Sodium Nitrite in Lung Transplant Patients to Minimize the Risk of Pulmonary Graft Dysfunction
This is a Phase IIA observational nonrandomized pilot investigation to evaluate the safety and efficacy of Sodium Nitrite administration for the reduction of PGD in patients undergoing lung transplant. The study will enroll 8 subjects, undergoing lung transplant at the University of Pittsburgh Medical Center (UPMC).
|Study Design:||Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Prevention
|Official Title:||Sodium Nitrite Administration at the Time of Lung Organ Procurement and Transplantation to Minimize the Risk of Pulmonary Graft Dysfunction|
- Incidence of grades 2+3 PGD grade during the first 72 hours post organ reperfusion. [ Time Frame: First 72 hours post organ reperfusion. ] [ Designated as safety issue: Yes ]The primary study endpoint is the incidence of grades 2+3 PGD based upon the worst PGD grade during the first 72 hours post organ reperfusion (T0-72 or D0-D3).
- Incidence of Methemoglobinemia during Nitrite infusion to the transplant [ Time Frame: 5, 30, and 60 minutes during the infusion; and at 5, 10, 30, 60, 90, 150 after the infusion. ] [ Designated as safety issue: Yes ]The safety of Sodium Nitrite administration will be assessed by measurement of methemoglobin levels during and after the nitrite infusion in the transplant recipient.
- Incidence of fall in patient's mean arterial pressure greater than 20% from recorded baseline requiring discontinuation of drug infusion. [ Time Frame: Monitored at 1 minute intervals during study drug infusion followed by 15 minute intervals for 1 hour. ] [ Designated as safety issue: Yes ]The safety of Sodium Nitrite administration will be assessed by change in mean arterial pressure greater than 20% from recorded baseline during and after the nitrite infusion in the transplant recipient.
- Incidence of acute and Chronic rejection [ Time Frame: Up to 12 months post Lung transplan ] [ Designated as safety issue: No ]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 and 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.
- Number of Ventilator Free Days (VFD) [ Time Frame: 8am through D30 post transplantation. ] [ Designated as safety issue: No ]Defined as the number of days off mechanical ventilation at 8am through D30 post transplantation.
- Number of ICU Free Days (IFD) [ Time Frame: Days outside the ICU through D30 post transplantation. ] [ Designated as safety issue: No ]Defined as the number of days outside the ICU through D30 post transplantation.
|Study Start Date:||October 2011|
|Estimated Study Completion Date:||December 2014|
|Estimated Primary Completion Date:||December 2013 (Final data collection date for primary outcome measure)|
Experimental: Sodium Nitrite
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 2.8L 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 PV (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
Same as the details in Arm Description.
Other Name: NDC Number 60267-079-02
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, Sodium Nitrite Injection USP (30mg/mL) NDC Number 60267-079-02) 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 IIA 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.
Please refer to this study by its ClinicalTrials.gov identifier: NCT01715883
|United States, Pennsylvania|
|University of pittsburgh||Recruiting|
|Pittsburgh, Pennsylvania, United States, 15213|
|Contact: Matthew Morrell, MD 412-648-6640|
|Contact: Suchitra Barge, MPH, MBBS 412-864-3290|
|Principal Investigator:||Matthew Morrell, MD||University of Pittsburgh|