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

NCT ID: NCT01715883

Last Updated: 2018-08-01

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE2
• Total Enrollment: 3 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2011-10-31
• Study Completion Date: 2017-05-31

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.

Conditions

Primary Graft Dysfunction

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: PREVENTION
• Blinding Strategy: NONE

Study Groups

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 2.8 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.

Group Type: EXPERIMENTAL

Sodium Nitrite

Intervention Type: DRUG

Same as the details in Arm Description.

Interventions

Sodium Nitrite

Same as the details in Arm Description.

Intervention Type: DRUG

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

• 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 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 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.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 70 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Gladwin, Mark, MD

INDIV

Sponsor Role: lead

Responsible Party

Matthew Morrell

Assistant Professor, Department of Medicine, Division of Pulmonary, Allergy and Critical care medicine

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Matthew Morrell, MD

Role: PRINCIPAL_INVESTIGATOR

University of Pittsburgh

Locations

University of pittsburgh

Pittsburgh, Pennsylvania, United States

Countries

United States

References

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Reference Type: BACKGROUND

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Reference Type: BACKGROUND

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Reference Type: BACKGROUND

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Reference Type: BACKGROUND

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Reference Type: BACKGROUND

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Reference Type: BACKGROUND

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Reference Type: BACKGROUND

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Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

PRO11030251

Identifier Type: -

Identifier Source: org_study_id