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

This study is currently recruiting participants. (see Contacts and Locations)
Verified October 2012 by University of Pittsburgh
Sponsor:
Information provided by (Responsible Party):
Matthew Morrell, University of Pittsburgh
ClinicalTrials.gov Identifier:
NCT01715883
First received: October 8, 2012
Last updated: October 24, 2012
Last verified: October 2012
  Purpose

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).


Condition Intervention Phase
Primary Graft Dysfunction
Drug: Sodium Nitrite
Phase 2

Study Type: Interventional
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

Resource links provided by NLM:


Further study details as provided by University of Pittsburgh:

Primary Outcome Measures:
  • 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).


Secondary Outcome Measures:
  • 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.


Other Outcome Measures:
  • 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.


Estimated Enrollment: 8
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)
Arms Assigned Interventions
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

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, 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.

  Eligibility

Ages Eligible for Study:   18 Years to 70 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Subjects undergoing lung transplantation.
  • Greater than 18 years of age. Ability to provide consent. Proxy consent will not be accepted

Exclusion Criteria:

  • • Recipient age > 70 years.

    • Recipient history of pulmonary hypertension (idiopathic PAH, or secondary PAH with mean PA > 30 mm Hg)
    • Recipient history of abnormal cardiac function (stents, prior CABG, LVEF <50%)
    • Recipient history of prior thoracotomy
    • 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 BSA
    • Patients undergoing retransplant
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01715883

Locations
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      
Sponsors and Collaborators
University of Pittsburgh
Investigators
Principal Investigator: Matthew Morrell, MD University of Pittsburgh
  More Information

Publications:

Responsible Party: Matthew Morrell, Assistant Professor, Department of Medicine, Division of Pulmonary, Allergy and Critical care medicine, University of Pittsburgh
ClinicalTrials.gov Identifier: NCT01715883     History of Changes
Other Study ID Numbers: PRO11030251
Study First Received: October 8, 2012
Last Updated: October 24, 2012
Health Authority: United States: Food and Drug Administration

Keywords provided by University of Pittsburgh:
Lung transplant
Pulmonary Graft Dysfunction
Sodium Nitrite

Additional relevant MeSH terms:
Primary Graft Dysfunction
Cardiovascular Diseases
Pathologic Processes
Postoperative Complications
Reperfusion Injury
Vascular Diseases

ClinicalTrials.gov processed this record on October 22, 2014