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

NCT01715883 | Terminated Phase 2 Results DMC

• 1 other identifier: PRO11030251
• Study Type: interventional
• Target: 3
• Locations: 1 country
• Sites: 1

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).

Conditions

Primary Graft Dysfunction

Keywords

Lung transplant; Pulmonary Graft Dysfunction; Sodium Nitrite

Outcome Measures

Primary Outcomes (2)

• 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

• 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 Outcomes (5)

• Number of Participants With Primary Graft Dysfunction Grades 2+3

  First 72 hours post organ reperfusion.

• Number of Participants With Acute Rejection

  Up to 12 months post lung transplant

• Number of Participants With Chronic Rejection

  Up to 12 months post lung transplant

• Number of Ventilator Free Days (VFD)

  Baseline through Day 30 post transplantation.

• Number of ICU Free Days (IFD)

  Day 30 post transplantation.

Study Arms (1)

Sodium Nitrite

EXPERIMENTAL

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.

Drug: Sodium Nitrite

Interventions

Sodium Nitrite DRUG

Same as the details in Arm Description.

Sodium Nitrite

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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

Sponsors & Collaborators

• Gladwin, Mark, MD: lead

Study Sites (1)

University of pittsburgh

Pittsburgh, Pennsylvania, 15213, United States

Location

Related 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.

  PMID: 18174545 BACKGROUND

• 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. doi: 10.1016/j.healun.2005.03.004. No abstract available.

  PMID: 16210115 BACKGROUND

• 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.

  PMID: 18785961 BACKGROUND

• 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.

  PMID: 19239481 BACKGROUND

• 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. doi: 10.1016/j.healun.2005.11.436. Epub 2006 Feb 28.

  PMID: 16563963 BACKGROUND

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

  PMID: 19131529 BACKGROUND

• 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. doi: 10.1016/j.healun.2004.11.049. Epub 2005 Jun 4. No abstract available.

  PMID: 16210116 BACKGROUND

• 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. doi: 10.1016/j.healun.2005.02.017. Epub 2005 Aug 8. No abstract available.

  PMID: 16210117 BACKGROUND

• Thabut G, Vinatier I, Stern JB, Leseche G, Loirat P, Fournier M, Mal H. Primary graft failure following lung transplantation: predictive factors of mortality. Chest. 2002 Jun;121(6):1876-82. doi: 10.1378/chest.121.6.1876.

  PMID: 12065352 BACKGROUND

• 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. doi: 10.1161/CIRCULATIONAHA.107.712133. Epub 2007 Sep 24.

  PMID: 17893272 BACKGROUND

MeSH Terms

Conditions

Primary Graft Dysfunction

Interventions

Sodium Nitrite

Condition Hierarchy (Ancestors)

Reperfusion Injury; Vascular Diseases; Cardiovascular Diseases; Postoperative Complications; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Nitrites; Nitrous Acid; Nitrogen Compounds; Inorganic Chemicals; Sodium Compounds

Limitations and Caveats

The clinical trial was terminated early due to lack of funding support, difficulty in recruiting patients and lack of support staff. Early termination leading to small numbers of subjects analyzed.

Results Point of Contact

• Title: Matthew Morrell, MD
• Organization: University of Pittsburgh

morrellmr@upmc.edu

412-647-8477

Study Officials

• Matthew Morrell, MD

  University of Pittsburgh

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: PREVENTION
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDIV
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Assistant Professor, Department of Medicine, Division of Pulmonary, Allergy and Critical care medicine

Study Record Dates

• First Submitted: October 8, 2012
• First Posted: October 29, 2012
• Study Start: October 1, 2011
• Primary Completion: May 1, 2017
• Study Completion: May 1, 2017
• Last Updated: August 1, 2018
• Results First Posted: August 1, 2018

Record last verified: 2018-05

Locations

US (1)