Intravenous Thyroxine for Heart-Eligible Organ Donors

A Multicenter Randomized Placebo-Controlled Trial of Intravenous Thyroxine for Heart-Eligible Brain Dead Organ Donors

This randomized controlled trial will evaluate whether intravenous thyroxine infusion given to brain-dead organ donors who are eligible to donate hearts for 12 hours will result in more hearts transplanted than saline placebo

Study Overview

• Status: Completed
• Conditions: Heart Failure; Brain Death
• Intervention / Treatment: Drug: Thyroxine; Drug: Saline

Detailed Description

Background: Brain death frequently induces hemodynamic instability and cardiac stunning. Impairments in cardiac performance are major contributors to hearts from otherwise eligible organ donors not being transplanted. Deficiencies in pituitary hormones (including thyroid stimulating hormone) may contribute to hemodynamic instability and replacement of thyroid hormone has been proposed as a means of improving stability and increasing hearts available for transplantation. Intravenous thyroxine is commonly used in donor management. However, small controlled trials have not been able to demonstrate efficacy.

Methods: This multicenter study will involve organ procurement organizations (OPOs) across the country. A total of 800 heart-eligible brain dead organ donors who require vasopressor support will be randomly assigned to intravenous thyroxine for at least 12-hours or saline placebo. The primary study hypothesis is that thyroxine treatment results in more hearts transplanted. Additional outcome measures are time to achieve hemodynamic stability (weaning off vasopressors) and improvement in cardiac ejection fraction on echocardiography.

Discussion: This will be the largest randomized controlled study to evaluate the efficacy of thyroid hormone treatment for organ donor management. By collaborating across multiple OPOs, it will be able to enroll an adequate number of donors and be powered to definitively answer the critical question of whether treatment increases hearts transplanted and/or provides other hemodynamic benefits.

• Study Type: Interventional
• Enrollment (Actual): 838
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • Arizona
    • Phoenix, Arizona, United States, 85013
      • Donor Network of Arizona
  • California
    • San Diego, California, United States, 92108
      • Lifesharing
  • Colorado
    • Denver, Colorado, United States, 80230
      • Donor Alliance
  • Florida
    • Maitland, Florida, United States, 32751
      • OurLegacy
  • Iowa
    • North Liberty, Iowa, United States, 52317
      • Iowa Donor Network
  • Kansas
    • Westwood, Kansas, United States, 66205
      • Midwest Transplant Network
  • Louisiana
    • Covington, Louisiana, United States, 70433
      • Louisiana Organ Procurement Agency
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Mid-America Transplant Services
  • Ohio
    • Cleveland, Ohio, United States, 44128
      • Lifebanc
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73132
      • LifeShare of Oklahoma
  • Texas
    • Dallas, Texas, United States, 75231
      • Southwest Transplant Alliance
    • San Antonio, Texas, United States, 78229
      • Texas Organ Sharing Alliance
  • Utah
    • Murray, Utah, United States, 84107
      • DonorConnect
  • Washington
    • Bellevue, Washington, United States, 98006
      • LifeCenter Northwest

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years to 55 years (Child, Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Declared dead by neurologic criteria (brain dead)
• Authorization for organ donation and research
• On one or more vasopressors and/or inotropes

Exclusion Criteria:

• Brain death declared more than 24 hours prior
• Only vasopressor is vasopressin
• Weight < 45 kg (100 lbs)
• Known coronary artery disease or history of myocardial infarction
• Known valvular heart disease
• Prior sternotomy or cardiac surgery
• Donor at VA hospital
• Received intravenous or oral thyroxine within past month
• Known HIV+ status
• Other reason donor is unable to receive study drug (determined by on-site personnel)

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Thyroxine; Intravenous thyroxine infusion	Drug: Thyroxine; Infusion prepared by mixing 500 μg of drug in 500-ml of normal saline (i.e. concentration of 1 μg/ml) and enclosing the bag in an opaque sleeve. Infusion started at 30 μg/hour (30 ml/hour) for twelve hours.
Placebo Comparator: Saline Placebo; Intravenous saline infusion	Drug: Saline; The placebo will be a 500-ml bag of normal saline (without active drug) also enclosed in an opaque sleeve. This infusion will also be started at 30 ml/hour for twelve hours.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Heart Transplanted	Whether heart is transplanted into living recipient	One week
Graft Function	30-day graft survival of hearts transplanted from study donors, obtained from SRTR recipient registry	30 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time Till Off Vasopressors	Time in hours from randomization to when weaned off vasopressors (except vasopressin)	72 hours
Weaned Off Vasopressors	Weaned off vasopressors within twelve hours	12 hours
Time to Order Echo	Time till hemodynamic stability permits ordering initial echocardiogram	72 hours
Ejection Fraction	Left ventricular ejection fraction measured on first echocardiography	72 hours
Lungs Transplanted	Whether the lungs were transplanted into a living recipient	72 hours

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Total Organs Transplanted	Total number of organs transplanted (incl. lungs, liver, kidneys, heart, pancreas)	One week

Collaborators and Investigators

• Sponsor: Washington University School of Medicine
• Collaborators: Mid-America Transplant
• Investigators: Principal Investigator: Rajat Dhar, MD, Washington University School of Medicine

Publications and helpful links

General Publications

• Dhar R, Stahlschmidt E, Yan Y, Marklin G. A randomized trial comparing triiodothyronine (T3) with thyroxine (T4) for hemodynamically unstable brain-dead organ donors. Clin Transplant. 2019 Mar;33(3):e13486. doi: 10.1111/ctr.13486. Epub 2019 Feb 12.
• Dhar R, Stahlschmidt E, Marklin G. A Randomized Trial of Intravenous Thyroxine for Brain-Dead Organ Donors With Impaired Cardiac Function. Prog Transplant. 2020 Mar;30(1):48-55. doi: 10.1177/1526924819893295. Epub 2019 Dec 5.
• Dhar R, Klinkenberg D, Marklin G. A multicenter randomized placebo-controlled trial of intravenous thyroxine for heart-eligible brain-dead organ donors. Trials. 2021 Nov 27;22(1):852. doi: 10.1186/s13063-021-05797-2.
• Dhar R, Marklin GF, Klinkenberg WD, Wang J, Goss CW, Lele AV, Kensinger CD, Lange PA, Lebovitz DJ. Intravenous Levothyroxine for Unstable Brain-Dead Heart Donors. N Engl J Med. 2023 Nov 30;389(22):2029-2038. doi: 10.1056/NEJMoa2305969.

Study record dates

Study Major Dates

• Study Start (Actual): December 1, 2020
• Primary Completion (Actual): November 6, 2022
• Study Completion (Actual): December 6, 2022

Study Registration Dates

• First Submitted: May 27, 2020
• First Submitted That Met QC Criteria: May 29, 2020
• First Posted (Actual): June 4, 2020

Study Record Updates

• Last Update Posted (Actual): January 10, 2024
• Last Update Submitted That Met QC Criteria: December 18, 2023
• Last Verified: December 1, 2023

More Information

Terms related to this study

• Keywords: Organ donor
• Additional Relevant MeSH Terms: Pathologic Processes; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurologic Manifestations; Neurobehavioral Manifestations; Death; Unconsciousness; Consciousness Disorders; Coma; Brain Death
• Other Study ID Numbers: ODRC-002

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Researchers within the study consortium only

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No