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| Name | Class |
|---|---|
| Mid-America Transplant | OTHER |
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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
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Thyroxine | Experimental | Intravenous thyroxine infusion |
|
| Saline Placebo | Placebo Comparator | Intravenous saline infusion |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Thyroxine | Drug | 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. |
| 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 |
| 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 |
| Measure | Description | Time Frame |
|---|---|---|
| Total Organs Transplanted | Total number of organs transplanted (incl. lungs, liver, kidneys, heart, pancreas) | One week |
Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Rajat Dhar, MD | Washington University School of Medicine | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Donor Network of Arizona | Phoenix | Arizona | 85013 | United States | ||
| Lifesharing |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 30689222 | Background | 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. | |
| 31802716 | Background | 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. |
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Researchers within the study consortium only
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| ID | Title | Description |
|---|---|---|
| FG000 | Thyroxine | Intravenous thyroxine infusion 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. |
| FG001 | Saline Placebo |
| Title | Milestones | Reasons Not Completed | |||||
|---|---|---|---|---|---|---|---|
| Initial Study Period (12 Hours) |
|
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot | Yes | No | No | Study Protocol: Appendix (Data Forms) | Dec 1, 2020 |
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| Saline | Drug | 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. |
|
| 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 |
| San Diego |
| California |
| 92108 |
| United States |
| Donor Alliance | Denver | Colorado | 80230 | United States |
| OurLegacy | Maitland | Florida | 32751 | United States |
| Iowa Donor Network | North Liberty | Iowa | 52317 | United States |
| Midwest Transplant Network | Westwood | Kansas | 66205 | United States |
| Louisiana Organ Procurement Agency | Covington | Louisiana | 70433 | United States |
| Mid-America Transplant Services | St Louis | Missouri | 63110 | United States |
| Lifebanc | Cleveland | Ohio | 44128 | United States |
| LifeShare of Oklahoma | Oklahoma City | Oklahoma | 73132 | United States |
| Southwest Transplant Alliance | Dallas | Texas | 75231 | United States |
| Texas Organ Sharing Alliance | San Antonio | Texas | 78229 | United States |
| DonorConnect | Murray | Utah | 84107 | United States |
| LifeCenter Northwest | Bellevue | Washington | 98006 | United States |
| 38048188 | Background | 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. |
| 34838132 | Derived | 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. |
Intravenous saline infusion 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. |
| Started Assigned Infusion |
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| Per-Protocol | Received assigned intervention for at least six hours |
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| Cross-over | Crossed-over to other intervention within 12 hours |
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| Stopped Infusion Early |
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| COMPLETED | Refers to completing donor care, with organ allocation outcomes available |
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| NOT COMPLETED |
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| Open-Label (T4 Beyond 12 Hours) |
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| ID | Title | Description |
|---|---|---|
| BG000 | Thyroxine | Intravenous thyroxine infusion 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. |
| BG001 | Saline Placebo | Intravenous saline infusion 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. |
| BG002 | Total | Total of all reporting groups |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean | Standard Deviation | years |
| |||||||||||||||
| Sex: Female, Male | missing data for 16 in T4 and 19 in NS group | Count of Participants | Participants |
| |||||||||||||||
| Race/Ethnicity, Customized | Missing data on 16 in T4 and 22 in NS group | Count of Participants | Participants |
| |||||||||||||||
| Region of Enrollment | Count of Participants | Participants |
| ||||||||||||||||
| Blood Group | Count of Participants | Participants |
| ||||||||||||||||
| Cause of Death | missing demographic data for 16 in T4 and 22 in NS group | Count of Participants | Participants |
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| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Primary | Heart Transplanted | Whether heart is transplanted into living recipient | Posted | Count of Participants | Participants | One week |
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| Primary | Graft Function | 30-day graft survival of hearts transplanted from study donors, obtained from SRTR recipient registry | Only out of those hearts that were transplanted (not all study participants) | Posted | Count of Units | hearts | 30 days | hearts | hearts |
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| Secondary | Time Till Off Vasopressors | Time in hours from randomization to when weaned off vasopressors (except vasopressin) | out of those who began study infusion on vasopressors | Posted | Median | Inter-Quartile Range | hours | 72 hours |
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| Secondary | Weaned Off Vasopressors | Weaned off vasopressors within twelve hours | out of those who began the study infusion still on vasopressors (i.e. some had been weaned off prior to infusion) | Posted | Count of Participants | Participants | 12 hours |
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| Secondary | Time to Order Echo | Time till hemodynamic stability permits ordering initial echocardiogram | Posted | Median | Inter-Quartile Range | hours | 72 hours |
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| Secondary | Ejection Fraction | Left ventricular ejection fraction measured on first echocardiography | only those who had echocardiography performed after study start | Posted | Mean | Standard Deviation | percentage of ejection fraction | 72 hours |
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| Secondary | Lungs Transplanted | Whether the lungs were transplanted into a living recipient | Posted | Count of Participants | Participants | 72 hours |
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| Other Pre-specified | Total Organs Transplanted | Total number of organs transplanted (incl. lungs, liver, kidneys, heart, pancreas) | Posted | Median | Inter-Quartile Range | organs | One week |
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1 week
Serious adverse event defined as donor instability resulting in cardiac arrest or premature donor loss.
Adverse events were collected for each arm combining all study periods, i.e. from study onset through end of donor management (organ recovery). These were not collected for each period (i.e. first 12 hours versus open-label period) separately.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Thyroxine | Intravenous thyroxine infusion 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. Donors were followed till organ recovery or end of management. | 419 | 419 | 2 | 419 | 51 | 419 |
| EG001 | Saline Placebo | Intravenous saline infusion 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. Donors were followed till organ recovery or end of management. | 419 | 419 | 3 | 419 | 16 | 419 |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Cardiac arrest / donor loss | Cardiac disorders | Systematic Assessment | Hemodynamic instability resulting in cardiac arrest and/or donor loss |
|
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Tachycardia | Cardiac disorders | Systematic Assessment |
| ||
| Hypertension | Cardiac disorders | Systematic Assessment |
| ||
| Atrial fibrillation | Cardiac disorders | Systematic Assessment |
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| Ventricular ectopy | Cardiac disorders | Systematic Assessment |
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| Ventricular tachycardia | Cardiac disorders | Systematic Assessment | not including unstable/leading to arrest |
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| Misc/Other | General disorders | Systematic Assessment | includes rash, electrolyte disturbance, respiratory distress, pulmonary edema, hypotension |
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Not blinded, open-label use of levothyroxine permitted in control group after 12 hours (only 50 donors in that group received open-label, plus three who crossed-over to levothyroxine immediately after randomization)
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. Rajat Dhar | Washington University in St. Louis School of Medicine | 3143622999 | dharr@wustl.edu |
| Dec 7, 2020 |
| Prot_003.pdf |
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan: Study Protocol and SAP | Nov 1, 2021 | Nov 22, 2021 | Prot_SAP_005.pdf |
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| ID | Term |
|---|---|
| D001926 | Brain Death |
| D006333 | Heart Failure |
| ID | Term |
|---|---|
| D001927 | Brain Diseases |
| D002493 | Central Nervous System Diseases |
| D009422 | Nervous System Diseases |
| D003128 | Coma |
| D014474 | Unconsciousness |
| D003244 | Consciousness Disorders |
| D019954 | Neurobehavioral Manifestations |
| D009461 | Neurologic Manifestations |
| D003643 | Death |
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D006331 | Heart Diseases |
| D002318 | Cardiovascular Diseases |
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| ID | Term |
|---|---|
| D013974 | Thyroxine |
| D012965 | Sodium Chloride |
| ID | Term |
|---|---|
| D013963 | Thyroid Hormones |
| D006728 | Hormones |
| D006730 | Hormones, Hormone Substitutes, and Hormone Antagonists |
| D024322 | Amino Acids, Aromatic |
| D000598 | Amino Acids, Cyclic |
| D000596 | Amino Acids |
| D000602 | Amino Acids, Peptides, and Proteins |
| D002712 | Chlorides |
| D006851 | Hydrochloric Acid |
| D017606 | Chlorine Compounds |
| D007287 | Inorganic Chemicals |
| D017670 | Sodium Compounds |
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