Extending Preservation and Assessment Time of Donor Lungs Using the Toronto EVLP System™ at a Dedicated EVLP Facility

A Phase 2, Multicenter, Open-label Study to Measure the Safety of Extending Preservation and Assessment Time of Donor Lungs Using Normothermic Ex Vivo Lung Perfusion and Ventilation (EVLP) as Administered by the SPONSOR Using the Toronto EVLP System™

This is a safety study to compare the safety of receiving a lung treated with the Toronto EVLP System™ by SPONSOR in SPONSOR's dedicated facility against standard lung transplantation.

Study Overview

• Status: Completed
• Conditions: Lung Disease
• Intervention / Treatment: Device: Toronto EVLP System™

Detailed Description

Human donor lungs allocated to a participating study transplant center (Study Center) for a specific recipient and meeting study EVLP donor lung inclusion/exclusion criteria will be assessed by SPONSOR for inclusion into the study.

Upon retrieval, donor lung(s) will be packaged and transported on ice to the SPONSOR's EVLP facility in Silver Spring, Maryland, no differently than when lungs are recovered, packaged, and transported to any transplant center for implantation.

The EVLP procedure will be performed by Certified Ex Vivo Lung Specialists using the Toronto EVLP System™ for up to 6 hours, collecting and relaying lung function assessment data hourly or as requested by the Study Center transplant surgeon. Additionally, the Study Center surgeon will have the capability to evaluate lung function data and monitor the procedure remotely through a dedicated video link.

Upon acceptance of an EVLP donor lung by the Study Center, the single lung or lung block is cooled down by the Toronto EVLP System™ to 10 degrees C. Thereafter, perfusion and ventilation are stopped and the lung is prepared for hypothermic storage and transport to the accepting Study Center.

• Study Type: Interventional
• Enrollment (Actual): 118
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Florida
    • Jacksonville, Florida, United States, 32224
      • Mayo Clinic Jacksonville
  • Illinois
    • Chicago, Illinois, United States, 60153
      • Loyola University Medical Center
  • Maryland
    • Baltimore, Maryland, United States, 21201
      • University of Maryland Medical Center
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan Health System
  • North Carolina
    • Durham, North Carolina, United States, 27705
      • Duke University Health System
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15213
      • UPMC
  • Virginia
    • Falls Church, Virginia, United States, 22042
      • Inova Fairfax Medical Campus

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Subject Inclusion Criteria:

In order to be eligible to participate in this study, an individual must meet all of the following criteria:

• Male or female patients
• All patients, 18 years of age or older
• Patient already on or added to the active waiting list for a single or bilateral lung transplant
• Patient or patient's representative provides informed consent for participation in the study at the time of study commencement or time of listing for transplant
• Patient or patient's representative reconfirms informed consent for the study on the day of lung transplant

Subject Exclusion Criteria:

A subject who meets any of the following criteria will be excluded from participation:

• Patients listed for same-side lung re-transplantation
• Patients listed for multiple organ transplantation including lung and any other organ
• Patients listed for live donor lobar transplant
• Patients with HIV, active Hepatitis B/C, or Burkholderia Cepacia
• Patients not initially consented into the study prior to the time of lung transplant
• Patients in the ICU at the time of initial lung offer requiring mechanical ventilation, ECMO or other Extracorporeal life support (ECLS).

Donor Lung Inclusion Criteria for EVLP Assessment:

The donor lung must meet at least one of the following criteria to proceed with EVLP:

• At the time of the clinical evaluation, the donor PaO2/FiO2 < 300 mmHg
• Donor received ≥ 10 units of blood transfusions
• Donation after Cardiac Death (DCD) donor
• Expected cold ischemic time > 6 hours
• Donor age ≥ 55 years old
• Study Center Investigator requires additional assessment ex vivo and/or extended preservation time

Donor Lung Exclusion Criteria for EVLP Assessment:

The donor lung is excluded from EVLP if at least one of the following criteria have been met:

• The donor lung has confirmed pneumonia and/or persistent purulent secretions identified via bronchoscopy
• Non-persistent purulent secretions that do not clear by hour 3 on EVLP
• The donor lung has confirmed evidence of aspiration
• The donor lung has significant mechanical lung injury or trauma
• The cold ischemic time, starting at donor aortic cross clamp/ initial flush (CIT-1), required to transport the lung from the donor site to start of the EVLP procedure at SPONSOR's facility > 10 hours

EVLP Lung Inclusion Criteria for Transplantation:

The donor lung must meet each of the following conditions post-EVLP for transplant suitability consideration by the Study Center Investigator:

• PvO2/FiO2 ≥ 350 mmHg at final EVLP evaluation time period
• and < 15% increase from baseline value (defined as the first hour collection point) to final value of pulmonary vascular resistance (PVR)
• and < 15% increase from baseline value to final value of peak airway pressure (PawP)
• and < 15% decrease from baseline value to final value of static lung compliance (Cstat)

• and the total preservation time (TPT) does not exceed the following:

  • the initial CIT-1 time from donor to EVLP > 1 hour and ≤ 10 hours
  • the EVLP time > 3 hours and ≤ 6 hours
  • the second CIT-2 from EVLP cool down to beginning of recipient implantation must be > 1 hour and ≤ 6 hours for the first lung
  • the second CIT-2 from EVLP cool down to beginning of recipient implantation must be > 1 hour and ≤ 10 hours for the second lung
• and Study Center Investigator deems lung function suitable for intended subject

EVLP Lung Exclusion Criteria for Transplantation:

The donor lung is excluded from transplant inclusion if at least one of the following criteria have been met:

• PvO2/FiO2 < 350 mmHg at final EVLP evaluation time period
• or ≥ 15% increase from baseline value to final value of pulmonary vascular resistance (PVR)
• or ≥ 15% increase from baseline value to final value of peak airway pressure (PawP)
• or ≥ 15% decrease from baseline value to final value of static lung compliance (Cstat)

• or TPT exceeds any of the following conditions:

  • CIT-1 < 1 hour or > 10 hours
  • EVLP < 3 hours or > 6 hours
  • CIT-2 < 1 hour or > 6 hours for first lung or > 10 hours for second lung
• or Study Center investigator deems lung function unsuitable for intended subject

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Diagnostic
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: EVLP Double Lung Group; Toronto EVLP System™ administered to double lungs.	Device: Toronto EVLP System™; Extending preservation and assessment time of donor lungs using the Toronto EVLP System
Experimental: EVLP Single Lung Group; Toronto EVLP System™ administered to single lungs.	Device: Toronto EVLP System™; Extending preservation and assessment time of donor lungs using the Toronto EVLP System
No Intervention: Control Group; Those patients receiving a single or double lung via conventional transplant.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Count of Participants With Primary Graft Dysfunction (PGD), Grade 3	Primary Graft Dysfunction is a scale published by the International Society of Heart and Lung Transplantation that uses patient oxygenation and radiographic results to score patients on a 0 (zero) to 3 (three) scale, with 3 being the most significant dysfunction.	72 Hours
Count of Participants Surviving	The number of participants that survived to 30 days post-transplant.	30 Days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
PGD Score	PGD Score (0-3) at 0, 24, 48 & 72 hours post-transplant	0, 24, 48 & 72 Hours
ICU Length of Stay		30 Days
Total Lung Preservation Time (TPT)		72 Hours
Time to First Extubation		Days
Hospital Length of Stay		Days

Collaborators and Investigators

• Sponsor: Lung Bioengineering Inc.

Publications and helpful links

General Publications

• Lyu DM, Zamora MR. Medical complications of lung transplantation. Proc Am Thorac Soc. 2009 Jan 15;6(1):101-7. doi: 10.1513/pats.200808-077GO.
• Pierre AF, Sekine Y, Hutcheon MA, Waddell TK, Keshavjee SH. Marginal donor lungs: a reassessment. J Thorac Cardiovasc Surg. 2002 Mar;123(3):421-7; discussion, 427-8. doi: 10.1067/mtc.2002.120345.
• Cypel M, Rubacha M, Yeung J, Hirayama S, Torbicki K, Madonik M, Fischer S, Hwang D, Pierre A, Waddell TK, de Perrot M, Liu M, Keshavjee S. Normothermic ex vivo perfusion prevents lung injury compared to extended cold preservation for transplantation. Am J Transplant. 2009 Oct;9(10):2262-9. doi: 10.1111/j.1600-6143.2009.02775.x. Epub 2009 Aug 6.
• Ware LB, Wang Y, Fang X, Warnock M, Sakuma T, Hall TS, Matthay M. Assessment of lungs rejected for transplantation and implications for donor selection. Lancet. 2002 Aug 24;360(9333):619-20. doi: 10.1016/s0140-6736(02)09774-x.
• Orens JB, Boehler A, de Perrot M, Estenne M, Glanville AR, Keshavjee S, Kotloff R, Morton J, Studer SM, Van Raemdonck D, Waddel T, Snell GI; Pulmonary Council, International Society for Heart and Lung Transplantation. A review of lung transplant donor acceptability criteria. J Heart Lung Transplant. 2003 Nov;22(11):1183-200. doi: 10.1016/s1053-2498(03)00096-2. No abstract available.
• Kawut SM, Reyentovich A, Wilt JS, Anzeck R, Lederer DJ, O'Shea MK, Sonett JR, Arcasoy SM. Outcomes of extended donor lung recipients after lung transplantation. Transplantation. 2005 Feb 15;79(3):310-6. doi: 10.1097/01.tp.0000149504.53710.ae.
• 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.
• Botha P, Trivedi D, Weir CJ, Searl CP, Corris PA, Dark JH, Schueler SV. Extended donor criteria in lung transplantation: impact on organ allocation. J Thorac Cardiovasc Surg. 2006 May;131(5):1154-60. doi: 10.1016/j.jtcvs.2005.12.037.
• Avlonitis VS, Wigfield CH, Golledge HD, Kirby JA, Dark JH. Early hemodynamic injury during donor brain death determines the severity of primary graft dysfunction after lung transplantation. Am J Transplant. 2007 Jan;7(1):83-90. doi: 10.1111/j.1600-6143.2006.01593.x.
• Suzuki Y, Cantu E, Christie JD. Primary graft dysfunction. Semin Respir Crit Care Med. 2013 Jun;34(3):305-319. doi: 10.1055/s-0033-1348474. Epub 2013 Jul 2.
• Bennett M, Horton S, Thuys C, Augustin S, Rosenberg M, Brizard C. Pump-induced haemolysis: a comparison of short-term ventricular assist devices. Perfusion. 2004 Mar;19(2):107-11. doi: 10.1191/0267659104pf729oa.
• Watanabe N, Sakota D, Ohuchi K, Takatani S. Deformability of red blood cells and its relation to blood trauma in rotary blood pumps. Artif Organs. 2007 May;31(5):352-8. doi: 10.1111/j.1525-1594.2007.00392.x.
• Cypel M, Yeung JC, Hirayama S, Rubacha M, Fischer S, Anraku M, Sato M, Harwood S, Pierre A, Waddell TK, de Perrot M, Liu M, Keshavjee S. Technique for prolonged normothermic ex vivo lung perfusion. J Heart Lung Transplant. 2008 Dec;27(12):1319-25. doi: 10.1016/j.healun.2008.09.003.
• Cypel M, Liu M, Rubacha M, Yeung JC, Hirayama S, Anraku M, Sato M, Medin J, Davidson BL, de Perrot M, Waddell TK, Slutsky AS, Keshavjee S. Functional repair of human donor lungs by IL-10 gene therapy. Sci Transl Med. 2009 Oct 28;1(4):4ra9. doi: 10.1126/scitranslmed.3000266.
• Cypel M, Sato M, Yildirim E, Karolak W, Chen F, Yeung J, Boasquevisque C, Leist V, Singer LG, Yasufuku K, Deperrot M, Waddell TK, Keshavjee S, Pierre A. Initial experience with lung donation after cardiocirculatory death in Canada. J Heart Lung Transplant. 2009 Aug;28(8):753-8. doi: 10.1016/j.healun.2009.05.009. Epub 2009 Jun 28.
• Yeung JC, Cypel M, Waddell TK, van Raemdonck D, Keshavjee S. Update on donor assessment, resuscitation, and acceptance criteria, including novel techniques--non-heart-beating donor lung retrieval and ex vivo donor lung perfusion. Thorac Surg Clin. 2009 May;19(2):261-74. doi: 10.1016/j.thorsurg.2009.02.006.
• Cypel M, Yeung JC, Liu M, Anraku M, Chen F, Karolak W, Sato M, Laratta J, Azad S, Madonik M, Chow CW, Chaparro C, Hutcheon M, Singer LG, Slutsky AS, Yasufuku K, de Perrot M, Pierre AF, Waddell TK, Keshavjee S. Normothermic ex vivo lung perfusion in clinical lung transplantation. N Engl J Med. 2011 Apr 14;364(15):1431-40. doi: 10.1056/NEJMoa1014597.
• Cypel M, Yeung JC, Keshavjee S. Novel approaches to expanding the lung donor pool: donation after cardiac death and ex vivo conditioning. Clin Chest Med. 2011 Jun;32(2):233-44. doi: 10.1016/j.ccm.2011.02.003. Epub 2011 Mar 25.
• Koike T, Yeung JC, Cypel M, Rubacha M, Matsuda Y, Sato M, Waddell TK, Liu M, Keshavjee S. Kinetics of lactate metabolism during acellular normothermic ex vivo lung perfusion. J Heart Lung Transplant. 2011 Dec;30(12):1312-9. doi: 10.1016/j.healun.2011.07.014. Epub 2011 Sep 17.
• Cypel M, Yeung JC, Machuca T, Chen M, Singer LG, Yasufuku K, de Perrot M, Pierre A, Waddell TK, Keshavjee S. Experience with the first 50 ex vivo lung perfusions in clinical transplantation. J Thorac Cardiovasc Surg. 2012 Nov;144(5):1200-6. doi: 10.1016/j.jtcvs.2012.08.009. Epub 2012 Aug 31.
• Yeung JC, Cypel M, Machuca TN, Koike T, Cook DJ, Bonato R, Chen M, Sato M, Waddell TK, Liu M, Slutsky AS, Keshavjee S. Physiologic assessment of the ex vivo donor lung for transplantation. J Heart Lung Transplant. 2012 Oct;31(10):1120-6. doi: 10.1016/j.healun.2012.08.016.
• Wigfield CH, Cypel M, Yeung J, Waddell T, Alex C, Johnson C, Keshavjee S, Love RB. Successful emergent lung transplantation after remote ex vivo perfusion optimization and transportation of donor lungs. Am J Transplant. 2012 Oct;12(10):2838-44. doi: 10.1111/j.1600-6143.2012.04175.x.
• Cypel M, Keshavjee S. The clinical potential of ex vivo lung perfusion. Expert Rev Respir Med. 2012 Feb;6(1):27-35. doi: 10.1586/ers.11.93.
• Munshi L, Keshavjee S, Cypel M. Donor management and lung preservation for lung transplantation. Lancet Respir Med. 2013 Jun;1(4):318-28. doi: 10.1016/S2213-2600(12)70064-4. Epub 2013 Feb 20.
• Mallea JM, Hartwig MG, Keller CA, Kon Z, Iii RNP, Erasmus DB, Roberts M, Patzlaff NE, Johnson D, Sanchez PG, D'Cunha J, Brown AW, Dilling DF, McCurry K. Remote ex vivo lung perfusion at a centralized evaluation facility. J Heart Lung Transplant. 2022 Dec;41(12):1700-1711. doi: 10.1016/j.healun.2022.09.006. Epub 2022 Sep 18.

Study record dates

Study Major Dates

• Study Start (Actual): July 18, 2015
• Primary Completion (Actual): November 21, 2018
• Study Completion (Actual): November 7, 2019

Study Registration Dates

• First Submitted: September 4, 2014
• First Submitted That Met QC Criteria: September 8, 2014
• First Posted (Estimate): September 9, 2014

Study Record Updates

• Last Update Posted (Actual): December 2, 2020
• Last Update Submitted That Met QC Criteria: November 16, 2020
• Last Verified: November 1, 2020

More Information

Terms related to this study

• Keywords: Lung Transplantation; Ex Vivo Lung Perfusion; EVLP; Lung Transplant; Toronto EVLP System™; PERFUSIX
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Lung Diseases
• Other Study ID Numbers: PXUS-14-001; 4766 (Sterling IRB)