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Deceased Organ Donor Interventions to Protect Kidney Graft Function

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02525510
Recruitment Status : Recruiting
First Posted : August 17, 2015
Last Update Posted : July 25, 2019
Sponsor:
Collaborator:
Oregon Health and Science University
Information provided by (Responsible Party):
Claus Niemann, University of California, San Francisco

Tracking Information
First Submitted Date  ICMJE August 6, 2015
First Posted Date  ICMJE August 17, 2015
Last Update Posted Date July 25, 2019
Actual Study Start Date  ICMJE July 26, 2017
Estimated Primary Completion Date July 26, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: July 25, 2017)
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.
Original Primary Outcome Measures  ICMJE
 (submitted: August 14, 2015)
Delayed Graft Function in Kidney Allografts [ Time Frame: 7 days ]
Change History Complete list of historical versions of study NCT02525510 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: July 25, 2017)
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.
Original Secondary Outcome Measures  ICMJE
 (submitted: August 14, 2015)
Patient and Allograft survival [ Time Frame: 1 year and 3 years ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Deceased Organ Donor Interventions to Protect Kidney Graft Function
Official Title  ICMJE A Randomized Trial of Mild Hypothermia and Machine Perfusion in Deceased Organ Donors for Protection Against Delayed Graft Function in Kidney Transplant Recipients
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.
Detailed Description

BACKGROUND: In the initial Mild Hypothermia Randomized Control Trial (RCT), in collaboration with the UNOS 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 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 UNOS 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 Type  ICMJE Interventional
Study Phase  ICMJE Not Applicable
Study Design  ICMJE 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
Condition  ICMJE
  • Brain Death
  • Organ Donation
  • Organ Transplant Failure or Rejection
  • Delayed Graft Function
Intervention  ICMJE
  • 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
  • Other: Pump Eligible - Hyporthermia 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.

  • Other: Pump Eligible - Hyporthermia 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: 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

  • Other: Not Pump Eligible - Hypothermia
    Deceased Donors will be kept mildly hypothermic (34-35 C) for at least 12 hours prior to organ recovery.
Study Arms  ICMJE
  • 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.
    Intervention: Other: Pump Eligible - Normothermia - Pump Both Kidneys
  • Active Comparator: Pump Eligible - Hyporthermia 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.
    Intervention: Other: Pump Eligible - Hyporthermia and Pump Right Kidney
  • Active Comparator: Pump Eligible - Hyporthermia 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.
    Intervention: Other: Pump Eligible - Hyporthermia and Pump Left Kidney
  • Active Comparator: Not Pump Eligible - Normothermia
    Deceased Donors will be kept normothermic (36.5-37.5 C) prior to organ recovery.
    Intervention: Other: Not Pump Eligible - Normothermia
  • 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.
    Intervention: Other: Not Pump Eligible - Hypothermia
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: July 25, 2017)
2800
Original Estimated Enrollment  ICMJE
 (submitted: August 14, 2015)
500
Estimated Study Completion Date  ICMJE July 26, 2021
Estimated Primary Completion Date July 26, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

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

Exclusion Criteria:

  • DCD Donor
  • Coagulopathy, Hemodynamic instability, Electrolyte deficiencies, Pre-existing kidney disease (per study protocol)
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Claus Niemann, MD 415-502-2162 Claus.Niemann@ucsf.edu
Contact: Darren Malinoski, MD 503-220-8262 ext 55613 malinosk@ohsu.edu
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02525510
Other Study ID Numbers  ICMJE 029669
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Claus Niemann, University of California, San Francisco
Study Sponsor  ICMJE University of California, San Francisco
Collaborators  ICMJE Oregon Health and Science University
Investigators  ICMJE
Principal Investigator: Darren Malinoski, MD Oregon Health and Science University
PRS Account University of California, San Francisco
Verification Date July 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP