A Multicenter Randomized Placebo-Controlled Trial of Intravenous Thyroxine for Heart-Eligible Brain Dead Organ Donors
Phase: PHASE3
Conditions: Brain Death, Heart Failure
Sponsor: Washington University School of Medicine

Cover Page 
 
Document: 
Study Protocol with SAP 
Study Title: 
 
 
 
A Multicenter Randomized Placebo-Controlled Trial of Intravenous Thyroxine 
for Heart-Eligible Brain Dead Organ Donors 
 
NCT number: 
NCT04415658 
Document Date: 01 November 2021 
 
 
Protocol ID: 
 
ODRC-002 
Version number: 
v.3.0 (01 November 2021) 
 
Study Principal Investigators: 
Rajat Dhar, MD (Washington University in St. Louis) 
Gary Marklin, MD (Mid-America Transplant)  
 
 
 

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Abstract 
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 hypotheses are 
that thyroxine treatment will result in a higher proportion of hearts transplanted and that these hearts will 
have non-inferior function to hearts not treated with thyroxine. 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 
intravenous thyroxine treatment increases hearts transplanted and/or provides other hemodynamic benefits. 
Trial registration:  registered at clinicaltrials.gov under NCT04415658 
Keywords 
Brain death; Organ donation; Heart transplant; Thyroid hormone; Donor management 
 
 

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Protocol Amendment History 
 
Protocol Version 
Date Final 
2.0 
01 December 2020 
3.0 
01 November 2021 
 
 
 
Revisions to v.3.0 
Change 
Rationale 
Affected 
Protocol Section 
Number of anticipated enrolling sites 
updated to 14 
Study underway with most sites 
activated 
Protocol Summary 
Sample size calculation clarified, 
including basis for assumptions of 
primary outcome rate in each group; 
clarified that test is one-sided and 
therefore reduced alpha from 0.05 to 
0.025. Statistical analysis now clearly 
specifies 97.5% one-sided confidence 
intervals will be constructed for 
difference between groups.  
This is a superiority study for 
primary outcome so one-sided 
test more appropriate 
(no change in sample size 
resulted from this modification). 
Justification for superiority 
design provided under 
Statistical methods. 
Sample size;  
Statistical methods 
Sample size / power estimate for safety 
outcome (recipient graft survival at 30-
d) refined; baseline rate justified at 96% 
based on updated SRTR data, modified 
non-inferiority margin from 10% to 6% 
and set one-sided alpha at 0.025. This 
resulted in larger required sample size 
of 336 recipients for 80% power. 
Calculation provided for expected 
number of recipients (n=320) based on 
revised 40% expectation of proportion 
of hearts transplanted 
More stringent non-inferiority 
margin based on feedback 
suggesting 90% as lower limit 
of acceptable graft survival; 
changed one-sided (non-
inferiority) alpha to 0.025 for 
more stringent testing of NI. 
Updated data on proportion of 
hearts transplanted expected in 
this donor population led to 
revised estimate of number of 
recipients for this analysis. 
Sample size; 
Statistical methods 
No longer plan for statistical comparison 
of baseline variables between study 
groups; instead we now pre-specify 
important covariates for adjustment of 
the primary outcome (age, blood 
group). Primary analysis remains with 
chi-square test but include subsequent 
multivariable model adjusting for age 
and blood group. 
The CONSORT statement on 
reporting RCTs recommends 
against comparing baseline 
variables between groups (as 
all differences will be chance 
imbalances occurring despite 
randomization). Instead 
adjustments should be 
prespecified based on relevant 
prognostic variables. 
Statistical methods 
Site will be included as a random effect 
in the multivariate model for outcomes 
(primary outcome and secondary 
outcomes) 
Randomization is stratified by 
site and imbalances in sample 
size and rates of hearts 
transplanted are expected 
between sites. Therefore, site 
should be included as a 
random effect in the model. 
Statistical methods 

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Secondary per-protocol analysis 
expanded to also be performed for 
safety outcome of graft survival 
Primary analysis remains 
intention-to-treat but per-
protocol analysis may be useful 
to demonstrate true effect of 
receiving agent on safety. 
Statistical methods 
Modified analysis of time-to-event 
outcomes to utilize Cox regression 
This approach allows 
adjustment for covariates in 
constructing Hazard Ratios 
Statistical methods 
Count outcome data (i.e. number of 
organs transplanted) will be analyzed 
using generalized estimating equations 
This is a more flexible approach 
than pre-specifying Poisson 
model for comparison of groups 
Statistical methods 
Better outline the process of 
safeguarding recipients as human 
subjects, including basis for waiver of 
recipient consent and monitoring for any 
safety concerns (e.g. interim analysis, 
oversight by DSMC) 
Recipients are human subjects 
and it is important to clearly 
delineate how their privacy and 
health is protected in this trial 
Ethics approval and 
consent to 
participate 
 
 
 

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Protocol Summary 
Title: 
A Multicenter Randomized Placebo-Controlled Trial of 
Intravenous Thyroxine for Heart-Eligible Brain Dead Organ 
Donors 
Precis: 
This randomized non-blinded study will compare intravenous 
thyroxine  (T4) to saline placebo in 800 brain dead organ donors 
who have provided authorization for research and are eligible for 
heart transplantation based on age and lack of exclusions 
Objectives 
Primary: Intravenous thyroxine (T4) will increase the proportion of 
hearts transplanted when given early after brain death to heart-eligible 
hemodynamically unstable potential organ donors 
Safety: Hearts transplanted from donors receiving T4 will have non-
inferior 30-day graft survival to those from the placebo group  
Secondary: T4 will reduce time to wean off vasopressors and improve 
cardiac ejection fraction 
Endpoints 
The primary outcome is the proportion of hearts transplanted (the 
number of hearts transplanted divided by the total number of potential 
donors).  
The safety outcome is proportion of hearts transplanted that maintain 
graft function at 30-days and 1-year. 
Secondary outcomes will include: 1) time from randomization to 
weaning off vasopressors: defined as being off all vasoactive agents 
(except for vasopressin); 2) proportion weaned off vasopressors by 12-
hours (same criteria as #1); 3) time achieving hemodynamic stability 
adequate to order first echocardiograph; 4) left ventricular ejection 
fraction measured on first donor echocardiography; 5) total number of 
organs transplanted 
Population 
We plan on enrolling 800 brain dead organ donors with 
authorization for donation and research in order to have 752 
evaluable subjects who receive the study drug or placebo 
Phase 
Three 
Number of Sites 
Est. 14 OPOs, 1 coordinating site for human (recipient) data 
Study Duration 
18-24 months 
 
 
 

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Abbreviations 
AOPO, Association of Organ Procurement Organizations 
BD, brain dead 
DSMC, data and safety monitoring committee 
LVEF, left ventricular ejection fraction 
OPO, organ procurement organization 
ODRC, Organ Donation Research Council 
OPTN, Organ Procurement and Transplant Network 
SRTR, Scientific Registry of Transplant Recipients 
T4, thyroxine 
TTE, transthoracic echocardiography 
UNOS, United Network for Organ Sharing 
 
 

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Administrative information 
Title {1} 
A Multicenter Randomized Placebo-Controlled 
Trial of Intravenous Thyroxine for Heart-Eligible 
Brain Dead Organ Donors 
 
Trial registration {2a and 2b}. 
Clinicaltrials.gov NCT04415658. Registered June 4, 2020.  
https://clinicaltrials.gov/ct2/show/NCT04415658  
Protocol version {3} 
3.0  
Funding {4} 
None  
(internal administrative support provided by Mid-America Transplant) 
Author details {5a} 
Rajat Dhar, Washington University in St. Louis School of Medicine 
Gary Marklin, Mid-America Transplant 
Name and contact information for 
the trial sponsor {5b} 
Mid-America Transplant 
1110 Highlands Plaza Drive, #100 
Saint Louis, MO 63110 
Role of sponsor {5c} 
Mid-America Transplant will not have any role in the design or analysis 
of the trial data. They will not have any role in the writing of the 
manuscript or the decision to submit the report for publication. 
 
 
 

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Introduction 
Background and rationale {6a} 
Brain death frequently induces hemodynamic instability and cardiac stunning (1, 2). Impairments in cardiac 
performance are major contributors to hearts from otherwise eligible organ donors not being transplanted (3). 
Deficiencies in pituitary hormones (including thyroid-stimulating hormone) may contribute to hemodynamic 
instability (4, 5).  Replacement of thyroid hormone has been proposed as a means of improving stability and 
increasing hearts available for transplantation (6). Intravenous thyroxine is now commonly used in donor 
management across the United States, either for all donors or only those with hemodynamic instability or 
those who are being considered for heart donation (7, 8). Large retrospective studies have found 
associations between use of hormonal resuscitation, including thyroid hormone, and more hearts 
transplanted (7, 9). However, several small controlled trials have not been able to confirm efficacy of thyroid 
hormone in improving heart function after brain death or increasing the chances of hearts being transplanted 
(10, 11).  
We recently performed two small parallel single-center randomized studies of thyroid hormone in heart-
eligible brain dead (BD) organ donors. The first evaluated whether intravenous triiodothyronine (T3) was 
superior to thyroxine (T4) in hemodynamically unstable BD donors with cardiac stunning (12). This was 
based on the rationale (supported by some experimental data) that T3 is the active hormone and its levels 
decline more rapidly after brain death (13). We were able to measure cardiac performance (left ventricular 
ejection fraction, LVEF) both immediately prior to starting infusion of T3 or T4 and immediately after eight 
hours of therapy. This physiologic proof-of-principle study demonstrated that LVEF improved comparably in 
both groups over this short time frame (from 38-45% to 50-53%) and both groups could be progressively 
weaned off vasoactive agents prior to organ recovery. Furthermore, after adjusting for group imbalances 
(likely due to small study size), hearts were transplanted in a similar proportion of the T3 and T4 groups (rate 
of heart utilization was 43% in this population). This study did not support the superiority of T3 (a more 
expensive intervention) over T4 in the management of unstable BD heart donors.  
Our next study aimed to test whether T4 infusion would be superior to placebo in heart-eligible donors with 
reduced LVEF despite being off vasopressors. Both studies aimed to enroll and start infusion within 12 hours 
of BD (at least defined by time when declaration occurred). Neither studies were blinded but evaluation of 
LVEF was performed blind to treatment allocation. Median improvement in LVEF was 10% with T4 
compared with 5% without thyroid hormone (p=0.24), although intention-to-treat efficacy analysis was limited 
by the fact that several of those randomized to T4 either did not receive or had this intervention discontinued 
prematurely due to emergent hypertension or tachycardia (14). There was a trend to more hearts being 
transplanted in the T4 group (59 vs. 27%, p=0.14) as well as more organs in total transplanted per donor 
(median of 5 vs. 3, p=0.009). Although this study suggested that thyroid hormone could be efficacious in 
increasing hearts transplanted, definitive conclusions were precluded by its small sample size (a 
consequence of enrolling at only one OPO) and group imbalances despite randomization. Therefore, we 
believe that there remains scientific equipoise and significant interest amongst the OPO and transplant 
communities in determining whether thyroid hormone does actually improve heart function and result in more 

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hearts transplanted.  
In fact, scientific research to determine the optimal interventions for donor management have been receiving 
increasing interest (15). To date, most studies have been retrospective and not adequately controlled (16, 
17). Recently, OPOs have begun collaborating more intently to answer important donor management 
questions. A council focused on research was formed as part of the Association of Organ Procurement 
Organizations (AOPO). This Organ Donation Research Council (ODRC) aims to bring together OPOs and 
interested parties (such as transplant physicians and scientists) to advance the science of organ and tissue 
donation. Collaborations nurtured as part of ODRC led to a multi-center randomized study that demonstrated 
that naloxone, frequently used (based on retrospective studies) to improve lung function, did not actually 
improve oxygenation or result in more lungs transplanted than a saline placebo (18). A few other randomized 
donor management studies have been performed (19-21). 
Objectives {7} 
Primary: Intravenous thyroxine (T4) will increase the proportion of hearts transplanted when given early after 
brain death to heart-eligible hemodynamically unstable potential organ donors 
Safety: Hearts transplanted from donors receiving T4 will have non-inferior graft survival to those from the 
placebo group at 30-days 
Secondary: T4 will reduce time to wean off vasopressors and improve cardiac ejection fraction  
Trial design {8} 
Randomized in parallel groups to intravenous thyroxine or saline placebo in 1:1 ratio 
Randomization will be in blocks, stratified by OPO site, allowing each site to serve as its own control (given 
heterogeneity in donor management protocols between OPOs) 
Administration of study drug or placebo will not be blinded 
Methods: Participants, interventions and outcomes 
Study setting {9} 
This study will be performed under the auspices of various Organ Procurement Organizations (OPOs) 
across the country (list of active sites available on clinicaltrials.gov). Participants will be patients already 
declared dead by neurologic criteria (i.e. brain dead) and who have provided authorization (first-person or by 
living surrogates) for both organ donation and for research. They may be physically located either/both in the 
hospitals in which they were declared and/or at an independent recovery/donor management facility of the 
OPO. The donor component has been deemed not to involve human subjects research and participating 
hospitals and OPOs are therefore not engaged in human subjects’ research. The coordinating site 
(Washington University in St. Louis) will be the research site responsible for collecting recipient outcome 
data. A waiver of consent has been obtained for de-identified collection of this human recipient data. 
 
 

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Eligibility criteria {10} 
Inclusion Criteria: 
1. Declared dead by neurologic criteria 
2. Provided authorization for organ donation and for research 
3. Donor age of 14-55 years (inclusive) and weight ≥ 45 kg (100 lbs) 
4. On one or more vasopressor and/or inotropes  (not including vasopressin) 
 
Exclusion Criteria: 
1. Brain death declared > 24 hours prior 
2. Known CAD or MI (by history, EKG, or previous cardiac cath)* 
3. Significant valvular heart disease (by history of echo)* 
4. Prior sternotomy or cardiac surgery* 
5. Donor at VA hospital 
6. Received intravenous or oral thyroid hormone in the past month 
7. Known HIV+ status 
8. Other reason preventing donor from receiving study drug (determined by on-site coordinator) 
* sufficient to exclude donor heart from being considered for transplantation 
Who will take informed consent? {26a} 
Donors are dead and their surrogates have all provided authorization for research. This is verified by organ 
procurement coordinators who are managing the donor management process. Recipients of organs from 
those enrolled in this study are human subjects but we have obtained a waiver of consent to collect de-
identified graft function/outcome data on those receiving hearts from donors enrolled in this trial.  
Additional consent provisions for collection and use of participant data and 
biological specimens {26b} 
All data utilized for analysis will be collected as part of donor care including standard UNOS and SRTR data 
variables (e.g. demographics). No additional biologic specimens will be collected. 
Interventions 
Explanation for the choice of comparators {6b} 
Intravenous thyroxine (T4) is commonly employed at almost all OPOs around the country as part of standard 
hormonal resuscitation, either for all donors or only those who are hemodynamically unstable (8). It is 
recommended (without level I evidence) in several donor management guidelines (22). It is usually given as 
an infusion with or without an initial bolus (protocols vary). A pilot randomized comparison of thyroid 
hormone formulations (T3 vs. T4) did not suggest any important benefits of T3 over T4 (12). Treatment with 
T4 will be compared to no thyroid hormone (during the first twelve hours, open-label T4 may be used after). 
 
Intervention description {11a} 
Study infusion (saline or thyroxine) will be commenced as soon as possible after randomization. Serum free 
T4 and TSH levels will be drawn prior to giving the drug. The T4 will be prepared by mixing 500 μg of drug in 

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500-ml of normal saline (i.e. concentration of 1 μg/ml) and enclosing the bag in an opaque sleeve. The 
placebo will be a 500-ml bag of normal saline (without active drug) also enclosed in an opaque sleeve. The 
infusion from this bag will be started at 30 ml/hour (corresponding to 30 μg/hour) and run for at least 12 
hours, unless adverse effects occur and the infusion is stopped prematurely (see titration protocol below). 
Vasoactive medications will be weaned as expeditiously as possible. When the donor is considered 
hemodynamically stable, initial transthoracic echocardiography (TTE) will be ordered and obtained as soon 
as possible. Repeat serum free T4 level should be drawn prior to organ recovery in both groups. Organ 
allocation will proceed per OPTN policy and routine allocation practices. All other aspects of donor 
management will also follow local OPO protocols.  
 
Criteria for discontinuing or modifying allocated interventions {11b} 
Titration protocol: T4 can be titrated down if: 
a) Systolic Blood Pressure above 180 mm Hg and increase of 30 mm Hg above baseline 
b) Heart rate over 120 bpm and increase by 20 bpm above baseline 
c) New tachyarrhythmia (atrial fibrillation, atrial flutter, superventricular tachycardia, ventricular 
tachycardia) or new onset ectopy (ventricular premature contractions > 6/min) 
d) Other significant change, at discretion of the coordinator 
The dose should be reduced in increments of 10 μg/hour (i.e. to 20 then 10μg/hour). The infusion can be 
discontinued if hemodynamic instability persists despite weaning.  
Open-label T4 can be given to the placebo group after 12-hours at the discretion of the managing team 
(whether for persistent hemodynamic instability, low EF on echo, or physician preference). T4 can also be 
continued beyond 12-hours of study infusion for the same reasons in the intervention group. 
 
Strategies to improve adherence to interventions {11c} 
There will be a one-month run-in period at each site where screening logs will be checked by the site and 
central study coordinators for completeness and accuracy. They will review all cases where donors were not 
enrolled within 24 hours or if other reasons for ineligibility were provided and provide feedback. The site and 
study coordinators will have weekly conference calls for the first month (and then monthly thereafter) to 
discuss issues with adherence. They will also provide feedback to individual OPO personnel if study 
protocols are violated. The study statistician will perform monthly audits of study data for completeness. 
 
Relevant concomitant care permitted or prohibited during the trial {11d} 
All standard OPO donor management practices will be continued throughout the study period until and 
including organ allocation and recovery. The only intervention prohibited is administration of thyroid hormone 
to those donors allocated to the placebo group for the first 12 hours after randomization.  
 
Provisions for post-trial care {30} 
Data collection on non-human organ donors ends at time of organ procurement or end of donor 
management (for authorized brain-dead potential donors who do not go on to donate organs).  

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Outcomes {12} 
The primary outcome for this study is the proportion of hearts transplanted (the number of hearts 
transplanted divided by the total number of potential donors – including those authorized but not recovered).  
The primary safety outcome for this study is 30-day graft survival in those receiving hearts from those 
enrolled in this study. This is defined by patient survival with the originally transplanted heart and no 
mechanical circulatory support. It will be assessed primarily at 30-days but also at 1-year. 
Secondary outcomes will include: 
1. Time from randomization to weaning off vasopressors: defined as being off all vasoactive agents, 
except for vasopressin (≤ 1 U/hr) 
2. Proportion weaned off vasopressors by 12-hours (same criteria as #1) 
3. Vasopressor-inotrope score at 12-hours (excluding vasopressin ≤ 1 unit/hour) 
4. Time achieving hemodynamic stability adequate to order first echocardiography  
5. Ejection fraction measured on first donor echocardiography 
6. Lungs and total thoracic organs transplanted 
7. Total number of organs transplanted 
8. Additional outcomes routinely collected from heart transplant recipients will also be aggregated and 
analyzed, including need for post-transplant mechanical circulatory support and other measures of 
primary graft dysfunction 
 
Safety endpoints: 
The following adverse events will be prospectively collected on all study donors. All events deemed either 
related or potentially related to the study drug infusion will be reviewed by the site coordinator. Any serious 
related events (defined as hemodynamic instability leading to cardiac arrest or donor loss prior to organ 
recovery) will be forwarded to the DSMC for additional review: 
1. Severe hypertension (systolic BP > 200 mm Hg) 
2. Tachycardia (HR > 150 and increased more than 20 over baseline) 
3. New/worsened tachyarrhythmia (SVT, Atrial fibrillation, Ventricular tachycardia or fibrillation) 
4. Cardiac arrest or any donor loss prior to the OR 
5. Fever – new, above 102 degrees Celsius 
6. New skin rash 
 

Participant timeline {13} 
 
STUDY PERIOD 
Heart Recipient 
 
Screening 
Allocation 
Infusion Period 
Organ 
Recovery 
TIMEPOINT 
 
t0 
2 
4 
6. 
.. 
12 
Time OR 
30-days 
1-year 
ENROLMENT: 
 
 
 
 
 
 
 
 
 
 
Eligibility screen 
X 
 
 
 
 
 
 
 
 
 
Confirm research 
authorization  
X 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
INTERVENTIONS: 
 
 
 
 
 
 
 
 
 
 
Thyroid hormone 
or saline infusion 
 
 
 
 
 
 
 
 
 
 
ASSESSMENTS: 
 
 
 
 
 
 
 
 
 
 
Vital signs and 
vasopressor doses 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Free T4 level 
 
X 
 
 
 
 
 
X 
 
 
TTE 
 
 
X                   X 
 
 
 
Heart  / Organs 
Transplanted 
 
 
 
 
 
 
 
X 
 
 
Heart Graft 
Survival 
 
 
 
 
 
 
 
 
X 
X 
 

Sample size {14} 
The proportion of potential heart donors who were able to provide a heart for transplantation in our pilot 
studies was between 30-60% (12, 14), a rate concordant with the recent literature (23). Proposed effect 
sizes of thyroid hormone treatment have ranged as high as an absolute increase of 20% or more in 
proportion of hearts transplanted in non-randomized studies (24); a large retrospective analysis of UNOS 
data found that those who received thyroid hormone (57% of 40,124 donors) had more hearts transplanted 
(7). The increase was from 25.8% without treatment to 35% with thyroid hormone (among all donors, not 
only those who were strictly heart-eligible, as required in this study). Based on our pilot data and this 
literature, we propose an absolute treatment effect size of 10% as the threshold for this study. In order to 
detect an increase in the proportion of hearts transplanted from 35% to 45%, we will need 752 total donors 
(376 per group), assuming 80% power and a one-sided alpha of 0.025. Because we expect some loss of 
donors after enrollment (e.g., clinical issues that interrupt adherence to the protocol), we will enroll a total of 
800 donors (400 in each study group).  
For our safety analysis in recipients of donor hearts, we have calculated a sample size necessary to 
demonstrate non-inferiority in graft survival. Based on recent data provided by SRTR, the expected 30-day 
graft survival after heart transplantation is 96%. We will test for a decrease of no greater than 6% in graft 
survival (i.e. from 96% to 90%; see Statistical Methods for a full explanation of assumptions and testing). 
With one-sided alpha of 0.025, we would need 336 recipients (168 per group) to have 80% power to exclude 
such a difference. Therefore, based on our sample size of 800 donors and an expectation that overall at 
least 40% of donor hearts will be transplanted, we expect a minimum of 320 recipients for this analysis; this 
sample size will provide a power of 78% for non-inferiority. It is likely that more than 40% of hearts will be 
transplanted; in fact, we saw in excess of 50% of hearts transplanted in our pilot data. Therefore we expect 
to have more than the required number of recipients to achieve 80% power. This sample size of recipients 
would also provide 80% power to demonstrate non-inferiority at the one-year survival endpoint.  
Recruitment {15} 
There are between 50 and 100 heart-eligible organ donors per year managed at most OPOs (of variable 
sizes) around the country. Therefore we are recruiting at least 10 OPO sites (est. 50 participants per OPO 
per year) in order to complete recruitment of adequate donors (n=800) within a 18-month study period.  
Assignment of interventions: allocation 
Sequence generation {16a} 
A random sequence of 1s and 0s will be computer-generated by the central coordinating site in blocks of 30 
for each participating OPO site (i.e. stratified by site). A web-accessible randomization sheet will be provided 
to each site with three such blocks (i.e. randomization key for 90 potential subjects).  
Concealment mechanism {16b} 
Only once eligibility has been confirmed will the on-site organ procurement coordinator will login to the 
website with the randomization list and determine (using the next available row) to which group the donor 
has been assigned. The coordinator will enter the UNOS# of the donor on the randomization form, as well as 

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the time and date of enrollment in the study before communicating the study assignment to OPO staff. The 
site study coordinator will review the randomization log to ensure that all eligible donors are being 
randomized and that sequential randomization rows are utilized.  
Implementation {16c} 
Randomization sequence of T4 vs. saline will be generated by the central coordinating statistician. 
Participants will be enrolled by the organ procurement coordinators at each site managing the donor after 
determining eligibility. They will determine the allocation to one of the study groups and assign participants to 
their randomized intervention. 
Assignment of interventions: Blinding 
Who will be blinded {17a} 
Care providers will not be blinded to study groups. Organ donors (being deceased) will be unaware of 
treatment. Assessment of cardiac function on echocardiography will also be blinded to study group. 
Procedure for unblinding if needed {17b} 
The study will not be blinded to coordinators or to those performing organ allocation (e.g. transplant 
surgeons). Furthermore, we will ensure that it is clearly documented in DonorNet that each participant is 
enrolled in this study. Each participant can also receive open-label T4 at the termination of the 12-hour study 
period, at the discretion of the physician or study team. 
Data collection and management 
Plans for assessment and collection of outcomes {18a} 
Each OPO will identify a site study coordinator who will be responsible for ensuring proper completion of 
data collection forms. The central coordinating OPO will create the data collection forms and distribute them 
to each study coordinator (data collection forms provided in Appendix). The central coordinating statistician 
will train each study coordinator on data collection and data entry procedures. Recipient data will be 
collected by the central site by matching donor UNOS IDs to the SRTR database of recipient and graft 
outcomes. No identifiable data on recipients will be collected and this data will not be shared with the sites. 
Plans to promote participant retention and complete follow-up {18b} 
No participants will be lost to follow-up as the final assessment occurs at organ recovery, which is available 
for all donors. However, it is possible that some donors may have incomplete data or may not finish the 
protocol once it is started. For example, a donor may be authorized for donation but may not become an 
organ donor (‘authorized, not recovered’ status). Such a donor does not undergo organ recovery and so will 
not have data at the final endpoint. However, we will analyze groups as randomized, i.e. by intention-to-treat, 
imputing these non-recovered donors as not having hearts transplanted. Similarly, we will analyze all those 
randomized to T4 within that study group even if they do not receive the drug or have it discontinued before 
12-hours.  
Data management {19} 
Study-specific data will be entered onto a paper data flowsheet (Appendix A) with the UNOS ID for each 

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participant and the assigned group marked at the top. This data sheet will be forwarded to the site study 
coordinator who will enter participant data into a secure REDCap database. This has built-in data validation 
and range checks. This study data will be supplemented by matching each enrolled donor (by UNOS ID) to 
their SRTR demographic data. This includes donor age, sex, and other important variables. The central 
coordinating statistician will perform data quality checks monthly and will work with the study coordinators at 
each OPO to resolve any quality issues. 
Confidentiality {27} 
No participant data will be shared outside of the study except when UNOS IDs are provided to the 
OPTN/SRTR to acquire data on whether transplanted hearts functioned and recipients survived. No recipient 
identifying data will be collected. 
Plans for collection, laboratory evaluation and storage of biological specimens for 
genetic or molecular analysis in this trial/future use {33} 
No biologic specimens will be collected for this trial or for future use. 
Statistical methods 
Statistical methods for primary and secondary outcomes {20a} 
We will present descriptive statistics for demographic and clinical variables, including by study group, but will 
not perform statistical comparisons of differences between study groups for baseline variables that should be 
balanced by randomization. We will first evaluate the primary outcome, the proportion of hearts transplanted, 
presenting the absolute and relative differences between the study groups, along with 97.5% one-sided 
confidence intervals. For our primary analysis, we will test the association between treatment and proportion 
of hearts transplanted, using a one-sided chi-square test at significant level of 0.025. Then we will proceed to 
a multivariate model that adjusts for potentially confounding variables and random site effect. The SRTR 
registry has developed comprehensive organ-specific risk-adjustment models (25). Older age and blood 
group are consistently the most important variables impacting whether hearts are transplanted. For this 
reason, we will include age and blood type as relevant pre-specified covariates. Since randomization was 
stratified by site, and imbalance in sample size across sites are expected, we will also include site as a 
random effects in our multivariate model. This will provide subject-specific measures of treatment effect, in 
terms of a conditional effect size and adjusted odds ratio (with 97.5% one bound confidence interval). 
Given that a systematic assessment of non-randomized studies using T4 for heart donors has suggested an 
improved rate of hearts transplanted, while prior small randomized studies have suggested no effect (i.e. no 
studies suggesting that T4 therapy results in worse heart outcomes) (10), we have selected a superiority 
design as most appropriate for our primary outcome. We are seeking to ascertain whether the addition of T4 
infusion to standard donor care results in more hearts transplanted. Therefore, our null hypothesis is that T4 
treatment results in an equal or lower rate of hearts transplanted, meaning our alternate hypothesis is that T4 
treatment is superior to no treatment. If the null hypothesis were not excluded, there would be no rationale to 
use T4 in addition to standard donor management and no benefit to focusing on a two-sided test evaluating 
whether it was worse than placebo. Therefore statistical tests will be one-tailed at a stringent significance 

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level of 0.025. We will also present the effect size with confidence intervals for all outcomes. The analysis 
will follow an intention-to-treat model. However, we will also perform a secondary per-protocol analysis, 
including only those receiving at least six hours of study infusion. We will also analyze only those in the 
placebo group who did not receive open-label T4, for a secondary analysis. 
We will analyze the primary safety endpoint of recipient graft survival using a non-inferiority method. Our 
baseline assumption, based on five-year data (from 2016 to 2020) provided by SRTR, is that 30-day graft 
survival for hearts will be 96%. We assume this baseline rate for both study groups, as there is no evidence 
to suggest that graft survival is lower in recipients of hearts from donors administered thyroid hormone. In 
fact, a recent study suggested treatment was associated with improved graft survival (23). The null 
hypothesis is that heart graft survival is lower in the T4 treated group by at least a clinically significant margin 
(set at 6%) compare with that observed in hearts transplanted from the placebo donors. This non-inferiority 
margin was selected with input of the data and safety monitoring committee (DSMC), including a thoracic 
transplant surgeon and ethicist. It aligns with that used in other trials assessing graft function after heart 
transplantation which used similar baseline assumptions (96% graft survival) but allowed more liberal 
margins (10%) (26). We believe that setting the lower limit of tolerance for this safety analysis at 90% graft 
survival is most appropriate. We will construct two-sided 95% confidence intervals for the difference in graft 
survival between the groups, allowing us to test for one-sided non-inferiority at alpha 0.025. This will be 
performed in the intention-to-treat cohort (i.e. all hearts from enrolled donors, by randomized study group) 
but we will also evaluate non-inferiority using a per-protocol methodology (i.e. evaluating outcomes in 
recipients who received hearts from donors who received at least six hours of T4 infusion compared to those 
who did not). 
Our plans for analyzing the secondary outcomes are as follows: for outcome measures that are time-to-event 
variables such as time to get off vasopressors and time to order first echo, we will perform Cox regression 
model to assess Hazard Ratio (95% confidence interval) between groups. We will calculate the vasopressor-
inotrope score, VIS (27) as: VIS = dopamine dose (µg/kg/min) + dobutamine dose (µg/kg/min) + 100 x 
epinephrine dose (µg/kg/min) + 100 x norepinephrine dose (µg/kg/min) + 10 x milrinone dose (µg/kg/min) + 
100 x phenylephrine dose (µg/kg/min) + 10,000 x vasopressin dose (U/kg/min – only for doses > 1 U/hour). 
We will compare the decrease in VIS from start of thyroid hormone or saline infusion until 12-hours (end of 
study infusion), using analysis of covariate method with predictor variables that include the baseline score 
and the treatment groups and adjusting for site effect.  Cardiac ejection fraction will be evaluated using a 
linear mixed model adjusting for random site effect. If normality assumption is violated, data transformation 
will be performed. Count data regarding thoracic and total organs transplanted will be compared using 
Generalized Estimating Equations, with study group as the independent variable and expected organs 
transplanted as a covariate. All secondary outcome analyses will be two-tailed test at a significance level of 
0.05.  
Interim analyses {21b} 
The DSMC statistician will perform one interim analysis when 376 donors have been enrolled with evaluable 
data. The trial may be terminated early if, based on the judgement of the DSMC, the interim findings 

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demonstrate either superiority or clear inferiority of T4 treatment compared to placebo (at a threshold of 
0.01). The trial may also be terminated if there is inferiority of graft outcomes in either group, observed at 30-
days in those hearts transplanted and observed for this period. The DSMC will provide recommendations to 
the study PIs, who will make final decisions about whether to stop or continue the trial. 
Methods for additional analyses (e.g. subgroup analyses) {20b} 
We will analyze the primary outcome (proportion of hearts donated) for each OPO individually. Sample sizes 
will vary between OPOs, so we may only have power to detect large effect sizes. Still, these OPO-specific 
analyses could provide valuable insights about trends at each OPO.  
We will perform prespecified subgroup analyses of: 
1. Time to start < 12 hours vs. > 12 hours from BD determination 
2. EF result (normal, > 50%, abnormal ≤ 50%) 
Methods in analysis to handle protocol non-adherence and any statistical methods 
to handle missing data {20c} 
Donors who are not managed according to the protocol (e.g., not managed properly on T4) will be included 
in the initial analyses following an intent-to-treat model. Subsequent analyses may exclude those cases in 
order to evaluate the impact of the protocol on donors who completed it successfully. 
 Plans to give access to the full protocol, participant level-data and statistical code 
{31c} 
The participant-level (donor) dataset will be made available to all study investigators and their respective 
OPOs. It may be provided to other OPOs, on request. No recipient outcome data will be shared. 
Oversight and monitoring 
Composition of the coordinating center and trial steering committee {5d} 
The coordinating center is comprised of the study PIs and the central study statistician. The coordinating 
center will be responsible for oversight of the study. The study statistician will review data entered by study 
sites for completeness and perform periodic checks for accuracy. The central study coordinator will ensure 
transfer of additional donor-related data and demographics for each enrolled donor to the central database 
on a quarterly basis. The respective study OPOs will provide donor data only and not be involved in 
collecting or analyzing recipient data. 
Composition of the data monitoring committee, its role and reporting structure {21a} 
The data and safety monitoring committee (DSMC) will be composed of several experienced but 
independent transplant researchers covering a wide range of expertise.  
 
 

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DSMC Member 
Expertise 
Institutional Affiliation 
Krista Lentine, MD, PhD 
CHAIR 
Transplant Physician and 
Researcher 
SRTR senior scientist 
Professor of Medicine with tenure, Co-director 
of Clinical Research, Medical Director of Living 
Donation, SSM Health Saint Louis University 
Transplant Center 
Farhan Zafar, MBBS 
Thoracic Transplant 
Surgeon (Pediatrics) 
Assistant Professor, Department of Surgery, 
University of Cincinnati 
Mark Schnitzler, PhD 
Transplant Researcher and 
Statistician 
SRTR senior scientist 
Professor of Surgery with tenure, Director of 
Clinical Research, SSM Health Saint Louis 
University Transplant Center 
Michael Souter, 
MB,ChB, DA, FNCS 
Medical director of organ 
procurement organization 
Professor and Chief of Anesthesiology, 
Harborview Medical Center, University of 
Washington Medicine 
Medical Director, LifeCenter Northwest OPO 
Jason Eberl, PhD 
Medical Ethicist 
 
Professor and Director, Albert Gnaegi Center 
for Health Care Ethics, Saint Louis University 
Jon Snyder, PhD, MS 
Transplant Epidemiology 
and Statistical Analysis 
Director, Scientific Registry of Transplant 
Recipients 
Director, Transplant Epidemiology, Hennepin 
Healthcare Research Institute 
 
 
The DSMC statistician (Mark Schnitzler) will analyze the primary outcome and primary safety data at the 
time of the interim analysis. These results will be shared with the entire DSMC, who will discuss and provide 
a recommendation on whether to continue recruitment or whether to terminate the study. The DSMC 
members are independent from the study investigators and are not involved in the procedures of the study in 
other than this review and the review of any serious safety events. 
Adverse event reporting and harms {22} 
Study data forms include prospective ascertainment of adverse events entered by the organ procurement 
coordinators caring for each donor (events listed under Outcomes, Safety Endpoints and shown on forms 
provided in Appendix A). Any events deemed either related or potentially related to the study drug infusion 
will be reviewed the site coordinator. The site coordinator will report all AEs that are unanticipated and/or 
serious to the central site, within 72 hours, for further review. This includes all cases of cardiac arrest or 
donor instability leading to loss of the donor prior to organ recovery. These events, with narrative review, will 
be forwarded to the DSMB for review within one week. Incidence of all AEs (by study group) will be provided 
to the DSMB monthly and also be analyzed as part of the interim safety analysis. In addition, outcomes in 
the recipients receiving hearts from study participants will be analyzed in the interim analysis to ensure non-
inferior graft function and survival. 
 

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Frequency and plans for auditing trial conduct {23} 
The study statistician (in consultation with the study coordinator and study PI) will audit data and conduct of 
the trial and oversee and feedback given to each site coordinator. 
Plans for communicating important protocol amendments to relevant parties (e.g. 
trial participants, ethical committees) {25} 
Any important amendments to the protocol will be communicated to each study site within one week of the 
change. These will also be updated on clinicaltrials.gov. 
Dissemination plans {31a} 
The final study results will be presented internally at the meeting of investigators (part of the Organ Donation 
Research Council at AOPO) and communicated to the OPO community using the AOPO-plus (restricted) 
web portal. Findings will be presented in abstract form with plans for simultaneous publication at a major 
transplantation meeting. 
Discussion 
This trial was discussed with at the AOPO councils: of medical directors and of the Organ Donation 
Research Council. Feedback from these groups was incorporated into the study protocol. All OPOs were 
invited to participate and sent a survey to gauge interest. 
Trial status 
Recruitment began on : 01 December, 2020 
Anticipated date of study completion: 31 December, 2022 
Acknowledgements 
We would like to acknowledge all the organ procurement coordinators who will perform the essential 
functions of this study and for caring for each of the donors involved in the study. We would also like to 
acknowledge each of the site coordinator for the study who collected all the data and ensured adherence to 
the study protocols and procedures.  
Authors’ contributions {31b} 
All site investigators who participate in the study planning, conduct, and review study results and analyses 
are eligible to be authors on manuscripts resulting from the study. No outside professional writers or 
consultants will be utilized. The study statistician and central coordinator will also be included as authors. All 
these meet the criteria for authorship laid out by the International Committee of Medical Journal Editors. Any 
other people meeting those criteria will also be invited as co-authors. All authors will read and approve the 
final manuscript(s). 
Funding {4} 
No specific funding or financial support is provided to the PIs for performance of this study. However, 
administrative support will be provided by the study sponsor for effort to coordinate the study and perform 
statistical analyses. The sponsor will not have access to the primary study data or be involved in its analysis 

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or interpretation. The sponsor will also not be involved in the writing of the manuscript. 
Availability of data and materials {29} 
The principal investigator will have final ownership over the dataset for this study. Data will be made 
available to any OPOs participating in the study and to other OPOs upon reasonable request. 
Ethics approval and consent to participate {24} 
This trial will not study or collect identifiable data on any human subjects. All donors enrolled in this study 
have been declared dead by neurologic criteria. However, this donor management study will be approved by 
the research/ethics committees at each participating OPO site. The study first received determination of non-
human subjects status from the Human Research Protection Office (HRPO) at Washington University in St. 
Louis (the academic affiliation of the PI). The individual OPOs will not be collecting data on recipients and so 
will not be engaged in human subjects’ research. However, recipient outcome is a key safety endpoint for 
this study. The central study coordinators will use the UNOS IDs to obtain de-identified recipient outcome 
data through UNOS/SRTR. As the recipients’ are human subjects, in order to collect recipient outcome data, 
we have obtained a waiver of recipient consent from the HRPO at the coordinating site. The collection of de-
identified recipient outcomes, as outlined, does not pose more than minimal risk to their privacy or safety. 
The study will not influence how hearts are allocated to particular recipients or means of allocation. Recipient 
consent would not be feasible at the time of study randomization as this occurs before heart allocation has 
begun, when the status of the heart and the identity of the recipient is unknown. The study intervention (T4, a 
standard practice in donor management) will be disclosed as part of the DonorNet platform that transplant 
centers/surgeons review. Although we do not mandate that information on the study and intervention be 
directly disclosed to those individuals ultimately receiving the donor hearts, this can be provided to recipients 
at their discretion. Furthermore, the use of T4 (or not) is not routinely disclosed in standard practice and so 
this was not felt to be a significant barrier to their autonomy and decision-making. Furthermore, we will 
monitor for any negative impact on recipients (as a group) through our interim analysis (as overseen by the 
DSMC) and halt the study if one group exhibits fewer hearts transplanted or worse graft outcomes. 
Consent for publication {32} 
Not applicable  
Competing interests {28} 
RD is a consultant for Mid-America Transplant.  
GM is an employee of Mid-America Transplant.  
 
Author details 
Rajat Dhar, MD 
Associate Professor of Neurology (Division of Neurocritical Care) 
Washington University in St. Louis 
 
Gary Marklin, MD 
Chief Medical and Research Officer 

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Mid-America Transplant 
Authors’ information (optional)  
RD is the outgoing chair of the Organ Donation Research Council at AOPO. He was been PI on several 
randomized trials in donor management including the multi-site RCT of naloxone that was recently published 
[18].  
 
 
 

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