Deceased Organ Donor Interventions to Protect Kidney Graft Function

Sponsor

University of California, San Francisco (Other)

Overall Status

Completed

CT.gov ID

NCT02525510

Collaborator

Oregon Health and Science University (Other)

1,427

Enrollment

Locations

Arms

58.2

Actual Duration (Months)

203.9

Patients Per Site

3.5

Patients Per Site Per Month

Study Details

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	N/A

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,

those that are "pump eligible" based on current practice (this group typically resembles traditional expanded criteria donors, but is increased in some areas) and
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

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.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 :

Jul 26, 2017

Actual Primary Completion Date :

Jun 1, 2022

Actual Study Completion Date :

Jun 1, 2022

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

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

Secondary Outcome Measures

Allograft and Recipient survival for all transplanted organs [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

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

	Site	City	State	Country	Postal Code
1	Donor Network of Arizona	Phoenix	Arizona	United States	85013
2	U C San Francisco	San Francisco	California	United States	94143
3	Donor Alliance	Denver	Colorado	United States	80246-1904
4	LifeSource	Minneapolis	Minnesota	United States	55411
5	Pacific Northwest Transplant Bank	Portland	Oregon	United States	97201
6	Southwest Transplant Alliance	Dallas	Texas	United States	75231
7	LifeGift	Houston	Texas	United States	77054