Deceased Organ Donor Interventions to Protect Kidney Graft Function

• ClinicalTrials.gov Identifier: NCT02525510
• Recruitment Status: Active, not recruiting
• First Posted: August 17, 2015
• Last Update Posted: February 2, 2021
• Sponsor: University of California, San Francisco
• Collaborator: Oregon Health and Science University
• Information provided by (Responsible Party): University of California, San Francisco

Study Description

Brief Summary:

To protect kidney function during the transplantation process by comparing mild hypothermia in the deceased organ donor before organs are recovered and pulsatile perfusion of the kidney after recovery and prior to transplantation.

Condition or disease	Intervention/treatment	Phase
Brain Death; Organ Donation; Organ Transplant Failure or Rejection; Delayed Graft Function	Other: Pump Eligible - Normothermia - Pump Both Kidneys; Other: Pump Eligible - Hypothermia and Pump Right Kidney; Other: Pump Eligible - Hypothermia and Pump Left Kidney; Other: Not Pump Eligible - Normothermia; Other: Not Pump Eligible - Hypothermia	Not Applicable

Detailed Description:

BACKGROUND: In the initial Mild Hypothermia Randomized Control Trial (RCT), in collaboration with the Organ Procurement and Transplant (OPTN) Region 5 Donor Management Goals (DMG) Workgroup and Web Portal, the research team was able to conduct a multi-center RCT examining the benefits of mild hypothermia in donors after neurologic determination of death (DNDDs) on the outcomes of kidney transplantation. The trial was stopped early by the Data and Safety Monitoring Board (DSMB) due to a significant positive benefit to kidney transplant recipients, including a 38% reduction in the odds of delayed graft function (DGF, the primary outcome measure of the trial). The results of this study have been published in the New England Journal of Medicine (July 2015). This research offers a zero-cost intervention that can substantially increase transplant success as well as the pool of potential donors.

To expand upon the success of the hypothermia study, the team is conducting a new RCT to test whether hypothermia is as effective as machine perfusion (MP) of kidneys from DNDDs. In an RCT conducted by the Eurotransplant International Foundation in 2009 (Moers et al. NEJM), the protective effect of MP (OR = 0.57) was similar to that found in the Mild Hypothermia Trial (OR = 0.62). However, the cost of MP can be very significant for organ procurement organizations (OPOs) and transplant centers. MP of kidneys from deceased donors has been increasingly adopted by many centers even though clinical and cost effectiveness studies remain uncertain in the United States. Between 2012 and 2014, out of 31,798 kidneys available for transplant, 11,998 (38%) of them were machine perfused. Over the same three-year period, the number of kidneys pumped annually increased by over 20%. This is an opportune time to investigate the effectiveness of MP compared to mild hypothermia, as there are enough OPOs currently using MP that if mild hypothermia was found to be a non-inferior intervention, there would be considerable cost savings. Similarly, over 60% of kidneys do not receive machine perfusion and findings that demonstrates a benefit of machine perfusion would likely lead to rapid increase in use. In addition, DGF still occurs in up to 56% of high-risk kidneys despite using one of these protective measures and their combined use may be the best approach moving forward. Either way, a new evidence-based standard will be created that will significantly affect the way kidney transplants are handled.

METHODS: This will be a pragmatic multi-site randomized controlled trial that bases enrollment on each OPO/Donation Service Area's current pumping criteria. There will be two main groups of DNDDs,

1. those that are "pump eligible" based on current practice (this group typically resembles traditional expanded criteria donors, but is increased in some areas) and
2. those that are lower risk and whose kidneys do not receive MP ("not pump eligible"). Kidneys from donors who are considered"pump eligible" currently receive MP based on their increased risk for failure. In this trial, "pump eligible" DNDDs will be randomized to one of three groups

(1) normothermia (36.5-37.5 C) plus MP of both kidneys (standard of practice control group), (2) mild hypothermia (34-35 C) plus MP of the left kidney only, and (3) mild hypothermia plus MP of the right kidney only.

In this manner, the same number of kidneys will be randomized to each of the three treatment strategies (MP alone, mild hypothermia alone, or MP + hypothermia). It is important to note that kidneys from "pump eligible"/higher risk DNDDs will still receive one form of protection and possibly two.

In contrast, "not pump eligible" DNDDs will only be randomized to one of two groups: (1) therapeutic mild hypothermia or (2) normothermia. Being that the Mild Hypothermia Trial was stopped early for efficacy in the overall DNDD population, there was insufficient statistical power to confirm a benefit in standard criteria donors (p=0.1 at stoppage). The purpose of this arm of the trial is to validate the protective effect of hypothermia in a larger sample size of lower-risk / "not pump eligible" donors.

The following objectives will be addressed by the trial:

Determine the non-inferiority of a hypothermia-only strategy to a standard pump-only strategy in high risk DNDDs

Evaluate the superiority of a combined hypothermia+MP strategy to both hypothermia or MP alone in high risk DNDDs

Evaluate the superiority of mild hypothermia versus standard of care normothermia in lower risk, "not pump eligible" DNDDs

Determine the safety of the hypothermia strategy with respect to the function of "bystander"organs (e.g., heart, lung)

This protocol has been approved by the OPTN Region 5 Research Committee. In addition, the following steps have been or will be taken:

A National communication was sent via TransplantPro to allow for a two-week period for public comment.

Only donors whose families and/or advanced directives (donor registry) have authorized research will be included in the study.

All organ offers from DNDDs enrolled in the study will include a message in the Donor Highlights section of DonorNet®, a copy of the study summary will be attached to the record, and allocation/transplantation will occur based on standard practice.

There will not be any interaction between the study team and the transplant recipients and no additional data will be collected.

Recipient graft function data will be derived from standard UNet forms and obtained from the OPTN in a de-identified format.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 1427 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment

Intervention Model Description

Enrolled donors will be divided into two populations based on local Organ Procurement Organization criteria:Pump Eligible and Not Pump Eligible.

Pump Eligible will include three arms. Not Pump Eligible will include two arms.

• Masking: Triple (Participant, Investigator, Outcomes Assessor)
• Primary Purpose: Prevention
• Official Title: A Randomized Trial of Mild Hypothermia and Machine Perfusion in Deceased Organ Donors for Protection Against Delayed Graft Function in Kidney Transplant Recipients
• Actual Study Start Date: July 26, 2017
• Estimated Primary Completion Date: March 31, 2021
• Estimated Study Completion Date: December 2021

Arms and Interventions

Arm	Intervention/treatment
Active Comparator: Pump Eligible - Normothermia - Pump Both Kidneys; Normothermia and Machine Perfusion Deceased Donors will be kept normothermic (36.5-37.5 C) prior to organ recovery. Recovered kidneys will receive machine perfusion prior to implantation.	Other: Pump Eligible - Normothermia - Pump Both Kidneys; Normothermia and Machine Perfusion Deceased Donors will be kept normothermic (36.5-37.5 C) prior to organ recovery. Recovered kidneys will receive machine perfusion prior to implantation.OPO's protocol
Active Comparator: Pump Eligible - Hypothermia and Pump Right Kidney; Deceased Donors will be kept mildly hypothermic (34-35 C) for at least 12 hours prior to organ recovery. Right Kidney will receive machine perfusion prior to implantation and the Left Kidney will receive cold storage.	Other: Pump Eligible - Hypothermia and Pump Right Kidney; Deceased Donors will be kept mildly hypothermic (34-35 C) for at least 12 hours prior to organ recovery. Right Kidney will receive machine perfusion prior to implantation and the Left Kidney will receive cold storage. Recovered kidneys will be placed in University of Wisconsin for cold storage until reimplantation.
Active Comparator: Pump Eligible - Hypothermia and Pump Left Kidney; Deceased Donors will be kept mildly hypothermic (34-35 C) for at least 12 hours prior to organ recovery. Left Kidney will receive machine perfusion prior to implantation and the Right Kidney will receive cold storage.	Other: Pump Eligible - Hypothermia and Pump Left Kidney; Deceased Donors will be kept mildly hypothermic (34-35 C) for at least 12 hours prior to organ recovery. Left Kidney will receive machine perfusion prior to implantation and the Right Kidney will receive cold storage.
Active Comparator: Not Pump Eligible - Normothermia; Deceased Donors will be kept normothermic (36.5-37.5 C) prior to organ recovery.	Other: Not Pump Eligible - Normothermia; Deceased Donors will be kept normothermic (36.5-37.5 C) prior to organ recovery. Pulsatile Perfusion of kidney grafts based on the respective OPO's protocol
Active Comparator: Not Pump Eligible - Hypothermia; Deceased Donors will be kept mildly hypothermic (34-35 C) for at least 12 hours prior to organ recovery.	Other: Not Pump Eligible - Hypothermia; Deceased Donors will be kept mildly hypothermic (34-35 C) for at least 12 hours prior to organ recovery.

Outcome Measures

Primary Outcome Measures :

1. Delayed Graft Function in Kidney Allografts [ Time Frame: 7 days ]
   The incidence of DGF in kidneys from deceased donors enrolled in this trial, obtained from publically available OPTN data.

Secondary Outcome Measures :

1. Allograft and Recipient survival for all transplanted organs [ Time Frame: 1 year ]
   Allograft and Recipient survival for all transplanted organs from deceased donors enrolled in this trial obtained from publically available OPTN data.

Eligibility Criteria

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

Criteria

Inclusion Criteria:

• > 18 years of age,
• Brain dead organ donor,
• Authorization for research

Exclusion Criteria:

• Donation after Cardiac Death (DCD) Donor
• Coagulopathy, Hemodynamic instability, Electrolyte deficiencies, Pre-existing kidney disease (per study protocol)

Contacts and Locations

Locations

United States, Arizona

Donor Network of Arizona

Phoenix, Arizona, United States, 85013

United States, California

U C San Francisco

San Francisco, California, United States, 94143

United States, Colorado

Donor Alliance

Denver, Colorado, United States, 80246-1904

United States, Minnesota

LifeSource

Minneapolis, Minnesota, United States, 55411

United States, Oregon

Pacific Northwest Transplant Bank

Portland, Oregon, United States, 97201

United States, Texas

Southwest Transplant Alliance

Dallas, Texas, United States, 75231

LifeGift

Houston, Texas, United States, 77054

Sponsors and Collaborators

University of California, San Francisco

Oregon Health and Science University

Investigators

• Principal Investigator: Darren Malinoski, MD; Oregon Health and Science University

More Information

Additional Information:

Open Science Framework 

Publications:

Niemann CU, Feiner J, Swain S, Bunting S, Friedman M, Crutchfield M, Broglio K, Hirose R, Roberts JP, Malinoski D. Therapeutic Hypothermia in Deceased Organ Donors and Kidney-Graft Function. N Engl J Med. 2015 Jul 30;373(5):405-14. doi: 10.1056/NEJMoa1501969.

Jochmans I, Watson CJ. Taking the Heat Out of Organ Donation. N Engl J Med. 2015 Jul 30;373(5):477-8. doi: 10.1056/NEJMe1507573.

Moers C, Smits JM, Maathuis MH, Treckmann J, van Gelder F, Napieralski BP, van Kasterop-Kutz M, van der Heide JJ, Squifflet JP, van Heurn E, Kirste GR, Rahmel A, Leuvenink HG, Paul A, Pirenne J, Ploeg RJ. Machine perfusion or cold storage in deceased-donor kidney transplantation. N Engl J Med. 2009 Jan 1;360(1):7-19. doi: 10.1056/NEJMoa0802289.

• Responsible Party: University of California, San Francisco
• ClinicalTrials.gov Identifier: NCT02525510
• Other Study ID Numbers: 029669
• First Posted: August 17, 2015
• Last Update Posted: February 2, 2021
• Last Verified: January 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by University of California, San Francisco:

Mild Hypothermia; Machine Perfusion; Kidney Transplantation

Additional relevant MeSH terms:

Brain Death; Delayed Graft Function; Pathologic Processes; Death; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Coma; Unconsciousness; Consciousness Disorders; Neurobehavioral Manifestations; Neurologic Manifestations