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

Primary Graft Dysfunction Clinical Trial

Official title:

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT01715883
• Other study ID #: PRO11030251
• Status: Terminated
• Phase: Phase 2
• Start date: October 2011
• Est. completion date: May 2017

Study information

• Verified date: May 2018
• Source: University of Pittsburgh
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 3
• Est. completion date: May 2017
• Est. primary completion date: May 2017
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 70 Years

Eligibility

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.

Related Conditions & MeSH terms

• Primary Graft Dysfunction

Intervention

Drug:
• Sodium Nitrite
Same as the details in Arm Description.

Locations

Country	Name	City	State
United States	University of pittsburgh	Pittsburgh	Pennsylvania

Sponsors (1)

Lead Sponsor	Collaborator
Gladwin, Mark, MD

Country where clinical trial is conducted

United States, 

References & Publications (10)

Bobadilla JL, Love RB, Jankowska-Gan E, Xu Q, Haynes LD, Braun RK, Hayney MS, Munoz del Rio A, Meyer K, Greenspan DS, Torrealba J, Heidler KM, Cummings OW, Iwata T, Brand D, Presson R, Burlingham WJ, Wilkes DS. Th-17, monokines, collagen type V, and primary graft dysfunction in lung transplantation. Am J Respir Crit Care Med. 2008 Mar 15;177(6):660-8. doi: 10.1164/rccm.200612-1901OC. Epub 2008 Jan 3. — View Citation

Christie JD, Carby M, Bag R, Corris P, Hertz M, Weill D; ISHLT Working Group on Primary Lung Graft Dysfunction. Report of the ISHLT Working Group on Primary Lung Graft Dysfunction part II: definition. A consensus statement of the International Society for Heart and Lung Transplantation. J Heart Lung Transplant. 2005 Oct;24(10):1454-9. Epub 2005 Jun 4. — View Citation

Christie JD, Van Raemdonck D, de Perrot M, Barr M, Keshavjee S, Arcasoy S, Orens J; ISHLT Working Group on Primary Lung Graft Dysfunction. Report of the ISHLT Working Group on Primary Lung Graft Dysfunction part I: introduction and methods. J Heart Lung Transplant. 2005 Oct;24(10):1451-3. — View Citation

de Perrot M, Bonser RS, Dark J, Kelly RF, McGiffin D, Menza R, Pajaro O, Schueler S, Verleden GM; ISHLT Working Group on Primary Lung Graft Dysfunction. Report of the ISHLT Working Group on Primary Lung Graft Dysfunction part III: donor-related risk factors and markers. J Heart Lung Transplant. 2005 Oct;24(10):1460-7. Epub 2005 Aug 8. — View Citation

Dejam A, Hunter CJ, Tremonti C, Pluta RM, Hon YY, Grimes G, Partovi K, Pelletier MM, Oldfield EH, Cannon RO 3rd, Schechter AN, Gladwin MT. Nitrite infusion in humans and nonhuman primates: endocrine effects, pharmacokinetics, and tolerance formation. Circulation. 2007 Oct 16;116(16):1821-31. Epub 2007 Sep 24. — View Citation

Huang HJ, Yusen RD, Meyers BF, Walter MJ, Mohanakumar T, Patterson GA, Trulock EP, Hachem RR. Late primary graft dysfunction after lung transplantation and bronchiolitis obliterans syndrome. Am J Transplant. 2008 Nov;8(11):2454-62. doi: 10.1111/j.1600-6143.2008.02389.x. Epub 2008 Sep 10. — View Citation

Kuntz CL, Hadjiliadis D, Ahya VN, Kotloff RM, Pochettino A, Lewis J, Christie JD. Risk factors for early primary graft dysfunction after lung transplantation: a registry study. Clin Transplant. 2009 Nov-Dec;23(6):819-30. doi: 10.1111/j.1399-0012.2008.00951.x. Epub 2009 Feb 20. — View Citation

Lee JC, Christie JD. Primary graft dysfunction. Proc Am Thorac Soc. 2009 Jan 15;6(1):39-46. doi: 10.1513/pats.200808-082GO. Review. — View Citation

Prekker ME, Nath DS, Walker AR, Johnson AC, Hertz MI, Herrington CS, Radosevich DM, Dahlberg PS. Validation of the proposed International Society for Heart and Lung Transplantation grading system for primary graft dysfunction after lung transplantation. J Heart Lung Transplant. 2006 Apr;25(4):371-8. Epub 2006 Feb 28. — View Citation

Thabut G, Vinatier I, Stern JB, Lesèche G, Loirat P, Fournier M, Mal H. Primary graft failure following lung transplantation: predictive factors of mortality. Chest. 2002 Jun;121(6):1876-82. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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	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.
Secondary	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
Secondary	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
Secondary	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.
Secondary	Number of ICU Free Days (IFD)	Defined as the number of days outside the ICU through Day 30 post transplantation.	Day 30 post transplantation.