Cold Lung Preservation for Lung Transplant

Recruiting at 7 trial locations

Overseen By Sharaniyaa Balachandran

Age: 18+

Sex: Any

Trial Phase: Academic

Sponsor: University Health Network, Toronto

Disqualifiers: Re-transplantation, Multi-organ, Single lung, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 1

Duration: 12 hours

300 Participants Needed

Trial Summary

What is the purpose of this trial?

Despite lung transplantation (LTx) being the most effective treatment for end-stage lung disease, its success rate is lower than that of other solid organ transplantations. Primary graft dysfunction (PGD) is the most common post-operative complication and a major factor in early mortality and morbidity, affecting \~25% of lung transplant patients. Induced by ischemia reperfusion, PGD represents a severe and acute lung injury that occurs within the first 72 hours after transplantation, and has a significant impact on short- and long-term outcomes, and a significant increase in treatment costs. Any intervention that reduces the risk of PGD will lead to major improvements in short- and long-term transplant outcomes and health care systems. One of the main strategies to reduce the risk and severity of post-transplant PGD is to improve pre-transplant donor lung preservation methods. In current practice, lung preservation is typically performed by cold flushing the organ with a specialized preservation solution, followed by subsequent hypothermic storage on ice (\~4°C). This method continues to be used and applied across different organ systems due to its simplicity and low cost. Using this method for the preservation of donor lungs, the current maximum accepted preservation times have been limited to approximately 6-8h. While the goal of hypothermic storage is to sustain cellular viability during ischemic time through reduced cellular metabolism, lower organ temperature has also been shown to progressively favor mitochondrial dysfunction. Therefore, the ideal temperature for donor organ preservation remains to be defined and should maintain a balance between avoidance of mitochondrial dysfunction and prevention of cellular exhaustion. In addition to that, safe and longer preservation times can lead to multiple advantages such as moving overnight transplants to daytime, more flexibility to transplant logistics, more time for proper donor to recipient matching etc. Building on pre-clinical research suggesting that 10°C may be the optimal lung storage temperature, a prospective, multi-center, non-randomized clinical trial was conducted at University Health Network, Medical University of Vienna and Puerta de Hierro Majadahonda University Hospital. Donor lungs meeting criteria for direct transplantation and with cross clamp times between 6:00pm - 4:00am were intentionally delayed to an earliest allowed start time of 6:00am and a maximum preservation time from donor cold flush to recipient anesthesia start time of 12 hours. Lungs were retrieved and transported in the usual fashion using a cooler with ice and transferred to a 10°C temperature-controlled cooler upon arrival to transplant hospital until implantation. The primary outcome of this study was incidence of Primary Graft Dysfunction (PGD) Grade 3 at 72h, with secondary endpoints including: recipient time on the ventilator, ICU Length of Stay (LOS), hospital LOS, 30-day survival and lung function at 1-year. Outcomes were compared to a contemporaneous conventionally transplanted recipient cohort using propensity score matching at a 1:2 ratio. 70 patients were included in the study arm. Post-transplant outcomes were comparable between the two groups for up to 1 year. Thus, intentional prolongation of donor lung preservation at 10°C was shown to be clinically safe and feasible. In the current study design, the investigators will conduct a multi-centre, non-inferiority, randomized, controlled trial of 300 participants to compare donor lung preservation from the time of explant to implant at \~10°C in X°Port Lung Transport Device (Traferox Technologies Inc.) vs a standard ice cooler. When eligible donor lungs become available for a consented recipient, the lungs will be randomized to undergo a preservation protocol using either 10°C (X°Port Lung Transport Device, Traferox Technologies Inc.) or standard of care. The primary outcome of the study is incidence of ISHLT Primary Graft Dysfunction Grade 3 at 72 hours. Post-transplant outcomes will be followed for one year.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

What data supports the effectiveness of the treatment Lung transplantation after 10°C donor lung preservation?

Research suggests that storing donor lungs at 10°C may improve lung transplant outcomes by extending the time lungs can be preserved before transplantation, potentially leading to better survival rates and lung function compared to traditional ice storage methods. ^{1 2 3 4 5}

Is cold lung preservation at 10°C safe for lung transplants?

Research suggests that preserving donor lungs at 10°C may be a promising method for lung transplants, potentially offering better outcomes compared to traditional ice storage. However, specific safety data for humans is not detailed in the available studies, and most research has been conducted on animal models. ^{1 2 3 4 6}

What makes the 10°C lung preservation treatment unique for lung transplantation?

The 10°C lung preservation treatment is unique because it allows donor lungs to be stored at a slightly higher temperature than the traditional ice-cold method, potentially extending the time the lungs can be preserved before transplantation, which can improve logistics and outcomes. ^{1 3 5 7 8}

Research Team

Elliot Wakeam, MD MPH

Principal Investigator

University Health Network, Toronto

Eligibility Criteria

This trial is for lung transplant recipients whose donor lungs are suitable for immediate transplantation without needing extra assessment. Donors can be after brain or cardiac death, but the lungs must not require ex vivo lung perfusion evaluation.

Inclusion Criteria

I have had a double lung transplant.

My organ donation will be after brain or heart stops.

The donor lungs I'm receiving are ready for transplant without needing further assessment.

Exclusion Criteria

I am interested in treatments that save my organs.

Re-transplantation

Participation in a contraindicating trial

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Donor lungs are preserved at either 10°C using the X°Port Lung Transport Device or at standard ice cooler temperatures, followed by transplantation.

12 hours

1 visit (in-person)

Post-transplant Monitoring

Participants are monitored for incidence of Primary Graft Dysfunction (PGD) Grade 3 at 72 hours post-transplant.

72 hours

Continuous monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment, including recipient time on the ventilator, ICU Length of Stay, hospital Length of Stay, 30-day survival, and lung function at 1-year.

1 year

Treatment Details

Interventions

• Lung transplantation after 10°C donor lung preservation
• Lung transplantation after standard ice cooler donor lung preservation

Trial Overview The study compares two methods of preserving donor lungs before a transplant: one uses a new device to keep the lungs at about 10°C, and the other uses standard ice cooler preservation at approximately 4°C. The goal is to see if the new method reduces severe lung injury post-transplant.

Participant Groups

Group I: 10°C lung preservation Experimental Treatment 1 Intervention

Group II: Standard lung preservation Active Control 1 Intervention

Lung transplantation after 10°C donor lung preservation is already approved in Canada, European Union, United States for the following indications:

Approved in Canada as Lung transplantation after 10°C donor lung preservation for:

• End-stage lung disease

Approved in European Union as Lung transplantation after 10°C donor lung preservation for:

• End-stage lung disease

Approved in United States as Lung transplantation after 10°C donor lung preservation for:

• End-stage lung disease

Who Is Running the Clinical Trial?

University Health Network, Toronto

Lead Sponsor

Trials

1,555

Recruited

526,000+

Puerta de Hierro University Hospital

Collaborator

Trials

77

Recruited

36,800+

Centre Hospitalier Universitaire Vaudois

Collaborator

Trials

269

Recruited

14,040,000+

St Vincent's Hospital, Sydney

Collaborator

Trials

35

Recruited

10,400+

Vanderbilt University

Collaborator

Trials

714

Recruited

6,143,000+

University of California, San Francisco

Collaborator

Trials

2,636

Recruited

19,080,000+

Mayo Clinic

Collaborator

Trials

3,427

Recruited

3,221,000+

Northwestern University

Collaborator

Trials

1,674

Recruited

989,000+

Geneve University

Collaborator

Trials

1

Recruited

300+

Hôpital Marie Lannelongue

Collaborator

Trials

1

Recruited

300+

Findings from Research

Preserving donor lungs at 10°C may significantly extend the cold ischemia time, which is crucial for successful lung transplants, potentially improving transplant logistics.

The report discusses two lung transplants from different donors using this innovative preservation method, suggesting that 10°C storage leads to excellent outcomes compared to traditional methods.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Donor lungs cold preservation at 10 °C offers a potential logistic advantage in lung transplantation. Gil Barturen, M., Laporta Hernández, R., Romero Berrocal, A., et al.[2023]

Pulmonary transplantation has become a successful treatment for end-stage lung disease, with current preservation techniques allowing for donor lungs to be safely stored for up to 6 hours before transplantation.

Recent advancements in lung preservation research, such as the use of colloid-based perfusates and free radical scavengers, show promise in extending the safe ischemia period and improving lung quality, potentially leading to better clinical outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lung preservation: a review of current practice and future directions. Kirk, AJ., Colquhoun, IW., Dark, JH.[2019]

In a study involving 37 canine lungs, using cold air storage at 4°C resulted in 100% survival after 4 hours, significantly outperforming conventional ice slush storage, which had only a 17% survival rate.

The cold air storage method also led to better oxygen levels and lower lung water content compared to ice slush, indicating it may be a more effective technique for preserving lungs for transplantation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Improved lung preservation with cold air storage. Kon, ND., Hines, MH., Harr, CD., et al.[2019]

Using glutathione (GSH) during hypothermic storage of lungs for transplantation significantly reduces lung injury, such as edema and inflammation, compared to traditional storage solutions, as shown in a study with mongrel dogs undergoing single-lung autotransplantation after 5-6 hours of preservation.

Despite the protective effects of GSH, the study indicates that the injury mechanisms differ between the transplanted lung and the nontransplanted lung, suggesting that while GSH helps, it does not completely prevent damage from the pulmonary reimplantation response.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Assessment of injury in transplanted and nontransplanted lungs after 6 h of cold storage with glutathione. Bryan, CL., Patefield, AJ., Cohen, D., et al.[2017]

The study found that flushing rat lungs at room temperature (F(Rt)) and storing them inflated on melting ice (S(ice)) resulted in significantly better lung graft function after transplantation, indicated by higher oxygen levels and lower injury markers compared to flushing at 4 °C.

Storage at 10 °C did not enhance lung preservation, suggesting that the combination of room temperature flushing and ice storage is optimal for reducing ischaemia-reperfusion injury in lung transplants.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Flush at room temperature followed by storage on ice creates the best lung graft preservation in rats. Munneke, AJ., Rakhorst, G., Petersen, AH., et al.[2013]

Ex-vivo lung perfusion is gaining acceptance as a method to extend the travel distance for donor lungs and reassess marginal donor lungs, potentially improving transplant outcomes.

Research is underway to evaluate the effectiveness of normothermic regional perfusion and to reassess the optimal temperature for static cold storage, with preliminary studies suggesting that warmer storage temperatures may allow for overnight lung storage before transplantation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lung preservation: from perfusion to temperature. Bromberger, B., Brzezinski, M., Kukreja, J.[2023]

The portable Organ Care System (OCS) Lung device was successfully used to preserve and transport donor lungs in a study involving 12 lung transplant patients, demonstrating its potential for safe organ preservation.

All patients and grafts survived for at least 30 days post-transplant, indicating that the OCS Lung can effectively support high-risk lung transplants, paving the way for further comparative studies against standard preservation methods.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Normothermic perfusion of donor lungs for preservation and assessment with the Organ Care System Lung before bilateral transplantation: a pilot study of 12 patients. Warnecke, G., Moradiellos, J., Tudorache, I., et al.[2022]

In a study involving 18 pigs, lungs preserved solely by hypothermic storage for 18 hours showed functional recovery comparable to sham-operated controls, indicating effective preservation without the need for flushing.

Lungs that were only cooled (hypothermia alone) outperformed those that were flushed with preservation solution, suggesting that hypothermic storage may be a superior method for lung preservation in transplantation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hypothermic storage alone in lung preservation for transplantation: a metabolic, light microscopic, and functional analysis after 18 hours of preservation. Müller, C., Hoffmann, H., Bittmann, I., et al.[2019]

References

1. Spain pubmed.ncbi.nlm.nih.gov

Donor lungs cold preservation at 10 °C offers a potential logistic advantage in lung transplantation. [2023]

2. Netherlands pubmed.ncbi.nlm.nih.gov

Lung preservation: a review of current practice and future directions. [2019]

3. Netherlands pubmed.ncbi.nlm.nih.gov

Improved lung preservation with cold air storage. [2019]

4. United States pubmed.ncbi.nlm.nih.gov

Assessment of injury in transplanted and nontransplanted lungs after 6 h of cold storage with glutathione. [2017]

5. Switzerland pubmed.ncbi.nlm.nih.gov

Flush at room temperature followed by storage on ice creates the best lung graft preservation in rats. [2013]

6. United States pubmed.ncbi.nlm.nih.gov

Lung preservation: from perfusion to temperature. [2023]

7. England pubmed.ncbi.nlm.nih.gov

Normothermic perfusion of donor lungs for preservation and assessment with the Organ Care System Lung before bilateral transplantation: a pilot study of 12 patients. [2022]

8. United States pubmed.ncbi.nlm.nih.gov

Hypothermic storage alone in lung preservation for transplantation: a metabolic, light microscopic, and functional analysis after 18 hours of preservation. [2019]