aspiration within the lungs Donor lungs have active infectious disease such as HIV, Hepatitis B, Hepatitis C, West Nile Virus (WNV), HTLV, or Syphillis (if this information not available at start of EVLP, it should be re-assessed prior to transplant). 5.3 POST-NPV-EVLP Donor Eligibility Criteria 5.3.1 Donor Inclusion Criteria to proceed with Transplant: Surgeon must be satisfied with the clinical evaluation and appearance of the lungs; if not, reason for refusal must be documented; Lungs show PaO2/FiO2 ratio ≥ 350mmHg; AND Deterioration of less than 15% from baseline for physiological measurements pulmonary vascular resistance (PVR), dynamic compliance and peak inspiratory pressure. 5.3.2 Donor Exclusion Criteria to proceed with Transplant: Lungs show a PaO2/FiO2 ratio of < 350mmHg; Greater than 15% functional deterioration across the following physiological parameters: PVR, dynamic compliance and peak inspiratory pressure; Donor lungs are positive for infectious disease such as HIV, Hepatitis B, Hepatitis C, West Nile Virus (WNV),HTLV, or Syphillis. 5.4 Recipient Eligibility Criteria 5.4.1 Recipient Inclusion Criteria Patients on our institution's waitlist requiring bilateral transplantation Male or Female 18 years of age or older Written informed consent provided. 5.4.2Recipient Exclusion Criteria Multi-organ recipient or re-transplant HIV, Hepatitis, or other infection that excludes subject from transplant in the study Subject is on hemodialysis or has chronic severe renal dysfunction Concurrent cardiac procedure Recipient is on Nova Lung, ECMO or on mechanical ventilation (CPAP and BiPAP not exclusionary)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Device Feasibility
Intervention Model: Single Group Assignment
Interventional Model Description: The purpose of this Phase I Early Feasibility Proof of Concept clinical trial will be to evaluate initial performance and safety of the NPV-EVLP device to assess and improve the function of marginal donor lungs. By nature, efficacy measures and outcomes of the device will also become evident from the results of this study. This is a prospective, non-randomized, interventional trial, taking place solely at the University of Alberta Hospital/Mazankowski Alberta Heart Institute. Lungs deemed marginal, based on standard lung donor criteria that meet the study's eligibility criteria, will be assessed on our NPV-EVLP device to determine suitability for lung transplantation. Objective assessment of quality will be made while the lungs are on the device based on pre-determined functional parameters of lung physiology. Once a total of 12 sets of lungs are transplanted after using the device, safety will be determined by post-operative lung function and recipient survival.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Experimental Group<br>After initial screening, appropriately obtained informed consent and confirmation of eligibility at time of transplant, those recipients (a total of 12 subjects) who agree to continue as participants will receive reconditioned marginal lungs should the lungs on the device meet acceptable criteria to proceed with clinical transplantation. | Device: NPV-EVLP<br>* Lungs deemed marginal based on standard lung donor criteria that meet study eligibility will be physiologically assessed during ex-vivo perfusion. NPV-EVLP of these lungs will be performed with the addition of numerous pre-determined additives. With respect to the decision of lung utilization post-EVLP, eligibility criteria listed in the Post-NPV-EVLP section of the trial will need to be met. Lungs will also be excluded if they are deemed unsuitable based on the clinical judgment of the lung transplant surgeon.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Patient survival post transplantation at Day30 | The primary end point is a co-primary endpoint comparing patient survival rates post transplantation at Day30 (Outcome 1) and rates of Primary Graft Dysfunction (PGD) Grade 3 in the first 72 hours (Outcome 2) with success measured only if both endpoints are met. | Day30 post-Transplant | 
| Primary Graft Dysfunction (PGD) Grade 3 in the first 72Hours | The primary end point is a co-primary endpoint comparing patient survival rates post transplantation at Day30 (Outcome 1) and rates of Primary Graft Dysfunction (PGD) Grade 3 in the first 72 hours (Outcome 2) with success measured only if both endpoints are met. | First 72Hours post-Transplant | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Primary Graft Dysfunction (PGD) Grades | PGD scores will be assessed a Grade of 0, 1, 2 or 3 (per ISHLT Guidelines) at Time0 (ICU Admission), Time24Hours (post-Transplant), Time48Hours (post-Transplant), and Time72Hours (post-Transplant) with respect to PaO2/FiO2 ratios and presence/absence of radiographic infiltrates consistent with pulmonary edema. | Time0 (ICU Admission), Time24Hours (post-Transplant), Time48Hours (post-Transplant), and Time72Hours (post-Transplant) | 
| ICU LOS | ICU length of stay (LOS) post-Transplant will be captured. | From admission to the ICU through to exact date of ICU Discharge (up to 30Days) | 
| Hospital LOS | Index hospital length of stay (LOS) length of stay post-Transplant will be captured until D/C. | From date of Transplant through to exact date of Index Hospital Discharge (up to 6Months) | 
| Duration of Mechanical Ventilation post-Transplant | The duration of Mechanical Ventilation post-Transplant will be captured until extubation. | Time0 (ICU Admission post-Transplant) through to exact time of extubation post-Transplant | 
| FEV1 | FEV1 results from spirometry efforts at 6Months and 1Year will be captured. | 6Months and 1Year | 
| Quality of Life (SF-36) | Quality of Life measured by the 36-Item Short Form Survey (SF-36) at 6Months and 1Year will be captured. | 6Months and 1Year |