Sodium Nitrite in Lung Transplant Patients to Minimize the Risk of Pulmonary Graft Dysfunction

Study Overview
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Brief Summary
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This is a Phase 2 observational nonrandomized pilot investigation to evaluate the safety and efficacy of Sodium Nitrite administration for the reduction of Primary Graft Dysfunction (PGD) in patients undergoing lung transplant. The study will enroll 8 subjects, undergoing lung transplant at the University of Pittsburgh Medical Center (UPMC).

Detailed Description
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While increasing numbers of patients with advanced lung disease are candidates for lung transplantation, the short- and long-term outcomes are severely compromised by graft dysfunction, primarily in the form of organ rejection. The earliest manifestation of lung allograft dysfunction, termed primary graft dysfunction (PGD), represents a form of ischemia-reperfusion acute lung injury, and occurs in its severest form (Grade 3) in from 10 to 35% of lung transplant recipients 1-6. PGD is the primary cause of early morbidity and mortality after transplantation and is strongly associated with the late development of chronic lung rejection or Bronchiolitis Obliterans Syndrome (BOS. Early graft dysfunction contributes significantly to the suboptimal outcomes of lung transplantation and to the failure of lung transplant recipients to achieve five-year survival rates comparable to patients who receive other solid organs such as the heart and liver. The risk of PGD further limits the time that lungs can be stored ex-vivo, therefore restricting the pool of available donors. A critical advance in the prevention of both early and late lung allograft dysfunction will occur if PGD can be successfully prevented or minimized. In this study, the investigators propose to test the hypothesis that administration of Sodium Nitrite to donor lungs and lung transplant recipients at the time of transplantation will be safe and will reduce the incidence of grades 2 and 3 PGD, thereby improving clinical outcomes with minimal toxicity. Sodium Nitrite will be obtained from a commercial preparation (Hope Pharmaceuticals) and the UPMC Pharmacy will prepare the formulations, which will be infused at three time points. First it will be infused into the preservation solution bag at the time of organ procurement from the donor, then to the allograft at the time of transplantation, and finally as a direct infusion into the organ recipient. The investigators plan to enroll total of 8 subjects undergoing lung transplantation for this Phase 2 observational non-randomized pilot investigation to evaluate the safety, efficacy, and pharmacokinetics of Sodium Nitrite administration when administered to the procured lung and lung transplant recipient, for the prevention of Primary Graft Dysfunction (PGD). It is anticipated that positive results from this trial lead to a larger clinical investigation of Sodium Nitrite administration directed at producing a reduction in PGD and perhaps secondary obliterative bronchiolitis; and will potentially allow for extended organ storage, extended use of more marginal organs, and more effective use of Donation after Cardiac Death (DCD) organs which undergo combination of warm and cold ischemia for organ procurement.

Official Title
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Sodium Nitrite Administration at the Time of Lung Organ Procurement and Transplantation to Minimize the Risk of Pulmonary Graft Dysfunction

Conditions
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Primary Graft Dysfunction

Intervention / Treatment
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* Drug: Sodium Nitrite


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects undergoing lung transplantation. Subjects in the age range of 18-70 years Ability to understand and provide consent. Proxy consent will not be accepted. Exclusion Criteria: Donor exclusion criteria Age > 55 years. Mechanical ventilation > 5 days prior to procurement Significant chest trauma or lung contusion Smoking history > 20 pack-year Ratio of arterial oxygen partial pressure to fractional inspired oxygen < 300 Donor radiograph with 2 quadrant infiltrates Donor that are determined single lung donors prior to transplant will be excluded. Recipient exclusion criteria Recipient age > 70 years. Recipient history of pulmonary hypertension (idiopathic pulmonary arterial hypertension, or secondary pulmonary arterial hypertension with mean arterial pressure > 30 mm Hg) Recipient history of abnormal cardiac function defined as prior coronary artery bypass graft (CABG) or left ventricular ejection fraction (LVEF) < 45 % Recipient history of open thoracotomy/prior pleurodesis as exclusion criteria. However patients who have had limited video-assisted thoracic surgery procedures for biopsies would NOT be excluded from the study. Recipient history of cirrhosis Recipient history of mechanical ventilation or extracorporeal support pre-operatively Recipient pre-operative hypotension defined by a systolic blood pressure less than 90 mm Hg not responsive to intravenous fluids or requirement for vasoactive medications Recipient preoperative history of renal insufficiency, dialysis or estimated glomerular filtration rate <30 ml/min/1.73 m2 body surface area Patients undergoing retransplantation Recipient history of significant coronary artery disease that is flow limiting and unable to be corrected by further percutaneous coronary artery interventions.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Sodium Nitrite<br>Sodium Nitrite will be administered at three time points: At the time of organ procurement, a pre-prepared syringe of sodium nitrite will be added to each of the 2.8 liter bags of Perfadex solution to flush the donor lungs. At the time of transplant just prior to reperfusion of lungs, the donor lungs are flushed with a cold pneumoplegia solution after the bronchial (1st) anastomosis and with warm pneumoplegia solution after the portal vein (3rd, last) anastomosis. The drug will be added to pneumoplegia solution just prior to both the flushes. Sodium Nitrite will be delivered intravenously to the recipient immediately prior to lung reperfusion as a single infusion at rate of 4 mL/min for the first 30 min, followed by 2.2 mL/min for the next 60 min. | Drug: Sodium Nitrite<br>* Same as the details in Arm Description.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety of Sodium Nitrite Administration Measured by Methemoglobin Levels | The safety of Sodium Nitrite administration will be assessed by methemoglobin levels during and 150 minutes after the nitrite infusion in the transplant recipient. | 150 minutes post infusion | 
| Safety of Sodium Nitrite Administration - Number of Participants With Fall in Patient's Mean Arterial Pressure Greater Than 20% | The safety of Sodium Nitrite administration will be assessed by the incidence of fall in patient's Mean Arterial Pressure greater than 20% from recorded baseline requiring discontinuation of drug infusion during and after the nitrite infusion in the transplant recipient. Mean Arterial Pressure will be monitored at 1 minute intervals during study drug infusion followed by 15 minute intervals for 1 hour. | Baseline and 1 hour post infusion | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Primary Graft Dysfunction Grades 2+3 | The primary study endpoint is the incidence of grades 2+3 Primary Graft Dysfunction (PGD) based upon the worst PGD grade during the first 72 hours post organ reperfusion. The severity of PGD is graded 0-3 based on the presence or absence of diffuse opacities on chest radiograph and the ratio of arterial oxygen pressure to inspired oxygen concentration. The grading system predicts post-lung transplant outcomes with Grade 3 being the worst. | First 72 hours post organ reperfusion. | 
| Number of Participants With Acute Rejection | To evaluate the efficacy of Sodium Nitrite infusion into the procured lungs and the lung transplant recipient in the prevention of delayed allograft complications including the incidence of acute rejection. Prevention of delayed allograft complications include clinically indicated spirometric and lung volume assessments of lung function performed as an indicator of Bronchiolitis Obliterans Syndrome (BOS), and evidence of pathological rejection by surveillance transbronchial lung biopsies. | Up to 12 months post lung transplant | 
| Number of Participants With Chronic Rejection | To evaluate the efficacy of Sodium Nitrite infusion into the procured lungs and the lung transplant recipient in the prevention of delayed allograft complications including the incidence of chronic rejection. Prevention of delayed allograft complications include clinically indicated spirometric and lung volume assessments of lung function performed as an indicator of Bronchiolitis Obliterans Syndrome (BOS), and evidence of pathological rejection by surveillance transbronchial lung biopsies. | Up to 12 months post lung transplant | 
| Number of Ventilator Free Days (VFD) | Defined as the number of days off mechanical ventilation at baseline through Day 30 post transplantation. | Baseline through Day 30 post transplantation. | 
| Number of ICU Free Days (IFD) | Defined as the number of days outside the ICU through Day 30 post transplantation. | Day 30 post transplantation. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Lung transplant, Pulmonary Graft Dysfunction, Sodium Nitrite