Clinical trial NCT01715883: Sodium Nitrite in Lung Transplant Patients to Minimize the Risk of Pulmonary Graft Dysfunction
Official title: Sodium Nitrite Administration at the Time of Lung Organ Procurement and Transplantation to Minimize the Risk of Pulmonary Graft Dysfunction
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Primary Graft Dysfunction
Keywords: Lung transplant
Pulmonary Graft Dysfunction
Sodium Nitrite
Lead sponsor: University of Pittsburgh
Sponsor class: OTHER
First posted: 2012-10-29
Enrollment: 3
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: PREVENTION

Brief summary: 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: 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Safety of Sodium Nitrite Administration Measured by Methemoglobin Levels
timeFrame: 150 minutes post infusion
measure: Safety of Sodium Nitrite Administration - Number of Participants With Fall in Patient's Mean Arterial Pressure Greater Than 20%
timeFrame: Baseline and 1 hour post infusion
Secondary outcomes:
measure: Number of Participants With Primary Graft Dysfunction Grades 2+3
timeFrame: First 72 hours post organ reperfusion.
measure: Number of Participants With Acute Rejection
timeFrame: Up to 12 months post lung transplant
measure: Number of Participants With Chronic Rejection
timeFrame: Up to 12 months post lung transplant
measure: Number of Ventilator Free Days (VFD)
timeFrame: Baseline through Day 30 post transplantation.
measure: Number of ICU Free Days (IFD)
timeFrame: Day 30 post transplantation.
Other outcomes:
Locations:
city: Pittsburgh
country: United States
facility: University of pittsburgh
state: Pennsylvania
Study officials:
affiliation: University of Pittsburgh
name: Matthew Morrell, MD
role: PRINCIPAL_INVESTIGATOR
References:
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